Toxicological Effects of Methylmercury (2000) / Chapter Skim
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Health Effects of Methylmercury
Health Effects of Methylmercury
Pages 147-249
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From page 147... ...
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 derivecT from case reports, descriptive studies of convenience samples, and ecological studies of rates.
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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 mollify risk. As with all epidemiological studies, the methoclological challenges of cohort studies inclucle accurate classification of exposure and outcome status and the assessment ant!
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in animals, chronic exposure to MeHg increased the incidence of renal tumors in male mice in some of the studies; however, the increase was observer] only at doses that were toxic to the kidneys.
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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 (SERF)
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Animal Studies The carcinogenic potential of MeHg was examined in several chronic exposure animal studies. Those studies are summarized in Table 5-2.
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group) were exposed to MeHg chloride at 0, 0.004, 0.020, or 0.10 mg/kg ner (lay for 2 vears.
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The incidence of renal tumors was increased in males in a study of TCR mice (60 per sex) fed diets containing MeHg chloride (0, 1.6, or 3.1 mg/kg per day)
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No renal tumors were seen in females. The incidence of renal tumors was also increased in male B6C3F~ mice following chronic exposure to MeHg chloride.
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Animal Studies A single dose of Hg chIoricle (HgCI) to male Swiss mice (2.2, 4.4, or 8.9 mg/kg)
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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.
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However, only the 5-pg/L concentration of MeHg chloride had that effect. At 16 weeks, lymphocyte proliferation clecreased in the rats exposed to MeHg chloride but increased in those exposed to MeHg sulfide.
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158 TOXICOLOGICAL EFFECTS OF METHYLMERCURY TABLE 5-3 Summary of Immunological Studies In Animals Species NOAEL LOAEL Effect Reference Rat None 3.9 ppm in diet of Reduced NK cell activity Ilback et al. dams in pups 1991 Rat None 5 ppb in water Altered mitogen response Ortega et al.
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(1997) exposed rats, in utero and cluring the nursing period to MeHg (maternal drinking-water concentrations of MeHg chloride at 5 or 500 ~g/L, or MeHg sulfide at 5 Go/.
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No studies were located that evaluated autoimmunity in humans following exposure to organic forms of Hg. Animal Studies Hg is one of the few chemicals which is able to induce loss of tolerance to self-antigens in animals.
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were produced. REPRODUCTIVE EFFECTS Human Stuclies in occupational exposure studies, paternal exposure to metallic Hg does not appear to cause infertility or malformations (Alcser et at.
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1978~. In Fischer 344 rats, oral doses of MeHg chloride at 10, 20, or 30 mg/kg administered on day 7 of gestation decreased fetal survival by 19.~%, 41.4%, and 91.~%, respectively (Lee and Han 1995~.
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A single dose of MeHg chloride at 11.5 mg/kg administered to pregnant guinea pigs on day 21, 2S, 35, or 42 of gestation caused half of the litters to be aborted (Tnouye and Kajiwara 1988~. Reproductive problems, including decreased conception rates, early abortions, and stillbirths were seen following exposure of female Macaca fascicuZaris monkeys to MeHg hydroxide at 50, 70, or 90 ,ug/kg per day for 4 months (Burbacher et al.
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Exposure of male rats to high doses of MeHg chloride (5 to 7 daily doses of 1, 2.5, or 5 mg/kg) before mating with unexposed females produced a dose-related increase in post-implantation losses and reduced litter size (Khera 1973a)
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1993~. However, renal toxicity has rarely been reported following human exposure to organic forms of Hg (see Table 5-5~.
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1962 vapors changes Occupational exposure to Hg Proteinuria Danziger and vapors Possick 1973 Occupational exposure to Hg Albuminuria Buchet et al. 1980 vapors (urinary > 50 Agog creatinine)
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1991~. Degeneration of the proximal tubules was observed in mice given MeHg chloride in the diet (0.11 mg/kg per day)
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Rats exposed to daily doses of ~ or 2.5 mg/kg per day from birth to 21 days of age (weaning) exhibited renal hypertrophy and altered renal function (elevated fractional excretions of water, glucose, sodium, chloride, osmotic particles)
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Increases in blood pressure and heart rate have also been reported following inhalation of high concentrations of metallic Hg (Hallee 1969; Soni et al. 1992; Bluhm et al.
