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Ecotoxicology and Environmental Safety 70 (2008) 349– 356

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Ecotoxicology and Environmental Safety

journal homepage: www.elsevier.com/locate/ecoenv

Frontier article

Toxicity of lithium to humans and the environment—A literature review

Hal Aral , Angelica Vecchio-Sadus
CSIRO Minerals, Box 312, Clayton South, Vic. 3169, Australia

a r t i c l e in fo abstract

Article history: Lithium concentrations in the surface and underground waters may be higher than general
Received 3 October 2007 environment in places where lithium-rich brines and minerals occur, and in places where lithium
Received in revised form batteries are disposed of. This review has indicated that lithium is not expected to bioaccumulate and its
13 February 2008 human and environmental toxicity are low. Lithium is not a dietary mineral for plants but it does
Accepted 24 February 2008
stimulate plant growth. Large doses of lithium (up to 10 mg/L in serum) are given to patients with
Available online 5 May 2008
bipolar disorder. At 10 mg/L of blood, a person is mildly lithium poisoned. At 15 mg/L they experience
Keywords: confusion and speech impairment, and at 20 mg/L Li there is a risk of death. A provisional recommended
Lithium
daily intake of 14.3 mg/kg body weight lithium for an adult has been suggested.
Toxicity
Crown Copyright & 2008 Published by Elsevier Inc. All rights reserved.
Toxicology
Environment
Occupational health and safety

1. Introduction in the dilute (0.01 M) sulphuric acid treatment of the concentrate.

Lithium is present in the earth’s crust to the extent of about
0.006 wt% (Habashi, 1997). It is the 27th most abundant element
in nature. The major lithium minerals with commercial value are
classified into three major groups:
(a) silicates (spodumene—LiAlSi2O6, petalite—LiAlSi4O10)
(b) micas (lepidolite—K[Li,Al]3[Al, Si]4O10[F,OH]2, zinnwaldite—
K[Li,Al,Fe]3[Al,Si]4O10[F,OH]2 and
(c) phosphates (mainly amblygonite—[Li, Na]Al[F, OH]PO4).
Lithium minerals are mined around the world in various places
such as Manona—Zaire, Bikita—Zimbabwe, Greenbushes—
Western Australia, La Corne and Bernic Lake—Canada, Kola
Peninsula—Russia and Altai Mountains—China to make various
lithium mineral products (Moore, 2007). The processing of lithium-
containing minerals in general comprises crushing, wet grinding in a
ball mill, sizing, gravity concentration and flotation using fatty acid
(oleic acid) as the collector. Tailings are discharged to storage areas,
and the decanted water is usually recovered for reuse.
The major lithium mineral in the ore is spodumene, which is
considered insoluble in water and dilute acids. However, a recent
unpublished work (Aral, 2007) has indicated that small amount of
dissolution may be occurring during processing of the ore
especially in the grinding stage with some additional dissolution
 Corresponding author. Fax: +61 03 9562 8919.
E-mail address: hal.aral@minerals.csiro.au (H. Aral).
The dissolved lithium found in the tailing dams of such lithium
mineral beneficiation plants could be as high as 13 mg/L.
Lithium is also found in natural brines (Salar de Atacama—Chile,
Salar de Hombre Muerto and Salar de Rincon—Argentina, and
Searle’s Lake and Clayton Valley in the USA) and lakes (Great Salt
Lake, USA; Zabuye Lake, Tibet; Dachaidan, Qinghai—China and
Dead Sea, Israel) (Habashi, 1997). The lithium content of these
brines varies from 20 mg/L in the Dead Sea to 1500 mg/L in Salar de
Atacama (Habashi, 1997; Moore, 2007). Geochemically, lithium is a
highly mobile element, therefore, the environmental and occupa-
tional health and safety risks related to lithium in brines are higher.
A source of lithium posing impact to the environment is spent
lithium batteries. Consumers routinely dispose of batteries along
with other garbage in the municipal solid waste (NEMA, 2001).
There is growing community concern about the health and
safety of workers and the impact on the environment coupled
with increasing company reporting and accountability. In the area
of lithium toxicity to humans and the environment, the informa-
tion is scattered across various scientific disciplines. The objective
of this study is to prepare a compilation and critically review the
leading international health, safety and environmental journals,
toxicological databases and websites to ascertain the impacts of
lithium on flora, fauna and humans. This literature search covered
the relevant sites of the ISI Web of Science (that indexed more than
5700 major journals across 164 scientific disciplines) and key
databases including Agency for Toxic Substances and Disease
Registry (ASTDR), Australian Safety and Compensation Council
(ASCC), Centers for Disease Control and Prevention (CDC), ECOTOX,
MEDLINE and TOXLINE.

0147-6513/$ - see front matter Crown Copyright & 2008 Published by Elsevier Inc. All rights reserved.
doi:10.1016/j.ecoenv.2008.02.026

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2. Environmental and toxicological impacts of lithium
2.1. Toxicology
The Australia Inventory of Chemical Substances (AICS, 2007)
has classified metallic lithium as a health, physiochemical and/or
ecotoxicological hazard according to the National Occupational
Health and Safety Commission (NOHSC) approved criteria for
classifying hazardous substances. Lithium, lithium aluminium
hydride, and lithium methanolate are found on the Danish list of
dangerous substances (Kjølholt et al., 2003). Lithium salts are not
very toxic except for the highly corrosive and irritant lithium
hydrides, lithium tetrahydroaluminate (LiAlH4) and lithium tetra-
hydroborate (LiBH4). Spodumene, the major lithium ore mined in
various places around the world, is an aluminium silicate. It
contains up to 8.0 wt% Li2O, and this lithium is tightly bound to
the crystal structure and, therefore, it alone does not pose a
toxicological problem. However, when spodumene is crushed, it
generates silica-rich dust which is a health and safety hazard.
Finely ground lithium minerals, especially lithium-containing
phosphate ores, are more susceptible to water and dilute acid
leaching than unground ores due to increased surface area (Aral,
2007).
Upon oral intake, metallic lithium is mildly toxic, however,
physical tolerance differs between individuals. The primary target
organ for lithium toxicity is the central nervous system (Kjølholt
et al., 2003), therefore, lithium is used therapeutically on
membrane transport proteins when treating manic depression.
Chemically, lithium resembles sodium but is more toxic. A lethal
dose of LiCl in rats has been measured at 526–840 mg/kg body
weight. In humans, 5 g of LiCl can result in fatal poisoning. Lithium
carbonate is applied in psychiatry in doses close to the maximum
intake level. At 10 mg/L of blood, a person is mildly lithium
poisoned, at 15 mg/L they experience confusion and speech
impairment, and at 20 mg/L Li there is a risk of death. In
therapeutic doses, damages on the central nervous system and
the kidneys have been reported.
Lithium does not have a known biological use and does not
appear to be an essential element for life (Léonard et al., 1995;
Lenntech, 2007). The amount of lithium in the human body is
approximately 7 mg. Lithium is absorbed from the gastrointestinal
tract (Casarett and Doull, 1987; Ellenhorn and Barceloux, 1988;
Linakis, 2007; Schrauzer, 2002) and excreted primarily through
the kidneys after approximately 24 h (Freeman and Freeman,
2006). Serum concentrations of lithium reach a peak about 30 min
after oral ingestion, followed by a plateau at 12–24 h. Lithium ions
cross the cell membrane slowly; this may account not only for the
prolonged excretion of lithium but also for the 6–10 days delay
needed to achieve the full therapeutic response in humans.
