Academic journal article Environmental Health Perspectives

A Revised Probabilistic Estimate of the Maternal Methyl Mercury Intake Dose Corresponding to a Measured Cord Blood Mercury Concentration

Academic journal article Environmental Health Perspectives

A Revised Probabilistic Estimate of the Maternal Methyl Mercury Intake Dose Corresponding to a Measured Cord Blood Mercury Concentration

Article excerpt

In 2001, the U.S. Environmental Protection Agency (EPA) adopted a revised reference dose (RfD) for methyl mercury (MeHg) of 0.1 [micro]g/kg/day. The RfD is based on neurologic developmental effects measured in children associated with exposure in utero to MeHg from the maternal diet. The RfD derivation proceeded from a point of departure based on measured concentration of mercury in fetal cord blood (micrograms per liter). The RfD, however, is a maternal dose (micrograms per kilogram per day). Reconstruction of the maternal dose corresponding to this cord blood concentration, including the variability around this estimate, is a critical step in the RfD derivation. The dose reconstruction employed by the U.S. EPA using the one-compartment pharmacokinetic model contains two areas of significant uncertainty: It does not directly account for the influence of the ratio of cord blood:maternal blood Hg concentration, and it does not resolve uncertainty regarding the most appropriate central tendency estimates for pregnancy and third-trimester--specific model parameters. A probabilistic reassessment of this dose reconstruction was undertaken to address these areas of uncertainty and generally to reconsider the specification of model input parameters. On the basis of a thorough review of the literature and recalculation of the one-compartment model including sensitivity analyses, I estimated that the 95th and 99th percentiles (i.e., the lower 5th and 1st percentiles) of the maternal intake dose corresponding to a fetal cord blood Hg concentration of 58 [micro]g/L are 0.3 and 0.2 [micro]g/kg/day, respectively. For the 99th percentile, this is half the value previously estimated by the U.S. EPA. Key words: cord blood, maternal, mercury, methyl mercury, Monte Carlo, one-compartment, pharmacokinetic, probabilistic, reference dose, RfD. doi:10.1289/ehp.7417 available via http://dx.doi.org/[Online 4 November 2004]

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In 2001, the U.S. Environmental Protection Agency (EPA) adopted a revised reference dose (RfD) for methyl mercury (MeHg) of 0.1 [micro]g/kg/day (U.S. EPA 2001a, 2001b; Rice et al. 2003), relying heavily on the assessment conducted by the National Research Council (NRC 2000). The RfD is based on neurologic developmental effects measured in children associated with exposure in utero to MeHg from the maternal diet. The NRC and U.S. EPA assessments employed a benchmark dose approach to derive the lower 95% confidence interval on the fetal cord blood mercury concentration, doubling the proportion of children in the lowest 5% of performance on tests of neurologic performance. The NRC identified a cord blood concentration of 58 [micro]g/L (ppb) total Hg based on analysis of the individual test judged to give the most sensitive and robust response, whereas the U.S. EPA identified a range of cord blood concentrations of 46-79 [micro]g/L based on consideration of several tests. These values are in fact concentrations, whereas the RfD is a dose--in this case, the maternal intake dose. The reconstruction of the maternal MeHg intake dose that resulted in the observed cord blood Hg concentration is a critical step in the RfD derivation. The dose reconstruction requires a pharmacokinetic model linking dose and blood concentration. Two different types of pharmacokinetic models have been used for this purpose--a physiologically based pharmacokinetic (PBPK) model (Clewell et al. 1999) and the one-compartment model (Stern 1997; Swartout and Rice 2000). In both types of models, the relationship between cord blood concentration and dose depends on several physiologic and metabolic parameters. The values of these parameters vary among individuals. The population variability in the value of these parameters results in variability in the output of these models. Thus, there is no unique relationship between a given cord blood Hg concentration and a single maternal intake dose. Rather, this relationship is described by a probability distribution. …

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