INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
SAFETY EVALUATION OF CERTAIN FOOD
ADDITIVES AND CONTAMINANTS
WHO FOOD ADDITIVES SERIES: 44
Prepared by the Fifty-third meeting of the Joint FAO/WHO
Expert Committee on Food Additives (JECFA)
World Health Organization, Geneva, 2000
IPCS - International Programme on Chemical Safety
First draft prepared by Dr D.C. Bellinger1, Dr M. Bolger2, Dr C.
Carrington2, Dr E. Dewailly3, Dr L.P.A. Magos4 and Dr B.
1Harvard Medical School, Boston, Massachusetts, USA;, 2US Food and
Drug Administration, Washington DC, USA; 3Centre de Sante Publique du
Québec, Québec, Canada, 4TNO BIBRA International Ltd, Carshalton,
Surrey, United Kingdom; and 5Novigen Sciences Inc., Washington DC,
Transfer from mother to offspring
Cleavage of carbon-mercury bond
Complexes with thiol radicals
Interaction with selenium
Renal and hepatic toxicity
Reproductive and developmental toxicity (other than
Exposure in utero
Exposure in utero and postnatally
Exposure after parturition
Extrapolation between species
Observations in humans
Development later in childhood
Sensory, neurophysiological and other end-points
Adult neurological, neurophysiological, and sensory function
Bias: Covariates, confounders and effect modifiers
Study in the Faroe Islands
Study in the Seychelles
Study in the Amazon Basin
Study in New Zealand
Study in Peru
Reanalysis of the study in Iraq
Estimates of dietary intake
Biomarkers of exposure
National intake estimates
Estimates based on WHO GEMS/Food diets
Estimates of intake by fish consumers at the 95th percentile
The Committee first evaluated methylmercury at its sixteenth
meeting (Annex 1, reference 30), when it established a provisional
tolerable weekly intake (PTWI) of 300 µg of total mercury per person,
of which no more than 200 µg should be present as methylmercury. At
its twenty-second and thirty-third meetings (Annex 1, references 47
and 83), the Committee confirmed the PTWI of 200 µg of methylmercury
(3.3 µg/kg bw) for the general population. At its thirty-third
meeting, the Committee noted that pregnant women and nursing mothers
may be at greater risk than the general population from the adverse
effects of methylmercury. The Committee considered the available data
insufficient to recommend a specific intake for this population group,
and it recommended that more detailed studies be undertaken.
At its present meeting, the Committee reviewed information that
had become available since the previous evaluation. The PTWI was not
reconsidered and was maintained at its present value. Two other WHO
publications have dealt with the effects of mercury and methylmercury
on human health (WHO, 1976, 1990). Relevant information from those
documents and the studies published since the report of the
thirty-third meeting are summarized and discussed in this monograph,
and the data were used to estimate the risks associated with exposure
to methylmercury. It should be noted that the doses given refer to the
mercury constituent of the organic mercury compound.
2. BIOLOGICAL DATA
The dermal absorption of methylmercury is similar to that of
inorganic mercury salts (Friberg et al., 1961). Studies of
occupational exposure and studies on rats (Fang, 1980) and mice
(Ostlund, 1969) both indicate that pulmonary absorption accounts for
95% of the dose. Methylmercury in ligated segments of intestines was
absorbed 17-35 times faster than was an inorganic mercury salt (Sasser
et al., 1978). In volunteers (Aberg et al., 1969; Kershaw et al.,
1980), in squirrel monkeys (Berlin et al, 1975a), and in macaque
monkeys (Rice et al., 1989), the peak concentration in blood was
reached within 6 h of ingestion; 95% of an ingested dose was absorbed
by volunteers (Nittinen et al., 1973), squirrel monkeys (Berlin et
al., 1975a), and rats (Walsh, 1982).
The distribution of methylmercury has three characteristics: (i)
a high concentration of mercury in blood and a high ratio of the
concentration in erythrocytes:plasma; (ii) greater ease of transfer
across the blood-brain and blood-placenta barriers than any other
mercury compound with the exception of elemental mercury vapour
(although the transfer of the latter is limited by its rapid
oxidation; Magos et al., 1989); and (iii) less renal deposition than
any other mercury compound.
Three days after a single intravenous dose of methylmercury to
rats at 0.5 µg/g, the blood concentration of mercury was 2.1 µg/ml and
that in the brain was 0.14 µg/g. In rats given the same dose as
mercuric acetate, the concentration of phenyl and methoxyethylmercury
was 0.042-0.068 µg/ml in blood and 0.018-036 µg/g in brain. The renal
concentration was 87% less in rats given methylmercury than in those
given the other mercury compounds (Swensson & Ulfvarson, 1967).
A high concentration of mercury in blood is associated with a
high concentration ratio in erythrocytes:plasma in every species
tested. The reported ratios are about 20 in humans (Miettinen, 1973;
Kershaw et al., 1980) and nearly 20 in squirrel monkeys (Berlin et
al., 1975a), guinea-pigs (Iverson et al., 1973), and sheep (Kostyniak,
1983). The ratio was 12 in hamsters (Omata et al., 1986), 9 in pigs
(Gyrd-Hansen, 1981), and 5-9 in mice (Ostlund, 1969; Sundberg et al.,
1998a) and rabbits (Berlin, 1963). In cats, the ratio was 42 (Hollins
et al., 1975), and in rats the reported ratios ranged from 128 to 288
(Ulfvarson, 1962; Norseth & Clarkson, 1970; Vostal & Clarkson, 1973).
The high ratio in rats has been attributed to the greater number of
thiol groups in rat haemoglobin (Naganuma & Imura, 1980), which
results in an eight times greater release of methylmercury from human
than from rat erythrocytes suspended in albumin (Doi & Tagawa, 1983).
Rat haemoglobin also has an increased capacity to bind alkyltin, which
has little affinity for thiol radicals (Rose & Aldridge, 1968). The
accumulation of methylmercury in rat blood is associated with
organ:blood concentration ratios of mercury that are lower than in any
Except in rats, the brain:blood ratios were greater than 1 in all
species tested (Table 1). The ratio was consistently high in monkeys,
and in all species it was higher after multiple dosing than after the
administration of a single dose. Differences in strain and sex
affected the concentration of mercury in blood of mice more than that
in brain. The concentration in the brain was higher in female than in
male mice. A similar sex difference in brain mercury concentrations,
but without a difference in the brain:blood ratio, was seen in rats.
Six to 12 days after four daily oral doses of methylmercury chloride
at 8 mg/kg bw, the concentration of mercury in brain was 8.8 µg/g in
female and 6.7 µg/g in male rats (Magos et al., 1981).
In heavily exposed squirrel monkeys, the brain stem had
approximately the same concentration as the cerebellum and most of the
cerebral regions, with the exception of the occipital lobe, which had
the highest concentration (Berlin et al., 1975c). The thalamus had
somewhat higher concentrations than the occipital pole (Vahter et al.
1994). In pigs, the concentrations in the cerebrum, cerebellum, and
optic nerve differed only slightly, and all had higher concentrations
than the spinal cord (Platonow, 1968). In guinea-pigs, the cerebellum
had the lowest concentration (Iverson et al., 1974). In rats, the
highest concentration was found in the spinal roots and ganglia,
closely followed by the cerebral cortex and the cerebellum (Somjen et
al., 1973a), but the concentrations in the cerebellum, medulla
oblongata and various areas of the cerebrum differed only slightly
(Magos et al., 1981).
Table 1. Organ:blood concentration ratios of mercury after treatment with methylmercury
Species Treatmenta Blood Organ:blood ratio Reference
Brain Liver Kidney
Squirrel monkey Single dose, 0.63 3.1 (cc) 5.9 5.1 Berlin et al.
8 days (1975b)
Squirrel monkey < 2 months, 1.4 5.3 - - Berlin et al.
9-22 days (1975c)
Macaque monkey < 2 months, 2.4 2.7 13 21 Evans et al.
1 day (1977)
Macaque monkey < 2 months, 2.0 3.1 - - Stinson et al.
1 day (1989)
Macaque monkey < 2 months, 1.1 4.4 (o) - - Vahter et al.
1 day (1994)
Macaque and < 2 months, 0.45 3.1 12 47 Kawasaki et
rhesus monkeys 1 day al. (1986)
Pig Single dose, 0.39 3.3 12 17 Gyrd-Hansen
28 days (1981)
Pig 4-10 doses, 1.8 1.8 (c) 11 8.5 Platonow
1 day (1968)
Rabbit Single dose, 0.08 5.4 10 17 Petersson et
7 days al. (1989)
Cat < 2 months, 14 2.1 (cc) 5.2 2.6 Charbonneau
1 day et al. (1974)
Guinea-pig < 2 months, 3.4 1.8 (of) 8.2 21 Iverson et al.
1 day (1974)
Table 1. (cont'd)
Species Treatmenta Blood Organ:blood ratio Reference
Brain Liver Kidney
Guinea-pig Single dose, 3.5 1.3 4.0 6.7 Iverson et al.
7 days (1973)
Rat, male Single dose, 3.5 0.08 - 1.2 Farris et al.
7 days (1977)
Rat, female Single dose, 36 0.08 0.4 1.1 Fang (1980)
Rat, male Single dose, 3.6 0.08 0.23 1.2 Thomas et al.
Rat, female 4-10 days 3.3 0.10 0.25 2.0 (1986)
Rat, male 4-10 doses, 40 0.07 (c) 0.3 1.7 Friberg (1959)
Rat, female < 2 months, 95 0.07 0.03 1.2 Magos &
1 day Butler (1976)
Hamster Single dose, 1.5 1.9 4.2 10 Omata et al.
16 days (1986)
Hamster 4-10 doses, 9.0 3.8 (cc) 5.5 9.8 Omata et al.
9 days (1986)
Table 1. (cont'd)
Species Treatmenta Blood Organ:blood ratio Reference
Brain Liver Kidney
Hamster Single dose. 1.7 2.5 5.1 12 Petersson et
7 days al. (1989)
Mouse, CBA Single dose, 0.17 0.77 3.2 14 Kostyniak
Mouse, CWV 8 days 0.04 1.4 3.3 16 (1980)
Mouse, NMRI, male Single dose, 0.05 0.9 8.1 20 Nielsen at al.
Mouse, NMRI, female 14 days 0.21 0.6 4.1 3 (1994)
c, cerebrum; cc, cerebral cortex; o, occipital pole; of, occipital and frontal lobes
a Type of dosing and number of days between last or single dose and sacrifice
Histochemical localization (by silver amplification) of mercury
showed a different distribution. The first deposits of mercury in rat
brain became apparent 10 days after exposure to 16 mg/L of
methylmercury chloride in drinking-water. The deposits were found
initially in the brain stem, then in the cerebral cortex and
supraoptic nucleus, and finally in the cerebellum and thalamus. After
20 days, the deposits in the cerebellar cortex were restricted to
Purkinje cells and Golgi epithelial cells and those in the spinal cord
to the anterior motor neurons; the granule cells of the cerebellar
cortex remained unstained (Moller-Madsen, 1990, 1991). Similar
staining was seen after daily intraperitoneal administration of
methylmercury chloride at 0.16-0.8 mg/kg bw (Moller-Madsen, 1990). As
the cerebellar granule cells are target cells for methylmercury
(Chang, 1977), the absence of staining indicates that only
demethylated mercury can be detected with the silver amplification
method. When the cortex of the calcarine sulcus of macaque monkeys was
stained by the same method, large deposits were seen in the astrocytes
and microglia after six months, whereas staining of neurons appeared
later and remained faint even after 18 months (Charleston et al.,
1995). In squirrel monkeys given weekly doses of [3H]methylmercury,
the amount in protein increased, and it was found in damaged but not
in undamaged neurons (Berlin et al., 1975a).
2.1.3 Transfer from mothers to offspring
220.127.116.11 Placental transfer
Methylmercury passes about 10 times more readily through the
placenta than other mercury compounds, like mercuric mercury and
phenylmercury (Suzuki et al., 1967). Consequently, when 2 mg of
methylmercury chloride were infused intravenously into female rats,
the whole-body retention 1 h later was higher in pregnant than in
non-pregnant rats, but the deposition in blood, kidney, liver, and
brain was lower, as the fetus acted as a sink for methylmercury
(Aschner & Clarkson, 1987). When pregnant rats were given a single
(King et al., 1976) or multiple doses of methylmercury (Magos et al.,
1980a), the fetal content of mercury increased daily, with no increase
in the fetal concentration.
The concentration ratio in fetal brain:maternal brain is > 1,
except in hamsters given a single dose of mercury at 0.32 mg /kg bw on
day 2 or 9 of gestation. One day before parturition, the maternal
brain concentration was higher than that of the fetus (Dock et al.,
1994a). In macaque monkeys (Stinson et al., 1989), rats (Satoh et al.,
1985a), and mice (Satoh & Suzuki, 1983) given longterm dietary
exposure to methylmercury, the concentration of mercury in fetal brain
consistently exceeded that of maternal brain by a factor of 1.5.
Similarly, when methylmercury was given to dams during gestation,
1.7-4.8 times higher concentrations were found in fetal than in
maternal brain in rats (Null et al., 1973; Aaseth, 1976; King et al.,
1976) and mice (Inouye et al., 1985), although the ratio to whole-body
concentration. was 1 in rats (Magos et al., 1980a) and < 1 in mice
The fetal:maternal concentration ratio was slightly > 1 in liver
and 0.3-0.5 in kidney (King et al., 1976; Wannag, 1976; Inouye et al.,
1986), and the ratio in blood was 1.1 (Burbacher et al., 1984) or 1.2
in macaque monkeys (Stinson et al., 1989) and 0.6 in rats (Wannag,
1976). In contrast to animals, the fetal: maternal blood ratio in
humans is high. Thus, the cord blood:maternal blood ratio in Inuits
with a high consumption of marine foods (Hansen et al., 1990) and in
Swedish women who ate large amounts of fish (Skerfving, 1988) was 3.2.
In the offspring of squirrel monkeys exposed to methylmercury,
the highest concentration in the brain was found in the pituitary
gland, followed by caudatus, striatum, thalamus, cerebrum, cerebellum,
medulla, and cervical spinal cord (Lögdberg et al., 1993). In rats,
the concentration was higher in the cerebellum than in the cerebrum
(Yamaguchi & Nunotani, 1974; King et al., 1976).
The passage of methylmercury from blood to milk is low, in
contrast to passage through the blood-brain and blood-placenta
barriers. The average concentration ratio for milk:maternal blood was
0.2 in hamsters (Nordenhäll et al., 1995a), 0.03 in guinea-pigs
(Yoshida et al., 1994), and 0.04 in mice (Sundberg et al, 1998a) and
rats (Sundberg et al., 1991). Inorganic mercury passes more readily
into milk than methylmercury: after injection of equivalent doses of
inorganic and methylmercury, the concentration of mercury in the milk
was five times higher with the inorganic form in lactating mice
(Sundberg et al., 1998b) and 2.5 times higher in guinea-pigs. In
guinea-pigs, the milk:maternal blood concentration ratio was 0.12 for
inorganic mercury and 0.023 for methylmercury, but the milk:plasma
concentration ratios were similar (Yoshida et al., 1994). One
consequence of the difference in the passage of inorganic and
methylmercury is that mothers poisoned with the organic form had 95%
less mercury in their milk than in their blood, and 40% of the mercury
in milk was inorganic (Bakir et al., 1973). This tendency was
confirmed in studies on women who ate large quantities of fish
(Skerfving, 1988; Oskarsson et al., 1996) and in experimental animals
(Nordenhäll et al., 1995b; Sundberg et al., 1998a,b).
In the milk of hamsters, the concentration of mercury decreased
with a half-time of four days, and 5% of the injected dose was
excreted in milk. The proportion of inorganic mercury in milk was 16%
on the first day and 22% after five to six days (Nordenhäll et al.,
1995a). An average of 1.7% of a maternal dose given on the day of
parturition was transferred to a litter (Nordenhäll et al., 1995b).
In suckling pups of mouse dams given a single intravenous
injection of methylmercury chloride at 0.4 mg/kg bw, the
concentrations of mercury in plasma and brain peaked after six to
seven days. While that in plasma then immediately decreased, the
concentration of mercury in brain showed no variation for a further
four days (Sundberg et al., 1998a). In pups of hamster dams given a
single dose of 3.2 mg/kg bw methylmercury chloride by gavage on the
day 1 post partum, the whole-body and tissue concentrations of
mercury increased for 10-15 days and then decreased. When the pups
were 21 days of age, 50% of the body burden was in the pelt
(Nordenhäll et al., 1995a).
The body burden of mouse pups was increased to a lesser extent by
exposure during lactation than by exposure in utero. In
cross-fostering studies, the body burden at 14 days of age was twofold
higher in pups exposed in utero than in those exposed by lactation
(Nielsen & Andersen, 1992). Similar differences were observed in
hamster pups (NordenhäIl et al., 1998).
Although loss of methylmercury during lactation is too small to
affect maternal clearance, the clearance half-time was significantly
lower in lactating women (Greenwood et al., 1978), rats (Magos et al.,
1981), and mice (Greenwood et al., 1978) than in non-lactating ones.
In animals, mercury is cleared by three main routes: in urine,
faeces, and hair. Faecal excretion predominates over urinary
excretion. While in humans excretion in hair is important only for
biological monitoring, in furry animals this route of excretion can
strongly alter clearance from the whole body and from toxicologically
important soft tissues (Table 2).
In volunteers who ingested a single dose, faecal excretion
reached a peak faster than urinary excretion; faecal excretion peaked
at 3% and urinary excretion at 0.11% of the dose (Miettinen, 1973). In
another study, the cumulative faecal excretion was 31% and urinary
excretion was 4% of the dose (Smith et al., 1994). In pigs, the ratio
of cumulative faecal:urinary excretion during the first 15 days after
a single dose was 17 (Gyrd-Hansen, 1981); in rats, the ratio was 4.8
in the first three days (Swensson & Ulfvarson, 1967). The ratio
decreased in rats with increasing dose and prolonged exposure (Magos &
Butler, 1976). In hamsters given a low dose, the ratio was 2.1 (Dock
et al., 1994a), while urinary excretion was greater than faecal
excretion after a renally toxic dose (Petersson et al., 1989),
probably because of loss of mercury with desquamated tubular cells.
Reports of concentrations in excreta also suggest the importance
of faecal over urinary excretion, if it is assumed that the difference
in volume (or mass) is not great. The faecal:urinary concentration
ratio was 100 for squirrel monkeys (Berlin et al., 1975a) and 50 for
cats (Hollins et al., 1975). Although faecal and urinary excretion
could be used to calculate the clearance half-time for the whole body,
this method (like chemical or radiochemical estimation of whole-body
burden) results in an underestimate of clearance from the
toxicologically important soft tissues in furry animals. In rats given
repeated oral doses of methylmercury, the contribution of blood to the
body burden declined to 28% and the contribution of the pelt increased
to 38% (Magos & Butler, 1976); 98 days after a single dose, the body
burden represented 12% of the dose and nearly 90% of the body burden
was in the fur (Farris et al., 1993). In hamster pups exposed to
methylmercury either in utero or by lactation, 80% of the body
burden was in the pelt by 28 days of age (Nordenhäll et al., 1998).
Correction for mercury in fur (Table 2) decreased the clearance
half-time by 33% in cats and by 44% in rats. As the only toxicological
significance of methylmercury in fur is as a source of intake during
grooming (Farris et al., 1993), the clearance half-time in blood is
more meaningful than that in the whole body; however, even values
based on total mercury result in underestimates of clearance since
decomposition is ignored. Clearance half-times show wide interspecies
variation, depending on the body mass of the species: the larger the
body mass, the longer the clearance half-time.
In adult mice exposed to unlabelled methylmercury before and
after a single dose of [203Hg]methylmercury, the clearance of
radiolabelled compound was not affected (Nielsen & Andersen, 1996).
Similarly, in rats, the biliary excretion of labelled mercury was not
influenced by treatment with unlabelled compound (Cikrt et al., 1984),
indicating complete distribution of label between the first and second
Clearance from offspring is slow during the first weeks of life.
Thus, the body burden of rats declined by 5% of the dose during the
first 10 days and by a further 25% during the next 12 days (Thomas et
al., 1988). Suckling hamsters (Nordenhäll et al., 1998) and mice
(Rowland et al., 1983; Sundberg et al., 1998a,b) show similar changes
in distribution and clearance.
Table 2. Clearance half-times (days) of methylmercury
Species Compartment Reference
Whole body Brain Blood
Human 72 - - Aberg et al. (1969)
- - 52 Kershaw et al. (1980)
74 - 50 WHO (1990)
44a - 44a Smith et al. (1994)
Squirrel monkey 134 - 49 Berlin et al. (1975b)
Macaque monkey - 47 14 Rice et al. (1989)
- - 24 Stinson et al. (1989)
- - 26 Vahter et al. (1994)
Pig - - 27 Gyrd-Hansen (1981)
Sheep - - 14 Kostyniak (1983)
Cat - - 39 Charbonneau et al.
