Developmental toxicity risk assessment: consensus building, hypothesis formulation, and focused research.

Risk assessment for developmental toxicity has become more defined over the last decade and the most recent EPA guidelines for developmental toxicity risk assessment were published in 1991. Development of approaches for risk assessment in this area have relied on building of consensus opinion among experts about the interpretation of developmental toxicity data. These discussions have aided in strengthening the scientific basis for risk assessment for developmental toxicity, including the default assumptions that must be used when more complete information on mechanisms of action and pharmacokinetics are unavailable. Such discussions continue on both a national and international basis. The EPA risk assessment guidelines outlined several major areas of research needed to strengthen risk assessment for developmental toxicity and led to the formulation of hypotheses to be tested in focused research projects. Several major research efforts have focused on dose-related mechanisms and biologically based modeling of specific agents, physiologically based pharmacokinetic models of pregnancy that can be scaled across species, and the influence of dose and duration of exposure on developmental outcomes, as well as the delineation of specific biomarkers of adverse developmental effects. Although such research initiatives will require a long-term effort, it is important that attention be focused now on those approaches that can improve the risk assessment process to avoid continued reliance on default approaches that have been used for the past 30 years or more. The impact of the EPA Guidelines for Developmental Toxicity Risk Assessment has been widespread. One of the main purposes for developing risk assessment guidelines by EPA was to communicate procedures to risk assessors inside the agency in an effort to promote consistency. In addition, the guidelines were to communicate to those outside the agency in private industry and other regulatory agencies how EPA would evaluate and interpret data. The developmental toxicity guidelines have standardized terminology used in developmental toxicity risk assessments. They also have influenced the revision of testing guidelines and the writing of new guidelines, such as the developmental neurotoxicity testing guidelines. More extensive use of developmental toxicity data within the RfD/RfC process was influenced by the guidelines, as well. More recently, the risk assessment guidelines have had a major impact on the harmonization of international testing and risk assessment guidelines through cooperative efforts with the World Health Organization under the auspices of the International Program on Chemical Safety (IPCS) and the Organization for Economic Cooperation and Development (OECD). We foresee these types of interagency and international cooperative efforts continuing as we attempt to make more efficient use of the limited resources available for testing, risk assessment, and research to better understand and prevent developmental toxicity.