The Risk Assessment Information System

Toxicity Summary for ARSENIC

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.

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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

April 1992

Prepared by: Dennis M. Opresko, Ph.D., Chemical Hazard Evaluation and Communication Group, Biomedical and Environmental Information Analysis Section, Health and Safety 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

The toxicity of inorganic arsenic (As) depends on its valence state (-3, +3, or +5), and also on the physical and chemical properties of the compound in which it occurs. Trivalent (As⁺³) compounds are generally more toxic than pentavalent (As⁺⁵) compounds, and the more water soluble compounds are usually more toxic and more likely to have systemic effects than the less soluble compounds, which are more likely to cause chronic pulmonary effects if inhaled. One of the most toxic inorganic arsenic compounds is arsine gas (AsH₃). It should be noted that laboratory animals are generally less sensitive than humans to the toxic effects of inorganic arsenic. In addition, in rodents the critical effects appear to be immunosuppression and hepato-renal dysfunction, whereas in humans the skin, vascular system, and peripheral nervous system are the primary target organs.

Water soluble inorganic arsenic compounds are absorbed through the G.I. tract (>90%) and lungs; distributed primarily to the liver, kidney, lung, spleen, aorta, and skin; and excreted mainly in the urine at rates as high as 80% in 61 hr following oral dosing (U.S. EPA, 1984; ATSDR, 1989; Crecelius, 1977). Pentavalent arsenic is reduced to the trivalent form and then methylated in the liver to less toxic methylarsinic acids (ATSDR, 1989).

Symptoms of acute inorganic arsenic poisoning in humans are nausea, anorexia, vomiting, epigastric and abdominal pain, and diarrhea. Dermatitis (exfoliative erythroderma), muscle cramps, cardiac abnormalities, hepatotoxicity, bone marrow suppression and hematologic abnormalities (anemia), vascular lesions, and peripheral neuropathy (motor dysfunction, paresthesia) have also been reported (U.S. Air Force, 1990; ATSDR, 1989; Franzblau and Lilis, 1989; U.S. EPA, 1984; Armstrong et al., 1984; Hayes, 1982; Mizuta et al., 1956). Oral doses as low as 20-60 g/kg/day have been reported to cause toxic effects in some individuals (ATSDR, 1989). Severe exposures can result in acute encephalopathy, congestive heart failure, stupor, convulsions, paralysis, coma, and death. The acute lethal dose to humans has been estimated to be about 0.6 mg/kg/day (ATSDR, 1989). General symptoms of chronic arsenic poisoning in humans are weakness, general debility and lassitude, loss of appetite and energy, loss of hair, hoarseness of voice, loss of weight, and mental disorders (Hindmarsh and McCurdy, 1986). Primary target organs are the skin (hyperpigmentation and hyperkeratosis) [Terada et al. 1960; Tseng et al., 1968; Zaldivar 1974; Cebrian et al., 1983; Huang et al., 1985], nervous system (peripheral neuropathy) [Hindmarsh et al., 1977, 1986; Valentine et al., 1982; Heyman et al., 1956; Mizuta et al., 1956; Tay and Seah, 1975], and vascular system [Tseng et al., 1968; Borgano and Greiber, 1972; Salcedo et al., 1984; Wu et al., 1989; Hansen, 1990]. Anemia, leukopenia, hepatomegaly, and portal hypertension have also been reported (Terada et al., 1960; Viallet et al., 1972; Morris et al., 1974; Datta, 1976). In addition, possible reproductive effects include a high male to female birth ratio (Lyster, 1977).

In animals, acute oral exposures can cause gastrointestinal and neurological effects (Heywood and Sortwell, 1979). Oral LD₅₀ values range from about 10 to 300 mg/kg (ASTDR, 1989; U.S. Air Force, 1990). Low subchronic doses can result in immunosuppression, (Blakely et al., 1980) and hepato-renal effects (Mahaffey et al., 1981; Brown et al., 1976; Woods and Fowler, 1977, 1978; Fowler and Woods, 1979; Fowler et al., 1979). Chronic exposures have also resulted in mild hyperkeratosis and bile duct enlargement with hyperplasia, focal necrosis, and fibrosis (Baroni et al., 1963; Byron et al., 1967). Reduction in litter size, high male/female birth ratios, and fetotoxicity without significant fetal abnormalities occur following oral exposures (Schroeder and Mitchener, 1971; Hood et al., 1977; Baxley et al., 1981); however, parenteral dosing has resulted in exencephaly, encephaloceles, skeletal defects, and urogenital system abnormalities (Ferm and Carpenter, 1968; Hood and Bishop, 1972; Beaudoin, 1974; Burk and Beandoin, 1977).

The Reference Dose for chronic oral exposures, 0.0003 mg/kg/day, is based on a NOAEL of 0.0008 mg/kg/day and a LOAEL of 0.014 mg/kg/day for hyperpigmentation, keratosis, and possible vascular complications in a human population consuming arsenic-contaminated drinking water (U.S. EPA, 1991a). Because of uncertainties in the data, U.S. EPA (1991a) states that "strong scientific arguments can be made for various values within a factor of 2 or 3 of the currently recommended RfD value." The subchronic Reference Dose is the same as the chronic RfD, 0.0003 mg/kg/day (U.S. EPA, 1992).

