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 (Nordstr?m 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).