Although lithium is not an essential element, it may influence
metabolism.
According to Schrauzer (2002), the average daily lithium intake
of a 70 kg adult (American) is between 0.65 and 3.1 mg/day. Major
dietary sources of lithium are grains and vegetables (0.5–3.4 mg
Li/kg food), dairy products (0.50 mg Li/kg food) and meat
(0.012 mg Li/kg food) (Weiner, 1991). In places like Chile where
lithium-rich salinas could contain up to 1500 mg/L Li, the total
lithium intake may reach 10 mg/day without evidence of adverse
effects to the local population. A review of the dietary intake of
lithium has indicated that the minimum human adult (physiolo-
gical) lithium requirement is estimated to be less than 0.1 mg/day.
Based on lithium intake data in different countries, a provisional
recommended daily intake of 1.0 mg lithium/day for a 70 kg adult
American was proposed, corresponding to 14.3 mg/kg body weight,
which can be derived by diet alone. People on special diets or
populations residing in naturally low lithium areas would require
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lithium supplements or other appropriate measures to meet this
intake. Lithium levels may be higher after physical exertion, in
certain diseases and in dialysis patients. The special needs of
children, adolescents and lactating mothers would need to be
considered.
Lithium has many industrial applications (reviewed in Birch,
1988). Although professional intoxications from the industrial
applications are possible, none have been reported. The most
common source of exposure to lithium and also of toxic
consequences is its intensive use in medicine following the
discovery of the psychotropic properties of lithium (Cade, 1949;
Schou, 1968). Lithium salts, especially the carbonate (Li2CO3) and
acetate (LiCH3COO) are extensively used in the treatment of
manic-depressive disorders. Lithium was first introduced into the
medical profession in the mid-1800s as a cure-all for many
common illnesses. Since its introduction, medical professionals
have been cognisant and wary of lithium toxicity. In fact, in 1949,
lithium was banned from use in the US because of excessive
toxicity and did not gain FDA approval for use in the treatment of
mania until 1970 (Strobusch and Jefferson, 1980). Other ther-
apeutic uses prior to the work of Cade (1949) had been described
for lithium salts, and an effect of lithium on embryonic
development has been recognised for at least 100 years. Lithium
also affects metabolism, neuronal communication, and cell
proliferation in a diverse array of organisms, from cellular slime
moulds to humans.
Non-supervised or indiscriminate therapeutic use of lithium
carbonate can produce certain toxic symptoms in the neuromus-
cular, cardiovascular and gastrointestinal system as well as more
serious renal damage (Price and Heninger, 1964) and can even
cause death (Litovitz et al., 1994). The serum (blood) level under
therapeutic lithium treatment should not exceed 11.1 mg/L Li and
must be carefully monitored. Nevertheless, patients on long-term
lithium treatment may suffer from severe neurotoxic effects while
serum lithium concentrations are normal (Stern, 1995).
Lithium has numerous effects in humans and in other
organisms (Moore et al., 1995). Phiel and Klein (2001) reviewed
the cause and effect of lithium and showed that therapeutic levels
of lithium are clearly able to inhibit functioning of multiple
enzymes in the body. Lithium, as a medicine, has multiple effects
on embryonic development, glycogen synthesis, hematopoiesis
(the formation and development of blood cells involving both
proliferation and differentiation from stem cells), and other
processes.
Lithium is the drug of choice for the treatment of recurrent
bipolar disorder for more than 50 years and has gained popularity
as a pharmacologic option in the treatment of other psychiatric
conditions (Léonard et al., 1995). The clinical importance of
lithium is two-fold (Phiel and Klein, 2001). Firstly, the therapeutic
window between effective dosing and toxicity is narrow, side
effects are common even within the therapeutic dose range, and a
significant number of patients do not respond. While antic-
onvulsants such as valproic acid offer an alternative mode of
therapy, an understanding of the targets of lithium (and of
valproic acid) will make it possible to identify additional therapies
for this common disorder. Secondly, little is known about the
pathogenesis of bipolar disorder or other mood disorders, and
therefore, identification of the molecular target of lithium can
shed light on the causes and origins of this disorder.
The combination of the increased use of lithium and its
extremely narrow therapeutic window enhances the potential for
increased toxicity. The therapeutic serum concentrations (Jaeger,
2003) are normally about 5.6–8.4 mg/L, mild toxicity is usually
seen at about 10.5–17.5 mg/L, moderate toxicity is seen at about
17.5–24.5 mg/L and severe symptoms are seen at 424.5 mg/L. In
one example, the vast majority (75–90%) of patients receiving
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maintenance lithium therapy for bipolar disorder become toxic at
some point during their course of therapy (Amdisen, 1988). In
1996, 5102 lithium exposures were reported to the American
Association of Poison Control Centers with nearly 75% of those
suffering exposure seeking medical attention (Litovitz et al., 1997).
The mechanisms by which lithium could bring about changes
in mood are still poorly understood. Among others, it has been
suggested (Manji and Lenox, 1994) that it may affect transcrip-
tional and post-transcriptional factors via protein kinase. It has
been reported (Schrauzer and Shrestha, 1990) that countries
where the drinking water contains little or no lithium have a
higher rate of crimes, suicides and police arrests for drug
addiction than countries where lithium levels in drinking water
are 0.07–0.170 mg/L. Several suicide attempts using lithium
carbonate have also been reported (Czeizel, 1994).
Gastrointestinal disturbances, oedema and tremor are com-
mon side effects of lithium treatment (Tandon et al., 1998). The
preliminary study of Kato et al. (1996) showed that the hand
tremor may be a potential indicator of overdose for the
therapeutic bipolar disorder treatment.
Lithium salts induce renal toxicological symptoms (sclerotic
glomeruli and tubular damage) (Chmielnicka and Nasiadek,
2003). The inability of the nephron to concentrate urine during
lithium treatment is correlated to the occurrence of histological
change. Lithium also produces many metabolic changes. In terms
of mineral metabolism, lithium competes with sodium, potas-
sium, magnesium, and calcium, in that order, and displaces them
from intracellular and bone sites in this progression. Interaction of
toxic metals and essential elements in the kidneys has been
demonstrated in biological and toxic aspects.
Sadosty et al. (1999) reported that following ingestion, serum
concentrations of lithium peaked at 1–12 h. Lithium is not protein
bound, and after ingestion it slowly equilibrates between the
extracellular and intracellular spaces. The delay in equilibration
between serum lithium concentrations and intracellular lithium
concentrations approximated 6–10 days. In the study by Chmiel-
nicka and Nasiadek (2003), the authors determined the dose-
dependent lithium concentrations in serum and urine and also an
estimation of some biochemical indicators of nephrotoxicity
detectable at an earlier stage. Rats were orally given lithium
carbonate, 10 mg Li/kg (group I) and 20 mg Li/kg (group II), five
times a week during 5 weeks. Control rats were treated with 0.9%
NaCl (group III) during the same period. During the experiment
the lithium concentration in serum and urine of rats was
dependent on the daily administration doses in comparison with
the control group. After the first week of intragastric exposure to
lithium carbonate in daily doses of 10 mg Li/kg body weight rats, a
notable increase of copper concentration in urine was observed.
