Plausibility of toxicological interaction between lead and methylmercury

Humans are exposed to both lead (Pb) and methylmercury (MeHg), two chemicals known to affect the developing nervous system. It is therefore important to know whether these chemicals interact toxicologically to develop reliable estimates of human health risks. The nature of the potential interaction and how it may change with dose are also critical factors which need to be understood and considered in risk assessment. The available toxicological literature was reviewed and yielded five animal studies which involved combined exposure to both metals. None of these studies examined developmental neurotoxicity, the key endpoint of interest. Doses in these studies were also in the range of 1–100?mg?kg^?1?day^?1, which is far above average exposure levels for Pb and MeHg in the U.S. population. The combined exposure literature is therefore uninformative concerning the potential for Pb–MeHg interaction. A subsequent evaluation of the available mechanistic data was conducted, looking for similarities in proposed modes of action relevant at low doses. Shared biological targets suggesting a potential for low dose interaction include protein kinase C, calcium homeostasis, and apoptosis. Whether interaction actually occurs, and the form the interaction might take, remains to be studied. A phased research program is proposed that may provide data needed to address this significant data gap and permit more robust Pb and MeHg risk assessment.