Elaine Z. Francis

Scientific and regulatory issues relevant to assessing risk for developmental neurotoxicity: An overview☆

The effects of chemical exposure on the developing nervous system have been documented in both humans and animals for a variety of agents. However, the comparability of these effects has not been carefully evaluated to determine the predictability of animal models to adverse effects in humans. A workshop sponsored by the U.S. Environmental Protection Agency (EPA) and the National Institute on Drug Abuse was held on April 11-13, 1989, to address the Qualitative and Quantitative Comparability of Human and Animal Developmental Neurotoxicity. Invited experts were asked to review the human and animal data on several agents that are known to cause developmental neurotoxicity in humans, including lead, methylmercury, selected abused agents, anticonvulsants, polychlorinated biphenyls (PCBs), ethanol and X-irradiation, and to make quantitative comparisons on a specific end point basis as well as on a functional category basis. In addition, they were asked to make quantitative comparisons when adequate dose-effect data were available. The data also were evaluated in the context of the proposed EPA developmental neurotoxicity testing battery to determine whether or not the battery would adequately detect the effects of each agent. Finally, four work groups were asked to reach consensus on issues relating to: 1) comparability of end points across species for developmental neurotoxicity; 2) testing methods in developmental neurotoxicity for use in human risk assessment; 3) weight-of-evidence and quantitative evaluation of data from developmental neurotoxicity studies; and 4) triggers for developmental neurotoxicity testing.

Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity: Summary and implications☆

The Workshop on the Qualitative and Quantitative Comparability of Human and Animal Developmental Neurotoxicity was convened by the U.S. Environmental Protection Agency (EPA) and the National Institute on Drug Abuse to address issues related to when testing should be required, what test methodologies should be required, and how the data should be interpreted and applied to the risk assessment process. The background material for Work Group discussions included presentations made at the Workshop by invited experts summarizing qualitative and quantitative human and experimental animal data on specific chemicals or classes of chemicals and EPAs proposed developmental neurotoxicity testing protocol. This overview: 1) summarizes the qualitative comparisons presented at the Workshop and attempts to make some quantitative comparisons of findings across mammalian species following exposure to developmental neurotoxicants, 2) brings the common themes that were discussed among the Work Groups together into a regulatory perspective, 3) provides a status report on EPAs developmental neurotoxicity protocol, and 4) identifies research needs in the development of test methodologies and improvement of risk assessments for developmental neurotoxicants.

Proceedings of the workshop on the acceptability and interpretation of dermal developmental toxicity studies

The workshop on The Acceptability and Interpretation of Dermal Developmental Toxicity Studies, held April 13-14, 1988, was organized by the U.S. EPAs Office of Research and Development and Office of Toxic Substances and was supported by the Agencys Risk Assessment Forum. The purpose of the workshop was to review the current state of knowledge on the use of the dermal route of exposure in developmental toxicity studies. In evaluating this area, three major issues were considered by the participants: (1) the evaluation of maternal toxicity in dermal developmental toxicity studies, (2) what types of pharmacokinetic data are necessary or desirable for the appropriate design and interpretation of these studies, and (3) what factors are important to consider in the design of dermal developmental toxicity studies. The participants concluded: (1) dermal developmental toxicity studies without any indication of maternal or developmental toxicity are inadequate for risk assessment unless accompanied by absorption data, (2) absorption data and limited pharmacokinetic data should be collected in every dermal developmental toxicity study, and (3) dermal developmental toxicity studies in which skin irritation is too marked should be considered inadequate for risk assessment. General recommendations made for all developmental toxicity studies regardless of the route of exposure were: signs of local irritation should be examined, and absorption/pharmacokinetic data should be developed. Areas in which additional research is needed to permit more complete assessment of dermal developmental toxicity studies were also identified.

Proceedings of the Workshop on One-vs Two-Generation Reproductive Effects Studies

The Workshop on One-vs Two-Generation Reproductive Effects Studies was held on October 21-22, 1987. It was organized by the USEPAs Office of Pesticides and Toxic Substances and Office of Research and Development and was supported by the Agencys Risk Assessment Forum. The purpose of the workshop was to address the central question: Is a single-generation reproductive effects study sufficient to assess the reproductive toxicity potential of chemicals that do not bioaccumulate? In response to this question, the panel of nine participants concluded that, by itself, a one-generation reproductive effects study is insufficient to identify all potential reproductive toxicants and that a two-generation study is needed for an adequate assessment. The panel did not support placing much importance on bioaccumulation as related to reproductive toxicity testing mainly because it is not the only critical factor that may account for effects in a second generation but not in the first. In studying broader issues, the panel accomplished several goals that hopefully may serve to direct future development in reproductive toxicity testing: (1) the purpose of a reproductive effects study was defined, (2) a minimal set of end points necessary for adequate evaluation of reproductive toxicity was determined, (3) some alternative reproductive effects test methods were recommended, (4) greater flexibility in choosing a test protocol on a case by case basis was encouraged, and (5) areas that need further research were identified.

An overview of the U. S. EPA proposed amendments to the guidelines for the health assessment of suspect developmental toxicants

The U.S. Environmental Protection Agency has recently proposed amendments to the Guidelines for the Health Assessment of Suspect Developmental Toxicants. These amendments expand and clarify points made in the original guidelines, and add new information based on advances in the field. For example, the original risk assessment guidance was developed around several basic assumptions that were implicit in the earlier document, but that are clearly stated in the proposed amendments. Also, several consensus workshops were held following the completion of the 1986 guidelines, and the conclusions of these workshops have been incorporated. These include workshops dealing with the relationship of maternal and developmental toxicity, and with the development of an approach for a weight-of-evidence classification. In addition, a reference dose for developmental toxicity (RfDT) is proposed, based on short-term exposure, to distinguish it from the Rf D for chronic exposure. Other proposed changes include the expansion of the functional developmental toxicity section to reflect the Agencys testing guidelines for developmental neurotoxicity, and the human studies section which now gives more guidance on the use of human data in risk assessment. A number of other minor proposed changes are discussed. The final amended guidelines are currently undergoing Agency review and should be completed within the next year.