117 (76b) - - Hollins et al. (1975)
Guinea-pig - - 13 Iverson et al. (1973)
Rat, female 34 26 14 Magos & Butler (1976)
Rat, male 24 - - Farris et al. (1993)
Rat, male 13a - 11 Farris et al. (1993)
Rat, male 11a,b - - Farris et al. (1993)
Hamster 7.7 - - Dock et al. (1994a)
Mouse, female 7.3 - - Clarkson et al. (1973)
Mouse, CR1:CD, - - 7 - Sundberg et al. (1998a)
Mouse, CBA, male approx. 1 7.4 - Kostyniak (1980)
Mouse, CFW, male 3.0 - - Kostyniak (1980)
Mouse, BALB/c, male - 15 5.0 Doi & Kobayashi (1982)
Mouse, C57Bl, male - 16 7.8 Doi & Kobayashi (1982)
Mouse, NMRI, male 6.3 - - Nielsen & Andersen (1991)
Mouse, NMRI, female 14 - - Nielsen & Andersen (1991)
a Clearance includes decomposition to inorganic form
b Half-time for whole body without hair
2.1.5 Biochemical aspects
18.104.22.168 Cleavage of carbon-mercury bond
Methylmercury is the most stable organic mercury compound. The
addition of even one carbon to the alkyl radical can accelerate
decomposition in brain and other tissues (Magos et al., 1985a).
The bond between the alkyl radical and mercury can be broken by
hydroxy radicals (Suda & Hirayama, 1992) and other reactive oxygen
species (Suda & Takahashi, 1992), which attack ethylmercury more
readily than methylmercury.
In rats given a single dose of methylmercury, the 1:1 ratio of
organic: inorganic mercury was reached after 50 days in liver and
after 14 days in kidney, the main site of accumulation of inorganic
mercury. Inorganic mercury represented less than 4% of the mercury in
brain during the first 23 days after a single dose (Norseth &
Clarkson, 1970) and only 3.4% after prolonged daily treatment (Magos &
Inorganic mercury in the brain is most likely formed by
decomposition in situ, as pretreatment with methylmercury did not
increase the concentration of mercury in the brains of rabbits treated
with inorganic mercury (Dock et al., 1994b). The slower clearance from
the brain may explain the 88% increase in the contribution of
inorganic mercury to total mercury in the brains of macaque monkeys
six months after a long exposure (Lind et al., 1988; Vahter et al.,
1994), and the concentration of inorganic mercury in the hypothalamus
was 6.6 times higher than that in monkeys exposed to inorganic mercury
for two to three months (Vahter et al., 1994).
The main site of decomposition of methylmercury is the intestinal
tract, where the portion secreted with bile or with cells shed from
the intestinal wall is decomposed and the remainder is reabsorbed
(Norseth & Clarkson, 1971). Most of the decomposition is carried out
by intestinal bacterial flora; disruption of this bacterial activity
by antibiotics prolonged the clearance half-time and decreased faecal
excretion in both rats and mice (Rowland et al., 1980, 1983). Both
demethylation and methylation occur. Caecal bacteria from rats
methylated 2.3% of inorganic mercury at a dose of < 0.1 µg/g and less
of doses > 0.1 µg/g (Rowland et al., 1977). Extrapolation of this
rate of synthesis to human populations with intakes of 4.6 µg of
inorganic mercury and 2.4 µg of organic mercury would add only 0.1 µg
to the daily intake of methylmercury.
The biliary excretion of methylmercury varies by species:
hamsters, rats, and mice excrete it readily, while guinea-pigs and
rabbits excrete 5 and 25 times less. The 'slow excretors' also
excreted significantly less reduced glutathione (GSH) than the 'fast
excretors' (Stein et al., 1988). Biliary excretion also depends on
age: in rats, the ability to excrete GSH and methylmercury develops
between 2 and 4 weeks of age (Ballatori & Clarkson, 1982).
22.214.171.124 Complexes with thiol radicals
Mercury compounds favour links with thiol ligands. Thiols of low
relative molecular mass offer transport, and those of high relative
molecular mass within cells offer anchorage for methylmercury,
targeting sulfydryl enzymes (Rothstein, 1970). The change from one
ligand to another ensures that diffusable thiol compounds can carry
methylmercury from the extracellular space to intracellular proteins
and vice versa. The high concentration of GSH within erythrocytes
suggests that exchange occurs between protein and GSH in these cells
(Rabenstein & Evans, 1978); however, other diffusable thiols, such as
cysteine, and unphysiological ones such as pencillamine,
N-acetylpenicillamine, and N-acetylcysteine, removed methylmercury
from erythrocytes when their concentration approached the
concentration of GSH (Kostyniak et al., 1975).
Complexing with L-cysteine or glutathione has particular
toxicological significance. In rats, injection of L-cysteine with
methylmercury changed the short-term distribution of the latter by
decreasing the plasma concentration and increasing the concentrations
in brain, liver, and kidney. D-Cysteine had similar effects but did
not increase the concentration of mercury in brain (Thomas & Smith,
1982). GSH had less effect on the brain uptake of methylmercury than
L-cysteine (Kerper et al., 1992). Increased uptake by brain was also
achieved by administration of a cysteine-supplemented diet (Farris et
al., 1977). The stimulatory effect of L-cysteine may be due to the
structural similarity between the methylmercury-cysteine complex and
L-methionine, which permits use of the same L-amino acid transport
system (Kerper et al., 1992). L-Cysteine can also increase the biliary
excretion of methylmercury, after a delay for conversion to GSH (Magos
et al., 1978).
GSH plays a key role in biliary secretion of methylmercury.
Consequently, compounds that deplete GSH decrease and compounds that
stimulate glutathione S-transferase increase the biliary excretion of
both GSH and methylmercury (Gregus & Varga, 1985). This effect is
modulated by the transport molecule ligandin (a glutathione
S-transferase): the biliary excretion of methylmercury was inhibited
by indocyanine green, a non-substrate ligand for ligandin (Magos et
al., 1979a). trans-Stilbene oxide, which induces glutathione
S-transferase activity, had no effect on the biliary excretion of GSH
or methylmercury (Gregus & Varga, 1985) but potentiated the effect of
GSH in rats (Magos et al., 1985b). The excreted methylmercury is
attached to GSH (Refsvik & Norseth, 1975) or to its metabolic product
(Ohsawa & Magos, 1974; Urano et al., 1988).
GSH also affects the renal handling of methylmercury. Depletion
of hepatic GSH by 1,2-dichlorobenzene resulted in a reduced blood GSH
concentration and a reduced renal content of methylmercury. Inhibition
of renal gamma-glutamyl-transpeptidase, a membrane enzyme that
catalyses the breakdown of GSH, decreased the renal deposition and
increased the urinary excretion of methylmercury. The sex difference
in the renal handling of methylmercury in some mouse strains may also
depend on the concentration and metabolism of renal GSH (Tanaka
et al., 1991)
Physiological agents that complex thiols do not affect urinary
excretion or whole-body clearance (Magos & Clarkson, 1976), while
unphysiological thiols of low relative molecular mass, such as
penicillamine, N-acetylpenicillamine, dimercaptosuccinic acid, and
dimercaptopropanesulfonate, accelerate clearance in both humans
(Clarkson et al., 1981) and experimental animals (Aaseth., 1976;
Magos, 1976; Planas-Bohne, 1981). Although clearance was accelerated
by dimercaptopropanol, this chelator consistently increased the
deposition of methylmercury in the brains of mice (Berlin et al.,
1965; Ogawa et al., 1976). Thiol-complexing agents mobilize
methylmercury more efficiently than inorganic mercury, as shown with
dimercaptosuccinic acid and penicillamine in mice (Friedheim & Corvi,
1975) and pencillamine in volunteers (Suzuki et al., 1976).
126.96.36.199 Interaction with selenium
Methylmercury has a greater affinity for selenium than for
sulfur, and the reaction of selenite with thiol groups such as GSH and
the sulfur radicals of proteins extends the possibility of
associations between selenium and methylmercury. The effects of
selenite cannot be extrapolated to the effects of selenium present in
food, however, because of differences in their decomposition to
selenide in food. Thus, selenite is twice as potent as
L-selenomethionine in forming volatile dimethylselenide (McConnel &
Roth, 1977) and four times as potent as selenium-enriched liver in
forming mercury-selenium complexes (Magos et al., 1983). The rate of
selenide formation from selenite is important in the formation of an
unstable adduct, bis(methylmercury)selenide, which carries
methylmercury through the blood-brain barrier (Magos et al., 1979b;
Naganuma & Imura, 1980). The availability of selenide for this
reaction is limited by methylation to dimethyl-selenide, which is
stimulated by methylmercury (Yonemoto et al., 1985).
Selenite can change the distribution of methylmercury in rats by
decreasing deposition in kidney and increasing deposition in brain,
independently of whether selenite is given 30 min before (Chen et al.,
1975), simultaneously with, or even days after methylmercury (Magos &
Webb, 1977). Both low (0.6 mg/L) and high (3 mg/L) concentrations of
selenium in drinking-water increased the uptake of mercury in the
brains of mice, the high dose more persistently than the low dose
(Wicklund Glynn & Lind, 1995). Within the brain, selenium did not
alter the subcellular distribution of methylmercury, while the mercury
compound shifted selenium from the cytosol to the mitochondrial
fraction (Prohaska & Ganther, 1977).
Selenite increased the fetal brain content of mercury without
increasing the fetal concentration, depending on the dose of
methylmercury given to mouse dams (Satoh & Suzuki, 1979). The
concentration of mercury in rat fetal brain was also unchanged by 1.3
mg/kg of selenite when the dams were given 1.6 or 4.8 mg/kg bw as
methylmercury on days 6-9 of gestation, although the fetal blood
concentration of mercury was increased by 1.4-and 2.8-fold,
respectively (Frederiksson et al., 1993). Seleno-L-methione had no
effect on the deposition of methylmercury in pups exposed prenatally,
but it increased the deposition of mercury in nearly all organs after
exposure during lactation (Nielsen & Andersen, 1992, 1995).
The role of selenite in the degradation of methylmercury is
amibiguous. Addition of selenite to liver homogenates for 90 min
increased the decomposition of phenylmercury but not of methylmercury
(Fang, 1974). Selenite in the presence of a reducing agent like GSH
(Iwata et al., 1982), cysteine (Baatrup et al., 1989), or hydroquinone
in vitro (Moller-Madsen & Danscher, 1991) induced some
decomposition, but the conditions were not physiological. Six months
after exposure of macaque monkeys to methylmercury for 12 months, the
concentration of inorganic mercury had declined, while the
concentration of selenium remained unchanged (Björkman et al., 1994),
which argues against a role for selenium in cleavage of methylmercury
in the brain. The final molar ratio of inorganic mercury to selenium
in these monkeys was 0.5. In contrast, persistent deposits with a 1:1
molar ratio were found in organs of rats treated with inorganic
mercury and hydrogen selenide (Groth et al., 1976), in the livers of
marine mammals (Koeman et al., 1973; Martoja & Viale, 1977), and in
the brains of retired mercury miners (Kosta et al., 1975).
2.2 Toxicological studies
2.2.1 Acute toxicity
Although methylmercury is almost completely absorbed from the
gastrointestinal tract, the enteric and parenteral LD50 values differ
widely. Thus, the LD50 values 24 h after intraperitoneal injection
were 9.5 mg/kg bw in rats, 20 mg/kg bw in hamsters, and > 14 mg/kg bw
in squirrel monkeys; after 30 days, the values were 8.1, 12, and
3.8-5.1 mg/kg bw, respectively. In these three species, most of the
deaths occurred within the first 24 h (Hoskins & Hupp, 1978). The
LD50 values after oral administration were 25 mg/kg bw in old rats
(450 g bw) and 40 mg/kg bw in young rats (200 g bw) (Lin et al.,
The difference in the LD50 values after administration by these
two routes may reflect the corrosive effect of methylmercury at the
site of contact. The risk of corrosion depends on the route of
administration, and it decreases in the order intraperitoneal =
subcutaneous > intubation > dose given in a small volume of water or
juice > supplemented food. The importance of corrosion is supported
by the dramatic reaction seen in rats 15 min after intraperitoneal
injection of doses > 3 mg/kg bw: the animals became lethargic, with
drooping heads and dulled eyes; some died after developing dyspnoea,
spasticity, and loss of the ability to walk. Animals given < 3 mg/kg
bw became drowsy but survived (Hoskins & Hupp, 1978). The rapidity of
this reaction suggests a corrosive effect and shock. The corrosive
effect is also reflected by the ulcerative oesophagitis seen in cats
dosed orally with methylmercury at 1.3 mg/kg bw per day (Davies &
Nielsen, 1977) and by the necrosis, oedema, and congestion of the
stomach in dogs dosed with 0.43 or 0.64 mg/kg bw per day (Davies et
al., 1977) and in pigs given 0.64 or 0.86 mg/kg bw per day (Davies et
al., 1976). All the affected animals also had renal and hepatic
These local effects should be taken into consideration in
interpreting more subtle outcomes. In rats dosed orally for two days
with 12 mg/kg bw per day as mercury or 8 mg/kg bw per day as
methylmercury chloride, decreased wakefulness and increased slow-wave
sleep peaked three days after the second dose, while the brain mercury
concentration peaked after nine days (Arito & Takahashi, 1991). A
confounding role of gastrointestinal inflammation could not be ruled
out. A reduced ability of mice to stand on their hind legs and to
move, seen 1 h but not 72 h after an intraperitoneal injection of 10
mg/kg bw as methylmercury chloride (Salvaterra et al., 1973),
indicates peritoneal irritation and possibly peritonitis rather than
2.2.2 Renal and hepatic toxicity
Experiments in mice suggest that males are more sensitive than
females. In long-term experiments, the incidence of chronic
nephropathy was higher in male than in female mice given diets
containing 10 mg/kg (equivalent to 1.5 mg/kg bw per day), and only
male mice had nephropathy when given 2 mg/kg in the diet (Hirano et
al., 1986; Mitsumori et al., 1990).
Clinical signs of neurotoxicity induced by methylmercury are
always accompanied by renal damage. In female rats dosed orally five
times a week with 0.84 mg/kg bw as methylmercury dicyandiamide for
8-12 weeks, the renal cortex was extensively damaged, with desquamated
cells in the tubules and inflammatory reactions and fibrosis in the
surrounding area. At the end of treatment, mild ataxia was observed in
some but not all animals (Magos & Butler, 1972). Male rats receiving
0.8 mg/kg bw per day as methylmercury chloride developed severe
diarrhoea and loss of appetite after two to four days, and necropsy
after 10 days of treatment showed ultrastructural changes in the pars
recta of the proximal tubules (Ware et al., 1975). Differences in the
time of onset of renal damage rather than in its severity were seen in
male rats given 8.5 or 1.7 mg/kg bw per day as methylmercury
hydroxide: renal lesions, mainly in the proximal tubules, were seen
one day after the last high dose and six days after the low dose
(Klein et al., 1973).
In comparisons of renal toxicity, male rats were usually more
sensitive than females, as indicated by increased serum creatinine
concentration and decreased bromosulphthalein excretion after single
oral doses of methylmercury chloride ranging from 4 to 40 mg/kg bw
(Yasutake et al., 1991); proteinurea in rats fed diets containing
methylmercury chloride at 0.5, 2.5, or 25 mg/kg for 12 weeks
(Verschuuren et al., 1976a); and deaths and renal lesions in rats
given 0.05 or 0.25 mg/kg bw per day as methylmercury chloride in food
(Munro et al., 1980). No difference in renal morphology was found
between the sexes after exposure to 2.5 mg/kg of diet for two years
(Verschuuren et al., 1976b), although the results suggested that
females were more sensitive than males to diets containing 2 mg/kg of
methylmercury chloride (equivalent to 0.2 mg/kg bw per day) for 84 or
142 days (Fowler, 1972).
The effect of methylmercury on the liver can be rapid and
lasting. Ultrastuctural changes were detected in the liver 1 h after a
single subcutaneous dose of 8 mg/kg bw as methylmercury chloride to
male rats, which developed into cytoplasmic degeneration during the
first day (Desnoyers & Chang, 1975). Similar changes were seen in the
livers of cats fed tuna fish containing 0.3-0.5 mg/kg of mercury daily
for 7-11 months (Chang & Yamaguchi, 1974).
A frequent response to methylmercury in experimental animals is
anorexia resulting in decreased weight gain or even loss of weight.
Anorexia precedes the neurological signs of methylmercury poisoning in
rats (Hunter et al., 1940; Herman et al., 1973), rabbits (Jacobs et
al., 1977), guinea-pigs (Falk et al., 1974), and mice (McDonald &
Harbison, 1977). In cats (Davies & Nielsen, 1977) and non-human
primates (Shaw et al., 1975; Evans et al., 1977), anorexia occurred
only after the onset of disorders of coordination and vision.
188.8.131.52 Small rodents
The species studied most extensively for neurotoxicity is the
rat, and few experiments have been conducted on other species.
Guinea-pigs were used to study the effect of methymercury on the
cochlea. Five weekly doses of 1.7 mg/kg bw as methylmercury hydroxide
for two to six weeks decreased body weight and locomotor activity and
damaged the outer rows of hair cells of the cochlea at two-and-a-half
turns from the cochlear base. The auditory tract was not damaged (Falk
et al., 1974). In a follow-up study, the damage was localized to the
sensory nerve end (Konishi & Hamrick, 1979).
The role of the granular layer of the cerebellum and the
posterior root fibres as a target of methylmercury was identified in
rats 60 years ago. The report of this study also described the
clinical course of severe poisoning as weight loss, ataxia, paralysis,
and death (Hunter et al., 1940). Axoplasmic and myelin degeneration of
posterior root fibres was produced by daily doses of 0.8 mg/kg bw as
methylmercury chloride (Chang & Hartmann, 1972), while the ventricular
root fibres and the dorsal root nerves remained intact after
administration of 1.6 mg/kg bw per day (Yup & Chang, 1981). The
vulnerability of dorsal root ganglia was explained by the extent and
duration of inhibition of amino acid incorporation (Cavanagh & Chen,
Female rats dosed orally five times a week with 0.84, 1.68, or
3.32 mg/kg bw as methylmercury dicyandiamide showed signs of ataxia
after 39, 25, and 10-12 doses, respectively. Owing to progressive
weakness, animals at the intermediate dose had to be sacrificed after
34 doses and those at the highest dose after 16 doses, when their
brain mercury concentrations were 10 and 16 µg/g, respectively.
Histological examination of the brain showed necrosis in the granular
layer of the cerebellum and, at the two higher doses, oedema in the
white matter; at the low dose, only mild damage involving few cells
was seen even after 59 doses, when the brain mercury concentration was
about 5 µg/g (Magos & Butler, 1972). The lack of damage at this dose
was corroborated by the lack of gross or histological effects in male
rats dosed with 0.8 mg/kg bw per day as methylmercury chloride for 28
weeks. A dose of 4 mg/kg bw per day caused weight loss, early toxic
signs, and decreased protein synthesis in the granule neurones. These
pathological changes were precipitated when the brain mercury
concentration was 3-6 µg/g. At higher concentrations, Purkinje cells
were also affected (Syversen, 1982).
After subcutaneous administration of 2 mg/kg bw as methylmercury
hydroxide five times a week to male rats, the first signs of
coordination disorder were detected after the fifteenth dose. The
earliest morphological change in the central nervous system was
shrinkage of cells and nuclear disintegration in the cerebellar
internal granular layer, the vermis, and the depth of the folia of the
hemispheres. These early changes progressed to more widespread
necrosis involving the putamen, corpus striatum, and the visual cortex
in the occipital lobe. The most severely affected parts of the
peripheral nervous system were the dorsal roots and the sciatic and
sural nerves (Herman et al., 1973). The concentration of mercury on
the fifteenth day was about 30% lower in the cerebral cortex than in
the cerebellum or spinal ganglia, but by day 29 the concentrations in
each of these tissues was nearly 14 µg/g (Somjen et al., 1973b).
Damage to the nervous system resulted in the formation of
autoantibodies that reacted with neurotypic and gliotypic proteins,
such as glial fibrillary acid protein, after seven days of exposure to
13 or 26 mg/kg of mercury as methylmercury chloride in the diet
(El-Fawal et al., 1996).
The dose-effect relationship for neurotoxicity differs in male
and female rats, as suggested by the response to four or five doses of
8 mg/kg bw as methylmercury chloride given by intubation. The flailing
reflex (rotation of the lower body when the animal is held loosely
under the forelimbs), hind-leg crossing, and damage in the granular
layer indicated that female rats were more affected than males. The
difference may be due to the 24-40% higher concentration of mercury in
the brains of female than of male rats (Magos et al., 1981). A
difference was seen also with age: in young rats, an intraperitoneal
injection of 8 mg/kg bw which resulted in approximately 2 µg/g of
brain, the morphological changes in the cerebellar hemisphere were
subtle, including nuclear swelling and increased heterochromatin, were
reversible, and were not accompanied by the formation of dark cells in
the granular layer. In older rats, 'dark cells' were a conspicious
feature (Syversen et al., 1981)
The relative merit of electrophysiology in the grading of
methylmercury poisoning was the subject of several investigations
(Somjen et al., 1973a; Fehling et al., 1975; Miyama et al., 1983). The
results were not consistent, and its advantage over simple clinical
observations remains questionable.
In male mice, dietary intake of methylmercury caused no loss of
body weight when the concentration was 10 mg/kg of diet as
methylmercury chloride, but 32 mg/kg of diet caused loss after 30 days
and 100 mg/kg of diet resulted nearly immediately in weight loss. Mice
at the intermediate dose showed signs of coordination disorders which
coincided with the onset of weight loss. A slight effect on head
positioning was observed earlier. No neurological signs were seen in
mice at the lowest dose (Suzuki & Miyama, 1971). In wild mice exposed
to methyl-mercury in their natural diet, the concentration of mercury
in hair correlated with deviant behaviour and decreased ability to
swim (Burton et al., 1977).
184.108.40.206 Non-human primates
In the first experiment performed on the toxicity of
methylmercury, one female macaque monkey was exposed by inhalation to
a concentration in air that was so high that it caused respiratory
irritation. The clinical events were ataxia, prostration, inability to
eat, and death after 21 days. The main damage to the nervous system
was in the sciatic nerve, posterior root ganglia, brain stem, and
cerebrum, where the frontal and occipital cortices were equally
affected while the cerebellar cortex was spared (Hunter et al., 1940).
