3

BIOLOGICAL VARIABILITY

INDIVIDUAL responses to MeHg exposure are variable. For example, individuals receiving the same dose of MeHg in the Iraqi accident did not all have the same effects. Even in controlled animal experiments, considerable variability in response is noted (Burbacher et al. 1988; Rice and Gilbert 1990). Differences in susceptibility to MeHg might be due to differences in the uptake, storage, transport, or metabolism of MeHg. Susceptibility to the effects of MeHg can also be predetermined by genetic polymorphisms that affect the delivery of MeHg to the target organs or affect the response of the target organs to MeHg. In addition, other external factors can influence vulnerability to the effects of MeHg. Factors that deserve consideration are age, gender, health status, nutritional status, and the intake of other foods or nutrients that might influence the absorption, uptake, distribution, and metabolism of MeHg. 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. The implications of that variability on the study of the toxicokinetics of Hg are discussed.

AGE-RELATED SUSCEPTIBILITY

Exposure to MeHg during the neonatal period, infancy and childhood has different effects due to the different stages of brain development and



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Toxicological Effects of Methylmercury 3 BIOLOGICAL VARIABILITY INDIVIDUAL responses to MeHg exposure are variable. For example, individuals receiving the same dose of MeHg in the Iraqi accident did not all have the same effects. Even in controlled animal experiments, considerable variability in response is noted (Burbacher et al. 1988; Rice and Gilbert 1990). Differences in susceptibility to MeHg might be due to differences in the uptake, storage, transport, or metabolism of MeHg. Susceptibility to the effects of MeHg can also be predetermined by genetic polymorphisms that affect the delivery of MeHg to the target organs or affect the response of the target organs to MeHg. In addition, other external factors can influence vulnerability to the effects of MeHg. Factors that deserve consideration are age, gender, health status, nutritional status, and the intake of other foods or nutrients that might influence the absorption, uptake, distribution, and metabolism of MeHg. 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. The implications of that variability on the study of the toxicokinetics of Hg are discussed. AGE-RELATED SUSCEPTIBILITY Exposure to MeHg during the neonatal period, infancy and childhood has different effects due to the different stages of brain development and

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Toxicological Effects of Methylmercury organ growth and the ratio of the MeHg concentration to body size. Age also affects the detection of toxic responses to MeHg, because some of the most sensitive end points examined — neurological development and cognitive ability — are dependent upon the age of the subject and the stage of cognitive maturation. There are also natural differences among individuals in performance on tests used. Therefore, the sensitivity of the test or assessment is dependent upon the developmental stage and age of the subject. In addition, many of the tests are carried out during periods of rapid development, which results in greater natural variation between individuals. Data from Japanese poisoning episodes provide strong evidence that susceptibility to MeHg changes with age. Takeuchi (1968) described three distinct patterns of MeHg neuropathology termed adult, infantile, and fetal Minamata disease. In autopsy cases following fetal exposures, clear evidence of interference with brain development was observed. Disorganized cell layers and misoriented cells were observed, providing evidence of disrupted cell migration. For fetal and infantile exposures, lesions were observed throughout the cortex. A more selective pattern of lesions, localized in the calcarine and precentral cortices, particularly in the depths of the sulci, was observed in adult cases. Lesions in the granular layer of the cerebellum were observed in all cases. Reports of age-related neurological effects due to MeHg exposure in Japan and Iraq have also been described (Bakir et al. 1973; Harada 1968; Marsh et al. 1980). In both cases, mothers with few or no symptoms gave birth to infants severely affected. Studies with animal models also have reported significant age-dependent effects from MeHg exposure. As in human cases, offspring are sometimes severely affected with little or no signs of toxicity in the mother (Spyker et al. 1972; Mottet et al. 1987). Thus, age needs to be considered in the design of studies of MeHg, including in the choice of end points and the determination of how to analyze the results. GENDER DIFFERENCES Several reports have described gender differences in the toxicokinetics and the toxicodynamics of MeHg. Evidence of gender-dependent MeHg metabolism has been reported in humans (Miettinen 1973) and

