The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for LITHIUM

NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.

EXECUTIVE SUMMARY
1. INTRODUCTION
2. METABOLISM AND DISPOSITION: 2.1 ABSORPTION 2.2 DISTRIBUTION 2.3 METABOLISM 2.4 EXCRETION
3. NONCARCINOGENIC HEALTH EFFECTS: 3.1 ORAL EXPOSURES 3.2 INHALATION EXPOSURES 3.3 OTHER ROUTES OF EXPOSURE 3.4 TARGET ORGANS/CRITICAL EFFECTS
4. CARCINOGENICITY: 4.1 ORAL EXPOSURES 4.2 INHALATION EXPOSURES 4.3 OTHER ROUTES OF EXPOSURE 4.4 EPA WEIGHT-OF-EVIDENCE 4.5 CARCINOGENICITY SLOPE FACTORS
5. REFERENCES

May 1995

Prepared by Dennis M. Opresko, Ph.D., Chemical Hazard Evaluation and Communication Program, Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, *, Oak Ridge, Tennessee.

Prepared for OAK RIDGE RESERVATION ENVIRONMENTAL RESTORATION PROGRAM.

*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under contract No. DE-AC05-84OR21400.

EXECUTIVE SUMMARY

Lithium is an alkali metal similar to magnesium and sodium in its properties (Birch, 1988; Arena, 1986) and has a molecular weight of 6.941 (Beliles, 1994). It does not occur in nature in its free form but is found in minerals such as spodumene, petalite, and eucryptite (Beliles, 1994). Lithium compounds are found in natural waters and in some foods. The average dietary intake is estimated to be about 2 mg per day (Beliles, 1994).

Inorganic salts or oxides of lithium have many uses. Lithium carbonate is used extensively as a therapeutic agent in the treatment of manic depressive affective disorders (Ellenhorn and Barceloux, 1988). Elemental lithium is a component of metal alloys; lithium hydride is used as a nuclear reactor coolant. Lithium hydroxide is used in alkaline storage batteries; lithium carbonate and lithium borate are used in the ceramic industry; and lithium chloride and fluoride are used in welding and brazing fluxes (Beliles, 1994). Lithium forms covalent bonds in organometallic compounds such as lithium stearate. Organo-lithium compounds are used as multipurpose greases, particularly in the automotive industry (Beliles, 1994).

Most common inorganic lithium compounds are water soluble to some extent: i.e., chloride, 454 g/L; carbonate, 13.3 g/L; hydroxide, 223 g/L; oxide, 66.7 g/L (Beliles, 1994)). Lithium hydride reacts with water to form a very basic solution of lithium hydroxide.

Soluble lithium compounds are readily absorbed through the gastrointestinal tract but not the skin; distribution is rapid to the liver and kidneys but slower to other organ systems (Jaeger et al., 1985). Lithium crosses the human placenta (ACGIH, 1991) and can also be taken up by infants through breast milk. Lithium is not metabolized and is excreted primarily in the urine.

The oral toxicity of most lithium compounds is relatively low; oral LD₅₀ values for several compounds and animal species range from 422-1165 mg/kg. Case histories described by Gosselin et al. (1984) indicate that doses of 12-60 g (171-857 mg/kg/day for a 70 kg person) can result in coma, respiratory and cardiac complications, and death in humans. A single oral dose of 40 mg/kg produced toxic lithium blood levels in a patient with a history of prior lithium use (Marcus, 1980). In contrast, for chronic therapeutic use, the standard dose of lithium carbonate is 1-2 g/day (14-28 mg/kg/day).

The nervous system is the primary target organ of lithium toxicity. Neurologic effects occurring during prolonged therapy often include minor effects on memory, motor activity, and associative productivity (Kocsis et al., 1993). Movement disorders (myoclonus, choreoathetosis), proximal muscle weakness, fasciculations, gait disturbances, incontinence, corticospinal tract signs, and a Parkinsonian syndrome (cogwheel rigidity, tremor) have been reported (Sansone and Ziegler, 1985). Cases of severe lithium neurotoxicity, which may occur during chronic therapy as a result of increased lithium retention, may be characterized by disorientation, incoherence, paralysis, stupor, seizure, and coma (Hall et al., 1979). Permanent brain damage has occurred in several patients on long-term lithium therapy (Gosselin et al., 1984).