Rhesus macaque and mulatta monkeys were given methylmercury in
pellets at doses of 0.01, 0.03, 0.1, or 0.3 mg/kg bw per day for 52
months or until signs of severe poisoning appeared. Exposure to the
lowest dose had no effect on body weight, and 0.03 mg/kg bw per day
depressed body-weight gain only marginally; however, daily doses of
0.1 or 0.3 mg/kg bw per day caused severe poisoning, with ataxia,
visual disturbances, blindness, tremor, spasms, paralysis, and death
or moribund condition at six and three months, respectively. At the
two lower doses, the average monthly concentrations of mercury in
blood between 12 and 52 months were 0.4 and 1.1 µg/ml. The mean
concentrations of mercury in the occipital lobe after 52 months were
0.7 µg/g and 2.3 µg/g at these doses; the cerebellum contained 10-26%
less than the occipital lobe. Histological examination of the brain
showed no abnormalities. In monkeys at the two highest doses, the
concentrations in the occipital lobe were 13 and 24 µg/g; the most
severe lesions were found in the occipital cortex and, within it, in
the primary visual cortex. No changes were seen in the cerebellar
cortex (Ikeda et al., 1973; Kawasaki et al., 1986). In this study, the
threshold dose of methylmercury that induced toxic effects after
long-term exposure was 0.03-0.1 mg/kg bw per day, resulting in
concentrations of mercury of 2-13 µg/g in brain and 0.7-21 µg/ml in
blood. The NOEL was 0.01 mg/kg bw per day.
In corroboration of this finding, daily doses of 0.068-0.085
mg/kg bw as methylmercury hydroxide given orally through a hypodermic
syringe for 68 weeks caused clinical signs or cortical lesions in only
3 of 15 macaque monkeys; the blood concentration of mercury was about
2 µg/ml. A daily dose of 1.1 mg/kg bw, resulting in a maximum blood
concentration of about 3 µg/g, led to death or a moribund condition.
The vision of these three monkeys was also affected (Finocchio et al.,
1980). Another study with macaque monkeys showed loss of peripheral
vision at blood concentrations > 2.2 µg/ml (Luschei et al., 1977).
These concentrations of mercury in blood correspond to 6-10 µg/g in
In squirrel monkeys, the visual cortex was invariably damaged,
and extension to adjacent areas increased with duration of exposure
and increasing brain mercury concentration. In one monkey who was
blinded, the maximum concentration in the occipital lobe 40 days after
termination of exposure was 6.6 µg/g (Berlin et al., 1975b), which,
assuming a 47-day half-time in brain, corresponds to 12 µg/g at the
end of treatment.
In macaque monkeys exposed for a long time but with no clinical
signs of poisoning, sensitivity to visual stimuli of low luminiscene
was reduced when the concentration of mercury was 2.6 µg/ml in blood
and 8.7 µg/g in the primary visual cortex. The concentrations were
somewhat higher in the calcarine side of the primary visual cortex and
in the lateral geniculate of the optic thalamus, where the optic
neurons from the retina are projected onto the primary visual cortex,
than in the lateral side of the occipital cortex. The borderline
between effect and no effect was not sharp: unaffected monkeys had
slightly higher concentrations of mercury in blood and in the
occipital cortex than monkeys that were moderately affected, although
they also were exposed for a shorter time. Constricted vision field,
somaesthetic impairment, and ataxia usually occurred together (Evans
et al., 1977),
The lesions seen in the brains of rhesus monkeys given
methylmercury hydroxide in fruit juice differed when it was given for
6-17 days or for 6.3-12 months. Two of four monkeys exposed acutely
and two of six exposed chronically had no clinical or histological
signs of poisoning. The maximum concentrations of mercury in blood
were < 1.1 µg/ml in unaffected monkeys and > 2.0 µg/ml in affected
monkeys. The two acutely poisoned monkeys had a blood mercury
concentration of 11 µg/ml. After acute poisoning, the most evident
histological lesions were seen in the lateral geniculate nucleus and
in large neurons in several areas. The cerebral and cerebellar
cortices, including the calcarine and insular cortices, were not
involved. Animals exposed chronically had damage to the cerebral
cortex which was maximal around the calcarine and lateral cerebral
sulci (Shaw et al., 1975).
The entry of methylmercury into brain, even at concentrations
below those that cause damage, precipitates an increase in the
reactive glial population. A similar reaction was produced after
infusion of inorganic mercury (Charleston et al., 1994).
220.127.116.11 Domestic animals
Few experiments have been reported on the toxicity of
methylmercury in domestic animals, and even fewer that would allow an
approximation of the threshold toxic dose. The oral dose that had no
effect was 0.1-0.2 mg/kg bw per day for calves exposed for 91 days
(Herigstad et al., 1972), 0.19-0.35 mg/kg bw per day for pigs exposed
for 60 days (Triphonas & Nielsen, 1973), 0.06-0.12 mg/kg per day for
dogs exposed for 55 days (Davies et al., 1977), and < 0.25 mg/kg bw
per day for cats exposed for 90 days, whether present naturally in
fish or added in pure form to the diet (Charbonneau et al., 1974). In
the central nervous system, the damage was more extensive in the
cerebellar granular layer in calves and cats and in the cerebral
cortex in pigs and dogs.
In rabbits given one to four doses of mercury at 5.8 mg/kg bw as
methyl-mercury acetate, the most sensitive areas of the nervous system
were the dorsal root and trigeminal ganglia, which showed degeneration
after two doses. In the cerebral and cerebellar cortices, damage was
seen two days after four daily doses. The more severely affected areas
were the II, III, and IV layers of the cerebral cortex and the
molecular and granular layers of the cerebellar cortex, where mainly
the cells of the small neurones, including granule and basket cells,
were damaged and the Purkinje cells spared (Jacobs et al., 1977), as
in a human case of methylmercury poisoning (Hunter & Russel, 1954).
2.2.5 Reproductive and developmental toxicity (other than
Treatment of male mice on seven consecutive days with
methylmercury chloride at doses of 1, 2.5, or 5 mg/kg bw per day
before mating with virgin females had no effect on fertility or
postimplantation losses but marginally reduced the number of viable
embryos (Khera, 1973). Intraperitoneal injection of male mice with 8.5
mg/kg bw per day as methylmercury hydroxide and serial matings with
young virgin females increased the number of dead implants during the
first 7.4 days in one strain but not in another. The same treatment of
females of the unresponsive strain slightly reduced the total number
of live implants (Suter, 1975).
Exposure to methylmercury chloride prolonged the length of the
menstrual cycle by 11% in mice fed 3.2 mg/kg of diet and by 27% at 6.4
mg/kg of diet. Exposure from 30 days before mating to day 18 of
gestation decreased maternal weight gain at the high dose. The loss
due to resorptions and deaths increased from 7.1% in the control group
to 12% in mice at 3.2 mg/kg of diet and to 44% at 6.4 mg/kg of diet.
The weight of fetuses on day 18 of gestation was also lowered. Both
doses increased the frequency of malformations to 17% of fetuses at
the low dose and 56% at the high dose (Nobunaga et al., 1979). A
follow-up experiment confirmed that exposure to 3.2 mg/kg of mercury
in the diet can cause postimplantation loss in some pregnant mice
(Satoh & Suzuki, 1983). If their food consumption is assumed to be 150
g/kg bw per day, the daily doses of methylmercury were 0.48 and 0.96
mg/kg bw. When selenite was added to the drinking-water in these two
studies, no effect was seen on postimplantation loss but the number of
malformations was increased, at least at the high dose.
Treatment of mouse dams on days 6-17 of gestation with 5 mg/kg bw
per day as methylmercury chloride by intubation reduced the number of
live pups, and pups born live died within two days. The number of live
pups and survival were not affected by 1 mg/kg bw per day, but there
was transitory inhibition of cerebellar cellular migration from the
external granular layer (Khera & Tabacova, 1973). When methylmercury
chloride was given orally on days 6-13 of gestation, the lowest dose
of 2 mg/kg bw per day caused only a few malformations, 4 mg/kg bw per
day decreased fetal weights and caused a large increase in the
frequency of malformations, and 4.8 mg/kg bw per day also increased
postimplantation loss (Fuyuta et al., 1978).
Postimplantation loss was not observed when dams were given 3, 5,
or 7 mg/kg bw per day as methylmercury chloride subcutaneously on days
13-15 of gestation, but the postnatal survival rates were 30%, 22%,
and 0, respectively (Nishikido et al., 1987). The outcome was similar
when mouse dams were given 16 mg/kg bw per day as methylmercury
chloride orally on one of days 13-17 of gestation. Postimplantation
loss was slight or nil, but only 11% of the liveborn pups survived for
eight weeks, apparently as a consequence of their inability to suck.
The spontaneous locomotor activity of live pups was depressed between
3 and 8 weeks, they had defects in righting and tail position, and, at
the end of 8 weeks, they had smaller brains than controls (Inouye et
al., 1985). Starvation, undernourishment, and the consequent general
weakness were probable contributory factors.
Long-term intake of 2.5 mg/kg of diet as methylmercury chloride
increased testicular but not ovarian weights in rats (Verschuuren et
al., 1976c). Exposure of males and females had no effect on fertility,
but the viability of their offspring was impaired (Verschuuren et al.,
1976b). If their daily food consumption is assumed to be 100 g/kg bw,
the daily dose was 0.25 mg/kg bw. Exposure of female rats to
methylmercury chloride at 8 mg/kg of diet from weaning until delivery
did not affect litter size, the frequency of stillbirths, birth
weight, survival, or weight gain up to weaning (Nixon, 1977).
The mating success of male rats declined by seven days after oral
treatment with methylmercury chloride at 2.5 or 5 mg/kg bw per day but
not at 1 mg/kg bw per day. The number of viable embryos per litter
decreased transiently when 2.5 or 5 mg/kg bw per day was given for
seven days, 1 mg/kg bw per day for 35 days, or 0.5 mg/kg bw per day
for 90 days (Khera, 1973).
Oral treatment of female rats with 0.25 mg/kg bw per day as
methylmercury chloride from weaning had no apparent adverse effect on
fetuses, and the only abnormality seen postnatally was eyelid lesions
associated with hardening of the lachrymal glands. A dose of 0.05
mg/kg bw per day had no effect (Khera & Tabacova, 1973).
Higher doses were usually used when administration was restricted
to the gestation period. In rats given 2, 4 or 6 mg/kg bw per day as
methylmercury chloride orally on days 7-14 or 18-20 of gestation,
resorptions, deaths, and malformations were observed at 6 mg/kg bw per
day. Malformations consisting mostly of cleft palate and vertebral
defects were seen in the offspring of dams at the two higher doses
(Fuyuta et al., 1978). When a single oral dose of 8, 16, or 24 mg/kg
bw as methylmercury chloride was given orally in saline on day 7 of
gestation, maternal body weight declined at all doses. The decrease in
the number of live fetuses on day 20 of gestation was 60% at 8 mg/kg
bw and > 90% at 16 mg/kg bw. A dose-dependent decrease in
ossification centres was seen. The concentrations of mercury in
maternal brain were 2.6, 9, and 21 µg/g, and those in fetal brain were
3.5, 11, and 15 µg/g (Lee & Han, 1995).
In hamsters, a single subcutaneous dose of 6.4 mg/kg bw as
methylmercury chloride on day 3, 5, or 9 of gestation caused some
maternal deaths, a high incidence of resorptions, decreased fetal
weights, and moderate to severe malformations, consisting mainly of
clubfoot and hydrocephalus. A dose of 1.6 mg/kg bw had no visible
effect on dams or offspring, but when given on days 1-14 of gestation
it increased the numbers of maternal deaths, resorptions, and
malformations although it did not decrease fetal weights (Harris et
In macaque monkeys, a daily oral dose of 50 or 70 µg/kg bw as
methylmercury hydroxide in fruit juice for 20 weeks decreased sperm
motility and increased the frequency of abnormal sperm tail forms,
with no significant change in serum testosterone concentration or
testicular morphology (Mohamed et al., 1987). In females given doses
including 90 µg/kg bw per day, exposure did not affect the menstrual
cycle, conception rate, or size of offspring at birth, but a maternal
blood concentration > 1.5 µg/ml decreased the number of viable
deliveries (Burbacher et al., 1988), and a concentration > 2 µg/ml
was toxic to the dams (Burbacher et al., 1984, 1988).
2.2.5 Developmental neurotoxicity
18.104.22.168 Exposure in utero
Mouse dams were given methylmercury hydroxide subcutaneously as a
single dose of 5.1, 6.8, or 10 mg/kg bw on day 10 of gestation. As the
rate of mortality of the neonates of dams treated with 10 mg/kg was
high, an additional group of dams were given 3.4 mg/kg bw on days
10-12. Central latency in the open-field behaviour test was increased
in the pups of dams given 10 mg/kg bw as a single or three divided
doses. Locomotion was decreased by exposure to 6.8 and 10 mg/kg bw at
postnatal day 24 but not at day 44 (Su & Okita, 1976). The righting
reflex and walking ability lagged behind those of controls
consistently in the pups of dams given 6.8 mg/kg bw subcutaneously on
day 9, but the difference was not significant (Satoh et al., 1985b).
Methylmercury given at a dose of 3.2 mg/kg bw to pregnant rats on
day 8 of gestation caused no significant change in the appearance of
pups, but samples of calcarine and cerebellar cortices, especially in
the granule cells of the cerebellum, showed focal weakening of the
nuclear envelope, myelin figure formation, focal cytoplasmic
degradation, and phagocytosis of cellular debris by macrophages (Chang
et al., 1977). In pups of hamster dams given methylmercury chloride
either as a single dose of 8 mg/kg bw on day 10 of gestation or 1.6
mg/kg bw daily on days 10-15, the early cerebellar changes were seen
in the external granular layer and in more extensively differentiated
neural elements in the molecular and internal granular layer (Reuhl et
al., 1981a). The sequelae of the early injuries, such as astrogliosis,
may have had clinical or physiological significance when the pups
reached the age of 275-300 days (Reuhl et al., 1981b).
When methylmercury chloride was given by gavage to rat dams at
doses of 0.02, 0.04, 0.4, or 4 mg/kg bw on days 6-9 of gestation, the
highest dose impaired swimming behaviour at 4-35 days of age, and the
doses of 0.04 and 4 mg/kg bw increased passiveness and decreased
habituation to an auditory startle 60-210 days postnatally. The
histological changes seen at the highest dose were mainly in the
dendritic spines of the pyramidal neurones (Stoltenberg-Didinger &
Markwort, 1990). Methylmercury chloride given in apple juice on the
same days of gestation at a dose of 1.6 mg/kg bw per day caused no
change in the clinical markers of adverse effects up to weaning. No
deficits in behavioural function, such as spatial learning in a
circular bath and maze learning for food reward, were seen at four to
five months of age (Frederiksson et al., 1996).
The effect of methylmercury on locomotion is ambiguous. When
given orally to rat dams on day 8 or 15 of gestation at a dose of 4 or
6.4 mg/kg bw, no consistent changes in spontaneous locomotor activity
were seen 4, 8, or 15 days postnatally. Activity was increased on
postnatal day 4 when the low dose was given on day 8 of gestation, on
postnatal day 8 when the low dose was given on day 15 or the high dose
on day 8 of gestation, and on postnatal day 15 when the low dose was
given on day 15 of gestation (Eccles & Annau, 1982a). The higher dose
given on day 15 did not affect locomotor activity on postnatal day 14,
21, or 60 (Cagiano et al., 1990), but 8 mg/kg bw given on day 4 of
gestation depressed locomotor activity at 110-140 days of age.
Avoidance learning was also depressed (Schalock et al., 1980).
The effect of 4 or 6.4 mg/kg bw as methylmercury chloride given
to rats on day 8 or 15 of gestation on two-way avoidance was tested at
nine weeks of age. Exposure increased the number of trials required to
reach the preset criterion; however, owing to variations within
groups, only the higher dose given on day 8 induced a significant
difference in reacquisition and both doses given on day 15 for
acquisition (Eccles & Annau, 1982b). The higher dose given on day 15
decreased the number of cortical muscarinic receptors by 53% in
14-day-old pups and by 21% in 21-day-old pups. Recovery from this
defect was complete at the age of 60 days, but the results of a
passive avoidance test even a few days before that age indicated
learning and memory deficits (Zanoli et al., 1994).
Female macaque monkeys were given methyl-mercury in apple juice
at 0.04 or 0.06 mg/kg bw per day for 198-747 days before mating.
Infants were separated from their mothers at birth and were tested 210
and 220 days after conception (50-60 days after birth). The test
indicated randomness in visual attention to novel stimuli. The mean
maternal blood concentrations at birth were 0.84 and 1.04 µg/ml, and
the blood concentrations of the offspring were 0.88 and 1.7 µg/ml
(Gunderson et al., 1988). The offspring of squirrel monkeys exposed to
methylmercury during the second half or the last third of pregnancy,
with maternal blood concentrations of 0.7-0.9 mg/ml, showed reduced
sensitivity to changes in the source of reinforcement, indicating
learning impairment at five to six years of age (Newland et al.,
22.214.171.124 Exposure in utero and postnatally
Mouse dams were exposed to 3.2 mg/L as methylmercury in
drinking-water from mating to parturition, and their pups were further
exposed up to postnatal day 30 during lactation. The litter weights of
exposed and control pups were similar. Males but not females showed
some decrease in the width of the external granular layer in a region
of the inferior lobe of the cerebellum on postnatal day 7, but not
later. The density of migrating cells in the molecular layer was also
decreased (Markowski et al., 1998).
The concentration of mercury was 10 µg/ml in blood and 1.4 µg/g
in the brains of rat pups exposed throughout gestation and lactation
via their dams and directly to the same concentration of mercury as
methyl-mercury chloride at 3.9 mg/kg of diet. No adverse effect was
seen clinically or histologically in the brain, even on morphological
maturation of neurons and astrocytes. The only deviation from control
values was an increase in noradrenaline activity in the cerebellum
(Lindström et al., 1991).
In a crossfostering study, rat dams received an approximate daily
dose of 2.5 mg/kg bw of methylmercury chloride in drinking-water, and
an additional group of pups was exposed only through drinking-water on
postnatal days 21-30. Only pups exposed prenatally or directly after
weaning had deficits in learning ability at day 30, and the effect
lasted at least until postnatal day 50 (Zenick, 1974). At day 30, the
action potential in the visual cortex was decreased in each group
(Zenick, 1976). Offspring of rat dams exposed to 1.2 or 4 mg/L as
methylmercury in drinking-water from two weeks before mating to
weaning showed a dose-dependent deficit in correct response when the
feedback was tactile kinetic perception. The methylmercury intake of
the dams was 0.12 or 0.25-51 mg/kg bw per day before and during
gestation and 0.22-0.38 or 0.53-0.95 mg/kg bw per day during lactation
Macaque monkey dams were given methylmercury chloride orally
three times a week at doses of 10, 25, or 50 µg/kg bw and were mated
when their blood concentration of mercury approached 90% of the
steady-state level. Treatment was continued during gestation. Infants
were separated from their mothers immediately after birth and given
the same dose of methylmercury until they were four years of age. The
blood mercury concentration of the infants at birth was 0.45-2.7
µg/ml, and their steady-state concentration reached 0.22-0.78 µg/ml.
Two of the five animals were severely intoxicated and could not be
tested for spatial or temporal visual function. Some inconsistent
defects in spatial vision at high and low luminescence and in
temporal vision at high luminiscence were seen. Temporal vision at low
luminescence was better in exposed than in control monkeys (Rice &
Gilbert, 1990). The auditory response was tested in the same monkeys
when they were 11 and 19 years of age, 7-15 years after the end of
exposure. The deterioration in hearing between 11 and 19 years was
more pronounced in exposed than in control monkeys. In 19-year-old
monkeys, the thresholds for all frequencies were higher in exposed
than in control monkeys (Rice, 1998).
126.96.36.199 Exposure after parturition
A single oral dose of 8 mg/kg bw as methylmercury chloride to
two-day-old mice resulted in a brain mercury concentration of 2.7
µg/g, reductions in the number of cells and the percentage of late
mitotic figures, and an increase in cells with reduced nuclear
diameter (Sager et al., 1982). A smaller reduction in cell numbers in
the granular layer of the cerebellum was seen after 4 mg/kg bw, but
the number and proportion of late mitotic figures (anaphase) remained
significantly lower than in controls at day 19 post partum (Sager et
Two-day-old rats were given methylmercury chloride at a dose of 5
mg/kg bw per day subcutaneously until loss of body weight and signs of
neurological impairment, including impaired vision (weak visual
placing response), became evident. At this point, the animals were
necropsied, and their visual cortices were studied. Degenerating
neurons were concentrated mainly in layer IV and were scattered in
layers II, III, V, and VI (O'Kusky, 1985). The same treatment led to
the spastic dyskinetic syndrome and to decreases in the specific
activity of glutamic acid decarboxylase (which synthesizes
gamma-aminobutyric acid) in the occipital cortex (O'Kusky et al.,
1988a) and in the tissue concentrations of serotonin and dopamine and
their metabolites (O'Kusky et al., 1988b). As the dose used in these
studies was high, pain and local irritation could have been
confounding factors at least on the concentrations of catecholamines
and serotonin In addition, renal function was certainly affected, as
even 0.85 mg/kg bw given as methylmercury hydroxide subcutane-ously
daily from the day of birth impaired the kidneys (Slotkin et al.,
Four infant monkeys were given methylmercury chloride at 0.5
mg/kg bw per day orally for 28-29 days from day 1 after birth. They
progressively became ataxic, blind, and comatose and were necropsied
at 35-43 days. Histopathological changes were marked in the cerebrum
and less severe in the cerebellum, where the Purkinje and granular
cells appeared normal (Willes et al., 1978). In an experiment in which
much lower doses were used, the blood mercury concentration of five
newborn macaque monkeys given 0.05 mg/kg bw per day orally in fruit
juice peaked at 1.2-1.4 µg/ml and declined after weaning to 0.6-0.9
µg/ml. At three to four years of age, they had impaired spatial vision
at both high and low luminescence (Rice & Gilbert, 1982). Continuation
of exposure to the same daily doses until seven years of age resulted
in an increased auditory threshold in four of five monkeys, at high
frequency (25 000 Hz) in one monkey and at middle frequencies in three
monkeys (Rice & Gilbert, 1992). When these monkeys reached the age of
13 years, some appeared to be clumsy and hesitant in large exercise
cages. Exposed monkeys required more time to collect 10 objects from a
recessed square and had a higher vibration threshold, but their motor
response time was normal (Rice, 1996).
