Ecotoxicology and Environmental Safety 70 (2008) 349– 356

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Ecotoxicology and Environmental Safety

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

Hal Aral Ã, Angelica Vecchio-Sadus

CSIRO Minerals, Box 312, Clayton South, Vic. 3169, Australia article info 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. The dissolved lithium found in the tailing dams of such lithium Lithium is present in the earth’s crust to the extent of about mineral beneficiation plants could be as high as 13 mg/L. 0.006 wt% (Habashi, 1997). It is the 27th most abundant element Lithium is also found in natural brines (Salar de Atacama—Chile, in nature. The major lithium minerals with commercial value are Salar de Hombre Muerto and Salar de Rincon—Argentina, and classified into three major groups: 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 (a) silicates (spodumene—LiAlSi2O6, petalite—LiAlSi4O10) brines varies from 20 mg/L in the Dead Sea to 1500 mg/L in Salar de (b) micas (lepidolite—K[Li,Al]3[Al, Si]4O10[F,OH]2, zinnwaldite— Atacama (Habashi, 1997; Moore, 2007). Geochemically, lithium is a K[Li,Al,Fe]3[Al,Si]4O10[F,OH]2 and highly mobile element, therefore, the environmental and occupa- (c) phosphates (mainly amblygonite—[Li, Na]Al[F, OH]PO4). tional health and safety risks related to lithium in brines are higher. A source of lithium posing impact to the environment is spent Lithium minerals are mined around the world in various places lithium batteries. Consumers routinely dispose of batteries along such as Manona—Zaire, Bikita—Zimbabwe, Greenbushes— with other garbage in the municipal solid waste (NEMA, 2001). Western Australia, La Corne and Bernic Lake—Canada, Kola There is growing community concern about the health and Peninsula—Russia and Altai Mountains—Chinatomakevarious safety of workers and the impact on the environment coupled lithium mineral products (Moore, 2007). The processing of lithium- with increasing company reporting and accountability. In the area containing minerals in general comprises crushing, wet grinding in a of lithium toxicity to humans and the environment, the informa- ball mill, sizing, gravity concentration and flotation using fatty acid tion is scattered across various scientific disciplines. The objective (oleic acid) as the collector. Tailings are discharged to storage areas, of this study is to prepare a compilation and critically review the and the decanted water is usually recovered for reuse. leading international health, safety and environmental journals, The major lithium mineral in the ore is spodumene, which is toxicological databases and websites to ascertain the impacts of considered insoluble in water and dilute acids. However, a recent lithium on flora, fauna and humans. This literature search covered unpublished work (Aral, 2007) has indicated that small amount of the relevant sites of the ISI Web of Science (that indexed more than dissolution may be occurring during processing of the ore 5700 major journals across 164 scientific disciplines) and key especially in the grinding stage with some additional dissolution databases including Agency for Toxic Substances and Disease Registry (ASTDR), Australian Safety and Compensation Council Ã Corresponding author. Fax: +6103 9562 8919. (ASCC), Centers for Disease Control and Prevention (CDC), ECOTOX, E-mail address: [email protected] (H. Aral). MEDLINE and TOXLINE.

