* Arsenic
sesquisulfide
* Arsenic
tersulphide
* Arsenic
trisulphide
* Arsenic
yellow
* Arsenious
sulphide
* Arsenous
sulphide
* Auripigment
* C.I. 77086
* C.I. pigment
yellow
* Diarsenic
trisulphide
* Kings Gold
* Orpiment

Chemical Relative Structural Identification numbers
name molecular formula
mass CAS RTECS UN

Arsenic 181,27 AsCl₃ 7784-34-1 CG1750000 1560
trichloride

Synonyms
and trade
names

* Arsenic
butter
* Arsenious
chloride
* Arsenous
chloride
* Caustic
arsenic
chloride
* Caustic
oil of
arsenic
* Fuming
liquid
arsenic

Arsenic 197,82 As₂O₃ 1327-53-3 CG3325000 1561
trioxide

Synonyms
and trade
names

* Arsenic
oxide
* Arsenic
(III)oxide
* Arsenic
sesqui oxide
* Arsenicum
album
* Arsenious
acid
* Arsenious
oxide
* Arsenious
trioxide
* Arsenite
* Arsenolite
* Arsenous
acid

* Arsenous
anhydride
* Arsenous
oxide
* Arsenous
oxide
anhydride
* Arsodent
* Claudelite
* Crude
arsenic
* Diarsenic
trioxide
* White
arsenic

Chemical Relative Structural Identification numbers
name molecular formula
mass CAS RTECS UN

Cupric 187,46 CuHAsO₃ 10290-12-7 CG3385000 1586
arsenide

Synonyms
and trade
names

* Schelle's
green

Gallium 144,64 AsGa 1303-00-0 LW8800000 n.a.
arsenide

Synonyms
and trade
names

* Gallium
monoarsenide

Potassium 399,65 KH(AsO₂)₂ 10124-50-2 38000000 1678
arsenite

Synonyms
and trade
names

* Arsenenous
acid,
potassium
salt
* Arsenious
acid

potassium
salt
* Arsonic
acid,
potassium
salt
* Fowlers
solution
* Potassium
metaarsenite

Chemical Relative Structural Identification numbers
name molecular formula
mass CAS RTECS UN

Sodium 129,9 NaAsO₂ 7784-46-5 CG367500 1686
arsenite 2027

Synonyms
and trade
names

* Arsenenous
acid,
sodium
salt
* Arsenious
acid,
sodium
salt
* Prodalumnol
* Sodanit
* Sodium
metaarsenite

INORGANIC (V)

Arsenic
pentoxide 229,84 As₂O₅ 1303-28-2 GC2275000 1559

Synonyms
and trade
names

* Arsenic
acid
* Arsenic
acid
anhydride
* Arsenic
oxide
* Arsenic (V)
oxide

* Diarsenic
pentoxide

Chemical Relative Structural Identification numbers
name molecular formula
mass CAS RTECS UN

Calcium 398,06 Ca₃(AsO₄)₂ 7778-44-1 CG0830000 1573
arsenate

Synonyms
and trade
names

* Arsenic
acid
calcium
salt
* Calcium
orthoarsenate
* Chipcal
* Pencal
* Spracal
* Tricalcium
arsenate

Lead 347,12 PbHAsO₄ 7784-40-9 CG0980000 1617
arsenate

Synonyms
and trade
names

* Acid
lead
arsenate
* Acid
lead
orthoarsenate
* Arsenate
of lead
* Arsenic
acid
lead salt
* Arsinette
* Gypsine
* Lead acid
arsenate
* Plumbous
arsenate
* Schultenite
* Soprabel

* Standard
lead
arsenate
* Talbot

Chemical Relative Structural Identification numbers
name molecular formula
mass CAS RTECS UN

*Potassium 180,04 KH₂AsO₄ 7784-41-0 CG1100000 1677
arsenate

Synonyms
and trade
names

* Arsenic
acid
monopotassium
salt
* Macquers
salt
* Monopotassium
arsenate
* Monopotassium
dihydrogen
arsenate
* Potassium
acid
arsenate
* Potassium
arsenate,
monobasic
* Potassium
dihydrogen
arsenate
* Potassium
hydrogen
arsenate

Sodium 302,88 Na₃AsO₄ 7631-89-2 CG1225000 1685
arsenate

Synonyms
and trade
names

* Arsenic
acid,
sodium
orthoarsenate

* Arsenic
acid,
sodium
salt
* Sodium
metaarsenate

* n.a.: not available
1.4 Identification numbers

1.4.1 CAS number

See table 1.3

1.4.2 Other numbers

See table 1.3

1.5 Main brand names, main trade names

1.6 Main manufactures, main importers

2. SUMMARY

2.1 Main risks and target organs

After absorption, arsenic may cause multi-organ failure.
The primary target organs initially are gastrointestinal
tract, the heart, brain and kidneys. The skin, bone marrow
and peripheral nervous system may be affected.

In severe poisoning, the patient may die early of
cardiovascular disturbances, mainly intravascular volume
depletion and severe shock.

2.2 Summary of clinical effects

In acute poisoning, symptoms begin usually within the
first hours following ingestion. Garlic-like odour of breath,
gastric content and faeces may be indicative.

Gastrointestinal disturbances (vomiting, gastrointestinal
pain, diarrhoea) are the main clinical effects.

After an apparent remission (1 to 2 days), several organs are
affected by the systemic action of inorganic arsenic
(cardiovascular, renal, hepatic and cutaneous
manifestations). This will produce hypotension, tachycardia,
ECG modifications of QT and T wave, airway irritation,
pulmonary oedema, haematuria, acute renal failure, acute
haemolysis, altered mental status, confusion, delirium,
convulsions, encephalopathy.

If the patient survives the cardiovascular failure, and after
a long convalescence, sequelae are observed, mainly
peripheral neuropathy and Mee's lines on nails.

2.3 Diagnosis

Diagnosis is based on history, symptoms, signs and
laboratory investigations, but treatment should start on
suspicion of poisoning. The diagnosis may be confirmed by
quantification of arsenic in urine in acute cases and hair in
chronic exposure.

In acute, massive arsenic ingestion, barium-like opacities on
abdominal X-ray may be demonstrated.

2.4 First-aid measures and management principles

Due to the toxic action of inorganic arsenic on the
gastrointestinal tract in acute poisoning, and the subsequent
liquid losses, special care to the fluid-electrolyte balance
is required to prevent cardiovascular toxicity. Hypovolemia,
cardiac arrhythmias and cardiovascular failure are the main
cause of early death.

Transport of the patient to an hospital and monitoring of
vital functions in an intensive care department is therefore
mandatory.

Gastric decontamination using gastric lavage and activated
charcoal is highly recommended. Whole bowel irrigation should
be considered if the presence of arsenic in the lower
gastro-intestinal tract is observed by X-ray. Maintain high
urine output with an alkaline pH. Chelation therapy using BAL
or DMSA or DMSP should be rapidly envisaged.

In the meantime, first aid should be commenced.

3. PHYSICO-CHEMICAL PROPERTIES

3.1 Origin of the substance

Arsenic is an ubiquitous element mainly present in the
lithosphere as arsenic minerals or arsenic impurities in
minerals or as arsenic in various rock types and fossil fuels
(NRCC, 1978). In soils, arsenic is present as arsenite
(As(III)) and arsenate (As(V)) and in an organic form.

Industrial and agricultural sources of arsenic may enhance,
sometimes in a dramatic way, the natural levels of arsenic:
mining activities, smelters, coal and coal combustion
by-products, withdrawal sludges, pesticides (Bhumbla, 1994;
NRCC, 1978).

