5

HEALTH EFFECTS OF METHYLMERCURY

THIS chapter begins with a brief review of the carcinogenicity of MeHg and its immunological, reproductive, renal, cardiovascular and hematopoietic toxicity. Because the central nervous system is widely viewed as the organ system most sensitive to MeHg, the remainder of this chapter focuses on the adverse effects of MeHg on neurological function. Neurological effects in infants, children, and adults are discussed. Studies carried out in populations exposed to high concentrations of MeHg are described, followed by a discussion of epidemiological data on populations exposed chronically to low concentrations of MeHg. Animal data following in utero, early postnatal, and adult exposure are also discussed.

The information available on the human health effects of MeHg are derived from studies of various designs. Each type of design has strengths and weaknesses and might be the most appropriate choice for a given set of circumstances. The methodology, strengths, and weaknesses of environmental epidemiological studies have been discussed in previous NRC reports (NRC 1991, 1997). The data on the Minamata and Iraqi episodes, the collection of which were initiated in response to the occurrence of recognizable illness in the population, are derived from case reports, descriptive studies of convenience samples, and ecological studies of rates. A major advantage of such studies is that the end points assessed are often of clear clinical significance. The inferences permitted from such studies, as described in greater detail in the following sec-



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Toxicological Effects of Methylmercury 5 HEALTH EFFECTS OF METHYLMERCURY THIS chapter begins with a brief review of the carcinogenicity of MeHg and its immunological, reproductive, renal, cardiovascular and hematopoietic toxicity. Because the central nervous system is widely viewed as the organ system most sensitive to MeHg, the remainder of this chapter focuses on the adverse effects of MeHg on neurological function. Neurological effects in infants, children, and adults are discussed. Studies carried out in populations exposed to high concentrations of MeHg are described, followed by a discussion of epidemiological data on populations exposed chronically to low concentrations of MeHg. Animal data following in utero, early postnatal, and adult exposure are also discussed. The information available on the human health effects of MeHg are derived from studies of various designs. Each type of design has strengths and weaknesses and might be the most appropriate choice for a given set of circumstances. The methodology, strengths, and weaknesses of environmental epidemiological studies have been discussed in previous NRC reports (NRC 1991, 1997). The data on the Minamata and Iraqi episodes, the collection of which were initiated in response to the occurrence of recognizable illness in the population, are derived from case reports, descriptive studies of convenience samples, and ecological studies of rates. A major advantage of such studies is that the end points assessed are often of clear clinical significance. The inferences permitted from such studies, as described in greater detail in the following sec-

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Toxicological Effects of Methylmercury tions, can be limited by methodological weaknesses, such as the absence of detailed information on the sampling frame or referral patterns that generated the study sample, the degree to which the study sample is representative of the population from which it was drawn, exposure histories of the subjects, detailed assessments of health status, and the nature of severity of possible confounding biases. Case-control studies, in which the exposure status (or history) of individuals with a certain health outcome (case) is compared with the exposure status of individuals without the health outcome (controls), can provide a much stronger basis for drawing inferences about exposure-disease associations. Among the challenges of such studies, however, are assembling a representative group of cases and a comparable group of controls, collecting adequate information on critical aspects of exposure history (which, in the case of long-latency diseases, might mean exposures that occurred decades before), and identifying the critical potential confounding biases. A case-control design, however, might be the only efficient way to study rare health outcomes. Cohort designs (e.g., cross-sectional, retrospective, and prospective) provide a number of advantages. Instead of being selected on the basis of outcome status, as in case-control studies, study subjects are either randomly selected from the target population or selected on the basis of particular exposure characteristics (e.g., over-sampling of extremes of exposure distribution). The former strategy might be used if the goal is to enhance the generalizability of the study inferences to the target population, and the latter might be used if the goal is to estimate, with the greatest precision, the nature of the dose-response relationship within a certain region of the dose distribution. Another advantage of a cohort design is that multiple health outcomes can be measured and related to the index of exposure. A cohort study that incorporates prospective assessments of the study sample generally provides opportunities to assemble more-comprehensive exposure histories of the study subjects and to examine the natural history of a dose-response relationship, including factors that modify risk. As with all epidemiological studies, the methodological challenges of cohort studies include accurate classification of exposure and outcome status and the assessment and control of confounding bias.

