International programme on chemical safety




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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


METHYLMERCURY


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.

Petersen5


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,

USA


Explanation

Biological data

Pharmacokinetics

Absorption

Distribution

Transfer from mother to offspring

Placental transfer

Lactation

Clearance

Biochemical aspects

Cleavage of carbon-mercury bond

Complexes with thiol radicals

Interaction with selenium

Toxicological studies

Acute toxicity

Renal and hepatic toxicity

Anorexia

Neurotoxicity

Small rodents

Non-human primates

Domestic animals

Reproductive and developmental toxicity (other than

neurotoxicity)

Developmental neurotoxicity

Exposure in utero

Exposure in utero and postnatally

Exposure after parturition

Carcinogenicity

Immunomodulation

Extrapolation between species

Observations in humans

Case series

Childhood development

Neurological status

Developmental milestones

Early development

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

Environmental mercury

Biomarkers of exposure

Intake assessment

Residues

National intake estimates

Estimates based on WHO GEMS/Food diets

Estimates of intake by fish consumers at the 95th percentile

Comments

Evaluation

References


1. EXPLANATION


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


2.1 Pharmacokinetics


2.1.1 Absorption


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).


2.1.2 Distribution


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

other species.


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

(µg/g)

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

(µg/g)

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)

4 days


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)

17 days


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

(µg/g)

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


2.1.3.1 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

(Childs, 1973).


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).


2.1.3.2 Lactation


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.


2.1.4 Clearance


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

injections.


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

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