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.

Fish consumption, omega-3 fatty acids, and environmental contaminants in relation to low-grade inflammation and early atherosclerosis

“…Additionally in the Fishermen study, potential negative confounding (Choi et al, 2008) was controlled for by adjusting means across omega-3 PUFA tertiles for environmental contaminants and vice versa. However, the models were stable regardless of large number of covariates, and the adjustments did not essentially change the results.…”

Prenatal Methylmercury Exposure and Genetic Predisposition to Cognitive Deficit at Age 8 Years

“…Several recent analyses based on Faroe and Seychelles cohort data have demonstrated an increase of the methylmercury adverse effects after adjusting the models for these potentially beneficial factors. 1,4,9 Furthermore, socioeconomic factors may be more favorable in mothers who consume more fish, especially larger fish that may contain higher toxicant concentrations. 7 If such negative confounding is not taken into proper account in the data analysis, the toxicity will be underestimated.…”

“…If the toxicant is measured with a greater imprecision than the confounder, the effect of the former will generally be biased toward the null. [9][10][11] Within a population, the apparent effects of risk factors will not be evenly distributed. Studies of genetic factors in intelligence have shown the strongest effect in upper social strata, where adverse risk factors may be less important than inheritance and more evenly distributed.…”

“…However, toxicant exposures may be associated with a profile of other risk factors, some of which being beneficial, and "negative confounding" could exist. 9 Exposure to methylmercury mainly originates from seafood, but dietary intake of contaminated seafood will also provide essential nutrients along with the toxicant. 1,2,4,7,9 As seafood represents an important source of n-3 fatty acids, confounding could be in the direction opposite to the toxicity due to the methylmercury exposure.…”

“…9 Exposure to methylmercury mainly originates from seafood, but dietary intake of contaminated seafood will also provide essential nutrients along with the toxicant. 1,2,4,7,9 As seafood represents an important source of n-3 fatty acids, confounding could be in the direction opposite to the toxicity due to the methylmercury exposure. Several recent analyses based on Faroe and Seychelles cohort data have demonstrated an increase of the methylmercury adverse effects after adjusting the models for these potentially beneficial factors.…”