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Methyl Bromide
Methyl Bromide NR Reed and L Lim, California Environmental Protection Agency, Sacramento, CA, USA Ó 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by Danny Villalobos and Marilyn Weber, volume 3, pp 71–74, Ó 2005, Elsevier Inc.
Background Methyl bromide is released to the atmosphere from natural and human activities. The ocean releases methyl bromide made by algae and kelp, and also serves as a sink for atmospheric deposition. Methyl bromide is formed in the burning of biomass. It was first marketed in 1961 as a fumigant to control pests in soil, commodities, and structures. Methyl bromide is an ozone-depleting substance (ODS). It breaks down stratospheric ozone through cyclical reactions in the presence of ultraviolet (UV) light. The ozone thinning results in increased UV radiation to the earth’s surface, a cause of serious worldwide health and ecological concerns (e.g., skin cancer, cataracts, damage to plants, and phytoplankton). Under the Montreal Protocol on Substances that Deplete the Ozone Layer, the complete phase out of methyl bromide uses is the year 2005 for developed counties and 2015 for developing counties. Qualified critical uses, quarantine and preshipment uses, and emergency uses are exempted. In the United States, the phase out and ban of methyl bromide uses are mandated by the Clean Air Act.
Chemical Profile l
Chemical Abstracts Service Registry Number: CAS 74-83-9 IUPAC Name: Bromomethane l Synonyms: Celfume, Curafume, Embafume, EPA Pesticide Chemical Code 053201, Halocarbon 40B1, Halon 1001, Haltox, MeBr, Monobromomethane, Terabol, Zytox l Chemical Class: Halogenated hydrocarbon l Chemical Structure: http://pubchem.ncbi.nlm.nih.gov/ image/structurefly.cgi?cid ¼ 6323&width¼400&height ¼ 400 l
l l l l l l l l l l
Molecular Formula: CH3Br Molecular Weight: 94.94 g mol1 Density: 3.974 g l1 (gas; 20 C); 1.7 g cm3 (liquid; 0 C) Vapor Pressure: 1620 mm Hg (216 kPa) at 25 C Boiling Point: 3.56 C Melting Point: 93.66 C Flash Point: None Conversion Factor: 1 ppm ¼ 3.89 mg m3 at 25 C Appearance: colorless gas Odor: odorless at low concentration and ambient temperature; sweetish at high concentration
Uses Methyl bromide is a broad-spectrum pesticide mainly used as a preplanting soil fumigant for the control of nematodes, insects,
270
weeds, and other soil-borne pests and diseases. It is injected into the soil and may be covered with a plastic tarp for a prescribed period after application. A tarp is also used in the fumigation of structures. Because its toxicity level is lower than the lower end of the odor threshold (approximately 80 mg m3; 20.6 ppm), chloropicrin, a noxious odorous agent, is often added to warn against overexposure. Methyl bromide is also used in greenhouses to treat soil and nursery stocks, and in sealed chambers to fumigate postharvest and nonfood commodities. It is released from the fumigated site or material during postapplication aeration period. Regulatory agencies establish safe use practices on the product labels. The nonpesticidal uses of methyl bromide include degreasing wool or extracting oil from plant products, and industrially as a methylating agent.
Environmental Fate and Behavior Methyl bromide is soluble in water (solubility at 15.2 g l1 at 20 C) and readily soluble in alcohol, chloroform, ether, carbon disulfide, carbon tetrachloride, and benzene. The Henry’s law constant of approximately 0.00734 atm-m3 mol1 (744 Pa-m3 mol1) indicates that it is readily released into the air after soil application. Methyl bromide undergoes biotic and abiotic degradation in water and soil. The hydrolysis half-life is 11–15 days in distilled water. The Koc is 7–32 l kg1 in different soil types. Depending on soil conditions, the half-life for aerobic hydrolysis is 4–57 days. Tarping the field after soil injection increases the degradation as well as delays and reduces release to air. Photolysis and breakdown through reaction with atmospheric hydroxyl radicals are slow. The estimated half-life in the troposphere is 0.2–1.7 years. With the measured Log Kow at 1.19–1.94, methyl bromide is not likely to bioaccumulate in aquatic organisms.
Exposure and Exposure Monitoring Inhalation is the major route of human exposure to gaseous methyl bromide. Workers handling liquid methyl bromide can also have dermal contact either directly or through accidental spills or contaminated clothing. Personal protective equipment, including self-contained breathing apparatus, may be required to minimize the exposure. Buffer zones that increase the distance between treatment sites and residential locations reduce the exposures of those who are nearby. Methyl bromide air concentration is measured by air sampling or estimated from air dispersion models. Consumers of fumigated postharvest commodities may be exposed to methyl bromide and inorganic bromide. Maximum residue levels (MRLs, or ‘Tolerances’ in the United States) of inorganic bromide are established for more than 90
Encyclopedia of Toxicology, Volume 3
http://dx.doi.org/10.1016/B978-0-12-386454-3.00163-9
Methyl Bromide
commodities. These are the highest concentrations allowable in or on the commodities. No MRLs or tolerances are established for methyl bromide, which has been detected in some treated commodities (e.g., nuts). At a given exposure concentration, children generally have higher overall body burden from all routes due to their higher intake (inhalation volume, amount of food intake) or contact on a per body weight basis.
