Sex Differences in Human and Animal Toxicology

Abstract

Sex, the states of being female or male, potentially interacts with all xenobiotic exposures, both inadvertent and deliberate, and influences their toxicokinetics (TK), toxicodynamics, and outcomes. Sex differences occur in behavior, exposure, anatomy, physiology, biochemistry, and genetics, accounting for female-male differences in responses to environmental chemicals, diet, and pharmaceuticals, including adverse drug reactions (ADRs). Often viewed as an annoying confounder, researchers have studied only one sex, adjusted for sex, or ignored it. Occupational epidemiology, the basis for understanding many toxic effects in humans, usually excluded women. Likewise, Food and Drug Administration rules excluded women of childbearing age from drug studies for many years. Aside from sex-specific organs, sex differences and sex × age interactions occur for a wide range of disease states as well as hormone-influenced conditions and drug distribution. Women have more ADRs than men; the classic sex hormone paradigm (gonadectomy and replacement) reveals significant interaction of sex and TK including absorption, distribution, metabolisms, and elimination. Studies should be designed to detect sex differences, describe the mechanisms, and interpret these in a broad social, clinical, and evolutionary context with phenomena that do not differ. Sex matters, but how much of a difference is needed to matter remains challenging.

Keywords: absorption; adverse drug reactions; distribution; excretion; metabolism; sex dimorphism; sex hormones.

Figure 1

Framework for sex differences in toxicology linking exposure, toxicokinetics and toxicodynamics (after Gochfeld 2007).

Figure 2

Sex differences in CYP1A1 across the life cycle in a laboratory population of the White-footed Mouse (Peromyscus leucopus)(Guo et al. 1993). Non-overlapping error bars indicate significant difference (P<0.05).

Figure 3

Five of the 24 genes examined by Joseph et al. (2015) appear to show significant sex differences. Most of the genes showed higher expression in males.