The US EPA reference dose for methylmercury: sources of uncertainty

The US Environmental Protection Agency (EPA) derived a reference dose for methylmercury in 2001, based on an extensive analysis by the National Research Council (NRC) of the National Academy of Sciences. The NRC performed benchmark dose analysis on a number of endpoints from three longitudinal prospective studies: the Seychelles Islands, the Faroe Islands, and the New Zealand studies. Adverse effects were reported in the latter two studies, but not in the Seychelles study. The NRC also performed an integrative analysis of all three studies. Dose conversion from cord blood or maternal hair mercury concentration was performed by EPA using a one-compartment pharmacokinetic model. A total uncertainty factor of 10 was applied for intrahuman pharmacokinetic and pharmacodynamic variability. There are numerous decisions made by the NRC/EPA that could greatly affect the value of the reference dose (RfD). Some of these include the choice of a linear model for the relationship between mercury body burden and neuropsychological performance, the choice of values of P0 and the benchmark response, the use of the "critical study/critical endpoint" approach in the interpretation of the maternal body burden that corresponds to the RfD, the use of central tendencies in a one-compartment pharmacokinetic model rather than the inclusion of the distributions of variables for the population of reproductive-age women, the assumption of unity for the ratio of fetal cord blood to maternal blood methylmercury concentrations, the choice of a total of 10 as an uncertainty factor, and the lack of dose-response analysis for other health effects such as cardiovascular disease. In addition, it may be argued that derivation of a RfD for methylmercury is inappropriate, given that there does not appear to be a threshold for adverse neuropsychological effects based on available data.