Acute inhalation exposures to inorganic arsenic can damage mucous membranes, cause rhinitis, pharyngitis and laryngitis, and result in nasal septum perforation (U.S. EPA, 1984). Chronic inhalation exposures, as occurring in the workplace, can lead to rhino-pharyno-laryngitis, tracheobronchitis, (Lundgren, 1954); dermatitis, hyperpigmentation, and hyperkeratosis (Perry et al., 1948; Pinto and McGill, 1955); leukopenia (Kyle and Pease, 1965; Hine et al., 1977); peripheral nerve dysfunction as indicated by abnormal nerve conduction velocities (Feldman et al., 1979; Blom et al., 1985; Landau et al., 1977); and peripheral vascular disorders as indicated by Raynaud's syndrome and increased vasospastic reactivity in fingers exposed to low temperatures (Lagerkvist et al., 1986). Higher rates of cardiovascular disease have also been reported in some arsenic-exposed workers (Lee and Fraumeni, 1969; Axelson et al., 1978; Wingren and Axelson, 1985). Possible reproductive effects include a high frequency of spontaneous abortions and reduced birth weights (Nordström et al., 1978a,b). Arsine gas (AsH₃), at concentrations as low as 3-10 ppm for several hours, can cause toxic effects. Hemolysis, hemoglobinuria, jaundice, hemolytic anemia, and necrosis of the renal tubules have been reported in exposed workers (ACGIH, 1986; Fowler and Weissberg, 1974).

Animal studies have shown that inorganic arsenic, by intratracheal instillation, can cause pulmonary inflammation and hyperplasia (Webb et al., 1986, 1987), lung lesions (Pershagen et al., 1982), and immunosuppression (Hatch et al. (1985). Long-term inhalation exposures have resulted in altered conditioned reflexes and CNS damage (Rozenshstein, 1970). Reductions in fetal weight and in the number of live fetuses, and increases in fetal abnormalities due to retarded osteogenesis have been observed following inhalation exposures (Nagymajtenyi et al., 1985).

Subchronic and chronic RfCs for inorganic arsenic have not been derived.

Epidemiological studies have revealed an association between arsenic concentrations in drinking water and increased incidences of skin cancers (including squamous cell carcinomas and multiple basal cell carcinomas), as well as cancers of the liver, bladder, respiratory and gastrointestinal tracts (U.S. EPA, 1987; IARC, 1987; Sommers et al., 1953; Reymann et al., 1978; Dobson et al., 1965; Chen et al., 1985, 1986). Occupational exposure studies have shown a clear correlation between exposure to arsenic and lung cancer mortality (IARC, 1987; U.S. EPA, 1991a). U.S. EPA (1991a) has placed inorganic arsenic in weight-of-evidence group A, human carcinogen. A drinking water unit risk of 5E-5(ug/L)^-1 has been proposed (U.S. EPA, 1991a); derived from drinking water unit risks for females and males that are equivalent to slope factors of 1.0E-3 (ug/kg/day)^-1 (females) and 2.0E-3 (ug/kg/day)^-1 (males) (U.S. EPA, 1987). For inhalation exposures, a unit risk of 4.3E-3 (ug/m³)^-1 (U.S. EPA, 1991a) and a slope factor of 5.0E+1 (mg/kg/day)^-1 have been derived (U.S. EPA, 1992).

1. INTRODUCTION

The toxicity of inorganic compounds containing arsenic depends on the valence or oxidation state of the arsenic (-3, +3, or +5), as well as on the physical and chemical properties of the compound in which it occurs. Trivalent (As⁺³) compounds such as arsenic trioxide (As₂O₃), arsenic trisulfide (As₂S₃), and sodium arsenite (NaAsO₂), are generally more toxic than pentavalent (As⁺⁵) compounds such as arsenic pentoxide (As₂O₅), sodium arsenate (Na₂HAsO₄), and calcium arsenate (Ca₃(AsO₄)₂). Trivalent arsenic interacts with sulfhydryl groups of proteins and enzymes; pentavalent arsenic substitutes for phosphate groups important in oxidative phosphorylation (Squibb and Fowler, 1983). The relative toxicity of the trivalent and pentavalent forms may also be affected by factors such as the water solubility of the compound. Although the more water soluble arsenic compounds are generally more toxic and more likely to have systemic effects, the less soluble compounds are more likely to cause chronic pulmonary effects if inhaled. One of the most toxic arsenic compounds is arsine gas (AsH₃) with arsenic in the -3 valence state.

It should be noted that laboratory animals are generally less sensitive than humans to the toxic effects of inorganic arsenic. In addition, in rodents the critical effects appear to be immunosuppression and hepato-renal dysfunction, whereas in humans the skin, vascular system, and peripheral nervous system are the primary target organs.

