ARSENIC
EXPLANATION
Arsenic was previously evaluated in the tenth and twenty-
seventh reports of The Joint FAO/WHO Expert Committee on Food
Additives (Annex 1, references 13 and 62). It was concluded at the
twenty-seventh meeting that "on the basis of the data available,
the Committee could arrive at only an estimate of 0.002 mg/kg bw as
a provisional maximum tolerable daily intake for ingested arsenic;
no figure could be arrived at for organic arsenicals in food"
(Annex 1, reference 62). Specifically, the monograph (Annex 1,
reference 63) stated that there was a need for information on:
1) arsenic accumulation in man exposed to various forms of
arsenic in the diet and drinking water;
2) the identification, absorption, elimination and toxicity
of arsenic compounds in food with particular reference to
arsenic in fish;
3) the contribution of arsenic in fish to man's body burden
of arsenic;
4) epidemiological studies on populations exposed to
elevated intakes of arsenic of known speciation.
Very limited data addressing the above four points were made
available to the Committee. The studies relevant to assessing the
significance of organoarsenicals in fish are presented.
DIETARY EXPOSURE
Arsenic is ubiquitous in the biosphere and occurs naturally in
both organic and inorganic forms. While arsenic can be found to a
small extent in the elemental form, the most important inorganic
arsenic compounds are arsenic trioxide, sodium arsenite, arsenic
trichloride (i.e. trivalent forms), and arsenic pentoxide, arsenic
acid and arsenites, such as, lead and calcium arsenates (i.e.
pentavalent forms). Common organic arsenic compounds are arsanilic
acid, methylarsonic acid, dimethylarsinic acid (cacodylic acid),
and arsenobetaine (AB). This latter compound (AB) is considered to
he the most predominant organoarsenical in marine animals. Other
organoarsenicals including, arsenocholine, dimethyloxyarsylethanol,
trimethylarsonium lactate, arsenic containing sugars and
phospholipids have also been found in fish (Lau et al., 1987;
Friberg et al., 1986).
Although arsenic compounds were commonly used in the past as
drugs, their main use today is as pesticides, veterinary drugs and
in industrial applications, such as, the manufacture of integrated
circuits and the production of alloys (Friberg et al., 1986; WHO,
1981)
In non-industrial areas, arsenic levels in air are of the
order of 0.02 µg/m3 and intakes from this medium would be 0.3 to
0.4 arsenic/day. Arsenic levels as high as 1.6 µg/m3 have been
reported in the vicinity of smelting operations. Both inorganic and
organic forms of arsenic have been shown to be present in air with
methylarsines comprising about 20% of the total (Friberg et al.,
1986; WHO, 1981; Ministry of Agriculture, Fisheries and Food, 1982:
Fowler, 1983, National Academy of Sciences, 1977; National Research
Council of Canada, 1978)
Arsenites and arsenates are the prevalent forms of arsenic
found in water although methylarsonic and dimethylarsinic acids
have been found at low levels. Most surface waters contain less
than µg/1 arsenic but levels as high as about a thousand µg/l have
been reported. Arsenic levels in groundwater are dependant on the
arsenic content of the bedrock. In some instances, several thousand
µg/l arsenic have been found in such waters. Based on these
findings, most persons consuming surface waters would ingest less
than 15 to 20 µg arsenic/day from this source but for some
individuals intakes from water consumption could reach as high as
6000 µg/day (Friberg et al., 1986; WHO, 1981; Ministry of
Agriculture, Fisheries and Food, 1982; Fowler, 1983; National
Academy of Sciences, 1977; National Research Council of Canada, 1978)
With the exception of fish, most foods contain less than
0.25 µg/g arsenic. Many species of fish contain between 1 and 10 g/g.
Arsenic levels at or above 100 µg/g have been found in bottom
feeders and shellfish. Both lipid- and water-soluble organoarsenic
compounds have been found but the water-soluble forms constitute
the larger portion of the total arsenic content. The nature of
these compounds has been shown to be mainly of the quaternary
arsonium type. As was mentioned above, arsenobetaine is believed to
be the most predominant species, but recent Canadian results
demonstrated a higher level of arsenocholine than arsenobetaine in
shrimps (Lau et al., 1987; Friberg et al., 1986; WHO, 1981;
Ministry of Agriculture, Fisheries and Food, 1982; Dabeka et al.,
1987).
Dietary arsenic intakes estimated from various countries range
from less than 10 µg/day to 200 µg/day. These values are not only
reflective of different dietary habits but mirror important
variations in assumptions used to calculate them. In one instance,
for example, detection limit values were used to calculate intakes
when no arsenic was detected. The estimated arsenic intake was more
than 13x greater than that estimated when a value of zero was used.
Nevertheless, these estimates do not likely represent potential
arsenic intakes of special sub-groups in the population, such as,
native people or fisherman and their families, who may regularly
consume large quantities of fish. Arsenic intakes by high fish
consumers can reach several thousand µg per day (Friberg et al.,
1986; WHO, 1981; Ministry of Agriculture, Fisheries and Food, 1982;
Dabeka et al., 1987).
