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    ARSENIC

    Explanation

         The Joint FAO/WHO Expert Committee on Food Additives (JECFA)
    considered arsenic at its meeting in October 1966 (World Health
    Organization, 1967) and concluded that "until further data are
    obtained, the maximum acceptable lead of arsenic can be placed at
    0.05 mg per kg body weight per day". The Committee was to have
    considered arsenic again at its meeting in April 1982 but decided
    (World Health Organization, 1982) to defer this item because there was
    not sufficient information available. The present evaluation considers
    the possibility of establishing a maximum tolerable daily intake
    according to the recommendation made by JECFA-26, 1982.

    Introduction

         This paper presents information on the sources of arsenic, the
    routes of human exposure to arsenic and the magnitude of this
    exposure; this is followed by information on biochemical aspects of
    arsenic and its toxicology. The bulk of the toxicological data relates
    to man. Any consideration of the impact of arsenic on human health
    must take into account the various common chemical forms of arsenic to
    which man is normally exposed. This aspect of arsenic in relation to
    human health is given special emphasis. A glossary of the formulae of
    various arsenic compounds referred to in this paper is attached as an
    appendix to this section.

    Occurrence

         Earth's crust. Arsenic is widely distributed and ranks
    twentieth among the elements in abundance in the earth's crust of
    which it forms 2-5  10-4% (Lenihan & Fletcher, 1977; National Academy
    of Sciences, 1977). It is generally found in chemical combination with
    metals, especially iron, copper and lead, either as arsenides or more
    commonly as arsenide sulfides. Coal has an average arsenic
    concentration of about 10 mg/kg, however some coals contain in excess
    of 1000 mg/kg (Cmarko, 1963). Virgin soils generally contain less than
    40 mg/kg arsenic, whilst contaminated soils may contain up to
    500 mg/kg (Walsh & Keeny, 1975).

         Water. In general, water contains less than 0.01 mg/l of
    arsenic (Ministry of Agriculture, Fisheries and Food, 1982; Durum et
    al., 1971; Quentin & Winkler, 1974) but concentrations of about 1 mg/l
    have been found in some drinking-waters (Borgone et al., 1977; Tseng,
    1977). Concentrations of up to 8.5 mg/l have been observed in some
    geothermal waters (Ritchie, 1961; Nakahara et al., 1978). Sea-water
    generally contains 0.001-0.008 mg/l (Penrose et al., 1977; Onishi,
    1969). A maximum arsenic limit of 0.05 mg/l has been established for
    water intended for human consumption (European Community, 1980; US

    Environmental Protection Agency, 1975). Certain bottled mineral waters
    have been found to contain 0.2 mg/l of arsenic (Ministry of
    Agriculture, Fisheries and Food, 1979).

         Air. The major sources of arsenic in air are coal burning and
    metal smelting where it is emitted as As2O3. Volatile arsenic
    compounds in air have been shown to arise from arsenic in soil and
    water as a result of methylation by microorganisms (Braman, 1975;
    Woolson, 1979). Concentrations of arsenic in air have been found
    (Cawse, 1977) to lie in the range <0.5-12.3 ng/m3 in rural and urban
    areas of the United Kingdom. However the situation in other countries
    will depend upon the degree of control over emissions to the air by
    industry and from domestic coal burning. The mean concentration of
    arsenic in air particulates at a site 2 km from a non-ferrous metal
    smelter was found to be 32 ng/m3 compared with 2 ng/m3 at a site
    remote from the smelter (Hislop et al., 1982).

         Food. With the exceptions of seafood, and animal and poultry
    offal, the concentration of arsenic in food appears to be generally
    <0.25 mg/kg. The actual concentrations determined depend upon the
    limits of determination of the method of analysis and the competence
    of the analyst. With the exceptions mentioned above recent information
    (Ministry of Agriculture, Fisheries and Food, 1982) indicates that the
    concentration of arsenic in food prepared for human consumption is
    commonly <0.02 mg/kg. Plant foods may be contaminated by the
    deposition of atmospheric arsenic emitted by industry (Hislop et al.,
    1982; Ministry of Agriculture, Fisheries and Food, 1982) or through
    the use of arsenical pesticides, such as lead arsenate (Crecelius,
    1977a). The use of lead arsenate in the United Kingdom declined
    rapidly between 1969 and 1972 as morel effective pesticides were
    discovered. In the United States of America the use of pesticides
    containing substantial amounts of arsenic has effectively been
    proscribed. Animal and poultry offal often contain elevated
    concentrations of arsenic because of the use of organoarsenical feed
    additives. These additives may be used as growth promoters in pigs
    and chickens or for medicinal purposes, such as the control of
    scour in pigs. Commonly used additives include arsonilic acid
    (4-aminophenylarsonic acid), 3-nitro-4-hydroxyphenylarsonic acid and
    4-nitrophenylarsonic acid. Concentrations of arsenic in pig and
    poultry liver and kidney often exceed 1 mg/kg and may reach 10 mg/kg
    if the arsenical additive is not withdrawn from the feed long enough
    before the animals or poultry are slaughtered. Average concentrations
    of arsenic in fish and shellfish are often greater than 5 mg/kg
    (Ministry of Agriculture, Fisheries and Food, 1982) and individual
    samples, especially Of bottom feeders such as plaice (Pleuronectes
    platessa) and the white meat of crabs (Cancer pagurus), sometimes
    exceed 30 mg/kg. "Health Food" tablets and powder made from kelp have
    been found (Walkiw & Douglas, 1975) to contain up to 50 mg/kg of
    arsenic. Whilst most beverages contain low concentrations of arsenic,

    it has been reported (Crecelius, 1977a) that some wines contain more
    than 0.1 mg/l of arsenic and that a sample of illicitly produced
    whisky contained more than 0.4 mg/l of arsenic (Gerhardt et al.,
    1980).