At the same time higher activity of N-acetyl-b-glucoaminidase
(NAG) in the urine of rats was also observed in comparison with
the control group. Increased urinary concentration of proteins was
noted also after the first week but after daily administered 20 mg
Li/kg.
The results of Chmielnicka and Nasiadek’s investigations
showed that oral administration of lithium carbonate-induced
renal toxicity in the rat as well as the injurious symptoms which
were found to be directly related to the dose effect and to the
concentration of this metal in serum and urine. Excretion of
lithium is predominantly by the kidney and approximately 80% of
lithium is reabsorbed by the proximal renal tubule and 20% is
excreted in the urine. Concentrations of lithium in the brain are
similar to those found in the plasma. The authors observed
disturbances in the kidney function in rats after lithium intoxica-
tion and also as a diuresis and proteinuric effect. The renal
elimination of lithium influences several factors, including sodium
and water balance. It is known that lithium competes with
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351
sodium and potassium at the renal tubular level, therefore,
sodium and water balance causes not only the serum level of
lithium but also its toxicity. The most important in lithium
toxicity is dehydration which will produce sodium and water
imbalance.
In a study by Tandon et al. (1998) lithium carbonate was
administered at a dose level of 1.1 g/kg food to rats fed normal
protein (18%), low-protein (8%) and high-protein (30%) diets for a
period of 1 month. A highly significant (53%) increase in the level
of lipid peroxidation was observed in protein-deficient rats but
this increase was marginal in rats fed a high-protein diet. Terao
et al. (2006) showed that a potentially beneficial effect of lithium
is that it may block the accumulation of amyloid-b (Ab) peptides
that cause dementia in mice.
2.1.1. Genetic toxicology
Léonard et al. (1995) reviewed the information available in the
literature on the genetic toxicology of lithium. Lithium causes
disturbances in the development of invertebrates. Development is
also inhibited in whole rat embryos cultured from day 9.5 (Klug
et al., 1992). In intact animals, results vary: several types of
abnormalities (e.g. reduced number and weight of the litter, more
resorptions, ‘wavy’ ribs, incomplete ossification) were observed
(see for example the review by Domingo, 1994). These discre-
pancies may be due to a different sensitivity of the species and
strains used the stress of daily injection and/or differences in
lithium concentrations present in serum during critical periods of
development. Pregnant mice given lithium carbonate over several
days yielding serum levels comparable to those in humans treated
for manic-depressive disorders did not show any effect, but six
times higher doses caused malformations in the offspring
(Smithberg and Dixit, 1982).
2.1.2. Teratogenicity
Teratogenicity is the ability to cause defects in a developing
foetus. It is a potential side effect of many drugs such as
thalidomide. In a study of the effect of lithium carbonate on
pregnant mice (Smithberg and Dixit, 1982), chronic exposure to
lithium doses that produced serum levels of the same order as
seen in patients was toxic but did not affect the entire litter nor
was it teratogenic to individual mice embryos. Many authors have
reported that lithium causes congenital defects, especially of the
cardiovascular system such as Ebstein’s anomaly (a rare cardiac
defect) when given to women during the first trimester of
pregnancy (reviewed in Briggs et al., 1983; Birch, 1988; Ferner
and Smith, 1991, 1992). This claim gave rise to the foundation of a
‘Register of Lithium Babies’ in Risskov (Denmark) and, later, of an
‘American Registry of Lithium Babies’ in San Francisco. A first
analysis of the records of 60 children borne by mothers who
received lithium treatment during the first trimester or the entire
pregnancy published in 1971 (Schou and Amdisen, 1971) did not
reveal any association of lithium treatment with a higher
teratogenic risk. A multi-center study of pregnancy outcome after
therapeutic lithium exposure during the first trimester also did
not show any significant teratogenic risk (Jacobson et al., 1992).
Others (Kallen and Tandberg, 1983; Kallen, 1988; Zalstein et al.,
1990) also conclude that lithium given in therapeutic doses is not
teratogenic.
Giles and Bannigan (1997) evaluated the maternal toxicity and
teratogenicity of lithium following intraperitoneal injection with
300 mg/kg body weight lithium carbonate (Li2CO3) in pregnant
CD-1 mice at the developmental stage of neurulation. Controls
were untreated or given equimolar amounts of NaCl or Na2CO3.
Their pharmacokinetic study showed that lithium was rapidly
absorbed from the peritoneal cavity after the above-stated dose,
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achieved peak serum levels of 68 mg/L within 1 h, had a half-life
in the blood of 5 h and was completely cleared by 16–24 h after
injection. Doses of Li2CO34300 mg/kg body weight were toxic to
adult CD-1 mice. At 3 h after treatment, cell death became evident
in the neuroepithelium. These experiments suggest that the
developing vascular system may be a target for lithium. In
addition, the possibility is discussed that lithium-induced cell
death in the neuroepithelium may lead to neural tube defects.
2.1.3. Mutagenicity
Mutagenicity is the ability to cause genetic mutations in
sperms, eggs other cells. Despite the extensive therapeutic use of
lithium carbonate, few investigations on the mutagenic potential
of lithium compounds have been carried out. Lithium could have
several ways of acting on DNA: Li binds selectively to DNA
(Kuznetsov et al., 1971); it competes with Mg2+ and may impair
DNA synthesis (Becker and Tyobeka, 1990) and DNA repair.
However, results on bacteria and isolated systems were incon-
clusive. No effect was seen with lithium chloride (LiCl) in strains
of Bacillus aluminium (Nishioka, 1975; Kanematsu et al., 1980) and
by King et al. (1979) with trilithium citrate (C6H5Li3O7) in the
Ames test on Salmonella typhimurium (34 mmol per test plate), in
the Escherichia coli test (10 mmol per test plate), in the host-
mediated assay with E. coli and in mice (28 mg/kg intraper-
itoneal), and in the sex-linked recessive lethality test in Drosophila
melanogaster (3 days feeding with 140 mg/L). High concentra-
tions of LiCO3 (3 mg/mL) slightly inhibited DNA synthesis in V79
Chinese hamster cells and human EUE fibroblasts, and this effect
was lessened by the addition of S9 fraction (a post-mitochondrial
supernatant fraction added to cell cultures during treatment with
certain chemicals in order to simulate mammalian metabolism)
(Slamenova et al., 1986). The same authors also observed more
single-strand breaks in DNA and a small increase in gene
mutations in V79 Chinese hamster ceils in the absence of S9. No
significant clastogenic and only a doubtful mutagenic action of
lithium were demonstrated. However, the percentage of poly-
chromatic erythrocytes with micronuclei increased in NMRI mice
treated with an intraperitoneal injection of 2  1.1 g/kg of lithium
citrate (King et al., 1979). This indicated that lithium could
interfere with chromosome distribution.