350 H. Aral, A. Vecchio-Sadus / Ecotoxicology and Environmental Safety 70 (2008) 349–356

2. Environmental and toxicological impacts of lithium lithium supplements or other appropriate measures to meet this intake. Lithium levels may be higher after physical exertion, in 2.1. Toxicology certain diseases and in dialysis patients. The special needs of children, adolescents and lactating mothers would need to be The Australia Inventory of Chemical Substances (AICS, 2007) considered. has classified metallic lithium as a health, physiochemical and/or Lithium has many industrial applications (reviewed in Birch, ecotoxicological hazard according to the National Occupational 1988). Although professional intoxications from the industrial Health and Safety Commission (NOHSC) approved criteria for applications are possible, none have been reported. The most classifying hazardous substances. Lithium, lithium aluminium common source of exposure to lithium and also of toxic hydride, and lithium methanolate are found on the Danish list of consequences is its intensive use in medicine following the dangerous substances (Kjølholt et al., 2003). Lithium salts are not discovery of the psychotropic properties of lithium (Cade, 1949; very toxic except for the highly corrosive and irritant lithium Schou, 1968). Lithium salts, especially the carbonate (Li2CO3) and hydrides, lithium tetrahydroaluminate (LiAlH4) and lithium tetra- acetate (LiCH3COO) are extensively used in the treatment of hydroborate (LiBH4). Spodumene, the major lithium ore mined in manic-depressive disorders. Lithium was first introduced into the various places around the world, is an aluminium silicate. It medical profession in the mid-1800s as a cure-all for many contains up to 8.0 wt% Li2O, and this lithium is tightly bound to common illnesses. Since its introduction, medical professionals the crystal structure and, therefore, it alone does not pose a have been cognisant and wary of lithium toxicity. In fact, in 1949, toxicological problem. However, when spodumene is crushed, it lithium was banned from use in the US because of excessive generates silica-rich dust which is a health and safety hazard. toxicity and did not gain FDA approval for use in the treatment of Finely ground lithium minerals, especially lithium-containing mania until 1970 (Strobusch and Jefferson, 1980). Other ther- phosphate ores, are more susceptible to water and dilute acid apeutic uses prior to the work of Cade (1949) had been described leaching than unground ores due to increased surface area (Aral, for lithium salts, and an effect of lithium on embryonic 2007). development has been recognised for at least 100 years. Lithium Upon oral intake, metallic lithium is mildly toxic, however, also affects metabolism, neuronal communication, and cell physical tolerance differs between individuals. The primary target proliferation in a diverse array of organisms, from cellular slime organ for lithium toxicity is the central nervous system (Kjølholt moulds to humans. et al., 2003), therefore, lithium is used therapeutically on Non-supervised or indiscriminate therapeutic use of lithium membrane transport proteins when treating manic depression. carbonate can produce certain toxic symptoms in the neuromus- Chemically, lithium resembles sodium but is more toxic. A lethal cular, cardiovascular and gastrointestinal system as well as more dose of LiCl in rats has been measured at 526–840 mg/kg body serious renal damage (Price and Heninger, 1964) and can even weight. In humans, 5 g of LiCl can result in fatal poisoning. Lithium cause death (Litovitz et al., 1994). The serum (blood) level under carbonate is applied in psychiatry in doses close to the maximum therapeutic lithium treatment should not exceed 11.1 mg/L Li and intake level. At 10 mg/L of blood, a person is mildly lithium must be carefully monitored. Nevertheless, patients on long-term poisoned, at 15 mg/L they experience confusion and speech