MERCURY - Child Health and the Environment

Mercury exists in the natural environment as methylmercury, mercuric sulfide (cinnabar ore), and mercuric chloride. Microbial biotransforma- tion of inorganic mercury creates virtually all of the methylmercury found in environmental media. Synthetic organic mercurials have been used as antimicrobial preservatives in vaccines, other medicines, paints, and seed grain. Elemental mercury is a dense, shiny, silver-white metal that is liq- uid at room temperature and has a relatively high vapor pressure. Uses of elemental mercury have included mercury cathodes for electrolysis of sodium chloride to produce chlorine gas and caustic soda, extraction of gold from ore, dental amalgam for repairing carious teeth, thermometers, barometers, mercury vapor lamps, electrical switches, and religious reme- dies and rituals in Latin America and Asia. Environmental inorganic mercury is a minor source of mercury exposure but inorganic mercury products have been used as disinfectants in diaper washes and as analgesics in teething powders for infants. The major issues explored in Part I of this chapter are the uncertainties about potential health risks of low-level exposure to methylmercury from dietary sources and elemental mercury from dental amalgam and other sources.

Methylmercury

Health Effects

Severe neurotoxicity of organic mercury was evident as early as 1866, when exposure in a chemistry laboratory killed two persons. Grave or fa- tal neurotoxic effects also occurred among syphilitics treated with di- ethylmercury (1887) and among workers engaged in organic mercury pes- ticide production during the early twentieth century. After acute adult methylmercury exposure, a latent period of several weeks or even a few months passes before symptoms appear. Methylmercury is extremely neurotoxic in the human fetus and the developing infant.

Molecular Mechanisms

About 95% of ingested methylmercury is absorbed and readily crosses placental and blood-brain barriers. After crossing the blood–brain and placental barriers, methylmercury enters tissues, where it is demethylated and oxidized to divalent mercury that readily reacts with sulfhydryl groups of proteins and thiols (e.g., tubulin, glutathione). Possible mech-

anisms for toxicity of methylmercury and divalent mercury include (Agency for Toxic Substances and Disease Registry, 1999b)

• Oxidative stress with generation of free radicals that attack protein and DNA

• Disruption of microtubule formation, impairing cell motility and control of chromosome movement during cell division

• Increased permeability of the blood–brain barrier

• Disruption of DNA replication and protein synthesis

• Interference with proteins involved in neuronal calcium metabolism In experimental animals, prenatal low-level methylmercury exposure in- hibits neuronal cell division and migration, key processes in the developing brain, causing widespread brain damage. Neonatal exposures cause focal cell loss, primarily in the cerebellum and occipital cortex.

Neurotoxicity: Epidemic Poisonings

Minamata. In 1953, a strange polio-like disease struck inhabitants of Minamata, Japan, most victims being coastal villagers who regularly ate fish from the adjacent bay. Onset of the epidemic coincided with the startup of acetaldehyde production at a coastal factory later shown to have used mercuric oxide as a catalyst. Investigators observed that stray cats developed neurotoxicity after eating local shellfish. A heat-stable compound present in shellfish and factory effluents caused neurotoxicity in experimental animals. The local government did not intervene at this stage, as requested by public health authorities, on the grounds that the causative agent was not identified with certainty. Researchers finally identified the neurotoxin as methylmercury in 1963, but it was not until 1968 that Japanese authorities officially recognized it as the causal agent and intervened.

Investigators identified over 2000 victims, including about 64 prenatally exposed infants (Harada, 1995). Affected infants generally appeared normal at birth but later developed signs and symptoms of severe neurotoxicity: mental retardation, abnormal reflexes, ataxia, dysarthria, involuntary movements, and cerebral palsy. None crawled, stood, or talked before age 3 years, and many could not walk at age 7 years. Some infants exhibited severe neurotoxic effects, while their mothers had mild or no symptoms. Autopsies of infants who died showed greatest brain damage among those exposed during the third trimester. Because they did not suspect mercury initially, investigators did not collect blood or hair sam- ples but many families followed the Japanese custom of preserving a dried

section of umbilical cord. Children born during 1950–1965, the peak period of acetaldehyde production, had the highest umbilical cord mercury levels. Fish mercury levels (10–30 ␮g/g) and average fish consumption (300 g/day) at Minamata were much higher than current levels in United States.

