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Arsenic

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Main manufactures, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Hazardous characteristics
4. USES
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High risk circumstance of poisoning
   4.3 Occupationally exposed populations
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. TOXICOLOGY
   7.1 Mode of action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
      7.2.4 Workplace standards
      7.2.5 Acceptable daily intake (ADI) and other guideline levels
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
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
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central Nervous System (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
         9.4.7.1 Endocrine system
         9.4.7.2 Reproductive system
      9.4.8 Dermatological
      9.4.9 Eye, ears, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.2.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Others
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)




    ARSENIC, INORGANIC

    International Programme on Chemical Safety
    Poisons Information Monograph 042
    Chemical

    1.  NAME

         1.1  Substance

              Arsenic, inorganic

         1.2  Group

         1.3  Synonyms
        Table 1 Arsenic and salts: synonyms, structure and identification
    numbers   (IPCS, 1992)

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

    INORGANIC (III)

    Arsenic sulfide      246,02      As2S3        1303-33-9       CG2638000        1557

    Synonyms
    and trade
    names

    * 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

             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 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