lithium treatment may suffer from severe neurotoxic effects while impairment, and at 20 mg/L Li there is a risk of death. In serum lithium concentrations are normal (Stern, 1995). therapeutic doses, damages on the central nervous system and Lithium has numerous effects in humans and in other the kidneys have been reported. organisms (Moore et al., 1995). Phiel and Klein (2001) reviewed Lithium does not have a known biological use and does not the cause and effect of lithium and showed that therapeutic levels appear to be an essential element for life (Leónard et al., 1995; of lithium are clearly able to inhibit functioning of multiple Lenntech, 2007). The amount of lithium in the human body is enzymes in the body. Lithium, as a medicine, has multiple effects approximately 7 mg. Lithium is absorbed from the gastrointestinal on embryonic development, glycogen synthesis, hematopoiesis tract (Casarett and Doull, 1987; Ellenhorn and Barceloux, 1988; (the formation and development of blood cells involving both Linakis, 2007; Schrauzer, 2002) and excreted primarily through proliferation and differentiation from stem cells), and other the kidneys after approximately 24 h (Freeman and Freeman, processes. 2006). Serum concentrations of lithium reach a peak about 30 min Lithium is the drug of choice for the treatment of recurrent after oral ingestion, followed by a plateau at 12–24 h. Lithium ions bipolar disorder for more than 50 years and has gained popularity cross the cell membrane slowly; this may account not only for the as a pharmacologic option in the treatment of other psychiatric prolonged excretion of lithium but also for the 6–10 days delay conditions (Leónard et al., 1995). The clinical importance of needed to achieve the full therapeutic response in humans. lithium is two-fold (Phiel and Klein, 2001). Firstly, the therapeutic Although lithium is not an essential element, it may influence window between effective dosing and toxicity is narrow, side metabolism. effects are common even within the therapeutic dose range, and a According to Schrauzer (2002), the average daily lithium intake significant number of patients do not respond. While antic- of a 70 kg adult (American) is between 0.65 and 3.1 mg/day. Major onvulsants such as valproic acid offer an alternative mode of dietary sources of lithium are grains and vegetables (0.5–3.4 mg therapy, an understanding of the targets of lithium (and of Li/kg food), dairy products (0.50 mg Li/kg food) and meat valproic acid) will make it possible to identify additional therapies (0.012 mg Li/kg food) (Weiner, 1991). In places like Chile where for this common disorder. Secondly, little is known about the lithium-rich salinas could contain up to 1500 mg/L Li, the total pathogenesis of bipolar disorder or other mood disorders, and lithium intake may reach 10 mg/day without evidence of adverse therefore, identification of the molecular target of lithium can effects to the local population. A review of the dietary intake of shed light on the causes and origins of this disorder. lithium has indicated that the minimum human adult (physiolo- The combination of the increased use of lithium and its gical) lithium requirement is estimated to be less than 0.1 mg/day. extremely narrow therapeutic window enhances the potential for Based on lithium intake data in different countries, a provisional increased toxicity. The therapeutic serum concentrations (Jaeger, recommended daily intake of 1.0 mg lithium/day for a 70 kg adult 2003) are normally about 5.6–8.4 mg/L, mild toxicity is usually American was proposed, corresponding to 14.3 mg/kg body weight, seen at about 10.5–17.5 mg/L, moderate toxicity is seen at about which can be derived by diet alone. People on special diets or 17.5–24.5 mg/L and severe symptoms are seen at 424.5 mg/L. In populations residing in naturally low lithium areas would require one example, the vast majority (75–90%) of patients receiving ARTICLE IN PRESS

