Cumulative risk assessment as the pathway to public health protection for behavioral neurotoxicity

The formulation of adverse outcome pathways (AOPs) based on high-throughput in vitro new approach methods linking biochemical/mechanistic data with an apical endpoint considered an adverse outcome (AO), is increasingly proposed to accelerate the process of risk assessment for environmental chemical exposures. While a laudable goal, this approach ignores the extensive evidence demonstrating context-dependence of neurotoxicological consequences, including behavioral toxicity of chemical exposures. Such contextual modifiers can include environmental conditions (poverty, psychosocial stress, behavioral experience/history), physiological conditions (sex, period of exposure, nutritional status, brain region, exposure parameters), and genetic background. Context dependence represents a serious omission for AOP formulation because an environmental context can alter a chemical's molecular targets, or potentially enhance toxicity through interactions with other contextual conditions, thus leading to potential underestimation of neurological risks due to such exposures. The integrative physiological basis of AOs requires cumulative risk assessments that model environmental contexts across scales of biology, i.e., integration and testing in whole-animal models. AOPs contribute to the derivation of cumulative risk considerations regarding factors to incorporate into cumulative risk assessments by defining risk factors with shared biological targets. Epidemiological and animal model studies can provide information to prioritize interactive effects of greatest magnitude. Additionally, a focus on how a single risk factor in different physiological contexts may attribute risk across multiple neurologic conditions, rather than to a single unique condition, would provide broader public health protection. Realistic acknowledgement of context-dependence is requisite to understanding both the etiological basis of neurological diseases and disorders and to human health protection.