Iraq. Methylmercury and other synthetic organic mercurials were used for several decades during the early twentieth century to protect seeds from fungal damage and improve crop yields. Unwitting use of methylmercury-treated seed grain for food caused several recognized epi- demics of severe neurotoxicity in Iraq during 1955–1972; the largest epidemic (1971–1972) involved over 6000 cases with several hundred deaths. Similar outbreaks occurred in other countries (Pakistan, Guatemala, Ghana), and these disastrous experiences finally led to worldwide bans of alkylmercurials for seed treatment.

As in Minamata, some prenatally exposed infants had substantial neurologic deficits even though their mothers reported no symptoms or only mild, transitory paresthesias (Amin-Zaki et al., 1979). Signs and symptoms among 32 prenatally exposed infants included microcephaly, irritability, exaggerated reactions to stimuli, and abnormal reflexes.

Among eight infants with severe cerebral palsy, six were blind and two had minimal sight; among their mothers, peak hair mercury levels occurred during the third trimester (average, 444 ␮g/g). Among infants with milder signs, the lowest peak maternal hair mercury level during pregnancy was 32 ␮g/g. Up to age 4 months, blood methylmercury among infants exceeded maternal levels, consistent with continued exposure through breast milk. Follow-up of severe cases to age 5 years showed persistent neurologic abnormalities and delayed developmental milestones, such as, inability at age 2 years to walk two steps without support or re- spond to simple verbal communication.

Among 49 Iraqi children aged 2–16 years with high postnatal exposures, about half had severe effects including ataxia, dysarthria, visual deficits (blurred vision, constricted fields, blindness), hearing deficits, glove and stocking numbness and paresthesias, involuntary movements, and incontinence (Amin-zaki et al., 1978). The severity of neurologic abnormalities was associated with estimated blood mercury concentrations near the end of the exposure period (using a blood mercury half-life of 56 days and extrapolating back in time from current blood levels). The degree of recovery over a 2-year follow-up period was inversely related to the initial severity of signs and symptoms; all children had persistent hyperreflexia, even those with initially mild poisoning. About a third of the initially blind children had recovered partial sight, and about a third

of the severely poisoned children remained physically and mentally in- capacitated (Amin-zaki et al., 1978). A WHO expert group reviewed dose–response data from Iraq and estimated risks of fetal neurotoxicity of 5% and 30%, respectively, at maternal hair mercury levels of 10–20 ␮g/g and 70⫹␮g/g (World Health Organization, 1990).

Neurotoxicity: Environmental Exposures

Studies of several fish-eating populations exposed to methylmercury at levels considerably below those in Minamata and Iraq have not shown consistent evidence of neurotoxic effects (Myers and Davidson, 1998). Re- sults from the two largest longitudinal studies, the Faroe Islands and Seychelles Islands birth cohort studies, are shown in Table 5–1. Faroe Is- lands residents eat diets rich in fish and marine mammals (pilot whales) containing relatively high concentrations of methylmercury, PCBs, and potentially protective antioxidants (selenium and vitamin E); the median maternal hair mercury level during pregnancy was 4.5 ␮g/g, much lower than at Minamata (41 ␮g/g) but higher than in the United States (⬍1 ␮g/g). Cord blood methylmercury levels were inversely related to scores on a standardized neurologic examination at age 2 weeks, inde- pendent of PCBs (Steuerwald et al., 2000). Breast-feeding was associated with higher infant hair mercury level at age 12 months and early developmental milestone attainment (sitting, creeping, and rising). Assessment at age 7 years, however, indicated that cord-blood mercury level was associated with deficits in language, attention, and visuospatial memory, in- dependent of cord blood PCB level (Grandjean et al., 1999).

The Seychelles Islands study population is remote from polluting in- dustry, consumes large amounts of fish but not whales, and has a low prevalence of tobacco and alcohol use among women. The median maternal prenatal hair mercury level during pregnancy was 5.9 ␮g/g, slightly higher than that of the Faroese women. Prenatal or postnatal mercury exposure indices were inconsistently related to developmental milestones or neurobehavioral scores up to age 5 years.

