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Arsine

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 Brand names, Trade names
   1.6 Manufacturers, 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 Other
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 and excretion
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)
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL ANALYSES 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
   8.6 References
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
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 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 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 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)



    ARSINE

    International Programme on Chemical Safety
    Poisons Information Monograph 044
    Chemical

    1.  NAME

        1.1  Substance

             Arsine

        1.2  Group

             Arsenic hydride

        1.3  Synonyms

             Arsenic trihydride; arsenic hydride;
             hydrogen arsenide; arseniuretted hydrogen; 
             arsenous hydride;arsenowodor (polish);
             arsenwasserstoff (german);
             monoarséniure trihydrique;
             arséniure d'hydrogène gazeux; 
             acide arsénhydrique (french)

        1.4  Identification numbers

             1.4.1  CAS number

                    7784-42-1

             1.4.2  Other numbers

                    NIOSH: CG 6475000
                    DOT: 2188
                    UN 2188

        1.5  Brand names, Trade names

             No data available

        1.6  Manufacturers, Importers

             Matheson Gas Products (USA); Phoenix Research Corp. (USA)

    2.  SUMMARY

        2.1  Main risks and target organs

             Arsine is a highly toxic gas. It has powerful haemolytic
             properties which can result in acute intravascular hemolysis
             and secondary renal failure. Mortality rate is high. A
             peripheral neuropathy can develop within months following
             acute poisoning.
             It is a human carcinogen.

        2.2  Summary of clinical effects

             The onset of symptoms is related to the inhaled
             concentration of arsine. Initial clinical manifestations
             generally occur 30 to 60 minutes after exposure, but may be
             delayed up to several hours. Symptoms include headache,
             nausea, vomiting, thirst, abdominal pain, shivering,
             hemoglobinuria. A garlicky odor of the breath may be noted.
             Anuria, jaundice, hypotension, metabolic acidosis and
             multiorgan failure may develop subsequently, as a consequence
             of massive hemolysis.
             Anemia is slowly reversible secondary to disturbances of
             erythropoiesis.
             Skin discoloration and lines on nails may occur.
             A sensory peripheral neuropathy may develop over months
             following acute poisoning.

        2.3  Diagnosis

             Acute: diagnosis is based on a history of exposure to
             arsine gas and early onset of headache, nausea and abdominal
             pain, dark red or brown discolouration of the urine and
             garlic-like odour on the breath.
             Chronic: arsine intoxication should be suspected when
             fatigue, muscular weakness, cramps and haemolytic anemia
             occur in workers potentially exposed to low
             concentration.

        2.4  First aid measures and management principles

             Inhalation: remove from exposure, monitor for
             respiratory distress, and administer supplemental oxygen.
             Maintain adequate hydration by starting intravenous fluids.
             Maintain urinary flow by correcting hypotension.
             Exchange transfusion or repeated transfusions of whole blood
             may be effective if significant haemolysis has occured.
             Dermal and eye exposure: immediately flush exposed areas
             with running water for at least 15 minutes.
    
             Toxic effects may have a delayed onset and exposed victims
             should be observed for a minimum of 24 hours.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Arsine is produced when metallic arsenides are
             decomposed by water or reducing acids.
             Main methods of manufacturing: hydrolysis of aluminium
             arsenide or treatment of aluminium arsenide with hydrogen
             chloride, reduction of arsenic trioxide with zinc in
             hydrochloric acid, decomposition of arsenides of
             electropositive metals. (HSDB, 1996)
             Arsenic is a widespread contaminant of many ores such as
             zinc, lead, and copper. Arsine can be formed, as a side
             reaction, when an acid or water contacts these arsenic
             bearing ores.
             Numerous industrial processes can lead to the accidental
             formation and liberation of arsine fumes, including the
             smelting and refining of metals (zinc), plating, galvanizing,
             soldering, electrolytic processing of hydrogen, preparation
             of acetylene from calcium carbide (Clayton & Clayton,
             1981).

