Modeling adverse environmental impacts on the reproductive system

When priority topics are being established for the study of women's health, it is generally agreed that one important area on which to focus research is reproduction. For example, increasing attention has been directed to env ironmental exposures that disrupt the endocrine system and alter reproducti on. These concerns also suggest the need to give greater attention to the u se of animal toxicologic testing to draw inferences about human reproductiv e risks. Successful reproduction requires multiple simultaneous and sequent ial processes in both the male and female, and the effect of toxicity on re production-related processes is time dependent. Currently, however, the ris k assessment approach does not allow for the use of multiple processes or f or considering the reproductive process response as a function of time. We discuss several issues in modeling exposure effects on reproductive functio n for risk assessment and present an overview of approaches for reproductiv e risk assessment. Recommendations are provided for an effective animal stu dy design for determining reproductive risk that addresses optimization of the duration of dosing, observation of the effects of exposure on validated biomarkers, analysis of several biomarkers for complete characterization o f the exposure on the underlying biologic processes, the need for longitudi nally observed exposure effects, and a procedure for estimating human repro ductive risk from the animal findings. An approach to characterizing reprod uctive toxicity to estimate the increased fertility risks in a dibromochlor opropane (DBCP)-exposed human population is illustrated, using several repr oductive biomarkers simultaneously from a longitudinal rabbit inhalation st udy of DBCP and an interspecies extrapolation method.