Environmental Health Perspectives Volume
103, Supplement 6, September 1995
[Citation
in PubMed]
Neurobehavioral Effects of Developmental Methylmercury Exposure
Steven G. Gilbert and Kimberly S. Grant-Webster
School of Public Health and Community Medicine, Department of Environmental
Health,
University of Washington, Seattle, Washington
Abstract
Methylmercury (MeHg) is a global environmental problem and is listed
by the International Program of Chemical Safety as one of the six most dangerous
chemicals in the world's environment. Human exposure to MeHg primarily occurs
through the consumption of contaminated food such as fish, although
catastrophic exposures due to industrial pollution have occurred. The fetus
is particularly sensitive to MeHg exposure and adverse effects on infant
development have been associated with levels of exposure that result in
few, if any, signs of maternal clinical illness or toxicity. High levels
of prenatal exposure in humans results in neurobehavioral effects such as
cerebral palsy and severe mental retardation. Prenatal exposure to MeHg
in communities with chronic low-level exposure is related to decreased birthweight
and early sensorimotor dysfunction such as delayed onset of walking. Neurobehavioral
alterations have also been documented in studies with nonhuman primates
and rodents. Available information on the developmental neurotoxic effects
of MeHg, particularly the neurobehavioral effects, indicates that the fetus
and infant are more sensitive to adverse effects of MeHg. It is therefore
recommended that pregnant women and women of childbearing age be strongly
advised to limit their exposure to potential sources of MeHg. Based on results
from human and animals studie on the developmental neurotoxic effects of
methylmercury, the accepted reference dose should be lowered to 0.025 to
0.06 MeHg µg/kg/day. Continued research on the neurotoxic effects
associated with low level developmental exposure is needed. -- Environ
Health Perspect 103(Suppl 6):135-142 (1995)
Key words: methylmercury, neurobehavioral, neurotoxicology, human
infant, monkeys, developmental, prenatal, risk assessment
This paper was presented at the Symposium on Preventing
Child Exposures to Environmental Hazards: Research and Policy Issues held
18-19 March 1994 in Washington, DC.
The authors thank Drs. Deborah C. Rice and Thomas M. Burbacher
and Rafael Ponce for discussions and comments on this manuscript. Preparation
of this manuscript was supported in part by National Institutes of Health
grant ES03745.
Address correspondence to Dr. Steven G. Gilbert, Department
of Environmental Health, XD-41, University of Washington, Seattle, WA 98195.
Telephone (206) 543-9780. Fax (206) 685-4696. E-mail:
sgg@u.washington.edu
Introduction
It is well established that prenatal exposure to certain toxic chemicals
can have profound and irreversible effects on the physical and mental development
of children. Of agents known to act as toxicants, those that cause central
nervous system damage (neurotoxicants) constitute a particularly significant
public health hazard. While episodes of high-dose neurotoxicant exposure
to children have shown clear evidence of neurological disorders, the more
subtle action of moderate to low dose neurotoxicant exposure on important
parameters of behavioral development is increasingly evident (1-3).
Laboratory-based research and documented incidents of human exposure to
neurotoxicants such as lead, alcohol, and methylmercury point to a continuum
of effects in exposed children ranging from subtle behavioral changes to
frank expression of neurological damage and death. In general, the long-term
consequences of developmental exposure to neurotoxicants are only now beginning
to receive scientific attention.
Although there are a number of important neurotoxicants, this article
focuses on the effects of developmental exposure to methylmercury (MeHg),
a prevalent environmental contaminant. The serious public health concerns
associated with MeHg exposure have resulted in world-wide attention, research,
and review (4-14). The aim of this article is to provide an updated
overview of the developmental effects of MeHg exposure, reexamine currently
recommended exposure guidelines, and highlight future research needs.
In recognition of the adverse effects of MeHg exposure, state and federal
government agencies and international agencies have developed recommendations
to limit MeHg exposure. For example, the U.S. FDA recommends a limit of
1 µg/g (1 ppm) mercury in the edible portion of fish. The U.S.