H. Aral, A. Vecchio-Sadus / Ecotoxicology and Environmental Safety 70 (2008) 349–356 351 maintenance lithium therapy for bipolar disorder become toxic at sodium and potassium at the renal tubular level, therefore, some point during their course of therapy (Amdisen, 1988). In sodium and water balance causes not only the serum level of 1996, 5102 lithium exposures were reported to the American lithium but also its toxicity. The most important in lithium Association of Poison Control Centers with nearly 75% of those toxicity is dehydration which will produce sodium and water suffering exposure seeking medical attention (Litovitz et al., 1997). imbalance. The mechanisms by which lithium could bring about changes In a study by Tandon et al. (1998) lithium carbonate was in mood are still poorly understood. Among others, it has been administered at a dose level of 1.1 g/kg food to rats fed normal suggested (Manji and Lenox, 1994) that it may affect transcrip- protein (18%), low-protein (8%) and high-protein (30%) diets for a tional and post-transcriptional factors via protein kinase. It has period of 1 month. A highly significant (53%) increase in the level been reported (Schrauzer and Shrestha, 1990) that countries of lipid peroxidation was observed in protein-deficient rats but where the drinking water contains little or no lithium have a this increase was marginal in rats fed a high-protein diet. Terao higher rate of crimes, suicides and police arrests for drug et al. (2006) showed that a potentially beneficial effect of lithium addiction than countries where lithium levels in drinking water is that it may block the accumulation of amyloid-b (Ab) peptides are 0.07–0.170 mg/L. Several suicide attempts using lithium that cause dementia in mice. carbonate have also been reported (Czeizel, 1994). Gastrointestinal disturbances, oedema and tremor are com- 2.1.1. Genetic toxicology mon side effects of lithium treatment (Tandon et al., 1998). The Leónard et al. (1995) reviewed the information available in the preliminary study of Kato et al. (1996) showed that the hand literature on the genetic toxicology of lithium. Lithium causes tremor may be a potential indicator of overdose for the disturbances in the development of invertebrates. Development is therapeutic bipolar disorder treatment. also inhibited in whole rat embryos cultured from day 9.5 (Klug Lithium salts induce renal toxicological symptoms (sclerotic et al., 1992). In intact animals, results vary: several types of glomeruli and tubular damage) (Chmielnicka and Nasiadek, abnormalities (e.g. reduced number and weight of the litter, more 2003). The inability of the nephron to concentrate urine during resorptions, ‘wavy’ ribs, incomplete ossification) were observed lithium treatment is correlated to the occurrence of histological (see for example the review by Domingo, 1994). These discre- change. Lithium also produces many metabolic changes. In terms pancies may be due to a different sensitivity of the species and of mineral metabolism, lithium competes with sodium, potas- strains used the stress of daily injection and/or differences in sium, magnesium, and calcium, in that order, and displaces them lithium concentrations present in serum during critical periods of from intracellular and bone sites in this progression. Interaction of development. Pregnant mice given lithium carbonate over several toxic metals and essential elements in the kidneys has been days yielding serum levels comparable to those in humans treated demonstrated in biological and toxic aspects. for manic-depressive disorders did not show any effect, but six Sadosty et al. (1999) reported that following ingestion, serum times higher doses caused malformations in the offspring concentrations of lithium peaked at 1–12 h. Lithium is not protein (Smithberg and Dixit, 1982). bound, and after ingestion it slowly equilibrates between the extracellular and intracellular spaces. The