Toxicological Effects of Methylmercury (2000) / Chapter Skim
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Biological Variability
Biological Variability
Pages 72-104
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From page 72... ...
The ability of the individual to compensate for damage caused by MeHg exposure would also affect susceptibility. This chapter discusses those factors that could underlie the variability in response to Hg exposure.
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From page 73... ...
Reports of age-related neurological effects due to MeHg exposure inlapan and Iraq have also been described (Bakir et al. 1973; Harada 1968; Marsh et al.
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That result might be due to higher metabolism and urinary-excretion rates for MeHg in sexually mature male mice compared with female mice (Hirayama and Yasutake 1986~. Animal data also indicate gender differences in the sensitivity to MeHg toxicity.
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From page 75... ...
At the other extreme, maInourishment could affect study results either by directly reducing the sensitivity of an end point tested or by exacerbating the effects of MeHg, thereby increasing the sensitivity to MeHg toxicity. Nutritionalfactors that disrupt neuronal development, such as iron or folate deficiencies, might increase the impact of MeHg on neural development.
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- Facilitation of neural development and health —direct:(e.g., breast-feeding, vitamin E, folate, omega-3 fatty acids) —indirect (e.g., low infection, very healthy population)
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Dietary Interactions and Confouncling Dietary factors can also confound studies of the effects of MeHg when consumption of a food contributes to the measured outcome through more than one component in that food. If a factor is associated with both MeHg exposure and outcome measures but is not part of the pathway by which MeHg effects neurological or other responses, it can be considered a confounding factor and must be controlled for in the analyses.
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1972~. In animals, selenium deficiency has been associated with enhanced fetotoxicit,v following MeHg exposure (Potter and Matrone 1974; Nishikido et al.
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Omega-3 Fatty Acicis Polyunsaturated fatty acids are essential for brain development. During perinatal development, docosahexaenoic acid (DHA)
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affects monoaminerg~c neruotransm~ssion and behavior in rats. Omega-3 fatty acids might enhance neurotoxicolog~cal function and their deficiency might contribute to lower test results, which would confound MeHg toxicological studies in- human populations.
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From page 81... ...
The applicability of these findings to human alcohol consumption and MeHg exposure patterns is unknown. Other Foods That Might Influence Hg Uptake Two studies indicated that the addition of milk to rodent diets increases the total body burden of Hg as well as Hg concentrations in the brain (Landry et al.
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From page 82... ...
supplementation in the diet has been shown to be protective against Hg toxicity in tissue cultures and animals models. For example, in studies of male "olden hamsters, the injection of 2 ppm a-tocophero} acetate completely prevented the neurotoxic effects and histological changes associated with injection of 2 ppm MeHg (Chang et al.
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From page 83... ...
pcarotene did not affect the activity of total glutathione peroxidase or selenium-dependent glutathione peroxidase. Beneficial Effects of Fish Consumption The committee is aware of the other nutritional advantages of diets rich in fish, including fish being a rich source of vitamin D, omega-3 fatty acids, protein, and other nutrients that might be marginal in some diets.
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(1999) , illustrated in Figure 3-2, attempts to characterize the distribution and redistribution of MeHg among several body compartments, including maternal hair and fetal cord blood.
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Model parameters denoted by k represent rate constants for MeHg. Model parameters denoted by Q represent plasma flow rates.
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per day) ; Wis the body weight (kilograms)
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When fetal-cord-blood MeHg concentration is the biomarker measured, He corresponding maternal-blood concentration can be estimated
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parameters according to the mathematic form of the model. The central-tendency value of the ingested dose corresponding to a given biomarker concentration could be estimated using the central-tendency value for each parameter of the model.
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In estimating the range of ingested doses which could have resulted in a given biomarker concentration, there are three main sources of variability errors in mode! selection, errors in estimation of model parameters, and true population variability (i.e., heterogeneity)
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, presents an ad hoc probabilistic assessment of interindividual toxicokinetic variability, using the one-compartment model, in the calculation of the ingested dose. The results of that analysis, however, were not used by EPA in the derivation of its RfD.
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From page 91... ...
parameters in either the one-compartment or the PBPK model, then the resulting ingested dose should approximate the 50th percentile of the population distribution. The ratio of the ingested dose corresponding to the 50th percentile of the distribution to the dose at the 5th percentile of the clistribution, therefore, is an estimate of the factor by which the central-tendency estimate of the ingested dose should be divided to make the dose estimate inclusive of the variability in 95% of the population.
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indicates that the absolute value of the central tendency of the distribution of ingested doses precticted by Stern
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The application of estimates based on the ratio of maternal-blood Hg concentration to estimates of cord-blood Hg concentration assumes that those two concentrations are equal. Some observations suggest that Hg concentrations in cord blood are larger than in maternal blood by at least 20-30 % (Dennis and Fehr 1975; Pitkin et al.
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Similarly, for estimates of the ingested close based on a benchmark blood Hg concentration, the data in Table 3-1 indicate that adjustment of a central-tendency estimate of the ingested dose by an uncertainty-factor adjustment-of about 2 takes into account 95-99% of the interindividual toxicokinetic variability. The use of uncertainty factors to adjust a central-tendency estimate of the ingested dose for interindividual variability is an indirect, or "backend," approach to accounting for such variability in the RfD.
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—Gender specific effects due to developmental exposure to MeHg typically indicate a greater sensitivity for male offspring. —Gender sensitivity in toxicity appears to be dependent on the species used and outcome studied.
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. —the ingested doses predicted by the one-compartment and PBPK models, therefore, are also probability distributions that reflect the likelihood that any given ingested dose could give rise to the critical biomarker concentration.
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From page 97... ...
Any biomarker-based RfD for MeHg should specifically address interindividual toxicokinetic variability in the estimation of dose corresponding to a given biomarker concentration. —The starting point for addressing interindividual toxicokinetic variability shouict be a central-tendency estimate of the ingested dose corresponding to a critical biomarker concentration (e.g., a benchmark hair concentration)
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From page 98... ...
For an RfD based on blood Hg concentration, an uncertainty factor adjustment of about 2 should be applied to the central-tendency estimate of dose to be inclusive of 95-99% of the toxicokinetic variability In the population. Because of the recognized nutritional benefits of diets rich in fish, the best method of maintaining fish consumption and minimizing Hg exposure is the consumption of fish known to have lower MeHg concentrations.
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1998. Dietary fish oil affects monoaminergic neurotransmission and behavior in rats.
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1981. Comparison of mercury levels in maternal blood, fetal cord blood, and placental tissues.
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1992. Deferoxamine inhibits methyl mercury induced increases in reactive oxygen species formation in rat brain.
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1972. Subtle consequences of methyl mercury exposure: Behavioral deviations in offspring of treated mothers.
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1995. Screening of potential transport systems for methyl mercury uptake in rat erythrocytes at 5 degrees by use of inhibitors and substrates.
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104 TOXICOLOGICAL EFFECTS OF METHYLMERCURY Yasutake, A., K Hirayama, and M
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