EPA has established a reference dose (RfD) for methylmercury at 0.3 µg/kg/day,
which is equivalent to consumption of 19 µg per day of MeHg for a
62 kg woman (15). The RfD is defined as an estimate of a daily
exposure to a human population that is likely to be without an appreciable
risk of deleterious effects during a life time and is meant to include sensitive
subgroups. The RfD typically is arrived at through standard risk assessment
procedures that include a careful evaluation of study results, determination
of the lowest observed adverse effect level (LOAEL) dose, and division of
the LOAEL by an appropriate uncertainty factor to yield a RfD. The World
Health Organization (WHO) does not use the RfD nomenclature but developed
a similar recommendation that is equivalent to 0.47 µg/kg/day in adults
(16) while noting that pregnant women, nursing mothers, and their
infants are likely to be at greater risk. A recent reevaluation of the RfD
for MeHg was done by Stern (14), who concluded that the RfD should
be lowered to 0.07 µg/kg/day based on human and animal studies on
developmental effects of MeHg. Upon review of the human and animal literature,
the authors of the current review reached a similar conclusion.
Mercury Contamination -- Methylmercury Exposure
Mercury is generally released into the environment in an inorganic form
by both natural and anthropogenic sources (4,11,16, 17). Natural
sources of mercury include emissions from volcanoes, degassing of the earth's
crust, and evaporation from water. Artificial sources of mercury include
industrial pollution, burning of fossil fuels, mining, refuse incineration,
and cremation. Natural emissions of mercury into the atmosphere have been
estimated to range from 2700 to 6000 metric tons per year, while world wide
mining of mercury is estimated to yield 10,000 tons per year (4).
It is estimated that human activities result in the release of 3000 tons
per year of mercury. A significant source of environmental mercury
contamination is gold mining in countries such as in Brazil (18,19).
Mercury release due to gold mining results in environmental contamination
through direct effluent discharge into local waterways and through
volatilization (18). Approximately 3 to 5 kg of mercury are used
to extract 1 kg of gold, of which 25 to 45% is lost during the amalgamation
process (20). Atmospheric mercury undergoes photochemical oxidation
and is then scavenged by atmospheric particulates or precipitation. Global
contamination occurs as the mercury is washed out of the atmosphere onto
soil, vegetation, and water (4,21).
The majority of environmental MeHg contamination has occurred through
the biotransformation of inorganic mercury to organic mercury (MeHg) in
a process termed methylation. During methylation, inorganic mercury is converted
into MeHg by microbial action, primarily in sediments of fresh and ocean
waters. Methylmercury readily enters the aquatic food chain and is biomagnified
as it accumulates in predatory fish such as swordfish, pike, and
ocean tuna. Larger and more long-lived fish tend to contain more MeHg.
Methylmercury contamination in fish can be significant; for example,
the total mercury in the edible tissues of shark and swordfish can
average as high as 1200 µg/kg (16). Marine mammal and fish
consumption, while not the only sources of MeHg exposure, are extremely
important routes of human exposure. This is particularly true for populations
depending on fish as a primary food source.
Methylmercury is readily absorbed and distributed throughout the body,
including the brain. In humans, MeHg brain levels are approximately six
times higher that blood mercury levels (22). This is in contrast
to rats, which have a brain-to-blood ratio of 0.06, and mice with a ratio
of 1.20. These differences in brain MeHg accumulation have important implications
for the extrapolation of human health guidelines from animal data. Methylmercury
also readily crosses the placenta and appears to accumulate in the fetus
so that fetal mercury levels are greater than maternal blood mercury levels
(23). The differential accumulation of MeHg in the brain and the
fetus are important factors in defining developmental MeHg neurotoxicity.
