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Domoic acid

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 manufacturers, 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 circumstances of poisoning
   4.3 Occupationally exposed populations
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inahalation
   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
   7.3 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 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 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), ADDRESS(ES), DATE(S) (INCLUDING UPDATES)
    DOMOIC ACID

    International Programme on Chemical Safety
    Poisons Information Monograph 670
    Chemical

    1.  NAME

        1.1  Substance

             Domoic acid

        1.2  Group

        1.3  Synonyms

             Amnesic shellfish poisoning

        1.4  Identification numbers

             1.4.1  CAS number

             1.4.2  Other numbers

        1.5  Main brand names, main trade names

             Not applicable.

        1.6  Main manufacturers, main importers

             Not applicable.

    2.  SUMMARY

        2.1  Main risks and target organs

             Amnesic shellfish poisoning (ASP) occurs after ingestion
             of bivalve molluscs or possibly fish contaminated with domoic
             acid. Gastro-intestinal symptoms may precede the neurological
             symptoms. These may be quite mild and the CNS may be the
             first target organ affected. Until now, only bivalve molluscs
             harvested in Prince Edward Island, Canada, have produced
             poisonings in humans. Domoic acid has been found in algae or
             dinoflagellates in Japan, the Mediterranean region, the East
             Coast of North and South America, and the West Coast of North
             America.

        2.2  Summary of clinical effects

             After a delay of a few hours to one-day post ingestion
             of molluscs contaminated with domoic acid, gastrointestinal
             symptoms appear. They may include nausea, vomiting, abdominal
             cramps, diarrhoea, haemorrhagic gastritis and anorexia. The

             neurological symptoms may occur after a delay of a few hours
             or up to three days according to the outbreak observed in
             1987. These consist of a wide variety of symptoms varied
             among patients: severe headaches, loss of balance or
             dizziness, vision disturbances, memory loss. In more severe
             cases (old age and renal insufficiency being the two main
             risk factors): symptoms included confusion, disorientation,
             mutism for up to two weeks; autonomic nervous system
             dysfunction for a few days to a few weeks (cardiac
             arrhythmias, unstable blood pressure, hiccoughs, bronchial
             hypersecretions which may require endo-tracheal intubation);
             involuntary chewing, grimacing, myoclonia, convulsions; coma.
             Death occurred in 4 of the 107 confirmed cases. Permanent
             sequelae included memory loss and peripheral
             polyneuropathy.

        2.3  Diagnosis

             The diagnosis is based on the history of ingestion of
             bivalve molluscs followed by characteristic symptoms.
             Laboratory confirmation by mouse bioassay on leftover food or
             HPLC analysis of stools or urine may be done in the following
             days. Environmental surveillance programs of phytoplanktons
             at-risk regions may be suggestive of a possibility of
             poisoning.

        2.4  First-aid measures and management principles

             Due to the risk of convulsions, emesis should not be
             induced. In severe cases with a short incubation period,
             gastric lavage after endo-tracheal intubation may be
             indicated. Activated charcoal may then be left in the
             stomach. Convulsions not clinically visible should be managed
             with diazepam 5 to 10 mg intravenous (IV) bolus, followed by
             repeated doses every 15 minutes if required, up to 30 mg. In
             children, 0.25 to 0.4 mg/kg per dose, up to 10 mg/dose.
             Severe cases should be admitted to the intensive care unit
             and monitored for convulsions, CNS depression, cardiovascular
             collapse or gastric haemorrhages. Treatment is symptomatic
             and no antidote is available.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Domoic acid was first isolated from the red alga
             Chondria armata. In 1975 it was identified as coming from the
             Mediterranean Alsidium corallinum It was later found in
             either microalgae species (diatoms) or macroalgae species
             (red algae) (IOC,1995). Bivalve molluscs are contaminated by
             filtering toxic dinoflagellates and accumulating the toxins
             in their digestive system. As for the crabs observed to

             contain domoic acid in Oregon, USA, the toxins concentrated
             mostly in the digestive system even if lower concentration
             could be found in the flesh. Dinoflagellate-eating fish may
             also become contaminated.

        3.2  Chemical structure

        3.3  Physical properties

             3.3.1  Colour

                    Colourless.

             3.3.2  State/form

                    Pure domoic acid appears as colourless crystal
                    needles. It is soluble in water, dilute mineral acids
                    and alkali hydroxide solutions. It is slightly soluble
                    in methanol and ethanol and insoluble in petroleum
                    ether and benzene (Jenkins, 1996).

