i

Toxic Cocktail
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Toxic Cocktail
How Chemical Pollution Is Poisoning
Our Br ains

Barbara Demeneix

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1
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Library of Congress Cataloging- in- Publication Data

Names: Demeneix, Barbara.
Title: Toxic cocktail : how chemical pollution is poisoning our brains /​
Barbara Demeneix.
Description: Oxford : Oxford University Press, [2017] | Includes index.
Identifiers: LCCN 2016011950| ISBN 9780190260934 (hardcover : alk. paper) |
ISBN 9780190260958 (epub)
Subjects: LCSH: Thyroid gland—​Effect of chemicals on. | Brain—​Effect of
chemicals on. | Brain—​Growth. | Pollution—​Physiological effect. |
Autism. | Mental illness.
Classification: LCC QP188.T54 D46 2017 | DDC 612.4/​4—​dc23
LC record available at http://​lccn.loc.gov/​2016011950

9 8 7 6 5 4 3 2 1
Printed by Sheridan Books, Inc., United States of America
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All scientific work is incomplete. … That does not confer upon us a freedom
to ignore the knowledge we already have, or to postpone the action that it
appears to demand at a given time.
Sir Austin Bradford Hill, “The Environment and Disease:
Association or Causation?”
Proceedings of the Royal Society of Medicine, 1965
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Contents

Acknowledgments  ix
Abbreviations  xi
Note to the Reader  xv

Introduction  1

1. Violet Vapors  11

2. A Molecule of Mystery  29

3. Thyroids in a Chemical Soup  49

4. Losing It: Undoing Brain Evolution  75

5. The Alarming Increase in Autism  93

6. From DNA to Epigenetics  113

7. Counting the Costs  137

8. Who Really Picks Up the Bill?  159

9. Time to Act and How to Act  179

Glossary  207
Notes  211
R efer ences  223
Index  245

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  ix

Acknowledgments

This book owes a great deal to many colleagues and friends.

I benefited from the expertise of four readers and critics:  Dr.  Tim Koreevar
(Erasmus University, Rotterdam); Dr.  Pete Taylor (Cardiff University, Cardiff,
Wales); Professor Ana Soto (Tufts University, Boston); and Michael Westlake. The
first three, all medically qualified research scientists, took time from their demand-
ing schedules to read the first draft with an eye to scientific accuracy and logic. Any
remaining errors are my responsibility. Prior to sending them the text, my friend
and most critical reader, Michael Westlake, had done a detailed read-​through, sug-
gesting improvements in expression and pushing me to rewrite where needed.
My editor at OUP, Joan Bossert, provided excellent editorial guidance. Both Joan
and Lynn Luecken gave me valuable input on structure and organization. Earlier
drafts were also read and corrected by family and friends with no scientific back-
ground to ensure the level was appropriate for other lay readers. So, my daughter,
Ariane; my sister, Louise Keeling; and my long-​standing friend, Brenda Swift, read
through most chapters, pointing out complex ideas that required better explana-
tion and providing insight through their queries. Another friend, Joanne Burden,
and my son, Laurent, participated in the brainstorming on titles, as did Aimée
Middlemiss and Matt Frost. Thanks to you all.
My team in Paris had, yet again, to put up with my preoccupation with the writing
and my lesser availability in the lab. I really appreciated your steadfastness. Special
mention to doctoral students past and present James Bowers, Jean David Gothié,
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x Acknowledgments

Lindsey Marshall, Michelle Leemans, and Bilal Mughal for your interest in these
ideas, your original thinking, and suggestions. Thanks also to Jean-Baptiste Fini for
driving forward the work on endocrine disruption during this hectic period and to
Sylvie Remaud for the groundbreaking work on neural stem cells and myelination.
So many ideas from these research fields fed into this book.
I also wish to thank Stéphane Horel. Stéphane’s work as an independent inves-
tigative journalist revealing the influence of industrial lobbying on European
decision-​making has been an inspiration to all of us working in the field of endo-
crine disruption.
The Endocrine Society is gratefully acknowledged for setting up the European
Task Force on Endocrine Disruption and for covering costs for travel to Brussels.
The contents of this book have gleaned much from discussions with all the members
of this task force, but especially from conversations with Tom Zoeller, Jean-​Pierre
Bourgignon, and Remy Slama.
Last, but not least, thanks go to my mentor and friend François Lachiver, who
inspired me to work on thyroid hormone. At 94, not only does he still keep me on
my toes with his insightful questions on new ideas in thyroid physiology but also he
generously allowed me to use his house in Burgundy as a writing sanctuary. Merci
encore Lachou.
  xi

Abbreviations

ACh Acetylcholine
AChE Acetylcholinesterase
ADHD Attention-​deficit/​hyperactivity disorder
AR Androgen receptor
ASD Autism spectrum disorder
BDNF Brain-​derived neurotrophic factor
BFR Brominated flame retardant
BDE Brominated diphenyl ether
BPA Bisphenol A
CDC Centers for Disease Control and Prevention
CH Congenital hypothyroidism
CHAMACOS Center for the Health Assessment of Mothers
and Children of Salinas
CNV Copy number variant
DBP Dibutyl phthalate
DDE Dichlorodiphenyldichloroethylene
DDT Dichlorodiphenyltrichloroethane
DEHP Diethylhexyl phthalate
DES Diethylstilbestrol
DSM Diagnostic and Statistical Manual of Mental Disorders
DZ Dizygotic (twins; nonidentical twins)
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xii Abbreviations

EDC Endocrine-​disrupting chemical

EPA Environmental Protection Agency (of the United States)
ER Estrogen receptor
HBCD Hexabromochlorodecane
HCB Hexachlorobenzene
ICCIDD International Council for the Control of Iodine
Deficiency Disorders
IGN Iodine Global Network
IQ Intelligence Quotient
MBP Monobutyl phthalate
MBP Myelin basic protein
MZ Monozygotic (twins; identical twins)
NHANES National Health and Nutrition Examination Survey
(of the United States)
NIEHS National Institute of Environmental Health Sciences (of the
United States)
NIH National Institutes of Health (of the United States)
NIS Sodium-​iodide symporter
OC Organochlorine
OP Organophosphate
PAN Pesticide Action Network
PBB Polybrominated biphenyl
PBDE Polybrominated diphenyl ether
PBT Persistent, bioaccumulative, and toxic
PCB Polychlorinated biphenyl
PDD/​NOS Pervasive developmental disorder/​not otherwise specified
PFC Perfluorinated compound
PFOA Perfluorooctanic acid
PFOS Perfluorooctane sulfonic acid
POP Persistent organic pollutant
PVC Polyvinyl chloride
REACH Registration, Evaluation, Authorization and Restriction
of Chemicals
SVHC Substance of very high concern
T3 Triiodothyronine (the most active form of thyroid hormone)
T4 Tetraiodothyronine (the prohormone from which T3 is produced
by deiodination)
TBBPA Tetrabromobisphenol A
TBT Tributyltin
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Abbreviations xiii

TCDD 2,3,7,8-​Tetrachlorodibenzo-​p-​dioxin
TDCPP Tris(1,3,chloro-​2 propyl) phosphate
TH Thyroid hormone
TPO Thyroid peroxidase
TR Thyroid hormone receptor
TRα Thyroid hormone receptor alpha (or THRA)
TRβ Thyroid hormone receptor beta (or THRB)
TRH Thyrotropin-​releasing hormone
TSH Thyroid-​stimulating hormone (or thyrotropin)
TTIP Trans-​Atlantic Trade and Investment Partnership
TTR Transthyretin
UNEP United Nations Environment Programme
WHO World Health Organization
WWF World Wildlife Fund
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Note to the Reader

Superscript numbers in text refer to end-​of-​book Notes. Bracketed numbers

indicate chapter references.

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  1

Introduction

Why is it that every pregnant woman is advised not to take any form of pharma-
ceutical product or drug, except on medical advice? The answer is that pregnancy,
and especially early pregnancy, is a sensitive period for effects of drugs on the devel-
oping fetus. The unfortunate irony is that, today, all pregnant women are unwit-
tingly exposed to a complex combination of chemicals, as are the fetuses and babies
developing in their wombs, from conception onward. Even worse, we know little
about the consequences of this exposure either on the generation first exposed or on
their own children.
The recommendation to “avoid all unnecessary medications” draws belatedly on
the observed consequences of prescribing inadequately tested (and often unneces-
sary or ineffective) drugs during pregnancy. Examples include thalidomide and
diethylstilbestrol (DES). Both drugs were marketed for use in early pregnancy: tha-
lidomide to reduce the symptoms of morning sickness and DES to avoid miscar-
riage. The horrendous effects of thalidomide were evident immediately on birth.
The babies had shortened arms and legs, some of them with fingers and hands
growing out of their shoulders. The effects of DES on the children exposed took a
couple of decades to be diagnosed. Prescribed between 1960 and 1975, it was more
than 20 years later that many of the daughters of women needlessly prescribed DES
were diagnosed with vaginal cancer, an unusual cancer, especially in young women.
Today, we know that even the granddaughters of the women involved have a higher
risk of this disease.
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2 Toxic Cocktail

These distressing examples demonstrate all too clearly four considerations that
must be better taken into account by governments and regulators addressing chemi-
cal regulation. First, early pregnancy is an exceptionally vulnerable period for expo-
sure to chemicals. Second, the placenta is not a barrier to passage of chemicals.
Third, it may be years before effects of exposure are actually detected. Last, even
though exposure may be limited to one generation, subsequent generations can also
be affected.
To these already-​disquieting facts, we need to add two other observations. It is
easy to see effects of drugs and chemicals on formation of limbs and even to measure
incidence of cancer. But, what about drugs and chemicals that surreptitiously affect
brain development or intellectual potential? As David Rall, a former director of the
US National Institutes of Health, reportedly asked: What if thalidomide, instead of
affecting limb development, had affected brain development, would it still be on the
market? The answer is “Probably yes.” The next question is, to my mind, the most
worrying. What are the long-​term effects on us as individuals and as a society of the
brain-​damaging cocktail of chemicals present in the environment?
For the last 50 or so years, we have all been inexorably contaminated with more
and more industrially produced chemicals. The US Environmental Protection
Agency (EPA) maintains a list of chemicals under the Toxic Substances Control Act
(TSCA).1 Today, about 85,000 chemicals produced at more than 10 tons per year
are on the list. This list does not include pesticides, cosmetics, and food additives
that are covered by other legislation. Not only are many of these chemicals found
in the bloodstream of every adult, but also they are present in amniotic fluid (the
liquid in the womb that surrounds the developing fetus). All children born today
are exposed, from conception onward, to a complex mixture of chemicals.
In parallel with this intensifying chemical exposure, we are witnessing an expo-
nential increase in autism spectrum disorder (ASD), with up to 1 in every 45 chil-
dren in the United States now being diagnosed with ASD [1]‌. Attention-​deficit/​
hyperactivity disorder (ADHD) is also increasing; at the same time, many observers
are noting significant and alarming IQ decreases across populations [2]. The indi-
vidual, societal, and economic costs of this insidious and tragic degradation of evo-
lution’s greatest success story, the human brain, is enormous [3].
How to explain the complex scientific ideas that I have been studying for decades,
some of which lie at the frontiers of current scientific knowledge? This book threads
together many lines of evidence, each derived from a wide spectrum of scientific and
epidemiological studies, that many of these chemicals are interfering with one of the
body’s most essential regulators of brain development: thyroid hormone.
Thyroid hormone is made in the thyroid gland, at the base of the neck, below
the voice box or larynx. The thyroid is an important gland, controlling growth and
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Introduction 3

development of the whole body, but especially that of the brain. During early life,
thyroid hormone is needed to orchestrate brain development so that all the pro-
cesses occur harmoniously. It modulates how many nerve cells are produced, how
they find the right place in the developing brain, what sort of cells they become,
and how they set up their interactions with each other. This hormone is also
needed to maintain brain function in adults. We become depressed and lose our
memory if we lack thyroid hormone or become nervous and anxious if the gland
is overactive. So, at all life stages, from fetus to old age, too much is as bad as too
little.
Thyroid hormone is part of our endocrine system. The endocrine system includes
all the glands that produce hormones: the sex steroids that govern our reproduction
(mainly testosterone in men and the female hormones estrogen and progesterone),
the stress hormone (glucocorticoid), and many others. Collectively, chemicals that
interfere with thyroid hormone, the sex hormones, or other hormones are called
endocrine-​disrupting chemicals (EDCs).
Most EDCs found in the environment are produced by human activity. Their
spectrum includes various types of products, ranging from pesticides and plasticiz-
ers to flame retardants and waterproofing agents. EDCs get into our bodies through
the air we breathe, the food we eat, the water we drink, and the cosmetics we put on
our skin. The term endocrine disruption was first introduced in 1991. The occasion
was a workshop organized by the World Wildlife Fund (WWF) at the Wingspread
Conference Center, a building designed by Frank Lloyd Wright, on the shores
of Lake Michigan. Theo Colborn, who later wrote the first book about the issue,
Our Stolen Future, was one of the driving forces bringing together the experts who
contributed to the Wingspread Consensus Statement in 1993. The proceedings of
this meeting formally articulated the global problem of endocrine disruption, with
respect to “alterations in sexual development” in both wildlife and humans. The
Wingspread statement was also constructed to emphasize the idea that developmen-
tal exposure could lead to disease later in life, a fact little recognized then but that
has become a central tenet today.
To increase awareness of the problems, the World Health Organization (WHO)
with the United Nations Environment Program (UNEP) published a report in
2012 on the state of the science of endocrine disruption [4]‌, almost simultaneously
with one commissioned by the European Union [5]. Certain regulatory bodies had
already started to tackle these questions at different levels. The European Union
introduced REACH2 in 2006, although EU legislation on endocrine disruption is
currently stalled (a point we return to further in this Introduction and discuss in
detail in Chapter 8). The United States has taken a different approach since 2009,
applying a large-​scale screening program, TOXCAST, on groups of compounds
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4 Toxic Cocktail

such as pesticides and substances suspected to disrupt natural endocrine systems,

including thyroid hormone and those controlling reproduction.
These programs are often described as “too little, too late.” And, indeed, it is too
late for those children already affected, whose impaired brain development can never
be corrected. However, as citizens we can make our voices heard so that govern-
ments recognize the need to apply these chemical screening programs as effectively
as possible, thereby ensuring the right of each child to fulfill his or her potential as a
sentient and responsible member of society.
To get into the story, the opening chapter relates the discovery and the impor-
tance of a key element in the narrative, iodine. The crucial point is that thyroid
hormone contains iodine. Unfortunately, many chemicals that we are exposed to
today (some of which are even found in amniotic fluid) interfere with the capacity
of our thyroid glands to capture the iodine needed to make the hormone. Yet, it has
been known for the better part of two centuries that mothers who lack iodine have
an increased risk of bearing children who are intellectually deficient. Until the first
half of the 20th century, lack of iodine in certain areas was linked to greater num-
bers of children being born with the dreadfully debilitating disease of cretinism.
Few people today know what cretinism is, let alone its cause. All cretins suffer
from irreversible intellectual deficiency, the hallmark of the disease. However, in
severe forms, those affected also have short stature, ill-​formed bones and mus-
cle, and poor eyesight and hearing. The insulting term cretin may be familiar to
some, but few people know its cause. In fact, cretinism is due to a lack of thyroid
hormone during fetal development in the womb, during pregnancy. Historically,
most often cretinism was attributable to iodine deficiency. My concern is that
we are currently witnessing a stealthy assault on brain development as a result
of exposure to chemicals interfering with iodine uptake and thyroid hormone
action. Even though, most fortunately, we no longer see individual cases of cretin-
ism, we know that children born to women who are deficient in either iodine or
thyroid hormone are less intelligent than children born to women who have the
right amounts of both.
Having outlined the importance of iodine, I move on to how thyroid hormone
was identified and how doctors learned of its importance for growth and brain
development in babies and children. Thyroid hormone is so crucial for the develop-
ing brain that all babies are screened in the first few days after birth to ensure they
have enough. It’s surprising to find that, despite the fact that it was discovered over a
hundred years ago, the last few years of scientific research have been rich in new find-
ings, many of which are exceedingly important for our story. One of these totally
unexpected and recent findings is that thyroid hormone is vital for early periods of
brain development before birth, specifically the first 3 months of pregnancy. These
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Introduction 5

findings also put into a new perspective the idea that thyroid-​disrupting chemical
exposure could be particularly damaging in early pregnancy.
Chapter 3 takes us through the main chemical categories with the potential to
interfere with this vital endocrine system. I present evidence that dozens, probably
hundreds, of chemicals released into and accumulating in the environment can
disrupt iodine availability and thyroid hormone action in our bodies and brains.
Between 1950 and 1970, the first generation of children underwent exposure to sig-
nificant levels of chemical exposure in early life. At that time, Rachel Carson’s pre-
scient Silent Spring [6]‌eloquently explained the links between excessive pesticide
usage and the dramatic decrease in bird populations in the United States. It was
perhaps the effects on the emblematic American bald eagle that riveted attention
to the problem, helped ban use of the pesticide DDT (dichlorodiphenyltrichloro-
ethane), and led to the founding of the EPA. However, it was also in this book that
she predicted that the harmful effects of the main culprits, including DDT, could
extend beyond birds and wildlife to human health.
Today, we know this to be the case. But since then, the number of chemicals in
the environment has risen exponentially. The chemical cocktails to which fetuses,
babies, and children are exposed include numerous pesticides, surfactants (nonstick
or waterproofing agents), flame retardants, plasticizers (phthalates and bisphenol
A  [BPA]), nitrates, and perchlorate. Thousands of these industrially produced
chemicals are found in the environment today, and we only have data on the tox-
icity of a handful of them. We all carry dozens of these chemicals around in us,
breathing them in and distributing them through our bloodstream, on a daily basis.
This is bad enough for adults, but if you’re a growing baby in your mother’s uterus,
it’s worse.
In 2011, a study from the United States screened pregnant women for 163 chem-
icals and found over 90% had at least 62 of these chemicals in their bodies [7].
A number of these chemicals interfere with thyroid hormone action in different
ways [8]. It is well documented that children born to mothers who have high blood
levels of certain of these chemicals have a higher risk of lost intellectual capacity or
increased risk of neurodevelopmental disease, such as autism or ADHD. To this,
one can add that iodine deficiency in mothers, still present today in many areas of
the world, can cause IQ loss of up to 18 points [9], and that even moderate iodine
deficiency can affect the severity of symptoms in children with autism [10]. We
know much less about the combined effects of multiple substances, or cocktails,
despite the fact that everyone today is exposed to complex mixtures of at least a
dozen or more chemicals.
Chapter 4 discusses the different data showing decreases in IQ over the last cen-
tury. Using the term IQ or intelligence quotient sometimes elicits outright skepticism
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6 Toxic Cocktail

and suspicion or, at the very least, a series of questions. What does the IQ number
represent, if anything? Aren’t there many different types of intelligence? In this
chapter, I define how I use the term IQ and describe how it is measured. I also look
into the debate on whether IQ was really rising in the second half of the 20th cen-
tury (the Flynn effect) and whether there has been an overall decrease in the last
hundred or so 150 years.
With these ideas in mind, Chapter 5 takes a hard look at the data we have on the
costs of IQ loss in children born to mothers who had high levels of certain chemi-
cals. These chemicals are what we might call the convicted brain drainers. With a
group of economists and statisticians, I was involved in counting the societal, eco-
nomic, and health costs of exposures to two main categories of chemicals in terms
of lost IQ and increased incidence of neurodevelopmental disease, such as autism or
ADHD. The economic costs range from the costs of caring for individuals affected
by disease to lost productivity across nations. Taken together, the figures calculated
were quite simply enormous, in the hundreds of billions of euros per year for Europe
and probably more for the United States. And, this was just for a few chemicals. It is
certain that, given the myriad chemicals to which we are exposed and the fact that
we have so few data on mixture effects, current estimates of risk and costs are seri-
ously underestimated.
In Chapter  6, I  discuss the huge increases in neurodevelopmental disease and
examine different theories regarding the causes. Genetic causes alone cannot account
for the exponential increases seen across different populations today. However,
genetic differences may render some individuals more susceptible to environmental
factors than others. Environmental factors include not only increased chemical pol-
lution but also changes in birthing methods (more frequent cesarean sections, for
instance). Changes in diagnostic methods and increased awareness have contributed
to some of the increase in neurodevelopmental disease, and more specifically autism,
until 2000. However, it has been estimated that diagnostic change accounts for only
a quarter of the increase since that year [11]. Since 1995, the published incidence of
ASD in 8-​year-​olds has increased from 1 in 500 children to 1 in 250 in 2001, reaching 1
in 68 in 2014. Most recent data from the US National Health Statistics Reports
cited an incidence of 1 in 45 children [1]‌. Equally disquieting is that in certain US
states up to 50% of the children diagnosed with ASD have IQs below 70. If one
includes those ASD patients with borderline intellectual deficiency (IQs below 85),
the numbers vary between 40% and 75%, according to state.
Autism is more frequent in boys than girls. For every five children diagnosed,
four are boys. This difference leads not illogically to the hypothesis that sex steroids,
particularly the male hormone testosterone, can exacerbate a genetic susceptibility
or can drive development of the disorder. There is no doubt that sex hormones and
  7

Introduction 7

other hormones affect brain development. Sex hormones also interact with thyroid
hormone to modulate many essential processes in brain development. How differ-
ent chemicals interact to affect the actions of sex hormones and thyroid hormone
on brain development will be an important topic for future research. However, in
this book I focus on thyroid hormone. This emphasis is determined, first, because
many authors consider thyroid hormone action to be the target of more chemicals
than any other endocrine system and, second, because the role of thyroid hormone
on brain development is so critical. In fact, the effects of thyroid hormone deficiency
on brain development are so marked that hypothyroidism in pregnant rats has been
used as a means of studying autism-​like symptoms in the pups [12].
Having said that genetics alone cannot account for the massive increase in autism
incidence, it is clear that some forms of autism have an identified genetic link, and
other genetic variants are found across a small percentage of cases. I deal separately
with the genetic evidence in Chapter 7 and show how we need to take the burgeon-
ing field of epigenetics on board to fully understand how environmental factors may
be exacerbating genetic traits in some individuals.
Epigenetics is a relatively new science, a frontier science, addressing among other
questions where, when, and how certain genes are expressed. Put simply, epigenetics
is the study of changes in gene activity that do not implicate changes in actual DNA
sequence. There are many examples of environmental and nutritional factors that
modulate gene expression through epigenetic mechanisms. An all too well-​known
example is the deleterious effect of maternal alcohol consumption on her baby’s brain
development. Other factors act favorably, like the effects of folate supplements in pre-
venting spina bifida and other neural tube defects. In each case, there are no changes
in DNA sequence, but the way that brain genes are expressed is modified.
Certain epigenetic changes in gene expression can be long lasting, as if written in
stone on the DNA. In this way, they can be involved in effects that pass from one
generation to another. Some endocrine disruptors have already been shown to affect
the development of more than one generation through epigenetic mechanisms, even
though only the first generation was exposed. An example is the increased risk of
vaginal cancer in the granddaughters of women prescribed DES (see the begin-
ning of this Introduction). The complexity of the issues is such that we are enter-
ing a domain where our scientific knowledge is significantly outpacing regulatory
decision-​making.
I learned a lot about regulatory decision-​making while writing this book. My
learning curve was most marked in understanding the history of lobbying by the
chemical industries. Reading Gerald Markowitz’s and David Rosner’s books on
industrial lobbying [13], in particular by the lead industry [14], made disturbingly
edifying reading, mitigated only by the extent of their knowledge and the force of
8

8 Toxic Cocktail

their arguments and insights. The issue of industrial lobbying is currently of enor-
mous relevance for Europeans and Americans. In Chapter 8, I explain how in early
2013 the European Parliament adopted a resolution by an overwhelming majority,
reminding the European Commission of their responsibilities to enact legislation
on EDCs. The date of December 2013 had been fixed 4 years earlier. However, as
detailed by Stéphane Horel [15], a relentless investigative journalist, in the summer
of 2013, the chemical industry came up with a series of ploys to block the legislation.
The tactics adopted by the industry have been successfully used many times before,
as in the tobacco and climate change debates. Tried-​and-​tested techniques were
wielded to create controversy where there was consensus and to denounce scientific
arguments in the name of “common sense.” These actions halted all progress on the
issue and the situation remains deadlocked today,3 to the detriment not only of the
health of EU citizens, but also future generations.
So, current generations are exposed, from conception onward, to unprecedented
levels of chemical pollution in terms of both number of different chemicals and
total amounts. The principal question is whether we can stop this vicious cycle of
increasing pollution and declining intellectual capacity. In Chapter 9, I provide a
series of arguments to show that the answer is yes. First, legislative action must be
taken by authorities. Second, actions can be levered by individuals. As with climate
change, we need to act at multiple levels and implicate international organizations,
national bodies, industry, and the general public. Unquestionably, stakeholders
from a spectrum of fields need to work in concert and rethink our production meth-
ods in agriculture and manufacturing, from energy generation to transport. Last,
but by no means least, individuals must be empowered to know about and control
their immediate environments and food sources.
The book concludes with examples of concrete actions that can be taken by indi-
viduals, associations, and governments to protect against intellectual loss, limit
exposure, and even reverse the trend through appropriate regulation. It is clear that
to be useful the ideas presented have to overcome dismay and propose ways for-
ward. As with climate change, the theories of Elinor (Lin) Ostrom, in 2009 the
first woman to receive the Nobel Prize for Economics, are exceedingly pertinent.
She argued that misuse of common resources, such as the overfishing of the oceans
or pollution of the atmosphere adversely affecting climate, health, and biodiversity,
needs to be addressed by polycentric approaches, with individuals working together
at community and national levels to change and enforce legislation. Perhaps she was
one of the original “think globally, act locally” activists! This logic can be seen as
motivating potential actions of individuals, associations, policymakers, and govern-
ments. One of the suggestions given is that our public health system must ensure
that women enter pregnancy with sufficient iodine to maintain thyroid hormone
  9

Introduction 9

supplies for themselves and the developing baby. This can be achieved by adding a
small amount of iodine to prenatal vitamin and mineral supplements—​an easy step
with huge health and financial benefits to society.
This simple measure must be accompanied by better legislation in the testing,
registration, and use of chemicals of all categories. This legislative gap is particularly
disquieting when it comes to chemicals that can act as EDCs. As the European
Commission had missed the deadlines for legislation on EDCs, Sweden and a num-
ber of other countries took the European Commission to court over their inac-
tion. In late 2015, the European Court of Justice judged that the commission had
breached European law. The commission argued that they were assessing the eco-
nomic consequences of the legislation, notably on the chemical industry. The court
replied that it was not the commission’s role to determine whether economic issues
were more important than health.
This legislation must be passed as a matter of urgency. To achieve this goal, we
need to work through different channels. Many of my scientific colleagues are
spending more and more time away from their labs to attend meetings and write
papers on the science behind these problems and their immense socioeconomic
costs, while continuing important research on the topic. Scientists and nonscientists
alike are acting through various bodies to inform others and to encourage policy
changes. These combined efforts should help thwart industry’s denial tactics and
their pressure on regulators and politicians. Such reasoning brings us back full circle
to Ostrom’s observations on misuse of common resources and the necessity to apply
polycentric approaches, with individuals acting at community and national levels to
bring about legislative change.
My hope is that this book will be one such step toward the goal of controlling
environmental pollution in the interests of protecting the potential and promise of
future generations.
10
  11

1
Violet Vapors

Investigating iodine: from smoking guns in Sicily

to gunpowder in Paris

What does Sicily, the largest island in the Mediterranean, conjure up for you? For
those with knowledge of the Greek classics, maybe it is the idyllic setting of Plato’s
utopian society. For many more of us, it is a great place for holidaying, where, as
the travel guides say, “Mountains meet the sea.” From mountains, our minds might
drift to the smoking volcano, Mount Etna. And from there to a rather less-​appealing
aspect of Sicily, perhaps smoking Mafia guns? Be that as it may, for a group of doc-
tors and scientists, Sicily was the ideal place to look for evidence of a metaphori-
cal smoking gun, a trail of events that have very real and irreversible effects on the
population.
The researchers set out to investigate what impact low iodine levels in pregnant
women had on the mental health and intelligence of their children. Why iodine?
They chose to look at iodine levels because this element is needed to make thyroid
hormone and, as explained in the Introduction, we all need thyroid hormone for
our brains to develop and function correctly. The second question is Why Sicily?
Well, even though Sicily is surrounded by sea, and even though the sea (but not sea
salt, on which more is discussed in the section Sea Salt Does Not Contain Iodine) is
a rich source of iodine, the central mountainous regions have low levels of this essen-
tial element in the soil. So Sicily, with contrasting mountainous and coastal areas,

11
12

12 Toxic Cocktail

was an excellent location to examine how relatively minor variations in mothers’

iodine supply during pregnancy affected their children’s intellectual development
and propensity to develop attention-​deficit/​hyperactivity disorder (ADHD). The
result was astonishing.
The team of scientists and clinicians, led by Professor Francesco Vermiglio, found
that pregnant mothers in the mountainous areas often had low iodine levels. As a
consequence, they were also frequently mildly hypothyroid. This means they did
not have enough thyroid hormone, neither for themselves nor for their growing
fetuses. The implications for their children later in life were striking. The differences
in average intellectual quotient (IQ) were massive. The children born to mothers
who had insufficient iodine and were slightly hypothyroid had average IQ scores a
full 18 IQ points lower than in children born to mothers in the coastal areas who
had sufficient iodine and enough thyroid hormone. And if this wasn’t enough, the
children of iodine-​deficient mothers had a far greater incidence of ADHD [1]‌. More
recently, iodine lack also has been shown to affect the severity of symptoms in autis-
tic children [2].
The Sicilian study was published in 2004. Legitimate questions might then be,
Was this the first demonstration of the importance of iodine for brain function? Did
we only find out about it in 2004? Are all governments ensuring pregnant women
have enough iodine? Unfortunately, the answer is a resounding No to all three ques-
tions. To get a perspective on this, we have to take a step back in time, a full 200 years,
in fact, to Paris in 1811, at the height of the Napoleonic Wars that remodeled Europe
from 1792 to 1812, before Bonaparte’s downfall after his defeat at Waterloo in 1815.
Thanks to Tchaikovsky’s 1812 Overture, most of us are aware that Napoleon
invaded Russia that year,1 having annexed large parts of what today are Italy, Austria,
Germany, Poland, Switzerland, and the Netherlands. To wage these wars, he needed
ammunition and gunpowder, a mixture of sulfur, charcoal, and potassium nitrate
(saltpeter). Here, a certain Bernard Courtois enters our story. Trained as a chemist
during his military service, on the death of his father he entered the family saltpeter
manufacturing business in Paris. Using his chemical knowledge, he set about to
find new ways of preparing the vital ingredient of gunpowder, potassium, critical to
Napoleon’s war efforts. Courtois’s starting material was seaweed. By subjecting the
seaweed to different chemical reactions, he was astonished to observe in some cases
a mysterious violet vapor emanating from his crucible. When allowed to cool, the
vapor formed grayish crystals. Fascinated by his discovery and unable to identify
the crystals, he sent samples to the leading French chemist of the day, Joseph Louis
Gay-​Lussac, also working in Paris.
In December 1813, Gay-​Lussac presented his results on the properties of the new
element to the French Academy of Science. In the paper he read to the academy,
  13

Violet Vapors 13

having given credit to Courtois for the discovery, Gay-​Lussac announced that he
chose the name iodine for the newly discovered element in allusion to the “very
beautiful violet” color of the gas, from the Greek iodes.
The hunt then began for sources of this new element iodine in different rocks,
plants, and animals. Many chemists joined the endeavor, including Humphry Davy
in England, the inventor of the miners’ lamp and the scientist who gave chlorine its
name. It soon became evident that although abundant in the sea, iodine is a much
rarer element in Earth’s crust, particularly in regions distant from the coast. On the
other hand, soil in coastal areas is relatively iodine rich (and so, consequently, are
plants grown on such soil). The reason is that iodine is a volatile element that evapo-
rates rapidly into the atmosphere. As iodine accumulates in the atmosphere over the
sea, it is dissolved into clouds; when precipitated in rain, it enters the soil. The same
mechanism, loss of volatile iodine into the atmosphere, explains why iodine is lost
during the preparation of sea salt.

How iodized salt eradicated cretinism

Amazingly, within 10  years of the discovery of iodine, a perceptive Swiss doctor,
Jean-​François Coindet [3]‌, made the astute observation that iodine was probably
the curative factor in the preparations of marine sponges or seaweed that had been
used since antiquity to treat goiters (large swellings at the base of the neck). Today,
we know that goiter is indeed caused by iodine deficiency. The thyroid is a butterfly-​
shaped gland at the front of the neck below the Adam’s apple. If there is not enough
iodine around, the thyroid overworks. The gland increases massively in size, produc-
ing the enlargement characteristic of goiter.
Goiter was always more common in women, particularly during pregnancy. We
now know that this greater incidence in pregnancy is attributable to the increased
need for iodine for making thyroid hormone, which in turn is essential for the baby’s
growing brain. Coindet’s observation linking iodine, seaweed, and the thyroid was
extraordinarily prescient, given that thyroid hormone had not yet been identified
(and would not be for another century). He suggested using iodine solutions to treat
goiter, but, as is often the case with groundbreaking ideas, the proposal was vehe-
mently rejected by his colleagues in the medical community.
The next episode in the story of iodine and brain development took place in the early
1850s when the French botanist Gaspard-Adolphe Chatin was carrying out measure-
ments of iodine concentrations in plants, rivers, and soils in different French regions.
He noticed that the areas with the lowest iodine concentrations in the environment
had the highest incidence not only of goiter, but also of another disease, cretinism.
Little was known about cretinism at the time. However, those affected by cretinism
14

14 Toxic Cocktail

could easily be recognized. Cretinism results in severe and irreversible intellectual

deficiency, deafness, cross-​eyes, and short stature. These features illustrate the vital
role of iodine-​containing thyroid hormone not only in brain development but also
in vision and hearing and in general body growth. In the next chapter, I explain how
thyroid hormone deficiency causes the marked pathological features of brain develop-
ment seen in cretinism and why subtle deficits of thyroid hormone during pregnancy
could be limiting intellectual potential today.
What is remarkable is that, more than 160 years ago, the then-​equivalent of the
French minister of health took stock of Chatin’s preliminary observations and in
1853 commissioned him to carry out a systematic assessment of iodine levels across
France. The next step was to correlate the levels of iodine with the incidence of the two
diseases, goiter and cretinism. The results of this survey confirmed Chatin’s hypoth-
esis. Luckily, at the same time, another French chemist, Jean-​Baptiste Boussingault,
was working on the iodine content of minerals in the Andes. Combining Chatin’s
and Boussingault’s observations led to the suggestion that iodine deficiency could
be treated with salt preparations with high iodine content.
So, even though the scientists did not know the mechanisms behind how iodine
supplementation prevented goiter and cretinism, 160 years ago the health authori-
ties took the necessary action to ensure these diseases were avoided. This foresighted
approach contrasts with the attitudes of many contemporary authorities responsible
for chemical regulation, who often will not regulate unless they have been provided
with a mechanism that explains the associations.
Despite the insightful work of these chemists and the efforts of the French
government, the deleterious effects of iodine deficiency in the soil on the physi-
cal and mental health of people living in inland areas often continued unabated,
with a high incidence of cretinism in certain areas, such as the European Alps,
well into the 20th century. Prior to the introduction of iodized salt in 1915, it was
estimated that in parts of Switzerland 1 in every 200 children was affected by
cretinism, nearly all the children had some form of goiter, and a third of young
men were deemed unfit for military service because of the size of their goiters
[4]‌. A British mountaineer, Edward Whymper, 2 related that once iodine supple-
mentation was brought in, many parents actually refused it so that their goitrous
sons would continue to avoid military service. According to Whymper, these
“benighted” backward people preferred their “wallets of flesh” (their goiters) to
the “Marshal’s baton.” In fact, traveling in Europe a decade later, Mark Twain,
cited by Zimmerman [3], commented: “I have seen the principal features of Swiss
scenery—​Mont Blanc and the goiter—​a nd now for home.” Despite Whymper’s
reference to these benighted people, there is no record of the general intellectual
capacity of these populations, although the fact that some Swiss cantons brought
  15

Violet Vapors 15

in iodization later than others allowed records to establish the significant reduc-
tion of mental deficiency, deafness, and short stature in individuals in those can-
tons that introduced the measures earliest.
Before the introduction of iodized salt, traditional medicine also exploited
empirically discovered, nonmarine sources to treat goiter. François Lachiver, my
predecessor directing thyroid research in the Natural History Museum in Paris,
was prompted by a visiting Afghan doctor to study iodine fixation in earthworms.
The doctor had related how, in the mountainous areas of Afghanistan with high
incidence of goiter, powdered earthworms were used in folk remedies. And, indeed,
Lachiver found that these lowly creatures have a remarkable capacity to concentrate
organic iodine, despite the fact that, like most invertebrates,3 they do not have a
thyroid gland. How exactly iodine is taken up and stored in earthworms remains an
unexplored question.

Of Papuans and colonialism, a tragic 20th-​c entury tale

Other geographical areas had long traditions of producing salt from iodine-​rich
sources. A  tragic reversal of tradition, causing an unprecedented increase in cre-
tinism, occurred in a group of tribal societies in Papua New Guinea when coloni-
zation put an end to traditional salt-​making practices. In 1999, Peter Pharoah [5]‌
gave a Memorial Lecture at the School of Tropical Medicine in Liverpool (United
Kingdom), relating the story of how he studied the rising incidence of cretinism in
the area, how he sought the cause, and how he resolved the problem.
Prior to the arrival of missionaries and colonial traders in the early 20th century,
different tribes in the valleys of Papua New Guinea had strict boundaries. Crossing
another tribe’s boundaries could cause intertribal war. However, centuries-​old cus-
toms had defined certain periods of the year when a “pax salina” or salt treaty was
enacted, and boundary rules were relaxed, allowing “salt routes” to be established.
During these periods different tribe members could travel to inland volcanic pools
and set up salt ovens, making salt according to a traditional method that was cer-
emoniously respected. Communities made enough salt not only to cover their own
needs but also to sell it. Salt was their currency for trading food, tools, and even
wives. It is useful to recall that the word salary (from the Latin word salarium for
“salt”) is derived from the time when salt was used as a form of currency or payment.
In the 1940s, the colonials and missionaries made industrial salt easily available.
This changed trading methods, with the result that the tribes dropped their salt-​
making practices, with the last salt oven abandoned in 1958.
Cretinism starting appearing in the late 1950s, at first with an incidence of about
1 in 100, then rocketing in the 1960s to reach the distressing tally of over 1 in 20
16

16 Toxic Cocktail

live births. British and Australian health authorities investigating the epidemic
came up with various hypotheses, but it was only when they analyzed the change
in salt-​making traditions that the answer was found. The traditional volcanic pool
source produced salt with twice the amount of iodine found in iodized salt pro-
duced for sale in Britain, whereas the salt provided by the traders was very probably
not iodized at all.
To correct the deficiency, doctors started giving pregnant women injections of
iodized oil. It was then that they documented that giving the iodine in early preg-
nancy had the greatest prophylactic (preventive) effect. If the woman came to the
clinic in late pregnancy or during breast-​feeding, the protective effect of iodine ther-
apy on the child’s brain development was less marked. This demonstration, result-
ing from an unfortunate situation, was probably the first to document the need
for iodine in early pregnancy to ensure proper development of the baby’s brain and
body and this despite the long history of research on iodine, thyroid hormone, and
cretinism.

A short history of goiter and cretinism

The history of the diagnosis and treatment of cretinism is equally edifying. Toward
the end of the 19th century, even before thyroid hormone had been isolated and
characterized, two prescient European doctors provided the first demonstrations of
the role of the thyroid in controlling brain maturation and metabolism. In a series
of reports, Portuguese and British doctors described the beneficial effects on the
physical and mental health of older patients suffering from severe hypothyroidism
(or myxedema4 as it was then called) of implanting sheep thyroid, injecting thyroid
extract, and later supplying “thyroid tablets.”
The links between the thyroid gland and the symptoms these doctors were try-
ing to treat derived from observations of a Swiss surgeon, Theodore Kocher, on the
negative consequences of surgery to remove large thyroid goiters in patients and
from experiments carried out in the 1880s on thyroidectomy in monkeys. Kocher
was particularly struck by the postoperative consequences on an 11-​year-​old young
girl whose goiter he had removed. Following the operation, she stopped growing,
became lethargic, and developed symptoms of cretinism. The reason she stopped
growing was that thyroid hormone is needed for growth of bones and muscle, not
just brain cells. So, he established that cretinism is associated not only with severe
irreversible intellectual disability but also with physical stunting. These symptoms
prompted Kocher to reexamine other patients whose thyroids had been removed
because of goiter during childhood. He consistently observed the same devastating
consequences of cretinism in all the children concerned. Kocher proposed that the
  17

Violet Vapors 17

link between goiter and cretinism was the thyroid gland. Despite the early skepti-
cism of most of his colleagues, he was justly awarded the Nobel Prize in 1909 for
his work.
Luckily, not all the medical community was as critical as his colleagues. In 1891,
George Murray [6]‌, working in Newcastle-​on-​Tyne (an industrial city in the north
of England), injected extract of sheep thyroid into a 46-​year-​old woman suffer-
ing from severe hypothyroidism. Murray described the mental “languor” (lack of
enthusiasm), social consequences (“a disinclination to see strangers”), and physical
effects (sensitivity to cold, lack of perspiration and menstruation) the patient expe-
rienced and how the symptoms were reversed by regular injections of sheep thyroid
extract. Besides major physical changes, Murray noted “the speech has become more
rapid and fluent. … She answers questions more readily, the mind has become more
active and the memory improved” (p. 171).
These early “clinical trials” were first carried out on adults who had become hypo-
thyroid in later life. Tests were then done on younger subjects suffering from cretin-
ism since birth. It is thought, given the geography and the local iodine supply of the
time, that the first adolescents treated by two British doctors in the 1890s were prob-
ably suffering from congenital hypothyroidism (CH). Congenital hypothyroidism
is due to a failure of the fetus to form a fully functional thyroid. More often, as we’ve
seen, cretinism is due to insufficient dietary iodine. In this case, despite the fact that
the thyroid gland has formed, it can’t make thyroid hormone because there’s not
enough iodine to do so.
Luckily, whatever the origin of the thyroid hormone deficiency in the young
patients treated in the 1890s, they responded well, with improvements in growth
and mental alertness. However, as they had had not had enough thyroid hormone in
the pre-​and postnatal periods, the period of most rapid brain growth, their intellec-
tual deficiency was irreversible, and only small improvements in mental ability were
seen. One of the doctors reported that giving thyroid tablets to a 14-​year-​old affected
by cretinism with the “brain condition of a two year-​old” had enabled the child to
become equivalent to a 3-​year-​old, although he quite rightly predicted that “after the
long sleep” the boy’s brain had suffered, the damage could never be fully corrected
[7]‌. Today, we know that the beneficial effects of treating CH with thyroid hormone
are time and dose dependent, increasing as a function of how fast the condition is
detected and treated. As many babies born with CH will appear normal at birth, the
importance of screening for an absent or underactive thyroid gland is vital.
Prior to the introduction of screening in the 1970s,5 many children with CH were
not given a diagnosis until months after birth. Often, the first signs of thyroid hor-
mone deficiency would be delay in closing of the skull bones around the fontanelles,
the soft spots in the baby’s head where the skull bones don’t yet meet and form
18

18 Toxic Cocktail

sutures. Failure for these bones to close at the expected times often indicates lack
of thyroid hormone, as skeletal development is dependent on the hormone. So, if
a delay were noted, corrective treatment would be started, but this would not usu-
ally be until between 3 and 6 months of age. As a result, most of the children with
CH never reached their full intellectual potential and often had IQ levels under
80. Even those diagnosed and given treatment within the first 3 months suffered
from residual learning problems. Many older pediatricians active today eloquently
compare the immense difference that this major public health measure has made,
enabling children who otherwise would have been doomed to an institutional-
ized or very difficult and limited life to have access to normal schooling and career
options. Furthermore, the cost of screening is infinitely less than that of raising and
supporting a child (and adult) with an intellectual deficiency.
There is a well-​documented increase in the incidence of reported CH in many
countries, including the United States, Japan, and Mexico [8–​10]. The potential
causes of this increase are discussed in detail in Chapter 5.

The crux of the matter: eradicating iodine deficiency

Iodine deficiency remains the greatest easily preventable cause of intellectual dis-
ability worldwide [11]. What is more, iodine deficiency is on the rise in certain
developed countries. It has been estimated [12] that 44% of European children have
insufficient iodine intake. Worse, the United Kingdom is 1 of the 10 most iodine-​
deficient countries worldwide [13]. Margaret Rayman, professor of nutrition at the
University of Surrey, has published powerful evidence that current iodine defi-
ciency in the United Kingdom, particularly in pregnant women, is having negative
effects on the neurodevelopmental outcome of children. Other authors have cal-
culated that avoiding even moderate iodine deficiency in pregnancy could increase
the overall IQ of the population slightly but significantly [14]. In this context, it is
important to reiterate the prescience of the health authorities in 1850 compared to
the apparent indifference of those of the present day.
Today, we have evidence from hundreds of articles showing the benefits to chil-
dren’s cognition of iodine supplementation in pregnancy. Studies from the United
Kingdom to Tasmania have shown that children born to mothers who were mod-
erately iodine deficient had lower IQs and more difficulties with spelling and read-
ing. More disquieting, perhaps, a recent Europe-​wide study showed that, of the
countries for which there was data on iodine levels in pregnancy, over two-​thirds
reported inadequate iodine intakes [15].
Possibly, this negligence may be accounted for by fact that the most obvious
physical manifestations of iodine lack (goiter and cretinism) are rarely encountered
  19

Violet Vapors 19

today. However—​and this will be a recurrent argument—​not only does iodine

insufficiency go undetected in many populations, but also there is universal expo-
sure to thyroid-​disrupting chemicals from conception onward. The two factors
together may well be reducing the intellectual potential of our children.
Four atoms of iodine6 are required to synthesize just one molecule of thyroid
hormone. Given the importance of thyroid hormone in multiple aspects of brain
development (see Chapter  2), it is not surprising to find that iodine deficiency
causes pronounced intellectual disability. In 1990, the World Health Organization
(WHO) set the target of eliminating iodine deficiency by 2000. However, despite
the progress made, estimates made a decade later suggested that 29% of the world’s
population was still at risk of iodine deficiency. Worse, in countries that had pre-
viously eliminated the risk, the problem is reappearing. The resurgence of iodine
deficiency is in part due to the decline in or abandonment of legislation on iodized
salt; it is also attributable to changes in food production methods. For instance, the
iodine content of cow’s milk varies according to methods used for the disinfection
of udders and whether conventional or organic farming methods are used [16]. In a
recent UK study, iodine content was, unfortunately, found to be about 40% lower
in organic milk than nonorganic milk, arguing for iodine supplementation in other
forms. Given that milk is a vital source of iodine, particularly in areas where the
use of iodized salt is not required by law but is optional, the decline in milk iodine
content is becoming a public health issue. Concern about iodine deficiency in the
general population is shared by many international bodies.7
Clearly, the most convenient and consistent form of iodine supplementation is
the use, preferably mandatory [17], of iodized salt not only in households but also
in the food industry. This solution is advocated by the Iodine Global Network
(IGN) (http://​ign.org/​index.cfm)8 and innumerable experts in the field, includ-
ing clinicians, basic scientists, and epidemiologists [18]. Many, but by no means
all, developed countries provide access to iodized salt. European countries that do
not make the use of iodized salt mandatory in the food industry and in table salt
include France, Germany, and the United Kingdom, the three largest in terms of
population.
Even in countries where it is available, it may not be generally used and may even
be difficult to find in standard retail outlets. For instance, a recent study in Italy
measuring iodine intake among schoolchildren showed that only 30% of households
were using iodized salt [19]. Another study, conducted in the United Kingdom, cal-
culated the availability of iodized salt in terms of supermarket provision and found
it amounted to less than 21% of sales of salt [20]. Friends of mine living in small
towns in the United Kingdom tell me their local grocery stores or even supermar-
kets do not stock iodized salt.
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20 Toxic Cocktail

A website is provided by WHO with overall data on global iodine status.9 Among
the tables presented, those covering the proportions of populations in different geo-
graphical areas that suffer from insufficient iodine intake are particularly eloquent.
Iodine intake can be estimated by looking at the amounts of iodine in urine, as
iodine that is not taken up by the thyroid is excreted in the urine. For instance, com-
paring the 2004 data on the percentage of the population in Africa versus Europe
with urinary iodine (UI) content below a critical level shows that it is in Europe
that the greater percentage of the population is at risk (56.9% in Europe vs. 42.6%
in Africa). This difference is probably related to the lack of legislation on usage of
iodized salt in many European countries.
Taking a more detailed look at UI values for children aged 6–​12, current data
indicate that about 44% of European children have insufficient iodine intakes [15]
(including children in Belgium, Estonia, France, Italy, Ireland). By contrast, chil-
dren in Egypt, Finland, Germany, and Tunisia have optimal intake. Other non-​
European countries where children’s UI levels indicate the greatest risk of iodine
insufficiency include Afghanistan, Algeria, Gambia, Kyrgyzstan, and Vietnam.
Even in the United States, which is generally considered to be iodine sufficient,
there are populations that are mildly iodine deficient.
The latest data from the US National Health and Nutrition Examination
Survey (NHANES) show that pregnant women are increasingly iodine deficient,
especially in the first two trimesters of pregnancy [21, 22]. It is important to recall
that the early months of pregnancy appear to be the most vulnerable period for
both iodine and thyroid hormone deficiency, leading to adverse effects on the
child’s cognition. So, this situation should be of particular concern for young
women of childbearing age [23, 24]. As Margaret Rayman’s group has shown, even
mild maternal iodine deficiency during pregnancy increases the risk of lower IQ
in the child [24], echoing the results from Sicily and many other studies.
To cite a region outside Europe and show the global significance, Tasmania pro-
vides an excellent example [25]. In Tasmania, a group of mothers were studied who
had normal levels of iodine or mild iodine deficiency during pregnancy but whose
children were given sufficient iodine later in childhood. Children whose mothers
had mild iodine deficiency did significantly worse at school, even when other socio-
economic factors, such as mothers’ education level, were taken into account.

Not only iodine, but also selenium

As we will discuss in the last section of this chapter, both excess and insufficient
thyroid hormone can have devastating, even fatal, consequences. Thyroid hormone
levels in our bodies have to be just right. It is therefore not that surprising to find
  21

Violet Vapors 21

that powerful control mechanisms have evolved to ensure the correct amounts of
hormone are available for use by various body organs at different life stages. A first
set of controls acts on the thyroid gland itself to ensure continuous production and
secretion of stable amounts of hormone into the bloodstream. A second set of con-
trols acts at the level of every organ in our bodies, including the muscles, liver, kid-
ney, heart, and brain. In fact, every cell within each organ can specifically tailor how
much thyroid hormone is available for use.
One of these major sets of controls involves special enzymes that, by removing
one iodine atom, either activate or degrade the hormone. These enzymes are called
deiodinases. They all have the defining feature of containing a rare element, sele-
nium. Thus, simply put, normal thyroid function requires a constant supply of two
rare elements: iodine and selenium.
The fact that selenium is a rare element is not the only problem to consider when
discussing our nutritional needs for these two elements. Another problem is that a
common environmental contaminant, mercury, can interfere with the availability
of selenium in our bodies. Environmental mercury contamination will be a recur-
rent theme in this book. I go into more detail in Chapter 5, where I deal specifically
with documented IQ loss as a function of mercury exposure. But, some background
is also relevant here given the links between selenium and iodine on the one hand
and mercury and selenium on the other.
In the 1970s, a series of industrial errors caused accumulation of mercury in fish in
Minamata, Japan, with population-​wide poisoning, neurotoxicity, and major effects
on brain development. Another example of mercury poisoning that was related to
food, homemade oatmeal, occurred in a Swedish family. While the whole family
was exposed, it was the unborn child of the mother eating the contaminated por-
ridge who was most severely affected, more so than the older children. This event
illustrates yet again the tremendous sensitivity of the fetus to chemical exposure
during the mother’s pregnancy. Here, it is important to underline the fact that
because mercury and selenium interact, mercury “chelates” or traps selenium. Thus,
the presence of mercury in the body will reduce the amount of selenium available to
make deiodinases and so limit thyroid hormone activation.
Environmental mercury is found in different forms, of which the main one is
methylmercury, produced by various industrial processes, such as coal-​fired power
stations and mining. Mercury can persist in our brains for years. It interacts with
selenium, forming mercury selenite, which is thought to be the form that accu-
mulates in the brain and exerts neurotoxic effects, such as inhibition of deiodin-
ase enzymes and the modification of thyroid hormone availability in the brain.
The study of mercury/​selenium interactions in physiological systems has a long
history. It led to the idea that nutritional selenium can protect against mercury
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22 Toxic Cocktail

toxicity, provided it is in excess. Both animal studies and epidemiological reports

substantiated this idea. For instance, in one series of experiments, rats were fed
with diets containing low-​, medium-​, or high-​selenium supplementation and then
exposed to different levels of methylmercury. The researchers found that one of the
early symptoms of mercury toxicity in the low-​selenium group was growth delay,
but if the rats were given higher amounts of selenium, not even the high-​mercury
dose had any adverse effect on growth.
Similarly, in a study on a Faroese population exposed to high levels of mercury
through consumption of whale meat, it was found that because of the high lev-
els of selenium in the whale meat, no deleterious effects of mercury contamina-
tion were detected. These concepts have led to the general recommendation that,
despite the risk of consuming mercury in fish, particularly those at the higher
end of the food chain such as tuna and swordfish, the significant amounts of
selenium in these sea fish not only can counterbalance the risk but also can be
beneficial as the fish have much more selenium than mercury. Interestingly, this
study revealed that it was not just the selenium in the fish that was providing
protection against neurotoxicity [26] but that other factors (possibly omega 3
and other unsaturated lipids) could also be acting positively on brain function.
Nevertheless, the authors wisely recommended that pregnant women preferably
eat fish that have less mercury contamination, such as those lower down the food
chain, like the flatfish, sole, or plaice [26].
Another point worth noting on the subject of mercury/​selenium interactions is
that the neutralizing effects of selenium on mercury can also be seen in plant physi-
ology and agriculture. Rice grown in soil that is rich in selenium takes up less mer-
cury than that grown in selenium-​poor soil. In inland China, consumption of rice
grown in areas with intense smelting and mining activities is a significant pathway
for methylmercury contamination. In certain regions, daily mercury intake exceeds
recommended doses, and in such cases, as rice does not have the neuroprotective
properties of fish (in terms of both the selenium and the omega 3 contents), the
physiological consequences of rice-​borne exposure may be greater. This could be an
argument for selenium enrichment in the soil or food.

Sea salt does not contain iodine

The major natural source of iodine is seawater. For comparison, tap water contains
between 100-​and 1,000-​fold less iodine. The fact that seawater contains high levels
of iodine leads to the common fallacy that because the sea is the major source of
iodine, then sea salt contains large amounts of iodine. This idea is totally erroneous
  23

Violet Vapors 23

because iodine is a volatile element (this means it evaporates or converts rapidly

into gaseous form). Sea salt is produced by evaporating seawater, leaving sodium
chloride (basic table salt) as a residue, but absolutely no iodine. Its volatile nature
results in iodine being lost along with the water in the evaporation process. So
the key take-​home message here is that sea salt does not contain iodine. Amazingly,
because they do not study chemistry or have forgotten the relevant information,
not all doctors, and not even all researchers working on thyroid physiology, are
aware of this fact. By way of an anecdote, at a recent thyroid hormone research
meeting, I asked three colleagues if they knew that sea salt did not contain iodine.
They didn’t. They also did not know the reason why. I  hope the readers of this
chapter could now tell them.
The fact that many people think sea salt is better for them because it is “natu-
ral” and “unmodified” is doubly unfortunate. First, it means that many consumers
today are spending significantly more money on special sea salts than on standard
iodized table salt on the erroneous grounds that sea salt is iodine rich. Second, they
are losing an easily obtained source of this vital element. Numerous scientific publi-
cations have documented the relative amounts of iodine in sea salt and iodized salt
and firmly established the absence of iodine in sea salt (for details, see Losing Our
Minds [27]).
Thus, the only salt to provide iodine is iodized salt. From a governmental perspec-
tive, this fact should be considered as the easiest way of ensuring iodine supplies for
the general population and therefore limiting the most common form of prevent-
able IQ loss. Two simple measures would be that, first, only iodized salt should be
sold in supermarkets; second, it should be the only salt used in the food industry.
However, many people are on restricted salt diets, including the large number of
people with high blood pressure, which is the case for certain pregnant women,
whose need for iodine and selenium is particularly high. Hence, dietary supplemen-
tation10 should be considered for certain categories of the population or the amount
of iodine added to table salt should be increased. Another point is that as iodine is
volatile, even when using iodized salt, it is better to add it at the end of cooking or at
table to avoid loss of iodine during cooking.
Another chemical element that can affect iodine uptake by the thyroid gland is
bromine. Bromine is present in the urban environment in the form of brominated
flame retardants, and in some countries, bromine-​containing chemicals are still
used in leaded gasoline. Because bromine is a halogen like iodine, it competes with
iodine for uptake by the thyroid. The negative effects of bromine will be exacerbated
by iodine deficiency. The discussion of the thyroid-​disrupting effects of brominated
and other halogenated compounds is continued in Chapter 3.
24

24 Toxic Cocktail

Food sources and recommended daily amounts

of iodine and selenium

Both iodine and selenium are categorized as rare elements, and yet  all humans
require a supply of each, with pregnant and nursing mothers needing the most.
Different official nutritional bodies set the current recommendations for adults at
between 90 and 100 micrograms iodine per day and 55–​75 micrograms selenium per
day. The current WHO iodine recommendation for pregnant and lactating women
is 250 micrograms per day. WHO also suggests a total intake of 120 micrograms
per day for children aged 6–​12 and 150 micrograms per day for adolescents. These
requirements can only be met by a well-​balanced diet rich in suitable sources of
iodine (see next section) and use of iodized salt. This is why most pregnant women
will need about half of their “extra” requirements as supplements. As pregnant
women often take vitamin and folic acid dietary supplements, it is easy to select
those with iodine. Look on the label and you will find indications on whether the
list of minerals includes iodine. The amount per tablet should be between 100 and
150 micrograms. This amount actually represents about half of a pregnant or breast-​
feeding woman’s daily requirements. But, it’s important to note that, as for any food
supplement or drug, one should never take more than the dose suggested on the
label. The other half will come from a well-​balanced diet, including use of iodized
salt, sea fish, and dairy products. Pregnant women should not use kelp (seaweed)
tablets as the excessively high amounts of iodine could damage their thyroid and
that of their child.
Certain foodstuffs contain reasonable levels of iodine, notably eggs, milk, and
certain breads. However, the iodine content of these products will depend on
the soil and the grain or cereal, or other foodstuffs, used to feed cattle or poultry.
Seaweed (kelp), as a marine product with iodine attached to proteins, is also a good,
but very variable, source; as mentioned, it should not be used during pregnancy and
breast-​feeding. Undoubtedly, the most reliable sources of both iodine and selenium
are sea fish and shellfish. Numerous publications have given results of analysis of
iodine and selenium in seafood and other sources.
In 1993, the UK government published a good reference source for the levels of
both iodine and selenium in shellfish and different sea fish. The report showed that
the best sources of iodine are mussels and mackerel (a 100-​gram serving of either
contains about 140 micrograms iodine, thereby virtually covering the daily require-
ments of an adult); shrimp and lobsters provide 100 micrograms per 100 grams. The
selenium content of each of these foods is also sufficient for a 100-​gram serving to
nearly cover the average daily needs, with mussels and shrimp averaging 50 micro-
grams per 100 grams and fish averaging 25–​30 micrograms per 100 grams. For those
  25

Violet Vapors 25

who can afford a serving of lobster from time to time, they can combine the feelings
of self-​indulgence and gastronomic pleasure and perhaps dispel the financial setback
with the comforting thought that a serving of lobster covers the better part of 2 days
of selenium and iodine requirements. What is more, if we lack iodine, then iodine is
stocked in the thyroid gland for future use; if we already have enough, then the extra
will be excreted in urine, as is the case for many vitamins.

Seafood as a driving factor in brain evolution?

Although much debated, it has been proposed that the consumption of iodine-​rich
foods supplied by a seafood diet could have played an important role in human brain
evolution. This theory takes into account that not only is seafood iodine rich but
also it is an excellent source of polyunsaturated fatty acids, especially omega 3 lipids,
another requirement for optimal brain development and function. Other authors
maintain that both iodine and additional essential nutrients for brain development
would have been amply supplied by a grain-​rich diet supplemented with meat. It can
usefully be reiterated here that the iodine content of plants is positively correlated
with proximity to the sea. Thus, populations of early humans living near the sea
would have benefited from this factor independently of fish consumption. The ani-
mals they ate would also be iodine enriched as a function of a food chain beginning
with plant life. Further away from marine coasts, the iodine content of foodstuffs
would have been variable, and generally less. A final point relevant to these issues is
that of the high selenium content of seafood. This double-​prong action, the com-
bined effects of selenium and iodine favoring thyroid hormone effects, could have
been central to brain evolution and development.
Another factor bolsters the argument that fish consumption was vital for human
brain evolution. It seems that our distant ancestors ate a lot of plant products with
high goitrogen content. Goitrogens or goitrins are natural substances that inhibit
thyroid gland function. Many of the plants domesticated in the Neolithic period
(including soy, millet, maize, turnips, and cabbage) contain goitrogens.
There is actually an intriguing case of severe hypothyroidism in the medical lit-
erature; a woman ate more than a kilo of raw cabbage every day [28] and developed
a severely underactive thyroid. The link is that vegetables from the cabbage fam-
ily contain an enzyme, myrosinase, that is released into the body if the vegetables
are eaten raw but is destroyed on cooking. This enzyme causes the breakdown of
other substances found in cabbage, namely glucosinolates, which in turn generates
a series of compounds (such as thiocyanates, nitriles, and oxazoldines) that inhibit
iodine uptake by the thyroid. This medical case echoes experiments performed a
26

26 Toxic Cocktail

century ago, when rabbits fed a diet of cabbage were observed to develop goiter.
Studies on the thyroid-​inhibiting properties of cabbage [29] led to the isolation of
different goitrogens from a number of foodstuffs [30].
Returning to the question of brain evolution in the context of a goitrogen-​rich
plant diet, foods rich in readily available iodine (and selenium), such as sea fish,
would be vital in these conditions to ensure optimal brain development and func-
tion. Intriguingly, this requirement for increased iodine supply in the context of
goitrogen-​rich vegetarian diets may be particularly pertinent in the contemporary
context, with increasing numbers of vegetarians eating similar diets, rich in goitro-
gens and low in iodine. Moreover, many vegetarians could be choosing to use sea
salt because of its supposedly unadulterated nature and the regrettable assumption
that it is iodine rich. They and their children could be particularly at risk for iodine
deficiency and its consequences on suboptimal thyroid function unless they take
iodine supplements.

Even in adults, too much or too little

thyroid hormone is problematic

Besides the need for thyroid hormone to ensure correct brain growth in the fetus
and young child, even in adolescents and adults the hormone is needed to maintain
many aspects of brain function (especially memory and mood) and general health,
particularly energy balance and body weight. Yet, too much thyroid hormone can
kill you rapidly (mainly due to adverse cardiac effects) and so will the absence of a
thyroid gland, albeit rather more slowly. In a recent endocrinology meeting, one of
my colleagues, David Sharlin (assistant professor at Minnesota State University),
quipped, “You can live without your gonads,11 but not without your thyroid.” And,
how right he is! Preoccupied as we might be with the steroid hormones, testosterone
and estrogen, that govern our reproduction and fertility, we can survive to a ripe
old age without the endocrine glands—​the testes and ovaries that produce these
hormones.12 But, having the right amount of thyroid hormone at the right time is
essential for normal existence and even survival.
Even mild thyroid hormone insufficiency will cause a spectrum of disorders in
children, adolescents, and adults. Whether mild or severe, hypothyroidism is associ-
ated with depression, anxiety, mood and memory problems, weight gain, increased
sensitivity to cold, dry skin, and constipation. In contrast, hyperthyroidism (or an
overactive thyroid) is associated with cardiac disorders, weight loss, irritability, and
sleep problems.
I have always been intrigued by thyroid hormone, probably because so many peo-
ple in my family suffer from thyroid disease. As an adolescent, I once came home
  27

Violet Vapors 27

to find my father in collapse due to misdiagnosed thyroid disease. Decades later,

in 1983 when undergoing a lot of stress at work helping a student finish a thesis,
I lost about 10 kilos in less than 2 months. My heart was beating at over a 100 beats
per minute, far too fast. My thyroid had gone into overdrive. Hyperstressed, I had
become hyperthyroid, just like my father. If I had not sought treatment to block the
activity of my thyroid gland, I would have died from heart problems. Like so many
other people, mostly women, my body had started producing an immune response
against my thyroid gland. In fact, the most common forms of thyroid disorders,
hypothyroidism (insufficient thyroid hormone) and hyperthyroidism (or excess
thyroid hormone—​hyperthyroxinemia or thyrotoxicosis, to use the clinical terms)
are both autoimmune diseases. An autoimmune disease is a pathological condition
caused by the production of antibodies against one’s own body.
About 150 autoimmune diseases are known, the large majority being much more
common in women than in men. Examples of autoimmune disease include type 1
diabetes (due to destruction of the insulin producing β-​cells in the pancreas) and
different forms of thyroid disease, including Graves disease (hyperthyroidism) and
Hashimoto’s disease (hypothyroidism), each due to antibodies acting on different
proteins associated with the thyroid gland. Women have a 1-​in-​8 chance of develop-
ing a thyroid-​related disorder in their life, higher than breast cancer risk.
Hyperthyroidism is easily diagnosed by its multiple symptoms (including rapid
weight loss and bulging eyes), so it is usually treated rapidly with drugs that block the
thyroid gland and thyroid hormone production. If severe or recurrent, the thyroid is
removed and thyroid hormone replacement therapy instituted. However, if hyper-
thyroidism is left untreated, it can result in a serious condition known in the medi-
cal literature as “thyroid storm,” which can be life threatening. Intriguingly, thyroid
storm can also, on rare occasions, result from acute trauma [31]. The most common
cause of death from the excess thyroid hormone that characterizes thyroid storm is
heart complications, such as tachycardia (too rapid heartbeat) and atrial fibrillation
(problems of cardiac conduction and arrhythmia). It should be noted that cardiac
complications are the main reason why thyroid hormone should not be prescribed
to obese patients who wish to use the metabolic-​stimulating and fat-​burning prop-
erties of the hormone to facilitate weight loss. In some countries, though, unscrupu-
lous doctors will prescribe the hormone, often with dire consequences [32].
An underactive thyroid, or hypothyroidism, is most often associated with
weight gain and various mood disorders. It is treated with a daily of dose of thy-
roid hormone that is adjusted according to the patient’s needs. It is interesting
to note that, today, thyroid hormone is the most prescribed drug on the mar-
ket, a fact undoubtedly related to the general increase in thyroid disease noted
worldwide.
28

28 Toxic Cocktail

Prolonged and severe hypothyroidism can, in exceptional circumstances, prove

fatal if not treated urgently. A rare clinical condition characteristic of severe thyroid
hormone deficiency is myxedema coma. The symptoms include edema (accumula-
tion of fluid in the limbs), cardiac problems, respiratory distress, hypothermia, and
coma and require immediate administration of thyroid hormone. Today, the cause
of extreme hypothyroidism will most often be failure of patients to take the thyroid
hormone prescribed by the clinician.

