Sex-associated variables - A framework for neurotoxicology

As the implementation of 'sex as a biological variable' policies have been enacted across the world, the study of sex differences or comparisons across the sexes has steadily increased. In the field of neurotoxicology, the study of sex-dependent variability is necessary due to the plastic nature of the brain and the response to factors that influence this variability such as gonadal hormones and sex chromosomal complement. The phrase 'sex differences' is not inherently wrong, but it is an underdefined generalization that creates a distinct binary. While this binary is reductive at best, it creates the expectation of direct comparison and therefore a standard of the two groups when sex is a spectrum containing a mosaic of factors. The generalization of sex to one, often undefined, factor reduces the rigor of the research and overlooks potential variability both within and between sexes. This review provides a guide to help break down sex differences into a conglomeration of variables that can then be assessed for differences. By examining the mechanisms underlying sex difference, research can also be applied to groups and individuals who do not fit into the prescribed binary. People with chromosomal differences, cisgender atypical endocrine profiles, and transgender, nonbinary, and gender diverse (TNG) individuals should have research that can be tailored to their unique experiences and provide additional insight as to how a particular drug or toxicant can impact them in a way that may not be a predicted response based on the binary of male and female.