delay in equilibration between serum lithium concentrations and intracellular lithium 2.1.2. Teratogenicity concentrations approximated 6–10 days. In the study by Chmiel- Teratogenicity is the ability to cause defects in a developing nicka and Nasiadek (2003), the authors determined the dose- foetus. It is a potential side effect of many drugs such as dependent lithium concentrations in serum and urine and also an thalidomide. In a study of the effect of lithium carbonate on estimation of some biochemical indicators of nephrotoxicity pregnant mice (Smithberg and Dixit, 1982), chronic exposure to detectable at an earlier stage. Rats were orally given lithium lithium doses that produced serum levels of the same order as carbonate, 10 mg Li/kg (group I) and 20 mg Li/kg (group II), five seen in patients was toxic but did not affect the entire litter nor times a week during 5 weeks. Control rats were treated with 0.9% was it teratogenic to individual mice embryos. Many authors have NaCl (group III) during the same period. During the experiment reported that lithium causes congenital defects, especially of the the lithium concentration in serum and urine of rats was cardiovascular system such as Ebstein’s anomaly (a rare cardiac dependent on the daily administration doses in comparison with defect) when given to women during the first trimester of the control group. After the first week of intragastric exposure to pregnancy (reviewed in Briggs et al., 1983; Birch, 1988; Ferner lithium carbonate in daily doses of 10 mg Li/kg body weight rats, a and Smith, 1991, 1992). This claim gave rise to the foundation of a notable increase of copper concentration in urine was observed. ‘Register of Lithium Babies’ in Risskov (Denmark) and, later, of an At the same time higher activity of N-acetyl-b-glucoaminidase ‘American Registry of Lithium Babies’ in San Francisco. A first (NAG) in the urine of rats was also observed in comparison with analysis of the records of 60 children borne by mothers who the control group. Increased urinary concentration of proteins was received lithium treatment during the first trimester or the entire noted also after the first week but after daily administered 20 mg pregnancy published in 1971 (Schou and Amdisen, 1971) did not Li/kg. reveal any association of lithium treatment with a higher The results of Chmielnicka and Nasiadek’s investigations teratogenic risk. A multi-center study of pregnancy outcome after showed that oral administration of lithium carbonate-induced therapeutic lithium exposure during the first trimester also did renal toxicity in the rat as well as the injurious symptoms which not show any significant teratogenic risk (Jacobson et al., 1992). were found to be directly related to the dose effect and to the Others (Kallen and Tandberg, 1983; Kallen, 1988; Zalstein et al., concentration of this metal in serum and urine. Excretion of 1990) also conclude that lithium given in therapeutic doses is not lithium is predominantly by the kidney and approximately 80% of teratogenic. lithium is reabsorbed by the proximal renal tubule and 20% is Giles and Bannigan (1997) evaluated the maternal toxicity and excreted in the urine. Concentrations of lithium in the brain are teratogenicity of lithium following intraperitoneal injection with similar to those found in the plasma. The authors observed 300 mg/kg body weight lithium carbonate (Li2CO3) in pregnant disturbances in the kidney function in rats after lithium intoxica- CD-1 mice at the developmental stage of neurulation. Controls tion and also as a diuresis and proteinuric effect. The renal were untreated or given equimolar amounts of NaCl or Na2CO3. elimination of lithium influences several factors, including sodium Their pharmacokinetic study showed that lithium was rapidly and water balance. It is known that lithium competes with absorbed from the peritoneal cavity after the above-stated dose, ARTICLE IN PRESS