Addition of 0.05% (500 ppm) lithium carbonate to the
drinking water of 6-month old rats for 3, 6 or 12 months slightly
reduced (Sram et al., 1990) unscheduled DNA synthesis induced in
blood lymphocytes by the alkylating agent N-methyl-N0 -nitro-N-
nitrosoguanidine (MNNG) (0.7 mg/L).
Lithium carbonate added at the start of a 72 h culture period at
concentrations equivalent to 0.1, 1.0 or 10 g of lithium carbonate
distributed in the body of a 70 kg person did not increase
structural chromosome aberrations in peripheral lymphocytes
(Timson and Price, 1971). Confirming their results on experi-
mental animals given toxic doses of lithium, Bille et al. (1975)
failed to observe cytogenetic changes in peripheral blood
lymphocytes of patients treated with lithium salts.
No aberrations were found in 19 lithium-treated manic-
depressive patients compared with 23 controls but the mitotic
index was significantly reduced (Genest and Villeneuve, 1971).
Similarly, negative results were reported by Garson et al. (1981)
and Banduhn et al. (1980) in peripheral lymphocytes of as many as
Table 1
Typical background concentrations of lithium in the environment
Fresh water (mg/L) Seawater (mg/L)
Typical background concentration 0.07– 40 170– 190
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77 patients studied, 50 of whom had been treated with lithium
sulphate, 17 with lithium carbonate and 10 with lithium acetate.
Also, 16 manic-depressive patients who had been given lithium
carbonate from 2 weeks to more than 2 years (seven of them for
more than a year) did not show aberrations in their lymphocytes
(Jarvik et al., 1971).
Addition of 8.4, 12.6 and 16.8 mg/L of lithium to the culture of
blood lymphocytes did not augment structural aberrations
(Friedrich and Nielsen, 1969), but, surprisingly, these authors
found a significant increase in breaks in lymphocytes derived
from three patients treated with lithium. The latter results remain
doubtful, particularly since the number of patients was too small
and no details on methods or number of cells analysed are given
in the paper. The increase in satellite association reported by de la
Torre and Krompotic (1975) also cannot be considered proof of a
mutagenic action of lithium in vitro, inasmuch as the authors did
not observe any significant increase in chromosome aberrations in
patients compared with control subjects.
2.1.4. Carcinogenicity
Léonard et al. (1995) indicated that no information on possible
carcinogenic effects of lithium compounds was available. How-
ever, this seems unlikely in view of the known biological
mechanisms of action of lithium.
2.2. Environmental toxicology
Lithium is generally found naturally in the aquatic and
terrestrial environment but in small concentrations (see Table 1)
(Bowen, 1979; Wedepohl, 1995; Sposito, 1986; Birch, 1988; Ribas,
1991).
2.2.1. Aquatic environments
Lithium is found primarily in ionic form in water. Lithium
metal reacts with water to form lithium hydroxide and hydrogen.
The lithium concentration in fresh water and sea water is on the
mg/L-level (Kjølholt et al., 2003). According to the literature
(Schrauzer, 2002; Lenntech, 2007) surface water contains lithium
at levels between 1 and 10 mg/L, seawater contains approximately
0.17 mg/L lithium (Mason, 1974) and the lithium concentrations in
ground water may reach 0.5 mg/L. Rivers generally contain around
3 mg/L Li whereas in the lithium-rich regions of northern Chile, the
lithium content of the surface waters could be as high as 5.2 mg/L.
Worldwide mineral water contains 0.05–1 mg/L lithium, however,
higher levels up to 100 mg/L can be found in some natural mineral
waters (Schrauzer, 2002).
A review of lithium in the aquatic environment in the US
(Kszos and Stewart, 2003) found that lithium was detected at low
concentrations (0.002 mg/L) in the major rivers of the US.
Further studies (Kszos et al., 2003) identified lithium concentra-
tions in surface waters were typically o0.04 mg/L but could be
elevated in contaminated streams.
Huh et al. (1998) studied lithium and its isotopes in the lower
reaches of 13 major rivers of the world and a number of major
lakes (Table 2). The lithium concentration (expressed as nano-
moles (nM)) varied from 96.5 for the Amazon River, 125 for the
Congo, 579 for the Ganges, to 813 for the Mississippi River. The
lithium isotopic composition appeared to be more a function of
Sediment (mg/kg) Soil (mg/kg) Earth’s crust (mg/kg) Atmosphere (ng/m3)
56 3– 350 20– 60 2
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the fractionation processes during partial weathering of alumi-
nosilicate rocks to form neoformed clays, and in the case of
evaporites (rock composed of minerals derived from the evapora-
tion of mineralised water), the concentration in the solution from
which the secondary lithium minerals precipitated, rather than
bedrock type or age. Comparison with the major element and
strontium isotope dataset suggested that the important processes
affecting river-dissolved lithium isotopic compositions are iso-
topic fractionation between solution and secondary minerals and
the degree of weathering. In addition is the effect of the bedrock
type makes the lithium isotopic system complicated.
Hamilton (1995) investigated the acute toxicity of boron,
lithium, selenate, selenite, uranium, vanadium and zinc to early
stages of development of Colorado squawfish (Ptychocheilus
lucius), razorback sucker (Xyrauchen texanus), and bonytail (Gila
elegans) in a water quality simulating the middle Green River. His
study showed that the overall rank order of toxicity to all species
and life stages combined from most to least toxic was vanadium
¼ zinc4selenite4lithium ¼ uranium4selenate4boron.
Kszos et al. (2003) evaluated the toxicity of lithium to
Pimephales promelas (fathead minnow), Ceriodaphnia dubia, and
a freshwater snail (Elimia clavaeformis). They found that for most
natural waters, the presence of sodium is sufficient to prevent
lithium toxicity. However, in areas of historical disposal or heavy
processing or use, an evaluation of lithium from a water quality
perspective would be warranted.
Studies (Lenntech, 2007; US EPA, 2008) have identified toxicity
levels in certain organisms (see Table 3). Effective concentration
(EC50) is the concentration of a material in water, a single dose
which is expected to cause a biological effect on 50% of a group of
test animals. Lethal concentration (LC50) is the amount of a
substance in air that, when given by inhalation over a specified
period of time, is expected to cause the death in 50% of a defined
animal population. The acute environmental effect concentration
(measured as EC50) on Daphnia magna was determined to be
33–197 mg/L, which is at least 1000 times higher than the level in
fresh water. Both lithium chloride and lithium sulphate have high
water solubility, and the compounds will dissociate in aqueous
environment. No lithium compounds are classified for adverse
environmental effects. No data regarding bioaccumulation of
lithium was found but based on its low affinity to particles, it is
not expected to bioaccumulate.
Table 2
Lithium concentrations of the world’s major lakes
Name
Lake Tanganyika
Caspian Sea
Lake Baikal
Dead Sea
Source: Huh et al. (1998). Reproduced with permission.
Table 3
Test results for environmental (aquatic) toxicity
Species Latin name (common name)
Mollusc Dreissena polymorpha (Zebra mussel)
Crustacean Daphnia magna (water flea)
Worm Tubifex tubifex (Tubicid worm)
Fish Pimephales promelas (fathead minnow)
Fish Tanichthys albonubes (white cloud mountain minnow)
Source: Lenntech (2007) and US EPA (2008). Reproduced with permission.
