Toxicological Effects of Methylmercury (2000) / Chapter Skim
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Dose Estimation
Dose Estimation
Pages 105-146
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From page 105... ...
There are several basic approaches to the estimation of MeHg exposure from dietary intake: collection of 105
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From page 106... ...
Duplicate-diet studies have been specifically applied to the estimation of MeHg exposure by Sherlock et al.
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From page 107... ...
Because fish are consumed relatively infrequently, the duration of the recording period might require many weeks to adequately capture infrequent consumers as well as variability in consumption among more frequent consumers. Furthermore, the design must be such that possible seasonal patterns of
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From page 108... ...
The National Purchase Diary conducted by the Market Research Corporation used dietary diaries over I-month periods between 1973 and 1974 (discussed in EPA 1997~. The fish-consumption portions of these diary data were used to estimate MeHg exposure in the U.S.
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From page 109... ...
consumed by frequent and infrequent consumers differ, or if the average portion size consumed by each group differs, the estimate of MeHg intake in the overall population will not be accurate. The CSF[T ciata used by EPA to estimate fish consumption Jacobs et al.
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From page 110... ...
Retrospective dietary data and diary data on fish consumption have frequently been used to stratify a study population into broad classes of MeHg intake before more quantitative estimation of exposure by measurement of Hg in biomarkers. Such data have also been used to provide a rough validation of biomarker analyses (e.g., Dennis and Fehr 1975; Skerfving 1991; Grandjean et al.
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From page 111... ...
With repeated consumption of a species of fish, total MeHg intake by consumers will approach the average concentration in that species. However, for populations with infrequent or sporadic consumption of a species, the effect of ignoring intraspecies variability in Hg concentrations could be significant.
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From page 112... ...
For the purposes of risk assessment, biomarker concentrations of MeHg serve two functions. First, a biomarker concentration is used as a surrogate for the unknown biologically relevant dose of MeHg in the developing fetal brain.
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From page 113... ...
Maternal ingestion of MeHg refers to the ingested dose, He magnitude of which depends on the amount of fish consumed and the concentration of MeHg in the fish. The concentration of Hg measured in the maternal blood, fetal blood, cord blood, maternal nails, and maternal hair are all biomarkers of exposure.
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From page 114... ...
For developmental neurotoxicity, the target organ is the developing fetal brain. The kinetics of MeHg transport among compartments is subject to interindividual variability at each step, and therefore, the more closely a compartment is kinetically related to the target tissue, the more closely the concentration measured in that compartment is likely to correlate with the concentration in the target tissue.
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From page 115... ...
A single blood sample showing an elevated concentration, without additional exposure information, does not provide a temporal perspective and d oes not permit differentiation between increasing peak concentrations, decreasing peak concentrations, and steady-state exposure. Conversely, a single blood sample obtained between peak exposures and showing a low blood Hg concentration provides no evidence of peak exposures.
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From page 116... ...
MeHg exposure during late fetal development, when brain structure is basically established, is likely to produce more function-specific effects on brain architecture. Even within early-to-middle fetal developmental stages, there might be discrete windows of sensitivity.
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From page 117... ...
If the Hg concentration in cord blood is 20-30% higher than that in maternal blood (because of a longer halflife in fetal blood) , the cord-blood Hg concentration would be more influenced than the maternal-blood concentration by exposures during the latter portion of the second trimester and the first half of the third trimester.
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From page 118... ...
In contrast, hair Hg concentration as a biomarker of MeHg exposure has the advantages of being able to integrate exposure over a known and limited time and recapitulate the magnitude and the timing of exposure. The ability to obtain such information from hair is predicated on two assumptions: that growing hair shafts incorporate Hg from the circulating blood in proportion to the concentration of Hg in the blood, and that hair shafts grow at a constant rate that does not vary significantly among individuals.
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From page 119... ...
That difference can lead to exposure misclassification for the period of interest. The potential for exposure misclassification due to collection of follicles in the terminal resting phase is a particular concern in singlestrand hair analysis for Hg.
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1967) , thus adding to the temporal uncertainty inherent in assessing MeHg exposure from hair analysis.
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As discussed for blood Hg analysis, temporal uncertainties might not be critical for individuals with steady-state MeHg concentrations. However, for individuals with variable or peak exposures that might occur at critical periods during development, the uncertainties in assigning a specific time during pregnancy to specific hair segments might result in significant misclassification of exposure.
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From page 122... ...
Such an approach to segmental hair analysis would not give an accurate indication of the magnitude or duration of the peak concentration in the maternal or fetal blood. To some extent, the sensitivity to peak exposures can be increased by analyzing smaller-length segments of hair corresponding to narrower periods of exposure.
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From page 123... ...
Despite those limitations, hair samples have the potential to provide temporal information on Hg exposures. An alternative to segmental hair analysis is continuous single-strand hair analysis using x-ray fluorescence (XRF)
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Overall, single-strand hair analysis by XRF appears to be a powerful too! with the distinct advantage of being able to determine short-term changes in exposure, including peak exposures.
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From page 125... ...