352 H. Aral, A. Vecchio-Sadus / Ecotoxicology and Environmental Safety 70 (2008) 349–356 achieved peak serum levels of 68 mg/L within 1 h, had a half-life 77 patients studied, 50 of whom had been treated with lithium in the blood of 5 h and was completely cleared by 16–24 h after sulphate, 17 with lithium carbonate and 10 with lithium acetate. injection. Doses of Li2CO34300 mg/kg body weight were toxic to Also, 16 manic-depressive patients who had been given lithium adult CD-1 mice. At 3 h after treatment, cell death became evident carbonate from 2 weeks to more than 2 years (seven of them for in the neuroepithelium. These experiments suggest that the more than a year) did not show aberrations in their lymphocytes developing vascular system may be a target for lithium. In (Jarvik et al., 1971). addition, the possibility is discussed that lithium-induced cell Addition of 8.4, 12.6 and 16.8 mg/L of lithium to the culture of death in the neuroepithelium may lead to neural tube defects. blood lymphocytes did not augment structural aberrations (Friedrich and Nielsen, 1969), but, surprisingly, these authors found a significant increase in breaks in lymphocytes derived 2.1.3. Mutagenicity from three patients treated with lithium. The latter results remain Mutagenicity is the ability to cause genetic mutations in doubtful, particularly since the number of patients was too small sperms, eggs other cells. Despite the extensive therapeutic use of and no details on methods or number of cells analysed are given lithium carbonate, few investigations on the mutagenic potential in the paper. The increase in satellite association reported by de la of lithium compounds have been carried out. Lithium could have Torre and Krompotic (1975) also cannot be considered proof of a several ways of acting on DNA: Li binds selectively to DNA mutagenic action of lithium in vitro, inasmuch as the authors did (Kuznetsov et al., 1971); it competes with Mg2+ and may impair not observe any significant increase in chromosome aberrations in DNA synthesis (Becker and Tyobeka, 1990) and DNA repair. patients compared with control subjects. However, results on bacteria and isolated systems were incon- clusive. No effect was seen with lithium chloride (LiCl) in strains 2.1.4. Carcinogenicity of Bacillus aluminium (Nishioka, 1975; Kanematsu et al., 1980) and Leónard et al. (1995) indicated that no information on possible by King et al. (1979) with trilithium citrate (C6H5Li3O7) in the carcinogenic effects of lithium compounds was available. How- Ames test on Salmonella typhimurium (34 mmol per test plate), in ever, this seems unlikely in view of the known biological the Escherichia coli test (10 mmol per test plate), in the host- mechanisms of action of lithium. mediated assay with E. coli and in mice (28 mg/kg intraperitoneal), and in the sex-linked recessive lethality test in Drosophila 2.2. Environmental toxicology melanogaster (3 days feeding with 140 mg/L). High concentrations of LiCO3 (3 mg/mL) slightly inhibited DNA synthesis in V79 Chinese hamster cells and human EUE fibroblasts, and this effect Lithium is generally found naturally in the aquatic and was lessened by the addition of S9 fraction (a post-mitochondrial terrestrial environment but in small concentrations (see Table 1) supernatant fraction added to cell cultures during treatment with (Bowen, 1979; Wedepohl, 1995; Sposito, 1986; Birch, 1988; Ribas, certain chemicals in order to simulate mammalian metabolism) 1991). (Slamenova et al., 1986). The same authors also observed more single-strand breaks in DNA and a small increase in gene 2.2.1. Aquatic environments mutations in V79 Chinese hamster ceils in the absence of S9. No Lithium is found primarily in ionic form in water. Lithium significant clastogenic and only a doubtful mutagenic action of metal reacts with water to form lithium hydroxide and hydrogen. lithium were demonstrated. However, the percentage of poly- The lithium concentration in fresh water and sea water is on the chromatic erythrocytes with micronuclei increased in NMRI mice mg/L-level (Kjølholt et al., 2003). According to the literature treated with an intraperitoneal injection of 2 1.1 g/kg of lithium (Schrauzer, 2002; Lenntech, 2007) surface water contains lithium citrate (King et al., 1979). This indicated that lithium could at levels between 1 and 10 mg/L, seawater contains approximately interfere with chromosome distribution. 0.17 mg/L lithium (Mason, 1974) and the lithium concentrations in Addition of 0.05% (500 ppm) lithium carbonate to the ground water may reach 0.5 mg/L. Rivers generally contain around drinking water of 6-month old rats for 3, 6 or 12 months slightly 3 mg/L Li whereas in the lithium-rich regions of northern Chile, the reduced (Sram et al., 1990) unscheduled DNA synthesis induced in lithium content of the surface waters could be as high as 5.2 mg/L. blood lymphocytes by the alkylating agent N-methyl-N0-nitro-N- Worldwide mineral water contains 0.05–1 mg/L lithium, however, nitrosoguanidine (MNNG) (0.7 mg/L). higher levels up to 100 mg/L can be found in some natural mineral Lithium carbonate added at the start of a 72 h culture period at waters (Schrauzer, 2002). concentrations equivalent to 0.1, 1.0 or 10 g of lithium carbonate A review of lithium in the aquatic environment in the US distributed in the body of a 70 kg person did not increase (Kszos and Stewart, 2003) found that lithium was detected at low structural chromosome aberrations in peripheral lymphocytes concentrations (0.002 mg/L) in the major rivers of the US. (Timson and Price, 1971). Confirming their results on experi- Further studies (Kszos et al., 2003) identified lithium concentra- mental animals given toxic doses of lithium, Bille et al. (1975) tions in surface waters were typically o0.04 mg/L but could be failed to observe cytogenetic changes in peripheral blood elevated in contaminated streams. lymphocytes of patients treated with lithium salts. Huh et al. (1998) studied lithium and its isotopes in the lower No aberrations were found in 19 lithium-treated manic- reaches of 13 major rivers of the world and a number of major depressive patients compared with 23 controls but the mitotic lakes (Table 2). The lithium concentration (expressed as nano- index was significantly reduced (Genest and Villeneuve, 1971). moles (nM)) varied from 96.5 for the Amazon River, 125 for the Similarly, negative results were reported by Garson et al. (1981) Congo, 579 for the Ganges, to 813 for the Mississippi River. The and Banduhn et al. (1980) in peripheral lymphocytes of as many as lithium isotopic composition appeared to be more a function of

