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AZASPIRACID SHELLFISH POISONING

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Azaspiracids (AZAs) are produced by marine dinoflagellates and are accumulated in bivalve molluscs that feed on toxic microalgae of the genus Protoperidinium. These toxins have been responsible for shellfish poisoning in Europe. AZA toxins may be found in digestive glands of shellfish or other tissues.

Specific Substances

    A) ORGANISMS/TOXIN
    1) Azaspiracid
    2) Azaspiracid-1
    3) Azaspiracid-2
    4) Azaspiracid-3
    5) Azaspiracid-4
    6) Azaspiracid-5
    7) Azaspiracid-6
    8) Azaspiracid-7
    9) Azaspiracid-8
    10) Azaspiracid-9
    11) Azaspiracid-10
    12) Azaspiracid-11
    13) Cardium edule
    14) Clams (Tapes phillipinarium) (SYNONYM)
    15) Cockles (Cardium edule)
    16) Crassostrea gigas
    17) 8-Methylazaspiracid (AZA2)
    18) 22-Demethylazaspiracid (AZA3)
    19) 3-Hydroxy-22-demethylazaspiracid (AZA4)
    20) 24-Hydroxy-22-demethylazaspiracid (AZA5)
    21) 8-Methyl-22-demethylazaspiracid (AZA6)
    22) Mytilus edulis
    23) Mytilus galloprovincialis
    24) Oysters (Crassostrea gigas) (SYNONYM)
    25) Panicum maximum
    26) Pecten maximus
    27) Protoperidinium
    28) Scallops (Pecten maximus) (SYNONYM)
    29) Tapes phillipinarium
    30) Molecular Formula: C47-H71-N-O12 (AZA4)

Available Forms Sources

    A) SOURCES
    1) ORIGIN - A ubiquitous alga belonging to a genus Protoperidinium spp. (James et al, 2004; James et al, 2003a). Azaspiracids are produced by marine dinoflagellates and are accumulated in bivalve molluscs that feed on toxic microalgae of the genus Protoperidinium (James et al, 2004; James et al, 2003).
    2) Initially, mussel digestive glands contain most of the azaspiracids, then AZAs migrate to other mussel tissues leading to persistent contamination. AZA1 is the predominant toxin in the digestive glands; AZA3 is predominant in other tissues. These toxins can persist in shellfish for up to 8 months (James et al, 2002; James et al, 2004).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH POISONING/EXPOSURE
    1) CDC CASE DEFINITIONS
    a) BACKGROUND
    1) Harmful algal blooms (HABs) are fast growing algae that are found worldwide, which can have a negative impact on the environment, as well as the health and safety of humans and animals. As part of the ongoing efforts by the Centers for Disease Control and Prevention (CDC), the Harmful Algal Bloom-related Illness Surveillance System (HABISS) collects data on the effects to human and animal health due to the potential environmental impact of HABs. It has developed case definitions for harmful algal bloom (HABs) toxin-related diseases as part of their national surveillance efforts to support public health decision-making. The following has been created to identify pertinent information related to a potential exposure to HABs. For further information regarding the reporting of suspected human illness due to HABs, please contact: Lorraine C. Backer, PhD, MPH, Senior Scientist and Team Lead, National Center for Environmental Health, CDC, Atlanta, GA at lfb9@cdc.gov or Rebecca LePrell, MPH, HABISS Coordinator, National Center for Environmental Health, CDC, at gla7@cdcd.gov.
    b) ACUTE SYMPTOMS
    1) Symptoms may include: vomiting, diarrhea, nausea, abdominal pain, chills, headache, and fever.
    c) CHRONIC SYMPTOMS (lasting more than 3 months)
    1) At present, no clinical evidence is available. May or may not be carcinogenic or cause chronic liver disease.
    2) ANIMAL DATA: Chronic intraperitoneal injection in mice did not cause diarrhea. Rather, mice showed progressive paralysis in limbs, dyspnea, and convulsion before death, suggesting the toxins effects are not limited to the intestinal organs.
    d) FATALITY RATE
    1) At the time of this review, no deaths have been reported.
    e) TIME TO ONSET OF SYMPTOMS
    1) Less than 24 hours
    f) DURATION
    1) Days
    g) ROUTE OF EXPOSURE
    1) Eating contaminated shellfish.
    h) CAUSATIVE ORGANISMS
    1) Protoperidinium (azaspiracid) may produce illness.
    i) TOXIN
    1) Azaspiracids (CAS number: 214899-21-5)
    j) VECTOR
    1) Contaminated bivalve shellfish which can include: scallops, mussels, clams, and oysters.
    k) MECHANISM
    1) Phosphorylase phosphatase inhibitor
    l) LIKELY GEOGRAPHIC DISTRIBUTION
    1) Europe and Japan
    m) DIFFERENTIAL DIAGNOSIS
    1) Other marine toxin poisonings (e.g. neurotoxic or paralytic shellfish poisoning), ciguatera fish poisoning, scombroid fish poisoning, pesticide poisoning including organophosphate poisoning, cholinesterase inhibitor poisoning, microbial food poisonings and food allergies.
    n) DIAGNOSIS
    1) May be based on the following: Clinical signs and symptoms and laboratory findings (e.g. mouse bioassay, HPLC).
    o) SUSPECT CASE
    1) Acute gastrointestinal illness following consumption of shellfish.
    p) CONFIRMED CASES
    1) Suspect cases along with confirmation by laboratory testing of the contaminated shellfish.
    q) ANIMAL SENTINEL DATA
    1) None known
    r) REFERENCE
    1) (HABISS Work-Group et al, Jan 12, 2009)