    Speciation relevant to human exposure

         Water. Water contains several arsenic compounds including
    methylarsonic acid, dimethylarsinic acid, arsenates and arsenites
    (World Health Organization, 1981). In sea water the major species is
    arsenate but up to one-third of the total arsenic may be present as
    arsenite (Andreae, 1978; Johnson, 1972). In some well-waters, having
    high concentrations of greater khan 0.1 mg/l of arsenic, more than 50%
    of the arsenic was present as arsenite (Harrington et al., 1978;
    Arguello et al., 1938; Bergoglio, 1964). The speciation of arsenic in
    bottled mineral waters in not known.

         Air. Air contains both inorganic and organic arsenic compounds.
    It is likely that As2O3 (arsenious oxide) is the major component of
    the total arsenic in air although it has been reported (Johnson &
    Braman, 1975) that methylarsine constituted about 20% of the total
    arsenic in air in rural and urban environments. Smoke inhaled from
    cigarettes contains about 10-15% of the arsenic present in the tobacco
    but the form of the arsenic in the smoke is not known.

         Food. There is no information available on the form of arsenic
    in pig and poultry offal, or in muscle tissue. Arsenic in wine has
    been found (Crecelius, 1977a) to be almost wholly inorganic; for
    arsenic Concentrations greater than 0.01 mg/l more than 75% of the
    arsenic was present as arsenite. There is little information available
    about the species of arsenic in food plants. In recently published
    experimental work (Pyles & Woolson, 1982) the authors indicate that
    arsenic residues in food plants are primarily organic in nature and
    may be similar to the water soluble organoarsenicals isolated from
    marine organisms. The speciation of arsenic in seafoods has been the
    subject of extensive study during the past five years. It has been
    found (Edmonds & Francesconi, 1981a) that about 80% of the arsenic in
    brown kelp (Ecklonia radiata) is present in sugar derivatives,
    specifically 2-hydroxy-3-sulfopropyl-5-deoxy-5-(dimethylarsenoso)
    furanoside and 2,3-dihydrodypropyl-5-deoxy-5-(dimethylarsenoso)
    furanoside. More than 90% of the arsenic present in the edible
    Japanese seaweed Konubu (Laminaria japonica) was present in an
    organically bound form, although another seaweed Hijiki (Hizikia
    fusiforme) was found (Fukui et al., 1981) to contain arsenate and
    arsenite at 60% and 20% respectively of the total arsenic. The same
    authors concluded that more than 90% of the arsenic present in shrimp
    and flatfish (Karoius bicoloratus) was organically bound possibly as
    an arseno-oligopeptide. Arsenobetaine (CH3+As(CH3)2CH2CO-2)
    has been positively identified (Edmonds & Francesconi, 1981b) as the
    species of arsenic present in lobster (Homarus americanus), in the

    school whiting (Sillago bassensis) (Edmonds & Francesconi, 1981c),
    in fish meal and shrimps (Norin & Christakopoulos, 1982) and in plaice
    (Pleuronectes platessa) (Luten et al., 1982); these last authors
    also suggest that arsenocholine may be present in plaice as a minor
    component of the total arsenic. A recent study (Flanjak, 1982) has
    found that, in general, much less than 5% of the arsenic in various
    species of prawn, crab and in crayfish is inorganic. The inorganic
    arsenic was 1% or less of the total arsenic content in the shellfish
    containing the higher concentrations (more than 10 mg/kg) of total
    arsenic.

    Normal and extreme intakes of arsenic by man

         Water. For normal populations, assuming consumption of
    1.5 litres of water daily, intakes of arsenic will be 0.015 mg/day or
    less; most of this arsenic is likely to be inorganic. Intakes from
    water which just satisfies government requirements in the United
    States of America and in Europe will be about 0.075 mg/day. Some
    individuals consume more that two litres of water each day even in
    temperate climates (Hopkin & Ellis, 1980) and for these individuals
    intakes will be higher. Individuals consuming water containing
    elevated concentrations of arsenic (0.2-0.5 mg/l) will have daily
    intakes in the range of 0.3-0.75 mg. Certain bottled mineral waters
    contain up to 0.2 mg/l of arsenic of unidentified species; it is
    reasonable to suppose that individuals who regularly drink these
    waters will have daily arsenic intakes from this source of 0.2 mg.

         Air. Assuming that an individual inhales 20 m3 of air each
    day, then in the United Kingdom for example, normal intakes of arsenic
    from air are unlikely to exceed 0.00024 mg/day (0.24 g/day). Even
    near smelters intakes will be no more than about 0.0006 mg/day
    (0.6 g/day). Most of the inhaled arsenic will be present as As2O3.
    It has been estimated that a smoker will take in less than 0.02 mg/day
    (World Health Organization, 1981) but the species of arsenic in
    cigarette smoke is not known. It is accepted (IARC, 1980) that long-
    term inhalation of arsenic, probably as As2O3, during industrial
    exposure is likely to cause an increased incidence of lung cancer.
    However, the intakes of arsenic from the air which can be associated
    with an increased incidence of lung cancer are at least three orders
    of magnitude greater than those to which non-industrially exposed
    individuals will be subjected. For this reason, and the fact that
    under normal conditions air contributes only a minute proportion,
    exposure to arsenic from this source is not discussed further in the
    present context of considering the possibility of establishing a
    maximum tolerable daily intake.

         Food. In general, food provides the main source of arsenic
    exposure for man. Daily arsenic intakes for a number of countries are
    summarized in Table 1.

