Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

1) Bromomethane
2) Embafume
3) MB
4) M-B-C Fumigant
5) Methane, bromo-
6) Monobromomethane
7) Molecular formula: C-H3-Br
8) CAS 74-83-9
9) AGEL TG 37
10) AGEL TG 67
11) BROM-O-GAZ
12) CHLOROPICRIN AND METHYL BROMIDE, MIXTURE
13) CHLOROPICRIN-METHYL BROMIDE MIXT.
14) EPA PESTICIDE CHEMICAL CODE 053201
15) MBC 33
16) METHYL BROMIDE AND CHLOROPICRIN MIXTURE
17) METHYL BROMIDE AND MORE THAN 2% CHLOROPICRIN MIXTURE, LIQUID
18) METHYL BROMIDE-CHLOROPICRIN MIXT.
19) METHYL, TRICHLORONITRO-, MIXTURE WITH BROMOMETHANE
20) TERR-O-GEL
21) VERTAFUME

1.2.1) MOLECULAR FORMULA
1) C-H3-Br

Available Forms Sources

A)

1) Methyl bromide takes the form of a colorless, transparent, volatile liquid or gas with a burning taste (Breeman, 2009; Bingham et al, 2001; HSDB , 2001). It is nearly odorless except at high concentrations where it has a chloroform odor. Due to its high olfactory threshold, it often provides little warning of its presence. Chloropicrin is typically added to commercial forms of methyl bromide to give it an intense odor. Because its vapor density is greater than that of air, it tends to accumulate near the floor or ground (Bingham et al, 2001; HSDB , 2001).
2) Methyl bromide is supplied in cylinders of compressed gas and small bombs for treatment of storage spaces.

B)

1) Methyl bromide is synthesized industrially by the action of hydrobromic acid on methanol. In one modification of this process, sulfuric acid is added to sodium bromide and methanol, then methyl bromide is removed by distillation (Budavari, 1996).

C)

1) Methyl bromide is a halogenated aliphatic hydrocarbon used in ionization chambers, for degreasing wool, extracting oils from flowers, nuts, and seeds, and as an insect fumigant for freight cars, mills, ships (naval shipping cargo holds), soil, vaults, and warehouses (Breeman, 2009; Bingham et al, 2001; Budavari, 1996). It has commonly been used in the food industry as a fumigant for insect control because it diffuses readily into all nooks and small spaces, is very effective at killing pests, and leaves no residue on food products (EPA, 1988).
2) Methyl bromide is also used as a methylating agent and a chemical intermediate, as a low-boiling solvent in aniline dye manufacture, as an intermediate in drug manufacturing (Bingham et al, 2001; Sittig, 1991). It is used as a fungicide, herbicide, nematocide, rodenticide, and insecticide (Bingham et al, 2001). It is used on agricultural crops; stored commodities; ornamentals; for soil, manure, mulch, and compost fumigation; in greenhouses, homes, grain elevators, mills, ships, and transportation vehicles (EPA, 1988). It is used to treat potatoes, tomatoes, and other crops (Lewis, 1993). It is used against fruit flies in citrus fruit shipments (Lewis, 1998).
3) "Because of its toxicity, there has been considerable concern against distributing this gas in small fire extinguishers" (Budavari, 1996). ACGIH (1991) reports that methyl bromide is no longer used as a refrigerant or as a fire extinguisher because of high incidence of injury and death. Since methyl bromide is odorless, it is often "stenched" with chloropicrin (0.25% and 2.0%) as a warning agent in all formulations, except those used for commodity fumigation (Bingham et al, 2001; EPA, 1988). Chloropicrin causes painful irritation to the eyes and has a disagreeable pungent odor (at low concentrations) (EPA, 1988). Chloropicrin vapor may disappear before the methyl bromide vapor and therefore may not serve as a reliable warning device (Clayton & Clayton, 1994).
4) Methyl bromide was traditionally used in fire extinguishers in aircraft engines and in submarines during World War II. It has been used as a refrigerant (Behrens & Dukes, 1986).
5) PESTICIDE

a) Since methyl bromide damages the ozone layer, the Declaration of Montreal was signed in January 2005 to prohibit the use of methyl bromide in the European Union (Breeman, 2009). However, it is still being used in many countries (eg, New Zealand) (Bulathsinghala & Shaw, 2014). In the United States, the use of methyl bromide is banned in homes and other residential locations. In March 2015, 4 family members (2 adults and 2 teens; age range, 14 to 49 years) who were vacationing in the US Virgin islands, presented with acute methyl bromide toxicity 2 days after a condominium below their unit was fumigated with methyl bromide. In addition, 37 patients were exposed to methyl bromide in the same condominium complex (Kulkarni et al, 2015).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Methyl bromide is used in ionization chambers, for degreasing wool, extracting oils from flowers, nuts, and seeds, and as an insect fumigant for freight cars, mills, ships (naval shipping cargo holds), soil, vaults, and warehouses. It has commonly been used in the food industry as a fumigant for insect control.
B) TOXICOLOGY: Methyl bromide, a halogenated aliphatic hydrocarbon, is an odorless, colorless liquid or gas at ambient temperatures. At low vapor concentrations, methyl bromide is not detectable by odor, but can still have serious toxic effects. Methyl bromide may be mixed with a strong-smelling irritant, chloropicrin, to provide warning of exposure, although dangerous levels can exist without warning. The unique characteristic of the low molecular weight halocarbons (and other fumigant gases) is their capacity to penetrate coverings and tissues, including rubber protective gear, fabrics, neoprene, skin, and mucous membranes. Dermal penetration is so efficient that exposed workers have been poisoned even when wearing an effective self-contained breathing apparatus. BROMISM VS METHYL BROMIDE TOXICITY: The exact mechanism of methyl bromide-induced CNS toxicity is still unclear. Several sources reported that methyl bromide acts directly as an alkylating agent on amino acids and bioactive proteins with sulfhydryl groups, resulting in a permanent cytotoxic effects. However, bromide ions temporarily displace chloride ions in neuronal cells resulting in impaired neurotransmission. Serum bromide concentration is poorly correlated with toxic effects of methyl bromide. S-METHYLCYSTEINE: In studies of humans and animals exposed to methyl bromide, s-methylcysteine, which is produced by a reaction between methyl bromide and cysteine, was detected in the circulatory systems. S-methylcysteine may be neurotoxic because of its structural analogy with gamma-aminobutanoic acid (GABA) and possible interactions with GABA receptors.
C) EPIDEMIOLOGY: Exposure is rare.
D) WITH POISONING/EXPOSURE

1) Methyl bromide is an eye, skin, and mucus membrane irritant. Absorption occurs readily through the lungs and to a lesser extent through the skin. Onset of toxicity may be delayed several hours, and may be limited to headache, nausea, vomiting, and visual changes. Dermal contact with the liquid can cause a tingling or burning sensation, itching, redness, and swelling; contact with large amounts may cause numbness or aching pain, blisters, papules, vesicles, or chemical burns. Other signs and symptoms may include blurred or double vision, nystagmus, cough, tachypnea, cyanosis, lethargy, profound weakness, dizziness, slurring of speech, hyperreflexia, albuminuria, hematuria, oliguria, anuria, impaired liver function, memory loss, confusion, delirium, euphoria, disorientation, agitation, and hallucinations.
2) At high airborne concentrations, pneumonitis, pulmonary edema, intracranial hemorrhage, hypotension, dysrhythmias, paralysis, seizures, and coma may occur. Metabolic acidosis has been reported in patients with methyl bromide-induced seizures or myoclonus. Central and peripheral neurologic sequelae such as organic brain syndrome and extrapyramidal effects have also been reported. If coma and seizures occur, few patients survive. Death may occur in a few days due to circulatory failure or pulmonary edema and multiple organ failure. In nonfatal cases, complete recovery may take several months. Neuropsychiatric sequelae may persist indefinitely.

0.2.20)

A) Methyl bromide was not teratogenic in rats; severe neurotoxicity and mortality have been noted in rabbits. In rats, a transient decrease in plasma testosterone and testicular nonprotein sulfhydryl concentrations have been noted.

0.2.21)

A) One study demonstrated a significant increased risk for stomach cancer with increasing methyl bromide use. An association between increased methyl bromide use and other cancers was not observed in this study.

Laboratory Monitoring

A)

B)

C)

D)

E)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is symptomatic and supportive. Treat agitation with benzodiazepines. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Maintain adequate ventilation and oxygenation with appropriate monitoring.

C) DECONTAMINATION

1) PREHOSPITAL: As methyl bromide is a gas at ambient temperatures, ingestion exposure is unlikely. Ingestion of liquid methyl bromide may result in burns of the oropharynx. Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration. Remove all clothing and immediately flush with water. Methyl bromide can penetrate ordinary rubber gloves. Blistered areas should be managed as burns. Patients with persistent dermal irritation or pain after decontamination should receive medical evaluation.
2) HOSPITAL: No data were available on the ability of activated charcoal to absorb methyl bromide. Consider activated charcoal following the ingestion of liquid methyl bromide if the overdose is recent, the patient is not vomiting, and is able to maintain their airway. DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting. Remove all clothing and immediately flush with water. Methyl bromide can penetrate ordinary rubber gloves. Blistered areas should be managed as burns. Patients with persistent dermal irritation or pain after decontamination should receive medical evaluation.

D) AIRWAY MANAGEMENT

1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias, significant CNS and respiratory depression, and persistent seizures.

E) ANTIDOTE

1) None. N-acetylcysteine has been used in patients with methyl bromide toxicity. However, the efficacy of n-acetylcysteine therapy has not been studied. Intravenous administration of N-acetylcysteine has been suggested as a treatment possibility based on the hypothesis that methyl bromide preferentially reacts with SH-groups. N-acetylcysteine would serve as a source of SH-groups to react with unbound methyl bromide.

F) ACUTE LUNG INJURY

1) Supplemental oxygen; PEEP and mechanical ventilation may be needed.

G) ENHANCED ELIMINATION

1) Hemodialysis lowers serum bromide levels but there is no evidence that dialysis affects a patient's outcome.