Fetal Sensitivity to Methylmercury Exposure
Methylmercury is an excellent example of a known neurotoxicant that is
also a prevalent and dangerous environmental pollutant. The effects of in
utero exposure to MeHg are quite different from the effects associated
with childhood or adult exposure (16). The fetus is more sensitive
to the toxic effects of MeHg and severe effects have been found in the offspring
of women showing little or no overt evidence of MeHg exposure (24-26).
Catastrophic exposures in both Japan and Iraq provided evidence that mercury-exposed
women delivered infants with severe behavioral and sensory deficits,
including deafness and blindness, without expressing significant clinical
signs or symptoms of mercury toxicity during pregnancy.
On both biological and neurobehavioral levels, there is strong evidence
of fetal sensitivity to MeHg. Prenatal exposure to MeHg appears to result
in a widespread pattern of adverse effects on brain development and organization
(13,16,27-29). This generalized pattern of MeHg-induced injury to
fetal brains is not seen in the adult brain, where MeHg exposure is characterized
by localized lesions at specific neural sites (30). Postmortem
studies from epidemic exposures in Japan and Iraq have revealed that MeHg
significantly alters the normal migration of neurons to the cerebellar
and cerebral cortices during brain development (27,28).
Examination of the brains of infants and animals exposed to MeHg in
utero has revealed changes in neuronal migration and distribution patterns,
cell loss (low neuronal abundance), and reduced brain size and gliosis (27,29,31,32).
Hypotheses explaining MeHg-mediated developmental neurotoxicity include
changes in intracellular cytoskeletal structure (33-35), oxidative
stress (36-38), alterations to membrane function and signal transduction
(39), decreased protein production (40), and changes in neurotransmission
(41).
Neurobehavioral Effects in Human Infants
The disruptive effects of in utero MeHg exposure on brain development
have been associated with a broad range of neurobehavioral alterations in
infancy and childhood. Published reports of studies involving mothers and
infants come primarily from Japan, Iraq, Canada, and New Zealand. There
are, however, additional reports of mother-infant pairs under study in the
Seychelles Islands, Greenland, and the Faroe Islands (Table 1). Methylmercury
exposure is usually estimated by blood or hair mercury levels and it is
generally accepted that the hair mercury concentration is 250 times that
of the blood (16).
The catastrophic human exposures that occurred in Minamata and Niigata,
Japan in the 1950s established that MeHg was fetotoxic (26,42). In
the Minamata Bay study, 23 children believed to have been exposed to MeHg
in utero showed evidence of mental retardation and cerebral palsy.
During pregnancy, levels of Hg exposure were not monitored in the mothers
of these children, but as a group these women showed little clinical evidence
of MeHg toxicity. More subtle neurobehavioral deficits were not systematically
studied in Japan; however, a general assessment of IQ in elementary and
junior high-school students in the Minamata school district and a control
district did not reveal any large differences in group performance (16).
In the city of Minamata, a separate study found a significant correlation
between level of MeHg in umbilical cord blood and occurrence of mental retardation
(16).
In Iraq, an investigation of 29 mother-infant pairs was initiated after
a serious outbreak of MeHg poisoning from consumption of contaminated bread
(43). Results indicated a significant relationship between prenatal
MeHg exposure and infant psychomotor retardation. Clear evidence of delays
in attaining developmental milestones (e.g., motor and speech retardation)
were evident in children with maternal hair MeHg levels less than 180 ppm.
Neurological symptoms such as increased muscle tone and exaggerated deep
tendon reflexes were primarily associated with maternal hair MeHg levels
higher than 180 ppm. A subsequent report detailed the results of 84 mother-infant
pairs (including the 29 discussed above), with peak maternal hair levels
ranging from 0.4 to 640 ppm (44). Severe neurological symptoms (e.g.,
blindness, deafness, failure to walk, talk, or stand by over 4.5 years)
were documented in five children. The lowest peak maternal hair level
associated with severe neurological problems was 165 ppm (range 165-320
ppm). These reports were the first to document more subtle impairments
in children exposed to lower levels of MeHg during gestation and suggested
a continuum of MeHg-related effects closely linked to maternal dose. Data
from Iraq were reevaluated in an effort to determine a dose-response relationship
between maternal hair levels of mercury and developmental effects (45).
