CHAPTER9

ENVIRONMENTAL AND NUTRITIONAL DISEASES

o
Under nutrition
O
Is the single leading global cause of health loss
(defined as morbidity and premature death).
Ischemic heart disease and cerebrovascular disease are the
leading causes of death in developed countries.
O
In these countries the main risk factors associated
with loss of healthy life are smoking, high blood
pressure, obesity, high cholesterol, and alcohol
abuse
In developing countries infectious diseases constitute 5 of
the 10 leading causes of death:
O
respiratory infections, human immunodeficiency
virus/acquired
immunodeficiency
syndrome
(HIV/AIDS), diarrheal diseases, tuberculosis, and
malaria.
Emerging infectious diseases (EIDs) constitute one of the
most important components of the global burden of disease.
EIDs are correlated with environmental, and socioeconomic
conditions, and include
1)
diseases caused by newly evolved strains or
organisms, such as rifampin/isoniazid-resistant
and
multidrug-resistant
(XDR)
tuberculosis,
chloroquine-resistant malaria, and methicillinresistant Staphylococcus aureus;
2)
diseases caused by pathogens endemic in other
species (e.g., wild mammals and birds) that
recently entered human populations, such as HIV
and severe acute respiratory syndrome (SARS);
3)
diseases caused by pathogens that have been
present in human populations but show a recent
increase in incidence, such as dengue fever

HEALTH EFFECTS OF CLIMATE CHANGE

that climate change will seriously impact human health by

increasing the incidence of several diseases
A.
Cardiovascular, cerebrovascular, and respiratory
diseases, caused by heat waves and air pollution
B.
Gastroenteritis and infectious disease epidemics,
caused by water and food contamination as a
consequence of floods, and disruption of clean
water supplies and sewage treatment, after heavy
rains and other environmental disasters
C.
Vector-borne infectious diseases, such as dengue
fever, malaria, West Nile virus infection, and
hantavirus
pulmonary
syndrome,
as
a
consequence of changes in vector number and
geographic distribution caused by increased
temperatures, crop failures, and more frequent El
Nino climate cycles
D. Malnutrition, caused by disruption of crops, mostly
in
tropical
locations
in
which
average
temperatures are near or above crop tolerance
levels; it is estimated that by 2080 agricultural
productivity may decline by 10% to 25% in some
developing countries as a consequence of
warming, while it may decrease or even increase
by up to 6% in developed countries with more
moderate climates
TOXICITY OF CHEMICAL AND PHYSICAL AGENTS

Toxicology

science of poisons

studies the distribution, effects and mechanism of

action of toxic agents

Also includes the study of the effects of physical

agents such as radiation and heat.
Basic principles relevant to the effects of toxic chemicals and
drugs:
o
Poison - quantitative concept strictly dependent on
dosage
o
Xenobiotics
exogenous
chemicals
in
the
environment in air, water, food and soil
may be absorbed into the body through
inhalation, ingestion and skin contact
o
Chemicals may be:
a.
excreted in urine, feces
b.
eliminated in expired air
c.
accumulate in bone, fat, brain or other
tissues

Some agents are not modified after entry in the

body
most solvents, drugs and xenobiotics are

metabolized to form inactive water

soluble products (Detoxification)

activated to form toxic metabolites

The reactions that metabolize xenobiotics into
nontoxic products or activate xenobiotics to
generate toxic compounds, and occur two phases:
A.
PHASE 1 Reactions
Chemicals undergo hydrolysis,
oxidation or reduction.
products of phase 1 reactions
are often metabolized into
water
soluble
compounds
through phase II reactions
B.
PHASE 2 Reactions
Include
glucuronidation,
sulfation, methylation and
conjugation with glutathione.
water soluble compounds are
readily excreted
Enzyme that catalyzes the
biotransformation
of
xenobiotics and drugs are
known as drug metabolizing
enzymes.
CYTOCHROME P450
most important catalyst of phase 1
reactions
located in the ER of the liver
also present in skin, lungs and GI
mucosa
large family of heme containing
enzymes
with
preferential
affinity
toward different substrates.
catalyzes reactions that either:
a.
detoxify xenobiotics
b.
activate
xenobiotics
into
active compounds that cause
cellular injury.
both types of reaction may produce as a
byproduct of ROS that causes cellular
injury.
ENVIRONMENTAL POLLUTION

AIR POLLUTION

Developing
countries:
airborne
microorganisms
contaminating food and water have long been a major
causes of morbidity and mortality
Industrialized nation: most widespread are the chemical and
particulate pollutants found in air

OUTDOOR AIR POLLUTION

Ozone
o
o
o

o
o

Smog - sulfur dioxide, carbon monoxide, ozone, nitrogen

dioxide, lead and particulate matter.
formed from the interaction of UV radiation and Oxygen in
the stratosphere
accumulates in the earth's ozone layer (10 to 30 miles above
the earth's surface)
Ground level ozone
ozone that accumulates in the lower atmosphere
most pernicious air pollutants
gas formed by the reaction of nitrogen oxides and
volatile organic compounds in the presence of sunlight.
Ozone toxicity is majorly mediated by production of free
radicals injure epithelial cells along the respiratory tract
and type 1 alveolar cells release of inflammatory
mediators
exposure is dangerous in those with asthma and emphysema
Ozone induced asthma - airway hyperactivity and
neutrophilia

Sulfur Dioxide
o
produced
a.
b.
c.

by
power plants burnings coal and oil
copper smelting
byproduct of paper mills

CHAPTER9
ENVIRONMENTAL AND NUTRITIONAL DISEASES
When released into the air, it may converted into sulfuric
acid and sulfuric trioxide causes burning sensation in the
nose and throat; difficulty in breathing; asthma attacks
Particulate Matter
o
soot
o
emitted by coal and oil fired power plants, industrial
processes burning these fuels; diesel exhaust
o
fine or ultrafine particles that are less than 10 um in
diameter are most harmful.
o
readily inhaled in the alveoli phagocytized by macrophage
and neutrophils release inflammatory mediators
(macrophage inflammatory protein 1a, endothelin)
o
acute exposure to diesel exhaust that cause particulate
matter may cause
a.
irritation to the eyes, throat and lungs
b.
induce asthma attacks
c.
cause myocardial ischemia
o
Exposure to particles greater than 10 um in diameter is of
lesser consequence ( removed in the nose; trapped by the
mucocilliary epithelium)
Carbon monoxide
o
CO
o
nonirritating
o
colorless, tasteless, odorless
o
produced by incomplete oxidation of carbonaceous materials
o
sources include:
1.
automotive engines
2.
industrial processes using fossil fuels
3.
wood and charcoal burning with an inadequate
supply of oxygen
4.
cigarettes smoke
o
low levels often found in ambient air may contribute to
impaired respiratory function
o
Chronic poisoning can occur.
o
CO is a systemic asphyxiant that kills by inducing CNS
depression
o
Hemoglobin has greater affinity for CO than O2;
carboxyhemoglobin doesnt carry O2
o
Systemic hypoxia - 20% to 30% saturated with COD
o
Unconsciousness and Death are likely with 60% to 70%
saturation
o

MORPHOLOGY
Chronic Poisoning by CO

develops because of carboxyhemoglobin (once

formed: stable)

Even with low level, persistent exposure to CO ,

carboxyhemoglobin may rise to life threatening
levels in the blood.

Slow developing hypoxia widespread changes in

the CNS; marked in the basal ganglia and
lenticular nuclei

Cessation of CO exposure - recovery; but there are

neurologic sequelae such as impairment of
memory, vision, hearing and speech

diagnosis
is
made
by
measuring
carboxyhemoglobin levels in the blood.