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

Absorption of water soluble inorganic arsenic compounds through the G.I. tract is very high. In humans, absorption rates of 96.5% for trivalent sodium arsenite and 94% for soluble pentavalent arsenic have been reported (Bettley and O'Shea, 1975; Pomroy et al., 1980). In contrast, G.I. absorption of the less soluble arsenic trisulfide and lead arsenate was reported to be only 20-30% in hamsters (Marafante and Vahter, 1987). In tests on humans, absorption of the insoluble arsenic selenide appeared to be neglible as indicated by the absence of an increase in urinary arsenic excretion (Mappes, 1977).

Absorption of arsenic in the lungs is dependant on particle size as well as water solubility; respirable particles (0.1-1 u) are carried further into the lungs and are therefore more likely to be absorbed (ATSDR, 1989). Estimates of pulmonary absorption may be complicated by the fact that some of the particles may be cleared from the lungs, then swallowed and absorbed through the G.I. tract. In studies on smelter workers exposed to arsenic dusts of about 5 u particle size, Lagerkvist et al. (1986) estimated that 75% of the dust would be deposited in the respiratory tract and 80% of this would be absorbed directly or through the stomach after mucocillary clearance.

2.2. DISTRIBUTION

Following absorption of trivalent or pentavalent arsenic compounds, arsenic is initially accumulated in the liver, kidney, lung, spleen, aorta, and skin. With the exception of the skin, clearance from these organs is rapid. Arsenic is also extensively deposited in the hair and nails (U.S. EPA, 1984).

2.3. METABOLISM

Arsenic compounds are subject to metabolic transformation. In both humans and animals, pentavalent arsenic compounds are reduced to trivalent forms and then methylated in the liver to less toxic methylarsinic acids (ATSDR, 1989).

2.4. EXCRETION

Arsenic is cleared from the body relatively rapidly and primarily in the urine. Urinary excretion rates of 80% in 61 hr following oral doses and 30-80% in 4-5 days following parenteral doses have been measured in humans (Crecelius, 1977; Hunter et al., 1942). Arsenic is also lost from the body in the hair and nails, since this represents a non-biologically available arsenic pool.

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

Common symptoms of inorganic arsenic poisoning are nausea, anorexia, vomiting, epigastric and abdominal pain, and diarrhea. Dermatitis (exfoliative erythroderma), muscle cramps, cardiac abnormalities, hepatotoxicity, bone marrow suppression and hematologic abnormalities (anemia and leukopenia), vascular lesions, and peripheral neuropathy (motor dysfunction, long axon Wallerian degeneration) have also been reported (U.S. Air Force, 1990; ATSDR, 1989; Franzblau and Lilis, 1989; U.S. EPA, 1984; Armstrong et al., 1984; Hayes, 1982; Mizuta et al., 1956).

Oral doses as low as 20-60 g/kg/day have been reported to cause toxic effects in some individuals (ATSDR, 1989). Severe exposures can result in acute encephalopathy, congestive heart failure, stupor, convulsions, paralysis, coma, and death. The acute lethal dose to humans has been estimated to be about 0.6 mg/kg/day (ATSDR, 1989). A dose estimated at 3 mg/day for a 1-2 month period was fatal to 1% of a group of infants receiving arsenic-contaminated milk (Hamamoto, 1955).

3.1.1.2. Animal

Monkeys exposed to acutely toxic doses of inorganic arsenic exhibit gastrointestinal distress and neurological effects. Adolescent and infant Rhesus monkeys receiving 5 daily oral doses of a complex inorganic arsenic compound containing the equivalent of 7.5 mg/kg of arsenic trioxide exhibited loss of condition, vomiting, diarrhea, salivation and uncontrolled shaking of the head (Heywood and Sortwell, 1979).

LD₅₀ values for inorganic arsenic compounds in laboratory animals range from about 10 to 300 mg/kg (ASTDR, 1989; U.S. Air Force, 1990).

3.1.2. Subchronic Toxicity

3.1.2.1. Human

Depending on the dose and duration, subchronic exposures to inorganic arsenic can cause toxic effects similar to those caused by acute and/or chronic exposures. Skin and vascular disorders, neuropathy, gastroenteritis, hepatotoxicity, and hematological abnormalities (anemia and leukopenia) have been reported in individuals exposed for time periods ranging from less than 6 months to 13 years (ATSDR, 1989; Huang et al., 1985).

Borgono and Greiber (1972) reported a 12% incidence of skin abnormalities in children whose drinking water contained 0.6-0.8 mg As/L. The earliest cases occurred about 4-5 years after the initial exposure. Cardiovascular effects, including Raynaud's syndrome, acrocyanosis, angina pectoris, hypertension, myocardial infarction, mesenteric thrombosis, systemic occlusive arterial disease, bronchiectasis, and recurrent broncho-pneumonia were also observed in this group of subjects (Zaldivar, 1980). The bronchiectasis and recurrent broncho-pneumonia were attributed to an immunosuppressive action of arsenic in the lungs. A significant decrease in the incidence of skin abnormalities was observed following a reduction in drinking water concentration to about 0.04 mg/L. After 4 years at the lower exposure, effects were rarely seen in children younger than 12 years old (Borgono et al., 1977).