    TABLE 1.  AVERAGE DAILY ARSENIC INTAKES FOR DIFFERENT COUNTRIES
                                                                       

               Arsenic intake
    Country       (g/day)        Reference
                                                                       

    Austria          27           Woidich & Pfannhauser, 1979
    Canada           36           Smith et al., 1975
    China            210          Hanzong, 1981
    Germany          83           Schelenz, 1977
    Japan          70-170         Horiguchi et al., 1978; Nakao, 1960;
                                  Ishizaki, 1979
    Korea            320          Lee et al., 1976
    Scotland         55           Cross et al., 1978
    UK               89           Ministry of Agriculture, Fisheries
                                  and Food, 1982
    USA              10           Mahaffey, 1975
                                                                       

         Information on the arsenic content of the diet can be obtained by
    different methods, and may involve either the collection of replicates
    of food eaten by individuals (duplicate diets), or "total diet
    studies" based on average food consumption statistics which provide
    intake figures for the national "average person". Because only a
    limited number of samples can be obtained using duplicate diets, most
    national data on dietary intakes are derived from total diet studies.
    In 1966 the average daily intake of arsenic was reported to range from
    400-1000 g (Schroeder & Balassa, 1966). It is apparent, however, that
    more recent estimates give a considerably lower figure in most
    instances. This is thought to reflect improvements which have taken
    place in analytical techniques in the intervening years. It is now
    possible to determine much lower concentrations of arsenic in
    foodstuffs than would have been feasible 10-15 years ago. Despite
    these improvements most foodstuffs still contain arsenic at
    concentrations either very near to, or below the present limit of
    determination. In the United Kingdom analyses are regularly carried
    out on a wide range of foods which, where appropriate, are prepared as
    for consumption. These foods are then classified into one of nine
    groups (Table 2). From a knowledge of the different proportions of
    these foodstuffs in the "average" diet, a figure for daily dietary
    intake may be calculated (Ministry of Agriculture, Fisheries and Food,
    1982). The process of cooking and preparing food appears to have
    little effect on its arsenic content (Pfannhauser & Woidich, 1979).

    
    TABLE 2.  ARSENIC CONTENT OF FOOD GROUPS DETERMINED IN THE 1978 UK TOTAL
              DIET STUDY (MINISTRY OF AGRICULTURE, FISHERIES AND FOOD, 1982)

                                                                          

                           Estimated     Mean arsenic    Estimated mean
          Food group     weight eaten    concentration    daily intake
                           (kg/day)         (mg/kg)           (g)
                                                                          

    1. Cereals               0.23            <0.02             <5
    2. Meat                  0.15            <0.03             <5
    3. Fish                  0.02             2.71             54
    4. Fats                  0.08            <0.02             <2
    5. Fruits/sugars         0.17            <0.02             <3
    6. Root vegetables       0.18            <0.02             <4
    7. Other vegetables      0.11            <0.02             <2
    8. Beverages             0.12            <0.005            <3
    9. Milk                  0.40            <0.01             <4
                                                                          

    Total                    1.46                             <81
                                                                          
    
         The most significant source of dietary arsenic is fish (including
    shellfish). In the United Kingdom fish forms 2% of the average diet by
    weight but accounts for about 75% of its arsenic content. For people
    who consume greater than average amounts of fish the proportion of
    arsenic coming from this source is likely to increase, as is the total
    amount of arsenic in their diets. In a study of 60 Chinese fishermen
    93% of their daily arsenic intake (210 g) was found to come from fish
    (Hanzong, 1981). The relatively large intakes of arsenic reported from
    Japan, China and Korea (Table 1) are likely to reflect the greater
    proportion of fish eaten in these countries compared to western ones.
    Whilst fish provides the main source of dietary arsenic, measurable
    concentrations may also occur in meat and meat products. This is the
    result of organoarsenical feed additives which may be used as growth
    promoters (especially for poultry and pigs). It has been found (Cross
    et al., 1978) that, after fish, pig and poultry meat are the next most
    important contributors to the dietary intake of arsenic. It is normal
    for a withdrawal period to be specified so that the arsenic levels in
    the livestock decrease prior to slaughter. Occasionally fruit and
    vegetables may also contain measurable amounts of arsenic following
    their exposure to arsenic-based pesticides.

         Extreme intakes of arsenic from food depend critically on
    individuals' dietary habits. Regular consumption of offal from pigs or
    poultry which have received arsenicals in their feed could provide
    about 0.1 mg/day (2 mg/kg of arsenic in the offal and regular
    consumption of 0.05 kg/day of offal); this arsenic is of unknown
    species. Fish accounts for about 75% of the average dietary arsenic
    intake in the United Kingdom, however the average fish Consumption 

    over the past 10 years has been in the range of 0.014-0.020 kg/day.
    Individuals who regularly consume fish are likely to eat up to
    0.2 kg/day in the United Kingdom (Sherlock et al., 1982) and possibly
    more in some other countries. In these instances the arsenic intakes
    from fish are likely to be about 1 mg/day assuming a balanced fish
    diet containing about 5 mg/kg of arsenic, a figure which has been
    observed in practice (Ministry of Agriculture, Fisheries and Food,
    1982 - Table 1, Appendix III). People who regularly consume bottom
    feeding fish and shellfish may have daily intakes greater than 1 mg.
    Virtually all of the arsenic intake from fish will be present as
    organoarsenic compounds, most probably arsenobetaine.