Cohort studies indicate that the risk of major congenital malformations among women receiving lithium during early pregnancy is slightly higher (4-12%) than that among control groups (2-4%) (Cohen et al., 1994). Evidence also suggests that women on lithium therapy may have a higher risk of premature births. In animals, reproductive and developmental effects (decrease in litter size, decrease in live pups, reduced growth, and increased incidence of cleft palate) have been reported in rodents exposed to lithium salts during gestation (Marathe and Thomas, 1986; Sechzer et al., 1992; Szabo, 1970; Chernoff and Kavlock, 1982). Subchronic and chronic oral RfDs have not been derived for lithium.

Limited information is available on the inhalation toxicity of lithium compounds. Lithium hydride is a respiratory tract irritant. In occupationally exposed workers, concentrations between 1 and 5.0 mg/m³ caused severe eye and nasal irritation as well as skin irritation; concentrations of 0.025 mg/m³ or less caused no adverse effects (Beliles, 1994). In animal studies, concentrations above 10 mg/m³ for 4-7 hours resulted in inflammation of the eyes, partial sloughing of mucosal epithelium of the trachea, lesions of the nose and forepaws, and erosion of the nasal septum (Spiegl et al., 1956).

Lithium combustion aerosols are also respiratory tract irritants. In a study in which rats were exposed for 4 hours to an aerosol consisting of 80% lithium carbonate and 20% lithium hydroxide, signs of toxicity included anorexia, dehydration, respiratory difficulty, perioral and perinasal encrustation, ulcerative or necrotic laryngitis, focal to segmental ulcerative rhinitis often accompanied by squamous metaplasia, and in some animals, suppurative bronchopneumonia or aspiration pneumonia, probably secondary to laryngeal lesions (Greenspan et al., 1986). The LC₅₀ (after 14 days) was estimated to be 1700 mg/m³ for males and 2000 mg/m³ for females. In a second study in which rats were exposed for 4 hours to an aerosol containing mostly lithium monoxide, some lithium hydroxide, and 12% lithium carbonate, the LC₅₀ value (after 14 days) was 940 mg/m³ (Rebar et al., 1986). Four-hour exposure to an aerosol containing primarily lithium hydroxide with 23% lithium carbonate resulted in an LC₅₀ of 960 mg/m³ (Rebar et al., 1986).

No information was found in the available literature on the subchronic, chronic, or developmental/reproductive toxicity of lithium compounds by the inhalation route. In addition, subchronic and chronic inhalation RfCs have not been derived for lithium.

Little information was found in the available literature on the carcinogenicity of lithium compounds. However, three patients on chronic lithium therapy developed leukemia, and one developed a thyroid tumor. Lithium has not been classified by EPA as to its potential carcinogenicity.

1. INTRODUCTION

Lithium is an alkali metal similar to magnesium and sodium in its properties (Birch, 1988; Arena, 1986) and has a molecular weight of 6.941 (Beliles, 1994). It does not occur in nature in its elemental form, primarily because it readily reacts with water to form lithium hydroxide (Beliles, 1994). It is found in minerals such as spodumene, petalite, and eucryptite (Beliles, 1994). Lithium is also found in natural waters (particularly mineral waters) as well as in foods. The daily dietary intake of lithium diet has been estimated to be about 2 mg (about 0.03 mg/kg/day for a 70 kg man) (Beliles, 1994).

Inorganic salts or oxides of lithium have many uses. Lithium carbonate and lithium borate are used in the ceramics industry, and lithium chloride and fluoride are used in welding and brazing fluxes (Beliles, 1994). Lithium carbonate is used extensively as a therapeutic agent in the treatment of manic depressive affective disorders (Ellenhorn and Barceloux, 1988); it has also been used as an antigout medication. In the 1940s, lithium chloride was used as a salt substitute for patients on a low-salt diet; however, this use was discontinued following the occurrence of lithium intoxication and death in some patients (Birch, 1988). In addition, lithium hydride is used as a nuclear reactor coolant. Lithium is also used in alloys, and the hydroxide is used in alkaline storage batteries. Lithium forms organometallic compounds (Birch, 1988), some of which have important industrial uses; lithium stearate and other fatty acid forms are used as multipurpose greases, particularly in the automotive industry (Beliles, 1994).

Lithium released into environmental media is likely to be present in the form of inorganic salts or oxides. Most common inorganic lithium compounds are water soluble to some extent, i.e., chloride, 454 g/L; carbonate, 13.3 g/L; hydroxide, 223 g/L; oxide, 66.7 g/L (Beliles, 1994). Lithium hydride reacts with water to form a very basic solution of lithium hydroxide.

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION

Soluble lithium compounds are readily absorbed from the gastrointestinal tract (Beliles, 1994). Lithium carbonate absorption is 95-100% complete within 1-6 hours after dosing (McEvoy et al., 1993). In contrast, absorption of lithium salts through the skin is very low (Beliles, 1994). Little lithium was absorbed into the body following 20 minutes exposure in a hot tub containing 40.5 ppm lithium ion (McCarty et al., 1994).