             3.3.3  Description

                    Domoic acid is an excitatory amino acid
                    containing the structure of glutamic acid and
                    resembling kainic acid (Todd, 1989). Three geometric
                    isomers of domoic acid have been described; they are
                    isodomoic acids D, E, and F. They have little
                    biological activity compared to domoic acid.

        3.4  Hazardous characteristics

             No data available.

    4.  USES

        4.1  Uses

             4.1.1  Uses

             4.1.2  Description

                    Seaweed Chondria armata may contain domoic acid
                    and extracts of the plant have been used in Japan as
                    an ascaricidal medication at a dose of 20 mg per
                    person without adverse effects (Daigo, 1959).  Its
                    insecticidal properties were also known since flies
                    die soon after landing on the seaweeds (Iverson,
                    1990).

        4.2  High risk circumstances of poisoning

             Until now, only one outbreak of ASP has been related to
             ingestion of contaminated shellfish cultured in the Cardigan
             river estuary of Prince Edward Island, Canada. However,
             domoic acid has been identified in the pennate
             phytoplanktonic diatom Nitzschia pungens in the coastal
             waters of Oregon and Washington States, USA. An outbreak
             involving pelicans and other waterfowls has been reported in
             Monterey Bay (Poisindex, 1996). Particular attention is being
             paid to the appearance of the " mucilage " in the high and
             middle Adriatic sea since it seems to originate from the
             diatoms among which there is a species of Nitzschia (Viviani,
             1992). The age and impaired renal function of the exposed
             individuals are prime factors of risk. In the 1987 outbreak,
             11 of the 13 patients admitted to the intensive care unit and
             all those who died were over 68 years old.
    
             The estuaries of rivers in Prince Edward Island where the
             first outbreak originated are still under surveillance. It is
             yet too early to identify with any confidence the high risk
             geographical areas of the world. The east coast of North and
             South America and the west coast of North America may be at
             risk. Japan (Takemoto & Diago, 1958), Korea and Norway may
             also be at risk (Fryxell, 1991).

        4.3  Occupationally exposed populations

             Not applicable.

    5.  ROUTES OF ENTRY

        5.1  Oral

             Ingestion of the seaweed Chondria armata extracts or the
             ingestion of contaminated shellfish are the only routes of
             entry that have been described up to now.

        5.2  Inahalation

             Not applicable

        5.3  Dermal

             Not applicable

        5.4  Eye

             Not applicable

        5.5  Parenteral

             Not applicable

        5.6  Other

             None.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Ingestion has been the only route of entry described.
             There has been a wide variation in the delay between
             ingestion and appearance of the first symptoms (15 minutes to
             38 hours, for an average of 5 hours). It is not known yet if
             this is related to factors of absorption, distribution, or
             sensitivity of the hosts. Animal studies have shown that,
             when given by mouth, approximately 10 times more toxins is
             required to produce toxicity than by parenteral route.

        6.2  Distribution by route of exposure

             No data available.

        6.3  Biological half-life by route of exposure

             No data available. The neurological symptoms appeared
             after 2 to 58 hours with an average of 16 hours. Recuperation
             from these neurological symptoms took between 24 hours to 12
             weeks.

        6.4  Metabolism

             No data available

        6.5  Elimination and excretion

             Studies in rats and mice on urinary and faecal excretion
             have shown that almost 100% of the administered dose is
             eliminated in the stools within a delay of 36 hours.

    7.  TOXICOLOGY

        7.1  Mode of action

             The toxicity of domoic acid on the nervous system is
             known to occur on excitatory amino acid receptors and on
             synaptic transmission. Two amino acids, l-glutamate and 
             l-aspartate are considered to be neurotransmitters and act 
             upon several receptor types. Three receptor sub-types have 
             been described for excitatory amino acids, the kainic acid 
             (KA) and the n-methyl-d-aspartate (NMDA) receptors being best
             characterized. The other one is the quisqualate receptor.
             Stimulation of the NMDA receptor by glutamate and other
             exogenous NMDA agonists open membrane channels permeable to
             Na+ , leading to Na+ influx and membrane depolarization.

             Domoic acid produces its action through pre and post synaptic
             non NMDA receptors in a way similar to kainic acid opening
             the channel to Ca++ and inducing cellular lethality (Todd,
             1993, Wright, 1990).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             In Japan, domoic acid was given to
                             humans at oral doses of 0.5 mg/kg body weight
                             without any ill effects. Doses of seaweed
                             extracts of 20 mg per person were used as
                             ascaricidal. In the 1987 outbreak, the
                             involved mussels were shown to contain
                             concentrations of domoic acid varying between
                             31 to 128 mg/100 g muscle tissue. The
                             ingested dose by symptomatic patients was
                             estimated to range between 60 to 290 mg
                             domoic acid per person.
    