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1999 Unspecified High Hg concentrations in Frustaci et al. 1999 myocardium of IDCM patients Prenatal exposure Increased blood pressure Sorensen et al.
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Findings were compared with Hg concentrations measured in myocarctial and muscle biopsies from age-matched patients with valvular (12 patients) or ischemic heart disease (13 patients)
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(1983, 1984) fe(l Sprague-Dawley rats diets containing MeHg chloride (males, 0, 0.011, 0.05, or 0.28 mg/kg per day; females, 0.014, 0.064, or 0.34 mg/kg per day)
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in Wistar rats, hypertension was induced after a 30-day exposure to MeHg chloride at 0.4 or 1.2 mg/kg per day (Wakita 1987~. The onset of hypertension occurred 42 days after the exposure period endect, and the effect persisted for more than ~ year.
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(1989) .examined the coagulability of blood in rats exposed to either a single dose of MeHg chloride at 17.9 mg/kg per day or 5 consecutive days of dosing at ~ mg/kg per day.
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According to Harada (1995) , all children identified as suffering from the most severe form of congenital Minamata disease (CMD)
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Those MeHg exposures were most likely more acute and involved higher exposures than those experienced by the residents of Minamata Bay. Early studies of the most severely affected children exposed to MeHg during fetal development were concordant with the Minamata findings.
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The most frequent neurological findings were increased limb tone and deep tendon reflexes with persisting extensor planter responses. Ataxia, hypotonia, and athetoid movements were also reported.
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dependent on the assumed background prevalence of the poor outcomes. (No data were available on the true background prevalence of the poor outcomes among Iraqi children.)
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(1995) concluded that the Iraqi data do not provide convincing evidence of any adverse neurodevelopmental effects of MeHg below maternal-hair concentrations of 80 ppm.
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(it, At) FIGURE 5-3 Plots of the logit and hockey-stick dose-response analysis of the relationship between CNS signs and maternal-hair concentrations during gestation.
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It appears that the background prevalence of developmental abnormality was extremely high among the Iraqi children who participated in the follow-up studies. The prevalence of delayed walking among children whose mothers had hair Hg concentrations below 10 ppm (and can be viewed essentially as a control group for the purpose of estimating background prevalence)
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182 in ._.
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of the girls. The only neurological findings significantly associated with prenatal MeHg exposure, either before or after adjustment for confounding, were abnormalities of muscle tone or reflexes in boys.
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. Fish consumption was the primary route of MeHg exposure, and maternal hair was used as the index of exposure (geometric mean, 7.05 ppm; range, 0.9 to 28.5 ppm)
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The statistical analyses focused on three end points selected due to their apparent sensitivity to prenatal MeHg exposure in the Iraq and Cree studies: overall neurological examination, increased muscle tone, and deep tendon reflexes in the extremities. The overall examination was considered to be abnormal if any findings judged to be pathological were present or if the examiner judged the child's speech or functional abilities to be below age level.
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The frequency of abnormal and questionable findings for limb tone or deep tendon reflexes was not significantly associated with maternal-hair Hg concentrations. Steuerwald et al.
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Maternal hair-Ha concentrations (mean, 4.08 ppm; range, 0.36-16.3 ppm; 10.4%, more than 10 ppm) were not significantly associated with NOS scores.
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Results were scored as automatic or questionable and poor. Hg concentration was not significantly associated with the number of tests on which a child's performance was considered automatic.
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A decrement in mean function that is too small to be cI~n~cally significant for the individual child might be quite important when it is considered from the standpoint of the impact on the population distribution of the affected function (Weiss 1998~. Age at Achievement of Deve/opmenta/ Milestones The association between the achievement of developmental milestones and prenatal MeHg exposure was evaluated in the main cohort of the SCDS by Myers et al.
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The mean age at which a child was consiclered to talk was not significantly associated with maternal-hair Hg in any of the models tested. In regressions stratified by child sex, a positive association was found between age at walking and maternal-hair Hg in boys (p = 0.043)
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obtained from the reduced model. The partial residuals have been resealed by adding the mean value of log of age at walking to each partial residual.
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. Three motordevelopment milestones commonly achieved between 5 and 12 months of age were selected for analysis: "sits without support," "creeps," and "gets up into standing position with support." The age at achievement was not significantly associated with either index of prenatal Hg exposure (cord-blood or maternal-hair concentrations)
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In conclusion, recent epidem~olog~cal studies provide scant evidence that prenatal MeHg exposures, at least those resulting in maternal-hair Hg concentrations below 30 ppm, are associated with the ages at which children achieve developmental milestones. Although the mean age at walking in the SCDS cohort was later among children whose mothers had high hair Hg concentrations, that association was limited to boys, and the risk of late walking did not appear to be dose related.