Laboratory Monitoring

    A) There are no widely available laboratory tests that are useful in the diagnosis of azaspiracids poisoning in clinical practice. Diagnosis is based on characteristic symptoms, along with testing the suspected contaminated seafood to support the diagnosis.
    B) Monitor serum electrolytes in patients who experience severe vomiting or diarrhea.
    C) Chromatographic techniques for determination of the concentration of azaspiracids in seafood have been developed for research and food safety monitoring.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) There is no specific antidote. Treatment is symptomatic and supportive.
    B) Emesis is NOT likely to be of value, since the toxin is acting hours after ingestion.
    C) Adsorption by activated charcoal is unknown. It may be useful but is untested.
    D) Monitor fluid and electrolyte balance in patients who experience severe vomiting or diarrhea. Administer intravenous fluids and antiemetics as indicated.

Range Of Toxicity

    A) A European Union limit for bivalve molluscs of 160 mcg/kg (0.16 mcg/g) for the combined concentrations of AZA1-AZA3 in total tissues has been proposed.
    B) Following intraperitoneal injections, the lethal doses AZA1, AZA4 and AZA5 to mice were 0.2 mg/kg, 0.47 mg/kg and less than 1 mg/kg, respectively, indicating that AZA1 is more toxic than AZA4 and AZA5.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) CDC CASE DEFINITIONS
    a) BACKGROUND
    1) Harmful algal blooms (HABs) are fast growing algae that are found worldwide, which can have a negative impact on the environment, as well as the health and safety of humans and animals. As part of the ongoing efforts by the Centers for Disease Control and Prevention (CDC), the Harmful Algal Bloom-related Illness Surveillance System (HABISS) collects data on the effects to human and animal health due to the potential environmental impact of HABs. It has developed case definitions for harmful algal bloom (HABs) toxin-related diseases as part of their national surveillance efforts to support public health decision-making. The following has been created to identify pertinent information related to a potential exposure to HABs. For further information regarding the reporting of suspected human illness due to HABs, please contact: Lorraine C. Backer, PhD, MPH, Senior Scientist and Team Lead, National Center for Environmental Health, CDC, Atlanta, GA at lfb9@cdc.gov or Rebecca LePrell, MPH, HABISS Coordinator, National Center for Environmental Health, CDC, at gla7@cdcd.gov.
    b) ACUTE SYMPTOMS
    1) Symptoms may include: vomiting, diarrhea, nausea, abdominal pain, chills, headache, and fever.
    c) CHRONIC SYMPTOMS (lasting more than 3 months)
    1) At present, no clinical evidence is available. May or may not be carcinogenic or cause chronic liver disease.
    2) ANIMAL DATA: Chronic intraperitoneal injection in mice did not cause diarrhea. Rather, mice showed progressive paralysis in limbs, dyspnea, and convulsion before death, suggesting the toxins effects are not limited to the intestinal organs.
    d) FATALITY RATE
    1) At the time of this review, no deaths have been reported.
    e) TIME TO ONSET OF SYMPTOMS
    1) Less than 24 hours
    f) DURATION
    1) Days
    g) ROUTE OF EXPOSURE
    1) Eating contaminated shellfish.
    h) CAUSATIVE ORGANISMS
    1) Protoperidinium (azaspiracid) may produce illness.
    i) TOXIN
    1) Azaspiracids (CAS number: 214899-21-5)
    j) VECTOR
    1) Contaminated bivalve shellfish which can include: scallops, mussels, clams, and oysters.
    k) MECHANISM
    1) Phosphorylase phosphatase inhibitor
    l) LIKELY GEOGRAPHIC DISTRIBUTION
    1) Europe and Japan
    m) DIFFERENTIAL DIAGNOSIS
    1) Other marine toxin poisonings (e.g. neurotoxic or paralytic shellfish poisoning), ciguatera fish poisoning, scombroid fish poisoning, pesticide poisoning including organophosphate poisoning, cholinesterase inhibitor poisoning, microbial food poisonings and food allergies.
    n) DIAGNOSIS
    1) May be based on the following: Clinical signs and symptoms and laboratory findings (e.g. mouse bioassay, HPLC).
    o) SUSPECT CASE
    1) Acute gastrointestinal illness following consumption of shellfish.
    p) CONFIRMED CASES
    1) Suspect cases along with confirmation by laboratory testing of the contaminated shellfish.
    q) ANIMAL SENTINEL DATA
    1) None known
    r) REFERENCE
    1) (HABISS Work-Group et al, Jan 12, 2009)

