Toxicological Effects of Methylmercury (2000) / Chapter Skim
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Risk Characterization and Public Health Implications
Risk Characterization and Public Health Implications
Pages 304-332
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From page 304... ...
2. An examination of the critical studies, end points of toxicity, and uncertainty factors used in the derivation of the RfD.
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The serious health impacts of high-level exposures have long been recognized. Between 1950 and 1975, major poisoning episodes in Japan and Iraq resulted in outbreaks of serious neurotoxic effects, including death, and led to the identification of developmental neurotoxicity as the health effect of greatest concern following high-level episodic exposure.
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From page 306... ...
Exposure levels measured by maternal-hair concentration and combined developmental effects were used to estimate a benchmark dose. The benchmark dose of II ppmof Hgin hair was calculated as the 95% Tower confidence limit on the maternal-hair concentration corresponding to a 10% extra risk level (Crump et al.
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From page 307... ...
of 10 was used in the derivation of the RfD to account for human-population variability, lack of a twogeneration reproductive study, and lack of data on sequelae resulting from longer durations of exposure (EPA 1997c) : RfD= BMDL UP Current RfD 1.1 ,ug/kg-day 10 = 0.1 ~g/kg-day.
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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.
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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 clisease, found an increase in deaths from renal disease among women but not men (Tamashiro et al.
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From page 310... ...
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.
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From page 311... ...
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.
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MeHg was significantly associated with poorer performance in the Faroe Islands and New Zealand studies, but not in the main Seychelles study. Much of the debate over the adverse effects of MeHg and the selection of a critical study for the RfD and other guidance has focused on the similarities and differences between the Faroe Islands and the Seychelles studies.
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The committee recommends a more inclusive approach to developing any future RfD or exposure guidance. Given the availability of well-clesigned epidemiological studies in which prenatal MeHg levels were within the range of generalpopulation exposures, contemporary exposure standards should consicler the findings of all three studies—the New Zealand, Faroe Islands, and Seychelles studies.
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These results are presented and discussed in detail in Chapter 7. Various analyses were conducted as part of the committee's consideration of the overall weight of the evidence of developmental neurotoxic effects from low-level MeHg exposure.
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The smoothed mean of the distribution of the various BMDs is 21 ppm, with a lower 5th percentile of 7 ppm. The mean of the distribution is in close agreement with the unsmoothed mean of the BMDs from the Farce Islands study (22 ppm)
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1998, 2000. Abbreviations: BMDL, lower 95% confidence limit on the benchmark dose; BMR, benchmark response; Wl, Woodcock-lohnson Tests of Achievement; CPT, Continuous Performance Test; CVLT, California Verbal Learning Test; TOLD, Test of Language Development; WISC-R:PIQ, Wechsler Intelligence Scale for Children-Revised performance IQ; WISC-R:FSIQ, Wechsler Intelligence Scale for Children-Revised Full-Scale IQ.
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For that study, dose-response data based on Hg concentrations in cord blood should be used to estimate the BMD. Because the data on the most sensitive end point—the Continuous Performance Test—were analyzed for only half the sample, the comm~ttee recommends that the BMDL based on the next most sensitive end point—the Boston Naming Test—be considered as a reasonable and representative point of departure for a revised RfD.
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Given the relatively small differences in BMDEs, a more consistent approach to the application of uncertainty factors could reduce the current inconsistencies between the EPA RfD and other risk guidance numbers. To identify sources of uncertainty in deriving the current MeHg RfD, EPA conducted an analysis of uncertainties (EPA 1997b, Vol.
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Any refinement of the current RfD will require consideration of sources of uncertainty. The committee has evaluated the bocly of evidence, focusing on the prospective epidemiological studies of neurotoxicity in children exposed in utero.
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gender, genetics, health status, nutritional influences including dietary interactions, and interindividual toxicokinetic and toxicodynamic variability. For example, data from Iraq indicate that although some individuals were sensitive to low levels of exposure, some members of the cohort were not sensitive to extremely high levels of exposure.
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On the basis of an evaluation of the sources of uncertainty in the key epidemiological studies, the committee identified two major categories of uncertainty, which should be considered in the determination of uncertainty factors for the revision of the RfD: · l:nterindividual toxicokinetic variability in dose reconstruction (see Chapter 3~. · Data-base insufficiency (i.e., because of consideration of possible low-dose sequelae and latent effects, and immunotoxicity and cardiovascular effects)
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Thus, the selection of an appropriate uncertainty-factor value for data-base insufficiency is inherently uncertain. Nonetheless, the committee believes that there is a reasonable possibility that significant immunotoxicity and cardiovascular effects, as well as neurotoxic sequelae, might occur at exposure levels below the dose corresponding to the neurodevelopmental BMD identified by the committee.
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from the Faroe Islands study; the 5 % lower bound BMD from the committee's integrative analysis; and the Iraq study BMDT, which is the point of departure for the current RfD. MOEs for the estimates of mean population levels range from 7.5 (New Zealand, most sensitive end point)
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324 .s be o A_ in .= In cn o x US A au a' o _` ~ _ O ~ a)
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The MeHg-associated performance decrements on the neuropsychological tests administered in the Farce Islands ancI New Zealanc! studies suggest that prenatal MeHg exposure is likely to be associated with poorer school performance.
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However, emerging evidence of other potential effects should also be considered in the calculation and the implementation of the EPA RfD. Given the availability of results from large prospective epidemiological studies, the Iraq study results should no longer be considered the critical study for the EPA RfD.
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The committee estimates that over 60,000 children are born each year at risk for adverse neurodevelopmental effects due to in utero exposure to MeHg. · There is a critical need for improved characterization of population exposure levels to improve estimates of current exposure, track trends, and identify high-risk subpopulations.
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The committee recommends that results from the Boston Naming Test in the Faroe Islands study be used in the calculation of the RfD. For that study, dose- response data based on Hg concentrations in cord blood should be modeled using the K-power mode!
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1995a. Neurodevelopmental test selection, administration, and performance in the main Seychelles child development study.
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1998. Effects of prenatal and postnatal methylmercury exposure from fish consumption on neurodevelopment:outcomes at 66 monts of age in the Seychelles child development study.
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1987. Fetal methylmercury poisoning: Relationship between concentration in single strands of maternal hair and child effects.
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2000. Mercury and methylmercury exposure in the New Jersey pregnant population.
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