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Toxicological Effects of Methylmercury CARCINOGENICITY None of the epidemiological studies found an association between Hg exposure and overall cancer rates; however, two studies found an association between exposure to Hg and acute leukemia. The interpretation of those results is difficult due to the small study populations, the problem of assessing historical exposures to Hg, and the inability of investigators to control for other risk factors. In animals, chronic exposure to MeHg increased the incidence of renal tumors in male mice in some of the studies; however, the increase was observed only at doses that were toxic to the kidneys. Therefore, the tumorigenic effect is thought to be secondary to cell damage and repair. MeHg did not cause tumors in female mice or in rats of either sex. Therefore, in the absence of a tumor initiator, long-term exposure to subtoxic doses of MeHg does not appear to increase tumor formation. On the basis of the available human and animal data, the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency (EPA) have classified MeHg as a “possible” human carcinogen. Human Studies Four epidemiological studies examined the effect of Hg exposure on cancer incidence or cancer death rate. Those studies are summarized in Table 5-1. Tamashiro et al. (1984) carried out a cohort study that evaluated the causes of death of 334 individuals who had survived Minamata disease (MD) and died between 1970 and 1980. Control cases were selected from deaths that occurred in the same city or town as the MD cases and were matched for sex, age and year of death. No significant difference in cancer death rates was observed between the subjects and the controls, suggesting that the risk of dying from cancer was not correlated with patient history of MeHg poisoning. Specific types of cancer, however, were not evaluated. Tamashiro et al. (1986) compared the death rates among residents of the Fukuro and Tsukinoura districts with those of age-matched residents of Minamata City. Residents of the two districts were assumed to have a higher intake of local seafood and higher Hg exposure than residents

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Toxicological Effects of Methylmercury TABLE 5-1 Summary of Cancer Studies in Humans Type of Study Size of Study Finding Reference Retrospective cohort 334 deaths in high-exposure cohort; 668 in low-exposure cohort No increase in cancer death rate; site-specific rates not analyzed Tamashiro et al. 1984 Retrospective cohort 416 deaths in high-exposure cohort; 2,325 deaths in low-exposure cohort Increased liver-cancer death rate among males in high-exposure cohort Tamashiro et al. 1986 Case-control study of hair Hg concentrations in leukemia patients 47 cases; 79 controls Increased hair Hg concentrations in acute leukemia patients Janicki et al. 1987 Retrospective cohort study of Minamata-disease (MD) survivors 1,351 MD survivors; 5,667 referents Increased leukemia death rate among MD survivors; relative risk, 8.35 Kinjo et al. 1996 of Minimata City. No statistically significant increase in the overall cancer mortality was observed. However, an increase in liver- cancer death rates was observed among males who resided in the areas thought to have high Hg exposure (standardized mortality ratio (SMR1), 250.5; 95% confidence interval (CI), 133.4-428.4). Males also had significantly higher mortality due to chronic liver disease and cirrhosis in those areas than in Minamata City. The investigators indicated that the increases could not be attributed solely to MeHg, because the alcohol consumption rates and the prevalence of hepatitis B infection were higher in the Fukuro and Tsukinoura districts than in Minamata City. The study is also limited by its failure to fully characterize Hg concentrations in subjects in each cohort. In a case-control study in Poland, Janicki et al. (1987) found a statisti- 1   The SMR is the ratio of the number of deaths observed in a study group divided by the number expected (based on age- or sex-specific rates in the general population) and multiplied by 100. An SMR greater than 100 indicates that the death rate was higher than would be expected.