Conclusion

Because a stable supply of iodine and thyroid hormone is vital at all life stages,
evolution has fashioned a system of checks and counterbalances to regulate the
signals from the various parts of the brain to the thyroid gland to ensure suf-
ficient iodine uptake and thyroid hormone production. At all life stages, these
controls in production and the tissue responses to thyroid hormone will adjust
to environmental factors such as temperature and food supply. Thyroid signal-
ing has evolved as a natural communication route to enable gene expression and
physiological responses to adapt to environmental signals. But, for us, the con-
cern today is the number of extraneous chemicals in our bodies that are con-
fusing these communication and adaptation systems, blocking iodine uptake,
changing thyroid hormone levels, and altering the normal genetic and physi-
ological responses both during development and in maturity. These ideas are the
topics of the next two chapters.
  29

2
A Molecule of Mystery

I’m sitting on the terrace of a popular Parisian café in early summer 2014; fair
enough, a bit of a cliché, but the coffee’s good, as is the gentle sunlight filtered
through the canopy of chestnut trees lining the street. It may be a busy street with
rather too much traffic, but then, nothing’s perfect. And indeed, life for most
today is certainly better than it was for many a hundred years ago, as I’m acutely
reminded by the series of giant photographs hanging on the railings of the Jardin de
Luxembourg just across the road. The landscapes depict sites of battles in the First
World War. Grim memories. But, try to imagine the dynamics of change ongoing in
Europe and the United States at the turn of the 20th century, before Europe threw
itself, and many nations beyond its borders, into a frenzy of mutual destruction.
The opening years of that century have been described as a golden period of social
stability and cultural progress played out against a backdrop of relatively peaceful
international relations. Yet, it was also already a time of change, a period in which,
at many levels, revolutionary thinking was occurring across wide swathes of tech-
nology and science, with the dawn of nuclear physics and the tidal wave of Freud’s
thinking in psychology and psychoanalysis. Needless to say, these radical ideas were
in turn cross-​fertilizing modernist movements across Europe in literature, art, and
architecture.
For our story also, it was a time of revolution. Scientists working on both sides
of the Atlantic succeeded in unraveling many mysteries of the thyroid gland and

29
30

30 Toxic Cocktail

thyroid hormone in the first years of the 20th century. At that time, fundamental
discoveries were made that had relevance not only to human health and clinical
applications, but also for understanding how substances produced by the thyroid
gland can transform tadpoles into frogs. Today, we know that all vertebrates,1
from fish and frogs to humans, produce and use thyroid hormone, and that thy-
roid hormone in all these different species has exactly the same chemical structure.
As evolution slowly crafted amazing new forms and functions for each vertebrate
group—​feathers and flight in birds; hair, placentas, and milk for mammals; read-
aptation to the sea for marine mammals like whales and dolphins—​some features
remained absolutely constant. And, one thing that has never been modified over
hundreds of millions of years of evolution is the structure of thyroid hormone: Not
one atom has changed between a tadpole and a human.
Even today, when I  explain to official regulators how tadpoles can be used to
measure the effects of chemicals on thyroid hormone action, I still receive incredu-
lous comments and questions about how an amphibian model, a tadpole, can be
relevant to humans. What seems to provoke even more surprise is that it can be
relevant to human brain development. The best answer to these doubts comes
from the reputed French thyroid clinician and researcher, Jacques Legrand, who is
reported to have pointedly said “Without a minimum of thyroid hormone at the
right time, a tadpole fails to become a frog and a human baby becomes a cretin.”
Yes, exactly the same molecule that is needed to orchestrate the metamorphosis of
a tadpole into a frog is required for optimal brain development in all vertebrates,
including humans. Without the right amount of thyroid hormone at the right
time during your development and growth, you, the person reading these lines,
would not be able to make sense of this sentence, let  alone the message of this
book. In fact, as the World Health Organization (WHO) notes, iodine deficiency,
which hampers thyroid function, is the world’s main cause of preventable mental
retardation.2
So, to understand how our knowledge of thyroid hormone has grown in the last
century, let’s travel back in time to Prague at the beginning of the 20th century.

Prague, 1912

When walking the cobblestone-​paved streets of Prague today, in what is now the
Czech Republic, one finds a city structure and architecture redolent of an illustri-
ous past resonating with musical echoes from Mozart to Janacek. When Mozart’s
Don Giovanni premiered there in 1787, the city was enjoying unparalleled architec-
tural activity and design, leading to an intellectual and artistic high point at the end
of the next century with the emergence of the Art Nouveau movement. The year
  31

A Molecule of Mystery 31

1912 saw the completion of the city’s most magnificent Art Nouveau building, the
Municipal House, a concert and exhibition hall where, at the end of the war, the
declaration of the Czechoslovak Republic was announced in 1918.
But, Prague in 1912 was a magnet not only for artists, but also for many writers
and scientists. Among the scientists working in the German University in Prague
in 1912 was one Joseph Frederick Gudernatsch, a medical doctor who also held a
research degree, a PhD in anatomy. Born in Germany in 1881, he had immigrated to
the United States in 1907 but spent his summers working in Europe. In spring 1910,
he chose to go to the Zoological Station of Naples to study the effects of extracts of
different tissues on the development of fish and frog eggs. His experiments, how-
ever, were unsatisfactory because the extracts, prepared in New York before he left
and kept in cold storage as he crossed the Atlantic, were unstable in the Naples labo-
ratory, where there was no icebox. So, the following year he returned to his alma
mater, the German University in Prague. There he obtained fresh horse tissues
from the local abattoir as well as pig, rabbit, dog, and cat tissues. Instead of making
extracts, he fed the tadpoles finely minced pieces of the different tissues, thymus,
muscle, testicle, ovary, and thyroid [1]‌.3 As a control, some tadpoles were given tap
water—​which, he noted, “in Prague is very rich in organisms.” I imagine he didn’t
drink the Prague water without boiling it first.
That summer, he made his key discovery. When the tadpoles were fed
minced thyroid gland tissue from horses, their rate of metamorphosis acceler-
ated. Gudernatsch observed that the thyroid-​fed tadpoles were the first to grow
their back legs, then their front legs, and to lose their tails at the completion of
metamorphosis. He also found that tadpoles fed pieces of other organs, such as
liver, brain, or muscle, did not show any change in their rate of metamorphosis.
Importantly, not only did he record that it was only thyroid tissue that accelerated
the process, but also that thyroid tissue from any of the animals tested—​pig, dog,
or cat—​had the same accelerating effect on metamorphosis. What Gudernatsch
was seeing then, although he couldn’t know it, was the first demonstration that
thyroid hormone had the same chemical structure and acted in the same way in
all of these animals.
It is intriguing that someone else was also thinking about metamorphosis in
Prague in 1912, not the biological aspects but its allegorical implications. It was
in Prague that same year that a certain Franz Kafka read a version of what was to
become his most famous story, The Metamorphosis, to a select group of friends, prior
to its publication in 1915. In fact, Prague in 1912 was an intellectual crucible. Albert
Einstein had taken up a professorship there in April 1911 and played an active part in
the literary and debating societies that Max Brod and Kafka also attended. I often
wonder whether Gudernatsch was also at some of these meetings and perhaps by
32

32 Toxic Cocktail

speaking about his work on metamorphosis had triggered certain thoughts in

Kafka’s mind.
So, in 1912, Gudernatsch showed that thyroid tissue accelerated metamorpho-
sis. But, what was the active substance in the thyroid? Well, that enigma only took
another 2 years to be solved.

New York, 1914

It takes a lot more than intelligence to win a Nobel Prize; it requires perseverance,
talent, and, according to many awardees, a lot of teamwork and a fair dose of seren-
dipity. However, the winners who mention the role of luck in their discoveries may
well be unduly modest, for as Louis Pasteur memorably said, “Chance favors the
prepared mind.”
In the case of the discovery of thyroid hormone, unusually, it was not a matter of
teamwork, but it did involve a certain amount of good fortune, exceptional intel-
ligence, and especially focused perseverance applied to a well-​defined problem. The
discoverer was Edward Calvin Kendall, working in the Mayo Clinic, Rochester,
Minnesota. Kendall’s middle name reflected his Connecticut-​based family’s strong
Protestant background that contributed to his self-​discipline and work ethic, but it
did not stop him from working on Christmas Eve and Christmas Day. For it was on
Christmas Day 1914 that the 25-​year-​old chemist became the first person to isolate
pure crystals of thyroid hormone. In the preceding days, despite his fatigue, he was
determined to complete his latest round of purification of the iodine-​rich hormone
from thyroid extracts; probably due to overwork, he had fallen asleep while waiting
for a solvent to evaporate from a reaction. When he awoke, he found a white crust
and a yellowish wax-​like substance around the crust. He redissolved the crust, and
when he went in the morning to check the result, he found it contained 60% iodine,
the highest he had yet succeeded in isolating. The high iodine content told him he
was on the right track. So, even though it was Christmas Eve, he started the whole
procedure again then and there so that he would have enough material to do a final
purification the following morning.
The Mayo Clinic had hired Kendall as the directors had a strong research interest
in the thyroid gland and an excellent reputation for treating thyroid disease that
attracted many patients. Kendall, a brilliant mathematics and engineering stu-
dent, had become interested in chemistry largely though the inspiration of an older
brother-​in-​law who had studied at Columbia University. Kendall followed in his
footsteps, going to Columbia in 1904, where he was awarded his PhD in chemis-
try just 6 years later and was immediately recruited by a pharmaceutical company
trying to isolate thyroid hormone. Not at ease with the relative scientific isolation
  33

A Molecule of Mystery 33

and the lack of intellectual freedom of working in an industrial setting, he first

moved to another hospital to pursue the same research topic and was then, thanks
to his growing reputation, invited to join the staff at the Mayo Clinic, beginning his
appointment in February 1914.
So, it was only 10 months later that he carried out these final steps of purification.
His focused work had borne its fruits, and, as the story goes, he realized on that day
that he had succeeded in purifying the first crystals of the main thyroid hormone
secreted by the thyroid gland, thyroxine or T4. In fact, when Kendall shared the
Nobel Prize for Physiology or Medicine with two other endocrinologists in 1950,
it was not in recognition of the work done on thyroxine, but for his research on
another hormone, the stress hormone corticosterone, that he and other colleagues
had pioneered in its applications for rheumatoid arthritis.
But, it was Kendall’s successful isolation of the active hormone in the thyroid gland
that led to the gradual replacement of thyroid extract with pure thyroxine to treat
patients who had had their thyroid removed or to supplement those whose produc-
tion of hormone was insufficient. Today, thyroxine is the most prescribed drug world-
wide,4 which is not surprising given that one in eight women has a thyroid disorder.
Amazingly, prescriptions for thyroxine exceed those of cholesterol-lowering drugs.
Before the discovery of the hormone, clinicians had tested thyroid gland extracts
to try to alleviate the symptoms of cretinism (see Chapter 1) and of patients who
had their thyroid removed because of extremely large goiters. The results of doctors
treating cretins in 1885 showed that some beneficial effects were seen in the young-
est children treated, but not if they were older. These results are relevant to us today.
They show the importance of the timing of the action of thyroid hormone in brain
development. Once brain development, with or without the right amount of thy-
roid hormone, has reached a critical time point, then no amount of hormone, or any
other treatment, can restore the lost intellectual capacity.
We are now fully aware of the importance of rapid thyroxine replacement to avoid
irreversible brain damage in the first years of life. This is why in most countries a
blood sample is taken from every newborn baby by means of a tiny needle prick
in its heel to check hormone levels. Just one drop of blood is needed, and it can
be absorbed on a piece of blotting paper. The sample is then taken to a laboratory
where, using a sensitive technique called radioimmunoassay, the exact amount of
thyroid hormone5 in the baby’s blood is determined.
The techniques of radioimmunoassay were developed by Rosalyn Yalow, who
worked with her colleague Solomon A.  Berson at the Veterans Administration
Hospital in New  York. Berson died in 1972. The Nobel cannot be given posthu-
mously, so in recognition of their mutual discovery, Rosalyn Yalow was awarded
the Nobel Prize in 1977. She was given half of the prize for “the development of
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34 Toxic Cocktail

radioimmunoassays for peptide hormones,” as she and Berson had developed the
method on insulin, a peptide hormone, although the technique was later modified
to measure thyroid hormone.
The work for which the other half of the remaining prize money was awarded
also concerned thyroid physiology. It was shared between Andrew Schally, work-
ing in the Veterans Hospital, New Orleans, and Roger Guillemin, born and edu-
cated in France but at the time of the award running a lab in the Salk Institute,
San Diego, California. The Nobel citation refers to their “discoveries concern-
ing peptide hormone production of the brain.” One wonders how Schally and
Guillemin felt about sharing half the prize when they had notoriously resisted
sharing any data. They had jealously kept their distance geographically and sci-
entifically. They were in knife-​edged competition in their race to purify peptides
from the hypothalami6 of a million pigs and sheep. Eventually, by 1969, they each
managed to isolate a few milligrams of a tripeptide, TRH, or thyrotropin-​releasing
hormone. As the Nobel citation humorously put it7: “Rarely have so many gained
so little from so much”—​a small amount of peptide, but powerful stuff.
Thyrotropin is the peptide that controls the production and release of TSH
(thyroid-​stimulating hormone) from the pituitary, a pea-​size organ at the base of the
brain. In turn, TSH, as its name suggests, stimulates the production and secretion
of thyroid hormone by the thyroid gland. One of the actions of TSH is to stimulate
uptake and fixation of iodine into a precursor molecule for making the hormone
itself. The hormone is released into the bloodstream and carried to all the different
tissues of the body. In the unborn fetus, as in the newborn baby and developing
child, thyroid hormone is needed for the harmonious development of all organs,
bone, muscle, intestine, and skin, but above all, the brain.

Thyroid hormone orchestration of brain development

It is difficult to summarize the intricate molecular and cellular interactions that

underlie the process that leads from a fertilized egg to the formation of early neural
structures to the elaboration and organization of the multitude of synapses (the
contact points between one neuron and another) that interact in a human brain.
The neurobiologist Steven Rose provided a striking image of the process [2]‌by
calculating that, if the brain developed at a constant rate during pregnancy, then
4,000 neurons would be born every single second. The brain does not actually
develop at a constant rate, and neurogenesis, or birth of new neurons, occurs at
different rates in different structures. Suffice it to say, by way of introduction, that
  35

A Molecule of Mystery 35

if something goes wrong during those early months of life in the uterus, it cannot
be corrected later.

Neurons and Glia Cells

Two main categories of cells are found in the brain: neurons and glia.

Neurons are the specialized cells that transmit electric impulses. They receive input
from other neurons via their afferent extensions called dendrites and send out axons
that make contacts, called synapses, with other neurons.
Glia cells are frequently described as the supporting cells that nurture neurons,
although their active roles in modulating neural transmission are increasingly well
documented.
There are three main types of glial cell: astrocytes and the two types of cells that
produce myelin, the fatty sheath around the nerve that speeds up nerve conduction.
In the brain, myelin is made by oligodendrocytes. In the rest of the nervous system
outside the brain (the peripheral nervous system, including the spinal cord), myelin is
made by Schwann cells.
A fourth type of “glia” cell is the microglial cell, which has a completely differ-
ent cellular origin. These brain-​specific immune cells are actually derived from bone
marrow–​derived cells that cross the blood-​brain barrier. Like some other cells with
roles in fighting disease, microglia can engulf dead cells. They also produce inflamma-
tory signals.

Let’s try to follow the main steps of the process of brain development from the
beginning. Fertilization, the fusion of a sperm with an egg, produces a zygote, which
is in fact an early embryo, even if it is only one cell, albeit a large one. The human
zygote then undergoes a series of cell divisions until it is a ball of about 200 cells that
can embed itself into the wall of the mother’s uterus and continue its development.
As the embryo develops, different parts of it become organized to form the future
organs. Gradually, at the anterior part of the embryo, a structure forms—​called the
neural tube—​that will become the brain. As the name suggests, the neural tube
is a hollow cylinder of cells in which the cells will proliferate by dividing, reorga-
nize, and migrate, making the tube bulge and constrict until gradually the differ-
ent regions of the brain start to become apparent and the cells start to differentiate
into different categories of brain cells. The two main types of brain cells are called
neurons and glial cells (see the box, Neurons and Glia), but there are hundreds of
different types of neurons and many varieties of glial cells.
The division, migration, and reorganization of cells continue, progressively
generating the hundred billion neurons and about 10 times as many glial cells
36

36 Toxic Cocktail

that compose the human brain at birth. As the neurons are generated, they
migrate away from the area where they originated. The process of migration is
tightly controlled by different factors. Once the final destination has been found,
the process of differentiation begins, each neuron making multiple contacts with
other neurons either close by or at significant distances, even in other brain areas.
A single neuron can establish between 1,000 and 10,000 contacts—​s ynapses—​
with other neurons, adding up to more than a trillion synapses in the human
brain. The process of synapse making, or synaptogenesis, does not stop at birth,
but continues throughout life. Along with the production of new neurons in
some restricted areas of the brain, the processes of constructing and deconstruct-
ing synapses continue ceaselessly and underlie the brain plasticity that allows
learning and memory.
Thus, the fascinating unfolding of human brain development involves a series
of cellular processes that can be summarized as cell division, migration, differenti-
ation, and synaptogenesis. To this sequence of events, we need to add the selective,
deliberate death of many neuronal cells that are generated during development,
with the pruning back of cell numbers paralleled by the pruning of connections
between neurons after bursts of synaptogenesis. It seems odd that the developing
brain first produces too many cells and synapses, but this burgeoning has prob-
ably been essential to evolutionary progress, allowing brains to adapt to new situ-
ations. The pruning back means that only those cells and connections that are
actively used are maintained, which can again focus expensive maintenance on
the most important connections, in turn providing an evolutionary advantage.
Another vital process that occurs during or after pruning is the wrapping of long
neurons with a fatty insulating layer, the myelin layer, a feature that speeds up
neuronal transmission. The specialized glial cells that produce the myelin in the
brain are the oligodendrocytes. Faster neuronal transmission provides the indi-
vidual with more efficient wiring and thus a more proficient nervous system. The
requirement of thyroid hormone for myelination was one of the first roles of thy-
roid hormone in the brain to be established, with many of the structural compo-
nents of myelin induced by the hormone. Lack of thyroid hormone significantly
delays myelination.
These numerous processes unfold with a strict choreographic timing that is char-
acteristic of each species. For instance, in humans, neuronal proliferation is already
active in the first months of fetal life and then continues at different rates until
2  years after birth. In some areas of our brains, such as the hippocampus impli-
cated in memory, proliferation and production of new neurons continue even in
the adult. At all life stages, this proliferative stage requires amplification of pools of
precursor cells. Studies in rats and amphibians showed that thyroid hormone affects
  37

A Molecule of Mystery 37

proliferation during neurogenesis in embryonic or fetal stages as well as during post-

natal and adult neurogenesis.
Migration of neurons, the process during which neurons leave the areas of prolif-
eration and find their place in the complexity of brain architecture, occurs mainly
during the second to the fifth month of pregnancy, with some neuronal migration
occurring after birth in certain brain regions. In many brain areas, neuronal precur-
sors migrate long distances to their final differentiation site. In particular, thyroid
hormone has been shown to be required for migration of precursors in the cerebral
cortex, hippocampus, and cerebellum.
Synapse formation, another thyroid hormone–​ dependent process, occurs
throughout development and even into adulthood, whereas myelination, the wrap-
ping of a fatty insulating layer around the longer neuronal axons to speed up neu-
ronal transmission, occurs largely in the last months of pregnancy and in the first
2 years of life in humans.
In rodents, such as the rat, both proliferation and migration continue actively
from the first week of gestation8 until 2 weeks after birth. Differentiation of neurons
and synaptogenesis are ongoing from the second week of gestation until well after
birth, and myelination starts just before birth and continues into the rat’s equivalent
of adolescence. Timing may be a bit different for humans, but for us, the important
message here is that thyroid hormone is needed for optimal unfolding of each of
these major processes of brain development in all animals. In short, thyroid hor-
mone is a key factor controlling proliferation, migration, differentiation, synapto-
genesis, and myelination in all brain areas and at all developmental stages, as well as
in the mature, adult animal.
This requirement for thyroid hormone is valid, whether the animal is a fish, a
bird, a mouse, or a human. Without the right amount of thyroid hormone at the
right time, each of these processes continues, but in a disorderly manner, causing
irreversible brain damage, such as seen in cretinism. And, of course, as we will see,
the critical sensitivity of these processes to having just the right amount of hormone
at key moments in development means that these periods of brain development are
vulnerable windows for chemical action and endocrine disruption. The effects of
thyroid hormone deficiency on brain development are so marked that hypothyroid-
ism in gestating rats can be used to study autism-​like symptoms in the pups [3]‌.
The cellular and molecular mechanisms underlying the effects of how thyroid
hormone acts on human and vertebrate brain development have been studied for
more than a century. However, in a major thrust of activity from the 1950s onward,
researchers used rodent models to try to understand how thyroid hormone exerts
such marked effects on brain development and, in particular, why there are such
restricted windows of time during which the hormone can act. A pioneer in the field
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38 Toxic Cocktail

was J. T. Eayrs, working in the University of Birmingham [4]‌, England, in the early
1950s. Then, 10  years later Jacques Legrand and Joseph Altman, working respec-
tively in France [5] and the United States,9 moved the field forward significantly.
These researchers and their teams were investigating what happened to the brains of
rat pups that had had their thyroid removed or pups born to mother rats that lacked
the hormone during gestation or when they were suckling the pups.
They found that pups born to mothers that didn’t have enough thyroid hormone
at any point, like pups that had their thyroids removed at birth, had smaller brains
that weighed less, with reduced numbers of neurons and glia cells and fewer syn-
apses in all the major brain areas. These decreases in size and neuronal number were
irreversible. Giving thyroid hormone later could not correct the effects. The behav-
ior of the pups was documented as well. Pups with insufficient thyroid hormone
developed less well, showing delayed reflexes and motor control.

Time is of the essence

Clinicians working in the late 1890s were already aware of the importance of timing
for hormone action and that time is of the essence.10 When treating cretinism, they
realized that thyroid gland extract had to be given as early as possible to avoid the
irreversible mental retardation damage associated with the disease. As mentioned,
this is the reason why all newborns are tested within a few days of birth to ensure
they have normal thyroid function. But it is only in the last couple of decades that
clinicians and researchers have become aware of the critical need for thyroid hor-
mone throughout pregnancy and particularly during the early months, the first
trimester.
The first thorough epidemiological studies showing that a mother’s thyroid hor-
mone levels during pregnancy are correlated with the child’s IQ and neurodevelop-
ment (see, for instance, [6]‌) appeared in the 1990s. Then, to the surprise of some,
the critical role of thyroid hormone during the early stages of brain development, in
the first 3 months of pregnancy, was revealed [7]. This surprise was not really justi-
fied. In fact, one of the most respected clinicians and researchers focusing on thy-
roid hormone and brain development, Gabriela Escobar del Rey, had been saying as
much for decades. I had the privilege of meeting Gabriela only once, about 10 years
ago, when I was lucky enough to sit next to her at a conference dinner and delight in
her brilliant conversation, wit, and immense knowledge. Based in Madrid, she and
her husband (also a doctor and researcher) had pioneered the concept that the preg-
nant mother’s thyroid hormone had a vital role to play in the development of the
child’s brain in the first months of pregnancy before the fetus had its own thyroid
gland. To prove her point, in 1993, she obtained brain tissues from miscarriages in
  39

A Molecule of Mystery 39

the first trimester of pregnancy; she found significant amounts of thyroid hormone
in the fetal brain and put forward the hypothesis that if the hormone was there, it
was there for a purpose. At that dinner, she also told me some of her theories on
how increasing iodine lack in Spain and elsewhere in Europe could be affecting the
intellectual development of children [8]. How prescient she was.
In the meantime, her data documenting the presence of thyroid hormone in very
young fetal brains had triggered some of the first epidemiological investigations into
levels of maternal thyroid hormone in early pregnancy and the children’s intellec-
tual development. Some of the first data sets came from a Dutch group [9]‌, who
showed that the lower the maternal thyroid hormone levels in the first trimester
of pregnancy, the greater the risk of delay in the child’s psychomotor development.
This discovery was later consolidated with even more data from the Netherlands
[7]. The findings clearly argue for a need for more data, greater prevention of iodine
deficiency, and monitoring of thyroid status during early pregnancy across different
populations and geographical areas.
One large-​scale study from outside Europe, in China, was published in 2010 [10].
These investigators examined 1,268 women between weeks 16 and 20 of pregnancy.
First, they found that about 10% of women screened had thyroid hormone prob-
lems, ranging from what is referred to as subclinical hypothyroidism that may or
may not be treated medically, to a level of hypothyroidism that should usually be
treated by hormone supplements, and to women with antibodies in their blood
against proteins expressed in the thyroid gland.11 They then examined the intel-
lectual development and motor skills of these women’s children when the children
were 2 years old. The children of the women with subclinical, marked hypothyroid-
ism, or even elevated thyroid antibodies all had significantly lower IQ scores than
those of women with no thyroid problems. And, the differences were large and sig-
nificant. For each of the conditions, the mean intelligence of the children in each
of these groups decreased by 8.9, 9.3, and 10.6 IQ points, respectively. So, even if a
pregnant woman has just a mild thyroid condition, such as increased antibodies, the
adverse consequences on her child’s brain can be severe.

Some brain areas are more sensitive than others

As Joseph Altman showed in the 1970s, the brains of hypothyroid rat pups are
smaller than those of normal pups. We have also known for a long while that brain-
power is not simply a matter of brain size. Elephants have larger brains than humans,
and generally women have smaller brains than men, but these differences largely dis-
appear when brain size is adjusted to body size. Even then, brain size does not show
a straightforward relationship to intelligence. Optimal brain function also depends
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40 Toxic Cocktail

on the numbers of connections, synapses, between neurons that have to be in the

right place. Other factors influencing brainpower include the speed of processing
of the information between the neurons themselves and the different anatomical
structures that make up the brain. Speed of processing is related to myelination.
Another related factor is getting the correct wiring between structures. Many other
elements enter the equation; one of them is the relative size of certain brain areas
compared to others.
During evolution, human brains have developed a particularly complex forebrain
[11] that includes the cerebral (or frontal) cortex (the large, convoluted hemispheres
at the front of our brains) and the hippocampus, a center of memory and learn-
ing. The size of the cerebral cortex has increased during vertebrate brain evolution,
growing from less than 5% of the brain in cats, to 17% in chimpanzees, to nearly 30%
in humans. The forebrain is the area of the brain that is responsible for most of our
higher-​order functions, from language and decision-​making to social behavior. Not
surprisingly, this area is often associated with psychiatric disease.
As mentioned, all of the essential processes of brain formation are affected in
hypothyroidism, but here the focus is on three areas of the brain that show the most
marked anatomical abnormalities due to insufficient thyroid hormone: the cerebral
cortex, the hippocampus, and the cerebellum.

The cerebral cortex

The cerebral cortex is part of the front of the brain, or forebrain. In humans, it is
a massive structure with four main lobes that envelope a large part of the brain.
The frontal lobe is the largest of the four in humans and ensures complex cognitive
or executive functions such as language and decision-​making. During evolution,
as during the unfolding of development of each individual, the expansion of the
cerebral cortex is a relatively late event. In humans, extensive growth of the frontal
cortex occurs in different stages of pregnancy and in early postnatal life, with some
parts laid down earlier than others. Given the marked intellectual deficiency of cre-
tinism associated with thyroid hormone deficiency, it was not surprising that early
researchers started to use rats to understand how the hormone acted on this part of
the brain and what happened to its structure if there was not enough, or even too
much, thyroid hormone.
Studies of the fine structure of the cerebral cortex in the 1960s and 1970s showed
that, as for the rest of the brain, there were fewer neurons if the brain had been
hypothyroid. Each of the neurons was smaller and had fewer synapses. Another
constant feature was delayed and reduced myelination. So, the principal problem
in hypothyroidism lay with the numbers and size of the individual neurons, the
  41

A Molecule of Mystery 41

connections between them, and as myelination was affected, the speed of transmis-
sion between neurons and different brain areas was slowed.
Since these early studies our knowledge has grown immensely. We now know
that the whole unfolding of the development of this essential part of our brains is
optimized by minute amounts of thyroid hormone that act on their receptors in
the nucleus of all the cells participating in brain development. These receptors read
how much thyroid hormone is present at each stage and in turn regulate complex
networks of genes that largely determine the programming of the interlocking pro-
cesses governing cell production, migration, and establishment of their interactions.
It is not surprising to find that any chemical that interferes with the amount of
hormone present can have devastating effects on the cognitive functions controlled
by this essential part of our brain.

The hippocampus: our main memory maker

One of first signs of hypothyroidism even in adults is memory loss, illustrating the
constant need for thyroid hormone to maintain optimal brain function, both dur-
ing childhood and in the mature brain. In fact, the hippocampus, an oddly struc-
tured brain region so called because of its loose resemblance to a seahorse (from the
Greek hippos for “horse” and campos for “monster”), is acutely sensitive to thyroid
hormone. Although it is too simple to say that all memories are stored in this brain
structure, the hippocampus is one of the first brain structures to suffer damage in
Alzheimer’s disease. Many studies showed that neuronal activity in the hippocam-
pus is involved in storage of short-​and long-​term memories.
Interestingly, in the human brain the hippocampus is one of the few sites, and
probably the most active, in which new neurons are born throughout life. Again,
this process of new neuron production, adult neurogenesis, is dependent on thyroid
hormone, a fact that can be related to the memory loss characteristic of low thyroid
hormone. However, as for other brain structures, effects of thyroid hormone defi-
ciency or excess on hippocampal function are most marked during development.
Hypothyroidism (whether mild or severe) in rats during fetal or early post-
natal life permanently affects cell numbers as well as the firing properties and
synaptic transmission of neurons in the developing hippocampus. These changes
are most probably related to major reductions in populations of parvalbumin
expressing interneurons in the hippocampus [12], reductions that are also seen
in the neocortex (frontal cortex). Interneurons are an important category of
neurons that connect between the sensory neurons that bring information to
the brain and the motor neurons that control actions. Interneurons increased in
number and variety as brains evolved. More interneurons mean more plasticity
42

42 Toxic Cocktail

and adaptive advantages due to more sophisticated networking between neurons

and between different brain structures. Not only are these neuronal populations
markedly affected by too much or too little thyroid hormone, but also postmor-
tem studies show that their numbers and connections are significantly modified
in different brain areas in many psychiatric diseases, including schizophrenia
and autism [13, 14].

The cerebellum: controlling movement, attention, and more

One of the structures examined most closely by the first researchers looking at the
effects of deficits of thyroid hormone on development was the cerebellum. The term
cerebellum actually means “little brain” in Latin. Situated at the base of the brain,
it does rather resemble a small version of the convoluted hemispheres at the front
of our brains. Like the frontal cortex, the cerebellum has a complex layered struc-
ture and contains some neurons with distinct shapes and connections—​basket cells,
chandelier cells, and some of the largest neurons in the brain, Purkinje neurons.
These neurons are named after a famous neuroanatomist, Jan Evangelista Purkinje.
Purkinje graduated from Prague University in 1818, but moved to Breslau (in what
is now Poland) 5 years later, where he founded what is often referred to as the first
physiology laboratory. Here, he requested a new microscope to carry out his research
into eye and brain structure using and pioneering new techniques to slice brains
into fine sections and examine their cellular structures.
Purkinje didn’t actually receive his much-​sought-​after microscope until almost
10 years later, in 1832, when he set about investigating the fine structures of differ-
ent organs, including the eye, heart, and brain. It was in 1837 that he first observed
the spectacular neurons in the hindbrain that bear his name. The effects of thyroid
hormone insufficiency on development of the highly specialized Purkinje cells and
of other large neurons in the cerebellum have probably been studied in most detail,
although thyroid hormone affects the differentiation and development of the whole
structure. Alterations in cerebellar development and function are also frequently
observed in patients with autism [15].
The cerebellum is traditionally thought of as the main control center for coor-
dination and planning of movement and motor learning. However, more recently
this structure has been shown to have major roles in many other aspects of behav-
ior. Important neuronal projections arise from the cerebellum and connect with
many other brain areas, notably the frontal cortex. These connections are involved
in controlling nonmotor behavior functions such as attention, memory, pain, and
addiction [16]. All of these projections from the cerebellum to other brain areas
go through the hub of the Purkinje cells. So, it’s easy to imagine that if Purkinje
  43

A Molecule of Mystery 43

cell development is impaired, so is the efficiency of interactions between different

brain areas.
In humans, the cerebellum develops during the seventh and eighth week of ges-
tation, in the middle of the first trimester of pregnancy. As growth proceeds, the
cerebellar cortex divides into three layers. Each layer harbors different, specialized
neuronal types and their interconnecting axons and dendrites. At the interface
between the outermost layer and the middle layer are the basket cells and chandelier
cells. These cells represent a main category of inhibitory interneurons found in the
cerebellum and in the frontal cortex. Many of them express the neurotransmitter,
GABA.12 A number of studies have shown that these GABA-​expressing interneu-
ron populations are affected in patients with autism and in animal models of the
diseases.
The names of the chandelier and basket cells derive from the dense crisscrossing
networks that their axonal outputs form on the Purkinje cells, the major cerebellar
cell type and the coordinators of cerebellar function. Purkinje neurons have enor-
mous dendritic networks and more synaptic connections with other neurons than
any other neuron identified. As such, their development, maturation, and function
are vital to innumerable higher brain functions, not just control and coordination
of movement.
Insufficient thyroid hormone in the first weeks of postnatal rodent life strongly
reduces Purkinje neuron size and synapses. It also delays differentiation of the dif-
ferent interneuron cells that innervate the Purkinje cells. Thus, hypothyroidism
during cerebellar development in both humans and rodents is associated with prob-
lems of fine motor movement and other neurological symptoms, such as ataxia (loss
of motor coordination that causes problems in walking and balance).
Giving developing rats increasing amounts of thyroid hormone results in increased
dendritic branching of Purkinje neurons. All of the different neurons in the cerebel-
lum respond to thyroid hormone. Researchers have found that thyroid hormone
regulates multiple genes implicated in cerebellar development and function. One of
the first to be studied was the Purkinje cell–​specific protein, Pcp-​2, but many others
have since been identified, including those encoding the nerve growth factors called
nerve growth factor (NGF) and brain-​derived neurotrophic factor (BDNF) needed
for neuronal differentiation. Problems with expression of BDNF (and of other genes
regulated by thyroid hormone) have been implicated in autism.
Some of the early research on the effects of hypothyroidism or hyperthyroid-
ism on the developing brain identified synaptogenesis, the setting up of connec-
tions between neurons, as one of the highly thyroid hormone–​dependent processes
in brain development. Studies of postnatal rodent brains showed that both too
little and too much thyroid hormone adversely affected synapse formation. This
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44 Toxic Cocktail

important observation underlines the fact that either too little or too much of the
hormone at crucial developmental stages can be equally detrimental. Synaptogenesis
continues throughout life and is involved in brain plasticity and learning. So, thy-
roid hormones are needed in adolescents and adults. It has been estimated that the
brains of animals that were hypothyroid from birth have about half the synapses
of control animals. Again, the cerebellum was identified as one of the major struc-
tures in which this process was adversely affected by both hypothyroidism and
hyperthyroidism.
There are many other brain areas that are extremely sensitive to changes in timing
of thyroid hormone availability during development, especially the sensory nervous
system—​eyes, ears, and nose for the sense of smell. All require thyroid hormone to
develop and function correctly. One system that has been studied in detail by Doug
Forrest, a Scot working at the National Institutes for Health in Bethesda, Maryland,
is the inner ear or cochlea. In a series of brilliant experiments on mice, Doug and
his team were able to show that minute variations in thyroid hormone availabil-
ity markedly affected neuronal differentiation and synaptogenesis in the develop-
ing ear. Other teams are now looking to see if there is any relationship between
the exquisite sensitivity of the developing ear to thyroid hormone and exposure to
chemical pollution.
Although many think the increase in numbers of children and adolescents with
hearing problems today is primarily related to using earphones at high volumes, it
is not unreasonable to test the hypothesis that it could be compounded or initiated
by increasing levels of pollution that affect thyroid hormone–​dependent ear devel-
opment. To resolve this question, epidemiological studies are needed, specifically
looking at children’s hearing capacities before they start using earphones and other
devices and correlating results with maternal thyroid levels and pollution expo-
sure. Given the time this could take, it is probably better to extrapolate results from
experimental models and different test paradigms so that precautionary measures
can be taken.

Getting thyroid hormone into the brain

It is difficult to measure brain concentrations of thyroid hormone even in experi-

mental animals. Obtaining an accurate measure is currently impossible in the brains
of people while they are alive. In the past decade, some clinicians and researchers
have tried to estimate how the brain responds to different levels of thyroid hormone
by using newly developed, sophisticated brain-​imaging techniques to look inside
patients’ brains. These methods have shown, for instance, that untreated hypothy-
roidism slows functioning of networks in the frontal cortex that are associated with
  45

A Molecule of Mystery 45

memory recall. Treating patients with thyroid hormone corrects these problems.
Yet, despite the enormous strides that brain imaging has made in recent decades,
this type of experiment still cannot quantify how much thyroid hormone our brains
are receiving. So, even today the best indication of the amounts of hormone reach-
ing our brains is judged indirectly by looking at how much thyroid hormone is cir-
culating in our blood.
One of the most respected scientists working on thyroid hormone distribution
in the blood and brain is Sam (Samantha) Richardson, currently a professor in the
Royal Melbourne Institute for Technology (RMIT) in Melbourne, Australia. For
most of her career, Sam has been fascinated by how evolution has co-​opted a pro-
tein that first showed up in bacteria into one of the main blood proteins that carry
thyroid hormone around the body. The protein she studies is called transthyretin,
or TTR for short. TTR is also expressed in the barrier that separates the brain from
the blood, where it has a vital role in shuttling the hormone across this barrier into
the brain.
Transthyretin is one of three distributor proteins in the blood along with
thyroxine-​binding globulin (TBG) and albumin. Together, these three proteins
bind more than 99% of the hormone circulating in our blood, only releasing tiny
amounts into the target tissues. Most vertebrates have the same main distributor
proteins but in varying relative amounts. In mammals, there is more albumin and
TBG than TTR. These differences have relevance to our story in understanding
how chemicals affect thyroid hormone availability to tissues such as the brain.
Although TTR is not the most abundant distributor protein in our bodies, nor in
the blood of rats often used for testing chemicals, it is of great importance for thy-
roid hormone distribution and, as mentioned, for ensuring that thyroid hormone
gets into the brain where it is most needed. Unfortunately, as discussed in the next
chapter, a plethora of chemicals interfere with binding of thyroid hormone to TTR.

Thyroid hormone disruption and the adult brain

I am often asked whether, besides affecting brain development, chemicals in the envi-
ronment could also be affecting brain function in adults, and in particular whether
they could be contributing to neurodegenerative disease symptoms and incidence
in older people. Well, the question is a good one, especially given the crucial roles
of thyroid hormone in maintaining neuronal metabolism, constitution, structure,
and synaptic plasticity, all of which are needed for memory and learning and gen-
eral brainpower. However, given that brain development is largely a one-​way street,
with damage caused in early development being irreversible, it is not surprising to
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46 Toxic Cocktail

find that most emphasis is currently, and quite rightly, placed on the idea that early
development is most critical.
But, that does not rule out detrimental effects at later stages, in adolescence, in
young adulthood, in the mature brain, and even in the aging brain. All clinical
endocrinologists can relate stories of patients displaying depression and anxiety that
were resolved by checking and then normalizing thyroid hormone levels. I even had
a student who told me how his father actually lost his job because of lethargy and
depression due to undiagnosed hypothyroidism. Fortunately, all was resolved when
he took thyroid hormone supplements. Disturbing stories like this can be found
online, with people suffering from thyroid problems going undiagnosed for years
until they lose their livelihoods and may even contemplate suicide.13
To these studies and anecdotes, one can add that thyroid hormone is known to
repress the gene that makes the Alzheimer protein, fragments of which accumu-
late in and damage the neurons, thus causing the disease symptoms. So, chemical
interference with thyroid hormone repression of the gene could well exacerbate the
accumulation of the protein and neuronal damage. Unfortunately, however, there
have been virtually no experimental studies, and few epidemiological studies have
looked at whether environmental chemicals are associated with neurodegenerative
disease. There is really only one exception, the link between Parkinson’s disease and
exposure to certain pesticides, including organophosphates.

How chemicals can hijack thyroid hormone action

on brain development

One of the main roles of thyroid signaling is to regulate gene expression in the
brain. Because numerous environmental factors interfere with thyroid hormone–​
dependent pathways, thyroid signaling can be seen as a bridge linking the environ-
ment to gene networks involved in brain development. To understand this idea, a
number of features of how thyroid hormone acts on the developing brain need to be
brought in to the discussion. This section may be a bit technical for some, in which
case, just skip it!
The first idea is that thyroid hormones act by changing the activity of genes in the
developing brain. Thyroid hormone binds to thyroid hormone receptors or TRs.
TRs are proteins found in the cell nucleus, where the DNA that makes up the genes
is located. TRs are members of a larger group or family of nuclear receptors, all of
which have a modular structure, rather like a Lego™ set.
The second idea is that TRs change their activity according to the amount of hor-
mone available. TRs have one bit of their Lego set structure that binds to DNA in
target genes and another part that forms a pocket to allow the hormone to bind. In
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A Molecule of Mystery 47

physiological situations, natural thyroid hormone will occupy this pocket. TRs act
as transcription factors by altering the transcription of genes according to whether
the pocket contains the hormone. This leads to the third idea that chemicals change
TR activity on gene regulation either by replacing the natural hormone in the
pocket or by modifying the amount of hormone that is available to enter the pocket
and modulate gene transcription.
Thus, TRs represent a highway through which environmental chemicals that
enter the body can modify thyroid hormone levels and then affect gene programs
and cellular processes involved in brain development. As thyroid hormone is also
implicated in controlling growth and metabolism, the chemicals can in addition
interfere with TR actions on body growth and energy balance.
It’s interesting to note that this hormone-​binding link to transcriptional regula-
tion has driven many pharmaceutical approaches to develop useful drugs that act
on nuclear receptors for treating cancer, metabolism, or cardiovascular disorders or
to act as contraceptives, as well as for questionable purposes, such as performance-​
enhancing steroids.
However, the downside is that environmental chemicals can hijack exactly the
same feature that permits pharmaceutical companies to design drugs that target
nuclear receptors. Besides thyroid hormone and TRs, many endocrine disruption
studies focus on nuclear receptors that control reproductive functions. These recep-
tors are the estrogen receptor (ER) and the androgen receptor (AR), that respec-
tively bind estrogen, the main female sex hormone, and the androgen testosterone,
the main male sex hormone. ERs and ARs represent crossroads by which environ-
mental signaling can modulate gene programs and thus the cellular processes that
govern reproductive capacity and fertility. Compounds that alter their activity have
been linked to breast cancer, prostate cancer, testicular cancer, and infertility in the
same way that chemicals affecting thyroid signaling have been linked to IQ loss and
neurodevelopmental disease.

Regulatory gaps

Chapter 1 opened with the data from Sicily showing that children born to moth-
ers with iodine deficiency lost up to 18 IQ points compared to mothers with suf-
ficient iodine. The present chapter has discussed the Chinese study that reported a
10 IQ point loss in children of mothers suffering from only mild maternal thyroid
dysfunction. However, these types of studies, the other extensive epidemiological
studies, and the masses of experimental results that provide mechanistic insight into
the effects have not yet convinced regulators of the risk constituted by low maternal
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48 Toxic Cocktail

thyroid hormone levels combined with chemical exposure, additively jeopardizing

the neurodevelopmental outcome of children.
Chapter 8 discusses the costs to the individual and society of small decreases
in IQ. As we will see, at the level of a society, the loss of just a couple of IQ points
can have devastating socioeconomic consequences. But, in the meantime we will
examine the data that document how different chemicals affect thyroid func-
tion, thyroid hormone availability, and brain development. There is a plethora of
data showing that many different chemical categories can interfere with thyroid
hormone production, distribution, and action on brain development at many
levels.
  49

3
Thyroids in a Chemical Soup

Duluth, Minnesota, June 2003

It’s the last day of a meeting organized by the Organization for Economic
Cooperation and Development (OECD),1 held at the US Environmental Protection
Agency’s (EPA’s) Duluth Ecology division on the edge of Lake Superior. The topic
under discussion is how to use amphibian metamorphosis as a test for chemicals
that might interfere with thyroid hormone signaling. About 20 scientists from
Europe, Canada, and the United States have gathered to thrash out ideas on how
to standardize an optimal protocol for the test and the best indicators to look for in
the tadpoles at the test’s completion. The scientific logic for screening with amphib-
ian metamorphosis is, as explained in Chapter 2, that any molecule that interferes
with the process that turns a tadpole into a frog also has the potential to affect brain
development in humans.
It’s a well-​chosen and rather picturesque site for a research center on environmen-
tal toxicology. Before going to the airport, I decide to mull over the conclusions of
the meeting while eating a sandwich at the edge of the lake. Lifting my sandwich
to my mouth puts a rapid end to lunch. A  well-​practiced and sharp-​eyed seagull
swoops down before I can take a bite and snatches the sandwich from my hand,
literally brushing wings against my face as it flies past. Quite a shock! On the other
hand, it may have done me a favor.

49
50

50 Toxic Cocktail

The sandwich was a local delicacy, made with smoked lake trout. Checking the
current guidelines from the Minnesota Department of Health shows that they
recommend that pregnant women or children under 15 should not eat more than
one portion of most lake fish per week.2 Well, I  was neither pregnant nor under
15 by a wide margin, and I didn’t even manage to get my weekly dose! But, I think
I  was better off without all the mercury, the perfluorinated compounds (PFCs)
and especially the polychlorinated biphenols (PCBs) that accumulate in the fish of
the Great Lakes. As we will see, all of these chemicals are thyroid hormone disrup-
tors. In fact, it was while working on groups of pregnant women living near a sister
lake to Lake Superior (Lake Michigan) that researchers first elucidated the links
between high levels of prenatal PCB exposure and their effects on thyroid signaling
and children’s IQ.
The PCBs, mercury, and PFCs are found universally, although thankfully not
in such high concentrations as in Great Lake fish. However, these are not the only
thyroid disruptors to which we are exposed on a daily basis. In this chapter, I’ll
go through the evidence for numerous other chemical categories that have thyroid-​
disrupting effects. But first, I’ll try to address the question of why so many chemical
categories affect thyroid signaling. Part of the answer could be the complexity of
thyroid hormone synthesis, control of its distribution and availability in the body,
and the tight regulatory controls in the brain and pituitary that govern how much
hormone is produced by the thyroid gland.3
Another part of the story could be the structure of thyroid hormone.
Schematically, the structure of the two main forms of thyroid hormone 4 can
be likened to a pair of spectacles. This “spectacle-​like” structure is due to the
fact that the hormones are composed of a pair of rings, or phenyl rings, to use
the chemical term. Chemists have always found the phenyl ring an extremely
versatile base for synthesizing new substances, particularly with other halogens,
such as bromine, fluorine, and chlorine, instead of iodine. Many halogenated
molecules look like thyroid hormone. Given this similarity of structure, it’s not
illogical to find that there are many opportunities for these chemicals to fool
our thyroid signaling systems. All the halogens are highly reactive and have
been used repeatedly by chemists to synthesize new products. The net result is
that the environment is now heavily polluted by a multitude of chemicals that
structurally resemble thyroid hormone. Many of these chemicals are confirmed
thyroid disruptors. For example, chlorine has been used over and over again to
make pesticides and plastics, a history dating back to the synthesis and produc-
tion of poison gases in the First World War. Large amounts of bromine were
used for an additive in leaded gasoline, and when leaded gasoline was phased
out bromine-​ based flame retardants became widely marketed. Regarding
  51

Thyroids in a Chemical Soup 51

fluorine, its particular chemical properties have made PFCs standard compo-
nents of waterproofing agents and nonstick pans.
The list is actually much longer—​so long, indeed, that many authors have sug-
gested that there are more chemicals in the environment that interfere with thy-
roid hormone signaling than with any other endocrine system.5 Often, when people
think of endocrine disruption, the first chemical categories that come to mind are
those that act like the steroid hormones estrogen and testosterone, the female and
male hormones, respectively, needed for reproduction. Chemicals that affect these
systems can be implicated in health problems and diseases that are relatively easy to
diagnose in individuals and, as a consequence, are easily measured by statisticians.
Examples include fertility problems, precocious (or early) puberty, as well as breast,
testicular, and prostate cancer. The increased incidence of these diseases, often asso-
ciated with exposure to chemicals having weak estrogenic actions, such as bisphenol
A  (BPA) and certain pesticides, has focused the attention of researchers and the
general public for a number of years.
But, chemicals that affect intellectual development and behavior are much more
difficult to detect in individuals, simply because there is such a large natural range
of capacities in different people. As mentioned in the Introduction, a past director
of the US National Institutes of Environmental Health Sciences (NIEHS), David
Rall, illustrated the problem eloquently by citing the case of thalidomide, the drug
that was prescribed for pregnant women in the 1960s with a view to preventing
morning sickness. It had no effect on the incidence of the symptoms, but it caused
dreadful deformities in the limbs of the babies. Rall is quoted as asking the rhe-
torical question: “If thalidomide had caused a 10-​point reduction in IQ, would its
effects be known?” Today, would we notice it among the thousands of chemicals
currently marketed?
Determining such effects on brain and behavior requires large-​scale studies at
the population level. More important, such studies need to look at maternal blood
or urine levels of chemicals during early pregnancy. This is because it’s during early
pregnancy that the brain grows extremely quickly and is particularly vulnerable to
any form of chemical pollution. In fact, it’s the whole of pregnancy and the first years
of life that are a particularly sensitive window for exposure to chemicals and for hor-
monal or nutritional deficiency. Many epidemiological studies showed associations
between chemical exposure or iodine deficiency, with the most marked effects if
they occur in the first 3 months of pregnancy. However, few studies that aimed to
assess risk of chemical exposure with developmental outcome have had the foresight
to carry out studies that included early pregnancy. Moreover, the fact that careful
epidemiological evidence is needed to link the effects of chemicals to IQ loss and
brain development means, in my opinion, that regulators should pay more attention
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52 Toxic Cocktail

to the experiments that demonstrate how chemicals affect thyroid hormone signal-
ing, particularly experiments using embryos or early developmental stages.
The other part of the story about why thyroid hormone is so sensitive to chemical
pollution relates to the multiple mechanisms implicated in producing, distributing,
activating, and metabolizing the hormone. For instance, one major target for chem-
ical pollution is iodine uptake by the thyroid gland itself. If a chemical blocks iodine
uptake, then all the other steps in producing the hormone will be less efficient, and
there will be less hormone available throughout the body. Other chemicals block
the enzymes needed to make the hormone in the thyroid gland. Numerous chemi-
cals displace the natural hormone from the blood proteins that distribute it around
the body. What is more, recent research suggested that some chemicals can actually
interfere with entry of the hormone into different cells, in both the brain and the
rest of the body. Finally, many chemicals can hinder the activation of thyroid hor-
mone in the target cells.
Having seen the multiple levels through which chemicals can challenge thyroid
hormone production and action, I’ll go back to the fish in the Great Lakes area and
take a closer look at one of their main contaminant classes, PCBs.
But first, a word of warning and an apology. The following discussion cannot
cover all the different chemical classes that have already been shown to have thy-
roid hormone-disrupting properties or all of those that are suspected of exerting
such effects. This is simply because of the huge number of chemicals with potential
thyroid-​disrupting effects. Rather, the emphasis is on categories of chemicals for
which there is either the most evidence of effects or concern over their high produc-
tion volumes.

The legacy of plastics: polychlorinated biphenols

The PCBs, legacy plastics,6 were first produced in 1929, and the rapid increase in
manufacture and diversification of electrical equipment from the 1930s onward saw
a massive increase in their use. Their high chemical stability and strong resistance to
heat with low flammability rapidly led to their wide usage in a range of components,
including electrical insulating materials, cooling fluids or lubricants, capacitors and
transformers, as well as in ink solvents, plasticizers, and even flame retardants. It is
precisely their resistance to heat and high chemical stability that make them such
persistent pollutants in the environment. New production of PCBs was banned in
Europe and in North America in 1979. However, production continued elsewhere
until 1993. About 1.7 million tons of PCBs were manufactured between 1930 and
1993, with nearly half (48%) produced by Monsanto in the United States [1]‌. Much
  53

Thyroids in a Chemical Soup 53

of this production is still in the environment, either in the forms of stocks requiring
disposal or as electrical equipment that is still in use.
Because PCBs belong to a class of chemicals that are particularly environmen-
tally persistent, the UN-​sponsored Stockholm Convention on protecting human
health and the environment has targeted them for elimination. However, despite
the nearly 40-​year-​old bans, levels in the atmosphere are only now decreasing, and
very slowly. This persistence recalls the problems encountered with the accumula-
tion of the pesticide DDT (dichlorodiphenyltrichloroethane) and its main metabo-
lite, DDE (dichlorodiphenyldichloroethylene), another major legacy pollutant.
Measuring the half-​life of a chemical in the body or in the environment gives us
an idea of the time it takes to degrade or eliminate half of the chemical in the system
under study. In the human body, the half-​lives of different PCBs range from a mat-
ter of months to over 15 years [2]‌. In water or the atmosphere, they can be longer. So,
it’s not surprising that, given the amounts of PCBs still present in different forms
in our environment, reductions beyond a certain level are going to be difficult to
attain, and we all will be contaminated with them for many decades.

Breathing in the banned PCBs today

Despite the widespread bans in the late 20th century, not only are there still large
stocks of PCBs stored in different places, but also contamination through air, water,
and food affects the whole of the globe. One of the most emblematic examples is con-
tamination of polar bears in the Arctic. As well as being endangered by climate
change and melting summer sea ice, polar bears are at the top of a predator food chain
and thus accumulate contaminants, particularly a class of chemicals known as persis-
tent organic pollutants (POPs). In 2002, polar bears were found to have four times
higher concentrations of PCBs in fat tissue than the ringed seals on which they feed
[3]‌. To many in the general public, the high levels of POPs in Arctic wildlife come as a
surprise, particularly given that their habitat is so far from any industrial site, but the
figures emphasize the extremely high general level of water and air pollution by PCBs.
PCBs are distributed not only through the food chain and water, but also through
the atmosphere, the air we breathe, whether we are at the North Pole or in a large city.
Professor Miriam Diamond and her team at the University of Toronto have for
the last decade been researching many aspects of environmental PCB contamina-
tion. In one of her articles on the topic, she related how the Stockholm Convention
set a target of achieving environmentally sound management and disposal of PCBs
by 2028. The convention was signed by 159 parties, but as of 2010, only 35 had
reported progress toward this goal [4]‌. So, there is a long way still to go. Interestingly,
54

54 Toxic Cocktail

Diamond started her career with a master’s degree in zoology, studying plumage
in redpolls, an Arctic bird, before switching to do another master’s degree in an
environmentally oriented domain, mining engineering, a topic that led her to envi-
ronmental problems caused by anthropogenic activity. Now a professor of chemical
engineering and applied chemistry, her work focuses on urban settings.
Among other topics, Diamond and her team have researched urban PCB atmo-
spheric contaminations in their city. They have estimated that there are between
300 and 800 tons of PCB stocks in Toronto, excluding those in landfill or waste-​
handling plants. The authors calculated exposures for people in the different parts
of the city. Highest exposures were found in commercially dense areas, such as those
with skyscrapers that have high electricity usage. They noted, not without a certain
amount of irony, that the highest concentrations were in the business area of the
city, which theoretically had the greatest financial capacity to do something about it
[4]‌. Similar levels of atmospheric PCB contamination have been reported for other
cities, including Chicago and Cleveland [5], with the authors of these articles under-
lining how these urban atmospheric sources contribute to the contamination of fish
in the Great Lakes.

PCBs as thyroid-​disrupting chemicals

The structural similarity of PCBs to thyroid hormone led them to be early sus-
pects as thyroid hormone disruptors, a suspicion that was later confirmed. There
are two main ways of determining whether a chemical acts as an endocrine dis-
ruptor. The first is to use epidemiological studies on large human populations
to see if there are any correlations with endocrine changes in people with dif-
ferent levels of exposure, a bit like taking a wide-​a ngle shot with a camera to
cover as much of the landscape as possible. Obviously, these studies have to bring
together experts with knowledge of statistics and public health issues, and they
have to take into account confounding factors that could influence the results in
multiple ways. For instance, if they are looking at effects of chemical exposure
on children’s development, the experts will take into account whether the child
was exposed as either a fetus or a newborn to parental smoking or maternal alco-
hol consumption, in addition to the chemicals. They will also take into account
socioeconomic status and level of parental education, as these obviously have an
impact on the child’s development and environment.
The other method to determine whether a chemical acts as an endocrine disrup-
tor is to use biological studies, either on cells or in certain cases on animals. Today,
quite rightly, all animal experiments have to be ratified through detailed examina-
tion by ethical committees at local and national levels. By carefully designing an
  55

Thyroids in a Chemical Soup 55

experiment, researchers not only can determine the effects of a given chemical on
thyroid hormone signaling without the confounding conditions in human epidemi-
ology but also can untangle the pathways that cause the problems. This information
can be useful at two levels: first for designing other replacement molecules devoid
of the adverse effects of the chemical studied and second for providing information
on mechanisms critical for regulatory decisions. I return to this point in Chapter 8,
where I discuss costs and responsibilities.
Most animal studies on the effects of PCBs on thyroid status have used rodent
models, mainly rats and to a lesser extent mice. In 1977, one of the earliest studies
on PCB effects on thyroid homeostasis was done [6]‌; this was 2 years before the
ban on PCB production in the United States. The introduction to the article,
describing already-​k nown effects of PCBs on liver, kidney, and reproduction,
makes one wonder why the compounds had not been banned already. The authors
focused on examining the effects of a commercial mixture of PCBs—​A roclor
1254 from Monsanto—​on thyroid gland function and thyroid hormone levels.
They mixed the compounds into the chow fed to adult rats at 50 and 500 parts
per million (controls were given chow and corn oil) for 12 weeks. After 6 weeks,
the higher dose had to be dropped to 250 parts per million because of toxic effects
and weight loss. Blood levels of thyroid hormone were reduced at both PCB doses.
The rats needed to eat PCB-​free chow for 9 months for thyroid levels to return to
normal.
These researchers didn’t look at effects of early exposure on brain development. It
was not until a good decade later that one of the leading researchers on the effects of
PCBs on thyroid hormone signaling and brain development, Professor Tom Zoeller,
started to look at this side of the story. Based at the University of Massachusetts, he
is not only an active researcher on chemical pollution and brain development, but
also—​and this is not surprising given the amounts of data he has amassed on the
topic—​an active voice in the community trying to raise awareness of the problems
with regulators and decision-​makers.
Zoeller started his research career working on deciphering the molecular mecha-
nisms that govern how the brain controls thyroid hormone production. But he soon
became interested in how environmental factors could affect thyroid signaling and
brain development, and an obvious group of chemicals to focus on was the PCBs.
In the course of a long series of high-​level articles over the last 20 years, work from
Zoeller’s team has shown that exposing pregnant rats to PCB mixtures changes
the expression of thyroid hormone–​dependent genes in the brains of their fetuses.
This in turn can change brain development. There seem to be multiple mechanisms
involved in relaying the effects of the presence of PCBs in the mother to modulating
thyroid hormone responses in the pups’ brains. One such mechanism could be that
56

56 Toxic Cocktail

PCBs induce maternal hypothyroidism by increasing the turnover or metabolism

of thyroid hormones in the mother’s liver. The starting point is that the mother’s
liver is stimulated by the presence of PCBs to degrade and eliminate the toxins,
a protective physiological response. But, if exposure is too high or lasts too long,
side effects occur. The liver can go into overdrive and also start degrading the
actual hormone. The problem is that the mother’s thyroid hormone is needed for
brain development of the fetus. A second mode of action could be the production
of degradation products that actually act on the thyroid hormone receptor (TR)
in the brain. Interaction with the very choosy ligand-​specific binding pocket of
the TR is rare. The far more common mechanism of thyroid disruption is through
decreasing hormone levels by activating metabolism and degradation in the liver.
Zoeller’s group is not the only one to document adverse effects of PCBs. For
instance, Abraham Brouwer’s group in the Netherlands has shown that PCB expo-
sure in pregnancy affects thyroid hormone signaling in the fetal brain. In 1996, this
team showed that different doses of PCBs given to female rats for 1 week in the
middle of gestation reduced both fetal plasma and brain levels of thyroid hormone
the following week [7]‌.
There are also many epidemiological7 studies in human populations that link
PCB burdens to negative effects on thyroid function and action. PCB levels are
associated with modified thyroid function [8]‌, with particularly strong correlations
in women [9]. This result is all the more disquieting as women, pregnant or not, are
more prone to develop autoimmune thyroid disease.
Just taking two examples from the many epidemiological studies available will
illustrate how PCB exposure affects thyroid signaling in pregnant women (a more
extensive coverage of the data is given in Losing Our Minds [see Note 3]). In 2005,
Larissa Takser and her colleagues working in maternity clinics in southern Quebec
found that high concentrations of environmental contaminants, including three dif-
ferent PCBs, were associated with lower amounts of thyroid hormone in pregnant
women and their babies’ cord blood [10]. Similarly, data from the CHAMCOS8
study [11, 12] showed that PCB exposure interfered with thyroid hormone levels in
both the mother’s blood and umbilical cord blood.
Dioxins, like PCBs, have a similar structure to thyroid hormones, and, like PCBs,
they constitute a large category of about 200 compounds. The most studied of the
dioxin toxins goes by the official name of 2,3,7,8-​tetrachlorodibenzo-​p-​dioxin (2,3,7,8-​
TCDD, or commonly TCDD). TCDD has one of the lowest-​recorded lethal doses
ever observed (LD50 or lethal dose to 50% of the population), being a mere 600 parts
per trillion or 0.6 micrograms per kilogram body weight in guinea pigs. A microgram
is one billionth of a kilogram. This lethal dose represents less than one-​tenth of a thou-
sandth of a standard tablet of paracetamol (acetaminophen).9
  57

Thyroids in a Chemical Soup 57

The dioxin toxin TCDD is an unwanted side product in the manufacture of a cer-
tain class of herbicides, so environmental levels are usually exceedingly low. However,
TCDD became infamous during the Vietnam War (mid-​1950s to 1975) because of
its presence, as a contaminant, in Agent Orange, a defoliating agent used by the US
Army [13]. As a consequence, the number of cancers and thyroid disease among US
veterans is reportedly higher than in control populations, as are the numbers of cases
of spina bifida, a neurological defect, in the babies that they fathered. Increased risk
of birth defects and cancer also has been reported in exposed populations [14].
Most dioxins are the by-​products of waste incineration plants, metal smelting,
and agrochemical synthesis. Increased levels of dioxins have been shown to cause
decreases in thyroid hormone levels in human population studies, notably in epi-
demiological studies that included pregnant women and their children. One of the
earlier studies was carried out in the Netherlands and published in 1994 [15]. A group
of pediatricians and endocrinologists studied the associations between dioxin and
PCB exposure and thyroid hormone levels in about 100 women and their newborns.
This and other studies demonstrated clear-​cut associations between the higher levels
of these contaminants and lower thyroid hormone levels in the mothers and babies.