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353
2.2.2. Terrestrial environments
On land, lithium can be found as lithium carbonate (Li2CO3),
lithium chloride (LiCl) or lithium oxide (Li2O). Lithium is found in
trace amounts in all soils primarily in the clay fraction, and to a
lesser extent in the organic soil fraction, in amounts ranging from
7 to 200 mg/g (Schrauzer, 2002). The source of lithium is usually
from sedimentary rocks (Chan et al., 1997). For example,
carbonates precipitated from evaporated lake water can have
high lithium concentrations, as demonstrated by a Dead Sea
aragonite with 19 ppm lithium. Some lithium in carbonate-rich
rivers, especially those that are not highly evaporitic, come from
associated shales, e.g., calcareous shales from the Ellis Group of
Yellowstone National Park contained 18 ppm lithium.
Authigenic clays (i.e., those occurring in the place where they
were originally formed) are enriched in lithium (200–500 ppm in
smectites) relative to other rock types (igneous rocks 30 ppm,
detrital clays 70–80 ppm) (Chan et al., 1997). Li+ has the weakest
sorption chemistry of all the alkalis, and its affinity with clays is
considered to be due to the isomorphic substitution of Mg2+ for
Al3+ in the octahedral layer leaving a vacant position to
accommodate Li+. Examination of lithium exchange in complex
soil solutions and pure clay mineral systems has shown that
lithium is selectively absorbed over other cations and apparently
fixed in a non-exchangeable form (Anderson, 1989). Adsorption
onto suspended sediments in rivers may also play a role but
preliminary experiments (Chan et al., 1997) suggested that only
about 1 ppm lithium is adsorbed onto clays and river sediments
(i.e., 10%). Lithium concentrations are in general proportional to
magnesium (due to ionic radius similarities) but only poorly
correlated with other major ions and even silicon and potassium
though these are almost exclusively from the weathering of
aluminosilicates. This is consistent with the tendency of lithium
to be retained in secondary clays, substituting for Mg2+ or
occupying the vacancy generated by Mg2+ substitution of Al3+.
Lithium is taken up by all plants and although it appears not to
be required for their growth and development, stimulation of
plant growth has been observed (Schrauzer, 2002; Lenntech,
2007). The amount of lithium in plants usually lies between 0.2
and 30 ppm due to preferential uptake or rejection across species.
Plants such as Cirsium arvense and Solanum dulcamera accumulate
lithium in concentrations of three- to six-fold over other plants.
Nightshade species may reach concentrations of up to 1 mg/g.
Salt-tolerant plants such as Carduus arvense and Holoschoenus
vulgaris may reach lithium contents of 99.6–226.4 mg/g. Lithium
concentrations in plant foodstuffs vary widely from 0.01 ppm (dry
basis) in bananas to 55 ppm in oats (Shacklette et al., 1978).
Li (mg/L) Lithium is relatively toxic to citrus plants.
There appears to be a greater uptake of lithium by plants in
0.014 acidic soils. Soil acidity increases the solubility of the heavier
0.280 metallic elements such as iron, nickel, cobalt, manganese and
2.0
copper, and to some extent also aluminium, lead and cadmium.
14.0
Plant lithium levels are directly and significantly correlated with
the concentrations of these elements. Calcium can be added to
Compound Exposure duration EC50 (mg/L) LC50 (mg/L)
LiCl 24 h 185–232
Li2SO4 24 h 33–197
Li2SO4 24–96 h 9.3–44.8
LiCl 26 days 1–6.4 1.2–8.7
LiCl 48 h 9.2–62
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354 H. Aral, A. Vecchio-Sadus / Ecotoxicology and Environmental Safety 70 (2008) 349–356

soils to prevent toxicity and the uptake of lighter minerals Table 4

(Schrauzer, 2002; Lenntech, 2007). Levels of lithium in selected emissions and waste products in Denmark (Kjølholt
et al., 2003)
Lithium in plants and animals interacts with sodium and
potassium as well as with enzymes requiring magnesium. Its Emission/waste type Li concentration
complexing properties are stronger than those of Na+ and K+ but
weaker than those of Mg2+. At concentrations attained during Compost
therapy, Li+ and Mg2+ are present in comparable concentrations; Compost from household waste 4.64 mg/kg
Compost from garden waste 4.69 mg/kg
thus, Li+ binds to sites not occupied by Mg2+. Once all Mg2+ sites
are saturated, Li+ substitutes for Na+ and K+. All alkali metal ions Landfill leachate
are exchanged more than 1000 times more rapidly than Mg2+; this Landfill 1 0.2 mg/L
Landfill 2 0.049 mg/L
may explain why lithium preferentially affects the activity of Mg2+
containing enzymes (Birch, 1976, 1988). Chlorophyll mutants were Stack gas from municipal solid waste incineration
produced in the progeny of Pisum abyssinicum plants (von Rosen, Incinerator 1, semi-dry gas cleaning o9.1 mg/m3
Incinerator 2, wet gas cleaning 1.0 mg/m3
1957) treated with lithium nitrate in addition to other nitrates
(Cu, Zn, Cr, Mn, Fe, Co, Ni, Al). This was most likely due to the Municipal solid waste gas cleaning residuals
presence of the other confirmed mutagenic metal nitrates. Landfill leachate, semi-dry gas cleaning 0.285 mg/L
Landfill leachate, wet gas cleaning 0.367 mg/L
In an early study (Morris, 1958), yeast (Saccharomyces
cerevisiae) was shown to take up limited amounts of lithium, Waste water and sludge from municipal waste water treatment plant
and growth inhibition occurred at high levels (115–400 ppm). Plant 1, effluent 11.4 mg/L
Plant 2, effluent 21.2 mg/L
Tsuruta (2005) examined the accumulation of lithium by micro-
Plant 1, sludge 6.06 mg/kg
organisms. Among the 70 strains of 63 species tested (20 bacteria, Plant 2, sludge 5.02 mg/kg
18 actinomycetes, 18 fungi and 14 yeasts), a high lithium
Road runoff retention basins, sediment
accumulations ability was exhibited by strains of the bacteria
Motorway 1 16.3 mg/kg
Arthrobacter nicotianae (1.0 mg/g dry weight cells) and Brevi- Motorway 2 15.5 mg/kg
bacterium helvovolum (0.7 mg/g dry weight cells). Further work
was pending to devise a practical approach for removing and Reproduced with permission.
recovering lithium from aquatic systems using various micro-
organisms. discarded lithium sulphur dioxide-type batteries and considered
Lithium in the environment is mostly sourced from lithium- these batteries to be hazardous waste.