H) PATIENT DISPOSITION

1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
2) OBSERVATION CRITERIA: Patients who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

I) PITFALLS

1) Failure to recognize that a product may contain methyl bromide or other dangerous insecticides/chemicals. Missing other possible etiologies for a patient’s symptoms. History of exposure may be difficult to obtain in some settings.

J) DIFFERENTIAL DIAGNOSIS

1) Includes other agents that cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers), dystonia or dyskinesia (eg, antipsychotics, neuroleptics), hepatotoxicity (eg, acetaminophen, ethanol), or seizures (eg, bupropion).

0.4.3)

A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
B) ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed.
C) Refer to Oral exposure for more information.

0.4.4)

A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.

0.4.5)

A) OVERVIEW

1) Remove all clothing and immediately flush with water. Methyl bromide can penetrate ordinary rubber gloves. Blistered areas should be managed as burns. Patients with persistent dermal irritation or pain after decontamination should receive medical evaluation.

Range Of Toxicity

A)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

1) Methyl bromide is an eye, skin, and mucus membrane irritant. Absorption occurs readily through the lungs and to a lesser extent through the skin. Onset of toxicity may be delayed several hours, and may be limited to headache, nausea, vomiting, and visual changes. Dermal contact with the liquid can cause a tingling or burning sensation, itching, redness, and swelling; contact with large amounts may cause numbness or aching pain, blisters, papules, vesicles, or chemical burns. Other signs and symptoms may include blurred or double vision, nystagmus, cough, tachypnea, cyanosis, lethargy, profound weakness, dizziness, slurring of speech, hyperreflexia, albuminuria, hematuria, oliguria, anuria, impaired liver function, memory loss, confusion, delirium, euphoria, disorientation, agitation, and hallucinations.
2) At high airborne concentrations, pneumonitis, pulmonary edema, intracranial hemorrhage, hypotension, dysrhythmias, paralysis, seizures, and coma may occur. Metabolic acidosis has been reported in patients with methyl bromide-induced seizures or myoclonus. Central and peripheral neurologic sequelae such as organic brain syndrome and extrapyramidal effects have also been reported. If coma and seizures occur, few patients survive. Death may occur in a few days due to circulatory failure or pulmonary edema and multiple organ failure. In nonfatal cases, complete recovery may take several months. Neuropsychiatric sequelae may persist indefinitely.

Vital Signs

3.3.3)

A) HYPERTHERMIA has been reported after methyl bromide intoxication, usually in the setting of prolonged myoclonus or seizures (O'Neal, 1987; Michalodimitrakis et al, 1997; Hezemans-Boer et al, 1988; Horowitz et al, 1998; Buchwald & Muller, 2001).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) DIFFICULTY IN FOCUSING: Early symptoms of methyl bromide exposure may include difficulty in focusing the eyes (Hathaway et al, 1996; Watrous, 1942; Grant & Schuman, 1993; Bingham et al, 2001; Buchwald & Muller, 2001). Visual disturbances may develop following inhalational exposure to small amounts of methyl bromide (Breeman, 2009).
2) EYE IRRITATION: Two employees lost consciousness after opening a cargo hatch from a shipping cargo container previously fumigated with methyl bromide. Both patients presented with sore throat, eye irritations, and hypersalivation (Breeman, 2009).
3) CONJUNCTIVITIS: Minimal exposure to methyl bromide may produce red eyes that resolve quickly (Rathus & Landy, 1961; Grant & Schuman, 1993; Hathaway et al, 1996). Irritation may develop after inhalation exposure (Goldman et al, 1987).
4) NYSTAGMUS: Nystagmus has been reported following methyl bromide exposure (Rathus & Landy, 1961; Grant & Schuman, 1993).
5) CORNEAL LESIONS: Liquid methyl bromide can cause severe corneal burns (Clayton & Clayton, 1994; HSDB , 2001).
6) OPTIC NEUROPATHY: Optic neuropathy was reported in a 32-year-old worker in the commercial and residential fumigation business for 13 years (Chavez et al, 1985). He had a history of two untreated acute exposures to methyl bromide during the course of his employment.
7) DIPLOPIA: Diplopia has been reported (Grant & Schuman, 1993).
8) PHOTOPHOBIA: Persistent photophobia lasting several weeks has been reported following acute intoxication (Buchwald & Muller, 2001).
9) BLINDNESS: Transient and permanent blindness have been reported (Grant & Schuman, 1993).
10) SEQUELAE: Possible permanent effects on vision and blindness may occur (Grant & Schuman, 1993) Raffle, 1994).
11) CHRONIC EXPOSURE: Decreased visual acuity, abnormal visual evoked potentials, an enlarged blind spot, optic atrophy, and dyschromatopsia have been reported in patients with methyl bromide toxicity from chronic exposure (De Haro et al, 1997).

3.4.4)

A) WITH POISONING/EXPOSURE

1) SEQUELAE: Possible permanent effects on hearing may occur (Raffle, 1994; (Bishop, 1992).

3.4.5)

A) WITH POISONING/EXPOSURE

1) ANIMAL DATA: Rats given 200 ppm MeBr for 1 to 6 hours had primary olfactory mucosal lesions in the sustentacular cell. The induced changes in the olfactory mucosa were associated with decreased P-450 dependent alkoxy-o-dealkylase activities, reduced glutathione (GSH), GSH transferase, and GSH reductase activities and lower metabolism of arachidonic acid (Thomas et al, 1989).

a) A single 6 hour exposure of male F-344 rats to 200 ppm of methyl bromide resulted in the destruction of all sensory and sustentacular cells, but left basal cells (which were attached to the basement membrane) undamaged (Morgan et al, 1989).
b) ANOSMIA: Methyl bromide exposure in rats resulted in a residual 15% to 20% olfactory epithelial damage at week 10 following exposure. These data indicate that even small amounts of olfactory epithelial destruction may render the animal incapable of perceiving certain olfactants. If these data apply to human workers, this may impact occupational health and safety, since smell is an early and sensitive warning signal of the presence of some dangerous chemicals (Hurtt et al, 1988).

3.4.6)

A) WITH POISONING/EXPOSURE

1) IRRITATION and burning sensation of the mouth and throat may occur following inhalation exposures (Goldman et al, 1987; CDC, 1990; Breeman, 2009).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) It is anticipated that shock may occur in massive exposures, with death resulting from multiple mechanisms including circulatory collapse (HSDB , 2001).
b) CASE REPORT: Tachycardia and refractory hypotension developed in a 43-year-old man who ingested and inhaled methyl bromide (Michalodimitrakis et al, 1997).
c) CASE REPORT: Tachycardia and shock were reported a day following inadvertent inhalation exposure in a 36-year-old woman who subsequently died (Horowitz et al, 1998).
d) CASE REPORT: Acute methyl bromide poisoning with shock was followed by chronic stupor and persistent action myoclonus in a 45-year-old woman (Hauw et al, 1986).

B) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) Inhalation of high concentrations of similar compounds, such as ethylene dichloride, may result in death from ventricular fibrillation (Hathaway et al, 1996) Nouchi et al, 1984).
b) CASE REPORT: A 22-year-old woman became combative and confused after intentionally opening a 5-gallon pressurized tank of methyl bromide in her car. Ambient air concentrations in her car were not obtained. She was decontaminated twice with water at the scene prior to transport to the hospital. Upon admission, she lost consciousness and developed seizures. Her initial rhythm progressed from supraventricular tachycardia to ventricular tachycardia and finally ventricular fibrillation. She died about an hour later despite supportive care and resuscitative efforts. The postmortem examination revealed marked pulmonary edema and congestion, bilateral serosanguineous pleural effusions, serosanguineous froth within the tracheobronchial tree, moderate laryngeal edema, marked erythema of the gastric mucosa, blood-tinged tenacious gastric mucous, antral and pyloric edema and moderate cerebral edema (Stromberg & Cumpston, 2013).

Respiratory

3.6.2)

A) IRRITATION SYMPTOM

1) Inhalation of methyl bromide may cause irritation to the upper respiratory tract, cough, chest tightness and burning in the nose (Kulkarni et al, 2015; Bingham et al, 2001) MMWR, 1990; (Hine, 1969; Herzstein & Cullen, 1990).

B) ACUTE LUNG INJURY

1) Respiratory irritation, with cough and production of frothy sputum, may progress to pulmonary edema in severe cases `(Hine, 1969; O'Neal, 1987; Michalodimitrakis et al, 1997; Bingham et al, 2001). Pulmonary edema may appear immediately, or it may be delayed (Marraccini et al, 1983) Raffle, 1994; (Zenz, 1994; Squier et al, 1992).
2) Fulminant respiratory failure with acute lung injury, seizures, coma, and death may occur following inhalational exposure to high doses of methyl bromide (Breeman, 2009).
3) CASE SERIES: Two employees lost consciousness after opening a cargo hatch from a shipping cargo container previously fumigated with methyl bromide. Both patients presented with sore throat, eye irritations, and hypersalivation. One patient developed multiple epileptic seizures. Chest x-rays revealed signs of pulmonary edema and acute respiratory distress syndrome. Both patients gradually recovered following supportive care, including treatment with n-acetylcysteine (a rate of 150 mg/kg in a fluid volume of 200 mL, saline 0.9% for the first 20 minutes, followed by the administration of 50 mg/kg in a fluid volume of 500 mL in the next 8 hours) to prevent liver failure, glycopyrronium bromide (0.2 mg IV) to reduce severe hypersalivation, amoxicillin/clavulanate potassium to prevent pneumonia, and valproic acid for seizures. The ambulance crew and other first responders (eg, policemen, firemen) developed mild symptoms (eg, sore throats, irritated eyes, and hypersalivation), but were not admitted to the hospital after a thorough decontamination (Breeman, 2009).
4) CASE REPORT: Severe edema of the lungs with increased alveolar macrophages and neutrophilic infiltrates was seen at autopsy in a 36-year-old woman who died 19 days following inadvertent inhalation exposure to methyl bromide fumigation. The patient was exposed after an adjacent building was fumigated and methyl bromide seeped into her house through underground conduits(Horowitz et al, 1998).