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Toxicological Effects of Methylmercury animal models (Thomas et al. 1986; Nielsen and Andersen 1991). However, this gender sensitivity does not apply in the same way for all outcomes. The Iraqi MeHg epidemic appeared to affect three times as many females as males (Magos et al. 1976). Epidemiological studies of human infants and children have reported gender specific effects on development with males exhibiting greater effects than females. (McKeown-Eyssen et al. 1983) In general, results in animal studies indicate that females exhibit a higher body burden of Hg per given dose than males. 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. Fowler (1972) and Yasutake et al. (1990) found that females are more likely to show renal toxicity following MeHg exposure. Yasutake and Hirayama (1988) found the gender differences to be strain sensitive following oral administration of MeHg chloride at 5 mg/kg per day since male Balb/cA mice died earlier than female Balb/cA mice, but female C57B/6N mice died earlier than male C57B/6N mice. Reports regarding the neurological effects have been mixed; females were found to be more susceptible than males in some studies, and males were observed to be more susceptible than females in others (Magos et al. 1976; Tagashira et al. 1980; McKeown-Eyssen et al. 1983; Vorhees 1985; Tamashiro et al. 1986a). GENETICS Aside from gender differences within a population, there is evidence of differences in sensitivity within populations that result in greater damage from a given exposure in one individual than in another. The extent to which that difference is due to familial characteristics compared with nutritional and environmentally mediated susceptibility remains to be determined. Differences in enzymatic expression might result in individual differences in sensitivity to MeHg. Currently, no evidence of polymorphisms affecting the metabolism or detoxification of MeHg exists. The lack of evidence, might be due to the inadequate study of those interactions in human populations and animal models. Therefore, the extent to which interindividual variability in effects at

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Toxicological Effects of Methylmercury similar doses is attributable to genetic differences in susceptibility remains unknown (Tamashiro et al. 1986). MECHANISMS OF NUTRITIONAL INFLUENCE ON MeHg HEALTH EFFECTS Overall, nutritional status and dietary interactions can affect the outcomes of MeHg studies, either by influencing the toxicity of Hg or by having effects on the end points measured. The main source of exposure to MeHg is through the food chain, largely through consumption of nonherbivorous fish and marine mammals, with smaller amounts contributed by intake of other fish and seafood. The nature of dietary exposures is such that consumption of one food group is generally related to a reduction or avoidance of other food groups. Establishing causality becomes particularly complex under those circumstances. Pathways through which diet and nutrients might affect the results of MeHg toxicity studies include the potential for attenuating a MeHg effect, exacerbating a MeHg effect, or acting as a confounder by causing toxicity due to other common food components or contaminants. Those three pathways are outlined in Figure 3-1. Potentially harmful effects of MeHg might be attenuated by protective effects of such nutrients as selenium and omega-3 fatty acids. At the other extreme, malnourishment 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. Nutritional factors that disrupt neuronal development, such as iron or folate deficiencies, might increase the impact of MeHg on neural development. Conversely, adequate levels of iron and folate in the diet might reduce the impact of MeHg. Such nutrient deficiencies could arise from an inadequate diet or, secondarily, from repeated infection, intestinal parasites, or excessive alcohol consumption. The available data for the birth weight, gestation, and weight of the children studied in the Faroe Islands, Seychelles, and New Zealand do not suggest that there are energy or macronutrient (protein, carbohydrate, and fat) deficiencies in these populations. However, micronutrient deficiencies, such as iron and zinc, due to low intake of fortified or unrefined grains, fruits, and vegetables are possible. There