2.2 DISTRIBUTION

Lithium is distributed rapidly to the liver and kidneys following ingestion, but equilibrium between serum and brain, bone and muscle is reached after 8-10 days (Jaeger et al., 1985). Both the pituitary and thyroid glands concentrate lithium (Ellenhorn and Barceloux, 1988). During chronic therapy, lithium levels in the brain are equal to those in the serum (Schou, 1976). In overdose patients, the lithium concentration in brain tissue may remain high even after blood serum levels are reduced (Jaeger et al., 1985). Lithium can be present in breast milk at 30-100% of the concentration in the mother's serum (Arena, 1986), and lithium can also cross the human placenta (ACGIH, 1991).

2.3 METABOLISM

Lithium is not bound to plasma proteins and does not undergo hepatic metabolism (Jaeger et al., 1985; Ellenhorn and Barceloux, 1988).

2.4 EXCRETION

Lithium is excreted primarily in the urine (Ellenhorn and Barceloux, 1988). Hullin et al. (1968) reported urinary lithium excretion rates of 40-91% in individuals receiving 500 mg lithium carbonate three times per day. Trautner et al. (1955) reported that 90-95% of a lithium dose could be recovered in the urine at a rate of approximately 30-60% in the initial 6-8 hours followed by a slow rate over the next 14 days. The half-life for the fast phase was about 24 hours. The rate of excretion of lithium is reduced when salt intake is limited (Beliles, 1994).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES

3.1.1 Acute Toxicity

3.1.1.1 Human

In patients not previously exposed to lithium, or in those on chronic lithium therapy, a single large dose may result in vomiting and diarrhea; however, delayed effects may occur hours or days later (Gosselin et al., 1984).

Therapeutic blood levels are only slightly below levels at which toxicity may occur, and any change in conditions, such as a slightly higher dose or increased lithium retention (resulting from reduced water or salt intake or increased water or salt excretion), may result in an acute toxic response (Birch, 1988). Case histories described by Gosselin et al. (1984) indicate that lithium doses of 12-60 g (171-857 mg/kg/day for a 70 kg person) can result in coma, respiratory and cardiac complications, and death. A single oral dose of 40 mg/kg produced toxic lithium blood levels in a patient with a history of prior lithium use (Marcus, 1980). Kolk et al. (1993) reported that in single-dose clinical trials using lithium carbonate (36.6 mEq) and lithium sulfate (36 mEq), no changes in cognitive performance or mood occurred in nine volunteers within the first 6 hours after dosing.

Signs and symptoms of lithium toxicity include anorexia; nausea; diarrhea; alopecia; weight gain; thirst; pretibial edema (sodium retention); polyuria; glycosuria; aplastic anemia; tremors; acne; muscle spasm; hypothyroidism; and, rarely, dysarthria, ataxia, impaired cognition, and pseudotumor cerebri (Arena, 1986; Ellenhorn and Barceloux, 1988). Severe leucopenia developed in one case of fatal lithium poisoning (Green and Dunn, 1985). Permanent cerebellar degeneration manifested by truncal ataxia, hyperreflexia, and an intention tremor occurred after an overdose (Bejar, 1985). Of a group of 22 patients suffering from a lithium overdose, two died, two had neurological symptoms, and five had abnormal renal function (Birch, 1988).

3.1.1.2 Animal

For lithium carbonate, oral LD₅₀ values of 710 mg/kg (Smyth et al., 1969) and 525 mg/kg (RTECS, 1995b) have been reported for the rat, 531 mg/kg for the mouse, and 500 mg/kg for the dog (RTECS, 1995b). For lithium chloride, oral LD₅₀ values of 526 mg/kg (rat), 1165 mg/kg (mouse), 800 mg/kg (rabbit), and 422 mg/kg (quail) have been reported (RTECS, 1995a).

Studies on mice and dogs have shown that a low sodium diet decreases lithium urinary clearance and increases toxicity. Radomsky et al. (1950) reported that dogs on a low-salt diet died within 30 days when dosed with 20 mg lithium chloride/kg/day; whereas those on a normal salt diet survived exposure to 50 mg/kg/day (Shito et al., 1992). In the latter case, a dose of 100 mg/kg/day was lethal within 42 days.

3.1.2 Subchronic Toxicity

3.1.2.1 Human

No information was found in the available literature on the subchronic toxicity of lithium compounds to humans by the oral pathway.