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache has been reported following the ingestion of AZA contaminated mussels (James et al, 2004).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL TRACT FINDING
    1) WITH POISONING/EXPOSURE
    a) Vomiting, diarrhea, and abdominal pain have been reported following the ingestion of AZA contaminated mussels. The gastrointestinal symptoms are similar both to diarrheic shellfish poisoning and to bacterial enterotoxin poisoning (James et al, 2004).
    b) CASE REPORTS - A bag of cooked and frozen mussels (1 Ib) from Ireland was purchased by a couple from Washington. The couple heated and ate the product and 5 hours later experienced abdominal pain, vomiting, and profuse watery diarrhea lasting for 24 to 30 hours (Klontz et al, 2009). The FDA confirmed the presence of AZA from several other packages with the same lot number as consumed by the couple.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) There are no widely available laboratory tests that are useful in the diagnosis of azaspiracids poisoning in clinical practice. Diagnosis is based on characteristic symptoms, along with testing the suspected contaminated seafood to support the diagnosis.
    B) Monitor serum electrolytes in patients who experience severe vomiting or diarrhea.
    C) Chromatographic techniques for determination of the concentration of azaspiracids in seafood have been developed for research and food safety monitoring.

Methods

    A) BIOASSAY
    1) One study showed that the diarrheic shellfish poisoning (DSP) mouse bioassay failed to adequately detect azaspiracids (AZAs) in mussels, due mainly to the unusual distribution of these toxins within shellfish tissue; AZAs can move from the digestive glands to other shellfish tissues (James et al, 2004; James et al, 2002).
    B) LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY
    1) Because of widespread human poisoning and the failure of the DSP mouse bioassay to detect AZAs in shellfish, a national surveillance program was initiated in Ireland using liquid chromatography-multiple tandem mass spectrometric (LC-MS) methods for weekly monitoring of AZAs in shellfish. In addition, a provisional limit of 0.1 mcg/g in whole cooked mussel meat has been established in Ireland. A European Union limit for bivalve molluscs of 160 mcg/kg (0.16 mg/kg) for the combined concentrations of AZA1-AZA3 in total tissues has been proposed, to be determined using LC-MS methods; however, due to the lack of availability of AZA standards, the implementation of these new regulations has been difficult in most countries (James et al, 2004; Vale, 2004).
    2) In one study, reversed-phase liquid chromatography with detection by positive electrospray multiple tandem mass spectrometry was used to separate azaspiracids (AZA1-3). The AZA poisoning concentrations were obtained in the adductor muscle (meat), gonad (roe), hepatopancreas (digestive glands), mantle and gill of scallops; toxins were mainly concentrated in the hepatopancreas (85%). AZA1-3 were found in phytoplankton and mussels; however, AZA3 was not found in the scallop samples (Magdalena et al, 2003a).
    3) A liquid chromatography/mass spectrometry (LC/MS) method has been used to detect AZA1 and its analogues, AZA2 and AZA3. These toxins were separated using reversed-phase LC and coupled, via an electrospray ionization (ESI) source, to an ion-trap mass spectrometer (Furey et al, 2002).
    4) The following AZAs concentrations have been reported in several European countries (James et al, 2004; Magdalena et al, 2003) and in the United States from mussels originally cultivated in Ireland (Klontz et al, 2009):
    LOCATIONAZAs CONCENTRATIONS
    United States (Washington, 2009)0.086, 0.115, 0.155, 0.117, 0.244 mg/kg in 5 packages of cooked, frozen mussels from Ireland
    Netherlands (mussels obtained from Killary Harbour, Ireland)AZA1 - 1.14 mcg/gAZA2 - 0.23 mcg/gAZA3 - 0.06 mcg/g
    IrelandAZAs - 30 mcg/g found in the digestive glands
    ItalyAZAs - 1 mcg/g (AZA1, 50%; AZA2, 6%; AZA3, 44%) found in the digestive glands
    FranceAZAs - 1.1 to 1.5 mcg/g in total tissues, mostly in the meat segment than in the digestive glands; 7 to 9 times the regulatory limit of 0.16 mcg/g
    SpainAZAs - 0.24 mcg/g (AZA1, 54%; AZA2, 29%; AZA3, 17%)