From this analysis, it was concluded that delayed onset of walking may occur
at maternal hair levels of 10 to 20 ppm, which is equivalent to maternal
blood mercury levels of 40 to 80 ppb.
The Iraq episode provided an opportunity for systematic follow-up of
MeHg-exposed infants and children (46,47). Standard clinical and
neurological tests including the Gesell Developmental Screening Exam were
used as neurobehavioral assessment measures. Offspring effects ranged from
hyperreflexia and delayed motor activity to microcephaly, cerebral
palsy, and death. Follow-up studies at approximately 5 years of age indicated
significant delays in psychomotor development and persistent pathological
reflexes in a substantial number of children who did not display clinical
signs during infancy. The clinical diagnoses of these children resembled
minimal brain dysfunction (MBD) syndrome.
In Canada, a study of prenatal MeHg exposure in 234 Cree Indian infants
and children did not find strong evidence of developmental abnormalities
(48). Anthropometric measurements, neurological exams, and the Denver
Developmental Scales were used as test measures with the children. The mean
maternal hair level in this study was 6 ppm. No effects on physical development
were noted for either males or females. Significant neurobehavioral
effects were limited to the finding that maternal exposure to MeHg
was related to abnormal muscle tone (deep tendon reflex) in male infants.
No effects of exposure to MeHg were noted in female infants and the authors
note the questionable clinical significance of this sex-specific
finding. Animal data, however, would suggest that there may be sex-related
effects of prenatal MeHg exposure, with males generally showing a greater
sensitivity to in utero exposure (29,49-52) .
Studies of children prenatally exposed to MeHg through maternal fish
consumption have been conducted in New Zealand (53). Approximately
1000 women were identified as frequent fish consumers and of these,
73 were identified as having maternal hair concentrations above 6 ppm
(range 6-86 ppm). At 4 years of age, 31 offspring from this group were assessed
with the Denver Developmental Screening Test. Evidence of a significant
increase in the risk of early sensorimotor dysfunction was documented in
the MeHg-exposed group. A dose-response relationship was established between
mean maternal hair MeHg levels and performance on the Denver Developmental
Screening Test.
A subsequent study evaluated 61 of the original 73 high-dose children,
at 6 to 7 years of age, on multiple assessments that included tests of intelligence
(WISC-R) and language development (TOLD) (54). Results showed that
exposed children who scored poorly on the Denver Developmental Screening
Test at 4 years of age tended to have decreased scores on the WISC-R intelligence
test later in childhood. These neurobehavioral effects were associated with
maternal blood MeHg levels of only 20 to 80 ppb.
Elevated levels of blood mercury in women of childbearing age have been
found in polar Inuit natives in Northern Greenland (55). The Inuits'
reliance on whale meat as a dietary mainstay is believed to be the primary
source of exposure. Of the women tested, 84% had blood MeHg levels that
exceeded the provisional limit set by the WHO (23 ppb). As expected, the
fetal levels of MeHg in cord blood (average value of 80.2 ppb) were higher
than maternal blood levels (average value of 38.1 ppb). An examination of
the relationship between cord blood MeHg and birthweight revealed that decreased
birthweights were associated with higher levels of fetal MeHg exposure (56).
Although information on the neurobehavioral status of these children is
not currently available, the cord blood MeHg levels are in the range of
values that have been associated with psychomotor retardation (53).
Samples of cord blood and maternal hair also were collected and assayed
for mercury from women living in the Faroe Islands (57,58). With
a sample size of 1000 infants, the mean mercury concentration in cord blood
was 24.2 ppb, and over 25% of the samples were above 40 ppb. This clearly
exceeds the WHO provisional limit for potential health effects and confirms
elevated in utero MeHg exposure. Faroese children as well as the
Inuit children of Northern Greenland should be considered at risk for neurobehavioral
alterations associated with in utero MeHg exposure.
