Development of Methylmercury Reference Dose
Dr. Kathryn Mahaffey
Office of Prevention, Pesticides and Toxic Substances
U.S. Environmental Protection Agency

Methylmercury: Current Understanding of Health Risks and US Exposures

Methylmercury is widely recognized as a neurotoxin affecting adults, children, and the developing fetus. Until the mid-1990s, peripheral neuropathy was considered to be the critical effect for methylmercury among adults. Paresthesias formed the basis of multiple organizations' evaluations of adverse effects; i.e., EPA, Food and Drug Administration, and the World Health Organization. Data from poisoning episodes during the 1960s and 1970s had shown that neurological problems among children exposed in utero to methylmercury whose mothers themselves demonstrated no or minimal symptoms. The vulnerability of the developing nervous system to a myriad of adverse effects following methylmercury exposures has been described in a broad array of studies in rodents, nonhuman primates, and humans. In 1995 EPA revised it's Reference Dose for methylmercury to be based on fetal protection.

• Between 1995 and present, there have been varied estimates of the methylmercury exposure level likely to be without adverse effects in populations including sensitive groups. The Committee on Toxicology of Methylmercury (organized under the auspices of the United States National Academy of Sciences) issued a report in July of 2000 which recommended the following: Neurodevelopmental effects observed in the Faroe Islands cohort study form the basis of US EPA's Reference Dose (RfD) for methylmercury.
• The preferred Benchmark Dose Lower Bound (BMDL) was 58µug/L of cord blood.
• An uncertainty factor (UF) of not less than 10 would be used in setting a RfD.

In the 2001 revision of US EPA's RfD for methylmercury, the BMDLs are based data showing adverse effects of methylmercury exposure on multiple tests of child development. The RfD is based on data from the Faroese cohort, with supporting analyses from the New Zealand study, and the integrative analysis of the two preceding studies and the Seychelle Islands study. The UF was 10 and the Modifying Factor (MF) was 1. The BMDL exposure parameters selected are associated with a doubling of the number of children with scores in a range considered clinically subnormal (i.e., the lowest 5% of the distribution) on multiple tests of neurobehavioral function. Multiple endpoints yielded BMDLs in the range of 32 to 79 µg/L in maternal blood for different neuropsychological effects in the offspring at 7 years-of-age corresponding to a range of daily maternal intakes of 0.596 to 1.472 µg/kg. The RfD remains 0.1 µg/kgbw/day associated with a cord blood of approximately 6 µg/L. This is not a "no observed adverse effect level". Within the Faroese cohort's data, effects at exposures less than those associated with a maternal hair mercury concentration of less than 10 ppm have been reported raising questions about whether or not a threshold for methylmercury's effects exists..

Blood mercury data from the first year of the fourth National Health and Nutrition Examination Survey (NHANES IV-99) indicated that the 90th percentile value for women ages16 through 49 years was 6.2 (95% CI 4.7 - 7.9) µg/L. These data are from a survey that is intended to be representative of the United States population as a whole. The 1999 data indicated that approximately 10% of adult women of child-bearing age had blood mercury levels above a level that US EPA considers protective from adverse effects of methylmercury on children's neurological development. Data from various locations in the United States indicate that more elevated exposures exist in some geographic areas. Case reports of blood mercury concentrations considerably in excess of the Reference Dose have been reported from Wisconsin and Massachusetts. The prevalence of these more serious elevations in blood mercury concentrations has not yet been determined.

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