3.2 Chemical structure

Chemical name : See table 1.3

Relative molecular mass : See table 1.3

Structural formula : See table 1.3

Table 2 Arsenic and salts: physico-chemical properties
(IPCS, 1992)

Arsenic Normal state Colour Odour Soluble Insoluble
compound (at room (g/litre)
temperature)

INORGANIC (III)

* Arsenic * Powder * Yellow-red n.a. * Hot water * Water
sulphide (slightly) (cold)
* Alkali
* Acids
* Ethanol

* Arsenic * Liquid * Colourless Acrid * Ethanol * (decomposed
trichloride (oily) smell * Ether by water)
* Concentrated
mineral acids

* Arsenic * Powder * White Odour * Water * Alcohol
trioxide (amorphous or less - cold (12) * Chloroform
crystalline) - 20EC (37) * Ether
- hot (115)
* Alkali
* HCl

Arsenic Normal state Colour Odour Soluble Insoluble
compound (at room (g/litre)
temperature)

* Cupric * Powder * Yellowish- n.a. * Acids * Water
arsenite green * Ammonia * Alcohol

* Gallium * Solid * Dark grey n.a. n.a. * Water
arsenide (cubic with
crystals) metallic
sheen

* Potassium * Powder * White n.a. * Water n.a.
arsenite * Ethanol
(Slightly)

* Sodium * Powder * White n.a. * Water n.a.
arsenite or greyish- (very)
white * Ethyl
alcohol
(slightly)

INORGANIC (V)

* Arsenic Powder * White n.a. * Cold n.a.
pentoxide (hygroscopic) water (1500)
* Hot
water (767)

* Calcium Powder * Colourless Odour- * Water n.a.
arsenate (amorphous) less (slightly)
* Dilute
acids

* Lead * Powder * White n.a. * Hot water
arsenate or solid (slightly) n.a.
(crystalline) * Dilute
nitric acid

* Caustic
alkalis

* Potassium * Powder * White n.a. * Cold n.a.
arsenate (crystalline) water (190)
* Hot
water (very)
* Acid
* Glycerol
* Ammonia

Arsenic Normal state Colour Odour Soluble Insoluble
compound (at room (g/litre)
temperature)

* Sodium * Powder * Clear Odour * Water (very) * Ether
arsenate colourless less * Alcohol
(slightly)

Arsenic compound Boiling point (EC) Melting point (EC) Sublimation (EC)

INORGANIC (III)

* Arsenic 707 300 -325 n.a.
sulphide

* Arsenic 130 16 n.a.
trichloride

* Arsenic 465 n.a. 315
trioxide

* Cupric n.a. Decomposes n.a.
arsenite

* Gallium n.a. 1238 n.a.
arsenide

* Potassium n.a. 300 (decomposes) n.a.
arsenite

* Sodium n.a. n.a. n.a.
arsenite

INORGANIC (V)

* Arsenic n.a. 315 (decomposes) n.a.
pentoxide

* Calcium Decomposes 1455 n.a.
arsenate

* Lead Decomposes 720 (decomposes) n.a.
arsenate

* Potassium n.a. 288 n.a.
arsenate

* Sodium 180 n.a. n.a.
arsenate

* n.a.: not available
3.3 Physical properties

3.3.1 Colour

See Table 2

3.3.2 State/Form

See Table 2

3.3.3 Description

See Table 2

3.4 Hazardous characteristics

See table 2

4. USES

4.1 Uses

4.1.1 Uses

4.1.2 Description

Arsenic salts are used as pesticides, wood
preservative, for glass manufacturing, in alloys,
electronics, paint pigment and in the manufacture of
dyestuffs.
Arsenic preparations are no longer recommended and are
rarely used for medical purpose. Some homeopathic
preparations (arsenicum album: As₂O₃) (Kerr &
Saryan, 1986) or "natural" remedies or preparations
(Asian herbal remedies: e.g. herbal tea for example)
(Gorby, 1988) may contain different arsenic compounds.

4.2 High risk circumstance of poisoning

The main sources of human exposure to arsenic are:

- Ingestion of contaminated water and /or food, mainly in
environmentally exposed populations. Many outbreaks of
arsenic poisoning are related to ingestion of water
obtained from contaminated wells.

- Ingestion of medicinal/homeopathic preparations
containing arsenic.

- Malicious or criminal activity, or for suicidal attempts.

4.3 Occupationally exposed populations

Inhalation of arsenic containing dusts or volatile
arsenicals during industrial or agricultural exposures.
Absorption through skin and mucous membranes during the
handling of arsenicals or through prolonged therapeutic usage
of arsenical preparations.

Main occupational exposures are the following:

- Workers (mainly roaster workers) engaged in the smelting
industries: copper, gold, lead, silver and zinc ores,
where arsenic is present as a contaminant or
by-product.

- Workers engaged in the manufacturing of pesticides,
herbicides and other agricultural products using arsenic
preparations and industrial or agricultural workers using
them.

- Arsenic in wood processing plants.

- Arsenic as desiccant or defoliant for the preparation of
cotton fields for harvesting.

- Various metallurgical or industrial activities like the
electrolysis of copper, or cadmium, with arsenic as a
contaminant.

5. ROUTES OF EXPOSURE

5.1 Oral

Oral absorption of arsenic is the main route of exposure
for the general population and may be accidental (ingestion
of arsenical pesticides by children) or, more rarely,
voluntary or criminal. During occupational exposure,
ingestion of inhaled arsenic dusts or direct contamination
through lack of occupational hygiene.

5.2 Inhalation

Inhalation exposure to dusts or aerosols containing
arsenic occurs mainly in industry (smelting of ores) or
agriculture (mixing and/or spraying pesticides) and can
produce toxic effects on the respiratory tract along with
systemic effects.

5.3 Dermal

Dermal absorption can result from topical application of
arsenical agents or from accidental contact with arsenicals
(eg. arsenic acid: Garb & Hine, 1977) and may result in
systemic toxicity.

5.4 Eye

Ocular contact with dusts or accidental splashing has
occurred in industry (Grant, 1986), resulting in local toxic
effects.

5.5 Parenteral

No data available.

5.6 Others

No data available.

6. KINETICS

6.1 Absorption by route of exposure

Oral absorption

Pentavalent arsenic compounds are almost totally absorbed
(till 90%) in most species. The absorption of trivalent
arsenic is limited, although the toxicity is greater because
of the high lipid solubility (Mahieu et al., 1981;
Schoolmeester & White, 1980).

Absorption by inhalation

Animals studies indicate a wide range of absorption according
to species, chemical form and particle size of arsenicals;
the clearance half-life from the lungs being from 30 minutes
to several days.

Several studies, involving workers exposed to inorganic
arsenic, indicate a rather good relationship between airborne
concentrations of inorganic arsenic and urinary excretion of
arsenic and its metabolites.

Skin absorption

Systemic poisoning involving prolonged cutaneous application
of arsenical agents (Robinson, 1975) or splashing on the skin
of arsenic acid (Garb & Hine, 1977) indicate an absorption of
inorganic arsenic through the skin.

6.2 Distribution by route of exposure

Once absorbed, arsenic is bound to haemoglobin,
leucocytes, and plasma proteins. It is cleared from the
intravascular space within 24 hours, and distributed in most
tissues (Jolliffee, 1991; Schoolmeester & White, 1980).

The ratio between red cell and plasma arsenic concentrations
increases with the level of exposure: from 1/1 for low
exposures to 3/1 for high environmental exposures (Vahter,
1983).