In mice exposed for two years to methylmercury at 0.4, 2, or 10
mg/kg of diet, renal tumours developed only in males at 10 mg/kg of
diet. The incidence of renal adenoma was 8% and that of carcinoma was
22% in B6C3F1 mice, the corresponding figures being 5% and 17% in ICR
mice. Nearly all male and female B6C3F1 mice at 10 mg/kg of diet had
chronic nephropathy, while only 78% male and 43% female ICR mice had
this pathological change (Mitsumori et al., 1990). The chronic insult
to the kidney may have contributed to the induction of cancer. In
groups of male and female rats fed diets containing methylmercury at
0.1, 0.5, or 2.5 mg/kg of diet for two years, the incidence of
pathological lesions and tumours was not increased (Verschuuren et
Exposure of mice to methylmercury in the diet at 3.2 mg/kg did
not affect body weight or kidney, liver, or spleen weight, but the
weight of the thymus and the number of thymocytes decreased by 22 and
50%, respectively. The lymphoproliferative response to T-and B-cell
mitogens was increased in both thymus and spleen, and natural killer
cell activity was decreased by 44% in spleen and by 75% in blood
(Ilbäck, 1991). In a cross-fostering study, when rat dams were exposed
to mercury as methylmercury at 3.2 mg/kg of diet 11 weeks before
mating, no consistent alterations were seen in the body weight,
lymphoid organ weights, or cell number and lymphoproliferative
response to Bcell mitogens of pups at the age of 15 days. The response
of thymocytes to T-cell mitogens increased by 30-48% and that of
splenocytes decreased by 12% only in pups exposed throughout
lactation; natural killer cell activity decreased by 42% after both
doses (Ilbäck et al., 1991). Mouse dams and pups exposed to
methylmercury at a concentration of 0.5 or 5 mg/kg of diet from 10
weeks before mating until weaning showed inconsistent effects on the
immune system (Thuvander et al., 1996).
2.2.9 Extrapolation between species
The doses used in experiments in rats and mice frequently
exceeded 1 mg/kg bw per day, which is within the range of the intake
of the Iraqi patients with severe methylmercury poisoning (Bakir et
al., 1973) and 140-330 times higher than the daily intake that would
cause paraesthesia in 5% of a population (WHO, 1976). Thus,
extrapolation of doses on the basis of body weight clearly results in
nonsense values. Table 3 shows that the clearance half-times of
methylmercury increase with mass, in the order mouse < rat < macaque
monkey < human, and that the concentrations in the whole body after a
unit dose follow the same order. The data in the Table are based on
the assumption that clearance from blood approximates clearance from
the whole body, and the clearance half-times are given as the daily
clearance in percent of the whole-body burden. The units for dose and
concentration are identical. As the half-time increases with body
mass, the concentration in the body after identical doses of
methylmercury also increases with body mass. Thus, allometric
extrapolation based on surface area can be used. The method of
correction, for example from the dose for mouse to the human dose, is:
human dose = mouse dose (0.3:70)0.3
With this allometric extrapolation, the dose in mice multiplied by
0.098 gives the equivalent human dose, while the multiplication factor
for the dose in rats is 0.20 and that for macaques is 0.42. The effect
of this extrapolation on steady-state concentrations is shown in Table
2.3 Observations in humans
Investigations of the possible neurodevelopmental effects of
prenatal exposure to methylmercury followed a sequence similar to
those of other neurotoxic exposures: case series of children who
manifested clinical signs of poisoning and then prospective cohort
studies of asymptomatic children considered to have 'low' exposure or
at least exposure lower than that at which clinical signs and symptoms
appear. The populations chosen were mostly those known to consume
large amounts of fish, which contain variable amounts of methylmercury
(see section 3). The goal of the latter studies is largely to
determine whether a dose-response relationship can be identified for
adverse neurodevelopmental effects associated with exposure to
methylmercury, in order to assess the significance to public health of
exposure in various populations.
Table 3. Clearance half-times and whole-body concentrations of methylmercury
Species Body Half-time Clearance Ratio of concentration:daily dosea
weight (days) (% body
(kg) burden) 10 days after After 10 At steady
single dose doses state
Human 70 52 0.014 0.87 9.4 75
Macaque 4 25 0.028 0.76 8.7 36
Rat 0.35 12 0.058 0.56 7.6 17
Mouse 0.03 7 0.099 0.37 6.3 10
a Same units as daily dose
2.3.1 Case series
The mass poisoning of persons living near Minamata Bay in Japan
in the 1950s first raised awareness of the severe neurological
sequelae associated with methylmercury poisoning, particularly when
experienced prenatally. The primary route of exposure in this episode
was the consumption of fish contaminated by methylmercury, which
bioaccumulated up the aquatic food chain. According to Harada (1995),
all children identified as suffering from the most severe form of
congenital Minamata disease showed mental retardation, primitive
reflexes, cerebellar ataxia, disturbances in physical growth,
dysarthria, and limb deformities, and most showed hyperkinesis (95%),
hypersalivation (95%), seizures (82%), strabismus (77%), and pyramidal
signs (75%). The incidence of cerebral palsy among children with the
disease was also increased, involving 9% of 188 births in three
villages. Some of the signs and symptoms, such as paroxysmal events,
hypersalivation, primitive reflexes, and ataxia, abated somewhat in
subsequent years, although others such as reduced intelligence and
dysarthria did not. Most patients with the severe form of the disease
were unable to function successfully in society. The mothers of many
affected children experienced only transient paresthesia, indicating
that fetal vulnerability exceeds that of mature individuals. Although
measurements of the body burden of mercury were not available until
several years after the episode, analyses of the mercury
concentrations in archived umbilical cord tissue from patients with
congenital Minamata disease suggest that the mean concentration in
maternal hair may have been approximately 41 µg/g (25-75th percentile:
20-59) (Akagi et al., 1998). The uncertainty associated with this
estimate is likely to be substantial, however, as case ascertainment
was undoubtedly incomplete, particularly among individuals who
suffered milder forms of the disease. For example, even if cases of
known disease are excluded, the prevalence of mental retardation among
children born between 1955 and 1958 in the contaminated area was 29%,
which is far higher than would have been expected and suggests that
congenital Minamata disease was not diagnosed in many children with
less severe forms. Thus, these data cannot provide precise estimates
of the minimum concentration of methylmercury required to produce this
A second episode of mass methylmercury poisoning occurred in Iraq
in the early 1970s, when seed grain treated with a fungicide
containing this compound was ground into flour and consumed and
resulted in 600 deaths and 6000 cases of methylmercury poisoning.
Thus, the exposure was probably more acute and involved higher doses
than those experienced by the persons living around Minamata Bay. The
results of early studies of the most severely affected children who
were exposed during fetal development were concordant with those in
Minamata: the children manifested severe sensory impairment
(blindness, deafness), general paralysis, hyperactive reflexes,
cerebral palsy, and impaired mental development (Amin-Zaki et al.,
1974). Several follow-up studies of the exposed population were
conducted. Marsh et al. (1987) identified 81 children who were in
utero at the time of the episode and collected information on their
neurodevelopmental outcomes from two sources: neurological examination
of each child and an interview with the mother about the age at which
the child achieved standard developmental milestones such as walking
and talking. The maximum concentrations of mercury in maternal hair
during the pregnancy, which were used as the index of fetal exposure,
ranged from 1 to 674 µg/g. Developmental retardation was defined as a
child's failure to walk a few steps unaided by 18 months of age or to
say two or three meaningful words by 24 months of age. A point system
was devised for the neurological examination, a score > 3 indicating
a definite abnormality. The prevalences of these indicators of poor
outcome were related to the concentrations of mercury in maternal
hair. The most frequent neurological findings were increased limb tone
and deep-tendon reflexes with persistent extensor plantar responses;
ataxia, hypotonia, and athetoid movements were also reported. Boys
appeared to be more severely affected than girls. Seven of the 28
children with the highest exposure and none of the 53 children with
lower exposure had had seizures.
Additional analyses of this data set were performed to identify
more precisely the shape of the dose-response relationship and, in
particular, the threshold for adverse neurodevelopmental effects, if
indeed one exists. Cox et al. (1989) obtained more accurate estimates
of peak exposure during pregnancy by applying an X-ray fluorescent
method to single strands of maternal hair. Using logit, hockey-stick,
and non-parametric kernel smoothing methods, they estimated a
population threshold of around 10 µg/g for the outcomes investigated.
The uncertainty associated with this estimate is heavily dependent,
however, on the estimated background prevalence of the poor outcomes.
For example, the upper bound of the 95% confidence interval for motor
retardation increases from 14 to 190 µg/g if the estimate of
background prevalence is changed from 0 to 4%. For neurological
abnormality, the upper bound of the 95% confidence interval for the
threshold estimate was 287 µg/g when a 9% background prevalence was
assumede. In later re-analyses of these data, Crump et al. (1995) and
Cox et al. (1995) demonstrated that the estimate of threshold depends
on the model used and is sensitive to the definition of abnormality.
In the case of delayed walking, the estimate was influenced by the
only four cases of delayed walking among the children of women whose
hair concentration of mercury was < 150 µg/g. The statistical
variability of the estimates of threshold appears likely to be
considerably greater than that of Cox et al. (1989). Crump et al.
(1995) concluded that the data from the Iraqi episode do not provide
convincing evidence of any adverse neurodevelopmental effect of
methylmercury at concentrations in maternal hair < 80 µg/g.
In evaluating these data, it is important to note that the
interviews were conducted when the mean age of the children was 30
months, but some of the children must have been considerably older at
this time, as the age at which children in the sample were reported to
have walked or talked was as much as 72 months. In addition, the birth
dates were generally not accorded significance, and maternal
recollection of the ages at which their children achieved milestones
were based on external events such as religious holidays. The extent
of the imprecision of these data is suggested by the strong digit
Table 4. Steady-state concentrations of methylmercury in humans after allometric
extrapolation of unit doses from three experimental species and comparison of
human and animal steady-state concentration ratios
Animal Concentration Human concentration Ratio at steady state
after equal doses (based on mass)
(based on surface)
Macaque 28 0.09 2.1
Rat 12 0.9 4.4
Mouse 6 1.0 7.5
Steady-state concentrations in animals are shown in the last column of Table 3.
preferences in the mothers' responses. For instance, an even number of
months was given for the estimated age at walking for 70 of the 78
children and for the estimated age at talking for 70 of 73 children;
75% of the estimates were multiples of six months. Finally, the extent
of selection bias in this cohort cannot be characterized because the
size of the base population from which it was drawn and the referral
mechanism that brought mothers and children to medical attention are
both unknown. For instance, women who knew that they had consumed
large amounts of contaminated grain and were concerned about their
children's welfare may have come forward, while women who consumed
equally large amounts of contaminated grain but whose children were
developing well may not. This issue is critical, because calculation
of a threshold requires a denominator (the size of the exposed
population) and the background prevalence of the adverse outcome in
order to estimate the 'added risk' associated with the exposure of
interest. In this regard, the background prevalence of developmental
abnormality appears to have been extremely high among the Iraqi
children who participated in the follow-up studies. The prevalence of
delayed walking among children whose mothers had concentrations of
mercury in hair < 10 µg/g, who can be viewed essentially as a control
group for estimating background prevalence, was 36% (11/31). In
contrast, in the population of children in the United States on whom
the Bayley scales of infant development were standardized (Bayley,
1969), the prevalence of delayed walking by this criterion was
approximately 5%. Similarly, the prevalence of delayed talking among
the Iraqi children was 22% (6/27), whereas 95% of 24-month-old
children in the standardization sample of the MacArthur communicative
development inventory were saying 50 words or more (Fenson et al.,
2.3.2 Childhood development
188.8.131.52 Neurological status
McKeown-Eyssen et al. (1983) studied 234 Cree children aged 12-30
months living in four communities in northern Quebec, Canada, whose
prenatal exposure to methylmercury was estimated on the basis of
maternal hair samples. Hair samples were collected from 28% of the
mothers during pregnancy, but the prenatal exposure of the rest of the
cohort was estimated from hair segments assumed to date from the
period of the pregnancy. The exposure index was the maximum
concentration of mercury in the segment of hair corresponding most
closely to the period from one month before conception to one month
after delivery. The mean concentration of mercury in maternal hair was
approximately 6 µg/g; it exceeded 20 µg/g in 6% of samples. One of
four paediatric neurologists who were unaware of the child's status of
exposure measured height, weight, and head circumference, identified
dysmorphology, and conducted a neurological examination, assessing
coordination, cranial nerves, and muscle tone and reflexes. The
neurologist then made a summary clinical judgement about the presence
of a neurological abnormality. None of the children was judged to have
an abnormal physical finding, but 3.5% of the boys ( n = 4) and 4.1%
of the girls ( n = 5) were considered to have a neurological
abnormality. The most frequent abnormality involved tendon reflexes,
which was seen in 11% of boys ( n = 13) and 12% of girls ( n = 14).
The only neurological finding that was significantly associated with
prenatal exposure to methylmercury, either before or after adjustment
for confounding, was abnormal muscle tone ( n = 2; increased tone in
legs only) or reflexes ( n = 13; five with isolated decreased
reflexes, six with generalized decreases, and two with generalized
increases) in boys ( p = 0.05). The risk for abnormal tone or
reflexes increased seven times with each 10-µg/g increase in prenatal
exposure to methylmercury (95% confidence interval, 1-51). After log
transformation of prenatal exposure, however, the p value for this
association increased to 0.14. When exposure was categorized, the
prevalence of tone or reflex abnormality did not increase in a clear
dose-related manner across the categories. In girls, the only
association identified was an unexpected inverse relationship between
prenatal exposure to methylmercury and incoordination, with a 60%
decrease in the probability of incoordination for each 10-µg/g
increment (odds ratio, 0.3; 95% confidence interval, 0.1-0.9;
p = 0.02). The authors noted several caveats with regard to the one
significant adverse association identified: the abnormalities of
muscle tone and reflexes in boys were isolated, mild, and of doubtful
clinical importance; the finding is not consistent with previous
results which suggest that increased exposure is expressed as severe
generalized neurological disease, including increases in tone and
reflexes; there was no coherent dose-response relationship; and there
was no consistency between the sexes. The finding may reflect chance,
lack of normality in the distribution of the exposure index, or
A study was conducted in Mancora, a fishing community on the
northern coast of Peru, in which hair samples and clinical data were
obtained for 131 infant-mother pairs. The mean concentration of
mercury in maternal hair was 7 µg/g (range, 0.9-28), with an average
peak of 8.3 µg/g. The small difference between the mean and the peak
was probably due to the stability of the fish consumption of the
mothers. The major outcomes measured were anthropmorphic end-points
(birth weight, head circumference, and height), maternal reports of
infant development (age at which the infant sat, stood, walked, and
talked), and neurological status (Marsh et al., 1995). The specific
elements of the neurological assessment conducted and the age at which
the infants were examined were not described. Tone was decreased in
two children, limb weakness was seen in one child, reflexes were
decreased in one child and increased in four, and an abnormal Babinski
reflex was seen in one child; increased tone, primitive reflexes, and
ataxia were not observed. None of the signs was significantly
associated with either the mean or the peak concentration of mercury
in maternal hair.
In the pilot phase of a cross-sectional cohort study of child
development in the Seychelles, 789 infants aged 5-109 weeks were
evaluated by one paediatric neurologist who was unaware of their
exposure status (Myers et al., 1995a). The mean concentration of
mercury in maternal hair was 6.1 µg/g (range, 0.6-36 µg/g). The
features assessed included mental status, attention, social
interactions, vocalization, behaviour, coordination, posture and
movements, cranial nerves II-XII, muscle strength and tone, primitive
and deep-tendon reflexes, plantar responses, and age-appropriate
abilities such as rolling, sitting, pulling to stand, walking, and
running. The statistical analyses focused on three end-points,
selected because of their apparent sensitivity to prenatal exposure to
methylmercury in the studies in Iraq and the Cree population: overall
neurological status, increased muscle tone, and deep-tendon reflexes
in the extremities. The result of the overall examination was
considered to be 'abnormal' if any findings judged to be pathological
were present, including abnormalities of cranial nerves (pupils,
extraocular muscles, facial or tongue movement, swallowing, or
hearing), increase or decrease in muscle tone or deep-tendon reflexes,
incoordination, involuntary movements, or poorly developed speech or
functional abilities. Findings that were considered to be neither
normal nor pathological were categorized as 'questionable'. Because
the frequency of abnormal findings was low (2.8%), the questionable
(11%) and abnormal categories were combined. No association was found
between the concentration of mercury in maternal hair and questionable
or abnormal results, the frequency ranging from 16% for hair
concentrations of 0-3 µg/g to 12% for hair concentrations > 12 µg/g.
The frequency of abnormalities of limb tone or deep-tendon reflexes
was about 8% and did not vary in a dose-dependent manner with the
concentration of mercury in maternal hair.
In the main study, which involved a cohort of 735 children, one
paediatric neurologist who was unaware of the exposure status of the
children conducted essentially the same neurological examination that
had been used in the pilot study but when the participants were 6.5
months old (Myers et al., 1995b). The results of the overall
examination were considered to be abnormal or questionable if changes
in muscle tone, deep-tendon reflexes, or other neurological features
were pathological or the examiner considered that a child's functional
abilities were not appropriate for his or her age. Abnormal or
questionable neurological scores were found for 3.4% ( n = 25) of the
children, a frequency too low to permit statistical analysis. For both
limb tone and deep-tendon reflexes, the frequency of abnormalities was
2%; questionable limb tone was found in approximately 20% of the
children and questionable deep-tendon reflexes in approximately 15%.
For neither limb tone nor deep-tendon reflexes was the frequency of
abnormal or questionable findings significantly associated with the
concentration of mercury in maternal hair.
In a study carried out in the Faroe Islands (Denmark), a
functional neurological examination was administered to children at
the age of 7 years as part of a general physical examination. The
examination focused in particular on motor coordination and
perceptual-motor performance (Dahl et al., 1996). The tests for
coordination included rapid pronation or supination, reciprocal
coordination (alternately closing and opening the fists), and finger
opposition (touching the pulpa of the thumb with the pulpa of the
other fingers of the same hand). The perceptual-motor tests included
catching a 15-cm ball thrown from a distance of 4 m, finger agnosia,
and double finger agnosia. The results were scored as automatic or as
questionable or poor. Exposure to mercury was evaluated on the basis
of the concentration in maternal hair at delivery, in umbilical cord
blood, and in children's hair obtained at about 12 months of age
Exposure to mercury was not significantly associated with the number
of tests on which a child's performance was considered to be
'automatic', as < 60% of the children achieved such a score on the
tests for reciprocal motor coordination, simultaneous finger movement,
and finger opposition; however, children with questionable or poor
performance for finger opposition had had significantly higher mean
exposure to mercury than children with automatic performance (24
versus 22 µg/L; p = 0.04) (Grandjean et al., 1997).
184.108.40.206 Developmental milestones
The association between the achievement of developmental
milestones and prenatal exposure to methylmercury was evaluated in the
main cohort of the study in the Seychelles (Myers et al., 1997; Axtell
et al., 1998). Information on the ages at which a child was able to
walk without support and to say words other than 'mama' or 'dada' was
elicited by means of an interview with the person with whom the child
spent five or more nights per week (the 'caregiver'), conducted at an
evaluation at 19 months. Such information was available for 738 of the
779 children. The statistical approaches explored included standard
multiple regression in which age at achievement of a milestone was
log-transformed, hockey-stick models to estimate the threshold
concentration of mercury in maternal hair associated with delay in
achieving a milestone, and logistic regression analyses of 'delayed
walking', a binary variable in which an abnormal response was defined
as > 14 months. Prenatal exposure to methylmercury was estimated
from the total mercury in the single longest segment of hair dating
from the index pregnancy; the mean concentration was 5.8 µg/g (range,
0.5-27), and 22% of the children had been exposed to > 10 µg/g. The
mean age at which a child was considered to talk was not significantly
associated with the concentration of mercury in maternal hair in any
of the models tested. In regression analyses stratified by sex, a
positive association was found between age at walking and exposure to
mercury for boys ( p = 0.043) but not for girls. The interaction term
'mercury × sex' in analyses of the complete cohort was not
statistically significant. The magnitude of the delay in the age at
which boys walked--a 10-µg/gincrease in the concentration of mercury
in maternal hair associated with an approximately two-week delay in
walking--was viewed by the authors as clinically insignificant, and
the association was not significant when four statistical outliers
were excluded from the analysis. Hockey-stick models provided no
evidence of a threshold, as the fitted curves were essentially flat. A
child's risk for 'delayed walking' was not associated with the
concentration of mercury in maternal hair.