        3.2  Chemical structure

             Molecular formula: AsH3
             Molecular weight: 77.93

        3.3  Physical properties

             3.3.1  Colour

                    Colourless

             3.3.2  State/Form

                    Gas

             3.3.3  Description

                    Density: 2.695
                    Melting point: -117 °C
                    Boiling point: -62.5 °C
                    Vapor pressure: 11 mm Hg at 20 °C
                    Dissociation pressure at 0 °C = 0.806 atm
                    Solubility in water: 28 mg/100 at 20 °C
                    Soluble in benzene, chloroform
                    Slightly soluble in ethyl alcohol and in alkalis
                    (Budavari, 1989).
    
                    Disagreeable garlic odour. The odour threshold of 0.5
                    ppm should not be considered a reliable indicator of
                    the presence of toxic concentrations of arsine
                    gas.

        3.4  Hazardous characteristics

             Decomposes when heated at 300 °C, depositing arsenic
             which volatilizes at 400°C.
             On exposure to light, moist arsine decomposes quickly
             depositing shiny black arsenic.
             Aqueous solutions are neutral.
             Traces are best removed by absorption in potassium
             permanganate solution or in bromine water.
             Extremely flammable when exposed to heat, sparks or
             flames.
             Moderately explosive when exposed to Cl2, HNO3, (K + NH3),
             on contact with warm and dry air or powerful shock
             (Budavari, 1989; Sax & Lewis, 1989; HSDB, 1996).

    4.  USES

        4.1  Uses

             4.1.1  Uses

                    Chemical used in synthesis; 
                    not otherwise specified
                    Other industrial/commercial product

             4.1.2  Description

                    Arsine has few industrial applications.
                    It is used as a doping gas in the processing of semi-
                    conductors in the microelectronics industry, and in
                    organic synthesis.
    
                    Arsine is stored under pressure in glass lined
                    cannisters.

        4.2  High risk circumstance of poisoning

             Most cases of arsine poisoning do not result from use of
             the gas itself; rather they occur when arsine is accidentally
             generated as by-product of a chemical reaction involving a
             metal containing an arsenic impurity and an acid or a strong
             alkali.
             Numerous industrial production processes can lead to the
             accidental formation and liberation of arsine fumes: smelting
             and refining of metals (zinc), plating, galvanizing,
             soldering, electrolytic processing of hydrogen. (Clayton &
             Clayton, 1981).
             Acute episodes of arsine poisoning may occur in environments
             unrelated to metal processing and be difficult to identify.
             Williams et al. (1981) described an arsine exposure involving
             artists working on the restoration of a famous painting,
             where nascent hydrogen came in contact with small amounts of
             arsenic in the paint.
    

             Another circumstance of poisoning is during the cleaning of
             tanks or drains that had been used to store arsenical
             compounds.
             Combustion products, which include arsine, may be present in
             runoff from fire control or dilution may cause
             pollution.

        4.3  Occupationally exposed populations

             Workers in the metallurgical industry involved in the
             production process and the maintenance of furnaces.
             Workers in the microelectronics industry (Sheehy & Jones,
             1993).
             Workers involved in the cleaning of storage tanks.

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Not relevant

        5.2  Inhalation

             Well absorbed. Important route in occupational exposure.

        5.3  Dermal

             Contact with arsine gas causes chemical burns. Contact
             with liquid arsine may cause tissue to freeze.
             It has been suggested that arsine can enter the body through
             cuts and breaks in the skin (Compton JAF, 1987 Military Chem
             Biol Agents, p 102, cited in HSDB, 1996).

        5.4  Eye

             Contact with arsine gas causes chemical burns. Contact
             with liquid arsine may cause tissue to freeze.

        5.5  Parenteral

             Not relevant

        5.6  Other

             No data available

    6.  KINETICS

        6.1  Absorption by route of exposure

             Arsine is rapidly and well absorbed by inhalation
             (Clayton & Clayton, 1981).

        6.2  Distribution by route of exposure

             Arsine is highly lipid soluble. After inhalation it can
             easily cross the alveolo-capillary membrane and the red blood
             cell membrane.
             It accumulates in its oxidized form, arsenite, in the red
             blood cells, liver, kidneys, spleen and lungs. Arsenite binds
             to haemoglobin, thus reducing its availability to bind oxygen
             (Clayton & Clayton, 1994).

