AN ASSESSMENT OF THE DEVELOPMENTAL TOXICITY OF INORGANIC ARSENIC

A critical analysis of the literature base regarding the reproductive and developmental toxicity of arsenic compounds, with emphasis on inor ganic arsenicals, was conducted. The analysis was stimulated by the gr eat number of papers that have purported to have shown an association between exposure of pregnant laboratory animals to arsenic compounds a nd the occurrence of offspring with cranial neural tube defects, parti cularly exencephaly, For the most part, the literature reports of arse nic developmental toxicity in experimental animals are inadequate far human risk assessment purposes. Despite the shortcomings of the experi mental database, several conclusions are readily apparent when the ani mal studies are viewed collectively. First, cranial neural tube defect s are induced in rodents only when arsenic exposure has occurred early in gestation (on Days 7 [hamster, mouse], 8 [mouse], or 9 [rat]), Sec ond, arsenic exposures that cause cranial neural tube defects are sing le doses that are so high as to be lethal (or nearly so) to the pregna nt animal. Third, the effective routes of exposure are by injection di rectly into the venous system or the peritoneal cavity; even massive o ral exposures do not cause increases in the incidence of total gross m alformations. Fourth, repetition of similar study designs employing ex aggerated parenteral doses is the source of the large number of papers reporting neural tube defects associated with prenatal arsenic exposu re. Fifth, in five repeated dose studies carried out following EPA Gui delines for assessing developmental toxicity, arsenic was not teratoge nic in rats (As-III, 101 mu mol/kg/d, oral gavage; 101 mu mol/m(3), in halation), mice (As-V, 338 mu mol/kg/d, oral gavage; est, 402 mu mol/k g/d, diet), or rabbits (As-V, 21 mu mol/kg/d, oral gavage), Data regar ding arsenic exposure and adverse outcomes of pregnancy in humans are limited to several ecologic epidemiology studies of drinking water, ai rborne dusts, and smelter environs, These studies failed to (1.) obtai n accurate measurements of maternal exposure during the critical perio d of organogenesis and (2) control for recognized confounders. The lon e study that examined maternal arsenic exposure during pregnancy and t he presence off neural tube defects in progeny failed to confirm a rel ationship between the two. It is concluded that under environmentally relevant exposure scenarios (e.g,, 100 ppm in soil), inorganic arsenic is unlikely to pose a risk to pregnant women and their offspring. (C) 1998 Elsevier Science Inc.