Download WHO Food Additive Series 13

MERCURY
Explanation
Mercury was evaluated for provisional tolerable weekly intake for
man by the Joint FAO/WHO Expert Committee on Food Additives in 1972
and in a document entitled "environmental Health Criteria. 1. Mercury"
(WHO, 1976). Since the publication of the latter document many studies
have been published, the most relevant of which have been summarized
below.
Uptake, distribution and half-life of mercury following ingestion
In a study using a modified whole-body counting technique, nine
male and six female volunteers were given orally approximately 22 µg
total Hg (as methyl 203Hg) in fish proteinate, and five male and three
female volunteers were given orally approximately 6 µg total Hg (as
inorganic 203Hg) in calf-liver paste. Approximately 20% of MeHg was
found in the head and 10-15% in the legs 30 days after administration
of MeHg. No significant amounts of 203Hg activity were found in the
head during the first 58 days after the administration of inorganic
Hg. A limited number of further measurements revealed the half-life of
MeHg in the head region to be between 60 and 400 days while the
half-life of inorganic Hg in the liver region was estimated to be of
the order of 90 days (Hattula and Rahola, 1975).
Elimination in the urine and faeces
Methyl mercury salts have been shown to be converted to inorganic
mercury in vivo and it is thought that intestinal microorganisms are
an important factor in this conversion. Five germ-free ICR-JCL female
mice and four conventional ICR-JCL female mice (controls), matched for
age and body weight, received 1.0 ml drinking-water, containing methyl
mercury chloride (MeHgCl) (20 µg total Hg) for one day. Faeces and
urine were collected every 24 hours thereafter, with the exception
of the faeces during the first four hours which were collected
separately. The mice were killed on day 10 and Hg levels in faeces,
urine, brain, liver, spleen and kidney measured. The amount of Hg
excreted in the urine was similar in both groups of mice. Germ-free
mice excreted 24% of the administered Hg in the faeces, compared with
46% by conventional mice. In addition, Hg levels in the tissues were
slightly higher for germ-free mice than for the controls (Nakamura et
al., 1977).
Acute studies
Rat
Groups of four male and four female weanling SPF-Wistar rats
(body weight 40-60 g) were given diets containing 0 (controls), 0.1,
0.5, 2.5, 12.5 and 250 ppm MeHgCl for two weeks. At the 250 ppm level
only, signs of CNS toxicity, weight loss and high mortality were
observed. The relative weights of the liver in females given 2.5 and
12.5 ppm and of the kidneys in females given 12.5 ppm were
significantly increased. Similar, but not statistically significant,
changes were observed in the males. Hg concentrations in the kidneys
increased significantly with increasing dietary levels of MeHgCl.
Hyperaemia and local haemorrhages of the brain observed in the 250 ppm
group could not be further studied owing to the advanced degree of
autolysis of the tissues (Verschuuren et al., 1976a).
Short-term studies
Rat
Groups of 15 male and 10 female weanling SPF-Wistar rats (body
weight 40-60 g) were given diets containing 0 (controls), 0.1, 0.5,
2.5 end 25 ppm MeHgCl for 12 weeks. Four males and three females died
before the end of the study. Most of the treatment-related effects
noted were reported in the group given 25 ppm and included: retarded
growth, reduced food intake, clinical signs of intoxication from week
nine onwards, increased neutrophil and decreased lymphocyte counts;
significant decreases in haemoglobin concentration, packed cell volume
and erythrocyte count (females only) as well as significant increases
in serum alkaline phosphatase, GPT and urea (males only). Analysis of
urine revealed increased protein and occasional presence of glucose
and blood. Activities of the liver enzymes aniline hydroxylase and
aminopyrine demethylase were increased whereas liver glycogen levels
were decreased; relative weights of kidneys, heart, adrenals and
thyroid in both sexes and of the pituitary, testes and brain in males
were significantly increased. In addition, histological changes were
observed in many organs (Verschuuren et al., 1976a).
Long-term studies
Rat
Groups of 25 male and 25 female weanling SPF-Wistar rats (body
weight 40-60 g) were fed diets containing 0 (controls), 0.1, 0.5 and
2.5 ppm MeHgCl for two years. No adverse effects relating to the
administration of MeHgCl were noted for body weight gain, food intake,
urinalysis, serum GPT, alkaline phosphatase and urea, microsomal liver
enzymes, histochemistry of the cerebellum and nature or incidence of
pathological lesions or tumours. Changes of significance included
increased neutrophil and decreased lymphocyte counts in males given
0.5 and 2.5 ppm after six months, as well as increased relative kidney
weight and histochemical changes in the kidney at the 2.5 ppm level
(Verschuuren et al., 1976c).