High-level prenatal methylmercury exposure causes similar behav- ioral and pathologic effects in young animals and humans, that is, mental retardation, cerebellar ataxia, primitive reflexes, dysarthria, and sei- zures. Relatively low prenatal exposures cause visual memory deficits, abnormal social behavior, and reduced growth at puberty in nonhuman primates, while low neonatal exposures produce visual spatial contrast sensitivity deficits. Monkeys exposed from birth to adulthood to low doses of methylmercury displayed visual recognition memory deficits during infancy, slower retrieval of treats, impaired fingertip vibration sense in middle age, and slight visual field deficits as adults (Rice and

TABLE5–1. Major Birth Cohort Studies of Mercury and Neurobehavioral Effects

Main Author, Population Population Exposures and Associations

Faroe Islands

Grandjean et al. (1992) 1023 mother–infant pairs; exposed to methylmercury, Cord blood mercury—median, 24.2 g/L; 75th percentile, 40 g/L;

PCBs, and other contaminants mainly from eating maternal hair mercury—median, 4.5 g/g; 13% exceeded 10 g/g pilot whales; marine fish minor source of

exposure

Grandjean et al. (1995) 583 infants followed to age 12 months; recorded age Early milestone development associated with breast-feeding and first sat without support, crawled, and stood increased infant hair mercury level at age 12 months but not

without support with maternal hair (at delivery) or cord blood mercury level

Grandjean et al. 917 children tested at age 7 years; clinical Inverse associations between cord blood and maternal hair (1997, 1999) examination and neurophysiologic mercury levels and scores on tests of language, attention,

and neuropsychologic tests memory, and visuospatial and motor functions that persisted at maternal hair mercury levels below 10 g/g; cord blood mercury most closely associated with language, attention, and memory deficits; concurrent child hair and blood mercury levels were less predictive but were inversely associated with visuospatial memory

Grandjean et al. (1998) 112 children whose maternal hair mercury level was High-exposure group had small deficits in motor function 10–20 g/g and 112 matched children whose (especially fingertapping), language, and memory maternal hair mercury level was 3 g/g,

age 7 years

Murata et al. (1999) Reanalysis of data on brainstem auditory evoked Maternal hair and cord blood but not child’s concurrent hair

potentials mercury level associated with brainstem auditory evoked

potential abnormalities

Budtz-Jorgensen et al. Estimated BMDs of cord blood mercury 95% confidence lower limit of estimated BMDs for cord blood (2000) for deficits in attention, language, mercury was about 5 g/L (equivalent to a maternal hair

and verbal memory scores at age 7 years mercury level of about 1 g/g)

Grandjean et al. (2001) 435 children age 7 years; measured PCB levels Association between cord tissue PCBs and deficits on 2 of 17 neuro- in umbilical cord tissue psychologic outcomes; possible interaction between PCBs and

mercury in highest mercury tertile

Seychelles Islands

Myers et al. (1995) 779 mother–infant pairs, methylmercury from Maternal hair total mercury during pregnancy—median, 5.9 g/g marine fish; infants tested at age 6 months (range, 0.5–27 g/g); no associations with neurodevelopmental (visual recognition memory and developmental scores at age 6.5 months

screening tests)

Davidson et al. (1995); 738 infants assessed at 19 months, 736 retested at No association between maternal hair mercury during pregnancy Myers et al. (1997) 29 months (infant development and behavior) and psychomotor or mental development scores or age at first

walking or talking

Axtell et al. (1998); 711 children aged 5.5 years No consistent associations between prenatal or postnatal mercury

Davidson et al. (1998); exposure indices and reduced neuropsychologic scores (including

Myers et al. (2000); overall indices, subscales, and recombined subscales); positive

Palumbo et al. (2000) association between postnatal mercury exposure and memory

subscale scores

Crump et al. (2000) Estimated maternal hair mercury BMDs for The average lower 95% confidence limit BMD for maternal hair neurologic tests, neuropsychologic tests, and mercury was about 25 g/g (range, 19–30 g/g)

developmental milestone data at four follow-up examinations (age 6, 19, 29, and 66 months)

Hayward, 1999). Animal studies have not yet replicated the usual pattern of human methylmercury exposure, that is, generally intermittent and related to fish consumption.

Other Effects

All three forms of mercury cumulate to higher levels in kidney than any other tissue and can cause toxicity ranging from increased urinary protein levels (indicative of renal tubular damage) to renal failure with nephrosis and necrosis of proximal tubules. For instance, infants dermally exposed to diapers washed with soap containing phenylmercury have increased urinary excretion of ␥-glutamyl transpeptidase. After exposure to organic mercury, children are more susceptible than adults to skin changes (acrodynia or “pink disease”) including rash followed by peeling skin on the palms of the hands and soles of the feet, itching, and joint pain.