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(1986) studied a cohort of New Zealand children for whom prenatal MeHg exposure was estimated on the basis of maternalhair samples as well as dietary questionnaires collected!
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also was unrelated to maternalhair Hg concentrations. The Bayley Scales of Infant Development (BSID)
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The secondary analysis of the PDI scores of children with the lowest and highest Hg concentrations was not conducted, because the full logistic regression mode} was not statistically significant. In the analyses of the six IBR items, maternal-hair Hg concentration was significantly associated only with examiner ratings of activity level during the test session and only in males.
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FIGURE 5-6 The 19-month and 29-month mental-developmental-index (MDI) partial residuals from the Bayley Scales of Infant Development.
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1996~. Among the Hg studies, the BSTD was administered only in the SCDS, and no significant associations were found between children's scores and their prenatal exposures.
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A battery of 26 psychological and scholastic tests was administerect, assessing the domains of general intelligence, language development, fine- and gross-motor coordination, academic attainment, and social adjustment. Multiple regression analyses of five primary end points were carried out: the Test of Language Development spoken language quotient (TOLD_SL)
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When these regressions were repeated on all 26 scholastic and psychological tests, 6 were associated with maternal hair-Ha (excluding the child with a level of 86 ppm) at p < 0.10: Clay Reading Test—concepts, Clay Reading Test—letter test, McCarthy Scales—general cognitive index, McCarthy Scales—perceptual-performance scale, Test of Language Development—grammar completion, and Test of Language Development—grammar understanding)
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For the total score on the Preschool Language Scale, increased prenatal and postnatal Hg concentrations were significantly associated with better scores (both p = 0.02~. For the applied problems score, increased postnatal Hg concentrations were associated with better scores (p = 0.05~.
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~ , . 0 5 10 15 20 25 Mecury Level, ppm FIGURE 5-8 Partial residuals for prenatal exposure.
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. in multiple regression analyses, increased cord-blood Hg concentration was significantly associated with worse scores on finger tapping (preferred hand, p = 0.05)
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, WISC-R block design, Boston Naming Test (no cues, cues) , and California Verbal Learning Test—Children (long-term reproduction)
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Language: Boston Naming Test score after cues (p = 0.02~. Memory: California Verbal Learning Test—Children long-delay recall (p = 0.004~.
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(The finger tapping, and Santa Ana dexterity tests could not be administered to children in that village.) Combining all four villages, children's hair Hg concentrations were significantly associated with their scores on finger tapping (both preferred and other hand; both p < 0.001)
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1997~. Visual acuity, contrast sensitivity, auditory thresholds, and visual-evoked potentials were not significantly associated with prenatal MeHg exposures.
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The authors concluded that although the end points assessed were generally unaffected at the blood Hg concentrations represented in the cohort of adults and children in the study area, the associations found were consistent with an effect of Hg at the level of the auditory nerve and the cochiear nuclear complex. Animal Studies Developmental Effects in Animals The results of nearly 30 years of experimental studies using various animal models have helped characterize the neurotoxic effects of MeHg following in utero or early postnatal exposures (see Table 5-~.
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215 U ~ ~ ~ ~ at ~ In a; u I_, of ~ _ ~ ~ '= o ~ ~ C ·= E ~ o , ~ E c, i E ~ ° In u au o Z oo Cal by ~ ~ o X o o I Z Z ° o ~ ~ o o o _ oo o ~ C ~ ~ C o C C _ — or ~4 a' a; a; a o cn 3 - o ~i ¢ o a)
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Feta/ Minamata Disease Experimental studies using nonhuman primates, cats, and rodent models exposed to high doses of MeHg have reported some or all of the cluster of neuropathological effects consistent with fetal Minimata disease (MD) that were first described from human autopsy cases following the catastrophic exposures in Minamata, Japan, and Iraq (Matsumoto et al 1965; Takeuchi 1968; Choi et al 1978~.
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1988~. The maternal dose of MeHg hydroxide at 50 ~g/kg per day was associated with developmental effects in offspring, but not with matemal toxicity or reproductive effects.
