Current Reference Dose Research Articles

U.S. EPA Reference Dose/Reference Concentration Methodology: Update on a Review of the Process

The U.S. Environmental Protection Agency (USEPA) has been reviewing several approaches to testing and risk assessment related to implementation of the Food Quality Protection Act (FQPA) and the Amendments to the Safe Drinking Water Act (SDWA), both signed into law in 1996. Based on recommendations from a review of issues related to children's health protection under these laws, the USEPA established the RfD Technical Panel to evaluate in depth the current reference dose (RfD) and reference concentration (RfC) process in general, and in particular with respect to how well children and other potentially sensitive subpopulations are protected. The RfD Technical Panel also was asked to consider scientific issues that have become of greater concern in RfD and RfC derivation (e.g., neurotoxicity, immunotoxicity), and to raise issues that should be explored or developed further for application in the RfD/RfC process. This paper provides the current status of the activities of the RfD Technical Panel. The Technical Panel has recommended that acute, short- term, and intermediate reference values should be set for chemicals, where possible, and that these values should be incorporated into the USEPA's Integrated Risk Information System (IRIS) Database. A review of current testing procedures is underway, including the endpoints assessed, life stages covered by exposure and outcome evaluation, and information that can be derived from current protocols on various durations of exposure. Data gaps identified for risk assessment include the types of pharmacokinetic data that should be collected, especially for developmental toxicity studies, the impact of aging on toxic responses occurring after early exposure as well as concomitant with exposure in old age, and information available on latency to response. The implications of the RfD Technical Panel's recommendations for various uncertainty factors are also being explored.

Determination of a site-specific reference dose for methylmercury for fish-eating populations.

Determination of a site-specific reference dose for methylmercury for fish-eating populations.

Hazard identification and dose response of ingested nickel-soluble salts.

People can ingest soluble nickel compounds as a normal constituent of food or as a contaminant in drinking water. This paper presents an assessment of the noncancer and cancer human health risks from ingestion of soluble nickel compounds. A reference dose (RfD) of 8 x 10(-3) mg Ni/kg/day in addition to the amount in food was calculated, based on albuminuria in female rats exposed to nickel sulfate in drinking water for 6 months (A. Vyskocil et al., 1994, Hum. Exp. Toxicol. 13, 689-693). This RfD is comparable to the current RfD based on decreased body weight in a chronic feeding study in rats (A. M. Ambrose et al., 1976, J. Food Sci. Technol. 13, 181-187). The potential for nickel-induced reproductive toxicity was also taken into account in the derivation of the RfD. There are a number of negative animal bioassays with soluble nickel salts, but all of them have deficiencies that preclude a definitive conclusion. According to EPA's 1996 draft cancer guidelines, the carcinogenic potential of oral exposure to soluble nickel "cannot be determined because there are inadequate data to perform an assessment."

DERIVATION OF U.S. EPA'S ORAL REFERENCE DOSE (RFD) FOR METHYLMERCURY

Mercury (Hg) cycles in the environment through a series of complex chemical and physical transformations that occur in air, soils, and water bodies. One component of the environmental mercury cycle is the formation of methylmercury (MHg) primarily by aquatic and marine microorganisms and the accumulation of MHg in foodwebs, particularly in piscivorous species. Human consumption of piscivorous fish and other piscivorus animals is the most common pathway of exposure to MHg. For non-carcinogenic toxic endpoints, the U.S. EPA typically develops a Reference Dose (RfD). This is generally interpreted to be a concentration of a chemical which can be consumed on a daily basis over a lifetime without expectation of adverse effect. There is substantial evidence in both animal and humans that MHg is a neurotoxicant in the adult and the child as well as a developmental neurotoxicant for the fetus. Epidemics of MHg poisoning in Japan and Iraq have resulted from high-dose exposures to MHg. In these epidemics adults, children, nursing infants and fetuses were affected by MHg. The epidemics demonstrate that neurotoxicity is the health effect of greatest concern and that effects on the developing human nervous system apparently occur at lower exposures than those affecting the adult nervous system. We describe how the data from the Iraqi MHg epidemic were used to derive the current RfD of 1.0 μg/Kgbw/day (U.S. EPA, 1995;).

Estimation of the Interindividual Variability in the One-Compartment Pharmacokinetic Model for Methylmercury: Implications for the Derivation of a Reference Dose

A critical step in the U.S. EPA's derivation of an Reference Dose (RfD) for methylmercury is conversion of the maternal hair Hg concentration of 11 ppm to average daily intake using the one-compartment pharmacokinetic model. A default uncertainty factor (UF) adjustment of 3 for interindividual variability was then applied to this conversion. A probabilistic (Monte Carlo) analysis is presented estimating the interindividual variability inherent in this dose conversion for women 18–40 years old based on data in the scientific literature. The dose of 1.1 μg/kg/day, calculated by the U.S. EPA to correspond to 11 ppm Hg in hair, is estimated in this analysis to be larger than 94–99% of corresponding doses. The application of a UF of 3 to this U.S. EPA value gives a dose which is estimated to be larger than 28–73% of corresponding doses. This analysis suggests that if the dose conversion in the RfD is intended to be inclusive of 95–99% of women 18–40, the daily intake should be set at 0.1–0.3 μg/kg/day. The RfD of 0.03–0.1 μg/kg/day, derived from this dose by the U.S. EPA's application of an additional UF of 3 for additional toxicologic concerns, is somewhat smaller than the current RfD of 0.1 μg/kg/day.