3.1.2.2 Animal

Histopathological examination of the kidneys of rats receiving lithium chloride in their diet revealed that the test animals exhibited focal cortical interstitial fibrosis and nephrotic atrophy (Ottosen et al., 1984; 1986). Rats given lithium carbonate in their diet (1.1 g/kg diet) for 1 month exhibited a reduction in blood levels of potassium, rubidium, and zinc (Singh et al., 1994). Following 4 months' treatment, copper and iron levels were also reduced, and bromine levels increased.

Dogs on a diet containing 20 or 50 mg lithium chloride/kg/day for up to 20 weeks exhibited diuresis, tremors, salivation, lethargy, anorexia, weight loss, muscular weakness, lymphopenia, azotemia, electrocardiographic changes, and renal tubular damage (Radomsky et al., 1950).

3.1.3 Chronic Toxicity

3.1.3.1 Human

Long-term exposure to lithium has occurred as a result of the use of lithium as a salt substitute and in the treatment of neurologic disorders. Ingestion of lithium chloride by individuals on low-salt diets resulted in numerous cases of intoxication and some deaths (Birch, 1988). Some of these patients may have ingested up to 14 g of the compound per day (Birch, 1988). Lithium carbonate is used in the treatment of recurrent affective disorders (manic depressive psychoses). In such cases, lithium carbonate is given orally at doses of 1-2 g/day. Some patients have received the medication for up to 20 years with minimal adverse effects. However, there may be a progressive appearance of side effects in other patients (Birch, 1988). Younger children may be more susceptible to side effects than older individuals (Campbell et al., 1991). Following initiation of therapy, many patients exhibit mild tremors, loose stools, nausea, thirst, increased frequency of micturition, and increased urinary volume (Birch, 1988; Hansen and Amdisen, 1978). After 5 days to 6 weeks, fatigue, lethargy, muscular weakness, polydipsia and polyuria, and electrocardiographic changes may develop (Birch, 1988). Both initial and later side effects may disappear completely or disappear only to reappear at a later stage (Birch, 1988). Long-term side effects, which may appear after prolonged therapeutic use, include hypothyroidism, leukocytosis, edema, weight gain, changes in kidney function, and mild memory impairment.

During the course of chronic lithium therapy, the development of a severe toxic response may be preceded by vomiting, diarrhea, coarse tremors, slurred speech, sluggishness, sleepiness, and vertigo, followed by unconsciousness, muscular fasciculations, seizures, kidney damage, coma, shock, hypotension, and cardiac arrhythmias (Birch, 1988).

The nervous system is the primary target organ of lithium toxicity. Neurologic effects occurring during prolonged therapy often include minor effects on memory, motor activity, and associative productivity (Kocsis et al., 1993). Movement disorders (myoclonus, choreoathetosis), proximal muscle weakness, fasciculations, gait disturbances, incontinence, corticospinal tract signs, and a Parkinsonian syndrome (cogwheel rigidity, tremor) have been reported (Sansone and Ziegler, 1985). Axelsson and Nilsson (1991) observed that, in patients who had been receiving lithium on average for 8.2 years, the incidence of abnormal involuntary muscle movements was 8%; seven years later the incidence had increased to 16%. Most of these conditions improve upon discontinuation of treatment (Kocsis et al., 1993). In a study of 91 children on lithium therapy (250-2100 mg/day), Silva et al. (1992) found that ataxia, fatigue, and enuresis were the most common side effects.

Cases of severe lithium neurotoxicity, which may occur during chronic therapy as a result of increased lithium retention, can include encephalopathy characterized by disorientation, incoherence, paralysis, stupor, seizure, and coma (Hall et al., 1979). Permanent brain damage occurred in several patients on prolonged lithium therapy (Gosselin et al., 1984).

Effects of lithium on the thyroid may be manifested as diffuse nontoxic goiter (euthyroid goiter, hypothyroid goiter), hypothyroidism, and exophthalmos with hyperthyroidism (Shopsin, 1970; Schou and Amdisen, 1968; Segal et al., 1973; Rabin and Evans, 1981). Bocchetta et al. (1991) reported that 51% of 150 patients on lithium therapy had goiters and 19% hypothyroidism. Cases of thyrotoxicosis with severe exophthalmos can undergo dramatic improvement within days following discontinuation of lithium therapy (Byrne and Delaney, 1993).

