Introduction/overview: gender-based differences in pharmacologic and toxicologic responses.

Gender may be the most important factor in mammalian development and response to exogenous agents. From believing sex-related differences required sheltering women to protect their reproductive capacity (Victorians thought exercise, education, train travel, and certain music neuro- and reprotoxic to females) to legislating a status of essential equality of the sexes may have increased women's health issues. Men and women often respond differently to drugs. Inclusion of women in phase I/II clinical trials is insufficient to identify gender-based differences in response; rather, animal models should be the basis for predicting gender-based differences in pharmacologic and toxicologic effects. Unfortunately, current animal models do not consistently demonstrate such differences. Use of commonly used species (e.g., rats and dogs) does not necessarily result in relevant evaluation of an agent in a species at appropriate development (age), physiological state, anatomy, metabolism, or kinetics for estimation of human risks. The need to test agents in relevant animal models and advances in metabolic, pharmacokinetic, and pharmacodynamic capabilities challenge us to improve methods by using the most relevant models for estimating human risk. We need to be concerned about gender-related differences and the dynamics of gender-based growth and development over the entire life cycle. We must also consider potential interactions of dietary supplements and other exogenous agents that can act as drugs or modulate the potential effects of drugs differently in men, women, and developing children of both sexes. To this end, the health benefits of genistein and the effects of this dietary agent in a multigeneration study in rats will be described. It is envisioned that this symposium will assist in re-recognition of the importance of gender-related differences in use and response to pharmaceuticals and result in optimization of nonclinical testing procedures to identify benefits and risks for human use of these agents.