C) ACUTE RESPIRATORY INSUFFICIENCY

1) Respiratory depression, dyspnea, and cyanosis may occur (Yamano Y, Kagawa J & Hanaoka T et al, 1994).

3.6.3)

A) ANIMAL STUDIES

1) RESPIRATORY DISORDER

a) Pulmonary damage has occurred in experimental animals (Clayton & Clayton, 1994).

Neurologic

3.7.2)

A) SEIZURE

1) Seizures, myoclonic jerks, and excitability are common in patients with severe poisoning and may occur within 24 hours of exposure (Kulkarni et al, 2015; Yamano Y, Kagawa J & Hanaoka T et al, 1994; Raffle et al, 1994; Zenz, 1994; Hathaway et al, 1996; Horowitz et al, 1998; Deschamps & Turpin, 1996; Mazzini et al, 1992; Prockop & Smith, 1986; Ishizu et al, 1988; Bishop, 1992; Bingham et al, 2001).

a) Myoclonus may be elicited by minimal sensory stimulation (Uncini et al, 1990; Hustinx et al, 1993; Hauw et al, 1986; Mazzini et al, 1992; Prockop & Smith, 1986).

2) Fulminant respiratory failure with acute lung injury, seizures, coma, and death may occur following inhalational exposure to high doses of methyl bromide (Breeman, 2009).
3) CASE SERIES: Two employees lost consciousness after opening a cargo hatch from a shipping cargo container previously fumigated with methyl bromide. Both patients presented with sore throat, eye irritations, and hypersalivation. One patient developed multiple epileptic seizures. Chest x-rays revealed signs of pulmonary edema and acute respiratory distress syndrome. Both patients gradually recovered following supportive care, including treatment with n-acetylcysteine (a rate of 150 mg/kg in a fluid volume of 200 mL, saline 0.9% for the first 20 minutes, followed by the administration of 50 mg/kg in a fluid volume of 500 mL in the next 8 hours) to prevent liver failure, glycopyrronium bromide (0.2 mg IV) to reduce severe hypersalivation, amoxicillin/clavulanate potassium to prevent pneumonia, and valproic acid for seizures. The ambulance crew and other first responders (eg, policemen, firemen) developed mild symptoms (eg, sore throats, irritated eyes, and hypersalivation), but were not admitted to the hospital after a thorough decontamination (Breeman, 2009).
4) Seizures may be refractory to anticonvulsant therapy (Palatnick & Tenenbein, 1998; Behrens & Dukes, 1986; Moosa et al, 1994; Horowitz et al, 1998).
5) CASE SERIES: Three exterminator employees developed severe methyl bromide poisoning after using 80 g/m(3) of a spray product containing 86% methyl bromide and 14% ethylene oxide to fumigate a storage room in a folklore museum. One employee left the museum after about 9 hours and developed only mild impaired consciousness. Laboratory results revealed a serum bromide concentration of 87.4 mcg/mL and urinary bromide concentration of 122.4 mcg/mg. He recovered gradually following supportive care. Patients 2 and 3 spent over 30 hours in the museum and reused the product repeatedly to increase the methyl bromide concentration to ensure adequate fumigation. Both patients developed generalized tonic-clonic seizures and impaired consciousness. Despite supportive care, including 4 dialysis sessions with direct hemoperfusion and 24-hour continuous hemodiafiltration, which reduced their serum bromide concentrations (from 164.9 mcg/mL to 6.6 mcg/mL in patient 2 and from 157.3 mcg/mL to 10.7 mcg/mL in patient 3), and long-term rehabilitation, both patients continued to have myoclonus and cognitive deficit, requiring long-term assistance. In addition, patient 3 experiences a major convulsive seizure once every several months and requires total assistance to complete activities of daily living (Yamano & Nakadate, 2006).
6) CASE REPORT: A 22-year-old woman became combative and confused after intentionally opening a 5-gallon pressurized tank of methyl bromide in her car. Ambient air concentrations in her car were not obtained. She was decontaminated twice with water at the scene prior to transport to the hospital. Upon admission, she lost consciousness and developed seizures. Her initial rhythm progressed from supraventricular tachycardia to ventricular tachycardia and finally ventricular fibrillation. She died about an hour later despite supportive care and resuscitative efforts. The postmortem examination revealed marked pulmonary edema and congestion, bilateral serosanguineous pleural effusions, serosanguineous froth within the tracheobronchial tree, moderate laryngeal edema, marked erythema of the gastric mucosa, blood-tinged tenacious gastric mucous, antral and pyloric edema and moderate cerebral edema (Stromberg & Cumpston, 2013).
7) CASE REPORT: A 33-year-old woman was found unresponsive and seizing after being accidentally exposed overnight to methyl bromide from a leaky cylinder (the cylinder was thought to contain propane) left in her home. Despite supportive therapy, the patient continued to seize for 3 weeks. An EEG revealed no activity and the patient was declared brain dead. Her 8-year-old son was also in the home and presented with lethargy, muscular incoordination, and fine motor tremors. The child required ongoing physical rehabilitation (Fontenot et al, 1998).
8) CASE REPORT: A 68-year-old developed painful, epileptiform, tonic, clonic spasms of the face, trunk, and limbs several hours after he had discharged several obsolescent aircraft fire extinguishers containing methyl bromide into the atmosphere. The generalized seizures were unresponsive to treatment with diazepam, phenytoin, chlormethiazole, and nitrous oxide. Paralysis with pancuronium and positive pressure ventilation was used successfully to control the seizures (Behrens & Dukes, 1986).
9) CASE REPORT: A 56-year-old man developed myoclonic seizures unresponsive to diazepam, clonazepam and phenytoin after exposure to methyl bromide while cleaning a rice silo. Seizures were controlled with thiopentone and pancuronium. The patient recovered with severe permanent neurologic impairment (Moosa et al, 1994).
10) CASE REPORT: A case of predominantly unilateral, spontaneous and intention myoclonus with giant and asymmetric somatosensory evoked potentials (SEP's) recorded on EEG, was reported in a patient approximately 3 days following an intentional methyl bromide intoxication in a 56-year-old male (Audry et al, 1985).
11) CASE REPORT: Several hours after fumigating a greenhouse with methyl bromide, a 35-year-old man developed jaw pain, abdominal cramps, diarrhea, twitching, and status epilepticus, unresponsive to high doses of diazepam and phenytoin. Seizures were eventually controlled using thiopental and neuromuscular blockade. The next day, hemodialysis for 9 hours decreased his bromide concentration from 2.8 mmol/L to 0.6 mmol/L (increased to 0.9 mmol/L after hemodialysis), but it had no effect upon his clinical course. Overall, he needed 3 weeks of tracheal intubation, 2 weeks of pentobarbital infusion for recurrent myoclonic seizures, as well as phenytoin, phenobarbital valproate, clonazepam and lamotrigine to ultimately control his myoclonus. A CT scan revealed possible right frontal demyelination. An EEG revealed cortical and spinal myoclonus. He eventually spent 7 months at a rehabilitation hospital. Because of severe permanent neurologic impairment, he continues to have severe disability with dystonic posturing, action myoclonus, generalized hyperreflexia and difficulties with the activities of daily living despite treatment with L-5-hydroxytriptophan and carbidopa/levodopa (Palatnick & Tenenbein, 1998).

B) CENTRAL NERVOUS SYSTEM DEFICIT

1) Dizziness, ataxia, confusion, malaise, lethargy, dizziness, speech disorders, psychosis, and coma have been reported and can occur within 24 hours of severe intoxication (Kulkarni et al, 2015; Breeman, 2009; Fontenot et al, 1998; Zwaveling et al, 1987; Hine, 1969; Watrous, 1942; Lewis, 1996; Hauw et al, 1986; Prockop & Smith, 1986; Buchwald & Muller, 2001).
2) CASE SERIES: In March 2015, 4 family members (2 adults and 2 teens; age range, 14 to 49 years) who were vacationing in the US Virgin islands, presented with acute methyl bromide toxicity 2 days after a condominium below their unit was fumigated with methyl bromide. All 4 patients had progressive neurologic symptoms, including generalized weakness, severe myoclonus, fasciculations, altered sensorium, and word-finding difficulty. Vomiting and diarrhea developed in 3 patients. Endotracheal intubation and mechanical ventilation were required in 3 patients. All 4 patients underwent 2 hemodialysis sessions and received benzodiazepines, phenobarbital, and propofol for sedation and symptom control. Both teens had severe symptoms and received a neuromuscular blocking agent (rocuronium). On the day of admission, serum bromide concentrations for all 4 patients ranged from less than 10 mg/dL to 13.6 mg/dL (3 of the 4 specimens were obtained after dialysis began). All 4 patients were discharged from acute-care hospitals about 3 months after the initial presentation. Because of the significant neurologic dysfunction, 3 of the 4 patients underwent inpatient physical rehabilitation (Kulkarni et al, 2015).
3) CASE REPORT: A 36-year-old woman developed coma (Glasgow Coma Score 5/15) with decerebrate posturing the day following a methyl bromide fumigation. Pupils became fixed and dilated; corneal and gag reflexes were absent. She died 19 days after the exposure (Horowitz et al, 1998).
4) CASE REPORT: A 32-year-old man presented with a 7-day history of cerebellar dysarthria, slurred speech, bilateral incoordination, and gait ataxia after occupational exposure to methyl bromide fumes. An MRI of his brain showed mild swelling and significant hyperintense lesions in the posterior pons, bilateral olivary nuclei, and dentate nuclei, with focal central restricted diffusion in the splenium of the corpus callosum on T2-weighted sequence. Following supportive treatment, including forced diuresis therapy with IV saline and loop diuretics, his symptoms gradually improved and a repeat MRI of the brain revealed significant resolution of the hyperintense lesions (Balagopal et al, 2011).
5) CASE SERIES: Three exterminator employees developed severe methyl bromide poisoning after using 80 g/m(3) of a spray product containing 86% methyl bromide and 14% ethylene oxide to fumigate a storage room in a folklore museum. One employee left the museum after about 9 hours and developed only mild impaired consciousness. Laboratory results revealed a serum bromide concentration of 87.4 mcg/mL and urinary bromide concentration of 122.4 mcg/mg. He recovered gradually following supportive care. Patients 2 and 3 spent over 30 hours in the museum and reused the product repeatedly to increase the methyl bromide concentration to ensure adequate fumigation. Both patients developed generalized tonic-clonic seizures and impaired consciousness. Despite supportive care, including 4 dialysis sessions with direct hemoperfusion and 24-hour continuous hemodiafiltration, which reduced their serum bromide concentrations (from 164.9 mcg/mL to 6.6 mcg/mL in patient 2 and from 157.3 mcg/mL to 10.7 mcg/mL in patient 3), and long-term rehabilitation, both patients continued to have myoclonus and cognitive deficit, requiring long-term assistance. In addition, patient 3 experiences a major convulsive seizure once every several months and requires total assistance to complete activities of daily living (Yamano & Nakadate, 2006).

