Appropriate use of animal models in the assessment of risk during prenataldevelopment: An illustration using inorganic arsenic

Background: Assessing risks to human development from chemical exposure typ ically requires integrating findings from laboratory animal and human studi es. Methods: Using a case study approach, we present a program designed to asse ss the risk of the occurrence of malformations from inorganic arsenic expos ure. We discuss how epidemiological data should be evaluated for quality an d criteria for determining whether an association is causal. In this case s tudy, adequate epidemiological data were not available for evaluating the p otential effect of arsenic on development. Consequently, results from appro priately designed, conducted, and interpreted developmental toxicity studie s, which have been shown to be predictive of human risk under numerous scen arios, were used. In our case study, the existing animal data were not desi gned appropriately to assess risk from environmental exposures, although su ch studies may be useful for hazard identification. Because the human and a nimal databases were deficient, a research program comprising modern guidel ine toxicological studies was designed and conducted. Results: The results of those studies in rats, mice, and rabbits indicate t hat oral and inhalational exposures to inorganic arsenic do not cause struc tural malformations, and inhalational exposures produced no developmental e ffects at all. The new study results are discussed in conjunction with cons iderations of metabolism, toxicokinetics, and maternal toxicity. Conclusions: Based on the available experimental data, and absent contrary findings from adequately conducted epidemiological studies, we conclude tha t exposure to inorganic arsenic by environmentally relevant routes poses no risk of the occurrence of malformations and little risk of other prenatal developmental toxicity in developing humans without concomitant and near-le thal toxicological effects in mothers. (C) 2000 Wiley-Liss, Inc.