Soluble inorganic compounds, well absorbed by
gastro-intestinal tract or by lungs, are rapidly distributed
to organs or tissues rich in proteins containing sulfhydryl
groups, and accumulate mainly in liver, kidneys, spleen and
adrenal gland (Quatrehomme, 1992).

In humans, not exposed occupationally or environmentally to
arsenic compounds, arsenic binds to the sulfhydryl groups in
keratin and can be detected in hair, nails, and skin 2 to 4
weeks after exposure. After 4 weeks, arsenic localizes in
bone, coinciding with decreasing levels in the liver and
kidneys (Jolliffe et al., 1991; Schoolmeester & White, 1980;
Winship, 1984).

Arsenic compounds can cross the placental barrier (Lugo,
1969).

6.3 Biological half-life by route of exposure

Blood clearance of arsenic occurs in three phases. In
phase 1, a rapid decline occurs within 2 to 3 hours; some
estimate that greater than 90% of arsenic clears from the
blood, with a half-life of 1 to 2 hours (Vahter, 1980;
McKinney, 1992). For the remaining arsenic, a more gradual
decline occurs in phase 2, from 3 hours to 7 days (estimated
half-life is 30 hours), followed by phase 3, a slower
elimination phase with an estimated half-life of 200 hours
(Vahter, 1980; Mealey, 1959)

6.4 Metabolism

After absorption inorganic arsenic is biotransformed
into two organic methylated derivatives:

- Monomethylarsenic (MMA) and
- Dimethylarsenic acid (DMA)

DMA seems to be produced by a subsequent methylation of the
MMA precursor (Buchet et al., 1981; Buchet & Lauwerys,
1985).

The methylation process is dose dependent and as the dose of
arsenic increases, a reduction of the percentage of DMA is
observed in urine while retention of arsenic is higher (EPA,
1984; Vahter, 1983).

Unusual metabolic processes have been reported in literature:

- Case of methylenetetrahydrofolate reductase deficiency,
with increased neurotoxicity of arsenic, in a 16-year-old
girl, exposed to arsenic from CCA, in Suriname (Brouwer et
al., 1992).

- Very little excretion of arsenic in urine, as MMA (about
2%), in native Andean women exposed to high levels of
arsenic in water (Vahter et al., 1995). In this case, a
genetic polymorphism in the control of the
methyltransferase activity has been postulated.

Compared with inorganic As, the methylated metabolites are
less reactive with tissue constituents, less acutely toxic,
less cytotoxic, and more readily excreted in the urine
(ATSDR, 1998).

6.5 Elimination by route of exposure

Inorganic arsenic compounds are mainly excreted via the
kidneys but the rate of urinary arsenic excretion depends
upon the chemical form of the compound ingested, the route of
exposure and the dose level (Vahter, 1983). Other secondary
routes of elimination are hair, nails, sweat and faeces.

Urinary excretion

Following absorption of inorganic arsenic, arsenic is
excreted in the urine as DMA (60%) MMA (20%) and inorganic
arsenic (20%) (Crecelius, 1977; Tam et al., 1979).
One day after an ingestion of an oral dose (10 µg of arsenic
as main pentavalent compound, i.e. arsenic acid 90%), 22.4%
is recovered in urine; 57.9% after 5 days (Tam et al.,
1979).
In the presence of insoluble inorganic compounds like arsenic
selenite, there is no urinary excretion (Mappes, 1977).
When multiple doses are administered, at steady state, 60% of
the dose is excreted in urine (Buchet et al., 1981).

It has been estimated that the daily excretion of arsenic
metabolites is 30 - 60% of the inhaled amount (ATSDR,
1998).

Other routes of excretion

- Faecal/biliary excretion

Only a few percent is excreted in faeces (Ishinishi et al.,
1986). This small faecal excretion (< 10%) is probably
related to a reabsorption by intestines of arsenic eliminated
by the bile.

- Sweat

Sweat in a hot, humid environment can eliminate 2 µg of As
per hour (Vahter, 1983).

- Skin

Desquamation of skin can contribute to an elimination of 0,1
to 0,2 µg of As per day (Molin, 1976).

- Hair and nails

Inorganic arsenic is incorporated to hairs or nails (Winship,
1984).

7. TOXICOLOGY

7.1 Mode of action

The toxicity of arsenic compounds is generally linked to
the soluble inorganic trivalent forms. The toxicity of
pentavalent inorganic compounds seems related to the in vivo
reduction of As(V) to As(III) (Harvey, 1970).

Inorganic arsenic compounds react with sulfhydryl (-SH)
groups of cellular proteins, thereby inhibiting cellular
oxidative processes (pyruvate and succinate oxidative
pathways) (Arena & Drew, 1986; Harvey, 1970; Schoolmeester &
White, 1980).

Competition with phosphorus in the oxidative phosphorylation
process is caused by inorganic compounds (Dickerson, 1994),
mainly in the pentavalent form (Harvey, 1970).

The diffuse toxic process of arsenic poisoning causes
widespread endothelial cellular toxicity, resulting in
capillary damage and tissue hypoxia precipitating generalized
vasodilatation and transudation of plasma. Gastrointestinal,
cardiac, renal, bone marrow, central nervous system, and
hepatic damage may be noted at different stages of arsenic
poisoning (Donofrio et al., 1987; Fincher & Koeker, 1987;
Jolliffe et al., 1991; Schoolmeester & White, 1980; Winship,
1984).

7.2 Toxicity

7.2.1 Human data

7.2.1.1 Adults

A certain tolerance is believed to
develop upon repeated long term exposure with
low doses as seen in arsenic-eaters in
Austria and Styria, in last century (Tardieu,
1867). Though not well documented in the
scientific literature, that tolerance could
be seen against acute poisoning (Foa,
1987).

In adults, the estimated lethal dose varies
from 50 to 300 mg of inorganic compounds
(Armstrong et al., 1984; Hindmarsh, 1986;
Vallee, 1960; Zaloga et al., 1985).

For As₂O₃, the lowest reported lethal
dose is about 120 mg (Arena, 1967). The fatal
dose of ingested arsenic trioxide has also
been reported to lie between 70 and 180 mg
(Vallee, 1960).

Severe toxicity has been reported with the
ingestion of as little as 1 mg As₂0₃, but
as little as 20 mg can be life threatening
(Schoolmeester et al., 1980; Winship,
1984).

7.2.1.2 Children

Subchronic oral exposure to only 3
mg/day was fatal in a number of children
exposed to arsenic via contaminated milk
(Hamamoto, 1955).

7.2.2 Relevant animal data

Experimental data suggest that animals are not
as sensitive to inorganic arsenic compounds as humans,
and that this difference is not due entirely to
differences in gastro-intestinal absorption (ATSDR,
1989).

7.2.3 Relevant in vitro data

No relevant data.

7.2.4 Workplace standards

American conference of Governmental Industrial
Hygienists (ACGIH)

- ACGIH (1995) consider arsenic, elemental
(7440-38-2) and inorganic arsenic compounds
(except arsine) as a confirmed human carcinogen,
and has set up the standard for arsenic at 0,01
mg/m³ (TLV-TWA: Threshold Limit Value - Time -
Weighted Average).

- ACGIH (1995) has adopted also a Biological
Exposure Indice (BEI) for arsenic and soluble
compounds including arsine (7784-42-1) of 50 µg/g
creatinine (inorganic arsenic metabolites in
urine), for a sampling time at the end of the
workweek.