In addition to arsenic from air, water and food, tobacco
treated with arsenate sprays may also be a route of exposure for
those persons who are smokers.
In summary, the intake of arsenic from air, excluding
industrial areas, is a minor portion of the total intake from all
sources. The intake of arsenic (primarily inorganic) from water is
generally low for most persons but can reach extremely high values
for those who consume waters containing naturally elevated arsenic
levels. Dietary arsenic represents the major source of arsenic
exposure for most of the general population. Persons who are high
consumers of fish may ingest significant amounts of arsenic
(primarily organic) from this food group.
BIOLOGICAL DATA
Arsenic in Fish and Seafood
Studies in mice have demonstrated that 98% of the dose of
arsenobetaine is absorbed whereas the absorption of arsenocholine
is slightly less (94%). Additional studies, using rats, mice and
rabbits demonstrated that the clearance of arsenobetaine from
plasma and most tissues was rapid and seemed to follow first order
kinetics. Longest retention was observed in cartilage, testes,
epididymis, and in rabbits, the muscle. 73As arsenobetaine was the
only labelled arsenic compound detected in the soluble extract of
tissues. Following an i.v. dose of 73As-labelled arsenocholine, the
clearance from the plasma and tissues was somewhat slower than for
arsenobetaine. Tissues with the longest retention times were
prostate, epididymis, testes, myocardium, liver, adrenal cortex,
pancreas, dental pulp and pituitary gland. In the tissues, the 73As
activity retained was found in the form of 73As arsenobetaine and
73As arsenophospholipids. Ninety-eight per cent of the dose of
arsenobetaine was excreted unchanged in the urine, whereas 66% and
9% of a single oral dose of arsenocholine was excreted in the urine
and feces, respectively, within three days. Following the
administration of arsenocholine, the majority of the arsenic in the
urine was arsenobetaine indicating that arsenocholine is oxidized
to arsenobetaine. Whole-body retention was greater following
arsenocholine compared to arsenobetaine (Vahter et al., 1983,
Marafante et al., 1984).
Studies in man
The fate of organic arsenicals has not been clearly defined in
man. It may be reasonably assumed that methylated compounds like
cacodylic acid (dimethylarsenic acid) are fairly quickly excreted
unchanged in the urine (Yamauchi & Yamamura, 1979). Limited
information on the organoarsenicals present in fish and other
seafood indicated that these compounds appear to be readily
excreted in the urine in an unchanged chemical form with most of
the excretion occurring within two days of ingestion (Freemam
et al., 1979). Volunteers who consumed witch flounder
(Glypotocephalus cynoglossus) excreted 75% of the ingested
arsenic in urine within eight days of eating the fish. The excreted
arsenic was in the same chemical form as in the fish. Less than
0.35% was excreted in the feces (Tam et al., 1982). Luten et
al., (1982) reported that 69-85% of the arsenobetaine from plaice
was excreted in the urine within five days. Fecal excretion was not
measured. Yamauchi & Yamamura (1984) reported that 90% of the
trimethylarsenic acid from prawns was excreted unchanged in the
urine within 60 hours. Fecal excretion was not determined in either
of these studies. There are no data on tissue distribution of
arsenic in humans following ingestion of arsenic present in fish
and seafood.
Short-term studies
Organoarsenicals in Seafood
There are no reports of toxicity in man or animals from the
consumption of organoarsenicals in seafood. The only toxicity study
available is an oral study conducted by Siewicki (1981) in rats.
Groups of 10 weanling, male, Sprague-Dawley-delivered rats were fed
one of five diets for 42 days either ad libitum or on a
restricted regimen. The five diets included a low arsenic control
(4.7 ppm), and a medium (15.8 ppm) and high (28.8 ppm) arsenic diet
supplement from either witch flounder tissues or cacodylic acid.
Animals were weighed weekly. Terminally, haemoglobin, hematocrit,
urine aminolevulinic acid and coproporphyrin levels and liver and
spleen weights were determined. Arsenic levels in the erythrocytes,
liver and spleen were measured. No treatment-related signs of
toxicity were noted for any of the parameters measured in any
group. Arsenic levels in the livers and spleens of rats fed the
28.8 ppm fish arsenic were seven and two times higher than the
controls. In rats fed 22.1 ppm arsenic from cacodylic acid, levels
of arsenic were 30 and 110 times higher than the controls.
Retention of arsenic in the erythrocytes of rats fed the 28.8 ppm
fish arsenic were similar to the controls, whereas it was 130 times
higher than controls in the rats fed the highest level (22.1 ppm)
of cacodylic acid. This indicated that arsenic from fish is not
bound to rat erythrocytes. Although this study is limited, it
demonstrated that weanling rats fed approximately 3 mg/kg bw/day
fish arsenic for 42 days did not develop any treatment-related
toxic effects.
COMMENTS
The previous evaluation was confirmed by assigning a PTWI of
0.015 mg/kg bw for inorganic arsenic, with the clear understanding
that the margin between the PTWI and intakes reported to have toxic
effects in epidemiological studies was narrow. The provisional
status of the maximum weekly intake was continued due to the desire
to lower the arsenic intake of those individuals exposed to high
levels of inorganic arsenic in drinking water. Further
epidemiological studies were recommended in such populations.