Central nervous system deficits (hearing loss, eye damage, abnormal EEGs, mental retardation, epilepsy), electrocardiographic changes (elevated ST wave and extended QT interval), and skin abnormalities (melanosis, desquamation, rashes, and hyperkeratosis) occurred in infants who had been fed arsenic-contaminated milk for 1-2 months (Hamamoto, 1955). It was estimated that the daily arsenic intake was about 3 mg/day (U.S. EPA, 1984).

3.1.2.2. Animal

Immunosuppression and hepato-renal toxicity have been identified as toxic effects in rodents. Immunosuppression, as measured by hemagglutination, radial immunodiffusion, and Cunningham plaque assays, was observed in mice exposed for 3 weeks to sodium arsenite levels of 0.5 ppm in drinking water (Blakely et al., 1980). Reported hepato-renal effects include: (1) mild swelling of renal tubular cell mitochondria and decreases in liver-derived serum enzymes (aspartate aminotransferase [AST] and alkaline phosphatase) in rats following 10 weeks exposure to 50 ppm dietary arsenate (Mahaffey et al., 1981); (2) functional and ultrastructural changes in the kidneys of rats exposed for 6 weeks to arsenate concentrations of 85 and 125 ppm in drinking water (Brown et al., 1976); (3) disruption of liver biosynthesis of heme and -aminolevulinic (ALA) synthetase activity in mice and rats exposed for 6 wk to 40 and 85 ppm arsenic in drinking water (Woods and Fowler, 1977, 1978); (4) alteration of hepatocyte mitochondrial structure and liver enzyme activity (monoamine oxidase, cytochrome oxidase) in rats and mice exposed for 6 weeks to 20-85 ppm sodium arsenate in drinking water (Fowler and Woods, 1979; Fowler et al., 1979); and (5) increases in serum AST and alanine aminotransferase (ALT) levels due to hepatocyte plasma membrane dysfunction in beagle dogs fed dietary levels of sodium arsenite equivalent to 4 mg/kg for 58 days followed by 8 mg/kg/day for an additional 125 days (Neiger and Osweiler, 1989).

In a six-month study in which rats were fed 250 ppm pentavalent or trivalent arsenic, Douglas and Blendermann (1961) found that trivalent arsenic caused bile duct lesions and a significant depression in growth.

Although arsenic-induced skin disorders are not commonly seen in rodents, eczema, hyperplasia, and hyperkeratosis were reported in two-week-old rats dosed for 40 days by stomach intubation with 2 mg/kg/day or 10 mg/kg/day of arsenic trioxide (Ishinishi et al., 1976). Avoidance conditioning responses were also impaired by these dose levels (Osato, 1977).

3.1.3. Chronic Toxicity

3.1.3.1. Human

General symptoms of chronic arsenic poisoning are weakness, general debility and lassitude, loss of appetite and energy, loss of hair, hoarseness of the voice, loss of weight, and mental abnormalities (Hindmarsh and McCurdy, 1986). Skin, neurological, and vascular disorders are the most common effects seen following long-term exposures.

Skin abnormalities, particularly hyperpigmentation and hyperkeratosis have been observed in populations exposed to arsenic in drinking water (Terada et al. 1960; Tseng et al., 1968; Zaldivar 1974; Cebrian et al., 1983; Huang et al., 1985). Tseng et al. (1968) reported an incidence rate of 18% for hyperpigmentation and 7% for hyperkeratosis in a Taiwanese population whose drinking water contained an average arsenic concentration of 0.4-0.6 ppm. Skin abnormalities were also reported in 40% of patients consuming Fowler's solution for 6-26 years (Fierz, 1965).

Arsenic-induced neurotoxicity is manifested as a peripheral neuropathy involving both sensory and motor nerves, and resulting in numbness and paresthesia, diminished sensations of touch, pain, heat, and cold, and muscle weakness (Hindmarsh et al., 1977; Hindmarsh and McCurdy, 1986; Valentine et al., 1982; Heyman et al., 1956; Mizuta et al., 1956; Tay and Seah, 1975).

Peripheral vascular disorders have been reported in several populations whose drinking water contained high arsenic levels (Tseng et al., 1968; Salcedo et al., 1984; Chen et al., 1988). Blackfoot disease (a condition caused by arteriosclerosis and thromboangiitis obliterans), which can result in gangrene of the lower extremities, occurred in 0.9% of one such population (Tseng et al., 1968; 1977). Epidemiological studies and mechanistic considerations have implicated arsenic as a possible causative factor in arteriosclerotic plaque formation and cardiovascular disease (Wu et al., 1989; Hansen, 1990; Penn, 1990).

Chronic oral exposures to arsenic reportedly have also resulted in anemia, leukopenia, liver swelling, and noncirrhotic portal hypertension (Terada et al., 1960; Viallet et al., 1972; Morris et al., 1974; Datta, 1976; Nevens et al., 1990).

3.1.3.2. Animal

Studies in rats have demonstrated no-adverse-effect levels of 1.4 (males) and 1.6 mg As/kg/day (females) for sodium arsenite and 2.8 (males) and 3.25 mg As/kg/day (females) for sodium arsenate (Byron et al., 1967). Similar studies on dogs revealed a no-adverse-effect level at 1.1 mg As/kg/day. A drinking water concentration of 5 ppm produced no toxic effects in rats when administered over an entire lifetime (Schroeder et al., 1968).