During chronic lithium therapy, changes in kidney function may appear as transient natriuresis, polydipsia/polyuria, nephrogenic diabetes insipidus, partial renal tubular acidosis, minimal change disease and nephrotic syndrome (Ellenhorn and Barceloux, 1988; Richman et al., 1980). In rare cases, acute renal failure may occur (Fenves et al., 1984). Nephrogenic diabetes insipidus was reported in 12% of patients on long-term lithium therapy, while glomerular filtration rate was reduced in 21% and maximum urinary concentrating capacity was reduced in 44% (Bendz et al., 1994). In a cross-sectional study of 740 lithium patients, Kehoe (1994) found a weak correlation between duration of treatment and decreased glomerular filtration rate (GFR). In a prospective 10-year follow-up study of 46 patients who had been on lithium therapy for an average of 20 years, Hetmar et al. (1991) found that GFR decreased significantly, but the decline was essentially dependent on increasing age and related to the occurrence of intoxication episodes and dosing schedule and not to length of treatment. It was noted that multiple daily dosing was more likely to produce adverse renal effects than a single dose per day. In a review of the available data, Walker (1993) concluded that although most lithium-induced effects on the kidney (e.g., polyuria/polydipsia) are reversible, chronic focal interstitial nephropathy, caused primarily by episodes of acute intoxication, may, in some cases, be irreversible.

In reviewing the available literature on the cardiovascular effects of lithium, Tilkian et al. (1976) reported that therapeutic doses of lithium may produce reversible T wave flattening and inversion in a patient's electrocardiogram, and, rarely, sinus node dysfunction or venticular arrhythmias. More serious complications such as hypotension and cardiac collapse usually occur only after episodes of acute intoxication and when the patient is comatose (Tilkian et al., 1976).

Several different dermatologic reactions have been observed in individuals on long-term lithium therapy (Beliles, 1994). One patient developed a folliculitis consisting of hyperkeratotic erythematous follicular papules on the arms, legs, and, at times, on the trunk. Another patient developed a papular pruritic dermatitis on the elbows while receiving 900 or 1200 mg/day of lithium carbonate, and a third patient developed acneiform eruptions on the face and shoulders after receiving 900 mg/day of lithium carbonate (Beliles, 1994). Lithium therapy may also trigger or aggravate psoriasis in some individuals (Beliles, 1994).

3.1.3.2 Animal

Information on the chronic toxicity of lithium compounds to animals by the oral pathway was not found in the available literature.

3.1.4 Developmental and Reproductive Toxicity

3.1.4.1 Human

Of 225 infants born to women treated with lithium during early pregnancy, 25 exhibited congenital malformations (including 6 cases of Ebstein's anomaly--a congenital cardiac abnormality) (Schardein, 1985). RTECS (1995b) lists eight individual cases of stillbirths, developmental effects, or other indicators of adverse effects on newborn (e.g., Apgar score) for women who were on lithium carbonate therapy during pregnancy. However, recent studies have indicated that the teratogenic risks associated with lithium use during pregnancy are lower than previous estimates (Cohen et al., 1994). In one cohort study, rates of congenital birth defects did not differ between lithium (2.8%) and control groups (2.4%), and birth weights were significantly higher in the lithium-exposed group than in the controls (Jacobson, 1992; Jacobson et al., 1993). The risk ratio was 1.5 (95% CI 0.4-6.7) for all congenital malformations, 1.1 (95% CI = 0.1-16.6) for cardiac anomalies, and 3.5 (95% CI = 0.1-84.9) for Ebstein's anomaly. In a second cohort study, the risk ratios were 3.0 (95% CI = 1.2-7.7) for all congenital malformations and 7.7 (95% CI = 1.5-41.2) for cardiac anomalies (Kallen and Tandberg, 1983). Although Ebstein's anomaly has been linked to maternal lithium exposure, four case-control studies failed to reveal any association between the incidence of this defect and lithium exposure (Cohen et al., 1994). A review of the available data led Cohen et al. (1994) to conclude that women on lithium therapy have a slightly increased risk of bearing children with major congenital malformations than women not exposed to lithium (4-12% vs. 2-4%).

Maternal exposure to lithium may increase the risk of premature births. Troyer et al. (1993) reported that mothers on lithium therapy had a 2.5 times higher incidence of premature births than manic-depressive mothers not on lithium therapy. A study of the records of the International Register of Lithium Babies indicated that 36% of the infants were born prematurely, 37% of the premature infants were large for their gestational age, and 15% of the term infants were large for their gestational age (Troyer et al., 1993).