    Toxicology of arsenic

         Absorption. The extensive range of arsenicals has not been
    comprehensively studied for absorption in man or in animals although a
    number of individual compounds have been investigated to varying
    degrees. Three routes of absorption have been established, the
    gastrointestinal tract, the lung and the skin (Lauwerys et al., 1978;
    Dutkiewicz, 1977). Water solubility and the physical form of inorganic
    arsenicals generally appear to have a greater influence on absorption
    than the chemical characteristics of individual compounds. Water
    soluble trivalent and pentavalent inorganic compounds, such as sodium
    arsenite (NaAsO2) and disodium hydrogen arsenate (Na2HAsO4) are
    well absorbed and presumptive evidence indicates that less soluble
    compounds like lead hydrogen arsenate (PbHAsO4) are comparatively
    poorly absorbed (Calvery et al., 1938; Done & Peart, 1971). In animal
    studies, composition of the concomitant diet may also affect
    gastrointestinal absorption of inorganic arsenicals with casein and
    hydrolysed casein reducing the amounts absorbed; arsenic binding to
    these foods was not evident (Nozaki et al., 1975). Experiments with
    human volunteers using 74As labelled arsenic acid showed that on
    average 58% of the total dose was excreted in urine after five days
    (Tam et al., 1979) and in similar experiments 62% was excreted in
    urine after seven days with 6% excreted in the faeces (Pomroy et al.,
    1980). These measurments indicate that arsenic in arsenic acid is well
    absorbed from the gastrointestinal tract in man. The implication of
    these findings in respect of man's exposure in the normal human
    environment require elucidation. The overall situation for
    organoarsenicals is not well defined. Excluding those compounds which
    are naturally present in marine foods it is considered that the
    trivalent organoarsenicals are generally poorly absorbed while the
    pentavalent forms are absorbed in varying amounts with some, for
    example the herbicide cacodylic acid (dimethylarsinic acid), almost
    completely absorbed (Goodman & Gilman, 1980; Stephens et al., 1977).
    Evidence suggests that marine food organoarsenicals may be readily
    absorbed by man from the gastrointestinal tract (Freeman et al., 1979;
    Crecelius, 1977b). In more recent work (Tam et al., 1982) volunteers
    consumed 10 mg of arsenic naturally present in fish. Faecal excretion

    of the arsenic after eight days was less than 0.35% of the total dose
    indicating almost complete absorption; the arsenic in the fish was an
    organoarsenic compound but was not thought to be arsenobetaine.

         Distribution of arsenic. The total human body content of
    arsenic has been estimated at between 3 and 4 mg, and tends to
    increase with age (National Academy of Sciences, 1977). Arsenic is
    widely distributed in the body including the liver, kidney, lung,
    spleen and skin, with the highest concentration in the hair and nails
    (due to high sulfydryl content of keratin; see under Arsenic
    Toxicity). Other sites, for example uterus, bone, muscle and neural
    tissue, have been shown to accumulate arsenic. Only total arsenic can
    be measured with accuracy in tissues because until recently the
    available analytical techniques changed the original valence state of
    the arsenic during the digestions of the tissues (Lauwerys et al.,
    1979). Differences in distribution between trivalent and pentavalent
    arsenic have not been elucidated in man. However, the rapid advances
    recently made in the analysis of fish tissue for arsenic should soon
    allow determination of the speciation of arsenic in man. Human studies
    with radiolabelled inorganic arsenic (74As) administered
    intravenously as trivalent arsenite (Mealey et al., 1959) and orally
    as the pentavalent compound arsenic acid (Pomroy et al., 1980),
    indicate a three compartment distribution. It appears that arsenic
    rapidly equilibrates in the extracellular space and there is
    subsequent distribution into a second and third compartment.
    Identification of these compartments is speculative but may include
    kidney, liver and muscle. Both studies reflect a small residual pool
    of arsenic held in the third compartment with a half-life of about
    10-40 days, perhaps longer. Placental transfer of arsenic can occur
    with deposition in the foetal tissues (Lugo et al., 1969; Ferm, 1977).

         Indices of human exposure. Blood and tissue concentrations of
    arsenic are unreliable indices of exposure due to the wide variation
    in blood arsenic concentrations in non-excessively exposed people, the
    lack of any generally accepted critical organ and the fact that only
    total arsenic, but not the species and valence state, has been
    accurately measured in human biological tissues (Lafontaine, 1978).
    Urinary arsenic has a wide normal variation being affected by fish
    consumption, but average values for exposed workers have been shown to
    be significantly raised. The concentration of arsenic in hair and
    nails may be useful in confirming intoxication by inorganic arsenic
    provided the sampling strictly avoids external contamination.

    Biotransformation and excretion of arsenic

         Observations in man. There is evidence that ingested arsenic in
    the form of inorganic trivalent and pentavalent compounds undergoes
    methylation prior to excretion in the urine along with unchanged
    inorganic arsenic (Crecelius, 1977b; Tam et al., 1979). The methylated
    compounds so far identified all contain arsenic in the pentavalent

    form (methylarsonic acid; dimethylarsinic acid, monomethylarsenic
    compounds) and could account for a substantial proportion of the
    original compounds ingested. The peak excretory level for the
    unchanged, minor inorganic component precedes that for the major,
    methylated compounds. Faecal excretion of arsenic from ingested
    inorganic compounds which are well absorbed accounts for only a small
    percentage of the administered quantity (Pomroy et al., 1980). The
    fate of organic arsenicals has not been clearly defined in man. It may
    be reasonably assumed that methylated compounds like cacodylic acid
    (dimethylarsinic acid) are fairly quickly excreted unchanged in the
    urine (Yamauchi & Yamamura, 1979). Limited information on the
    organoarsenicals present in fish and other seafood indicates 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 (Freeman et al., 1979; Crecelius, 1977b).
    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 (Tam et al., 1982).

         Observations in animals. Recent work (Sabbioni et al., 1983)
    has shown large species variations in the biotransformation and
    excretion of arsenic. Preliminary experiments showed that, whilst the
    rat retained nearly 10% of dietary arsenic, of unknown speciation,
    retention in the rabbit was about 0.03%. Rabbits and mice rapidly
    excreted radiolabelled arsenic given i.v. as arsenite (0.04 mg As/kg
    bw), the majority of the arsenic being excreted as dimethylarsenic
    acid with the remainder as inorganic arsenic compounds. The rat
    excreted very little arsenic and had a blood arsenic concentration
    more than 300 times greater than that in the mouse. In contrast the
    marmoset monkey excreted only inorganic arsenic compounds with a rate
    of excretion intermediate between that of the rat and the rabbit. None
    of the animals excreted monomethyarsenic acid which is found in human
    urine after exposure to arsenate or arsenite. Rabbits were given
    arsenobetaine or arsenocholine by i.v. injection (4 mg As/kg bw). The
    arsenobetaine was rapidly excreted unchanged with 70% of the dose
    being excreted in three days. Excretion of arsenic given as
    arsenocholine was slightly slower with about 40-50% of the dose being
    excreted as arsenobetaine, presumably following in vivo oxidation,
    within two days. No inorganic arsenic or dimethylarsenic acid was
    found in any of the urine samples. Only 2-3% of the arsenic was
    excreted in the faeces within three days.