based grease (lithium hydroxide monohydrate) in vehicles and
leaching from alkali granitic rocks. A 7-week exposure of earth-
2.3. Exposure limits and regulations
worms (Eisenia fetida) identified a mortality rate at lithium
chloride concentrations of approximately 70 mg/kg soil (US
EPA, 2008). A limited investigation of the levels of lithium and According to the material safety data sheet (Chemwatch,
other elements in major emissions and waste streams was 2004), lithium does not have an occupational exposure limit,
conducted in Denmark in 2001 (Kjølholt et al., 2003). In the however, data are normally available for lithium compounds. For
Danish study, lithium was found in all environmental samples example, the American Conference of Governmental Industrial
especially compost, waste water, sewage sludge and sedi- Hygienists (ACGIH, 1992) has recommended an exposure limit
ment from road runoff retention basins (Table 4). The concentra- data of 25 mg/m3 of lithium hydride for respirable dust or fumes
tion in effluent from waste water treatment plants was low for TLV-TWA (time-weighted average concentrations for a normal
and was not considered as being acutely toxic to aquatic 8 h working day and a 40 h working week to which all workers
organisms. may be repeatedly exposed without adverse effects). The same
A source of lithium posing impact to the environment is spent exposure limit has been quoted by others (CDC, 2007; Deutsche
lithium batteries. Consumers routinely dispose of batteries along Forschungsgemeinschaft, 1992).
with other garbage in the municipal solid waste (NEMA, 2001). According to the Australian Capital Territory Environment
Spent consumer lithium batteries disposed in this manner are Protection Regulation (EPA, 2005), lithium is listed as a pollutant
generally considered not to pose environmental or safety hazards. that causes environmental harm in irrigation water supplies. The
This is based on the assumption that lithium metal (that reacts concentration of lithium entering waterways should be less than
violently with water to produce explosive hydrogen gas) is no or equal to 2.5 mg/L.
longer reactive as the metallic lithium and is converted into a non-
reactive lithium oxide once the battery is discharged. Lithium
batteries can often be associated with heavy metals such as cobalt 3. Conclusions
and manganese, and could contain an organic solvent (propylene
carbonate and 1,2 dimethoxyethane) solution of lithium perchlo- The primary findings of this review were:
rate, acetonitrile solution with lithium bromide (US EPA, 1984).
Lithium thionyl chloride batteries have a non-aqueous thionyl  Lithium is found in all organs and tissues. It is uniformly
chloride solution containing lithium aluminium chloride. Liquid distributed in body water, absorbed from the intestinal tract
thionyl chloride vapourises upon exposure to air and the fumes and excreted primarily through the kidneys.
are highly toxic (DPPEA, 2000). Lithium sulphur dioxide batteries  Based on lithium intake data in different countries, a provi-
typically contain strips of lithium metal as the anode as well as a sional recommended daily intake of 1.0 mg lithium/day for a
non-aqueous electrolyte consisting primarily of sulphur dioxide 70 kg adult American has been proposed. Major dietary sources
(SO2) and smaller concentrations of acetonitrile (CH3CN) and a are grain and vegetables and animal-derived foods. In some
lithium salt, typically lithium bromide (LiBr). Acetonitrile (CH3CN) areas, the drinking water is a source of lithium.
will decompose to form toxic cyanide fumes when heated (US  Human lithium deficiency diseases have not been observed.
EPA, 1984). The US Environmental Protection Agency (US EPA, However, some observations have suggested that low lithium
1984) made a statement on the regulatory status of spent and/or intakes cause behavioural defects.

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 ARTICLE
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H. Aral, A. Vecchio-Sadus / Ecotoxicology and Environmental Safety 70 (2008) 349–356
 Persons at risk of developing lithium deficiency are those with
kidney disease and dialysis patients.
 The reproductive effects of lithium are highly unlikely in an
occupational setting but may pose a risk to those being treated
for manic-depressive disorders. Lithium compounds are not
significantly clastogenic (capable of causing breakage of
chromosomes) and, based on studies on microorganisms, only
a doubtful mutagenic activity. Information on teratogenic
effect is contradictory.
 Lithium is taken up by plants. It does not appear to be required
for growth and development but it has been observed to
stimulate plant growth.
 At high levels in the soil, lithium is toxic to all plants but
uptake and sensitivity to lithium are species dependent. In
general, more lithium is taken up by plants from acidic soils
than alkaline soils.
 Lithium batteries are generally considered not an environ-
mental hazard except when containing toxic (heavy) metals
and disposed of in large quantities.
The literature survey has indicated that lithium is not expected
to bioaccumulate, and that its human and environmental toxicity
are low. Neither lithium intake from food and water nor from
occupational exposure presents a toxicological hazard. It does not
appear to pose a large threat to flora and fauna neither on land nor
in water. A release of lithium-containing waste can result in wide
dispersal due to low biological uptake and sorption to particulate
matter. Only in one Australian jurisdiction, the concentration of
lithium entering waterways has been limited to less than or equal
to 2.5 mg/L. Based on the information gathered in this report, the
lithium brine and mineral processing industries should be in a
position to set self-regulatory guidelines on occupational expo-
sures from handling lithium, and discharge limits for waste
waters.
This review has identified a number of areas where further
research is required. For example, on the human side, determining
the amount of lithium that is beneficial to health would assist in
establishing recommended daily intake levels. It could also be
useful to obtain a better understanding of the mechanisms by
which lithium could bring about change in the mood. Under-
standing the molecular target of lithium could shed light on the
cause and origins of bipolar disorder and may make it possible to
identify additional therapies for this disorder. On the animal side,
further research is required to determine the lithium require-
ments for different animal species and measuring the lithium
levels at which behavioural defects are observed. On the
environmental side, further testing of chronic sub-lethal toxicity
and modelling biotic ligand toxicity is recommended.
Acknowledgments
This literature review study was funded by Talison Minerals
(formerly Sons of Gwalia) the world’s largest lithium mineral
producer in Australia. The authors wish to thank Talison Minerals’
Pat Scallan and Ray Hoes for their permission to publish this
paper. We also thank for the reviewers for helpful comments on
the manuscript.
References
ACGIH, 1992. Threshold limit values and biological exposure indices for
1992–1993. In: American Conference of Governmental Industrial Hygienists,
Cincinnati, OH.
Amdisen, A., 1988. Clinical features and management of lithium poisoning. Med.
Toxicol. 3, 18–32.
FOR HKMA CME MEMBER USE ONLY. DO NOT REPRODUCE OR DISTRIBUTE
355
Anderson, M.A., Bertsch, P.M., Miller, W.P., 1989. Exchange and apparent fixation of
lithium in selected soils and clay minerals. Soil Sci. 148, 46–52.
Aral, H., 2007. Lithium and sulphate in the waste streams of Sons of Gwalia’s
Greenbushes Operations—Part 2. Unpublished CSIRO Minerals Report, DMR-
3248, 43pp.
AICS, 2007. Australia Inventory of Chemical Substances. /www.nicnas.gov.au/
Industry/AICS/ViewChemical.asp?SingleHit=1&Chemical_Id=10984&docVerS.
Banduhn, N., Obe, G., Miller-Oerlinghausen, B., 1980. Is lithium mutagenic in man?
Pharmakopsychiatrie/Neuropsychopharmakologie 13, 218–227.
Becker, R.W., Tyobeka, E.M., 1990. Lithium enhances proliferation of HL60
promyelocytic leukemia cells. Leukemia Res. 14, 879–884.
Bille, P.E., Jensen, M.K., Jensen, J.P.K., Poulsen, J.C., 1975. Studies on the
haematologic., cytogenetic effects of lithium. Acta Med. Scand. 198, 281–286.
Birch, N.J., 1976. Possible mechanisms for biological action of lithium. Nature 204,
681.