Toxicokinetics Inhalation studies with 14C-methyl bromide showed that it is rapidly absorbed, and to a similar extent, in rats (48%), dogs (40%), and humans (50%). The absorption in rats was reduced at higher concentration (310 ppm; 1206 mg m3), compared to at 170 ppm. The absorption in rats was approximately 90% through oral or intraperitoneal administration. Methyl bromide is readily distributed to tissues with high levels in the lungs and nasal turbinates after inhalation and in the liver after oral or intraperitoneal exposure. Lower levels are detected in tissues such as the kidney, testes, adrenals, and brain. The tissue 14C-radioactivity is likely associated with metabolites because methyl bromide is rapidly metabolized to methanol, bromide, and CO2 through glutathione conjugation. Bromide ion has been detected in the blood and tissues of humans exposed to high concentrations. In rats, the expired air and urine are the primary routes of excretion. After inhalation, oral, or intraperitoneal exposure, 85% of the dose was eliminated within 65–72 h. Most (32–47%) of the absorbed dose was found in the expired air as CO2 and 16–40% in the urine. Some intact methyl bromide (4–20%) has been detected in the expired air. Very low level (1–2%) is excreted in the feces.
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Animal The inhalation LC50 in rats are 2830 ppm (30 min), 780 ppm (4 h), and 302 ppm (8 h). The LC50 in mice are 1700 ppm (30 min) and 405 ppm (4 h). The oral LD50 in rats is 104–214 mg kg1. Methyl bromide–induced neurotoxicity included tremors, ataxia, hypothermia, prostration, decreased activity, and labored breathing. The reported lowest observed effect levels (LOELs) are 233 ppm for 7 h (dogs), 338 ppm for 4 h (rats), 125 ppm for 8 h (rats), and 700 ppm for 1 h (mice). With short-term exposure (7 h day1) in dogs, decreased activity was reported at 50 ppm (14 days), 100 ppm (9 days), and 158 ppm (2 days). Methyl bromide causes olfactory damage in rodents. Epithelial degeneration, metaplasia, and reduced function were observed at or above 200 ppm (4–6 h) in rats, and metaplasia at 338 ppm (4 h) in mice. Other rat tissues showed degeneration after 6 h per day exposure for 5 days including the adrenals (at 175 ppm), and liver and brain (at 250 ppm).
Human Accidental deaths are mainly associated with the very high methyl bromide concentration (>6000 ppm) used in structural fumigation. Death is due to respiratory paralysis and circulatory failure. In acute exposure (250 ppm for 2 h), the early symptoms of acute toxicity included headache, dizziness, nausea, and vomiting. Continued exposure resulted in more severe neurotoxicity such as visual and speech disturbances, extremity numbness, mental confusion, and hallucination. Delayed onset and persistence of neurotoxicity are possible when exposed to high concentrations. Direct skin exposure to methyl bromide (9000 ppm) resulted in erythema with multiple vesicles and bullae at the contact site.
Chronic Toxicity Mechanism of Toxicity
Animal
Methyl bromide is a methylating agent and can bind irreversibly to sulfhydryl groups of enzymes and proteins. Methyl bromideinduced neurotoxicity has been attributed to its inhibition of the detoxification enzyme glutathione-S-transferase (GST), and depletion of glutathione in the brain. The degeneration of rat olfactory epithelium may also be related to the inhibition of GST as well as the generally high metabolic activity at this site. Glutathione involvement in the toxicity is demonstrated by the higher survival in rats given exogenous glutathione when exposed to a lethal dose of methyl bromide. Methyl bromide genotoxicity may be associated with DNA alkylation. The role of bromide is unclear because its level has not correlated with the symptoms of poisoning in humans.
In rats, mortality was observed at 400 ppm for 3 weeks and 90 ppm for 2 years but not at 120 ppm for 13 weeks. In mice, mortality occurred at 100 ppm for 20 weeks but not at 33 ppm for 2 years. No death was found in dogs at 5 ppm for 6 weeks. In rabbits, lethality was reported at 66 ppm for 2–10 weeks. Monkeys at 100 ppm for 11 exposures showed severe neurotoxicity. Subchronic or chronic inhalation exposure resulted in toxicity of the central nervous system, nasal tissue, and the heart in rodents. In rats with a 6 h per day, 5 days per week regimen, 13 weeks of exposure resulted in reduced brain weight at 30 ppm, decreased motor activity at 70 ppm, and death at 140 ppm. The LOELs for nasal cavity degeneration and hyperplasia were 30 ppm for 12–24 months or 3 ppm for 24–29 months. At 30 ppm, reduced kidney weight was found at 1 year and brain weight at 29 months. With a 4 h per day, 5 days per week regimen, heart lesions were observed at 150 ppm for 11 weeks and at 300 ppm for 6 weeks. In mice with a 6 h per day, 5 days per week regimen, 13 weeks of exposure resulted in changes in hematology parameters at 40 ppm and reduced weight gain and neurotoxicity at 120 ppm. In addition, neurotoxicity and lesions in the brain, heart, and nasal tissues
Acute and Short-Term Toxicity Methyl bromide is highly irritating to the skin and eyes and is moderately toxic by the oral and inhalation routes. Toxicity by the inhalation route is both time and concentration dependent, with the central nervous system as the target organ for both animal and human.
