TEMPORAL ISSUES IN REPRODUCTIVE RISK ASSESSMENT

While there is increasing interest in characterizing reproductive hazards, reproductive endpoints are complex, difficult to characterize, and variable across populations and across time in the same individual. It is generally appreciated that rime is a critical variable; however, it is seldom fully considered in the characterization of reproductive risks. For example, female fecundity varies with cycle day, and while both male and female fecundity are dependent on historical performance they also vary over time in a given individual. In addition, sensitivity of the male and female reproductive systems to toxicants varies during ovarian and spermatogenic cycles. Initial characterization of toxic effects on fecundity has considered the time necessary to achieve a particular endpoint, such as time to pregnancy. However, analysis of time in the calculation of benchmark doses has not been considered for quantitative characterization of reproductive risks. This article suggests an approach for characterizing risks to reproduction in the context of fecundity and fertility, reviews temporal factors in reproduction, and discusses an approach for the analysis of time-dependent factors in the calculation of benchmark doses for reproductive toxicity. Total sperm counts from a rabbit inhalation experiment with dibromochloropropane were utilized to explore this approach. Three variance-stabilizing transformations (cube root, logarithmic, and an optimal transformation obtained using an additivity and variance stabilizing algorithm) were explored. Two longitudinal data analysis techniques using random effects models and generalized estimating equations were used to characterize the dose-response relationships and calculate specific benchmark doses for alteration of spermatogenesis by dibromochloropropane. These analyses suggest approaches for defining the most appropriate transformations to stabilize variance and methods for dealing with time in experiments designed to characterize reproductive response to toxicants. Similar analyses are necessary for other biomarkers of male and female reproductive function before benchmark doses are calculated to protect human reproductive health.