Evaluation of the Uncertainty in an Oral Reference Dose for Methylmercury Due to Interindividual Variability in Pharmacokinetics

Abstract

An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 microgram/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 microgram/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 microgram/kg/day and an MRL of 0.3 microgram/kg/day.

Exposure analysis of five fish-consuming populations for overexposure to methylmercury

“…There is uncertainty associated with toxicodynamic variations across the populations, although given the cohort sizes and types, this variation may be small ( Renwick, 1993;Dourson et al, 1996;ATSDR, 1997 ). The interindividual pharmacokinetic variability associated with determining a tolerable intake level based on hair mercury levels could be accounted for through the use of an uncertainty factor of three applied to a central tendency estimate of the intake doses corresponding to the maternal hair concentration (Renwick, 1993;Stern, 1997;Clewell et al, 1999 ). In total, these variabilities and the lack of ability to address long -term and /or delayed sequelae warrant an additional reduction of one order of magnitude in the daily -intake range of 0.35 to 0.8 g /kg /day.…”

Pharmacokinetics of toxic chemicals in breast milk: use of PBPK models to predict infant exposure.

“…Due to the nature of the studies, it was not possible to measure the amount ingested to determine administered dose. However, Byczkowski and Lipscomb (36) were able to develop a PBPK model for the lactating woman and nursing infant based on a previous model for the pregnant human (37). By accounting for the differences in physiology (38) and using the description of kinetics from the pregnant human model, Byczkowski and Lipscomb (36) used the lactation model to describe MeHg distribution from real-world exposures measured in maternal hair and milk, as well as infant blood, at both toxic and environmentally relevant doses.…”

Temporal error in biomarker-based mean exposure estimates for individuals

“…We assume that simple linear toxicokinetics hold for mercury, although recent toxicokinetic models for mercury typically include multiple compartments and other potential departures from our model (Clewell et al, 1999). It is unlikely that fine adjustment of our approach using a more detailed toxicokinetic model would substantially alter our conclusions, but we have not yet investigated this possibility.…”