Cat
Adult cats were fed dosages of 3, 8.4, 20, 46, 74 and 176 µg
Hg/kg/day for 39 months either as methylmercury chloride or as
methylmercury contaminated fish. Total mercury blood levels in whole
blood were followed monthly. Complete haematology as well as
biochemical and microscopic urinalysis were performed monthly.
Neurological examinations were conducted monthly and at increasingly
frequent intervals as the animals developed signs of methyl-mercury
toxicity. Complete gross and histopathological examinations were
conducted on all animals. No significant differences on toxicity
between groups receiving methylmercury chloride or methylmercury
contaminated fish were observed. The lowest effect dose was 46 µg
mercury/kg body weight/day where non-progressive neurological signs
developed after 60 weeks of treatment. Pathological changes, observed
at 46, 74 and 176 µg mercury/kg bodyweight/day, were limited to the
central nervous system and consisted of neural degeneration with
replacement by reactive and fibrillary gliosis. No compound-related
effects were noted in the groups receiving 20, 8.4 or 3 µg mercury/kg
body weight/day (Charbonneau et al, 1976).
A recent study (Hollins et al., 1975) has demonstrated a
whole-body half-time for clearance of methylmercury in cats of 76 days.
This is comparable to the value of 78 days reported in humans (WHO,
1976). Hollins et al. (1975) also indicated that the dose of
methylmercury required to produce a critical brain level of
methylmercury in the cat was approximately 10 times that required for
humans. This would suggest a minimum effect dose of methyl-mercury in
humans of 1/10 that in the cat or approximately 4 µg/kg body
weight/day.
Reproduction (embryotoxicity)
The developing foetus has shown the greatest degree of
sensitivity to the toxicity of methylmercury (WHO, 1976). This is
borne out by a recent study in which pregnant mice received a single
intraperitoneal injection of 0.4 or 8 mg/kg methylmercury
dicyandiamide on day seven, nine or 12 of gestation. Fostering and
cross-fostering procedures were carried out at birth to partition the
effects of prenatal and postnatal exposure on two parameters: survival
and weight gain. Prenatal exposure caused twice the level of mortality
as postnatal exposure and the effect was greatest when administered
late in the period of organogenesis. There were no apparent effects on
the maternal animals (Spyker and Spyker, 1977). These data indicate
that in utero exposure to methylmercury may be more critical than
postnatal exposure via the mother's milk.
Pregnant Sprague-Dawley rats were given labelled MeHgCl by
intubation (10 µg/kg) on either days 10, 13, or 19 of pregnancy. The
dams were killed 24-72 hours after administration of the compound and
Hg levels of brain, kidneys, liver, heart, placenta and whole foetus
determined. The foetal brain concentration was 3.4 times higher than
the maternal brain concentration. The foetal brain was shown to
accumulate 19 times more as a percentage of its whole-body weight
compared to the maternal brain/body ratio (King et al., 1976).
Degenerative and hyperplastic changes in the neonatal kidney
after in utero exposure to Hg were studied by Chang et al., 1976a
and b. Injection of MeHgCl into pregnant Sprague-Dawley rats on the
eighth day of pregnancy resulted in degenerative changes in the
proximal convoluted tubules.These changes included accumulation of
lysosomes, enlargement of apical vacuoles, cytoplasmic vacuolation and
extrusion of large cellular casts into the tubular lumen. In addition
hyperplastic changes were reported in the distal convoluted tubules
including hyperplastic thickening of the tubular linings. The number
of mitotic cells was also increased.
Degenerative changes in the developing nervous system after
in utero exposure to Hg were studied by Chang et al., 1977. Pregnant
Sprague-Dawley rats were injected with MeHgCl on the eighth day of
pregnancy; tissue samples of the cerebral and cerebellar cortex were
taken from selected pups at birth. Although the pups appeared to be
physically normal, ultrastructural examination revealed various
degenerative changes, the most prominent being disruption and myelin
figure formation of the nuclear membranes together with large areas of
focal degradation and endothelial damage.
In a three-generation reproduction study, groups of 20 female and
10 male SPF-Wistar rats were fed diets containing 0 (controls), 0.1,
0.5 and 2.5 ppm MeHgCl. No adverse effects were noted on fertility or
lactation indices or the 21-day body weights of the pups, but the
viability index was impaired at the 2.5 ppm level in the F1 and F2
generations. No treatment-related effects were noted in body weight
gain, food intake, haematology or urinalysis. The relative weights of
kidneys, heart, spleen, brain and thyroid were increased at the
2.5 ppm level of all generations, but no significant histological
changes observed.