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Methyl Bromide
were found at 100 ppm for 20 weeks and decreased motor activity at 10 and 33 ppm for 6 and 12 months. Rabbits exposed to 65 ppm (7.5 h per day, 4 days per week) for 4 weeks showed impaired nerve conduction velocity and eye blink reflex, but they were not affected at 27 ppm (7.5 h per day, 25 h per week for 20 weeks). In dogs, one 6-week study suggested a neurotoxicity LOEL for unresponsiveness at 5 ppm methyl bromide (7 h per day, 5 days per week). However, another study reported no treatment-related neurotoxicity at 20 ppm.
lethal mutations in male rats or structural chromosomal aberrations in rat bone marrow. There is limited evidence of genotoxicity in human. In one study, soil fumigators had elevated sister chromatid exchanges in lymphocytes and S-methylcysteine adducts in the blood. In another study, fumigators showed increased hypoxanthineguanine phosphoribosyl transferase gene mutation in the lymphocytes and increased micronuclei in oropharyngeal cells.
Human
Carcinogenicity
Repeated exposures have been associated with peripheral neuropathies, impaired gait, behavioral changes, and mild liver and kidney dysfunction. Visual impairment secondary to optic nerve atrophy has been reported. Workers exposed to methyl bromide reported to have lower performance in neurobehavioral tests and some also showed mild neurological dysfunctions. However, several confounding factors may have influenced these findings.
There is no clear evidence of carcinogenicity in animals or humans even though methyl bromide showed genotoxicity. A 2-year inhalation study with methyl bromide in Fischer 344 rats showed increased pituitary adenomas in 100 ppm males. Other inhalation toxicity studies did not show carcinogenicity in rats (up to 90 ppm) or mice (up to 100 ppm). Preneoplastic lesions (hyperplasia and metaplasia) of the olfactory epithelium were reported in rats and mice. Methyl bromide given by gavage caused forestomach tumors in rats. In a study of male pesticide applicators in Iowa and North Carolina, methyl bromide use was associated with a statistically significant increase of prostate cancer cases. However, the results are not definitive because of potential recall bias and lack of actual exposure data. The 1986 weight of evidence evaluation by the International Agency for Research on Cancer concluded that methyl bromide is not classifiable as to its carcinogenicity to humans (Group 3).
Reproductive and Developmental Toxicity In rabbits, methyl bromide caused developmental toxicity above 20 ppm (7 h per day during gestation days 7–19). Gall bladder agenesis occurred in fetuses of dams exposed to 80 ppm in two studies. Rat fetuses of dams exposed at 70 ppm (7 h per day during gestation days 1–19) showed delayed skull ossification. No developmental toxicity was found in rats or rabbits from oral exposure. In a two-generation study, rats were exposed to methyl bromide (6 h per day, 5 days per week) during premating, gestation, and lactation. The pups were exposed to methyl bromide in utero during gestation and through the milk during lactation. Effects observed in the F1 and F2, but not the F0, included decreased pup body weights (30 or 90 ppm of F1 and F2 litters), fertility index (second mating of the 30 or 90 ppm of F1 adults), and absolute brain weight and cerebral cortex width (90 ppm of F1 adults).
Clinical Management There is no antidote for methyl bromide poisoning. Medical intervention is limited to treatment of the symptoms and monitoring for potential delayed effects. There is no specific laboratory test to detect the presence of or diagnose an exposure to methyl bromide. Serum bromide level can be increased but it does not accurately predict clinical course.