        6.3  Biological half-life by route of exposure

             Half-life of the oxidised form (As3+) after ingestion is
             7 hours (Baselt, 1988).
             It may be prolonged in the presence of impaired renal
             function (Risk & Fuortes, 1991).

        6.4  Metabolism

             Arsine is gradually converted to arsenite (As3+) and
             further monomethylarsonic and dimethylarsinic acids.
             Methylation is the most significant route of detoxification
             in mammals, including humans (Clayton & Clayton, 1994).

        6.5  Elimination and excretion

             Inorganic arsenic and the monomethylarsonic and
             dimethylarsinic acids are primarily excreted in the urine,
             over a long period of time.
             Following inhalation of inorganic arsenic compounds, the
             fractions in the urine are approximately 20% inorganic
             arsenic, 20% methylarsonic acid, and 60% dimethylarsinic acid
             (Clayton & Clayton, 1994).

    7.  TOXICOLOGY

        7.1  Mode of action

             Arsine is highly lipid soluble. It can easily cross the
             alveolo-capillary membrane and into the red blood cell.
             Blair et al., (1990) performed in vitro experiments on red
             blood cells exposed to arsine gas. They provided evidence
             that arsine depletes the reduced glutathione content of the
             red blood cells, resulting in an oxidation of sulfhydryl
             groups in hemoglobin and, possibly, red cell membranes. These
             effects produce membrane instability with rapid and massive
             intravascular hemolysis.
             Arsine also binds to haemoglobin to form an arsine-
             haemoglobin complex (Gosselin et al., 1982).
             Hatlelid et al., (1996) demonstrated that arsine-induced
             haemolysis of dog red blood cells was completely blocked by

             carbon monoxide preincubation and was reduced by pure oxygen
             compared to incubations in air. They suggested that a
             reaction occurs between arsine and hemoglobin in the heme-
             ligand binding pocket or with the heme iron.
    
             In a case report of death occurring within 24 hours after
             exposure, the kidneys had severe injury.  The renal tubules
             were dilated and the epithelium  displayed vacuolization to
             complete necrosis, even though it had been too short a time
             for haematuria to develop (Browning, 1969). Hirata et al.
             (1990, cited in Clayton & Clayton, 1994) has demonstrated in
             hamsters that glutathione depletion increases arsine-induced
             nephrotoxicity. These observations suggest a direct toxic
             effect on the kidney.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             The odour threshold, of 0.5 ppm, can
                             produce clinical toxicity and may not provide
                             an adequate warning (Budavari, 1983).
                             Exposure to 3 to 10 ppm can cause symptoms
                             within a few hours (US EPA, 1982).
                             Symptoms of arsine toxicity have been
                             observed with brief exposure to 30 ppm (100
                             mg/m3) (Risk & Fuortes, 1991).
                             A half-hour exposure at 25 to 50 ppm (80-160
                             mg/m3) is considered lethal (Blackwell &
                             Robbins, 1979).
                             Inhalation of 250 ppm (800 mg/m3) of arsine
                             gas is instantly lethal (NIOSH, 1979).
                             The IDLH (Immediately Dangerous to Life and
                             Health) concentration is 6 ppm (NIOSH,
                             1990).

                    7.2.1.2  Children

                             No data available.

             7.2.2  Relevant animal data

                    Animals exposed 3 hours a day to concentrations
                    between 0.5 and 2 ppm experienced red blood cell
                    toxicity within a few weeks (ACGIH, 1986).
                    No effects on the hematopoeitic system were observed
                    following a single exposure to 0.5 ppm arsine, which
                    is 10 times the TLV set by the ACGIH, but a 90-day
                    arsine exposure to 0.025 ppm (one-half the TLV) caused
                    a significant anemia in rats (Clayton & Clayton,
                    1994).

             7.2.3  Relevant in vitro data

                    No data available.