In a special seven-week study involving the F3a generation, 20
female and 10 male weanling rats obtained from the four different
treatment groups were given diets containing 25 ppm MeHgCl. Evidence
of clinical toxicity in the form of signs of paralysis were seen at
the end of the feeding period, although there was no apparent
difference between the groups (Verschuuren et al., 1976b).
Special behavioural studies
Monkey
Small doses of methylmercury were administered to rhesus monkeys
(Macaca mulatta) daily for periods of up to 17 months. Blood was
sampled for mercury concentration and routine clinical diagnostic test
at intervals. Behavioural tests sensitive to changes in peripheral
visual fields and in accuracy and rapidity of hand movements were
conducted continuously during the course of exposure. The blood
mercury levels increased initially to peak values at one to two
months, then after three to five months of dosing the blood mercury
levels began to decline even though the dose remained constant. It was
postulated that this decline in blood mercury was due to a stimulation
in mechanisms of methylmercury excretion. No deficits were detected in
the behavioural parameters tested prior to the development of
neurological signs of toxicity (Luschei et al., 1977). Several studies
have demonstrated behavioural effects (WHO, 1976) and Evans et al.
(1975) observed onset of tunnel vision in monkeys exposed to
methylmercury prior to the development of neurological signs of
toxicity. The question of whether or not behavioural effects
definitely occur prior to neurological signs is unresolved.
Effects of mercury on man
Acute
In four cases of MeHg poisoning, due to the consumption of a pig
(the feed of which had been contaminated with Hg-dressed grain) the
neurological damage was reported to be severe in all cases but greater
for the younger children. The most severe manifestations occurred in a
child who had been exposed in utero. The two younger children
(including the transplacental case) both, six years later, displayed
severe neurological inpairment, manifested by blindness, spastic
quadriparesis and increased tendon reflexes (Snyder and Seelinger,
1976).
Short-term
Associated with the neurological disorders seen in the Minamata
outbreak of Hg poisoning was renal tubular dysfunction; the quantities
of urinary renal tubular epithelial antigen and ß-2-microglobulin and
the ratios of these proteins to albumin were significantly (P <0.05)
higher than those in healthy control subjects. The values observed
were reported to be almost identical with values found in patients
with tubular proteinuria (Iesato et al., 1977).
Sub-cellular effects
Chromosome analyses of cultured lymphocytes from 21 men and seven
women occupationally exposed to Hg and its phenyl and ethyl compounds
or amalgams showed statistically significant increases in rate of
aneuploidy compared with those of seven control subjects. No
statistically significant differences, with the exception of ethyl-Hg
exposure, were found in the frequency of cells with chromosomal
aberrations, although the observed frequencies were higher for exposed
subjects (Verschaeve et al., 1976).
Epidemiology
The assessment of signs of methylmercury poisonings and blood
mercury values was conducted on 89 inhabitants of two Indian
reservations, Grassy Narrows and White Dog in Ontario, Canada, who
were consuming mercury-contaminated fish. Thirty-seven of the 89
patients examined revealed sensory disturbances. Other effects such
as disturbance of eye movement (19 cases), impaired hearing (40
cases), contraction of visual field (16 cases), tremor (21 cases),
hyporeflexia (20 cases), ataxia (8 cases), dysarthria (5 cases) were
also observed. The neurological symptoms observed are characteristic
of mercury poisoning. The symptoms were considered mild and many of
them were thought to be caused by other factors. Blood mercury values
for this population indicated that a significant number of individuals
had blood mercury levels above 100 ppb with several above 200 ppb
(Harada et al., 1976). These data on the Canadian Indian population
are in close agreement with those in which parasthesia was observed in
Iraqi patients exposed to methylmercury with blood mercury levels
between 200 and 300 ppb (WHO, 1976).
REFERENCES
Chang, L. W. and Sprecher, J. A. (1976) Degenerative changes in the
neonatal kidney following in-utero exposure to methylmercury,
Environ. Res., 11, No. 3, 392-406
Chang, L. W. and Sprecher, A. (1976) Hyperplastic changes in the rat
distal tubular epithelial cells, following in utero exposure to
methylmercury, Environ. Res., 12, No. 2, 218-223
Chang, L. W., Reuhl, K. R. and Lee, G. W. (1977) Degenerative changes
in the developing nervous system as a result of in utero exposure to
methyl-mercury, Environ. Res., 14, No. 3, 414-423
Charbonneau, S. M., Munrow, I. C., Nera, E. A. and Armstrong, F. A. J.