Acrodynia was more common in the past, when mercury-containing lax- atives, worming medications, teething powders, and diaper rinses were widely used. There is limited animal and inadequate human evidence that methylmercury is carcinogenic, and the EPA concluded that it is unlikely to be a human carcinogen at exposure levels generally encountered from environmental sources.

Exposures

Given the high toxicity of mercury, it is surprising that only Germany and the United States appear to have collected nationally representative data on mercury levels in children and reproductive-age women (Table 5–2) (Centers for Disease Control and Prevention 2001b, 2001c; Seifert et al., 2000).

Exposure Biomarkers

Blood mercury, about 95% of which is bound to red blood cells, has a half- life of about 50 days and thus reflects recent exposure. The half-life of methylmercury in the blood of lactating women is about half that in non- lactating women due to excretion in breast milk. The cord blood mercury concentration is about 20%–30% higher than that of maternal blood and reflects fetal exposure during late gestation, the period of greatest sus- ceptibility to neurotoxicity. Maternal blood and hair but not breast milk mercury levels are associated with methylmercury exposure from fish consumption. About 90% of methylmercury is excreted in bile/feces and the remainder in urine and breast milk. Incomplete development of bili- ary transport systems contributes to a longer half-life of methylmercury in infants compared to adults.

Hair grows at the rate of about 1 cm per month, and the mercury content in a given segment of hair is about 250-fold that in blood at the time the segment was formed. Maternal hair mercury levels correlate strongly with those in fetal brain, cord blood, and newborn hair; thus seg- mental hair mercury analysis is valuable for retrospective mercury exposure estimation. Published studies vary as to whether they measured total mercury or methylmercury, but over 80% of total mercury in hair from fish-eating populations is methylmercury. Women exposed during the major poisoning incidents had hair mercury levels of up to 700 ␮g/g in Minamata (median, 41 ␮g/g) and over 400 ␮g/g in Iraq. Mothers in longitudinal studies of fish-eating populations all had hair mercury levels below 40 ␮g/g.

TABLE5–2. Norms and Health-Based Limits for Selected Metals in Human Specimens

Sample Norm or Limit

Mercury

Blood (age 1–5 years) 1.4 ␮g/L (CI 0.7–4.8), 90th percentile^a Blood (age 6–14 years) 1.1 ␮g/L, 90th percentile^b

Blood (women age 16–49 years) 6.2 ␮g/L (CI 4.7–7.9), 90th percentile^a

Cord blood 5 ␮g/L (BMDL)^c

Hair (age 1–5 years) 0.4 ␮g/g (CI 0.3–1.8), 90th percentile^d Hair (women age 16–49 years) 1.4 ␮g/g (CI 0.9–1.7), 90th percentile^d

Maternal hair 1 ␮g/g (BMDL)^c

25␮g/g (BMDL)^e 10–20␮g/g (BMD)^f 12␮g/g (BMDL)^g

Urine (age 6–14 years) 1.9 ␮g/g creatinine, 90th percentile^b Arsenic

Urine (age 6–14 years) 14.1 ␮g/g creatinine, 90th percentile^b Cadmium

Blood (age 1–19 years) 0.4 ␮g/L (CI 0.3–1.0), 90th percentile^a Blood (age 6–14 years) 0.3 ␮g/L, 90th percentile^b

Urine (age 6–14 years) 0.15 ␮g/g creatinine, 90th percentile^b

aCenters for Disease Control and Prevention (2001a).

bSeifert et al. (2000).

cBudtz-Jorgensen et al. (2000).

dCenters for Disease Control and Prevention (2001c).

eCrump et al. (2000).

fWorld Health Organization (1990).

gNational Academy of Sciences (2000).

BMDL⫽benchmark dose limit (lower 95% confidence limit on BMD).

BMD⫽benchmark dose.