A sidestep from PCBs to a notorious brain drainer: alcohol

One of Zoeller’s first articles on the topic of how environmental chemicals affect
brain development was not actually on PCBs but on another well-​known brain
drainer10:  alcohol. When a pregnant women drinks alcohol, there is a risk of the
child being born with not only pronounced intellectual impairment but also obvi-
ous changes in the shape of the head and face, especially with unusually wide-​
spaced eyes. Put together, these features characterize fetal alcohol syndrome (FAS).
However, the cellular and molecular mechanisms causing these deformities are still
largely unknown. Zoeller and his colleagues in fact contributed a significant part
of the solution to the puzzle when they used experimental studies in rats to show
that alcohol consumption reduces circulating thyroid hormone levels and changes
the levels of TRs in the brain [16, 17]. Given that the mother’s thyroid hormone lev-
els and then the child’s own thyroid hormone are essential for brain development,
this alcohol-​induced reduction in thyroid hormone could be a major contributor
to FAS. Furthermore, the symptoms of FAS parallel those of prenatal and postna-
tal hypothyroidism (lack of thyroid hormone) at every level:  behavior, cognition,
and neurological changes, including changes in cellular and synaptic organization.
Some authors have gone further and made direct links to autism spectrum disor-
der and hypothyroidism [18], a topic that we return to in Chapter 5. One can also
draw parallels with the fact that iodine lack, which causes hypothyroidism and
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58 Toxic Cocktail

intellectual deficits, and FAS are the two most common easily preventable causes of
mental retardation.
As Zoeller focused more on PCBs, the work linking alcohol, FAS, and thyroid
signaling has been taken much further by Eva Redei, a professor in the Department
of Psychiatry, Behavior, and Physiology at Northwestern University, Chicago.
Professor Redei, who first obtained a PhD in chemistry in Hungary, has been
studying similarities between FAS and other disorders of the brain for more than
10 years. Her team has shown that prenatal thyroid hormone treatment can reverse
some of the autism-​like behavioral effects of in utero alcohol exposure in rats [19].
More recently, she has focused on how alcohol could affect the selenium-​containing
enzymes that determine how much thyroid hormone is available in the brain. She
found that alcohol given to gestating rats reduces the amounts of thyroid hormone
generated in specific areas of the brain, including the hippocampus, a structure
implicated in memory and learning and one of the brain regions most affected in
FAS. Even more disturbing is that, in the male pups, expression of the genes control-
ling thyroid hormone availability in the hippocampus was modified in the long term
by epigenetic mechanisms (see Chapter 6). As we will see, epigenetic changes alter
gene expression without actually modifying the gene sequence. Epigenetic changes
occurring during development can be conserved into adulthood and in some cases
be passed on to the next generation—​quite a cause for concern.

Mercury as a thyroid mugger

Another contaminant associated with PCBs in fish in the Great Lakes and else-
where is mercury. Environmental mercury has a number of industrial sources,
including coal combustion, metal smelting, and production of batteries and
fluorescent lamps. As mercury is one of the most notorious neurotoxic agents to
accumulate in fish, health authorities suggest that pregnant women and children
should not eat fish from polluted waters, such as the Great Lakes or the Baltic Sea,
more than once a week. And, even then they should only eat small fish and never
the larger fish. The reason behind the recommendation to avoid the largest fish is
that mercury buildup is greatest in the bigger fish at the top of the food chain. As
mercury accumulates in the fish, two factors will influence how much mercury a
given fish contains: what it eats and how old it is. Fish that live on bits of aquatic
plants or the small plankton floating in the water will have mercury contents that
are relatively low. When eaten by the larger carnivorous fish, the mercury they con-
tain will be taken up and stored by the next fish and so on. So, the oldest and the
largest fish, at the top of the food chain, have the greatest level of all the contami-
nants, not only mercury.
  59

Thyroids in a Chemical Soup 59

Some of the neurotoxic effects of mercury involve thyroid hormone signaling.

This is because mercury, like other heavy metals such as lead, chelates selenium. The
term chelates means that mercury forms a chemical complex with selenium, making
it unavailable to perform its biological role. As explained in Chapters 1 and 2, sele-
nium is a rare element needed to make the enzymes that activate thyroid hormone.
So, the greater the mercury load in the body, the less selenium there is to activate
thyroid hormones. As the sea is rich in both iodine and selenium, the best sources
of both elements are seafood, including fish, shellfish, and crustaceans (lobsters and
crabs). It’s somewhat unfortunate that the foodstuffs that provide the most iodine
and selenium can also be sources of mercury contamination.
What should one do? And, what should health authorities recommend for fish
consumption from sources that are not heavily polluted? As it happens, there are
three reasons to eat seafood from relatively unpolluted waters. These reasons are
all related to the beneficial nutrients in seafood:  iodine, selenium, and omega 3
fatty acid. To this one can add the high protein content without the cholesterol
of red meat. So, it seems that the benefits far exceed the risk of mercury pollution.
Even better, the high levels of selenium will act at two levels: not only making the
enzymes needed for thyroid hormone activation, but also to provide extra selenium
that protects the body from mercury by capturing and helping to eliminate it.

Nonstick chemicals that stick around

As if two major thyroid hormone–​disrupting classes of chemicals in Great Lakes

fish were not enough, as we will now see, the third major category of contami-
nants found in these fish, the PFCs, also share thyroid-​disrupting properties.
Unfortunately, PFCs were easy to market, as their use in a variety of products made
life a lot easier for many, at least in the short term. PFCs have surfactant or surface
protection properties that make them of industrial interest for literally thousands
of applications, many of which end up in both the home environment and the gen-
eral environment. They are found in stain-​and oil-​resistant coverings, including the
coatings of cardboard packaging for fast foods, water-​and stain-​resistant materi-
als, floor polishes, and fire-​fighting foams. One of the widest uses is in production
of fluoropolymers for nonstick cooking pans, such as those sold under the trade
name Teflon. Another notorious source is the lining of packaging for microwaved
popcorn—​so your popcorn comes with generous lashings of PFCs.
Two main categories of PFCs are of particular concern, as they are exception-
ally persistent and therefore bioaccumulate extensively in the environment:  per-
fluorooctanic acid (PFOA, also known as C8) and perfluorooctane sulfonic acid
(PFOS). What’s more, until recently these two PFCs had the highest production
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60 Toxic Cocktail

rates, so they are intensely researched for their environmental levels and effects on
biodiversity and human health.
Significant changes were made on PFC legislation in 2015. That year saw not only
the completion of the phaseout of one of the major PFC forms, PFOA, but also the
introduction of new registration rulings from the US EPA aiming to ensure that
banned products, like PFOA, do not reenter the market and the environment. The
stories around PFCs, and especially PFOA, abound with many disturbing examples
of industry failing to provide information on health risks posed by their products
and, once convicted of causing harm, failing to provide adequate follow-​through in
compensation cases.
There is another reason that 2015 was significant for PFCs. One of the major pro-
ducers of PFCs sold the part of their company that makes these chemicals. It would
seem that the company left the market because of increasing documentation on the
environmental and health havoc caused by these halogenated substances, which in
turn is leading to less-​certain profits. This action follows on from the EPA’s PFOA
Stewardship Program. Under this program, the main American companies produc-
ing PFCs were to start reducing production in 2010 with a view to a complete phase-
out by 2015. However, a number of other companies continue to manufacture PFCs,
and, in the meantime, the number of different PFCs and their presence in human
populations and in the environment has risen dramatically.
The history of legislation on PFCs is a tale of industrial deception and willful
harm to the environment and health of local populations. In the late 1990s, the EPA
was made aware of studies showing significant levels of PFCs in human populations
and in the environment. One of the manufacturers, 3M, ceased production, but the
EPA had to go as far as bringing another company, DuPont, to court for hiding
information on contamination with PFCs. The EPA has a ruling that manufactur-
ers (or distributors) have 30 days to inform them if there is any new evidence that any
substance is creating risk. According to the EPA website, DuPont concealed infor-
mation on the accumulation and health risks of PFOA for a full 20 years (between
1981 and 2001). The case against DuPont concluded in 2005 with the company being
ordered by the EPA to pay $10.25 million for these violations. This amount is the
largest payment ever made for chemical contamination.11
A number of studies carried out on different groups of people with varying risks
of PFC exposure have shown significant levels of contamination and concomi-
tant effects on thyroid hormone signaling. One extensive study examined thyroid
function associations with PFC load in close to 11,000 children living near Teflon
production plants [20]. In 2001, residents near such plants in mid-​Ohio and West
Virginia had filed a successful class action against the manufacturers for contam-
ination of drinking water with PFOA, and blood levels of the children near the
  61

Thyroids in a Chemical Soup 61

mid-​Ohio plant were nearly eight times national levels. Researchers found there was
a significantly increased risk of hypothyroidism as a function of PFOA levels. In
fact, a scientific panel has established that five main categories of disease could be
linked to PFOA exposure, including thyroid disease and kidney and testicular can-
cer. Despite the clear-​cut rulings of the panel (members of which were selected by
both the plaintiffs and the company), DuPont has regularly tried to wangle its way
out of recognizing responsibility12 and attempted to place the onus on the plaintiffs
to prove the association with PFOA exposures.
Unfortunately, a similar case of groundwater exposure by PFCs has been reported
around military airbases in the United States and Sweden.13 In these cases, the water
supplies nearby were contaminated by use of firefighting foams with high PFC levels.
The PFCs, particularly the more volatile precursors, enter the atmosphere during
manufacturing, use, and disposal. Global distribution occurs through the atmo-
sphere, rivers, and oceans. Small wonder that both PFOA and PFOS have been
reported worldwide in humans and in fauna from the North to South Poles [21].
Studies of urban contamination have shown that indoor concentrations are higher
than outdoor levels. Not surprisingly, given their use as stain-​and waterproofing
agents, one report showed that the most elevated levels of PFCs were found in shops
selling outdoor equipment, furniture, or carpets [22].
So, what do we know about PFCs and thyroid function in pregnancy? Some
researchers have looked at levels of PFCs in pregnant women, measuring both
maternal and umbilical cord blood levels. PFCs cross the placenta, so it is logical to
expect significant negative correlations between maternal PFC values and fetal thy-
roid hormone levels—​precisely what a South Korean study found [23]. In another
study, conducted in Sweden, a group led by Anna Karrman measured levels in
mothers’ breast milk. In certain respects, the result seemed reassuring in that, even
though the mothers’ blood had high PFC levels (and so the children had probably
undergone prenatal exposure), the levels in breast milk were only 1/​100 (1%) of the
mothers’ blood levels. However, the authors quite rightly point out that the babies
are still receiving significant amounts of PFCs, and more work on the adverse effects
is needed.
Work on rodents has shown that PFCs are transferred to fetuses through the pla-
centa and to pups during lactation. For instance, a Chinese study showed that PFC
transfer is associated with adverse effects on thyroid hormone equilibrium both
before birth in rat fetuses and in the lactating pups [24]. The authors concluded that
these findings are “matters of great concern.” Yet, despite these data and the levels
of contamination in human populations, to date no epidemiological studies have
looked at possible linkages between maternal prenatal PFC levels and their child’s
neurodevelopmental outcome.
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62 Toxic Cocktail

In adults, professional exposure or proximity to production sites causes the

most significant contamination. A study on workers in a PFC manufacturing site
showed high levels that were inversely correlated to thyroid hormone levels. In
another study, higher PFC levels in people living near such sites were associated
with modifications of thyroid function and increased probability of thyroid dis-
ease [20]. Data on exposure in the general US population from the NHANES14
study also showed significant associations with PFOA and PFOS exposure and
thyroid disease in women and with PFOS exposure and thyroid disease in men [25].
Regarding the mechanisms involved, a number of in vivo and in vitro studies with
animals showed that PFCs lower circulating thyroid hormone levels by displac-
ing the hormone from transthyretin (TTR) binding, which then increases thyroid
hormone metabolism in the liver. These thyroid hormone–​lowering mechanisms
are shared by many chemical categories, including those examined next:  flame
retardants.

Flame retardants: why are we playing with fire?

We have already seen that two types of halogen-​substituted compounds, chlorine

as in PCBs and fluorine as in PFCs, can interfere with thyroid hormone signaling.
Now, we move on to the other principal halogen, bromine. Brominated flame retar-
dants (BFRs) have been used for decades in various forms: in electronic equipment,
plastics, paints, and textiles such as foams and padding as well as curtains and car-
pets. There was an enormous rise in the production of BFRs after the ban on leaded
gasoline (petrol) came into force, initially in the United States, at the end of the
1970s and belatedly in Europe and other countries.
You may well be wondering what bromine has to do with lead in gasoline. The
story is once again—​to make use of the title of the book by Gerald Markowitz and
David Rosner—​a depressing tale of “deceit and denial” by industry [26]. Suffice it
here to say that when lead was, unnecessarily, added to gasoline, more chemicals
had to be added to stop the accumulation of lead and lead oxide from damaging the
engine. The most appropriate compounds for this molecular scavenging were our
old friends the usefully reactive halogens, bromine and chlorine, which were added
in the form of dichloroethane and dibromoethane. The mixture added to gasoline
was coyly termed TEL, hiding both the leaded component, tetraethylene lead, and
making no mention of the bromine additions—​adding evil to evil.
When the brain-​damaging and general health problems of lead caused the US
government to act, the bromine industry lost its lucrative sales to the gasoline indus-
try. Therefore, it needed to diversify its products, hence the concomitant increase
in BFRs.
  63

Thyroids in a Chemical Soup 63

From the late 1970s onward, different classes of BFRs started to appear on the
market, with the main ones, in historical order of appearance polybrominated
biphenyls (PBBs), polybrominated diphenyl ethers (PBDEs), hexabromochlorodec-
ane (HBCD), and the more recently introduced tetrabromobisphenol A (TBBPA).
In fact, their staggered order of appearance is largely accounted for by the fact that
as the harmful nature of one category is proven, another poorly tested compound
takes its place. All of them have thyroid hormone–​disrupting actions. Each of these
categories of flame retardants contains at least one bromine atom covalently bound
to a carbon atom. The bromine-​carbon bond is easily broken by heat, and the bro-
mine atoms that are released slow the combustion process. BFR history is peppered
with disquieting stories of precocious commercialization, well ahead of testing, fol-
lowed by delayed withdrawal.
It is impossible to discuss control of flame retardants without referring to the
work of a multitalented individual, Arlene Blum. Many authorities consider that
flame retardant use today is excessive and that the risks have long outweighed the
benefits, but few have gone as far in their actions as Blum. Her motivation could
well derive from the fact that few know the chemistry and the dangers of these
chemicals as well as she does. In fact, she was directly involved with the first stud-
ies of one of the most notorious compounds, tris(2,3-​dibromopropyl) phosphate
or Tris-​BP [27]. In 1977/​1978, with a group of fellow chemists, she coauthored a
set of three highly visible articles on the mutagenic15 effects of a flame retardant
used—​unbelievably—​in children’s pajamas. One of the articles was tellingly titled
“Another Flame Retardant … and Its Expected Metabolites Are Mutagens” [28].
When rat studies showed Tris-​BP to be a potent mutagen (i.e., had the capacity
to induce changes in DNA sequences), it was replaced by its chlorinated analogue,
which in turn was shown to give rise to equally mutagenic metabolites [29].
No doubt, when Arlene Blum and colleagues demonstrated the mutagenic effects
of Tris-​BP in one of the research community’s most respected journals, Science,
they thought this should be enough to convince regulators to act. She left chemis-
try for a while to concentrate on her other passion, mountaineering. Among other
achievements, in 1978 she led an all-​women team, and the first American team, to
the summit of Annapurna.16 Then, in 2006 she was spurred back into action in
chemistry again, having realized that TDCPP, one of the chlorinated derivatives of
the same chemical, Tris-​BP, she had identified as a mutagen 30 years previously in
children’s sleepwear was not only still in production but also widely used in furnish-
ings. To counteract the excessive and often totally unnecessary use of TDCPP, as
well as other flame retardants and environmentally damaging chemicals in general,
in 2008 Arlene Blum founded the Green Science Policy unit (http://​greenscience-
policy.org/​about/​). The institute’s current focus is the reduction of unnecessary use
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64 Toxic Cocktail

of flame retardants. In 2010, Blum was one of the lead authors on the “San Antonio
Statement,” also signed by about 200 other scientists. This document [30] clearly
stated the documented dangers of brominated and chlorinated flame retardants and
advocated increased responsibility and control of their use on a global scale.
Innumerable studies, in human populations and with animal models, have
shown BFRs to be potent thyroid-​disrupting chemicals. Put succinctly, their actions
on thyroid hormone signaling can be multiple, but two principal actions can be
highlighted:  first, interference of the BFRs with thyroid hormone metabolism
and distribution and, second, bromine inhibition of iodine uptake by the thyroid
and BFRs consequent reduction of thyroid hormone synthesis, hence their strong
thyroid-​disrupting capacity. What is more, the inhibitory effects of BFRs on iodine
uptake will be exacerbated by iodine deficiency.
A final point before moving on: Not all flame retardants contain bromine; many
others, especially the newer ones, contain another halogen, chlorine. At the begin-
ning of the section, we referred to TDCPP, a substance used in the manufacture
of polyurethane foam, including that destined for use in baby products, such as
car seats. Interestingly, this chemical class has a structural similarity to a common
organophosphate pesticide, chlorpyrifos, discussed in the section on pesticides.
Many recent reports have shown that this mutagenic substance, TDCPP, is now
a virtually ubiquitous urban contaminant and a thyroid hormone disruptor. In one
study, TDCPP was found in 99% of offices and vehicles as well as in house dust,
and its main metabolite was present in 100% of urine samples [31]. Another study
found the metabolite in 91% of samples, and its levels were correlated with levels
in the home environment, as measured in house dust [32]. Even though TDCPP is
not brominated, it has been shown to interfere with thyroid hormone signaling and
action both in laboratory experiments (see [33]) and from studies on human popula-
tions [34]. No doubt of interest to many reading these lines, in these latter studies,
TDCPP was also shown to affect sperm quality in men.

Pesticides: a persistent problem

More than 50 years have passed since Rachel Carson’s Silent Spring was published
[35]. Ironically, this book, with its evocative title of absent dawn choruses, could
have been and should have been a wake-​up call for the authorities. Rachel Carson,
a US government biologist, had observed population decreases in many animal
groups, from fish to birds, and attributed the abrupt declines to the use of the insec-
ticide DDT. Carson astutely realized that DDT spraying not only was reducing the
insect populations on which many animal groups fed but also was accumulating
in the fish and birds and affecting their reproduction and the quality of their eggs.
  65

Thyroids in a Chemical Soup 65

Carson’s farsighted work was one of the factors in the campaign that led to
the ban on the general use of DDT in 1972. Before the ban, metabolites of DDT
had been accumulating in the environment and, despite the ban, have to a lesser
extent continued to do so. Effects on reproductive capacity are the most serious
in birds at the top of the food chain, including the emblematic American bald
eagle. These metabolites are so persistent they are still with us today. All of us have
significant amounts of the main metabolite DDE in our bodies. Quite rightly, the
adverse reproductive effects recorded by Carson on wildlife began to cause con-
cern among health authorities, who worried that DDT might be exerting similar
effects in humans, as indeed it does. We’ll see in Chapter 8 how women exposed to
high levels of DDT in their mother’s wombs have a significantly greater incidence
of breast cancer more than 50 years later. Yet, in the half century since Carson
issued her warnings, and despite the close scrutiny and regulation to which pes-
ticides are subject, the numbers of chemicals produced and used in agriculture
have increased inexorably. And, of course, pesticides and herbicides (to keep down
weeds) not only are used in farming, but also have extended use in golf courses,
parks, and gardens. So, in some countries, urban environments can be as contami-
nated as rural areas.
In the summer of 2013, the European Food Safety Authority (EFSA) published
two important reports of key relevance to our story. The first dealt with the ques-
tion of hazard assessment of endocrine-​disrupting chemicals (EDCs) in food17; the
second specifically addressed the toxicological effects of pesticides.18 This second
report focused almost exclusively on adverse effects of pesticides on development
of the nervous system (the brain) and on thyroid hormone action. In the report,
the scientists concluded that, of the 287 pesticides they examined, no fewer than
101 had effects on thyroid signaling, and nearly as many could affect development
of the nervous system. One many well ask, How are these pesticides allowed on the
market? Why do we accept such high use on crops we consume?
The answer is complex but has a lot to do with how much of the chemicals are left
on the product before they reach the consumer, whether they are naturally degraded,
and whether the effects observed in rat and mice studies are considered “relevant
to humans.” Too often, the industrial chemists responsible for presenting the data
to the authorities argue that the effects on thyroid hormone pathways observed in
rats are not relevant to humans. And, most often the regulatory bodies acquiesce.
I have often questioned and argued against the phrase not relevant to humans, both
publically in meetings and in my scientific publications. Thyroid hormone signaling
uses the same mechanisms in all vertebrates. So, if a substance causes adverse effects
in rats, mice, or tadpoles, it is highly probable that it will cause adverse effects in
humans, particularly in pregnant women and children.
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66 Toxic Cocktail

As I write, I am reminded of a cartoon shown by a student at a scientific meet-

ing. The drawing portrayed a mouse looking up at a man equipped with mask and
goggles as he sprayed pesticides on plants. The caption has the mouse saying: “Are
you going to eat with the mask on, too?” This was a great way of getting a point
across. However, it is not only through the food we eat that we are exposed but
also through the air we breathe. We now know that children living close to areas
of intense pesticide spraying have a higher risk of being diagnosed with autism [36].
In EU regulations, pesticides are somewhat euphemistically called “plant protec-
tion products,” the idea being that we need to protect plants from the action of pests,
such as insects and rot-​inducing fungi, so that crop yields are increased. Increased yields
are continually needed, we are told, to feed the burgeoning world population. In the
final chapter, I show that these arguments are not fully justified. In short, many studies
revealed that significantly reduced pesticide usage can actually increase yields. The rea-
soning is often that overuse of pesticides kills the harmless insects, birds, and rodents
that would otherwise keep down the pests that damage the crops. To paraphrase a com-
ment made by Joe Thornton in his excellent book, Pandora’s Poison [37], describing
the unnecessary and excessive harm to health and biodiversity caused by the chlorine
industry: When you take pesticides out of the equation, you need to add in two other
factors: knowledge (of biodiversity) and work. It seems there is one thing that we don’t
lack in Europe at the moment, and that is labor. But, encouraging people to change
careers and, most importantly, enabling people to pay more for better quality food is a
complex matter requiring input from sociologists, economists, and politicians.

The pervasive phthalate plasticizers

Phthalates constitute a large group of chemicals with exceedingly wide uses. Their
broad spectrum of applications includes plasticizers for medical devices (especially
single-​use disposable items such as catheters or tubing and plastic pouches); chil-
dren’s toys; personal care products (shampoo, soap, and cosmetics); some forms of
food packaging, including cardboard, polyvinyl chloride (PVC); and even the cap-
sules of certain medications. PVC serves in a spectrum of industrial plastics for both
the automobile and the building industries, with examples of use including window
frames and floor or wall coverings (such as paints). Other uses include coated fabrics
(artificial leather for bags and book covers). Phthalates are not chemically bound to
the main components, so they can leach from these sources into the household envi-
ronment, making them a common indoor pollutant, particularly in household dust.
Phthalate use in the plastics industry dates from the 1920s, when phthalate-​based
compounds replaced strongly smelling camphor as a plasticizer. In 2010, phthalates
  67

Thyroids in a Chemical Soup 67

represented 70% of the US plasticizer market [38], with plastic production at that
time estimated at over 300  million tons and global production of the principal
phthalate, DEHP (diethylhexyl phthalate), at between 1 and 4 million tons.19
Sources of contamination are numerous, and the principal routes include inges-
tion (household dust, food); skin (personal care products); and inhalation from
paints and other building materials. Vinyl products are particularly rich in the
phthalate DEHP and so represent a potential source of human contamination.
Most notably, disposal of DEHP-​containing materials by incineration and land-
fill leads to release of DEHP into the environment, into rivers, surface water, and
drinking water. A  series of studies of Chinese rivers showed systematic thyroid
hormone–​disrupting activities and that phthalates were the main source of these
adverse effects. What is more, these thyroid-​disrupting effects were not removed
by drinking water treatment [39]. In addition, epidemiological studies showed that
phthalates cross the placenta and are found in breast milk and infant formula, rais-
ing the specter of continued exposure through early development from conception
onward.
Much of the research on the effects of phthalates on the endocrine system has
focused on male sexual development. This is because phthalates are increasingly
documented as antiandrogens, being able to interfere with the action of male sex
hormones. However, the effects of phthalate exposure are not limited to a single
endocrine system; thyroid hormone production is also affected. In fact, the first
rodent studies showed greater effects of phthalates on the thyroid than on any other
gland. Similarly, studies of human populations showed clear-​cut associations with
thyroid function. In short, it seems the more phthalates you have in the blood, the
less thyroid hormone your body will make.
The consequences of phthalate exposure in pregnant women and children and
the children’s development have also been researched. Different studies showed that
phthalate exposure negatively affects thyroid hormone homeostasis in pregnant
women [40] and IQ in children [41].

A mixed bag of thyroid disruptors: antimicrobials,

ultraviolet filters, and a few more

Not long ago, one of the main manufacturers of soaps and toothpastes used to add an
antibacterial chemical to many of its products; this chemical is strongly suspected of
being a thyroid hormone disruptor. Although the manufacturer has stopped using
it in soap, it continues to include the ingredient in one of the company’s best-​selling
toothpastes. The arguments given are that the antibacterial ingredient could help
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68 Toxic Cocktail

fight plaque formation and that a number of American authorities have approved
its use. The chemical in question is the antimicrobial triclosan.
Triclosan is not only found in certain toothpastes. Along with the more noto-
rious class of chemicals, the parabens, triclosan is increasingly used as an antimi-
crobial in personal care products—​soaps, deodorants, mouthwash, face and body
creams—​and cosmetics. Usage of these antimicrobials has become so widespread
that most human populations are widely exposed to parabens and triclosan on a
regular basis. First introduced in the 1970s, they have inexorably gained ground. It is
difficult to find data on paraben production, but individual companies boast annual
production capacities of over 2,500 tons. In the European Union today, triclosan
production has been estimated at around 1,000 tons and is thought to be a major
contributing factor to the growing problem of antimicrobial resistance.20 The first
reports of the antithyroid effects of parabens date from 1981, whereas the first suspi-
cions of similar effects for triclosan date from 25 years later. A toxicologist interested
in brain development and thyroid hormone, Kevin Crofton, working at the EPA,
first noticed the similarity of the chemical structures of triclosan and thyroid hor-
mone and raised the possibility that triclosan could be a thyroid hormone disruptor.
His team published the first data sets showing this to be the case in 2007. Crofton
no longer carries out research in the lab but has become involved in directing the
computational toxicology program at the EPA.21
Studies in human populations have shown that women and girls have levels of
these chemicals in their bodies up to five times higher than men, probably because
women use more cosmetic products. Some of these studies look at the effects of
exposure to these chemicals on blood hormone levels. Such studies showed that lev-
els of both chemical classes are differentially associated with changes in circulating
thyroid hormone levels, and similar results have been reported from animal studies.
Skin is a barrier for water in most situations, but not for chemicals in cosmetics,
which are often soluble in lipids (fatty molecules), a feature that helps them pen-
etrate the skin. So, it is to be expected that greater use of cosmetics will raise the
levels of antimicrobials in women. But, many cosmetics contain other EDCs besides
the antimicrobials, notably ultraviolet (UV) filters. This is the case even for nail pol-
ish, some components of which could be light sensitive. Most of the major thyroid-​
disrupting UV filters have been removed from the market, but the action of some of
the substitutes may need closer examination.
Not surprisingly, many authorities recommend reduction of cosmetic use during
pregnancy. To avoid using too much sunscreen, protective clothing such as long-​
sleeved shirts and wide-​brimmed hats are preferable (and probably far better for
your skin).
  69

Thyroids in a Chemical Soup 69

From fertilizers and fireworks to airbags

We have seen that many categories of halogenated compounds can interfere with
the normal distribution of thyroid hormone in the blood and activate degradation
of the hormone by the liver. Other compounds, such as mercury, can inhibit the
selenium-​containing enzymes that activate thyroid hormone in the target tissues.
Besides these multiple thyroid-​disrupting processes that occur outside the thyroid
gland, other contaminants act on the capacity of the thyroid gland to make thyroid
hormone. This is the case for three common environmental pollutants:  perchlo-
rate, nitrate, and thiocyanate. All of these block uptake of iodine by the thyroid
gland, and if the thyroid gland cannot take up iodine, then it cannot make thyroid
hormone.
Unfortunately, both perchlorate and nitrate are found in groundwater in many
areas. Perchlorate is the most potent iodine uptake blocker, so potent in fact that
substances similar to perchlorate are used clinically to treat hyperthyroidism and to
block thyroid hormone production. Given this clear antithyroid effect and the gen-
eralized exposure, at least in the United States, the urgent question is not whether it
is active but the severity of human exposure, particularly in children and pregnant
women, and whether perchlorate contamination is another potential contributor to
the rise in autism spectrum disorders and neurodevelopmental disorders.
Perchlorate is a strong oxidant used in rocket propellants, ammunition, road
flares, fireworks, and airbag deployment. Because of its prevalence of use and extreme
stability, it has become a widespread contaminant in water used for drinking and
for irrigation (and thus in food). Exposure data show perchlorate contamination
to be generalized in the US population [42], with the highest levels in children.
Interestingly, in this study urinary perchlorate was associated with increased pro-
duction of thyroid-​stimulating hormone (TSH) by the pituitary gland (indicating
the bodies’ need to produce more thyroid hormone), whatever its iodine status.
Thyroid status was even more abnormal if urinary iodine was low. Thus, the uni-
versal contamination of water supplies with perchlorate combined with frequent
iodine lack in susceptible populations is a clear risk factor for adversely affecting
thyroid function in women and, of greatest concern, in those of childbearing age.
Most drinking water is contaminated with not only perchlorate but also nitrate,
which acts on exactly the same system to block iodine uptake by the thyroid.
Human samples of urine show there is generally more nitrate than perchlorate, and
it is often nitrate that represents the greater problem. Nitrate is used in fertilizers.
Consequently, nitrate levels in water (including drinking water) of regions with
intense agriculture are often well above the recommended limits.
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70 Toxic Cocktail

Levels of these chemicals in samples of urine, and amniotic fluid, are among the
highest of all the chemical contaminants we have discussed. 22 A colleague, who now
works in the British Public Health system, told me that she used to live in Norfolk,
a county in eastern England with intense agriculture. To protect her children (their
thyroids and their brains) from the high levels of nitrate in the drinking water, she
installed a water purification system (reverse osmosis; see Chapter 9) in the house.
But, I asked her, What about the other children—​were there no effects on thyroid
function and general intelligence? “Oh,” she replied, “of course, the teachers would
say the children were ‘normal for Norfolk!’ ” And indeed, effects of nitrate in drink-
ing water on thyroid function in humans have been documented on both sides of
the Atlantic. As could be predicted, given its antithyroid effects, the nitrate content
of tap water has been associated with higher TSH levels and increased thyroid vol-
ume in humans [43], that is, with inhibition of the thyroid axis and consequent
thyroid enlargement (as seen in goiter provoked by iodine deficiency).
The final well-​known iodine uptake inhibitor is thiocyanate. Certain vegetables,
such as those in the cabbage family, naturally contain thiocyanates, although con-
sumption of raw vegetables of this group (cabbage, Brussels sprouts, cauliflower,
kale, bok choy, and broccoli) has to be excessive (over 1 kilogram per day on a regu-
lar basis) to reach levels that will inhibit thyroid function. In contrast, cassava con-
sumption in certain parts of Africa has been documented as being linked to goiter
and cretinism [44]. Another source of thiocyanate is cigarette smoke.

Last but not least, a soy product, genistein: a risk

for soy-​f ed infants?

Today, another antithyroid factor from plant sources is increasingly present in our
food:  soy-​based products. Soy product use is rising, as there are more and more
lactose-​intolerant consumers in the general population. Another factor is that
soy is an excellent vegetarian source of proteins. So far so good—​but soy is rich in
genistein.
Genistein is an isoflavone or flavonoid, belonging to a large group of chemicals,
the polyphenols. In small amounts, many of these polyphenols have numerous
potential health benefits. An example is resveratrol, which is found in red wine
and has been much researched for its potential antiaging properties. Genistein and
another isoflavone found in soy, daidzein, are referred to as phytoestrogens because
of their estrogenic activity on vertebrate estrogen receptors.23 The evolution of phy-
toestrogen production is fascinating and is exemplified by the nitrate-​fi xing legumi-
nous plants, such as soy and red clover. The production of flavones by these plants
and their associated bacteria must have conferred an evolutionary advantage to the
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Thyroids in a Chemical Soup 71

plants to be so conserved. Interestingly, many of these flavones act through the same
receptors as natural estrogens in our bodies.
Products containing genistein are sold in different guises, with marketing over-
whelmingly directed at perimenopausal and postmenopausal women. Products
are also publicized as a means of reducing intake of either cholesterol or lactose.
However, at high levels, both genistein and diadzein inhibit thyroid hormone pro-
duction, a finding documented in animal studies and in humans. In 2002, two bio-
chemists published a review of the effects of these compounds on thyroid function
[45]. In their work, they described a number of clinical studies in which soy intake
in humans was associated with either appearance of goiter or reductions in circulat-
ing thyroid hormone levels.
Many people think that there is no risk in feeding soy milk to babies and children
because they consider that children from Asian countries where soy consumption
is high (such as Japan) must be exposed through the mother’s breast milk, and no
adverse effects have been reported. This belief, however, is not based on experimen-
tal results. Breast milk of mothers eating soy has far less phytoestrogen content than
soy formula. So, the phytoestrogens are not being passed on in breast milk. In fact,
the amounts of genistein and daidzein consumed by infants on soy formula are
between four and six times greater (on a body weight basis) than for an adult who is
a regular consumer of soy products.
One article has reported the levels of genistein in the blood of soy-​fed children
[46]. The authors concluded their abstract by emphasizing that, in infants fed
on soy, the circulating levels of isoflavones are tens of thousands times higher
than natural estrogen hormones at the same developmental period. They then
stated that these levels “may have long-​term health benefits for hormone depen-
dent diseases.” The explanation for this unfounded statement may stem from the
fact that, as stated in the acknowledgments listed in the article, a producer of soy
formula (US Department of Agriculture [USDA] data 24) funded the research.
And, this is not by any means the only example of irresponsible scientific report-
ing on the topic.
Despite this type of data and those on the goitrogenic effects of soy, many authors
consider that even though between 20% and 25% of infant formula sold in the United
States is soy based, this presents no health risk (see, for example, [47]). The article
cited is based on a 5-​year study comparing growth statistics in children fed breast
milk, milk-​based formula, or soy formula. In fact, the article provides no actual data
on children but mainly refers to data on piglets. It makes no mention of the risks to
either thyroid function or to the need for iodine supplementation in the diet if fed
soy. One of the authors of this article stated that he was a member of the Scientific
Advisory Board of the Soy Nutrition Institute. This fact may again help to explain
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72 Toxic Cocktail

why the abstract concluded with the ambiguous and speculative statement that soy
formula “may be even advantageous for bone growth.”
Such irresponsible reporting of data may well be contributing to the increased
used of soy-​based infant formula. Even though there are situations, such as intoler-
ance to cow’s milk, where soy formula has to be introduced, the long-​term effects
of feeding babies soy formula have yet to be established on general health and more
particularly on reproductive health, thyroid hormone status, and the overall conse-
quences on behavior and mental health.
I conclude with a word of advice. If you are a regular soy user, make sure you have
a reliable source of iodine, from iodized salt or marine fish.

Our daily chemical cocktail

The list of chemicals presented in this chapter with thyroid-​disrupting characteris-

tics is not exhaustive; this is for two reasons. First, few of the thousands of chemicals
in the environment have been fully tested. Second, the reader may become bored
with list upon list of data on the different categories of known thyroid disruptors.
The examples given should suffice to illustrate the problem.
This leads to a final comment on chemical exposure. Having been through some
of the main categories of chemicals that have been documented to interfere with
thyroid hormone production or action, it is important to bring into the picture the
potential effects of combined exposure to multiple chemicals. The thickening of the
chemical soup brings more than one set of problems. First, this is simply in terms of
the effects of mixtures of low doses of chemicals on one endocrine system, such as
the thyroid hormone system. A second problem is that the mixtures can affect more
than one endocrine system.
A recent study by Teresa Woodruff, a clinical endocrinologist and a past presi-
dent of the Endocrine Society,25 exemplified the problem in a particularly disqui-
eting manner. For a large group of pregnant US women, her team examined the
concentrations of 163 substances belonging to 12 main chemical classes in the urine
and blood. The analysis published in 2011 is often cited. The study showed that all
the pregnant women (99%–​100%) examined were contaminated with 8 of the 12
categories searched for, and that within categories the numbers of individual chemi-
cals could range from 4 to 12.
We know that most of these compounds cross the placenta, as different studies
have shown significant levels of these chemical categories in samples of amniotic
fluid in various parts of the world. Further, experimental data from different groups
and work being carried out in my laboratory by Jean-Baptiste Fini, show that over
two-​thirds of these compounds are thyroid hormone disruptors. Exposure to these
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Thyroids in a Chemical Soup 73

chemicals is not limited to the United States, but is a global problem. So, we can
deduce that every child conceived today is exposed, not only from birth but also
from day 1 of conception onward, to a brain-​sapping cocktail of multiple chemicals.
To this sorry picture, we can add that there are many other chemicals that,
although they may not affect thyroid hormone signaling and brain development
directly, could still exacerbate the impact of thyroid disruptors on brain develop-
ment by causing additive or synergistic effects. For instance, some pesticides do
not affect thyroid hormone signaling directly but might act on synaptic func-
tion, communication between nerve cells. Such effects would be aggravated if the
mother’s supply of iodine or thyroid hormone is insufficient or by coexposure to
other thyroid-​disrupting chemicals. And, as usual and as established for many situ-
ations, the earlier during brain development the effects occur, the more severe the
outcome is.
74
  75

4
Losing It
Undoing Br ain Evolution

Were we smarter in the 19th century?

In 2013, soon after I’d finished writing Losing Our Minds, a paper published in the
journal Intelligence caused quite a stir. With the title, “Were the Victorians Cleverer
Than Us?” it proposed that average intelligence has significantly decreased since the
end of the 19th century. The publication attracted my attention as it linked with
certain ideas I’d been working on for the previous 3 years. Michael Woodley and
his two coauthors compared historical and recent data sets on reaction speed as a
reflection of neuronal efficiency and IQ (I define the use of the term IQ in the sec-
tion on the Flynn effect and explain how these concepts interrelate). They also took
a completely different perspective from mine to explain the decreased IQ. However,
the important point is that, despite the difficulties of comparing IQ over time and
the discussions on their potential causes, many lines of evidence point to a general
decline in average IQ.
My central argument here is that chemical pollution affecting thyroid hormone–​
dependent brain development could well be a major contributing factor to this
decrease. It is safe to say that without thyroid hormone the brains of all vertebrates
would not have evolved to reach such efficient cognitive, sensory, and motor control
systems. More important, without an efficient thyroid gland capable of trapping
precious iodine combined with sophisticated physiological controls ensuring the

75
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76 Toxic Cocktail

right amount of thyroid hormone is delivered at the right developmental time, evo-
lution of the human brain would not have reached its amazing complexity.
Exposure to thyroid hormone–​disrupting chemicals is ubiquitous and present
from womb to tomb. So we have to ask the uncomfortable question whether our
own actions are undoing human brain evolution.
It is often said that there is no living structure more complex than the human
brain. Understanding how the human brain develops consciousness, intelligence,
and language is one of the major challenges of the 21st century. Although pro-
grammers can create forms of artificial intelligence and write software with the
calculating power to beat Kasparov at chess, it is still not known how our brains
integrate, sift, and act on the information produced by the hundred billion neu-
rons and trillions of synapses that form its hardwiring. Put another way, the
human brain has at least 10 times more neurons than the total world population,
with each neuron having thousands of contacts with other neurons—​a lot of data
processing!
In fact, two major projects on either side of the Atlantic are seeking to understand
how the human brain works. The US and European projects were launched in 2013
and are currently paralleled by similar programs in China. While the precise ques-
tions asked and methods slightly differ, the overall objective is the same, namely, to
understand how our brains make us human.
In April 2013, President Obama announced funding of the BRAIN Initiative,1
with the ambition to map all the connections of the human brain. Standing for
Brain Research through Advanced Innovative Neurotechnologies®, BRAIN is on a
comparable scale to the Human Genome Project launched more than 20 years ear-
lier. The initiative is run by the National Institutes of Health (NIH), and $46 mil-
lion was invested2 in 2014 into what the director of the NIH called “the next
moonshot.” However, according to the official NASA site, putting Neil Armstrong
on the moon in 1969, eight years after John F. Kennedy announced the project, cost
$30 billion (around $200 billion today after inflation), so $46 million to understand
the brain seems rather paltry, even if similar amounts are to be invested every year
for the next decade.
The scheme run by the European Commission, the Human Brain Project,3 is
investing about a billion euros to delve into how the neuronal circuits that underlie
cognition, information processing, and decision-​making actually function. One of
the main aims is to use the knowledge to provide leads into applications in infor-
mation technology and computing. Doing so involves developing and exploiting
techniques that provide new insights into brain structure and organization at the
molecular, cellular, and circuitry levels, including imaging techniques that pro-
duce amazing multicolor three-​dimensional (3D) pictures of neuronal networks
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Losing It: Undoing Brain Evolution 77

and the use of supercomputers to provide working models of how circuits operate in
different brain areas.
The American endeavor is not irrelevant to another announcement Barack
Obama made during his first term of office. In 2010, he officially changed the term
mental retardation to intellectual disability. This statement came 2 years before the
publication of US figures showing autism spectrum disorder (ASD), which con-
cerns many children with severe intellectual disability, had reached 1 in 88 chil-
dren [1]‌, nearly a 60-​fold increase compared to 1975 [2]. Two years later, the same
institution, the Centers for Disease Control and Prevention (CDC), published
data showing ASD incidence at 1 in 68 children. Then, in late 2015, the US Health
Interview Survey published statistics based on parental reporting of children identi-
fied by a health professional as having a developmental disability, including ASD.
The results showed the disquieting figure of 1 in 45 children with ASD [3]. Because
ASD is more common in male children, the incidence among boys in the CDC
data published in 2014 was 1 boy in 42 [4] (see also Chapter 5, which discusses how
sex hormones could interact with thyroid hormone to affect brain development).
Attention-​deficit/​hyperactivity disorders (ADHD) is even more prevalent than
ASD in children and adults, with up to 11% of children being affected.
It is hoped these research initiatives will provide new insights and therapeutic
options for many neurological and mental disorders. But, expectations for these
projects to provide preventive strategies to reverse the frightening trend on the
incidence of ASD are probably overoptimistic and possibly misdirected, in that
at present, environmental influences are receiving comparatively little attention.
In Chapter  6, I  provide some background to the current research and funding
emphasis on genetic causes of these diseases and suggest ways forward that take into
consideration how genetic susceptibilities could be exacerbated by environmental
factors acting through epigenetic mechanisms.
In parallel to the increases in neurodevelopmental disease, certain statistics show
decreases in IQ scores and other tests of mental acuity among schoolchildren and
young adults in different parts of the Western world. These studies are independent
of those derived from studies of chemical exposure. The concomitant increases in
neurodevelopmental disease and apparent decreases in IQ scores could almost be
taken as a first indication that we have managed to start a process of decline in brain
capacity.
Many authors consider that acquiring greater knowledge of human brain evolu-
tion is essential to understanding the origins of brain diseases specific to humans,
such as ASD, schizophrenia, and dyslexia. To be able to take such an approach, we
have to ask how the human brain has evolved the key features that distinguish it
from other primates, such as the chimpanzee. One part of the answer is that it is not
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78 Toxic Cocktail

only a matter of increased brain size with respect to other primates and hominids
(some early humans had larger brains than modern humans [5]‌) that determines the
differences, but also increases in size of specific brain regions, such as an enlarged
cerebral cortex or neocortex, the area that covers our brains and is responsible for
our remarkable cognitive capacity. Other contributing factors are changes in brain
organization, the timing of neurodevelopmental events [6], and the complexity of
interactions between different structures.
A number of features important for our discussion stand out in this evolutionary
process of increasing the functional capacity of our brains. One difference is the
change in developmental time needed for brain development in humans as opposed
to monkeys and apes. Compared to our closest cousins, chimpanzees, we humans
have extended periods of brain growth, starting from the time spent in the womb
and continuing with the longer period of parental care (childhood). It is thought
that this extended growth period could have favored our extensive, and distinctive,
cultural learning. Another idea, related to a change in growth period, is the role of
modifications in timing of different processes implicated in brain development, as
well as the enormous increase in the energy requirements of the human brain.
In terms of changes in developmental timing, human brains show longer (and
also sometimes faster) periods of growth both before and after birth compared to
chimpanzees. Brain growth encompasses all the major processes of brain develop-
ment: production of new neurons by cell division, migration of the new cells to other
brain areas, extension of dendrites and axons to connect with other neurons, forma-
tion of synapses and myelination of the long connections between distant neurons.
Myelin is the fatty insulating layer that surrounds the nerve, rather like the plastic
casing surrounding metal wires that conduct electricity. Myelination of long neu-
rons increases the speed at which neuronal messages travel from one neuron to the
next. The acquisition of myelin was a critical feature of evolution of all vertebrates,
from fish to humans, but changes in the timing of myelination are also [7]‌a defining
feature of human versus chimpanzee brain development. How and when myelin is
formed will in turn determine the efficiency of connections among different regions
of the growing brain and underlie how the child acquires higher-​order functions
such as interaction with others and decision-​making.
Another feature that has changed during the evolution of our brains is the
amount of energy we use and the metabolic systems that are involved in how we use
it. For instance, our brains only represent 2% of our body weight, but they consume
more than 20% of our energy supply. Thinking can be exhausting work!
Without wishing to overwork the main ideas in this book, thyroid hormone is,
as detailed in Chapter  2, essential to all the cellular processes that contribute to
brain development and growth. One of the processes increasingly linked to the
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Losing It: Undoing Brain Evolution 79

specification of the human brain, as compared to the chimpanzee brain, is the size of
progenitor populations that give rise to neurons and all the other cells in the brain.
Today, we know thyroid hormone controls the size of the pool of neuronal stem
cells and the progenitors to which the stem cells give rise [8]‌. So, too much or too
little thyroid hormone will reduce the size of the stem niche in the brain. Thyroid
hormone also contributes to controlling progenitor cell differentiation, neuronal
migration, myelination, production and maintenance of synapses, and even control
of energy use.
It is not surprising, then, to find that many authors link the roles thyroid hor-
mone signaling acquired during evolution to the functions the hormone plays in
primate brain development and metabolic needs. In 2001, a group of scientists from
the University of California at San Diego [9]‌reported that their analysis of blood
protein differences between great apes and humans showed major and specific dif-
ferences in thyroid hormone metabolism. This article was picked up by others, who
extended the arguments [10], underlining the importance of thyroid hormone for
many of the features that gave Homo sapiens unique advantages over other homi-
nids, including sustained exertion during chase-​hunting as well as improved cog-
nition. More specifically, it has been argued that the increased diets of fish and
seafood containing iodine enabled the rapid brain evolution of early hominids and
particularly that of our species, Homo sapiens, over the last hundred thousand years
or so. But, what if these time-​crafted acquisitions in brain development, capacity,
and sagacity were being surreptitiously, and swiftly, eroded—​a sort of brain evolu-
tion in rather rapid reverse?

The Flynn effect

There is currently a great deal of debate regarding whether IQ in the Western world
is going up—​the so-​called Flynn effect—​or down. However, for the purposes of
this discussion, it is important to clarify that whichever is the case, increasing or
decreasing IQ, current evidence obtained on numerous well-​designed cohorts on
effects of early developmental exposure to pollutants shows such exposure to be
detrimental, with the most exposed children showing lower IQ scores than less-​
exposed children. So, if IQ scores were really trending upward, possibly due to edu-
cation or nutrition, then scores could have been even higher if the children had not
been exposed to certain forms of chemical pollution. On the other hand, if they are
decreasing as suggested by the Woodley data, then the decline can be associated in
large part with chemical pollution.
To be in a position to judge the evidence for an increase in IQ scores—​the Flynn
effect—​versus the data suggesting that, on the contrary, IQ is decreasing—​often
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80 Toxic Cocktail

referred to as an anti-​Flynn effect—​we need to understand what is referred to when

psychologists use the term IQ.
So first, what is IQ? A German psychologist, William Stern, was the first to mea-
sure and compare the IQ of a group of schoolchildren in 1912. He used the term
Intelligenzquotient, or IQ, as a means of scoring results obtained in testing, and
comparing, children’s mental ability [11]. IQ distribution, or the range of intellec-
tual abilities, was, and still is, determined by taking the median score obtained by a
group of children in a given age bracket as 100, with each standard deviation from
the median representing 15 IQ points on either side of the median4 value. Most bio-
logical characteristics, such as height, organ size, or even longevity in a given spe-
cies, display a regular distribution around the median and make a bell-​shaped curve,
often called a normal distribution or Gaussian distribution after the 19th-​century
German mathematician Gauss. IQ curves obey this normal, bell-​shaped distribu-
tion (see Figure 7.1 in Chapter 7).
The next question is, What is the Flynn effect? The name of James Flynn, cur-
rently an emeritus professor at the University of Otago in New Zealand, is most
often associated with his documentation of the large increases in IQ scores observed
between 1945 and the late 1990s. James Flynn is a political philosopher whose
work on psychology and intelligence has influenced many fields. In particular, he
has argued against the misuse of incorrectly standardized IQ tests in many situa-
tions, for instance, in determining whether criminals are intellectually deficient and
should therefore be exempt from the death penalty in countries, such as the United
States, where it is still in force. He has also taken a strong stand against alleged racial
differences in intellectual ability and has continually emphasized the role of envi-
ronment over genes in determining performance in IQ tests.
According to Flynn himself [12], the eponymous effect was first attributed to
him by the psychologist Richard J. Herrnstein and his political scientist coauthor
Charles Murray. As Flynn says in his introduction to What Is Intelligence?: Beyond
the Flynn Effect, not only should the concept have been attributed to a fellow
researcher Reed Tuddenham, who made the first observations on huge IQ gains in
US military conscripts between World Wars I and II, but also it has a number of
inherent problems. Most important, either children in the second half of the 20th
century were a lot brighter than their parents or there is a problem with the way that
intelligence is measured by IQ tests. In brief, he argued that IQ testing can only be
usefully applied in a given social structure at a given time, and there is little founda-
tion for comparing the same tests applied to people or children with different life
experiences, cultural backgrounds, or educational levels.
This reasoning is why it is appropriate to use IQ data obtained on cohorts (large
groups) of children from similar socioeconomic backgrounds in a specific year to
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Losing It: Undoing Brain Evolution 81

analyze whether, for instance, the children of mothers that had higher or lower
levels of a particular chemical substance at a defined time during their pregnancy
displayed differences in neurodevelopment and IQ levels. For instance, many of the
studies referred to in further discussion examined maternal blood or urine levels
of flame retardants or plasticizers in the first trimester of pregnancy and carried
out IQ tests on their children when they were all at the same age. The point here is
that the children tested in a given cohort will have many environmental factors in
common (year of birth, same geographical area, often the same school system), and
those factors that are not standardized (mother’s age, educational level, smoker or
non-smoker) can be adjusted for during the statistical analysis. The researchers can
then test whether different levels of the substance in the mother’s urine or blood can
be correlated with the child’s intelligence, as judged by a standardized IQ test when
the child is old enough to be tested.
Returning to Flynn’s comment that the potential increase in IQ begs the ques-
tion of what IQ tests actually measure, this issue is also relevant to our discus-
sion, as these tests are used to evaluate children’s intellectual development in the
exposure studies. So it is important to examine not only what IQ tests measure
but also how average IQ is determined. The question of what capacity is actually
measured in an IQ test is a vast subject and the topic of innumerable books and
theses.
One way of addressing the question is to look at two commonly used
tests:  Raven’s Progressive Matrices and the Weschler Intelligence Scale for
Children® (WISC), which is the children’s version of the Weschler Adult
Intelligence Scale ® (WAIS). The WISC test is most often used in cohort stud-
ies comparing IQ. Designed by an American psychologist, David Weschler, in
1949, WISC testing was first introduced in 1950 and was originally composed
of up to 16 different tests, although all are rarely used together. The WISC test
can be applied using images, so there is no need for prior reading skills. The 10
most commonly used subtests are the following, although different countries
and authorities use some and not others:

• Information: Questions such as “On which continent is a given country?”

test the child’s general knowledge.
• Arithmetic: According to the child’s age, the question will require some cal-
culation, for instance, the question:  “If four oranges cost six euros—​how
much do seven cost?”
• Vocabulary: The child may be asked the meaning of a word that is not com-
monly used, such as debilitating. This test assesses both extent of vocabulary
and the ability to form concepts. It requires some previous knowledge.
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82 Toxic Cocktail

• Comprehension: This test is conceived to assess “common sense” knowledge

and could include questions such as “Why are streets numbered in order?”
or “Why do you switch off lights when leaving a room?”
• Picture Completion: This requires indicating missing parts from an incom-
plete picture.
• Block Design:  The child is asked to use blocks to replicate a two-​color
design; this tests a number of abilities, from spatial visualization and analy-
sis to dexterity and visual motor coordination.
• Object Assembly: As this test requires the child to assemble puzzles depict-
ing common objects, it tests much the same skills as the Block Design test
and has been dropped in later versions of WISC.
• Coding: This test provides a key (like a row of shapes with different marks
on them or numbers in the same boxes as different symbols) and requires
reproducing the marks or symbols on a test set of shapes or numbers. It mea-
sures dexterity, nonverbal memory, and nonverbal associative learning.
• Picture Arrangements: Here, the idea is to reorder a set of scrambled picture
cards to tell a story.
• Similarities: by asking a question such as “In what way are ‘dogs’ and ‘rabbits’
alike?” this test appraises verbal concept formation and logical thinking.

It is generally the case that children doing well on one subtest do well on most of
them. To see how well an individual’s test results correlate, a mathematical method
can be used that measures the relationship between scores on different cognitive
tests. The quantified result is referred to as g, meaning general intelligence, first used
by a British psychologist, Charles E. Spearman5 (1863–​1945), in 1927. However, it is
important to note that, despite coining the term g, Spearman was reluctant to use
this simple term as he felt it could not reflect the complexity of the construct and the
methodology used to calculate it.
Today, despite Spearman’s reservations about oversimplifying the concept, the
idea that g does represent general intelligence is broadly accepted, and this accep-
tance is largely due to the extension and development of Spearman’s thoughts by a
fellow psychologist, an American, Arthur Jensen [13]. Jensen’s work, published in
1998, expanded on Spearman’s by incorporating 70 years of international research
on psychology and testing. It promoted the concept of g and explained how g is
derived by a rigorous statistical method and is based on the theory that “a general
mental ability enters into every kind of activity requiring mental effort” [13, p. 18].
Jensen was known for his beliefs in the stronger influence of genes rather than
environment on mental capacity and the introduction to The g Factor underlines
this thinking. Flynn, however, has strongly criticized this idea.
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Losing It: Undoing Brain Evolution 83

The other frequently used IQ test is Raven’s Progressive Matrices. Here, two
key facts need to be taken on board for our discussion: First, Raven’s test is rarely
used in the cohort studies on chemical exposure that we will be discussing; sec-
ond, it is this test that shows the greatest increase in scores between 1945 and
the end of the last century. So, what does Raven’s test measure? Raven’s test usu-
ally involves a set of three designs with a fourth piece missing and six to eight
candidate pieces to fill the gap. It thus measures the capacity to do on-​the-​spot
problem-​solving with no previous acquired knowledge (other than that of solv-
ing this type of problem). It requires determining the logic of a set of reference
images.
By examining the results on two main types of test—​W ISC and Raven’s—​used
for measuring IQ over 50  years, Flynn noted a number of inconsistencies in the
results, especially between those on different subtests of the WISC. He noticed that
if you break down scores in different WISC subtests, then those that have a similar
basis to Raven’s, such as the Similarities subtest, show the most dramatic increase in
scores (around 25 points), whereas Arithmetic and Vocabulary subtest scores show
much lower gains (less than 3 points). His observations led him to identify four
paradoxes, which are summarized next.

The Flynn effect has its paradoxes

James Flynn himself underscored the fact that if IQ was indeed increasing, then this
finding would incur a number of paradoxes that we should try to deal with. Some
readers might find this section a bit overly academic. It can be skipped without los-
ing the thread of the main arguments.
The first paradox derives from the increased scores seen in Raven’s matrices and in
certain subtests of the WISC, but not in arithmetic. This discrepancy led Flynn to
wonder how children’s intelligence can improve in one area of mental effort but not
in their ability to solve numerical problems. For Flynn, the answer was in the dif-
ferences in what WISC subtests measure, namely, a spectrum of different cognitive
skills that can be modified as a function of social priorities. Thus, testing or calculat-
ing g is only valid in a static social context. As the cohort studies we will be looking
at fulfill this criterion, that is, they compare children in a given age group at a given
time, we can use the data to compare IQ between exposed and nonexposed groups.
The second paradox is that if the large gains in IQ, up to 18 points in two genera-
tions, really reflect increases in intelligence, then we should be struck by the unex-
pected capacity of today’s children to learn increasingly complex tasks—​and this is
simply not the case. This paradox is somewhat similar to—​and the reverse of—​the
third paradox.
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84 Toxic Cocktail

The third paradox is the intellectual disability paradox, resulting from calculating
what would have been the IQs of the great-​grandparents of the current generation
on the basis of 18-​point IQ gains in two generations or 36 points in four generations.
Such a difference would make the generation born at the beginning of the 20th
century seriously intellectually challenged, with an average IQ below 70. Flynn
makes short shrift of this paradox, stating that our predecessors a century ago were
obviously not intellectually handicapped. Their intelligence, and their use of it, was
rooted in everyday experience. The difference lies in our greater, and educationally
determined, capacity to use abstractions and logic, being able to go further with
acquired concepts and do problem-​solving on the spot.
The final paradox derives from studies of identical twins separated at birth. Many
such studies, but as detailed in Chapter 6 not all, show identical twins have simi-
lar IQs, a result that is generally taken to reveal a strong influence of genes on IQ.
However, as just pointed out, the increases in IQ that were driving the observed
Flynn effect between 1950 and 1980 cannot be accounted for by genes because
there’s been no change in the human genome during that time. This last result sug-
gests that the environment is a stronger component. So, the paradox is, How can the
environment be both weak (showing less influence than genes in the case of some
twin studies) and strong (in the case of IQ gains)? To resolve it, Flynn argued that
the strong genetic similarities between twins separated at birth will take advantage
of feedback loops that operate between environment and performance. So, a genetic
intellectual advantage will help both twins in different environmental settings. For
instance, it could give both twins an edge to make the best of schooling, realize the
importance of homework, and get into a better academic group—​factors that will
multiply the initial genetic advantage and result in closely shared twin IQ.
Finally, after dealing with each of these paradoxes, Flynn pointed out that to ask
whether increased IQ is really a reflection of increased intelligence is the wrong
question because it makes the (incorrect) assumption that gains in one test reflect
gains in all cognitive functions, and this is clearly not the case.
What then is the evidence for a reduction in IQ over the last 100 years?