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Toxicological Effects of Methylmercury FIGURE 3-1 Hg nutrient interactions. Source: Modified from NIEHS 1998. is insufficient information on the extent of breast-feeding of the infants to determine whether the use of other sources of milk and milk substitutes affected the outcome because of inadequate levels of iron, vitamins, and other minerals in those sources. The effects of such deficiencies on neurobehavioral end points might be evident long before any clinical signs of deficiency are present, and such deficiencies might not

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Toxicological Effects of Methylmercury have been obvious in the study populations. Although those deficiencies could affect the risk estimate, an artifactual response will be seen only if those deficiencies are disproportionally distributed among the individuals exposed to MeHg at different doses. Dietary Interactions and Confounding 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. Because the primary source of exposure is from fish consumption, it is difficult to determine whether the Hg in that source is the only cause of the fish-related effects. Other contaminants that could be present in fish, such as polychlorinated biphenyls (PCBs) or dichlorodiphenyltrichloroethane (DDT), could confound a study. High fish consumption could also result in the absence of another important food or nutrient from the diet. Conversely, fish consumption might be associated with the intake of protective substances, such as selenium and omega-3 fatty acids. Such an association was seen by Osman et al. (1998), who examined blood MeHg and selenium concentrations in Polish children from Katowice. The understanding of the causal relationship between MeHg and adverse effects, therefore, would be greatly enhanced by information on the intake of all dietary constituents and adjustment for other toxicants. Availability of quantitative dietary information and incorporation of that information into assessments of MeHg effects could improve the analysis of the studies. It is important to remember that fish and shellfish are high-quality food sources of protein and nutrients and that they are low in saturated fats. They contain nutrients that are essential for proper central-nervous-system development and function, and they might have potential health benefits in the prevention of cardiovascular disease and cancer. A reduction in the consumption of fish and shellfish might result in dietary patterns that are generally more harmful.

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Toxicological Effects of Methylmercury Selenium Although the effect of selenium on MeHg toxicity has not been well documented in humans, it has been known for over two decades that organic and inorganic selenium can influence the deposition of MeHg in the body and protect against its toxicity in animals (Ganther et al. 1972). In animals, selenium deficiency has been associated with enhanced fetotoxicity following MeHg exposure (Potter and Matrone 1974; Nishikido et al. 1987). At the other extreme, the toxicity of MeHg can be enhanced in the presence of very high selenium supplementation (as in its absence) (Nobunaga et al. 1979). Over 40 studies have examined the interaction of selenium and mercury in various systems. These have recently been reviewed by Chapman and Chan (2000). Selenium also influences tissue deposition in a form- and dose-dependent manner. Administration of seleno-methionine increased MeHg and total Hg content in the blood of rats exposed to MeHg through fish consumption. Administration of selenium dioxide lowered Hg concentrations by 24-29% in the blood and liver of rats in the same model system. Selenite supplementation in the diet of female rats before mating, during gestation, and during lactation antagonized the central-nervous-system effects following in utero exposure to MeHg (Fredriksson et al. 1993). Selenium injection during gestation has been shown to increase Hg concentrations in the neonatal brain (Satoh and Suzuki 1979), whereas ingestion has been shown to reduce brain levels (Fredriksson et al. 1993). Therefore, animal experiments show that selenium might be protective in terms of neurodevelopmental responses but this is not clear. The selenium dose, form, and exposure route (injection vs ingestion) might affect the tissue deposition profiles. Although selenium appears to have a protective effect in animals, no association has been confirmed in humans. The mechanism by which selenium influences the deposition of Hg is not established. Proposed mechanisms include the formation of seleno-MeHg complexes, a selenium-induced release of MeHg from sulfhydryl bonds in the blood, and tissue-specific mechanisms that influence intracellular uptake (Glynn and Lind 1995). Garlic Garlic might be an important effect modifier in MeHg studies. Many

