From the NAS to your ear Mike:
Neurotoxicity in children exposed in utero is the health outcome selected by EPA for the current MeHg RfD. The RfD is based on data from the Iraqi poisoning episode, where the population consumed high levels of MeHg from treated seed grain. The critical study for the RfD conducted by Marsh et al. (1987) identified 81 children who had been in utero during the episode and examined their neurodevelopmental outcomes. Maternal-child pairs were selected from one of five Hg-hair-concentration groups, and the combined incidence of developmental effects (late walking, late talking, mental symptoms, seizures, or increased neurological score) was determined for each group. Exposure levels measured by maternal-hair concentration and combined developmental effects were used to estimate a benchmark dose. The benchmark dose of 11 ppm of Hg in hair was calculated as the 95% lower confidence limit on the maternal-hair concentration corresponding to a 10% extra risk level (Crump et al. 1995). In this report, the lower confidence limit is referred to as the BMDL. The following section describes how EPA derived the current RfD from that value.
A ratio of 250:1 was used to convert hair Hg concentration (mg of Hg/kg of hair) to blood Hg concentration (mg of Hg/L of blood) to derive the RfD critical dose (EPA 1997c):
11 mg/kg of hair would correspond to 11/250 = 44 µg/L of blood.
The following equation was used to obtain a daily dietary intake of MeHg that results in a blood Hg concentration of 44 µg/L:
d = daily dietary intake (micrograms of MeHg per kilogram of body weight per day),
C = concentration in blood (44 µg/L),
b = elimination constant (0.014 days-1),
V = volume of blood in the body (5 L),
A = absorption factor (expressed as a unitless decimal fraction of 0.95),
f = fraction of daily intake taken up by blood (unitless, 0.05), and
bw = body-weight default value of 60 kg for an adult female.
Using that equation, the total daily quantity of MeHg ingested by a 60-kg female to maintain a blood Hg concentration of 44 µg/L or a hair Hg concentration of 11 ppm would be
A composite uncertainty factor (UF) of 10 was used in the derivation of the RfD to account for human-population variability, lack of a two-generation reproductive study, and lack of data on sequelae resulting from longer durations of exposure (EPA 1997c):
As the calculation shows, the application of UFs has a major influence on the quantification of the final RfD. Although the scientific rationale for the application of these factors is strong, it must be recognized that choosing the ultimate magnitude of the UFs is a policy decision, which is influenced by professional judgment, public-health goals, and the regulatory mandates of EPA.
EVALUATING THE RfD?END POINTS OF MeHg TOXICITY
The committee reviewed human epidemiological results and animal
toxicity data to examine potential human health effects and evaluate the use of neurotoxicity in children exposed in utero as the health end point for the derivation of the RfD. Other end points evaluated are carcinogenicity and immunological, reproductive, renal, and cardiovascular toxicity. Chapter 5 presents an in-depth presentation of the health effects of MeHg. The following is a summary of major findings.
Studies in humans of the carcinogenic effects of MeHg are inconclusive. Although no studies have found an association between MeHg and overall cancer death rates in humans, two studies (Kinjo et al. 1996; Janicki et al. 1987) have found associations between Hg exposure and acute leukemia. Interpretation of these findings is limited because of small study populations and lack of control for other risk factors. Renal tumors have been observed in male mice (Mitsumori et al. 1981; Hirano et al. 1986) but only at or above the maximum tolerated dose. Hg has also been shown to cause chromosomal damage and aneuploidy in a number of in vivo and in vitro systems. On the basis of the available human, animal, and in vitro data, the International Agency for Research on Cancer (IARC) and EPA have classified MeHg as a ?possible? (EPA Class C) human carcinogen (EPA 2000).
Occupational studies suggest that Hg exposure can affect the immune system in humans (Dantas and Queiroz 1997; Moszczynski et al. 1999). In vitro and animal studies have shown that Hg can be immunotoxic. They suggest that exposure to MeHg can increase human susceptibility to infectious diseases and autoimmune disorders by damaging the immune system (Ilbäck et at. 1996). Animal studies have also shown that prenatal and perinatal exposure to MeHg produce long-term effects on the developing immune system (Wild et al. 1997). Immunological studies in animals are summarized in Table 5-3.