Mild hyperkeratosis has been reported in mice exposed for a lifetime to arsenic oxide in drinking water at a concentration of 0.01% (Baroni et al., 1963).

Bile duct enlargement with hyperplasia of the glandular elements, focal necrosis, and fibrosis was seen in rats receiving dietary arsenic levels of 125 and 250 ppm as sodium arsenite and 250 and 400 ppm as sodium arsenate for up to two years (Byron et al., 1967). Lifetime (29 mo) exposure to lead arsenate at a dietary level of 1850 ppm also caused bile duct lesions in rats (Kroes et al., 1974).

3.1.4. Developmental and Reproductive Toxicity

3.1.4.1. Human

A high male-to-female birth ratio (157 to 100) was reported for a population that may have been exposed to elevated arsenic levels in their drinking water 10 to 11 months earlier (Lyster, 1977).

3.1.4.2. Animal

Chronic exposure of pregnant mice to 5 ppm sodium arsenite in drinking water resulted in a slight reduction in litter size and a higher male/female ratio (increased from 0.93 to 1.71), but no adverse effects on fetal development (Schroeder and Mitchner, 1971). Oral doses as high as 120 mg/kg/day of sodium arsenate were reported to be fetotoxic but not teratogenic to rats (Hood et al., 1977). Oral doses of 25-40 mg/kg of sodium arsenite caused prenatal mortality and a low, but non-significant, incidence of fetal malformations (exencephaly) in mice (Baxley et al., 1981).

3.1.5. Reference Dose

3.1.5.1. Subchronic

• ORAL RfD: 0.0003 mg/kg/day (U.S. EPA, 1992)
• UNCERTAINTY FACTOR: 3
• NOAEL: 0.0008 mg/kg/day, epidemiological study.
• COMMENT: The same study applies to the subchronic and chronic RfD (see Section 3.1.5.2).

3.1.5.2. Chronic

• ORAL RfD: 0.0003 mg/kg/day (U.S. EPA, 1991a)
• UNCERTAINTY FACTOR: 3
• MODIFYING FACTOR: 1
• NOAEL: 0.0008 mg/kg/day, epidemiological study
• CONFIDENCE:
  Study: Medium
  Data Base: Medium
  RfD: Medium
• VERIFICATION DATE: 11/15/90
• PRINCIPAL STUDIES: Tseng, W.P. 1977; Tseng et al., 1968
• COMMENT: The NOAEL was based on an arithmetic mean of 0.009 mg/L in drinking water (range 0.001-0.17 mg/L), a daily water consumption of 4.5 L, and an arsenic intake in food of 0.002 mg/day. A LOAEL of 0.014 mg/kg/day for hyperpigmentation, keratosis, and possible vascular complications, was based on an arithmetic mean of 0.14 mg/L in drinking water (4.5 L/day), and 0.002 mg/kg in food. The UF of 3 is to account for both the lack of data to preclude reproductive toxicity as a critical effect and to account for some uncertainty in whether the NOAEL of the critical study accounts for all sensitive individuals.
• NOTE: U.S. EPA (1991a) states that "strong scientific arguments can be made for various values within a factor of 2 or 3 of the currently recommended RfD value, i.e., 0.1-0.8 g/kg/day"; therefore, considerable flexibility is allowed in formulating regulatory decisions.

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

Inorganic arsenic dusts can cause respiratory irritation and mucous membrane damage leading to rhinitis, pharyngitis or laryngitis. Several weeks exposure to high concentrations can result in nasal septum perforation (U.S. EPA, 1984). Although inhalation exposures to most inorganic arsenic compounds are not usually associated with acute lethality (ATSDR, 1989); exposure to 250 ppm of arsine gas is instantly fatal and several hours exposure to concentrations as low as 10 ppm can produce toxic symptoms and may also be fatal (Fowler and Weissberg, 1974; NIOSH, 1979). Arsine causes severe hemolysis, hemoglobinuria, jaundice, hemolytic anemia, and necrosis of the renal tubules (ACGIH, 1986; Fowler and Weissberg, 1974).

3.2.1.2. Animal

Intratracheal instillation studies indicate that inorganic arsenic can have direct toxic effects on respiratory tissue. Trivalent arsenic oxide and gallium arsenide were shown to cause pulmonary inflammation and hyperplasia in rats (Webb et al., 1986, 1987), and calcium arsenate caused lung lesions in hamsters; however, arsenic trioxide and arsenic trisulfide did not have such an effect (Pershagen et al., 1982).

The pulmonary immune response can be affected by inorganic arsenic compounds. Hatch et al. (1985) reported significant increases in mortality of mice due to infectious streptococcal challenge following intratracheal injection of sodium arsenite, and Aranyi et al. (1985) reported similar increases in mortality as well as decreases in pulmonary bactericidal activity to Klebsiella pneumonia following single and multiple inhalation exposures to arsenic trioxide.