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Toxicological Effects of Methylmercury compounds (or their metabolites) in garlic could act as metal chelating or complexing agents and increase MeHg excretion. Such chemicals can be converted to thiols or include thiols (diallyldisulfide, diallyltrisulfide, propylallyldisulfide, and diallylsulfide), glutathione, vitamin C, and thiol amino acids (see review by Block 1985 ). Garlic also contains selenium (0.72-1.52 µg of selenium per gram of garlic), which, as previously discussed, might influence Hg toxicokinetics. Animal studies support a protective role of garlic against Hg toxicity (Cha 1987; Rhee et al. 1985). Male Sprague-Dawley rats were simultaneously administered MeHg (4 ppm), cadmium, and phenylmercury in their drinking water as well as 8% peeled, crushed raw garlic (Allium satirum) in the feed (200 ppm allicin) for 12 weeks. Results indicate a statistically significant reduction in Hg tissue concentrations compared with rats that did not receive garlic (Cha 1987). It is not clear from that study whether the garlic removed Hg that had been deposited in the tissues or whether it prevented its accumulation before deposition. Severe pathology was noted in the kidneys of rats receiving the MeHg in the absence of garlic, and only mild or no damage was noted in MeHg-exposed rats receiving 6.7% or 8 % garlic, respectively. Interpretation of that study must be done cautiously, however, because the effects might be due to cadmium and not Hg toxicity. It should also be noted that the protection is against the renal effects of MeHg, not the neurotoxicity. In an earlier paper, Rhee et al. (1985) exposed rats (40 per group) intraperitoneally to MeHg (5 mg/kg of body weight per day) for 8 days. One group also received garlic. Tissue Hg concentrations were lower in the garlic-exposed animals than in the rats that did not receive garlic. It should be noted that the doses of garlic used in those studies (6-8% by animal weight) are well above the expected garlic content in the human diet, even in those cultures that use relatively high amounts of garlic in their cooking. More extensive study of the interactions between garlic and MeHg is needed. Omega-3 Fatty Acids Polyunsaturated fatty acids are essential for brain development. During perinatal development, docosahexaenoic acid (DHA), an omega-3 fatty acid, accumulates in membrane phospholipids of the nervous

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Toxicological Effects of Methylmercury system. Deficiency in DHA impairs learning and memory in rats (Greiner et al. 1999). The ratio of omega-3 to omega-6 fatty acids might also be important. The largest source of omega-3 fatty acids, in particular eicosapentanoic acid and its metabolite DHA, in the human diet is oily fish, such as salmon, herring, and other cold- water fish. Chalon et al. (1998) demonstrated that fish oil affects monoaminergic neruotransmission and behavior in rats. Omega-3 fatty acids might enhance neurotoxicological function and their deficiency might contribute to lower test results, which would confound MeHg toxicological studies in human populations. Individuals consuming less fish might perform more poorly. Individuals on a diet high in fish might demonstrate the competing effects of enhanced function from these fatty acids and reduced function because of the presence of MeHg in the same food source. A case-control study in Greece concluded that low fish intake is associated with an increased risk of cerebral palsy (Petridou et al. 1998). Populations eating diets rich in fish might have enhanced neural development that could mask adverse effects on development caused by MeHg. Therefore, controlling for intake of essential fatty acids in MeHg studies is important. That can be done by measuring biomarkers of long-term exposure to fatty acids, such as adipose tissue (Kohlmeier and Kohlmeier 1995). However, there is no evidence to date that supplementation of omega-3 fatty acid to the diet of a well-nourished term infant further enhances neurological development or attenuates the toxic effects of Hg. Protein The type and amount of protein consumed might affect the uptake and distribution of Hg in the body. Low protein intakes have been associated with increased Hg in the brain of the mouse (Adachi et al. 1994; Adachi et al. 1992). Sulfur amino acid ingestion might also increase blood, renal, and hepatic concentrations of Hg. Cysteine appeared to enhance transport of MeHg to the brains of rodents (Aschner and Clarkson 1987; 1988; Aschner and Aschner 1990; Hirayama 1985) when the amino acid was injected into the animals at the time of oral dosing or injection of MeHg chloride. There is some indication that