In a re-analysis of these data, Axtell et al. (1998) used
semiparametric generalized additive models with smoothing techniques
to identify lack of linearity. These models are less restrictive than
those used by Myers et al., which require strong assumptions about the
true functional form of a relationship. The major finding of Axtell et
al. was that the association between age at walking and the
concentration of mercury in maternal hair in boys was not linear,
walking being achieved at a later age as exposure increased from 0 to
7 µg/g but at a slightly earlier age as the concentration increased
beyond 7 µg/g. The size of the effect associated with the increase
from 0 to 7 µg/g was small, corresponding to a delay of less than one
day in the achievement of walking. Because no clear dose-response
relationship was seen at concen-trations > 7 µg/g, the authors
considered that the association found at lower concentrations did not
reflect a causal effect of mercury on the age at walking.
Data on developmental milestones were also collected in the study
in Peru (Marsh et al., 1995). The ages of the children at the time the
mothers were questioned about these events was not stated, although
the study was conducted prospectively and data were apparently
collected throughout the women's visits to postnatal clinics.
Regression analyses, including analyses stratified by sex, showed no
significant association between the concentration of mercury in
maternal hair and the ages at which the children sat, stood, walked,
or talked. The rates of developmental retardation were substantial,
especially for speech (13/131), although the criteria used to define
this outcome were not stated. The children's birthweight, height, and
head circumference were also unrelated to the concentration of mercury
in maternal hair.
The ages at which children achieved motor milestones were
investigated in a birth cohort of 1022 children born during a 21-month
period in 1986-87 in the Faroe Islands (Grandjean et al., 1995a). The
data were obtained from interviews with the mothers and from the
observations of district health nurses who had visited the homes of
the children on several occasions during their first year of life.
Complete data were available for 583 children (57% of the cohort).
Three motor milestones commonly achieved between 5 and 12 months of
age were selected for analysis: sitting without support, crawling, and
standing with support. The age at achievement of the three milestones
was not significantly associated with the concentration of mercury in
cord blood or maternal hair, but a significant negative association
was found between the age at achievement of all three milestones and
the concentration of mercury in children's hair at 12 months. The
authors concluded that this association reflected residual confounding
by duration of breast-feeding, since nursing was associated with both
higher hair mercury concentrations in children at 12 months of age and
more rapid achievement of milestones. This finding suggests that the
beneficial effects of nursing on early motor development are
sufficient to compensate for any slight adverse impact that prenatal
exposure to low concentrations of methylmercury may have on these
220.127.116.11 Early development
In the study of Cree people reported by McKeown-Eyssen et al.
(1983), the Denver developmental screening test (Frankenburg et al.,
1981)was administered to all children aged 12-30 months. The scores
were reported as the percentage of items passed on each subscale
(gross motor, fine motor, language, personal and social) and on the
entire test. Although quantitative estimates of the associations
between test scores and the concentration of mercury in maternal hair
(mean, 6 µg/g; 6% > 20 µg/g) were not provided, the authors reported
that they found no significant association compatible with an adverse
effect of methylmercury, before or after adjustment for confounding
Kjellström et al. (1986, 1989) studied a cohort of children in
New Zealand whose prenatal exposure to methylmercury was estimated on
the basis of maternal hair samples and dietary questionnaires
collected during the pregnancy. Although nearly 11 000 women
participated in the initial phase during which information on exposure
was obtained, Kjellström et al. focused on 935 women who had reported
eating fish more than three times per week during the pregnancy. The
74 children of 73 women whose concentration of mercury in hair was
> 6 µg/g were considered to have had heavy exposure to mercury. Three
controls were matched to each of these children on the basis of ethnic
group, sex, maternal age, maternal smoking, area of maternal
residence, and the duration of maternal residence in New Zealand. The
concentration of mercury in maternal hair was 3-6 µg/g for one of each
of the controls, whose mother ate fish more than three times per week,
and 0-3 µg/g for the other two, whose mothers had a lower consumption
of fish. There were 57 fully matched sets of four children and four
incomplete sets, for a cohort of 237 children. Evaluations conducted
when the children were four years of age indicated that about 50% of
children with heavy exposure to mercury and 17% of the children in the
control group had an abnormal or questionable result on the Denver
developmental screening test.
In the pilot phase of the Seychelles study, a revised version of
the Denver test was administered to 789 children aged 1-25 months by
one examiner who was unaware of their exposure status (Myers et al.,
1995a). No association was found between the concentration of mercury
in maternal hair during pregnancy (mean, 6.6 µg/g) and the results on
the test when normal and questionable results were combined in the
conventional manner, although the prevalence of abnormal findings was
so low (three children, < 1%) that statistical analysis was not
meaningful. When abnormal and questionable (n = 65; 8%) results were
grouped, as was done in the study in New Zealand (Kjellström et al.,
1986), a higher concentration of mercury in maternal hair was
significantly (p = 0.04; one-tailed test) associated with a poor
outcome. This result was largely attributable to the higher frequency
of abnormal or questionable results (13%) among children with the
heaviest exposure to mercury (> 12 µg/g), in contrast to the
frequency of approximately 7% among children in each of the other four
groups (0-3, 3-6, 6-9, and 9-12 µg/g).
In the main study in the Seychelles, the revised Denver
developmental screening test was administered to a cohort of 740
children (mean concentration of mercury in maternal hair during
pregnancy, 5.9 µg/g; interquartile range, 6 µg/g) aged 6.5 months by
one examiner who was unaware of their exposure status (Myers et al.,
1995b). The frequency of results considered to be abnormal (three
children; 0.4%) or questionable was very low (11; 1.5%), precluding
meaningful statistical analysis. The Fagan test of infant intelligence
(Fagan, 1987), an assessment of visual recognition memory or novelty
preference, was also administered to 723 of the children at the same
age. The mean percent novelty preference in the entire cohort was 60%,
which is similar to that observed in other cohorts, and varied by <
1% across categories of concentration of mercury in maternal hair. The
index of perfor-mance on visual attention (the time required to reach
visual fixation criterion in familiarization trials) was also
unrelated to the concentration of mercury.
The Bayley scales of infant development were administered to
children in this cohort at the ages of 19 months ( n =738) and 29
months ( n =736) by examiners who were unaware of their exposure
status (Davidson et al., 1995a). Six items of the infant behaviour
record, a rating scale, were also completed by the examiner for
children aged 29 months, to assess activity, attention span,
responsiveness to the examiner, response to the caregiver,
cooperation, and general emotional tone. The Bayley scales yield two
primary scores: the mental development index and the psychomotor
development index. At both ages, the scores for mental development
were similar to the expected mean for children in the United States,
but the children's psychomotor development index scores were markedly
higher: at 19 months, approximately 200 of the children achieved the
highest possible score. Accordingly, the psychomotor development
scores at both ages were expressed as a binary variable, dividing the
distribution at the median score. The mental development scores were
not significantly associated with the concentration of mercury in
maternal hair during pregnancy. Similar results were obtained in a
secondary analysis that included only children with the lowest (< 3
µg/g) or highest (> 12 µg/g) concentration of mercury in maternal
hair. The scores at 19 months for the items on the mental development
scale designed to assess perceptual skills, dichotomized because of
the skewing, were not associated with exposure to mercury. The scores
for this index at 29 months could not be evaluated because of 'a
pronounced celling effect'. A psychomotor development index score
below the median was not significantly associated with the
concentration of mercury in maternal hair in the full logistic
regression model, but was associated with this exposure index
( p = 0.05) in a reduced model in which adjustment was made for a
smaller number of covariates selected a priori. A secondary analysis
of the psychomotor development index scores of children with the
lowest and highest exposure to mercury was not conducted because
statistical significance was not achieved in the full logistic
regression model. In analyses of the six items for infant behaviour,
the concentration of mercury in maternal hair was significantly
associated only with the examiner's ratings of children's activity
during the test session and only in boys. The score decreased by one
point (on a nine-point scale) for each 10 µg/g.
In general, the use of screening tests such as the Denver test in
studies of neurobehavioural toxicology is not recommended because of
their insensitivity to variations within the range of normal
performance (Dietrich & Bellinger, 1994). More detailed instruments,
such as the Bayley scales of infant development, have proven to be
sensitive to prenatal exposure to a variety of neurotoxicants,
including lead (Bellinger et al., 1987; Dietrich et al., 1987;
Wasserman et al., 1992) and polychlorinated biphenyls (PCBs; Rogan &
Gladen, 1991; Koopman-Esseboom et al., 1996). The only study of
exposure to mercury in which the Bayley scales were administered was
the study in the Seychelles, which found no significant association
between children's scores and prenatal exposure. It is notable that
the psychomotor development index scores were so high in this cohort
that the distribution had be split at the median and analysed as a
categorical variable. The median value was not provided by Davidson et
al. (1995a) but was derived from a figure in the paper of Davidson et
al. (1995b); it appeared to be approximately 130, or two standard
deviations above the expected population mean. The mental development
index scores were close to the expected population mean. It is
questionable, however, whether statistical analysis of scores > 130
versus < 130 allows assessment of a potential adverse effect of
prenatal exposure to mercury on early motor development.
18.104.22.168 Development later in childhood
In the study in New Zealand, the 237 children in the 57 fully
matched groups participated in a follow-up evaluation of
neurodevelopmental status at 6 years of age (Kjellström et al., 1989).
The mean concentration of mercury in maternal hair in the group with
heavy exposure was was 8.3 µg/g (range, 6-86 µg/g; all but 16, 6-10
µg/g). Extensive information was collected on possible confounding
factors such as social class, medical history, and nutrition. A
battery of 26 psychological and scholastic tests was administered to
assess general intelligence, language development, fine and gross
motor coordination, academic attainment, and social adjustment.
Multiple regression analyses were conducted of five primary
end-points: language development and spoken language; the revised
Wechsler intelligence scale for children for both performance and
fill-scale intelligence quotient (IQ) (Wechsler, 1974); the McCarthy
scales of children's perceptual performance abilities; and the
McCarthy scale of motor ability (McCarthy, 1972). In addition, robust
regression methods were applied, involving the assignment of weights
to observations, depending on their position within the distribution.
In these analyses, the concentration of mercury in maternal hair was
associated with poorer scores (p values ranging from 0.0034 to 0.074)
for full-scale IQ, language development, visual and spatial skills,
and gross motor skills. The findings in the unweighted regression
analyses were similar in direction although generally less
significant. The poorer mean scores of the children with heavier
exposure to mercury were largely attributable to those whose mothers
had concentrations in their hair < 10 µg/g, for whom the mean average
concentration during pregnancy was 13-15 µg/g and the mean peak
monthly concentration was about 25 µg/g. The concentration of mercury
in maternal hair accounted for relatively little variance in the
outcome measures and generally less than covariates such as social
class and ethnic group.
In additional analyses of this data set, Crump et al. (1998)
found that when the concentration of mercury in maternal hair was
expressed as a continuous rather than as a binary variable, none of
the 26 scores was associated with exposure to mercury at p < 0.10.
The results were heavily influenced, however, by the results of a
child whose mother had a concentration of mercury of 86 µg/g--more
than four times the next highest level--despite the fact that the
child's scores were not outliers by the usual criteria. When the data
for this child were excluded, the scores on six end-points (Clay
reading concepts or reading letters [Clay, 1979], McCarthy general
cognitive index, McCarthy perceptual performance index, grammar
completion, and grammar understanding) were inversely associated with
the concentration of mercury in maternal hair at the 10% level.
Several features of the study in New Zealand are noteworthy,
including the efforts made to collect data on potential confounding
variables and the broad battery of standardized outcome measures,
administered by trained examiners. In contrast to the acute, heavy
exposure of the Iraqi population, the cohort in New Zealand received
chronic, low exposure, which was probably fairly constant over time,
reflecting well-established food consumption patterns. In addition,
the concentration of mercury in maternal hair was measured
As part of the pilot phase of the study in the Seychelles,
children who reached the age of 66 months underwent developmental
assessment (Myers et al., 1995c). Of the 247 eligible children, 217
(88%) were given a battery of tests consisting of the McCarthy scales
of children's abilities, a preschool language scale, and two subtests
of the Woodcock-Johnson tests of achievement (Woodcock & Johnson,
1989): letter and word identification and applied problems. The median
concentration of mercury in maternal hair in 73 children whose mothers
had had a concentration of mercury in their hair > 9 µg/gor < 4
µg/g was 7.1 µg/g(range, 1-36). The rate of missing values was
substantial for some end-points: e.g. 34% for the general cognitive
index of the McCarthy scales. Increased concentrations of mercury in
maternal hair were associated with significantly lower general
cognitive scores ( p = 0.024), the scores declining approximately
five points between the lowest (< 3 µg/g) and the highest (> 12
µg/g) categories of exposure. A similar association was found on the
perceptual performance subscale of the McCarthy scales ( p = 0.013).
The children's scores on the auditory comprehension scale of the
preschool language test were also inversely associated with the
concentrations of mercury in maternal hair ( p = 0.0019), the scores
declining approximately 2.5 points across the range of exposure to
mercury. In additional analyses, exclusion of several outliers or
influential data points reduced the estimates of the effect of mercury
substantially, sometimes to nonsignificance. It is important to note
that in the pilot phase of the study information was not collected on
several key variables that frequently confound the association between
exposure to neurotoxicants and child development, specifically
socioeconomic status, maternal intelligence, and quality of the home
In the main study in the Seychelles, 711 children from the
original cohort of 779 were evaluated at 66 months of age (± 6 months)
by a battery of standardized neurodevelopmental tests (Davidson et
al., 1998). The major domains assessed were general cognitive ability
(McCarthy scales), expressive and receptive language (preschool
language scale), reading achievement (letter and word recognition in
the Woodcock-Johnson tests), arithmetic (applied problems test in the
Woodcock-Johnson tests), visual and spatial ability (Bender Gestalt
test; Koppitz, 1963), and social and adaptive behaviour (child
behaviour checklist). The total amount of mercury in a segment of
maternal hair during pregnancy served as the index of prenatal
exposure to methylmercury (mean, 6.8 µg/g; SD, 4.5, range, 0.5-27),
whereas the total amount of mercury in a 1-cm segment of hair obtained
from a child at 66 months served as the index of postnatal exposure to
methylmercury (mean, 6.5 µg/g; SD, 3.3; range, 0.9-26). For none of
the six primary end-points did the pattern of scores suggest an
adverse effect of either prenatal or postnatal exposure to mercury,
and in fact the associations that were found indicated enhanced
performance among children with heavier exposure. Greater prenatal and
postnatal exposures to mercury were both significantly associated with
better total scores for expressive and receptive language (both p =
0.02), and heavier postnatal exposure was associated with a better
score for arithmetic ( p = 0.05). Among boys, higher postnatal
exposure to mercury was associated with fewer errors on the test for
visual and spatial ability ( p = 0.009).
In the study in the Faroe Islands, 917 (90.3%) of the surviving
members of the birth cohort of 1022 singleton births were submitted to
comprehensive evaluations at approximately 7 years of age (Grandjean
et al., 1997). The neuropsychological battery included three
computer-administered tests from the neurobehavioural evaluation
system (finger tapping, hand-eye coordination, continuous performance
test), the tactual performance test, three subtests of the revised
Wechsler intelligence scale for children (digit span, similarities,
block design), the Bender Gestalt test, the California verbal learning
test for children (Delix et al., 1994), the Boston naming test (Kaplan
et al., 1983), and the nonverbal analogue profile of mood states.
Parents were asked to respond to selected items on the child behaviour
checklist. The primary index of exposure to methylmercury was the
concentration of mercury in umbilical cord blood (geometric mean, 22.9
µg/L; interquartile range, 13-41; n = 894). Estimates were also
available of the con-centration of mercury in maternal hair at
parturition (geometric mean, 4.3 µg/g; interquartile range, 2.6-7.7;
n = 914); in the child's hair at 12 months of age (geometric mean,
1.1 µg/g; interquartile range, 0.7-1.9; n = 527); and in the child's
hair at 7 years (geometric mean, 3 µg/g; interquartile range, 1.7-6.1;
n = 903).
Not all of the children were able to complete all of the tests,
and in some cases (e.g. finger opposition test, mood test) failure was
associated with significantly higher mercury concentrations. Sensory
functions including visual acuity, contrast sensitivity, auditory
thresholds, and visual evoked potentials were not significantly
related to prenatal exposure to mercury. Peaks I, III, and V of the
brainstem auditory evoked potential at both 20 and 40 Hz
( p = 0.01-0.1) were slightly delayed in children with higher
concentrations of mercury in cord blood, although at neither frequency
was the interpeak latency associated with exposure. In multiple
regression analyses, an increased concentration in cord blood was
significantly associated with worse scores on finger tapping
(preferred hand, p = 0.05), continuous performance (in the first
year of data collection only; false negatives, p = 0.02; mean
reaction time, p = 0.001), digit span in the revised Wechsler
intelligence scale for children ( p = 0.05), the Boston naming test
(no cues, p = 0.0003; with cues, p = 0.0001), and the California
verbal learning test (short-term reproduction, p = 0.02; long-term
reproduction, p = 0.05).
For two end-points (block design and visial-spatial copy
errors), associations with mercury in cord blood ( p < 0.05) were
found when an alternative approach to adjustment for confounders was
applied. The results were similar when the 15% of the cohort whose
mothers had had > 10 µg/g of mercury in their hair were excluded from
the analyses. No significant interactions between mercury and sex were
identified, indicating that the associations were similar for boys and
girls. In general, the children's test scores were more strongly
associated with the concentration of mercury in cord blood than in
maternal hair or in samples of children's hair collected at 1 and 7
years of age, but it was not stated whether any of the associations
In an additional set of analyses (Grandjean et al., 1998), the
investigators compared the neuropsychological scores of two groups of
children: 112 whose mothers' hair had contained 10-20 µg/g (median, 12
µg/g) of mercury at the time of parturition and 272 children whose
mothers' hair had contained < 3 µg/g (median, 1.8). The two groups
were matched by age, sex, year of examination, and maternal IQ. The
median concentrations of mercury in cord blood also differed
substantially: 59 µg/L versus 12 µg/L, respectively. The group with
heavier exposure scored significantly lower than the other children on
6 of the 18 end-points (one-tailed p value, 0.05): finger tapping
(both hands), hand-eye coordination (average of all trials), block
design in the revised Wechsler intelligence scale for children, the
Boston naming test (no cues, cues), and the California verbal learning
test (long-term reproduction). The results of these analyses differ in
certain respects from those of the main analyses. First, the set of
end-points on which the two groups differed is similar to but not
completely identical with the set found in the main analyses to be
significantly associated with the concentration of mercury in cord
blood. Moreover, in contrast to the main analyses, interaction terms
between mercury concentration and sex were significant for several
scores, including errors in the test for visual-spatial ability,
short-term reproduction in the California verbal learning test, all
three finger-tapping conditions, reaction time in the continuous
performance test, and average hand-eye coordination. In all these
tests, associations were found for boys but not for girls.
In a cross-sectional study, Grandjean et al. (1999) evaluated 351
children aged 7-12 who were living in villages in the Amazon Basin. In
three of the villages, in which the population frequently consumed
fish contaminated by gold-mining activities downstream, the
concentration of mercury in the hair of 80% of children was > 10
µg/g. In a fourth village, where the fish was not contaminated, only
1% of children had concentrations of mercury in their hair > 10 µg/g.
The aspects of neurobehavioural function evaluated included manual
dexterity, short-term auditory memory, nonverbal memory, and
visual-spatial skills. The concentration of mercury was associated
with worse performance on the Santa Ana formboard test for manual
dexterity (Lezak, 1995) and a copying test for visual-spatial skills.
22.214.171.124 Sensory, neurophysiological, and other end-points
In the study in the Faroe Islands, the evaluation at seven years
also included assessments of visual acuity and near-contrast
sensitivity, otoscopy and tympanometry, neurophysiological tests
(pattern reversal visual evoked potentials at 30' and 15', brainstem
auditory evoked potentials at 20 and 40 clicks/s, postural sway), and
cardiovascular function (Grandjean et al., 1997; Sorensen et al.,
1999). Peaks I, III, and V of the brainstem auditory evoked potential
at 20 and 40 Hz were slightly delayed in children who had had higher
concentrations of mercury in their cord blood ( p < 0.01-0.1),
although the interpeak latency was not associated with the mercury
concentration at either frequency. In additional analyses (Murata et
al., 1999a), data from the second year of data collection (1994) were
excluded because of concern about the accuracy of electromyography.
Higher concentrations of mercury in maternal hair and cord blood were
associated with lower peak III latencies and longer peaks I-III
latencies. Of the four conditions under which postural sway was
assessed, only that with the eyes closed and not standing on foam
approached significance ( p = 0.09). Visual acuity, contrast
sensitivity, and variation in heart rate were not related to exposure.
Additional preliminary analyses suggested that both systolic and
diastolic blood pressure increased with concentrations of mercury in
cord blood < 10 µg/L (14 and 15 mm Hg for an increase from 1 to 10
µg/L), and that, in boys, the variation in heart rate decreased with
increasing concentration in cord blood (47% for an increase in cord
blood mercury from 1 to 10 µg/L) (Sorensen et al., 1999).
In a cross-sectional study of 149 children in the Madeira Islands
(Portugal), Murata et al. (1999b) examined the association between the
concentrations of mercury in maternal and children's hair and visual
and brainstem auditory evoked potentials. As the dietary habits were
stable, the current concentration of mercury in maternal hair was
assumed to be a reliable estimate of the concentration during
pregnancy. The children's hair concentrations were not significantly
associated with any peak latencies and with only one interpeak
interval. The concentrations of mercury in maternal hair were
significantly associated with the I-III and I-V interpeak intervals at
both 20 and 40 Hz and with the latencies of peaks III and V at both
frequencies. Only the latency of pattern reversal visual enoked
potential at 15 min was significantly associated with the
concentration of mercury in maternal hair.