Evidence for an anti-​F lynn effect

A number of studies started to show a flattening of the Flynn effect since the 1980s,
notably in Scandinavia and the United Kingdom, but more recent data suggest that
such leveling off or stagnation is now turning into a decrease. One recent article
that has attracted a lot of attention by identifying an “anti-​Flynn” effect, or overall
loss of intelligence, over the last century is the one referred to in the opening para-
graph, “Were the Victorians Cleverer Than Us?” [14]. Published in late 2013, this
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Losing It: Undoing Brain Evolution 85

article presents results of a meta-​analysis, that is, a study that compared numerous
previously published results. They analyzed 16 data sets on how fast people react to
a visual stimulus, their reaction time (RT). The results they used span a period of
120 years, starting in 1884, hence the reference to the Victorians, and their central
result was that there has been a 14-​point IQ loss over this period.
The data analyzed by Woodley and his colleagues had in fact been brought to
their attention by a publication from another academic, Irwin Silverman of Bowling
Green University, Ohio. Silverman had compiled and compared these same sets
of results 3  years previously [15]. But, in turn, Silverman’s comparison included a
reanalysis of data published 20 years earlier by Ronald Johnson and his collabora-
tors [16] from the University of Hawaii, who had obtained and analyzed the massive
original data sets of Sir Francis Galton from the 1880s and 1890s.
Galton was a Victorian polymath and a second cousin (or half-​cousin) of Charles
Darwin.6 The last child of nine in a wealthy family, his father died when he was in
his early 20s, leaving him enough money to devote his life to his passion, science.
Among other ideas, Galton was intrigued by individual differences and thought
that everything, from beauty and intelligence to the effect of prayer, should be mea-
surable. His research made significant advances in numerous fields, from geography,
meteorology (he was the first to describe an anticyclone), and exploring to psychol-
ogy and statistical methods. His particular interest in individual differences was
no doubt the driving force not only for his work on reaction times, but also for his
invention of fingerprints as a means of identification.
In 1884, Galton set up his first anthropological measurement laboratory in the
International Health Exhibition (IHE), held under the patronage of Her Majesty
Queen Victoria in South Kensington, London. The purpose of the series of interna-
tional exhibitions that were held in London starting with the Fisheries Exhibition
in 1883 was, as described in the official catalogue of the IHE, to satisfy the interest of
the public in subjects of paramount importance to the community. By dealing with
the topic of “Health, Both Bodily and Mental,” the aim was to cover all aspects of
what constituted a healthful life, suggesting, as the slogan of the exhibition phrased
it, “From labour health, from health contentment springs.”
The catalogue makes fascinating reading. The two main divisions of the
exhibition—​Health and Education—​covered groups of specialized stands on food;
clothing; dwellings (including water supply and drainage, lighting, ventilation, and
reduction of smoke and combustion products); crèches; primary schools; art teach-
ing; apprenticeship schools; schools for the blind, deaf and dumb; and gyms, physi-
cal education, and sanitary requirements for school buildings. Exhibits included
ideal public health laboratories, ambulances, workshops, and models of the London
water supply system.
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86 Toxic Cocktail

It seems that Sir Francis set up his laboratory to take advantage of the thousands
of visitors and to acquire the maximum number of measurements of “Human Form
and Faculty,” as quoted by Johnson et al. [16]. Intriguingly, the individuals tested
paid for the tests, as Galton thought they would be interested in their performance,
in the same way that designers of self-​tracking and self-​measuring apps today know
that consumers will pay to be told how they are doing compared to others—​possibly
a basic human need or motivation. From early on, Galton’s preoccupation with the
idea that everything should be measurable led him to realize that the validity of any
statistic was largely a function of sample size and how cofounding factors are taken
into account, again a concern of scientists and epidemiologists setting up cohorts
today. With this in mind, he accumulated data on over 1,700 people of all ages and
walks of life in the IHE laboratory he set up later in the magnificent Romanesque
South Kensington Museum (now the Natural History Museum), opened in 1881 on
the site of earlier international exhibitions.
However, what Galton lacked compared to today’s scientists was the computer
power to analyze the mountains of results generated. This limitation meant that
despite efforts to tackle certain aspects of the data in the 1920s and 1930s, it was
not until Johnson and colleagues were given access to photocopies of the data in
the 1980s, the better part of a century later, that the data, and most important the
methodology, could be fully exploited.
Galton was clearly influenced by Darwin’s thinking, in that he argued strongly
that the hereditary component to character and intelligence outweighed that of the
environment, leading to the founding of the eugenics movement around 1883, which
was 30 years after the publication of the Origin of Species [17]. In passing, it should be
noted that Darwin himself was anything but a eugenicist, with his Descent of Man,
published in 1871 [18], representing a culmination of research largely motivated by a
belief in racial equivalence, in line with the drive for the abolition of slavery promi-
nent in Great Britain at that time and in which the Darwin family was very active.7
Today, eugenics has acquired strongly negative associations, particularly stem-
ming from the idea that selection, by allowing reproduction between the “best” ele-
ments in a population, should lead to superior physical and mental fitness of the
descendants. These concepts are also relevant to many contemporary discussions,
including the ethics of embryo selection, the use of genetic technology to edit
unborn children’s genes, and the reproductive rights of minorities such as the intel-
lectually disabled.
Many examples on the unpredictability of results arising from genetic technol-
ogy come from the genetic engineering of farm animals. For instance, some breed-
ers believed it would make sense to introduce the gene for growth hormone into
pigs or salmon, the simplistic idea being that the animals would use their feed more
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Losing It: Undoing Brain Evolution 87

efficiently and grow faster. The first experiments, carried out in the 1990s, were soon
abandoned as the pigs, like other animals on which these experiments were tried
out, had problems with their bones, immune systems, and kidneys. Most often, the
end result was early death. None of these projects was a commercial success.
We can take the argument further by addressing the ethical problems raised
today by in vitro fertilization embryo selection and by asking how far one should
go in genetic counseling of future parents. As underlined by the title of an article
in Nature 20 years ago, “When Is Prenatal Diagnosis ‘Eugenics’?” [19]. The ques-
tion is certainly a valid one. Genetic selection is allowed in many countries for cer-
tain genetic conditions—​for instance, in the United States for Down syndrome.
Even so, some authors consider these actions to be a new form of eugenics or
“neoeugenics” [20].
These ideas bring us back to Woodley and colleagues, although in its obverse
form of dysgenics as opposed to eugenics. Whereas eugenics, put simply, is the
selective breeding of people with supposedly desirable qualities such as intelli-
gence, “dysgenics” is higher reproductive rates in people with what could be termed
“lesser” qualities. In fact, Woodley did not use the term eugenics at all or refer to
racial or ethnic differences because the data sets used do not mention these distinc-
tions. However, he did use the term dysgenics and argued that genetic causes and
not environmental factors have driven the 14-​point loss in IQ score that he and his
fellow authors documented. Woodley argued that the last century’s improvements
in public health have enabled survival and reproduction of increasing numbers of
less-​healthy and less-​intelligent individuals. In Victorian times, the wealthier (and
better-​educated) members of society had the greatest numbers of surviving chil-
dren. Woodley argued that such a situation is no longer the case today; in many
societies those with the better socioeconomic status and education have fewer chil-
dren, hence, the emphasis of the dysgenic argument and the rejection of environ-
mental, or phenotypic, factors.
Apart from the considerations already mentioned, a number of problems are
associated with the dysgenic argument as the cause of IQ loss. First and foremost,
it smacks strongly of biological determinism and genetic determinism or the over-
riding influence of genes compared to that of the environment. Many authors have
written excellent critiques of biological determinism, including Richard Lewontin,
Steven Rose, and Leon Kamin [21]. There is solid evidence that genes and intel-
ligence are not simple linear associations. As discussed in Chapter 6, when we deal
with epigenetics and how it could related to the causes of autism, even in identical
twins (with exactly the same gene sets) there can be significant differences in IQ as
well as verbal reasoning [22]. These differences may be explained in part through
prenatal placental blood supply and nutrition modulating gene expression and
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88 Toxic Cocktail

growth. But, these differences also underscore how important environmental fac-
tors can be in determining physical and mental health outcomes of a given gene set.
Second, not only did Woodley and colleagues see dysgenics as the driving fac-
tor, they also considered that environmental factors do not enter into the equation.
They argued that, if anything, since the ban on lead in petrol, environmental factors
adversely affecting brain growth are decreasing. As we will see, this is an erroneous
oversimplification, and environmental factors could equally well, if not more prob-
ably, be exerting harmful effects on general brain development. Blood levels of one
of the main environmental culprits, the heavy metal lead, may well be decreasing,
but that of other chemicals known to affect IQ, such as organophosphate pesticides
[23] and other biocides, industrial chemicals (polychlorinated biphenyls [PCBs]),
phthalates, bisphenol A, (BPA), flame retardants, and surfactants are almost cer-
tainly exerting cocktail effects that adversely affect brain development. As all of
these chemical groups can affect thyroid hormone action, an endocrine factor essen-
tial for normal brain development, thyroid hormone disruption is a front-​line candi-
date for effects on reaction time, notably through myelination—​a point we return
to further in this section.
While discussing genetic causes, it is important to underline that many studies
involving people—​such as those studies determining IQ—​categorize subjects on
the basis of ethnic origins. This categorization is understandable in some instances.
The US CDC (http://​w ww.cdc.gov/​), which provides data on American health,
breaks down data sets according to racial/​ethnic origins, with the main ones being
Hispanic, non-​Hispanic black, non-​Hispanic white, non-​Hispanic Asian, non-​
Hispanic American Indian/​A laska Native. Obviously, such distinctions used in the
context of epidemiology allow social and geographical disparities to be determined
and so permit focus on efforts to correct them. However, as for any data set, distinc-
tions made on the basis of racial/​ethnic origins, educational level, or socioeconomic
class can be misused.
The Woodley article received a number of criticisms by fellow psychologists,
including Silverman and Flynn. Some critics wondered whether the methods used
by Galton to determine reaction time were less accurate than the electronic methods
used for most of the more recent tests. However, this does not seem to be the case as
certain authors have even rebuilt the apparatus used by Galton. Another important
question raised by critics is what reaction times actually represent in terms of brain
function and neurophysiology. How can a measure of the speed at which a person
reacts to a visual stimulus with an appropriate movement be equated with intel-
ligence? Or, to take this question further, how can data on reaction time be used
to derive a measure of general intelligence, g, first defined by Charles Spearman as
discussed in this chapter. According to Woodley, it was Jensen who on numerous
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Losing It: Undoing Brain Evolution 89

occasions suggested that the speed of reaction be used as a biological marker of dif-
ferent neuronal mechanisms critical for brain function, neurophysiological activity,
and hence general intelligence. In fact, many other respected researchers in com-
parative aspects of psychology have used reaction time as a measure of intelligence,
including Professor Ian Deary from Edinburgh University. One of Deary’s interests,
among others, is the biology of aging and especially cognition during aging, and he
has extensively exploited reaction time data to investigate links between intelligence
and longevity.8
The link between mechanisms underlying neurophysiological activity and gen-
eral intelligence led Woodley and colleagues to reflect on how dysgenics could be
acting to reduce brain function. More specifically, they asked the question in terms
of which genes and which processes. One of the processes they highlighted, quite
justifiably, was myelination. As explained in the first section of this chapter, myelin
speeds up rates of transfer of neuronal signals. So, myelin thickness is a key ele-
ment of reaction times, affecting both the speed of the brain’s registering that a light
source has come on and the response, pressing a button. One of the major effects
of hypothyroidism (lack of thyroid hormone) during development is insufficient
myelin formation. Thyroid hormone activates numerous genes essential for myelin
production and ensures maturation of the specialized cells that produce myelin
[24,  25]. These facts support the hypothesis that chemicals affecting thyroid hor-
mone signaling will reduce myelination and lengthen reaction times. Such effects
could well contribute to the decrease in general intelligence observed in Woodley’s
studies.
A final criticism against the dysgenic arguments and their associated reduction-
ist, genetic view of intelligence is the increased knowledge we have with respect to
epigenetics as one of the major processes through which environmental factors can
modulate gene expression. These ideas are discussed in more detail in Chapter 6.
Woodley and Silverman’s key common result was that, on the basis of increased
reaction times, there has been a decrease in IQ of 1.23 points per decade, produc-
ing a loss of 14 points between Victorian times and today. Such a decrease in IQ
may seem impossible to many. Yet, Michael Woodley’s article is not the only one
to report important decreases in IQ in the latter part of the 20th century. Another
article that provides interesting results and a perspective on cognitive declines in
the United Kingdom between 1975 and 2003 is that of Shayer and colleagues [26].
Between 2000 and 2003, they tested 69 sets of year 7 students, giving a total sample
size of 10,023 students. In particular, they used tests developed by the renowned
Swiss developmental psychologist Jean Piaget (1896–​1980). Piaget was interested in
how children develop their thinking capacities. One reasoning test used is known
as the “Volume and Heaviness” test, and it assesses how children conceive of relative
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90 Toxic Cocktail

weights and volumes. For instance, in part of the test, the child will be given a block
of metal such as brass and a solid block of plastic with exactly the same volume and
asked if the brass bar will displace more, less, or the same amount of water when
placed in a measuring cylinder. Of course, the answer is “the same,” as it is the vol-
ume of the block and not its weight that determines how much water is displaced.
The average success rate for 12-​year-​old boys in this test in 1975/​1976 was 54%, and
this had dropped to an astonishing 17% by 2002. Taking the results of the 10 sub-
tests together, Shayer and his colleagues concluded that the supposed Flynn effect
on general increases in IQ was seriously compromised by these results.
More recently, using a similar approach to that of Woodley and his coauthors,
Jakob Pietschnig and Martin Voracek reanalyzed numerous data sets on IQ from
1909 to 2013 [27]. Despite observing a clear Flynn effect over the century, with the
most marked increases between 1920 and 1940, they made some interesting obser-
vations on the overall gain. First, they noted that when comparing tests carried out
on children and adults (with appropriate level tests for each), the gains were greater
for adults than children. This result suggests that the increases previously observed
were not maintained in following generations. Second, they noted decreased gains
in recent decades, potentially indicating a reversal of IQ gains as reported by others.
One of the publications cited by Pietschnig and Voracek is an analysis of IQ in
military conscripts in Finland [28]. Finland is of interest to this discussion from
a number of points of view. First, as Silverman pointed out in his analysis [15],
only one study in recent times, a Finnish study on military recruits done in 1991,
actually showed reaction times in the same range as those observed by Galton.
Second, Finland is one of the most consistently highest scorers in the Program
for International Student Assessment (PISA) tests run by the Organization for
Economic Cooperation and Development (OECD). Third, it is also one of the few
European and North American countries to have maintained military service into
the 21st century. Finland thus represents a highly successful system of education with
a means of comparing IQ over recent decades. In their 2013 publication, Dutton and
Lynn [28] compared Finnish conscript data from 1988 to 2009. They noted that the
second period examined, 1997–​2006, showed a decrease of 2 IQ points in all the
tests used to assess IQ. Dutton and Lynn noted that similar negative Flynn effects
have been reported in six other European countries and in Australia.
A similar loss of capacity in young adults has been reported by the OECD.
In 2013, they published a comparison of adult skills across 24 of the wealthier
countries.9 In this report, the literacy and numeracy skills of the younger UK
adults (between ages 16 and 24)  were found to be the lowest of the UK adult
population. More disquieting was the finding that the United Kingdom was the
only developed country in which this group of young adults had lower skills than
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Losing It: Undoing Brain Evolution 91

those of retirement age. In the United States, the numeracy skills of 55-​to 65-​year-​
olds were on average similar to those in the other countries assessed. In contrast,
the scores for 16-​to 24-​year-​olds were the lowest of all the countries examined.
Clearly, this is a multifactorial situation with a spectrum of causes to be taken
into account, from economic changes, size of classes, curricula taught, teacher
training, school and home environments, nutrition, and, of course, increased use
of electronic devices. However, as the OECD emphasized, whatever the cause,
for many countries, the skill sets of future generations are set to decline unless
something is done about it. I obviously ask whether exposure to different chemi-
cals affecting thyroid signaling might be contributing. With respect to the data
from the United Kingdom, one may also wonder to what extent the documented
iodine lack in England [29] is implicated. As we saw in Chapter 1, iodine is an
essential component of thyroid hormone. Lack of iodine reduces amounts of thy-
roid hormone needed for brain development. What is more, iodine deficiency is
increasing in many countries worldwide.
All this brings us back to the point made at the beginning of this chapter, namely,
that whether or not there is an overall Flynn effect today or an anti-​Flynn effect,
chemical pollution or iodine lack will be eroding the former and exacerbating the
latter. In other words, if there is a Flynn effect with a trend to increasing intelli-
gence, then the increase would be greater if it were not for chemical pollution affect-
ing thyroid signaling. On the contrary, if we are observing an anti-​Flynn effect, and
even if it involves dysgenic components as suggested by Woodley and colleagues,
then thyroid disruption will be making matters worse.
92
  93

5
The Alarming Increase in Autism

Paris–​M arseille, May 2015

It’s 5:30 in the morning when I leave my flat. I’m surprised to find myself serenaded
by a polyphonic dawn chorus. Even in downtown Paris, we still can enjoy the beauty
of the blackbird-​dominated daily vocal challenges. But, given my current preoccu-
pations, the melodies’ magic is somewhat dampened by thoughts of Rachel Carson’s
foreboding of a spring when no birds would sing. As I set out, my ideas go quickly
from the effects of chemical pollution on birds and wildlife, to associations of the
same chemicals with brain development and disease, the topic of a talk I’m giving in
Marseille later that morning.
Grabbing a takeaway espresso, I board the high-​speed train. Soon after 9, I’ll be
there. Speeding through 660 kilometers of ever-​changing landscapes, open pastures
spotted with white Charolais cattle, and brilliant yellow gorse bushes surrounding
red-​roofed Beaujolais villages, we skirt Lyon and head straight into the heart of what
was once the largest port on the Mediterranean. A brief glimpse of the sea from the
taxi while leaving the station brings to mind thoughts of Phoenician navigators, cen-
turies of exchanges between civilizations and the less-​happy trans-​Mediterranean
migrations of the early 21st century. But, I won’t be spending much time reflecting
on history, ancient or modern, or gazing out to sea today. What I will get is a better
perspective on Yehezkel Ben-​Ari’s theory of chloride equilibrium in the brain and
its implication in autism spectrum disorders (ASDs). Professor Ben-​Ari has invited

93
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94 Toxic Cocktail

me to his institute to present my ideas on environmental factors as potential causes

of neurodevelopmental diseases and to discuss his theories on the subject. I have a
feeling we’ll find lots of common ground—​and indeed we did.

Oxytocin and autism: a multifaceted enigma

Ben, as he’s called in French academia, is a highly original and colorful personal-
ity. Tall and eloquent, he has a reputation for groundbreaking scientific ideas. His
research focuses on the molecular events that underlie communication between
neurons, especially during brain development. One of his most seminal recent dis-
coveries is that, during birth, the same hormone that induces the contractions of
the womb, oxytocin, also induces spectacular changes in the electrophysiological
properties of an important class of brain neurons [1]‌.
After birth, in the postnatal brain, the activity of these neurons is normally inhib-
ited in response to a major neurotransmitter, gamma-​aminobutyric acid (GABA).
But, oddly enough, before birth these same neurons are actually activated by this
neurotransmitter. During the normal birth process, oxytocin is released by the
mother’s brain into her blood supply. Ben-​Ari’s work on rats has shown that, besides
inducing womb contraction, when oxytocin reaches the brain of the pups about to
be born, oxytocin induces major shifts in the equilibrium of chloride ions inside and
outside the neurons in the pups’ brain. This means that, after delivery, neurons that
previously responded to GABA by being activated are now silenced when GABA is
released.
Therefore, oxytocin does much more than induce womb muscle contractions.
Besides inducing this radical shift in brain chloride equilibrium, it actually acts as
an anesthetic on the baby during the birth; afterward, this same hormone is released
from the mother’s brain to stimulate milk ejection from the breast in response to the
baby’s suckling.
Oxytocin deficiency has been linked to ASD more than once and in a variety
of ways. Probably the main interest in linking oxytocin to autism, besides its role
in birth and brain chlorine balance, derives from the role that the hormone plays
in favoring social interactions [2]‌, not only between mothers and babies but also
between partners. Levels of the hormone or differences in receptor subtypes have
been associated with trust, altruism, and empathy [3]. One of the most newsworthy
reports related that pair bonding in human males (i.e., the tendency to be monoga-
mous toward their partners) could be related to which of the two most common
genetic variant oxytocin receptors their brains produce [4]. It has also been sug-
gested that nasal sprays containing oxytocin improve interactions in autistic
patients, although clinical trials were inconclusive. This negative result is probably
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The Alarming Increase in Autism 95

due to the fact that the need for the hormone in determining brain function and
structure occurs in early development, either prenatally or during birth [1], and pos-
sibly not so much once the brain is formed.
Returning to the effect of oxytocin on chloride balance in the brain during
delivery, Ben-​A ri’s team showed that if a mouse pup (and by inference a human
baby) is not exposed to oxytocin during the birth process, as is the case in an elec-
tive cesarean (or “C”) section when the uterus is not induced to contract, then
the chloride-​based switch from activation to inhibition doesn’t occur. The result
is that neurons that should be silent continue firing and remain constantly active.
This failure to switch to inhibitory mode entails a lot of unruly brain activity.
Many animal models of ASD display problems with the interneuron populations
and their targets, the activity of which should be modulated by oxytocin during
birth. Still more impressive are the results from the clinical trials that Ben-​A ri’s
group instigated. The idea was to find another way to correct the chloride balance
in the brain, and instead of belatedly giving oxytocin (as in the nasal spray trials),
the scientists used a diuretic that increased urine flow. The trials compared chil-
dren’s behavior, social interaction, and attention capacities when given either pla-
cebo or a well-​k nown diuretic. By continually increasing urine flow, the diuretic
also caused chlorine to be excreted; this in turn changed brain levels of chloride
ions. The results showed that the treatment had positive effects on patients’ behav-
ior and interaction. Such palliative treatments provide real hope for children with
ASD and their families.

“Too posh to push”: double jeopardy for autism risk?

In popular jargon today, mothers who choose to give birth by C-​section have been
described as “too posh to push.” Babies born by elective C-​sections are, by defini-
tion, not exposed to the same oxytocin levels as those born by either vaginal deliv-
ery or emergency C-​section. In an emergency C-​section, the baby will most likely
already have undergone a series of oxytocin-​induced contractions during the labor
process that led up to the operation. So, according to Ben-​Ari’s theory, there should
be a significantly higher incidence of ASD in children born by elective cesarean, but
not by emergency cesarean. A report [5]‌appeared in 2015 that reanalyzed published
data testing the association between C-​section and the risk of developing ASD
and attention-​deficit/​hyperactivity disorder (ADHD). The authors did not distin-
guish between elective versus emergency C-​section but found an increased risk for
ASD for children born by C-​section overall. There were far fewer data available for
ADHD, so the link between delivery mode and developmental disease was more
tenuous.
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96 Toxic Cocktail

Clearly, my own theory is that one of the main confounders or contributing

factors is prenatal exposure to pollution, especially thyroid hormone disruptors.
Interestingly, rat pups born to mothers that lack thyroid hormone also have delayed
activation-​to-​inhibition switches in the same interneuron populations and in the
same brain areas as those studied by Ben-​Ari’s team. So, it is probable that exposure
to thyroid-​disrupting chemicals will induce similar effects on chloride equilibrium.
In the meantime, Brazil, a country with inordinately high numbers of women
who choose not to push, has recently changed its legislation to allow private health
insurers to refuse to pay for cesarean deliveries performed without a medical rea-
son,1 such as when there is a risk for the mother or the baby of going through a nor-
mal vaginal delivery. Such could be the case for a difficult breech presentation, when
the head is not in the normal position for birth, or the risk of the womb rupturing at
the level of a scar from a previous cesarean delivery. The World Health Organization
(WHO) considers that C-​sections should only be carried out in about 15% of births.
Currently, Brazil holds the world record for elective C-​sections, at over 50%, with
the United States coming in second at 30%. It is “an epidemic,” as the Brazilian
health minister is quoted as saying. And, the trend really seems to be driven by
either parent’s status or convenience for doctors. In private hospitals, the rate hovers
between 80% and 90% of deliveries, whereas it is closer to 40% in public hospitals.
If, as appears to be the case, many wealthier Brazilians are indeed too posh to push,
then the consequences for their descendants could be alarming.
Another factor possibly linked to the C-​section and ASD hypothesis is the gut
microbiome, the essential bacteria inside our intestines. Today, we know that no
less than 90% of the cells in our bodies are in fact bacteria in the gut microbiome.
This key component in our physiology contributes to the correct functioning of our
immune system, our digestion, and even our brain activity. The increased knowl-
edge of the role these microbes play in how our bodies’ function has been considered
by some to be the greatest advance in scientific understanding this century.2 But,
what’s this got to do with C-​sections and ASD risk? Well, when a woman goes into
labor, the contractions get stronger until the amniotic sac around the baby breaks,
usually referred to as “the waters breaking.” With the rupture of the membranes
around the baby, the bacteria in the mother’s vagina, which are similar to some of
the bacteria in the mother’s gut, will get into the womb, and the baby’s gut will
be populated by the mother’s microbiological flora. So, babies born by planned
C-​section aren’t exposed to the mother’s bacteria on the way out. These babies are
actually missing a vital contribution to their physiology because a dose of the mother’s
bacteria kick-​starts not only the baby’s digestive system but also its immune system.
A final point on the association between C-​section and neurodevelopmental dis-
ease risk is that elective sections are usually carried out a couple of weeks before the
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The Alarming Increase in Autism 97

calculated end of pregnancy, mostly to avoid the mother going into natural child-
birth. Consequently, the last 2 or 3 weeks of growth in the womb, considered to be
essential to brain maturation, are cut short. Many statistical analyses show signifi-
cant links between premature births and ASD risk [6]‌.
So, if we bring together Ben-​Ari’s oxytocin/​chloride link with induced, slightly
premature births, the microbiota theory, and the thyroid hormone–​disruptor the-
ory, we already have four sets of “environmental factors” that could be implicated
in ASD etiology (the medical term for “causes”). Their interactions could be signifi-
cant in contributing to the rise in ASD. The first US statistics on ASD frequency,
published in 1975, placed frequency around 1 in 5,000. Ten years later, incidence was
estimated at twice that, 1 in 2,500. Data from the US Centers for Disease Control
and Prevention looking at incidence across a number of US states were published
in 2014. Analyzing these data sets (collected in 2010) on 11 different communities
across the United States, the Autism and Developmental Disabilities Monitoring
(ADDM) group3 showed the estimated incidence (see Figure 5.1) [7]‌reached 1 in 68
children and 1 in 42 boys. In one state, New Jersey, the incidence was 1 in 45 chil-
dren and 1 in 27 boys. Thus, if one compares the statistics published in 2001 against
those published in 2014, incidence had increased fourfold. Worse, as mentioned in
the Introduction, statistics published at the end of 2015 placed incidence of ASD in
the United States at 1 in 45 children [8]. If this current rate of increase (doubling

1 in 68

1 in 88

1 in 110

1 in 150

1 in 166

1 in 250

1 in 500
1 in 2500
1 in 5000

1975 1985 1995 2001 2004 2007 2009 2012 2014

Figure 5.1  The ever-​i ncreasing incidence of ASD. Neither the diagnostic criteria for ASD nor the
human genome have changed since 2000. Yet, in this period, ASD incidence in the US population
has increased nearly fourfold. Similar increases are documented in other countries where data
are available.
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98 Toxic Cocktail

every 6 or 7 years) is maintained to 2042, then 1 in every 2 children born will suffer
from ASD. Or, as calculated and publicized by some researchers, if the exponen-
tial curve is followed (i.e., an accelerating rate of increase), the 1-​in-​2 figure will be
reached by 2025. I sincerely hope the curve flattens before then.
It is important to note at this point that about 95% of the money targeted for ASD
research goes directly to research aimed at finding genetic causes for the disease [9]‌.
Most of the time, this money will be used to carry out genome-​wide sequencing
efforts on children and their parents. As we all know, the human genome cannot
have changed significantly in the last decades. And yet, the increases we are seeing
occur despite no change in diagnostic method since 2000 [7]. If there are genetic
susceptibilities, then environmental factors must be exacerbating their effects, a
point we return to further in detail in Chapter 6 when we discuss epigenetics.
In parallel to the increase in ASD, there are even more marked increases docu-
mented in ADHD. Here, the genetic causes are even more elusive. Different esti-
mates place the incidence of ADHD in both the United States and Europe at
around 10% of children.
In the next section, we take a look at the history of ASD and ADHD and the
doctors who defined the symptoms. We’ll see that, at least for ASD, the origi-
nal theories erroneously placed the onus on the immediate family environment,
especially the mother’s relation to the child. Then, in recent decades the emphasis
has become increasingly gene driven. In the next chapter, we’ll try to understand
how the gene-​centered theories of ASD have arisen and, more important, why
they have become so dominant over other potential explanations and evidence.
We’ll also see how new knowledge of epigenetic4 mechanisms is at once shedding
light on the debate and making us more aware of the potential effects carried
over from one generation to another through these same mechanisms. But, let’s
start with the history of the discoveries of the disorders and how the first ideas
about family environment and autism were formulated and, in some cases, the
damage done.

Dr. Kanner’s canny intuition

In 1943, a New York–​based psychiatrist, Leo Kanner, described a new syndrome in

which affected children displayed “inborn disturbances of affective contact.” His
original article describing the syndrome was republished in 1968 [10] and is available
for consultation on the web. Titled “Autistic Disturbances of Affective Contact,”
the article used the word autism for the first time and permanently linked Kanner
with the disease. In fact, autism was originally referred to as Kanner syndrome.
A number of the detailed observations made and discussed by Kanner retain their
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The Alarming Increase in Autism 99

pertinence today. Not the least is the fact that he predicted the condition to have a
higher incidence than suggested on his small sample size.
It’s worth taking a brief look at his biography because it provides a glimpse of
the political turmoil of Eastern Europe at the turn of the 20th century, turmoil
that continues today in different guises. A portrait, probably done late in life and
reproduced in Neumarker’s account of Kanner’s time in Berlin [11], shows a rather
sad-​looking individual. Here was a man who had had three nationalities by his 30s
and probably had taken an uncomfortably close look at many human foibles. Born
in 1884 to an Orthodox Jewish family in Kleketow, a village in Galicia (then part
of the Austro-​Hungarian Empire not far from the Polish border [11] and today part
of Ukraine), Kanner moved to Berlin in 1906. His hopes to live by his pen, writing
poetry [12], were soon replaced by more realistic ambitions.
On the eve of the First World War, he registered as a medical student and attended
lectures by leading figures, in the fields of not only anatomy and medicine but also
theology [11]. As he was born Austrian, when war broke out he had to carry out
his military service as a medical officer in the Austrian-​Hungarian Army. Despite
the responsibilities, he managed to continue his studies. On qualifying in 1919, he
changed his nationality from Austrian to Prussian (German) to be able to practice.
He took a position as an assistant in cardiology at the Charité Hospital in Berlin,
then as now an internationally recognized center for excellence in clinical research
and teaching.
Kanner presciently realized that, given the political situation, his professional life
would be easier in the United States. So, with his wife and 1-​year-​old daughter, he
moved there in 1924, taking up a position in a state hospital in South Dakota. It was
there that he started to develop his interest in child psychiatry [12] before complet-
ing a fellowship in the subject in 1928 at the Johns Hopkins Hospital in Baltimore.
That year, the director asked him to direct what was to be the first children’s psy-
chiatric service in America. In 1943, he published his seminal article, the first to use
the term autism.
This article relates how Kanner established the new syndrome by observing 11
children, each with “fascinating peculiarities,” but sharing an “inability to relate
themselves … to people and situations from the beginning of life”5 [10, p. 242]. One
of the little boys, Donald, showed no interest in candy and ice cream, spent hours
repeating stereotyped gestures or movements such as spinning blocks, and was obvi-
ously happiest when left alone. Yet, according to his parents, by the age of 2 he could
count to 100 and recite the alphabet forward and backward—​surely not unintel-
ligent but, as Kanner said, “peculiar.” Donald’s aversion to social interaction, or as
Kanner phrased it, lack of “social awareness” or “extreme autistic aloneness,” is prob-
ably the basis for his choice of the term autism to define his new syndrome. Autism
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derives from the Greek autos or “self” and ismos or “state.” The term was apparently
first introduced into the medical literature by the 19th-​century Swiss psychiatrist
Paul Bleuler.
Returning to Kanner’s intuition about the frequency of the disease, as he stated
in his article [10, p. 242], although he only described 11 examples, the syndrome “is
probably more frequent than indicated by the paucity of observed cases.” However,
one thing Kanner could not predict was the exponential increase in incidence seen
since 1975. The first statistics on ASD frequency carried out then, a few years before
his death in 1981, placed frequency around 1 in 5,000, whereas, as mentioned in the
section Too Posh to Push, the incidence has now reached 1 in 45 children [8]‌.
In 1943, Kanner also identified the three common traits that characterize the
syndrome:  problems with communication, repetitive behavior, and lack of social
interaction. These features have provided the core of ASD diagnosis for over half a
century and are still part of the diagnosis today (see the Diagnostic and Statistical
Manual of Mental Disorders, 5th edition [DSM-​5] [13]).
Another key point in Kanner’s original article is the “inborn” nature of the condi-
tion, that is, the fact that it is present at birth and is not the result of inappropriate
parenting. Unfortunately, despite his insistence that the children diagnosed had an
innate incapacity to interact affectively with their parents, following Kanner’s pub-
lication many parents, particularly mothers, were made to feel that their children’s
autistic behavior stemmed from their own failure to interact sufficiently with them.
The idea, later enshrined in the notion of the cold or “refrigerator” mother [14], pos-
sibly derived from Kanner’s observation that in the group studied there were “very
few really warmhearted fathers and mothers.” In turn, the concept was taken up by
many leading psychologists and psychoanalysts as a causative factor in the etiology
of the disease, and it recalls the old dichotomy of nature versus nurture with, on this
interpretation, the parents’ nurturing overriding the child’s nature.
Kanner’s further observation, which still holds with today’s statistics and knowl-
edge, concerns the ratio of affected boys to affected girls. Eight of the eleven children
in Kanner’s group were boys, and, interestingly, they were all brought to Kanner
for diagnosis and treatment at a much earlier age than the three girls. The average
age of the boys was just under 4 years (age range 2–​6 years), while that of the girls
was 9 years old (7, 8, and 11 years). As will be regularly emphasized, boys are diag-
nosed with autistic characteristics about four to five times more frequently than
girls. Some ideas on why girls are less frequently diagnosed with ASD and ADHD
are discussed in the next chapter, when we consider the evidence for genetic causes
of the disorders.
Another aspect of Kanner’s commentary that still has significant resonance
is that many of the symptoms could have led, and sometimes did, to a diagnosis
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The Alarming Increase in Autism 101

of childhood schizophrenia. Both disorders cover a large spectrum of symptoms

and phenotypes. Autism, like schizophrenia, is often termed an umbrella disease
because of its wide range of possible forms, with ASD covering a range of behav-
ioral disorders and intellectual abilities. A number of current areas of research are
showing overlap between ASD and schizophrenia, notably in terms of genetic sus-
ceptibility, similar neurological deficits, treatments [15], and—​of obvious relevance
to our discussion—​underlying problems with thyroid hormone signaling. Animals
lacking thyroid hormone are used as a model for autism, and there is an increased
risk of ASD in children born to hypothyroid mothers [16,  17]. Similarly, various
authors have described the multiple links between modified thyroid hormone sig-
naling and schizophrenia [18]. An important common idea is the link between thy-
roid hormone and environmental influence. In fact, a number of genes associated
with schizophrenia are also thyroid hormone–​regulated genes [19].
A final point is that the parents who consulted Kanner were all described as
“highly intelligent,” with most of the fathers having academic, research, or legal
backgrounds and with 9 of the 11 mothers having a college education. This dispro-
portionate frequency of ASD among the children of those engaged in knowledge
work has today almost come to be expected, although there are few data to support
the idea. Also, when appraising the families described in Kanner’s observations, we
should take into account the cost of consulting a highly reputed psychiatrist in the
United States in the late 1930s or early 1940s, which would likely to have been pro-
hibitive for parents with lower incomes.

Drs. Asperger and Rett add to the complexity

During the same period that Kanner was noting the “peculiarities” of his 11 patients,
another Austrian psychiatrist, Hans Asperger, was examining children displaying
similar asocial characteristics. As many authors have underlined, the main differ-
ence between Kanner’s subjects and the four boys studied by Asperger in Vienna was
that the latter all had normal intelligence and use of language. However, they had a
tendency to speak in monologues [20]. In contrast, three of Kanner’s cases were so
withdrawn that they did not speak. This difference in language skills, potentially
reflecting higher intellectual capacity, in conjunction with the shared repetitive
behavior and lack of social communication skills, has led to the idea that Asperger’s
syndrome constitutes the “high-​functioning” end of the autism spectrum.
Rett’s syndrome is another neurodevelopmental disorder that is classified under
the umbrella of ASD, as patients share a number of autistic features, including with-
drawal and eye gaze avoidance. This syndrome has a number of distinctive and dis-
turbing features. One of the most characteristic, which occurs in the early stages
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of the disease, is repetitive handwringing caused by loss of controlled hand move-

ment. It was this feature that was spotted by yet another Viennese pediatrician,
Dr. Andreas Rett, in the mid-​1960s. In 1966, Rett published a paper in German in
which he described a group of 22 patients, all girls. However, the English-​speaking
community only became fully aware of the syndrome in 1983 when a Swedish physi-
cian reported the condition in 35 girls [21]. Even though the defective gene respon-
sible for the condition is expressed in all cells, brain cells are the most affected. This
is why the symptoms of intellectual disability and loss of purposeful movements
and speech are the most characteristic features. One of the most distressing charac-
teristics of the disease for parents of the girls affected is that they show apparently
normal development for the first year of life, but then their development stagnates
before a slow deterioration sets in over the next 20 years. The girls often die of respi-
ratory failure. Fortunately, the incidence of Rett’s syndrome is low, fewer than 1 in
10,000 live births (in girls), only a tiny fraction of the figure for ASD.
The reason why Rett’s syndrome is mostly found in girls is because the gene respon-
sible for most cases of the disorder, MEPC2, is located on one of the two female chro-
mosomes, the X chromosomes. Boys have one X chromosome and a Y chromosome.
If a mutation occurs, they have no backup copy and so they rarely survive.

Sir George Still makes the first diagnosis of ADHD?

According to the American Psychiatric Association,6 the current reference work

on psychiatric disorders, DSM-​5, describes ADHD as a pattern of behavior that
falls into two categories of symptoms: inattention and/​or hyperactivity and impul-
sivity. For the diagnosis to be made, six characteristic behavior patterns should be
recorded, ranging from difficulty sustaining attention, failure to pay close attention
to details, problems organizing activities and tasks, excessive talking, and fidgeting,
to difficulty sitting still.7 A layperson’s description might use terms such as “overac-
tive” or “turbulent” or “unable to focus.” To be conclusive, such patterns need to be
observed in at least two settings, usually home and school. Like ASD, the incidence
of diagnosis fluctuates but shows a clear upward trend over the last 50 years.
In fact, closer scrutiny of the psychiatric literature over a couple of centuries
reveals accounts of children with similar features. Most authors attribute the first
description to Sir George Still (1868–​1941), who classified pathological hyperactiv-
ity as “a defect of moral control”! Still is generally considered to be the founder of
the study of children’s diseases, pediatrics.
An excellent, comprehensive historical account has been given by a group of
authors [22] who provide details of observations that pre-​dated the work of Still,
where children displayed many symptoms in common with those used to diagnose
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The Alarming Increase in Autism 103

ADHD today. In particular, they cited the work of an Edinburgh practitioner, Sir
Alexander Crichton, who published in 1798 a three-​volume treatise on mental ill-
ness. Crichton had studied medicine in Leiden and practiced in three different
European cities, two of which have particular resonance for their schools of psy-
chiatry and psychoanalysis: Paris and Vienna, the latter, as we have seen, where Rett
and Asperger practiced. In the second volume of Crichton’s treatise, he described
his observations of children with one of the main symptoms of what today would
be classified as ADHD, that is, the incapacity to attend with constancy to any one
object and frequently changing the object of their attentions. Crichton presciently
reflected that the condition could be inborn or may develop later, was due to ner-
vous hypersensitivity, and made education difficult. He also observed that symp-
toms generally lessened with age. This idea that the symptoms of ADHD attenuate
with age was generally accepted until recently. However, numerous studies are
showing its persistence in late adolescents and adults, with adverse effects on work
capacity [23, 24].
A timeline of disease incidence published on the US Centers for Disease Control
and Prevention (CDC) site gives data on numbers of children affected with the
dates that different drugs to treat the disease were brought to the market.8 The data
on incidence dates to the early 1970s. At that time, estimates put the number of
children affected at about 5% (5 of 100). Then, just 10 years later, surveys carried out
in 1982 and 1983 came up with figures at double those levels, with incidence reaching
nearly 12 children in a group of 100.
It is interesting to note that it was exactly at this time, 1982, that a new, slow-​
release form of Ritalin (the commercial name for methylphenidate) was introduced
as a treatment for ADHD. This form, Ritalin-​SR, is more slowly absorbed by the
body and so is supposed to maintain more constant blood levels compared to the
standard form. The indications for Ritalin and Ritalin-​SR prescriptions can be
found on the Internet.9 Described as a stimulant of the nervous system, it’s interest-
ing (and more than a little worrying) that it is not really known how the drug acts.
Given that, as a stimulant, it will be like taking caffeine or amphetamines, it’s hard
to see how it helps children control their behavior.
A recent review of the question, published in an excellent journal [25], starts out
by commenting that for decades drugs used as stimulants could also induce cogni-
tive defects.10 The authors proposed that response to the drug (in this case, nervous
system stimulation) is a function of dose. This means that the stimulant effect occurs
at a certain dose level, with low doses having no effect and high doses inhibiting
the response. These types of responses to drugs are often referred to as “inverse U-​
shaped” dose-​response curves—​because they are like an upside-​down letter U. Such
responses are commonly observed in natural physiological and endocrine responses
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and in responses to endocrine-​disrupting chemicals (EDCs) [26]. So, in the case of

ADHD and Ritalin, the idea could be that the high concentrations of the drug push
the body’s overactive stimulatory activity into an inhibitory zone [25].
According to a 2012 Guardian newspaper report,11 prescriptions of Ritalin in the
United Kingdom increased fourfold over the period 2000–​2010, with 90% of the
prescriptions being for school-​aged children, some as young as 3 years. The article
quoted a representative of the Association of Educational Psychologists as stating
that there was particular concern that, as effects wear off, increasing doses had to be
used and that often Ritalin would be given as part of a cocktail with other drugs,
about which there is insufficient knowledge of the possible combined effects. Ritalin
prescription has long been questioned, in terms of both its long-​term effects on the
children and the potential overdiagnosis of ADHD resulting from the marketing
campaign for the drug.
In the years following the introduction of Ritalin-​SR (early 1980s), ADHD
incidence fluctuated between 4% and 16%, seemingly as a function of diagnos-
tic method. No doubt because of these large variations, the National Survey of
Children’s Health (NSCH) was begun in the early 2000s. Using standardized diag-
nostic methods, the first NSCH report put ADHD incidence at 8% in 2004, then
10% in 2007, and around 11.5% in 2011—​a slow but steady increase that makes one
think of the increase in ASD. Although the increase was not as steep as with ASD,
which grew threefold from less than 0.5% in 2004 to 1.5% in 2010, it is still signifi-
cant. Also, given the sheer numbers of children affected, over 10% of US children,
one has to consider not only the effects on these children (and perhaps the effects of
overmedication on some of them), but also the effects on their parents, their school-
ing, their teachers, and society.

And dyslexia?

The incidence of dyslexia is increasing worldwide. According to association web-

sites in the United States and the United Kingdom, incidence can be as high as 15%
or more. Estimating incidence can be confused by the overlap of symptoms with
ADHD. Generally, children with dyslexia have different types of reading difficul-
ties (or problems with arithmetic) despite normal intelligence. Not surprisingly,
children with reading difficulties will have decreased attention spans and tend to be
less assiduous. The fact that in many countries testing often involves financial outlay
by parents will lead to underdiagnosis. But, if a diagnosis is made at the appropri-
ate time, in some education systems children can qualify for extra help at school
and even extra time for exams. Even if there are national detection procedures and
testing for children who are clearly falling behind at school, some children with
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The Alarming Increase in Autism 105

reading and learning difficulties will not be noticed, tested, or diagnosed (or even if
they are noticed, their parents may not be able to afford to pay for dyslexia testing).
Consequently, these children will not receive the extra tuition time and exam time
they need.
Another frightening fact is that significant percentages of prison populations
consist of people with major learning difficulties, such as dyslexia. In the state of
Texas, a group of psychologists tested a randomly selected group of 253 recently
admitted inmates and found that about 50% of them had reading difficulties [27].
The authors contrasted this figure with their estimate of dyslexia at 20% in the gen-
eral population. Katherine Moody12 and her colleagues began their article by saying
that up to 80% of some prison populations are in fact functionally illiterate. Such
statistics are not exactly surprising. A child with reading and learning difficulties,
particularly in socioeconomic communities with little access to remedial help, will
have a higher risk of dropping out of school. The next step will often be problems
with getting a job and taking up a recognized role in society. As they are of normal
intelligence, it is to be expected that their frustration could lead them to find other
ways of surviving in society. Dostoevsky, Dickens, and Balzac have only too vividly
depicted the negative spirals of people with social insertion problems and financial
difficulties, rendering them prone to take up criminal activities.
So, can we identify the neurological problems that specifically underlie dys-
lexia? Are there identifiable features that fit into the spectrum of those seen with
other neurodevelopmental disorders such as ADHD? In fact, it has been estimated
that between 25% and 40% of children with reading difficulties also suffer from
ADHD [28].
As mentioned, one of the key features of dyslexia is reading difficulties [29].
Reading is clearly a human characteristic that has a biological basis, but like spoken
language cannot be acquired outside a social and cultural environment. Researchers
have sought to determine the neurological basis of difficulties with both reading
and mathematics and the overlap between the two. Such studies are facilitated by
the recent improvements in noninvasive brain imaging (MRI or magnetic resonance
imaging), as well as making use of classic behavioral studies.
Vinod Menon, a researcher from Stanford, and two colleagues recently reviewed
a large set of MRI studies addressing the cognitive and neurological basis of how the
brain acquires reading and mathematics skills [29]. They underlined that, in both
cases, the learning process had a common ground in representing and remembering
or retrieving the significance of symbols and forms of pattern recognition. The skill
set will also require attention control and use of working memory. With reading
difficulties, the questions of sound recognition and processing are also implicated.
Menon and colleagues started from the premise that reading difficulties will have
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106 Toxic Cocktail

a neurobiological origin, and that given the complexity of the tasks, different brain
regions will be involved. They cited MRI studies showing that children (and adults)
with reading difficulties have less activation of and less recruitment between neuro-
nal networks in key parts of the brain, especially the left side of the frontal cortex.
These differences may be core, causative features or be the result of the children
having not yet mastered the skill sets—​once again, the chicken-​and-​egg problem.
Other researchers have looked for common genetic causes of dyslexia. At best,
studies showed small effects arising from a small number of genes that will often be
subject to modulation by environmental factors. This result is not surprising given
that dyslexia, like other neurodevelopmental disorders, is often classed as a “complex
multi-​factorial disorder” [30]. We’ll be looking at the genetic studies on ASD and
ADHD in the next chapter, but as few studies exist on the implication of genes in
dyslexia, I’ll cover them briefly here. Studies of families with many cases of dyslexia
led to the identification of the first associated gene [31], DYXC1, which codes for
a protein implicated in neuronal migration during brain development. Since this
pioneering work, a handful of other genes linked to dyslexia have been identified.
Three genes come up regularly in different screens [32] and are implicated in growth
of axons (the connecting structure between one neuron and another) and neuronal
migration.
Whether the neurobiological structures identified as underused are the cause or
the consequence of the neurological problem, and whether certain genes are impli-
cated, reading difficulties are more frequent in children born to mothers who were
iodine or thyroid hormone deficient during pregnancy [33, 34]. So, yet again, thy-
roid hormone deficiency will affect all of the brain development processes identified
as genetically linked in dyslexia [35], as in other neurodevelopmental disorders [36].
Few studies have yet been conducted on environmental exposure to given chemical
categories and dyslexia. Part of the problem is defining the disorder and its overlap
with many other learning difficulties. Here again, the fact that the children (and
adults) with these difficulties have normal intelligence and are not easily spotted
in a class exacerbates the problem. So, it’s important to start researching whether
and how the environment, with or without effects on genetic susceptibilities, can
modulate the neuronal circuits affected in dyslexia [35].

The enigma of increasing congenital hypothyroidism

Along with the surges in ASD and ADHD, more and more children are being born
with disorders affecting thyroid gland development. The clinical term for this syn-
drome is congenital hypothyroidism, which I’ll abbreviate to CH. Increases in CH
numbers are being seen worldwide, from the United States [37] to Japan [38] and
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The Alarming Increase in Autism 107

Mexico [39]. In New York State, CH incidence increased by 138% between 1978 and
2005, whilst across the United States (excluding New York States), the increase was
73% between 1987 and 2002, reaching similar levels to those reported in Mexico,
around 42.2 cases per 100,000 births (1:2,300 births) [40]. The causes of this increas-
ing incidence are subject to debate, but they include diagnostic change, increased
frequency of preterm birth and low birth weight (both of which are characterized
by transient hypothyroidism), and environmental factors. However, many authors
considered that potential environmental risk factors need to be identified [41]. In
some countries, such as Mexico, the rate of CH is clearly correlated with other birth
defects [39], suggesting the implication of environmental factors. The effects of CH
on brain development will depend on the severity of the deficiency and, crucially, on
how soon after birth the thyroid hormone replacement treatment is started.
The rise in CH could in turn be linked to the increases in neurodevelopmental
disorders, and the link could be twofold. First, the lower amounts of thyroid hor-
mone produced by the developing baby with CH will need to be supplemented,
if possible, by the mother’s thyroid hormone; otherwise, brain development will
be affected, and risk of neurodevelopmental disease will increase. Second, chemi-
cals affecting thyroid gland development could also be affecting the action of the
already-​low thyroid hormone levels in the brain.
Why more babies are born with CH is debated. Again, as for ASD, changed diag-
nosis is a possible contributing factor. Three other factors also are often cited: more
babies with low birth weights, more preterm births, and environmental factors as
yet unidentified. In some countries, such as Mexico, the rate of CH is clearly cor-
related with other birth defects [39], strengthening the environmental hypothesis.
In one study carried out in Turkey, despite the fact that many mothers have mild-​to-​
moderate iodine deficiency, most of the mothers of babies born with CH appeared
to have had enough iodine [42]. So, it seems other causes were implicated in the
CH cases. Here again, it should be noted that genetic causes have only been associ-
ated with 2% of the cases of thyroid problems [40], leaving the great majority of
cases with unknown causes, clearly suggesting other environmental factors, such as
chemical exposure.
Abnormalities in thyroid gland formation, or CH, are the most common endo-
crine disorders seen in newborn children. Failure to correct CH or iodine deficiency
remains the leading cause of preventable intellectual disability. The need to diagnose
CH early led to the instigation in the 1970s of thyroid hormone screening in new-
borns (see Chapter 2). One of the indirect advantages of universal screening for CH
was that it provided data on prevalence of the condition, surprisingly constant world-
wide, being 1 in 3,500 births in the 1980s. Overall, the historical expected rate of
CH is around 1 in 3,000 to 4,000 births, with a rate twice as high in girls as in boys.
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108 Toxic Cocktail

Nobody knows why there are more cases among girls. However, the data on inci-
dence in the United States are showing changes in this ratio. For instance, in Texas,
which had a historical rate of 2 girls to 1 boy, the ratio since 2001 has shifted to 1.5 girls
for each boy [37], suggesting that more boys are being born with CH.
Other countries with documented increased rates of CH include New Zealand
and Japan. In Japan, a threefold increase has been reported since screening began
in 1979. One study showed a clear positive association of severity with the moth-
er’s levels of organochlorine pollutants [43]. In this case, a mere twofold increase
in pesticide contamination and a threefold increase in dioxin-​like contamination
compared to controls were found in cases of severe CH, where the individuals con-
cerned had been classed as cretins. Unfortunately, no similar studies on the extent
of maternal chemical burden and incidence of CH are available for other countries.
Until more data are available on the incidence of CH in other countries and
the potential association with chemical exposure is investigated, the enigma of
this increased incidence will remain unsolved. Suffice it to say that if there is an
increase in the number of CH cases, then more subtle disorders of thyroid function
might be occurring during development and could be missed by pediatricians and
health workers. Along with the increased numbers of confirmed CH, such mild
thyroid disorders could also be contributing to the increased incidence of ASD
and ADHD.

Environmental factors and

neurodevelopmental disease

It is notoriously difficult to organize and even more difficult to obtain funding for
running longitudinal or prospective studies of prenatal environmental exposure
and disease incidence. To do so, one has to bring together a large cohort, or set
of patients, in this case mother-​and-​child pairs. Ideally, there should be hundreds
(preferably at least a thousand) of mothers, who then provide blood or urine samples
at different points during their pregnancies. The next step is to maintain contact
with the families and encourage them to stay in the study, enabling the follow-​up
with the children’s behavior many years later. Despite these difficulties, a number of
cohorts have been established, and research groups have been able to determine the
associations between the incidence of ASD and birthing methods (see the section
Too Posh to Push), premature birth, birth weight [44], maternal infection during
pregnancy [45], and maternal thyroid hormone levels or antibodies against thyroid
gland proteins [36, 46, 47].
Nutrition also is important. Besides being clearly linked to IQ loss in children
(see Chapter 1), maternal iodine deficiency has also been associated with increased
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The Alarming Increase in Autism 109

risk for both ASD [48] and ADHD. On the other hand, a protective effect of taking
prenatal vitamins and minerals has been documented [49].
Analyzing risk as a function of exposure to a given set of chemicals is more dif-
ficult. Levels of chemical exposure will show greater distributions than cases of
C-​section or not, presence of infection or not, and whether the child is born pre-
maturely or not. Thyroid hormone levels will often not be the best indicators of
correlation for two reasons. First, there are high individual variations in thyroid
hormone levels. Second, given the number of chemicals to which we are all exposed
today, and the variations in exposure as a function of time, analyzing effects of one
chemical by itself requires large data sets. Despite these difficulties, and the general
paucity of these long-​term studies, when we carried out our study on economic costs
of exposure to endocrine-​disrupting compounds and risk of neurodevelopmental
disease and IQ loss, we were able to find well-​analyzed studies for three categories of
chemicals relating to ASD or ADHD incidence. It’s interesting to note that most of
the articles were published in the last several years, so the epidemiological data are
slowly coming to light.
Risk of developing ADHD was strongly linked to maternal exposure during
pregnancy to the flame retardant polybrominated diphenyl ether (PBDE) in one
study [50] and to organophosphate pesticide exposure in another [51]. Yet another
study linked children’s PBDE levels at the time of testing to ADHD behavior [52].
A European study also showed that PBDE exposure before or after birth was associ-
ated with some symptoms of ADHD [53].
A review of the data on environmental factors and ASD risk appeared in 2014
[54]. The authors found the strongest published evidence for traffic-​related air pol-
lution; metals, particularly mercury; and some pesticides. Regarding chemicals with
endocrine-​disrupting effects, in our study on cost we highlighted two studies show-
ing a higher probability of developing autistic-​like behaviors as a function of mater-
nal levels of phthalates (used, for instance, in plastics; see Chapter 3) [55] and certain
brominated flame retardant PBDEs [56]. In addition, organophosphate pesticide
exposures showed a strong association with IQ loss [57].
When we carried out our costing study with Leo Trasande, there were virtually
no prospective studies of pesticide exposure and ASD risk. However, a group of
researchers interested in the potential link between pesticide exposure [58] and
autism risk applied a different and somewhat-​novel approach [59]. Janie Shelton and
her colleagues took advantage of the fact that when pesticides are used in the United
States, the farmer is required to report when, where, and how much of a given pes-
ticide is applied. The researchers compared the official records for California pesti-
cide usage between 1997 and 2008 with the addresses of 970 mothers during their
pregnancies. All the mothers were enrolled in the Childhood Autism Risks From
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Genetics and Environment (CHARGE) study. Addresses were classed according

to whether they were within 1.25, 1.5, and 1.75 kilometers of applications of differ-
ent pesticide categories. The closer the pregnant women lived to pesticide applica-
tion, the greater was the risk of their children having ASD. In fact, living within 1.5
kilometers of application increased ASD risk by 60% [59]—​strong evidence of an
environment-​ASD connection.

Tying it together: from thyroid hormone disruption

to autism and IQ loss

We have already discussed the disturbing parallels between many aspects of thyroid
hormone deficiency in early development and the symptoms of ASD and of ADHD.
Researchers use hypothyroid mice as models of ASD [17, 36]. Evolution has honed
the modulatory actions of thyroid hormone on brain development over hundreds of
millions of years. The mechanisms used by the thyroid gland to capture iodine and
convert it into the hormone are identical from fish and frogs to humans, as is the hor-
mone itself. The structural parts of the proteins that act as receptors for the hormone
and govern transcription in the nucleus of every cell in our bodies are also conserved.
Once nature has selected a winning team, there’s no place for substitution.
How does thyroid hormone change tadpoles into frogs and orchestrate the devel-
opment of the human brain? As previously elaborated, but the ideas are important,
it’s got a lot to do with the question of how come we share 98% of our genome with
chimpanzees. The genes and many of the mechanisms may be the same, but when,
where, and how they enter the developmental scenario is what makes the difference.
It’s all about timing (when), in which tissue (where), and how much hormone gets
to the target. All these factors will modulate our developmental progress. For us
humans, part of the story is protracted development that allows for greater brain
development and more brain plasticity. All of this means longer times for thyroid
hormone to modulate the different processes described in Chapter 2. Any modifica-
tion of these processes can have adverse effects.
Evolution has tinkered with these when, where, and how much variables, espe-
cially by changing how much hormone gets into target cells at key developmental
time points. These local changes are largely wrought by changing the expression and
activity levels of the enzymes that activate and inactivate thyroid hormone in the
tissues. Not only are these enzymes particularly sensitive to the presence of heavy
metals such as mercury, but also too many chemicals in the environment can modu-
late the amounts of hormone available at the different time points, and too much
is as bad as too little. The multiple mechanisms by which chemicals change thyroid
hormone availability were summarized in Chapter 3.
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The Alarming Increase in Autism 111

Other environmental causes have been linked to increased ASD. Without dimin-
ishing their individual importance, it has to be emphasized that chemical pollution
interfering with thyroid hormone action will exacerbate each mechanism. First,
birthing methods that interfere with the essential actions of oxytocin on the babies’
brains will be worsened in the event of thyroid hormone disruption because the
same neuronal populations and the same ion-​conducting channels need thyroid
hormone to mature. Also, oxytocin production in the brain is lower if there is not
enough thyroid hormone [60, 61].
As detailed, three other factors that increase ASD risk are premature birth, low
birth weight [44], and maternal infection during pregnancy [45]. One of our bod-
ies’ first responses to infection is to reduce circulating thyroid hormone levels. So,
besides the direct effects of the virus or bacteria, the presence of thyroid-​disrupting
chemicals will aggravate the situation, with both infection diminishing thyroid
hormone levels and chemicals potentially inhibiting the action of any hormone still
circulating. The question of low birth weight, particularly if it reflects slow inter-
uterine growth, is more of a chicken-​and-​egg situation. Numerous endocrine regu-
lations control growth rates. A major player is growth hormone, released from the
pituitary. However, one of its main actions on growth is to drive the production of
other growth factors (actually called the insulin-​like growth factors or IGFs) by the
liver. And, guess what? The production of IGFs is a thyroid hormone–​dependent
process. So, changes in thyroid hormone availability will also affect growth and
birth weight. Exposure to pesticides and polychlorinated biphenyls (PCBs) reduces
intrauterine growth [62], providing plausible direct and indirect links between the
EDCs and birth weight.
Of course, all this cuts back to the fact that increased incidence of CH is also
associated with preterm birth. As twins and other multiple pregnancies are fre-
quently born early, the incidence of CH is higher in these groups. In Italy, Antonella
Olivieri’s group has been following the incidence and characteristics of CH for a
number of years [63]. Her data showed that, in the Italian population, there are
three times as many twins in the CH group than in the general population [64]. The
Italian database has been exploited to assess potential genetic and environmental
causes. The authors [64] considered that, although genetic factors cannot be ruled
out, the contributions of environmental factors exacerbating genetic predisposition
are a plausible explanation.

Conclusion

The incidence of ASD is rising dramatically. ADHD numbers are also increas-
ing. Data collected in 2011 and available by 2015 on the US CDC website13 show
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112 Toxic Cocktail

that ADHD affects 11% of US children. To this grim picture, we have to add
the numbers of children showing difficulties with reading and writing—​features
of dyslexia. Unexplained increases are also being seen in children born without
thyroids—​CH. Diagnostic change and greater social awareness can account for
no more than 40% of the ASD increase [9]‌. Given that the human gene pool
has not changed, environmental causes must be implicated in all these increases.
Despite vastly improved genetic sequencing methods and the amazing sums of
money invested looking for genetic causes of autism, not that many genetic varia-
tions in DNA sequence have been formally linked to ASD. Clearly, there is a
need to focus more on environmental factors, particularly their impact on cel-
lular responses and on how environmental factors affect gene expression (gene ×
environment interactions), especially during early development. Studies of asso-
ciations of exposure with disease incidence should examine more closely critical
developmental windows, especially early pregnancy, and then take genetic sus-
ceptibilities into account. Given that determining environmental causes offers
the most scope for curbing the ASD epidemic, I join many of my colleagues in
arguing that the precautionary principle should be applied while more research
is directed to identifying the principal culprits and determining replacement
strategies.
  113

6
From DNA to Epigenetics

The genes-​v ersus-​e nvironment straitjacket

What makes us what we are? What determines how tall we grow? How bright we
are? Our capacity to resist stress? How much we weigh? Even how successful we
are in life? For many people, it’s in our genes; for others, it’s all down to the envi-
ronment where we are brought up—​back to the old nature-​versus-​nurture debate,
with inborn talents weighing against acquired capacities. To my mind, it’s a mis-
take to overemphasize one or the other. The environment affects how our genes are
expressed, and in turn our genes are implicated in our responses to the environment.
Some of the difficulty may lie with what we understand by “the environment.”
It’s not just what’s outside our bodies, the quality of the air we breathe, the chal-
lenges and stresses we deal with on a day-​to-​day basis, and the food we eat. When
we’re talking about how the environment affects our cells and our genes, we have
to think at multiple levels. We need also to bring our internal bodily environment
into the equation again. This means taking into account the constitution of the
blood circulating around our bodies, what’s in the lymph, the liquid that bathes our
tissues that make up the organs (liver, muscle, etc.), and even the composition of
the liquids inside the cells themselves. Don’t forget that 75% of our bodies is made
up of water in the form of different fluids. All this—​blood, lymph, intracellular
compartments—​constitutes our internal environment, the environment inside our
bodies.

113
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114 Toxic Cocktail

The composition of this internal environment affects the way our cells function
and thus has to be kept fairly constant, within certain limits of chemical composi-
tion (such as acidity and salt concentrations) and temperature.1 The study of how
our bodies control our internal environment is part of the science of physiology.
Physiology is the study of how organisms control their functions and activities.
It includes the nervous, respiratory, skeletal, circulatory, and endocrine systems.
Physiological controls over tissue and cellular functions are exerted at many levels,
and environmental regulation of gene expression is part and parcel of these controls,
especially during development.

Development as a plastic process

Our internal and external environments modify gene expression at all ages.
However, it’s during early development, especially in the womb and in early child-
hood, that our bodies are most sensitive to the modulating effects of both the inter-
nal and the external environments on gene expression. As beautifully illustrated
and discussed by Scott Gilbert [1]‌, there are innumerable examples of how environ-
mental factors change developmental outcome across the whole of the animal (and
plant) kingdom. One example familiar to many is the fact that feeding royal jelly to
an otherwise-​ordinary larva produces an egg-​laying queen bee. A larva with exactly
the same gene set but not fed royal jelly at a key stage in development becomes a
sterile worker bee.
Metamorphosing tadpoles provide two spectacular cases. Tadpoles of a tree frog
can change shape and develop a red “warning” tail if they sense chemical cues of a
predator in the water. The tadpoles of a species of toad go even further. If they sense
a reduction in water level, they speed up metamorphosis, with some tadpoles grow-
ing faster than others and actually developing jaws to cannibalize their siblings.
Such examples of environmental plasticity have been documented from the 19th
century on, well before the gene was even defined.
In fact, our physiological systems have been selected through evolution to per-
mit rapid and longer-​term adaptations to environmental change not only during
development, but also as adults. Our endocrine systems are geared for driving these
adaptations, with the thyroid axis a key player in many of them.2 As temperatures
become colder in the winter, we ramp up our thyroid hormone production. The
greater amount of thyroid hormone in our blood drives the burning of energy stores
to produce more heat in our muscles and fat stores. This is why people with an over-
active thyroid gland lose weight fast, as they’re burning up their energy stores to
produce heat, even though they may not need it. People with an underactive thyroid
gland put on weight because they burn up less energy and stock more food as fat.
  115

From DNA to Epigenetics 115

Similarly our bodies respond to illness or fasting by turning down our thyroid hor-
mone production, an adaptation that conserves energy.
Furthermore, evolution has integrated adaptable mechanisms to ensure that the
environments we experience in early life set up appropriate physiological mecha-
nisms for later. Being preadapted to adverse conditions could provide a selec-
tive survival advantage if the situation persists. Conditions experienced in early
development—​in humans, in the mother’s womb—​can determine how we respond
to our environment as children, adolescents, and adults. Today, this concept is
known as the developmental origin of adult disease (DOAD) hypothesis. It is often
referred to as the Barker hypothesis, as David Barker was one of the first to popular-
ize these ideas in the 1980s [2]‌. The concept also has far-​reaching implications for
evolutionary biology as well as health (see [3]).
Today, in fact, DOAD is no longer a hypothesis. It has a strong factual basis
with many well-​documented examples from epidemiology and experimental work.
These findings exemplify how environmental challenges modify our physiology
in the long term. Here we’ll take a look at one of the most striking examples, a
historical case built on outcomes of children conceived during a short, but severe,
famine experienced by the Dutch population in the final year of the Second World
War, from late 1944 into spring 1945. The adverse health consequences on the
babies that suffered intrauterine growth restriction have been documented on the
middle-​aged survivors over half a century later. Effects range from metabolic dis-
orders such as diabetes to cognitive impairments during aging [4–​7]. In fact, the
severe food shortages were followed by a period of postwar prosperity that allowed
for the babies to catch up on their growth once the famine was over. In the 1960s
and 1970s, Barker and colleagues were observing that in other countries adults who
had been born with low birth weight were more susceptible to cardiovascular dis-
ease. However, there were too many other socioeconomic differences, such as social
class, in the various cohorts for the theory to gain general acceptance. In the case
of the Dutch winter study, on the other hand, all pregnant women in the western
part of the Netherlands were exposed to severe food intake restriction, receiving
as little as 400–​800 calories per day. Fortunately, this tragic episode lasted only a
few months, but it meant that the health of the offspring as adults could later be
related to whether the mothers were exposed in early, mid-​, or late pregnancy. Thus,
the effects of calorie restriction and “catch-​up” growth could be related to exposure
time in pregnancy. It turns out that early pregnancy was the most vulnerable period
for maternal calorie restriction, being associated with increased risk of metabolic
disease in middle age and increased risk of developing neurodegenerative disease.
These data showing that the early part of pregnancy is a particularly critical win-
dow for later development recall those showing that IQ is most affected by iodine or
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116 Toxic Cocktail

thyroid hormone deficiency, or chemical exposure, during the first months of preg-
nancy (see Chapters 1–​3). The mechanisms are not fully understood but probably
have a lot to do with two features of early fetal development. First, it’s in these early
months that the brain and other organs are being structured. Second, in this period,
the placenta is growing fast, and its growth rate is determined by food restriction.
Any change in placental growth will then affect the baby’s development later in
gestation. No great leap of the imagination is required to take these arguments a
step further, to Professor Ian Deary’s theory of why intelligent people live longer
[8]‌. As well as the usual arguments based on greater success in school leading to
higher incomes, better nutrition, and less-​dangerous jobs, Deary proposed that
the building of a well-​structured brain during early fetal life will go hand in hand
with a well-​functioning metabolic system and general body structure that will serve
the individual well into old age. The findings of the Dutch hunger study certainly
support this hypothesis. It all fits with the often-​quoted lines of the Roman poet
Juvenal, “Mens sana in corpore sano”: a healthy mind in a healthy body. From what
we now know, this dictum applies from conception onwards.