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Toxicological Effects of Methylmercury leucine might inhibit MeHg uptake (Mokrzan et al. 1995). In contrast, in vitro studies indicate that methionine might stimulate MeHg uptake (Alexander and Aaseth 1982; Wu 1995). Alcohol Ethanol has been shown to potentiate MeHg toxicity in mice and rats (Takahashi et al. 1978; Turner et al. 1981). Five studies conducted in rodents examined the potential for alcohol interactions with MeHg. These studies indicate that the coconsumption of alcohol with MeHg can potentiate toxicity, particularly in the kidney (Takahashi et al. 1978 as cited in Chapman and Chan 2000; Rumbeiha et al. 1992; Tamashiro et al. 1986b; Turner et al. 1981; McNeil et al. 1988). Ethanol administered to male rats in conjunction with daily injections of MeHg chloride has resulted in a dose-dependent increase in tissue concentrations of both total Hg and MeHg in the brain and kidneys and in the morbidity and mortality of these animals. 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. 1979; Rowland et al. 1984). Landry et al. (1979) showed a 56% increase in the whole-body retention of Hg in female BALB/c mice fed liquid diets of evaporated whole milk as compared with their standard diet. That increase was attributed to the binding of heavy metals to the milk triglycerides, enhancing gut absorption. Those findings of an increased retention of MeHg with a diet containing evaporated milk were confirmed by Rowland et al. (1984). There are strong indications that wheat bran, but neither cellulose nor pectin, when consumed concurrently with MeHg administration, might reduce Hg concentrations in the brain. In a study of male BALB/c mice, a dose-response relationship between brain Hg concentrations and the percentage of wheat bran was seen across 0%, 5%, 15%, and 30% wheat bran in the diet. The highest dose of wheat bran decreased the half-time

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Toxicological Effects of Methylmercury of Hg elimination by 43%, and decreased the brain Hg concentrations by 24%. Corresponding reductions were seen in the Hg concentrations in the blood of the bran-fed animals. Reductions of that magnitude have been associated with a lower incidence and severity of symptoms of neurotoxicity in rats. The effect has been attributed partially to binding of the Hg to bran, reducing its absorption from the gut and decreasing intestinal transit time. Using evidence of an increase in mercuric Hg in the large intestines of the bran-fed mice, it has also been hypothesized that wheat bran increased the rate of demethylation of organic Hg in the gut (Rowland et al. 1986). Vitamin E The protective effect of coconsumption of α-tocopherol 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 golden hamsters, the injection of 2 ppm α-tocopherol acetate completely prevented the neurotoxic effects and histological changes associated with injection of 2 ppm MeHg (Chang et al. 1978). The hypothesized mechanism is an antioxidant effect related to lipid peroxidation and to the prevention of neuronal degeneration ( Kling and Soares 1982; Kling et al. 1987; Chang et al. 1978; Kasuya 1975; Park et al. 1996; Prasad et al. 1980). Nutrient Enhancement of Toxicity In addition to the effects of protein, milk, and alcohol discussed earlier, four other nutrients have been implicated in the enhancement of MeHg toxicity: vitamin A, vitamin C, iron, and β carotene. Welsh (1977) reported in an abstract that vitamin A (10,000 IU/kg) decreased the time of onset of Hg toxicity in Fischer 344 rats given methylmercuric chloride at 10-15 ppm in drinking water. Vitamin C was shown to increase the absorption of Hg from the gastrointestinal tract, shortening the survival time of guinea pigs exposed to methylmercuric iodide at 8 mg/kg per day (Murray and Hughes 1976). The iron chelator, deferoxamine, was shown to inhibit the formation of reactive oxygen species in the cerebel-