METALS AS ENVIRONMENTAL POLLUTANTS

LEAD
o
o
o
o

o
o
o
o
o

o
o

Acute Poisoning by CO
consequence of accidental exposure or suicidal
attempt
light skinned individuals: marked by characteristic
generalized cherry-red color of the skin and
mucous membrane (may be caused high levels of
carboxyhemoglobin)
Death occurs rapidly - morphologic changes may
not be present
Longer survival: brain may be edematous, with
punctate hemorrhages and hypoxia-induced
neuronal changes
not specific morphologic changes; may stem from
hypoxia
INDOOR
o
o
o
o

AIR POLLUTION
Tobacco smoke - most common pollutant
CO, nitrogen dioxide and asbestos
volatile
substances
containing
polycyclic
aromatic
hydrocarbons
Wood smoke

contains various oxides of nitrogen and carbon

particulates

may not be an irritant

predisposes lung infection and may contain
carcinogenic polycyclic hydrocarbons
Bioaerosols

microbiologic agents capable of causing infectious

diseases such as Legionnaire's disease, viral
pneumonia and common cold

less threatening allergens such as pet dander,

dust mites, fungi and molds responsible for
rhinitis, eye irritation and asthma
Radon

radioactive gas

derived from uranium

present in soil and homes

can cause lung cancer in uranium miners

Formaldehyde

poorly ventilated trailers

at concentrations of 0.1 ppm or higher, causes

breathing difficulties and a burning sensation in
the eyes and throat

can trigger asthma attacks

classified as carcinogen
"Sick Building Syndrome"

consequence of exposure to one or more of the

aforementioned indoor building pollutants

may also be caused by poor ventilation

lead exposure occurs through contaminated air, food and

water.
sources include mining, foundries, batteries and spray
painting.
Flaking lead paining in older houses and soul contamination young individuals; ingestion up to 200 mg/day can occur
Subclinical lead poisoning

occur in children exposed to levels below 10 ug/dL

causes low intellectual

capacity, behavioral
problems such as hyperactivity and poor
organizational skills
In adults, lead poisoning occurs mainly as an occupational
hazard.
Most of the absorbed lead (80% to 85%) is incorporated in
the bone and developing teeth, where it competes with
calcium.
Lead half-life in bone: 20 to 30 years
Peripheral neuropathies dominate in adults
Children absorb more than 50% of ingested lead.

higher intestinal absorption and more permeable

blood brain barrier of children create a
high
susceptibility to brain damage.
Neurotoxic effects of lead are attributed to the inhibition of
neurotransmitters caused by the disruption of calcium
homeostasis.
other effects of lead are:

lead in children:

interferes with normal remodeling of cartilage and

primary bone trabeculae in the epiphyses
increased bone density (detected as radiodense
lead lines)

inhibits the healing of fractures by increasing

chondrogenesis
and
delaying
cartilage
mineralization

inhibits the activity of 2 enzymes involved in heme

synthesis:
1.
-aminolevulinic acid dehydrates
2.
Ferrochelatase
catalyzes the incorporation of iron
into porphyrin
inhibition
causes
rise
in
protoporphyrin levels

microcytic, hypochromic anemia- most obvious

abnormality caused by deficiency in heme; stems
from the suppression of hemoglobin synthesis
diagnosis of lead poisoning requires constant awareness of
its prevalence.

Children:basis on the neurologic and behavioral

changes; unexplained anemia with basophilic
stippling of the red cells;

CHAPTER9
ENVIRONMENTAL AND NUTRITIONAL DISEASES

Definitive diagnosis requires detection of elevated

blood levels of lead and free red cell
protoporphyrin

MORPHOLOGY

major anatomic targets of lead toxicity are the:

a.
bone marrow and blood
b.
nervous system
c.
gastrointestinal tract
d.
kidney

Bone marrow changes occur early; characteristic

inhibition of ferrochelatase by lead appearance of

scattered ringed sideroblasts

Scattered ring sideroblasts - red cell precursor with iron

laden mitochondria; detected with Prussian blue stain

Peripheral blood

defect in hemoglobin synthesis appears as microcytic,

hypochromic, anemia

anemia often accompanied by mild hemolysis

punctuate basophilic stippling of the red cell

Brain damage is prone to occur in children

can be subtle, producing mild dysfunction or it can be

massive and lethal

sensory,
motor,
intellectual
and
physiological
impairment; reduced IQ, retarded psychomotor
development, blindness, psychoses, seizures and coma.

Severe: marked brain edema, demyelination of the

cerebral and cerebellar white matter and necrosis of
cortical neurons accompanied by diffuse astrocytic
proliferation.

In adult, CNS is less often affected but frequently a

peripheral demyelinating neuropathy appears, typically
involving the motor nerves of the most commonly used
muscles

extensor muscle of the waist and the fingers

are the first to be affected - waistdrop

paralysis of the peroneal muscle - footdrop

GI tract

Lead "colic" is characterized by extremely severe,

poorly localized abdominal pain

Kidney

may develop proximal tubular damage with intracellular

lead inclusions

Chronic renal damage leads to interstitial fibrosis and

renal failure

Decrease in uric acid secretion - leads to gout

(saturnine gout)
MERCURY
o
there are three forms of mercury:
1.
metallic mercury (elemental mercury)
2.
inorganic mercury compounds (mercuric chloride)
3.
organic mercury (methyl mercury)
o

o
o
o

the main sources of exposure to mercury are

a)
contaminated fish (methyl mercury)
b)
mercury vapors released from metallic mercury in
dental alamgams
Minamata disease

cerebral palsy

deafness

blindness

mental retardation

major CNS defects in children exposed in utero.

(developing brain is extremely sensitive to methyl
mercury)
lipid solubility of methyl mercury and metallic mercury
facilitate their accumulation in the brain, disturbing
neuromotor, cognitive, and behavioral functions.
Mercury binds with high affinity to thiol groups, a property
that contributes to its toxicity.
Intracellular glutathione, acting as thiol donor, is the main
protective mechanism against mercury-induced CNS and
kidney damage

o
ARSENIC
o
found naturally in soils and water
o
used in products such as wood preservers, herbicides and
other agricultural products
o
may be released from mines and smelting industries.

o
o

o
o

arsenic trioxide: used in the treatment of relapsing acute

promyelocytic leukemia
most toxic forms of arsenic are the trivalent compounds
a.
arsenic trioxide
b.
sodium arsenite and
c.
arsenic trichloride.
If ingested in large quantities, arsenic causes acute toxic
effects
consisting
of
severe
disturbances
of
the
gastrointestinal, cardiovascular, and central nervous system
that are often fatal.
Effects may be attributed to interference with mitochondrial
oxidative phosphorylation

trivalent arsenic can replace the phosphates in

adenosine triphosphate.
Neurologic effects occur 2 to 8 weeks after exposure and
consists of a sensorimotor neuropathy that causes
parasthesias, numbness and pain
most serious consequence of chronic exposure: increased
risk for the development of cancers in almost all tissues, but
particularly in the skin and lungs.