Genotoxicity
Ecotoxicology
Methyl bromide is a direct-acting mutagen in in vitro studies with Salmonella typhimurium strains TA100 and TA1535, Escherichia coli, and Saccharomyces cerevisiae. It induced thymidine kinase forward mutation in mouse lymphoma assay, and sister chromatid exchanges in Chinese hamster ovary cells. In in vivo studies, methyl bromide increased micronuclei formation in peripheral erythrocytes and sister chromatid exchanges in bone marrow cells of female mice exposed by inhalation (100 or 200 ppm) for 2–12 weeks of exposure. Tissue DNA adducts were detected after oral (0.58–8 mg kg1 in rats), intraperitoneal (417 mg g1 in mice), or inhalation (36 ppm in mice, 131–263 ppm in rats) exposures. No unscheduled DNA synthesis in rat hepatocytes or sperm abnormalities was found in mice. Methyl bromide (up to 70 ppm for 5 days, 7 h per day) also did not cause dominant
Aquatic organisms may be exposed to methyl bromide in surface water contaminated by field runoff. The acute lethality concentration for methyl bromide in several fish species ranged from 0.7 to 20 mg l1. The LC50 is 3.9 mg l1 (96 h) for rainbow trout, 2.6 mg l1 (48 h) for Daphnia, and 2.2 mg l1 (24 h) for algae. Bromide is the major methyl bromide degradate in water. Compared to methyl bromide, its acute toxicity is lower by at least 4000-fold in fish and Daphnia and at least 2400-fold in algae. Due to partitioning of methyl bromide from water into the air, chronic exposure of aquatic organisms is unlikely. Inhalation is the major route of exposure to methyl bromide for nontarget terrestrial species. No acute or chronic toxicity data are available for birds. Toxicity to rodents and other mammals are presented in the acute, short-term, and chronic toxicity sections.
Methyl Bromide
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Other Hazards
Further Reading
The liquid or gas cylinders of methyl bromide can explode from pressure build up in the heat of fire. In the presence of oxidizers and depending on the source of fire and heat, combustion of methyl bromide produces toxic gas and vapor, e.g., bromine, hydrogen bromide, carbonyl bromide, and carbon monoxide.
Lim, L.O., 2002. Methyl Bromide Risk Characterization Document, Volume I – Inhalation Exposure. Department of Pesticide Regulation, California Environmental Protection Agency, Sacramento, CA. http://www.cdpr.ca.gov/docs/risk/ rcd.htm. National Institute for Occupational Safety and Health (NIOSH), 2007. Pocket Guide to Chemical Hazards. Department of Health and Human Services, Centers for Disease Control and Prevention. DHHS (NIOSH) Publication No. 2005-149. September 2007. http://www.cdc.gov/niosh/docs/2005-149/pdfs/2005-149.pdf. United States Environmental Protection Agency (USEPA), 2005. Revised Draft Methyl Bromide Environmental Fate and Ecological Risk Assessment – Following the Review of 30-Day Error Correction Comments. Environmental Fate and Effects Division, Office of Pesticide Program, U.S. Environmental Protection Agency, Washington, DC. EPA-HQ-OPP-2005-0123-0029. http://www.regulations.gov/#! documentDetail;D¼EPA-HQ-OPP-2005-0123-0029 United States Environmental Protection Agency (USEPA), 2007. Acute Exposure Guideline Levels (AEGLs) for Methyl Bromide (CAS Reg. No. 74-83-9)-Interim, NAC/Interim 1:10/2007. National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, U.S. Environmental Protection Agency, Washington, DC. http://www.epa.gov/opptintr/aegl/pubs/rest113.htm. United States Environmental Protection Agency (USEPA), 2007. Methyl Bromide: Phase 5 Health Effects Division (HED) Human Health Risk Assessment for Soil, Greenhouse, and Residential/structural Uses. Health Effects Division, Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC. http://www.regulations.gov/#!documentDetail;D¼EPA-HQ-OPP2005-0123-0285. United States Environmental Protection Agency (USEPA), 2009. Amended Reregistration Eligibility Decision for Methyl Bromide (Soil and Non-food Structural Uses). Prevention, Pesticides and Toxic Substances (7508P), United States Environmental Protection Agency, Washington, DC. http://www.epa.gov/oppsrrd1/REDs/ methylbromide-red-amended.pdf.
Exposure Standards and Guidelines l
American Conference of Governmental Industrial Hygienists Threshold Limit Value: 1 ppm (4 mg m3) Time weighted average; (Skin) – potential for dermal absorption l National Institute for Occupational Safety and Health Immediately Dangerous to Life or Health Concentration: 250 ppm (9725 mg m3) – a potential occupational carcinogen l Occupational Safety and Health Administration Permissible Exposure Limit: 20 ppm (80 mg m3; Ceiling); (Skin) – potential for dermal absorption
See also: Toxicity Testing, Developmental; Neurotoxicity; Pesticides; Chloropicrin; Health Assessments; National Institute for Occupational Safety and Health; Volatile Organic Compounds; Carcinogen Classification Schemes; Carcinogenesis; Federal Insecticide, Fungicide, and Rodenticide Act, US; Genetic Toxicology; International Agency for Research on Cancer; Regulation, Toxicology and; Respiratory Tract Toxicology; Risk Assessment, Human Health; Ò Ecotoxicology; ACGIH (American Conference of Governmental Industrial Hygienists); Carcinogen–DNA Adduct Formation and DNA Repair; Children’s Environmental Health; Glutathione; Ozone; Environmental Fate and Behavior.