             7.2.4  Workplace standards

                    TLV-TWA : 0.05 ppm or 0.016 mg/m3 (ACGIH,
                    1995)
                    NIOSH recommends a ceiling of 0.002 mg/m3
                    The ACGIH has proposed a Biological Exposure Indice
                    (BEI) of 50 œg of arsenic in the urine per gram of
                    creatinine for monitoring exposure to arsine.

             7.2.5  Acceptable daily intake (ADI)

                    No data available

        7.3  Carcinogenicity

             Arsine and airborne arsenic compounds have been
             associated with carcinogenicity (Hubert et al., 1988). An
             increased risk of lung cancers has been reported in several
             epidemiological studies (Kuratsune et al., 1974; Lee-
             Feldstein, 1983 cited in Clayton & Clayton, 1994).
             Arsine is a human carcinogen (RTECS, 1991).
             In 1994, NIOSH has recommended that arsine be regulated as a
             potential human carcinogen.
             The free radicals produced in the reduction of arsenite to
             dimethylarsinic acid damage DNA and are responsible for the
             carcinogenicity and potential genotoxicity of arsenic
             (Yamanaka et al., 1991 cited in Clayton & Clayton,
             1994).

        7.4  Teratogenicity

             Morrissey et al. (1990) reported an animal experiment
             where pregnant mice and rats were exposed to arsine at
             concentrations of 0.025, 0.5, or 2.5 ppm. Although arsine
             caused increases in maternal spleen size and measurable
             levels of arsenic in maternal blood and fetal livers, it did
             not adversely impact fetal development based on the end
             points used.
             Several studies have reported an increased rate of
             miscarriage among women who work in the semiconductor
             industry, where arsine is used in the manufacture of
             microchips (LaDou, 1983; Calabrese et al., 1987).

        7.5  Mutagenicity

             Arsenic compounds have mutagenic activity in the sister
             chromatid exchange test (Andersen, 1983).
             Cytogenetic effects including endoreduplication, chromosomal

             aberrations and sister chromatid exchanges, have been
             reported in Syrian hamster embryo cells in a dose-dependent
             manner with sodium arsenite (Clayton & Clayton, 1994).

        7.6  Interactions

             No data available

    8.  TOXICOLOGICAL ANALYSES 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

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Not relevant

             9.1.2  Inhalation

                    Initial clinical manifestations often occur 30
                    to 60 minutes after exposure, but can be delayed up to
                    several hours, depending on the concentration and
                    duration of the exposure. Symptoms include headache,
                    nausea, vomiting, thirst, abdominal pain, bile-
                    containing diarrhea, and shivering, accompanied by a
                    sensation of cold and paresis in the limbs.
                    Haemoglobinuria develops a few hours after exposure. A
                    garlic-like odour on the breath may be noted. Anuria,
                    jaundice, hypotension, metabolic acidosis and
                    multiorgan failure may develop subsequently, as a
                    consequence of massive haemolysis.
                    A sensory peripheral neuropathy may develop over the
                    first months after acute poisoning.
                    A transient pulmonary edema ascribed to a local
                    irritant action of the gas may occur (Gosselin et al.,
                    1984).

             9.1.3  Skin exposure

                    Redness of the skin. Frostbite may result from
                    freezing of tissues on exposure to liquid
                    arsine.

             9.1.4  Eye contact

                    Watering eyes, photophobia, blurred vision and
                    red staining of conjunctiva appear early after
                    exposure; these may be due to local irritant activity
                    of arsine.

             9.1.5  Parenteral exposure

                    Not relevant

             9.1.6  Other

                    No data available

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Not relevant.

             9.2.2  Inhalation

                    Animal: subacute or chronic exposure to low
                    arsine concentrations causes major persistent
                    splenomegaly and slight suppression of bone marrow
                    erythroid precursors in mice (Hong et al., 1989).
                    Human: clinical signs include asthenia, anorexia,
                    headache, myalgias. Low grade hemolytic anemia and
                    basophilic stippling may develop after chronic
                    exposure (Goldfrank & Bresnitz, 1986).
                    A progressive peripheral neuropathy may develop.
                    Characteristic fingernail changes (Mees' lines) may be
                    observed (Risk & Fuortes, 1991).
                    Blood arsenic concentrations and urinary arsenic
                    excretion are increased.
                    Lung cancers have been reported. (Kuratsune et al.,
                    1974).

