Glenn Rice

Evaluation of the Cardiovascular Effects of Methylmercury Exposures: Current Evidence Supports Development of a Dose-Response Function for Regulatory Benefits Analysis

Background The U.S. Environmental Protection Agency (U.S. EPA) has estimated the neurological benefits of reductions in prenatal methylmercury (MeHg) exposure in past assessments of rules controlling mercury (Hg) emissions. A growing body of evidence suggests that MeHg exposure can also lead to increased risks of adverse cardiovascular impacts in exposed populations. Data extraction The U.S. EPA assembled the authors of this article to participate in a workshop, where we reviewed the current science concerning cardiovascular health effects of MeHg exposure via fish and seafood consumption and provided recommendations concerning whether cardiovascular health effects should be included in future Hg regulatory impact analyses. Data synthesis We found the body of evidence exploring the link between MeHg and acute myocardial infarction (MI) to be sufficiently strong to support its inclusion in future benefits analyses, based both on direct epidemiological evidence of an MeHg–MI link and on MeHg’s association with intermediary impacts that contribute to MI risk. Although additional research in this area would be beneficial to further clarify key characteristics of this relationship and the biological mechanisms that underlie it, we consider the current epidemiological literature sufficiently robust to support the development of a dose–response function. Conclusions We recommend the development of a dose–response function relating MeHg exposures with MIs for use in regulatory benefits analyses of future rules targeting Hg air emissions.

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;).

A feasibility study of cumulative risk assessment methods for drinking water disinfection by-product mixtures.

Humans are exposed daily to complex mixtures of chemicals, including drinking water disinfection by-products (DBPs) via oral, dermal, and inhalation routes. Some positive epidemiological and toxicological studies suggest reproductive and developmental effects and cancer are associated with consumption of chlorinated drinking water. Thus, the U.S. Environmental Protection Agency (EPA) conducted research to examine the feasibility of evaluating simultaneous exposures to multiple DBPs via all three exposure routes. A cumulative risk assessment approach was developed for DBP mixtures by combining exposure modeling and physiologically based pharmacokinetic modeling results with a new mixtures risk assessment method, the cumulative relative potency factors (CRPF) approach. Internal doses were estimated for an adult female and an adult male, each of reproductive age, and for a child (age 6 yr) inclusive of oral, dermal, and inhalation exposures. Estimates of the daily internal doses were made for 13 major DBPs, accounting for activity patterns that affect the amount of human contact time with drinking water (e.g., tap water consumed, time spent showering), building characteristics (e.g., household air volumes), and physicochemical properties of the DBPs (e.g., inhalation rates, skin permeability rates, blood:air partition coefficients). A novel cumulative risk assessment method, the CRPF approach, is advanced that integrates the principles of dose addition and response addition to produce multiple-route, chemical mixture risk estimates using total absorbed doses. Research needs to improve this approach are presented.

Tools for Comparative Analysis of Alternatives: Competing or Complementary Perspectives?

A third generation of environmental policy making and risk management will increasingly impose environmental measures, which may give rise to analyzing countervailing risks. Therefore, a comprehensive analysis of all risks associated with the decision alternatives will aid decision-makers in prioritizing alternatives that effectively reduce both target and countervailing risks. Starting with the metaphor of the ripples caused by a stone that is thrown into a pond, we identify 10 types of ripples that symbolize, in our case, risks that deserve closer examination: direct, upstream, downstream, accidental risks, occupational risks, risks due to offsetting behavior, change in disposable income, macro-economic changes, depletion of natural resources, and risks to the manmade environment. Tools to analyze these risks were developed independently and recently have been applied to overlapping fields of application. This suggests that either the tools should be linked in a unified framework for comparative analysis or that the appropriate field of application for single tools should be better understood. The goals of this article are to create a better foundation for the understanding of the nature and coverage of available tools and to identify the remaining gaps. None of the tools is designed to deal with all 10 types of risk. Provided data suggest that, of the 10 types of identified risks, those associated with changes in disposable income may be particularly significant when decision alternatives differ with respect to their effects on disposable income. Finally, the present analysis was limited to analytical questions and did not capture the important role of the decision-making process itself.