Skin:

hyperpigmentation and hyperkeratosis;

followed by the development of basal
and squamous cell carcinomas

arsenic induced is different from sunlight

induced: often multiple; usually appear
on palms and sole.

may involve defects in nucleotide excision repair

mechanism that protect against DNA damage.

arsenic
in
drinking
water:
nonmalignant
respiratory disease

CADMIUM
o
occupational and environmental pollutant generated by
mining, electroplating and production of nickel-cadmium
batteries which are usually disposed of as household waste
o
Food is the most important source of cadmium exposure for
the general population
o
Toxic effects of cadmium
a.
obstructive lung disease - caused by necrosis of
alveolar macrophages
b.
kidney damage - consisting of tubular damage
that may progress to end stage renal disease
o
exposure may also cause skeletal abnormalities associated
with Ca loss.
o
known to cause Itai-Itai (ouch-ouch)

combination of osteoporosis and osteomalacia

associated with renal disease

o
Elevated risks of lung cancer, which has been demonstrated
in workers occupational and in populations living near zinc
smelters
o
Cadmium is not directly genotoxic
o
most likely produces DNA damage through the generation of
ROS.
OCCUPATIONAL HEALTH RISKS: INDUSTRIA AND AGRICULTURAL
EXPOSURES
o
o
o

Work related accidents - biggest problem in developing

countries
Work related diseases - more frequent in industrialized
countries
Fraction of global disease attributed to occupational
exposure include:

13% - chronic obstructive pulmonary disease

9% - lung cancer

2% -leukemia
Some of the important agents that contribute to
occupational diseases:

ORGANIC SOLVENTS
o
chloroform and carbon tetrachloride

found in degreasing and dry cleaning agents and

paint removers.

acute exposure can cause dizziness and confusion,

leading to CNS depression and even coma.

lower levels are toxic for the liver and kidneys.

o
benzene and 1,3-butadience

risk for leukemia

CHAPTER9
ENVIRONMENTAL AND NUTRITIONAL DISEASES

Benzene is oxidized by hepatic CYP2E1 to toxic

metabolites that disrupt the differentiation of
hematopoietic cells in the bone marrow dose
dependent marrow aplasia, increased risk of acute
myeloid leukemia

POLYCYCLIC HYDROCARBONS
o
may be released during combustion of fossil fuels,
particularly when coal and gas are burned at high
temperatures (steel foundries)
o
tar and soot
o
most potent carcinogens
o
industrial exposure is implicated in the development of lung
and bladder cancer
ORGANOCHLORINES
o
synthetic lipophilic products
o
resist degradation
o
organochlorines used as pesticides include:
a)
DDT (dichlorodiphenyltrichloroethane)
b)
Lindane
c)
Aldrin
d)
Dieldrin
o
nonpesticide organochlorines include:
a) polychlorinated biphenyls (PCBs)
b) dioxin (TCDD; 2,3,7,8-tetrachlorodibenzo-p-dioxin)
o
most organochlorines are endocrine disruptors with antiestrogenic or anti-androgenic activity
DIOXINS AND POLYCHLORINATED BIPHENYLS
o

o
o

can cause skin disorders such as

folliculitis

dermatosis known as chloracne - characterized by

acne, cyst formation, hyperpigmentation and
hyperkeratosis; found in the face, and behind the
ears.
toxins can cause abnormalities in the liver and CNS
PCBS induce CYPs

MINERAL DUSTS
o
causes Pneumoconiosis

chronic, non-neoplastic lung disease

includes diseases induced by organic and

inorganic particulates and chemical fume and
vapor induced non neoplastic lung diseases
o
most common pneumoconiosis are caused by exposures to
a)
coal dust (mining of hard coal)
b)
silica (sandblasting, stone cutting)
c)
asbestos (mining, fabrication, insulation work)
d)
beryllium (mining, fabrication)
o
exposure always occurs in workplace
VINYL CHLORIDE
o
used in the synthesis of polyvinyl resins
o
exposure leads to development of angiosarcoma of the liver
(uncommon type of hepatic tumor)
PHTHALATES
o
lab animals: causes endocrine disruption and testicular
dysgenesis syndrome (hypospadias, chryptochordism and
testicular cell abnormalities)
o
Phthalates are widely used plasticizers found in plastics and
in medical containers (blood and serum bags)
EFFECTS OF TOBACCO

Tobacco is the most common exogenous cause of human

cancers, being responsible for 90% of lung cancers
The main culprit is cigarette smoking, but smokeless tobacco
(snuff, chewing tobacco, etc.) is also harmful to health and
an important cause of oral cancer
Smoking is the most preventable cause of human death. It
reduces overall survival through dose-dependent effect

Substance

tumor promotion
Phenol

Tumor promotion; mucosal irritation

Benzopyrene

Carcinogenesis

Carbon monoxide

Impaired oxygen transport and utilization

Formaldehyde

Toxicity to cilia; mucosal irritation

Oxides of nitrogen

Toxicity to cilia; mucosal irritation

Nitrosamine

Carcinogenesis

Organ-Specific Carcinogens in Tobacco Smoke

Organ

Carcinogen

Lung, larynx

Polycyclic aromatic hydrocarbons 4(Methylnitrosoamino)-1-(3-pyridyl)-1-buta-none (NNK),

polonium 210

Esophagus

N-Nitrosonornicotine (NNN)

Pancreas

NNK (?)

Bladder

4-Aminobiphenyl, 2-naphthylamine

Oral cavity
(smoking)

Polycyclic aromatic hydrocarbons, NNK, NNN

Oral cavity
(snuff)

NNK, NNN, polonium 210

Smoking and Other Diseases

Cigarette smoking is strongly linked to the development of

atherosclerosis and its major complication, myocardial
infarction

Maternal smoking increases the risk of spontaneous

abortions and preterm births and results in intrauterine
growth retardation

Exposure to environmental tobacco smoke (passive smoke

inhalation) is also associated with some of the same
detrimental effects that result from active smoking
EFFECTS OF ALCOHOL

Effects of Selected Tobacco Smoke Constituents

Substance

Effect

Tar

Carcinogenesis

Polycyclic aromatic
hydrocarbons

Carcinogenesis

Nicotine

Ganglionic stimulation and depression;

Effect

After consumption, ethanol is absorbed unaltered in the

stomach and small intestine. It is then distributed to all the
tissues and fluids of the body in direct proportion to the
blood level.

Less than 10% is excreted unchanged in the urine,

sweat, and breath. The amount exhaled is
proportional to the blood level and forms the basis
of the breath test used by law enforcement
agencies
Drowsiness occurs at 200 mg/dL
stupor at 300 mg/dL, and
coma, with possible respiratory arrest, at higher levels.
The rate of metabolism affects the blood alcohol level.
Chronic alcoholics can tolerate levels of up to 700 mg/dL, a
situation that is partially explained by accelerated ethanol
metabolism caused by a five- to ten-fold induction of liver
CYPs
The effects of alcohol also vary by age, sex, and body fat
Most of the alcohol in the blood is biotransformed to
acetaldehyde in the liver by three enzyme systems
consisting of
a.
alcohol dehydrogenase (ADH),
b.
microsomal ethanol-oxidizing system (MEOS), and
c.
catalase
Alcohol Dehydrogenase
o
main enzyme system involved in alcohol
metabolism
o
located in the cytosol of hepatocytes
At high blood alcohol levels, the microsomal ethanoloxidizing system participates in its metabolism.

CHAPTER9
ENVIRONMENTAL AND NUTRITIONAL DISEASES

o
o

Acute
o
o
o
o
o
o

Catalase, which uses hydrogen peroxide as substrate, is of

minor importance, since it metabolizes no more than 5% of
ethanol in the liver.
Acetaldehyde produced by alcohol metabolism through ADH
or MEOS is converted to acetate by acetaldehyde
dehydrogenase (ALDH), which is then utilized in the
mitochondrial respiratory chain
The microsomal oxidation system involves CYPs, particularly
CYP2E1 located in the smooth endoplasmic reticulum
Induction of CYPs by alcohol explains the increased
susceptibility of alcoholics to other compounds metabolized
by the same enzyme system, which include drugs,
anesthetics, carcinogens, and industrial solvents
when alcohol is present in the blood at high concentrations,
it competes with other CYP2E1 substrates and delays drug
catabolism, potentiating the depressant effects of narcotic,
sedative, and psychoactive drugs in the central nervous
system
oxidation of ethanol produces toxic agents and disrupts
metabolic pathways
Acetaldehyde is responsible for some of the acute effects of
alcohol and for the development of oral cancers.
efficiency of alcohol metabolism varies between populations,
depending on the
a.
expression levels of ADH and ALDH isozymes, and
b. presence of genetic variants that alter enzyme
activity.