(1976) Chronic toxicity in methylmercury in the adult cat. In:
Trace substances in environmental health-X. A symposium, Columbia,
Mo., United States of America, University of Missouri, pp. 435-439
Evans, H. L., Leties, V. G. and Weiss, B. (1975) Behavioral effects of
mercury and methylmercury, Fed. Proc., 34, 1858-1867
Harada, M., Fujino, T., Akagi, T. and Nishigaki, S. (1976)
Epidemiological and clinical study and historical background of
mercury pollution on Indian Reservations in Northwestern Ontario,
Canada, Bulletin of the Institute of Constitutional Medicine,
Kumamoto University, Kumamoto, Japan, 26, 169-184
Hattula, T. and Rahola, T. (1975) The distribution and biological
half-time of 203Hg in the human body according to a modified
whole-body counting technique, Environ. Physiol. Biochem., 5.
No. 4, 252-257
Hollins, J. G., Willes, R. F., Bryce, F. R., Charbonneau, S. M. and
Munro, I. C. (1975) The whole body retention and tissue distribution
of (203Hg) methylmercury in adult cats, Toxicol. appl. Pharmacol.,
33, 438-449
Iesato,
tubular
antigen
86, No.
K., Wakashin, M., Wakashin, Y. and Tojo, S. (1977) Renal
dysfunction in Minamata disease. Detection of renal tubular
and beta-2-microglobin in the urine, Ann. intern. Med.
6, 731-737
King, R. B., Robkin, A. and Shepard, T. H. (1976) Distribution of
203Hg in pregnant and fetal rats, Teratology, 13, No. 3, 275-280
Luschei, E., Mottet, N. K. and Shaw, C. M. (1977) Chronic
methylmercury exposure in the monkey (Macaca mulatta), Arch.
environm. Hlth, 32, 126-131
Nakamura, I., Hosokawa, K., Tamura, H. and Miura, T. (1977) Reduced
mercury excretion with feces in germfree mice after oral
administration of methyl mercury chloride, Bull. Env. Contam.
Toxicol., 17, No. 5, 528-533
Snyder, R. D. and Seelinger, D. F. (1976) Methylmercury poisoning,
J. Neurol. Neurosurg. Psychiat., 39, 701-704
Spyker, D. A. and Spyker, J. M. (1977) Response model analysis for
cross-fostering studies: prenatal versus postnatal effects on
offspring exposed to methylmercury dicyandiamide, Toxicol. appl.
Pharmacol., 40, 511-527
Verschaeve, L., Kirsch-Volders, M., Susanne, C., Groetenbriel, C.,
Haustermans, R., Lecomte, A. and Roossels, D. (1976) Genetic damage
induced by occupationally low mercury exposure, Environ. Res., 12,
306-316
Verschuuren, H. G., Kroes, R., Den Tonkelaar, E. M., Berkvens, J. M.,
Helleman, P. W., Rauws, A. G., Schuller, P. L. and Van Esch, G. J.
(1976) Toxicity of methylmercury chloride in rats. I. Short term
study, Toxicology, 6, 85-96
Verschuuren, H. G., Kroes, R., Den Tonkelaar, E. M., Berkvens, J. M.,
Helleman, P. W., Rauws, A. G., Schuller, P. L. and Van Esch, G. J.
(1976) Toxicity of methylmercury chloride in rats. 2. Reproductive
study, Toxicology, 6, 97-106
Verschuuren, H. G., Kroes, R., Den Tonkelaar, E. M., Berkvens, J. M.,
Helleman, P. W., Rauws, A. G., Schuller, P. L. and Van Esch, G. J.
(1976) Toxicity of methylmercury chloride in rats. 3. Long-term
toxicity study, Toxicology, 6, 107-123
World Health Organization (1972) Evaluation of certain food additives
and the contaminants mercury, lead and cadmium, sixteenth report of
the Joint FAO/WHO Expert Committee on Food Additives, WHO Food
Additive Series, No. 4
World Health Organization (1976) Environmental health criteria.
1. Mercury
See Also:
Toxicological Abbreviations
Mercury (EHC 1, 1976)
Mercury (ICSC)
Mercury (WHO Food Additives Series 4)
MERCURY (JECFA Evaluation)