In summary, a review of the human data on the developmental effects of
MeHg exposure indicates that maternal hair levels of 10 to 20 ppm are potentially
harmful to fetal development. This is equivalent to maternal blood levels
of 40 to 80 ppb of mercury, assuming a mercury hair-to-blood ratio of 250.
To determine a LOAEL, the blood mercury levels must be converted to an estimate
of daily consumption (i.e., dose) that would result in the equivalent blood
levels. Based on kinetic modeling of MeHg, it is estimated that the long-term
daily consumption of 1 µg of mercury will result in blood mercury
levels of 1 µg/l or 1 ppb (16). Thus, the consumption of 40
µg of mercury per day would result in a blood mercury level of 40
ppb; which for a 62-kg woman would be equivalent to 0.645 µg/kg/day.
If the typically used uncertainty factor of 10 is used to account for sensitive
individuals (in this case fetal development), the resulting NOAEL or RfD
would be 0.06 µg/kg/day.
Neurobehavioral Effects in Animals
As discussed above, human exposure to MeHg during prenatal development
results in a continuum of effects ranging from blindness, deafness, seizures,
abnormal reflexes, and retarded motor development, to far more subtle
learning, memory, and psychological effects (5,9,25,26,47,59). Adverse
effects of MeHg exposure can occur at human brain levels estimated to be
as low as 0.3 ppm (45).
While animal studies using high levels of MeHg exposure have produced
effects similar to those of humans, there have been few efforts to characterize
the more subtle effects of low-dose exposure to MeHg during development.
Early effects of in utero exposure have been documented in nonhuman
primate infants. As part of a larger study examining the maternal reproductive
and offspring developmental effects of chronic exposure to MeHg, female
Macaca fascicularis monkeys were exposed to daily doses of MeHg throughout
pregnancy (0, 50, 70, or 90 µg/kg/day). Maternal blood MeHg levels
averaged 1.28, 1.62, and
2.03 ppm, respectively, for the three treated groups. Maternal blood MeHg
levels above 1.5 ppm were associated with a significant decrease in
number of viable births (60).
During infancy, effects of prenatal exposure were found on measures of
cognitive and social development in the offspring of the MeHg-exposed monkeys.
In utero exposure to MeHg was related to delayed attainment of object
permanence (61), deficits in visual recognition memory (62,63),
and abnormal social behavior (64). These results, frequently based
on test procedures developed for use with human infants, show that in
utero exposure to MeHg is related to delays in the attainment of important
cognitive milestones. The social behavior of the MeHg-exposed infants in
established play groups was characterized by a significant decrease
in play behavior and an increase in nonsocial behavior. Exposed infants
were less likely to engage in species-appropriate play behavior and spent
more time alone, distancing themselves from other monkeys in the group.
In this same group of animals, a latent effect of prenatal exposure to MeHg
indicated puberal growth retardation in exposed males (49). Exposed
males exhibited significantly decreased weight gain during the juvenile
stages of growth (3-5 years of age) but did catch up to the average weight
of control males by early adulthood. Subsequent studies in adulthood with
these animals have found very slight effects on an intermittent schedule
of reinforcement (fixed-interval/fixed-ratio) (65). In
this group of animals, overall study results do not support long-term deficits
in adult learning and memory abilities (66). However, preliminary
results indicate there may be deficits in adult visual function. Results
from this group of monkeys indicate that developmental effects are seen
at maternal exposures of 50 µg/kg MeHg/day.
Confirmation of the developmental effects of MeHg exposure is evident
from Canadian studies in which monkeys were exposed to MeHg either post-
or pre- and postnatally (birth to 7 years of age) at 25 or 50 µg/kg/day.
In one study, infants were tested on a fixed-interval operant learning
task. Exposed infants showed slight alterations in performance, indicating
a possible disruption of time perception (67). In the same study,
MeHg exposure was not related to learning impairments on discrimination
reversal tests. Developmental exposure to MeHg was also shown adversely
to affect visual, auditory, and somatosensory function in monkeys (67-71).