About 50% of Asians have very low

ALDH activity, due to the substitution of
lysine for glutamine at residue 487 (the
normal allele is termed ALDH2*1 and the
inactive variant is designated as
ALDH2*2).

The ALDH2*2 protein has dominantnegative activity, such that even one
copy of the ALDH2*2 allele reduces
ALDH activity significantly.

Individuals homozygous for the ALDH2*2

allele are completely unable to oxidize
acetaldehyde
and
cannot
tolerate
alcohol, experiencing nausea, flushing,
tachycardia, and hyperventilation after
its ingestion
Alcohol oxidation by ADH causes the reduction of
nicotinamide adenine dinucleotide (NAD) to NADH, with a
consequent decrease in NAD and increase in NADH.

NAD is required for fatty acid oxidation in the liver

and for the conversion of lactate into pyruvate.

Its deficiency is a main cause of the accumulation

of fat in the liver of alcoholics.

The increase in the NADH/NAD ratio in alcoholics

also causes lactic acidosis
Metabolism of ethanol in the liver by CYP2E1 produces
reactive oxygen species and causes lipid peroxidation of cell
membranes.

However, the precise mechanisms that account for

alcohol-induced cellular injury in the liver have not
been well defined.

Alcohol also causes the release of endotoxin

(lipopolysaccharide) from gram-negative bacteria
in the intestinal flora, which stimulates the
production of TNF (tumor necrosis factor) and
other cytokines from macrophages and Kupffer
cells, leading to hepatic injury
alcoholism
exerts its effects mainly on the CNS, but it may induce
hepatic and gastric changes that are reversible if alcohol
consumption is discontinued.
Even with moderate intake of alcohol, multiple fat droplets
accumulate in the cytoplasm of hepatocytes (fatty change or
hepatic steatosis).
The gastric changes are acute gastritis and ulceration.
In the CNS, alcohol is a depressant, first affecting subcortical
structures (probably the high brain stem reticular formation)
that modulate cerebral cortical activity.
Consequently, there is stimulation and disordered cortical,
motor, and intellectual behavior.
At progressively higher blood levels, cortical neurons and
then lower medullary centers are depressed, including those
that regulate respiration. Respiratory arrest may follow.

Chronic Alcoholism
o
The liver is the main site of chronic injury; chronic alcoholism
causes alcoholic hepatitis and cirrhosis

Cirrhosis is associated with portal hypertension

and an increased risk for the development of
hepatocellular carcinoma.
o
In the gastrointestinal tract, chronic alcoholism can cause
massive bleeding from gastritis, gastric ulcer, or esophageal
varices (associated with cirrhosis), which may prove fatal.
o
Thiamine (vitamin B1) deficiency is common in chronic
alcoholics.

The principal lesions resulting from this deficiency

are peripheral neuropathies and the WernickeKorsakoff syndrome; cerebral atrophy, cerebellar
degeneration, and optic neuropathy may also
occur
o
Alcohol has diverse effects on the cardiovascular system.
Injury to the myocardium may produce dilated congestive
cardiomyopathy (alcoholic cardiomyopathy,).

Chronic alcoholism is also associated with an

increased incidence of hypertension.

Moderate amounts of alcohol (about 2030 gm of

daily intake, corresponding to approximately 250
mL of wine) have been reported to increase highdensity lipoprotein (HDL) levels and inhibit platelet
aggregation, thus protecting against coronary
heart disease.

heavy alcohol consumption, with attendant liver

injury, results in decreased levels of HDL,
increasing the likelihood of coronary heart disease
o
Excessive alcohol intake increases the risk of acute and
chronic pancreatitis
o
The use of ethanol during pregnancyreportedly in very low
amountscan cause fetal alcohol syndrome

It consists of microcephaly, growth retardation,

and facial abnormalities in the newborn, and
reduction in mental functions as the child grows
older.

It is difficult to establish the minimal amount of

alcohol consumption that can cause fetal alcohol
syndrome, but consumption during the first
trimester of pregnancy is particularly harmful
o
Chronic alcohol consumption is associated with an increased
incidence of cancer of the oral cavity, esophagus, liver, and,
possibly, breast in females.

Acetaldehyde is considered to be the main agent

associated with alcohol-induced laryngeal and
esophageal cancer, in that acetaldehyde-DNA
adducts have been detected in some tumors from
these tissues.

Individuals with one copy of the ALDH2*2 allele

who drink are at a higher risk of developing cancer
of the esophagus.
o
Ethanol is a substantial source of energy (empty calories).
Chronic alcoholism leads to malnutrition and nutritional
deficiencies, particularly of the B vitamins.

Vitamins: Major Functions and Deficiency Syndromes

Vitami
n

Functions

Deficiency
Syndromes

FAT-SOLUBLE
Vitamin A component of visual pigment
A

Night blindness,
xerophthalmia,
blindness

Maintenance of specialized epithelia

Squamous
metaplasia

Maintenance of resistance to infection

Vulnerability to
infection,
particularly measles

Vitamin Facilitates intestinal absorption of

D
calcium and phosphorus and
mineralization of bone

Riskets in children

Vitamin Major antioxidant; scavenges free

Spinocerebellar

Osteomalacia in
adults

CHAPTER9
ENVIRONMENTAL AND NUTRITIONAL DISEASES
Vitami
n

Functions

Deficiency
Syndromes

radicals

degeneration

Vitamin Cofactor in hepatic carboxylation of

K
procoagulantsfactors II
(prothrombin), VII, IX, and X; and
protein C and protein S

Bleeding diathesis
( Chapter 14 )

WATER-SOLUBLE
Vitamin B1
(thiamine)

As pyrophosphate, is
Dry and wet beriberi,
coenzyme in decarboxylation Wernicke syndrome,
reactions
Korsakoff syndrome
( Chapter 28 )

Vitamin B2
(riboflavin)

Converted to coenzymes
flavin mononucleotide and
flavin adenine dinucleotide,
cofactors for many enzymes
in intermediary metabolism

Ariboflavinosis, cheilosis,
stomatitis, glossitis,
dermatitis, corneal
vascularization

Niacin

Incorporated into
nicotinamide adenine
dinucleotide (NAD) and NAD
phosphate, involved in a
variety of redox reactions

Pellagrathree Ds:
dementia, dermatitis,
diarrhea

Vitamin B6 Derivatives serve as

(pyridoxine) coenzymes in many
intermediary reactions

Megaloblastic pernicious
anemia and
degeneration of
posterolateral spinal cord
Maintenance of myelinization tracts ( Chapter 14 )
of spinal cord tracts

Vitamin C

Serves in many oxidationScurvy

reduction (redox) reactions
and hydroxylation of collagen

Folate

Essential for transfer and use Megaloblastic anemia,

of one-carbon units in DNA
neural tube defects
synthesis
( Chapter 14 )

Pantothenic Incorporated in coenzyme A

acid

No nonexperimental
syndrome recognized

Biotin

No clearly defined clinical

syndrome

o
o

HRT effects depend on the type of estrogen/progesterone

used, mode of drug administration, age of the person at the
start of the treatment, the duration of the treatment and the
presence of associated disease:
a)
HRT increased the risk of breast cancer after a median time
of 5 to 8 years. - lobular carcinomas and ductal-lobular
cancer
b)
HRT has a protective effect on the development of
atherosclerosis and coronary disease in women under age 60
; no protection in women who started HRT at an older age
c)
HRT increases the risk of venous thromboembolism,
including deep vein thrombosis, pulmonary embolism and
stroke

more pronounced in the first 2 years of treatment

other risk factors immobilization, hypercoagulable

states caused by prothrombin or factor
Leiden
mutations
ORAL CONTRACEPTIVES

nearly always contain a synthetic estradiol + variable

amount of progestin; some preparations only contain
progestin.