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Toxicological Effects of Methylmercury cally significant increase in the Hg content in hair collected from 47 patients with leukemia compared with 52 healthy unrelated subjects (mean 1.24 versus 0.49 ppm). The Hg content in hair from a subgroup of 19 leukemia patients was also significantly greater than that from 52 healthy relatives who had shared the same home for at least 3 years (0.69 versus 0.43 ppm). When those data were analyzed for specific types of leukemia, only patients with acute leukemia had significantly higher hair Hg concentrations. No significant difference was seen in the Hg content in hair collected from nine patients with chronic granulocytic leukemia or from 15 patients with chronic lymphocytic leukemia compared with the healthy unrelated subjects. The study is limited by the small study population, inadequate description of case and control populations, uncertainty about the source of Hg exposure, and lack of adjustment for other leukemia risk factors. In addition, all the hair Hg concentrations were within normal limits. Kinjo et al. (1996) compared cancer death rates for a cohort (1,351 cases) of MD survivors with those of a referent population (5,667 subjects) who lived in the same region of Japan and consumed fish daily. After adjusting for age, gender, and length of follow-up period, they found no excess relative risk (RR) for overall mortality, all cancer deaths combined, or all noncancer deaths combined. Analysis of site-specific cancers found that Minamata survivors were less likely to die of stomach cancer than the referent population (RR, 0.49; 95% confidence interval (CI), 0.26-0.94). However, on the basis of five observed deaths, survivors were eight times more likely than the referent population to have died from leukemia (RR, 8.35; 95% CI, 1.61-43.3). Animal Studies The carcinogenic potential of MeHg was examined in several chronic exposure animal studies. Those studies are summarized in Table 5-2. Newberne et al. (1972) carried out a 2-year multigeneration study in which Sprague-Dawley rats (30 per sex) were fed diets with MeHg doses of 0 or 0.008 mg/kg per day. Tumor incidence was similar in both groups; however, the maximum tolerated dose (MTD) was not achieved. A 2-year feeding study conducted by Verschuuren et al. (1976) also failed to provide evidence of carcinogenic effects. Rats (25 per sex per

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Toxicological Effects of Methylmercury TABLE 5-2 Summary of Cancer Studies in Animals Animal Dose (mg/kg/d) Tumor response Study Duration (wk) Reference Sprague-Dawley rat 0, 0.008 None 104 Newberne et al. 1972 Rats, unspecified strain 0, 0.004, 0.02, 0.1 None 104 Verschuuren et al. 1976 Sprague-Dawley rats     130 Mitsumori et al. 1983, 1984 Males 0, 0.01, 0.05, 0.28 None     Females 0, 0.01, 0.06, 0.34 None     Swiss Albino mice 0, 0.19, 0.95a None Weaning to death Schroeder and Mitchener 1975 ICR mice     78 Mitsumori et al. 1981 Males 0, 1.6, 3.1 0/37, 11/16, NA     Females 0, 1.6, 3.1 0, 0, NA     Swiss mice 0, 0.03, 0.07, 0.27 Increased tumor response to urethane 15 Blakley 1984 ICR mice     104 Hirano et al. 1986 Male 0, 0.03, 0.15, 0.73 1/32, 0/25,     Female 0, 0.02, 0.11, 0.60 0/29, 13/26         None in any group     B6C3F1 mice 0, 0.03, 0.14, 0.69 0/60, 0/60, 104 Mitsumori et al. 1990 Male 0, 0.03, 0.13, 0.60 0/60, 13/60     Female   0/60, 0/60,         0/60, 1/60     a0.95 mg/kg per day for 70 days and then 0.19 mg/kg per day thereafter due to high mortality at 0.95 mg/kg per day. Abbreviation: NA, not available. Mitsumori et al. (1983, 1984) also exposed Sprague-Dawley rats to MeHg chloride in feed (males, 0, 0.011, 0.05, or 0.28 mg/kg per day; group) were exposed to MeHg chloride at 0, 0.004, 0.020, or 0.10 mg/kg per day for 2 years. Survival decreased in the mid- and high-dose groups, and kidney weights increased in the high-dose group. However, tumors occurred at similar rates in all the groups.