C) EXTRAPYRAMIDAL DISEASE

1) WITH POISONING/EXPOSURE

a) Occurrence of a protracted extrapyramidal syndrome following low-level methyl bromide exposure has been documented in several cases.
b) CASE REPORT: Six months following an acute exposure to methyl bromide in the workplace, an exposed worker had residual effects including weakness, myoclonus, and marked intention tremor of his right arm. Pyramidal tract and cerebellar involvement were suspected (Longley & Jones, 1965).
c) CASE REPORT: Two produce inspectors developed severe neurologic illness after prolonged exposure to methyl bromide-treated grapes. The first patient, a 22-year-old man, developed lack of concentration, dizziness, visual disturbances (ie, decreased visual acuity and peripheral vision), difficulty maintaining balance, and difficulty with tandem gait. His serum bromide was estimated to be 58.7 mg/dL on his last work day. His symptoms gradually improved and he recovered completely several months later. The second patient, a 52-year-old man, developed lightheadedness, difficulty with speech, respiratory symptoms, decreased libido, trouble speaking, nausea, vomiting, ataxia, memory difficulty, hypertension, and tandem gait difficulty. All screening tests were normal. His serum bromide was estimated to be 85 mg/dL on his last work day. His symptoms gradually resolved (Centers for Disease Control and Prevention (CDC), 2011).

D) HEADACHE

1) WITH POISONING/EXPOSURE

a) Headache has been reported (Kulkarni et al, 2015; Breeman, 2009; Zwaveling et al, 1987; Watrous, 1942; Raffle et al, 1994; Zenz, 1994; Hathaway et al, 1996; CDC, 1990) and may persist for several months (Reidy et al, 1994; Buchwald & Muller, 2001).

E) SECONDARY PERIPHERAL NEUROPATHY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Early peripheral neuropathy (one week after exposure) and central nervous system toxicity were reported in a 32-year-old male following an accidental dermal exposure. Axonal neuropathy was diagnosed with nerve conduction velocity testing. At 3 months postexposure, central nervous system toxicity was no longer evident, but peripheral neuropathy was persistent (Lifshitz & Gavrilov, 2000).

F) SEQUELA

1) WITH POISONING/EXPOSURE

a) Depression, slow mentation, poor memory, neurosis, muscle paralysis, and ataxia may be long-term or permanent disabilities associated with methyl bromide poisoning (Buchwald & Muller, 2001; Hine, 1969). Other long-term effects have included severe action myoclonus, difficult speech, cognitive impairment, muscular atrophy, peripheral neuropathy and seizure disorders (Mazzini et al, 1986; (Prockop & Smith, 1986).
b) CASE REPORT: Superficial pain and light touch sensory modalities were decreased in a stocking-glove distribution and vibration sensation was decreased in the feet of a 42-year-old male nine months after an exposure to methyl bromide (Shield et al, 1977).
c) CASE REPORT: Myoclonus unresponsive to phenytoin, diazepam, chloral hydrate, and chlorazepate as well as ataxia and speech difficulties were residual effects reported in a 41-year-old female following exposure to methyl bromide (Shield et al, 1977).
d) CASE REPORT: Severe myoclonus somewhat controlled with clonazepam and phenobarbital developed in a 13-year-old girl who slept in a room a few hours after it had been sprayed with methyl bromide. After 4 weeks the girl was unable to ambulate without assistance. At the 2 year follow-up using a clonazepam and phenobarbital regime, the myoclonus had improved enough for the girl to return to school(Uncini et al, 1990).
e) CASE REPORT: Severe persistent myoclonus developed in 2 men after methyl bromide intoxication; one also demonstrated slight distal leg weakness and dysesthesia (Hustinx et al, 1993).
f) Permanent disabilities have been reported in persons without pulmonary symptoms, suggesting these effects may be a direct effect of methyl bromide on the CNS (Longley & Jones, 1965).
g) CASE REPORT: Five months following an acute methyl bromide fumigation exposure, an adult male still experienced dysarthria, myoclonic twitching, intention tremors, and difficulty standing without assistance (Deschamps & Turpin, 1996).
h) CASE REPORT: A 33-year-old woman was found unresponsive and seizing after being accidentally exposed overnight to methyl bromide from a leaky cylinder (the cylinder was thought to contain propane) left in her home. Despite supportive therapy, the patient continued to seize for 3 weeks. An EEG revealed no activity and the patient was declared brain dead. Her 8-year-old son was also in the home and presented with lethargy, muscular incoordination, and fine motor tremors. The child required ongoing physical rehabilitation (Fontenot et al, 1998).
i) CASE REPORT: Several hours after fumigating a greenhouse with methyl bromide, a 35-year-old man developed jaw pain, abdominal cramps, diarrhea, twitching, and status epilepticus, unresponsive to high doses of diazepam and phenytoin. Seizures were eventually controlled using thiopental and neuromuscular blockade. The next day, hemodialysis for 9 hours decreased his bromide concentration from 2.8 mmol/L to 0.6 mmol/L (increased to 0.9 mmol/L after hemodialysis), but it had no effect upon his clinical course. Overall, he needed 3 weeks of tracheal intubation, 2 weeks of pentobarbital infusion for recurrent myoclonic seizures, as well as phenytoin, phenobarbital valproate, clonazepam and lamotrigine to ultimately control his myoclonus. A CT scan revealed possible right frontal demyelination. An EEG revealed cortical and spinal myoclonus. He eventually spent 7 months at a rehabilitation hospital. Because of severe permanent neurologic impairment, he continues to have severe disability with dystonic posturing, action myoclonus, generalized hyperreflexia and difficulties with the activities of daily living despite treatment with L-5-hydroxytriptophan and carbidopa/levodopa (Palatnick & Tenenbein, 1998).

G) ELECTROENCEPHALOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Slight EEG changes were noted in 10 of 33 methyl bromide fumigators (Verberk et al, 1979).
b) CASE REPORT: EEG showed centro-encephalic spike discharges, consistent with myoclonic jerks in a fumigator following methyl bromide exposure (Deschamps & Turpin, 1996).
c) CASE REPORT: Spikes, multiple spikes, and slow waves, sometimes in conjunction with myoclonic jerks, were shown on EEG in a 45-year-old female following accidental methyl bromide exposure (Hauw et al, 1986).

H) TOXIC ENCEPHALOPATHY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 34-year-old man died 30 days following an acute inhalation exposure to methyl bromide. Histopathologic examination of his brain revealed distribution of lesions similar to those seen in Wernicke's encephalopathy. The patient also had clinical evidence of peripheral neuropathy (Squier et al, 1992).

I) CHRONIC POISONING

1) WITH POISONING/EXPOSURE

a) CASE SERIES: CHRONIC LOW LEVEL EXPOSURE: In one study, fumigators using methyl bromide did not perform as well as those not exposed on 23 of 27 behavioral tests (Anger et al, 1986). The group of fumigators using methyl bromide were by definition exposed potentially to methyl bromide 80% or more of the work period.
b) CASE REPORTS: Chronic exposure to methyl bromide was associated with ataxia, nystagmus, wide based gait, hyperactive deep tendon reflexes, optic neuritis, paresthesias, fatigability and dizziness in two men (De Haro et al, 1997). Effects resolved after 5 months in one man but paresthesias remained in the other.
c) CASE REPORTS: A 24-year-old man with a history of chronic exposure to methyl bromide for 3 years presented with a 2-week history of ataxic gait, paresthesia of both legs, paroxysmal vertigo, decreased pain and vibratory sense on both feet, impaired cerebellar signs and hyperactive reflexes in all extremities. Similar symptoms, but less severe, were reported in his 14 co-workers. Following the termination of gas exposure, his symptoms improved gradually (Suwanlaong & Phanthumchinda, 2008).

3.7.3)

A) ANIMAL STUDIES

1) EDEMA CEREBRAL

a) DOG: Following an accidental acute exposure to methyl bromide, a pet dog was found dead with evidence of recent vomiting and diarrhea. Necropsy revealed cerebral edema, most significant in the depths of the cortical sulci (Squier et al, 1992).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH POISONING/EXPOSURE

a) Nausea and severe vomiting may occur (Kulkarni et al, 2015; Breeman, 2009; Hathaway et al, 1996; Watrous, 1942; Letz et al, 1984; Yamano Y, Kagawa J & Hanaoka T et al, 1994; Zenz, 1994; Lewis, 1996; Buchwald & Muller, 2001).

B) LOSS OF APPETITE

1) WITH POISONING/EXPOSURE

a) Anorexia is an early symptom of methyl bromide exposure (Hathaway et al, 1996) and it may persist for a week or more (Watrous, 1942).

C) DIARRHEA

1) WITH POISONING/EXPOSURE

a) Diarrhea may occur following inhalation of methyl bromide (Kulkarni et al, 2015; Palatnick & Tenenbein, 1998; O'Neal, 1987; Reidy et al, 1994; Buchwald & Muller, 2001).

D) ABDOMINAL CRAMPS

1) WITH POISONING/EXPOSURE

a) Abdominal cramps have been reported following inhalation of methyl bromide (Palatnick & Tenenbein, 1998) .

E) GASTROINTESTINAL HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Gastrointestinal bleeding developed in a 43-year-old man with severe methyl bromide poisoning after deliberate ingestion and inhalation (Michalodimitrakis et al, 1997).