The relationship between blood mercury concentration and auditory
function was investigated by Counter et al. (1998) in 36 children and
39 adults living in a gold-mining region in Ecuador and 15 children
and 19 adults living in a control area. Mercury is liberated as a
vapour in the process by which gold is extracted from alluvial
sediments, making occupational exposure among gold miners a
significant problem. Some of the mercury is methylated by aquatic
organisms, enters the food chain, is biomagnified, and is consumed in
fish. The concentration of mercury in blood was significantly higher
in the individuals in the gold-mining area (18 µg/L) than in the
control area (3 µg/L). Neurological and otological examinations were
carried out on all persons, and audiological evaluations consisting of
determinations of the conduction thresholds of pure tones in air in
each ear at 0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz were carried out on 40
individuals in the study area; brainstem auditory evoked potentials
were measured on 19 subjects. The absolute latencies of waves I, II,
III, IV, and V and the interpeak latencies of I-III, III-V, and I-V
were measured for the left and right sides. The concentration of
mercury in blood was significantly associated with the hearing
threshold at 3 kHz in the right ear for children only. A borderline
association was found between blood mercury and I-III interpeak
transmission time on the left side.
2.3.3 Adult neurological, neurophysiological, and sensory function
The effects of chronic exposure to methylmercury on adult
neurological function are being assessed by Lebel and colleagues in
fish-eating populations living along the Tapajos River in the Amazon
Basin who were exposed to mercury released during the extraction of
gold from soil or river sediments. Lebel et al. (1996) studied 29
young adults aged 15-35 years (14 female and 15 male), randomly
selected from among participants in a previous survey. The geometric
mean concentration of mercury in hair was 14 µg/g (range, 5.6-38). The
subjects underwent a battery of quantitative behavioural sensory and
motor tests, including tests of visual function (near and far acuity,
chromatic discrimination, near-contrast sensitivity, peripheral visual
fields) and motor function (maximum grip strength, manual dexterity).
Individuals with elevated concentrations of mercury in hair had
reduced chromatic discrimination; the three persons with
concentrations > 24 µg/g had reduced contrast sensitivity, while
those with concentrations > 20 µg/g tended to have reduced peripheral
visual fields. The associations found between hair mercury
concentration and motor function were sex-specific, as more heavily
exposed women but not men tended to have lower scores in tests for
manual dexterity and grip strength.
In a subsequent study, Lebel et al. (1998) assembled another
sample of 91 individuals aged 15-81 years, representing approximately
38% of the adult population of the village being studied. Four indices
of exposure were derived on the basis of the concentration of mercury
in a hair sample: mean total concentration averaged over all 1-cm
segments of the sample, total mercury in the first centimeter, maximum
total mercury in any segment, and methylmercury in the first
centimeter. People who had > 50 µg/g in at least 1 cm of hair were
excluded. The mean concentration of methylmercury in hair was
approximately 13 µg/g. The assessments included the same tests of
motor and visual function that were used in the previous study and, in
addition, a clinical neurological examination which was administered
to a random sample of 59 members of the cohort. The examination
included the Branches' alternate movement task, which requires
imitation of a prescribed sequence of hand movements. Abnormal
performance on the test was significantly associated with all indices
of exposure to mercury, while abnormal visual fields were associated
with mean and peak concentrations of mercury. Patellar and bicepital
hyperreflexia were not associated with any index. Higher
concentrations of mercury, most notably peak concentrations, were
associated with poorer scores in the intermediate and higher
frequencies of near visual contrast sensitivity (in the absence of
near visual acuity loss) and in the test for manual dexterity, with
greater muscular fatigue. In women, but not men, grip strength varied
with peak mercury concentration. For many end-points, the associations
with mercury in hair were stronger in younger (< 35 years) than in
Beuter and Edwards (1998) studied the association between the
concentration of mercury in hair and the frequencies of four types of
tremor: resting, kinetic, postural with visual feedback (static), and
postural without visual feedback (proprioceptive). The subjects were
adults aged > 40 whose mercury levels had been monitored annually
for 25 years (1970-95). The group with heavy exposure consisted of 36
Cree people from northern Quebec, Canada (26 women and 10 men). The
maximum individual concentration of mercury in hair ranged from 2.2 to
61 µg/g, while the mean annual maximum concentration ranged from 2.2
to 31 µg/g. The group considered to have light exposure to mercury
consisted of 30 adults from the Montreal area (18 women and 12 men),
but the mercury levels for this group were not reported. Significant
differences between the two groups were found in several aspects of
static tremor (drift, amplitude differences, skewness, asymmetry,
one-dimensional entropy, asymmetric decay of the autocorrelation
function) and of kinetic tremor (mean tracking error, power in the
3-4-Hz range, peaked velocity distribution).
2.3.4 Bias: Covariates, confounders, and effect modifiers
Analysis of the potential biases that may have occurred in the
major epidemiological studies of exposure to methylmercury forms part
of the assessment. The three main studies are those in the Faroe
Islands, the Seychelles, and the Amazon Basin, for which information
bias, selection bias, and confounding factors are reviewed, with the
methods of control used. Short descriptions of new data or analyses in
the studies in New Zealand, Peru, and Iraq are also reviewed.
Such biases could affect the internal and/or the external
validity of the studies. Selection bias could occur, for example, if a
portion of the population had a different probability of participating
in the study than the general population or if individuals with
particular health conditions did not participate. Information bias can
occur when the outcome measure is affected by knowledge of exposure
status. Confounding factors, the major potential sources of bias in
these studies, are associated with both exposure and outcome but are
not part of their causal relationship.
126.96.36.199 Study in the Faroe Islands
Selection bias: Selection bias could have occurred in the study
in the Faroe Islands at the time of recruitment or during the
follow-up. The children who were examined were comparable to those in
the full birth cohort, which represented 75% of all 1367 births that
occurred during during the sampling period. The non-participants were
born mainly in two small hospitals (with respective participation
rates of 46 and 33%; Grandjean & Weihe, 1993) and had had heavy
exposure to mercury, especially in one hospital (275 nmol/L vs 114
nmol/L in the capital city, Torshavn). Because of this problem, the
exposure of the overall cohort is lower than that of the background
population. The loss of subjects from the study was low (9.7%), and
the non-participants (106 persons) having somewhat lower exposure (18
µg/L) than the participants (23 µg/L), owing to the lower
participation rate of children born in Torshavn.
Some tests, such as the paper-and-pencil and tactual performance
tests, were not performed by 85 of the children who had heavier
exposure to methylmercury (30 µg/L) than those who completed these
tests (22 µg/L). The results of these tests were not considered in the
final analyses, however, because of problems in scoring and unusual
distributions of data. In general, the very high participation rate
obtained in the study reduces the likelihood of major selection bias.
Information bias: This type of bias was not likely to occur in
the study since the children's exposure status was not known to the
examiners, the children, or their parents. The report does not,
however, state whether the parents were told the concentrations of
mercury in cord blood or in maternal or children's hair. Some of the
responses on the questionnaire could have been affected by this kind
Confounding factors: In such studies, numerous confounding
factors could affect associations between exposure to mercury and
neurodevelopmental outcomes. Those most relevant to the study in the
Faroe Islands are as follows:
* Mother's age: Since mercury accumulates in the body and older
people tend to have a more traditional diet, age is potentially
positively associated with exposure to mercury. No data were
provided on the relationship between the mother's age and the
body burden of mercury, and it is not clear whether maternal age
is associated with child development. Factors such as prematurity
and maternal cognitive function may differ according to a
mother's age at the time of the birth of a child. Maternal age
was not taken into account in the regression analyses.
* Birth weight: Low birth weight is known to be associated with
delayed neurodevelopment, particularly in premature infants (body
weight < 2500 g). Birth weight could also be associated with
fish consumption, as in some observational studies and clinical
trials, omega-3 fatty acids in fish oil or in fish meal were
reported to increase the duration of gestation and increase
birth weight (Olsen et al., 1993), although Foldspang and Hansen
(1990) reported an association between lower birth weight and
mercury concentration in Greenland. Low birth weight is generally
rare among newborns in the Faroe Islands, whose weights are on
average 200 g higher than in Denmark (Olsen et al., 1993). In the
Faroe Islands cohort, the number of fish dinners was positively
associated with birth weight. This potential confounder would
bias the results towards the null hypothesis: that seafood
increases both exposure to mercury and birth weight. Birth weight
was not taken into account in the final analysis.
* Breast-feeding: Breast-feeding was not considered as a
confounding factor in the analysis, as methylmercury is not
transferred to nursing infants. The concentrations of mercury in
hair were two to three times higher among infants who were
breast-fed for > 12 months than those breast-fed for 0-3 months
(Grandjean et al., 1995b). Breast-feeding is related to parental
behaviour that could affect brain development, and breast milk
provides essential nutrients, such as docosahexanoic acid, which
are important for brain development. Because the statistical
analyses were based on the concentrations of mercury in
children's hair at 12 months of age, however, the effects of
breast-feeding were taken into account indirectly.
* omega-3 fatty acids: omega-3 fatty acids are polyunsaturated,
long-chain (20-22 C) fatty acids with five or six double-bonds
starting from the third carbon after the methyl terminal group.
They are essential lipids and are not synthesized by the human
organism but are derived from the diet, seafood being the major
source. The main polyunsaturated fatty acids are eicosapentanoic
acid and docosahexanoic acid, although docosapentanoic acid is
also found in sea mammals. In sea mammal blubber or lipids,
polyunsaturated fatty acids represent 25-30% of all lipids, with
a lower proportion in pilot whales. Eicosapentanoic acid is
reported to protect against cardiovascular disease, and
docosahexanoic acid is a major component of brain lipids and
retina and is essential for visual acuity and optimal brain
development. It is now added to most infant formulas. The
concentration of polyunsaturated fatty acids in the phospholipids
of newborns and mothers in this cohort is not known but would be
expected to be higher than that in urban populations. Olsen et
al. (1986) reported that erythrocyte membranes from pregnant
women in the Faroe Islands contained 20% more polyunsaturated
fatty acids than those of women on the mainland and that the
quantity was related to the consumption of fatty fish and sea
mammals. Since mercury and PCBs are both found in seafood, their
concentrations would be expected to correlate with that of
polyunsaturated fatty acids. Since the latter enhance brain
development and vision, this confounding effect would bias the
results towards the null hypothesis. Polyunsaturated fatty acids
were not considered in the final analysis.
* Selenium: Selenium is an essential trace element, of which
seafood is a good source. The concentrations of selenium vary
considerably in human populations, presumably reflecting selenium
levels in the environment. Although the efficacy of this element
as an antidote against mercury in humans remains controversial
(WHO, 1990), selenium has been shown to counteract the toxicity
of methylmercury in many experimental systems (reviewed by
Whanger, 1992), including neuron cultures (Park et al., 1996).
Both selenium and vitamin E reduced the toxic response of the
nervous system to exposure to mercury (WHO, 1990). Studies in
rodents suggest that supplementation of the maternal diet with
selenite provides partial protection against some adverse effects
resulting postnatally from exposure to methylmercury in utero
(Frederiksson et al., 1993). In the study in the Faroe Islands,
the median concentration of selenium in whole umbilical cord
blood was 1.4 µmol/L, and a slight but significant increase was
seen with the number of fish dinners per week. The authors
reported that the concentration of selenium in this population
was high. Although most of the available data on selenium are
derived from measurements in plasma samples, and are therefore
underestimates of the whole-blood concentrations, comparative
geometric means are available for Norway (Saami; 1.5 µmol/L), the
Russian Federation (Kola Peninsula; 1.1 µmol/L), and Canada
(Nunavik; 3.7 µmol/L) (Arctic Monitoring and Assessment
Programme, 1998). In the Faroe Islands cohort, selenium
concentration was positively associated with mercury
concentration ( r = 0.35; p < 0.001), indicating that
exposure to mercury is associated with that to selenium. Although
selenium cannot be considered a confounder per se (because it is
not known to be associated with the outcomes), it could bias the
study results towards the null hypothesis. Selenium was not
considered at the final step of the regression analysis.
* Polychlorinated biphenyls and persistent organic pollutants:
Tooth whales are known to accumulate lipophilic compounds such as
PCBs and other persistent organochlorine environmental
pollutants. The average concentration of PCBs (expressed as
Aroclor 1254) in 39 samples of pilot-whale blubber from the Faroe
Islands was 17 mg/kg (Simmonds et al., 1994), and the average
intake was 1700 µg/person per week (3.5 µg/kg bw per day). As the
total average concentration of DDE, a ubiquitous persistent
organic pollutant, was 12 mg/kg, the intake of both these
compounds and PCBs might be expected to be high among pregnant
women and their offspring in the Faroe Islands. Extensive
epidemiological data are available on the neurodevelopmental
effects of prenatal exposure to PCBs and persistent organic
pollutants (Rogan& Gladen, 1991; Koopman-Esseboom et al., 1996;
Jacobson & Jacobson, 1997), although controversy persists about
the long-term effects of prenatal exposure to PCBs. Since PCBs
may be a risk factor for adverse neurobehavioural development,
however, and since they are found in large quantities in pilot
whales, they should be considered an important potential
confounder. The PCB concentration in cord tissue was strongly
correlated with that of mercury (r = 0.38 when PCBs were
expressed on the basis of lipid and 0.44 when expressed as wet
weight). As serum samples were not taken, PCBs were measured in a
subsample of 436 stored samples of cord tissue from the 443
children seen in 1993. This adjustment decreased the size of the
cohort by 50% and consequently decreased the power of the study.
The samples were divided, and PCBs were measured in two
laboratories, but data on the duplicate analysis have not been
reported. The total concentration of PCBs was calculated by
multiplying the sum of PCB congeners 138, 153, and 180 by two.
The relative reliability of measurements in cord tissue as
compared with plasma or serum lipids is not known. No paired
measurements of lipophilic compounds were made in cord tissue or
established tissue matrices (e.g. cord blood and tissue). It
would have been desirable to express all concentrations on the
basis of lipids because umbilical cord thickness and lipid
content vary among newborns; the cord length is generally around
58 cm but can range from 20 to 100 cm (Abgoola, 1978). A short
cord is associated with fetal akinesis or maldevelopment of the
central nervous system (Ente & Penzer, 1991). As the water
content of cord tissue (89%) varies according to the content of
Wharton's jelly, this tissue is a poor biomarker for lipophilic
compounds like PCBs and persistent organic pollutants.
Furthermore, the water content decreases with length of gestation
(Sloper et al., 1979); thus, if the lipid content of cord tissue
increases with gestational age, the amount of PCBs measured in
whole cord tissue will be affected not only by the actual
exposure but also by newborn developmental factors. In the Faroe
Islands cohort, the lipid content of cord tissue was 2.2 mg/g
(0.22%); no SD was given. The mean total concentration of PCBs in
the subsamples was 1.1 ng/g wet weight, and the lipid
concentration can be calculated to be 1.1 × 454 = 508 µg/kg or
0.51 µg/g. The value should, however, have been reported as 1.02
µg/g, since the authors did not multiply the sum of the three PCB
congeners by 2, as was done previously (P. Grandjean, personal
communication, 1999). This calculated concentration is still less
than the previously reported concentration of PCBs in breast-milk
samples from women in the Islands, which were analysed in four
pools: range, 1.9-3.5 µg/g; average of four pools, 2.5 µg/g lipid
basis (Grandjean et al., 1995a). This concentration is close to
those found in consumers of Arctic sea mammals (Dewailly et al.,
1989, 1993). Thus, umbilical cord appears to be unreliable tissue
for measuring exposure to PCBs; however, the effect of expressing
PCBs on a whole weight basis on the statistical power of the
study is mitigated by the wide variation in PCB concentrations
between individuals. The fact that mercury correlates less with
PCBs expressed on a lipid basis than when expressed on a whole
weight basis probably reflects this imprecision, and PCBs should
have been adjusted for on a lipid basis. The reliability of cord
tissue for measuring PCB and persistent organic pollutants needs
to be clearly demonstrated.
Because PCBs and persistent organic pollutants are
associated with both exposure to methylmercury and child
development in this study, and because any confounding effects of
PCBs will lead to a false-positive association between exposure
to methylmercury and child development, the confounding role of
PCBs and persistent organic pollutants should be reassessed in
order to determine the role of methylmercury in the adverse
effects reported in this study.
* Smoking: Smoking is unlikely to be an important confounding
factor in this study as it is not known to be a source of
mercury. It is, however, strongly associated with low birth
weight, which in turn is a risk factor for poor cognitive
development. In the cohort study, 40% of the women smoked while
pregnant, but smoking was not associated with mercury
concentration or with outcome.
* Alcohol consumption: Alcohol consumption during pregnancy is a
major cause of abnormal fetal brain development. It is also often
related to dietary habits. It is well known that alcohol
consumption among pregnant women is difficult to measure. In the
study in the Faroe Islands, alcohol consumption during pregnancy
was considered to be low; occasional consumption was reported by
24% of the women. Alcohol consumption was negatively associated
with exposure to mercury and was unexpectedly associated with the
results of some of the tests. The association may be due to the
inclusion of women in Torhavn, who drink more and eat less pilot
whale, thus having less exposure to mercury. The means by which
alcohol consumption was measured is not described, even in the
reference cited (Grandjean et al., 1992), and this factor was not
considered in the final analysis. Since exposure to alcohol and
mercury were negatively associated, any confounding effect would
lead to the null hypothesis.
* Maternal cognitive level: Since maternal cognition is associated
with child development and could affect dietary habits, it is
considered to be an important potential confounding factor. The
maternal score on Raven's progressive matrices was available for
92.5% of the mothers, and a significant negative association
(r = -0.13; p < 0.001) was found with exposure to mercury.
Maternal cognitive level was included in the final regression
* Socioeconomic status: Exposure to mercury and consumption of
pilot whale could be associated with socioeconomic status and
health outcomes. Most of the association between mercury and
socioeconomic status is due to the fact that the women in
Torshavn, who may have been better educated, were less exposed to
mercury because their diet was less traditional. Thus, more
highly exposed children were likely to belong to families of
lower socioeconomic status, as was found in analyses in which
mothers in unskilled occupations had significantly greater
exposure while children in day care had significantly less
exposure. Day care, maternal education, paternal education, and
paternal employment were therefore included in the final
analysis. The methods used to measure socioeconomic status were
not described. Such details would be valuable since the
association between concentration of mercury and neurological
outcomes decreased after adjustment for socioeconomic variables.
* Age of the children: The age of the children at the time of
testing was also included in the final analysis since age was
associated with the results of the neuropsychological tests.
A review of all the potential confounding factors indicates that
PCBs and socioeconomic factors were the most probable sources of bias
in the study in the Faroe Islands. Adjustment for the city of
residence (Torshavn or settlements) and for PCBs expressed on the
basis of lipids may decrease the impact of these factors.
188.8.131.52 Study in the Seychelles
In the study in the Seychelles, the confounding factors that were
identified and used in the final regression analyses were the same at
testing at 6.5, 19, 29, and 66 months. The concentration of mercury in
maternal hair was used as the marker of prenatal exposure. In general,
most of the confounding factors were selected for their potential
association with childhood development but not with exposure to
mercury and were as follows: intelligence of the caregiver (Raven's
score), birth weight, gestational age, sex, birth order, history of
breast-feeding, medical history of the child and of the mother, age of
the mother, maternal tobacco and alcohol use during pregnancy, home
environment, parental education, family income, and language spoken at
home. A reduced model with a limited number of variables was also
used. No association was found between prenatal exposure to mercury
and developmental outcomes at 6.5, 19, 29, or 66 months of age. The
following section focuses on whether potential biases can explain the
lack of association.
Selection bias: As the study population comprised 50% of all
births, some selection bias could have occurred. Recruitment was
restricted to Mahé Island for practical reasons and because 90% of the
population live on it. No information was provided about the reason
for the non-participation of 45% of the eligible population. The
authors speculated that the reasons may have included no contact with
the family, lack of understanding of the study, conflicting
responsibilities, refusal to allow their child to be examined, or
superstition about removal of hair from themselves or their child. The
second reason stated raises the possibility that the selected
population was better educated than the non-participants, as suggested
by the low percentage (3%) of abnormal or questionable scores on the
revised Denver developmental screening test when compared with other
studies. Exclusion of 18 children from the study could have resulted
in a 'healthy child' effect. There is no major potential information
bias, because both the mothers and the examiners were unaware of the
exposure status of the children to mercury.
Confounding factors: The most relevant confounding factors for
the study in the Seychelles are as follows:
* Polychlorinated biphenyls: PCBs (28 congeners) were measured in
49 randomly selected serum samples from children aged 5.5 years,
and no PCBs were detected, as was to be expected on an island in
the Indian Ocean. It would, however, have been helpful to know
whether other potentially neurotoxic chlorinated compounds were
detected, as they are often present in the Southern Hemisphere.
For example, DDT is used extensively for malaria control in
Mauritius and Madagascar and other islands of the Indian Ocean.