7.2.5 Acceptable daily intake (ADI) and other guideline
levels

International standards

- Provisional tolerable weekly intake (PTWI)

0.015 mg/kg/body weight for inorganic arsenic. There
is a narrow margin between the PTWI and intakes
reported in epidemiological studies to have toxic
effects (FAO/WHO, 1989).

- Reference dose (RfD)

0.0003 mg/kg/day is the oral reference dose
established by the EPA for inorganic arsenic (IRIS,
1996)

- Drinking water guidelines

0.01 mg/As (total)/L is the provisional guideline
value recommended by the World Health Organization
(WHO, 1996).

- Air quality guidelines

No safe level for arsenic can be recommended, because
there is no known safe threshold (WHO, 1987).

7.3 Carcinogenicity

American Conference of Governmental Industrial
Hygienists (ACGIH)

ACGIH (1995) consider As elemental (7440-38-2) and inorganic
compounds (except arsine) as confirmed human carcinogen.

Environmental Protection Agency (EPA)

Inorganic arsenic is classified by EPA as a group A
carcinogen (a known human carcinogen), under the EPA
classification (ATSDR, 1989)

International Agency for Research on Cancer (IARC)

In humans, exposure to inorganic arsenic via drinking water
(contaminated wells), drugs (Fowler's solution) and
pesticides can lead to skin cancers.

Respiratory cancers have been observed in workers
manufacturing arsenical pesticides and among copper smelter
workers, exposed to inorganic arsenic, but also to other
toxic substances (IARC, 1990).

There is inadequate evidence for the carcinogenicity of
arsenic compounds in animals (IARC, 1990).

There is sufficient evidence that inorganic arsenic compounds
are skin and lung carcinogens in humans. The data suggesting
an increased risk for cancer at other sites are inadequate
for evaluation (IARC, 1990).

Arsenic and arsenic compounds are classified by IARC in the
group 1: "The agent is carcinogenic to humans".

7.4 Teratogenicity

In animals, inorganic arsenic compounds are embryo
lethal or teratogenic (Barlow & Sullivan, 1982):

- sodium arsenate: hamster, mouse, rat
- sodium arsenite: mouse

Although sodium arsenate has been shown to be teratogenic and
embryo toxic in several experimental animals, intravenous and
intra peritoneal doses to produce this effect are greater
than or equal to 20 mg/kg (Beaudouin, 1974; Ferm et al.,
1971; Ferm & Carpenter, 1968).

In humans, arsenic can cross the placental barrier. Some
studies indicate an accumulation of arsenic in infant tissues
with age and a more sensitivity of infants to arsenic, with
long term brain damage (Barlow & Sullivan, 1982). There is
however, little evidence concerning effects of arsenic in
pregnancy (Barlow & Sullivan, 1982). Spontaneous abortions
and low weight babies reported in people working or living
close to a smelter can be linked to arsenic but also to many
other toxic compounds (Nordström, 1979). In many experimental
studies on reproductive effects of inorganic arsenical
compounds, maternal and developmental toxicity occur at the
same dose administered. But various evidence from the basic
science literature indicates that developmental toxicity is
not secondary to maternal toxicity (Golub, 1994).

7.5 Mutagenicity

There is limited evidence that arsenic may be mutagenic
in people exposed to inorganic arsenic compounds (drugs,
occupational exposure) with effects persisting for many years
(Barlow & Sullivan, 1982).

Inorganic arsenic compounds can produce detectable
cytogenetic changes, in vivo, in human somatic cells (Hantson
et al., 1996); but theses changes, seen with sister chromatid
exchanges (SCEs), occur at very high doses.

7.6 Interactions

Phosphorus (P)

Arsenic can compete with phosphorus in the oxidative
phosphorylation process and this can lead to the replacement
of phosphorus in the bone, where it may remain for many years
(Arena & Drew, 1986; Ellenhorn & Barceloux, 1988).

Selenium (Se)

It has been suggested that arsenic could form complexes with
GSH-peroxidase, Se-dependent enzyme, thereby depleting body
stores of enzymatically active selenium.

8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS

8.1 Material sampling plan

8.1.1 Sampling and specimen collection

8.1.1.1 Toxicological analyses

8.1.1.2 Biomedical analyses

8.1.1.3 Arterial blood gas analysis

8.1.1.4 Haematological analyses

8.1.1.5 Other (unspecified) analyses

8.1.2 Storage of laboratory samples and specimens

8.1.2.1 Toxicological analyses

8.1.2.2 Biomedical analyses

8.1.2.3 Arterial blood gas analysis

8.1.2.4 Haematological analyses

8.1.2.5 Other (unspecified) analyses

8.1.3 Transport of laboratory samples and specimens

8.1.3.1 Toxicological analyses

8.1.3.2 Biomedical analyses

8.1.3.3 Arterial blood gas analysis

8.1.3.4 Haematological analyses

8.1.3.5 Other (unspecified) analyses

8.2 Toxicological analyses and their interpretation

8.2.1 Tests on toxic ingredient(s) of material

8.2.1.1 Simple qualitative test(s)

8.2.1.2 Advanced qualitative confirmation test(s)

8.2.1.3 Simple quantitative method(s)

8.2.1.4 Advanced quantitative method(s)

8.2.2 Tests for biological specimens

8.2.2.1 Simple qualitative test(s)

8.2.2.2 Advanced qualitative confirmation test(s)

8.2.2.3 Simple quantitative method(s)

8.2.2.4 Advanced quantitative method(s)

8.2.2.5 Other dedicated method(s)

8.2.3 Interpretation of toxicological analyses

8.3 Biomedical investigations and their interpretation

8.3.1 Biochemical analysis

8.3.1.1 Blood, plasma or serum

8.3.1.2 Urine

8.3.1.3 Other fluids

8.3.2 Arterial blood gas analyses

8.3.3 Haematological analyses

8.3.4 Interpretation of biomedical investigations

8.4 Other biomedical (diagnostic) investigations and their
interpretation

In acute, massive ingestions, barium like opacities may
be demonstrated by abdominal X-ray (Adelson et al., 1961;
Gousios & Adelson, 1959; Gray et al., 1989; Hilfer & Mandel,
1962; Levin-Scherz et al., 1987; Lee et al., 1995).

8.5 Overall interpretation of all toxicological analyses and
toxicological investigations

Interpretation: The use of urinary arsenic excretion as
the sole determinant for chelation therapy may lead to
inaccurate assessment of tissue burden and over estimate the
risk of toxicity. Less toxic, water soluble forms of arsenic
such as organoarsenicals or sodium arsenate are excreted
rapidly after acute exposure and urinary arsenic levels
obtained shortly after exposure may not accurately reflect
tissue or target organ levels (Hayes, 1982; Monier-Williams,
1949; Schoolmeester & White, 1980; Schroeder & Balassa,
1966).

Recent ingestion of seafood rich in organic arsenic may lead
to false positive diagnosis of arsenic poisoning, especially
if no speciation is done of the type of arsenic measured in
urine.

Biomedical analysis

A slightly increased liver enzymatic activity is observed in
severe acute poisoning.

Fluid losses are often accompanied by electrolyte
disturbances.

Acid-base disturbances may occur.

Oliguria, anuria are observed in severe cases. Monitor renal
functions (serum creatinine).

Other investigations

As inorganic arsenic compounds are radio-opaque, an X-ray of
the abdomen will be useful, in all cases of acute inorganic
arsenic ingestion.

