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 µg/day). Even
near smelters intakes will be no more than about 0.0006 mg/day
(0.6 µg/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 (µg/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 µg (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) (µg)
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 µg) 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)