Relevant WebSites http://www.cdpr.ca.gov – California Environmental Protection Agency http://ozone.unep.org – United Nations Environment Programme http://www.epa.gov – United States Environmental Protection Agency http://www.osha.gov – United States Occupational Safety and Health Administration
Background Methyl bromide is released to the atmosphere from natural and human activities. The ocean releases methyl bromide made by algae and kelp, and also serves as a sink for atmospheric deposition. Methyl bromide is formed in the burning of biomass. It was first marketed in 1961 as a fumigant to control pests in soil, commodities, and structures. Methyl bromide is an ozone-depleting substance (ODS). It breaks down stratospheric ozone through cyclical reactions in the presence of ultraviolet (UV) light. The ozone thinning results in increased UV radiation to the earth’s surface, a cause of serious worldwide health and ecological concerns (e.g., skin cancer, cataracts, damage to plants, and phytoplankton). Under the Montreal Protocol on Substances that Deplete the Ozone Layer, the complete phase out of methyl bromide uses is the year 2005 for developed counties and 2015 for developing counties. Qualified critical uses, quarantine and preshipment uses, and emergency uses are exempted. In the United States, the phase out and ban of methyl bromide uses are mandated by the Clean Air Act.
Chemical Profile l
Chemical Abstracts Service Registry Number: CAS 74-83-9 IUPAC Name: Bromomethane l Synonyms: Celfume, Curafume, Embafume, EPA Pesticide Chemical Code 053201, Halocarbon 40B1, Halon 1001, Haltox, MeBr, Monobromomethane, Terabol, Zytox l Chemical Class: Halogenated hydrocarbon l Chemical Structure: http://pubchem.ncbi.nlm.nih.gov/ image/structurefly.cgi?cid ¼ 6323&width¼400&height ¼ 400 l
l l l l l l l l l l
Molecular Formula: CH3Br Molecular Weight: 94.94 g mol1 Density: 3.974 g l1 (gas; 20 C); 1.7 g cm3 (liquid; 0 C) Vapor Pressure: 1620 mm Hg (216 kPa) at 25 C Boiling Point: 3.56 C Melting Point: 93.66 C Flash Point: None Conversion Factor: 1 ppm ¼ 3.89 mg m3 at 25 C Appearance: colorless gas Odor: odorless at low concentration and ambient temperature; sweetish at high concentration
Uses Methyl bromide is a broad-spectrum pesticide mainly used as a preplanting soil fumigant for the control of nematodes, insects,
270
weeds, and other soil-borne pests and diseases. It is injected into the soil and may be covered with a plastic tarp for a prescribed period after application. A tarp is also used in the fumigation of structures. Because its toxicity level is lower than the lower end of the odor threshold (approximately 80 mg m3; 20.6 ppm), chloropicrin, a noxious odorous agent, is often added to warn against overexposure. Methyl bromide is also used in greenhouses to treat soil and nursery stocks, and in sealed chambers to fumigate postharvest and nonfood commodities. It is released from the fumigated site or material during postapplication aeration period. Regulatory agencies establish safe use practices on the product labels. The nonpesticidal uses of methyl bromide include degreasing wool or extracting oil from plant products, and industrially as a methylating agent.
Environmental Fate and Behavior Methyl bromide is soluble in water (solubility at 15.2 g l1 at 20 C) and readily soluble in alcohol, chloroform, ether, carbon disulfide, carbon tetrachloride, and benzene. The Henry’s law constant of approximately 0.00734 atm-m3 mol1 (744 Pa-m3 mol1) indicates that it is readily released into the air after soil application. Methyl bromide undergoes biotic and abiotic degradation in water and soil. The hydrolysis half-life is 11–15 days in distilled water. The Koc is 7–32 l kg1 in different soil types. Depending on soil conditions, the half-life for aerobic hydrolysis is 4–57 days. Tarping the field after soil injection increases the degradation as well as delays and reduces release to air. Photolysis and breakdown through reaction with atmospheric hydroxyl radicals are slow. The estimated half-life in the troposphere is 0.2–1.7 years. With the measured Log Kow at 1.19–1.94, methyl bromide is not likely to bioaccumulate in aquatic organisms.
Exposure and Exposure Monitoring Inhalation is the major route of human exposure to gaseous methyl bromide. Workers handling liquid methyl bromide can also have dermal contact either directly or through accidental spills or contaminated clothing. Personal protective equipment, including self-contained breathing apparatus, may be required to minimize the exposure. Buffer zones that increase the distance between treatment sites and residential locations reduce the exposures of those who are nearby. Methyl bromide air concentration is measured by air sampling or estimated from air dispersion models. Consumers of fumigated postharvest commodities may be exposed to methyl bromide and inorganic bromide. Maximum residue levels (MRLs, or ‘Tolerances’ in the United States) of inorganic bromide are established for more than 90
Encyclopedia of Toxicology, Volume 3
http://dx.doi.org/10.1016/B978-0-12-386454-3.00163-9
Methyl Bromide
commodities. These are the highest concentrations allowable in or on the commodities. No MRLs or tolerances are established for methyl bromide, which has been detected in some treated commodities (e.g., nuts). At a given exposure concentration, children generally have higher overall body burden from all routes due to their higher intake (inhalation volume, amount of food intake) or contact on a per body weight basis.