Table 1 Typical background concentrations of lithium in the environment

Fresh water (mg/L) Seawater (mg/L) Sediment (mg/kg) Soil (mg/kg) Earth’s crust (mg/kg) Atmosphere (ng/m3)

Typical background concentration 0.07– 40 170–190 56 3– 350 20– 60 2 ARTICLE IN PRESS

H. Aral, A. Vecchio-Sadus / Ecotoxicology and Environmental Safety 70 (2008) 349–356 353 the fractionation processes during partial weathering of alumi- 2.2.2. Terrestrial environments nosilicate rocks to form neoformed clays, and in the case of On land, lithium can be found as lithium carbonate (Li2CO3), evaporites (rock composed of minerals derived from the evapora- lithium chloride (LiCl) or lithium oxide (Li2O). Lithium is found in tion of mineralised water), the concentration in the solution from trace amounts in all soils primarily in the clay fraction, and to a which the secondary lithium minerals precipitated, rather than lesser extent in the organic soil fraction, in amounts ranging from bedrock type or age. Comparison with the major element and 7to200mg/g (Schrauzer, 2002). The source of lithium is usually strontium isotope dataset suggested that the important processes from sedimentary rocks (Chan et al., 1997). For example, affecting river-dissolved lithium isotopic compositions are iso- carbonates precipitated from evaporated lake water can have topic fractionation between solution and secondary minerals and high lithium concentrations, as demonstrated by a Dead Sea the degree of weathering. In addition is the effect of the bedrock aragonite with 19 ppm lithium. Some lithium in carbonate-rich type makes the lithium isotopic system complicated. rivers, especially those that are not highly evaporitic, come from Hamilton (1995) investigated the acute toxicity of boron, associated shales, e.g., calcareous shales from the Ellis Group of lithium, selenate, selenite, uranium, vanadium and zinc to early Yellowstone National Park contained 18 ppm lithium. stages of development of Colorado squawfish (Ptychocheilus Authigenic clays (i.e., those occurring in the place where they lucius), razorback sucker (Xyrauchen texanus), and bonytail (Gila were originally formed) are enriched in lithium (200–500 ppm in elegans) in a water quality simulating the middle Green River. His smectites) relative to other rock types (igneous rocks 30 ppm, study showed that the overall rank order of toxicity to all species detrital clays 70–80 ppm) (Chan et al., 1997). Li+ has the weakest and life stages combined from most to least toxic was vanadium sorption chemistry of all the alkalis, and its affinity with clays is ¼ zinc4selenite4lithium ¼ uranium4selenate4boron. considered to be due to the isomorphic substitution of Mg2+ for Kszos et al. (2003) evaluated the toxicity of lithium to Al3+ in the octahedral layer leaving a vacant position to Pimephales promelas (fathead minnow), Ceriodaphnia dubia, and accommodate Li+. Examination of lithium exchange in complex a freshwater snail (Elimia clavaeformis). They found that for most soil solutions and pure clay mineral systems has shown that natural waters, the presence of sodium is sufficient to prevent lithium is selectively absorbed over other cations and apparently lithium toxicity. However, in areas of historical disposal or heavy fixed in a non-exchangeable form (Anderson, 1989). Adsorption processing or use, an evaluation of lithium from a water quality onto suspended sediments in rivers may also play a role but perspective would be warranted. preliminary experiments (Chan et al., 1997) suggested that only Studies (Lenntech, 2007; US EPA, 2008) have identified toxicity about 1 ppm lithium is adsorbed onto clays and river sediments levels in certain organisms (see Table 3). Effective concentration (i.e., 10%). Lithium concentrations are in general proportional to