Act by inhibiting ovulation and preventing implantation

currently prescribed OCs contain a much smaller amount of

estrogen - associated with fewer side effects

dosage and delivery system

Oral contraceptive is associated with the following

conditions:
a)

Cheilosis, glossitis,
dermatitis, peripheral
neuropathy ( Chapter
28 )

Vitamin B12 Required for normal folate

metabolism and DNA
synthesis

Cofactor in carboxylation
reactions

red wine contains resveratrol, a polyphenolic compound that

increases life span in worms and flies, promotes longevity in
mice, and protects mice against diet-induced obesity and
insulin resistance.
Resveratrol contributes to the protective effect against
cardiovascular disease in moderate wine drinkers and
possibly provides the clue to the French paradox, a wineand food-loving population with a low incidence of obesity
and cardiovascular disease.
The effects of resveratrol on longevity have been attributed
to its activation of protein deacetylases of the Sir2 (sirtuin)
family of enzymes, which include histone deacetylases.
However, because resveratrol also interacts with various
other proteins, ongoing studies seek to identify the precise
mechanisms of its protective effects

INJURY BY THERAPEUTIC DRUGS and DRUGS OF ABUSE

INJURY BY THERAPEUTIC DRUGS (ADVERSE DRUG REACTION)
HORMONAL REPLACEMENT THERAPY

most common type of HRT: estrogen+progesterone

estrogen therapy alone is used only in hysterectomized

women.

THROMBOEMBOLISM

Oral contraceptive use results in 3x increase risk

of
venous
thrombosis
and
pulmonary
thromboembolism

risk is increased in carriers of prothrombin and

factor V Leiden mutations.

consequence of an acute phase response, with

increases in C-reactive protein and coagulation
factors), and reduction in anticoagulants (protein S
and anti-thrombin III)
b)
CARDIOVASCULAR DISEASE

OC increase the risk of myocardial infarction in MI

in smoking and women at all ages and in
nonsmoking women over age 35

over 35 - risk is higher

c)
CANCER

OC reduce the incidence of endometrial and

ovarian cancers

do not increase the lifetime risk for development

of breast cancers
d)
HEPATIC ADENOMA

older women who have used OCs for prolonged

periods of time

tumors appear as large, solitary and wellencapsulated mass

ANABOLIC STEROIDS

synthetic versions of testosterone; for performance

enhancement, they are use at doses that are about 10 to
100 times higher than therapeutic indications

high concentration of testosterone inhibits production and

release of LH and FSH by a feedback mechanism
increases the amount of estrogen, which are produced from
anabolic steroids

multiple effects include:

a.
stunted growth in adolescent
b.
acne
c.
gynecomastia
d.
testicular atrophy
e.
growth of facial hair and menstrual changes in
women

other effects include psychiatric problems and premature

heart attacks

Hepatic cholestasis may develop in individuals receiving

orally administered anabolic steroids
ACETAMINOPHEN

most commonly used analgesic

common

intentional over dosage is the most common cause of

acetaminophen toxicity

At therapeutic dosage, about

CHAPTER9
ENVIRONMENTAL AND NUTRITIONAL DISEASES

a.
b.

95% of acetaminophen undergoes detoxification in

the liver by phase II enzymes; excreted in the
urine as glucuronate or sulfate conjugates.
5% or less is metabolized through the activity of
CYPs (prim. CYP2E) to NAPQI (N-acetyl-pbenzoquinoneimine), a highly reactive metabolite

NAPQI

normally conjugated with glutathione (GSH)

when taken in larger doses, unconjugated NAPQI
accumulates causes hepatocellular injury
centrilobular necrosis and liver failure

injury
produced
by
NAPQI
involves
two
mechanisms:
covalent binding by hepatic protein

causes damage to cellular membranes as well as

mitochondrial dysfunctions
depletion of GSH

depletion causes hepatocytes to be more

susceptible to ROS-induced injury
Since alcohol induces CYP2 in the liver, toxicity can occur at
lower doses in chronic alcoholics
window between the usual dose (0.5 gm) and the toxic dose
(15 to 25 gm)
toxicity begins with nausea, vomiting, diarrhea and shock
followed in a few days by evidence of jaundice.
Overdose can be treated at its early stage (w/n 12 hours) by
administration
of
N-acetylcysteine;
(N-acetylcysteine
restores GSH)
in serious overdose liver failure - liver transplantation for
survival

ASPIRIN (ACETYLSALICYLIC ACID)

overdose may result from accidental ingestion of a large

number of tablets by young children

adults: suicidal.

source of salicylate poisoning is the excessive use of

ointments containing oil of wintergreen (methyl salicylate).

Acute salicylate overdose:

causes alkalosis
as a consequence of the
stimulation of the respiratory center in the medulla

followed by metabolic acidosis and accumulation

of pyruvate and lactate caused by uncoupling of
oxidative phosphorylation and inhibition of the
Krebss cycle.

Metabolic acidosis enhances the formation of non-ionized

formed salicylates diffuse into the brain produce effects
from nausea to coma

ingestion of 2 to 4 gm by children or 10 to 30 gm by adults

may be fatal

Chronic aspirin toxicity (salicylism)

develop in person who take 3 gm or more daily for

long periods of time for treatment of chronic pain
or inflammatory conditions.

manifested by headache, dizziness, ringing in the

ears, hearing impairment, mental confusion, etc.

acute erosive gastritis - produce overt or covert GI

bleeding gastric ulceration

bleeding tendency: aspirin acetylates platelet

cyclooxygenase

irreversibly
blocks
the
production of thromboxane A2

petechial hemorrhage may appear in the skin and

internal visceral

Analgesic nephropathy - mixtures of Aspirin and phenacetin

or acetaminophen can cause tubulointerstitial nephritis with
renal papillary necrosis
INJURY BY NONTHERAPEUTIC AGENTS (DRUG ABUSE

Drug abuse - use of mind-altering substances beyond

therapeutic norms.

COCAINE
o
extracted from the leaves of the coca plant
o
usually prepared as water soluble powder, cocaine
hydrochlorine
o
diluted with talcum powder, lactose or other look-alikes.
o
can be snooted or dissolved in water and injected SQ or IV
o
Crystallization of the pure alkaloids yields nuggets of crack so called because of the cracking or popping sound it makes
when heated to produce vapors that are inhaled.

o
o
o
o
o

Crack is far more potent than cocaine.

produces an intense euphoria and stimulation - one of the
most addictive drugs
physical dependence does not generally occur, the
psychologic withdrawal is profound and can be extremely
difficult to treat.
intense cravings - first several months after abstinence; can
recur
acute overdose can produce seizures, cardiac arrhythmia
and respiratory arrest

