An Objective Uncertainty Factor Adjustment for Methyl mercury Pharmacokinetic Variability

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Abstract
While default uncertainty factor (UF) adjustments have been proposed for pharmacokinetic variability in the derivation of Reference Doses (RfDs), few attempts have been made to derive chemical-specific UFs for such variability. In recent epidemiologic data on the neuro-developmental effects of MeHg, Hg concentration in either hair or blood is the point-of-departure for RfD derivation. The application of a pharmacokinetic model to derive an intake dose from the measured biomarker concentration allows examination of the inter-individual variability in the relationship between intake dose and biomarker concentration through specification of the variability in model parameters. Three independent studies of this variability, using different models and/or different parameter values, are compared. While differences in central tendency estimates give different predictions of the intake dose corresponding to a given biomarker concentration, normalization of the central tendency estimate resulted in strong agreement among the studies. Starting with Hg concentration in hair or blood, and dividing a central tendency estimate of the corresponding intake dose by a UF of 2 to 3, accounts for 95 to 99% of the variability in the relationship between intake dose and biomarker concentration. This variability, however, encompasses only a portion of the maternal ingestion-to-fetal brain pathway. It is therefore likely that this UF underestimates the overall pharmacokinetic variability in this pathway.

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