3.1.4.2 Animal

Exposure of pregnant rats to 50 mg/kg/day lithium carbonate on gestation days 6 to 15 caused no adverse developmental effects; however, at 100 mg/kg/day, there were significant reductions in the number of implantations and number of live fetuses, and a significant decrease in fetal body weight (Marathe and Thomas, 1986). Addition of lithium (1000 ppm lithium carbonate) to the diet of rats during gestation and/or during lactation (total exposure period up to 21 days) resulted in decreased growth in both the dams and the pups, and a significant reduction in litter size (Ibrahim and Conolty, 1990). In newborn rats, anatomical and behavioral maturation was delayed in animals born to dams receiving lithium (3.0 mEq/kg/day) in drinking water before and during gestation (Sechzer et al., 1992). Maternal neglect was evidenced by absence of nest building, short and infrequent periods of nursing, failure to retrieve pups, and poor grooming of pups.

In tests conducted by Szabo (1970), dose-related increases in the incidence of cleft palate were seen in fetuses of mice dosed orally with lithium carbonate for 10 consecutive days during pregnancy (0.4% at 200 mg/kg/day, 6% at 300 mg/kg/day, and 16 and 30% at 465 mg/kg/day). Chernoff and Kavlock (1982) reported that 400 mg lithium carbonate (polytronned)/kg/day on gestation days 8-12, resulted in a significant reduction in the number of newborn mice alive on post-natal days 1 and 3. Smithberg and Dixit (1982) found that reproduction was severely affected when strain 129 mice were given lithium carbonate in drinking water (2 mg/mL) during pregnancy. Only two litters survived among the 16 treated animals; one contained 4 fetuses and the other only 2. The resorption rate was 60% of all implantation sites counted. Messiha (1993) reported that maternal exposure to lithium (1 mEq in drinking water) from mating through weaning resulted in increases in weanling liver, kidney and spleen weights, and decreases in brain and testes weights. Enzyme changes were suggestive of possible effects on the heart and liver.

Kelley et al. (1978) reported that swine fed lithium (3000 mg Li₂CO₃/kg food = 1.6 g Li/day or 1.2 mEq/kg bw/day) during pregnancy gave birth to fewer live piglets (p less than 0.05), more mummies and stillbirths (p less than 0.01), and lighter litters (p less than 0.01) than controls. In addition, fewer of the liveborn piglets survived to 21 days of age.

3.1.5 Reference Dose

A reference dose (RfD) has not been derived for any lithium compound.

3.2 INHALATION EXPOSURES

3.2.1 Acute Toxicity

3.2.1.1 Human

Some lithium compounds are strong irritants. In occupationally exposed workers, lithium hydride concentrations of 1-5.0 mg/m³ were associated with severe eye and nasal irritation as well as skin irritation (Beliles, 1994). Exposures to 0.50-1.0 mg/m³ produced eye and nasal irritation and coughing, and concentrations of 0.10-0.50 mg/m³ were associated with nasal irritation and coughing. No irritant effects were reported in workers exposed to 0-0.025 mg/m³, and concentrations of 0.025-0.10 mg/m³ caused only a tickling sensation in the nose as well as some nasal discharge (Beliles, 1994). At high concentrations, the caustic action of lithium hydride may also cause pulmonary lesions (Birch, 1988).

3.2.1.2 Animal

Mice, rats, rabbits, and guinea pigs were exposed to lithium hydride concentrations of 5-55 mg/m³, for 4-7 hours or to 5 mg/m ³ (average of 4 hours/day for 5 days) (Spiegl et al., 1956). All exposures were intensely irritating, and caused coughing and sneezing. Concentrations above 10 mg/m³ resulted in inflammation of the eyes, partial sloughing of mucosal epithelium of the trachea, lesions of the nose and forepaws, and in a few animals, erosion of the nasal septum. Pulmonary emphysema, without bronchial lesions, occurred in animals exposed to 5 mg/m³ for 20 hours over 5 days; this was attributed to secondary effects of dyspnea, coughing, and sneezing and not to direct damage to the alveoli.

Exposure of rats to lithium combustion aerosols (80% lithium carbonate and 20% lithium hydroxide) once for 4 hours resulted in 14-day LC₅₀ values of 1700 mg/m³ (95% CL 1300-2000 mg/m³) in males and 2000 mg/m³ (95% CL 1700-2400 mg/m³) in females (Greenspan et al., 1986). Signs of toxicity included anorexia, dehydration, respiratory difficulty, perioral and perinasal encrustation, ulcerative or necrotic laryngitis, focal to segmental ulcerative rhinitis often accompanied by squamous metaplasia, and in some animals, suppurative bronchopneumonia or aspiration pneumonia, probably secondary to laryngeal lesions.