             9.2.3  Skin exposure

                    No data available.

             9.2.4  Eye contact

                    No data available.

             9.2.5  Parenteral exposure

                    Not relevant

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             The prognosis and outcome depend on the severity of
             exposure.
             In the acute mild clinical form with headache, asthenia,
             myalgia, nausea and transient moderate hemoglobinuria,
             complete recovery generally occurs within one to two
             weeks.
             In severe cases the clinical course may be prolonged due to
             haemolysis and secondary renal failure. Anaemia reverses
             slowly. The peripheral neuropathy improves over several
             months.
    

             Death may occur within hours after acute exposure in the case
             of massive inhalation, as a result of acute cardiac failure
             (Benowitz, 1992).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Moderate and transient sinus tachycardia
                    secondary to haemolysis or anemia, hypovolemia or
                    acute pulmonary edema.
                    Hypotension and cardiovascular shock due to direct
                    effects on the myocardium and hyperkalemia (Benowitz,
                    1992).
                    ECG: elevation of the T-wave, various degrees of heart
                    block.
                    General vasoconstriction due to peripheral
                    hypoxia.

             9.4.2  Respiratory

                    Dyspnea secondary to haemolysis and hypoxia.
                    Transient pulmonary edema.
                    (Hotz & Boillat, 1991).

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             Headache, dizziness, pyrexia.
                             Impairment of consciousness, agitation,
                             anxiety, disorientation, delirium,
                             hallucination. Coma.

                    9.4.3.2  Peripheral nervous system

                             Paresthesia, numbness, burning
                             sensations.
                             A delayed peripheral sensory-motor neuropathy
                             may develop over the first few months after
                             the acute phase of poisoning, peaking at the
                             3rd month and resolving within 6 to 9 months
                             (Gosselin et al., 1982). The neuropathy is
                             usually both less common and milder than that
                             induced by arsenic, though its occurence may
                             be underestimated.

                    9.4.3.3  Autonomic nervous system

                             Hyperpyrexia

                    9.4.3.4  Skeletal and smooth muscle

                             Shivering, muscular cramps. Tissue
                             necrosis of skeletal muscle (Hesdorffer et
                             al., 1986).

             9.4.4  Gastrointestinal

                    Nausea, vomiting, abdominal cramps and diarrhea
                    appear early and are usually transient, but they can
                    be severe, and result in dehydration (Gosselin et al.,
                    1984).

             9.4.5  Hepatic

                    Early onset of acute jaundice due to hemolysis.
                    Hepatomegaly. Moderate elevation of liver enzymes
                    (Hotz & Boillat, 1991).

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Dark red or green discoloration of
                             the urine due to haemoglobinuria. Oliguria
                             proceeding to prolonged anuria.
                             Necrosis of the tubular epithelium (Browning,
                             1969).

                    9.4.6.2  Other

                             No data

             9.4.7  Endocrine and reproductive systems

                    Several studies have reported an increased
                    number of miscarriages among women occupationally
                    exposed to low arsine concentrations (LaDou, 1983;
                    Calabrese et al., 1987).

             9.4.8  Dermatological

                    Bronzing of the skin.
                    The skin lesions usually encountered with arsenic
                    poisoning include hyperpigmentation and
                    hyperkeratosis. They are rarely observed.
                    Streaks across fingernails (Mees' lines) may appear
                    after acute exposure.

             9.4.9  Eye, ear, nose, throat: local effects

                    Watering eyes, photophobia, blurred vision and
                    red staining of conjunctiva appear early after
                    exposure; they may be due to the local irritant
                    activity of arsine (Clayton & Clayton, 1981).
                    Tinnitus is a rare occurence.