Visual psychophysical studies with these monkeys have shown treatement-related
deficits in spatial contrast sensitivity and facilitation of low-luminance
temporal contrast sensitivity (69). Subsequent studies have described
overt sensory-motor deficits (i.e., lack of coordination in exercise
cages) and a loss of vibration sensitivity (70-72). These effects
were observed at the lowest doses tested (25 µg/kg), which is characteristic
of many studies with MeHg.
In rodents, one of the most frequent findings related to prenatal
MeHg exposure is an increased rate of intrauterine death (10). Studies
on the developmental effects of MeHg on rats (Table 2) and mice (Table 3)
have provided a means of examining specific hypotheses regarding the
mechanisms of action of MeHg. These studies also provide information on
the levels of maternal exposure at which no adverse effects are observed
in the offspring. Typically, pregnant rats or mice were dosed with MeHg
for a restricted period of time during gestation. To compensate for the
short exposure periods, relatively high doses of MeHg were often used. The
most common neurological deficit observed was altered locomotion or
exploratory behavior (73-78). These findings are consistent
with results from high-exposure human studies which revealed significant
delays in aspects of motor development such as crawling, standing, and walking.
Learning deficits have also been observed following developmental exposure
to MeHg (77-81).
The most comprehensive study to assess the developmental effects of MeHg
in rats was done as part of the Collaborative Behavioral Teratology Study
(78). In this multilaboratory study, using the same testing protocol,
pregnant rats were exposed to either 2 or 6 mg/kg of MeHg on days 6 through
9 of gestation. These studies found dose-related changes in behavior characterized
by increased levels of activity and impaired learning of auditory startle
habituation in exposed pups. Lower doses of MeHg were not examined, so a
NOAEL could not be determined. Two studies have assessed the effects of
low-level prenatal exposure to MeHg using schedule-controlled operant behavior
(82,83). In these studies, rats were dosed with either 0.005, 0.01,
0.05, or 2.0 mg/kg MeHg during days 6 through 9 of gestation. The offspring
were then tested on a differential reinforcement of high rate schedule.
This task requires the subject to respond to a lever a specified number
of times within a fixed period to receive a reinforcement (e.g., two
responses are required within 1 sec). No adverse effects were observed at
a dose of 0.005 mg/kg. All other treated groups had reduced success rates.
Although no blood or brain mercury levels were reported, it is estimated
that the brain Hg levels were as low as 0.04 ppm, well below levels thought
to produce adverse effects in humans.
In summary, results from monkey studies indicate that a LOAEL for developmental
effects is evident at a dose of 25 µg/kg/day of MeHg. Rodent studies
indicate effects may be observed at doses as low as 10 µg/kg/day of
MeHg, with effects replicated at 50 µg/kg/day. Using the results from
the monkey studies, a NOAEL of 2.5 µg/kg/day is derived using the
standard procedure of dividing the LOAEL by a factor of 10. To convert a
NOAEL derived from animal studies to one for humans, an uncertainty factor
of 10 is typically used to account for interspecies differences. An additional
uncertainty factor of 10 is then applied to account for sensitive individuals
in the human population. Using a factor of 10 is appropriate given the sensitivity
of the developing nervous system to the adverse effects of MeHg. The above
risk analysis indicates that a more conservative RfD for MeHg exposure would
be 0.025 µg/kg/day, which would provide a level of safety for the
developing nervous sytem.
Neurobehavioral Effects of Other Neurotoxic Compounds
Methylmercury clearly is not the only compound that can adversely affect
the developing nervous system. Lead is one of the best studied environmental
neurotoxicants and is a good example of the problems associated with understanding
the effects of very low levels of exposure (84-86). The widespread
exposure of children to lead made it possible to perform numerous human
epidemiology studies that convincingly demonstrated that low-level exposure
is harmful to the developing nervous system (87). Animal studies,
particularly those in monkeys, confirmed that low-level exposure to
lead had adverse developmental effects (88). The consequences of
the deleterious effects of lead on normal childhood development are just
beginning to be examined (85,89).