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Toxicological Effects of Methylmercury dose from a benchmark hair Hg concentration is generated using point estimates of the central tendency for each model parameter, then dividing this initial estimate by an uncertainty factor of 2 would result in a dose that includes approximately 95% of the interindividual toxicokinetic variability in the population. Dividing the initial estimate by an uncertainty factor of 2-3 would include approximately 99% of the interindividual toxicokinetic variability. Similarly, for estimates of the ingested dose 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 “back-end,” approach to accounting for such variability in the RfD. A direct, or “front-end,” approach would be to select as the starting point for the derivation of the RfD the ingested dose that corresponds to a given (e.g., benchmark) hair or blood Hg concentration for the percentile of the population variability that is to be accounted for. In that case, no uncertainty-factor adjustments would be necessary to account for toxicokinetic variability in the dose conversion. For example, with reference to Figure 3-4, if the benchmark (or NOAEL) hair concentration is 11 ppm and the RfD is intended to include the toxicokinetic variability in 95% of the population, then the corresponding ingested dose would be approximately 0.2 µg/kg per day. The difficulty with using such an approach is that, in the direct approach the estimate of the absolute value of the ingested dose is the critical determination. Whereas in the uncertainty factor approach the estimate of the relative variability in the ingested dose is critical. As discussed previously, for a given hair concentration the absolute value of the ingested dose for any given percentile of the population is not consistent in the analyses of Stern (1997), Swartout and Rice (2000), and Clewell et al. (1999). The analysis of Stern (1997) predicts lower absolute values of the ingested dose for a given percentile of the population than the other two analyses. Therefore, the use of the direct approach requires that a choice be made among the probability distributions predicted by those analyses. The differences in the analyses are due to the use of different data sets for parameter estimates, and there is no clear basis for choosing one data set over another. Even when central-tendency estimates and uncertainty

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Toxicological Effects of Methylmercury factors are used, the most appropriate value for each model parameter must be selected. Selection of different values for model parameters could underlie differences in the modeling results. The advantage of the uncertainty-factor approach, however, is that the choice for each model parameter is explicit. That allows for a more reasoned and detailed discussion of those choices. The analyses of Stern (1997), Swartout and Rice (2000), and Clewell et al. (1999) all discuss their choices of parameter estimates. The information presented in those discussions should be considered in the selection of the central-tendency estimates of the individual parameters. CONCLUSIONS Sensitivity to the toxic effects of MeHg is related to the age at which exposure occurs. Because of that, the fetus and young infants exposed during periods of rapid brain development are particularly vulnerable. Sex differences appear to affect the metabolism, tissue uptake, excretion and toxicity of Hg. 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. Dietary nutrients and supplements might protect against the toxicity of MeHg. Data regarding the relative presence or absence of such nutrients and supplements either in the populations studied or in the United States are not available. The lack of that information contributes to overall data-base uncertainty, but it does not detract from the suitability of those studies for determining the risk associated with MeHg. In addition to the above factors, intraindividual differences are clearly noted in responses to similar exposures. Those are explained, in part, by nutritional factors that might exacerbate or attenuate the effects of Hg toxicity in the host. Currently unknown genetic susceptibilities could be expected to play a role in response variability. In any MeHg risk assessment in which the exposure metric is a Hg

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Toxicological Effects of Methylmercury biomarker concentration, it is necessary to use a toxicokinetic model to estimate the ingested dose that gave rise to the critical biomarker concentration (e.g., benchmark or NOAEL concentration). The simpler and more easily manipulated one-compartment model and the more complex but more realistic PBPK model have been used for that purpose. The parameters in those models are variables whose possible values are described by probability distributions reflecting the interindividual variability in the population. 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. Failure to consider interindividual toxicokinetic variability can result in an RfD that is not protective of a substantial portion of the population. Interindividual toxicokinetic variability can be addressed in the derivation of the RfD by application of an uncertainty factor to a central- tendency estimate of the ingested dose. It is uncertain which values are most appropriate for the model parameters used to derive the central-tendency estimates. The basis for each choice should be carefully considered with reference to discussions already presented in the published analyses of toxicokinetic variability. RECOMMENDATIONS Future studies of MeHg exposures in humans should include a thorough assessment of the diet during the periods of vulnerability and exposure. They should involve assessment of the nutritional adequacy of the group, including the assessment of nutritional and environmental factors that might attenuate or exacerbate the effect of MeHg on the health end points measured. Dietary assessment should be conducted concurrently with the exposures, because retrospective assessment is influenced by many factors, including memory, changes in eating behavior,