(EC50) is the concentration of a material in water, a single dose magnesium (due to ionic radius similarities) but only poorly which is expected to cause a biological effect on 50% of a group of correlated with other major ions and even silicon and potassium test animals. Lethal concentration (LC50) is the amount of a though these are almost exclusively from the weathering of substance in air that, when given by inhalation over a speciﬁed aluminosilicates. This is consistent with the tendency of lithium period of time, is expected to cause the death in 50% of a deﬁned to be retained in secondary clays, substituting for Mg2+ or animal population. The acute environmental effect concentration occupying the vacancy generated by Mg2+ substitution of Al3+.

(measured as EC50)onDaphnia magna was determined to be Lithium is taken up by all plants and although it appears not to 33–197 mg/L, which is at least 1000 times higher than the level in be required for their growth and development, stimulation of fresh water. Both lithium chloride and lithium sulphate have high plant growth has been observed (Schrauzer, 2002; Lenntech, water solubility, and the compounds will dissociate in aqueous 2007). The amount of lithium in plants usually lies between 0.2 environment. No lithium compounds are classiﬁed for adverse and 30 ppm due to preferential uptake or rejection across species. environmental effects. No data regarding bioaccumulation of Plants such as Cirsium arvense and Solanum dulcamera accumulate lithium was found but based on its low afﬁnity to particles, it is lithium in concentrations of three- to six-fold over other plants. not expected to bioaccumulate. 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 Table 2 concentrations in plant foodstuffs vary widely from 0.01 ppm (dry Lithium concentrations of the world’s major lakes basis) in bananas to 55 ppm in oats (Shacklette et al., 1978).

Name Li (mg/L) Lithium is relatively toxic to citrus plants. There appears to be a greater uptake of lithium by plants in Lake Tanganyika 0.014 acidic soils. Soil acidity increases the solubility of the heavier Caspian Sea 0.280 metallic elements such as iron, nickel, cobalt, manganese and Lake Baikal 2.0 copper, and to some extent also aluminium, lead and cadmium. Dead Sea 14.0 Plant lithium levels are directly and signiﬁcantly correlated with Source: Huh et al. (1998). Reproduced with permission. the concentrations of these elements. Calcium can be added to

Table 3 Test results for environmental (aquatic) toxicity

Species Latin name (common name) Compound Exposure duration EC50 (mg/L) LC50 (mg/L)

Mollusc Dreissena polymorpha (Zebra mussel) LiCl 24 h 185–232

Crustacean Daphnia magna (water ﬂea) Li2SO4 24 h 33–197

Worm Tubifex tubifex (Tubicid worm) Li2SO4 24–96 h 9.3–44.8 Fish Pimephales promelas (fathead minnow) LiCl 26 days 1–6.4 1.2–8.7 Fish Tanichthys albonubes (white cloud mountain minnow) LiCl 48 h 9.2–62

Source: Lenntech (2007) and US EPA (2008). Reproduced with permission. ARTICLE IN PRESS

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 Lithium in plants and animals interacts with sodium and et al., 2003) 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 3 produced in the progeny of Pisum abyssinicum plants (von Rosen, Incinerator 1, semi-dry gas cleaning o9.1 mg/m 3 1957) treated with lithium nitrate in addition to other nitrates Incinerator 2, wet gas cleaning 1.0 mg/m (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 In an early study (Morris, 1958), yeast (Saccharomyces Landfill leachate, wet gas cleaning 0.367 mg/L 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 Tsuruta (2005) examined the accumulation of lithium by micro- Plant 2, effluent 21.2 mg/L 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 accumulations ability was exhibited by strains of the bacteria Road runoff retention basins, sediment 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 microorganisms. 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 3 ment from road runoff retention basins (Table 4). The concentra- data of 25 mg/m 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. ARTICLE IN PRESS

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