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    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 g/m3 and intakes from this medium would be 0.3 to
    0.4 arsenic/day. Arsenic levels as high as 1.6 g/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 g/1 arsenic but levels as high as about a thousand g/l have
    been reported. Arsenic levels in groundwater are dependant on the
    arsenic content of the bedrock. In some instances, several thousand
    g/l arsenic have been found in such waters. Based on these
    findings, most persons consuming surface waters would ingest less
    than 15 to 20 g arsenic/day from this source but for some
    individuals intakes from water consumption could reach as high as
    6000 g/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 g/g arsenic. Many species of fish contain between 1 and 10 g/g.
    Arsenic levels at or above 100 g/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 g/day to 200 g/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 g 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)