In another study in which rats were exposed for 4 hours to an aerosol containing mostly lithium monoxide, some lithium hydroxide, and 12% lithium carbonate, the LC₅₀ value (after 14 days) was 940 mg/m³ (95% CL 730-1200 mg/m³) (Rebar et al., 1986). Four-hour exposure to an aerosol containing primarily lithium hydroxide with 23% lithium carbonate resulted in an LC₅₀ of 960 mg/m³ (95% CL 830-1200 mg/m³) (Rebar et al., 1986). Both exposures resulted in necrotizing laryngitis and ulcerative rhinitis.

3.2.2 Subchronic Toxicity

Information was not found in the available literature on the subchronic toxicity of lithium compounds to humans or animals by the inhalation pathway.

3.2.3 Chronic Toxicity

Information was not found in the available literature on the chronic toxicity of lithium compounds to humans or animals by the inhalation pathway.

3.2.4 Developmental and Reproductive Toxicity

Information was not found in the available literature on the developmental or reproductive toxicity of lithium compounds to humans or animals by the inhalation pathway.

3.2.5 Reference Dose/Concentration

Reference concentrations have not been derived for any lithium compounds.

3.3 OTHER ROUTES OF EXPOSURE

3.3.1 Acute Toxicity

3.3.1.1 Human

Dermal contact with lithium hydride may cause a severe chemical burn (ACGIH, 1991). In atmospheres containing 0.5 mg/m³ lithium hydride, the skin becomes inflamed, and lacrimation occurs. Low concentrations are irritating to the eyes and high concentrations may cause permanent eye injury (ACGIH, 1991). Dermal contact with dusts generated from lithium/aluminum alloys have also been found to cause an intense irritant action, and long-term exposure can result in hydrolytic destruction of the epidermis (Bencze et al., 1991). This effect is primarily due to the formation of highly basic lithium hydroxide in the presence of water.

3.3.1.2 Animal

LD₅₀ data for lithium carbonate are reviewed by RTECS (1995b). Intraperitoneal LD₅₀ values of 156 mg/kg (rat) and 236 mg/kg (mouse), subcutaneous LD₅₀ values of 434 mg/kg (rat) and 413 mg/kg (mouse), and intravenous LD₅₀ values of 241 mg/kg (rat) and 497 mg/kg (mouse) have been reported. LD₅₀ values for lithium chloride are as follows: 499 mg/kg (rat) and 828 mg/kg (mouse) by subcutaneous injection; 514 mg/kg (rat), 600 mg/kg (mouse), and 492 mg/kg (cat) by intraperitoneal injection; 4.8 mg/kg (rat) and 14.0 mg/kg (mouse) by intracerebral injection; and 363 mg/kg (mouse) by intravenous injection (RTECS, 1995a). Lethal effects also resulted from subcutaneous lithium chloride doses of 450 mg/kg to cats, 531 mg/kg to rabbits, 620 mg/kg to guinea pigs, 513 mg/kg to pigeons, and 885 mg/kg to frogs (RTECS, 1995a). A dose of 100 mg of lithium chloride resulted in moderate eye irritation in rabbits, and 200 mg resulted in severe skin irritation in rabbits (RTECS, 1995a).

Intraperitoneal injections (500 mg/kg over 10 days) or subcutaneous injections (678 mg/kg over 8 days) of lithium chloride in rats caused changes in liver and spleen weight and increased urine volume (RTECS, 1995a). An intraperitoneal dose of 20 mg/kg produced a 2C fall in body temperature in rats (Perkinson et al., 1969). Subcutaneous injections in mice (total dose 5540 mg/kg over 17 days) resulted in weight loss and changes in urine composition (RTECS, 1995a).

Rats injected subcutaneously with lithium chloride (2 meq/kg/day for 8 days) exhibited a nephrotoxic response as indicated by an increase in urine volume and decrease in urine osmolality (Qureshi et al., 1992). Intraperitoneal administration of 8 mmol/kg/day of lithium chloride for 2-4 days to rats resulted in acute renal failure as shown by increased serum urea concentration (indicative of reduced glomerular filtration), decreased inulin clearance, and decreased renal plasma flow (Thomsen and Olesen, 1978).

3.3.2 Subchronic Toxicity

Information was not found in the available literature on the subchronic toxicity of lithium compounds by other routes of exposure.

3.3.3 Chronic Toxicity

No information was found in the available literature on the chronic toxicity of lithium compounds by other routes of exposure.

3.3.4 Developmental and Reproductive Toxicity

3.3.4.1 Human

No information was found in the available literature on the developmental or reproductive toxicity of lithium compounds in humans by other routes of exposure.