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Toxicological Effects of Methylmercury females, 0, 0.014, 0.064, or 0.34 mg/kg per day) for up to 130 weeks. Effects were seen in the central nervous system, kidney, arterial wall, and spleen. The MTD was achieved in males in the mid-dose group and exceeded in males and females in the high-dose group. No increase in tumor incidence was observed. A lifetime study conducted in Swiss albino mice failed to detect a tumorigenic response (Schroeder and Mitchener 1975). Groups of mice (54 per sex per group) were exposed from weaning until death to methylmercuric acetate in drinking water at two doses. The low-dose group received 1 ppm (0.19 mg/kg per day) and the high dose group received 5 ppm (0.95 mg/kg/day) for the first 70 days and then 1 ppm thereafter due to high mortality at the higher dose. Although no increase in tumors was noted, interpretation of the study is limited because of cessation of the high-dose exposure and failure to conduct complete histological examinations. The incidence of renal tumors was increased in males in a study of ICR mice (60 per sex) fed diets containing MeHg chloride (0, 1.6, or 3.1 mg/kg per day) for 78 weeks (Mitsumori et al. 1981). The majority of mice in the high-dose group died by week 26 of the study. Males in the low-dose group had significantly higher numbers of renal epithelial adenocarcinomas (0 of 37 in control group; 11 of 16 in low-dose group) and renal adenomas (1 of 37 in control group; 5 of 16 in low-dose group) than controls. No renal tumors were observed in females in any group. Blakley (1984) exposed female Swiss mice to MeHg chloride (approximately 0, 0.03, 0.07, or 0.27 mg/kg per day) in drinking water for 15 weeks. After 3 weeks of exposure, mice were given urethane in a single intraperitonal dose of 1.5 mg/kg. No more than one tumor per mouse was seen in the absence of urethane. With urethane, a statistically significant trend was seen for an increase in the size (0.7, 0.73, 0.76, and 0.76 millimeters (mm) at 0, 0.03, 0.07, and 0.27 mg/kg per day, respectively) and number of tumors per mouse (21.5, 19.4, 19.4, and 33.1 at 0, 0.03, 0.07, and 0.27 mg/kg per day, respectively). These findings suggest that MeHg may act as a tumor promoter. In a follow-up study to Mitsumori et al. (1981), Hirano et al. (1986) fed MeHg chloride to ICR mice (60 per sex) at lower doses (males, 0, 0.03, 0.15, or 0.73 mg/kg per day; females, 0, 0.02, 0.11, or 0.6 mg/kg per day) for 104 weeks. Kidney and reproductive-system effects indicated that

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Toxicological Effects of Methylmercury the MTD was exceeded at the highest dose. An increased incidence of renal epithelial tumors (adenomas and adenocarcinomas) occurred in males. In males in the high-dose group, 10 of the 13 tumors were adenocarcinomas; the incidence of renal epithelial adenomas was not increased. No renal tumors were seen in females. The incidence of renal tumors was also increased in male B6C3F1 mice following chronic exposure to MeHg chloride. Mitsumori et al. (1990) fed B6C3F1 mice (60 per sex) MeHg chloride (males, 0, 0.03, 0.14, or 0.69 mg/kg per day; females, 0, 0.03, 0.13, or 0.60 mg/kg per day). Following 104 weeks of exposure, adverse effects were seen in the central nervous system, kidney, and testis. The MTD was achieved in males in the mid-dose group and in females in the high-dose group. The MTD was exceeded in males in the high-dose group. The incidence of renal epithelial carcinomas and renal adenomas was significantly increased in males in the high-dose group. Although chronic exposure to MeHg increased the incidence of renal tumors in male mice in some studies, that effect was observed only at doses that were toxic to the kidneys and is thought to be secondary to cell damage and repair. Exposure to MeHg did not increase tumor rates in female mice or in rats of either sex. GENOTOXICITY Human Studies Evidence that human exposure to Hg causes genetic damage is inconclusive. Several investigators have reported higher rates of chromosomal aberrations among workers who were exposed to elemental or inorganic forms of Hg (Popescu et al. 1979; Verschaeve et al. 1976; Barregard et al. 1991). However, questions have been raised regarding the influence of possible confounders, such as age or simultaneous exposure to other toxicants on these findings. In a recent occupational study, Queiroz et al. (1999) reported a significant increase in the percentage of micronuclei in Hg-exposed workers when compared with unexposed controls. Skerfving et al. (1970, 1974) reported a positive correlation between blood Hg concentrations and chromosomal aberrations in the lympho-