F) EXCESSIVE SALIVATION

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Two employees lost consciousness after opening a cargo hatch from a shipping cargo container previously fumigated with methyl bromide. Both patients presented with sore throat, eye irritations, and hypersalivation (Breeman, 2009).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Of 6 patients dermally exposed to methyl bromide during building fumigation, all had elevated lactate dehydrogenase (256 to 456 U/L) and one developed a slightly elevated AST (34 U/L) (Zwaveling et al, 1987).
b) CASE REPORT: Mild elevations of AST (98 U/L), ALT (167 U/L), LDH (429 U/L), GGT (187 U/L), and Alk Phos (177U/L) developed in a 56-year-old man with severe methyl bromide toxicity (Moosa et al, 1994).
c) CASE SERIES: Mild elevations in hepatic enzymes were reported in 2 of 10 patients with methyl bromide toxicity in one series (Hine, 1969) and 1 of 3 patients in another (O'Neal, 1987).
d) CASE REPORT: Mild elevation in hepatic enzymes were reported in one man with chronic methyl bromide toxicity (De Haro et al, 1997). Transaminase levels returned to normal when he was off work for two weeks.
e) CASE SERIES: In 3 out of 4 cases of severe methyl bromide poisoning, AST and LDH serum levels were above normal (Ishizu et al, 1988).

B) LARGE LIVER

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Jaundice and hepatomegaly were associated with methyl bromide exposure in a 6-year-old male. Bromide was not detectable in serum by the gold chloride method. There were no sequelae noted at one month follow-up (Shield et al, 1977).
b) CASE REPORT: A 25-year-old male operating a fork-lift used to transfer boxes of almonds in and out of fumigating chambers, developed jaundice, decreased ability to estimate distances, slight motor incoordination, and malaise during the third month of the forth season as a laborer. He could not recall any specific incident of an acute exposure. Blood bromide concentration during hospitalization was 150 ppm. At follow-up 2 years after hospitalization he was working in construction and had normal findings on physical examinations (Hine, 1969).

C) HEPATIC NECROSIS

1) CASE REPORT: Large foci of centrilobular necrosis of the liver with normal portal vasculature was reported at autopsy of a 36-year-old woman following a fatal methyl bromide exposure (Horowitz et al, 1998).

Genitourinary

3.10.2)

A) NEPHRITIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Uremia and nephritis with degenerative changes in the tubules were noted in a patient exposed to methyl bromide while fighting a fire for 1.5 hours (Benatt & Courtney, 1948). Tubular damage to the kidneys has been reported in fatal cases (Zenz, 1994; Hathaway et al, 1996).
b) CASE REPORT: Anuria appeared rapidly in a fumigator following a massive exposure to methyl bromide. Spontaneous recovery occurred (Deschamps & Turpin, 1996).

B) RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) Acute renal failure may occur following an acute inhalational exposure to methyl bromide (Kulkarni et al, 2015).
b) CASE REPORT: Acute renal failure developed in a 36-year-old woman with acute methyl bromide poisoning complicated by prolonged seizures, hypotension and rhabdomyolysis (Horowitz et al, 1998).

C) ABNORMAL RENAL FUNCTION

1) CHRONIC TOXICITY

a) Chronic exposure to methyl bromide may result in CNS depression or kidney injury (HSDB , 2001).

D) IMPOTENCE

1) WITH POISONING/EXPOSURE

a) CHRONIC: Following chronic occupational exposure (12 years) to methyl bromide, a 43-year-old man developed erectile dysfunction due to peripheral polyneuropathy. A nerve conduction test revealed a diffusive sensory-motor polyneuropathy, which included reduced vibration sense below both iliac crests, disturbed position sense on both lower extremities and a tingling sensation below the lower half of the calf. Erectile dysfunction improved with sildenafil (Park et al, 2005).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis has been reported in patients with methyl bromide-induced seizures or myoclonus (O'Neal, 1987; Michalodimitrakis et al, 1997).

Hematologic

3.13.2)

A) LEUKOCYTOSIS

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Zwaveling et al (1987) noted moderate leukocytosis ranging from 10.3 to 18.2 X 10(9)/L in all of 6 patients exposed by dermal route to methyl bromide during building fumigation (Zwaveling et al, 1987).

Dermatologic

3.14.2)

A) BULLOUS ERUPTION

1) WITH POISONING/EXPOSURE

a) Methyl bromide is an intense vesicant with the capacity to penetrate protective clothing. Skin blisters are produced, but are rarely deep enough to destroy entire skin layer. Spillage of liquid fumigant on the skin is likely to result in injury ranging from erythema to vesiculation (HSDB , 2001; Lifshitz & Gavrilov, 2000; Hathaway et al, 1996). The inflammation and blistering can be delayed for 15 to 20 hours. Healing is gradual, often taking several weeks (Lifshitz & Gavrilov, 2000).
b) Methyl bromide readily penetrates clothing, including leather (Zwaveling et al, 1987).
c) Generally erythema and pain develop within a few hours of dermal exposure, and may progress to blistering within 12 hours (Jarowenko & Mancusi-Ungaro, 1985; Zwaveling et al, 1987; Hezemans-Boer et al, 1988).
d) Skin, in areas that are relatively moist and subject to mechanical stress (axillae, groin, labia, penis, navel and under the belt), may be particularly affected (Zwaveling et al, 1987; Hezemans-Boer et al, 1988).
e) These skin lesions have been reported in persons wearing "protective clothing" consisting of overalls over daily clothing, work shoes, airway protection, and PVC gloves (Hezemans-Boer et al, 1988).
f) CASE REPORT: Shortly after exposure to methyl bromide fumigation, an acne-like rash was reported on the back and face of a worker. Two weeks postexposure, facial redness was noted (Buchwald & Muller, 2001).

B) URTICARIA

1) WITH POISONING/EXPOSURE

a) CASE SERIES: Urticarial rash occurred in 2 of 6 workers one week after dermal exposure to methyl bromide during building fumigation (Zwaveling et al, 1987).

C) CHEMICAL BURN

1) WITH POISONING/EXPOSURE

a) Methyl bromide is corrosive to skin. Severe burns may occur (Clayton & Clayton, 1994; Lewis, 1996; Lifshitz & Gavrilov, 2000).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Patients who experience protracted seizures or myoclonus following methyl bromide intoxications are at risk for developing rhabdomyolysis and elevated CPK serum levels.
b) CASE REPORT: Rhabdomyolysis was reported in 2 patients who developed seizures and persistent myoclonus after methyl bromide poisoning (Hustinx et al, 1993).
c) CASE REPORT: A 36-year-old female developed refractory seizures within 24 hours of accidental methyl bromide inhalational exposure. The following day, she developed rhabdomyolysis with CPK peaking at 14,060 U/L. The patient died 19 days post-exposure with multiorgan system failure (Horowitz et al, 1998).

B) JAW PAIN

1) WITH POISONING/EXPOSURE

a) Jaw pain has been reported following inhalation of methyl bromide (Palatnick & Tenenbein, 1998).

Endocrine

3.16.2)

A) THYROIDITIS

1) CASE REPORT: A 34-year-old man died 30 days post-exposure to methyl bromide. Post-mortem studies revealed lymphocytic thyroiditis (Squier et al, 1992).

B) HYPOGLYCEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 36-year-old woman with methyl bromide poisoning presented with status epilepticus and a blood glucose of 20 milligrams/deciliter (Horowitz et al, 1998).

Reproductive

3.20.1)

A) Methyl bromide was not teratogenic in rats; severe neurotoxicity and mortality have been noted in rabbits. In rats, a transient decrease in plasma testosterone and testicular nonprotein sulfhydryl concentrations have been noted.

3.20.2)

A) FETOTOXICITY

1) ANIMAL STUDIES

a) Methyl bromide was not teratogenic in rats; severe neurotoxicity and mortality have been noted in rabbits (Hayes & Laws, 1991).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS74-83-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: Methyl bromide
b) Carcinogen Rating: 3

1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

3.21.2)

A) One study demonstrated a significant increased risk for stomach cancer with increasing methyl bromide use. An association between increased methyl bromide use and other cancers was not observed in this study.

3.21.3)

A) NEOPLASM

1) IARC (Methyl bromide) (RTECS , 2001)

a) Animal - Limited evidence
b) Human - Inadequate evidence
c) Group 3

2) An association between increased methyl bromide use and an increased risk of stomach cancer was found in a study of pesticide applicators with follow-up from 1993 to 2007. Among the 53,588 applicators studied, 14.6% (7814) used methyl bromide, mostly before enrollment. Based on 15 exposed cases, the risk of stomach cancer increased significantly with increasing methyl bromide use (rate ratio (RR), 1.42; 95% CI, 0.51 to 3.95 and RR, 3.13; 95% CI, 1.25 to 7.8 for low- and high-use, respectively, compared with non-use; p=0.02). None of the other cancer types studied (prostate, lymphohematopoietic, non-Hodgkin lymphoma, leukemia, oral cavity, colon, rectal, lung, bladder, kidney, melanoma) had a statistically significant association with increasing methyl bromide use. While a nonsignificant elevated risk of prostate cancer was observed for the highest exposure group compared with the non-exposed group with follow-up from 1993 to 1998 based on 18 exposed cases (RR, 1.52; 95% CI, 0.9 to 2.59), the association did not persist with longer follow-up, as it diminished over time. A nonsignificant elevated risk of prostate cancer was also observed for those exposed to methyl bromide and who had a family history of prostate cancer (RR, 1.46 for any use compared with non-use; 95% CI, 0.97 to 2.2), as compared to those without a family history (RR, 0.91; 95% CI, 0.75 to 1.1; p=0.19); however, an exposure-response relationship among those with a family history was not observed (Barry et al, 2012).
3) METHYL BROMIDE: Is potentially carcinogenic (Boorman et al, 1986; Danse et al, 1984; Lewis, 1996).