9. CLINICAL EFFECTS

9.1 Acute poisoning

9.1.1 Ingestion

Symptoms begin usually within the first hour
following ingestion.
Gastrointestinal disturbances are the main clinical
effects: vomiting, oesophageal and abdominal pain,
bloody rice water diarrhoea (Quatrehomme, 1992).
Metallic taste and garlic odour of breath or faeces
can be noted (Lee, 1995).
After an apparent remission (1 to 2 days), several
organs are affected by the systemic action of
inorganic arsenic, resulting in the following delayed
effects:
Cardiovascular: hypotension, tachycardia,
dysrrhythmia, prolonged QT interval, torsades de
pointes, myocarditis, cardiovascular failure and coma;
Renal: albuminuria, haematuria, oliguria, anuria,
renal failure; Hepatic: toxic hepatitis; Cutaneous:
various eruptions; Neurological: hyperpyrexia, toxic
delirium, convulsions, tremor, coma; Respiratory:
pulmonary oedema, ARDS, respiratory failure.
If patient survives the cardiovascular failure,
hepatic and renal impairment and central and
peripheral nervous system damage may develop
(Armstrong, 1984; Goldsmith, 1980; Bolliger et
al.,1992; Greenberg et al., 1979; Ellenhorn,
1997).

After a long convalescence, sequelae may be
observed:
Sensorimotor polyneuropathy, usually symmetrical, may
occur one to three weeks after the beginning of the
intoxication (Campbell, 1989; Donofrio, 1987; Bansal,
1991; Wesbey, 1981).
The encephalopathy may be stated (Fincher & Koerker,
1987)
Mee's lines i.e. transverse white striae on the nails
appear several weeks after absorption (Aldrich, 1904;
Mees, 1919; Sass, 1993).

9.1.2 Inhalation

Irritation of the respiratory tract: dyspnoea,
accompanied by cough, thoracic pain during inspiration
(Hathaway et al., 1991).

9.1.3 Skin exposure

Following accidental splashing of an arsenic
acid solution, local effects (pain and swelling at the
site of contact) were noted, followed several hours
later by gastrointestinal disturbances: nausea,
vomiting, diarrhoea, stomach pains. In the next days,
neurological effects and peripheral neuropathy were reported (Garb &
Hine, 1977).

9.1.4 Eye contact

Ocular irritation: eyelids dermatitis,
conjunctivitis. Corneal necrosis has been observed
with exposition to arsenic trichloride: AsCl₃ (Grant,
1986).

9.1.5 Parenteral exposure

No data available.

9.1.6 Other

No data available.

9.2 Chronic poisoning

9.2.1 Ingestion

During chronic ingestion of inorganic arsenic
compounds, the following effects are noted:
gastrointestinal disturbances: nausea, vomiting,
diarrhoea, metallic taste;
Sensorimotor symmetrical polyneuropathy, polyneuritis,
psychiatric disturbances are the more frequent
effects.
Haematological effects: anaemia; aplastic anaemia was
reported in one case (Kjeldsberg & Ward, 1972). More
rarely, cardiovascular, renal, hepatic problems
occur.
Cutaneous signs: hyperkeratosis, melanosis, Mee's
lines.

9.2.2 Inhalation

Local effects on mucous membranes -
irritation, perforation of the nasal septum are noted.
Systemic effects are rarely observed.

9.2.3 Skin exposure

Local irritation signs are observed with
chronic cutaneous contact: ulcerations, vesiculation
(Zaloga et al., 1985).
Inorganic arsenic compounds may act as contact
allergens (ATSDR, 1989).

9.2.4 Eye contact

Dermatitis of the eyelids and conjunctivitis
have been reported in the literature.

9.2.5 Parenteral exposure

No data available.

9.2.6 Other

No data available.

9.3 Course, prognosis, cause of death

In case of severe acute poisoning by ingestion,
gastrointestinal disturbances begin within the first 20 to 30
minutes and are marked: diffuse capillary damage results in
haemorrhagic gastroenteritis. Nausea, vomiting abdominal pain
and watery, profuse diarrhoea is noted; sometimes the term
"arsenical cholera" has been used. Intense thirst,
retrosternal pain, dysphagia, marked dyspnea, fluid-
electrolyte disturbances, oligo-anuria, delirium are
observed. In severe cases, extensive tissue third spacing of
fluids combined with fluid loss from gastroenteritis may lead
to hypotension, cardiovascular failure and death. If prompt
treatment is not initiated, death may occur within 12 to 24
hours and the mortality rate is high, 50 to 75% (Evreux et
al., 1968, Gosselin et al., 1984)

Survivors of severe poisoning (after a vigorous fluid
replacement therapy) may develop a peripheral neuropathy and
skin lesions, which were only seen formerly in chronic
poisoning (Gosselin et al., 1984). Recovery from arsenical
neuropathy is generally poor, even after treatment with
chelating agents (Kew et al., 1993; Murphy et al., 1981).

9.4 Systematic description of clinical effects

9.4.1 Cardiovascular

Cardiac effects

Acute poisoning:
Cardiotoxicity may manifest itself as non-specific ECG
changes: QT prolongation, ST depression, or T wave
inversion. Minor ECG changes may remain for as long as
6 to 8 weeks. Cases of torsade de pointes, ventricular
tachycardia, ventricular fibrillation, asystole have
been reported by Beckman et al., 1991; Campbell &
Alvarez, 1989; Goldsmith, 1980; 1990; Levin-Scherz et
al., 1987; Poklis & Saady, 1990, Schoolmeester &
White, 1980; St-Petery et al., 1970; Wang & Mazzia,
1969). Death may occur secondary to dysrrhythmias.

Chronic poisoning:
An increase of the frequency of mortality by
cardiovascular diseases has been observed in workers
exposed to As₂O₃ in a copper smelter (Axelson et
al., 1978). Myocardial infarction and arterial
thickening has been observed in children exposed to
inorganic arsenic via drinking water (Rosenberg, 1974;
Zaldivar, 1974). Toxic myocardial action of inorganic
arsenic was reported in vineyard workers, exposed
chronically to arsenic pesticides with
electrocardiographic abnormalities: QT prolongation, T
wave depression or inversion (Haguenoer & Furon,
1982). Interstial myocarditis resulting in fatal
ventricular arrhythmias has been reported after
chronic exposure to arsenic (Hall & Robertson,
1990).

Vascular effects

Acute poisoning
The toxic action of arsenic on blood vessels result in
fluid leakage into the intestinal space with
subsequent intravascular volume depletion and severe
hypotension (Hall & Robertson, 1990).

Chronic exposure
Raynaud's syndrome was observed in Chile, infants and
children showing more severe symptoms than adults
(Rosenberg, 1974; Zaldivar, 1980) exposed to high
inorganic arsenic concentrations in drinking
water.

In vineyard workers, peripheral vascular disturbances
have been reported: endoangiitis, gangrene of the
extremities, atrophic acrodermatitis, peripheral
circulatory troubles (Ishinishi et al., 1986; Grobe,
1976).
Black-foot disease, as described in Taiwan, is a
gangrene of the extremities, due to peripheral
vascular disorders (Tseng, 1977), prevalence of the
disease being 8.9 per 1000.
Hypertension has been linked to long-term arsenic
exposure (Chen et al., 1995) and increased prevalence
of cerebrovascular disease, particularly cerebral
infarction was observed

9.4.2 Respiratory

Local effects in acute poisoning by inhalation
are irritation of the respiratory tract: rhinitis,
pharyngitis, laryngitis and tracheobronchitis, with
cough, pain during inspiration and dyspnoea (Hathaway,
1991).
Massive inhalation and swallowing of substantial
amounts of crude arsenic dust (more than 80%
As₂O₃) has been responsible for the death, within
several hours, of a worker. At autopsy, trachea and
main bronchi showed widespread mucosal and submucosal
haemorrhages and there was intense visceral congestion
(Gerhardsson et al., 1988).