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Toxicological Effects of Methylmercury cytes of 23 people who consumed Hg-contaminated fish. However, their findings have been questioned because of experimental problems, such as failure to identify smokers. In addition, significant effects were found only from lymphocyte cultures that were set up several days after collection, and the incidence of aneuploidy in the control and exposed groups was lower than expected. Wulf et al. (1986) reported an increased incidence of sister chromatid exchange in humans who ate Hg-contaminated seal meat. However, information on smoking status and exposure to other heavy metals was not provided for those individuals, making interpretation of the study difficult. More recently, Franchi et al. (1994) reported a correlation between the incidence of micronuclei in peripheral lymphocytes and blood Hg concentrations in a population of fishermen who had eaten Hg-contaminated seafood. Animal Studies A single dose of Hg chloride (HgCl) to male Swiss mice (2.2, 4.4, or 8.9 mg/kg) induced a dose-related increase in the frequency of chromosomal aberrations and the percentage of aberrant cells in bone marrow (Ghosh et al. 1991). Chronic exposure of cats to MeHg at doses of 0.0084, 0.02, or 0.046 mg/kg per day for 39 months produced a significant increase in the number of nuclear abnormalities in bone-marrow cells and inhibited DNA repair (Miller et al. 1979). The response, however, was not dose related. In Vitro Studies MeHg has been shown to cause DNA damage in cultured Bacillus subtilis (Kanematsu et al. 1980); chromosomal aberrations and aneuploidy in human lymphocytes (Betti et al. 1992); and DNA damage in cultured human nerve and lung cells, Chinese hamster V-79 cells, and rat glioblastoma cells (Fiskesjo 1979; Costa et al. 1991). Inorganic Hg concentrations greater than 10 µM have been shown to inhibit mammalian DNA polymerase activity in whole-cell extracts and in purified enzyme preparations (Williams et al. 1987; Robison et al. 1984). Sekow-

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Toxicological Effects of Methylmercury ski et al. (1997) demonstrated the ability of mercuric ion to impair the fidelity of synthesome-mediated DNA replication at HgCl concentrations as low as 1 µM. IMMUNOTOXICITY The immune system appears to be sensitive to Hg. Although there are no data on the effect of MeHg on immune function in humans, occupational studies indicate that Hg compounds can affect the immune system. Animal studies have demonstrated MeHg effects on immune-cell ratios, cellular responses, and the developing immune system. Autoimmune effects have also been associated with exposure to elemental Hg. Human Studies The effect of MeHg on the human immune system has not been studied. However, occupational exposure to elemental Hg has been found to alter certain immune parameters. Queiroz and Dantas (1997a, b) evaluated B- and T-lymphocyte populations among 33 workers in a Brazilian Hg production facility. At the time of the study, all the workers had urinary Hg concentrations below 50 µg/g of creatinine. Analysis of T-cell populations found a reverse CD4+-to-CD8+ ratio that was haracterized by a reduction in the number of CD4+ lymphocytes. That alteration was significantly correlated with urinary Hg concentrations. B-lymphocyte counts were also significantly reduced in this cohort; however, that effect was not correlated with urinary Hg concentrations. Analysis of serum antibody levels found increased immunoglobulin E levels but did not detect anti-DNA or anti-nucleolar antibodies. The researchers reported a moderate negative correlation between length of exposure to Hg and IgE levels (Dantas and Queiroz 1997). Moszczynski et al. (1995) studied lymphocyte subpopulations (T cells, T-helper cells, T-suppressor cells, and natural killer cells) in the peripheral blood of 81 men occupationally exposed to metallic Hg vapors and 36 unexposed men. The average Hg concentration in the workplace air was 0.0028 mg/m3. Urinary Hg concentrations ranged from 0 to 240