The reproductive effects of MeHg exposure have not been evaluated in humans. However, an evaluation of the clinical symptoms and outcomes of over 6,000 MeHg-exposed Iraqi citizens found a low rate of pregnancies (79% reduction) among the exposed population (Bakir et al. 1973). That provides suggestive evidence of an effect of MeHg on human fertility. Animal studies, including work in nonhuman primates, have found reproductive problems, including decreased conception rates, early fetal losses, and stillbirths (Burbacher et al. 198
The kidney is sensitive to inorganic Hg exposure, and renal damage has been observed following human ingestion of organic forms of Hg. Renal effects from organic Hg exposure have been observed only at exposure levels that also cause neurological effects. Renal damage was observed in the victims of the Iraqi poisoning, and an evaluation of death rates in an area of Minamata City, which had the highest prevalence of Minamata disease, found an increase in deaths from renal disease among women but not men (Tamashiro et al. 1986). Several reports of animal studies have also described MeHg-induced renal toxicity.
The cardiovascular system appears to be a target for MeHg toxicity in humans and animals. Blood-pressure elevations have been observed in occupationally exposed men (Höök et al. 1954) and in children treated with mercurous chloride for medical conditions. More recently, there is evidence that suggests effects at low levels of exposure. A recent study of 1,000 children from the Faroe Islands found a positive association between prenatal exposure to MeHg, and blood pressure and heart rate variability at age 7 (Sørensen et al. 1999). A Finnish cohort study of 1,833 men linked dietary intake of fish and Hg concentrations in hair
and urine with increased risk of acute myocardial infarction (AMI) and coronary heart disease and cardiovascular disease (Salonen et al. 1995). Men who consumed at least 30 g of fish a day had a 2.1 higher risk of AMI. Cardiovascular effects have also been observed in several animal models of MeHg toxicity.
The toxic effects of MeHg in the brain have been well documented in human and animal studies. Although both the adult and fetal brains are susceptible, the developing nervous system is more sensitive to the toxic effects of MeHg than is the developed nervous system. It should be pointed out however, that few studies of MeHg effects in adults have investigated the sensitive and subtle types of neurologic endpoints recently examined in children exposed in utero. Studies of Minamata victims indicate that prenatal exposure caused diffuse damage in the brain and adult exposure caused focal lesions. About 10% of the total body burden of MeHg is found in the brain. After ingestion, MeHg accumulates in the brain where it is slowly converted to inorganic Hg. On the basis of available studies, neurodevelopmental effects appear to be a sensitive end point for MeHg toxicity. There is an extensive human data base on neurodevelopmental effects, including studies of populations following high-dose poisonings and chronic low-level Hg exposure. In general, experimental animal studies have reported a continuum of neurodevelopmental effects similar to those reported in studies of humans exposed to MeHg. Of the three major long-term prospective studies, the Faroe Islands study reported an effect of low-level prenatal exposure on children's performance on neurobehavioral tests particularly in the domains of attention, fine-motor function, confrontational naming, visual-spatial abilities, and verbal memory. Similar effects were not found in the main Seychelles study; however, the smaller New Zealand study found effects on standardized tests of cognitive and neuromotor function that were similar to those administered in the main Seychelles study, and there was preliminary evidence of similar effects in the Seychelles pilot study.
SELECTION OF THE END POINT FOR THE RfD
The findings of the committee regarding the end points of MeHg toxicity support the selection of neurotoxicity in children exposed in utero as a suitable end point for the development of the RfD based on the available data. These effects have been well documented in a number of investigations, including prospective epidemiological studies examining low-dose chronic exposure through consumption of contaminated fish and seafood. Evidence from animal studies is consistent with the neurotoxicity findings in humans.
Given the limits of the available data, developmental neurotoxicity is the most sensitive, well-documented health end point. Therefore, its use as the basis for the RfD should be protective for other adverse effects that occur at higher doses of exposure. However, there is emerging evidence of potential effects on both the immune and cardiovascular systems at low doses of exposure. Although these effects are not well understood, emerging data underscore the need for continued research and raise the possibility of adverse effects to other organ systems at or below the current levels of concern for developmental neurotoxicity.
EXAMINATION OF THE CRITICAL STUDIES FOR THE RfD
The traditional approach to development of an RfD and other public-health-based risk guidance numbers is to select a critical study that is well conducted and provides the most sensitive, or lowest, no-observed-adverse-effect level (NOAEL), lowest-observed-adverse-effect level (LOAEL), or a lower 95% confidence limit on the benchmark dose (BMDL). The relevance of the study exposure levels and pathways to the population of concern should also be considered.
The current EPA RfD is based on developmental neurotoxic effects in children exposed in utero to high-level episodic exposure from bread made with grain treated with MeHg as a pesticide (Marsh et al. 1987). Although that study was judged the most appropriate at the time of the development of the current RfD, a number of recognized sources of uncertainty, including possible selection bias in the cohort, cannot be controlled. In addition, the exposure scenario in Iraq is not comparable
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