                             The brains of three patients who died during
                             the Canadian outbreak showed severe damage to
                             the hippocampus and amygdaloid nucleus. There
                             were also lesions in the anterior claustrum,
                             nucleus accumbens, and thalamus (Carpenter,
                             1990).

                    7.2.1.2  Children

                             No data available.

             7.2.2  Relevant animal data

                    Studies were done in mice using contaminated
                    mussels extracts and purified domoic acid toxins.
                    Intra peritoneal and oral administrations were
                    studied. Scratching, roll, tremor and convulsions were
                    observed both with the extracts and the pure toxin.
                    The no-observable-effect-level was 12 g (24 ppm in
                    the mussel's tissue). Death occurred at a dose of 100
                    g (5 mg/kg). Studies were also done on monkeys fed
                    with blended mussels' digestive glands to give doses
                    of 19.868 to 28.470 g of domoic acid. the first
                    gastro-intestinal symptoms occurred between 2.75 to 6
                    hours and consisted in vomiting, anorexia and
                    diarrhea. The neurological symptoms occurred between
                    15 minutes and 6 hours. They consisted in withdrawal
                    and wet-dog shakes, disorientation, glassy-eye stare,
                    prostration, weakness, and trembling. Other studies
                    using pure domoic acid given intraperitoneally (i.p.),

                    showed that within 2 minutes, the animals suffered
                    from mastication, salivation, projectile vomiting, and
                    later, retching, weakness, teeth grinding, fixed gaze
                    and lethargy. Brain lesions were observed at autopsy
                    in the most severely affected animals. Gastric and
                    duodenal ulcers were produced in rats given shellfish
                    extracts containing domoic acid (Glavin,
                    1990).

             7.2.3  Relevant in vitro data

                    Preliminary studies do not show evidence of
                    mutagenicity or genotoxicity.

        7.3  Carcinogenicity

             No data available

        7.4  Teratogenicity

             Preliminary studies do not indicate evidence of
             teratogenicity.

        7.5  Mutagenicity

             No evidence of mutagenicity in the preliminary
             studies.

        7.6  Interactions

             No data available

    8.  TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                             HPLC analysis were done on diluted
                             specimens samples from patients. No easily
                             available standardized methods have been
                             published. Analytical methods used in
                             different countries have been described
                             (I.O.C., 1995).

                    8.1.1.2  Biomedical analyses

                             No specific laboratory analysis are
                             specifically useful except those required by
                             the medical status of the patients. A CT-scan
                             should be performed.

                    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)

                             A modification of the mouse bioassay
                             used for PSP toxin is available.

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

                             HPLC quantification methods have
                             been described.

             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

             Sample collection
    
             It is important to collect any left-over food for later
             analysis. Geographical location of origin for the involved
             shellfish should be identified. Samples of shellfish from the
             same origin should be collected and kept refrigerated. Blood
             and urine samples should also be kept for subsequent
             analysis.
    
             Biomedical analysis
    
             No specific biomedical analysis is required except a CT scan.
    
             Toxicological analysis
    
             Gastric content, blood, urine and stool samples should be
             collected for later analysis if required.
    

             Other investigations
    
             As required by the clinical status of the patients

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    The incubation period is extremely variable:
                    from 15 minutes to 38 hours. In the 1987 outbreak, 93%
                    of the 145 Canadian patients suffered from
                    gastrointestinal symptoms and 26% of neurological
                    symptoms. The gastro-intestinal symptoms were nausea,
                    vomiting, abdominal cramps, diarrhoea, and anorexia.
                    The neurological symptoms were headaches, dizziness,
                    ataxia, loss of memory. Hypotension and tachycardia
                    were also noted. The most severe cases observed in
                    older patients (over 68 years old) who suffered from
                    confusion, convulsions, coma, long-term brain damage
                    and memory loss. Three patients died within 24 days
                    after hospitalisation, two of septic shock and one
                    died of a heart attack three months after being
                    released from hospital.

             9.1.2  Inhalation

                    Not relevant.

             9.1.3  Skin exposure

                    Not relevant.

             9.1.4  Eye contact

                    Not relevant.

             9.1.5  Parenteral exposure

                    None reported.

             9.1.6  Other

                    Not relevant.

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    No data available.

             9.2.2  Inhalation

                    Not relevant.

             9.2.3  Skin exposure

                    Not relevant.

             9.2.4  Eye contact

                    Not relevant.

             9.2.5  Parenteral exposure

                    None reported.

             9.2.6  Other

                    Not relevant.