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Toxicological Effects of Methylmercury µg/L, and concentrations in the blood varied from 0 to 30 µg/L. Stimulation of T-lymphocytes — manifested by an increased number of T cells, T-helper cells, and T-suppressor cells — was observed. Animal Studies Effects on the Adult Immune System Work in animals has demonstrated that Hg can effect immune function (see Table 5-3). Ilbäck (1991) found that oral exposure to MeHg altered the ratio of lymphocyte subpopulations, enhanced lymphoproliferation in response to B- and T-cell mitogens, and depressed natural-killer-cell activity in mice. Exposure of female Balb/c mice to MeHg (3.9 ppm) in the diet (equivalent to 0.5 mg/kg per day) for 12 weeks significantly decreased thymus weight (22%) and cell number (50%). Lymphoproliferation in response to T- and B-cell mitogens was increased, and natural-killer-cell activity was decreased in exposed mice. Red- blood-cell counts were slightly higher in exposed mice than in unexposed mice, and white-blood-cell counts were unaffected. Thompson et al. (1998) evaluated the effects of low-dose MeHg exposure in mice. Mice were exposed to MeHg at 0, 3, or 10 ppm in the drinking water for 4 weeks. MeHg altered the proportion of splenocyte and thymocyte subpopulations and caused dose-dependent decreases in splenocyte glutathione concentrations and mitogen-stimulated calcium flux. Rats were exposed to MeHg (chloride or sulfide; concentrations of 5 or 500 µg/L) in drinking water for 8 or 16 weeks (Ortega et al. 1997). An 8-week exposure to both concentrations of MeHg sulfide enhanced the lymphocyte response to conconavalin A. However, only the 54-µg/L concentration of MeHg chloride had that effect. At 16 weeks, lymphocyte proliferation decreased in the rats exposed to MeHg chloride but increased in those exposed to MeHg sulfide. Those data indicate that the effects of MeHg on T-cell proliferation are dependent upon the dose, duration, and chemical form of the MeHg exposure. Prolonged exposure to MeHg increased the susceptibility of mice to

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Toxicological Effects of Methylmercury mance of children prenatally exposed to “safe” levels of methylmercury. Environ. Res. 77(2):165-172. Grandjean, P., R. White, A. Nielsen, D. Cleary, and E.C. de Oliveira Santos. 1999. Methylmercury neurotoxicity in Amazonian children downstream from gold mining. Environ. Health Perspect. 107(7):587-591. Gunderson, V.M., K.S. Grant, T.M. Burbacher, J.F. Fagan, 3d, and N.K. Mottet. 1986. The effect of low-level prenatal methylmercury exposure on visual recognition memory in infant crab-eating macaques. Child Dev. 57(4):1076-83. Gunderson, V.M., K.S. Grant-Webster, T.M. Burbacher, and N.K. Mottet. 1988. Visual recognition memory deficits in methylmercury-exposed Macaca fascicularis infants. Neurotoxicol. Teratol. 10(4):373-9. Hallee, T.J. 1969. Diffuse lung disease caused by inhalation of mercury vapor. Am. Rev. Respir. Dis. 99(3):430-6. Harada, M. 1995. Minamata Disease: Methylmercury poisoning in Japan caused by environmental pollution. Crit. Rev. Toxicol. 25(1):1-24. Harada, M. 1997. Neurotoxicity of methylmercury: Minamata and the Amazon. Pp. 177-188 in Mineral and Metal Neurotoxicology, M. Yasui, M.J. Strong, K. Ota, and M.A. Verity, eds. Boca Raton, FL: CRC Press. Harada, M., H. Akagi, T. Tsuda, T. Kizaki, and H. Ohno. 1999. Methylmercury level in umbilical cords from patients with congenital Minamata disease. Sci. Total Environ. 234(1-3):59-62. Hirano, M., K. Mitsumori, K. Maita, and Y. Shirasu. 1986. Further carcinogenicity study on methylmercury chloride in ICR mice . Nippon Juigaku Zasshi (Jpn. J. Vet. Sci.) 48(1):127-135. Höök, O., K.D. Lundgren, and A. Swensson. 1954. On alkyl mercury poisoning: With a description of two cases. Acta Med. Scand. 150(2):131-137. Hu, H., G. Moller, and M. Abedi-Valugerdi. 1999. Mechanism of mercury-induced autoimmunity: Both T helper 1- and T helper 2-type responses are involved. Immunology 96(3):348-57. Hua, J., L. Pelletier, M. Berlin, and P. Druet. 1993. Autoimmune glomerulonephritis induced by mercury vapour exposure in the Brown Norway rat. Toxicology 79(2):119-29. Hughes, J.A., and Z. Annau. 1976. Postnatal behavioral effects in mice after prenatal exposure to methylmercury . Pharmacol. Biochem. Behav. 4(4):385-391. Hultman, P., and H. Hansson-Georgiadis. 1999. Methyl mercury-induced autoimmunity in mice. Toxicol. Appl. Pharmacol. 154(3):203-11. Hunter, D., R.R. Bomford, and D.S. Russell. 1940. Poisoning by methyl mercury compounds. Quart. J. Med. 9(July):193-213. Ilbäck, N.G. 1991. Effects of methyl mercury exposure on spleen and blood

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