Expanding the test set: Chemicals with potential to disrupt mammalian brain development.

High-throughput test methods including molecular, cellular, and alternative species-based assays that examine critical events of normal brain development are being developed for detection of developmental neurotoxicants. As new assays are developed, a "training set" of chemicals is used to evaluate the relevance of individual assays for specific endpoints. Different training sets are necessary for each assay that would comprise a developmental neurotoxicity test battery. In contrast, evaluation of the predictive ability of a comprehensive test battery requires a set of chemicals that have been shown to alter brain development after in vivo exposure ("test set"). Because only a small number of substances have been well documented to alter human neurodevelopment, we have proposed an expanded test set that includes chemicals demonstrated to adversely affect neurodevelopment in animals. To compile a list of potential developmental neurotoxicants, a literature review of compounds that have been examined for effects on the developing nervous system was conducted. The search was limited to mammalian studies published in the peer-reviewed literature and regulatory studies submitted to the U.S. EPA. The definition of developmental neurotoxicity encompassed changes in behavior, brain morphology, and neurochemistry after gestational or lactational exposure. Reports that indicated developmental neurotoxicity was observed only at doses that resulted in significant maternal toxicity or were lethal to the fetus or offspring were not considered. As a basic indication of reproducibility, we only included a chemical if data on its developmental neurotoxicity were available from more than one laboratory (defined as studies originating from laboratories with a different senior investigator). Evidence from human studies was included when available. Approximately 100 developmental neurotoxicity test set chemicals were identified, with 22% having evidence in humans.

The use of developmental neurotoxicity data in pesticide risk assessments.

Following the passage of the Food Quality Protection Act, which mandated an increased focus on evaluating the potential toxicity of pesticides to children, the number of guideline developmental neurotoxicity (DNT) studies (OPPTS 870.6300) submitted to the U.S. Environmental Protection Agency (EPA) Office of Pesticide Programs (OPP) was greatly increased. To evaluate the impact of available DNT studies on individual chemical risk assessments, the ways in which data from these studies are being used in pesticide risk assessment were investigated. In addition, the neurobehavioral and neuropathological parameters affected at the lowest observed adverse effect level (LOAEL) for each study were evaluated to ascertain whether some types of endpoints were consistently more sensitive than others. As of December 2008, final OPP reviews of DNT studies for 72 pesticide chemicals were available; elimination of studies with major deficiencies resulted in a total of 69 that were included in this analysis. Of those studies, 15 had been used to determine the point of departure for one or more risk assessment scenarios, and an additional 13 were determined to have the potential for use as a point of departure for future risk assessments (selection is dependent upon review of the entire database available at the time of reassessment). Analysis of parameters affected at the study LOAELs indicated that no single parameter was consistently more sensitive than another. Early assessment time points (e.g., postnatal day (PND) 11/21) tended to be more sensitive than later time points (e.g., PND 60). These results demonstrate that data generated using the current guideline DNT study protocol are useful in providing points of departure for risk assessments. The results of these studies also affirm the importance of evaluating a spectrum of behavioral and neuropathological endpoints, in both young and adult animals, to improve the detection of the potential for a chemical to cause developmental neurotoxicity.