         Arsenic toxicity. It is common practice to express arsenic
    exposure in terms of elemental arsenic (As) but this masks the
    pharmacokinetic and toxicological differences of the range of arsenic
    compounds present in the environment. Arsenic is rarely present in the
    free state in the environment but is widely distributed as both
    inorganic and organic compounds. Arsenic exists in the -3, +3 and +5
    oxidation states, with As0 as the elemental form. Organic and

    inorganic arsenic in +3 (trivalent) and +5 (pentavalent) forms exist
    either as naturally occurring or as synthetic substances including
    industrially prepared chemicals such as the organoarsenic pesticides.
    Arsine (AsH3) although very toxic is most unlikely to be encountered
    except in industry. The toxicological potentials of the arsenicals
    broadly conform to a pattern of the trivalent forms (both +3 and -3)
    being more toxic than the pentavalent forms, and inorganic compounds
    more toxic than organic compounds but there are exceptions to these
    generalizations. Factors such as solubility, particle size, rate of
    absorption, metabolism and excretion can have a significant influence
    on toxicity. Using information from a vareity of sources of human and
    animal observations, groups of arsenical compounds have been ranked in
    decreasing order of toxicity (Penrose, 1974): arsines (trivalent
    inorganic or organic); arsenite (inorganic); arsenoxides (trivalent
    with two bonds joined to one oxygen, e.g. R-As = O where R is an alkyl
    group); arsenate (inorganic); pentavalent arsenicals such as arsonic
    acids; arsonium compounds (four organic groups with a positive charge
    on the arsenic - akin to arsenobetaine CH3+As(CH3)2-CH2-CO-2);
    metallic arsenic.

         Many of the toxicological effects of arsenic, especially the
    trivalent form are believed to be associated with its reaction with
    cellular Sulfhydryl (-SH) groups (Peters, 1949, Peters, 1963; National
    Academy of Sciences, 1977)  Thus tissues rich in oxidative Systems are
    often affected, particularly the gastrointestinal tract, kidney,
    liver, luug and epidermis. The overall effect produced by the
    consequent inhibition of enzyme systems essential to cellular
    metabolism is the depression of fat and carbohydrate metabolism and
    cellular respiration. Pentavalent arsenic is capable of uncoupling
    mitochondrial oxidative phosphorylation. This effect may be due to a
    competitive substitution of arsenate for inorganic phosphate and the
    formation of an arsenate ester which is quickly hydrolysed. The
    significance of this action of pentavalent arsenic is unclear but it
    may relate to the neurological manifestations of arsenic toxicity
    (Buck, 1978). For many years interest in the toxicological effects of
    arsenical substances has had an emotive content and opinion exists
    that on occasions arsenic has been wrongly identified as the cause of
    episodes of poisoning and its etiological significance in some
    diseases inadequately proven (Frost, 1977). However, there is no doubt
    that arsenical compounds can be toxic, with morbidity and sometimes
    mortality in animals and man.

    Human studies

         In acute or subacute poisoning the clinical signs include fever,
    diarrhoea, emaciation, anorexia, vomiting, increased irritability,
    exanthemata and hair loss (Buck, 1978). In infants poisoned through
    consumption of contaminated milk formula the signs usually appeared
    within a few weeks of exposure at dose levels estimated to be

    1.3-3.6 mg/day of inorganic pentavalent arsenic (World Health
    Organization, 1981). Similar signs have been observed in adults after
    consuming about 3 mg/day of arsenic for two to three weeks.

         The presenting signs of chronic toxicity are often dermatological
    (melanosis, keratosis, desquamation, finger-nail changes),
    haematological (anaemia, leucopaenia) or hepatic enlargement (Buck,
    1978). These findings have usually been reported in people receiving
    Fowler's solution (arsenic trioxide dissolved in hydrochloric acid,
    neutralized with potassium hydroxide and diluted with chloroform-water
    to give a final solution containing 7.6 g As/1). The daily dose of
    arsenic from Fowler's solution may be as high as 10 mg (Pearson &
    Pounds, 1971).

         Dermatological effects of chronic ingestion of low doses of
    inorganic arsenic compounds show initially as cutaneous vasodilation
    than later as hyperpigmentation and hyperkeratosis with subsequent
    atrophy and degeneration of the skin. Limited evidence suggests that
    after a period of time malignant tumours develop.

         Blood and hone marrow are affected by inorganic arsenic with
    anaemia and leucopaenia. It is possible that an inhibition of folic
    acid metabolism may account for some of the haematological effects of
    arsenic toxicity (Van Tongeren, 1975). In addition, disturbance of
    mitochondrial haemobiosynthesis by inorganic arsenate results in
    porphyrinuria (Woods & Fowler, 1977). Although organoarsenicals seem
    rarely to affect the haemopoietic system, agranulocytosis has been
    reported (Goodman & Gilman, 1980).

         The liver is particularly susceptible to the toxic effects of
    inorganic arsenic compounds. There is fatty infiltration, central
    necrosis and cirrhosis. The hepatic parenchyma is usually involved and
    there may also be pericholangitis, with total effects ranging from
    mild disturbances to acute yellow atrophy and death.