For the back-calculation of the average ingested dose corresponding to a given biomarker critical concentration, the maternal-hair Hg compartment and the cord-blood Hg compartment are equally distant kinetically from ingestion (see Figure 4-~. The estimation of the ingested dose corresponding to a critical biomarker concentration requires the intermediate estimation of the corresponding maternal-blood Hg concentration.
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From page 126... ...
1999~. Overall, in comparing maternal hair and cord blood as possible biomarkers of in utero MeHg exposure, each has significant advantages and disadvantages.
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From page 127... ...
The utility of cord blood and hair as biomarkers of MeHg exposure can be substantially improved by linking them to accurate dietary intake information. Data on frequency, amount, and type of fish consumption in the period during and immediately preceding pregnancy can provide information on the overall variability in exposure as well as on peak exposures.
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From page 128... ...
Presumably then, the analytical errors in the analyses of hair Hg concentrations in both studies are highly comparable. It appears that all cord-blood Hg analyses used for dose response were carried out in the laboratory of the Faroe Islands group (i.e., Odense University)
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From page 129... ...
The extent to which that error might affect the interpretation of the dose-response relationship based on the New Zealand study is not clear. EXPOSURE AND DOSE ASSESSMENT IN THE SEYCHELLES, FARCE ISLANDS, AND NEW ZEALAND STUDIES Exposure in the Seychelles studies was measured as total Hg in maternal-hair samples.
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From page 130... ...
More specific information about intraindividual exposure variability or peak exposures cannot be deduced from these data. Data from this segmental analysis was not used in dose-response assessment.
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From page 131... ...
As discussed above, cord-blood Hg concentration is influenced by exposure over an indeterminate time period, possibly including the latter part of the second trimester but weighted most heavily toward the latter part of the third trimester. Assuming a delay of about 20 days between incorporation of Hg into a growing hair strand and its appearance above the scalp, a 3-cm hair sample proximal to the scalp would reflect average exposure from the end of the second trimester to the second-third of the third trimester.
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From page 132... ...
Although that suggests low-to-moderate intraindividual variability in MeHg intake over time, generalization to the entire cohort is not warranted because of the small sample size. The relative magnitude of potential peak exposures from sporadic consumption of whale meat is possible to estimate.
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From page 133... ...
As discussed previously, a rapid doubling in Hg exposure during that period, such as that resulting from a few successive high-Ha fish meals, for a I-cm segment would be reflected as a 50% increase compared with neighboring segments with no such peak exposures. Analysis of these segments would likely detect significant peaks in exposure but would not necessarily provide accurate information on the absolute magnitude of those peaks.
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From page 134... ...
However, those data suggests that MeHg exposure in the New Zealand cohort might have been relatively spiky as opposed to constant and regular. It is interesting that the peak exposures were not regularly distributed across the period of gestation.
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From page 135... ...
(1999) noted in the Faroe islands study that cord-blood MeHg appeared to better predict deficits In cognitive functions (language, attention, and memory)
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From page 136... ...
Those include incorrectly considering exposures that occurred during developmental periods during which there is little or no vulnerability of the observed developmental endpoints to MeHg; failing to identify peak concentrations that might be more toxicologically relevant than the measured average concentrations; and using portions of hair with Hg concentrations that accumulated before or after pregnancy. Generally, exposure misclassification biases to the null—that is, use of an incorrect exposure level in a regression analyses of outcome data leads to decreased power to detect a real effect.
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From page 137... ...
On the other hand, prospective data on all sources of Hg exposure, such as vaccines and dental amalgams and, in particular, dietary intakes of MeHg are essential to understanding the effects of environmental Hg exposures on any outcomes. Quantitative dietary intake data on intakes of all marine food sources can and should be collected in any serious study of this contaminant.
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From page 138... ...
Segmental analysis can isolate specific periods of gestation, but peak exposures might be inadequately represented. Continuous single-strand analysis is a powerful technique that can recapitulate MeHg exposure during the entire period of gestation with accurate representation of peak exposures.
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From page 139... ...
. RECOMMENDATIONS · Quantitative dietary intake data on patterns of consumption of the primary sources of MeHg including all marine food sources, should be collected in all prospective studies of MeHg exposure.
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From page 140... ...
NHANES IV data should be examined when it becomes available to determine if it satisfies those needs. · To detect exposure variability, archived hair strands from both the Seychelles and the Farce Islands studies should be analyzed by continuous single-strand XRF analysis.
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1995a. Monitoring methylmercury during pregnancy: Maternal hair predicts fetal brain exposure.
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1998. Prenatal exposure to methylmercury in ~e Faroe Islands and neurobehavioral performance at age seven years.
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Pp. 6-12 in Hair Analysis: Application in the Biomedical and Environmental Sciences.
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1981. Comparison of mercury levels in maternal blood, fetal cord blood, and placental tissues.
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1989. The ~ntrapartum content of toxic metals in maternal blood and umbilical cord blood.
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From page 146... ...
U.S. Food and Drug Administration survey of methyl mercury in canned tuna.
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