3.21.4)

A) CARCINOMA

1) MICE: Methyl bromide was not carcinogenic in mice by the inhalation route in an NTP study (US Dept Health & Human Services, 1992).
2) RATS: Methyl bromide was not carcinogenic in long term feeding (Mitsumori et al, 1990) and inhalation (Reuzel et al, 1991) studies in rats. Methyl bromide was found to be carcinogenic by RTECS criteria with the presence of gastrointestinal tumors in rats (RTECS , 2001).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Serum inorganic bromide levels may be useful in confirming exposure if intake of inorganic bromide can be excluded. However, if measured late in the course of poisoning, bromide levels are often normal, thus only variably helpful. Serum bromide concentration is poorly correlated with toxic effects of methyl bromide.
B) Monitor vital signs and mental status. Monitor for seizures and CNS depression. Onset of symptoms may be sudden and delayed.
C) Obtain an ECG, and institute continuous cardiac monitoring in symptomatic patients.
D) Monitor arterial blood gases, pulse oximetry, and obtain a chest x-ray in any patient with respiratory symptoms.
E) Monitor liver enzymes and kidney function following a significant exposure.

4.1.2)

A) TOXICITY

1) In general, routine laboratory testing for methyl bromide has not been reliable. Measurable levels of the parent compound (methyl bromide) are not feasible due to its rapid reduction, a result of a direct tissue chemical reaction (Buchwald & Muller, 2001).
2) Serum inorganic bromide levels may be useful in confirming exposure if intake of inorganic bromide can be excluded. If measured late in the course of poisoning, bromide levels are often normal, thus only variably helpful (Buchwald & Muller, 2001). In the case of clinical toxicity, bromide is used primarily as a marker of exposure. Clinical correlation with extent of morbidity is inconsistent.

a) Values in excess of 5 mg/100 mL organic bromide are generally toxic. Symptoms of poisoning have been reported at blood bromide concentrations as low as 28 mg/L (Zatuchni & Hong, 1981). Bromide, however, is not thought to be the toxin responsible for symptoms after methyl bromide exposure. Serum bromide is detectable after methyl bromide exposures due to the long half-life (12 days) of methyl bromide.

3) BROMIDE TOXICITY: In several studies, serum bromide concentrations were significantly higher in occupationally exposed workers (mean +/- standard deviation [SD] = 15.33 +/- 1.9 mg/L) than in control (mean +/- SD = 4.13 +/- 1.05 mg/L). Although a small amount of bromide is released following the metabolism of methyl bromide, bromide is toxic only following very high doses and cellular bromide concentrations are unlikely to reach toxic levels in patients with methyl bromide exposure (Bulathsinghala & Shaw, 2014).
4) EXPERIMENTAL: Late confirmation of acute methyl bromide poisoning has been reported using s-methylcysteine adduct testing in blood proteins. The adduct has been obtained on serum albumin by GC/MS analysis (Buchwald & Muller, 2001).

a) S-METHYLCYSTEINE, a methylene bromide adduct, was detected by HPLC and GC/MS in globin and serum albumin from exposed fumigators and following acute intoxications (Buchwald & Muller, 2001; Goergens et al, 1994). In studies of humans and animals exposed to methyl bromide, s-methylcysteine, which is produced by a reaction between methyl bromide and cysteine, was detected in the circulatory systems. S-methylcysteine may be neurotoxic because of its structural analogy with gamma-aminobutanoic acid (GABA) and possible interactions with GABA receptors (Bulathsinghala & Shaw, 2014).

B) BLOOD/SERUM CHEMISTRY

1) Monitor serum electrolytes, glucose, and renal and liver function tests in patients with significant exposure.

4.1.3)

A) URINARY LEVELS

1) In one patient who developed generalized seizures following methyl bromide exposure, the urinary bromide concentration was 269.7 mcg/mL on admission to hospital (Yamano Y, Kagawa J & Hanaoka T et al, 1994).

4.1.4)

A) OTHER

1) Monitor vital signs and ECG in patients with significant exposure.
2) EEG

a) In patients with methyl bromide toxicity, abnormal EEG patterns, consistent with the early stages of encephalopathy, have been observed (Bulathsinghala & Shaw, 2014).

Radiographic Studies

A)

1) MRI of the brain may be useful in patients with neurologic findings. In a patient with cerebellar dysfunction after methyl bromide exposure, magnetic resonance imaging of the brain showed bilateral symmetrical lesions with abnormal high signal intensity on T2 weighted images and fluid-attenuation inversion recovery sequences of the dentate nuclei of cerebellum, periventricular area of the fourth ventricle, inferior olivary nuclei, and inferior and superior colliculi (Suwanlaong & Phanthumchinda, 2008).
2) Symmetric brainstem and cerebellar lesions have been observed in patients exposed to methyl bromide. Based on the clinical course and resolution of MRI abnormalities, it is suggested that methyl bromide exposure causes energy deprivation syndrome (Bulathsinghala & Shaw, 2014).
3) CASE REPORT: A 32-year-old man presented with a 7-day history of cerebellar dysarthria, slurred speech, bilateral incoordination, and gait ataxia after occupational exposure to methyl bromide fumes. An MRI of his brain showed mild swelling and significant hyperintense lesions in the posterior pons, bilateral olivary nuclei, and dentate nuclei, with focal central restricted diffusion in the splenium of the corpus callosum on T2-weighted sequence. Following supportive treatment, including forced diuresis therapy with IV saline and loop diuretics, his symptoms gradually improved and a repeat MRI of the brain revealed significant resolution of the hyperintense lesions (Balagopal et al, 2011).

Methods

A)

1) Yamano et al (1987) described a headspace gas chromatography method for the determination of bromide ion in plasma of workers exposed to methyl bromide (Yamano et al, 1987).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with severe symptoms despite treatment should be admitted.

6.3.1.2) HOME CRITERIA/ORAL

A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

A)

B)

C)

D)

E)

Oral Exposure

6.5.1)

A) SUMMARY

1) As methyl bromide is a gas at ambient temperatures, ingestion exposure is unlikely. Ingestion of liquid methyl bromide may result in burns of the oropharynx. Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression or persistent seizures and subsequent aspiration.

B) INHALATION

1) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
2) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
3) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

C) DERMAL

1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. Rescue personnel and bystanders should avoid direct contact with contaminated skin, clothing, or other objects (Burgess et al, 1999). Since contaminated leather items cannot be decontaminated, they should be discarded (Simpson & Schuman, 2002).

D) EYE

1) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

6.5.2)

A) SUMMARY: No data were available on the ability of activated charcoal to absorb methyl bromide. Consider activated charcoal following the ingestion of liquid methyl bromide if the overdose is recent, the patient is not vomiting, and is able to maintain their airway. Remove all clothing and immediately flush with water. Methyl bromide can penetrate ordinary rubber gloves. Blistered areas should be managed as burns. Patients with persistent dermal irritation or pain after decontamination should receive medical evaluation.
B) ACTIVATED CHARCOAL

1) No data were available on the ability of activated charcoal to absorb liquid methyl bromide.
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).

C) DILUTION

1) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).

6.5.3)

A) SUPPORT

1) MANAGEMENT OF MILD TO MODERATE TOXICITY

a) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.

2) MANAGEMENT OF SEVERE TOXICITY

a) Treatment is symptomatic and supportive. Treat agitation with benzodiazepines. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Maintain adequate ventilation and oxygenation with appropriate monitoring.

B) MONITORING OF PATIENT

1) Serum inorganic bromide levels may be useful in confirming exposure if intake of inorganic bromide can be excluded. However, if measured late in the course of poisoning, bromide levels are often normal, thus only variably helpful. Serum bromide concentration is poorly correlated with toxic effects of methyl bromide.
2) Monitor vital signs and mental status. Monitor for seizures and CNS depression. Onset of symptoms may be sudden and delayed.
3) Obtain an ECG, and institute continuous cardiac monitoring in symptomatic patients.
4) Monitor arterial blood gases, pulse oximetry, and obtain a chest x-ray in any patient with respiratory symptoms.
5) Monitor liver enzymes and kidney function following significant exposure.

C) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

D) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

7) RECURRING SEIZURES

a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:

1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)

b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

E) ACUTE LUNG INJURY

1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

F) EXTRAPYRAMIDAL SIGN

1) The extrapyramidal syndrome by low-level methyl bromide exposure may require months of treatment with oral sedatives or tranquilizers.

G) EXPERIMENTAL THERAPY

1) N-ACETYCYSTEINE

a) Should systemic toxicity occur following dermal exposure to methyl bromide, intravenous administration of N-acetylcysteine has been suggested as a treatment possibility based on the hypothesis that methyl bromide preferentially reacts with dermal SH-groups. N-acetylcysteine would serve as a source of SH-groups to react with unbound methyl bromide. This treatment cannot be recommended until further studies are done to confirm efficacy (Zwaveling et al, 1987).
b) CASE SERIES: Two employees lost consciousness after opening a cargo hatch from a shipping cargo container previously fumigated with methyl bromide. Both patients presented with sore throat, eye irritations, and hypersalivation. One patient developed multiple epileptic seizures. Chest x-rays revealed signs of pulmonary edema and acute respiratory distress syndrome. Both patients gradually recovered following supportive care, including treatment with n-acetylcysteine (a rate of 150 mg/kg in a fluid volume of 200 mL, saline 0.9% for the first 20 minutes, followed by the administration of 50 mg/kg in a fluid volume of 500 mL in the next 8 hours) to prevent liver failure, glycopyrronium bromide (0.2 mg IV) to reduce severe hypersalivation, amoxicillin/clavulanate potassium to prevent pneumonia, and valproic acid for seizures. The ambulance crew and other first responders (eg, policemen, firemen) developed mild symptoms (eg, sore throats, irritated eyes, and hypersalivation), but were not admitted to the hospital after a thorough decontamination (Breeman, 2009).

2) DIMERCAPROL

a) One of the proposed mechanism of methyl bromide toxicity is methylation of sulfur groups on enzymes, particularly pyruvate dehydrogenase complex and alpha-ketoglutarate complex; therefore, the use of 2,3-dimercaptopropanol or dimercaprol has been suggested (Stromberg & Cumpston, 2013).

