Total imprecision of exposure biomarkers: implications for calculating exposure limits

Abstract

Background: Assessment of the imprecision of exposure biomarkers usually focuses on laboratory performance only. Unrecognized imprecision leads to underestimation of the true toxicity of the exposure. We have assessed the total imprecision of exposure biomarkers and the implications for calculation of exposure limits.

Methods: In a birth cohort study, mercury concentrations in cord blood, cord tissue, and maternal hair were used as biomarkers of prenatal methylmercury exposure. We determined their mutual correlations and their associations with the child's neurobehavioral outcome variables at age 7 years. With at least three exposure parameters available, factor analysis and structural equation modeling could be applied to determine the total imprecision of each biomarker. The estimated imprecision was then applied to adjust benchmark dose calculations and the derived exposure limits.

Results: The exposure biomarkers correlated well with one another, but the cord blood mercury concentration showed the best associations with neurobehavioral deficits. Factor analysis and structural equation models showed a total imprecision of the cord-blood parameter of 25-30%, and almost twice as much for maternal hair. These imprecisions led to inflated benchmark dose levels. Adjusted calculations resulted in an exposure limit 50% below the level recommended by the U.S. National Research Council.

Conclusions: The biomarker imprecisions of 25-50% much exceeded normal laboratory variability. Such imprecision causes underestimation of dose-related toxicity and therefore must be considered in the data analysis and when deriving exposure limits. Future studies should ideally include at least three exposure parameters to allow independent assessment of total imprecision.

Figure 1

Path diagram for a structural equation model linking mercury exposure to adverse effects, while taking into regard confounders. The estimated true exposure (Hg) is modeled as a latent parameter based on mercury concentrations in cord blood (B), umbilical cord tissue (UC), maternal full-length hair (H), and maternal short-segment hair (SH). In addition, the maternal pilot whale meat intake during pregnancy (Whale) is taken into account. Two latent effect parameters (Motor and Verbal) are likewise based on clinical test outcomes analysis [Budtz-Jørgensen et al., 2002]. Motor and verbal function may be correlated (indicated by double-headed arrow) and potential confounders are allowed to be associated both with the latent exposure and to the latent effect variables.