Acute respiratory failure occurs infrequently in acute
arsenic poisoning and is usually due to the muscle
weakness. Pulmonary oedema, either noncardiogenic from
capillary leaking, or cardiogenic from myocardial
depression may occur. Adult respiratory distress
syndrome (ARDS) has been reported (Bolliger, 1992;
Greenberg, 1979; Schoolmeester & White, 1980; Zaloga
et al., 1985).

9.4.3 Neurological

9.4.3.1 Central Nervous System (CNS)

Neurological symptoms range from
vertigo or altered mental status to seizures
or toxic encephalopathy (Campbell & Alvarez,
1989; Poklis & Saady, 1990; Schoolmeester &
White, 1980).
Encephalopathy has been observed in acute or
subacute poisoning by ingestion contaminated
drinking water from well (Armstrong, 1984)
and deliberated ingestion of arsenic trioxide
(Danan et al., 1985).

In chronic poisoning encephalopathy was
observed after ingestion (Freeman & Couch,
1978), inhalation of fumes during a smelting
process of antimony ore (Beckett et al.,
1986) or from wood treated with ammoniated
copper arsenate (Morton & Caron, 1989).

9.4.3.2 Peripheral nervous system

The most common long-term sequela
associated with arsenic poisoning, occurring
usually 7 to 14 days after ingestion, is a
polyneuropathy, which is the result of a
direct toxic effect leading to damage of the
peripheral nerve bodies (Bansal et al., 1991;
Campbell & Alvarez, 1989; Donofrio et al.,
1978; Wesbey & Kunis, 1981).
Peripheral neuropathy occur in acute or in
chronic poisonings. It is frequently a
progressive ascending and painful
polyneuritis, involving both sensory and
motor neurons. It is due to a
demyelimination of axons.
Paresthesias, numbness, tingling sensations,
pain in extremities. Muscular weakness is
commonly observed.
Electromyographic disturbances are observed
(Hindmarsh et al., 1977) and the reduction of
nerve conduction velocity, without symptoms,
has been noted (Feldman et al., 1979).
In severe poisoning, motor palsy may
predominate.

9.4.3.3 Autonomic nervous system

No data available.

9.4.3.4 Skeletal and smooth muscle

In a case of acute massive arsenic
poisoning a severe rhabdomyolysis was observed
(Fernandez-Sola et al., 1991).

9.4.4 Gastrointestinal

Gastrointestinal disturbances, such as severe
gastritis or gastroenteritis are the first and
prominent manifestations of acute toxicity by
ingestion. These gastrointestinal effects can lead to
a choleriform syndrome ("arsenical cholera").

Digestive lesions are not due to a corrosive effect on
the gastrointestinal mucosa, but are the consequence
of vascular damage of the mucosa with subsequent fluid
loss. Thus, the first symptoms may be delayed for
several hours. Symptoms are the following: nausea,
vomiting, severe gastroenteric pain, sensation of
burning in the mouth and thorax, profuse and sometimes
bloody diarrhoea, dehydration.
If fluid losses are important, the clinical course may
be cardiovascular collapse, shock and death.
(Quatrehomme, 1992, Moore, 1994)
Stools and emesis may have a garlic like odour.

In cases of poisoning by inhalation, these
gastrointestinal effects are delayed later and less
prominent than after ingestion.

During chronic occupational exposure, gastrointestinal
disturbances are not common.

9.4.5 Hepatic

Patients may develop hepatomegaly, jaundice,
portal hypertension or pancreatitis caused by the
direct effect of arsenic. However, Labadie et al.
(1990) suggested that arsenic induced hepatic injury
is caused by vascular and not hepatocellular
damage.

In chronic occupational exposures, hepatomegaly with
jaundice may be observed, evolving in some cases
toward cirrhosis, as seen in vineyard workers
(Haguenoer & Furon, 1982) or in copper smelter workers
(Axelson et al., 1978).

Jaundice, with sometimes ascites, has been described
after prolonged arsenical medication (Haguenoer &
Furon, 1982; Ishinishi et al., 1986).

Non-cirrhotic portal hypertension has been observed in
chronic arsenic intake (Guha Mazumdar & Das Gupta,
1991; Nevens et al., 1990).

Hepatic angiosarcoma and hepatocellular carcinomata
have been reported (Lander et al., 1975; Regelson et
al., 1968; Roth, 1957).

9.4.6 Urinary

9.4.6.1 Renal

Renal failure is caused by
vasodilatation leading to increased
glomerular filtration and capillary
permeability. The resulting protein leakage
may cause acute tubular necrosis or diffuse
interstitial fibrosis (Cullen et al.,
1995).
Acute renal tubular necrosis and also
cortical necrosis (Gerhardt et al., 1978)
have been reported in severe acute poisoning
(ATSDR, 1989).
Tubulo-interstitial nephritis has been
reported in chronic poisoning (Prasad &
Rossi, 1995).

9.4.6.2 Other

No data available.

9.4.7 Endocrine and reproductive systems

9.4.7.1 Endocrine system

Chronic oral exposure to inorganic
arsenic has been linked to the induction of
diabetes mellitus (Lai et al., 1994).

9.4.7.2 Reproductive system

See 7.4 Teratogenicity

9.4.8 Dermatological

In acute poisoning, melanosis, hyperpigmentation
and exfoliative dermatitis have been described,
but dermatologic effects are mainly seen after
chronic ingestion or inhalation exposure
(Zaloga et al, 1985; Schoolmeester & White, 1980;)

Chronic local effects include local irritation
- erythema, painful ulcerations, dermatitis (neck,
face, eyelids, forearms, hands), vesiculation (Zaloga
et al., 1985).
Skin lesions, occurring in environmentally, medically
or occupationally exposed populations are frequently
observed:

melanosis, generally seen on eyelids, temples,
neck, nipples, axillae and, in severe cases, on chest,
back and abdomen (Ishinishi et al., 1986; ATSDR,
1989); sometimes accompanied by punctiform leucoderma
("raindrop" pigmentation).
hyperkeratosis, commonly seen on the palms and
soles, either as warts or diffuse plaque and
characterised by thickening of corneal layer (Sass et
al., 1993).
other skin lesions may evolve to a Bowen's disease
(Haguenoer & Furon, 1982).

Skin lesions are now rare in industry: only one case
of hyperkeratosis was described during the last
decades (Frost, 1967).
However, skin alterations, skin malignant tumors and
Bowen's disease have been found frequent among wine
growers, during the 1960-1977 period (Lüchtrath,
1983).

9.4.9 Eye, ears, nose, throat: local effects

Dermatitis of the eyelids and conjunctivitis
characterised by redness, swelling and pain is seen in
acute or chronic exposure by inhalation. No valid
evidence of injury of the optic nerve by inorganic
arsenic can be found in the literature (Grant,
1986).

Irritation of the nose and pharynx, causing acute or
chronic rhino-pharyngo-tracheo-bronchitis has been
observed (Buchanan, 1962).

Perforation of the nasal septum has been observed in
arsenic-exposed workers (Ishinishi et al.,
1986).

9.4.10 Haematological

Bone marrow depression/failure and haemolysis
may develop.
The peripheral haematologic abnormalities associated
with arsenic intoxication include leucopenia, anemia
and thrombocytopenia (Kyle & Pease, 1965; Lerman et
al., 1980; Selzer & Ancel, 1983; Rezuke et al., 1991;
Terada et al., 1962; Van Tongeren et al., 1965;
Westhoff et al., 1975).