Gene-​focused blinkers

Why is it, then, that, despite our expanding understanding of how the environ-
ment affects and interacts with the genome, the drumbeat of biological determin-
ism has been amplified inexorably by the media and, to some extent, by the research
community itself? In the general media, “Its part of his or her DNA” has become a
popular (and annoying) catchphrase to explain passions, drives, and behavior and
even to justify people’s actions. Sometimes, it seems as if the gene-​deterministic
view of human nature has completely sidelined the contribution of environmental
factors.
In fact, the nature-​versus-​nurture arguments go back thousands of years. In
what is considered one of the first texts on political theory, The Republic, written
around 380 bc [9]‌, Plato famously recommended sterilization of criminals and
the feeble-minded to stop them breeding and so avoid transmission of their char-
acteristics. Yet, at the same time, he realized, using the metaphors of values of dif-
ferent metals, that “gold-​quality” parents could have “bronze-​quality” children.
Clearly, things weren’t seen as that straightforward even then.
Yet, today, for just about every disease, most research for underlying causes will
focus in large part on genetic links. That environmental factors might be acting
alone or exacerbating genetic susceptibilities is often disregarded, even ignored.
Whether it’s autism spectrum disorder (ASD), attention-​ deficit/​
hyperactivity
  117

From DNA to Epigenetics 117

disorder (ADHD), dyslexia, or cancer, the culprit has to be first and foremost a
faulty gene set. Where does this blinkered viewpoint come from? Probably, it is
in large part from scientists’ own fascination with genes. Another reason is that
genetic approaches, especially with their ever-​increasing power, have indeed solved
many medical and research problems. We’ll return to these successes in the section
on gene studies on ASD further in the chapter.
In 1953, the journal Nature published James Watson’s and Francis Crick’s paper
on their landmark discovery: the double-​helix structure of DNA that defined the
genetic code [10]. The Nobel Prize, shared between them and a colleague, Maurice
Wilkins, followed less than a decade later.3 These discoveries hastened the pace of
our understanding of how genes contribute to building cells, tissues, and organ-
isms. Most people today have at some point acquired the knowledge that DNA
makes RNA and RNA makes proteins. Indeed, part of the DNA in the genes is
transcribed into messenger RNA, which is then translated into the proteins that
form the structure of our cells, the enzymes that digest food in our intestines, the
antibodies to defend us against disease, the building blocks of our muscles, and so
on. Since that crucial discovery, genetic research has accelerated. Today, numerous
examples of the human genome have been sequenced and annotated. In parallel,
genomes of many animals and plants also have been run through the sequencers.
And, there are lots of surprises.
One of the biggest surprises was to find not only that we share 98% of our genome
with chimpanzees, but also that there are fewer genes that actually make protein
than first thought. Today, about 22,000 genes are known. In the early days of human
genome sequencing, the bets were on for anything between 30,000 and 100,000
genes. The latest analyses have led some scientists to propose that only 19,000 genes
actually code for proteins (the building blocks of our cells) [11]. Some of another
3,000 or so genes code for RNA that will never make protein. These RNAs are
called, quite logically, noncoding RNA. Some are really small, microRNAs, about
20 nucleotides long. Both noncoding RNA and microRNA have important roles in
controlling the activity of other genes.
So, what’s the rest of the genome doing? Why has evolution kept large stretches
of DNA that apparently don’t code for anything? The simple answer is that most of
the genome is “regulatory DNA,” and it is involved in regulating the genes that do
in fact produce protein or forms of RNA. These parts of the genes are called coding
sequences (because they code for protein). Most of the other DNA regulates when
and where the coding genes are expressed. We now know that much of the difference
between chimps and us is more about “when and where” genes are expressed and
make their products, rather than differences in the coding sequences themselves.
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118 Toxic Cocktail

These changes in gene expression that determine when and where in the body
genes are turned on or off to make protein or to be silenced are loosely referred to
as “epigenetic changes” or “epigenetic regulations.”4 This term comes from the idea
that the regulations are “above the gene,” as opposed to within its actual sequence.
We’ll look into the mechanisms that underlie epigenetic regulations further in the
chapter. But, it’s important to realize here that it is mainly through these types of
regulations, the opening up or closing down of genes making RNA and protein,
that the when, where, and how much of gene expression is determined.
I’ve just mentioned how environmental changes affect our development and
physiology, the way our body works. In recent years, much has been learned about
how differences in timing and differences in the level of gene expression can be mod-
ulated by environmental signals. We know that many of these adaptive changes in
our physiology are played out through changes in levels of gene expression.5
Another important point here is that our bodies are using the same genes to adapt
to different physiological situations, by changing how active they are and how much
protein the cell produces from a given gene. As already emphasized, there are no
changes in gene sequences, just a change in gene activity. Similar changes in gene
expression—​increases and decreases at given time points—​underpin much of our
developmental progress, how fast and how well our bodies and our brains grow,
when puberty sets in and how aging affects our bodies.
Thus, a lot of the differences between people are more to do with how the envi-
ronment affects our growth and physiology than they are to do with genetic dif-
ferences. Just as we share 98% of our genome with chimpanzees, we also share well
over 99% with each other—​and that includes the regulatory bits, not just the coding
sequences. In view of these facts, we really have to ask—​as parents, decision-makers,
and researchers—​why it is that gene-​centric approaches override all other approaches.

Genes outplay environment in research funding

The gene-​centric emphasis appears to derive its impetus from a number of sources.
Given the importance that patient associations, charities, and government funding
bodies currently attach to genetic causes, it’s worth trying to understand how this
emphasis came to supplant environmental factors.
There are numerous reasons for the overemphasis of funding bodies to put money
into genetic causes rather than supporting research on environmental factors. Some
are more justifiable that others. But, broadly speaking, one can say that cost and
convenience are trumping reason and responsibility.
First and foremost, it seems reasonable to look for genetic causes of disease given
that genetic research has solved many medical enigmas. Examples are plentiful and
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From DNA to Epigenetics 119

range from the identification of the genetic cause of the neurodegenerative disorder
Huntington disease [12] to the implication of the BRCA gene in certain forms of
breast cancer. However, the success stories of finding genetic causes has in turn led
to an overriding and deterministic mindset that prioritizes genetic causes to many
diseases, including cancer and autism. When this type of scientific thinking pre-
cludes consideration of other factors, it is referred to as reductionism. This is because
it has a tendency to reduce the complexity of biological phenomena to elementary
components. Unfortunately, this reductionist approach is conceptually easier than
thinking about development as a continual interplay between environment, tissue
and cellular context, and genes.
Other reasons have more to do with expediency. Information on genomes is being
obtained faster and cheaper. So, it’s relatively easy for research groups and compa-
nies to carry out large-​scale genetic analyses. The speed of gene sequencing today
enables results to be produced (but not necessarily analyzed) in a matter of weeks. In
contrast, gathering epidemiological evidence from longitudinal or prospective stud-
ies to determine associations between prenatal exposure and disease incidence is
expensive and requires years to complete, by which time many children and families
will have been unnecessarily exposed.
Another factor that may be less obvious to many is that screening chemicals
involves experimentation. This often means research on animals, so antivivisection-
ist groups either insidiously or actively support the chemical industry in their lobby-
ing against testing and regulation of chemicals.
Last, but certainly not least, placing the onus on genes rather than on environ-
mental causes lightens any governmental or regulatory responsibility.
The focus on genetic research in neurodevelopmental disease reflects a more gen-
eral gene-​centered research environment. Just for the record, well before the current
ideology of “a gene for everything,” in 1984, a trio of scientists—​the evolutionary
geneticist and philosopher, Richard Lewontin; the neurobiologist, Steven Rose; and
the psychologist, Leon Kamin—​wrote an excellent critique of the biological and
genetic determination of social inequality [13]. A more humorous, but equally bit-
ing, attack has been made by John Cleese of “Monty Python” fame. His delightfully
cutting and ironic take on the “genes can explain everything” set of assumptions,
even belief in God, can be found online.6
If it’s not all genes, it also is not only the environment. Fortunately, research into
the new field of epigenetics is accelerating rapidly, bringing unprecedented insight to
our understanding of how the environment affects gene expression. Epigenetics may
not explain everything, but it certainly helps. Indeed, at the time of writing, many
scientists who have spent decades researching the genetic basis of ASD are increas-
ingly incorporating “environmental” and “epigenetic” arguments into their work.
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120 Toxic Cocktail

Enter epigenetics

A short excursion into understanding epigenetic regulation is needed to obtain a

perspective on how the environment can modulate expression of different genes.
But first, a quick reminder: DNA in the genes makes RNA, RNA makes protein.
Special machinery in the cell can read DNA sequences and transcribe them into
RNA. If a gene sequence is changed, we say it is mutated. Most often, a muta-
tion will radically change gene expression or the protein made from that gene.
In contrast, simply put, epigenetics is the study of how changes in expression of
genes arise without actually changing the sequence of the gene, that is, without
modifying or mutating the DNA sequence. In scientific terms, we say that epi-
genetic mechanisms produce changes in gene expression by altering the structure
of the chromatin (the proteins wrapped around the DNA, the DNA itself, and
the RNA being produced). Changes in the way the chromatin is wrapped up
determine whether the transcriptional machinery can get to the DNA to pro-
duce RNA. If the chromatin is “open,” RNA can be produced and used to make
protein. If the chromatin is closed, no RNA is made, and the gene is silent.
So, some genes can be open for transcription when others are closed. These
changes may be short term, a matter of seconds or even minutes. In other situa-
tions, they are open and active in the long term, for the lifetime of the cell, and
are then transmitted to daughter cells. Some epigenetic marks last throughout
a person’s life, and others can even be “handed down” from one generation to
the next.
Perhaps an illustration of how epigenetic modifications determine different
responses from the same gene sets will help. Not many people are aware that tadpoles
and frogs (of the same species) have exactly the same genomes (DNA sequences).
But, the tadpole expresses and uses different gene sets compared to those used in
the frog. To change from a tadpole to a frog, the tadpole produces a surge of thyroid
hormone that induces a series of epigenetic switches. These epigenetic changes do
not alter any DNA sequence, but they turn off certain genes and turn on others.
Some other genes will continue to be expressed independently of the thyroid hor-
mone peak. The net result is the major structural changes in the different tissues of
the tadpole as it gradually metamorphoses into a frog. When a female frog lays eggs
or when a male frog produces sperm, most of these epigenetic changes are wiped out
and things start afresh.
However, in some cases, the epigenetic marks are resistant to erasure and become
indelible. In such situations, there will be transgenerational transmission of the
marks, and they will be inherited by the offspring.
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From DNA to Epigenetics 121

The basics of epigenetics

Epigenetic mechanisms include methylation (adding a chemical group, a methyl

group) of the DNA sequence in the gene itself or modification of the histone pro-
tein. The histones are special proteins that pack the DNA within the chromosome
and form the chromatin.
One class of epigenetic changes involves methylation of specific nucleotides (the
subunits that make up the DNA). The nucleotides in the DNA have one of four
bases: adenosine, thymidine, cytosine, and guanine. Most methylation occurs on
the cytosine bases and is carried out by special enzymes, the DNA methyltrans-
ferases (DNMTs). Often, when part of a gene is strongly labeled with methylation
signals, it is silenced and not read by the transcriptional machinery. So, no RNA,
and hence no protein, is made.
A second group of epigenetic modifications includes the different signals that can
be added to the histone proteins. Specific enzymes can label different amino acids
in the histones with special chemical markers. The chemical labels are most often
either “acetylation” (addition of an acetyl group) or “methylation” added to a spe-
cific amino acid, usually a lysine. According to the position of the labeled lysine, on
which histone protein at which position, the marks can be read differentially by the
transcriptional machinery. Combinations of marks can be repressive (no transcrip-
tion), permissive (transcription is activated), or paused (transcription ready to go but
held in check). An amazingly precise genetic code.
One of the most reputed scientists and original thinkers to explain how epigenetics
helps resolve many knotty questions concerning biological and genetic determinism
is Professor Eva Jablonka from the University of Tel Aviv and author of Evolution
in Four Dimensions [14]. Her amusing, but serious, classification of gene-​centered
determinism as “genetic astrology” underlines the displaced hopes people place in
convenient and simplistic classifications as they search for the origins of complex
phenomena. She and her coauthor, Marion Lamb, cogently argued that heredity
is much more complex than gene sequences, and that in the light of recent knowl-
edge we can revisit Darwin’s theory of evolution. Jablonka and Lamb proposed that
we need to move beyond the idea that evolution only advances by natural selection
acting on gene mutations that arise by chance and take on board three new dimen-
sions. The subtitle of Evolution in Four Dimensions, namely, Genetic, Epigenetic,
Behavioral, and Symbolic Variation in the History of Life, refers to the concepts that
need to be added to genetics, that is, epigenetics, behavior, and language [14]. For
the purposes of the discussion here, I’ll limit consideration to epigenetics, a topic
increasingly present in media reports. Today, even though the mechanisms are not
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122 Toxic Cocktail

yet fully understood, the concepts of epigenetics and the closely related ideas that
environmental factors can influence gene expression (gene × environment interac-
tions) are among the most exciting and fast-​moving areas in science. Perhaps these
ideas are so revolutionary that many decision-​makers involved in chemical regula-
tion have yet to take in the full implications of the findings. Not only are these con-
cepts in themselves complex to understand, but also their implications for potential
transgenerational effects of chemicals are critical to current regulatory questions.
One potential reason that even many scientists have had difficulty accepting is the
notion of how the environment can induce potentially transgenerational epigenetic
changes and that these ideas may be viewed as Lamarckism. So, who was Lamarck?
Lamarck, a professor at the Natural History Museum in Paris, was the first person
to come up with a theory of evolution. One of the cornerstones of his theory of how
animals evolve is often referred to as the “transmission of acquired characteristics.”
Put simply—​his book on the subject ran to a couple of hundred pages—​Lamarck’s
basic idea was that by adapting to their environment animals could acquire charac-
ters or certain features favorable for that environment. If enough individuals of the
same species acquired these characteristics, and if those individuals possessing that
character reproduced among themselves, then these new features could be passed on
to future generations.
Historically, objections to this theory came from two fronts. First, Darwin pro-
duced a better-​argued theory based on the concept of natural selection and survival
of the fittest. Even though neither Darwin nor Lamarck had any knowledge of
genetics,7 Darwin’s concepts were furnished with more convincing examples. His
theory was based on numerous observations, ranging from the selection of favor-
able traits by pigeon breeders to the varied beaks of finches adapting to diverse food
sources (such as hard grains or insects) on different islands in the Galapagos. The
second problem for Lamarck’s approach was that, in the 20th century, some scien-
tists tried to demonstrate the validity of his theory with fanciful or even, in some
cases, falsified data. So, until the convincing recent demonstrations of transgenera-
tional effects based on epigenetic mechanisms, scientists referring to Lamarckian
modes of transmission were considered retrograde and even heretical. In contrast,
today the term Lamarckism provides a somewhat anachronistic anchor for the cur-
rent demonstrations of transgenerational transmission of environmentally deter-
mined information.

Digging for autism-​r elated genes

Like most other mental disorders, ASD is defined, and most often diagnosed, on
the basis of the clinical symptoms or features rather than by its causes (or etiology).
  123

From DNA to Epigenetics 123

This situation contrasts with, say, a diagnosis of meningitis—​inflammation of the

membranes around the brain—​a condition that in children can cause severe mental
disability or death. In meningitis, there is an immediate alert, a fever, caused vari-
ously by a virus, bacteria, or even a fungus. To discern which treatment will be best,
samples of body fluids are taken and tests run to look for the causative pathogen,
although antibiotics will be given immediately as a first-​level response. For ASD,
things are much more complicated. Although infections, particularly maternal
infections, are often viewed as potential causes or contributing factors to ASD, most
often its etiology is not known. What is more, the diagnosis will probably be made
years after the events affecting brain development have occurred.
As underlined previously, over the past 25 years, most research into the causes of
ASD has been funneled into genetic research, often with good reason. Primarily,
there are many examples of the clear causative role of defective genes for a certain
number of physical and mental diseases diagnosed in childhood. A few examples
can illustrate the point:  muscular dystrophy (a muscle-​wasting disease due to a
mutation in a muscle protein), hemophilia (uncontrolled bleeding due to a muta-
tion in a factor needed for blood clotting), and a number of severe X-​linked mental
retardation syndromes, including fragile X syndrome and Allen-​Herndon-​Dudley
disease, with the latter caused by a mutation in a transporter for thyroid hormone.
In fact, all of these diseases are more common in boys, the reason being that boys—​
with their one X chromosome and one Y chromosome—​only have one copy of the
chromosome (chromosome X) on which the defective genes are found. Girls, with
two copies of the X chromosome, therefore have a better chance of inheriting a copy
of the good gene from one parent.
Other genetic diseases affect both sexes, such as certain diseases of rapid aging,
or progeria while, as mentioned, some cancers (e.g., breast cancer) will affect women
carrying the wrong copies of the BRCA genes. On the other hand, it is now known
that in most cases smoking, not our gene set, causes lung cancer. But, we all have
anecdotes of people who smoked all their lives and didn’t die of lung cancer. This
simple observation implies that just as some gene sets increase susceptibility to envi-
ronmentally caused disease, others can enhance protection.
So far, about 600 genes with mutations or subtle variations have been associated
with one or another of the different clinical manifestations of ASD, although it’s
safe to say that only about 200 are found with any regular frequency. According to
Simons Foundation Autism Research Initiative,8 only 16 are classed as “high con-
fidence,” with evidence for consistent and recurring associations. The other gene
categories range from strong, suggestive, minimal or untested to syndromic. About
40 genes are classed as syndromic. At first sight, “syndromic” might sound more
convincing, as it might be thought to be related to autism syndrome, but in fact
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124 Toxic Cocktail

it’s not. Syndromic genes are not only found in patients with ASD. The symptoms
associated with a defect in these genes may not be required for ASD diagnosis, or
else the symptoms are characteristic of other diseases with features that may or may
not be part of the autism spectrum. Examples include the X-​linked disorders men-
tioned, such as the FMR1 gene that causes fragile X syndrome. Most studies on frag-
ile X syndrome show that of those suffering from this—​fortunately rare—​disease
(which causes severe mental retardation), only 20% to 30% display autistic features.
The other features are a range of physical characteristics, such as elongated faces
and flat feet. With regard to the associated intellectual deficiency, the symptoms
are more pronounced in boys than girls, who usually compensate with their “good”
copy of the gene on the other X chromosome.
These different classifications for ASD-​linked gene variants, ranging from syn-
dromic to weak, strong, or high confidence, raise a number of interesting points.
First, the fact that many gene variants show up in only a few studies could point
to environmental causes above and beyond the actual gene sequence. Second, it
strengthens the idea that many different genes can be implicated in the spectrum
of disorders characteristic of ASD. And third, it brings in the idea that problems
with expression of a given gene can cause different forms of mental disease and
even physical problems. This multiplicity of causes and effects also applies to other
mental diseases, such as schizophrenia, characterized by a wide spectrum of symp-
toms and phenotypes, and has been aptly and succinctly described by Sebat and
colleagues [15] in the title of a review:  “One Disorder, Multiple Mutations; One
Mutation, Multiple Disorders.” Another idea, increasingly present in the literature,
is that, more often than not, it is not one gene by itself that causes a problem or the
disease, but rather it is interactions between variations in groups of genes, or, more
importantly, the proteins produced by these different genes, that most affect brain
development and function.
Many studies looking for genetic links to ASD started off with family studies
of twins and closely inbred families with a high incidence of ASD. The literature
makes interesting, sometimes shocking, reading. Looking at the data on the num-
ber of children with ASD born to families where marriage between first cousins
and even double first cousins9 is permitted can sometimes give insight into a few
cases of familial autism. Sadly, this was the case for one consanguineous family in
which four of the five children were diagnosed with ASD. The parents were actu-
ally double first cousins (i.e., the husband and wife had the same four grandparents)
[16]. The mutation was tracked to the SYNE gene, a gene already identified as a rare
variant in one other patient with ASD and in another with bipolar disorder. Total
lack of SYNE causes yet another neuronal disorder, cerebellar ataxia (an incapacity
to coordinate movements). So, this is a case of familial ASD caused by a gene that
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From DNA to Epigenetics 125

can give rise to many other mental disorders—​one gene, multiple disorders. This
is clear-​cut, but unfortunately not useful for explaining the increased incidence of
autism across other populations.
Then, as different genetic investigatory methods (see the next section) improved,
the field expanded exponentially, and twin or family studies could be supplemented
by genome sequencing of individuals diagnosed with ASD. Such cases, with just one
member of the family displaying ASD, are often referred to as sporadic cases because
there is no previous history of the disease in the families concerned. Sporadic cases
can have either genetic or environmental causes or, of course, causes that implicate
environmental exacerbation of a genetic susceptibility.

A short guide to gene-​h unting methods and genetic

terms used in autism research

Chromosome abnormalities: By squashing cells (often blood cells), staining the mate-
rial in the nucleus, and using an ordinary microscope, scientists are able to examine
the overall structure and shape of chromosomes to look for short or extra long ones,
to examine them, and to count them to check the right number are in each cell.
Microarray analysis:  This technique uses a series of thousands of DNA spots,
each containing a small, standardized sequence of genetic material from a reference
human genome on a solid support. Microarrays can be used to match material from
a patient or an experimental group, and information can be obtained on differences
in sequence or levels of expression of genes.
Exome sequencing: This technique involves sequencing all the protein-​coding
genes in a genome. It is quicker and less onerous than doing the full sequence.
Indels: This term is shorthand for insertion and deletion of small variants in a
genome.
SNPs: Single-​nucleotide polymorphisms (SNPs) are, as their nomenclature sug-
gests, changes in just one nucleotide in a stretch of DNA. The changes may or may
not have functional consequences for the way the gene is transcribed or on the
protein made.
Whole-​genome sequencing:  This approach contrasts with exome sequencing in
that the full genome is sequenced; that is, not only the DNA that codes for protein,
but all the regulatory sequences as well. As regulatory (or noncoding sequences)
can account for up to 99% of the genome, the cost is much greater than exome
sequencing. However, sequencing costs have diminished dramatically over the last
decade, falling from close to US$100 million in 2001 to about US$4,000 in 2015
(according to the US National Human Genome Research Institute, https://​w ww.
genome.gov).
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126 Toxic Cocktail

De novo mutations: These are new sequence changes in the genetic information
that are not present in the parents’ somatic (cells in the main body) genome, but
arise in the germline—​the cells that produce the gametes or reproductive cells (i.e.
the sperm or the eggs). These new mutations or variations arise during division of
the germ cells and are therefore present in the sperm or the egg prior to fertilization,
so introducing the genetic variation into the genome of the offspring. Such varia-
tions do not always produce effects, but they can.
Some de novo mutations generate copy number variations (CNVs), which are
insertions or deletions of relatively large sequences of nucleotides (>50 kilobases) in
the DNA sequence. Other de novo mutations are smaller variations called indels (as
discussed previously in this section).

New mutations or old ones

Despite the enormous investment in research into the genetic causes of ASD, the
current consensus is that only between 5% and 15% of patients with ASD have an
identifiable chromosomal rearrangement or single-​gene disorder, possibly linked to
another known pathology. The genomes of another 5%–​10% of patients harbor one
or more genetic modifications (either inherited or de novo modifications; see the
preceding section on gene-​hunting methods and research terms) that confer dem-
onstrated increased risk of developing the disorder. Thus, the great majority of ASD
cases cannot be tracked to obvious genetic causes. Perhaps what is more striking is
that, in many of the studies that have combed the genome looking for associations
between small genetic variants and increased risk of ASD, equal numbers of new
variations were found in brothers and sisters not suffering from the disease. Given
these surprises, it’s important to take a closer look at the approaches and the results.
I’ll cut to the chase and begin in 2012, when a slew of studies appeared on genetic
associations for ASD risk. Underlining the media attention expected from the
results, most of these genetic studies appeared in the highest-​ranking, most visible,
journals:  Nature [17], Science [18], and Cell [19]. Others appeared in other highly
respected scientific journals:  PLoS Genetics [20–​22] and Neuron [23]. The find-
ings of these articles were summarized in a short review in the prestigious Nature
Reviews in Genetics [24] and in more specialized journals [25]. But, looking at the
results in detail can rather dampen one’s enthusiasm for these approaches and the
hopes they inspire.
First, we need to understand the source of the hype around the approaches used
and the anticipation of the results. Many of the studies were looking for de novo
mutations. The reasoning was that these were more likely to be associated with
the sporadic cases (not in families with a history of autism). De novo mutations
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From DNA to Epigenetics 127

are new genetic variations arising in the child but not found in the genome of
either of the parents. These variants can result in gene sequences that cannot be
read by the transcriptional machinery, in which case we speak of missense or non-
sense sequences. Other variants can result in the way that the RNA produced
from the DNA sequence is edited. These variants are called splice site modifica-
tions. Geneticists were only able to find these small variations when the power of
sequencing techniques increased dramatically toward the end of the first decade of
the 21st century.
The series of publications reported strong associations of de novo mutations
(defined in the preceding section) with ASD, and another reported a couple of rare
recessive mutations [17, 18, 22–​24, 26, 27]. All of the studies focused on family trios
(parents and an affected child) or quads (parents with one affected and one nonaf-
fected child). Certain findings were consistent across studies:  Many of the genes
identified in more than one patient were brain-​expressed genes that had often been
associated with neurodevelopmental disorders. In addition, the rates of de novo
mutation were similar in each study, around 2 × 10–​8 per base pair per generation.
The human genome contains about 3 billion (3 × 10​9) base pairs. So, in an aver-
age genome, there might be a few minor errors made in copying the DNA during
cell division as sperm or eggs undergo their final divisions. Interestingly, about four
times as many variations were of paternal, as opposed to maternal, origin. Moreover,
the frequency of mistakes increased significantly with paternal age. One of the rea-
sons there are fewer errors in the maternal contribution is that the genome in the
eggs (the ova) is largely prepared during development. Following puberty, only one
egg is brought to maturation each month and released without undergoing multiple
rounds of division and replication, as is the case for sperm.
In all, these intensive studies into de novo mutations led to the identification of
just over 100 candidate ASD genes. Most often, only single-​mutation events were
observed, and no single gene could be established as a strong risk factor. In an
attempt to take these approaches and observations further, one group involved in
the initial exome sequencing [26] turned the methodology on its head. Instead of
looking at all the exomes of a restricted number of patients, they took a set of “can-
didate” genes and looked for mutations in these genes in thousands of patients with
ASD. Succinctly, they chose 44 of the genes identified by either exome sequencing
or the previous CNV approaches and other associative studies and looked for muta-
tions in these genes in DNA samples from 2,446 ASD cases. Six of the 44 genes
showed recurrent de novo mutations. The genes identified mainly had roles in chro-
mosome remodeling, cell proliferation/​cycling, and neuronal conduction. Despite
this relative success, the authors estimated that only 1% of sporadic ASD cases will
implicate mutations in these six genes.
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128 Toxic Cocktail

This figure in itself might have been sufficient to temper the excitement elicited
by the results, but two other findings were even more surprising. First, despite the
large range of the studies and the thousands of genomes sequenced and compared,
the total number of mutations identified as causing gene disruption was only 127,
and only 6 were found in more than one affected subject [24]. But, perhaps the
most surprising finding was that the rates of new mutations in patients and con-
trol genomes were no different from those in children without any sign of ASD.
Similarly, girls were found to carry as many genetic variants as boys, and, as known
from the epidemiology, girls have a much lower risk of developing the disease.
The new research suggests that the reduced incidence of ASD in girls is due to
a protective effect because the numbers of de novo risk mutations are similar in
both sexes. So, girls can carry a significantly higher genetic risk load (i.e., have more
genetic variants) before developing ASD traits [28]. Solid data showed that male-​
specific factors such as testosterone enter the equation [29], making matters worse
for boys. Excess testosterone production or exposure during fetal life has been regu-
larly implicated as a contributing cause in ASD [29]. Differences in steroid levels
could in turn modulate responses to environmental factors or unmask a genetic sus-
ceptibility. Conversely, exposure to chemical pollution can modulate steroid pro-
duction in gender-​dependent ways. One example is the unexplained greater effects
of intrauterine exposure to phthalates on the production of steroids by male fetuses,
an effect not seen if the fetus is a girl [30]. It is all complicated, but it boils down to
girls being more protected to the inevitable (but very small) number of changes in
the genome that occur between their parents producing their sperm and egg, fertil-
ization, and subsequent development.
In other words, we’ve all got a tiny number of genetic variants, but in very few
cases will these variants predispose us to ASD. Further factors will be needed to tip
the balance and produce the signs of the disease.
Together, these reports underlined that, by themselves, de novo mutations play
limited roles in ASD, and that loss of function of one gene will rarely increase risk
significantly. Nevertheless, the different brain processes and pathways identified
by the sequencing methodologies are useful for understanding the disease. These
processes are often interrelated and, not surprisingly, are linked to brain develop-
ment and intellectual capacity. In one of the studies [26], the authors went a step
further than gene identification and analyzed protein-​protein interactions that
could occur or be modified as a function of the gene variations identified. They
also included in the exercise the proteins encoded by genes previously identified
as linked to ASD. The pathways implicated included chromatin remodeling (as in
epigenetic changes, see the section on the basics of epigenetics) and neuronal signal
conduction.
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From DNA to Epigenetics 129

Overall, though, these studies showed that, despite finding several hundred genes
that can be associated in varying degrees with ASD, not only is there no common
genetic cause for the syndrome but also the problems of brain development encoun-
tered in ASD are polygenic (i.e., involve changes in many genes and therefore many
biological processes). Like many other genetic modifications previously identified,
the de novo mutations thus need to be combined with other risk factors to cause the
disease. Clearly, some of these risk factors can be environmental factors.
The finding that small genetic variations do not by themselves represent risk fac-
tors for ASD was hammered home in another genetic study that appeared 3 years
after the main group of studies [31]. The research hit the media with titles such as
“Surprising Findings,” then relaying the idea that most autistic siblings have dif-
ferent genetic risk factors. The publication was from a group of researchers led by
Stephen W. Scherer from the Toronto Hospital for Sick Children, who is respon-
sible for the MSSNG project (https://​w ww.mss.ng/​). The MSSNG project has just
put thousands of genomes from patients with autism online so that other research-
ers can probe the resources to find the missing complexities that underline ASD.
Scherer and his colleagues carried out whole-​genome sequencing (i.e., full
sequences, not just the exomes) on quartets of 85 families. This Canadian-​based
study chose families in which both children had been diagnosed with ASD. This
feature differed from the quartet studies done in 2012, in which the genome of
four members of the family were sequenced, but most often the sequencing was of
the exomes of one child with ASD and one child without ASD symptoms. In the
Toronto study, the researchers scrutinized the genomes of the mother, father, and
each of the children (with ASD), starting from the premise that risk of recurrence
of ASD is high in families (between 12% and 19%). They thus hypothesized that if
there were genes responsible for the ASD diagnosis, then there would be a higher
probability of finding them when two children from the same family had the dis-
ease. Yet again, most of the results did not fit with the hypothesis tested. In the large
majority (70%) of cases, when two children from the same family had ASD, varia-
tions or mutations were found in different genes. So, there was little commonality or
concordance between the chance mutations. It is possible, however, that each gene
variant could have increased susceptibility to a given environmental factor or yet
another gene variation.
If determining genetic links to ASD is difficult, it is even more difficult when
it comes to ADHD. Insufficient genome-​wide studies searching for de novo vari-
ants have been applied to ADHD phenotypes to even begin to explain the immense
heterogeneity of the disorder in association with specific gene variants. It has been
estimated that 12,000 genomes will have to be sequenced (controls and patients) to
obtain significant results and associated genes from this approach [25].
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130 Toxic Cocktail

Identical twins may not be that identical

Given the ambiguous results from the genetic studies of siblings with or without
ASD, one might think that going back to twin studies should improve the chances
of success for identifying causative genes. The study of twins (where one or both
have ASD) has been used for decades to try to unravel the contribution of genetics
to different pathologies or biological differences, from height and aging to cardio-
vascular disease, schizophrenia, and ASD. Twin studies most often exploit compari-
sons between either identical (monozygotic, MZ) or nonidentical (dizygotic, DZ)
twin pairs. MZ twins have exactly the same genome sequence, whereas DZ twins
are like other siblings, either two brothers or two sisters or a brother and sister pair
(where in each case the genomes are only 50% similar). As each gene exists in two
copies (called alleles), a pair of siblings or DZ twins with the same mother and father
receive a random allele for each gene from the mother’s genome and a random allele
of the father’s genome. In contrast, with identical twins, as it’s the same egg fertil-
ized with the same sperm, the two contributions from the mother’s and the father’s
genomes are exactly the same in each twin.
At the experimental level, early studies would often rely on methods that used high-​
power microscopes to examine the chromosomes in the nuclei of twins and search
for abnormalities—​short or missing chromosomes or rearrangements (explained
in the short guide to gene-​hunting methods section)—​shared between MZ twins
(with exactly the same gene sequences) or with differences in chromosome structure
between DZ twins (with their different but partially shared genome sequences). It’s
often assumed that because MZ twins are born into the same family they share not
only the same genome but also the same environment, beginning with the same uter-
ine environment they were in for the better part of 9 months. By extension, we might
assume that the prenatal and postnatal genome and environment interactions (gene
× environment) of MZ twins are exactly the same, identical even. At first sight, this
supposition seems reasonable. But, is it? Well, this is not altogether true. In fact, as
more is learned about twin development on the one hand and epigenetic influences
on gene expression on the other, there are many grounds to call it into question.
Depending on the stage at which the fertilized egg separates into two individ-
ual embryos, identical MZ twins will share their placenta and less often amniotic
fluid. Less frequently, MZ twins share both placenta and amniotic fluid, and, also
rarely, if separation occurs very early in development, neither placenta nor amniotic
fluid is shared. In this last case, the situation will be similar to DZ twins, which
always have separate fertilized ova and thus separate placentas and amniotic fluid.
So, we can already see that in most cases “identical twins” are not as identical as one
might think.
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From DNA to Epigenetics 131

A first contributing factor can be differences in blood supply from different

parts of the shared placenta, leading to differing growth rates. A small advantage in
growth for one twin early on can then be accentuated as growth continues. These
differences in growth will often implicate epigenetic changes in gene expression. As
already mentioned in the discussion in the section Development as a Plastic Process
on the Dutch hunger winter, this variance in intrauterine growth and birth weight
can have significant effects on propensity to disease later in life. The lack of similar-
ity can be evident at birth, when often MZ twins will show even greater disparity in
birth weights than DZ twins.
Researchers have looked at the epigenetic signatures of cord blood cells from
MZ twins [32, 33]. They found significant dissimilarities between the epigenetic
marks on genes implicated in metabolism and cardiovascular function. These
differences were most pronounced for twins with separate placentas. As these
authors underlined, when cells divide, the process inherently introduces more
variation in epigenetic marks than in replicating DNA. So, it’s not entirely sur-
prising that epigenetic marks differ between MZ twins. The interesting point
is that the researchers were able to find linkages between these epigenetic dif-
ferences and certain physiological processes that significantly affect growth and
development.
It’s perhaps this aspect of dissimilar prenatal uterine environments affecting iden-
tical gene sequences that is the most interesting in terms of what we can learn today
from twin studies on how environment can affect a given genetic susceptibility and
how this can influence ASD risk. To develop these ideas, we’ll take a closer look at
one study that examined differences between cognitive features and ASD symp-
toms in sets of MZ twins. The study in question [34] appeared in 2009 and was
based on 14 sets of MZ twins and 14 control subjects. The MZ twins, all boys, were
selected on the basis that they were discordant for ASD symptoms. More precisely,
in each set of MZ twins, one brother had a more severe ASD classification than the
other, who exhibited fewer ASD features.
The authors took advantage of the latest technologies in brain imaging to exam-
ine brain structures in the different twins and a set of control boys of the same
age (8  years old). Their hypothesis was that, because differences in brain struc-
ture between patients with ASD and controls are well documented, comparing
brains of discordant MZ twins would show more specific anatomical variations.
Unfortunately, probably because of the limited number of patients, they weren’t
able to discern differences within pairs of MZ twins, but only differences between
the controls and the twins. Nonetheless, the data set is rich in other information
pertinent to the epigenetics and genetics of the ASD discussion. Most notably,
there were significant differences between the twins in terms of IQ, as well as in
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132 Toxic Cocktail

short-​term memory, quantitative reasoning, and verbal reasoning, with the twins
with the most marked ASD symptoms performing less well in the tests.
Another study from a Japanese group looked for epigenetic marks on different
genes in MZ twins displaying large differences in IQ [35]. Their gene-​hunting
experiment was carried out on blood cells, as they obviously couldn’t take brain
cells from their subjects. Given this major limitation, it’s not surprising that the
gene search proved inconclusive, with no genes in the blood cells identified as
epigenetically different in the twins with higher (or lower) IQ. But, again, it’s of
interest to note that in these 17 pairs of “identical twins,” all twin pairs had large
differences in IQ, with more than one pair having over 30 IQ point differences
in their scores. In one twin pair, one twin had an IQ of 67 and the other an IQ
of 112.
These results demonstrated that, with exactly the same genetic information, dif-
ferences in uterine environment can have a major impact on brain development and
function. In such instances, the most probable explanation is modulation of expres-
sion of genes implicated in brain development.

Epigenetics and your food supplements

We’ve just seen that MZ twins can differ in their epigenetic regulations and that
this divergence can be related to their growth rates and their cognitive potential.
Some of these differences might be due to differences in nutrient supplies, which
in turn are related to disparities in placenta blood supply. These findings recall the
Dutch hunger data that demonstrated how nutrition in early stages of embryonic
development affects propensity to cardiac disease and neurodegenerative disease
in later life. Today, we know more about how epigenetic changes brought about
during development can be identified and related to these adverse outcomes.
The Dutch hunger study took 50 years for the results on outcome to fit together.
Fortunately, as knowledge progresses, we can design studies to provide more rapid
information on the importance of epigenetic regulations for brain development.
Examples are becoming more numerous; here I cite two examples of research that
looked for effects of use of either prescribed drugs or food supplements during the
period before and after conception on epigenetic regulations, brain development,
and ASD risk.
Valproate is a drug used to treat epilepsy and that until recently was one of the few
medications that pregnant women suffering from the disorder were allowed to take.
To reduce the symptoms of epilepsy, valproate reduces certain forms of neuronal
transmission. However, valproate also acts by modifying chromatin structure and
inducing epigenetic regulations. We often use it for these purposes when carrying
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From DNA to Epigenetics 133

out experiments on epigenetics in the lab. So, in some ways it’s not surprising to find
that children born to women who needed to take the drug during their pregnancy
have a higher risk of ASD. The idea that there could be a link between valproate pre-
scription and ASD was first suggested in 2001 [36], but it was not until over 10 years
later that the cohort studies demonstrated the link conclusively [37].
Folic acid or folate, a form of vitamin B, was one of the first supplements given
to pregnant women as a preventive strategy in the 1990s. Today, 78% of pregnant
women in the United States take folic acid supplements in different forms. The rec-
ognition of the importance of this vitamin is such that flour in the United States
and Canada is fortified with folic acid. Supplementation was originally prescribed
as a means of reducing severe nervous system deformations, including neural tube
defects such as spina bifida (failure of the nervous system–​forming tube to close) or
anencephaly (lack of head formation) [38]. These recommendations were brought
in without real knowledge of how folate prevented these malformations. The rec-
ommendations were based on the observations that mothers who had low levels of
a number of micronutrients (vitamins and minerals), but particularly folate, had
a higher probability of giving birth to a child with a neural tube problem. Today,
we know that folic acid is tightly implicated in specific methylation processes that
are involved in many epigenetic phenomena. These include both DNA methylation
and histone methylation. Given the effects of folate on epigenetic signaling, many
authors have asked whether folate supplementation has other roles in brain develop-
ment beyond the protective effect on neural tube formation.
A number of large-​scale prospective cohort studies in the United States [39] and
Europe [40, 41] have looked at this question, notably with respect to ASD risk. All
data sets pointed to a protective effect of taking folate supplements in the month
prior to conception and for the first 3 months of pregnancy. The US study found
that the protective effect of folate in reducing ASD risk was most marked in women
and children who had a genetic variation in one of the genes encoding an important
enzyme in folate metabolism, the MTHFR gene. This point illustrates two impor-
tant and recurrent ideas: first, that genetic susceptibility can be exacerbated or alle-
viated by environmental factors and, second, that that these factors, like epigenetic
mechanisms, can be implicated in ASD etiology.

Into the unknown

The mere fact that the scientific journal Epigenetics was founded in 2006 gives one
an idea of how recent the scientific ideas are on the topics. Since then, journals con-
cerned with epigenetics have appeared at the rate of almost one a year. Prior to the
year 2000, some 3,000 scientific papers could be found using the key word epigenetic.
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134 Toxic Cocktail

Today, looking the same term up on a standard medical research publication search
engine gives about 50,000 publications.
The trouble is that when it comes to testing chemicals for their effects at the level
of epigenetic regulations we are quite simply at the limits of our knowledge. Few of
our testing methods for screening actually take into account short-​and long-​term
effects that are played out at the level of epigenetic regulation. Some testing methods
will pick up more general developmental or toxic effects, many of which may impli-
cate epigenetic mechanisms. But, to date, few tests have been designed or ratified by
the authorities to actually determine whether a chemical has an effect on epigenetic
regulatory mechanisms.
Our lab is currently testing various experimental methods that we hope can be
adapted for large-​scale screening. Mainly, we’re looking for epigenetic changes occur-
ring in the neural stem cells in the brain. We are focusing on these important cells,
as we want to know how chemicals affect their biology during brain development.

Research funding of environmental causes is too low

Even though gene × environment interactions are increasingly being considered in

research on ASD [42, 43], for reasons outlined previously, over the last 20 years the
main focus in understanding the disorders has been on genetic causes. This focus has
been reflected in the funds directed to research on ASD. It has been estimated that
more than 96% of research funds allocated in the United States for ASD research
goes to genetic studies. Kathrine Weintraub, an independent journalist, published a
review of ASD epidemiology, causes, and cost in 2011 [44]. She gave figures for US
federal government funding of autism research for the decade prior to her review as
being over US$1 billion for genetic causes as opposed to only $40 million for envi-
ronmental factors. This imbalance is surprising, even shocking. Many authors, par-
ticularly over the last decade, have been pointing out not only that environmental
causes are likely [45], but also, given the increase in ASD incidence, there is a certain
urgency to identify them. In my view, the focus of funding should go more toward
not only environmental factors that could be implicated in the increased incidence
of ASD and IQ loss, but also how these factors act on brain organization during
development and whether epigenetic modifications of already-​identified ASD sus-
ceptibility genes are potentially implicated.

How much do we need to know to act?

A quick reminder (see Introduction and Chapter  3) of the prescient comment

from David Rall when he contrasted the obvious effects of thalidomide against
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From DNA to Epigenetics 135

surreptitious effects of chemicals on IQ might be useful here. The thalidomide

tragedy demonstrated all too sadly that when a chemical produces a physical
deformity, it is quickly spotted (with echography, the problems can even be seen
before birth) and relatively straightforward to associate a particular drug with
an adverse outcome. The example also underlined the particularly sensitive time
window of early pregnancy, although the whole of pregnancy is a vulnerable
period. In fact, thalidomide can be safely used in cancer therapy because it blocks
the growth of blood vessels. But, this is not why it was prescribed. So, an effect
that can be put to therapeutic use in (nonpregnant) adults can have devastat-
ing consequences depending on the timing of exposure, especially if developing
fetuses are exposed.
This dreadful example can serve to illustrate the problems that decision-​makers
and regulators are grappling with today. How do we find the chemical culprits in
the mixtures to which we are exposed from conception to old age? How do we iden-
tify those with epigenetic effects? Here, we have to bear in mind that the effects of
the mixtures present in the womb affect our health until the end of life, irrespective
of whether they are still present. What is worse, some could be exerting epigenetic
mechanisms that affect future generations as well.
Another distressing example, mentioned in the Introduction, comes again
from the pharmaceutical industry and again concerns pregnant women.
Diethylstilbestrol (DES), was prescribed (again ineffectively) to reduce risk of
miscarriage in early pregnancy. Exposure induced vaginal cancer in the daugh-
ters and the granddaughters of the women who used it. Furthermore, increasing
evidence shows that prenatal exposure to DES is also associated with increased
risk of psychiatric disease [46].
Where do these findings take us in terms of ethics and transgenerational respon-
sibilities? The question of responsibilities arises not only in relation to children’s
health, both mental and physical, but also in terms of the environmental legacy that
we build. I  address such questions in Chapters  7 and 8, then conclude on a cau-
tiously positive note in the final chapter. The optimism derives from our awareness
of the problem that gives us the power to act.
136
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7
Counting the Costs

San Diego, March 2015

I am sitting in the shade of a large indigo umbrella, looking out over the marina in
front of the San Diego conference center in California—​can’t complain: Scientific
research has its advantages. This week I am attending the 2015 Endocrine Society
meeting. The blue of the umbrella merges into the unbroken azure of the sky and
away into the cobalt of the Pacific beyond the bay. I sit working on my laptop, an
object emblematic of the creativity of California today, Silicon Valley. Actually,
I’m closer to another renowned Californian site, the legendary Salk Institute, a
hub of groundbreaking biological and medical science, named after Jonas Salk who
invented the polio vaccine in 1955. Few people today are aware of the scourge of
polio prior to general immunization: Hospital wards were filled with children in
iron lungs, and many lives were broken by the disease.1 This absence of awareness
might contribute the reluctance of many parents to vaccinate toddlers and children
against potentially debilitating diseases, a point we return to in the discussion of the
fallacy of the link between autism and vaccination.
Today, it’s a different “absence of awareness” that is worrying me, a concern
provoked by a conversation with two journalists at a press conference I attended.
Because of the importance of the findings presented and their relevance to Europe,
the press conference was held simultaneously in San Diego and Brussels. As one of
the authors of the papers presented, I was in the room. Leo Trasande from New York

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University presented the data. Leo had just led a collaboration of about 20 scientists
from different academic and international foundations in an exercise to assess the
economic costs incurred by health problems attributable to endocrine disruption
[1]‌. The costs, calculated for the European Union, amounted to a staggering €157
billion per annum, with IQ loss and neurodevelopmental disease accounting for the
largest part of that sum, being around €150 billion every year.
Not surprisingly, the story was picked up and relayed across Europe and the
United States by a number of television and newspaper channels, alerting the pub-
lic and authorities to the sums involved. But, in the press room there was also dis-
sent. One journalist openly questioned the findings of the paper on IQ loss. Having
contributed to that work, I  went across to him after the conference and tried to
understand his point of view. My hope was that I could possibly provide some more
arguments to back up those Leo had given. He dismissed my comments, saying,
“The generation that gave us such powerful computers, the Internet and commu-
nication systems can’t be less intelligent than the previous generations.” What he
failed to grasp, and what by definition we failed to communicate well enough, was
that effects on a population level are almost impossible to see from an individual
perspective.
And, in some ways, looking at the wealth ostentatiously displayed in the marina,
feeling the warmth of the sun on my back, I briefly had a glimpse of the comfort zone
lived in by those that reject scientific evidence, whether it be for climate change,
the moon landing, the safety of vaccines, the theory of evolution, and, of course,
endocrine disruption. In some ways, it’s so much easier to enjoy the sunshine of San
Diego rather than worry about climate, biodiversity, and environmental imbalance.
Only a hardened pessimist could be such a Cassandra on a day like today. Life is
too short, and there’s too much to enjoy for worrying about global changes that
many prefer to think are unrelated to human activity and therefore inevitable. It’s
more reassuring to gaze out over the horizon of blue and be blissfully unaware of
the islands of plastic, the Great Garbage Patch, floating further out in the Pacific,
to forget that California is suffering its worst-​ever drought, and that the incidence
of autism in California increased 12-​fold in the 20 years between 1987 and 2007.2
What about effects of endocrine disruption on IQ loss and neurodevelopmental
disease? Indeed, when the 60-​year-​old journalist from California looks at his own
family and friends, when he takes in the general productivity and standard of liv-
ing of the society immediately around him, we can understand why he questioned
our data. But, unfortunately, limiting one’s field of vision to your own sphere can
obscure the evidence at a wider scale. To be aware of the shifts in IQ, we have to look
at the population level, using statistics of thousands of children, not just our own
children and grandchildren. It’s obvious that there are still many very intelligent,
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Counting the Costs 139

creative people in our societies, founding visibly successful companies like Apple,
Microsoft, or Facebook. However, the question is more to do with what proportion
of the population has the creative ability to conceive the science and transfer the
knowledge to ensure the potential of such companies. The other side of the coin is
the number of people who can’t contribute to these advances, and more precisely
how many people will need institutional care today, as compared to a few decades
previously. Of course, it’s not the less-​creative people who are going to be appearing
on the screens of our tablets, phones, computers, or televisions. We’ll be far more
likely to see and hear about the successful entrepreneur, artist, musician, sports per-
sonality, and even the occasional scientist.

Counting the cost of IQ loss

The data that Leo was presenting covered the economic costs of disease that our
international panels calculated as reasonably attributable to endocrine-​disrupting
chemical (EDC) exposure. In our own study [2]‌, we looked at EDC exposure and
the ensuing consequences on IQ loss and risk of neurodevelopmental disease. To
be able to do these calculations, we need to have access to so-​called longitudinal
studies. These are often called prospective studies, as in these cases researchers
will ask pregnant women if they are willing to take part in a long-​term study that
could continue for years after their children are born. If the mothers agree, then the
researchers take samples of blood or urine from the women at defined times in their
pregnancy. The samples are then used to measure certain chemicals and so deter-
mine not only maternal exposure to the given chemical, but also fetal exposure.
This reasoning is based on the fact that the placenta is not a barrier for chemicals.
On the contrary, there’s a large amount of epidemiological data showing high lev-
els of thyroid-​disrupting chemicals in amniotic fluid, on the other side of the “pla-
cental divide.” In fact, the unborn baby is swallowing and recycling amniotic fluid
throughout pregnancy.
In a prospective or longitudinal study, the researchers will keep track of the moth-
ers and their babies and aim to obtain data on their children’s neurodevelopmental
scores between 3 and 7 years later. Such studies are expensive, often recruiting 1,000
mother-​child pairs to ensure a sufficient number of mothers will follow through.
Therefore, not many researchers receive the funding to set up these large-​cohort
studies, and this is the main reason why there are so few longitudinal data sets. In
fact, for our economic analysis of IQ loss related to maternal exposure, we only had
solid prospective data for just two categories of chemicals. And yet, we know (as
explained in Chapter 3) that there are dozens of chemical categories that affect thy-
roid hormone signaling and therefore potentially cause IQ loss.
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140 Toxic Cocktail

The data sets we used concerned a group of brominated flame retardants called
polybrominated diethyl ethers, or PBDEs [3–​5], and a category of organophosphate
pesticides [6–​8]. In each case, the data sets were from the United States, and both
showed exposure was significantly associated with IQ loss. We’ll focus on the data
for PBDE exposure here first.
There were three PBDE data sets, each covering cohorts of mothers and children
from different areas of the United States. One was the HOME (Health Outcome
and Measures of the Environment) study, based in Cincinnati, Ohio [3]‌; another
was the CHAMACOS (Center for the Health Assessment of Mothers and
Children of Salinas) study, based in California [5]; and the third examined mothers
and babies in New York City [4]. In all cases, maternal exposure to high levels of one
type of PBDE, known as PBDE-​47, was associated in the children with IQ losses of
between 4 and 5 IQ points [3–​5]. The fact that all the studies were consistent in their
findings, across a wide geographical range, was a strong indication of causality and
gave us extra confidence in the data.
Before going on to explain how we calculated the costs in our study, let’s take a
look at what consequences a 5-​point loss in children’s IQ can have in terms of a larger
population, such as at the level of a whole country. After all, given that the samples
in the cohorts analyzed covered the United States from the West Coast to the East
Coast, such a simulation is not irrelevant. For the diagram given in Figure 7.1, to
make the reasoning clearer, we used a population of 250 million people, about half
the population of the European Union and slightly more than two-thirds that of the
United States.
The upper graph in the figure shows how IQ is distributed in a population of 250 mil-
lion people. The average IQ will be in the middle and set at 100. In the same way that
height shows a natural distribution across groups of people, biological variation also
accounts for IQ distribution from the more intelligent, on the right-​hand side of the
curve, to the less intelligent on the left. This representation is the bell-​shaped curve
referred to Chapter 4. In a normal distribution, about 6 million will have IQs over
130; these are the more gifted members of our society, people often associated with
innovation in the arts and science. Exceptionally intelligent people, the Mozarts and
Einsteins, will have even higher IQs, estimated at around 150 or more. In our theoreti-
cal population of 250 million, another 6 million will have IQs below 70. People with
IQs below 70 are considered intellectually disabled. It is not unusual for children and
adults with IQs below 70 to be unable to cope with the complex demands of day-​to-​
day life. Many require sheltered workplaces with supported accommodation and com-
munity care or, for difficult cases, institutionalized care for much of their lives [9, 10].
The lower curve in the figure shows the IQ distribution if circumstances cause a
5-​point IQ loss across the whole population, leading to a population-​wide shift to
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Counting the Costs 141

Average IQ = 100

6 million intellectually disabled 6 million gifted

40 80 100 120 160

70 130

Average IQ = 95
increase decrease

9.4 million intellectually disabled 2.4 million gifted

40 80 100 120 160

70 130

Figure 7.1  A 5-​point IQ loss at a population level has major consequences on the number of
gifted people and number of those with low IQ. Succinctly put, such a loss increases the number of
intellectually disabled persons by well over 50% while significantly reducing the number of gifted
people. See text for further explanation. (Adapted from B. Weiss, 2008 (reference 16).)

the left of the distribution. As a result, not only does the average IQ go down to 95
as compared to the previous distribution, but also, at the top end of the distribu-
tion, instead of 6 million gifted people, there will only be 2.4 million. On the other
hand, at the other extreme the number of children and adults requiring lifelong
assistance in some form increases from 6 million to 9.4 million. In other words, the
balance between gifted and assisted becomes seriously skewed, decreasing the gifted
and increasing the mentally challenged.3
The types of economic costs that will be incurred by this type of shift range from
the cost of extra schooling, care in the community, or lifelong care in institutions
and lost parental earnings to the reduced contribution of those concerned to the
economic fabric of society. It is the latter aspect that is most often considered when
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142 Toxic Cocktail

addressing the costs of IQ loss. In 2001, two Canadian economists [11] calculated
that a 5-​point loss in IQ through childhood neurodevelopmental disorders and
hypothyroidism, much of which had environmental causes, cost the United States
up to US$326 billion per annum. For children and adults with a neurodevelopmen-
tal disease, costs will be more related to long-​term care and loss of parental income.
The lifetime cost of a child with ASD can reach US$3.5 million. Thus, as a func-
tion of increasing incidence, costs at national levels are continually rising. For
instance, in 2009 it was calculated that at the level of the UK costs were £25 bil-
lion per annum [12], but the latest figures put the cost at £34 billion in the United
Kingdom and US$126 billion in the United States.4 Moreover, the lifetime cost of
caring for an autistic child with intellectual disability is far greater than for a child
without (about US$2.4 million with intellectual disability vs. US$1.4 million with-
out intellectual disability). The Autism Speaks site (see Note 4) provides a report on
an economic analysis showing that in the United States alone the cost of caring for
autistic patients is greater that the gross domestic product (GDP) of 139 countries.
Similarly, as the symptoms of ADHD do not necessarily diminish with age but can
persist in adulthood, the costs per individual are around US$15,000 to US$17,000
per year, which over a lifetime translates to around US$1 million. The Centers for
Disease Control and Prevention (CDC) site puts the annual societal cost of ADHD
disease at up to US$52 billion, based on a prevalence of 5%.5 However, the most
recent data presented by the CDC6 showed almost twice that incidence (about 10%
of US children), and given the lifetime cost cited previously, one could calculate
an upper estimate that would be over US$100 billion. Putting together the cost of
ASD (US$126 billion) and the cost of ADHD care, one reaches a range of US$176
billion to US$226 billion per annum in the United States.
Returning to our analysis of the PBDE data and IQ, an important fact is that
the amounts of flame retardant chemicals (PBDEs) in the mothers’ blood ranged
from low-​to high-​exposure levels. The 4-​to 5-​point IQ losses were in the highest-​
exposure group, and luckily not all the women in the cohort had these high levels of
PBDE exposure. However, two points need to be made here.
First, as discussed further in this chapter, a number of well-​researched studies
have shown that, unfortunately, when pregnant women have been exposed to any
one of a series of chemicals, the highest levels of exposure are often associated with
similar IQ point losses in their children. Therefore, we can expect the cocktails
of chemicals to which we are all exposed to be exerting combinatory effects, even
though it is possible that the actual concentration of each chemical is not as high as
seen in the most exposed groups in each of the studies.
A second point is that even if women are exposed only to low levels of this
PBDE—​and no other chemical—​then at a population level we could still be seeing
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Counting the Costs 143

a small erosion of IQ that could have significant effects on society. The effects of a
lower level of exposure to a single chemical across a population the size of that of the
United States or the European Union can be calculated. This is precisely what we
did with Leo Trasande for PBDEs and organophosphate pesticides.
To take the lower-​exposure levels into account, a group of us went through some
of the studies to calculate what levels of exposure are found in the European Union
and then calculated how such levels of exposure related to IQ loss in the US stud-
ies. From these calculations, we could then work out the expected IQ loss across
the exposed population in the European Union. Other economists and statisti-
cians have already computed what a 1-​or 2-​point IQ loss costs a society in monetary
terms. So, putting the three sets of calculations together—​exposure levels, predicted
IQ loss, and cost of that IQ loss—​we could estimate a range of potential costs to
European society on a yearly basis. We gave ranges of economic costs that reflected
our confidence in the results.
Six of us worked on the question over a number of months. Our first meeting
was in Paris after Leo had set up the groups and explained how we should work. We
met twice over the course of the study, first in Paris and later, as the work advanced,
in Copenhagen. In Paris, Leo explained how we’d be using the same type of meth-
odology as the International Panel on Climate Change7 and the World Health
Organization (WHO). A main part of the work was to weigh evidence and deter-
mine how much confidence, as scientists with different backgrounds and expertise,
we could have in the data and the methodology.
What were our scientific backgrounds? Leo is a public health specialist as well as a
trained pediatrician from New York University and has garnered an immense inter-
national reputation for his work. Sitting around the table in Paris to work with him
on IQ loss and neurodevelopment associations were four other professors: Martine
Bellanger, a brilliant French economist and statistician; Tom Zoeller, whose work
on thyroid hormone, alcohol, and brain development was mentioned in Chapter 3;
Philippe Grandjean, who like Leo trained as a doctor before doing a research PhD
in epidemiology; and myself. Philippe is internationally known for his stance on
brain-​draining chemicals, but he is best known for his work on mercury as a brain
drainer. He and Martine had already worked together on economic costing of mer-
cury contamination and IQ loss in Europe [13]. Philippe holds double academic
appointments in the University of Southern Denmark and Harvard School of
Public Health. For a while, we also had another pediatrician, Roberto Bertollini,
working with us. However, as Roberto works for WHO, to avoid any problems with
conflict of interest, he withdrew his authorship from the final manuscript.
What result did this meeting of minds produce? The bottom line was that
exposure to either organophosphate pesticides or PBDE-​47 could each reduce IQ
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144 Toxic Cocktail

significantly on the one hand and increase risk of autism and ADHD on the other
hand. The greatest costs were incurred for IQ loss. In Europe, the cost attributable
to these chemicals could amount to hundreds of billions of euros every year. Leo is
currently working on calculating the costs for the United States.

Correlations and causality: smoke screens

of denial versus action

Despite the solid credentials of the panel, our work had not been out long before
it received its first (and to date only) criticism [14]. As is often the case with denial
statements, the commentary was short, superficial, and unresearched. It came in the
form of an unreferenced letter from two authors unknown for any work in the field
of endocrinology. Their criticisms focused on the fact that few cohorts were stud-
ied and suggested that the animal studies used to provide evidence of mechanisms
were irrelevant. Actually, the authors even managed to slip in an entirely spurious
comment on the fact that in one study, that of the CHAMACOS group, most of
the participants were living below the poverty level. Were we supposed to consider
that associations between mother’s levels of pesticide exposure and their children’s
mental development are irrelevant in such groups? These critics also noted that in
the New York study no significance was found in the white population. Here again,
their comment was misleading and unfounded. In the New York study, the white
population represented only about one-​fi fth of the cohort (38 of a total of 150 moth-
ers), so it was not surprising that in that small group the findings did not reach
significance. On the other hand, our critics chose to ignore that both studies on
organophosphate pesticide exposure showed significant correlations between moth-
ers’ pesticide levels and their children’s neurodevelopmental scores. In fact, this
example was yet another case of the doubters and deniers attempting to disparage
solid science with flimsy smokescreens designed to cloud the issues.
The metaphor of smokescreens is not irrelevant. Probably one of the best-​
documented cases of doubt-​driven denial was that provided by Darrell Huff when
he bore witness in favor of the tobacco industry in 1965. Huff was a freelance jour-
nalist. In 1954, he came to prominence as the author of How to Lie With Statistics
(New York: Norton), which became the bestselling book on statistics in the sec-
ond half of the 20th century. He and his sponsors, the tobacco industry, certainly
seem to have taken his book title seriously when they got him to testify in those US
Senate committee hearings in 1965.
As cited by Tim Harford, the “Undercover Economist” for the Financial Times
in 2015,8 Huff argued that even though smoking correlated with lung cancer, there
was no formal demonstration of causality. Tim Harford indicated that Huff even
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Counting the Costs 145

argued that correlation is not causation by illustrating his case with the observa-
tion that, in Danish houses, the number of stork nests on the roof correlates with
the number of children born! Huff pointed out that we all know that storks don’t
deliver babies, but as Harford said, larger houses have larger roofs, accommodating
both more stork nests and more children. Here, two correlated effects (more chil-
dren and more storks) can be accounted for by reference to a third element (larger
houses), but there is no direct relation between more storks and more children. So, if
there is an observed correlation between two variables, we need first to ask whether
a causal relationship might exist (rather than both being accounted for by some
other factor), and if so, what causal mechanisms between the two observations can
be adduced, in this case the size of the roof. Finally, we need then to examine the
evidence in support of the hypothesized causality. Returning to tobacco, needless
to say history has shown that the correlations were unquestionably attributable to
a causal relationship (supported by evidence of cell damage by carcinogenic sub-
stances such as tars in cigarette smoke) between smoking and lung cancer (as well as
other diseases).
One of the most prominent epidemiologists who argued that smoking was indeed
a causal factor in the development of lung cancer was Sir Austin Bradford Hill
(1897–​1991). Hill trained as an economist after tuberculosis put an end to a career
in medicine. From economics, he went on to statistics and epidemiology, taking
up a professorship in medical statistics in the London School of Tropical Medicine
in 1947. It was just 3  years later, in 1950, that he cosigned with another eminent
British epidemiologist, Sir Richard Doll, the first key paper linking smoking to lung
cancer [15]. Bradford Hill went on to establish a series of nine criteria that should
be fulfilled for a correlation to be considered as having sufficient evidence of bear-
ing a causal relationship to the incidence of the disease or outcome. These criteria
include the strength of the effect and the consistency or reproducibility of the find-
ings. Other factors include plausibility and experimental evidence (demonstrating
a biological mechanism when data are available). If such data are available, then one
would expect another criterion to be fulfilled—​that of “coherence.”
Today, in the endocrine disruption debate, despite many examples fulfilling all of
the Bradford Hill criteria, experts are continually being challenged when they pro-
duce epidemiological evidence on associations between disease incidence and expo-
sure to certain chemicals, even when backed up with experimental data. So, often
we are told correlations are only correlations and don’t imply causation. Similar crit-
icisms have continually been exploited by scientists from industry (or even scientists
from academia with interests in deflecting action) and by lobbyists acting on behalf
of industry. Other examples include lead in gasoline and brain development and
cardiovascular disease, asbestos and mesothelial cancer, mercury and brain disease.
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Without both (clearly demonstrated causation based on established mechanisms

and the demonstration that the mechanism is linked in turn to an adverse effect on
health [adverse outcome]), we are repeatedly told that nothing can be done about
the risk and that no precautionary action can be taken.
Conversely, and equally unfortunately, sometimes some people will make their
decisions on when to act without either reliable epidemiological evidence or any
knowledge of mechanisms of action. Unfounded associations can be given wide
press coverage. One of the most notorious examples is the fallacy of the linkage
between autism incidence and vaccination that arose from a disgraceful example
of editorial negligence and criminal scientific behavior. It also illustrates the pub-
lic’s need to attribute a cause to the startling increase in ASD incidence. The main,
supposedly “scientific,” evidence for the vaccine-​autism legend was the irrespon-
sible publication in 1998 by the respected British medical journal, The Lancet, of
a paper linking cases of chronic enterocolitis and regressive developmental disor-
der in 12 children with the triple vaccine for measles, mumps, and rubella (MMR).
The article reported that 8 of the 12 sets of parents attributed the loss of language
skills and the developmental regression to the MMR vaccine. Twelve years later, the
Lancet retracted the article after the senior author, Dr. Wakefield, was found guilty
of unethical conduct; of selecting the children, some of whose parents were try-
ing to sue the vaccine manufacturers; and of accepting money for his research from
lawyers acting on behalf of the parents, who obviously had an interest in positive
associations being published. Since the original publication, besides the loss of pub-
lic trust in vaccinations, useful money has been diverted into studies that disproved
the findings. To these, what should have been unnecessary costs, one also has to take
into account the public health cost of the renewed incidence of measles in certain
areas, some cases of which can be fatal and others can have lasting sequels.
Given the importance of these debates, I briefly summarize the “correlation-​and-​
causes problem” next and include some ideas on why and when the precautionary
principle should be invoked. The argument that correlation is not a demonstration
of causality is always present in discussions on endocrine disruption, as it is in the
acrimonious, decades-​long debate on climate change.
In both cases, correlations are presented between anthropogenic (human) activity
and global changes. For climate change, an association is drawn between increased
production of CO2 , largely due to the burning of fossil fuels, and increased global
temperatures. In terms of endocrine disruption, endocrinologists observe massive
increases in noncommunicable diseases (i.e., diseases not caused by an infectious
agent such as a bacteria or a virus), including metabolic disease (such as obesity and
diabetes); neurodevelopmental disorders (such as ASD and ADHD); reproductive
cancers (breast, prostate, and testicular cancer); and infertility incidence. All of
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Counting the Costs 147

these upsurges in incidence are paralleled by increases in numbers and concentra-

tions of chemicals with EDC activity in the environment. Masses of experimental
data provide plausible mechanisms linking chemicals to outcome.
Loose associations based on spurious observations, whether based on just a few
cases or derived from large data sets, can be used irresponsibly, as in the “vaccination-​
causes-​autism” scaremongering. So, to be able to answer the argument that “cor-
relation is not a demonstration of cause,” we need substantial bodies of evidence
from epidemiology combined with plausible mechanisms, most often derived from
experimental work. Then, we can ask, Does the evidence we have fit with the scien-
tific theory?
In the case of climate change, theory tells us that pumping CO2 into the atmo-
sphere will, all else being equal, increase global temperatures. Thus, billions of tons
of CO2 from the burning of fossil fuels are likely to be a major factor in the observed
temperature increase.
In the case of endocrine disruption, we know that natural hormones act at very
low doses (in the range of parts per billion), so it is plausible that the increasing
numbers and amounts of human-​made chemicals present in the environment and in
our bodies are acting on these regulatory systems at low exposure levels.
In both cases, because the evidence fits the theory, we have to ask ourselves,
What is the cost of inaction? The next logical question is then: Should the precau-
tionary principle should be applied? And if so, when? As Philip Handler, former
president of the American Academy of Science, is quoted as saying: “A sensible
guide would be to reduce exposure to hazard whenever possible, to accept sub-
stantial hazard only for great benefit, and no hazard at all when the benefit seems
trivial” [16].
In fact, the “we can’t act until we know the mechanisms underlying the effect”
argument has long been deployed by skeptics, going back far further than the debate
around smoking and lung cancer. An often-​quoted example is that of the British phy-
sician John Snow (1813–​1858), who proposed that a water pump was the source of a
major cholera outbreak in London in 1854. Considered to be one of the first epidemi-
ologists, Snow fought against the prevailing ideas that diseases such as the plague and
cholera were caused by bad air or “miasma.” Worse, at that time, poor people were
considered more liable to fall sick due to their moral depravity, which weakened their
constitutions. Even though he was working a decade before Louis Pasteur’s formal
demonstration of the germ theory of disease, Snow argued that diseases such as chol-
era, yellow fever, and typhoid fever were transmitted from person to person by “impu-
rities” in water. In the case of cholera, he suspected that the disease started in the
intestines. His theory proposed that a series of events started with drinking water con-
taminated by sewage waste from a previously infected person [17]. By drawing a map of
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the cholera cases in the area with the worst outbreak, he identified a water pump
as the origin of most cases. Because his theory was disputed and even ridiculed, he
resorted to removing the handle from the pump—​whereupon the epidemic ceased.
The case of Ignaz Semmelweis (1818–​1865) and his analysis of the cause of puer-
peral, or childbed, fever is perhaps more tragic. In 1847, at the age of only 26, working
as an obstetrician in Vienna, he proposed that women (and their babies) died from
childbed fever by being contaminated by doctors who had been carrying out autop-
sies on decomposing bodies. He compared the statistics of the numbers of deaths
due to fever in hospitals where doctors went from autopsies to delivering babies and
in hospitals where only midwives were trained. As the midwives were not allowed
to carry out autopsies, there were virtually no cases of puerperal fever in their hospi-
tal. Despite these statistics and other ingenious demonstrations, Semmelweis could
never persuade his colleagues to wash their hands between carrying out autopsies
and tending to women in childbirth. In short, in the absence of knowledge of mech-
anisms, he was derided. The disputes provoked severe depression in Semmelweis,
and in 1865 he was committed to a mental institution. Within 2 weeks he was dead,
probably from injuries incurred when restrained [18].
Thus, even in the absence of an established mechanism, the existence of a hypoth-
esis to explain a linkage between two phenomena (in the preceding case, puerperal
fever and unwashed hands), coupled with an observed correlation, may be sufficient
to warrant acting on the precautionary principle. At the same time, it is important
to continue to seek a mechanism to further ground the hypothesis. Furthermore,
failure to find such a mechanism (as in the case of children’s vaccines and autism)
can point to other possible explanations (such as fraudulent behavior) for the sup-
posed correlation.
Perhaps the bottom line for us looking at the question of disruption of thyroid
hormone action on brain development would be that there is a wide range of basic
evidence and observational studies showing strong, plausible, and dose-​response
associations of various EDCs with thyroid function. Nonetheless, due to the com-
plexity of the underlying physiology and the limitations of epidemiology, we still
lack knowledge on the extent of thyroidal effects of EDCs. As such, there is an
urgent need to organize further randomized interventional studies on the topic and
combine this approach with well-​designed experimental data.

