Abstract:
Methylmercury (MeHg) is a pollutant of world-wide concern. MeHg exposure in utero may lead to an increased risk of central nervous system abnormalities, particularly for children born to populations with high levels of fish consumption. Due to the seriousness of the risk posed by MeHg in the environment, it is important to integrate existing MeHg exposure and toxicity data in a manner that may help identify the likelihood of adverse health effects. This dissertation project involved the development of a comprehensive biologically-based does-response (BBDR) model that describes the toxicokinetics and toxicodynamics of MeHg in the developing rat. Specifically, the work involved the following: (1) development of a computer model of MeHg disposition in the pregnant rat and developing embryo; (2) collection of toxicokinetics data on MeHg disposition in the pregnant rat and embryo during early organogenesis; (3) collection of data on changes in cell cycle kinetics and cell number in the developing rat midbrain; (4) collection of data on the effects of MeHg on cell cycle kinetics during gestation; (5) use of the collected laboratory data to develop and refine a BBDR model and to evaluate the model's predictive accuracy. The resulting model was able to predict impacts from MeHg exposure that were consistent with results reported from in vivo teratology studies. It is expected that the model could be revised with limited effort to address other chemicals of environmental concern and other species of interest including humans. With increasing emphasis on evaluating the risk for children's health, nonstandard approaches such as BBDR models will receive greater attention. With further refinement and careful application, it is our hope that models such as ours will provide a valuable tool for making informed health policy decisions concerning the risks to children from environmental agents.