Site-specific reference dose for methylmercury for fish-eating populations

The purpose of the analysis reported here was to derive a site-specific reference dose (RfD) for methylmercury, specifically for a population exposed through the chronic ingestion of contaminated fish. A study of the neurodevelopmental toxicity of methylmercury conducted on a fish-eating population in the Seychelles Islands was determined to be the most applicable for the development of the site-specific RfD. The analysis, which made use of the benchmark dose approach as an alternative to the traditional no-observed-adverse effect-level (NOAEL) approach, physiologically based pharmacokinetic (PBPK) modeling, and Monte Carlo uncertainty analysis, was designed to provide information on the distribution of acceptable ingestion rates across the population, rather than a single point estimate. Benchmark dose modeling over the wide range of neurodevelopmental endpoints reported in the Seychelles study yielded a BMDL (95% lower confidence limit) tolerable concentration of methylmercury in maternal hair of 21 ppm. This hair concentration was then converted to an expected distribution of daily ingestion rates across a population of U.S. women of childbearing age using Monte Carlo analysis with a PBPK model to evaluate the impact of interindividual variability. An uncertainty factor of 3 was applied in consideration of results from similar studies in New Zealand and the Faroe Islands that could be construed to suggest the possibility of effects at maternal hair concentrations below 10 ppm. Based on the analysis described above, the distribution of acceptable daily ingestion rates (RfDs) ranges from approximately 0.3–1.1 μg/kg/day, with a population median (50th percentile) of 0.5 μg/kg/day.