The anemia, usually associated with arsenic, has
normocytic indices (Kyle & Pease, 1965; Terada et al.,
1962). Megaloblastic anaemia has been reported rarely
(Lerman et al., 1980; Westhoff et al., 1975).

Macrocytosis without anaemia has been reported by
Heaven et al., 1994.

Severe dyserythropoiesis has been reported after
ingestion of kelp supplements (Pye et al., 1992).

9.4.11 Immunological

An immunosuppressive effect has been elicited
on mice exposed to sodium arsenite at doses of 0,5 ppm
to 10 ppm via drinking water (Blakely, 1980).

No data available in humans.

9.2.12 Metabolic

9.4.12.1 Acid-base disturbances

No data available.

9.4.12.2 Fluid and electrolyte disturbances

In acute poisoning by ingestion, fluid
losses are severe and are followed by
electrolyte disturbances.

9.4.12.3 Others

Hyperthermia can be seen in the
acute phase of the intoxication.

9.4.13 Allergic reactions

Contact dermatitis have been observed in
workers exposed to As₂O₃ (Ishinishi et al.,
1986).

Positive dermal patch tests have been observed in
workers (ATSDR, 1989; Haguenoer & Furon, 1982).

9.4.14 Other clinical effects

In chronic exposure, the presence of white
striae in fingernails, i.e. Mee's lines is frequently
observed.

Cases of alopecia would have been observed (Haguenoer
& Furon, 1982).

Breath, perspiration, and stools of poisoned patients
intoxicated may have a garlic like odour.

9.4.15 Special risks

Pregnancy

Inorganic arsenic crosses the placental barrier. A
case of neonatal death has been reported, following
acute maternal intoxication (Lugo et al., 1969).

Breast-feeding

Arsenic can be present in human milk (WHO, 1989).

9.5 Others

No data available.

9.6 Summary

10. MANAGEMENT

10.1 General principles

After ingestion, aggressive decontamination by gastric
lavage is recommended. Activated charcoal should be left in
the stomach.
Due to the toxic action of inorganic arsenic on the
gastrointestinal tract in acute poisoning, and the subsequent
fluid losses, special care to the fluid-electrolyte balance
is required to prevent cardiovascular toxicity (hypovolemia,
arrhythmias, cardiogenic shock).

Admission of the patient into the intensive care unit of the
hospital is therefore mandatory in order to allow close
monitoring of vital signs. Antidote treatment with BAL or
DMSA or DMSP should be initiated as soon as the diagnosis is
reasonably established.

10.2 Life supportive procedures and symptomatic treatment

In case of hypotension, place patient in Trendelenburg
position and administer IV fluids. If the response is
inadequate, administer dopamine or norepinephrine
(levarterenol) at the dosage required (See
IPCS-INTOX Treatment Guide on shock and hypotension).

If gastrointestinal hemorrhage occurs, blood products may be
necessary.

Arrhythmias, may be controlled by standard measures.

Morphine may be necessary to control abdominal pain.

10.3 Decontamination

Ingestion

Aggressive decontamination with gastric lavage is
recommended. Prior control of convulsions and protection of
airway is required.

Activated charcoal, has been suggested, although its efficacy
has not been proven.

Cathartics do not seem useful.

Whole bowel irrigation may be useful if arsenic is visible
using abdominal X-ray (Mahieu et al., 1987; Lee et al.,
1995).

Skin

If material has been spilled on the skin, immediately remove
the patient from the source of contamination, remove all
contaminated clothing, and wash affected areas with soap and
water (IPCS, 1992).

Eye

If the material is in the eyes, flush with clean water for at
least 15 minutes (IPCS, 1992).

10.4 Enhanced elimination

Haemodialysis may enhance elimination of free inorganic
arsenic or arsenic-BAL chelate (Mahieu et al., 1987;
Winchester, 1977). Especially in cases of early anuria,
haemodialysis is an effective arsenic elimination method
(Mathieu et al., 1992). If a combination with chelator
therapy is chosen, then BAL should be used because it has
been shown that arsenic-BAL complexe cross dialyser membranes
(Varizi et al., 1980), while for instance arsenic-DMSA
complexes do not pass the dialyser membrane (Sheabar et al.,
1989).

But its use has been recommended essentially in situations of
concomitant renal failure (Vaziri, 1980).

10.5 Antidote treatment

10.5.1 Adults

Dimercaprol (BAL):

3 to 5 mg/kg intramuscularly every 4 hours for 2 days,
then every 12 hours for 7 to 10 days until recovery or
until oral therapy can be started (Gorby, 1988).

Caution must be taken to avoid decreased urine pH,
which may result in dissociation of the BAL-arsenic
complex, increasing the risk of renal failure (Poklis
& Sandy, 1990; Reynolds, 1996). Urine alkalization
reduces the risk of renal failure and also promotes
the excretion of the BAL-arsenic complex (Reynolds,
1996).

BAL has many side effects a.o. painful injection,
nausea, vomiting, chest- and abdominal pain,
headaches, fever, hypertension, central nervous system
depression, and seizures. Peak side effects are noted
10 to 30 minutes after injection and usually subside
in 30 to 50 minutes. It is contraindicated in patients
with renal or hepatic impairment, pregnant patients,
and in patients with glucose-6-phosphate dehydrogenase
(G6PD) deficiency (Schoolmeester & White, 1980).

Besides its many side effects, it has been suggested
that the lipophilic BAL could serve as a carrier for
arsenic across the blood-brain barrier. Some authors
indeed found in the brain of the rabbits treated with
BAL higher arsenic concentrations than in the control
animals (Aposhian, 1984; Kreppel et al., 1990).
However Tsutsumi et al., (1983) found the arsenic
content in the brain following BAL treatment
unchanged, while Graziano et al. (1978) found the
arsenic concentration in the brain even decreased,
compared to controls.

D-Penicillamine:

25 mg/kg four times per day for a total of 5 days with
a maximum of 2 g/day. Although it has been advocated
for the treatment of As, based on anecdotal case
reports, Kreppel et al. (1989, 1990) using a
controlled experimental model, demonstrated that it
was ineffective in preventing the lethal action of
arsenic. The findings of Aposhian et al. (1983)
confirmed this experiment.

Also many side effects are reported: Hypersensitivity
reactions, leucopenia, eosinophilia, thrombocytopenia,
optic neuritis, and nephrotoxicity.

Dimercaptosuccinic acid (DMSA):

10 mg/kg every 8 hours for 5 days.

Side effects are rare, but include reversible
elevation in serum transaminases, gastrointestinal
symptoms, leucopenia, and hypersensitivity. DMSA is 20
to 30 times less toxic than BAL and can be given to
patients with G6PD deficiency without causing
haemolysis.

2,3-dimercaptopropanesulphonate (DMPS):

5 mg/kg every 4 hours intravenously for 24 hours with
transfer to oral DMPS 400 mg every four hours.

It has been reported to be effective in a severe acute
arsenic poisoning (Moore et al., 1994).

Because of its relatively few side-effects and proven
efficacy in the treatment of arsenic poisoning in
animal studies, DMPS may be the preferred agent as an
oral chelator for arsenic poisoning (Cullen et al.,
1995).

Regardless of the chelator that is chosen, therapy can
be terminated if the arsenic level is < 5 µg/L after
5 days (Kreppel et al., 1990).

Drastic antidote therapy, for instance by BAL, could
be limited by measuring the extent of methylation of
arsenic (the natural detoxifying mechanism). This can
be performed by the determination of monomethylarsenic
acid (MMA) and dimethylarsenic acid (DMA) in urine
(Mahieu et al., 1981).