        9.3  Course, prognosis, cause of death

             The evolution of the disease may vary from days to
             months. Younger patients seem to have more digestive
             problems. Older patients (over 60 years of age) more
             frequently require admittance to an intensive care unit, have
             a greater risk of developing severe neurological symptoms,
             permanent brain damage and memory loss or even of dying.
             Beside age, renal insufficiency seems to be a significant
             risk factor. Coma, encephalopathy, convulsions,
             cardiovascular collapse are the causes of death. The
             effective control of convulsions, even those that are not
             clinically observed or that do not modify the EEG seems to be
             the most difficult challenge in reducing mortality or
             permanent brain damage.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Tachycardia, peripheral vasodilation with
                    hypotension have been described. Severely poisoned
                    patients were also hemodynamically unstable.

             9.4.2  Respiratory

                    Severely ill patients had increased pulmonary
                    secretions and required frequent suctioning. One
                    patient had recurrent pulmonary edema.

             9.4.3  Neurological

                    9.4.3.1  CNS

                             Headache was the most prominent
                             symptom with confusion, disorientation,
                             dizziness, unsteadiness and memory loss.
                             Convulsions occurred without EEG epileptiform
                             activity. Mutism, agitation and loss of
                             contact with their environment were also
                             described. The more severe cases became
                             comatose. Short term memory was the main
                             persistent symptom and some patient were
                             unable to recognize their family members or
                             carry out simple tasks.

                    9.4.3.2  Peripheral nervous system

                             General weakness, transient
                             symmetric hyper-reflexia, fasciculation,
                             presence of Babinski signs. One patient
                             developed transient spastic hemiparesis which
                             surprisingly disappeared only to be followed
                             by a similar contra lateral hemiparesis.
                             Hiccup, grimacing and disconjugate gaze were
                             also described. Some patient also developed
                             complete external ophtalmoplegia which were
                             transient.

                    9.4.3.3  Autonomic nervous system

                             Piloerection was described.

                    9.4.3.4  Skeletal and smooth muscle

                             General weakness.

             9.4.4  Gastrointestinal

                    Nausea, vomiting, diarrhoea and abdominal
                    cramps are common.

             9.4.5  Hepatic

                    No effect observed

             9.4.6  Urinary

                    9.4.6.1  Renal

                             No effect observed. However, renal
                             insufficiency was a significant risk
                             factor.

                    9.4.6.2  Other

                             None.

             9.4.7  Endocrine and reproductive systems

                    No effect observed.

             9.4.8  Dermatological

                    Piloerection.

             9.4.9  Eye, ear, nose, throat: local effects

                    None.

             9.4.10 Haematological

                    Increased leucocytes count is related to
                    bacterial infections.

             9.4.11 Immunological

                    None.

             9.4.12 Metabolic

                    9.4.12.1 Acid base disturbances

                             Respiratory and metabolic acidosis
                             in severe comatose cases.

                    9.4.12.2 Fluid and electrolyte disturbances

                             Fluid and electrolyte imbalances
                             may follow vomiting and diarrhoea.

                    9.4.12.3 Others

             9.4.13 Allergic reactions

                    None reported.

             9.4.14 Other clinical effects

                    None.

             9.4.15 Special risks

                    Age was by far the most important risk factor
                    since all the patients who died or suffered permanent

                    brain damage were over 68 years old. Renal
                    insufficiency was another risk factor. Only one
                    outbreak in humans has been reported from ingestion of
                    mussels harvested in Prince Edward Island,
                    Canada.

        9.5  Other

             None.

        9.6  Summary

             In one outbreak which occurred in 145 individuals who
             ingested mussels harvested in Prince Edward Island in 1987,
             and were shown to contain domoic acid. The following symptoms
             were reported: gastro-intestinal; nausea, vomiting, abdominal
             cramps and diarrhea occurred after a delay of 15 minutes to
             38 hours. Neurological symptoms appearing after a delay of 2
             to 58 hours; headache, dizziness, loss of balance, confusion,
             disorientation, memory loss, mutism, agitation, hiccups,
             spastic hemiparesis, external ophthalmoplegia, convulsions,
             coma. Four patients died. No antidote are available and the
             management is symptomatic. The most difficult aspect of the
             treatment is related to the effective control of convulsions
             which are not always observed clinically and may not show
             epileptiform activity on EEG.

    10. MANAGEMENT

        10.1 General principles

             There is no specific antidote for domoic acid
             poisoning. Only supportive and symptomatic treatment is
             required. Since age is an important risk factor, patients
             over 60 years old should be closely monitored along with
             those with renal insufficiency.