             9.4.10 Haematological

                    Haemolysis may be severe in the first two or
                    three days after exposure, leading to errors in the
                    interpretation of blood cell count (red blood cell
                    count, leucocyte count, hematocrit), because of the
                    formation of "ghost cells", which are red blood cells
                    which have lost their hemoglobin content.
                    The amount of free haemoglobin in the plasma can
                    increase by as much as one third of the total
                    haemoglobin level (Gosselin et al., 1982).
                    Anemia ensues subsequent to haemolysis. It may develop
                    very quickly and may be severe. It is of the
                    normochromic, normocytic and megaloblastic type and is
                    poorly reversible (Ringenberg et al., 1988). The slow
                    reversal of anemia can necessitate repeated
                    transfusions.
                    A leukocytosis and signs of disseminated intravascular
                    coagulation can be observed  during the haemolytic
                    phase (Gosselin et al., 1982).

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             A metabolic acidosis can be
                             observed in severe cases, due to haemolysis
                             and/or renal failure.

                    9.4.12.2 Fluid and electrolyte disturbances

                             Fluid disturbances are due to
                             haemolysis, gastro-intestinal disturbances
                             and renal failure.
                             Plasma potassium level is usually within
                             normal range in the first hours after
                             poisoning; hyperkalemia is always associated
                             with severe renal function impairment and
                             acidosis.

                    9.4.12.3 Others

                             The serum level of free bilirubin
                             fraction is increased.

             9.4.13 Allergic reactions

                    No data available

             9.4.14 Other clinical effects

                    No data available

             9.4.15 Special risks

                    No data available

        9.5  Other

             No data available

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Inhalation:
             Make a proper assessment of circulation and neurological
             status. Monitor for respiratory distress, administer
             supplemental oxygen.
             Maintain adequate hydration by starting intravenous fluids.
             Maintain urinary flow by correcting hypotension and
             dehydration. Some advocate the use of diuretics if these
             measures do not maintain urine output.
             Exchange transfusion or repeated transfusions may be
             necessary if major haemolysis has occured.
    
             Dermal and eye exposure: immediately flush exposed areas
             with running water for at least 15 minutes.
    
             Effects may be delayed, keep victim under observation.

        10.2 Life supportive procedures and symptomatic/specific treatment

             Respiratory and cardiovascular support as
             necessary.
             Maintain adequate hydration with intravenous fluids and keep
             a brisk urinary flow with the use of diuretics if
             required.
             Correct acidosis and disturbances of fluid and electrolytes
             as necessary.
    

             Haemodialysis should be performed in case of severe renal
             failure, and may be considered to enhance clearance of
             arsenic from the body.
             Repeated transfusions of whole blood for correction of
             haemolysis and prolonged anemia.

        10.3 Decontamination

             Dermal and eye exposure: immediately flush exposed
             areas with running water for at least 15 minutes.

        10.4 Elimination

             The most important treatment of haemolysis is exchange
             transfusion which can remove the plasma haemoglobin and the
             arsine-hemoglobin complexes.
             Haemodialysis is indicated in severe renal failure.

        10.5 Antidote treatment

             10.5.1 Adults

                    The administration of DMSA (dimercaptosuccinic
                    acid) should be considered in case of elevated arsenic
                    blood level.
                    Fournier et al. (1988) administered successfully 30
                    mg/kg in 3 divided doses for 5 days to two patients
                    poisoned by arsenic salts.
                    DMSA was successfully used at 30 mg/kg/d in four 5
                    day-courses, in a patient with acute organo-arsenate
                    poisoning (Shum & Whitehead, 1994).
                    For heavy metal poisoning (mercury, lead and arsenic),
                    Reynolds (1996) recommends a dosage regimen of 10
                    mg/kg orally every 8 hours for 5 days, then every 12
                    hours for an additional 14 days.

             10.5.2 Children

                    No data available

        10.6 Management discussion

             The indications for treatment with a chelating agent
             should be discussed to limit the development of a delayed
             peripheral neuropathy even though its effectiveness has not
             been clearly evidenced in arsine poisoning (Pairon et al.,
             1992). DMSA is preferred over BAL which is contraindicated in
             patients with renal impairment.
             According to Gosselin et al. (1982), haemodialysis appears to
             be more effective than blood exchange in removing arsenic
             from the body. In the setting of arsine poisoning
             haemodialysis combined with DMSA may enhance clearance
             although data is lacking.
    

