Studying toxicants as single chemicals: does this strategy adequately identify neurotoxic risk?

Despite the fact that virtually all chemicals exposure of humans are to mixtures, and that these mixed exposures occur in the context of numerous other risk modifiers, our current understanding of human health risks is based almost entirely on the evaluation of chemicals studied in isolation. This paper describes findings from our collaborative studies that prompt questions about these approaches in the context of neurotoxicology. The first section describes studies investigating the interactions of maternal Pb exposure with maternal stress. Examined across a range of outcome measures, it shows that maternal Pb can modulate the effects of maternal stress, and, conversely, stress modifies the effects of Pb. Further, effects of Pb+stress could be detected in the absence of an effect of either risk factor alone, and, moreover, the profile of effects of Pb alone differs notably from that of Pb+stress. Collectively, interactions were not systematic, but differed by brain region, gender and outcome measure. A second section describes outcomes of studies examining combined exposures to the pesticides paraquat (PQ) and maneb (MB) during development which likewise reveal potentiated effects of combined exposures. They also demonstrate examples of both progressive and cumulative neurotoxicity, including a marked vulnerability following gestational exposure to MB, to the effects of PQ, a pesticide with no structural relationship to MB. The ability of current hazard identification and risk assessment approaches to adequately identify and encompass such effects remains an important unanswered question. One consideration proposed for further evaluating potential interactions that may be of significance for the nervous system is based on a multi-hit hypothesis. It hypothesizes that the brain may readily compensate for the effects of an individual chemical itself acting on a particular target system, but when multiple target or functional sites within that one system are attacked by different mechanisms (i.e., multiple chemical exposures or chemical exposures combined with other risk factors), homeostatic capabilities may be restricted, thereby leading to sustained or cumulative damage.