        10.2 Life supportive procedures and symptomatic/specific treatment

             Convulsions may be difficult to diagnose since they may
             not be clinically observable and may not modify the EEG.
             Aggressive treatment may be required in order to prevent
             permanent brain damage. Comatose patients will require early
             endotracheal intubation since excessive bronchial secretions
             are frequently observed.

        10.3 Decontamination

             Emesis should not be performed because of the risk of
             convulsions. Activated charcoal may be given in conscious

             patients without convulsions. Gastric lavage may be indicated
             if ingestion is recent and patient is comatose. Prior control
             of convulsions is required and endotracheal intubation
             performed beforehand.

        10.4 Enhanced elimination

             There is no information available on methods which may
             accelerate elimination of this toxin.

        10.5 Antidote treatment

             10.5.1 Adults

                    None available

             10.5.2 Children

                    None available

        10.6 Management discussion

             The main difficulty in the management of poisoning by
             domoic acid is related to the effective control of
             convulsions. Standard methods using diazepam, diphenyl
             hydantoin, phenobarbital and penthobarbital (see IPCS
             Treatment Guide on convulsions), should be used until more
             specific antidotes are developed.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             J. Teitelbaum
    
             "In November 1987, 145 patients in Canada developed
             gastrointestinal and neurological symptoms following
             consumption of mussels from Prince Edward Island. The
             excitatory neurotoxin domoic acid was subsequently detected
             in the mussels associated with this mass intoxication.
    
             In the following sections, 3 cases will be presented,
             illustrating certain aspects of this new clinical
             syndrome.
    
             Case 1
    
             The patient, an 84-year-old man, was followed for a pituitary
             adenoma diagnosed in 1985, rectal carcinoma resected in 1982
             with no recurrence, and osteoarthritis. Medications included

             Indocid(R) and Entrophen(R) as needed. He did not smoke or
             abuse ethanol. Prior to mussel ingestion, the patient was
             entirely self-sufficient and still involved in the management
             of his real estate company. The patient ate a very large
             portion of Prince Edward Island mussels in his home at around
             1800 hours on 19 November 1987. According to his family,
             about 1 hour later he began to have nausea, and protracted
             vomiting, lasting through the night. The patient was brought
             to hospital the next morning because of somnolence,
             confusion, and disorientation. On arrival, the patient was
             dehydrated, with a blood pressure of 110/80 and a pulse of
             100. He was febrile, with a rectal temperature of 38.5C.
             General examination revealed a right lower lobe pneumonia but
             was otherwise unremarkable. Neurological examination revealed
             marked disorientation in all 3 spheres, with confusion and
             intermittent delirium. Cranial nerves were normal. Motor
             examination showed normal bulk, with increased tone in the
             left upper extremity. Strength was mildly decreased in the
             left upper extremity with increased reflexes on the left.
             Plantar responses were flexor bilaterally.
    
             Over the nest few days the patient continued to deteriorate.
             He remained quite confused, with a high fever despite
             antibiotic therapy. By 10 days post-ingestion he reached his
             maximum disability. He was comatose but breathing
             spontaneously, with intact brain stem reflexes. Intubation
             was performed for airway protection from excessive bronchial
             secretions.
    
             Approximately 7 days post-ingestion, the patient developed
             focal motor seizures of the right arm, as well as generalized
             tonic clonic and absence-type convulsions. As well, he was
             noted to have facial myoclonus and uncontrolled chewing
             movements. Seizures were extremely difficult to control,
             being unresponsive to phenytoin and requiring large doses of
             intravenous diazepam and phenobarbital.
    
             Routine laboratory data during this acute phases revealed a
             polymorphonuclear leucocytosis, increased urea with a mild
             increase in creatinine compatible with dehydration, and an
             increase in creatine kinase CK (MM) likely due to seizures.
             Lumbar puncture, done on 2 occasions, was completely normal.
             Electroencephalograms repeated many times during the acute
             illness showed diffuse slowing, with epileptic or
             epileptiform activity mainly in the left temporal area.
             Cranial computed tomography showed only diffuse atrophy,
             consistent with age.
    
             Electromyographic studies, performed 4 weeks post-ingestion,

             showed widespread denervation with normal conduction
             velocities. The patients slowly improved over the next 4 to 6
             weeks. By 3 months post-ingestion, he was alert, with normal
             language, judgement and social skills. He was disoriented to
             place and time, with no recall of his acute illness. The
             patient was unable to retain any new information despite
             relatively normal retrograde memory function. Cranial nerves
             were intact. Tone and strength were normal, but there was
             marked wasting of the hands and feet. Reflexes were now
             decreased to 1+ except for the ankles, where they were
             unobtainable. Sensory examination was normal except for very
             mildly decreased vibration sense in the lower extremities.
             Pneumonia developed and the patient died 3 years after the
             intoxication. At the autopsy, the brain showed complete
             neuronal loss in the hippocampi. The amygdalia showed patchy
             neuronal loss in medial and basal portions, with neuronal
             loss and gliosis in the overlying cortex (Cendes, 1995).
    