United States and German biomonitoring surveys showed that mercury levels were generally low; in the United States, about 10% of women had hair mercury levels within one-tenth of potentially hazardous levels, indicating a relatively narrow margin of safety. Average hair mercury levels in local studies in the United States have usually been under 1 ␮g/g, that is, about the level expected for exposure at the EPA reference dose for methylmercury. A Canadian methylmercury screening program tested almost 40,000 aboriginal persons during 1972–1992 (Wheatley and Par- adis, 1998). Inuit communities dependent on diets high in fish and sea mammals had the highest average cord blood and adult mercury levels;

over 30% of reproductive-age Inuit women had hair methylmercury levels over 10 ␮g/g. Blood mercury levels varied substantially by season, corresponding to high consumption of fish and seafood in the early fall and early winter.

Risk Management

It was not until the late 1960s and 1970s that investigators discovered the ability of aquatic microbes to methylate mercury and the bioaccumulation of methylmercury from concentrations in water to 1 million-fold higher levels in predators such as tuna and marine mammals atop the aquatic food chain. By then, however, vast amounts of mercury from chlor-alkali, pulp and paper, mining, and other industries had been discharged into aquatic environments worldwide. The largest current users of mercury are chlor-alkali plants (production of chlorine and caustic soda) and electrical/electronic industries (electric lighting, wiring, switches, batteries).

Air

Analyses of mercury in peat and lake sediments in remote parts of North America indicate that mercury emissions into air have increased about fivefold since the beginning of the industrial period. The major sources of air emissions are coal-fired utility/industrial boilers (50%), municipal waste combustors (20%), and medical waste incinerators (10%). Future mercury emission levels will be heavily influenced by increasing use of coal to meet energy needs, especially since emissions from municipal and medical waste combustion declined 50%–75% during the 1990s in the United States.

Airborne mercury emissions from natural and anthropogenic sources disperse in the environment by long-range atmospheric transportation.

Elemental mercury vapor tends to remain airborne, while inorganic mercury is rapidly cleared to soil and water compartments, deposition being enhanced by precipitation. Modeling indicates that the highest deposition

rates of airborne mercury in the United States occur in the southern Great Lakes region, the Ohio River valley, the northeastern states, and other scattered areas. Because atmospheric mercury deposition accounts for much of the mercury in fish in the northeastern United States, even mod- est increases in atmospheric mercury loading could further elevate levels in fish. Air mercury levels over the Atlantic Ocean increased until about 1990 and have continued to increase in northern Canada and Alaska due to long-range transport of increasing global emissions.

Phenylmercuric acetate was used as a fungicide/bactericide to pro- long the shelf life of interior latex paint up to 1990 in the United States and was the source for two reported cases of childhood mercury poisoning (acrodynia). At that time, the EPA permitted interior latex paint to contain up to 300 ppm mercury but did not require a label warning about the presence and concentration of mercury; paint used in the home of one patient actually contained about 950 ppm mercury, or three times the EPA limit. After application, phenylmercuric acetate apparently breaks down and releases elemental mercury. Air mercury levels were greatly elevated during application of latex paint and decreased rapidly thereafter but remained above background levels for at least several years, reflecting continued mercury release. Subsequent investigations showed that exposed children had higher urinary mercury levels than older persons. Even in homes where paint contained less than 200 ppm mercury, air mercury levels were up to 1.5 ␮g/m³ (median, 0.3 ␮g/m³), with some homes exceeding the ATSDR acceptable indoor concentration for continuous exposure of 0.5 ␮g/m³(Beusterien et al., 1991). By 1991, all registrations for mercury compounds in paints had been canceled by the EPA or volun- tarily withdrawn by manufacturers. This occurrence shows the impor- tance of regulatory measures to ensure that children are not exposed to toxicants in the indoor environment arising from the use of household products.

Reduced mercury emissions can be achieved through manufacturing controls (product substitution, process modification, and materials sepa- ration), coal cleaning, and flue gas treatment technologies. Specific ex- amples of manufacturing controls include replacement of mercury cathodes in chlor-alkali plants, reduced use of mercury in household batteries and fluorescent lights, and removal of mercury-containing materials (e.g., batteries, fluorescent lights, thermostats) from wastes prior to incineration. Conventional cleaning methods reduce the coal mercury content by about half, and control devices on utility and industrial boilers can re- move over 90% of mercury emissions.

Under the Clean Air Act, the EPA has set rules for municipal and medical waste incineration with the goal of reducing mercury emissions

Dalam dokumen Child Health and the Environment (Halaman 121-138)