10.5.2 Children

BAL:

3 mg/kg intramuscularly every 4 hours for 2 days, then
every 12 hours for 7 to 10 days until recovery or
until oral therapy can be started.

d-Penicillamine:

25 mg/kg four times per day for a total of 5 days with
a maximum of 1 g/day.

DMSA:

10 mg/kg or 350 mg/m² every 8 hours for 5 days.
Because of its relatively low in side-effects and
proven effective in the treatment of arsenic poisoning
in animal studies, DMSA may be the preferred agent as
an oral chelator for arsenic poisoning. (Cullen et
al., 1995).

Regardless of the chelator that is chosen, therapy can
be terminated if the arsenic level is < 5 µg/L after
5 days (Kreppel et al., 1990).

10.6 Management discussion

BAL (re)distribution of arsenic to the brain has to be
evaluated. In the mean time the use of the water-soluble
dithiols, like DMSA or DMPS, should be preferred as antidotes
for arsenic when available. Another advantage of these two
drugs is the fact that they cause fewer side-effects.

11. ILLUSTRATIVE CASES

11.1 Case reports from literature

Beer epidemic of 1900

A large outbreak of poisoning by inorganic arsenic, among
beer drinkers, was detected in the north of England by the
mid of 1900. Among the sources of arsenic contributing to the
contamination of beer, we can note (Abbot, 1984):

* Sulfuric acid, used to produce glucose for fermentation
from various starches and produced from purification of
Spanish pyrites, with a high white arsenic (As₂O₃)
content.
* Malt, dried or kilned over local gas coke. Recording of
deaths among beer-drinkers occurred at mid 1900. Deaths
were ascribed to alcoholism and nervous system
disturbances (peripheral or multiple neuritis). Inorganic
arsenic (contaminated sulfuric acid) as a cause of death
was pointed out several months later and the amount of
arsenic used in the preparation of beer was estimated to
several tons. The total number of cases, recorded in
several locations, was estimated to about 6000 and the
number of death to about 70.

Until the discovery of the other source of arsenic
(contaminated malt), once again the diagnosis of arsenic
poisoning was difficult to establish based on the symptoms
only and was ascribed to alcoholic neuritis.

Mass poisoning by sodium arsenite

This episode of criminal mass poisoning by inorganic arsenic
occurred in Argentina in 1987 (Roses et al., 1991). An
acaricide containing an aqueous solution of 45% weight volume
of sodium arsenite was intentionally poured over meat, in a
butcher's shop. Of the 718 subjects who had purchased
contaminated meat, 207 were tested for urine arsenic i.e.
symptomatic patients and non symptomatic individuals
requesting to have an urinary analysis. No treatment was
given to patients having urine arsenic concentration below 75
µg/dL. Patients of other groups (As urine: 76-500 µg/dL and
As urine > 500 µg/dL) were treated with BAL. Symptomatology
occurred at all levels and abdominal pain was recorded at the
lowest urine arsenic levels while vomiting, nausea and
systemic symptoms tended to increase at higher levels. Follow
up of treated patients showed that all were asymptomatic one
month after treatment and subsequently an early detection was
useful.

Acute oral arsenic trioxide intoxication (Mahieu et al.,
1987)

Thirty minutes after having voluntarily ingested ten small
bags of 1 g of arsenic trioxide (for veterinary purpose) a 27
years old woman was presenting gastrointestinal disturbances:
epigastric pain, nausea, vomiting, dysphagia, metallic taste.
Three hours later, she was admitted to a local hospital where
gastric lavage and intestinal washout (Mannitol 20%) were
done. Diuresis (Mannitol 20%) was initiated. BAL (250 mg
IM) was administered. Thirteen hours post-ingestion, she was
transferred, somnolent, to an university hospital (BP:90/60
mng/Hg) hypovolemia, oliguria). Opacities in digestive bowel
were detected with an abdominal X-ray.

Main therapeutic measures were the following:
* Volume replacement, under the control of a central venous
catheter (albumin, plasma)
* Large osmotic diuresis (mannitol 20%)
* "Intestinal washout" with Mannitol 20% and enema
* Duodenal probe, under gastroscopy (aspiration of duodenal
content and bile)
* Extra-corporeal dialysis (haemodialysis with
hemoperfusion): two periods (4 h) at the first and the
second day of hospitalization.
* BAL treatment, until the 8^th day.
* Sulfo-adenosyl-L-methionine (Samyr 7), a methyl group
donor, given after 48 h by IV, IM and introduodenal
routes, with simultaneous administration of vitamin B₁₂
for the last two routes.

Evolution of the patient was favourable.

* Digestive symptomatology has persisted during 3 days.
* At day 3, a diffuse cutaneous erythema was noticed, with a
more or less pronounced swelling of the face.
* At day 4, hepatalgia with a light cytolysis was noticed.

Patient was discharged from the intensive care at day 10.

Subacute arsenic poisoning (Kew et al., 1993)

A 35-year-old Asian man presented with a three month history
of progressive weakness of his hands and legs associated with
distal sensory disturbances. The patient had become aware of
the symptom six weeks after an Indian ethnic practitioner had
started treating him for atopic eczema. On examination Mees
lines were present in the finger nails and there was
hyperkeratosis of the soles of the feet. Symmetrical wasting
and weakness was present in the upper and lower limbs and all
tendon reflexes were absent. Cutaneous sensation was impaired
in a glove and stocking distribution. He could not stand
from a sitting position without using his arms and walked

with difficulty unsupported. Electromyography suggested a
peripheral sensoria-motor neuropathy. The presence of an
increased urinary concentration of inorganic arsenic (63
µg/L; normal < 2 µg/L) and a hair arsenic concentration of
20 µg/g on x-ray fluorescence spectrometry (normal < 1 µg/g)
confirmed arsenic intoxication. Chelation therapy with DMPS
100 mg daily for three weeks and later DMSA 400 mg three
times daily for two weeks was given without objective
improvement in muscle strength. Two years after the onset of
symptoms the patient was still unable to return to
work.

12. ADDITIONAL INFORMATION

12.1 Specific preventive measures

No relevant information.

12.2 Other

Other useful references:

Environmental Protection Agency (EPA), Jacobson-Kram D,
Mushak P, Piscator M, Sivulka DJ, Chu M, Gibb HJ, Thorslund
TW, Crump KS (1984) Health assessment document for inorganic
arsenic. Final report EPA 600/8-83-021F. Environmental
Protection Agency, Research Triangle Park.

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14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)

Author: Jean-Louis Benedetti, M.D.
Centre de Toxicologie du Québec
Centre Hospitalier Universitaire de Québec (CHUQ)
Pavillon Centre Hospitalier de l'Université Laval
(CHUL)
2705 Boulevard Laurier
Sainte-Foy, Québec
Canada, G1V 4G2
Tel: 1-418-6542254
Fax: 1-418-6542148
E-mail: ctqdoc@riq.qc.ca

Reviewer: Prof. Dr. A.N.P. van Heijst
Baarnseweg 42A
3735 MJ Bosch en Duin
Netherlands
Tel: 31-30-2287178
E-mail:a.vanheijst@pobox.ruu.nl

Date: July 1996

Peer Reviewed, Sao Paulo INTOX-11, October 21, 1999.
(Drs W. Temple, New Zealand- co-ordinator; B. Groszek, Poland; J.
de Kom, Surinam;
J.C. Rios Bustamante, Chile; J.C. Piola, Argentina).

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