Arsenic in drinking-water
Background document for development of WHO Guidelines for Drinking-water Quality
Effects on laboratory animals and in vitro test systems
1 Long-term exposure
There were significant reductions in cardiac output and stroke volume in male Wistar rats and female New Zealand rabbits ingesting drinking-water containing 50 mg of arsenic(III) per litre for 18 and 10 months, respectively. In contrast, there was no effect on cardiac function in rats following ingestion of the same concentration of arsenic(V) for 18 months (Carmignani et al., 1985).
2 Reproductive and developmental toxicity
Teratogenic effects of arsenic in chicks, golden hamsters and mice have been reported (Hood & Bishop, 1972; Zierler et al., 1988). Arsenate was teratogenic in the offspring of pregnant hamsters following exposure on days 4–7 of gestation by minipump implantation (Ferm & Hanlon, 1985). The specific form of arsenic responsible for teratogenesis is not known, but it may be arsenite (Hanlon & Ferm, 1986). Other workers did not observe teratogenicity in studies in which mice or rabbits were orally administered arsenic acid at 0–48 mg/kg of body weight per day on gestation days 6–15 and at 0–3 mg/kg of body weight per day on gestation days 6–18, respectively (Nemec et al., 1998). The above data indicate that although arsenic is teratogenic when given by parenteral routes, it is considerably less potent when given by the oral route.
3 Mutagenicity and related end-points
Arsenic does not appear to induce point mutations in bacterial and mammalian assays, although it can induce chromosome breakage, chromosomal aberrations and sister chromatid exchange in a linear, dose-dependent fashion in a variety of cultured cell types, including human cells (Jacobson-Kram & Montalbano, 1985; US EPA, 1988). Arsenic(III) is about an order of magnitude more potent than arsenic(V) in this respect (US EPA, 1988). Methylated trivalent arsenic metabolites have also been reported to be genotoxic in vitro and to show significantly greater potency than arsenic(III) (Mass et al., 2001). Arsenic has been shown to be capable of causing chromosome damage in bone marrow cells of mice in in vivo assays (Deknudt et al., 1986; Tinwell et al., 1991; Das et al., 1993; Choudhury et al., 1996). The mechanism of arsenic genotoxicity is not clear, although several mechanisms have been proposed, including reactive oxygen species and the inhibition of DNA repair (IPCS, 2001).
Arsenic has not been found to be carcinogenic in traditional animal bioassays. In a study of the potential of arsenic compounds to act as promoters, a significant increase in the incidence of kidney tumours was observed in male Wistar rats injected intraperitoneally with a single dose of diethylnitrosamine (30 mg/kg of body weight) and, from day 7, given the maximum tolerated dose (160 mg/litre) of arsenic(III) in drinking-water for 25 weeks (Shirachi et al., 1986). Other studies using mice with specific genetic characteristics have shown carcinogenic effects (IPCS, 2001), and these may be of value in studying the potential mechanism by which arsenic causes cancer. Animal models of arsenic carcinogenicity have been extensively reviewed by Wang et al. (2002).