Chemical contaminants that are largely the contribution of industrial processes and their byproducts pervade the environment. Every human is exposed to a multiplicity of such agents and carries their signatures in their tissues. They include heavy metals, solvents, pesticides, cosmetics, plastic products, and other components contributed by a staggering array of manufacturing processes, manufactured items, and their wastes. They exert effects on virtually all organ systems and act through a wide variety of toxic mechanisms.
Researchers in toxicology and the environmental health sciences continue to produce a torrent of publications attesting to the health risks engendered by these agents. Despite this mountain of information, we remain relatively ignorant about one vital aspect: their differential impact on males and females. The Institute of Medicine (IOM) report, Does Sex Matter (Wizemann and Pardue, 2001) emphasized the need to examine differences between male and female responses in the research enterprise because of wide gaps between males and females in disease patterns, in response to therapeutic interventions such as drugs, and to external agents. For current neurotoxicology, the predominant question is how environmental chemicals modify brain function and behavior as a function of sex.
Questions about sex differences in disease, in environmental health, and in toxicology have come to assume an importance not accorded them a relatively short time ago. It was only in 1985 that NIH mandated the inclusion of women in clinical trials, followed by other government initiatives (Figure 1). The Society for Women’s Health Research was founded in 1990 in an effort to include women in major medical research studies and to address “…the need for more information about conditions affecting women exclusively, disproportionately, or differently than men.” The IOM report (pp. 1–2) described Its theme and rationale in this way:
…Over the past decade new discoveries in basic human biology have made it increasingly apparent that many normal physiological functions—and, in many cases, pathological functions—are influenced either directly or indirectly by sex-based differences in biology. This realization, however, has been slow in coming… Historically, the research community assumed that beyond the reproductive system, such differences do not exist or are not relevant. Still, …scientific evidence of the importance of sex differences throughout the life span abounds.
In 2005, the Scientific Group on Methodologies for the Safety Evaluation of Chemicals (SGOMSEC) held a workshop on Gender Differences and Human and Ecological Risk that extended the arguments in the IOM report to toxicology. The SGOMSEC report addressed in detail a number of topics especially pertinent to toxicology. These include sex-specific effects on germ cell mutagenesis, sex differences as an element in health risk assessment, and sex differences in how wildlife are affected by environmental chemicals. As in the IOM report, the authors stressed the fundamental role of sex at every level of biological organization. One of the issues seen as critical is the tactic, used in many investigations, to classify sex as a “confounder,” a tactic that essentially strips its significance from the analysis (Gochfeld, 2007).
Much the same lack of attention or even awareness is common in laboratory research. Wald and Wu (2010), reviewing ten research areas, entitled their article “Of Mice and Women” to underscore the persistent bias. Sometimes, It is only when regulations call for both sexes to be studied, as in cancer bioassays, that both males and females are included. In this instance, it would be ludicrous to not do so; the disparate vulnerabilities and biological substrates are too overwhelming, as in mammary cancers. Many other disciplines, however, often ignore sex differences. The IOM report (p. 1) remarks almost plaintively that, “…scientists have paid much less attention to the direct study of these differences at the basic cellular and molecular levels.” Allegedly mechanistic studies relying on in vitro models tend to ignore sex; few carry out such studies using a culture medium reproducing the in vivo environment of the intact organism. Take the example of how estrogen receptors are distributed in the brain. In weanling rats, females exhibited higher counts and densities of ERα than males (Schlenker and Hansen, 2006). In adult rats, Zhang et al (2002) observed clear differences in the amount of ER-beta immunoreactivity between males and females. Given the number of additional, similar findings, and sex differences in circulating hormones, is it reasonable to study neuronal phenomena in vitro when the hormones governing sex differences are lacking in its milieu?
Sex differences in the response to environmental endocrine disruptors (EEDs) were one of the factors generating discussion about these chemical classes. Endocrine disruption surfaced as a critical element in environmental health research about 15 years ago. During 2009, 37 articles centered on endocrine disruptors were published in Environmental Health Perspectives, which publishes articles from many disciplines. They exemplify the scope of questions currently being addressed, ranging from in vitro, to whole animal, to epidemiological, to exposure assessment in approach. One of the subjects that EED research has highlighted is the difference between male and female sensitivity to environmental chemicals and the forms in which they might emerge. It feeds on questions that have risen to the apex of public curiosity and discussion, such as why girls, by some criteria (though not all), seem to be outperforming boys academically.
This review examines aspects of sex differences critical to neurotoxicology (cf., Becker et al, 2005). Although it centers on questions and studies that have irrupted into intense public debates, such as sex differences in mathematical talent, analogous questions are equally meaningful for laboratory research. One aim of this article is to highlight the connections between the two arenas and to encourage laboratory researchers to consider the implications of their work for the wider issues that prompt changes in policy.