         The effect of inorganic arsenic on the circulatory system appears
    to be dose related with mild vasodilation in response to small doses,
    and larger doses producing generalized capillary dilatation with
    increased permeability. The response is pronounced in the splanchic
    area especially on exposure to the trivalent inorganic arsenic
    compounds. A high prevalence of a peripheral vascular disease has
    been observed in people exposed to inorganic arsenic in water at
    concentrations of about 0.5 mg/l, corresponding to intakes of
    0.5-1 mg/day.

         Renal involvement is often apparent in acute or subacute arsenic
    poisoning but usually only the more severe cases of chronic arsenic
    exposure show overt kidney effects. Varying degrees of renal tubular
    necrosis and degeneration result in toxic arsenic nephrosis The
    neurological system may be affected by chronic exposure to inorganic
    arsenic compounds with the development of peripheral neuritis and in
    severe cases there is involvement of the spinal Cord. A substantial

    number of patients surviving severe acute arsenic poisoning later
    develop a variety of neurological problems. It is thought that organic
    arsenic compounds rarely affect the nervous system (Goodman & Gilman,
    1980).

    Teratogenicity of arsenic

         Observations in animals. Sodium and potassium arsenate and
    sodium arsenite have been investigated in animal studies for
    teratogenic effects. The arsenicals have been administered as
    single doses at specific times of gestation via the intravenous,
    intraperitoneal or oral routes and also by feeding or dermal
    application throughout most of the pregnancy (National Academy of
    Sciences, 1977; Hood, 1977; Hood et al., 1979). A variety of animals
    has been studied including mice, rats, hamsters, rabbits and sheep. It
    appears that parenterally administered single doses of sodium arsenite
    of about 10 mg/kg bw in mice produce significant foetal abnormalities
    compared with 20-40 mg/kg or greater for sodium arsenate in mice, rats
    and hamsters.

         Oral dosages over the short term require to be about three times
    greater than the corresponding parenteral dosages to produce foetal
    effects. The feeding of four pregnant ewes throughout most of the
    pregnancy with 0.5 mg/kg potassium arsenate had no effect (National
    Academy of Sciences, 1977). Recognizing the species variation in
    susceptibility to teratogenic effects of chemical substances and the
    amounts of arsenicals administered experimentally the significance of
    these animal studies to the human situation with average environmental
    exposure remains undetermined. Nevertheless, the occurrence of foetal
    abnormalities in animals exposed to inorganic arsenicals (albeit at
    relatively high dosages and in artificial circumstances) is to be
    noted.

         Observations in man. Survey information from an ore smelting
    plant in Sweden which emitted arsenic, lead, mercury, cadmium and
    sulfur dioxide into the environment showed an increase in foetal
    abnormalities in children born to female workers who continued
    employment at the smelter during pregnancy (Nordstrom et al., 1979).
    No data are available which implicate arsenic independently as a human
    teratogen.

    Mutagenicity of arsenic

         Sodium and potassium arsenite, sodium arsenate, arsenic
    trichloride and a number of organoarsenicals have been assessed for
    mutagenic properties in a variety of systems. Chromosomal aberrations
    have been detected in both mammalian and non-mammalian cells exposed
    in vitro to inorganic, including sodium arsenite and arsenate, and
    organic arsenicals. The effect of arsenicals as a group in the
    Rec-assay (Bacillus subtilis) and Reversion-assay (Escherichia
    coli; Salmonella typhimurium) have been variable although sodium

    arsenite, the only compound to be tested in both screens, gave
    positive results (Leonard & Lauwerys, 1980). Studies on lymphocytes
    from workers (Nordenson et al., 1978) and patients (Petres et al.,
    1977; Nordenson et al., 1979) either currently or previously exposed
    to arsenic showed an increased frequency of chromosomal aberrations
    over comparable controls. A similar study (Burgdorf et al., 1977)
    revealed a significantly higher frequency of sister chromatid exchange
    but no increase in chromosomal aberrations. In vitro exposure of
    normal human lymphocytes to sodium arsenate has produced a dose-
    dependent increase in sister chromatid exchange and chromosomal
    aberrations (Zanzoni & Jung, 1980). The mechanism by which chromosomes
    are affected by arsenicals is unclear. Inhibition of DNA repair has
    been proposed (Rossman et al., 1977) and, more fundamentally, the
    inhibition of phosphorus incorporation into nucleic acid (Petres et
    al., 1977) with consequent malformation of DNA and messenger RNA. The
    mutagenic potential of arsenicals is somewhat difficult to reconcile
    with the negative outcome of animal carcinogenicity studies (Lauwerys
    et al., 1978) but would support the tumour data accumulated in man.

    Carcinogenicity of arsenic

         Observations in animals. The carcinogenicity of inorganic
    arsenic has been investigated in a variety of animal species, and
    using different routes of administration. Inorganic arsenic has
    frequently been tested by skin application and found not to be
    carcinogenic. Neither has lead nor sodium arsenate fed to rats at
    doses of about 2 mg daily shown evidence of carcinogenicity. Several
    studies in which inorganic trivalent and pentavalent arsenic compounds
    were administered orally to rodents and dogs have shown no evidence of
    carcinogenic effect (Fairhall & Miller, 1941; Boroni et al., 1963;
    Byron et al., 1967; Kroes et al., 1974). In a strain of mice with a
    high incidence of spontaneous mammary tumours administration of
    arsenite enhanced the growth rate of tumours (Schrauzer & Ishmael,
    1974; Schrauzer et al., 1978). In one study (Ivankovic et al., 1979) a
    significant number of rats given a mixture of calcium arsenate, copper
    sulfate and calcium oxide (a preparation similar to one used in the
    past as a pesticide to treat vines) by a single intratracheal
    instillation developed lung rumours. The causative agent cannot be
    identified with certainty but it is possible that arsenic might have
    been an important factor. The IARC (IARC, 1980) considered that all of
    the animal studies, both positive and negative, suffer from some
    inadequacies, therefore firm conclusions cannot be drawn.