Adverse Effects of Cocaine

Cardiovascular Effects
most serious physical effects of cocaine; behaves as
sympathomimetic
facilitates neurotransmission both in:
a)
CNS - blocks the reuptake of dopamine
b)
adrenergic nerve endings - blocks the reuptake of both
epinephrine and norepinephrine while stimulating the
presynaptic release of NE net effect: accumulation of NE
and EPI in the synapse results in excess stimulation
manifested by tachycardia, hypertension, and peripheral
vasoconstriction
myocardial
ischemia
by
causing
coronary
artery
vasoconstriction and enhancing platelet aggregation and
thrombus formation.
dual effect of cocaine 1.
increased myocardial oxygen demand by its
sympathomimetic action
2.
decreasing coronary blood flow

two effects that sets in Myocardial ischemia

may lead to myocardial infarction

also precipitates lethal arrhythmia by enhanced sympathetic
activity as well as by disrupting normal ion transport in the
myocardium.
Central Nervous System

Hyperpyrexia - caused by aberrations of the dopaminergic

pathways that control the body temperature

seizures
Pregnancy

may cause decreased blood flow to the placenta fetal

hypoxia and spontaneous abortion
Other effects

perforation of the nasal septum

decreased lung diffusing capacity

development of cardiomyopathy
HEROIN

derived from the poppy plant

related to morphine
cut (diluted) with an agent (talc or quinine)
self-administered SQ or IV
effects are varied; may include somnolence, euphoria,
hallucinations, sedation.

adverse effects related to:

o
pharmacologic action of the action
o
reaction to the cutting agents or contaminants
o
hypersensitivity reactions to the drug
o
diseases contracted incident to the use of infected
needles.
Adverse Effects of Heroin
Sudden Death

related to overdose - ever present risk because drug purity is

generally unknown

can also occur if heroin is taken after tolerance for the drug
is lost.

mechanism of death includes profound respiratory

depression, arrhythmia and cardiac arrest and severe
pulmonary edema.
Pulmonary injury

includes:
o
moderate to severe edema
o
septic embolism from endocarditis lung abscess
o
opportunistic infections
o
foreign body granuloma from talc and other
adulterants

CHAPTER9
ENVIRONMENTAL AND NUTRITIONAL DISEASES

granuloma occur principally in the lungs; sometimes found in

the mononuclear phagocyte system
examinations often highlights trapped talc crystals,
sometimes enclosed within foreign body giant cells

Infection

common

sites commonly affected are: skin&SQ tissues, heart valves,

liver and lungs

10% had endocarditis - takes a distinctive form involving

right sided heart valves, particularly the tricuspid.

most are caused by S.aureus but fungi and a multitiude of

other organisms

Viral hepatitis - most common among addicted persons;

sharing of dirty needles
Skin

cutaneous lesions - telltale signs of heroin addiction

acute changes: abscess, cellulitis, and ulceration due to

subcutaneous injections

Sequelae of repeated intravenous inoculations include:

1.
scarring at injection sites
2.
hyperpigmentation over commonly used veins
3.
thrombosed veins
Renal Problems
two forms are
a)
amyloidosis - secondary to skin infections
b)
focal glomeruloscelrosis
both induce heavy proteinemia and nephrotic syndrome
o

METHADONE, originally used in the treatment of heroin

addiction, is increasingly being prescribed as a painkiller

AMPHETAMINES
METHAPHETAMINE
o
o
o
o
o

speed, meth
closely related to amphetamine but has stronger effects in
the CNS
acts by releasing dopamine in the brain inhibits
presynaptic neurotransmission at cortical synapses slows
glutamate release
produces a feeling of euphoria followed by a crash
long term use leads to violent behaviors, confusion, and
psychotic features that include paranoia and hallucinations

MDMA
o
o
o
o
o
o
o

3,4 methylenedioxymethamphetamine
"ecstasy"
generally taken orally
euphoria and hallucinogen-like feeling : lasts for 4 to 6 hours
effects are due to an increase in serotonin release in CNS
serotonin released is coupled with the interference of
serotonin synthesis reduction in serotonin that is only
slowly replenished
MDMA use reduces the number of serotonergic axon
terminals in the striatum and the cortex - may increase the
peripheral effects of dopamine and adrenergic agents

MARIJUANA
o
o
o
o
o
o

pot
cannabis
sativapsychoactive
substance
9tetrahydrocannabinol (THC).
5% to 10% of THC is absorbed when it is smoked in a handrolled cigarette (joint).
untoward anecdotal effects may be allergic or idiosyncratic.
beneficial effects of marijuana
a)
treat nausea secondary to cancer chemotherapy
b)
decrease pain in some chronic conditions that are
difficult to treat
Functional and Organic CNS consequences of marijuana:
a.
distorts sensory perception
b.
impairs motor coordination

effects clear in 4 to 5 hours

if continued, these changes may progress to

cognitive and psychomotor impairments
c.
increases heart rate and sometimes bp
d.
may causes angina in person with coronary artery
disease.

in the respiratory system, marijuana causes:

a.
laryngitis
b.
pharyngitis
c.
bronchitis
d.
cough
e.
hoarseness
f.
asthma-like symptoms along with significant
airway obstruction
Endogenous Cannabinoid System

cannabinoid receptors CB1 and CB2

Endocannabinoids - endogenous lipid ligands

participates in the regulation of hypothalamicpituitary-adrenal axis and modulates the control of

appetite, food intake, and energy balance as well
as fertility and sexual behavior.

OTHER DRUGS

PCP (Phenylcyclidine) - anesthetic;

Oxycontin, vicodin - analgesic

ketamine - anesthetic agent use in animal surgery

glue sniffing - toluene containing; cognitive abnormalities,

bran damage
INJURY BY PHYSICAL AGENTS
MECHANICAL TRAUMA
o
type of injury depends on the:
a.
shape of the colliding object
b.
amount of energy discharge at the impact
c.
tissues or organ that bear the impact.
o
All soft tissues react similarly to mechanical forces
o
Patterns can be divided into
a.
abrasions
b.
contusions
c.
lacerations
d.
incised wounds
e.
puncture wounds
Morphology
Abrasion
o
wound produced by scraping or rubbing
o
results in the removal of the superficial layer
o
may remove only the epidermal layer
Contusion
o
bruise
o
injury produced by a blunt object
o
characterized by damage to blood vessels and extravasation
of blood into tissues
Laceration
o
tear or disruptive stretching of tissues caused by the
application of force by a blunt object
o
in contrast to incision, most lacerations have intact bridging
blood vessels and jagged, irregular edges
Incision
o
inflicted by a sharp instrument
o
bridging blood vessels are severed
Puncture
o
caused by a long, narrow instrument
o
penetrating puncture: instrument pierces the tissue
o
perforating puncture : traverses a tissue to also create an
exit wound
o
Gunshot wounds - special
Vehicular accident
o
most common causes of mechanical injury
o
typical injuries result from
1.
hitting a part of the interior of the vehicle or being
hit by an object that enters the passenger
compartment during the crash
2.
being thrown from the vehicle
3.
being trapped in a burning vehicle
o
pattern of injury relates to whether on or all three mentioned
are operative
THERMAL INJURY
THERMAL BURNS
o
clinical significance of a burn injury depends on the following
factors:
a.
depth of burns
b.
percentage of body surfaces involved

CHAPTER9
ENVIRONMENTAL AND NUTRITIONAL DISEASES
c.