Exposure of mice to arsine concentrations as low as 2.5 ppm caused significant decreases in red blood cells, hematocrit and hemoglobin, as well as significant increases in white blood cell counts, and mean corpuscular volume of RBC. Erythropoiesis in bone marrow cells was impaired and erythropoiesis in the spleen was increased (Hong et al., 1989).

3.2.2. Subchronic Toxicity

3.2.2.1. Human

Subchronic inhalation exposures to inorganic arsenic are expected to cause toxic effects similar to those resulting from chronic exposures (see Section 3.2.3).

3.2.2.2. Animal

Rats exposed for 3 months to 46 g/m³ of arsenic trioxide aerosol exhibited altered conditioned reflexes and CNS damage as evidenced by pericellular edema and neuronal cytolysis in the brain (Rozenshstein, 1970).

Rats exposed to 0.025 ppm arsine gas for 90 days developed anemia (Blair et al., 1990). Higher exposure levels (primarily 2.5 ppm) resulted in bone marrow hyperplasia, increased splenic hemosiderosis and extramedullary hematopoiesis, decreased packed cell volume, increased delta-aminolevulinic acid dehydratase activity, and increased relative spleen weight. Similar effects were seen in mice and hamsters.

3.2.3. Chronic Toxicity

3.2.3.1. Human

Information on the inhalation toxicity of inorganic arsenic is derived primarily from occupational exposure studies, particularly those involving smelter workers. Early studies identified chronic respiratory diseases (rhinitis, pharyngitis, laryngitis, tracheobronchitis, and pulmonary insufficiency) and blood disorders (leukopenia) in exposed workers (Lundgren, 1954; Kyle and Pease, 1965). In one study, a 23% incidence of relative neutropenia occurred in 130 smelter workers exposed to arsenic air concentrations averaging less than 0.5 mg/m³ (Hine et al., 1977).

Neurological disorders (peripheral nerve dysfunction indicated by abnormal nerve conduction velocities) have been documented in smelter workers exposed to arsenic concentrations of <=0.5 mg/m³ (Feldman et al., 1979; Blom et al., 1985; Landau et al., 1977). Chronic encephalopathy, evidenced by cognitive impairment and psychological symptoms was reported in two workers exposed to arsenic fumes for 14-18 months (Morton and Caron, 1989). Abnormal electromyograms were reported for populations living near an arsenic mine and smelter (Takahashi, 1974). Hearing losses have been reported in children living near a coal-fired power plant burning high-arsenic content coal (U.S. EPA, 1984).

Chronic exposure of smelter workers to low levels of atmospheric arsenic (<=0.5 mg/m³) caused subtle changes in the peripheral vascular system, as indicated by an increased incidence of Raynaud's syndrome (white fingers) and increased vasospastic reactivity in fingers exposed to low temperatures (Lagerkvist et al., 1986). Higher rates of cardiovascular disease have also been reported in some arsenic-exposed workers (Lee and Fraumeni, 1969; Axelson et al., 1978; Wingren and Axelson, 1985).

Dermatitis, hyperpigmentation, and hyperkeratosis were observed in early studies of workers exposed to inorganic arsenic (Perry et al., 1948; Pinto and McGill, 1953); however, it is not known to what degree the reported effects were due to direct skin contact and accidental ingestion of the arsenic dust.

Chronic exposure to very low levels of arsine gas may have a cumulative effect in causing anemia (Fowler and Weissberg, 1974).

3.2.3.2 Animal

Glaser et al. (1986) exposed male Wistar rats to aerosols (<0.3 m MMAD) of arsenic trioxide for 18 months at concentrations of 0, 60, and 200 g/m³. The animals were observed for one year after the termination of the exposures and no adverse effects on body weight, hematology, clinical chemistry, or macro- or microscopic structure of internal organs were reported.

3.2.4. Developmental and Reproductive Toxicity

3.2.4.1. Human

A significantly higher frequency of spontaneous abortions (11% vs 7.6%) and significantly reduced birth weights were recorded for a population living near a copper smelter when compared with control populations (Nordström et al., 1978a,b).

3.2.4.2. Animal

Nagymajtenyi et al. (1985) exposed mice for 4 hr/day to an aerosol of arsenic trioxide (28.5 mg/m³) on days 9-12 of gestation, and found a significant reduction in fetal weight and in the number of live fetuses. In addition, there was a significant increase in the number of fetuses with retarded osteogenesis and an increase in the frequency of chromosomal aberrations (chromosome breaks and chromatid exchanges). Concentrations of 2.9 mg/m³ and 0.26 mg/m³ caused no significant changes, except a slight decrease in fetal weight.

3.2.5. Reference Dose/Concentration

Subchronic and chronic RfCs for inorganic arsenic have not been derived.

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Information on the acute toxicity of inorganic arsenic to humans by other routes of exposure was not available.

3.3.1.2. Animal

Intraperitoneal LD₅₀ values of 4-20 mg/kg for various inorganic arsenic compounds have been reported (ATSDR, 1989).