             Case 2
    
             A 71-year-old male professor was treated for mild Parkinson's
             disease and peptic ulcers. His medications prior to ingestion
             included Artane(R) and cimetidine. There was no history of
             alcohol abuse. He ate Prince Edward Island mussels on the
             evening of 22 November 1987. He developed only mild nausea
             with no vomiting, diarrhoea or abdominal pain. Twenty-four
             hours later, the patient was brought to his physician for
             mild somnolence, generalized weakness, and somewhat abnormal
             behaviour. This intelligent man did not act normally, would
             forget what he was being told, and seemed unable to deal with
             the demands of his work. No precise diagnosis was made. For
             the next 3 days the patient still felt that he was much more
             fatigued than usual and his hands did not have their normal
             strength. As well, he noted decreased concentration,
             inability to remember faces, and difficulty with meetings
             that had just been planned, either forgetting the date of the
             meeting or what he was supposed to say. Four months later,
             the patient felt his memory was much improved and strength
             was subjectively back to normal. On physical examination
             4 months post-ingestion, motor cortical functions and cranial
             nerves were intact. Strength was normal despite a mild
             decrease in bulk of the small muscles in the hands and feet.
             Reflexes were absent. Sensory examination revealed decreased
             vibration sense in the lower extremities.
    
             Full biochemical work-up done 4 months post-ingestion was
             unremarkable. Cranial computed tomography, with and without
             contrast, was normal. An electroencephalogram showed mild
             generalized slowing of background activity. On
             neuro-psychological testing, his IQ was 130, language skills
             were normal, and the only abnormality was a decrease in
             visuospatial delayed recall.
    

             Electromyographic studies showed evidence of chronic and
             active denervation with mild diffuse axonal sensorimotor
             neuropathy. This could be compatible with either motor neuron
             and dorsal root ganglion lesions, or diffuse axonal
             damage.
    
             Case 3
    
             A 69-year-old, right-handed man with well-controlled adult
             onset diabetes, hypertension, and atherosclerosis, ingested
             Prince Edward Island mussels on 20 November 1987. His
             medications prior to ingestion included Euglucon(R),
             methyldopa and enteric aspirin. His alcohol intake was
             moderate, and he smoked 25 cigarettes per day. Three hours
             after ingestion, the patient developed severe nausea and
             vomiting. Twenty hours post-intoxication, he was
             unresponsive. A few hours after that, the patient developed
             gastrointestinal bleeding and went into shock due not only to
             hypovolemia, but also to a massive vaso-dilatation which
             spontaneously resolved 10 hours later. While comatose, the
             patient had retained intact brainstem reflexes. Ten days
             post-ingestion, the patient developed a novel motor syndrome.
             While verbally unresponsive, he was found to have a paresis
             of his right side with ipsilateral increase in tone and
             reflexes. This lasted 24 to 36 hours, resolved, re-appeared
             on the left side for another 24 to 36 hours, and then
             resolved completely. At the same time, he developed complete
             external ophtalmoplegia, absence of caloric or oculocephalic
             reflexes. Despite this, the patient could blink, swallow, and
             breathe. Over the next 10 days his eye movements became
             disconjugate and then slowly returned to normal. No seizures
             were noted. Over the next 12 weeks the patient improved,
             slowly regained consciousness and became alert. His language
             was normal and he was noted at this time to have a severe
             problem with recent memory and concentration. He had some
             retrograde amnesia but the most striking finding was an
             inability to retain new information. His motor examination 12
             weeks post-ingestion revealed decreased muscle bulk in his
             hands and his feet, but his strength seemed to be normal as
             were his reflexes. Sensory examination revealed decreased
             sensation to light touch and pain over the feet and hands,
             with a decrease in vibration in the lower extremities.
             Position sense was normal. Complete blood count and
             biochemical profile were performed on the day of arrival in
             hospital. Polymorphonuclear leukocyte count was elevated, as
             were urea and creatinine. CK(MM) was mildly elevated as well.
             Computed cranial tomography, with and without contrast, was
             normal. Cerebrospinal fluid analysis was unremarkable. He had
             multiple electroencephalograms done. At 5 days after
             ingestion he had some generalized slowing of activity more

             marked on the left hemisphere. Two weeks later, the
             electroencephalogram (EEG) pattern was compatible with a
             metabolic encephalopathy, with no epileptiform activity
             noted. Four months later, the EEG had improved, with mild to
             moderate generalized disturbance of background activity.
             Electromyographic studies performed 4 weeks after ingestion
             revealed marked active denervation in proximal and distal
             muscle groups with normal conduction velocities. Four months
             later, denervation was improved, and there was evidence of
             mild sensorimotor axonal neuropathy.
    