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Many of the studies using rodent models have also focused on examin~ng the effects of MeHg exposure on neurobehavioral development. One of the largest studies to examine the effects of developmental exposure to MeHg in rats was the "Collaborative Behavioral Teratology Study" (CBTS)
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Rats exposed prenatally to MeHg displayed impaired learning on a shuttlebox avoidance test (Eccles and Annau 1982a,b) , and a s~ngle dose of 10 mg/kg per day on gestation day 4 with no cross-fostering of dams (in utero plus lactational exposure)
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reported interactive behavioral effects following exposure of rats to MeHg and metallic Hg vapor. Exposure to Hg vapor at I.S mg/m3 for I.5 hours per day on gestation days 14-19 was related to hyperactivity and decreased spatial learning.
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More recently, monkeys exposed to MeHg at 10-50 ~g/kg per day in utero plus 4 years postnatally showed a greater deterioration in auditory function with increasing age when tested at I! and 19 years of age (Rice 1998~.
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. Subjects underwent a battery of quantitative behavioral, sensory, and motor tests, including tests of visual functions (near and far acuity, chromatic discrimination, near contrast sensitivity, and peripheral visual fields)
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, which requires imitation of a prescribed sequence of hand movements. Abnormal performance on the BAMT was significantly associated with all measures of Hg exposure, and abnormal visual fields were associated with mean hair Hg and peak Hg concentrations.
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. Nested analyses were carried out in which the six Cree with the highest hair Hg concentrations (mean of annual maximum hair concentrations greater than 24 ppm; range, 24.34-31.10 ppm)
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Studies using monkeys, rodents, and cats have reported effects consistent with adult MD (Harada 1995~. Some of those studies are summarized in Table 5-12.
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226 Cal ¢ ¢ .s U
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Studies using adult animal models of chronic low-dose MeHg effects have been sparse, most likely because of the focus on neurodevelopmental effects following in utero or early postnatal MeHg exposure. CONCLUSIONS · MeHg is highly toxic.
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· Damage to the renal tubules and nephron has been observed following human exposure to inorganic and organic forms of Hg. However, symptoms of renal damage have been seen only at Hg exposures that also caused neurological effects.
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The smaller New Zealand study also observed associations, as did a large pilot study conducted in the Seychelles. Recent studies in adults suggest that hair Hg concentrations below 50 ppm are significantly associated with disturbances of the visual system (chromatic discrimination, contrast sensitivity, and peripheral fields)
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The risk of fatal and nonfatal heart disease must be considered in the development of a reference dose for this contaminant. · Research is needed to determine the long-term implications of the neuropsychological and neurophysiological effects of low-level prenatal MeHg exposure detected in children, specifically whether
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From page 232... ...
1998. Methylmercury dose estimation from umbilical cord concentrations in patients with Minamata disease.
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1998. Semiparametric modeling of age at achieving developmental milestones after prenatal exposure to methylmercury in the Seychelles child development study.
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1999. The effects of methylmercury exposure on visual and auditory functions in nonhuman primates.
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1989. Dose-response analysis of infants prenatally exposed to methyl mercury: An appIication of a single compartment model to single-strand hair analysis.
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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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1978. Evoked potential alterations following prenatal methyl mercury exposure.
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1995. Neurobehavioral effects of developmental methylmercury exposure.
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1986. The effect of low-level prenatal Methylmercury exposure on visual recognition memory in infant crab-eating macaques.
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1991. Methyl mercury exposure via placenta and milk impairs natural killer (NK)
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1991. An integrated study of the morphological and gross-elemental consequences of methyl mercury intoxication in rats,
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1995b. The Seychelles study of fetal methylmercury exposure and child development: Introduction.
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1997. Effects of prenatal methylmercury exposure from a high fish diet on developmental milestones in the Seychelles Child Development Study.
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1994. Prolonged behavioral effects of in utero exposure to lead or methyl mercury: Reduced sensitivity to changes in reinforcement contingencies during behavioral transitions and in steady state.
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1995. Effects of developmental methylmercury exposure or lifetime lead exposure on vibration sensitivity function in monkeys.
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1970. Chromosome breakage in humans exposed to methyl mercury through fish consumption.
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2000. Maternal seafood diet, methylmercury exposure, and neonatal neurological function.
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1985. Methyl mercury ototoxicity in mice determined by auditory brainstem responses.
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1992. Truncal hypesthesia in patients with Minamata disease.
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