Negative Confounding in the Evaluation of Toxicity: The Case of Methylmercury in Fish and Seafood

Abstract

In observational studies, the presence of confounding can distort the true association between an exposure and a toxic effect outcome if the confounding variable is not controlled either in the study design or the analysis phase. While confounding is often assumed to occur in the same direction as the toxicant exposure, the relationship between the benefits and risks associated with fish and seafood consumption is a classic example of negative confounding: the exposure to methylmercury occurs from fish and seafood which are also associated with beneficial nutrients, thereby counteracting the signs of mercury toxicity. Mercury and nutrients may affect the same epidemiological outcomes, but most studies addressing one of them have ignored the potential negative confounding by the other. This article reviews the existing evidence of effects of both nutrient and contaminant intakes as predictors of neurodevelopmental and cardiovascular outcomes. Substantial underestimation of the effects of mercury toxicity and fish benefits occurs from the lack of confounder adjustment and imprecision of the exposure parameters. Given this inherent bias in observational studies, regulatory agencies should reconsider current dietary advisories to provide better guidance to consumers in making prudent choices to maintain a nutritious diet with seafood that is low in mercury concentrations. Attention should also be paid to the occurrence of negative confounding in other connections.