             Blood exchange should be performed only in cases with massive
             haemolysis. The total exchanged volume should not represent
             more than two times the body blood volume.
             Follow-up: monitor signs of peripheral sensory-motor
             neuropathy.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Gosselin et al. (1982) reported four cases of acute
             arsine poisoning.
             While engaged in the repair of a zinc furnace, four workers
             were accidentally exposed to arsenious hydride (ASH3)
             fumes. Acute intravascular haemolysis developed within a few
             hours. On admission, the patients immediately underwent
             exsanguinotransfusion; 8.2 to 10.2 L of blood were exchanged
             through a continuous perfusion pump at the rate of 1 L/hour.
             Two patients resumed diuresis during transfusion, but the
             other two required repeated haemodialysis. Between the 10th
             and 30th day, while renal function was gradually returning to
             normal, mild megaloblastic anemia developed. This was
             followed during the 3rd month by clinical and electric
             evidence of polyneuritis of the lower and upper limbs, which
             subsequently resolved. Regular measurements of arsenic levels
             in the blood and urine were performed between and during
             exsanguinotransfusion and haemodialysis. On admission the
             arsenic blood level was extremely high in one patient: 6850
             µg/L.
    
             Risk & Fuortes (1991) described a case of chronic
             occupational exposure to arsine in a 35-year-old male. The
             illness progressed for half a year until the diagnosis was
             made. Signs and symptoms included episodes of nausea,
             headache, dizziness and progressive lower extremity weakness
             and paresthesiae. Visits to several physicians and hospitals
             led to treatment for ulcers, hepatitis and other diseases.
             Severe liver dysfunction and marked leucocytopenia of unknown
             etiology were found. The patient developed recuring intense
             focal headaches, nausea, low grade fever, paresthesia and
             hepatic and renal impairment, and was transferred to a
             referral hospital. Suspicions of arsenic toxicity were
             entertained because of progressive neuropathy and the
             characteristic Mees' lines in the fingernails. Serum arsenic
             level was normal (10 pg/mL). However, a 24-hour urine
             collection two months later revealed arsenic excretion of
             11.3 mg/24 hour (450 times higher than normal). Penicillamine
             chelation was undertaken and led to high arsenic excretion.
             After an initial brief bout of worsening symptoms, there was
             significant amelioration.

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             Standard industrial hygiene procedures should be
             employed to reduce workplace exposure to the lowest possible
             level.
             NIOSH (1994) recommends that occupational exposures to
             carcinogens be limited to the lowest feasible
             concentration.
             Respiratory protection should be available and used.
             In preemployment medical examination, special attention
             should be given to past or present kidney disease and anemia.
             Periodic examination should include tests to determine
             arsenic levels in the blood and urine. The general status of
             the blood and renal and liver functions should also be
             evaluated (HSDB, 1996).
             Following occupational exposure to arsine notification tothe
             appropriate health authorities and a site inspection should
             be made.

        12.2 Other

             No data

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

        Author:     MO Rambourg Schepens
                    Centre Anti-Poisons de Champagne Ardenne
                    Centre Hospitalier Universitaire.
                    F-51092 REIMS cedex. FRANCE
    
                    e-mail: marie-odile.rambourg@wanadoo.fr
    
        Reviewer:   WA Watson
                    Emergency Medicine
                    Truman Medical Center.
                    2301 Holmes Street. Kansas City, MO, USA
    
                    e-mail: wawatson@CCTR.UMKC.EDU
    
        Date:       June 1997
    
        Peer review: Oslo (2 July, 1997) Members of group: Marie-Odile
        Rambourg, Bill Watson, Rob Dowsett, Barbara Groszek, Michael
        Ruse
    
        Editor:     Dr M. Ruse (August, 1997)
    
        Editor:     Dr. M. Ruse (July, 1997)
    



See Also:
        Arsine (ICSC)