3.3.2. Subchronic Toxicity

3.3.2.1. Human

Information on the subchronic toxicity of inorganic arsenic to humans by other routes of exposure was not available.

3.3.2.2. Animal

Intraperitoneal injections of sodium arsenate solution at a dose level of 0.2 mg/kg for two months, resulted in inner ear damage and hearing loss in guinea pigs (Aly et al., 1975).

3.3.3. Chronic Toxicity

3.3.3.1. Human

Skin contact with inorganic arsenic dusts in occupationally exposed workers has been associated with direct dermatitis, allergenic hypersensitivity, and conjunctivitis (U.S. EPA, 1984; Pinto and McGill, 1953; Holmqvist, 1951).

3.3.3.2. Animal

Weekly injections of up to 10 mg/kg/day, for 18 months did not produce signs of neuropathy in rats (Schaumburg, 1980).

3.3.4. Developmental and Reproductive Toxicity

3.3.4.1. Human

Information on the developmental and reproductive toxicity of inorganic arsenic to humans by other routes of exposure was not available.

3.3.4.2. Animal

Some inorganic arsenic compounds cause teratogenic effects when administered parenterally. Intravenous injections of sodium arsenate into hamsters on day 8 of gestation at dose levels of 15, 17.5, or 20 mg/kg/day resulted in exencephaly, encephaloceles, skeletal defects, and urogenital system abnormalities in fetuses (Ferm and Carpenter, 1968). Intraperitoneal injections of sodium arsenate, at doses levels of 30 mg/kg/day or higher, resulted in similar terata in rats and mice (Hood and Bishop, 1972; Beaudoin, 1974; Burk and Beaudoin, 1977).

3.4. TARGET ORGAN/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organs

1. Skin: Hyperpigmentation and hyperkeratosis in humans.
2. Nervous System: Peripheral neuropathy and CNS effects in humans.
3. Cardiovascular System: Peripheral and cardiovascular disorders in humans.

3.4.1.2. Other Target Organs

1. Blood: Hematological changes (anemia, leukopenia).
2. Liver: Liver swelling in humans; cirrhosis and portal hypertension in animals.
3. G.I. System: Gastroenteritis in humans and monkeys at high doses.
4. Reproductive Effects: Increased male to female birth ratio in animals and possibly in humans.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organs

1. Skin: Dermatitis and possibly hyperpigmentation and hyperkeratosis in humans.
2. Nervous System: Peripheral neuropathy and CNS effects in humans.
3. Cardiovascular System: Peripheral vascular disorders in humans.

3.4.2.2. Other Target Organs

1. Respiratory system: Rhinitis, laryngitis, tracheobronchitis, pulmonary insufficiency, and nasal septum perforation.
2. Blood: Hematological changes (anemia, leukopenia).
3. Developmental Effects: Increase in spontaneous abortions, reduction in birth weight observed in animals and humans.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

4.1.1. Human

Epidemiological studies have revealed a close association between arsenic concentrations in drinking water and increased incidences of skin cancers, including squamous cell carcinomas and multiple basal cell carcinomas (U.S. EPA, 1987). Tseng et al. (1968) reported skin cancer rates of 2.6, 10.1 and 21.4 per 1000 in Taiwanese populations whose drinking water contained <=0.30, 0.30-0.59, and >=0.6 ppm As, respectively. No cases of skin cancer were seen in a control population of 7500 whose drinking water contained 0.001-0.017 ppm As. Cebrian et al. (1983) reported a 3.6-fold increase in skin lesions thought to be associated with epidermoid or basal cell carcinomas, in residents of a Mexican town whose drinking water contained 0.4 ppm As.

Chronic oral exposure to arsenic has also been linked to various types of internal cancers, including those of the liver, bladder, and respiratory and gastrointestinal tracts (U.S. EPA, 1987; IARC, 1987; Sommers and McManus, 1953; Reymann et al., 1978; Dobson et al., 1965; Chen et al., 1985, 1986).

4.1.2. Animal

Of the many studies conducted on laboratory animals, only a few have been able to show a positive association between oral exposure to arsenic and increased tumor incidence. Knoth (1966/67) reported increased incidences of adenocarcinomas of the skin, lung, peritoneum, and lymph nodes in NMRI mice dosed with arsenic trioxide or Fowler's solution once per week for 5 months (estimated total dose 7 mg/animal). Katsnelson et al. (1986) reported that arsenic trioxide induced a low incidence of adenocarcinomas at the site of its implantation in the stomach of rats. In addition, Shirachi et al. (1983) reported that sodium arsenite enhanced the incidence of renal tumors induced in rats by intraperitoneal injection of the carcinogen N-nitrosodiethylamine.

