Framework for gender differences in human and animal toxicology.

Differences in exposure, anatomy, physiology, biochemistry, and behavior between males and females are a dominant theme in biology, transcending the plant and animal kingdoms. Yet differences due to sex and gender have not received adequate attention in human or animal toxicology nor always in epidemiology. Generalizations are often made about species' responses to xenobiotics, without data or consideration of female/male differences. Despite the leading role that pharmacology and drug development play in elucidating toxicokinetics, gender studies are relatively recent. Phenomenologic or clinical observations of sex differences often go unexplored, but pharmaceutical companies recognize the importance of enhanced understanding of toxicokinetics and toxicodynamics and emphasize the value of translational or integrational research--bringing laboratory findings to bedside applications and bedside questions to laboratory study. However, for many years Food and Drug Administration guidelines specifically precluded participation of females in many drug studies. Many occupational epidemiology studies, on which much of our understanding of toxic effects is based, begin by excluding women and minorities. Sex differentiation begins in the embryo under genetic and hormonal control. Changes affecting exposure, susceptibility, risk, and health continue throughout life. This paper provides a framework for analyzing the level(s) at which gender differences arise. The framework addresses exposure, toxicokinetics, toxicodynamics, and modulating influences. Men and women differ in many aspects of vulnerability to xenobiotics and other stressors, beginning with their opportunities for exposure. Toxicokinetic differences mainly involve metabolism, with few differences in absorption yet demonstrated. In addition, lifestyle, psychosocial, and hormonal factors modify the kinetics and responsiveness. Some phenomena fit the Classic Sex Hormone Paradigm in which castration (with and without hormone replacement) and administration of the opposite sex hormone demonstrate the primary regulatory role of sex hormones. Many phenomena, however, differ between males and females without showing a clear-cut relationship with the sex hormones. Since every cell both has a sex chromosome (X or Y) and is exposed to hormones, elegant techniques are just beginning to tease apart genetic from hormonal influences. Wherever possible, studies should use balanced gender and gender x age designs and should analyze data by sex and interactions, rather than simply adjusting for (discarding) gender. Power should be adequate, or lack of power (if inevitable) should be clearly stated.