internal injuries caused by the inhalation of hot

and toxic fumes
d.
promptness and efficacy of therapy, especially
fluid and electrolyte management and prevention
or control of wound infections
o
New classification of burns:

superficial

partial thickness

full thickness
Superficial burns

first degree burns

confined to the epidermis

Partial thickness burns

second degree burns

involve injury to the dermis

Full thickness burns

third degree burns

extend to the SQ tissue

also involve damage to the muscle tissue underneath the

subcutaneous tissue
HYPOVOLEMIC SHOCK
o
burns more than 20% of the body surface
o
rapid shift of body fluids into the interstitial compartments burn site and systemic
o
protein from the blood is lost into the interstitial tissue
generalized edema (pulmonary edema)
o
hyper metabolic state - associated with excess heat loss and
an increased need for nutritional support
o
40% of the body surface is burned - resting metabolic rate is
doubled.
ORGAN SYSTEM FAILURE FROM BURN SEPSIS
o
serum and debris provide nutrients
o
brain injury compromises blood flow blocking the
effective inflammatory responses
o
Pseudomonas aeruginosa - most common offender
o
S aureus, C sp - may also be involved
o
cellular and humoral defenses against infections are
compromised; lymphocyte and phagocyte functions are
impaired.
o
Grafting - split-thickness skin grafts; dermal substitutes
RESPIRATORY INSUFICIENCY - INJURY TO THE AIRWAYS
o
may develop within 24 to 48 hours
o
direct effect of heat on mouth, nose and upper airways
o
Water soluble gases such as chlorine, sulfur oxide and
ammonia react with water form acids or alkalis
(upper airways) inflammation and swelling partial or
complete airway obstruction.
o
Lipid soluble gases nitrous oxide and products of burning
plastics reach deeper airways pneumonitis

Its onset is sudden, with prostration and collapse

results from a failure of the cardiovascular system to
compensate for hypovolemia, secondary to water depletion.
o
After a period of collapse, which is usually brief, equilibrium
is spontaneously re-established
Heat stroke
o
associated with high ambient temperatures, high humidity,
and exertion.
o
Thermoregulatory mechanisms fail, sweating ceases, and the
core body temperature rises to more than 40C multiorgan dysfunction that can be rapidly fatal.
o
The underlying mechanism is marked generalized
vasodilation, with peripheral pooling of blood and a
decreased effective circulating blood volume.
o
Hyperkalemia, tachycardia, arrhythmias, and other systemic
effects are common.
o
Necrosis of the muscles (rhabdomyolysis) and myocardium
may occur as a consequence of the nitrosylation of the
ryanodine receptor type 1 (RYR1) in skeletal muscle.
o
RYR1 is located in the sarcoplasmic reticulum and regulates
the release of calcium into the cytoplasm.
o
Inherited mutations in RYR1 occur in the condition called
malignant hyperthermia, characterized by a rise in core body
temperature and muscle contractures in response to
exposure to common anesthetics.
o
RYR1 mutations may also increase the susceptibility to heat
stroke.
o
Elderly persons, individuals undergoing intense physical
stress (including young athletes and military recruits), and
persons with cardiovascular disease are potential candidates
for heat stroke.
o
o

HYPOTHERMIA
o
o
o
a.

b.

hypertrophic scars: consequence of continuous angiogenesis in the

wound caused by excess neuropeptides (substance P) release from
injured nerve endings.
MORPHOLOGY
o
Grossly:
a.

full thickness burns are white or charred, dry and

anesthetic (destruction of nerve endings)
b.
partial thickness burns are pink or mottled with
blisters; painful
Histologically:

devitalized tissue reveals coagulative necrosis are

found adjacent to the vital tissue (quickly
accumulates inflammatory cells)

marked exudation

Direct effects
o
mediated by physical disruptions within cells by
high
salt
concentrations
caused
by
the
crystallization of intra- and extracellular water
Indirect effects
o
circulatory changes, which vary depending on the
rate and duration of the temperature drop.
o
Slowly
developing
chilling
may
induce
vasoconstriction
and
increased
vascular
permeability, leading to edema and hypoxia. Such
changes are typical of trench foot.
o
With
sudden,
persistent
chilling,
the
vasoconstriction and increased viscosity of the
blood in the local area may cause ischemic injury
and degenerative changes in peripheral nerves. In
this situation, the vascular injury and increased
permeability with exudation become evident only
after the temperature begins to return to normal.
o
However, during the period of ischemia, hypoxic
changes and infarction of the affected tissues may
develop (e.g., gangrene of toes or feet).

ELECTRICAL INJURY
o
o

HYPERTHERMIA
Prolonged exposure to elevated ambient temperatures can
result in :
Heat cramps
o
result from loss of electrolytes via sweating.
o
Cramping of voluntary muscles, usually in association with
vigorous exercise, is the hallmark.
o
Heat-dissipating mechanisms are able to maintain normal
core body temperature
Heat exhaustion
o
the most common hyperthermic syndrome.

High humidity, wet clothing, and dilation of superficial blood

vessels resulting from the ingestion of alcohol hasten the
lowering of body temperature
At a body temperature of about 90F, loss of consciousness
occurs, followed by bradycardia and atrial fibrillation at lower
core temperatures
Hypothermia causes injury by two mechanisms:

arise from contact with low-voltage currents, or high-voltage

currents carried by high-power lines or lightning
Injuries are of two types:
(1) burns and
(2) ventricular fibrillation or cardiac and respiratory
center failure, resulting from disruption of normal
electrical impulses.
o
The type of injury and the severity and extent of
burns depend on the strength (amperage),
duration, and path of the electric current within
the body
Voltage in the household and workplace (120 or 220 V) is
high enough that with low resistance at the site of contact
(as when the skin is wet), sufficient current can pass through
the body to cause serious injury, including ventricular
fibrillation.

CHAPTER9
ENVIRONMENTAL AND NUTRITIONAL DISEASES
o
o

If current flow continues long enough, it generates enough

heat to produce burns at the site of entry and exit as well as
in internal organs.
An important characteristic of alternating current, the type
available in most homes, is that it induces tetanic muscle
spasm, so that when a live wire or switch is grasped,
irreversible clutching is likely to occur, prolonging the period
of current flow.
Currents generated from high-voltage sources cause similar
damage; however, because of the large current flows
generated, these are more likely to produce paralysis of
medullary centers and extensive burns.
Lightning is a classic cause of high-voltage electrical injury.

INJURY PRODUCED BY IONIZING RADIATION

o
o
o

Collision of electrons with other molecules releases electrons

in a reaction cascade, referred to as ionization
ionizing radiation has sufficient energy to remove tightly
bound electrons.
The main sources of ionizing radiation are
a.
x-rays and gamma rays (electromagnetic waves of
very high frequencies)
b.
high-energy neutrons
c.
alpha particles (composed of two protons and two
neutrons), and beta particles, which are essentially
electrons.
At equivalent amounts of energy, alpha particles induce
heavy damage in a restricted area, whereas x-rays and
gamma rays dissipate energy over a longer, deeper course,
and produce considerably less damage per unit of tissue.

Main Determinants of the Biologic Effects of Ionizing Radiation

Rate of delivery
o
Although the effect of radiant energy is cumulative
o
divided doses may allow cells to repair some of
the damage between exposures.
o
fractionated doses of radiant energy have a
cumulative effect only to the extent that repair
during the recovery intervals is incomplete.
o
Radiation therapy of tumors exploits the general
capability of normal cells to repair themselves and
recover more rapidly than tumor cells, and thus
not sustain as much cumulative radiation damage

Field size.
o
The body can sustain relatively high doses of
radiation when delivered to small, carefully
shielded fields, whereas smaller doses delivered to
larger fields may be lethal

Cell proliferation
o
rapidly dividing cells are more vulnerable to injury
than are quiescent cells
o
Except at extremely high doses that impair DNA
transcription, DNA damage is compatible with
survival in nondividing cells, such as brain and
myocardium
o
in dividing cells, certain types of mutations and
chromosomal abnormalities are recognized by cell
cycle checkpoints, which initiate events that lead
to growth arrest and apoptosis.
o
tissues with a high rate of cell division, such as
gonads, bone marrow, lymphoid tissue, and the
mucosa of the gastrointestinal tract, are extremely
vulnerable to radiation, and the injury is
manifested early after exposure.