4.2. INHALATION EXPOSURES

4.2.1. Human

Occupational exposure studies of smelter and pesticide workers have shown a close association between exposure to arsenic and lung cancer mortality (IARC, 1987; U.S. EPA, 1991a). A dose- and duration-dependent increased frequency of respiratory tract cancers was found in copper smelter workers exposed to air-borne arsenic concentrations averaging up to 62 mg/m³ (arithmetic mean) (Lee and Fraumeni, 1969; Lee-Feldstein, 1983, 1986, 1989). Standardized mortality ratios (SMR) as high as 981 and a maximum relative risk of 6 were reported (Lee-Feldstein, 1986, 1989). At another smelter, lung cancer mortality rates were correlated with cumulative arsenic exposure as measured by urinary arsenic excretion values, and arsenic concentrations of 10 mg/m³ were linked to a SMR greater than 200 (Enterline and Marsh, 1982; Enterline et al., 1987). Similarly, in a study of Swedish smelter workers, a clear positive dose-response relationship was found between cumulative arsenic exposure and lung cancer mortality and the overall SMR was 372 (Järup et al., 1989). Both proportionate mortality and cohort studies of pesticide workers have also shown an increased incidence of lung cancer deaths (Ott et al., 1974; Mabuchi et al., 1979).

An increased risk of lung cancer may also occur in non-occupationally exposed populations living in areas with high atmospheric levels of arsenic resulting from industrial emissions. Higher lung cancer rates have been reported in residents living near smelters (Brown et al., 1984; Pershagen 1985) and near an arsenic pesticide manufacturing plant (Matanoski et al., 1981).

4.2.2. Animal

Several animal studies have shown an association between tumor induction and exposure to arsenic by inhalation or intratracheal instillation. Ivankovic et al. (1979) reported that lung tumors developed in 9 of 15 BD IX rats given a single intratracheal instillation of Bordeaux mixture (4% calcium arsenate containing 0.07 mg As). In another study, calcium arsenate induced a borderline increase in lung adenomas following intratracheal instillation, but arsenic trisulfide had no effect on tumor incidence. Perinatal treatment of mice with arsenic trioxide resulted in the induction of lung adenomas (Rudnay and Börzsönyi 1981), and intratracheal instillation of the same compound in hamsters resulted in respiratory tract carcinomas, adenomas, papillomas and adenomatoid lesions (Ishinishi et al., 1983; Pershagen et al., 1984a,b).

4.3. OTHER ROUTES OF EXPOSURE

Osswald and Goerttle (1971) reported a high incidence (11/19) of lymphocytic leukemia or lymphomas in female Swiss mice injected intravenously with 0.5 mg As/kg (as sodium arsenate) once per week for 20 weeks. In a second study with pregnant mice injected subcutaneously with 0.5 mg/kg, once per day for 20 days during pregnancy, 11 of 24 developed the same types of tumors.

DiPaolo and Casto (1979) reported that sodium arsenate induced cell transformations in vitro in Syrian hamster embryo cells, and Casto et al. (1979) reported that sodium arsenite enhanced virus-induced cell transformation.

4.4. EPA WEIGHT-OF-EVIDENCE

4.4.1. Oral

Classification -- A; human carcinogen (U.S. EPA, 1991b)

Basis -- Increased skin cancer incidence in several populations consuming drinking water with high arsenic concentrations.

4.4.2. Inhalation

Classification -- A; human carcinogen (U.S. EPA, 1991a)

Basis -- Increased lung cancer mortality in populations exposed primarily through inhalation.

4.5. CARCINOGENICITY SLOPE FACTORS

4.5.1. Oral

• SLOPE FACTOR: 1.0E-3 (ug/kg/day)^-1 (females) and 2.0E-3 (ug/kg/day)^-1 (males) (U.S. EPA, 1987). These slope factors were based on unit risks of 3E-5 (females) and 7E-5 (ug/L)^-1 (males) that were used to derive a single drinking water unit risk as shown below.
• DRINKING WATER UNIT RISK: 5E-5 (ug/L)^-1 (U.S. EPA, 1991a).
• PRINCIPAL STUDIES: Tseng et al., 1968; Tseng, 1977
• VERIFICATION DATE: Not given.
• COMMENT: The final unit risk is the arithmetic mean of the unit risks derived for females and males in a population in Taiwan exposed to arsenic in drinking water. Uncertainties associated with this unit risk involve the dose-response relationship, particularly in regard to (1) differential mortality due to other arsenic-induced diseases, (2) the possibility that ingestion of arsenic-contaminated foods contributed to the effects, and (3) the shape of the dose-response curve at low doses. A memorandum from the EPA administrator noted that the "uncertainties associated with ingested inorganic arsenic are such that estimates could be modified downwards as much as an order of magnitude, relative to risk estimates associated with most other carcinogens."

4.5.2. Inhalation

• SLOPE FACTOR: 5.0E+1 (mg/kg/day)^-1 (U.S. EPA, 1992)
• INHALATION UNIT RISK: 4.3E-3 (ug/m³)^-1 (U.S. EPA, 1991a)
• PRINCIPAL STUDIES: Brown and Chu, 1983a-c, Lee-Feldstein, 1983; Higgins, 1982; Enterline and Marsh, 1982.
• VERIFICATION DATE: 01/13/88
• COMMENT: The final unit risk is the geometric mean of the geometric means for distinct exposed populations of workers at two different copper smelters. It was assumed that the increase in age-specific mortality was a function only of cumulative exposure. The unit risk should not be used if the air concentration exceeds 2 ug/m³ (U.S. EPA, 1992).

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