Metal exposures in an inner-city neonatal population

OBJECTIVES We measured concentrations of lead (Pb), manganese (Mn), chromium (Cr), and copper (Cu) in umbilical cord whole blood and examined sources of environmental Pb exposures in a predominantly African-American population. METHODS Between April and July 2006, we collected reproductive histories, questionnaires, and blood samples from 102 women, aged 16-45 years, who delivered at a Memphis, TN hospital. RESULTS The prevalence of preeclampsia and low birth weight infancy in the study population was 11% and 10%, respectively. Twenty-eight percent of mothers reported living near a potential Pb-contaminated area, while 43% lived in a residence built before 1978. Geometric mean (GM) concentrations for umbilical cord blood in the study population were 1.3, 3.5, 9.0, and 52.0 microg/dL for Pb, Mn, Cr, and Cu, respectively. Six neonates had cord blood Pb (CBL) concentrations above 10 microg/dL, while 20 had CBL concentrations > or =2 microg/dL. GM umbilical CBL levels were higher in neonates born to women living near a potential Pb-contaminated area (2.2 vs. 1.1 microg/dL) and those with friends, family or household members exposed to lead products (1.6 vs. 1.1 microg/dL). Some evidence of an exposure-response relationship was also detected between all four metal concentrations and an increasing number of maternal lead exposures. After adjustment for confounding, proximity to a Pb-contaminated area was the strongest environmental determinant of CBL levels among neonates with CBL concentrations of > or =2 microg/dL (odds ratio=5.1; 95% CI=1.6, 16.7). CONCLUSIONS Metal concentrations were elevated in this population, and CBL levels were associated with proximity to Pb-contaminated areas.

Calculation of soil-water and benthic sediment partition coefficients for mercury

To accurately model mercury transport to water bodies, an assessment of this pollutants behavior in the watershed is critical. Partition coefficients, defined as an estimate of the ratio of the pollutant concentration sorbed onto soil/sediment particles to the pollutant concentration dissolved in pore water at equilibrium, is an important term in multimedia models. In this paper, partition coefficients are calculated for two broad species of mercury: inorganic mercuric mercury (Hg-II) and methylmercury (MHg). Although there is considerable variability in the calculated values, the approximate mean values for the soil-water partition coefficients range from 3.3 x 10(3) to 6.0 x 10(4) L/kg for Hg-II and 2.0 x 10(1) to 6.7 x 10(3) L/kg for MHg. For the benthic sediment partition coefficients, the values range from 5.7 x 10(3) to 9.9 x 10(5) L/kg for Hg-II, and 6.5 x 10(2) to 1.1 x 10(5) L/kg for MHg.

Research Issues Underlying the Four-Lab Study: Integrated Disinfection By-Products Mixtures Research

Chemical disinfection of drinking water is a major public health triumph of the 20th century, resulting in significant decreases in morbidity and mortality from waterborne diseases. Disinfection by-products (DBP) are chemicals formed by the reaction of oxidizing disinfectants with inorganic and organic materials in the source water. To address potential health concerns that cannot be answered directly by toxicological research on individual DBPs or defined DBP mixtures, scientists residing within the various organizations of the U.S. Environmental Protection Agencys Office of Research and Development (the National Health and Environmental Effects Research Laboratory, the National Risk Management Research Laboratory, the National Exposure Research Laboratory, and the National Center for Environmental Assessment) engaged in joint investigation of environmentally realistic complex mixtures of DBP. Research on complex mixtures of DBP is motivated by three factors: (a) DBP exposure is ubiquitous to all segments of the population; (b) some positive epidemiologic studies are suggestive of potential developmental, reproductive, or carcinogenic health effects in humans exposed to DBP; and (c) significant amounts of the material that makes up the total organic halide portion of the DBP have not been identified. The goal of the Integrated Disinfection Byproducts Mixtures Research Project (the 4Lab Study) is provision of sound, defensible, experimental data on environmentally relevant mixtures of DBP and an improved estimation of the potential health risks associated with exposure to the mixtures of DBP formed during disinfection of drinking water. A phased research plan was developed and implemented. The present series of articles provides the results from the first series of experiments.

Component-Based and Whole-Mixture Techniques for Addressing the Toxicity Of Drinking-Water Disinfection By-Product Mixtures

Chemical disinfection of water is of direct public health benefit as it results in decreased water-borne illness. The chemicals used to disinfect water react with naturally occurring organic matter, bromide, and iodide in the source water, resulting in the formation of disinfection by-products (DBPs). Despite the identification of several hundred DBPs, more than 50% of the mass of total organic halide formed during chlorination remains unidentified. The toxic contribution of the DBPs that are formed and present but not yet chemically identified, the unidentified fraction, has been largely unexplored. A better understanding of the potential for adverse human health consequences associated with exposure to the DBPs present in drinking water will be gained by integration of knowledge on the toxicity of individual DBPs; simple, defined DBP mixtures; complex, environmentally realistic DBP mixtures with partial chemical characterization; and the unidentified fraction.

A probabilistic characterization of the health benefits of reducing methyl mercury intake in the United States.

We developed a probabilistic model to characterize the plausible distribution of health and economic benefits that would accrue to the U.S. population following reduction of methyl mercury (MeHg) exposure. MeHg, a known human developmental neurotoxicant, may increase fatal heart attack risks. Model parameters reflect current understanding of the relationships between MeHg intake, health risks, and societal valuation of these risks. The expected monetary value of the annual health benefits generated by a 10% reduction in U.S. population exposure to MeHg for one year is

Identification of developmentally toxic drinking water disinfection byproducts and evaluation of data relevant to mode of action

860 million; 80% of this is associated with reductions in fatal heart attacks and the remainder with IQ gains. The plausible distribution of the benefits is quite broad with 5th and 95th percentile estimates of approximately