Inhalation Exposure

6.7.1)

A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

6.7.2)

A) SUPPORT

1) Refer to the oral sections for treatment information.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

6.9.1)

A) DERMAL DECONTAMINATION

1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. Rescue personnel and bystanders should avoid direct contact with contaminated skin, clothing, or other objects (Burgess et al, 1999). Since contaminated leather items cannot be decontaminated, they should be discarded (Simpson & Schuman, 2002).

6.9.2)

A) EXPERIMENTAL THERAPY

1) N-ACETYLCYSTEINE

a) Should systemic toxicity occur following dermal exposure to methyl bromide, intravenous administration of N-acetylcysteine has been suggested as a treatment possibility based on the hypothesis that methyl bromide preferentially reacts with dermal SH-groups.
b) N-acetylcysteine would serve as a source of SH-groups to react with unbound methyl bromide. This treatment cannot be recommended until further studies are done to confirm this (Zwaveling et al, 1987).
c) CASE SERIES: Two employees lost consciousness after opening a cargo hatch from a shipping cargo container previously fumigated with methyl bromide. Both patients presented with sore throat, eye irritations, and hypersalivation. One patient developed multiple epileptic seizures. Chest x-rays revealed signs of pulmonary edema and acute respiratory distress syndrome. Both patients gradually recovered following supportive care, including treatment with n-acetylcysteine (a rate of 150 mg/kg in a fluid volume of 200 mL, saline 0.9% for the first 20 minutes, followed by the administration of 50 mg/kg in a fluid volume of 500 mL in the next 8 hours) to prevent liver failure, glycopyrronium bromide (0.2 mg IV) to reduce severe hypersalivation, amoxicillin/clavulanate potassium to prevent pneumonia, and valproic acid for seizures. The ambulance crew and other first responders (eg, policemen, firemen) developed mild symptoms (eg, sore throats, irritated eyes, and hypersalivation), but were not admitted to the hospital after a thorough decontamination (Breeman, 2009).

B) BURN

1) APPLICATION

a) These recommendations apply to patients with MINOR chemical burns (FIRST DEGREE; SECOND DEGREE: less than 15% body surface area in adults; less than 10% body surface area in children; THIRD DEGREE: less than 2% body surface area). Consultation with a clinician experienced in burn therapy or a burn unit should be obtained if larger area or more severe burns are present. Neutralizing agents should NOT be used.

2) DEBRIDEMENT

a) After initial flushing with large volumes of water to remove any residual chemical material, clean wounds with a mild disinfectant soap and water.
b) DEVITALIZED SKIN: Loose, nonviable tissue should be removed by gentle cleansing with surgical soap or formal skin debridement (Moylan, 1980; Haynes, 1981). Intravenous analgesia may be required (Roberts, 1988).
c) BLISTERS: Removal and debridement of closed blisters is controversial. Current consensus is that intact blisters prevent pain and dehydration, promote healing, and allow motion; therefore, blisters should be left intact until they rupture spontaneously or healing is well underway, unless they are extremely large or inhibit motion (Roberts, 1988; Carvajal & Stewart, 1987).

3) TREATMENT

a) TOPICAL ANTIBIOTICS: Prophylactic topical antibiotic therapy with silver sulfadiazine is recommended for all burns except superficial partial thickness (first-degree) burns (Roberts, 1988). For first-degree burns bacitracin may be used, but effectiveness is not documented (Roberts, 1988).
b) SYSTEMIC ANTIBIOTICS: Systemic antibiotics are generally not indicated unless infection is present or the burn involves the hands, feet, or perineum.
c) WOUND DRESSING:

1) Depending on the site and area, the burn may be treated open (face, ears, or perineum) or covered with sterile nonstick porous gauze. The gauze dressing should be fluffy and thick enough to absorb all drainage.
2) Alternatively, a petrolatum fine-mesh gauze dressing may be used alone on partial-thickness burns.

d) DRESSING CHANGES:

1) Daily dressing changes are indicated if a burn cream is used; changes every 3 to 4 days are adequate with a dry dressing.
2) If dressing changes are to be done at home, the patient or caregiver should be instructed in proper techniques and given sufficient dressings and other necessary supplies.

e) Analgesics such as acetaminophen with codeine may be used for pain relief if needed.

4) TETANUS PROPHYLAXIS

a) The patient's tetanus immunization status should be determined. Tetanus toxoid 0.5 milliliter intramuscularly or other indicated tetanus prophylaxis should be administered if required.

C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

A)

1) Hemodialysis rapidly lowers serum bromide levels because it is highly water soluble. However, there is no evidence that water soluble bromide is the toxin but rather a product of metabolism. Therefore, there is no evidence that dialysis can affect a patient's outcome. Although bromide concentrations may help with the diagnosis of methyl bromide, it does not correlate with the level of toxicity (Stromberg & Cumpston, 2013).
2) CASE REPORT: Five hours of hemodialysis reduced the serum bromide level from 120 mg/L to less than 10 mg/L in one patient with severe methyl bromide poisoning (Moosa et al, 1994). However, the patient suffered severe permanent neurologic disability secondary to severe poisoning with protracted seizures.
3) CASE REPORT: In one patient who developed generalized seizures following methyl bromide exposure, hemodialysis was associated with a decrease in the serum bromide level from 204.9 mcg/mL on admission to 5.6 mcg/mL on the second hospital day (Yamano Y, Kagawa J & Hanaoka T et al, 1994). However, it is unclear that this procedure changed the clinical outcome, as the patient continued to have seizures until the 28th hospital day and could not move around in a wheelchair until the 38th hospital day.

B)

1) CASE SERIES: Three exterminator employees developed severe methyl bromide poisoning after using 80 g/m(3) of a spray product containing 86% methyl bromide and 14% ethylene oxide to fumigate a storage room in a folklore museum. One employee left the museum after about 9 hours and developed only mild impaired consciousness. Laboratory results revealed a serum bromide concentration of 87.4 mcg/mL and urinary bromide concentration of 122.4 mcg/mg. He recovered gradually following supportive care. Patients 2 and 3 spent over 30 hours in the museum and reused the product repeatedly to increase the methyl bromide concentration to ensure adequate fumigation. Both patients developed generalized tonic-clonic seizures and impaired consciousness. Despite supportive care, including 4 dialysis sessions with direct hemoperfusion and 24-hour continuous hemodiafiltration, which reduced their serum bromide concentrations (from 164.9 mcg/mL to 6.6 mcg/mL in patient 2 and from 157.3 mcg/mL to 10.7 mcg/mL in patient 3), and long-term rehabilitation, both patients continued to have myoclonus and cognitive deficit, requiring long-term assistance. In addition, patient 3 experiences a major convulsive seizure once every several months and requires total assistance to complete activities of daily living (Yamano & Nakadate, 2006).

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Abstracts

Case Reports

A)

1) A 68-year-old developed painful, epileptiform tonic, clonic spasms of the face, trunk, and limbs several hours after he had discharged into the atmosphere several obsolescent aircraft fire extinguishers containing methyl bromide. He was treated with anticonvulsant therapy that included diazepam initially, followed by phenytoin, without effect on the seizures.

a) Intravenous chlormethiazole and then nitrous oxide by inhalation were also tried and failed to control the seizures. Muscle paralysis with pancuronium and positive pressure ventilation was started and continued until the generalized seizures were no longer evident (day 7 of admission).
b) Neurologic improvement was noted over the next week until he developed signs of deep vein thrombosis of the left calf. He died 16 days after admission of multiple pulmonary emboli with large emboli occluding both pulmonary arteries despite heparin therapy (Behrens & Dukes, 1986).

2) A 33-year-old woman sailor developed vomiting, dyspnea, and generalized seizures one to two days after leaving a Japanese port where methyl bromide fumigation of timbers in the cargo hold of the ship was done. Metabolic acidosis was noted on admission to hospital. Serum bromide level was 204.9 mcg/mL and urinary bromide concentration was 269.7 mcg/mL. Chest x-ray and brain CT scan were normal.

a) Following hemodialysis on the second hospital day, serum bromide level was in the normal range (5.6 mcg/mL). Seizures stopped on the 28th hospital day. On the 38th hospital day, the patient could move about in a wheelchair (Yamano Y, Kagawa J & Hanaoka T et al, 1994).

3) METHYL BROMIDE: Six workers wearing cotton/polyester coveralls over street clothes, PVC gloves, working shoes, and breathing pressurized air through a tight fitting face mask developed skin lesions and mean plasma bromide concentration of 9 +/- 1.4 mg/L following building fumigation with methyl bromide. Calculated methyl bromide air concentration in the building was 10,000 parts per million (Zwaveling et al, 1987).

Range Of Toxicity

Summary

A)

Minimum Lethal Exposure

A)

1) Fatalities have been reported following both acute and chronic exposure (HSDB , 2001; Hine, 1969).
2) Fatal poisoning has resulted from exposure to relatively high airborne concentrations of methyl bromide vapor (from 8,000 ppm for a few hours to 60,000 ppm for a brief exposure). Nonfatal poisoning has resulted from exposure to airborne concentrations of 35 to 500 ppm (Breeman, 2009; Bingham et al, 2001; Hathaway et al, 1996; Lewis, 1996). Another source reported exposure levels from 1600 to 60,000 ppm can result in death, depending on the duration of exposure (Breeman, 2009).

Maximum Tolerated Exposure

A)

1) NON-OCCUPATIONAL (RESIDENTIAL) BYSTANDERS: An acute (1 day) inhalational exposure to methyl bromide concentrations of 0.33 ppm or higher for a 24-hour time weighted average (TWA) (Kulkarni et al, 2015).
2) OCCUPATIONAL HANDLERS AND BYSTANDERS: An acute (1 day) inhalational exposure to methyl bromide concentrations of 1 ppm or greater for an 8-hour time weighted average (TWA) (Kulkarni et al, 2015).