Birch, N.J., 1988. Lithium. In: Seiler, H.G., Sigel., H., Sigel, A. (Eds.), Handbook on the
Toxicity of Inorganic Compounds. Marcel Dekker, New York, pp. 382–393.
Bowen, H.J.M., 1979. Environmental Chemistry of the Elements. Academic Press,
New York.
Briggs, G.G., Bodendorfer, T.M., Freeman, R.K., Yaffe, S.J., 1983. Drugs in Pregnancy
and Lactation. William and Wilkins, Baltimore.
Cade, J.F., 1949. Lithium salts in the treatment of psychotic excitement. Med. J.
Aust. 36 (2), 349–352.
Casarett, LJ., Doull, J., 1987. Toxicology: The Basic Science of Poisons, sixth ed.
McGraw-Hill, New York.
CDC, 2007. Centre for Disease Control /www.cdc.gov/niosh/pdfs/ab_p2abb.pdfS.
Chan, L.H., Sturchio, N.C., Katz, A., 1997. Lithium isotope study of the Yellowstone
hydrothermal system. EOS Trans. Am. Geophys. Union 78, F802 (abstr).
Chemwatch, 2004. Material safety data sheet—Lithium. Chemwatch No. 1415-2, 28
March.
Chmielnicka, J., Nasiadek, M., 2003. The trace elements in response to lithium
intoxication in renal failure. Ecotoxicol. Environ. Safety 55, 178–183.
Czeizel, AE., 1994. Budapest registry of self-poisoned patients. Mutat. Res. 312,
157–163.
De la Torre, R., Krompotic, E., 1975. The in vivo and in vitro effects of lithium on
human chromosomes and cell replication. Teratology 131, 131–138.
Deutsche Forschungsgemeinschaft, 1992. Maximum Concentrations at the Work-
place and Biological Tolerance Values for Working Materials, Report no. 28.
VCH, Weinheim.
Domingo, J.L., 1994. Metal-induced developmental toxicity in mammals: a review.
J. Toxicol. Environ. Health 42, 123–141.
DPPEA, 2000. Battery disposal. North Carolina Division of pollution prevention and
environmental assistance, July 1997, TI#13300 (revised March 2000).
/www.p2pays.org/ref/07/06033.htmS.
EPA, 2005. Australian Capital Territory Environment Protection Regulation.
/www.legislation.act.gov.au/sl/2005-38/current/pdf/2005-38.pdfS.
Ellenhorn, M.J., Barceloux, D.G., 1988. Medical Toxicology: Diagnosis and Treat-
ment of Human Poisoning. Elsevier, New York.
Ferner, R.E., Smith, J.M., 1991. Disorders of the fetus and infant. In: Davies, D.M.
(Ed.), Oxford Textbook of Adverse Drug Reactions, fourth ed. Oxford University
Press, Oxford, pp. 62–98.
Ferner, R.E., Smith, J.M., 1992. Lithium and pregnancy. Lancet 339, 869.
Freeman, M.P., Freeman, S.A., 2006. Lithium: clinical considerations in internal
medicine. Am. J. Med. 119, 478–481.
Friedrich, U., Nielsen, J., 1969. Lithium and chromosomal abnormalities. Lancet 2,
435.
Garson, O.M., Latimer, N.I., Chiu, E., Dixon, K., 1981. Chromosome studies of
patients on long-term lithium therapy for psychological disorders. Med. J. Aust.
2, 37–39.
Genest, P., Villeneuve, A., 1971. Lithium, chromosomes and mitotic index. Lancet 1,
1132.
Giles, J.J., Bannigan, J.G., 1997. The effects of lithium on neurulation stage mouse
embryos. Arch. Toxicol. 71 (8), 519–528.
Habashi, F., 1997. Handbook of Extractive Metallurgy, vol. 4. Wiley-VCH, New York.
Hamilton, SJ., 1995. Hazard assessment of inorganics to three endangered fish in
the Green River, Utah. Ecotoxicol. Environ. Safety 30, 134–142.
Huh, Y., Chan, L.H., Zhang, L., Edmond, J.M., 1998. Lithium and its isotopes in major
world rivers: implications for weathering and the oceanic budget. Geochim.
Cosmochim. Acta 62 (12), 2039–2051.
Jacobson, J., Jones, K., Johnson, K., Ceolin, L., Kaur, P., Sahn, D., Donnenfeld, A.E.,
Rieder, M., Santelli, R., Smythe, J., Pastuszak, A., Eirnarson, T., Koren, G., 1992.
Prospective multicenter study of pregnancy outcome after lithium exposure
during first trimester. Lancet 339, 530–533.
Jaeger, A., 2003. Lithium. Medicine. Medicine Publishing Co. Ltd, p. 58.
Jarvik, L.F., Bishun, N.P., Bleiweiss, H., Kato, T., Moralishvili, E., 1971. Chromosome
examinations in patients on lithium carbonate. Arch. Gen. Psychiat. 24,
166–168.
Kallen, B., 1988. Comment on teratogen update: lithium. Teratology 38, 597–598.
Kallen, B., Tandberg, A., 1983. Lithium and pregnancy. Acta Psychiatr. Scand. 68,
134–139.
Kanematsu, N., Hara, M., Kada, T., 1980. Assay and mutagenicity studies on metal
compounds. Mutat. Res. 77, 109–116.
Kato, T., Fujii, K., Shiori, T., Inubushi, T., Takhashi, S., 1996. Lithium side effects in
relation to brain lithium concentration measured by lithium-7 magnetic
resonance spectroscopy. Prog. Neuro-Psychopharmacol. Biol. Psychiat. 20,
87–97.
 FOR HKMA CME MEMBER ARTICLE
USE ONLY. IN
DO PRESS
NOT REPRODUCE OR DISTRIBUTE
356 H. Aral, A. Vecchio-Sadus / Ecotoxicology and Environmental Safety 70 (2008) 349–356
King, M.C., Beikirch, H., Eckhardt, K., Gocke, E., Wild, D., 1979. Mutagenicity studies
with X-ray contrast media, analgesics, antipyretics, antirheumatics and some
other pharmaceutical drugs in bacterial Drosophila and mammalian test
systems. Mutat. Res. 66, 33–43.
Kjølholt, J., Stuer-Lauridsen, F., Skibsted Mogensen, A., Havelund, S., 2003. The
Elements in the Second Rank—Lithium. Miljoministeriet, Copenhagen, Den-
mark /www2.mst.dk/common/Udgivramme/Frame.asp?pg ¼ http://www2.
mst.dk/udgiv/publications/2003/87-7972-491-4/html/bill08_eng.htmS.
Klug, S., Collins, M., Nagao, T., Merker, H.J., Neubert, D., 1992. Effect of lithium on
rat embryos in culture: growth, development, compartmental distribution and
lack of protective effect of inositol. Arch. Toxicol. 66, 719–728.
Kszos, L.A., Stewart, A.J., 2003. Review of lithium in the aquatic environment:
distribution in the United States, toxicity and case example of groundwater
contamination. Ecotoxicology 12 (5), 439–447.
Kszos, L.A., Beauchamp, J.J., Stewart, A.J., 2003. Toxicity of lithium to three
freshwater organisms and the antagonistic effect of Sodium. Ecotoxicology 12
(5), 427–437.