Toxicokinetics Inhalation studies with 14C-methyl bromide showed that it is rapidly absorbed, and to a similar extent, in rats (48%), dogs (40%), and humans (50%). The absorption in rats was reduced at higher concentration (310 ppm; 1206 mg m3), compared to at 170 ppm. The absorption in rats was approximately 90% through oral or intraperitoneal administration. Methyl bromide is readily distributed to tissues with high levels in the lungs and nasal turbinates after inhalation and in the liver after oral or intraperitoneal exposure. Lower levels are detected in tissues such as the kidney, testes, adrenals, and brain. The tissue 14C-radioactivity is likely associated with metabolites because methyl bromide is rapidly metabolized to methanol, bromide, and CO2 through glutathione conjugation. Bromide ion has been detected in the blood and tissues of humans exposed to high concentrations. In rats, the expired air and urine are the primary routes of excretion. After inhalation, oral, or intraperitoneal exposure, 85% of the dose was eliminated within 65–72 h. Most (32–47%) of the absorbed dose was found in the expired air as CO2 and 16–40% in the urine. Some intact methyl bromide (4–20%) has been detected in the expired air. Very low level (1–2%) is excreted in the feces.
271
Animal The inhalation LC50 in rats are 2830 ppm (30 min), 780 ppm (4 h), and 302 ppm (8 h). The LC50 in mice are 1700 ppm (30 min) and 405 ppm (4 h). The oral LD50 in rats is 104–214 mg kg1. Methyl bromide–induced neurotoxicity included tremors, ataxia, hypothermia, prostration, decreased activity, and labored breathing. The reported lowest observed effect levels (LOELs) are 233 ppm for 7 h (dogs), 338 ppm for 4 h (rats), 125 ppm for 8 h (rats), and 700 ppm for 1 h (mice). With short-term exposure (7 h day1) in dogs, decreased activity was reported at 50 ppm (14 days), 100 ppm (9 days), and 158 ppm (2 days). Methyl bromide causes olfactory damage in rodents. Epithelial degeneration, metaplasia, and reduced function were observed at or above 200 ppm (4–6 h) in rats, and metaplasia at 338 ppm (4 h) in mice. Other rat tissues showed degeneration after 6 h per day exposure for 5 days including the adrenals (at 175 ppm), and liver and brain (at 250 ppm).
Human Accidental deaths are mainly associated with the very high methyl bromide concentration (>6000 ppm) used in structural fumigation. Death is due to respiratory paralysis and circulatory failure. In acute exposure (250 ppm for 2 h), the early symptoms of acute toxicity included headache, dizziness, nausea, and vomiting. Continued exposure resulted in more severe neurotoxicity such as visual and speech disturbances, extremity numbness, mental confusion, and hallucination. Delayed onset and persistence of neurotoxicity are possible when exposed to high concentrations. Direct skin exposure to methyl bromide (9000 ppm) resulted in erythema with multiple vesicles and bullae at the contact site.
Chronic Toxicity Mechanism of Toxicity
Animal
Methyl bromide is a methylating agent and can bind irreversibly to sulfhydryl groups of enzymes and proteins. Methyl bromideinduced neurotoxicity has been attributed to its inhibition of the detoxification enzyme glutathione-S-transferase (GST), and depletion of glutathione in the brain. The degeneration of rat olfactory epithelium may also be related to the inhibition of GST as well as the generally high metabolic activity at this site. Glutathione involvement in the toxicity is demonstrated by the higher survival in rats given exogenous glutathione when exposed to a lethal dose of methyl bromide. Methyl bromide genotoxicity may be associated with DNA alkylation. The role of bromide is unclear because its level has not correlated with the symptoms of poisoning in humans.
In rats, mortality was observed at 400 ppm for 3 weeks and 90 ppm for 2 years but not at 120 ppm for 13 weeks. In mice, mortality occurred at 100 ppm for 20 weeks but not at 33 ppm for 2 years. No death was found in dogs at 5 ppm for 6 weeks. In rabbits, lethality was reported at 66 ppm for 2–10 weeks. Monkeys at 100 ppm for 11 exposures showed severe neurotoxicity. Subchronic or chronic inhalation exposure resulted in toxicity of the central nervous system, nasal tissue, and the heart in rodents. In rats with a 6 h per day, 5 days per week regimen, 13 weeks of exposure resulted in reduced brain weight at 30 ppm, decreased motor activity at 70 ppm, and death at 140 ppm. The LOELs for nasal cavity degeneration and hyperplasia were 30 ppm for 12–24 months or 3 ppm for 24–29 months. At 30 ppm, reduced kidney weight was found at 1 year and brain weight at 29 months. With a 4 h per day, 5 days per week regimen, heart lesions were observed at 150 ppm for 11 weeks and at 300 ppm for 6 weeks. In mice with a 6 h per day, 5 days per week regimen, 13 weeks of exposure resulted in changes in hematology parameters at 40 ppm and reduced weight gain and neurotoxicity at 120 ppm. In addition, neurotoxicity and lesions in the brain, heart, and nasal tissues
Acute and Short-Term Toxicity Methyl bromide is highly irritating to the skin and eyes and is moderately toxic by the oral and inhalation routes. Toxicity by the inhalation route is both time and concentration dependent, with the central nervous system as the target organ for both animal and human.