* omega-3 fatty acids: omega-3 fatty acids were not measured in the
study in the Seychelles. Most studies on the fatty acid content
of fish have been conducted in the Northern Hemisphere, but
analysis of the fatty acids in lipid extracts from tropical
seafood in Australia showed that the content of arachidonic acid
represented 4.8-14% of the total. The seafood contained almost no
linoleic acid but was a rich source of omega-3 fatty acids
(14-31% of the total). Thus, seafood from tropical waters, unlike
seafood from colder waters, is a natural source of
polyunsaturated fatty acids in both the omega-6 and omega-3
series (O'Dea & Sinclair, 1982). Since omega-3 fatty acids are
concentrated in fatty fishes, and these predators often contain
high concentrations of mercury, the concentration of omega-3
fatty acids in the blood of Seychellois can be expected to
correlate strongly with the concentrations of mercury in blood or
hair. In a report of a workshop on methylmercury (National
Institute of Environmental Health Sciences, 1998), it was noted
that omega-3 fatty acids had been measured in randomly selected
cord blood samples and found to be 'in the normal range';
however, there is no abnormal range for these fatty acids, and
the toxicological paradigm does not apply to nutrients. It
remains to be determined whether the concentration of
docosahexanoic acid in cord plasma phospholipids approaches 1.5%,
as observed in western urban areas with low fish intake, or is
closer to 7-8%, as observed in Inuit newborns. The range, the
distribution, and the correlation with mercury should also be
measured. omega-3 fatty acids thus appear to be a major potential
confounding factor, which could explain the absence of
associations, although some positive correlations were seen
between mercury concentration and child development. Since fatty
acids can be analysed in only 0.5 ml of serum, plasma, or
erythrocyte membranes, they could be measured in a large number
of archived cord blood samples. An alternative option will be to
measure them in the blood of mothers attending the next
* Selenium: As mentioned above, selenium could counteract the
neurotoxicity of mercury but is not a true confounder since it is
not known to be related to child development. A high selenium
intake could therefore explain the lack of an association. No
data were available on the selenium status of inhabitants of the
region or of the concentration in fish. The workshop report
(National Institute of Environmental Health Sciences, 1998) notes
that selenium was measured in randomly selected cord blood
samples and found to be 'in the normal range', but it is unclear
whether that refers to values of 1.2, 1.5, or 4 µmol/L. It
remains to be determined whether the concentration of selenium
correlates strongly to fish consump-tion and to exposure to
The role of fish nutrients (mainly omega-3 fatty acids and, to a
lesser extent, selenium) could have masked an association between
exposure to mercury and child development. It is also possible that
the participants in the study were better educated than the
non-participants and that the study did not have sufficient power
because of the low background prevalence of abnormal test results.
184.108.40.206 Study in the Amazon Basin
In the preliminary study (Lebel et al., 1996), neurological
dysfunction (sensory and motor performance) was investigated in 29
adults selected randomly from two villages. Little effort was made to
document potential confounding factors, and only age, location, and
alcohol and tobacco consumption were included in the regression
analysis. In the second study (Lebel et al., 1998), on 91 adults in
one village, near visual contrast sensitivity and manual dexterity
were investigated. The participation rate was 40%. Although
sociodemographic information, smoking and drinking habits, medical and
work histories, and level of education were recorded, the only
potential confounder associated with the results of clinical
examination and neurofunctional tests was age, although other relevant
exposures may not have been considered. As malaria is endemic in the
region, various pesticides (DDT, organophosphates, carbamates, and
pyrethroids) may have been used, most of which are neurotoxic. Thus,
some of the participants may have been exposed to these pesticides
either directly (sprayed) or from consumption of contaminated fish. It
is not known whether exposure to pesticides was associated with the
fish diet or the area of residence. The reliability of the measurement
of alcohol consumption, another potential confounding factor, is
questionable since only three participants reported taking two drinks
or more per week.
220.127.116.11 Study in New Zealand
The study carried out in New Zealand has basic weaknesses
(Kjellström et al., 1986, 1989). Although no confounding was found
from socioeconomic factors, health status, and maternal smoking
(Kjellström et al., 1986), smoking was not graded, and neither alcohol
consumption nor previous pregnancy outcomes were reported. Maternal
consumption of alcohol can cause borderline mental deficiency (see,
e.g. Berkow, 1988), and the children of smokers have lower scores than
those of nonsmokers on most tests of intellectual function and
intelligence at four and seven years of age. Moreover, minor
neurological disorders are more common in children of women who smoke
(Murphy, 1984). Additionally, a matching problem was recognized by the
authors when they reduced the number of pair comparisons from the
original 31 to 23 for ethnic differences or pairing of a New
Zealand-born mother with an immigrant or both, and thus the results of
11 and not 12 of the Denver tests were positive in the group exposed
to mercury. The correct numbers show no significant difference between
children exposed to mercury and reference children: three and not two
positive results and eight and not ten negative results were found
(chi2 = (8-2)2/(8 + 2) = 3.6; p > 0.05). Thus, nine Pacific
Islander pairs were responsible for 10 of the positive responses, and
the other 14 pairs were responsible for only six, indicating that the
effect of ethnic group in this study should be analysed thoroughly.
Irrespective of exposure, the scores on the Denver developmental
screening test were significantly higher among Pacific Islanders than
people of other ethnic groups: 16 positive responses in Pacific
Islanders (57%) and 6 in others (37%) and 12 negative responses in
Pacific Islanders and 28 in others (chi2 = 8.8; p < 0.005). As 25
of the 28 Pacific Islanders were immigrants, a significant difference
would also be expected between the children of immigrant and New
Zealand-born mothers, as was the case: positive responses in six
children of New Zealand-born mothers (18%) and in 15 of immigrant
mothers (54%) and negative responses in 28 and 13, respectively (chi2
= 5.9; p < 0.02). The Pacific Islanders were at greater risk than
Europeans or Maoris, with four positive responses among Pacific
Islanders and one among others and one negative response among Pacific
Islanders and 20 among others (p = 0.034; Fisher exact test).
In the second stage of the study, on six-year-old children, the
exposed group had been increased to 57 and their performance was
compared with that of three groups ( n = 59, 60, and 58) of reference
children in a battery of tests. The larger number of children ensured
satisfactory matching for ethnic group and length of residence in New
Zealand, but the presentation of the data does not allow verification
of the distribution of positive responses by ethnic group in the
exposed and reference groups. This is unfortunate in view of the
results of the first stage of the study and the fact that the ratio of
Pacific Islanders to non-Pacific Islanders was 2 (66% of all children
were Pacific Islanders). Furthermore, the greatest differences between
the exposed and reference groups were found in the tests for spoken
language (8.6%) and the Wechsler test for full-scale IQ (5.3%), out of
16 psychological tests, but the differences in the results of these
two tests were more than twofold greater between Pacific Islanders and
Europeans, 25 and 12%, respectively. Comparison of the results of 16
psychological tests for the children of exposed and of reference
mothers (48 comparisons) gave only two significant differences ( p =
0.034 and 0.045), which are approximately those expected by chance.
Regression analysis showed significant differences in the test
for spoken language, the revised Wechsler intelligence scale for
children, and the McCarthy scales for perceptual performance, but a
clear association with exposure to mercury was seen only at
concentrations in maternal hair >10 µg/g and only when a weighted
regression analysis was used and 14 confounding factors were accounted
for. The reliability of the 'accounting' is questionable when each of
14 confounding variables introduces its own error; when other
statistical manipulations, such as adjusting for outliers, although
they are legitimate for eliminating one source of error, may have been
the source of another type of error; when at least one confounder
(ethnic group) was associated with larger differences in two of the
three tests that correlated with maternal exposure to mercury than was
maternal exposure; and when the highest concentrations of mercury in
hair (> 10 µg/g) accounted for only about 2% of the overall variance.
18.104.22.168 Study in Peru
The study in Peru was conducted between 1981 and 1983 in a
fishing community (Marsh et al., 1995), and hair samples and clinical
data were obtained from 131 mother-infant pairs. Major information
bias is unlikely to have occurred because the neurologists were
unaware of exposure status, but it is not reported whether the mothers
were informed about their exposure to mercury. Recall bias about their
children's development is possible if the mothers knew their exposure
Selection bias could have occurred in this study because hair
samples were obtained from 369 mothers and only 194 of their children,
and complete data were available for only 131 mother-infant pairs. The
reason for this 65% reduction is not described but may have resulted
in selection bias, with greater participation of healthier infants. No
data are available to compare participants and non-participants.
Furthermore, the participation rate among all pregnant mothers in
Mancora during the recruitment period was not reported, and selection
of healthy mothers might also have occurred. Although information was
collected on several potential confounders, including alcohol and
tobacco use, none was considered in the final statistical analysis.
The authors stated that Mancora women drank little or no alcohol, that
the group did not contain any smokers, and that there was little
In this study, the role of nutrients in fish is of major
importance. The authors noted that the difference in the results of
their study and that carried out in Iraq could be due to the
difference in the origin of mercury. They discussed the possible role
of selenium in seafood and the possibility that the infants were
protected against the neurotoxic effects of methylmercury by high
selenium intake from their mothers during the pregnancy, but no data
on selenium concentrations in fish or in biological samples from the
infants or their mothers were available. Another potential nutrient,
which was not discussed in the report, is polyunsaturated fatty acids
and especially docosahexanoic acid, which is present in large
quantities in fatty predator fishes, which are known to accumulate
methylmercury. Polyunsaturated fatty acids may have acted as a
confounding factor in this study, as they are associated with both
exposure to methylmercury and infant development.
This cohort study was therefore possibly affected by selection
bias, and fish nutrients may have masked (polyunsaturated fatty acids)
or mitigated (selenium) the neurotoxicity of methylmercury.
22.214.171.124 Reanalysis of the study in Iraq
The importance of the study in Iraq is that it is still used as
the basis for the assessment of risks to human health risk by WHO and
regulatory agencies. The consequences of exposure were investigated in
adults and in 81 30-month-old children who had been exposed prenatally
(Marsh et al., 1987). Although the heavily exposed infants showed
deficits similar to those reported in Minamata Bay, Japan, efforts
were made to investigate the group with lighter exposure. Selection
bias could have occurred, for example, if the participants had
experienced patent clinical symptoms and volunteered to participate,
leading to an overrepresentation of severe cases. No data are
available on how representative of the background population the
participating children were. Information and recall bias are, however,
the most important biases in this retrospective study, since precise
information on ages at walking and talking and even age at testing was
difficult to obtain, as there was no birth registry, and it had to be
obtained from the mothers. It has been reported elsewhere that mothers
underestimate the age at walking by 0.4 months (Piles, 1935, cited by
Marsh et al., 1987). If such imprecision is equally distributed with
respect to exposure status, this error will decrease the power of the
study and bias the results towards the null hypothesis. It is unlikely
that the mothers were less accurate in their answers to questionnaires
because of exposure to mercury. The incident resulted in contaminated
bread, and this basic food is expected to be consumed by the entire
population regardless of socioeconomic status, level of education, or
3. ESTIMATES OF DIETARY INTAKE
3.1 Environmental mercury
In the environment, methylmercury is produced from inorganic
mercury in natural and anthropogenic sources as a result of microbial
activity. Microbial methylation of inorganic mercury occurs in the
upper sedimentary layers of lakes and sea bottoms, and the
methylmercury formed is rapidly taken up by living organisms in the
aquatic environment. A number of studies of mercury forms in air have
shown that, except in industrial areas, near volcanoes, and mercury
ore deposits, the concentration of total mercury in air is < 10
ng/m3, of which mono-and dimethylmercury account for approximately
22%. As the intake of the general population of methylmercury from air
is estimated to be < 0.04 µg/day, air is considered to be an
insignificant source (WHO, 1990).
The mean concentrations of total mercury in rivers, lakes, and
groundwater range from 10 to 50 ng/L. It can form stable complexes
with various organic ligands in water, but the resulting methylmercury
compounds are rapidly taken up by biota, since < 1 ng/L has been
found in unpolluted waters. If consumption of 1.5-2 L of water daily
is assumed, the intake of methylmercury from this source would be <
0.002 µg/day (WHO, 1990).
Most foods except fish contain very low concentrations of total
mercury (< 0.01 µg/g), which is almost entirely inorganic mercury.
Fish and shellfish contain higher concentrations, and over 90% is in
the form of methylmercury because fish feed on aquatic organisms that
contain this compound, ultimately originating from microorganisms
which biomethylate inorganic mercury. The amount of methylmercury in
fish correlates with a number of factors, including the size and age
of the fish, the species (e.g. larger, older, predatory species like
shark and swordfish usually contain higher concentrations), and, for
freshwater species, the mercury content of water and sediment and the
pH of the water. The concentration of methylmercury in most fish is
generally < 0.4 µg/g, although fish species higher up the aquatic
food chain, such as swordfish, shark, walleye, and pike, may have
concentrations up to several micrograms per gram. The intake of
methylmercury from fish depends on fish consumption and the
concentration of methylmercury in the fish consumed. Many people eat
< 20-30 g of fish per day, but certain groups eat 400-500 g per
day. Thus, the daily dietary intake of methylmercury can range from
< 0.2 to 3-4 µg/kg bw (WHO, 1990). The ranges of concentrations of
methylmercury in various fish species are shown in Table 5.
3.2 Biomarkers of exposure
Two approaches are used currently to assess the body burden of
methylmercury: one based on dietary modelling and the other on
biomarkers. Each has limitations which prevent their use in making
unequivocal estimates of exposure. The outcomes of dietary models
depend on differences in approach and in assumptions, and their
reliability remains to be confirmed. Despite the limitations of the
existing data sets, biological measures of exposure, such as the
concentrations of methylmercury in hair or blood, provide a useful
start for discussions of exposure since they allow a biologically
based validation of dietary models.
The two most popular media for quantifying methylmercury in the
body are blood and hair. Quantitative relationships between exposure
(daily intake) and concentrations in blood and hair were first
established in the study in Iraq and naturally involved many
assumptions, for instance that hair grows at a rate of 1 cm per month.
The relationship between the concentrations of mercury in blood and
hair was verified in several studies, in which the concentrations in
hair ranged from 0-13 µg/g (Netherlands) to 20-325 µg/g (Japan). In
two communities in the United Kingdom, one being a fishing community,
the concentrations in hair ranged from 0.1 to 21 µg/g. These studies
showed that every microgram increase in blood concentration resulted
in a 140-370-µg/g increase in the concentration in hair, although the
regression lines in six of ten studies gave hair:blood concentration
ratios of 230-280. Thus, a ratio of 250 gives a relatively acceptable
extrapolation from one media to the other (WHO, 1990).
Under stable dietary conditions, the concentrations of
methylmercury in blood and hair can be used to predict the possible
effects of methylmercury on health, since the concentrations are
directly proportional to the concentrations of methylmercury in the
brain (Phelps et al., 1980; Cernichiari et al., 1995). The
concentration in hair is about 250 times greater than that in blood at
the time the hair strand is formed. Once formed, a strand grows at a
rate of approximately 1 cm per month and thus provides a record of
previous exposure to methylmercury. Approximately 80% of the mercury
present in the strand is methylmercury (Phelps et al., 1980;
Cernichiari et al., 1995). Hair and blood can both be used to document
exposure, but hair is preferred because it involves a simple,
uninvasive sampling procedure that allows monitoring of the intake of
methylmercury. Total mercury concentrations are typically used to
characterize exposure to methylmercury from fishery products, since
total mercury and methylmercury concentrations are linearly related
and it is less costly to determine total mercury. Although
measurements of total mercury can provide an upper bound of the
concentration of methylmercury in hair, the dose to the brain, and
intake from the diet, they may provide misleading evidence of exposure
and dose if certain hair treatment formulations (cold-wave solutions
and hair relaxers) which extract methylmercury have been used.
Reductions of over 60% have been observed (WHO, 1990).
Table 5. Estimated concentrations
of mercury in fish
Species mg/kg of fish
From WHO (1990)
Studies of the concentrations of mercury in hair provide a set of
data for describing the range of exposures. Two large studies of
women's hair were conducted during the early 1980s. One involved 2000
women aged 15-45 who were part of a dietary panel that was intended to
be geographically and demographically representative of the population
of the United States (Smith et al., 1997). They maintained monthly
diaries of seafood consumption, recording species and amount. At
three-month intervals, hair samples were obtained by cutting strands
of hair close to the scalp from the occipital region. These were
provided by 1437 of the women (72%), were cut into 4-cm segments
corresponding to the three-month period associated with each diary
(i.e. one month before and one month after the month covered by the
diary), and analysed for methylmercury by an electron capture gas
chromatographic method. The concentrations in the hair of women who
had eaten some seafood during the one-month period covered by the
diary were compared with those of women who ate no seafood during that
period. The authors reported that the distribution of methylmercury
concentrations in the two groups was approximately log-normal and that
99.72% of all hair samples had concentrations < 3.9 µg/g.
The concentrations in four samples exceeded 3.9 µg/g (4.4, 5.9, 6.0,
and 6.3 µg/g), and the arithmetic mean for all samples was 0.48 µg/g.
The distribution of concentrations reveals that 90% of all values were
< 1.3 µg/g.
In another analysis, the results were statistically weighted to
reflect the population and were adjusted by season to provide annual
population estimates. The mean, median, and maximum weighted annual
concentrations of mercury in hair were 287, 204, and 3505 µg/kg,
respectively; the 90th percentile concentration was 531 µg/kg. The
mean concentration for men (260 µg/kg) was about 20% lower than that
for women (315 µg/kg), suggesting that use of hair treatments that can
alter hair mercury concentrations was not widespread in the study
population. The mean and median concentrations for children nine years
and younger were 177 and 133 µg/kg, respectively. For the 59 women of
child-bearing age, the mean was 347 µg/kg and the maximum was 1585
µg/kg. A four-day dietary survey included in the study showed that 21%
of the people surveyed reported eating fish during the survey. Those
who had eaten fish at least once during the survey had a mean hair
concentration of 418 µg/kg, while those who had not eaten fish had a
mean concentration of 326 µg/kg(Smith et al., 1997).
3.3 Intake assessment
Estimation of the intake of a contaminant is complicated by the
skewed distribution of residues, since contaminants do not reach food
through controlled or predictable agricultural or manufacturing
processes. It is often possible to control contamination, and those
controls should achieve the maximum impact on potential intakes.
Rational decision-making requires estimates of the major contributors
to intake and the likely impact of proposed controls.
Methylmercury can be ingested as a result of the presence of
mercury in food, water, or air. This assessment is limited to food and
is based on the conservative assumption that all of the results
reported were for methylmercury. National governments may wish to
consider other potential sources of intake and add them to estimates
of intake from foods in order to estimate total intake. Virtually all
of the available data derived from monitoring are for total mercury.
The Committee had received data from 25 countries representative of
all regions of the world, and several countries submitted estimates of
the intake of mercury by their populations. When data on infant or
child intake were available, they were included.
The WHO Global Environment Monitoring System-Food Contamination
Monitoring and Assessment Programme (GEMS/Food) has collected data on
food contamination through a network of participating institutes in
over 70 countries around the world since 1976. It has also developed
five regional and cultural diets for use in estimating the intakes of
a wide range of the world's populations. The diets were derived from
food balance sheets compiled by FAO, and thus provide data that are
comparable across different countries and regions of the world. They
are based on the countries' annual food production, imports, and
exports and do not take into account waste at the household or
individual level; they are thus expected to be overestimates of
consumption of actual food intakes, by about 15%. The data do not,
however, permit the analysis of intakes by subgroups such as children
These diets include estimates of fish consumption. The Committee
used the diets in combination with available data on residues of
mercury to estimate typical mercury intakes. The mercury intake of
high consumers of fish was determined on the basis of analyses by
Australia and the United States. The potential impact of establishing
limits was determined in a Monte Carlo simulation model.
Most of the data on residues were available to the Committee in
summarized form. The United States Total Diet Study and the Australian
Market Basket studies indicate the ranges of residues in a variety of
fish species and products (Table 6; Food & Drug Administration,
1993-96; Australia New Zealand Food Authority, 1998). The United
States also provided information on residues in fresh tuna, swordfish,
and shark from a survey by the National Marine Fisheries Services.
Although data were reported for various oceans, no clear differences
were found. These data are similar to those reported by WHO (1990) and
also show that some species have higher concentrations than others,
including the commonly consumed tinned tuna, flake, and estuarine
fish. A true representative average value cannot be selected.
Table 6. Mercury in fish from Australia and the United States
Fish Concentration (mg/kg) 95th percentile
Calamari rings 0.02 Trace-0.03 NA
Fish, estuarine 0.12 0.09-0.15 NA
Flake fillet (fried) 0.33 0.04-0.80 NA
Tuna, tinned 0.22 0.08-0.56 NA
Tuna, tinned 0.18 0.46
Tuna, fresh 0.2 0.45
Shark 0.96 2.4
Swordfish 0.7 1.1
Data for Australia from the Australia New Zealand Food Authority (1998)
and those for the United States from Food & Drug Administration (1993-96).
Total mercury and not methylmercury was measured in these studies.
NA, not available
An average or mean concentration of mercury residue is
appropriate for estimating the intake of methylmercury in the WHO
GEMS/Food regional diets. The Committee concluded that concentrations
based on estuarine fish, tuna, or flake fillet would be appropriate
for this purpose, and the average values for tinned tuna and flake
fillet were used to provide a range of estimates of regional intakes
3.3.2 National intake estimates
Estimates of the intake of mercury are available for the
populations of 25 countries (Table 7), which provide a good measure of
differences in intake across populations and subgroups, including
infants and children. More than one study was available for some
countries. For example, Australia provided estimates of intake from
their market basket study (Australia New Zealand Food Authority, 1998)
and from their 'diamond' model, and the United States provided an
assessment based on their total diet study and a Monte Carlo
simulation that included additional data on residues in fish
(Carrington, 1999). The 'diamond' model permits assessments for
individuals, including high consumers, because it includes data from
the 1995 National Nutrition Survey and data on water consumption. The
intakes ranged from 0.7 to 5.6 µg/kg bw per week, depending on the
method used, the subgroup evaluated, and the residue data used.
Australia and New Zealand estimated intake for a variety of age
groups, including young children.