             Discussion
    
             As these three cases demonstrate, acute manifestations of
             domoic acid intoxication are variable. The common features
             are those of nausea and vomiting, followed by varying degrees
             of confusion, disorientation, changes in level of
             consciousness, and seizures in some cases. Motor
             abnormalities (hemiparesis, ophthalmoplegia) were seen
             transiently in two cases during the acute phase. The residual
             memory abnormality and sensorimotor neuropathy/axonopathy are
             rather unique late manifestations that have now been studied
             in a larger population of affected patients.

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

        12.2 Other

             Special identification features
    
             The Prince Edward Island incident involved mussels (Mytilus
             edulis). The toxin has also been identified in Dungeness
             crabs and razor clams (Siliqua patula) in Washington and
             Oregon States. The blooms of phytoplankton causing domoic
             acid poisoning cannot be identified visually as for the " red
             tides " of PSP poisoning. The seaweeds Chondria armata, C.
             baileyana and Alsidium corallinum are known to contain domoic
             acid. Shellfish do not feed on them and bivalve molluscs and
             other shellfish may become contaminated by filtering
             phytoplanktons such as the diatoms Nitzschia pungens
             (involved in the PEI incident), F. multiseries, N.
             pseudolicatissima and N. pseudoseriata.
    
             Habitat
    
             Very little is known about the natural habitat of the
             phytoplanktons like the diatoms Nitzschia pungens which may

             contain domoic acid. The PEI incident occurred in mussels
             cultivated in river estuaries. Incidents occurred in areas
             were water exchange is slow.
    
             Distribution
    
             The only documented outbreak described to date in humans
             occurred in Montreal from mussels cultivated in Prince Edward
             Island in 1987. Since then, domoic acid has been found in
             razor clam (Siliqua patula) and Dungeness crabs (Cancer
             magister) in the coastal waters of Oregon and Washington. An
             incident involving seabirds which consumed contaminated fish
             was also described in Monterey Bay. Occurrence of toxin has
             been reported in other areas of the world including Korea and
             Norway.

    13. REFERENCES

        Brown JA, Nijjar MS (1995) The release of glutamate and
        aspartate from rat brain synaptosomes in response to domoic acid
        (amnesic shellfish toxin) and kainic acid.  Mol Cell Biochem, Oct
        4, 151(1): 49-54.
    
        Cendes F, Anderman F A, Carpenter S, Zatorre RJ & Cashman NR
        (1995) Temporal lobe epilepsy caused by domoic acid intoxication:
        evidence for glutamate receptor-mediated excitotoxicity in humans. 
        Ann Neurol, 37: 123-126.
    
        Daigo K (1959) Studies on the constituents of Chondria armata.II.
        Isolation of an anthelmintical constituent. Yakugaku Zasshi (J
        Pharm Soc Japan) 79: 353-356.
    
        Fryxell GA, Roelke DL, Valencie DL & Cifuentes LA (1991) The
        toxin-producing Nitzschia pungens f. multiseries HASLE: field
        results and experimental comparisons. Abstr. 5 th Int. Conf. Toxic
        Marine Phytoplankton. Newport, RI, Oct. 28- Nov. 1, pp 46.
    
        Glavin GB & Bose R (1990) Domoic acid-induced neurovisceral toxic
        syndrome: characterization of an animal model and putative
        antidotes. Brain Res Bull, 24: 701-703.
    
        Intergovermental Oceanographic Commission (1995) Amnesic shellfish
        poisoning (ASP). Manual and guides No. 31, Unesco, HAB publication
        series.
    
        Iverson F, Truelove J, Tryphonas L & Nera EA (1990) The toxicology
        of domoic acid administered systematically to rodents and primates
        In: Proceedings of a Symposium, Domoic Acid Toxicity, Hynie I &
        Todd ECD ed. Ottawa, Ontario, Canada Disease Weekly Report: 
        15-19.
    

        Jenkins (1996) Domoic acid in Oregon Seafood harvest. Internet WWW
        page ExToxNet at HTTP:
        <HTTP://ace.orst.edu/cgi-bin/mfs/01/tics/domoic.asc? 6#mfs>
        version current at March 5, 1996.
    