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Toxicological Effects of Methylmercury food fortification, and use of prenatal and postnatal vitamin and mineral supplementation. Dietary assessment should be conducted on a person-specific basis, with particular effort to estimate quantitatively individual consumption and consumption patterns of fish and pilot whale. For all the studies, the estimates of consumption of fish (and whale meat as appropriate) should be used with information on MeHg concentrations in the food to estimate possible MeHg intake by pregnant women, young children, and adults. Attempts should be made to validate estimates of intake by using experimental data on the relationship between hair Hg concentration and diet intake. Future studies should include a standardized measure of the duration of breast-feeding and the quantity of breast milk ingested by infants. The dose of MeHg is dependant on the amount of milk ingested and the MeHg content of the milk. Historical recording of duration of breast-feeding is likely to be biased; therefore, a prospective diary of breast-feeding and weaning should be considered. Studies using animal models should examine changes in the dose response characteristics of Hg effects associated with nutritional or genetic factors. 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 should be a central-tendency estimate of the ingested dose corresponding to a critical biomarker concentration (e.g., a benchmark hair concentration). The central-tendency estimate of the ingested dose should be based on careful consideration of the several possible and sometimes contradictory data sets for each parameter. A starting point for such consideration is the discussion of parameter distributions presented in the analyses of Stern (1997), Swartout and Rice (2000), and Clewell et al. (1999). An uncertainty-factor adjustment should be applied to any central-tendency estimate of the ingested dose corresponding to the critical biomarker concentration.

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Toxicological Effects of Methylmercury For an RfD based on maternal-hair Hg concentration, an uncertainty-factor adjustment of 2 should be applied to the central-tendency estimate of dose to be inclusive of 95% of the toxicokinetic variability in the population. An uncertainty-factor adjustment of 2-3 should be applied to be inclusive of 99% of the toxicokinetic variability. 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. REFERENCES Adachi, T., A. Yasutake, and K. Hirayama. 1992. Influence of dietary protein levels on the fate of methylmercury and glutathione metabolism in mice. Toxicology 72(1):17-26. Adachi, T., A. Yasutake, and K. Hirayama. 1994. Influence of dietary levels of protein and sulfur amino acids on the fate of methylmercury in mice. Toxicology 93(2-3):225-23. Alexander, J., and J. Aaseth. 1982. Organ distribution and cellular uptake of methyl mercury in the rat as influenced by the intra- and extracellular glutathione concentration . Biochem. Pharmacol 31(5):685-690. Andersen, H.R., and O. Andersen. 1993. Effects of dietary alpha-tocopherol and beta- carotene on lipid peroxidation induced by methyl mercuric chloride in mice. Pharmacol. Toxicol. 73(4):192-201. Aschner, M., and J.L. Aschner. 1990. Mercury neurotoxicity: Mechanisms of blood-brain barrier transport . Neurosci. Biobehav. Rev. 14(2):169-176. Aschner, M., and T.W. Clarkson. 1987. Mercury 203 distribution in pregnant and nonpregnant rats following systemic infusions with thiol-containing amino acids. Teratology 36(3):321-328. Aschner, M., and T.W. Clarkson. 1988. Uptake of methylmercury in the rat brain: Effects of amino acids. Brain Res. 462(1):31-39. ATSDR (Agency for Toxic Substances and Disease Registry). 1999. Toxicological Profile for Mercury (Update). U.S. Department of Health and Human Services, Public Health Service. Agency for Toxic Substances and Disease Registry Atlanta, GA. March.

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