Slovakia determined the concentrations of mercury in a study which
duplicate samples of meals were consumed and statistically representative
samples were collected four times a year; estimates of the mercury intake
of infants who were breast-fed or who consumed milk formula were also
provided (Ursínyová & Hladíková, 1997, 1998).
3.3.3 Estimates of intake based on WHO GEMS/Food diets
The Committee estimated the typical intakes of mercury by
consumers by using the average total consumption of all species of
fish and shellfish from the GEMS/Food regional diets and a range of
typical concentrations of methylmercury in fish. For these analyses,
it was assumed that all species would contain one of two
concentrations of methylmercury: the first analysis (Table 8) assumed
a concentration of 0.2 mg/kg of fish, and the second analysis (Table
9) assumed 0.33 mg/kg of fish. These concentrations are in the range
of the average and median values in several countries. As some
species, such as shark and swordfish, often contain concentrations of
mercury residues above these two limits, frequent consumers of these
fish will have correspondingly higher intakes of mercury.
3.3.4 Estimates of intake by fish consumers at the 95th percentile
Australia and the United States also estimated the intake of high
consumers (Table 10). Australia used the actual consumption and two
assumptions about the concentrations of mercury in the fish that were
consumed. In the first analysis, it was assumed that fish contained
0.2 mg/kg, and in the second analysis it was assumed that predatory
fish contained 0.64 mg/kg of fish. The United States took into account
variability in both residue concentrations and food consumption
patterns, using a Monte Carlo simulation to predict the most likely
distribution of mercury intake across each population subgroup. The
analysis was repeated after exclusion of residues at concentrations
over certain limits to simulate the effect of prohibiting fish
containing > 1 or > 0.5 mg/kg.
Although methylmercury can occur in other foods, it is found
primarily in fish. In other foods, mercury is present mainly as
elemental mercury. The Committee noted the variation in concentrations
of methylmercury in fish, both within and between species, and also
noted that fish from polluted waters usually have higher mercury
concentrations than those from unpolluted bodies of water. When
intakes of total mercury were provided, the Committee assumed
conservatively that all of the mercury was methylmercury. A 'typical'
concentration of methylmercury must be established to permit
estimation of intake from the WHO GEMS/Food regional diets. A
'typical' concentration should correspond to the concentrations that
are consumed 'on average' by consumers and should therefore represent
the usual concentrations in commonly consumed species of fish. The
Committee concluded that concentrations based on estuarine fish, tuna,
or flake fillet would be appropriate for this purpose. For these
analyses, the average concentrations found in tinned tuna and flake
fillet were used to derive a range of estimates of regional intakes of
Data on the concentrations of mercury residues in food and/or
assessments of mercury intake were submitted to the Committee by 25
countries which represent the major regions of the world. The WHO
GEMS/Food diets include estimates of fish consumption in each of five
regional diets. The Committee used information from these sources to
estimate typical methylmercury intakes of 0.3-1.1 µg/kg bw per week,
depending on the region of the world. These values are predicated on
the assumption that all fish and shellfish contain methylmercury at
200 µg/kg of fish. If all fish and shellfish that are consumed contain
methylmercury at 330 µg/kg of fish, the intake ranged from 0.5 to 1.8
µg/kg bw per week.
The methylmercury intake of consumers in Australia who were
considered to have a high intake of fish was estimated on the
assumption that the fish contained methylmercury at either 200 or 640
µg/kg of fish. The estimated intakes for consumers in the 95th
percentile were 2.1 and 5.6 µg/kg bw per week, respectively. As these
values are based on the assumption that all fish contain these
concentrations, they are highly conservative estimates of extreme
intake. A probability analysis was conducted in the USA to provide a
more realistic estimate of the intake of methylmercury by consumers in
the 95th percentile, by taking into account variation in both fish
consumption and residue concentrations in the fish that are consumed.
The analysis covered the entire distribution of consumption and
methylmercury residues in fish. An estimate was also provided from a
simulation model of the potential impact of establishing limits on
intake of methylmercury, by repeating the analysis after excluding
residue concentrations that exceeded theoretical regulatory limits of
1000, 500, or 200 µg/kg of fish. The results of the analysis are
presented in Table 10 for consumers in the 95th percentile in three
population groups. These results suggest that the intake of the adult
population will be below the PTWI as long as individuals eat fish with
'typical' concentrations of methylmercury.
The Committee also specifically evaluated the potential intake of
children and infants. The WHO GEMS/Food diets do not include separate
estimates for children, but several countries provided estimates of
the intake of mercury by children and infants. Comparison of the
intake by adults and children in each country shows that children
consume two to three times more mercury than the adult population on
the basis of unit body weight. Nevertheless, the concentrations of
mercury in the hair of children are similar to those in adult hair,
indicating that children have similar body burdens to those of adults.
Therefore, the higher intakes of children would not necessarily result
in an equivalent increase in risk, and, if children are not more
sensitive than adults to methylmercury, the PTWI would be appropriate
for both adults and children. In simulations conducted in the USA,
children were found to have intakes below the PTWI. Although data were
not available to permit equivalent analyses for other countries, the
results can be expected to be similar as long as the concentrations in
fish and the fish consumption are similar to those seen in the USA.
Studies of the kinetics of methylmercury showed that its
distribution in tissues after ingestion is more homogeneous than that
of other mercury compounds, with the exception of elemental mercury.
The most important features of the distribution pattern of
methylmercury are high blood concentrations, high ratios of
erythrocyte:plasma concentration and high concentrations of deposition
in the brain. Another important characteristic is slow demethylation,
Table 7. Estimates of intake of methylmercury, assuming all residues
measured as mercury are actually methylmercury
Country Estimate Populationa Reference
Australia 0.7-4.3b 9-month-old infants Australia New
0.7-3.4b 2-year-old children Zealand Food
0.4-1.7b Adult women Authority (1998)
0.3-1.8b 12-year-old girls
0.3-1.7b Adult men
0.3-1.6b 12-year-old boys
Australia 0.3 Adults WHO (1992)
Belgium 1.63 All Jorhem et al. (1998)
Belgium 1.6 Adults WHO (1992)
China 1.20 All Chen & Gao (1993)
China 0.63 Standard man (58 kg) Gao (1999)
1.61 2-7 year-old children (16.5 kg)
1.69 8-12-year-old children (29.4 kg)
0.42 20-50-year-old men (63 kg)
0.41 20-50-year-old women (53 kg)
Cuba 1.6 Adults WHO (1992)
Denmark 0.09 All Jorhem et al. (1998)
Denmark 1.8 Adults WHO (1992)
Finland 0.22 All WHO (1992)
Finland 0.3 Adults WHO (1992)
France 1.4 Adults WHO (1992)
Germany 0.07 All Jorhem et al. (1998)
Germany 1.6 Adults WHO (1992)
Germany 0.6-0.7c Adult Becker et al. (1998)
Table 7. (continued)
Country Estimate Populationa Reference
Guatemala 1.26 All WHO (1992)
Italy 1.5 Adults WHO (1992)
Japan 0.50 All (55 kg bw) Jorhem et al. (1998)
Netherlands 1.05 All Jorhem et al. (1998)
Netherlands 1.2 Adults WHO (1992)
New Zealand 0.6 Adults WHO (1992)
Poland 2.0 Adults WHO (1992)
Slovakiad 0.9 Children (vegetarian) Ursínyová &
0.8 Children (non-vegetarian) Hladikova (1998)
Sweden 0.7-0.82 All Jorhem et al. (1998)
Sweden 0.3 Adults WHO (1992)
Thailand 0.3 Adults WHO (1992)
United Kingdom 0.3 Adults WHO (1992)
United Kingdom 0.35 All Ministry of Agriculture,
Fisheries & Food (1991)
Table 7. (continued)
Country Estimate Populationa Reference
United States 0.30 60-65-year-old men Food & Drug
0.23 60-65-year-old women Administration
0.23 70-year-old men (1993-96)
0.20 2-year-old children
0.16 40-45-year old men and women
0.15 25-30-year-old men
0.14 6-year-old children
0.12 70-year-old women
0.11 25-30-year-old women
0.10 14-16-year-old boys
0.08 10-year-old children
0.06 14-16-year-old girls
a Body weights in parentheses are assumptions.
b Low end of range based on assumption that samples with no detectable
mercury have none; high end of range based on assumption that the lowest
observable concentration of residue is present in samples with no
c Low end of range, people who do not eat fish; high end, fish consumers
d Low end of range, breast-fed infants; high end, infants fed cow's milk;
formula-fed infants had intermediate values.
Table 8. Mercury intake if all fish contain 200 µg/kg
(mean residue in tuna in Australia and the United States)
and consumption levels are those of GEMS-Food regional diets
Code Commodity Fish intake (g/person per day)
Middle Far African Latin European
Eastern Eastern American
Fish and seafood
WC Crustaceans, fresh frozen 0.3 2.3 0.0 1.5 3.0
MD Dried fish 0.3 2.8 4.4 4.8 0.8
WS Demersal, frozen whole 0.0 0.0 0.9 0.5 3.8
WS Demersal, frozen fillets 0.0 0.0 0.0 1.3 5.0
WS Demersal, cured 0.0 0.3 0.6 4.5 0.5
WS Demersal 2.0 3.0 2.4 0.0 9.0
WF Freshwater, tinned 0.0 0.0 0.0 0.0 0.8
WF Freshwater, frozen whole 0.0 0.0 0.0 0.0 0.3
WF Freshwater, cured 0.3 0.5 1.4 0.0 0.0
WD Freshwater diadrom, fresh 1.3 5.3 4.7 1.3 1.5
WS Marine fish (not otherwise 2.8 5.2 5.1 18.3 2.8
specified), fresh frozen
WS Marine fish (not otherwise 0.0 1.0 0.0 0.3 0.0
IM Molluscs except 0.0 4.0 0.5 0.8 8.3
IM Molluscs, tinned 0.0 0.0 0.0 0.0 0.8
WS Pelagic, tinned 1.8 0.8 0.5 4.8 4.8
WS Pelagic, frozen whole 0.3 2.0 0.7 0.3 1.3
WS Pelagic, cured 0.0 1.0 2.4 0.0 0.3
WS Pelagic marine fish, fresh 4.3 5.8 13 7.0 3.8
Total fish intake per day (g/person) 13 35 36 45 46
Table 8. (continued)
Code Commodity Fish intake (g/person per day)
Middle Far African Latin European
Eastern Eastern American
Estimated intake of mercury
Total (µg/person per day) 2.6 7.0 7.2 9.0 9.2
Total (µg/person per week) 18 49 50 63 64
Total (µg/kg bw per week) 0.3 0.8 0.9 1.1 1.1
(for 60-kg adult)
% of PTWI (3.3 µg/kg bw) 9% 25% 26% 32% 33%
for 60-kg adult
Residue concentration that would 2.2 0.82 0.78 0.63 0.61
be less than PTWI (mg/kg of fish)
assuming a 60-kg adult consumes
fish with this concentration on a
Table 9. Mercury intake if all fish contain 330 µg/kg
(mean residue in flake fish in Australia) and consumption
levels are those of GEMS-Food regional diets
Commodity Fish intake (g/person per day)
Middle Far African Latin European
Eastern Eastern American
Fish and seafood
Crustaceans, fresh frozen 0.3 2.3 0.0 1.5 3.0
Dried fish 0.3 2.8 4.4 4.8 0.8
Demersal, frozen whole 0.0 0.0 0.9 0.5 3.8
Demersal, frozen fillets 0.0 0.0 0.0 1.3 5.0
Demersal, cured 0.0 0.3 0.6 4.5 0.5
Demersal 2.0 3.0 2.4 0.0 9.0
Freshwater, tinned 0.0 0.0 0.0 0.0 0.8
Freshwater, frozen whole 0.0 0.0 0.0 0.0 0.3
Freshwater, cured 0.3 0.5 1.4 0.0 0.0
Freshwater diatom, fresh 1.3 5.3 4.7 1.3 1.5
Marine fish (not otherwise 2.8 5.2 5.1 18.3 2.8
specified), fresh frozen
Marine fish (not otherwise 0.0 1.0 0.0 0.3 0.0
Molluscs except cephalopods, 0.0 4.0 0.5 0.8 8.3
Molluscs, tinned 0.0 0.0 0.0 0.0 0.8
Pelagic, tinned 1.8 0.8 0.5 4.8 4.8
Pelagic, frozen whole 0.3 2.0 0.7 0.3 1.3
Pelagic, cured 0.0 1.0 2.4 0.0 0.3
Pelagic marine fish, fresh 4.3 5.8 13 7.0 3.8
Total fish intake
per day (g/person) 13 35 36 45 46
Table 9. (continued)
Commodity Fish intake (g/person per day)
Middle Far African Latin European
Eastern Eastern American
Estimated intake of mercury
Total (µg/person per day) 4.3 12 12 15 15
Total (µg/person per week) 30 80 84 100 110
Total (µg/kg bw per week) 0.5 1.3 1.4 1.7 1.8
(for 60-kg adult)
% of PTWI (3.3 µg/kg bw) 15% 40% 43% 53% 54%
for 60-kg adult
Table 10. Estimated intake of methylmercury by fish consumers at the 95th percentile
Country Population 95th percentile consumer
1. Using point estimates for consumption and mercury residues in fish
Australia Total population 2.1-5.6 µg/kg bw per week
Women of child-bearing age 1.4-4.9 µg/kg bw per week
2. Using distributions of consumption and mercury residues in fish and a Monte Carlo
Scenario 1: No limit, e.g. assuming current distribution of residues in fish as sampled
in the United States
Children 2-5 years All seafood 1.5 µg/kg bw per week
Women All seafood 0.8 µg/kg bw per week
Total US population All seafood 0.9 µg/kg bw per week
Scenario 2: Limit of 1 mg/kg of fish, assuming all residues above the limit are
eliminated from the food supply
Children 2-5 years All seafood 1.4 µg/kg bw per week
Women All seafood 0.7 µg/kg bw per week
Total US population All seafood 0.9 µg/kg bw per week
Scenario 3: Limit of 0.5 mg/ kg of fish, assuming all residues above the limit are
eliminated from the food supply
Children 2-5 years All seafood 1.4 µg/kg bw per week
Women All seafood 0.6 µg/kg bw per week
Total US population All seafood 0.8 µg/kg bw per week
Table 10. (continued)
Country Population 95th percentile consumer
Scenario 4: Limit of 0.2 mg/kg of fish assuming all residues above the limit are
eliminated from the food supply
Children 2-5 years All seafood 0.8 µg/kg bw per week
Women All seafood 0.4 µg/kg bw per week
Total US population All seafood 0.5 µg/kg bw per week
which is a critical detoxification step. Methylmercury and other
mercury compounds have a strong affinity for sulfur and selenium.
Although selenium has been suggested to provide protection against the
toxic effects of methylmercury, no such effect has been demonstrated.
A variety of effects have been observed in animals treated with
toxic doses of methylmercury. Some of these, such as renal damage and
anorexia, have not been observed in humans exposed to high doses. The
primary tissues of concern in humans are the nervous system and
particularly the developing brain, and these have been the focus of
Methylmercury induces neurotoxicity in small rodents such as mice
and rats at doses that usually also affect other organ systems.
Moreover, the maternal dose that damages the nervous system of
offspring exposed in utero also results in maternal toxicity. The main
neurological signs are impairment of coordination and pathological
changes in selected areas of the brain and spinal cord. Similar
effects are seen in domestic animals. In cats, no difference in
toxicity was observed between methylmercury naturally present in fish
and methylmercury added in pure form to the diet.
Similar effects of methylmercury were observed in four-year
studies in non-human primates, in which the techniques used to detect
neuronal damage included pathological and behavioural tests and
investigations of the visual and auditory systems. Although the number
of animals included in these experiments was small, the NOEL was 10
µg/kg bw per day (expressed as mercury and corresponding to a
steady-state blood concentration of 0.4 µg/L).The clearance, half-life
and blood concentrations of methylmercury at steady-state depend on
the body surface area. On the basis of body weight, small animals are
much less sensitive to methylmercury than are humans, while the
sensitivity of non-human primates is similar to that of humans.
The two biomarkers used most frequently for quantifying the
burden of methylmercury in the human body are blood and hair
concentrations. Establishment of a quantitative relationship between
exposure (daily intake) and concentrations in blood and hair began
with a study of accidental consumption of grain treated with
methylmercury fungicide in Iraq. Although the weight of evidence
suggested that every microgram per litre increase in blood
concentration results in an increase of 140-370 µg/kg of hair, in six
of ten studies, the ratio of hair:blood concentration was 230-280. The
Committee concluded that a ratio of 250 is a reasonable central
estimate of the ratio of hair:blood concentration. The approximate
relationships between weekly intake and blood concentration of mercury
at steady state indicate that intake of 1 µg of mercury per kg bw per
week in the form of methylmercury corresponds to a concentration of
mercury of 10 µg/L of blood and 2.5 mg/kg of hair.
Since the Committee's previous consideration of methylmercury, a
considerable amount of data have become available on the possible
neurobehavioural effects of prenatal and postnatal exposure. The most
relevant data are from two large prospective epidemiological studies
of cohorts assembled from the populations of the Faroe Islands and the
Seychelles, who eat large amounts of seafood. The prenatal exposure of
the two cohorts to mercury appears to have been similar. The geometric
mean concentration of mercury in the hair of mothers during pregnancy
was 4.3 µg/g (interquartile range, 3-8 µg/g) in the Faroe Islands and
6.8 µg/g (range, 0.5-27 µg/g) in the Seychelles. In the Faroe Islands,
the geometric mean concentration in umbilical cord blood was 23 µg/L
(interquartile range, 13-41 µg/L). In the Faroes, no association was
seen between the extent of prenatal exposure to mercury and
performance in clinical or neurophysiological tests, although
significant decrements were observed in the children's scores in tests
of functions such as fine motor skill, attention, language,
visual-spatial skills, and memory. When the 15% of the children whose
mothers had had hair concentrations of mercury greater than 10 µg/g
were excluded from the analyses, most of the associations were still
apparent. In the study in the Seychelles, no adverse effects
associated with exposure to mercury were reported.
Several differences between the studies may have contributed to
the apparent discrepancy in the findings. First, the children were
evaluated for neurobehavioural end-points at different ages and with
different tests. In the Faroe Islands, the first neurobehavioural
evaluation was conducted when the children were 84 months (seven
years) of age, whereas in the Seychelles, the children were assessed
at 6, 19, 29, and 66 months of age. As the capabilities of young
children change rapidly, the scores at different ages may reflect
performance in qualitatively different types of tasks, and scores
achieved by children of different ages cannot be compared easily. In
addition, although early childhood development was assessed in both
studies, different batteries of tests were used. In the Faroes, the
battery consisted of tests that focus on specific aspects of language,
memory, fine motor function, attention, and visual-spatial skills. In
the Seychelles, the main test was a general test of development that
includes performance in many aspects of neurological function,
although general tests of language, visual-spatial skills and academic
achievement were also used. Even though some types of neurological
function were assessed in both studies (e.g. language and memory), the
differences in the specific tests used make the findings difficult to
Second, the two study cohorts may also differ with regard to
exposure to other factors that can affect the neurobehavioural
development of children. In the Faroes, many potential confounding
factors were addressed in the analysis, including exposure to
polychlorinated biphenyls (PCBs). Pilot whale is the major source of
both methylmercury and PCBs in this population, and PCBs are thought
to adversely affect the neurodevelopment of children exposed
prenatally. When PCBs were measured in samples of umbilical cord
tissue (blood and plasma were not available) from one-half of the
Faroe Islands cohort, the average PCB concentration in cord tissue
lipids was lower than that previously reported in breast milk lipids
in the same population, indicating that cord tissue concentration may
not be an appropriate indicator of the burden of PCBs. In the
Seychelles, potential confounding exposures were not addressed, but it
has been suggested that the finding that a higher intake of mercury
was associated with higher scores in some tests of development is a
result of nutritional factors or mitigating substances present in
Third, the intake patterns of the two cohorts may have differed.
Most of the methylmercury consumed in the Faroes is from pilot whale,
which is eaten less frequently than fish but contains more mercury per
serving. In contrast, the source of methylmercury in the Seychelles is
fish, which is consumed almost daily. Therefore, the intake of
methylmercury in the Faroes may be episodic, with high peak
concentrations of intake. Although the effect of methylmercury on
neurobehavioural development has generally been presumed to be a
function of cumulative intake, short-term peak intake may also be
Further follow-up of these cohorts, with greater coordination
between the study organizers, would be helpful for addressing some of
the issues of assessment. For example, the cohort in the Seychelles
was evaluated at 96 months with many of the same tests as were used in
the Faroe Islands, and the results are expected to become available in
the near future.
The Environmental Health Criteria monograph on methylmercury
(WHO, 1990) cited the need 'for epidemiological studies on children
exposed in utero to concentrations of methylmercury that result in
peak concentrations of mercury in maternal hair below 20 µg/g, in
order to screen for those effects only detectable by available
psychological and behavioural tests'. This proposal arose from an
evaluation of data from a study in Iraq, which implied that adverse
effects were seen with peak concentrations of 10-20 µg/g of maternal
The studies in the Faroe Islands and the Seychelles that were
evaluated by the Committee did not provide consistent evidence of
neurodevelopmental effects in children of mothers whose intake of
methylmercury yielded hair burdens of 20 µg/g or less. The Committee
could not evaluate the risks for the complex and subtle neurological
end-points used in these studies that would be associated with lower
intakes. In the absence of any clear indication of a consistent risk
in these recent studies, the Committee recommended that methylmercury
be re-evaluated in 2002, when the 96-month evaluation of the
Seychelles cohort and other relevant data that may become available
can be considered. The Committee noted that fish contribute
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