The convicted brain drainers that decrease IQ: flame

retardants from coast to coast and beyond

I have just mentioned the data on PBDEs as causative agents of IQ loss in children
born to mothers who had high levels of these flame retardants in their bodies when
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Counting the Costs 149

pregnant. In the most exposed mothers, the children born showed between 4 and
5 lost IQ points whether they were living in California, New  York, or Ohio. To
my knowledge, no epidemiological studies have failed to show effects. Every study
showed significant IQ decreases. So, you might well ask, why are these products still
used? Why weren’t they fully tested before being released on the market? How come
it’s taken so long for people to recognize their dangers?
The answer to the first question is that these products are belatedly being phased
out. The chemistry is complicated, hence the phaseout also is complicated and rid-
dled with loopholes for different PBDEs as manufacturers have constantly sought
ways of keeping these products on the market. But, PBDEs were on the market for
the better part of 50  years before the phaseout began. Production started in the
1960s and then increased rapidly at the end of the 1970s following the bans on bro-
minated additives in leaded gasoline (see Chapter 3 for an explanation of why bro-
minated chemicals were added to the already-​toxic leaded gasoline).
Much of the PBDE manufactured and destined for use in furniture (in the form
of polyurethane foam) was based in the United States and Canada. Three principal
mixtures have been marketed, classified according to the average number of bro-
mine atoms added: 5 (penta-​BDE), 8 (octa-​BDE), or 10 (deca-​BDE). In 2001, world
production was about 66,000 tons [19]. It was recognized in the early 2000s that
PBDEs were persistent and rapidly accumulating in the environment. This find-
ing led to the penta-​and octa-​BDE forms being banned in the European Union in
2004 and the deca-​BDEs in 2008. However, this form, with its 10 bromine atoms,
is registered, and hence permitted, for specific applications in the European Union.
Some US states banned the penta-​and octa-​PBDEs in 2003, followed by a nation-
wide ban on US manufacture of these two forms of PBDE in 2004. But, as of 2008,
deca-​BDEs were still in production in the United States, and it was not until the end
of 2009 that a 3-​year phaseout was agreed on.
Unfortunately, when both the EU and US authorities ruled that production
of PBDEs should be limited to the deca-​PBDE form (which contains 10 bromine
atoms), they overlooked the fact that this form could be broken down into the
banned octa-​and penta-​BDE forms (with 8 and 5 bromine atoms, respectively). In
fact, the form of PBDE most associated with IQ loss (called PBDE-​47) has only
four bromine atoms, but it seems to be the most stable and therefore the one that
bioaccumulates most.
If you consult the Environmental Protection Agency (EPA) site for informa-
tion on PBDEs today,9 you are directed to a fact sheet for parents on reducing
their child’s exposure to flame retardants. In the downloadable pamphlet, the
reader is told that a number of studies “indicate that exposure to certain flame
retardants may be associated with a range of health effectings, including reduced
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IQ, Learning Disorders, Reduced Fertility and Thyroid Disruption.” As these

flame retardants are not chemically bound to the materials they are used with,
whether they be plastics, foam, textiles such as curtains and carpets, or electronic
components they leach out. This means they are continually released into the
atmosphere; for instance, every time you sit on a foam-​fi lled cushion or sofa,
you have a fair chance of getting a waft of PBDEs. From the atmosphere, they
settle and accumulate in household dust. Small wonder then that levels of PBDE
in toddlers crawling around the floor are often higher than for adults or older
children. It is also no surprise that the EPA site in 2015 indicated “some reports
indicate levels are increasing.” Why, then, are these are increasing despite the ban
more than 10 years earlier?
It has been suggested that sources of the increase could be imported products that
haven’t been checked for their conformity to US standards. Of course, the other
possibility the EPA mentions10 is the breakdown of the permitted deca-​PBDE into
the banned lower brominated forms. Perhaps someone should have thought of that
before giving market authorization! Well, it’s never too late to recognize the errors
of the past. Unfortunately, for many children, it is too late to start their brain devel-
opment again in a PBDE-​free environment.
Even though manufacturing of PBDEs was largely based in North America,
significant levels of PBDEs in breast milk and other body fluids are found world-
wide: in Taiwan [20], in Japan [21], in Spain [22], in Tunisia [23]—​in fact, everywhere
people have looked. Levels in Europe are about 10 times lower than in the United
States, but we all have our share. PBDEs have repeatedly been shown to be potent
thyroid hormone disruptors. To cite just a few examples, PBDEs have been shown
to alter different aspects of thyroid hormone signaling in humans—​including preg-
nant women [24]—​in lambs [25], in laboratory models such as rats and mice, and in
wildlife [26]. So, given the need for thyroid hormone for optimal brain development
at all stages of life, it is not surprising to find that if pregnant women are exposed to
high levels of PBDEs, then their children score less well on IQ tests.

Mind-​m ugging pesticides

When we were in Copenhagen poring over the data for EDC-​related IQ loss, we all
were stunned at the final figures we came up with once we’d taken a certain class of
pesticides, the organophosphates, into account. First, the economist and statistician
in the group, Professor Martine Bellanger, set about researching the exposure levels
in different European countries, including Germany [27], Italy [28], and France [28].
She also came up with data from Norway, the Netherlands, and Spain. The next
step was to take the prospective studies carried out in the United States on mothers’
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Counting the Costs 151

exposure levels and the IQs of their children. By so doing, Martine was able to cal-
culate how many IQ points could be lost per child born to a European mother with
a given exposure level.
Even though there were only three longitudinal studies, the data were consistent
across areas and very worrying. One study used the CHAMACOS cohort already
mentioned [6]‌. In this work, the authors were looking at chlorpyrifos, one of the
main organophosphate pesticides. The group studied was predominantly composed
of farmworker families from California agricultural communities. The research-
ers wanted to know not only what levels of exposure mothers were facing but also
the children’s exposure levels, and then they wanted to see if these exposure levels
affected brain development.
The researchers asked for samples of urine from about 300 pregnant women and
from their children at different ages up to the age of 6. When the children were
7 years old, their neurodevelopmental scores were assessed using well-​standardized
intelligence tests. The statistical analysis was clear. Only prenatal (and not postna-
tal) exposure affected IQ. This result fits with recent knowledge on two fronts. First,
the general idea that the earlier in development exposure to a chemical occurs, then
the worse the outcome; second, it corresponds to the vulnerable window of early
pregnancy when thyroid hormone levels are critical for brain development.
To better analyze the result and to test for correlations between pesticide expo-
sure and IQ, the pesticide levels found in mothers’ or children’s urine were divided
into five sets, from highest to lowest. The children born to mothers with the highest
exposure levels scored 7 IQ points less in the tests than the children whose mothers
were least exposed. Similar findings were reported for children in the two cohorts
studied in New York City [7, 27]. Even though the children were younger in these
studies, the neurodevelopment scores were significantly lower if mothers had high
organophosphate pesticide levels [7]‌or if the umbilical cord blood showed high lev-
els of prenatal exposure [8]. Again, IQ scores in the highest-​exposure groups were a
full 6 points below those with lower prenatal levels.
In the same manner that we’d carried out the PBDE analysis, once we had expo-
sure levels in European populations on the one hand and data on how different levels
of exposure were associated with IQ loss on the other, Martine could set to work on
her statistical analysis of economic costing. In the meantime, Tom Zoeller and I were
researching the scientific literature to find epidemiological studies and mechanistic
data on how chlorpyrifos affects the endocrine system, particularly thyroid signaling.
We came up with numerous articles from human epidemiology and from animal
studies showing complex effects of chlorpyrifos on thyroid hormone levels [29–​31].
Intriguingly, this pesticide was designed to act as an insect neurotoxin. It is
thought to act principally by inhibiting an enzyme, acetylcholinesterase, expressed
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in the nervous system of insects, but it’s also essential to our brain function. This
enzyme breaks down excess levels of an important neurotransmitter, acetylcholine,
at synaptic junctions (links between neurons). As these pesticides inhibit acetyl-
cholinesterase, there is a buildup of the neurotransmitter acetylcholine both in the
brain and where neurons meet muscles in the rest of the body. This excess synap-
tic stimulus causes neuronal overactivity, spasms and convulsions, and even death.
Using pesticides to inhibit this enzyme creates two problems. First, not only insects,
but also all other animals, including fish, birds, and humans, have the enzyme in
their nervous systems; second, even at concentrations below those needed to inhibit
the target enzyme acetylcholinesterase, the chemical can affect other physiological
systems. And, one of those “off-​target” effects seems to be interfering with the thy-
roid hormone axis at different levels. Oddly, epidemiology studies showed different
effects in women and men and more marked effects on hormone levels at different
ages [30]. Similarly, in vitro studies on neurons growing in culture showed effects
of the pesticide that were independent of effects on the enzyme—​puzzling indeed.
Finally, is not irrelevant to note that many nerve gases, such as sarin, which was used
by terrorists in the Tokyo underground attack in 1995, are also acetylcholinesterase
inhibitors.
But, whatever the multiple modes of action of chlorpyrifos, high levels of expo-
sure in pregnant women were robbing their children of vital brainpower. When we
finally put all the data together, the data on exposure in Europe (which uses more
organophosphates than the United States), with those data on IQ losses as a func-
tion of exposure level, we came up with a range of figures for the economic costing
of IQ loss that even at the low end were frightening (€46.8 billion per annum) and at
the top end were staggering (a massive €195 billion per annum). Given the work on
off-​target effects of the pesticide, we were fairly confident that a high proportion of
them were attributable to endocrine disruption, especially interference with thyroid
hormone action on brain development. All this amounts to a needless and avoidable
burden on Europe’s economy, brain potential, and future capacity.
Before leaving the pesticide story, here is just one reminder. The organophos-
phate pesticides are just one category of insecticides that have been used in the
environment for decades without full testing of their toxic and off-​target effects.
As mentioned in Chapter 3, in 2013 the European Food Safety Authority (EFSA)
looked at the data sets on nearly 300 pesticides. It concluded that over one-​third
of them had effects at some level of thyroid signaling, and another third dis-
played neurotoxic effects. Putting this information together, and knowing that
thyroid hormone is needed for brain development, one can hardly be surprised
to find “associations” between pesticide usage and neurodevelopmental disease
incidence.
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Counting the Costs 153

Currently, our lab in Paris is taking a hard look at a couple of fungicides, man-
cozeb and maneb. Both of these fungicides are metabolized (broken down) in the
body into two thyroid-​disrupting chemicals, ethylene thiourea and ethylene urea
[32]. It is known that agricultural workers and their families who are exposed to
either mancozeb or maneb have a higher incidence of these metabolites and higher
incidence of thyroid disease [33]. The consequences on their children’s development
have not been studied, but they are raising concern [34]. We are setting up experi-
ments to test effects of exposure to these chemicals on thyroid disruption and brain
development in early embryos. We’re using lab-​grown frog embryos, as they are
excellent models for early development of all vertebrates, including mammals and
humans. So far, we haven’t found any epidemiological data on levels of exposure in
the general public, so it will be impossible to confront our findings with any epi-
demiological data. The European Commission is also looking at the data on these
fungicides with a view to appraise whether to renew the authorizations for them
after 2017. It is hoped our experimental data will be available in time to inform the
decision-​making process.

An incomplete lineup of other culprits

We have just seen that maternal exposure to high levels of either organophosphate
pesticides or PBDE flame retardants caused 5-​point IQ losses in the intellectual
ability of the cohorts’ children. But, what if you’re unlucky enough to be born to
a mother who was exposed to both? How many IQ points do you lose then? And,
what about the dozens of other chemicals that are usually found in amniotic fluid?
The short answer to all of these questions is: We simply do not know.
In Chapter  3, we listed some of the different chemicals that have so far been
found in amniotic fluid. We also presented the evidence for their actions as thy-
roid hormone disruptors. Many of these chemicals also have already been linked
to IQ loss. Those with the thickest files of evidence are mercury, polychlorinated
biphenyls (PCBs), and perchlorate, an iodine uptake inhibitor. Of course, iodine
deficiency itself is associated with significant IQ loss. Here again, we are at the limits
of our knowledge. We simply do not know what are the effects on children’s brains
if their mothers are both iodine deficient and exposed to multiple thyroid hormone
disruptors.

Mercury still matters

As mentioned in Chapter 1, the cases of mercury contamination of fish in Japan in

the 1950s and grain contamination in Iraq in the 1970s brought the brain-​draining
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effects of this metal to the forefront of neurotoxicology studies in the 20th century.
If there was one take-​home message from these tragic cases,11 it was that, like all
brain drainers, developing fetuses and infants are the most sensitive to the effects of
mercury. Given their impact, one would like to think that lessons have been learned,
but mercury continues to contaminate universally today.
In Chapter  1, we saw that mercury forms a chemical complex with selenium.
Selenium is a vital element in the enzymes that activate and inactivate thyroid
hormone. So, high mercury levels change levels of thyroid hormone availability.
Interestingly, the morphological, cellular, and functional consequences of mercury
poisoning have parallels with lack of thyroid hormone during brain development
and ASD, including reduced populations of specialized neurons in the cerebellum
[35]. Today, we can see the link between these two ideas: Mercury inhibits produc-
tion of the active form of thyroid hormone, thereby producing a sort of local and
general hypothyroidism. Thus, mercury-​induced effects on reduced thyroid hor-
mone availability will interfere with brain development and exacerbate the neuro-
toxic effects of any other environmental factors.
Over the past century, mercury exposure could have resulted from three main
sources: consumption of organic mercury in the form of methylmercury, most often
from eating contaminated fish; mercury vapor released from mercury-​based tooth
fillings; and, in some countries until 2000, use of a mercury-​based preservative,
thimerosal, in vaccines. This mercury-​based component of vaccines is probably the
reason that vaccines were sometimes [36], without any hard evidence, associated
with cases of autism. However, in Europe and the United States, thimerosal was
withdrawn from use in vaccines in 1999, although whether it is still useful in certain
situations, such as tropical countries, is a matter of ongoing debate. Use of mercury
in tooth amalgams has also been radically reduced in most countries.
Today, most of the forms of mercury in the environment are by-​products of mul-
tiple industrial processes, notably fossil fuel burning (with coal-​fired power plants
major sources), the wood pulp industry, and factories that use mercury electrodes.
Discharges can enter freshwater and seawater, where bacteria in sediment can trans-
form inorganic mercury to methylmercury. This methylmercury can then enter the
food chain through fish.
Many think that mercury contamination is not relevant to us today and that
only high levels of contamination present any risk. Unfortunately, this is not
the case. In fact, the methods that Martine Bellanger applied to estimate the
economic costs of organophosphate or PBDE exposure had already been honed
when she was working with Philippe Grandjean on mercury [13]. In this study,
carried out with a number of European colleagues, they calculated mercury expo-
sure using samples of hair from nearly 2,000 women of childbearing age in 17 EU
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Counting the Costs 155

countries. Hair accumulates various metals and metabolites and is often used in
forensic, clinical, and research studies as a noninvasive means of assessing expo-
sure. Distinct differences were found in levels of contamination of about nearly
7,000 samples across Europe. Levels in hair were used to calculate how many
children were born with mercury levels in excess of the recommended limits and
hence to calculate IQ loss across populations. These Europe-​w ide calculations on
the economic consequences of IQ loss led to a conservative estimate of between
€8 billion and €9 billion a year. Thus, mercury, especially methylmercury, even at
low levels, remains a problem today. So, mercury pollution and the major contri-
bution of coal-​fi red plants to climate change [37] provide two strong arguments
to replace them with cleaner renewable energies.

PCBs as IQ drainers

The story of PCB exposure and IQ loss brings us back to Lake Michigan, discussed
in Chapter  3. I  mentioned there the data on how PCBs affect thyroid function.
Here, we take a look at the data on PCBs and IQ loss.
Rachel Carson’s Silent Spring [38] had alerted health authorities to the pos-
sibility that DDT (dichlorodiphenyltrichloroethane) exposure could be affecting
humans and not only fish and birds. Fortunately, these ideas triggered studies into
the amounts of DDT and its metabolites in human milk and the relationship of
the level of the metabolites to breast-​feeding duration. A pilot study took place in
North Carolina [39]. Analysis of milk detected not only the insecticide but also
high quantities of PCBs, a category of chemicals that we now know, largely thanks
to Tom Zoeller’s work, significantly modify thyroid levels in exposed groups [40].
Like DDT metabolites, PCBs were known to accumulate in animal tissues and,
as they are soluble in fat, particularly in adipose tissue. Milk has a high fat content,
and it was logical to check breast milk for PCB content. Michigan was chosen for
detailed study not only because of the probability of consumption of contaminated
fish from the lake but also because an industrial accident had contaminated local
dairy farms in 1973 and 1975 with a similar chemical, polybrominated biphenyl
(PBB). The local health authority covered the cost of PBB measurements in nursing
mothers’ milk and proposed PCB testing as well, but at the mother’s expense. Over
1,000 nursing mothers paid to have their breast milk analyzed for PCB content [41].
In 1981, the values of PCBs in these milk samples obtained in 1977 and 1978 were
published [42]. Significant contamination was found in 75% of samples. Further, it
was estimated that the babies, as they were growing and building tissues, would be
assimilating and not eliminating most of the PCBs, so concern was raised for the
long-​term health effects of this postnatal exposure.
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156 Toxic Cocktail

It was, however, not until nearly a decade later, in 1990, that the first associations
of PCBs with adverse effects on intelligence and behavior were fully documented
by Joseph and Sandra Jacobson and a colleague [43]. The Jacobsons had managed
to obtain data on amounts of different species of lake fish eaten by 8,482 mothers
who were due to give birth in 1980–​1981 in the Michigan area. Different fish species
were known to accumulate greater or lesser amounts of PCBs, so 339 of the mothers
who had reported eating trout or salmon (at the top of the food chain) from Lake
Michigan and 110 control mothers who had not eaten these fish were requested to
join the study. Over 300 agreed. PCB exposure was evaluated at the birth of infants
of these mothers by analysis of maternal serum, umbilical cord blood, and, shortly
after, breast milk.
Levels of PCBs in breast milk were 100 times greater than those in any serum
sample, whether from maternal or umbilical cord blood. Despite the fact that
maternal levels of PCBs were only slightly higher in women who had eaten lake fish
compared to those who had not, already at birth significant differences were found
in fetal and postnatal growth and in short-​term memory during infancy as a func-
tion of PCB exposure. The main lesson to be learned from the Jacobsons’ study is,
as they emphasized, that despite the higher levels in milk, it was the prenatal PCB
levels, deduced from umbilical cord values, that showed the largest associations with
neurodevelopmental potential, underlining the importance and the vulnerability of
this window of brain formation and growth.
When the children reached the age of eleven, 212 of them participated in a new
series of tests, based on reading and arithmetic skills, to see whether the differ-
ences between exposed and control groups were still present. Children’s blood levels
of PCBs were also measured at this time. The average IQ of all the children was
107, but the average IQ of the 30 children in the highest-​exposure group was 6.2
points lower. So, yet again, for pregnant women, exposure to a high level of just one
thyroid-​disrupting chemical can knock more than 5 IQ points off their children’s
intelligence.

Iodine uptake blockers: what does

the epidemiology tell us?

In Chapter 3, we looked at the effects of perchlorate on thyroid function and went

through the data on what it is used for, namely, explosives, rocket propellants, air-
bags, and fireworks. The take-​home messages were that it is a potent inhibitor of
iodine uptake, and that there are significant amounts of perchlorate in the environ-
ment. Therefore, it wasn’t difficult to come up with the hypothesis that if pregnant
women were exposed to high levels of perchlorate, then it could adversely affect their
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Counting the Costs 157

levels of iodine and thyroid hormone and then the developing brain of their chil-
dren. Although the idea may be obvious, obtaining the funding to set up a cohort of
pregnant women, obtain measures of perchlorate exposure, relate exposure levels to
thyroid function, and then carry out longitudinal studies on the cognitive outcome
of their children is not. But, Pete Taylor, a young clinical endocrinologist working
in Cardiff, Wales, managed to do it.
With colleagues from Italy, Ireland, and the United States, Pete analyzed urine
levels of perchlorate in a number of women from Cardiff, Wales, and Turin, Italy
[44]. Perchlorate was found in the urine of all the mothers, and iodine levels were
low. The next step was for Pete and his colleagues to look for associations between
prenatal perchlorate levels for these mothers and their children’s IQ scores at age
3. The results confirmed the hypothesis. Women with the highest perchlorate expo-
sure had increased risk of their children being in the lowest group for IQ scores. Of
the different cognitive tests used to measure overall IQ, the most marked effects
were seen on children’s verbal expression.
Also in Chapter 3, the environmental levels of two other chemicals that can inter-
fere with iodine uptake, namely, nitrate and thiocyanate, were discussed. Nitrate is
probably an even greater worry in terms of inhibiting iodine uptake than perchlo-
rate. Even though it is less potent in its action on the thyroid gland, because there is
so much more nitrate in the water supply, it could represent an even greater threat
than perchlorate. Only one group, a group working for the US government, has
focused on measuring actual levels of all of these factors in amniotic fluid. Their
results showed high levels of all three iodine uptake inhibitors in amniotic fluid
from American mothers [45]. The highest concentrations were for nitrate and thio-
cyanate. Unfortunately, at present, there are no data on either maternal exposure
levels or children’s cognitive capacity as a function of nitrate levels.12

There is no safe level for lead exposure

Before moving on, it’s important to mention the two classic IQ drainers, lead and
alcohol. The effects of maternal alcohol consumption on brain development and
children’s IQ are now notorious, but unfortunately, some women still are not able
to heed the warnings. The link between modifications in thyroid signaling and alco-
hol were discussed in Chapter  3. Regarding lead, the main sources of this heavy
metal in the environment, paint and gasoline, have been removed by legislation in
the Northern Hemisphere. Leaded gasoline was an awful idea of Thomas Midgely
Junior, who certain authors have described as “the most damaging single organism
to have ever existed” [46]. Despite many deaths in the factory producing the addi-
tives and the fact that demonstrating its supposedly innocuous nature nearly killed
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158 Toxic Cocktail

Midgely, the US automobile industry introduced leaded gasoline, along with its
brominated antioxidants, in the 1930s. The United States was also the first to legis-
late against it in the 1970s. Europe and China took until the year 2000 to enforce
their rulings (see Chapter 1 of Losing Our Minds [see Note 10] for a full account).
Unfortunately, children and adults in many countries are still exposed to high levels
of lead, despite the fact that most epidemiologists today consider that there is no
safe level for lead exposure.
In 2011, the United Nations carried out a costing study, taking into account that
many countries are still in the grip of leaded gasoline. The research calculated the
multiple benefits of a global phaseout, which would reduce not only intellectual
damage but also cardiovascular disease and criminality. The link between urban
lead exposure and criminality is a sequence of events starting with lower IQ, learn-
ing problems, greater school dropout rates, lack of qualifications, unemployment,
and an increased tendency to turn to crime. The United Nations estimated that
the amount saved by legislation could reach US$2.4 trillion per year (4% of global
GDP). The UN report referred to WHO statistics showing that, in developing
countries, between 15 million and 18 million children were affected by brain dam-
age caused by leaded gasoline.
It is worth noting that in all these studies of leaded gasoline, it is impossible to
unravel the effects that are caused by lead itself and those due to the brominated
additives that could be targeting thyroid hormone signaling more directly. Given
that the increase in autism seen in the United States has increased most significantly
since the removal of leaded gasoline from the environment, one has to ask which
other environmental pollutants are implicated.
The UN report also underlined that rather than being a burden on econo-
mies, taking environmentally favorable actions produces national and interna-
tional benefits at multiple levels. An optimistic conclusion would be that such
arguments should inform current governmental decisions on other known brain
drainers. The same arguments can be applied to regulating those chemicals for
which we may not yet have epidemiological evidence from long-​term cohort
studies, but for which we have good data from experimental studies on their
effects on thyroid hormone signaling and brain development. However, whether
such evidence will convince regulators remains to be seen, a point I return to in
the final chapter.
  159

8
Who Really Picks Up the Bill?

Fact or fiction

For a change, let’s start off with a movie, Idiocracy.1 Made in 2006 by Mike Judge,
the story involves a “volunteer” selected by the military to undergo a hibernation
experiment. The protagonist, Private Joe Bowers, is a librarian of average intelli-
gence and therefore considered as somewhat dispensable to day-​to-​day military life.
Joe is supposed to go into a state of dormancy for 1  year as a way of testing the
army’s hibernation protocol. Needless to say, the experiment goes wrong. Joe wakes
up 500 years later, in 2505, and discovers he’s the brightest person alive, and this by
a wide margin. Human intelligence has plummeted, and a sex-​driven dystopia has
taken over. For the previous 500 years, the more intelligent members of society have
been too preoccupied and interested in other things to start families, while every-
one else has been reproducing prolifically.
In Chapter 4, I explained that a similar argument was used by Woodley and col-
leagues in 2013 to account for the decrease in IQ documented in the 100 years sepa-
rating the Victorian era from the present [1]‌. The trouble is that, today, IQ loss and
increases in neurodevelopmental disease are occurring simultaneously. If there is a
dysgenic2 component contributing to this increase, it is undoubtedly being exacer-
bated by endocrine disruption.
As the graphs on autism-​related disorders show (see Figure 5.1), the increase is not
straightforwardly arithmetic (a straight line), but exponential (curving upward). In

159
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160 Toxic Cocktail

the United States, the incidence of autism spectrum disorder (ASD) quadrupled
between 2000 and the statistics published in 2014 [2]‌. So, if the incidence were to
continue to double every 6 or 7 years, half the US male population born in 2042
would be on the autistic spectrum. But, as the steepening of the graph shows, the
increase accelerated between the 2000 and 2014 publications, each based on data
collected 4 years before. Reassuringly, the latest publication from same group, ana-
lyzing data collected in 2012, showed the ASD incidence had stabilized at 1 in 68
children [3]. However, if one looks closely at statistics [2], depending on the state
where the data were collected, up to 45% of children with ASD had IQs below 70,
the threshold for intellectual disability. Even worse, if those with borderline intel-
lectual disability (IQ between 70 and 85) are grouped with those with IQs below
70, then the percentage of children diagnosed with ASD who are either intellectu-
ally deficient or on the borderline is well over 50%, and as high 60% in some states.3
Taking such statistics with the other data on IQ loss cited in Chapter 4 doesn’t bode
well for the level of general intelligence in 2025, let alone the 2505 of Idiocracy.

Imbroglios in Brussels

The year 2015 was a particularly demanding one for scientists, regulators, and poli-
ticians concerned with researching and regulating endocrine-​disrupting chemicals
(EDCs). Like the various participants in the UN conference on climate change,
held in Paris in December 2015,4 scientists involved in EDC work find themselves in
the midst of a debate, played out at the level of the EU Commission in Brussels, that
all too often is reduced to an “industry-​versus-​scientists” scenario. The public is to
a large extent held hostage between these opposing camps, given little opportunity
to come to terms with the implications of the debate. Even more rarely do they have
the opportunity to express an opinion, apart from when they go to the voting booth
and decide whether climate change or the health costs incurred by EDCs are more
important than local jobs (assuming such concerns enter the political debate).
Therefore, for many scientists the time has come to engage and to explain. To
revisit the words of the blind soothsayer Tiresias in Sophocles’ Oedipus Rex as he
bewails the metaphorical blindness of those who refuse to act on the truth even
when it is explained to them: “Alas, Alas, What use is knowledge, if knowledge is
not used?” Today, many scientists consider that knowledge about EDCs is not being
acted on. Worse, some of us believe that it’s being willfully ignored, at great cost to
human health, the environment, and biodiversity.
In June 2015, I twice took the train to Brussels to participate in workshops and
seminars on the different aspects of EDC identification and regulation. Between
these two trips, I  spent 2  days in Organization for Economic Cooperation and
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Who Really Picks Up the Bill? 161

Development (OECD) meetings in Paris on EDC testing. I’d already been to

Brussels in February and was back there for more workshops in November. All the
time spent travelling and at these meetings, however interesting and important they
are, is time out of my lab and time not spent with my students or writing papers
and (of course) applying for research grants to keep the work going. But, many of
us scientists feel there’s a certain urgency. We consider that we have a responsibil-
ity to explain the knowledge we have gained in the last decade to regulators and
politicians.
But, how do we explain to regulators the epigenetic effects of chemicals as they
are revealed one by one? What about mixture effects, as yet virtually unstudied
and not taken into account in exposure or risk calculations? How do we foresee
the delayed effects of exposure to these mixtures in the womb on health problems
10 or 50 years later? And, what about the transgenerational effects? What are the
economic consequences? The effects on social and political structure? Can chemists
design compounds that are more beneficial to human health and the environment?
As we’ll see in the next chapter, it is not impossible to find answers to these various
questions, even if doing so entails rethinking a lot of our ideas about what we expect
from our society today and what we provide as legacy for future generations.
In the meantime, ensuring that our voices as scientists are heard in this debate is
crucial. Excuses are constantly being made for regulatory decisions to be postponed
yet again. To understand the delays, one has to go back over the last few years of
exchanges between the EU Parliament, the EU Commission, and the main players
in the chemical industry both sides of the Atlantic, who pay close attention regard-
ing how Europe regulates the production and use of chemicals.
The other factor to take into account is the constantly growing public awareness
of the health problems linked to chemicals present in the environment. It was prob-
ably thanks to this increased level of knowledge among the general public that in
March 2013 the European Parliament adopted in a single reading a 35-​resolution
text [2012/​2066(INI)] calling on the European Commission to enact appropriate
policy on EDCs.5 Although nonbinding, this resolution was meant to reaffirm the
political will of the European elected representatives to legislate on EDCs. Indeed,
the law drafted in 2009 originally stated that the EU Commission had to define
scientifically EDCs before December 2013. Yet, when I attended that workshop on
June 1, 2015, nothing had been defined. One might well ask: Why have they done so
little between 2009 and June 2015?
By way of a prelude to answering these questions, it is no exaggeration to say that
the March 2013 resolution from the EU Parliament prompted further action from
industry on both sides of the Atlantic. They had been participating in the debate for
years, even before the first rulings on pesticides with potential EDC effects back in
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2009. But now, the chips were down, and they were going to have to move fast—​and
they did.
Their first, most visible, step was to employ a method that has been tried, tested,
and proven effective in many previous cases, from tobacco and asbestos to lead in
gasoline and human contributions to climate change. It is simple: create a scientific
controversy around the issue—​effect guaranteed. Show that even scientists working
on the topic concerned have certain differences of opinion on the matter, and things
will inevitably stall. In this case, two parallel approaches were applied. In June 2013,
a group of scientists signed a letter to Anne Glover, the chief scientific advisor to
the then-​president of the EU Commission, José Manuel Barroso. A month later, to
ensure that the letter received the attention of the media, the same basic message
was presented in an editorial published simultaneously in no less than 14 differ-
ent toxicological journals [4–​6]. It appeared online on July 9, 2013. As revealed by
the tenacious investigative journalist Stéphane Horel in her excellent overview of
European EDC legislation “A Toxic Affair” [7]‌, of the 18 toxicologists who signed
this editorial all but one of them had ties with industry.
It was a short editorial, just over a page in length. After all, it’s better to stick to
broad statements and not to enter into details when creating controversy. In fact,
the title of the editorial was long enough and set the stage. It announced that not
only did the authors consider that the precautionary recommendations on EDCs
proposed by the EU Commission scientifically were unfounded, but also that these
recommendations defied common sense and well-​established science. When the
term common sense is used in such a context, it recalls Einstein’s dictum: “Common
sense is the collection of prejudices acquired by age eighteen.” It certainly seems that
prejudice rather than reason was foremost in the minds of those signing this edito-
rial. By flagrantly failing to declare their conflicts of interest, insofar as 17 of the 18
signatories had ties with the industrial sectors concerned by EDC regulation, they
were ignoring the rules of current scientific publishing standards.
The immediate aftermath of the letter to Glover and of the editorial was twofold.
First, there was a riposte from over a hundred respected endocrinologists. Detailed
and closely argued letters presenting the known effects of EDCs on health were
published with appropriate detail and references in a series of major endocrinology
journals, including Endocrinology and Andrology [8, 9], and environmental health
journals [10, 11]. One reply described the editorial as “largely ignoring the continued
efforts of many scientific expert groups at European and international levels as well
as the expertise and competence of European decision makers,” oversimplifying
endocrinology, ignoring endocrine programming during development, and “blur-
ring … the border between what constitutes science and what belongs to the realm
of political, societal and democratic choices” [10].
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Who Really Picks Up the Bill? 163

Second—​the most damaging effect—​the commission had been handed the

excuse it needed to procrastinate on any action in terms of regulation. In a highly
visible attempt to resolve the apparent controversy, Anne Glover convened a meeting
between six representatives of both sides. The encounter took place one afternoon
in October 2013. As clearly stated in the minutes of the meeting,6 “The participants
quickly agreed,” a consensus being reached on definitions of EDCs, on the existence
of nonmonotonic dose responses7 and the difficulties of determining thresholds for
EDCs. However, the question of potency8 was raised and not resolved in the short
meeting. So, there wasn’t that much to discuss. There were—​and this is still the
case—​no major disagreements on basics.
Yet, despite this rapidly obtained consensus on most points, notably definition,
no final proposal regarding the scientific criteria to identify EDCs has, as of early
June 2016, been published by the European Commission. Worse, as stated by repre-
sentatives of the commission at the meeting on June 1, 2015, the commission contin-
ues to justify its inaction by suggesting that controversy still exists and needs to be
resolved. Industry’s tactics have paid off well—​for them.

Other players weigh in

In the 2 years between the parliamentary resolution and the workshop in Brussels,
I  met a number of people working for the US government. Most often, these
encounters would be at the OECD, and many of our American counterparts were
working in the Environmental Protection Agency (EPA). Depending on whether
one spoke to someone with a research role or to an administrator, the ideas and
opinions would differ slightly. It was evident that some administrators were
clearly and openly very worried about the effects on the economy of the pending
EDC legislation and keeping active contact with the decision-​makers in Brussels
on the topic.
In “A Toxic Affair” Stéphane Horel [7]‌noted that the US chemical industry had
argued that the United States stood to lose €4 billion on imports into the European
Union per year.9 US pressure came on top of EU industry lobbying, preparing the
ground for the scientists tied to industry who had penned the letter to the commis-
sion. The timing of the letter from the industry-​linked toxicologists, their edito-
rial (June/​July 2013), and the pressure from both the EU and US industry couldn’t
have been better. Soon after these events, a letter from the secretary general of the
commission, Catherine Day, was addressed to the head of the commission’s envi-
ronment department telling him “to stand down” on the EDC criteria [7]. The
EDC dossier was later transferred from the directorate general (DG) dealing with
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environment to the DG responsible for health. The pressure from industry on both
sides of the Atlantic continues unabated. It was evident both in the June 2015 work-
shop and in the OECD meetings I attended later that month.

Taking the public’s opinion into account—​or not

One of the other actions instigated by the commission since 2013 was a public consul-
tation on the question of regulating EDCs. The online questionnaire was complex.
It offered four possible options for legislation dealing with the questions of defining
and regulating EDCs. Not surprisingly, many interested nonscientists among my
acquaintance asked me to explain the terms used and what the implications were
regarding each of the options. I suggested they follow the advice of a well-​respected
nongovernmental organization (NGO), the Health and Environment Alliance
(HEAL), which had posted an easy-​to-​follow guide on the web. In fact, the option
(option 3) proposed by HEAL was exactly the same as the option defended by the
Endocrine Society in its extensive, scientifically argued response. The Endocrine
Society is a US-​based organization with global reach. As a European member of
the Endocrine Society, and a member of their Task Force on Endocrine Disruption,
I  have been directly involved in their efforts to explain the science of EDCs to
decision-​makers in Europe (and the United States). I also participated in preparing
their response to the public consultation.
The results of the public consultation were presented at the workshop on June 1,
2015, and a report analyzing the responses to the questionnaire on EDCs by the EU
Commission was published a month later.10 This consultation apparently obtained
one of the highest-​ever responses to a public consultation organized by the commis-
sion, obtaining 27,000 responses from individuals, organizations, and governments.
The statistics and what the commission has done with them so far are quite telling,
so we’ll look a little closer at them. We’ll start with the response from individuals.
The overwhelming contribution, in fact 95% of the responses (25,000), came from
individuals via the main NGO campaigns. This figure underlines not only that
people are aware that many of the chemicals act as EDCs, but also that they want
their governments to do something about it. Of these responses received through
the NGOs, 67% were from women aged between 25 and 54. This statistic reflects
the concerns of mothers and potential mothers regarding their children as well as
those of other women in relation to their own health. Their understandable disquiet
is shared by the EU Parliament. In the resolution adopted in 2013, the EU parlia-
ment specified, in point 4,11 that the need to protect women from the potential risks
of EDs is of utmost importance. So, what did the commission do with this over-
whelming response provided by individuals through organizations in which they
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Who Really Picks Up the Bill? 165

had confidence? In the June workshop, a representative of the commission openly

said they would focus on the other replies, virtually implying that those from the
NGOs would be ignored. (I’m tempted to say: So much for the public’s contribution
to the public consultation.)
Where do we go from here? The commission’s next move was to launch an impact
assessment. The general idea was presented at the June workshop. Put concisely, the
aim is to weigh the cost to industry (mainly pesticide producers and farmers) ver-
sus the health benefits to individuals and society. Here again, scientists, particu-
larly endocrinologists and public health economists, need to enter the debate and
be heard. With a group of other scientists present at the workshop, I worked on a
statement that underlined the upside-​down thinking being used to delay legislation
by proposing an impact assessment. As we pointed out in our commentary [12], an
impact assessment would make sense if policy options were being examined but not
when enacting laws and regulations that have been passed.
In fact, a number of members of European Parliament (MEPs) used similar argu-
ments when first getting wind of the impending impact assessment in 2013. As cited
by Stéphane Horel [7]‌, a group of eight MEPs wrote to the then-​president of the
European Commission, José Manuel Barroso: “This decision is surprising, as one
would expect scientific criteria to be based on objective scientific studies and not on
an impact assessment, which is rather a tool to inform political decisions” [7, p. 17].
When the new health commissioner, Vytenis Andriukaitis, was instated in 2015, he
received a similar letter, signed by even more MEPs.

The exorbitant health costs of EDC-​l inked disease

In Chapter 7, I introduced the costing exercise in which I had participated, led by

Leo Trasande from New York University. I also went through the analytic and sta-
tistical methods we used. Here, it’s important just to recapitulate some of the figures
before viewing them in the context of some counterarguments from industry. The
overall result of our costing exercise was that the cost of EDC-​related disorders,
including infertility, metabolic disorders (including obesity), neurodevelopmental
disorders, and IQ decline, amounted to a stunning €157 billion per annum [13].
More significantly, given the topic of this book and no doubt the long-​term con-
sequences for society, by far the largest fraction of the total costs, €150 billion per
annum, was due to chemicals affecting brain development [14], either neurodevel-
opment disease or IQ loss. One might comment that only leaves €7 billion for all
the other diseases. The reason is that IQ loss and neurodevelopmental disease can be
more easily related to exposure during pregnancy, mainly because of the closer time
frame between exposure and measurement or diagnosis. Most of the other diseases
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occur in adults. As a consequence, it is far more difficult to obtain reliable data and
relate disease to exposure. By far the greatest contributor to the €150 billion was,
given EU exposure levels, IQ loss due to organophosphate pesticides. As we said
in the article, this figure is probably the tip of the iceberg. The large majority of
the chemicals that have been documented as present in amniotic fluid today can,
in one way or another, interfere with thyroid hormone signaling. We have no data
on effects of prenatal exposure to these chemicals and IQ for most of the chemi-
cals taken individually, let alone in combination. To this, we can add that we have
little idea regarding whether potential effects are limited to a single generation. As
we saw when discussing the unfounded use of diethylstilbestrol (Chapter 6, in the
section How Much Do We Need to Know to Act? and in the section And Our
Grandchildren further in this chapter), maternal exposure to a chemical can affect
more than one generation.
It may be useful to reiterate another statistic already mentioned in Chapter  1,
that of the 18-​point IQ difference observed in children born to iodine-​replete versus
iodine-​deficient mothers in Sicily [15]. The relevance of these data from one part of
Europe is strengthened by the data on iodine deficiency [16] in the United Kingdom
and the more general uncertainty about whether other populations in Europe share
this problem [17, 18]. In 2015, a team of researchers looked at the cost cost/​benefit of
iodine supplementation for pregnant women in areas where there is mild or moder-
ate iodine deficiency [19]. The authors estimated that iodine supplementation dur-
ing pregnancy lowered health costs for the mother and increased lifetime earnings
for the child, principally due to an average increase of 1.2 IQ points per child. This
figure may not seem much per child, but at a population level and at an economic
level, the consequences are enormous.
We can also ask what the US would save in health costs by regulating EDCs. Leo
Trasande, who led the EU study discussed [13], is applying the same approach to
calculate similar costs in the United States. Given the relative size of the US and EU
economies and the higher health costs in the United States, the latter stands to gain
even more than the European Union by regulating EDCs.

Health and environment benefits outweigh

industry costs

What about the other side of the story and costs to industry of EDC legislation? As
we’ll see in the discussion in this section, arguments are put forward regarding job
losses and reduced agricultural yield, but few studies have attempted actually to cost
the consequences of applying EDC legislation.
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Who Really Picks Up the Bill? 167

Despite this absence of hard economic costing data, the pesticide producers, mainly
represented by the European Crop Protection Association (ECPA), are among
the most vociferous industry lobbies fighting legislation—​and they are not alone.
A number of other associations responded to the public consultation, also saying that
existing legislation is sufficient and that more stringent future legislation would be
harmful to them. This was the position of the chemical manufacturers represented by
the European Chemical Industry Council (CEFIC; http://​w ww.cefic.org/​). A num-
ber of large multinational companies are prominent members of CEFIC, including
the major German-​based chemical manufacturers Bayer and BASF and the oil com-
panies ExxonMobil Europe and BP. Many CEFIC members are also pesticide pro-
ducers and had representatives at the June workshop. The plastics industry also has
its association, Plastics Europe (http://​w ww.plasticseurope.org). In their response to
the EU public consultation, they largely subscribed to the opinions of CEFIC.
Members of the European Parliament have told me that they have even received
letters from the toy industry, which is apparently concerned about the impact on
their business of EDC legislation. It’s probable that one of toy manufacturers’ main
concerns is centered on the regulation of certain phthalates, used to make plastics
more pliable. They also have their association, Toy Industries of Europe (http://​
www.tietoy.org/​toy-​safety/​other-​community-​legislation/​). The website makes no
mention, however, of their position with respect to endocrine disruption.
The CEFIC website has a page devoted to “so-​called endocrine disruptors”12;
they state that “despite claims to the contrary … endocrine disruptors are already
addressed by the current strict EU regulatory framework, in a number of legal
instruments such as REACH (Regulation on the Registration, Evaluation and
Assessment of Chemicals), the Water Frameworks Directive, the Biocides Directive
and the Pesticides Regulation. This legislation, applying to all chemical substances,
ensures that chemical products placed on the market are safe. There is, then, no legal
vacuum where endocrine disruptors are concerned.”
If their claim is justified, that is, if current regulatory rulings ensure that all chem-
ical products on the market are harmless to our health and to the environment,
then the question arises as to why noncommunicable diseases such as cancer, dia-
betes, infertility, and neurodevelopmental disorders are inexorably increasing and
IQ decreasing? Why is there such an acute loss of biodiversity, for instance, among
pollinators and bird populations? Why did the EU Parliament instruct the commis-
sion to act on the issue? Why, indeed, has the commission been financing research
into EDCs over the last 15 years? Why also did the toxicologists who receive fund-
ing from the chemical industry agree so rapidly with the endocrinologists on many
points at the meeting with Anne Glover, namely, that EDs could be defined, that
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these chemicals had particular characteristics such as nonmonotonic dose responses,

and that thresholds for ED action are difficult to determine experimentally?
How are we to account for these major differences in opinion between industry
representatives on the one hand and more or less everyone else on the other? One
does not have to be unduly cynical to suppose that it stems from the corporate bot-
tom line: Maximizing profits is the imperative, and anything that threatens this is
liable to be challenged.
As we’ve seen, estimates of health costs of EDCs, especially the effects on brain
development and IQ loss, mainly due to pesticides, amount to about €157 billion
per annum. We’ll see in the rest of this section that this figure is far higher than
any costs to industry arising from regulation of pesticides on the basis their EDC
propensity. The health costs/​benefits data are one side of the story. What about the
environmental costs? We’ll deal with these first.
Estimations of environmental costs need to go further than absolute numbers of
animal and plant species lost and take into account effects on ecosystem equilib-
rium, already under serious threat due to climate change. As predicted by Rachel
Carson over 50  years ago [20], bird populations are primary targets. One of the
most upsetting examples of EDC effects is on migratory birds. Migratory birds
follow the seasons for breeding purposes, with the longer days of summer ensur-
ing greater food resources for them and their young. Those most familiar to us in
Europe, insectivores such as swallows and swifts, arrive in the spring, spend the
summer here, then fly south in autumn, in some cases as far as South Africa. Other
migratory patterns are even more impressive. The winner for stamina is the wader
known as the bar-​tailed godwit, which flies nonstop from the Arctic to Tasmania
or New Zealand at the end of the Northern Hemisphere’s summer and back again
as the seasons change. To be able to fly these immense distances, birds first need
to store food as fat, then to change their muscle physiology, their metabolism, and
how they produce their energy for long distances—​much like a runner preparing
for a marathon. Thyroid hormone is essential for all of these complex physiological
changes. Christy Morrisey from the University of Saskatchewan has shown that
the same types of chemicals affecting development of our brains are also interfering
with these metabolic adaptions. But, migratory birds also use their brains to navi-
gate. Unfortunately, the same chemical thyroid hormone disruptors also damage
these intricate neuronal mechanisms. So, the birds have to deal with disruption of
the navigation systems in the brain and reduced metabolic capacity. It is no small
surprise that we are seeing fewer and fewer of these emblematic birds in our sum-
mers. Apart from the tragedy of the vision of a swallow-​less summer, we’d have more
insects to deal with, making it tempting to many to use more chemicals to fight
them off. When will we ever learn?
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Who Really Picks Up the Bill? 169

Another example, this time in relation to primates, concerns a project carried

out by my team in collaboration with Sabrina Krief, a primatologist trained as a
veterinarian, who also works at the Natural History Museum in Paris. Sabrina and
her colleagues from Makerere University in Uganda are currently investigating the
effects of pesticides on chimpanzee and bonobo populations in Uganda. Given the
sensitivity of these groups of chimpanzees to human intervention, Sabrina and her
colleagues have to use strictly noninterventionist methods to obtain samples of feces
and urine. Sabrina has already observed marked facial malformations in the chimps
that feed on cultivated maize. Our starting hypothesis puts together the two ideas
that severe thyroid hormone deficiency during fetal development affects face shape
(as seen in cretins) and that many of the pesticides used are known thyroid hormone
disrupters. The role of my team is to analyze the thyroid hormone levels and derive
potential associations between pesticide exposure and craniofacial malformations.
We’d love to find a way of assessing their brain development, but this is currently
not possible.
Effects on chimpanzee face structure may possibly seem of lesser significance than
other effects on biodiversity. However, as demonstrated for thalidomide, it’s easier to
see malformations on limbs and faces than other less-​obvious forms of disease, such
as cancers that develop late in life or effects on brain development. Furthermore, in
the case of the chimpanzees, it’s one of the few endpoints we can ethically measure
without interference. Well-​documented examples of EDC effects on biodiversity
abound, from problems with sex organ development and decreased alligator pop-
ulations in Florida to the alarming decline in amphibian populations worldwide.
In all of these situations, it is probable that multiple causes interact, with climate
change exacerbating susceptibility to disease and the effects of endocrine disruption
on reproduction and development. One final example from the many I could cite
is the polar bear population in the Arctic, another particularly difficult species to
study in the wild. I mentioned the high levels of polychlorinated bisphenyls (PCBs)
and other persistent organic pollutants (POPs) in the bears in Chapter 3. These high
levels of POPs, along with climate change that is reducing their habitat, are seriously
compromising their adaptive and reproductive capacities [21].
Despite these demonstrations of the effects of EDCs on wildlife, few studies have
addressed the costs involved, but things could change soon. Since 2000, there has
been a major increase in the number of researchers and authorities carrying out
costing exercises on the value of biodiversity, often loosely referred to as the “green
economy.” Such exercises have addressed ecosystems as varied as Danish heathlands
[22], the value of tropical forests around coffee plantations [23], and the potential
contributions of protected nature areas to reducing poverty [24]. Few, however, have
so far addressed the question in the context of EDC-​related costs. This situation
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is not really so surprising given that studies of the economic value of biodiversity
only started recently. We can, however, make useful reference to the report pub-
lished after the UN-​sponsored conference on biodiversity held in Nagoya, Japan, in
2010. Known as the Sukhdev report [25] after its first author, Pavan Sukhdev, this
report estimated the contribution of services provided by ecosystem diversity at an
astonishing 40% of global gross domestic product (GDP) per annum. It is hoped we
won’t have to wait too long for an estimate of EDC-​related environmental costs to
be added to the health costs.
It is difficult to find current estimates of costs from the pesticide industry and
farmers arising from applying EDC regulations. Perhaps one reason is that the
last time they estimated the costs of regulation to their industry the amounts were
paltry in comparison to health costs. In 2005, during the run-​up to the rulings on
REACH, there was a predictable outcry from industry about the costs being exces-
sive, with a number of interested parties and stakeholders openly criticizing the
REACH program. Various governments said it would hamper trade, and represen-
tatives of the chemical industry claimed that the additional costs entailed would
blunt their competitive edge. (From a very different angle, opposition was also
voiced by animal rights groups on the grounds that the legislation would engender
overuse of animal experimentation.)
However, according to an article by Karl de Meyer that appeared on April 28,
2005, in the French financial newspaper Les Echos (edition 19402, p. 24), the chemi-
cal industry itself had asked the accounting firm KPMG to assess the cost of apply-
ing REACH regulations to 152 substances in four sectors (electricity, automobile,
flexible packaging, and inorganic products). The report estimated that the cost to
the chemical industry of applying REACH over 11  years to these substances was
not significantly different from that already estimated by the EU Commission, that
is, in the region of €2.3 billion (or about €0.2 billion per annum). As the chemical
industry (grouped under CEFIC) expected a total turnover of €615 billion in that
period, this figure represented less than 0.5% of the total. In contrast, without the
hindsight of the current epidemiology on IQ loss and neurodevelopmental disease,
the European Union conservatively estimated prospective savings to healthcare bills
to be on the order of €50 billion over 30 years (or about €1.7 billion per year). No
wonder that, even then, before current data on health costs led to an upward revi-
sion of these figures, the article in Les Echos recommended the chemical industry
should tone down its criticisms of REACH.
Returning to the more recent debate, during the public consultation in 2014/​2015,
one organization that did try to estimate costs was the UK National Farmers Union
(NFU). In partnership with two other major UK groups, the Crop Protection
Association (CPA) of the United Kingdom and the Agricultural Industries
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Who Really Picks Up the Bill? 171

Confederation (AIC) of the United Kingdom, they commissioned a report on the

costs and consequences from phasing out the Plant Protection Products (pesticides)
that would need to be replaced under the EDC rulings. The report identified 18 pes-
ticides at high risk of being banned under the new regulations. Potential losses were
calculated in terms of decreases in yields (and consequent increased dependency on
imports) and job losses in the agricultural sector, followed by knock-​on effects in
food-​manufacturing industries. The report suggested yields could drop between “5
and 50%”—​a considerable margin. Interestingly, job losses were predicted mainly in
the wider economy, food processing and manufacturing, not actually in agriculture
itself. Overall costs in terms of reduced yield and job losses in agriculture amounted
to €1.6 billion per annum, to which the authors of the report added €2.5 billion in
costs to the food-​processing and manufacturing sectors. But, what about the health
benefits or cost of IQ loss? Given that the United Kingdom represents about 13% of
the EU population, its “share” of the costs due to pesticide-​dependent IQ loss would
be about €20 billion per annum. So, the United Kingdom would make significant
savings by legislating on pesticides with EDC-​like activity.
What is more, other voices from the agricultural sector are arguing against the
position taken by official UK agriculture organizations. One such person is Paul
François. He was present at the June workshop in Brussels representing an associa-
tion of French farmers, Phytovictims,13 whose health has been damaged by pesti-
cide usage. As president of this group, he spoke eloquently not only of how his own
health had suffered but also of the increasing numbers of different illnesses that are
now recognized by the French government as occupational diseases related to acute
or long-​term pesticide exposure. The list includes certain forms of cancer, such as
non-​Hodgkin lymphoma, myeloma, and leukemia, as well as cognitive impairment
and the neurodegenerative Parkinson and Alzheimer diseases. Equally important
was his own testimony that, as a cereal producer exploiting hundreds of acres, he
had been able to reduce pesticide usage by 50% without any reduction in yield. We
return to this point about excessive use of pesticides in Chapter 9 when we move on
to discuss the actions that can be taken by individuals and communities to reduce
EDC exposure.
It is hoped these arguments on health risks to farmers will be taken into account
in the impact assessment carried out by the EU Commission, even though the assess-
ment itself can be seen as yet another delaying tactic to placate industry lobbying.
The professed aim is to weigh health benefits versus industry costs. As we saw, there
are no scientific arguments for carrying out this impact assessment. In the meantime,
societal costs are being incurred, particularly in terms of babies exposed in utero.
In Brussels, I exchanged some ideas on the commission’s impact assessment with
one of the scientists involved in the process. We were both aware that current test
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methods, particularly for thyroid hormone, are so inadequate that the impact assess-
ment would inevitably be inaccurate. As most EDC tests are not yet implemented
and only two OECD tests look specifically at thyroid disruption, the number of
chemicals currently on the market adversely affecting thyroid hormone signaling
cannot be determined. Hence, neither the impact on industry of phasing out cer-
tain chemicals nor their health impact can be properly estimated. It was exactly
this point that was hammered home at the meeting on June 30, 2015, by Professor
Andreas Kortenkamp of Brunel University, United Kingdom.14 Andreas is the
first author of a major report, most often referred to as the “Kortenkamp report,”
commissioned by the European Union on the question of assessing EDCs [26].
As expected, like the report jointly mandated by the World Health Organization
(WHO) and the United Nations Environment Programme (UNEP) that appeared
the following year, 2012 [27], the Kortenkamp report [26] has been much maligned
by industry, which views it as a direct assault on their interests rather than a docu-
ment designed to protect public health and the environment.
In the June 2015 workshop, Andreas was specifically asked to deal with the ques-
tion of the impact assessment. He underlined that current tests do not address vul-
nerable windows of development (such as early embryogenesis, when all the different
organs, including the brain, of the future baby are being formed) and that in many
cases the number of experimental points used for testing are insufficient. So, given
the lack of relevant tests and the sparsity of data available when applying such tests
as do exist, it is impossible for the impact assessment to reach a valid conclusion.
As already mentioned, the chemical industry argues that one of its concerns is
potential loss of jobs. Apart from the suggestion that it might be better to encourage
the chemists employed by these industries to synthesize “green” molecules that are
less damaging to health and the environment,15 another riposte is that if we continue
in the current vein, there’ll be no shortage of caring jobs in the community, and in
institutions and hospitals caring for children and adults requiring lifelong assistance.
Isn’t it therefore better, both for public health (not only in Europe, but world-
wide) and for the global environment, to legislate now, while working with the
industries concerned, to lessen the adverse impacts by encouraging investment in
alternative chemicals?

With a little help from my friends: when

governments act together

It’s not only associations and individuals who are expressing their dissatisfaction
with the delays and the consequences. One strong positive note is the example
of the Swedish government, which in 2014 started legal proceedings against the
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Who Really Picks Up the Bill? 173

European Commission for failing to enact the legislation previously adopted by the
parliament.
The text of the action16 calls on the commission to enact the decisions taken by
the parliament in the 2012 biocides regulation. The text concludes with the follow-
ing sentence: “Order the commission to pay the costs of the action.” This phrase no
doubt is limited to the cost of the court case, probably a few thousand euros. Had
it implied that the commission should pay the costs of inaction, the bill could be
several orders of magnitude greater, up to hundreds of billions of euros per year in
health costs incurred by the failure to act.
In fact, when the chemical industry complains of the costs it might incur, at the
same time there are other industries lining up to take advantage of the situation.
There are chemical companies investing in green chemistry and start-​ups creating
novel screening methods. Another player waiting on the sidelines in expectation
of large returns is the reinsurance industry. Reinsurance is a special type of insur-
ance that provides a way of distributing risk when major financial liabilities may
be incurred. In 2012, the industry organized a forum, and published a report,17
on the emerging risk of endocrine disruption (and by implication, the consequent
market opportunity). The four organizers were from reinsurance companies based
in Germany and Switzerland, countries with significant chemical industries. The
report made a number of statements that the commission itself might like to pon-
der. For instance, the first paragraph states:

Human and animal life is widely exposed to many artificial substances that
interfere with the sensitively constructed hormonal system. Substances that
interfere with hormones are called Endocrine Disrupting compounds/​chemi-
cals (EDC). EDCs are a truly emerging risk. There is strong evidence for nega-
tive effects on animal organisms and mounting evidence for effects on human
health. Evidence is mounting that specific substances are connected to human
bodily injuries. For the risk management of liability insurers it is crucial to
monitor this emerging risk.

So, contrary to what the chemical industry is saying, the reinsurance industry is
arguing that the risk is “truly emerging,” and this could lead to liability suits.
The action initiated by Sweden was supported by a number of other countries,
the European Parliament, and the European Council of Ministers.18 In the case of
the EU Council, nearly all EU countries (21) voted in favor of the motion, with
only 4, including the United Kingdom, abstaining or not participating. The hearing
was held in the European Court of Justice in early November 2015, and the judg-
ment was rendered on December 16, 2015. The court ruled that the EU Commission
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174 Toxic Cocktail

had breached EU law by not acting on defining scientific criteria for EDCs. For the
moment, the commission is ignoring the ruling and carrying on with the impact
assessment.19 It will be interesting to see how the commission reacts in the future
and whether the opinions of the public, their parliaments, the scientists working on
EDCs, and NGOs are ultimately taken into account.
This strong stance by Sweden and other countries is indicative of the positive
moves that decision-​makers and politicians can make, and that reinsurance compa-
nies will be following closely. Also of interest to reinsurers are class actions, through
which individuals and groups sue companies on behalf of damage to a larger group
of persons (the “class”). For the moment, such lawsuits are uncommon in Europe,
although they are frequently deployed in the United States. One of the most well-​
documented class actions was brought by a group of US residents against a major
chemical company producing perfluorinated compounds. The residents’ ground-
water had been heavily polluted by effluent from the company’s factory, causing a
series of adverse effects on them and on their children’s mental and physical health.
The story is redolent of the film Michael Clayton: The hero leads a class action suit
brought against a company making weed killer it knew to be carcinogenic.

And our grandchildren

The number of chemicals manufactured and destined for industrial, agricultural, or

personal use has increased steadily over the last century, with consequent pollution
of the environment. Production of plasticizers such as bisphenol A (BPA) and PCBs
and the pesticide DDT (dichlorodiphenyltrichloroethane) was amplified from the
1950s onward. It is estimated that since then about 1,000 new chemicals have been
introduced every year, with the result that well over 85,000 chemicals are currently
on the EPA register, and 143,000 are registered in the European Union. For many
of these substances, no toxicology data have been obtained. The first generations
to undergo significant postnatal exposure to a variety of compounds were those
born in the 1940s and 1950s. In turn, the children born between the late 1950s and
1970s were probably the first to be exposed in the womb to mixtures. This genera-
tion began to start families 20–​30 years later, producing a second generation of chil-
dren exposed prenatally. Not only was this second generation exposed to an even
greater spectrum of chemicals in utero but also, as illustrated in Figure 8.1, their
mother’s and father’s germinal cells (the cells that later produce the eggs and the
sperm, respectively) that combined to produce them would have been subjected to
any substances present in their own mother’s body.
It has never been straightforward to relate health problems in adults to exposure
on the part of their parents. The principal reason is the chronology. It’s far easier,
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Who Really Picks Up the Bill? 175

F1
F2
F0

Figure 8.1  Exposure of a pregnant woman to chemicals that cause epigenetic modifications

can affect three generations. In the fetus, the germ cells that will produce the eggs or sperm of
the third generation are forming. Thus, when the mother (usually referred to as generation F0
in scientific publications) is exposed, so is the fetus (F1) and so are germ cells in the fetus. These
germ cells will generate the gametes that will participate in the child’s future progeny (F2). Hence,
maternal exposure can, through epigenetic mechanisms, potentially affect three generations in a
single exposure. Because epigenetic marks are heritable, they can then be passed on to successive
generations. As explained in the text, one epigenetic mechanism that can be affected by endocrine
disruptors is DNA methylation. It is during fetal life that the developing germ cells undergo
successive waves of DNA methylation, demethylation, and remethylation [28]. The question of how
EDCs present in the amniotic fluid affect these successive waves of methylation in the fetus needs
to be investigated urgently.

especially logistically, if exposure and effect are closer together, as when relating
maternal exposure or nutritional status to children’s neurodevelopment. For this
reason, the costing exercise led by Leo Trasande had the most reliable data on neu-
rodevelopmental disease and IQ loss and less so on cancer and infertility. However,
if samples are kept long enough, the data can be usefully analyzed.
One such example understandably gained a lot of media attention in 2015. The
study was led by Dr. Barbara A. Cohn, an epidemiologist from the Public Health
Institute in Berkeley, California. I met Barbara at one of the first EDC costing meet-
ings in Paris with Leo Trasande, when she enthusiastically told me about the great
potential of her work. Barbara is the guardian, so to speak, of a very precious cohort
of blood samples collected from women giving birth in California during the 1950s.
The blood has been stored frozen for over half a century. This large sample (9,300
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176 Toxic Cocktail

daughters and as many sons) provides the basis for the type of prospective (or longi-
tudinal) analysis sorely lacking in studies of early EDCs and effects on adult disease.
By carrying out analyses of stable metabolites years later, Barbara’s group was able
to correlate the levels of DDT to which the girls were exposed during their mother’s
pregnancy and their own incidence of breast cancer diagnosed 52 years later [29].
Their main finding was that the higher the DDT exposure levels in the mother, the
higher the risk of breast cancer five decades later in the daughters. In fact, the high-
est levels increased risk nearly fourfold (3.7 times to be exact). Bringing the mothers’
own history of breast cancer, their weight, and a number of other factors into the
risk calculation did not change the result. The only significant factor to increase
breast cancer risk was maternal DDT exposure—​a terrible legacy.
To recap, today the situation is exacerbated by three factors. The first is simply
the number of chemicals present in the environment; the second is the unknown
effects of the mixtures that are present in mothers and, most important, accumulat-
ing in amniotic fluid. Finally, as we have just seen, the effects may not be limited to
current populations, but through epigenetic mechanisms may potentially extend to
subsequent generations.