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were found at 100 ppm for 20 weeks and decreased motor activity at 10 and 33 ppm for 6 and 12 months. Rabbits exposed to 65 ppm (7.5 h per day, 4 days per week) for 4 weeks showed impaired nerve conduction velocity and eye blink reflex, but they were not affected at 27 ppm (7.5 h per day, 25 h per week for 20 weeks). In dogs, one 6-week study suggested a neurotoxicity LOEL for unresponsiveness at 5 ppm methyl bromide (7 h per day, 5 days per week). However, another study reported no treatment-related neurotoxicity at 20 ppm.
lethal mutations in male rats or structural chromosomal aberrations in rat bone marrow. There is limited evidence of genotoxicity in human. In one study, soil fumigators had elevated sister chromatid exchanges in lymphocytes and S-methylcysteine adducts in the blood. In another study, fumigators showed increased hypoxanthineguanine phosphoribosyl transferase gene mutation in the lymphocytes and increased micronuclei in oropharyngeal cells.
Human
Carcinogenicity
Repeated exposures have been associated with peripheral neuropathies, impaired gait, behavioral changes, and mild liver and kidney dysfunction. Visual impairment secondary to optic nerve atrophy has been reported. Workers exposed to methyl bromide reported to have lower performance in neurobehavioral tests and some also showed mild neurological dysfunctions. However, several confounding factors may have influenced these findings.
There is no clear evidence of carcinogenicity in animals or humans even though methyl bromide showed genotoxicity. A 2-year inhalation study with methyl bromide in Fischer 344 rats showed increased pituitary adenomas in 100 ppm males. Other inhalation toxicity studies did not show carcinogenicity in rats (up to 90 ppm) or mice (up to 100 ppm). Preneoplastic lesions (hyperplasia and metaplasia) of the olfactory epithelium were reported in rats and mice. Methyl bromide given by gavage caused forestomach tumors in rats. In a study of male pesticide applicators in Iowa and North Carolina, methyl bromide use was associated with a statistically significant increase of prostate cancer cases. However, the results are not definitive because of potential recall bias and lack of actual exposure data. The 1986 weight of evidence evaluation by the International Agency for Research on Cancer concluded that methyl bromide is not classifiable as to its carcinogenicity to humans (Group 3).
Reproductive and Developmental Toxicity In rabbits, methyl bromide caused developmental toxicity above 20 ppm (7 h per day during gestation days 7–19). Gall bladder agenesis occurred in fetuses of dams exposed to 80 ppm in two studies. Rat fetuses of dams exposed at 70 ppm (7 h per day during gestation days 1–19) showed delayed skull ossification. No developmental toxicity was found in rats or rabbits from oral exposure. In a two-generation study, rats were exposed to methyl bromide (6 h per day, 5 days per week) during premating, gestation, and lactation. The pups were exposed to methyl bromide in utero during gestation and through the milk during lactation. Effects observed in the F1 and F2, but not the F0, included decreased pup body weights (30 or 90 ppm of F1 and F2 litters), fertility index (second mating of the 30 or 90 ppm of F1 adults), and absolute brain weight and cerebral cortex width (90 ppm of F1 adults).
Clinical Management There is no antidote for methyl bromide poisoning. Medical intervention is limited to treatment of the symptoms and monitoring for potential delayed effects. There is no specific laboratory test to detect the presence of or diagnose an exposure to methyl bromide. Serum bromide level can be increased but it does not accurately predict clinical course.
