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

Abstract

Background Assessing risks to human development from chemical exposure typically requires integrating findings from laboratory animal and human studies. Methods Using a case study approach, we present a program designed to assess the risk of the occurrence of malformations from inorganic arsenic exposure. We discuss how epidemiological data should be evaluated for quality and criteria for determining whether an association is causal. In this case study, adequate epidemiological data were not available for evaluating the potential effect of arsenic on development. Consequently, results from appropriately designed, conducted, and interpreted developmental toxicity studies, which have been shown to be predictive of human risk under numerous scenarios, were used. In our case study, the existing animal data were not designed appropriately to assess risk from environmental exposures, although such studies may be useful for hazard identification. Because the human and animal databases were deficient, a research program comprising modern guideline toxicological studies was designed and conducted. Results The results of those studies in rats, mice, and rabbits indicate that oral and inhalational exposures to inorganic arsenic do not cause structural malformations, and inhalational exposures produced no developmental effects at all. The new study results are discussed in conjunction with considerations of metabolism, toxicokinetics, and maternal toxicity. Conclusions Based on the available experimental data, and absent contrary findings from adequately conducted epidemiological studies, we conclude that 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‐lethal toxicological effects in mothers. Teratology 62:51–71, 2000. © 2000 Wiley‐Liss, Inc.

Reproductive consequences of oral arsenate exposure during pregnancy in a mouse model

“…While an in-depth discussion of environmentally relevant dose selection in laboratory animal studies is outside the scope of this report, it is important to note that the doses used in most laboratory animal studies are high when compared to doses likely to be encountered in exposed human populations (DeSesso, 2001;Holson et al, 2000a). Lethal doses calculated per kg of body weight for small laboratory animals are generally observed to be substantially higher than the observed and estimated lethal doses in humans: in summary, laboratory animals are generally less sensitive to toxicants.…”

“…Available studies have lacked a sufficient cohort size to demonstrate associations with specific malformations, and the majority of human epidemiological studies have relied on proxy measures of exposure (e.g., distance from a smelter) that are subject to various degrees of misclassification. In the few studies in which maternal exposure was directly evaluated, measurements were not taken during the relevant embryological period of neural tube closure (Holson et al, 2000a).…”

“…These studies have demonstrated that As crosses the placenta and preferentially accumulates in the neuroepithelium of developing hamster, mouse, and monkey embryos (Hanlon and Ferm, 1977;Lindgren et al, 1984), and that maternal As exposure is teratogenic. Furthermore, As is associated with an increased risk of NTDs when the exposure occurs specifically during the period of neural tube closure (Holson et al, 2000a). However, criticism regarding the design of these studies has hampered the use of evidence from animal models for policy decisions.…”

“…However, criticism regarding the design of these studies has hampered the use of evidence from animal models for policy decisions. Common deficits ascribed to the early experimental animal literature on As teratogenicity include: use of environmentally non-relevant routes of exposure, lack of qualitative or quantitative assessment of maternal toxicity, lack of a dose-response design, insufficient number of animals per treatment group, incomplete identification of test substance, partial description of methods, and inadequate reporting of results (Holson et al, 2000a). While many of these issues have been addressed as the field of teratology has matured, conflict has continued over the issues of dose and route of As administration.…”

“…While many of these issues have been addressed as the field of teratology has matured, conflict has continued over the issues of dose and route of As administration. It has been suggested that teratogenicity is only reached in laboratory animal studies when As doses are so high as to induce maternal toxicity, especially in the case of the few oral studies available for review (Holson et al, 2000a). In the current study, we address concerns regarding dose and route of administration by evaluating the teratogenicity of oral exposure to As using an inbred mouse strain, LM/Bc/Fnn, that does not exhibit an underlying rate of spontaneous neural malformations, yet is highly sensitive to As-induced NTDs.…”