Endocrine active substances and dose response for individuals and populations

Dose-response characteristics for endocrine disruption have been major focuses in efforts to understand potential impacts on human and ecological health. Issues include assumptions of thresholds for developmental effects, effects at low doses with nonmonotonic (e.g., "U-shaped") behaviors, population vs. individual responses, and background exposures (e.g., dietary phytoestrogens). Dose-response analysis presents a challenge because it is multidisciplinary, involving biologists and mathematicians. Statistical analyses can be valuable for evaluating issues such as the reproducibility of data as illustrated for contradictory findings on low-dose effects. Mechanistically based modeling provides insights into how perturbations of biological systems by endocrine active substances can create different dose-response behaviors. These analyses have demonstrated that higher order behaviors resulting from the interaction of component parts may appear highly nonlinear, thresholded, low-dose linear, or nonmonotonic, or exhibit hysteresis. Some effects need to be evaluated as population impacts. For example, alterations in male:female ratio may be important at the population level even though not adverse for the individual. Descriptions of the contributions of background exposures to dose-response behaviors are essential. The challenge for improving dose-response analyses is to better understand how system characteristics create different dose-response behaviors. Such generalizations could then provide useful guidance for developing risk assessment approaches.