Oxygen effects and hypoxia.

o
The production of reactive oxygen species from
the radiolysis of water is the most important
mechanism of DNA damage by ionizing radiation.
o
Poorly vascularized tissues with low oxygenation,
such as the center of rapidly growing tumors, are
generally less sensitive to radiation therapy than
nonhypoxic tissues.

Vascular damage
o
Damage to endothelial cells, which are moderately
sensitive to radiation, may cause narrowing or
occlusion of the blood vessel leading to impaired
healing, fibrosis, and chronic ischemic atrophy
o
Late effects in tissues with a low rate of cell
proliferation such as brain, kidney, liver, muscle,

and subcutaneous tissue, may include diverse

lesions such as cell death, atrophy, and fibrosis.
These effects are associated with vascular damage
and the release of pro-inflammatory cytokines in
irradiated areas.

MORPHOLOGY

Cells surviving radiant energy damage show a wide range of

structural changes in chromosomes, including deletions,
breaks, translocations, and fragmentation.

The mitotic spindle often becomes disorderly, and polyploidy

and aneuploidy may be encountered.

Nuclear swelling and condensation and clumping of

chromatin may appear; sometimes the nuclear membrane
breaks down.

Apoptosis may occur.

All forms of abnormal nuclear morphology may be seen.

Giant cells with pleomorphic nuclei or more than one nucleus

may appear and persist for years after exposure.

At extremely high doses of radiant energy, markers of cell

death, such as nuclear pyknosis, and lysis appear quickly

Radiant energy may induce a variety of cytoplasmic

changes, including cytoplasmic swelling, mitochondrial
distortion, and degeneration of the endoplasmic reticulum.

Plasma membrane breaks and focal defects may be seen.

The histologic constellation of

cellular pleomorphism

giant-cell formation

conformational changes in nuclei, and

abnormal mitotic figures creates a more than

passing similarity between radiation-injured cells
and cancer cells, a problem that plagues the
pathologist when
evaluating post-irradiation
tissues for the possible persistence of tumor cells

At the light microscopic level, vascular changes and

interstitial fibrosis are prominent in irradiated tissues;

During the immediate post-irradiation period, vessels may

show only dilation.

With time, or with higher doses, a variety of degenerative

changes appear, including endothelial cell swelling and
vacuolation, or even dissolution with total necrosis of the
walls of small vessels such as capillaries and venules.

Affected vessels may rupture or thrombose. Still later,

endothelial cell proliferation and collagenous hyalinization
with thickening of the media are seen in irradiated vessels,
resulting in marked narrowing or even obliteration of the
vascular lumens.

At this time, an increase in interstitial collagen in the

irradiated field usually becomes evident, leading to scarring
and contractions.
Total-Body Irradiation
o
o

Exposure of large areas of the body to even very small doses

of radiation may have devastating effects. Dosages below 1
Sv produce minimal or no symptoms.
higher levels of exposure cause health effects known as
acute radiation syndromes, which at progressively higher
doses involve the hematopoietic, gastrointestinal, and
central nervous systems.

Acute Effects on Hematopoietic and Lymphoid System

Radiation directly destroys lymphocytes, both in the
circulating blood and in tissues (nodes, spleen, thymus, gut).
With sublethal doses of radiation, regeneration from viable
precursors is prompt, leading to restoration of a normal
lymphocyte count in the blood within weeks to months.
Hematopoietic precursors in the bone marrow are also quite
sensitive to radiant energy, which produces a dosedependent marrow aplasia.
Very high doses of radiation kill marrow stem cells and
induce permanent aplasia (aplastic anemia), whereas with
lower doses the aplasia is transient.
The circulating granulocyte count may first rise but begins to
fall toward the end of the first week.
Levels near zero may be reached during the second week.
If the patient survives, recovery of the normal granulocyte
count may require 2 to 3 months.
Platelets are similarly affected, with the nadir of the count
occurring somewhat later than that of granulocytes;
recovery is similarly delayed.

10

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CHAPTER9
ENVIRONMENTAL AND NUTRITIONAL DISEASES
Red cell counts fall and anemia appears after 2 to 3 weeks
and may persist for months.
Fibrosis
A common consequence of radiation therapy for cancer is
the development of fibrosis in the tissues included in the
irradiated
Fibrosis may occur weeks or months after irradiation as a
consequence of the replacement of dead parenchymal cells
by connective tissue, leading to the formation of scars and
adhesions
Vascular damage, the killing of tissue stem cells, and the
release of cytokines and chemokines that promote an
inflammatory reaction and fibroblast activation are the main
contributors to the development of radiation-induced fibrosis
Common sites of fibrosis after radiation treatment are the
lungs, the salivary glands after radiation therapy for head
and neck cancers, and colorectal and pelvic areas after
treatment for prostate cancer
DNA Damage and Carcinogenesis

Ionizing radiation can cause multiple types of damage in

DNA, including single-base damage, single- and doublestranded breaks, and DNA-protein cross-links.

In surviving cells, simple defects may be repaired by various

enzyme systems present in most mammalian cells

the most serious damage to DNA is caused by doublestranded breaks (DSBs).

Two types of mechanisms can repair DSBs in mammalian

cells:
a.
homologous recombination and
b.
nonhomologous end joining (NHEJ), with NHEJ
being the most common repair pathway.

DNA repair through NHEJ often produces

mutations, including short deletions or
duplications,
or
gross
chromosomal
aberrations such as translocations and
inversions.

If the replication of cells containing DSBs is

not stopped by cell cycle checkpoint
controls, cells with chromosomal damage
persist and may initiate carcinogenesis
many years later.

More recently it has been recognized that

these abnormal cells may also have a
bystander effect, that is, they may
promote
growth
of
non-irradiated
surrounding cells through the production of
growth factors and cytokines
Human Diseases Associated with Occupational Exposures
Organ/Syste
m

Effect

Toxicant

Cardiovascular Heart disease

system

Carbon monoxide, lead,

solvents, cobalt, cadmium

Respiratory
system

Nasal cancer

Isopropyl alcohol, wood dust

Lung cancer

Radon, asbestos, silica,

bis(chloromethyl)ether, nickel,
arsenic, chromium, mustard gas,
uranium

Chronic
obstructive lung
disease

Grain dust, coal dust, cadmium

Hypersensitivity

Beryllium, isocyanates

Irritation

Ammonia, sulfur oxides,

formaldehyde

Fibrosis

Silica, asbestos, cobalt

Peripheral
neuropathies

Solvents, acrylamide, methyl

chloride, mercury, lead, arsenic,
DDT

Nervous
system

Ataxic gait
Central nervous
system depression

Chlordane, toluene, acrylamide,

mercury

Organ/Syste
m

Effect

Toxicant

Cataracts

Alcohols, ketones, aldehydes,

solvents
Ultraviolet radiation

Urinary system Toxicity

Reproductive
system

Mercury, lead, glycol ethers,

solvents

Bladder cancer

Naphthylamines, 4aminobiphenyl, benzidine,

rubber products

Male infertility

Lead, phthalate plasticizers,

cadmium

Female
Lead, mercury
infertility/stillbirths
Teratogenesis

Mercury, polychlorinated
biphenyls

Hematopoietic
system

Leukemia

Benzene

Skin

Folliculitis and
acneiform
dermatosis

Polychlorinated biphenyls,
dioxins, herbicides

Cancer

Ultraviolet radiation

Gastrointestina Liver
l tract
angiosarcoma

Vinyl chloride

May He give you the desire of your heart and make all your plans
succeed
We will shout for joy when you are victorious and will lift up our
banners in the name of our God
Psalm 20:4-5