Another important widespread environmental contaminant and neurotoxicant
is the lipid soluble polychlorinated biphenyls (PCBs). This family of over
200 chemicals was used primarily as insulators in electrical equipment.
Production of PCBs was banned in the 1970s following recognition of their
toxicity and environmental persistence. These lipid-soluble compounds are
mobilized during pregnancy, thus exposing the infant in utero and
are also readily excreted in breast milk during lactation. The neurotoxic
effects of in utero exposure to PCBs are well documented and have
been carefully reviewed (90-94). It is interesting to note that the
effects of PCBs appeared to be more related to in utero exposure
than to postnatal exposure through breast milk.
The voluntary consumption of neurotoxic substances during pregnancy can
also result in an array of neurobehavioral effects. Alcohol consumption
during pregnancy produces a well-documented syndrome of adverse effects
on the nervous system that range from subtle deficits in learning and
memory to severe developmental disorders (95-97). Animal studies
with alcohol have made important contributions to the understanding of fetal
alcohol effects and demonstrate the comparability of human and animal findings
(98). Studies on the long-term impact of prenatal alcohol exposure
demonstrate the individual and societal consequences of early neurotoxicant
exposure (95,97,99). Other drugs such as cocaine also affect nervous
system development (100).
Conclusions and Recommendations
Methylmercury is a compound worthy of scientific and societal concern.
It is clear that MeHg is a widespread environmental contaminant and a potent
neurotoxicant that adversely affects the developing nervous system. Mercury
continues to be released into the environment by both natural and human-generated
sources. It is readily converted to MeHg and accumulates in the food supply,
primarily in fish and marine mammals. MeHg is readily absorbed and
distributed throughout the body, including the brain and the fetus. Fetal
exposure appears to be at a level that is greater than maternal blood levels.
Studies of humans exposed to elevated levels of MeHg clearly demonstrate
its neurotoxic potential. Animal studies using rodents and nonhuman primates
have confirmed the neurotoxic potential of MeHg. However, research
into cellular and molecular mechanisms has yet to produce an understanding
of MeHg sufficient to allow accurate prediction of its neurotoxicity.
Furthermore, human and animal studies on the neurobehavioral effects of
developmental MeHg exposure have not determined a level of exposure that
is convincingly harmless to the developing fetus.
In many ways, our understanding of the neurotoxic potential of MeHg is
similar to that of lead 20 years ago; MeHg is a known neurotoxicant at high
levels of exposure but there is little understanding of its effects at lower
levels of exposure. The failure to adequately characterize the functional
effects of low-level MeHg exposure has compromised the formulation of a
sound policy regarding the safe levels of MeHg exposure, particularly for
pregnant women or women of child bearing age. Examination of the results
of human studies on the effects of MeHg indicate that maternal hair levels
of 10 to 20 ppm may result in adverse effects on fetal outcome. Making the
appropriate assumptions and calculations, a level of exposure not expected
to be hazardous (RfD) would be 0.06 µg/kg/day. Evaluation of results
from animal studies on the developmental effects of MeHg provided an estimated
RfD of 0.025 µg/kg/day. The human and animal RfDs are in very good
agreement.
Given the current state of knowledge with regard to MeHg exposure, the
following recommendations are offered:
- reduce environmental release of all forms of mercury;
- consider restricting the global production and sale of mercury;
- strongly advise pregnant women and women of child bearing age to limit
their exposure to sources of MeHg;
- establish an RfD (reference dose) for MeHg of 0.025 to 0.06 µg/kg/day;
- continue research to determine a level of MeHg exposure that would
not harm the developing nervous system;
- continue research to understand the underlying molecular mechanisms
of action of MeHg;
- assess the long-term neurodegenerative effects of developmental MeHg
exposure.
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