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 µg (24 ppm in
the mussel's tissue). Death occurred at a dose of 100
µg (5 mg/kg). Studies were also done on monkeys fed
with blended mussels' digestive glands to give doses
of 19.868 to 28.470 µg 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 38.5°C.
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 Québec
CHUL
Sainte-Foy
Québec
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)