Kuznetsov, I.A., Lukanin, A.S., Tsurkanov, L.F., 1971. Effect of ions of the alkaline
metals on the secondary structure of DNA. IV. Thermal denaturing deoxyr-
ibonucleates of alkaline metals in solution with a low ionic strength. Biofizika
16, 144–145.
Lenntech, 2007. Lithium and water: reaction mechanisms, environmental impact
and health effects. /www.lenntech.com/elements-and-water/lithium-and-
water.htmS.
Léonard, A., Hantson, Ph., Gerber, G.B., 1995. Mutagenicity, carcinogenicity
teratogenicity of lithium compounds. Mutat. Res./Rev. Genet. Toxicol. 339
(3), 131–137.
Linakis, J.G. 2007. Toxicity, lithium. eMedicine, 8 January 2007. /www.emedicine.
com/EMERG/topic301.htmS.
Litovitz, T.L., Clark, L.R., Soloway, R.A., 1994. 1993 annual report of the American
Association of Poison Control Centers Toxic Exposure Surveillance System. Am.
J. Emerg. Med. 12 (5), 546–548.
Litovitz, T.L., Smilkstein, M., Felberg, L., Klein-Schwartz, W., Berlin, R., Morgan, J.L.,
1997. 1996 annual report of the American Association of Poison Control Centers
Toxic Exposure Surveillance System. Am. J. Emerg. Med. 15 (5), 447–500.
Manji, H.K., Lenox, R.H., 1994. Long-term action of lithium: a role for transcriptional
and posttranscriptional factors regulated by protein kinase C. Synapse 1, 11–28.
Mason, B., 1974. Principles of Geochemistry, third ed. Wiley, New York.
Moore, J.A., 1995. IEHR Expert Scientific Committee. An assessment of lithium
using the IEHR evaluative process for assessing human developmental and
reproductive toxicity of agents. Reprod. Toxicol. 9 (2), 175–210.
Moore, S., 2007. Between rock and salt lake. Ind. Miner. June, 58–69.
Morris, E.O., 1958. Yeast growth. In: Cook, A.H. (Ed.), The Chemistry and Biology of
Yeasts. Academic Press Inc., New York, p. 301.
NEMA, 2001. Spent consumer lithium batteries and the environment,
National Electrical Manufacturers Association, March 2001. /www.nema.org/
gov/ehs/committees/drybat/upload/SpentConsumer_Lithium_Batteries_and_
the_Environment.docS.
Nishioka, H., 1975. Mutagenic activities of metal compounds in bacteria. Mutat.
Res. 31, 185–189.
Phiel, C.J., Klein, P.S., 2001. Molecular targets of lithium action. Annu. Rev.
Pharmacol. Toxicol. 41, 789–813.
Price, L.H., Heninger, G.R., 1964. Lithium in the treatment of mood disorders. Drug
Ther. 331, 591–598.
FOR HKMA CME MEMBER USE ONLY. DO NOT REPRODUCE OR DISTRIBUTE
Ribas, B., 1991. Lithium. In: Merian, E. (Ed.), Metals and their Compounds in the
Environment, fourth ed. VCH, Weinheim, pp. 1014–1023.
Sadosty, A.T., Groleau, G.A., Atcherson, M.M., 1999. The use of lithium levels in the
emergency department. J. Emerg. Med. 17 (5), 887–891.
Schou, M., 1968. Lithium in psychiatric therapy and prophylaxis. J. Psychiatr. Res. 6,
67–95.
Schou, M., Amdisen, A., 1971. Lithium teratogenicity. Lancet 1, 1132.
Schrauzer, G.N, 2002. Lithium: occurrence, dietary intakes, nutritional essentiality.
J. Am. Coll. Nutr. 21 (1), 14–21.
Schrauzer, G.N., Shrestha, K.P., 1990. Lithium in drinking water and the incidence of
crimes, suicides and arrests related to drug addictions. Biol. Trace Elem. Res.
25, 105–114.
Shacklette, H.T., Erdman, J.A., Harms, T.F., Papp, C.S.E., 1978. Trace elements in plant
foodstuffs. In: Oehme, F.W. (Ed.), Toxicity of Heavy Metals in the Environment,
fourth ed. Marcel Dekker, New York, pp. 25–68.
Slamenova, D., Budayova, E., Gabelova, A., Moravkova, A., Panikova, L., 1986. Results
of genotoxicity testing of mazindol (degonan), lithium carbonicum (contem-
nol) and dropropizine (ditustat) in Chinese hamster V79 and human EUE cells.
Mutat. Res. 169, 171–177.
Smithberg, M., Dixit, P.K., 1982. Teratogenic effects of lithium in mice. Teratology
26, 239–246.
Sposito, G., 1986. Distribution of potentially hazardous trace metals. In: fourth
edSigel, H. (Ed.), Metal Ions in Biological Systems, vol. 20. Marcel Dekker,
New York, pp. 1–20.
Sram, R.J., Binkova, B., Topinka, J., Fojtikova, I., 1990. Inhibition of DNA repair
synthesis in the rat by in vivo exposure to psychotropic drugs and reversal
of the effect by co-administration with a—tocopherol. Mutat. Res. 244,
331–335.
Stern, R., 1995. Lithium in the treatment of mood disorders. New Engl. J. Med. 332,
127–128.
Strobusch, A.D., Jefferson, J.W., 1980. The checkered history of lithium in medicine.
Pharm. Hist. 22, 72–76.
Tandon, A., Dhawan, D.K., Nagpaul, J.P., 1998. Effect of lithium on hepatic lipid
peroxidation and antioxidative enzymes under different dietary protein
regimens. J. Appl. Toxicol. 18 (3), 187–190.
Terao, T., Nakano, H., Inoue, Y., Okamoto, T., Nakamura, J., Iwata, N., 2006. Lithium
and dementia: a preliminary study. Prog. Neuropsychopharmacol. Biol.
Psychiat. 30 (6), 125–1128.
Timson, J., Price, D.J., 1971. Lithium and mitosis. Lancet 1, 93.
Tsuruta, T., 2005. Removal and recovery of lithium using various microorganisms.
J. Biosci. Bioeng. 100 (5), 562–566.
US EPA, 1984. Letter from Jack W. McGraw to Mr. Dick Bruner. (yosemite.epa.gov/
OSW/rcra.nsf/Documents/CC7D81DF307086C085256611005AC8EC).
US EPA, 2008. ECOTOX retrieval database.
von Rosen, G., 1957. Mutations induced by the action of metal ions in pisum.
Hereditas 43, 644–664.
Wedepohl, K.H., 1995. The composition of the continental crust. Geochim.
Cosmochim. Acta 59, 1217–1232.
Weiner, M.L., 1991. Overview of lithium toxicology. In: Schrauzer, G.N., Klippel, K.F.
(Eds.), Lithium in Biology and Medicine. Hydrogen Substitution in Lithium-
Aluminosilicates. VCH Verlag, Weinheim, pp. 83–99.
Zalstein, E., Koren, G., Einarson, T., 1990. A case control study on the association
between first trimester exposure to lithium and Ebstein’s anomaly. Am. J.
Cardiol. 65, 817–818.