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) There are no widely available laboratory tests that are useful in the diagnosis of azaspiracids poisoning in clinical practice. Diagnosis is based on characteristic symptoms, along with testing the suspected contaminated seafood to support the diagnosis.
    B) Monitor serum electrolytes in patients who experience severe vomiting or diarrhea.
    C) Chromatographic techniques for determination of the concentration of azaspiracids in seafood have been developed for research and food safety monitoring.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS
    1) Emesis is not likely to be of value since symptoms occur hours after ingestion.
    B) ACTIVATED CHARCOAL
    1) The effectiveness of activated charcoal is unknown.
    2) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Emesis is not likely to be of value; activated charcoal has not been tested.
    B) ACTIVATED CHARCOAL
    1) Adsorption by activated charcoal is unknown. It may be useful but is untested. Do not combine with cathartic.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) There is no specific antidote. Treatment is symptomatic and supportive.
    2) Fluid and electrolyte replacement may be necessary.

Range Of Toxicity

Summary

    A) A European Union limit for bivalve molluscs of 160 mcg/kg (0.16 mcg/g) for the combined concentrations of AZA1-AZA3 in total tissues has been proposed.
    B) Following intraperitoneal injections, the lethal doses AZA1, AZA4 and AZA5 to mice were 0.2 mg/kg, 0.47 mg/kg and less than 1 mg/kg, respectively, indicating that AZA1 is more toxic than AZA4 and AZA5.

Minimum Lethal Exposure

    A) ANIMAL STUDIES
    1) Following intraperitoneal injections, the lethal doses AZA1, AZA4 and AZA5 to mice were 0.2 mg/kg, 0.47 mg/kg and less than 1 mg/kg, respectively, indicating that AZA1 is more toxic than AZA4 and AZA5 (Ofuji et al, 2001).

Maximum Tolerated Exposure

    A) A European Union limit for bivalve molluscs of 160 mcg/kg (0.16 mcg/g) for the combined concentrations of AZA1-AZA3 in total tissues has been proposed, to be determined using LC-MS methods; however, due to the lack of availability of AZA standards, the implementation of these new regulations has been difficult in most countries (James et al, 2004; Vale, 2004).

Pharmacology Toxicology

Toxicologic Mechanism

    A) In animal studies, AZA1 effects included degeneration of epithelial cells and necrosis of the lamina propria in the villi of the small intestine, fat accumulation in the liver and degeneration of hepatocytes, reduction of non-granulocytes and damage to T- and B-cells in the spleen. Overall, AZA1 induced a far greater degree of tissue injury and slower recovery time when compared with okadaic acid (James et al, 2004; Ito et al, 2002).
    B) In one animal study, 25 mice were administered AZA twice at 300 to 450 mcg/kg doses. Erosion and shortened villi in the stomach and small intestine, edema, bleeding, and infiltration of cells in the alveolar wall of the lung, fatty changes in the liver, and necrosis of lymphocytes in the thymus and spleen were observed. In addition, low doses of AZA (50, 20, 5 and 1 mcg/kg) were administered twice a week up to 40 times to four groups of mice; 9 of 10 at 50 mcg/kg and 3 of 10 at 20 mcg/kg were sacrificed prior to the completion of 40 injections because of severe weakness. Interstitial pneumonia and shortened small intestinal villi were observed in all mice. Lung tumor were noted in 4 mice, 1 out of 10 (10%) at 50 mcg/kg and 3 out of 10 (30%) at 20 mcg/kg. Hyperplasia of epithelial cells in the stomach of 6 mice out of 10 were observed after the administration of 20 mcg/kg (Ito et al, 2002).
    C) CYTOTOXICITY STUDIES - When neuroblastoma cells were used, AZA1 disrupted cytoskeletal structure, inducing a time- and dose-dependent decrease in F-actin pools. In addition, a link between F-actin changes and diarrhogenic activity has been suggested and this may be relevant to explain the severe gastrointestinal disturbance (vomiting, diarrhea, and stomach cramps) typical of AZA poisoning. AZA1 was found to induce a significant increase in Ca2+ concentrations in lymphocytes. Elevation of Ca2+ concentrations can lead to cell death (Roman et al, 2002).

References

General Bibliography

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    3) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
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    5) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
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    7) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
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    9) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
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    21) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    22) Ofuji K, Satake M, McMahon T, et al: Structures of azaspiracid analogs, azaspiracid-4 and azaspiracid-5 causative toxins of azaspiracid poisoning in Europe. Biosci Biotechnol Biochem 2001; 65(3):740-742.
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    24) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
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