         Observations in man. in 1979 an IARC Working Group considered
    "there is sufficient evidence that inorganic arsenic compounds are
    skin and lung carcinogens in humans. The data suggesting an increased
    risk at other sites are inadequate for evaluation" (IARC, 1980). As
    indicated above, animal data only provides corrobative evidence in the
    case of respiratory tract exposure and the production of lung tumours

    but, as was explained in considering routes of human exposure to
    arsenic, air constitutes an insignificant proportion of the whole,
    except in situations of occupational exposure.

         A relationship has been demonstrated between cancer,
    particularly of the skin, and human overexposure to inorganic
    arsenic through drinking-water or oral medication, by means of
    epidemiological surveys and case histories (Arguello et al., 1938;
    Bergoglio, 1964; Tseng et al., 1968; Tseng, 1977; Jackson & Grainge,
    1975; Robson & Jeliffe, 1963; Braun, 1958; Somers & McManus, 1953;
    Pinto et al., 1977; Osburn, 1969; Neubauer, 1947; Zaldivar et al.,
    1981). Epidemiological studies in areas with a raised arsenic content
    in drinking water have suggested a relatively high incidence of skin
    cancer which increased with increases in the arsenic concentration in
    the drinking-water and the age of the individual (Tseng et al., 1968;
    Tseng, 1977; Cebrian et al., 1983). it has been estimated that
    0.2 mg/l of arsenic in drinking-water would lead to a 5% life-time
    risk of skin Cancer (World Health Organization, 1981). Skin cancer
    does not occur in the absence of other toxic effects due to arsenic.
    In other Studies (Arguello et al., 1938; Bergoglio, 1964) observations
    suggest that exposure to elevated concentrations of arsenic in
    drinking-water may have caused an increased incidence of alimentary
    and respiratory tract cancer.

    Chronic exposure and effects

         Observations in man. Inorganic arsenic has been assessed to
    have a biological half-life of from two to 40 or more days, depending
    upon body distribution (Mealey et al., 1959; Pomroy et al., 1980) and
    therefore has the potential to accumulate from the daily amounts
    absorbed from environmental exposure. In circumstances where continued
    daily intakes of arsenic exceed the total daily elimination
    accumulation will occur. The normal content of arsenic in the human
    body has been estimated at between 3 and 4 mg (National Academy of
    Sciences, 1977) and by inference these total tissue deposits of
    arsenic may be tolerated by man without untoward effects. However
    prolonged exposure to increased amounts of arsenic can produce chronic
    toxic effects and there appears to be a related increased prevalence
    of a number of diseases including malignant tumours. The clinical
    conditions observed in populations which ingest raised amounts of
    arsenic over prolonged periods are illustrated by studies in regions
    with elevated levels in water: Cordoba, Argentina (Arguello et al.,
    1938; Bergoglio, 1964), Antofagasta, Chile (Zaldivar et al., 1981;
    Zaldivar & Guiller, 1977); Borgono et al., 1977) and a defined area on
    the west coast of Taiwan (Tseng et al., 1968; Tseng, 1977). In the
    Cordoba region it was found that palmo-planar hyperkeratosis was the
    commonest manifestation shown by the inhabitants and about 12% of
    epitheliomas diagnosed at a local regional dermatological clinic were
    in patients showing signs of chronic arsenicism. The mortality in this
    region due to cancer was higher than in comparable non-arsenical
    areas, with respiratory and alimentary cancers accounting for nearly

    three-quarters of the deaths from cancer. Assessment of clinical
    conditions present in 180 Antofagasta inhabitants revealed an
    increased prevalence of hyperkeratosis, chronic cough, Raynaud's
    syndrome and chronic diarrhoea in patients exhibiting abnormal skin
    pigmentation. Infants and children with chronic arsenic poisoning
    showed much greater severity of symptoms than adult and senile
    patients. Almost 20% of children with chronic arsenical dermatosis had
    Raynaud's syndrome. Autopsy examination of four children with chronic
    arsenicism demonstrated fibrous thickening of small- and medium-sized
    arteries with significant luminal obliteration. A general survey of
    about 40% of the population of the defined area in Taiwan identified
    overall prevalence rats per thousand for skin cancer, 10.6; keratosis,
    71.0; and hyperpigmentation, 183.5. All three conditions tended to
    increase with age. Blackfoot disease (a local term for peripheral
    vascular disorder resembling thromboangiitis obliterans) which results
    in gangrene of the extremities, especially the feet, had an overall
    prevalence of 8.9 per thousand. This prevalence increased with
    duration of exposure and arsenic content of the water. Very similar
    prevalence rates have been found in a recent study (Cebrian et al.,
    1983) of a population in Mexico exposed to arsenic from drinking-
    water.

    Arsenic concentration in water and chronic toxic effects.

    Identification of the arsenic chemical species and content in the
    water of areas with endemic arsenicism would assist in the assessment
    of tolerable arsenic intakes by ingestion of food and water.

         Comprehensive data are not available but the information derived
    from a number of studies is of some value. In Cordoba samples at
    separate sites showed Sodium arsenite levels up to 4.5 mg/l (2.6 mg/l
    arsenic), sodium arsenate at 1.6 mg/l (0.64 mg/l arsenic) and arsenic
    trioxide at 2.8 mg/l (2.1 mg/l arsenic). The chemical species of the
    arsenic in Antofagasta is not known but the arsenic concentrations
    ranged from 0.05 to 0.96 mg/l with a geometric mean of 0.598 mg/l for
    the period 1955-1970.