Genotoxicity
Ecotoxicology
Methyl bromide is a direct-acting mutagen in in vitro studies with Salmonella typhimurium strains TA100 and TA1535, Escherichia coli, and Saccharomyces cerevisiae. It induced thymidine kinase forward mutation in mouse lymphoma assay, and sister chromatid exchanges in Chinese hamster ovary cells. In in vivo studies, methyl bromide increased micronuclei formation in peripheral erythrocytes and sister chromatid exchanges in bone marrow cells of female mice exposed by inhalation (100 or 200 ppm) for 2–12 weeks of exposure. Tissue DNA adducts were detected after oral (0.58–8 mg kg1 in rats), intraperitoneal (417 mg g1 in mice), or inhalation (36 ppm in mice, 131–263 ppm in rats) exposures. No unscheduled DNA synthesis in rat hepatocytes or sperm abnormalities was found in mice. Methyl bromide (up to 70 ppm for 5 days, 7 h per day) also did not cause dominant
Aquatic organisms may be exposed to methyl bromide in surface water contaminated by field runoff. The acute lethality concentration for methyl bromide in several fish species ranged from 0.7 to 20 mg l1. The LC50 is 3.9 mg l1 (96 h) for rainbow trout, 2.6 mg l1 (48 h) for Daphnia, and 2.2 mg l1 (24 h) for algae. Bromide is the major methyl bromide degradate in water. Compared to methyl bromide, its acute toxicity is lower by at least 4000-fold in fish and Daphnia and at least 2400-fold in algae. Due to partitioning of methyl bromide from water into the air, chronic exposure of aquatic organisms is unlikely. Inhalation is the major route of exposure to methyl bromide for nontarget terrestrial species. No acute or chronic toxicity data are available for birds. Toxicity to rodents and other mammals are presented in the acute, short-term, and chronic toxicity sections.
Methyl Bromide
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Other Hazards
Further Reading
The liquid or gas cylinders of methyl bromide can explode from pressure build up in the heat of fire. In the presence of oxidizers and depending on the source of fire and heat, combustion of methyl bromide produces toxic gas and vapor, e.g., bromine, hydrogen bromide, carbonyl bromide, and carbon monoxide.
Lim, L.O., 2002. Methyl Bromide Risk Characterization Document, Volume I – Inhalation Exposure. Department of Pesticide Regulation, California Environmental Protection Agency, Sacramento, CA. http://www.cdpr.ca.gov/docs/risk/ rcd.htm. National Institute for Occupational Safety and Health (NIOSH), 2007. Pocket Guide to Chemical Hazards. Department of Health and Human Services, Centers for Disease Control and Prevention. DHHS (NIOSH) Publication No. 2005-149. September 2007. http://www.cdc.gov/niosh/docs/2005-149/pdfs/2005-149.pdf. United States Environmental Protection Agency (USEPA), 2005. Revised Draft Methyl Bromide Environmental Fate and Ecological Risk Assessment – Following the Review of 30-Day Error Correction Comments. Environmental Fate and Effects Division, Office of Pesticide Program, U.S. Environmental Protection Agency, Washington, DC. EPA-HQ-OPP-2005-0123-0029. http://www.regulations.gov/#! documentDetail;D¼EPA-HQ-OPP-2005-0123-0029 United States Environmental Protection Agency (USEPA), 2007. Acute Exposure Guideline Levels (AEGLs) for Methyl Bromide (CAS Reg. No. 74-83-9)-Interim, NAC/Interim 1:10/2007. National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, U.S. Environmental Protection Agency, Washington, DC. http://www.epa.gov/opptintr/aegl/pubs/rest113.htm. United States Environmental Protection Agency (USEPA), 2007. Methyl Bromide: Phase 5 Health Effects Division (HED) Human Health Risk Assessment for Soil, Greenhouse, and Residential/structural Uses. Health Effects Division, Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC. http://www.regulations.gov/#!documentDetail;D¼EPA-HQ-OPP2005-0123-0285. United States Environmental Protection Agency (USEPA), 2009. Amended Reregistration Eligibility Decision for Methyl Bromide (Soil and Non-food Structural Uses). Prevention, Pesticides and Toxic Substances (7508P), United States Environmental Protection Agency, Washington, DC. http://www.epa.gov/oppsrrd1/REDs/ methylbromide-red-amended.pdf.
Exposure Standards and Guidelines l
American Conference of Governmental Industrial Hygienists Threshold Limit Value: 1 ppm (4 mg m3) Time weighted average; (Skin) – potential for dermal absorption l National Institute for Occupational Safety and Health Immediately Dangerous to Life or Health Concentration: 250 ppm (9725 mg m3) – a potential occupational carcinogen l Occupational Safety and Health Administration Permissible Exposure Limit: 20 ppm (80 mg m3; Ceiling); (Skin) – potential for dermal absorption
See also: Toxicity Testing, Developmental; Neurotoxicity; Pesticides; Chloropicrin; Health Assessments; National Institute for Occupational Safety and Health; Volatile Organic Compounds; Carcinogen Classification Schemes; Carcinogenesis; Federal Insecticide, Fungicide, and Rodenticide Act, US; Genetic Toxicology; International Agency for Research on Cancer; Regulation, Toxicology and; Respiratory Tract Toxicology; Risk Assessment, Human Health; Ò Ecotoxicology; ACGIH (American Conference of Governmental Industrial Hygienists); Carcinogen–DNA Adduct Formation and DNA Repair; Children’s Environmental Health; Glutathione; Ozone; Environmental Fate and Behavior.
Relevant WebSites http://www.cdpr.ca.gov – California Environmental Protection Agency http://ozone.unep.org – United Nations Environment Programme http://www.epa.gov – United States Environmental Protection Agency http://www.osha.gov – United States Occupational Safety and Health Administration