        Olney JW (1990) Excitotoxicity: An overview In: Proceedings of a
        Symposium, Domoic Acid Toxicity, Hynie I & Todd ECD ed. Ottawa,
        Ontario, Canada Disease Weekly Report: pp 47-58.
    
        Peng YG, Clayton EC, Means LW, Ramsdell JS (1997) Repeated
        independent exposures to domoic acid do not enhance symptomatic
        toxicity in outbred or seizure-sensitive inbred mice. Fundam Appl
        Toxicol, Nov, 40(1): 63-67.
    
        Perl TM, Bedard L, Kosatsky T et al. (1990) An outbreak of toxic
        encephalopathy caused by eating mussels contaminated with domoic
        acid. N Engl J Med, 322: 1775-1780.
    
        Poisindex (1999) Domoic acid. Micromedex, vol. 99.
    
        Slikker W Jr, Scallet AC, Gaylor DW (1998) Biologically-based
        dose-response model for neurotoxicity risk assessment. Toxicol
        Lett, Dec 28, 102-103: 429-433.
    
        Sobotka TJ, Brown R, Quander DY, Jackson R, Smith M, Long SA, et
        al. (1996) Domoic acid: neurobehavioral and neurohistological
        effects of low-dose exposure in adult rats. Neurotoxicol Teratol,
        Nov-Dec,18(6): 659-670.
    
        Takemoto T, Daigo K (1958) Constituents of Chondria armata. Chem
        Pharm Bull, 6: 578-580.
    
        Teitelbaum J (1990) Clinical presentation of acute intoxication by
        domoic acid: Case observations In: Proceedings of a Symposium,
        Domoic Acid Toxicity, Hynie I & Todd ECD ed. Ottawa, Ontario,
        Canada Disease Weekly Report: 5-6.
    
        Todd ECD (1989) Amnesic shellfish poisoning - A new seafood toxin
        syndrome In: Proceedings of the 4th International Conference on
        Toxic Marine Phytoplankton, Lund, Sweden, June 26-30 1989. pp
        504-508.
    
        Trudlove J, Mueller R, Pulido O, Martin L, Fernie S, Iverson F
        (1997) 30-day oral toxicity study of domoic acid in cynomolgus
        monkeys: lack of overt toxicity at doses approaching the acute
        toxic dose. Nat Toxins, 5(3): 111-114.
    
        Truelove J, Mueller R, Pulido O, Iverson F (1996) Subchronic
        toxicity study of domoic acid in the rat. Food Chem Toxicol, Jun,
        34(6): 525-529.
    

        Vecsei L, Dibo G, Kiss C (1998) Neurotoxins and neurodegenerative
        disorders. Neurotoxicology, Aug-Oct, 19(4-5): 511-514.
    
        Viviani R (1992) Eutrophication, marine biotoxins, human health.
        Science Total E, Suppl: 631-662.
    
        Watters MR (1995) Organic neurotoxins in seafoods. Clin Neurol
        Neurosurg, May, 97(2): 119-124.
    
        Wright JLC, Bird CJ, de Fritas ASW, Hampson D, McDonald J &
        Quilliam MA (1990) Chemistry, biology and toxicology of domoic
        acid and its isomers In: Proceedings of a Symposium, Domoic Acid
        Toxicity, Hynie I & Todd ECD ed. Ottawa, Ontario, Canada Disease
        Weekly Report: 21-26.
    
        Xi D, Peng YG, Ramsdell JS (1997) Domoic acid is potent neurotoxin
        to neonatal rats. Nat Toxins, 5(2): 74-99.
    
        Zaman L, Arakawa O, Shimosu A, Onoue Y, Nishio S, Shida Y, Noguchi
        T (1997) Two new isomers of domoic acid from a red alga, Chondria
        armata. Toxicon, Feb, 35(2): 205-212.
    
        Zatorre RJ (1990) Memory loss following domoic acid intoxication
        from ingestion of toxic mussels In: Proceedings of a Symposium,
        Domoic Acid Toxicity, Hynie I & Todd ECD ed. Ottawa, Ontario,
        Canada Disease Weekly Report: 101-104.

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

        Author:     Albert J. Nantel
                    Director
                    Centre de Toxicologie du Qubec
                    CHUL
                    Sainte-Foy
                    Qubec
                    Canada
    
        Date:       May 1996.
    
        Peer
        review:     Marseilles, France, June 1996
                    (Members: R. Rotter, A.J. Nantel, A. Brown, K.
                    Hartigan-Go, H. Ravn and P. Gopalakrishnakone)
    


    See Also:
       Toxicological Abbreviations