Lack of justice for individuals

To address the question of levels of exposure, many governments are currently

endeavoring to obtain population-​wide data on levels of chemicals in blood and
urine at different ages. One of the most comprehensive databases is that of the
US Centers for Disease Control and Prevention (CDC), which provides regular
updates on their reports documenting population-​wide exposure to environmental
chemicals (http://​w ww.cdc.gov/​exposurereport/​‎ ). Europe is just getting around to
setting up a similar scheme. The commission launched a call in September 2015 for
research proposals to carry out human biomonitoring on a European scale. Known
as the European Human Biomonitoring Initiative (EHBMI), it is expected to run
for 5 years from 2016 and to cover three broad areas: sampling and analytical work
by national laboratories with an appropriate database; a research program to assess
the impact of chemical exposure on human health; and translation of results into
policymaking.
We will therefore have to wait for a minimum of 5 years before we have an idea
of current exposure levels to a defined group of chemicals and certainly a few more
years for the full data analysis and idea of exposure impact. Meanwhile, will there be
no regulation? No restrictions? More IQ loss and more cases of ASD? What are our
responsibilities to the unborn individuals who will be unwittingly exposed?
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Who Really Picks Up the Bill? 177

I began the chapter with a science fiction film, the scenario for which in retro-
spect may not be so fictional. I’ll close with a prize-​winning science fiction story
from 1959, Flowers for Algernon, by Daniel Keyes. The story was so successful that
it was later expanded into a full-​length novel, then made into a film and even a
musical, although there’s not much to sing about in the story. Flowers for Algernon
is narrated by an intellectually deficient man, Charlie Gordon. Charlie is chosen to
undergo surgery to increase his intelligence. The operation had already been success-
fully tested on a laboratory mouse, Algernon. Charlie watches Algernon succeed in
different tests and becomes attached to him. After surgery, Charlie’s IQ triples. But,
at the same time Algernon’s skills start to decline. The initial increase in Charlie’s
IQ, besides leading to the loss of his job in a bakery, gives him sufficient time to
acquire awareness of the societal stigma of his previous condition and, most acutely,
to fear and observe its return with the decline of his own intelligence. His last poi-
gnant wish is for someone to place flowers on Algernon’s grave.
The question I  am not alone in asking today is:  Are we observing a collective
decline in intellectual skills, a kind of brain evolution in reverse? If so, then my sec-
ond question has to be: What can be done about it?
In the next chapter, I present a series of ideas to halt and reverse the accumula-
tion of untested chemicals in the environment known to have an adverse impact on
human intelligence and development.
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9
Time to Act and How to Act

We can make a difference

So far, we’ve had illustrations from novels and films but not yet from fairy tales.
The one I have in mind is the tale of the Pied Piper of Hamelin. A rat-​entrancing
musician clad in multicolor clothes rids a town of its pests. The council members
are overjoyed with the result but not the bill. In the face of the town’s refusal to
pay, the piper leads away the town’s children—​a disquieting trade-​off bearing some
uncomfortable parallels to the current situation. Today, we have different industries
presenting arguments about loss of profits, with authorities reluctant to take the
necessary steps to protect future generations. This final chapter argues that there are
many actions we can take to turn this situation around to avoid a disastrous ending.
We can act as individuals in our daily lives and amplify these actions by working
within organizations and as electors, encouraging measures that can be significant
and worthwhile. Even though for many the current situation seems to have gone
beyond the point of no return, there is an urgent need for collective action to coun-
teract inertia by elected representatives and collusion by industrial lobbies. We can
make a difference to better protect not only ourselves but also future generations.
Individual action and lifestyle choices can limit exposure to certain chemical
categories. Clearly, pregnant women and nursing mothers need to be informed of
potential risks so they can take precautionary action, and the medical profession
needs to be encouraged to help. Ensuring that women do not enter pregnancy in a

179
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180 Toxic Cocktail

state of even mild iodine lack is a first inexpensive requirement with immense cost
benefit. Other lifestyle choices, particularly with regard to diet, avoidance of alcohol
during pregnancy, and reduced use of certain consumer products, can bolster pro-
tection against exposure to and the action of some pollutants.
However, in the longer run, appropriate legislation must be introduced and will
be more effective than individual action. But, given the time frame, both have a role
to play. Efforts to modify legislation are most effective through collective action.
In this chapter, I provide examples of organizations and associations that are rais-
ing awareness of chemical pollution in general or of specific categories of chemicals,
such as pesticides and flame retardants.
In the legislative debate on the adoption of precautionary principles as opposed to
waiting for proof of damage, many arguments are presented in defense of nonaction.
Apart from the standard arguments that the industries concerned create jobs, and
that without the chemicals industry we’d return to the Stone Age, many authorities
and individuals consider that things can’t be that bad because we’re living longer
than ever before.
The last argument can be questioned at many levels. The current increase in lon-
gevity is by definition based on data from populations that were born in the 1920s
and early 1930s. These birth cohorts were among the first to benefit from improve-
ments in perinatal care and reduction in early infant mortality, better sanitation,
vaccinations, and antibiotics, together reducing the incidence of infectious disease
and the associated childhood mortality. But, these cohorts were also born just
before the main waves of introduction of plastics, DDT (dichlorodiphenyltrichlo-
roethane), leaded gasoline, and many of the other substances discussed in Chapter 3.
So, none of the healthy seniors currently playing golf and dancing into their 90s
underwent the in utero exposure of the following generations.
Furthermore, recent data from the United States show that decreases in longev-
ity are now being seen [1]‌. Most striking are the recent 4-​year decreases in longevity
seen in less-​educated white women [2]. In this light, it is interesting to recall the
overall correlation between longevity and intelligence [3]. Thus, given the premises
of this book, one can wonder whether the causes underlying such declines in lon-
gevity are in fact related to the rise in behavioral and neurodevelopmental problems
that have been creeping up since the mid-​1970s. The logic would be that children
with such behavioral problems would be the most likely to fail in the education
system and then tend to lead less-​healthy lives.
In some countries, such as Russia, declines in longevity have been evident for
many years. In China, worsening of air quality and disparities in pollution are con-
tributing to marked decreases in life expectancy [4]‌. To this, we can add that in all
developed countries the gap between life span and healthy life span is widening. Life
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Time to Act and How to Act 181

expectancy may still generally be rising, but our healthy life span is not. This diver-
gence means we spend more years in ill health. The increasing gap also implies that
the toll of noninfectious (noncommunicable) diseases such as neurodegenerative
disorders, cancer, and cardiovascular and metabolic diseases is constantly eroding
healthy life span, while the burden of care is further amplified as overall longev-
ity increases. In other words, we are keeping sick people alive longer with noncom-
municable diseases, many of which have been repeatedly linked to environmental
factors. To these statistics, one should add the increased incidence of cancers in chil-
dren and young adults [5] and the global increases of all forms of cancer, especially
breast and prostate cancer [6].
There’s another argument frequently put forward by those opposed to regulat-
ing endocrine-​disrupting chemicals (EDCs), especially when talking about chemi-
cals that affect thyroid hormone levels. It’s based on somewhat-​limited knowledge
of endocrine systems and exemplifies the old adage that “a little knowledge can be
a dangerous thing”—​especially, I  would add, in the mind of a hurried regulator.
Many toxicologists argue that the thyroid hormone axis has evolved to compensate
for changes in circulating hormone levels. They contend that if a chemical causes a
decrease in thyroid hormone blood levels, then physiological regulations will over-
ride chemical disruption.
Four counterarguments can be given here. The first is that during critical win-
dows of development, a slight change in thyroid hormone availability can have
major, irreversible effects, notably on early brain development, before the body’s
compensation mechanisms can come into play. The second is that, during devel-
opment, even as the body’s regulatory mechanisms are set up, they may be less
able to respond. Third, given the continual exposure to complex chemical mix-
tures, even a mature endocrine system can be overridden. Finally, increasing evi-
dence, including epidemiological studies in humans, shows that compensatory
adjustments made during development most often induce detrimental effects in
the longer term.
How early exposure can cause late adverse effects was discussed in Chapter 6 in
the section on development as a plastic process and the theory of the developmen-
tal origin of adult disease hypothesis (DOAD). Today, many data sets bolster this
theory. One example is the incidence of metabolic disease in Dutch adults whose
mothers were subjected to severe calorie restriction during the last winter of World
War II [7]‌. Another is the increased risk of breast cancer in women whose mothers
were exposed to higher levels of DDT during their pregnancy [8]. Similarly, experi-
mental work suggests that if there are problems with thyroid hormone regulation
in early life (such as a mother having too much or too little thyroid hormone), these
can have long-​term impacts on the thyroid gland of the next generation [9].
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182 Toxic Cocktail

The individual matters

Overall, it’s not really that surprising, given the evidence on the number of chemi-
cals in the environment, that many people are tempted to shrug their shoulders and
say that things have gone so far that there is nothing we can do other than make
the best of a bad situation. Another argument from the pessimists is that the levels
of contaminants found in the fauna in the supposedly pristine environments of the
Arctic and Antarctic suggest that any attempt to reduce individual exposure is a lost
cause. Yet, strong evidence exists that it is worth the effort because small changes in
behavior can have significant effects on certain forms of chemical load. Individuals
can make a difference to their own and their children’s lives, both immediately and
by collective action in the longer term.
As detailed in this chapter, this maxim is particularly true for choices of organic
versus standard produce, paying attention to the way food and drink are packed and
prepared, and being careful about personal care items. Fetuses, babies, and toddlers
are the most vulnerable to exposure and have the greatest risk of incurring adverse
effects on their brains and behavior later in life. With this is mind, one might think
that the precautionary advice that follows is most pertinent for pregnant women
and mothers of young children. However, the information has relevance for us all.
The explanations can help everyone understand the arguments and choose whether
to apply the suggestions to their own lifestyles. If they do, they will probably be
adopting habits that will ultimately be better for their own health as well as that of
their children.
Many lifestyle choices can affect personal exposure levels. The recommendations
from the UK Royal College of Obstetricians and Gynecologists (RCOG) published
in 2013 for pregnant and nursing mothers make a good starting point for discussion
[10]. The report emphasized awareness of food choices, personal care and household
products, and pharmaceuticals available without prescription, including herbal
treatments. As the title of the 2013 report underlines, many of the linkages between
chemicals and adverse effects on children’s health are as yet unproven, but poten-
tially damaging. Thus, applying a precautionary approach is not scaremongering as
some have suggested, but simply applying the rule that most mothers would sub-
scribe to, namely, doing their best to provide the most favorable start to their child’s
life. Many authors have drawn parallels between personal choices and actions that
can lead to reduction of chemical exposure with the early recommendations on
using seat belts in cars or not smoking, two examples that started off as advisory and
later led to legislative action.
To simplify, the recommendations on individual actions given here are organized
into two categories: first, food sources and packaging, and second, furnishings and
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Time to Act and How to Act 183

household and electronic equipment. Arguments in favor of breast-​feeding are also

given, in view of its importance and the anxiety many women experience when
hearing about the levels of chemical exposure to which we are subjected.
At the end of the chapter I  summarize, in a list of bullet points, the different
actions that the individual can take to reduce chemical exposure.

Food sources: the case for organic products to reduce pesticide exposure

As a general rule, it is important that, whenever possible, pregnant women replace as

much conventional produce as possible with organically grown equivalents. Current
data on the effects of exposure on brain development, particularly in children of
farm workers or women living near agricultural areas (see end of this section), argue
strongly for the application of the precautionary principle in reducing the pesticide
exposure of pregnant and nursing mothers.
The consumption of organically grown food, especially fruit, vegetables, and
grain produce, rather than conventionally grown equivalents, has been shown
to significantly reduce pesticide exposure. Cynthia Curl and her colleagues from
the University of Washington, Seattle, have been investigating this topic for over
10 years. They were among the first groups to analyze pesticide metabolites in the
urine of children eating organically grown produce as compared to children on con-
ventional diets [11]. Fourfold reductions of median total dimethyl metabolites of
organophosphate pesticides were found in the former group. The same team also
compared pesticide metabolite levels in adults consuming organic produce. They
asked people how often they bought organic food and then classed the respondents
into three groups: those who never bought organic fruit and vegetables, those who
occasionally did, and those who often or always did. As expected, they found the
lowest urinary levels of organophosphate pesticide breakdown products in the peo-
ple who used organic products most regularly [12].
Another research team did a “before-​and-​after” experiment to test whether
organic food consumption reduced pesticide exposure. Lu and colleagues [13]
recruited 23 schoolchildren, aged between 3 and 11, in Seattle, Washington, in the
summer of 2003. To be sure that there was no other source of pesticides besides food,
they checked that none of the families participating in the study used pesticides at
home, as this could have been another major potential source of contamination. The
experimental setup was a longitudinal study that involved collecting evening and
morning urine samples from the children for a 3-​day period on control diets; a 5-​day
period on organic fruit, vegetables and grain; followed by a 6-​day period on control
diets again. Meat and milk produce were not changed during the experiment as
these foodstuffs contain less of the pesticides monitored.
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184 Toxic Cocktail

Two main classes of organophosphate pesticides—​chlorpyrifos and malathion—​

were monitored by measuring their metabolites in the urine. Recall that, as described
in Chapter 7, chlorpyrifos exposure has been associated with brain abnormalities
[14], and prenatal exposure to chlorpyrifos is associated with reduced IQ and work-
ing memory [15]. One of the off-​target effects of chlorpyrifos is to modulate thyroid
hormone levels in human and in animal models [16]. Similar thyroid hormone–​
disrupting effects from malathion have been seen in animal models.
Returning to the data of Lu and colleagues, when the children consumed organic
food, the levels of the pesticides dropped immediately and significantly, remain-
ing low for the 5 days spent eating organic produce and increasing as soon as the
children were provided with conventional fruit, vegetables, and grain. When on
control standard diets, mean levels of the malathion pesticide metabolites ranged
between around 4 to over 250 micrograms per liter. In contrast, when children ate
the organic diet, average levels were barely detectable. Similarly, for the chlorpyrifos
metabolites, a fivefold decrease was observed on the organic diet.
One argument that is often put forward in the pesticide debate is the greater
need for pest control to increase yield to feed a growing world population. By way
of counterargument, apart from the fact that excess pesticide usage is detrimental
to the health of farmers and of the general population [17] and water quality and
the environment as a whole [18], there is abundant evidence that pesticide reduc-
tion does not necessarily result in decreased production [19–​21] or lower quality or
nutritional value.
An article from a French group underlined this idea [22]. Their findings are par-
ticularly important because France is one of the biggest European pesticide users.
Apart from strict organic farming methods with no synthetic (chemical) fertiliz-
ers or pesticides, farming methods can be rationalized to reduce pesticide use by
so-​called integrated cropping systems [22]. These methods involve use of naturally
resistant plants, less plowing and tilling of the soil, and reduced use of nitrogen-​
based fertilizers. The study compared these methods to traditional intensive farm-
ing with high pesticide use and found that, depending on the type of area, yields
could be maintained to within about 10% (between 5% and 13%) of current levels.
Furthermore, as mentioned, other crops can produce increased yields with reduced
pesticide usage [20].
As Joe Thornton emphasized in his excellent analysis of the organochlorine
industry and its effects [23], when transitioning to organic methods, reduction of
pesticides requires putting something else into the equation (i.e., work and infor-
mation on crops and biodiversity). It is obviously a difficult exercise to calculate
the longer-​term socioeconomic cost benefits of reductions in herbicide/​pesticide
usage, embracing not only direct health and biodiversity benefits but also other
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Time to Act and How to Act 185

multifactorial inputs, such as land management, farm-​labor employment possibili-

ties, and the impact of urbanization of populations, but perhaps it is time to incor-
porate these interactions and their consequences into the calculations.
What is more, some reduction in yields would not necessarily be a problem, even
with a growing population. The first consideration to bear in mind is the amount
of food that goes to waste. A  few years ago, the United Nations Environment
Programme (UNEP) published an edifying report on the problem of wastage.1 It
estimated that about one-​third of world food production, equivalent to more than
half of the annual global cereal production, goes to waste. The authors pointed out
that besides the excess fertilizers and pesticides used, which in turn damage health
and the environment, food waste is a primary source of the potent greenhouse gas
methane. Compared to carbon dioxide (CO2), the greenhouse effect of methane is 23
times greater. In addition, food wastage entails the unnecessary production of CO2
through increased fuel and transport. UNEP also made another salient point: Food
wastage equates with water wastage because agriculture uses more water than any
other sector. Thus, the possible small reductions in yield associated with a 50% reduc-
tion in pesticide usage should hardly be a concern if better food distribution and use
are instigated. The economic, general, and mental health benefits to the farmers and
to consumers are obvious, as are the environmental factors. Conversely, reduced pes-
ticide and fertilizer use implies declining revenues to the multinationals producing
them. It is not unreasonable to infer, therefore, that the industry’s attempts to block
EDC legislation in the European Union are driven by the profit motive—​another
example of the conflict between the public good and corporate interests.
The most detailed data on when, where, which, and how much pesticide is used
comes from the United States. This information has enabled scientists to analyze
the linkage between pesticide exposure in areas close to agricultural sites and inci-
dence of autism spectrum disorder (ASD). One of the first reports on this topic was
by Roberts and colleagues [24]. The team looked at the relationship between time of
pregnancy, proximity to pesticide application, and the types of pesticide used. The
results revealed that living close to pesticide application could increase ASD risk
up to sixfold! The greatest risk was incurred in the first 2 months of pregnancy, and
the highest correlations were with organochlorine-​based pesticides. The observa-
tion that the first 2 months of pregnancy were the most vulnerable underlines the
particular sensitivity of the developing brain at the stage when the nervous system is
just forming. The study’s findings have been replicated and consolidated by Shelton
and colleagues [25], again showing that living near pesticide application areas during
pregnancy increases ASD risk. In this case, the pesticides implicated were organo-
phosphates. In Chapter 7, I also presented reports linking pesticide exposure to IQ
loss [15, 26, 27].
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186 Toxic Cocktail

Yet again, the question arises regarding why regulatory tests haven’t picked up
on these effects. Unfortunately, current pesticide neurotoxicity tests are most often
carried out on adult animals and rarely examine closely effects of exposure on brain
structure and function during the more sensitive developing or embryonic stages
[28]. The fact that many pesticides and other chemicals are considered safe is in large
part due to limitations in testing or interpretation of the tests that are run (see also
Chapter 3 and the section Mind-​Mugging Pesticides in Chapter 7).

Seafood

Food choices for pregnant and nursing mothers are by no means limited to the
dichotomy of organic versus conventional fruit and vegetables. Many other factors
enter the equation, including the risk-​benefit analysis of amounts and sources of fish
and seafood eaten. It is important to remember that marine fish and shellfish are
excellent sources of iodine and selenium. These elements, along with other nutri-
tional factors, such as high protein and long-​chain polyunsaturated fatty acids (such
as omega 3), all lie on the “benefit” side of the equation. The risk factors include con-
tamination with mercury, tributyltin (TBT) and dioxins/​PCBs (polychlorinated
bisphenols), each of which generally increases with consumption of fish species that
are higher up the food chain. In the case of the dioxins and PCBs, the higher the
lipid content of the fish, the higher the level of contamination [29]. Herring, mack-
erel, trout, and salmon are examples of the most “oily fish.” Yet, despite these risks,
eating fish has been shown on balance to be beneficial.
Of particular interest in this context is a study by Philip Grandjean’s team [30],
carried out on Faroe Islanders, whose diet comprises a high proportion of pilot
whale meat. They examined the linkage between neurodevelopmental outcomes
and the consumption of fish and seafood, including whale meat, which tends to
have notoriously high levels of mercury. They were particularly interested in the
potential protective effects of selenium on brain development against mercury (see
Chapter 1) in the fish. Their calculations were based on levels of these elements in
umbilical cord blood and the neurodevelopmental status of children at 7 years of
age. The authors concluded [30] that because fish consumption can be associated
with beneficial effects on neurodevelopmental outcomes, fish should be eaten dur-
ing pregnancy, while avoiding marine sources that are high in mercury contamina-
tion, such as whale meat (although clearly whether or not to eat whale meat is not a
concern for many of us).
A European consortium studying dietary fat requirements during pregnancy and
lactation [31] reached a similar conclusion. They suggested that regular (e.g., once
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Time to Act and How to Act 187

or twice a week) consumption of oily fish is beneficial, but emphasized one excep-
tion: This exception to the “benefit-​over-​risk” argument was the need to avoid herring
or wild salmon from the Baltic while pregnant or nursing [31]. The recommendation
is well founded. Despite reductions in pollution of the Baltic environment, these
fish still contain high levels of PCBs, a persistent class of thyroid-​disrupting chemi-
cals. This contamination is the basis of the general recommendation for pregnant
women in Scandinavia (and elsewhere) to avoid Baltic fish. The same reasoning
probably underlies the advice in the pamphlet produced by RCOG (see the section
The Individual Matters), to the effect that eating oily fish (notably tuna) should be
avoided or limited to once a week if you are pregnant or nursing. A final point is to
remember that one easy-​to-​apply rule that can significantly reduce intake of most of
the principle contaminants when eating oily fish is to remove the skin [32].

Fresh food versus packaged food and prepared meals

Many studies have shown that reducing the consumption of processed and pack-
aged food can strongly diminish body levels of plasticizers, and eating organic food
lowers the intake of pesticides. Many people will say that the cost of organic produce
is prohibitive; on the other hand, the savings that result from the switch to prepar-
ing one’s food rather that buying prepacked ready-​to-​eat microwave produce can be
considerable. A further environmental benefit is the reduced generation of plastic,
metal, and paper packaging compared to the consumption of processed food.
This is not to say that packaging is unnecessary. Most foodstuffs need some
protection during transport and shelf display to prevent damage that can lead to
degradation and food wastage. However, a better balance between protection and
marketing ploys needs to be sought in the interests of both the consumer and the
environment. Simply put, consumers benefit immediately from the lower exposure
to unnecessary plasticizers and in the longer term from a less-​polluted environment.
Taking the case of bisphenol A  (BPA) exposure, a study from the National
Health and Nutrition Examination Survey (NHANES) group in the United
States showed that the main factors increasing exposure to the plasticizer BPA
were soft drinks (soda) and food prepared outside the home, including school
meals [33]. Canned foods, particularly canned fish, corn, and soups [34], are a
major source of BPA exposure in food. One notorious category of canned products
that increase BPA exposure is canned sodas or soft drinks, such as juices and colas,
that leach BPA from the plastic linings of the metal cans. Urinary levels of BPA
and phthalates have been associated repeatedly with obesity in population studies
and in experimental models [35–​37]. Thus, consumption of canned sodas combines
two obesity-​linked culprits, sugar and EDCs.
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188 Toxic Cocktail

The case of phthalates is particularly puzzling because this category of plasticizer is

generally no longer added to food wrappings or used in plastic water bottles made of
polyethylene terephthalate (PET), at least not in the United States [38]. Apparently,
confusion arises from the chemical terms: The plasticizer phthalates are orthoph-
thalates, which are distinct from PET [39]. Yet, phthalate levels in foodstuffs, par-
ticularly those that are lipid rich, such as diary products, display increased levels as a
function of packaging and preparation [39]. These increased levels could result from
food-​processing methods, another reason to prefer home-​prepared foods.

The case for breast-​feeding versus formula

The prevailing opinion in the field today is that the enormous benefits of breast-​
feeding easily override the risk of transferring chemicals to the child. Evolution has
honed human breast milk composition to provide maximum nutritional and immu-
nological benefit to the baby, with physiologically appropriate changes occurring in
composition during the early postnatal period. Many reviews have identified the
advantages for the child [40], to which it can be added that breast-​feeding is associ-
ated with a reduced risk of breast cancer [41] and ovarian cancer [42] for the mother.
First, exposure to chemicals through breast milk or formula is always less damag-
ing than in early pregnancy. The explanation lies in the concept of sensitive develop-
mental windows, with one of these windows being the early stages of pregnancy. It
was only more recently that epidemiological and experimental studies have identi-
fied the period of early fetal growth as a vulnerable window to both thyroid hor-
mone deficiency and chemical exposure. This stage was previously understudied due
to the focus on other periods of vulnerability, specifically later pregnancy and the
first years of postnatal life. As a reminder, I can mention two of the most studied
thyroid hormone–​disrupting chemicals (i.e., methylmercury and PCBs), regarding
which many epidemiological reports showed greater risk of exposure during early
pregnancy than with breast-​feeding (see, for example, [43, 44]).
A second major advantage of breast milk is that it contains high levels of iodine
(on the condition that the mother is iodine sufficient, taking iodine supplementa-
tion if necessary). In contrast, even in countries such as Switzerland where iodiza-
tion of salt ensures iodine sufficiency among schoolchildren and adults, babies who
are being weaned can sometimes suffer from iodine lack [45]. As explained and dis-
cussed in this chapter in the section Ensuring Sufficient Iodine Supplies at National
Levels for Children and Pregnant Women, if a woman is planning pregnancy it is
advisable not only to take folic acid and vitamin supplements, but also to ensure an
adequate supply of iodine before, during, and after pregnancy (especially if breast-​
feeding). In the absence of any thyroid disorder, a sufficient iodine intake ensures
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Time to Act and How to Act 189

normal production of thyroid hormone. In turn, adequate thyroid hormone lev-

els in the mother and then in the developing child will lessen concomitant effects
of chemicals affecting brain growth, irrespective of whether such chemicals act
directly through thyroid disruption or through other related mechanisms.
A final advantage is that breast milk has lower levels of phthalates and BPA than
most formula preparations. A team of German researchers measured the amounts
of phthalates in breast milk and formula [46]. Their results were clear: There was no
advantage to using formula to reduce exposure. The problems of soy-​based formula,
with high levels of genistein and other phytoestrogens, were discussed in Chapter 3.
Besides potentially causing inappropriate activation of estrogen receptors in differ-
ent parts of the body, these phytoestrogens act as thyroid inhibitors.

Drinking water: bottled or tap, filtered or unfiltered

The public health issues and economics of water usage are immense, causing con-
cern among consumers and even international conflict in some cases. The debates
are complex and go far beyond the scope of this chapter. To maintain focus on
the question discussed here, namely, what individuals can do to limit exposure to
thyroid-​disrupting EDCs, we consider the arguments for and against tap versus
bottled water. In most developed countries, water supply to houses is highly regu-
lated, and tap water is a safe and ecologically sounder option than bottled water, at
least with respect to two of the major groups of EDCs (i.e., BPA and phthalates)
[47]. Much depends on the characteristics of your house, particularly the pipes that
carry the water to the tap and its water supply. Information on tap water quality
should be available from your local supplier. If the quality is questionable (high
levels of nitrate, for example), the most effective action will be to contact associa-
tions addressing these questions at local and national levels and, in the meantime,
to drink water from recyclable glass bottles if available locally.
Currently, most households in developed countries are using the same water they
drink to shower, water the garden, and wash their clothes or even the car. It is evi-
dent that this situation is wasteful, and that if drinking water standards are to be
maintained, more rational use of the supply has to be instigated. In many countries,
from Australia to France, householders in independent dwellings are increasingly
motivated to collect rainwater from roof runoff to water the garden, run the wash-
ing machine, and flush the toilet, thereby reducing wastage of water for drinking
and showering. Others have suggested that a potential solution combining health
benefits and economic advantage would be to deliver 2 liters of glass-​bottled puri-
fied water per person to each household every day, in the same way that milk was
once delivered to the door in the United Kingdom and United States.
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190 Toxic Cocktail

Depending on the site and time of year, certain water treatment plants do not
remove all traces of organic substances, such as pesticides, perchlorate, and nitrate.
As a result, in some areas tap water can contain significant amounts of these contam-
inants. Two chemical classes with strong antithyroid actions that show significant
variations as a function of measurement site are perchlorate and nitrates. Taking
perchlorate first, different countries and, within the United States, individual states
apply, or simply recommend, varying limits for perchlorate in drinking water sup-
plies. Drinking water can contain perchlorate from two sources: the groundwater
supply itself or chlorination disinfection methods, particularly through the addi-
tion of hypochlorite.
The current general ruling in the United States, set by the Environmental
Protection Agency (EPA), is 15 micrograms per liter, although Massachusetts, for
example, has a much lower limit. In the early 2000s, high levels of perchlorate in
drinking water supply to a residential area, and the lack of state or federal rulings
on admissible levels at the time (2001–​2002), led local authorities to convene an
independent committee for guidance. Using a weight-​of-​evidence approach, consid-
eration of sensitive life stages and the risk of iodine insufficiency brought the limit
down to 2 micrograms per liter [48]. The EPA is currently working on measuring
and removing perchlorate from drinking water. It is also expected to issue a state-
ment in the coming year about the risks/​benefits of introducing a ruling to regulate
the perchlorate levels in drinking water. At present, there is no recommended limit
for perchlorate levels in the EU directive for drinking water.
As we’ve seen, nitrate in the water supply is largely derived from intensive agricul-
tural practices. In France, a World Wildlife Fund (WWF) study published in 2011
reported that about half of the tap water sources had values over 20 milligrams/​liter,
with some over the maximum permitted limit of 50 milligrams/​liter.2 As empha-
sized in Chapter 3, both nitrate and perchlorate perturb thyroid hormone availabil-
ity by inhibiting iodide uptake by the thyroid gland. Nitrate is more than 100-​fold
less active as a competitor for iodide transport by the thyroid than perchlorate.
However, the fact that it is present at 1,000-​fold greater concentrations in tap water
(nitrate is found in the milligrams/​liter range and perchlorate in the micrograms/​
liter range) means that both represent significant thyroid-​inhibiting capacity. This
figure argues, yet again, for the importance of iodine supplementation, especially
during pregnancy, as nitrate values are even higher than perchlorate in amniotic
fluid (see Chapter 3).
Much research focuses on comparing methods for removing these compounds,
which, along with estrogenic factors and pesticides, can figure among the most
common organic micropollutants of drinking water. Not surprisingly, they are of
increasing concern on the part of the public and their suppliers. Thus, many people
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Time to Act and How to Act 191

prefer the extra security of filtering their tap water using home-​based filtering sys-
tems. Most of the methods proposed are actually modifications of the methods
used on a larger scale for both wastewater treatment and production of tap water.
These methods include sand filtration or ultrafiltration (UF), powdered activated
carbon (PAC), chlorination, ion exchange resins, use of ultraviolet (UV) light, and
ozonization.
Although combinations of different methods at the source will remove most con-
taminants, the questions of cost and who should foot the bill inevitably arise. An
example that could be usefully copied by others is that of the Swiss government.
As of 2016, they introduced a micropollutant tax (about $9.6 per resident) to cover
filtering wastewater to remove micropollutants, including pesticides, cosmetics,
hormones, and drugs, from used water.3 This step will reduce contamination of the
environment and also ensure that the water that is subsequently subjected to treat-
ment for provision of tap water has a lower level of micropollutants.
Four main types of home water treatment methods are available, each with its
own drawbacks. The most commonly used is a carbon or charcoal filter, usually in
the form of a jug or an on-​tap appliance. These can also be installed as an under-
sink appliance at the entry of the main drinking water supply. In both cases, the fil-
ters need to be changed regularly and consequently create landfill waste. Although
probably not as voluminous as plastic bottles for an equivalent amount of water,
recycling filter waste is more difficult. Carbon filters remove mainly chlorine and
some chlorinated compounds, estrogen, lead, and copper. Depending on the water
source, they may also remove some PCBs, along with pesticides and herbicides. They
do not remove nitrate or perchlorate.
Reverse osmosis systems can be installed by specialized companies. These sys-
tems use power to membrane filter the water under pressure. In certain respects,
the water quality is better than by filtering, as perchlorate and nitrate are efficiently
removed by this method. However, they are exceedingly wasteful, in terms of both
energy and water, with between 5 and 10 times more water lost than filtered. Two
other methods are home-​based UV sources to kill bacteria (although this should
not be a problem in most areas) and distillation units. Downsides are that they are
energy consuming and require regular cleaning and maintenance.
Overall, given the limited spectrum of chemicals removed and the environmental
cost of most routine household devices, a reasonable guideline would be to draw
water for drinking the night before and leave the chlorine to evaporate. However,
nitrate does not evaporate, even during boiling; as a result, boiling concentrates
nitrate as water is lost. To avoid nitrate buildup, boiled water should not be subjected
to a second round of boiling. With regard to perchlorate, probably the most effec-
tive immediate measure is to ensure an adequate supply of iodine. A longer-​term
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192 Toxic Cocktail

objective is collective action and lobbying to ensure that both nitrate and perchlo-
rate levels in drinking water are better regulated.
A final point concerns bottled water. Besides the transport cost and the carbon
footprint incurred, other drawbacks of bottled water vary according to its source
and container. Plastic bottles are lighter and therefore incur lower transport costs
but have higher plasticizer content, in particular BPA from polycarbonate bottles
and the filters used to prepare the water. Phthalates are not added to the plastic
used for water bottles but potentially enter during the manufacturing process [49]
or during storage in hot weather [50]. Water from plastic bottles does, however,
contain more chemicals with estrogenic activity (usually BPA or one of its substi-
tutes) than glass-​bottled water [51] or tap water. However, a recent study of Spanish
women found that a more worrying source of phthalates than bottled water was use
of household cleaning materials, including glass and oven cleaners and degreasing
substances [52]. This result brings us to our next group of potential EDC sources: the
home environment.

Choice of furnishings, household products, and electronic equipment

The main worry about household furnishings, insulating materials, and elec-
tronic equipment is their brominated and chlorinated flame-​retardant content.
This problem is particularly acute in some countries and US states with strin-
gent flammability standards for furniture components, especially cushions and
sofas, as is the case for the United States in general and California in particular.
However, largely thanks to Arlene Blum and her Green Science Policy Institute,
in 2014 the California State administration finally announced that it was modi-
fying the rulings for flammability, originally drawn up in the 1970s. The basic
idea is to change the flammability test from an open flame test, which requires
high levels of brominated or chlorinated flame retardants to resist ignition, to a
“smolder” test. This new ruling was long resisted by the chemical industry, argu-
ing that public safety was at risk. It’s good to see that the links between neuro-
developmental and behavioral disorders and environmental pollution, including
flame retardants, were finally taken into account in passing the new rulings,
even though this provides yet another example of belated action decades after
introducing virtually untested chemicals and allowing them to accumulate in
the environment. The more stringent flammability standards for furniture estab-
lished for California were often applied on a wider scale. Products manufactured
for export in California had to meet the most stringent requirements to reduce
flammability, even if imported into a country with less ​exacting regulations. This
fact, along with the persistence of the chemicals concerned in the environment,
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Time to Act and How to Act 193

contributes to universal contamination from polybrominated diphenyl ethers

(PBDEs) (see Chapter 3), one of the main categories of brominated flame retar-
dants (BFRs). Although many new flame retardants are being introduced to
replace BFRs, few toxicity data are available, so it is wise to apply a precaution-
ary principle until more is known. As mentioned in Chapter 3, in 2013/​2014 the
EPA, under its Toxic Substance Control Act, began focusing on close testing of
23 substances of concern,4 including no less than 20 flame retardants. Most of
these chemicals are named, but at least 4 are covered by company confidentiality,
precluding independent assessment.
As well as household furniture, flammability requirements apply to car seats
and electrical components. A recent US study showed that car dust contains lev-
els of a new chlorinated flame retardant 10 times higher than house dust [53].
Hence, perhaps this is the logic for the suggestion made by the RCOG report
that pregnant and nursing mothers should avoid buying a new vehicle but keep
their previous car, in which many of the flame retardants in the furnishings will
have already been released into the atmosphere. The authors of the car and house
dust study [53] also found the chemical V6 in the foam used in baby products,
where it represented over 4% of the foam weight. A banned flame retardant and
carcinogen, tris-​(2-​chloroethyl) phosphate (TCEP), was a consistent cocon-
taminant of V6, probably being introduced as a side product during manufac-
ture. There are few toxicity data on V6 and virtually nothing on its potential
endocrine-​d isrupting properties.
One way of avoiding flame retardants in bedding is to use pure wool mattresses.
Wool, like many natural products (e.g., hemp that can be used for insulation and
cotton for clothing), is far less flammable than synthetic foam. Consequently, pure
wool mattresses (and cushions) can be used without the addition of flame retardants.
Electronic equipment such as computers, e-​book readers, tablets, and mobile
phones contain flame retardants because they heat up during use. In turn, heat
favors the release of volatile components. It is unrealistic today to suggest that we
should limit our exposure to electronic equipment. Air and dust levels of flame
retardants are highest in offices, probably in large part due to the concentration of
such equipment. Apart from the energy savings, it is therefore wise to shut down
electronic equipment at night, especially in the home environment and if devices are
in the bedroom. So, air rooms as often as possible.

Reduction of household pesticide use

Pesticide use in the home can involve controlling parasites on pets or wider use
against household pests, particularly in lower-​income communal dwellings [54].
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194 Toxic Cocktail

Some of the studies on exposure levels comparing organic and conventional food
also looked at levels of pesticides in children’s urine as a function of use of pesticides
at home [55], and others have examined this exposure route [56] as a component of
environmental exposure from multiple sources. As might be expected, long-​term
or acute use increases exposure, as judged by urine levels, leading many authors to
argue that better management strategies are required to reduce the use of poten-
tially harmful pesticides inside dwellings. For instance, studies in New York City
have shown inverse relationships between maternal blood levels of chlorpyrifos due
to residential pesticide use and infant birth weight [57]. In turn, as emphasized in
Chapter 5, low birth weight is a risk factor for many neurodevelopmental disorders.
Thus, even if personal choice can be a factor in limiting use and therefore expo-
sure of pregnant women and children in individual settings, we need legislation to
improve housing conditions and protect those in areas of high residential density
from excessive pesticide use and exposure.
Other, avoidable, sources of pesticide use around the house include flypapers, flea
powders and shampoos for dogs and cats, and garden products, including insecti-
cides and fungicides (such as antigreenfly or antimold sprays). One insecticide often
used in pet products is the well-​documented thyroid disruptor fipronil [58, 59]. It is
wise to keep the use of these products to the strict minimum and not to apply them
near children.

Nongovernmental and collective actions

Associations with wide environmental scope of action

A good way to act more effectively is to work with others toward a common goal,
within either an association or a political party. What is more, according to research-
ers at the Erasmus University in the Netherlands, doing so can actually improve
one’s sense of well-​being.5 There’s more than one reason to get involved!
A number of nongovernmental organizations (NGOs) are concerned with the
more responsible regulation and use of chemicals, environmental contamination,
and the consequent deleterious effects on human health. The WWF (http://​w ww.
worldwildlife.org/​) has sponsored various studies of chemical exposure. As well as
the one already mentioned carried out by WWF in France on drinking water, its
two reports on contamination of European populations by mixtures of chemicals
were game changers in the REACH (Registration, Evaluation, Authorization and
Restriction of Chemicals) debate in 2004/​2005.6
The Health and Environment Alliance (HEAL; http://​w ww.env-​health.org) is
one of the most active associations in terms of providing an excellent platform of
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Time to Act and How to Act 195

information to the public on a variety of environmental issues that affect health,

whether it be through climate change, air quality, pesticides in general, or endocrine
disruption. It maintains an informative and up-​to-​date website. As its name sug-
gests, HEAL represents a number of organizations working toward the common
goals of improving both the environment and health. The 70 organizations that
HEAL federates range from health professionals to groups that represent specific
sectors of the population, such as women or youth groups. In the United States, two
organizations doing similar work are the Environmental Working Group (http://​
www.ewg.org/​) and the National Resources Defense Council (https://www.nrdc.
org). A similar organization is based in the United Kingdom: Client Earth, which
is run by lawyers (http://​w ww.clientearth.org).
Greenpeace (http://​w ww.greenpeace.org/​usa) is clearly an international forerun-
ner in defending the environment. Its current priorities include action around sus-
tainable agriculture and reduction of chemical exposure through research into safer
products.
The Chemicals, Health, and Environment Monitoring Trust or CHEM Trust
(http://​w ww.chemtrust.org.uk), works more specifically on the problem of chemi-
cals in the environment. Set up in 2007, CHEM Trust focuses on the effects of
persistent organic pollutants (POPs) on biodiversity and health. The organization
is active in promoting legislation on better use of chemicals. In the United States,
one nonprofit organization working toward solutions for chemical production and
usage that are more environmentally friendly and sustainable is the GreenBlue
Institute (http://​greenblue.org/​).
There are also women’s groups on both sides of the Atlantic that address these
issues. In the United States, there is Women’s Voices for the Earth (http://​w ww.
womensvoices.org/​), and in Europe, Women in Europe for a Common Future
(http://​w ww.wecf.eu/​). The relevance of these organizations is not only that women
bear babies and often have the most responsibility in raising children, but also that
women use most of the cleaning products that can contain EDCs. To this, one can
add that women are the targets of advertising by the cosmetic industry and on aver-
age use far more cosmetic products than men.
Another form of group action, which is especially relevant in the context of the
US legal framework, is class action. The Master Settlement Agreement exemplifies
the effectiveness of this type of action. This agreement resolved the case brought by
a group of state attorneys general against the US tobacco industry in 1999 and not
only awarded billions of dollars to healthcare services toward the cost of caring for
smokers but also changed legislation on the advertising and sales of tobacco prod-
ucts [60]. In the context of environmental pollution and effects on public health,
examples of successful class action include one brought by people resident near a
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196 Toxic Cocktail

chemical plant producing perfluorooctanic acid (PFOA), used for manufacturing

nonstick pans [61]. This settlement included the initiation of a project to follow the
health of children exposed by contamination of drinking water with PFOA, now
known to interfere with thyroid hormone signaling.
It is hardly surprising, given the high use of flame retardants in the United States,
that there are a number of organizations researching and providing information on
the (lack of) testing and use of flame retardants. One of them, the Green Science
Policy Institute (http://​greensciencepolicy.org/​), was founded in 2008 by Arlene
Blum. As mentioned, largely through Blum’s work promoting legislation on BFRs,
the institute succeeded in significantly reducing use of flame retardants.
This institute and other bodies working toward approaches that are more envi-
ronmentally sustainable and less health endangering are up against strong lobby-
ing by well-​organized industries. I discussed the general lobbying activities of the
chemical industry in Chapter 8, but with regard to flame retardants in particular,
it’s worth looking at the Chicago Tribune website. This excellent site7 recounts
the collusion of various industrial groups in the promotion of unnecessary use
of toxic BFRs and lists examples of lobbying by tobacco companies and the bro-
mine industry as well as distortion of scientific information by representatives
of the chemical industry and scientists alike. To this, one can add that the risk
of smoking causing house fires in the United States and the European Union
has dropped dramatically with increased awareness of the health risks associ-
ated with tobacco and the associated reduction in smoking, notably smoking
indoors and around children. Many house fires began with carelessly discarded
cigarettes. A number of scientific publications have argued against the unneces-
sary and excessive use of flame retardants [62] that has led to their unrelenting
buildup in environment, even in areas at great distances from regions of high
usage [63].

Biocides and pesticides

Production of pesticides increased sevenfold between 1950 and 2000, reaching over
3.5 million tonnes per annum. As has been argued at multiple points in this book,
we need more investment in sustainable agricultural practices for humankind to
benefit from, and not further degrade, ecosystem potential. Many regulators con-
sider that pesticides and biocides are the most carefully scrutinized by testing and
therefore are better regulated. However, as underlined at many points in this book,
the testing methods used can overlook vulnerable windows of development, and in
many cases adverse effects (e.g., on thyroid hormone levels) seen in rats are not taken
into consideration in the final decision-​making process.
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Time to Act and How to Act 197

Regarding actions by individuals, many policy changes in pesticide usage are

driven by public concerns about health. These can be usefully channeled through
NGOs such as the Pesticide Action Network (PAN), which has groups working
in North America (http://​w ww.panna.org) and Europe (http://​w ww.pan-​europe.
info). Given the strong lobbying by the chemical industry on this topic, it’s impor-
tant that public opinion aids NGOs, such as the PAN groups, to be effective in their
actions. PAN Europe is also a member of HEAL.

Political and regulatory levels

Ensuring sufficient iodine supplies at national levels
for children and pregnant women

Ensuring that women have sufficient iodine to avoid even transient and mild hypo-
thyroidism is vital not only throughout pregnancy, but also during the first months
before the fetal thyroid is formed. This period has been shown repeatedly to be a
particularly sensitive window of vulnerability for associations between chemical
load and later neurodevelopmental and behavioral outcomes.
Chapter 1 explained that iodine deficiency is not solely of historical interest, but
is currently present in mild-​to-​moderate forms in various parts of Europe. Worse,
iodine intake is falling in many countries worldwide. In the context of chemical
pollution, iodine insufficiency will no doubt exacerbate the consequences of thyroid
hormone–​disrupting chemicals on brain development.
In just 2015 alone, no fewer than 80 articles touched on the problem of iodine and
pregnancy. In 2013, among the 17 articles that demonstrated yet again [64] or dis-
cussed the risk of maternal iodine lack on children’s later neurodevelopment, one of
them was wisely titled “Sufficient Iodine Intake During Pregnancy: Just Do It” [65],
and another was called “Iodine and Pregnancy: A Call to Action” [66]. Much of
the debate concerns regional differences, with certain authors arguing that in many
regions iodine intake is sufficient and supplementation unnecessary. However, a
number of medical authorities consider that prevention is vital and recommend
well-​dosed iodine supplementation during pregnancy.
Today, it seems logical to ensure that women do not enter pregnancy with any
risk of iodine lack. Two principal arguments can be put forward: first, the disas-
trous economic consequences of the loss of a few IQ points at a population level (see
Chapter 7 for figures on cost estimates) and, second, the risk of exposure to such a
wide spectrum of chemicals, which can exacerbate the adverse effects of the lack of
iodine on thyroid hormone signaling. Thus, governments have the responsibility to
guarantee sufficient iodine levels in their populations. The cost benefit in the long
term is immense at national levels, in both social and economic terms [67]. For the
individual, governmental failure to act is a form of social injustice.
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198 Toxic Cocktail

Iodine sufficiency at the population level can be achieved either by legislation cov-
ering the iodization of salt (not only for sale in households, but also for use in the
food and agricultural industries) or by increased awareness in the medical profes-
sion. In the latter case, the recommendations of the World Health Organization
(WHO) need to be taken into account. This organization, along with UNICEF
and the Iodine Global Network (IGN), has increased the recommended iodine
intake for pregnant and lactating women from 200 to 250 micrograms per day. Some
antenatal vitamin and mineral preparations include both iodine and selenium. If
antenatal supplements contain 150 micrograms of iodine, then the rest should come
from a well-​balanced diet. This combination should ensure there is no risk of over-
dosing. Alternatively, as iodine is efficiently stocked in the thyroid gland, one way of
ensuring iodine supply for women of childbearing age is to provide iodine injections
every 3 months or even to give a dose of iodine-​enriched oil once a year [68]. Doctors
and nurses need to be made more aware of the need for iodine supplementation, and
medical associations should inform governments of the importance of implement-
ing methods for preventing iodine lack.

We need better international regulation of endocrine-​disrupting chemicals

Currently, about 85,000 chemicals are on the US EPA Toxic Substances Control
Act (TSCA) inventory, with between 700 and 1,000 extra added each year. The
outcome of a ruling enacted in 1976, the inventory covers substances authorized for
manufacture in or imported in to the United States at levels above 10 metric tons.
But—​and this is important—​the TSCA list does not even include substances cov-
ered by other types of legislation pertaining to pesticides, foodstuffs and food addi-
tives, and cosmetics. So, if one groups these different categories, it’s hard to imagine
the total number of chemicals currently authorized. One can wonder how so many
compounds that have later been shown to persist in the environment or to be det-
rimental to wildlife and human health have been ratified for widespread use. Next,
I summarize the current procedures for marketing or importing chemicals in the
United States and the European Union. Simply put, in the United States today one
can put a substance on the market within 3 months. All too many examples show
that more than 30 years will be needed to take it off the market.

Getting a chemical on the market in the United States

Under a recent agreement between the US government and industry, the procedure
for marketing a new chemical in the United States will undergo a major, much-​
needed and long-​awaited reform.8 According to an editorial in the scientific journal
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Time to Act and How to Act 199

Nature [69], “The 1976 Toxic Substance Control Act (TSCA) must be one of the
worst pieces of environmental legislation ever devised” (p. 6). The procedure applied
for the last 40 years (1976–​2016) is described on the EPA’s website.9 Succinctly put, in
the United States, a first step for a company to manufacture or import a new chemi-
cal is to address a Premanufacturing Notice (PMN) to the EPA. The EPA has to
review the PMN and reply to the company within 90 days. As many PMNs include
little or no toxicity or fate data, at the moment the EPA uses several risk screening
approaches to facilitate assessment in the absence of specific data. The approaches,
which include computer modeling, are deployed to enable rapid evaluation of poten-
tial risks and making risk-​management decisions for the new chemicals within the
90-​day time frame prescribed by TSCA. It is hoped this complete lack of in-​depth
toxicological and endocrine-​disrupting appraisal will change under the new rulings.
Currently, if the EPA considers that there is a risk to health or the environment
or there is insufficient information to ascertain risk to health or the environment,
it will issue a special order to prohibit or limit production. Over 90% of PMNs are
accepted without modification (i.e., without suggestion of restriction or regulation).
The EPA receives up to 1,000 PMNs every year. This means that about 900 new
chemicals can be ratified for production or import annually. If the chemical is only
to be produced or imported at low volume—​less than 10,000 kilograms (10 metric
tons) per year—​then it is exempt from the registration process.
After obtaining a favorable response to the PMN, the company has 30 days from
the start of manufacture or import to inform the EPA of commencement with a
Notification of Commencement of Manufacture or Import.

Getting a chemical on the market in the European Union

In 2006, the European Union brought in the REACH regulations.10 The European
Chemical Agency is responsible for registration, which underwent a staggered pro-
cess: Companies had until November 2010 to register substances manufactured or
imported at amounts equal to or above 1,000 tonnes per year. This limit is now at
1 tonne per year for any substance produced or imported into the European Union
that is carcinogenic, mutagenic, or toxic to reproduction.
The REACH procedure is more stringent than that of the EPA. In the registra-
tion submission, companies have to state whether the substance is a hazard, and
this requires information on substance identity, physicochemical properties, mam-
malian toxicity, ecotoxicity, environmental fate (including if and how the chemical
is degraded), as well as details of the manufacturing process and uses. Finally, risk
management measures have to be described.
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200 Toxic Cocktail

International cooperation on regulation of chemicals

As with problems related to climate change, the question of regulating chemi-

cals, particularly those that persist and accumulate in the environment, cannot
be addressed without cooperation between individual nations. Many international
bodies have committees with activities aimed toward reaching agreement on differ-
ent aspects of chemical regulation. The Organization for Economic Cooperation
and Development (OECD) plays a key role in proposing and ratifying testing
procedures. In the field of endocrine disruption, the OECD has committees on
reproductive endocrinology and physiology, as well as thyroid signaling. To grapple
with the complexities, in 2012 the OECD set up its Adverse Outcome Pathway
committee,11 the members of which propose and determine which tests can be
used to determine adverse effects in different settings for a spectrum of signaling
pathways. The title of the committee reflects the terminology of the WHO defini-
tion of endocrine disruption (WHO, 2012). This definition, originally proposed
by WHO’s committee for the International Programme for Chemical Safety
(IPCS) is as follows: Endocrine disruption occurs by “an exogenous substance or
mixture that alters function(s) of the endocrine system and consequently causes
adverse health effects in an intact organism, or its progeny, or (sub) populations.”
The term adverse is much debated. How long lasting, or to what extent, does a
change in a hormone level, gene response, or physiological process need to be for
it to be adverse? Clearly, the answer depends on the time of exposure and the tis-
sue considered. For instance, a small change in thyroid hormone availability dur-
ing early development of the brain can have irreversible consequences. In an adult,
transient change in thyroid hormone levels will be less harmful. So, it’s going to
require a lot of work by these committees to determine how to apply the “adverse
consequence” concept. At the best of times, the OECD takes years, most often a
decade, to ratify a specific test. As a consequence, despite the best intentions of
many OECD officials and time invested by many committee members, it will be
at least another decade before any legislation arises from the work on these adverse
outcome pathways.12
But, international cooperation can be successful and determinant. One such
example came in May 2013 when a joint UN convention was signed to promote
synergy and strengthen cooperation between the Basel, Rotterdam, and Stockholm
conventions (http://​synergies.pops.int/​Secretariat/​VisionStatement/​) to better
protect the environment and human health from toxic chemicals. The agreement
can be consulted as the “Geneva Statement on Sound Management of Chemicals
and Waste.” At the outset, each of these conventions covered, respectively, trans-
port of hazardous waste, trading of hazardous chemicals and pesticides, and POPs.
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Time to Act and How to Act 201

Another example, discussed in Chapter 8, is the action taken by Sweden and a group
of other EU countries against the EU Commission in 2014, a case they won in the
European Court of Justice in late 2015.
Other examples of international cooperation are less satisfying. One recent exam-
ple includes the failure of the European Food Safety Association (EFSA) to take a
sufficiently clear position on the need for testing the endocrine-​disrupting potential
of chemicals [70], including pesticides. This decision, published in March 2013, was
criticized by a number of parties for pandering to industry and failing to recog-
nize the dangers of endocrine disruption. The EFSA statement on the lack of need
to improve EDC testing was surprising given that they published another report
[71] just 4 months later, on July 12, 2013, in many ways contradicting the first. This
one, specifically addressing the question of pesticide neurotoxicity and effects on
thyroid signaling, stated that of 287 pesticides screened, 68 were noted as “having
specific effects on the nervous system,” and over one-​third, 101, “were identified as
affecting the thyroid or thyroid hormone systems.” The panel also drew attention
to the absence of systematic testing of pesticides for developmental neurotoxicity.
In the wake of the first publication (in March 2013), a number of NGOs drew his-
torical parallels with the ways in which politicians had failed to counter lobbying
by the tobacco, lead, and asbestos industries in previous decades. Three members
of this EFSA group, with ties to industry [72], were also among those signing the
legislation-​blocking letter to Anne Glover, to which I  referred in Chapter  8—​so
much for the lack of endocrine-​active effects of pesticides.

How to respect ethics in animal research and still test thousands of chemicals

Today, we are faced with a major predicament. Thousands of chemicals are produced
at significant tonnage, but because of the current regulatory scenarios described, the
large majority of them have not been tested for their toxicological or endocrine-​
disrupting effects before being released onto the market. Testing the effects of chem-
icals on biodiversity or human health requires biological systems, most often cells or
animals. There are, of course, numerous ethical problems with animal research, and
every effort must be made to apply the principles of the three “Rs”: reduce, refine,
and replace animals in testing. Yet another often-​heard criticism of animal research
is that no animal model can predict what will happen in humans. The choice of
testing thalidomide on rats is often cited, as these rodents, unlike highly sensitive
species such as rabbits and humans, are insensitive to the teratogenic effects of the
drug due to interspecies differences in metabolic capacity [73]. This is an important
concept, that is, that many toxic endocrine-​disrupting effects are not exerted by the
primary or parent compound but by a metabolite produced in the organism itself.
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202 Toxic Cocktail

However, these effects can be studied, as discussed further in the following mate-
rial, because some alternative methods do have metabolic competence.
As there are many interspecies differences in metabolism, it is often suggested that
if the aim is to protect human health (in contrast to testing primarily for effects on
biodiversity), then one should use either human cells in culture or multiple animal
models or potentially multiple computer-based, or in silico, approaches upstream of
a range of in vitro animal cell lines. Certainly, the principles of comparative physiol-
ogy teach us that although many processes are evolutionarily conserved and com-
mon to all vertebrates, there are many differences in metabolism, sensitivity, and
timing of processes such as receptor or enzyme expression, and of course differences
in timing of phases of brain development. Examples of processes that are largely
conserved extend from the basic principles of gene regulation to complex endocrine
processes, such as thyroid hormone synthesis and action.
There is no doubt that future testing strategies will involve multiple layers of tests
that incorporate both new animal models and in vitro approaches using animal and
human cells, all of which can be coupled to in silico analysis. However, in the case
of human cell lines, the question must be raised regarding where one finds the first
human cells to test or to derive the lines.
Many cells line have been obtained from patients or fetuses without appropri-
ate ethical consent from the person or parents concerned. Many think that a less​
problematic answer lies in cloning, possibly by transforming and multiplying easily
obtainable cells such as white blood cells. Recent advances enable biologists to gen-
erate stem cells from a variety of sources and then to reprogram them into another
tissue. The original work [74] led to a Nobel Prize for Yamanaka, the senior author.
The different tissue types derived can be used for testing effects of chemicals
across a variety of different cells, such as liver cells or neurons. However, deriving
human cells for chemical testing by cloning methods means that the tests are car-
ried out on cells that are not really representative of the initial cells (cloning, by any
means, introduces changes and errors in chromosomal number or organization).
Furthermore, tests will most usually be carried out on a single type of cell:  neu-
rons or liver or skin cells. This situation, using cell types in isolation, is a long way
from the complexity of an intact organism such as the human body. In all physi-
ological systems, there is continual communication between organs, tissues, and
cells. Moreover, the chemical signals used for communication undergo continual
metabolism and recycling, producing new molecules from old.
Not surprisingly, alternative models for chemical testing are needed to resolve
this conundrum. One of the most explored is the use of fish and amphibian embryos
[75]. These embryos have lots of advantages including accessibility, numbers, trans-
parency, and size. First, regarding accessibility, fish and amphibian eggs are laid in
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Time to Act and How to Act 203

water, and the embryos hatch as free-​living organisms. This feature is of course very
different from what goes on in mammals like us, where the eggs and the whole pro-
cess of fertilization and early development are hidden away inside the mother. So,
working on mammalian embryos raises the experimental problem of development
inside the mother and the ethical problem of using the adult mother to obtain the
embryos. This is not the case for fish fry and frog embryos. Next, for the numbers,
fish and amphibian embryos come in large batches of hundreds or thousands of eggs
being laid simultaneously, not just the 6 to 10 produced by mice. These early fish and
amphibian embryos are virtually transparent, allowing the use of fluorescent mark-
ers to follow gene transcription and organ development. Their small size allows for
screening methods that can be adapted for robotized, high-​throughput screening.
This means that methods developed for looking at cells in a dish can sometimes be
used to screen hundreds of chemicals on embryos. This feature provides screening
that is more rapid, costs less, and produces less chemical waste than if larger animals
are used.
The trump card is that amphibians and fish share many features with mammals
in terms of organ development and signaling molecules, particularly endocrine
signaling. As mentioned, thyroid hormone is exactly the same in fish, amphibians,
birds, and mammals, including humans. What is more, the processes and molecules
implicated in hormone production and action are also similar. Finally, the meta-
bolic capacity of some of these fish or frog embryo model systems resembles that of
mammals.

A short guide to some environmentally friendly,

precautionary actions to limit individual
exposure to EDCs

I am often asked what can the individual do, given the universal exposure that we
are all experiencing. There are quite a few actions that can make a difference. In the
text, I explain exactly how they reduce our exposure levels, but in the meantime,
here’s the list:

• Consume organically grown grain, vegetables, fruit, and dairy products

whenever possible.
• If using nonorganic fruit and vegetables, wash thoroughly before eating.
• Limit the use of commercially prepared and packaged foods.
• Avoid storing food, particularly fatty foods, in plastic containers; use glass,
silicone, or ceramic whenever possible.
• Do not microwave food in plastic containers.
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204 Toxic Cocktail

• Avoid giving flexible plastic teething toys to babies and use glass feeding
bottles.
• Limit the use of pesticides and similar products in the home, on pets, and in
the garden.
• Do not use household products containing antibacterial agents.
• Limit the use of spray-​on waterproofing agents.
• Prefer cast iron or stainless steel pans to nonstick varieties.
• Do not overuse sunscreens and cosmetics, especially those containing anti-
microbials (such as triclosan or parabens) and phthalates, when pregnant or
breast-​feeding.
• Avoid use of polyvinyl chloride (PVC) flooring and carpets, particularly in
children’s rooms. For insulation materials, consider using natural products
such as hemp.
• If pregnant, avoid buying new sources of foam-​fi lled furniture or seating
(such as in new cars).
• Prefer natural wool mattresses to foam products, especially for children.
• Wash clothes that may have been treated with flame retardants before
wearing.
• Don’t feel obliged to have the biggest flat-​screen television possible, and if
you do have one, switch it off when not in use, especially if sleeping in the
same room, to avoid heat-​dependent release of flame retardants into the
atmosphere.
• The same precautionary principles apply for computers and mobile phones.
Prefer use of hand-​free devices, a step that will reduce electromagnetic field
exposure.13
• Air rooms, especially children’s bedrooms, as often as possible to avoid accu-
mulation of EDCs in the atmosphere.
• If pregnant, limit the use of “over-​the-​counter” drugs and painkillers. Prolonged
use of acetaminophen (paracetamol) during pregnancy has been linked to
childhood respiratory problems [76, 77]. Likewise, prolonged acetaminophen
use in the second trimester of pregnancy when the male reproductive organs
are being formed has been associated in some studies with increased risk of
reproductive disorders in newborn boys [78]. Studies in mice suggested that
acetaminophen use in that period should not exceed 1 week [79].

Final comments: individual action

cannot substitute for policy

Examples have been provided demonstrating that individuals can act to help reduce
their exposure and to lobby industry and regulators into action. But, what about
  205

Time to Act and How to Act 205

people who are unaware of the dangers? Or the societal cost of those who choose
to ignore recommendations? Or people who have no choice but to be subjected
to exposure? For instance, it’s clear that many people simply cannot afford to buy
organic produce or to move out of housing that continually needs treatment to limit
rodents or insects.
Many factors enter this debate, which covers numerous political and ethi-
cal considerations and weighs arguments regarding who is responsible and who
should act. Numerous studies have demonstrated the greater efficiency of pol-
icy over lifestyle choices [80]. Simply taking the case of children growing up in
disadvantaged areas, such as, but not only, those in farming communities [81],
underlines the need for legislation. Such children can be doubly exposed to pes-
ticides, both from intensive agriculture and from the excessive use of pesticides
to control insects in substandard dwellings, not to mention the higher levels of
iodine uptake-​blocking nitrates found in the water of such areas with intensive
agriculture. Unsurprisingly, in view of what has been argued in this and pre-
vious chapters, children in these communities, prenatally exposed to cocktails
of thyroid-​d isrupting chemicals, tend to have more behavioral problems, do less
well in school, and have fewer career opportunities. In extreme cases, they can
become a burden on society.
The causes of their disadvantages are specific, material, identifiable, and, given the
political will to introduce and enforce appropriate legislation, preventable. Failure
to correct future injustices is also a failure to recognize that human intelligence and
ingenuity conceived and produced the current vast array of untested and potentially
dangerous substances. It should be possible for human intelligence and ingenuity to
find the means to control and eliminate their nefarious consequences. If not, then
future generations could well find themselves lacking the intelligence and ingenuity
ever to do so.
206
  207

Glossary

Chromatin: Chromatin is the mixture of nucleic acids (DNA and RNA) with the proteins
wrapped around it (mainly histones).
DNA: Deoxyribonucleic acid. This is the nucleic acid that makes the famous double helix with
sequences of nucleotides that form matching pairs through their bases: cytosine (C) and
guanine (G) or thymidine (T) and adenosine (A).
Dendrite: Dendrites are the processes that extend out from the body of the neuron to receive
input from axons, the output extensions of other neurons. Each neuron will have one axon
and multiple dendrites.
Dysgenics: Can be considered to be the opposite of eugenics, favoring increased
representation of individuals that are less well adapted, such as those weaker or more prone
to disease or less intelligent. The increase in the less well adapted occurs at the expense of
better-​adapted members of the population.
Embryogenesis: The early stages of development of an embryo when all the different organs,
brain and nervous system, intestine and liver, skeleton, limbs, muscle, and skin are formed.
Endocrine disruptor or endocrine-​disrupting chemical: Endocrine disruptors are defined
by the World Health Organization as exogenous compounds or mixtures that alter
function(s) of the endocrine system and consequently cause adverse effects in an intact
organism, its progeny, or (sub)populations.
Endocrine system: The endocrine system comprises all the different hormonal systems of
the body. It includes the glands that produce hormones that govern reproduction, the
sex hormones or sex steroids, such as estrogen and testosterone, and stress hormones, the
glucocorticoids and thyroid hormone.