B)

1) INHALATION

a) Two men developed nausea and vomiting followed by coma, myoclonus, and seizures after workplace exposure estimated as an airborne concentration greater than 200 ppm (800 mg/m(3)) for 2 hours (Hustinx et al, 1993).
b) Symptoms consistent with methyl bromide and chloropicrin exposure have been reported in persons living in communities surrounding the site of field fumigation. Weather conditions in the area may have contributed to the exposures. Most common symptoms reported were non-specific and included headache and eye and throat irritation. There were also reports of shortness of breath and one child who was hallucinating. Air samples were not taken at the time of the incident. Blood bromide concentrations were not measured in any of the exposed population (Goldman et al, 1987).
c) Severe poisoning with some fatalities resulted from soil disinfection by injection of methyl bromide into greenhouse soil. These workers measured airborne methyl bromide levels following application rates from 30 to 3,000 ppm. They found peak values of 200 ppm existing for a few seconds upon initial injection with airborne levels above the soil declining to 4 ppm 5 days post-treatment (ACGIH, 1986).
d) Upon entering a building with an airborne methyl bromide concentration of 17 grams/m(3), 2 men equipped with rapidly saturable respiratory cartridges rapidly began to feel ill with nausea, dyspnea, and seizures developing in one. Long-term neurological damage was reported in the seizure victim 5 months post-exposure (Deschamps & Turpin, 1996).
e) CASE SERIES: Three exterminator employees developed severe methyl bromide poisoning after using 80 g/m(3) of a spray product containing 86% methyl bromide and 14% ethylene oxide to fumigate a storage room in a folklore museum. One employee left the museum after about 9 hours and developed only mild impaired consciousness. Laboratory results revealed a serum bromide concentration of 87.4 mcg/mL and urinary bromide concentration of 122.4 mcg/mg. He recovered gradually following supportive care. Patients 2 and 3 spent over 30 hours in the museum and reused the product repeatedly to increase the methyl bromide concentration to ensure adequate fumigation. Both patients developed generalized tonic-clonic seizures and impaired consciousness. Despite supportive care, including 4 dialysis sessions with direct hemoperfusion and 24-hour continuous hemodiafiltration, which reduced their serum bromide concentrations (from 164.9 mcg/mL to 6.6 mcg/mL in patient 2 and from 157.3 mcg/mL to 10.7 mcg/mL in patient 3), and long-term rehabilitation, both patients continued to have myoclonus and cognitive deficit, requiring long-term assistance. In addition, patient 3 experiences a major convulsive seizure once every several months and requires total assistance to complete activities of daily living (Yamano & Nakadate, 2006).

C)

1) A 49-year-old man developed neurological, cardiovascular, hematological, and biochemical abnormalities following exposure to methyl bromide for more than 140 hours but recovered completely following supportive treatment. The initial bromide concentration was 18 mg/100 mL (Nagaratnam et al, 1979).
2) Some patients who recovered from severe intoxication have had persistent central nervous system effects, including vertigo, depression, hallucinations, anxiety, and inability to concentrate (Hathaway et al, 1996).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CONCENTRATION LEVEL

a) In several studies, serum bromide concentration was significantly higher in occupationally exposed workers (mean +/- standard deviation [SD] = 15.33 +/- 1.9 mg/L) than in controls (mean +/- SD = 4.13 +/- 1.05 mg/L). Bromide is toxic only following very high doses. Although a small amount of bromide is released following the metabolism of methyl bromide, cellular bromide concentrations are unlikely to reach toxic levels in patients with methyl bromide exposure (Bulathsinghala & Shaw, 2014).
b) Concentrations of bromide in unexposed persons may range from 0.5 to 2 mg/dL, depending on foods consumed (Jarowenko & Mancusi-Ungaro, 1985). Symptoms may occur at concentrations as low as 2.8 mg/dL. Severe symptoms have been reported with a serum concentration of 12 mg/dL (Clark et al, 1945).
c) The mean plasma bromide concentration directly following exposure was 9 +/- 1.4 mg/L in workers wearing "protective clothing" and breathing pressurized air following building fumigation with methyl bromide (Zwaveling et al, 1987).
d) Symptoms of poisoning have been reported with blood bromide levels as low as 28 mg/L (Zatuchni & Hong, 1981).
e) Inorganic blood bromide levels have ranged as low as 40 mg/L (Marracini et al, 1983) and 50 ppm to as high as 656 mg/L in human fatalities (Hine, 1969).

2) CASE REPORTS

a) One patient who developed generalized seizures following methyl bromide exposure had a serum bromide level of 204.9 mcg/mL and a urinary bromide concentration of 269.7 mcg/mL on admission to hospital. Following hemodialysis on the second hospital day, the serum bromide level decreased to 5.6 mcg/mL (Yamano Y, Kagawa J & Hanaoka T et al, 1994).
b) A 36-year-old woman was reported to have a serum bromide level of 27 mg/dL (normal: less than 4.8 mg/dL) the day following inadvertent methyl bromide inhalation, and a urine bromide of 6.2 mg/dL (normal: less than 1.6 mg/dL) a day later. The patient subsequently died 19 days after the exposure (Horowitz et al, 1998).
c) A postmortem serum bromide level was 148 mg/L in an adult who died after spending 45 to 90 minutes in a restaurant that had been fumigated with methyl bromide. Levels in 5 other exposed employees ranged from 40 to 101 mg/L (Fuortes, 1992).
d) A 40-hour post-exposure blood bromide concentration of an adult was 156 mg/L. Five months after the exposure, long-term neurologic effects still persisted (Deschamps & Turpin, 1996).
e) A 49-year-old man developed neurological, cardiovascular, hematologic, and biochemical abnormalities following exposure to methyl bromide for more than 140 hours but recovered completely following supportive treatment. The initial bromide concentration was 18 milligrams/100 milliliters (Nagaratnam et al, 1979).
f) CHRONIC: A man with a history of chronic exposure to methyl bromide for 3 years presented 2 weeks after experiencing symptoms of cerebellar and brainstem abnormalities. Methyl bromide serum concentration was 8.18 mg/dL (Suwanlaong & Phanthumchinda, 2008).
g) CHRONIC: Following chronic occupational exposure (12 years) to methyl bromide, a 43-year-old man developed erectile dysfunction due to peripheral polyneuropathy. Methyl bromide levels were 37.1, 11.2, and 28.8 mg/L in urine, serum, and cerebrospinal fluid, respectively (Park et al, 2005).

Workplace Standards

A)

1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.

a) Adopted Value

1) Methyl bromide

a) TLV:

1) TLV-TWA: 1 ppm
2) TLV-STEL:
3) TLV-Ceiling:

b) Notations and Endnotes:

1) Carcinogenicity Category: A4
2) Codes: Skin
3) Definitions:

a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
b) Skin: This refers to the potential significant contribution to the overall exposure by the cutaneous route, including mucous membranes and the eyes, either by contact with vapors or, of likely greater significance, by direct skin contact with the substance. It should be noted that although some materials are capable of causing irritation, dermatitis, and sensitization in workers, these properties are not considered relevant when assigning a skin notation. Rather, data from acute dermal studies and repeated dose dermal studies in animals or humans, along with the ability of the chemical to be absorbed, are integrated in the decision-making toward assignment of the skin designation. Use of the skin designation provides an alert that air sampling would not be sufficient by itself in quantifying exposure from the substance and that measures to prevent significant cutaneous absorption may be warranted. Please see "Definitions and Notations" (in TLV booklet) for full definition.

c) TLV Basis - Critical Effect(s): URT and skin irr
d) Molecular Weight: 94.95

1) For gases and vapors, to convert the TLV from ppm to mg/m(3):

a) [(TLV in ppm)(gram molecular weight of substance)]/24.45

2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:

a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance

e) Additional information:

B) NIOSH REL and IDLH Values for CAS74-83-9 (National Institute for Occupational Safety and Health, 2007):

1) Listed as: Methyl bromide
2) REL:

a) TWA:
b) STEL:
c) Ceiling:
d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
e) Skin Designation: Not Listed
f) Note(s): See Appendix A

3) IDLH:

a) IDLH: 250 ppm
b) Note(s): Ca

1) Ca: NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A).

C) Carcinogenicity Ratings for CAS74-83-9 :

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Methyl bromide

a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.

2) EPA (U.S. Environmental Protection Agency, 2011): D ; Listed as: Bromomethane

a) D : Not classifiable as to human carcinogenicity.

3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Methyl bromide

a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: Methyl bromide

a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).

5) MAK (DFG, 2002): Category 3B ; Listed as: Methyl bromide

a) Category 3B : Substances for which in vitro or animal studies have yielded evidence of carcinogenic effects that is not sufficient for classification of the substance in one of the other categories. Further studies are required before a final decision can be made. A MAK value can be established provided no genotoxic effects have been detected. (Footnote: In the past, when a substance was classified as Category 3 it was given a MAK value provided that it had no detectable genotoxic effects. When all such substances have been examined for whether or not they may be classified in Category 4, this sentence may be omitted.)

6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D) OSHA PEL Values for CAS74-83-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):

1) Listed as: Methyl bromide
2) Table Z-1 for Methyl bromide:

a) 8-hour TWA:

1) ppm: 20

a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.

2) mg/m3: 80

a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.

3) Ceiling Value: (C) - An employee's exposure to this substance shall at no time exceed the exposure limit given.
4) Skin Designation: Yes
5) Notation(s): Not Listed

Toxicity Information

7.7.1)

A) References: ACGIH, 1991 EPA, 1986; HSDB, 2001 ITI, 1995 Lewis, 1996 OHM/TADS, 1999 RTECS, 2001

1) LD50- (INHALATION)RAT:

a) 2700 ppm for 30M

2) LD50- (ORAL)RAT:

a) 214 mg/kg

3) LD50- (SUBCUTANEOUS)RAT:

a) 135 mg/kg

4) TCLo- (INHALATION)HUMAN:

a) 35 ppm (RTECS , 2001)

5) TCLo- (INHALATION)HUMAN:

a) 35 ppm -- GIT

Pharmacology Toxicology

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Physicochemical

Physical Characteristics

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Molecular Weight

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Other

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1) LOW: 80 mg/m(3) (HSDB , 2001)
2) HIGH: 4000 mg/m(3) (HSDB , 2001)

Animal Toxicology

References

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METHYL BROMIDE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

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Treatment Overview

Range Of Toxicity

Summary Of Exposure

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General Bibliography