Neurotoxicology risk assessment guidelines: developmental neurotoxicology

Abstract

EPA's Neurotoxicity Risk Assessment Guidelines were recently published in final form in the Federal Register (1998). This document was developed over a period of nearly ten years and is intended to establish operating principles used in the evaluation of data for neurotoxicity risk assessment. The guidelines contain a number of assumptions and definitions of key concepts, as well as guidance as to the evaluation of various behavioral and structural changes produced by chemical exposure in humans and animals. With regard to developmental neurotoxicity, risk assessors should be aware that chemical-induced neurotoxicity in adults may not always be a good predictor of developmental neurotoxicity. Adverse effects on the developing nervous system can occur prior to conception up to the time of sexual maturity, depend on the time of exposure relative to a critical state of nervous system development, can be seen at any time during the lifespan of the organism, may lead to delayed onset or latent effects, and may elicit compensatory mechanisms that obscure underlying neurotoxicity. Adverse effects include persistent alterations in function or structure of the nervous system or a change in the time or appearance of any endpoint. Relative to neurotoxicity in adult animals, there are several special concerns in hazard characterization of developmental studies, including maternal toxicity, the use of the litter as the statistical unit, and time of exposure relative to the ontogeny of various structural or functional endpoints. Dose-response evaluation of data from developmental studies is similar to that for adults, although a safety factor of 10 may be applied to protect children's health. The guidelines also note that exposure patterns of children differ from those of adults resulting in a greater intake of chemicals on a per body weight basis. The guidelines note several research needs, including more information on mechanisms of developmental neurotoxicity, mechanistically based dose-response models, impact of early exposure to chemicals on late-onset disease, studies on threshold, and experiments on potential interactions between chemicals in mixtures.