An ignored risk factor in toxicology: The total imprecision of exposure assessment.

Quality assurance of exposure biomarkers usually focuses on laboratory performance only. Using data from a prospective birth cohort study in the Faroe Islands, we have assessed the total imprecision of exposure biomarkers. As biomarkers of prenatal methylmercury exposure, mercury concentrations were determined in cord blood, cord tissue, and maternal hair. We determined their mutual correlations and their associations with the child's neurobehavioral effect variables at age 7 years. The exposure biomarkers correlated well with one another, but the cord blood mercury concentration showed the best associations with neurobehavioral deficits. Because at least three exposure parameters were available, factor analysis and structural equation modeling could be applied to determine the total imprecision of each biomarker. For the cord-blood parameter, the total imprecision was 25-30%, and almost twice as much for maternal hair. The total imprecision of these biomarkers much exceeded the normal laboratory variability of less than 5%. Such imprecision can cause underestimation of dose-related toxicity, and data analysis should therefore include sensitivity analyses that take this factor into account. Ignoring preanalytical imprecision may cause serious bias.