         In Taiwan the arsenic content of the well-water ranged from 0.01
    to 1.82 mg/l with many of the wells having an arsenic content of
    around 0.4-0.6 mg/l. The chemical form of the arsenic is unknown. In
    Nova Scotia (Grantham & Jones, 1977) the medical findings associated
    with a Survey of well-water for arsenic content revealed that out of
    33 people using water with arsenic concentrations >0.1 mg/l, 23 (70%)
    had mild symptoms and signs possibly attributable to arsenic poisoning
    whereas only 25 out of 86 people (29%) consuming Water with arsenic at
    0.05-0.1 mg/l were similarly affected. In the study made in Mexico
    (Cebrian et al., 1983) the water contained 0.41 mg/l of arsenic of
    which 30% was present as arsenite and the remainder as arsenate. In
    the exposed population nearly 22% showed at least one of the cutaneous
    signs of chronic arsenic poisoning against 2.2% in a control
    population.

    Comments

         Apart from Conditions of occupational exposure, the oral route
    of exposure is the only one of signifance. The most important
    toxicological data are derived from studies of human exposure to
    drinking-water. The available epidemiological evidence allows the
    tentative conclusion that arsenicism can be associated with water
    supplies containing an upper arsenic concentration of 1 mg/l or
    greater, and concentration of 0.1 mg/l may give rise to presumptive
    signs of toxicity. The chemical species of arsenic present in the
    drinking-water were not clearly determined but it would be reasonable
    to consider them to be inorganic arsenic. Assuming a daily water
    consumption of 1.5 litres (by no means an extreme figure), it seems
    likely that intakes of 1.5 mg/day of inorganic arsenic are likely to
    result in chronic arsenic toxicity and daily intakes of 0.15 mg may
    also be toxic in the long term to some individuals. In addition the
    use of arsenical pesticides may increase the exposure to inorganic
    arsenic by the oral route, in some individuals. Oral treatment of
    patients with solutions of inorganic arsenic is likely to result in
    intakes at least as great as those from arsenical water supplies.

         Extensive evidence indicates that, apart from instances of
    accidental contamination of food by (inorganic) arsenic, in general
    the intake of arsenic from the diet is minute. Fish is the major
    source of arsenic intake from the diet; the arsenic in fish is bound
    into complex organic molecules. The available evidence indicates that
    arsenic from fish is well absorbed by man and that about 75% of the
    absorbed arsenic is excreted within five to 10 days. There is limited
    data to suggest arsenic from fish is excreted unchanged. Daily intakes
    of arsenic from fish are likely to be as high as 0.8 mg in some
    sectors of the population. Unlike the situation with arsenic in
    drinking-water there is no evidence to suggest that people who
    regularly consume large amounts of fish suffer ill-effects from the
    arsenic in it. But as there is little information on the arsenic
    compounds in fish and their toxicological potential, comprehensive
    chemical identification and toxicological assessment of members of
    this group of arsenicals is desirable. Arsenic intakes from other
    components of the diet are generally low and are unlikely to present
    any hazard to health. There is some evidence to suggest that arsenic
    in plant food is also combined in organic compounds. The widespread
    use of arsenic additives in animal feeds will expose some individuals
    to increased intakes of arsenic of unknown speciation. Consequently
    the search for and use of alternative chemicals which do not leave
    undesirable residues in food should be encouraged.

         In conclusion, ill-effects associated with elevated exposures to
    inorganic arsenic via the oral route are most likely to occur through
    consumption of arsenical drinking-water. In contrast exposure to
    inorganic arsenic from the diet is generally minute. The available
    evidence indicates that there is a case for considering naturally

    occurring organic arsenic compounds separately from inorganic. In
    respect of inorganic arsenic compounds there is epidemiological
    evidence of an association between the overexposure of humans to
    inorganic arsenic from drinking-water and increased cancer risk. Human
    exposure to levels of arsenic below those which cause arsenicism do
    not appear to carry a carcinogenic risk. Whilst intakes of organic
    arsenic compounds from the fish component of the diet do not appear to
    be a cause for concern, there is a need to establish the toxicity of
    the organic arsenic compounds in fish and the chemical forms of
    arsenic in other foods. There are insufficient data to recommend a
    maximum tolerable daily intake for arsenic from food.

         There is a need for information on the following:

         (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.

    EVALUATION

         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 inorganic arsenic; no figure could be
    arrived at for organic arsenicals in food.

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    APPENDIX

    ARSENIC COMPOUNDS REFERRED TO IN THE TEXT

    Arsenides, such as cobaltdiarsenide CoAs2

    Arsenide sulfides, such as copper arsenide sulfide CuAsS

    Arsenious oxide, sometimes known as arsenic trioxide, As2O3
    (trivalent)

    Arsonilic acid, 4-aminophenylarsonic acid(pentavalent)

    Arsonic acids, generally RAs(OH)2 (pentavalent)

    Methylarsonic acid CH3AsO(OH)2 (pentavalent)

    Dimethylarsinic acid, known as cacodylic acid, (CH3)2AsO(OH)
    (pentavalent)

    Arsenates, such as Na2HAsO4 (pentavalent)

    Arsenites, such as NaAsO2 (trivalent, derived from arsenous acid
    As(OH)3)

    Methylarsine, CH3AsH2 (trivalent)

    Arsine, AsH3 (trivalent)

    Arsenic trichloride, AsCl3 (trivalent)

    Arsonium salts, general formula (R4As+)X- this type of compound
    would be similar to arsenobetaine, CH3A+s (CH3)2 CH2CO2-
    (pentavalent)

    Arsenoxide, general term for compounds in the class RAsO (trivalent)

    Arsenocholine (CH3 As+ (CH3)2 CH2CH2OH)OH- (pentavalent)

    Arsenic sugars (identified by Edmonds & Francesconi, 1981a)
    (pentavalent)

    Arsenic acid, either HAsO3 or H3AsO4 (pentavalent)
    


    See Also:
       Toxicological Abbreviations
       Arsenic (EHC 18, 1981)
       Arsenic (ICSC)
       Arsenic (WHO Food Additives Series 24)
       ARSENIC (JECFA Evaluation)
       Arsenic (PIM G042)