Organic forms of arsenic present in sea foods need different
consideration from the inorganic arsenic in water. There are many
regional and ethnic populations who consume large quantities of
fish that result in organoarsenic intakes of about 0.05 mg/kg
bw/day. There have been no reports of ill-effects among these
groups but further investigation of these populations would be
desirable to assess the implications for human health of exposure
to naturally occurring organoarsenic compounds in marine products.
Further investigations of the type and levels of organoarsenic
compounds naturally occurring in marine products and further animal
studies on these specific compounds are highly desirable.
EVALUATION
Estimate of provisional tolerable weekly intake
0.015 mg/kg b.w.
Further work or information
1. In order to define more clearly levels of inorganic arsenic
which may result in adverse effects, the Committee recommends that
further epidemiology studies be undertaken in populations exposed
to elevated inorganic arsenic occurring naturally in drinking
water.
2. The Committee considers that it would be desirable to carry
out epidemiology studies involving consumers of large quantities of
fish to assess more fully the human health implications of exposure
to naturally occurring organoarsenic compounds in marine products.
3. Further investigation of the types and levels of
organoarsenic compounds naturally occurring in marine products is
recommended.
4. Arsenic organoarsenic compounds of unknown toxicity are
present in marine products; further animal studies should be
undertaken with the identified compounds.
REFERENCES
Dabeka, R.W., McKenzie, A.D. & Lacroix, G.M.A. (1987). Dietary
intakes of lead, cadmium, arsenic and fluoride by Canadian adults:
a 24-hour duplicate diet study. Food Additives and Contaminants,
4, No.1, pp. 89-102.
Fowler, B.A. (editor) (1983). Biological and environmental effects
of Arsenic, Topics in Environmental Health, Elsevier Science
Publisher, Amsterdam, New York, Oxford, Vol. 6.
Freeman, H.C., Uhthe, J.F., Fleming, R.B., Oduse, P.H., Ackman,
R.G., Landry, G. & Musial, C. (1979). Clearance of arsenic ingested
by man from arsenic contaminated fish. Bull. Environ. Contain.
Toxicol., 22, 224-229.
Friberg, L., Nordberg, G.F. & Vook, V.B. (1986). Handbook on the
toxicology of metals, 2nd edition, Elsevier Science Publisher,
Amsterdam, New York, Vol. II, pp. 43-83.
Lau, P.-Y., Michalik, P., Porter, C.J. & Krolik, S. (1987).
Identification and confirmation of arsenobetaine and arsanocholine
in fish, lobster and shrimp by a combination of fast atom
bombardment and tandem mass spectrometry. Biomedical and
Environmental Mass Spectrometry, 14, pp. 723-732.
Luten, J.B., Riekwel-Booy, G. & Rauchbaar, A. (1982). Occurrence of
arsenic in plaice (Pleuronectes platessa), nature of organo-
arsenic compound present and its excretion by man. Environ.
Health Perspect., 45, 165-170.
Marafante, E., Vahter, M., & Dencker, L. (1984). Metabolism of
arsenocholine in mice, rats, and rabbits. Sci. Total Environ.,
34, 223-240.
Ministry of Agriculture, Fisheries and Food (1982). Survey of
arsenic in food, Her Majesty's Stationary Office, London.
National Academy of Sciences (1977). Arsenic, Committee on Medical
and Biologic Effects of Environmental Pollutants, Washington, D.C.
National Research Council of Canada (1978). Effects of arsenic in
the Canadian environment. NRCC 15391, Ottawa, Canada.
Siewicki, T.C. (1981). Tissue retention of arsenic in rats fed
witch flounder or cacodylic acid. J. Nutr., 111, 602-609.
Tam, G.K., Charbonneau, S.M., Bryce, F. & Sandi, E. (1982).
Excretion of a single oral dose of fish-arsenic in man. Bull.
Environ. Contain. Toxicol., 28, 669-673.
Vahter, M., Marafante, E., & Dencker, L. (1983). Metabolism of
arsenobetaine in mice, rats and rabbits. Sci. Total Environ., 30,
197-211.
WHO (1981). Environmental Health Criteria 18: Arsenic,
International Programme on Chemical Safety, World Health
Organization, Geneva.
WHO (1984). Guidelines for drinking-water quality, World Health
Organization, Geneva, Vol. 1, p. 53.
Yamauchi, H. & Yamamura, Y. (1979). Urinary inorganic arsenic and
methylarsenic excretion following arsenate-rich seaweed ingestion.
Jpn. J. Ind. Health, 21, 47-55.
Yamauchi, H. & Yamamura, Y. (1984). Metabolism and excretion of
orally ingested trimethylarsenic in man. Bull. Environ. Contain.
Toxicol., 32, 682-687.
See Also:
Toxicological Abbreviations
Arsenic (EHC 18, 1981)
Arsenic (ICSC)
Arsenic (WHO Food Additives Series 18)
ARSENIC (JECFA Evaluation)
Arsenic (PIM G042)