207
208

208 Glossary
Endocrinology: The study of the endocrine system.
Epigenetics: Meaning literally “above the gene,” epigenetics is most often defined today as the
modification of gene activity by changes in chromatin structure and DNA methylation.
These changes, which can be short term or longer term, underlie how genes are actively
transcribed or silenced at different stages of development and in response to different
environmental signals. Some epigenetic marks are transmitted from one generation of
individuals to another. When and how genes are expressed at different times during
development largely determine major differences between species with similar genomes (e.g.,
chimpanzees and other primates, including humans).
Eugenics: Selective breeding or reproduction of the healthiest (and often the most intelligent)
members of a population to increase fitness and overall intelligence.
Germinal cell: These are the cells that will produce the sperm in the male and the oocytes
(eggs) in the female and so produce the next generation of individuals.
Halogen: Halogens represent a series of four principle chemical elements: iodine, chlorine,
fluorine, and bromine.
Histone proteins: The histones are special proteins that pack the DNA within the
chromosome and with the DNA (and RNA that is being made) form the chromatin.
Indel: An indel is shorthand for insertion and deletion variants in a genome.
In silico: This is the use of analytical methods that employ computer-​based programs, such
as determining how a series of chemical structures might interact with a particular set of
protein structures, such as a nuclear receptor.
In vitro: Experimental methods that are carried out on cells in culture or in test tubes and do
not use animal models.
In vivo: Experimental methods that are carried out in animal models
Legacy pollutant or legacy chemical: A chemical that has been banned but due to its
persistence and resistance to degradation is still present in the environment. One example is
the pesticide DDT.
Metabolite: A substance produced from another one during the body’s metabolic process.
Some metabolites are more potent than the initial, or parent, compound.
Methylation: The addition of a chemical group, a methyl group, either to one of the bases
in the DNA sequence, most often a cytosine, or to one of the amino acids in the histone
proteins that pack the DNA in the chromatin.
Nonmonotonic dose response (NMDR): A cellular or physiological response to a drug,
chemical, or physiological signal that does not give a straight line. Classical toxicology is
based on the idea that the more there is of a substance, the greater the response. However,
most natural endocrine signals show complex curves as a function of increasing hormone,
often with a flattening of response or even a U-​shaped curve, with highest doses having less
effect than lower doses. This type of response, with lower doses being more effective than
higher doses, can also be found with endocrine-​disrupting chemicals.
Nucleotide: Both DNA and RNA are composed of a string of subunits, or nucleotides.
Nucleotides are composed of a five-​carbon ring sugar that is connected to a phosphate group
and a nitrogen base. In the DNA, the sugar is a deoxyribose, and in the RNA it is a ribose.
Four types of deoxynucleotides are used to make DNA. Another combination of four
ribonucleotides composes RNA strands.
  209

Glossary 209
Pluripotent: The capacity of a cell, most often a stem cell, to divide and give rise to all the
different types of cells in a tissue.
RNA: Ribonucleic acid is a ribbon-​like single-​strand ribonucleic acid with different
bases: cytosine (C), guanine (G), adenosine (A), or uracil (U).
Single-​nucleotide polymorphisms (SNPs): SNPs represent changes in just one nucleotide
in a stretch of DNA. The changes may or may not have functional consequences on the
way the gene is transcribed or on the protein that is made if the SNP occurs in a coding
sequence.
Teratogen: A chemical or drug causing malformations in a developing embryo and has
teratogenic actions.
210
  211

Notes

Introduction

1. The United States Toxic Substance Control Act (TSCA), introduced in 1976, is currently
undergoing revision following a decision taken in the US Congress on May 24, 2016. For more
details, see the Chapter 9 section Political and Regulatory Levels.
2. REACH involves European legislation covering Registration, Evaluation, Authorization
and Restriction of Chemicals.
3. The criteria for defining EDCs will largely determine the framework of the legislation. The
European Commission stated that these criteria will be set by mid-​2016.

Chapter 1

1. Tchaikovsky’s 1812 Overture famously incorporates excerpts of the French national anthem
“The Marseillaise” and the orchestral equivalent of cannon shots.
2. Edward Whymper, Scrambles Amongst the Alps in the Years 1860–​1869. Philadelphia,
PA: Lippincott; 1872, p. 130.
3. By opposition to vertebrates that have backbones, invertebrates are animals without back-
bones. Different types of invertebrates include the worms, mollusks (such as squid and snails),
insects, and the crustaceans (crabs, lobsters, etc.).
4. Myxedema is still used in some instances to describe the effects of severe hypothyroidism
in humans. Technically, the term derives from and refers to the thickened skin condition that
characterizes marked thyroid hormone deficiency.
5. Today, the screening is based on blood levels of thyroid-​stimulating hormone (TSH). As
explained in Chapter 2, and as the name of the hormone suggests, TSH stimulates the thyroid
gland to produce thyroid hormone. If levels of thyroid hormone are too low, the body produces
211
212

212 Notes
more TSH to maximize production. If the thyroid gland is absent or malformed, TSH levels
will be very high.
6. Another fascinating fact related to iodine is that iodine is a halogen, and thyroid hormone
is virtually the only complex halogenated molecule produced by the vertebrate body. Halogens
represent a series of four very reactive chemical elements: iodine, chlorine, fluorine, and bro-
mine. Chemists designing new molecules have long exploited the high reactivity and versatility
of the halogens. Chlorine is used in the manufacture of myriad chemicals and polymers, such
as PVC (polyvinyl chloride), chlorine-​based pesticides, plastic products and their by-​products,
including polychlorinated bisphenols (PCBs) and dioxins. Fluorinated molecules are used to
make impermeable wrappings (such as the liners of popcorn containers), waterproofing sprays
for clothes and shoes, and the nonstick coatings of saucepans, frying pans, and other kitchen-
ware. These compounds and their history are discussed in Chapter 3. Suffice it to say that all
of these chemical categories, many of which accumulate inexorably in the environment, have
thyroid hormone–​disrupting properties.
7. See, for instance, information on the World Health Organization website: http://​w ww.
who.int/​nutrition/​publications/​micronutrients/​iodine_​deficiency/​.
8. The Iodine Global Network was previously known as the International Council for the
Control of Iodine Deficiency Disorders (ICCIDD).
9. See http://​w ww.who.int/​v mnis/​d atabase/​iodine/​iodine_​d ata_ ​status_ ​s ummary/​
en/index.html for tables and maps.
10. Certain authorities express concern about the potential risks of universal salt iodization
programs. The argument is that in some populations that are severely iodine deficient the rein-
troduction of iodine can induce thyroid problems in a few people, even though most people
will excrete any excess iodine in their urine. These transient health problems can be treated.
However, experts concur that the overall enormous benefits of salt supplementation for the gen-
eral population far outweigh the small risk of iodine excess for a few. Ideally, salt iodization
programs should be accompanied by population monitoring.
11. The gonads are the testes in men and the ovaries in women. These endocrine glands pro-
duce the male sex hormones, mainly testosterone in men, and the female sex hormones, estrogen
and progesterone, in women.
12. Removing other endocrine glands can also be lethal. Examples include the parathy-
roids and the pancreas. Also, severe lack of any hormone can be debilitating and cause disease.
Examples include osteoporosis induced by estrogen deficiency.

Chapter 2

1. The vertebrates are the large group of animals with backbones that encompasses the fish,
amphibians, reptiles, birds, and mammals, including primates and humans.
2. See further information at http://​w ww.who.int/​nutrition/​topics/​idd/​en/​. Consulted
June 8, 2016.
3. It is interesting to note that many cultures, especially the French and Chinese, have
invented recipes for just about every part of a cow, pig, or sheep, including the brain, thymus,
and intestines. But, no country cooks and serves thyroid gland. This could well be because of
the negative effects of too much thyroid hormone. Interestingly, there is one case in the medical
  213

Notes 213
literature of a slaughterhouse in Minnesota that, by including thyroid gland from pieces of neck
meat in ground beef, caused hundreds of cases of severe hyperthyroidism (thyrotoxicosis) in
1984–​1985.
4. As a quick search on the Internet will show (try “most prescribed drugs”), in recent years,
different formulations of thyroxine regularly top the list of the most prescribed drugs in most
countries. In some ways, the ease of producing the replacement therapy and its general applica-
bility has limited research into novel thyroid hormone–​like substances or even into understand-
ing the details of thyroid-​signaling physiology.
5. Today, most hospitals and laboratories test the hormone in the pituitary that stimulates
the thyroid, TSH or thyroid-​stimulating hormone. This is because if a baby lacks thyroid hor-
mone, the TSH levels increase; this is a more constant marker than thyroid hormone levels.
6. The hypothalamus (plural hypothalami), located at the base of the middle brain, com-
municates with the pituitary, just below it, to control the function of all the main endocrine
glands:  the thyroid; the adrenals, which produce the stress hormone corticosterone; and the
ovaries and testes, which produce estrogen and testosterone, respectively.
7. See https://​w ww.nobelprize.org/​nobel_​prizes/​medicine/​laureates/​1977/​presentation-​
speech.html for the presentation speech by Professor Rolf Luft given at the award ceremony.
Consulted June 6, 2016.
8. In rats and mice, gestation, the period from fertilization to birth, lasts 3 weeks. So, each
week is roughly equivalent to 3 months of fetal development in human pregnancy.
9. Joseph Altman also made one of the first observations on the birth of new neurons in the
adult brain. He cautiously titled his paper, published in the prestigious journal Science in 1962, “Are
New Neurons Formed in the Brains of Adult Mammals?” Today, we have lots of firm evidence
showing that they are; again, neurogenesis in the adult brain is dependent on thyroid hormone.
10. “Time is of the essence,” a legal term used in contract law in England and the United
States, introduces the idea that those signing the contract must complete their work within an
agreed time. The implication is that a delay will result in material damage, particularly pertinent
for thyroid hormone action and brain development.
11. For reasons that are not yet fully understood, the thyroid gland is often a target against
which our bodies produce antibodies in autoimmune disease. Again, for reasons that are not
clear, women are far more prone to autoimmune disease in general and, in particular, for auto-
immune thyroid disease, such as Graves’ disease, a common form of hyperthyroidism, and
Hashimoto disease, a form of hypothyroidism.
12. GABA, for gamma-​aminobutyric acid, is one of the main inhibitory neurotransmitters
produced in the brain. Release of GABA from a synapse is usually associated with a dampening,
slowing-​down effect on the activity of the next neuron.
13. A particularly harrowing account of a writer who reached this point appeared on the Daily
Mail website in 2013:  http://​w ww.dailymail.co.uk/​health/​article-​2449153/​W hy-​did-​doctors-​
20-​years-​spot-​faulty-​thyroid.html. Consulted June 8, 2016.

Chapter 3

1. The Organization for Economic Cooperation and Development (OECD) centralizes the
activity of a number of committees that suggest, optimize, and ratify tests for chemicals, includ-
ing those suspected of endocrine-​disrupting activity.
214

214 Notes
2. For certain forms of trout, the larger ones that are at the end of the food chain and have
accumulated the most chemicals, the recommendation is quite simply: Do not eat.
3. More details on these physiological control systems are given in my previous book, Losing
Our Minds: How Environmental Chemicals Affect Intelligence and Mental Health. (New York,
NY: Oxford University Press; 2014).
4. The two main forms of thyroid hormone are T4 (thyroxine) and T3 (triiodothyronine),
with 4 and 3 atoms of iodine, respectively.
5. As a quick reminder, the endocrine system comprises all the different hormonal systems
of the body. Besides thyroid hormone, it includes the glands that produce the hormones that
govern reproduction (the sex hormones or sex steroids, such as estrogen and testosterone) and
stress hormones (the glucocorticoids).
6. A  legacy chemical or legacy pollutant is a chemical that is no longer manufactured or
allowed on the market and yet is still present in the environment as it is persistent and nonbio-
degradable. Unfortunately, there are dozens of chemicals in this category still present despite
the fact they were banned decades ago. Examples include the pesticide DDT and PCB, both of
which can be found in amniotic fluid today.
7. Here, we discuss epidemiological data on chemicals and thyroid hormone function.
The epidemiological data on exposure to PCBs and other chemicals and their associations
with delay in brain development and IQ are discussed with other epidemiological data in
Chapters 5 and 7.
8. CHAMCOS is the acronym for the Center for Health Assessment of Mothers and
Children of Salinas. This center, based in the agricultural Salinas Valley in California, has orga-
nized a large cohort of children followed from birth onward to investigate how environmental
exposure affects the health of pregnant women and their children.
9. Just to show how toxic TCDD is, we can use paracetamol (acetaminophen) as an example.
The recommended dose for paracetamol is 1 or 2 tablets at a time. As each standard tablet contains
500 milligrams (a milligram is one-​millionth of a kilogram), 2 tablets contain 1 gram (or a thou-
sandth of a kilogram), for someone weighing 100 kilos (a large man), this would work out to 10
milligrams per kilogram body weight. This is 10,000 times more than the lethal dose of TCDD.
10. A number of authors have used the term brain drain to denote loss of intellectual poten-
tial from one country to another. But, I  think that the first person to use the actual term
brain-​drainer to describe a chemical that is linked to either neurobehavioral disease or IQ loss
was Philippe Grandjean in his book, Only One Chance (New  York, NY:  Oxford University
Press; 2013).
11. See http://​yosemite.epa.gov/​opa/​admpress.nsf/​68b5f2d54f3eefd28525701500517fbf/​fdcb-
2f665cac66bb852570d7005d6665. Consulted August 16, 2015.
12. See http://​w ww.levinlaw.com/​news/​dupont-​cant-​back-​out-​agreement-​compensate-​those-​
injured-​duponts-​chemical-​used-​teflon. Consulted August 16, 2015.
13. See https://​theintercept.com/​2015/​12/​16/​toxic-​firefighting-​foam-​has-​contaminated-​u-​s-​
drinking-​water-​with-​pfcs/​. Consulted May 16, 2016.
14. The NHANES is a large US-​based study that examines chemical exposure in large sec-
tions of the population. NHANES stands for US National Health and Nutrition Examination
Survey (http://​w ww.cdc.gov/​nchs/​nhanes.htm).
15. A chemical with mutagenic effects causes changes in the DNA sequence in cells. In some
cases, these changes in the sequence of DNA deregulate cellular controls and can cause cancer.
  215

Notes 215
16. According to one website, one means of raising money for this expedition was ensured by
marketing T-​shirts with the slogan, “A woman’s place is on top.”
17. See http://​w ww.efsa.europa.eu/​en/​efsajournal/​pub/​3132.htm. Consulted June 8, 2016.
18. EFSA PPR Panel (EFSA Panel on Plant Protection Products and Their Residues), 2013.
Scientific Opinion on the identification of pesticides to be included in cumulative assessment
groups on the basis of their toxicological profile. EFSA Journal 2013. 11(7): p. 3293. doi:10.2903/​
j.efsa.2013.3293.
19. See http://​w ww.cpsc.gov/​pagefiles/​126519/​chappres.pdf and https://​w ww.epa.gov/​
assessing-​and-​managing-​chemicals-​under-​tsca/​phthalates. Consulted June 8, 2016.
20. See http://​ec.europa.eu/​health/​scientific_​committees/​consumer_​safety/​docs/​sccs_​o_​
023.pdf. Consulted June 8, 2016.
21. As there are so many chemicals already in the environment that have not been tested for
their effects on human health or animals, the EPA set up their computational toxicology pro-
gram. In this program, computer-​based analyses of chemical and molecular biology data speed
up the evaluation process, permitting a first level of assessment of potential toxicology.
22. Centers for Disease Control and Prevention, 2013 Data on Exposure to Environmental
Chemicals in the United States.
23. As a reminder, estrogen is the main female reproductive or sex hormone. In target tissues,
estrogen binds to its nuclear receptor, ER.
24. See http://​w ww.ers.usda.gov/​media/​330194/​fanrr39-​1g_​1_​.pdf. Consulted November
16, 2015.
25. The Endocrine Society (http://​w ww.endocrine.org/​) was founded in the United States
in 1918 and has since become a global organization. In 2013 it set up a European task force of
10 scientists from different EU countries to provide information on EDCs to decision-​makers
discussing potential legislation on these chemicals. Focus was on the health problems caused by
these chemicals. I am a member of this task force.

Chapter 4

1. See http://​braininitiative.nih.gov. Consulted May 16, 2016.

2. See http://​w ww.nih.gov/​news/​health/​sep2014/​od-​30.htm. Consulted August 26, 2015.
3. See https://​w ww.humanbrainproject.eu. Consulted May 16, 2016.
4. The median is the midpoint of a ranked set of numbers. It is not the same as the mean,
another measure of average, which is derived from the total amount divided by the number of
members of the set. Thus, for 10 people where 4 have an income of €10,000, 5 have €20,000, and
1 has €100,000, the median is €20,000. The mean is higher, being €24,000 (4 × 10 + 5 × 20 + 1 ×
100 = €240,000, divided by 10 equals €24,000). The standard deviation reflects the amount of
variation or dispersion in the sample.
5. Charles Spearman came to study psychology and intelligence indirectly. First, he stud-
ied mathematics and engineering, then because of an interest in philosophy and particularly
Indian philosophy, he joined the British Army in the hope that he would be sent to India and
could study philosophy in his spare time. His readings in philosophy led him to psychology.
In 1904, before completing his PhD, he published his most important paper, “ ‘General intelli-
gence’ Objectively Determined and Measured,” which set the stage for his lifetime’s work, most
of which was carried out when he was professor and head of the Psychology Department in the
216

216 Notes
University of London. Elected to both the Royal Society in Britain and the American Academy
of Science, but dogged by ill health in old age, he committed suicide by defenestration at the
age of 82.
6. Both Galton and Darwin shared the same grandfather, Erasmus Darwin FRS, but Charles
Darwin was born to Robert Darwin, a son from Erasmus’s first marriage, and Francis Galton
was the son of Frances Darwin, a daughter of Erasmus’s second wife.
7. For a discussion of Darwin’s research into human evolution see James Moore’s “Darwin’s
Progress and the Abolition of Slavery” (Progress in Human Geography, 2010. 34(5): pp. 555–​582.
doi:10.1177/​0309132510362932).
8. Professor Deary has an interesting theory on the link between longevity and intelligence
which he developed in an essay, “Why Do Intelligent People Live Longer?” (Nature, 2008.
456(7219):  pp.  175–​176). The basic notion, other than more obvious socioeconomic and life-
style (such as better diet) advantages gained by intelligence, was that during early development,
when the different organs are being formed, if the brain undergoes optimal development, then
this will also apply to the other organs, such as the liver and heart. This model links with the
developmental origin of adult disease or DOAD theory discussed in Chapter 6. The two ideas
have major relevance to the increases currently observed in the incidence of noncommunicable
diseases (diabetes, cancer, and neurodevelopmental disorders), decreased IQ, and the decreased
longevity seen in some populations (discussed in Chapter 9).
9. Organization for Economic Cooperation and Development, OECD Skills Outlook
2013:  First Results From the Survey of Adult Skills. Paris, France:  OECD. http://​d x.doi.org/​
10.1787/​9789264204256-​en.

Chapter 5

1. See http://​w ww1.folha.uol.com.br/​internacional/​en/​brazil/​2015/​01/​1571572-​government-​

measures-​to-​control-​caesarean-​section.shtml. Consulted May 12, 2015.
2. See Clive Cookson’s commentary in the Financial Times, June 12, 2015, http://​w ww.
ft.com/​ i ntl/​c ms/​s/​2 /​013a8490- ​ 0 e9c-​ 1 1e5- ​ 9 ae0- ​ 0 0144feabdc0.html#axzz49EN0OxsR.
Consulted May 20, 2016.
3. See http://​w ww.cdc.gov/​ncbddd/​autism/​addm.html. Consulted June 8, 2016.
4. Epigenetics is explained in detail in Chapter 6. Briefly, it can be said here that an epigen-
etic regulation is a mode of changing gene expression that does not implicate a change in DNA
or gene sequence.
5. Italics were used in the original text.
6. See http://​w ww.dsm5.org/​documents/​adhd%20fact%20sheet.pdf. Consulted May 21, 2016.
7. See Note 6.
8. See http://​w ww.cdc.gov/​ncbddd/​adhd/​data.html. Consulted December 12, 2015.
9. See https://​w ww.pharma.us.novartis.com/​product/​pi/​pdf/​ritalin_​ritalin-​sr.pdf. Consulted
December 12, 2015.
10. The review also provides a recommended and readable account of the history of use of
cocaine, caffeine, and other stimulants.
11. See http://​w ww.theguardian.com/​society/​2 012/​may/​06/​r italin-​a dhd-​shocks-​c hild-
psychologists. Consulted December 12, 2015.
  217

Notes 217
12. A short commentary by Dr. Moody can be found at http://​w ww.educationupdate.com/​
archives/​2008/​DEC/​html/​spec-​-​dyslexia.html. Consulted June 23, 2015.
13. See http://​w ww.cdc.gov/​ncbddd/​adhd/​data.html. Consulted June 20, 2015.

Chapter 6

1. Claude Bernard (1813–​1878) elaborated the first theory of a “constant internal environ-
ment” inside the body. He referred to it as “la constance du milieu intérieur.” Claude Bernard
founded the Comparative Physiology Laboratory in the Natural History Museum in Paris.
I actually have the honor of working in the oak-​f urnished office designed for him. He is often
referred to as the father of physiology and experimental medicine. Later, an American physiolo-
gist, Walter Cannon (1871–​1945), took up the idea and coined the term homeostasis. It is this
term that is used today to refer to the concept of the physiological controls that maintain the
stability of our bodies’ internal environment. Many of these control centers are located in the
hypothalamus at the base of the brain (see Chapter 2 for a description of how specialized neu-
rons in the hypothalamus control the activity of the thyroid gland).
2. See the section in Chapter 8 on health and environmental benefits outweighing industry
costs, which provides a rapid overview of how disruption of the thyroid axis affects the physiol-
ogy of migratory birds at multiple levels.
3. Many consider that Rosalind Franklin should have shared authorship of the Nature arti-
cle. She first trained as a physical chemist at Cambridge at a time when it was exceedingly dif-
ficult for women to have academic careers. After a period in Paris, working for the National
Center for Scientific Research (Centre National de la Recherche Scientifique, CNRS), the
French national research institution, she returned to the United Kingdom. She carried out the
x-​ray crystallography on DNA when working in Birkbeck College, London. Apparently, it was
Wilkins who showed her results to Watson and Crick. She could not, however, share the Nobel
Prize with them, first because her contributions were not recognized at the time, and second,
more pragmatically, because the prize is never awarded posthumously. Rosalind Franklin had
died of ovarian cancer in 1958, at the age of 38.
4. Certain authors restrict the term epigenetic regulations to relatively long-​term changes in
gene expression that last through a cell’s lifetime and are transmitted to daughter cells. Other
scientists see all regulatory changes that require opening or closing of the structures around the
genes as some form of epigenetic regulation. Here, I use the term in the latter sense, to encom-
pass all changes that switch gene transcription on and off, whether short term or longer term.
5. Not all physiological adaptations involve changes in gene expression. To illustrate this
point, I return to the example of how we respond to temperature changes. Our bodies can react
to a change in room temperature by adjusting how much blood is delivered to the skin. The
small blood vessels, the capillaries, will expand to deliver more blood and allow more heat loss
when we feel hot and will contract, thereby reducing heat loss, when we are cold. If we’re outside
and it’s really cold, our fingers may even go white due to the capillaries contracting so much. If
our skin is bare, our hairs stand on end, trapping an insulating layer of warm air between the
skin and the colder air outside. All these are rapid physiological changes. On the other hand,
if a cold winter sets in, especially if we spend a lot of time outside, at this point the brain will
stimulate the thyroid gland to make more thyroid hormone. The extra thyroid hormone then
burns up more fat stores to produce the heat to raise our body temperature and keep us warm.
218

218 Notes
These long-​term adjustments require changes in gene expression in the brain, in the thyroid,
and in the muscle and brown fat cells. In these cells, the levels of two key proteins are increased
by making the genes that encode these proteins more active. One gene encodes an enzyme that
activates thyroid hormone, and the higher levels of thyroid hormone inside the cell stimulate
the gene that makes a heat-​producing protein in the mitochondria, the cell’s power furnace. So,
in this case, bringing changes in gene expression into play is more a matter of how long and how
intense the environmental challenge lasts. Once the cold phase has passed, our bodies literally
turn down the heat production.
6. See https://​w ww.youtube.com/​watch?v=-​M-​vnmejwXo. Consulted May 15, 2015.
7. In 1866, the monk Gregor Mendel (1822–​1884) published his observations on variation
and heredity from crossing different types of peas (color, plant height, and pod shape among
other features). However, it was not until 1900 that his writings were “rediscovered” and made
known independently by a German and a Dutch biologist. Mendel’s concepts of heredity were
later taken up by an English biologist, William Bateson (1861–​1926). Bateson coined the term
genetics to describe the mechanisms of inheritance. Putting together the concepts of “genes”
with Darwin’s theory of natural selection led to the elaboration of the “modern synthesis,” a the-
ory of evolution that has held sway until the recent introduction of epigenetics into the picture.
8. See https://​gene.sfari.org/​autdb/​GS_ ​Home.do. Consulted August 28, 2015.
9. As opposed to “standard” first cousins, who share only one set of grandparents, for double
first cousins both sets of grandparents are the same. It takes some working out. Most couples
have four sets of grandparents: The woman and man each have two separate sets. First cous-
ins share one set and have two separate sets. Double first cousins have only two sets between
them. For instance, if two sets of grandparents have a number of children (the parents), and if
a woman and man from each set of parents intermarry again, their children will be double first
cousins. I suggest drawing a diagram to get the picture. I don’t mind admitting I had to do it! In
most societies, marriage even between first cousins is rarely allowed or recommended because
of the risk of increasing adverse gene dosage, so marriage between double first cousins is almost
unthinkable.

Chapter 7

1. I keep a picture of a polio ward in the 1950s in my office. The black-​and-​white photo, given
to me many years ago by Dr. Charles Nicolls from the University of California, Berkeley, shows
a ward of about 50 children in the critical stages of poliomyelitis, when the virus has affected
the muscles that allow them to breathe. Iron lungs, which encased the whole of their bodies
other than their heads, were needed to mechanically move air in and out of their lungs. Mirrors,
placed by their heads, allowed the children to see more of the room around them. Balloons
were placed near their mouths to check the machines were working properly. Charles Nicolls
was an active member of a group of scientists involved in explaining to the general public the
importance of ethically supervised animal research to advance knowledge. I often ask students
and visitors if they know what the photo represents—​few do. The guesses can be extraordinary,
ranging from concentration camps to clinical trials!
2. See http://​w ww.dds.ca.gov/​Autism/​docs/​AutismReport_​2007.pdf. Consulted May
31, 2016.
  219

Notes 219
3. These increases and decreases are actually underestimates. If the figures are put into an
Excel chart, the calculated increase in numbers of intellectually challenged is over 80%.
4. See http://​w ww.autismspeaks.org/​about-​us/​press-​releases/​annual-​cost-​of-​autism-​triples.
Consulted May 31, 2016.
5. See http://​w ww.cdc.gov/​ncbddd/​adhd/​data.html. Consulted May 31, 2016.
6. See http://​w ww.cdc.gov/​nchs/​fastats/​adhd.htm. Consulted May 31, 2016.
7. Intergovernmental Panel on Climate Change. Guidance notes for lead authors of the
IPCC Fourth Assessment Report on Addressing Uncertainties. http://​w ww.ipcc.ch/​meet-
ings/​a r4-​workshops-​express-​meetings/​u ncertainty-​g uidance-​note.pdf. July 2005. Accessed
June 8, 2016.
8. See timharford.com/​2015/​04/​cigarettes-​damn-​cigarettes-​and-​statistics/.​ Consulted May
31, 2016.
9. See https://​w ww.epa.gov/​sites/​production/​fi les/​2016-​05/​documents/​flame_​retardant_​
fact_ ​sheet_​3-​22-​16.pdf. Consulted May 31, 2016.
10. See https://​w ww.epa.gov/​assessing-​and-​managing-​chemicals-​under-​tsca/​polybrominated-​
diphenyl-​ethers-​pbdes. Consulted May 31, 2016.
11. I gave a detailed history of these tragic events in Losing Our Minds: How Environmental
Chemicals Affect Intelligence and Mental Health (New York, NY: Oxford University Press; 2014).
12. In 2014/​2015, I put together a large EU consortium with some of the leading clinicians
and basic scientists working on economics, iodine and thyroid physiology, measurement of
chemicals in urine and blood, and water testing and purification, to address these specific
questions. Unfortunately, the project, based on four large EU mother-​child cohorts from four
different countries, was not funded. The experts reviewing the project said it was timely with
well-​developed methodologies. The main reason given for not funding it was that “the impact
of iodine deficiency in European countries as well as its interaction with endocrine disrupting
chemicals was not sufficiently substantiated.” This was a hard pill to swallow, given it was the
topic of the research to be done! Since the project was submitted, even more evidence has accu-
mulated on different aspects of this topic, notably hitting the headlines in the UK media. See,
for instance, http://​w ww.dailymail.co.uk/​news/​article-​3191683/​Every-​mother-​iodine-​boost-​
baby-​s-​brain-​Taking-​supplement-​i ncrease-​child-​s-​IQ-​help-​development-​early-​months.html.
Consulted November 23, 2015.

Chapter 8

1. One of my American colleagues, Dave Sharlin, brought the film to my attention when
we were talking about the ideas in this book. Dave, associate professor at Minnesota State
University in Mankato, is also author of the quip, “You can live without your gonads, but not
without your thyroid” mentioned in Chapter 1.
2. Dysgenic means the increased reproduction of less-​well-​adapted, less-​intelligent, people
over the better adapted (see Glossary).
3. In a normal IQ distribution, about two-​thirds of the population will score between 85
and 115, about 15% over 115, and another 15% below 85. The minimum requirement for the US
military is an IQ of 85.
4. See http://​w ww.cop21paris.org. Consulted June 8, 2016.
220

220 Notes
5. See http://​w ww.europarl.europa.eu/​sides/​getDoc:2012/​2066 (INI). Consulted January
9, 2016.
6. See http://​ec.europa.eu/​archives/​commission_​2010-​2014/​president/​chief-​scientific-​
adviser/​documents/​minutes_​endocrine_​disruptors_​meeting_​241013_​final.pdf. Consulted
June 8, 2016.
7. Assessment of nonmonotonic dose responses, like the effects of low doses of chemicals,
has been a key element of the endocrine-​disrupting chemical (EDC) debate. It means that a sub-
stance can elicit a physiological response that is not simply a straight linear increase or decrease
as a function of the dose. In fact, most hormones have nonlinear dose responses, with the effects
flattening or reversing at high doses. This feature is called desensitization and makes risk assess-
ment more difficult.
8. Potency is a tricky concept and is almost impossible to determine experimentally without
exceedingly detailed experiments that take into account windows of exposure and differential
responses according to the tissue studied. It is in fact so difficult to define and virtually impos-
sible to determine, at least with current testing protocols, that by simply raising the question of
potency, the chemical industry has given regulators a red herring that will distract them from
legislating for a long while.
9. They estimated that the global annual trade impact would be €65 billion annually.
10. See http://​ec.europa.eu/​health/​endocrine_​disruptors/​docs/​2015_ ​public_​consultation_​
report_​en.pdf. Consulted June 1, 2016.
11. Resolution 4 states: “[The European Parliament …]: Considers that protecting women
from potential risks of endocrine disrupters for their reproductive health is of utmost impor-
tance; calls, therefore, on the Commission to prioritise research funding to study the effects of
hormone disrupters on women’s health, and to support long-​term studies monitoring women’s
health over large spans of their lives, thus allowing an evidence-​based assessment of the long-​
term and multi-​generational effects of exposure to endocrine disrupters.”
12. See http://​w ww.cefic.org/​Policy-​Centre/​Environment-​-​health/​Endocrine-​Disruption-​
Modulators/​. Consulted June 8, 2015.
13. See http://​w ww.phyto-​victimes.fr/​ (in French). Consulted June 8, 2016.
14. Professor Kortenkamp also underlined in his presentation at the June 30, 2015, Brussels
workshop organized by PAN-​ Europe (http://​w ww.disruptingfood.info/​images/​PAN_​
Kortenkamp_​30_ ​June_​2015.pdf, consulted on August 6, 2015)  that despite the fact that the
OECD had been ratifying different endocrine disruptor test methods and guidelines, none were
implemented in the United States or Europe.
15. The relatively new branch of chemistry known as green chemistry focuses on creating new
molecules by methods that reduce or eliminate the use or generation of hazardous substances.
The change in methods can apply to the design, manufacture, or application of the chemical
products synthesized. As for many new scientific disciplines, such as epigenetics, the field has
spawned a number of new journals (see also Chapter 9).
16. See http://​curia.europa.eu/​juris/​document/​document.jsf?text=&docid=160359&pageInd
ex=0&doclang=en&mode=lst&dir=&occ=first&part=1&cid=246487. Consulted December
20, 2015.
17. See http://​w ww.thecroforum.org/​endocrine-​disruptors/​. Consulted December 20, 2015.
18. The European Council of Ministers, or the “EU Council” as it is often called, represents
the executive governments of each of the EU member states.
  221

Notes 221
19. A video of the press conference given by a representative of the EU Commission can be
found at http://​ec.europa.eu/​avservices/​video/​player.cfm?ref=I114375 (consulted December 20,
2015). At the time of writing, early June 2016, it seems the EU Commission will concede to
industry’s pressure and choose to include potency in the criteria used to define EDCs. This posi-
tion is contrary to all advice from the Endocrine Society and its representatives.

Chapter 9

1. See http://​w ww.unep.org/​newscentre/​Default.aspx?DocumentID=2726&ArticleID=9611/​.

Consulted June 4, 2016.
2. The report, written in French, is available online: http://​w ww.wwf.fr/​vous_​informer/​rap-
ports_ ​pdf_​a _​telecharger/​?1205/​eau-​robinet-​eau-​bouteille. Consulted June 4, 2016.
3. See http://​w ww.drydeninformationcentre.com/​switzerland-​government-​announces-​
micropollutant-​tax. Consulted June 4, 2016.
4. See http://​w ww.epa.gov/​oppt/​existingchemicals/​pubs/​assessment_​chemicals_​list.html.
5. See http://​worlddatabaseofhappiness.eur.nl/​. Consulted June 4, 2016.
6. The WWF sponsored two studies:  the three-​generation analysis in 2005  (http://​w wf.
panda.org/​what_​we_​do/​how_​we_​work/​p olicy/​w wf_​europe_​environment/​news/​? uNew-
sID=23635, consulted June 4, 2016) and one on members of the EU Parliament (MEPs) in 2004
(http://​w wf.panda.org/​what_​we_​do/​how_​we_​work/​policy/​w wf_​europe_​environment/​news/​
?uNewsID=12622, consulted June 4, 2016). The EU parliamentary study managed to obtain
blood samples from 47 volunteers (including 39 MEPs) from 17 countries. The highest number
of chemicals found in any one sample was 54. Over a dozen chemicals were found in all samples.
The chemical with the highest concentration in any single sample was a flame retardant, PBDE,
which registered 18 nanograms per gram serum. In the study comparing grandmothers, moth-
ers, and children, blood samples were taken from members of 13 families from 12 EU countries
and examined for up to 107 chemicals. Key observations included the fact that every person was
carrying a chemical cocktail of at least 18 substances, with the levels of certain compounds, the
PDBE flame retardants and BPA, displaying the highest levels in the younger generation. One
substance found in all samples (but not examined in the MEP study) was galaxolide, an artificial
musk added to cosmetics and household cleaning products (yes, both) as a fragrance.
7. See http://​media.apps.chicagotribune.com/​flames/​index.html. Consulted June 4, 2016.
8. As of May 2016, the TSCA is under discussion for revision; see http://​w ww.nature.com/​
news/​why-​the-​historic-​deal-​to-​expand-​us-​chemical-​regulation-​matters-​1.19973 (consulted June
1, 2016). Both the White House and industry agreed on the need for better regulation of chem-
ical safety. However, the exact implications of the revision are not yet known. It is expected
that the EPA will place greater onus on companies to show that the substances they manufac-
ture or import present no risk for health independent of economic considerations. However,
many NGOs consider the terms of the agreement will still be too favorable to industry. See, for
instance, https://​w ww.epa.gov/​reviewing-​new-​chemicals-​under-​toxic-​substances-​control-​act-​
tsca/​epas-​review-​process-​new-​chemicals (consulted June 4, 2016).
9. See https://​w ww.epa.gov/​reviewing-​new-​chemicals-​under-​toxic-​substances-​control-​act-​
tsca/​epas-​review-​process-​new-​chemicals. Consulted June 4, 2016.
10. See http://​echa.europa.eu/​regulations/​reach. Consulted June 4, 2016.
222

222 Notes
11. The OECD committee is called the Adverse Outcome Pathways, Molecular Screening
and Toxicogenomics; see the website:  http://​w ww.oecd.org/​chemicalsafety/​testing/​adverse-​
outcome-​pathways-​molecular-​screening-​and-​toxicogenomics.htm. Consulted June 4, 2016.
12. As I  represent France on some of these committees, including the Adverse Outcome
Pathways committee and the one addressing testing for thyroid hormone and other endocrine
disruptors, I can vouch that this is an optimistic scenario.
13. See WHO information at http://​w ww.who.int/​mediacentre/​factsheets/​fs193/​en/​.
Consulted June 4, 2016.
  223

R EFER ENCES

Introduction

1. Zablotsky, B., et al., Estimated prevalence of autism and other developmental disabilities fol-
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Chapter 2

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81. Sexton, K., et  al., Biomarker measurements of concurrent exposure to multiple envi-
ronmental chemicals and chemical classes in children. J Toxicol Environ Health A, 2011.
74(14): pp. 927–​942.
  245

Index

References to figures and notes are denoted by an italicized f and n

acetaminophen, 56, 204, 214n9 Association of Educational Psychologists, 104

ADHD. See attention-​deficit/​hyperactivity astrocytes, 35
disorder (ADHD) attention-​deficit/​hyperactivity disorder
Adverse Outcome Pathways, Molecular (ADHD), 2, 5–​6, 106, 117, 146
Screening and Toxicogenomics, cesarean sections and, 95
222n11–​12, 200 costs per individual, 142
Agent Orange, 57 diagnosis by Still, 102–​4
Agricultural Industries Confederation environmental factors, 108–​9, 112, 116–​17
(AIC), 170–​71 maternal exposure to flame retardants, 109
albumin, 45 genetic links, 129
alcohol, brain development, 57–​58 girls with ASD and, 100
Allen-​Herndon-​Dudley disease, 123 incidence of, 77, 98, 108, 111–​12
Altman, Joseph, 38, 39, 213n9 iodine and, 12
Alzheimer's disease, 41, 46, 171 thyroid hormone deficiency and, 110
amphibian metamorphosis, 30–​31, 49, 114, autism. See autism spectrum disorder (ASD)
120, 203 Autism and Developmental Disabilities
Andriukaitis, Vytenis, 165 Monitoring (ADDM), 97
androgen receptor (AR), 47 Autism Speaks, 141
animal research, ethics, 170, 222 autism spectrum disorder (ASD), 2, 5, 6, 23
antimicrobials, thyroid disruptors, 67–​68 costs, 143
Aroclor 1254 (Monsanto), 55 C-​section births and, 95–​98
artificial intelligence, 76 environmental factors, 77, 108–​9, 112,
ASD. See autism spectrum disorder (ASD) 116–​17, 119
Asperger, Hans, 101, 103 epigenetics and, 133–​34

245
246
246
autism spectrum disorder (ASD) (Cont.)
genes and, 122–​29
genetic terms in research, 125–​26
girls with, 6, 100, 128
hypothyroidism and, 7, 37
identical twins, 130–​32
incidence of, 6–​7, 77, 97f, 111–​12, 128
iodine and, 5, 12
oxytocin and, 94–​95, 111
pesticides and early pregnancy, 185
thyroid hormone disruption, 110–​11
autoimmune diseases, 27
axons, 35, 37, 43, 78, 106, 207
Barker, David, 115
Barker hypothesis, 115
Barroso, José Manuel, 162, 165
Bateson, William, 218n7
Bellanger, Martine, 143, 150–​51, 154
Ben-​A ri, Yehezkel, 93–​97
Bernard, Claude, 217n1
Berson, Solomon A., 33–​34
Bertollini, Roberto, 143
biocides, 167, 196–​97
bisphenol A (BPA), 5, 51, 88, 174, 187, 189,
192, 221n6
Bleuler, Paul, 100
Blum, Arlene, 63–​64, 192, 196
Boussingault, Jean-​Baptiste, 14
Bradford Hill Criteria, 145–​46
brain
cerebellum, 42–​44
cerebral cortex, 40–​41
getting thyroid hormone into, 44–​45
hippocampus, 41–​42
seafood in evolution of, 25–​26
sensitivity of certain areas to thyroid
hormone, 39–​44
brain-​derived neurotrophic factor (BDNF), 43
brain development
humans and primates, 77–​78
neuronal migration, 37, 79, 106
synapse formation, 36–​37, 43–​44
thyroid hormone and, 78–​79
thyroid hormone disruption and, 45–​46, 172
thyroid hormone orchestration of, 34–​38
BRAIN Initiative (Brain Research through
Advanced Innovative Neurotechnologies),
76, 214n1
Index
BRCA gene, breast cancer, 119, 123
breast-​feeding formula vs., 188–​89
Brod, Max, 31
brominated flame retardants (BRFs), 62–​64
bromine, 23, 50, 62–​64, 149, 196, 212n6
Brouwer, Abraham, 56
Cannon, Walter, 217n1
Carson, Rachel, 5, 64–​65, 93, 155, 168
CDC (Centers for Disease Control and
Prevention), 77, 88, 97, 103, 111, 142, 176
cerebellum, function and structure, 42–​44
cerebral cortex, function and structure, 40–​41
cesarean section, autism and, 95–​98
CHAMACOS (Center for Health Assessment
of Mothers and Children of Salinas) study,
56, 140, 144, 151, 214n8
CHARGE (Childhood Autism Risks From
Genetics and Environment)
study, 109–​10
Chatin, Gaspard-​Adolphe, 13–​14
CHEM (Chemicals, Health, and Environment
Monitoring) Trust, 195
chimpanzees, brain development, 77–​78
chlorpyrifos, 64, 151–​52, 184, 194
chromatin, 120, 121, 128, 132, 207, 208
class actions, 60–​61, 174, 195–​96
coding sequences, 117–​18, 209
Cohn, Barbara A., 175–​76
Coindet, Jean-​François, 13
Colborn, Theo, 3
collective action, 179–​82, 192, 194–​97
colonialism, 15–​16
common sense, 162
congenital hypothyroidism (CH),
17–​18, 106–​8
copy number variations (CNVs), 126–​27
Courtois, Bernard, 12–​13
cretin, term, 4
cretinism, 4
history of, 16–​18
incidence in Papua, New Guinea, 15–​16
iodized salt and prevention of, 13–​16
thyroid gland extracts, 33, 38
Crichton, Sir Alexander, 103
Crick, Francis, 117, 217n3
Crofton, Kevin, 68
Crop Protection Association (CPA), 170
Curl, Cynthia, 183
  247

Index 247
daidzein, 70–​71 EFSA PPR Panel (EFSA Panel on Plant
daily recommendations, iodine and Protection Products and Their
selenium, 24–​25 Residues), 215n18
Darwin, Charles, 85–​86, 121–​22, Einstein, Albert, 31, 140, 162
216n6–​7, 218n7 embryogenesis, 172, 207
Darwin, Erasmus, 216n6 endocrine-​disrupting chemicals (EDCs), 3, 7,
Darwin, Robert, 216n6 8–​9, 109, 201
Davy, Humphry, 13 actions to limit exposure to, 203–​4
Day, Catherine, 163 affecting future generations, 175–​76
DDE (dichlorodiphenyldichloroethylene), birth weight, 111
53, 65 considering public opinion, 164–​65
DDT (dichlorodiphenyltrichloroethane), 5, 53, cosmetics, 68
64–​65, 155, 174, 176, 180–​81, 214n6 debate, 220n7
Deary, Ian, 89, 116, 216n8 definition, 8–​9, 207, 221n19
de Escobar, Gabriela, 38 drinking water debate, 189
DEHP (diethylhexyl phthalate), 67 emerging risk, 173
deiodinases, 21 hazard assessment of, 65
dendrites, 35, 43, 78, 207 health and environmental cost vs
de novo mutations, 126–​29 benefits, 166–​72
Descent of Man (Darwin), 86 health costs of EDC-​linked disease,
development 165–​66, 168
environment interacting with home environment, 192, 195
genes, 116–​18 IQ loss, 139, 140, 143, 150, 170
as process, 114–​16 legislation, 162–​63, 166–​67, 185, 201,
developmental origin of adult disease (DOAD) 211n3, 215n25
hypothesis, 115, 181, 216n8 regulation of, 160–​63, 170–​71, 172–​74,
Diagnostic and Statistical Manual of Mental 181, 198
Disorders, 5th edition (DSM-​5), 100, Endocrine Society, 72, 137, 164, 215n25, 221n19
102, 216n6 endocrine system, 3–​5, 7, 51, 67, 72, 114, 151, 181,
Diamond, Miriam, 53–​54 200, 207, 214n5
diethylstilbestrol (DES), 1, 135, 166 environmental mercury, 21
dioxins EPA. See US Environmental Protection
contamination, 108 Agency (EPA)
manufacturing by-​products, 212n6 epigenetics, 7, 119, 120, 208, 216n4
in seafood, 186 basics of, 121–​22
TCDD (2,3,7,8-​tetrachlorodibenzo-​p-​ epigenetic regulations, 217n4
dioxin), 56–​57, 214n9 explaining effects of chemicals, 161
DNA (deoxyribonucleic acid), 117, 120, exposure of pregnant woman to
207, 217n3 chemicals, 175f
Doll, Sir Richard, 145 food supplements and, 132–​33
double first cousins, 124, 218n9 estrogen, 3, 26, 51, 71, 191, 212n11–​12, 213n6,
Down syndrome, 87 214n5, 215n23
drinking water, public health, 189–​92 estrogen receptor (ER), 47, 70, 189
Duluth, Minnesota (June 2003), 49–​52 ethics, animal research for chemicals, 201–​3
dysgenics, 87–​89, 91, 159, 207, 219n2 EU. See European Union (EU)
dyslexia, 77, 104–​6, 112, 117 eugenics, 86–​87, 208
European Chemical Agency, 199
Eayrs, J. T., 38 European Chemical Industry Council
EFSA, 65–​66, 152, 201 (CEEIC), 167
248
248
European Commission, 8–​9, 165, 211n3
definition of EDCs, 161–​63
Human Brain Project, 76, 215n3
industry lobbying, 145, 163–​64
legislation relating to EDCs, 8–​9,
160–​61, 173
European Crop Protection Association
(ECPA), 167
European Food Safety Authority (EFSA), 65,
152, 201, 215n18
European Human Biomonitoring Initiative
(EHBMI), 176
European Union (EU), 3, 8
costs of IQ loss and neurodevelopmental
disease, 6, 138
EDCs in, 166, 185, 198
getting new chemical on market, 199
health risks and smoking, 196
IQ loss, 140, 143, 170
PBDE manufacture in, 149
production of triclosan, 68
registered chemicals, 174
regulations, 66
Evolution in Four Dimensions (Jablonka), 121
exome sequencing, 125, 127
fetal alcohol syndrome (FAS), 57–​58
Fini, Jean-​Baptiste, 72
First World War, 29, 50, 80, 99
flame retardants, 196
brominated (BFRs), 62–​64
IQ loss and, 148–​50
flavones, 70–​71
Flowers for Algernon (Keyes), 177
fluorine, 50–​51, 62, 212n6
Flynn, James, 80, 83
Flynn effect, 6, 75, 79–​83
evidence for anti-​Flynn effect, 84–​91
paradoxes of, 83–​84
folate, 7, 133
folic acid, 24, 133, 188
food sources
fresh vs. packaged or prepared
meals, 187–​88
organic products vs. non-​organic (pesticide
treated), 183–​86
food supplements, epigenetics and, 132–​33
Forrest, Doug, 44
fragile X syndrome, 123–​24
Index
François, Paul, 171
Franklin, Rosalind, 217n3
fungicides, 153, 194
GABA (gamma-​aminobutyric acid), 43,
94, 213n12
Galton, Sir Francis, 85–​86, 88, 90, 216n6
gasoline, leaded, 23, 50, 62, 149, 157–​58, 180
Gay-​Lussac, Joseph Louis, 12–​13
gene expression, 7, 216n4, 217n4, 217–​18n5
environmental factors, 87, 89, 112, 114,
118–​20, 122
epigenetic changes, 7, 58, 130–​31
thyroid signaling, 28, 46
genes-​vs-​environment, 113–​14
genetics
autism, 6–​7, 98, 100
identical twins, 130–​32
mutations, 126–​29
terms in autism research, 125–​26
genetic susceptibility, 6, 66, 98, 101
genistein, 70–​72
germinal cell, 174, 208
Gilbert, Scott, 114
glial cells, 35–​36
Glover, Anne, 162–​63, 167, 201
goiter
history of, 16–​18
iodine and, 13–​15
Grandjean, Philippe, 143, 154, 186, 214n10
Graves disease (hyperthyroidism), 27, 213n11
green chemistry, 173, 220n15
Greenpeace, 195
Green Science Policy Institute, 63, 192, 196
Gudernatsch, Joseph Frederick, 31–​32
Guillemin, Roger, 34
halogens, 208
flame retardants with, 62, 64
interfering with thyroid, 23, 69
reactivity, 50, 212n6
Handler, Philip, 147
Harford, Tim, 144–​45, 219n8
Hashimoto's disease (and hypothyroidism),
27, 213n11
Health and Environment Alliance (HEAL),
164, 194–​95, 197
health costs, EDC-​linked disease, 165–​66
Herrnstein, Richard J., 80
  249

Index 249
hexabromochlorodecane (HBCD), 63 Intelligence (journal), 75
Hill, Sir Austin Bradford, 145 Intelligenzquotient (IQ), 80
Hippocampus, memory and, 41–​42 International Council for the Control of Iodine
histone proteins, 121, 208 Deficiency Disorders (ICCIDD), 212n8
homeostasis, 55, 67, 217n1 International Health Exhibition (IHE), 85, 86
Horel, Stéphane, 8, 162, 163, 165 International Panel on Climate Change, 143
household furnishings, 192–​93 International Programme for Chemical Safety
How to Lie With Statistics (Huff), 144 (IPCS), 200
Huff, Darrell, 144–​45 in vitro, 62, 87, 152, 202, 208
human brain evolution, seafood in, 25–​26 in vivo, 62, 208
Human Brain Project, 76, 215n3 iodine, 4, 11–​13, 212n6
human genome, 84, 97f, 98, 117, 125, 127 children and pregnant women, 197–​98
Human Genome Project, 76 early pregnancy and, 16
Huntington disease, 119 eradicating deficiency, 18–​20
hyperthyroidism food and recommended amounts, 24–​25
cerebellum, 43–​44 iodine update blockers, 156–​57
too much thyroid hormone, 26–​28 name, 13
hyperthyroxinemia, 27 salt iodization programs, 212n10
hypothalamus, 34, 213n6, 217n1 sea salt lacking, 22–​23
hypothyroidism, 16–​17 Iodine Global Network (IGN), 19, 198, 212n8
cerebellum, 43–​44 IQ (intelligence quotient), 2, 5–​6
cerebral cortex, 40 anti-​Flynn effect, 84–​91
hippocampus, 41 Flynn effect, 79–​83
medical literature, 25–​26 iodine and, 12, 20
pregnancy, 39 maternal thyroid hormone, 47–​48
too little thyroid hormone, 26–​28 IQ (intelligence quotient) loss, 141f
counting the cost of, 139–​44
identical twins, 130–​32 flame retardants and, 148–​50
Idiocracy (film), 159, 160 iodine deficiency and, 12, 20
indels, 125, 126, 208 pesticides and, 150–​53
individual action, 179–​82, 204–​5 thyroid hormone disruption, 110–​11
breast-​feeding vs. formula, 188–​89
drinking water choices, 189–​92 Jablonka, Eva, 121
food sources, 183–​86 Jacobson, Joseph, 156
fresh food vs. packaged and prepared Jacobson, Sandra, 156
meals, 187–​88 Jensen, Arthur, 82, 88
household furnishings and products, Judge, Mike, 159
192–​93
lifestyle choices, 182–​83 Kafka, Franz, 31–​32
pesticide use, 193–​94 Kamin, Leon, 87, 119
seafood, 186–​87 Kanner, Leo, 98–​101
industrial lobbying, 7–​8, 163–​64 Kanner syndrome, 98
infants Karrman, Anna, 61
breast-​feeding vs. formula, 188–​89 Kendall, Edward Calvin, 32–​33
soy formula, 70–​72 Kennedy, John F., 76
in silico, 202, 208 Keyes, Daniel, 177
intellectual disability, 77, 84, 102, 107, 142, 160 Kocher, Theodore, 16
intelligence, 19th century, 75–​79. See also IQ Kortenkamp, Andreas, 172, 220n14
(intelligence quotient) Krief, Sabrina, 169
250

250 Index
Lachiver, François, 15 National Farmers Union (NFU), 170
Lamarckism, 122 National Health and Nutrition Examination
Lamb, Marion, 121 Survey (NHANES), 20, 62, 187, 214n14
leaded gasoline, 23, 50, 62, 149, National Institutes of Environmental Health
157–​58, 180 Sciences (NIEHS), 51
legacy chemical, 208, 214n6 National Institutes of Health, 2, 44, 76
legacy pollutant, 53, 208, 214n6 National Survey of Children's Health
legislation, 9, 164–​66 (NSCH), 104
Legrand, Jacques, 30, 38 nature-​vs.-​nurture debate, 100, 113, 116
Lewontin, Richard, 87, 119 nerve growth factor (NGF), 43
lobbying, 7–​8, 119, 163–​64, 167 neural tube, 7, 35, 133
Losing Our Minds (Demeneix), 23, 56, 75, 158, neuronal migration, 37, 79, 106
214n3, 219n11 neurons, 35
Luft, Rolf, 213n7 New York (1914), thyroid hormone
research, 32–​34
malathion, 184 NHANES. See National Health and Nutrition
mancozeb, 153 Examination Survey (NHANES)
maneb, 153 Nicolls, Charles, 218n1
Markowitz, Gerald, 7, 62 NIEHS. See National Institutes of
Mayo Clinic, 32–​33 Environmental Health Sciences (NIEHS)
Mendel, Gregor, 218n7 NIH. See National Institutes of Health
Menon, Vinod, 105 nitrate, 5, 12, 69–​70, 157, 189–​92, 205
mental retardation, 30, 38, 58, 77, 123–​24. nongovernment action, collective and, 194–​97
See also intellectual disability nonmonotonic dose response (NMDR), 163,
mercury 168, 208, 220n7
contamination in fish, 153–​55, 186 nuclear receptors, 46–​47, 208, 215n23
environmental contamination, 21 nucleotide, 117, 121, 125–​26, 208
thyroid hormone and, 58–​59
mercury/​selenium interactions, 21–​22 Obama, Barack, 76, 77
metabolite, 53, 63–​65, 153, 155, 176, 183–​84, Oedipus Rex (Sophocles), 160
201, 208 oligodendrocytes, 35, 36
The Metamorphosis (Kafka), 31 Organization for Economic Cooperation
methylation, 121, 133, 175f, 208 and Development (OECD), 49, 90–91,
methylmercury, 21–​22, 22, 154–​55, 188 160–61, 163–​64, 172, 200, 213n1,
methylphenidate, 103 220n14, 222n11
Michael Clayton (film), 174 organophosphates pesticides, 140, 150–​52, 153
microglial cell, 35 Origin of Species (Darwin), 86
Midgely, Thomas, Jr., 157–​58 Ostrom, Elinor (Lin), 8, 9
Moody, Katherine, 105, 217n12 Our Stolen Future (Colborn), 3
Morrisey, Christy, 168 oxytocin
Mozart, Wolfgang Amadeus, 30, 140 autism and, 94–​95
MRI (magnetic resonance imaging), chloride link, 97
105–​6
MSSNG project, 129 Pandora's Poison (Thornton), 66
Murray, Charles, 80 paracetamol, 56, 204, 214n9
Murray, George, 17 Parkinson's disease, 46, 171
mutations, 126–​29 parvalbumin, 41
myelin, 35, 78 Pasteur, Louis, 32, 147
myxedema, 16, 211n4 perchlorate, 5, 69, 153, 156–​57, 190–​92
  251

Index 251
perfluorinated compounds (PFCs), polyethylene terephthalate (PET), 188
50–​51, 59–​62 polyvinyl chloride (PVC), 66, 204, 212n6
perfluorooctane sulfonic acid (PFOS), 59–​62 potency, 163, 220n8, 221n19
perfluorooctanic acid (PFOA), 59–​62 Prague (1912), thyroid hormone research, 30–​32
persistent organic pollutants (POPs), 53, 169, pregnancy
195, 200 drugs and, 1–​2
Pesticide Action Network (PAN), 197 early pregnancy as a sensitive period, 135, 151
pesticides iodine in early, 16, 166
biocides and, 196–​97 iodine supplements during, 24
chlorpyrifos, 64, 151–​52, 184, 194 thyroid hormone levels during, 38–​39
food sources and, 183–​86 primates, brain development, 77–​78
household use, 193–​94 Program for International Student Assessment
IQ loss and, 150–​53 (PISA), 90
persistence of, 64–​66 Purkinje, Jan Evangelista, 42
Pesticides Regulation, 167 Purkinje cells, 42–​43
Pharoah, Peter, 15 Purkinje neurons, 42–​43
phthalates, 66–​67, 88, 109, 128, 167, 187–​89, 188,
192, 204 radioimmunoassay, 33–​34
physiology, 114 Rall, David, 2, 51, 134
phytoestrogens, 70–​71, 189 Raven's Progressive Matrices, 81, 83
Phytovictims, 171 Rayman, Margaret, 18, 20
Piaget, Jean, 89 REACH (Regulation on the Registration,
Pietschnig, Jakob, 90 Evaluation and Assessment of Chemicals),
Plant Protection Products, 171 3, 167, 170, 194, 199, 211n2
Plastics Europe, 167 Redei, Eva, 58
Plato, 116 regulations
pluripotent, 209 endocrine disrupting chemicals, 198
polybrominated biphenyls (PBBs), 63, 155 ethics and animal research of
polybrominated diphenyl ethers (PBDEs) chemicals, 201–​3
ADHD and, 109 European Union for new chemical on
concentration in blood samples, 221n6 market, 199
flame retardants, 63, 109, 140 international cooperation for chemicals,
IQ losses, 140, 142–​43, 148–​49, 151, 153–​54 200–​201
manufacture and use, 149–​50 iodine, 197–​98
persistence in environment, 149, 193 United States for new chemical on
polychlorinated biphenols, 50 market, 198–​99
breathing in banned PCBs today, 53–​54 The Republic (Plato), 116
legacy plastics, 52–​58 research, correlations and causality, 144–​48
as thyroid disrupting chemicals, 54–​57 research funding
polychlorinated biphenyls (PCBs), 50, 58, 62, 88, endocrine disruption, 138
111, 153, 169 environmental causes of neurodevelopmental
autism spectrum disorder (ASD) risk, 111 disease, 118–​19, 134
brain development, 88 genes and environment, 118–​19
breathing in banned, 53–​54 genetic causes of neurodevelopmental
IQ loss, 153, 155–​56 disease, 77, 118–​19
legacy of, 52–​58 Rett, Andreas, 101–​2, 103
as thyroid-​disrupting chemicals, 54–​57 Rett's syndrome, 101–​2
polychlorinated bisphenols, dioxin and, Richardson, Sam (Samantha), 45
186, 212n6 Ritalin, 103–​4
252

252 Index
Ritalin-​SR, 103–​4 tetrabromobisphenol A (TBBPA), 63
RNA (ribonucleic acid), 117–​18, 120–​21, tetraethylene lead (TEL), 62
127, 209 thalidomide, 1–​2, 51, 134–​35, 169, 201
Rose, Steven, 34, 87, 119 Thornton, Joe, 66, 184
Rosner, David, 7, 62 thyroid-​disrupting chemicals
Royal College of Obstetricians and antimicrobials, 67–​68
Gynecologists (RCOG), 182, 187, 193 flame-​retardants as, 61–​64
mercury as, 21, 58–​59
Salk, Jonas, 137 miscellaneous, 67–​69
Salk Institute, 34, 137 PCBs as, 54–​57
salt iodization programs, 212n10 perfluorinated compounds (PFCs) and
Schally, Andrew, 34 pregnancy, 61–​62
Scherer, Stephen W., 129 pesticides as, 64–​66
schizophrenia, 42, 77, 101, 124, 130 phthalates as, 66–​67
Schwann cells, 35 soy-​derived products as, 70–​72
seafood thyroid gland, 29–​30, 212–​13n3
brain evolution, 25–​26 thyroid hormone, 2–​3
contamination, 186–​87 autism and IQ loss, 7, 37, 110–​11
sea salt, lacking iodine, 22–​23 brain development and evolution, 78–​79
seaweed (kelp), 24 disruption and adult brain, 45–​46
Second World War, 80, 115, 181 forms of, 214n4
selenium, 20–​22 halogenated molecules and, 50
food and recommended amounts, 24–​25 mercury and, 58–​59
mercury-​, interactions, 21–​22 problems for too little or too much, 26–​28
Semmelweis, Ignaz, 148 sensitivity of brain to, 39–​44
Sharlin, David, 26, 219n1 structure of, 50
Shelton, Janie, 109, 185 thyroid gland and, 29–​30
Sicily, iodine, 11–​13 thyroid hormone, research on
Silent Spring (Carson), 5, 64, 155 brain development, 34–​38
Silverman, Irwin, 85, 88–​90 chemicals hijacking, action on brain
Simons Foundation Autism Research development, 46–​47
Initiative, 123 discovery of, 32–​34
single-​nucleotide polymorphisms (SNPs), getting into the brain, 44–​45
125, 209 regulatory gaps, 47–​48
Snow, John, 147 thyroid gland, 29–​30
soy formula, 70–​72 timing for hormone action, 38–​39
Soy Nutrition Institute, 71 thyroid hormone receptors (TRs), 46–​47, 57
soy product use, 70–​72 thyroid-​stimulating hormone (TSH), 34,
Spearman, Charles E., 82, 88, 215–​16n5 69–70, 211–​12n5, 213n5
spina bifida, 7, 57, 133 thyroid storm, 27
Still, Sir George, 102–​4 thyroid tablets, 16, 17
Sukhdev, Pavan, 170 thyrotoxicosis, 27, 213n3
synapse formation, 37, 43 thyrotropin, 34
thyrotropin-​releasing hormone (TRH), 34
Takser, Larissa, 56 thyroxine-​binding globulin (TBG), 45
Taylor, Pete, 157 thyroxine (T4), 33, 213n4, 214n4
TCDD (2,3,7,9-​tetrachlorodibenzo-​p-​dioxin), TOXCAST screening program, 3
56–​57, 214n9 Toxic Substances Control Act (TSCA), 2, 193,
teratogen, 201, 209 198–​99, 211n1, 215n19, 219n10, 221n8–​9
  253

Index 253
transthyretin (TTR), 45, 62 valproate, 132–​33
Trasande, Leo, 109, 137–​39, 143–​44, 165–​66, 175 vegetarian diets
triclosan, 68, 204 and genistein rich soy, 70
triiodothyronine (T3), 214n4 and iodine, 26
tris(1,3,chloro-​2 propyl) phosphate Vermiglio, Francesco, 12
(TDCPP), 63–​64 Vietnam War, 57
tris(2,3-​dibromopropyl)phosphate (Tris-​BP), 63 Voracek, Martin, 90
tris-​(2-​chloroethyl) phosphate (TCEP), 193
Tuddenham, Reed, 80 water
Twain, Mark, 14 drinking, choices, 189–​92
twins, monozygotic and dizygotic, 130–​32 reverse osmosis systems, 191
Water Frameworks Directive, 167
ultraviolet (UV) filters, 68 Watson, James, 117, 217n3
United Nations Environment Programme Weintraub, Kathrine, 134
(UNEP), 3, 172, 185 Weschler, David, 81
United States, 80, 91, 99, 154, 174, 192 Weschler Adult Intelligence Scale
ADHD in, 98, 142, 144 (WAIS), 81
ASD in, 2, 97, 101, 134, 138, 142, 160 Weschler Intelligence Scale for Children
cesarean sections, 96–​97 (WISC), 81–​83
collective actions, 194–​96 whole-​genome sequencing, 125, 129
congenital hypothyroidism, 18, 106–​8 Whymper, Edward, 14
costs of IQ loss, 6, 140, 142, 166 Wilkins, Maurice, 117, 217n3
drinking water, 189–​90 Women in Europe for a Common
dyslexia, 104 Future, 195
folic acid and pregnancy, 133 Women's Voices for the Earth, 195
genetic selection, 87 Woodley, Michael, 75, 79, 85,
getting new chemical on market, 198–​99 87–​91, 159
groundwater contamination, 61, 69 Woodruff, Teresa, 72
infant formula, 71 World Health Organization
leaded gasoline, 62, 158 (WHO), 172
longevity, 180 cesarean section, 96
PBDE manufacture, 149–​50 endocrine disruption, 3, 200
PCB production, 55 iodine, 19–​20, 24, 30, 198
perchlorate, 157 IQ loss, 143
pesticides and, 5, 109, 150–​53, 185 leaded gasoline, 158
plasticizers, 187–​88 nutrition, 212n7
screening, 3, 5 World War I, 29, 50, 80, 99
urinary iodine (UI), 20, 69 World War II, 80, 115, 181
US Department of Agriculture (USDA), World Wildlife Fund (WWF), 3, 190, 194,
71, 215n24 221n2, 221n6
US Environmental Protection Agency (EPA), 2, Wright, Frank Lloyd, 3
49, 60, 149–​50, 163, 190, 193, 199
US National Health Statistics Reports, 6 Yalow, Rosalyn, 33–​34
US National Human Genome Research
Institute, 125 Zoeller, Tom, 55–​58, 143, 151, 155
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