3.3.4.2 Animal

Intraperitoneal injections of lithium chloride (total dose 809-1250 mg/kg) in rats during pregnancy caused developmental abnormalities (eye, ear and craniofacial), effects on fertility (post-implantation mortality), abortions, and reductions in litter size (RTECS, 1995a). Malformations of the eye (62%), cleft palate (39%), and external ear (45%) were observed in the offspring of rats injected intraperitoneally with 50 mg/day of lithium chloride on days 1, 4, 7, and 9 of gestation, followed by 20 mg/day until day 17 (Wright et al., 1970). Subcutaneous injections of lithium chloride in male rats resulted in altered hormone levels and adverse effects on spermatogenesis (RTECS, 1995a).

In mice, intraperitoneal injection of lithium chloride during pregnancy (total dose 320 mg/kg) or subcutaneous injection (total dose 1240 mg/kg) caused adverse developmental effects, including craniofacial abnormalities (RTECS, 1995a). In strain 129 mice, intraperitoneal injection of lithium carbonate (200 mg/kg or one-half the LD₅₀) on day 8, 9, or 10 of gestation caused a significant increase (41.6%) in malformations (e.g., fused ribs and/or vertebral defects and exencephaly) (Smithberg and Dixit, 1982).

3.4 TARGET ORGAN/CRITICAL EFFECTS

3.4.1 Oral Exposures

3.4.1.1 Primary Target Organs

Nervous system: Neurologic effects in humans range from changes in memory and motor activity, proximal muscle weakness, fasciculations, gait disturbances, and incontinence, to encephalopathy (including disorientation, incoherence, paralysis, stupor, seizure, and coma). Movement disorders (myoclonus, choreoathetosis), and a Parkinsonian syndrome (cogwheel rigidity, tremor) have been reported (Hansen and Amdisen, 1978; Beliles, 1994; Ellenhorn and Barceloux, 1988). Permanent brain damage may occur following acute exposures.
Development: Risk of major congenital malformations among women receiving lithium during early pregnancy is slightly higher (4-12%) than that among control groups (2-4%) (Cohen et al., 1994). There is also evidence that lithium may cause an increase in the incidence of premature births. Lithium has been shown to cause reproductive and developmental effects in rodents; however, these effects occur primarily at or near dose levels that are maternally toxic (Cohen et al., 1994).

3.4.1.2 Other Target Organs

Kidney: During chronic therapeutic administration, lithium may cause changes in kidney function which are usually reversible upon discontinuation of treatment; however, acute renal failure has been reported in one case (Ellenhorn and Barceloux, 1988). In animals, the kidney is a primary target organ. Cases of cortical interstitial fibrosis and/or renal tubular damage have been reported in rodents and dogs following subchronic oral exposures to lithium.
Thyroid: Hypothyroidism is a common side effect of prolonged lithium therapy; however, symptoms are usually reversible upon discontinuation of treatment.
Heart: Cardiac complications of chronic lithium therapy may involve hyperkalemia, dysrhythmia, and hypotension (Tilkan et al., 1976). Serious cardiac complications may occur in cases of acute overdoses (Ellenhorn and Barceloux, 1988).
Gastrointestinal system: Mild gastrointestinal upset (nausea, vomiting, and diarrhea) often occurs with the initiation of lithium therapy (Ellenhorn and Barceloux, 1988).

3.4.2 Inhalation Exposures

3.4.2.1 Primary Target Organs

Respiratory system: Exposures to lithium hydride and lithium combustion aerosols can result in acute respiratory tract irritation.

3.4.2.2 Other Target Organs

Skin and eye: Exposures to lithium hydride can result in skin and eye irritation.

4. CARCINOGENICITY

4.1 ORAL EXPOSURES

Little evidence suggests that inorganic or organic lithium compounds are carcinogenic in humans; however, in case reports cited by RTECS (1995b), three individuals maintained on chronic lithium therapy developed leukemia, and one other patient developed a thyroid tumor. No long-term animal carcinogenicity studies have been conducted on lithium.

4.2 INHALATION EXPOSURES

Information on the carcinogenicity of lithium compounds to humans or animals following inhalation exposures was not found in the available literature.

4.3 OTHER ROUTES OF EXPOSURE

In a study cited by RTECS (1995a), mice injected intraperitoneally with lithium chloride over 7 days (total dose 882 mg/kg) developed lymphoma.

4.4 EPA WEIGHT-OF-EVIDENCE

Lithium and lithium compounds have not been classified by EPA as to their carcinogenicity in humans or animals.

4.5 CARCINOGENICITY SLOPE FACTORS

No slope factors have been calculated for lithium.

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Last Updated 10/31/97