Which of the following is a potential harmful effect of the chemical methyl bromide?

Methyl Bromide

Methyl bromide has been used as a refrigerant, insecticide, fumigant, and fire extinguisher, but its use has been banned in many countries because of its ozone-depleting properties. Its high volatility may lead to work-area concentrations sufficient to cause neurotoxicity from inhalation. Following acute high-level exposure, an interval of several hours or more may elapse before the onset of symptoms. Because methyl bromide is odorless and colorless, subjects may not even be aware that exposure has occurred, so chloropicrin, a conjunctival and mucosal irritant, is commonly added to methyl bromide to warn of inhalation exposure. Acute methyl bromide intoxication leads to an encephalopathy with convulsions, delirium, hyperpyrexia, coma,pulmonary edema, and death. Acute exposure to lower concentrations may result in conspicuous mental changes, including confusion, psychosis or affective disturbances, headache, nausea, dysarthria, tremulousness, myoclonus, ataxia, visual disturbances, and seizures. The electroencephalogram (EEG) may show frontally predominant slow waves or polyspike-wave complexes, while magnetic resonance imaging (MRI) reveals involvement of the dentate nucleus, brainstem, and splenium of the corpus callosum (De Souza et al., 2013).

Long-term, low-level exposure may lead to a polyneuropathy in the absence of systemic symptoms. Distal paresthesias are followed by sensory and motor deficits, loss of tendon reflexes, and an ataxic gait. Visual disturbances, optic atrophy, and upper motor neuron deficits may occur also. Calf tenderness is sometimes conspicuous. The CSF is unremarkable. Electrodiagnostic study results reveal both sensory and motor involvement. Gradual improvement occurs with cessation of exposure.

The basis of the neurotoxicity is uncertain but methyl phosphates formed in cells may contribute to its neuron-specific toxicity via cholinesterase inhibition (Bulathsinghala and Shaw, 2014). Treatment is symptomatic and supportive. Hemodialysis may help in removing bromide from the blood. Chelating agents are of uncertain utility.

Abstract

Methyl bromide (74-83-9) is a natural substance and manufactured as a fumigant to control pests in the soil, food and nonfood commodities, and structures. Its pesticidal use has declined because of the phase out under the Montreal Protocol for ozone-depleting substances. Toxicity in human and animals is mainly from inhalation of methyl bromide gas. Methyl bromide is a neurotoxicant. It also causes respiratory, cardiovascular, reproductive, and developmental toxicities in animals. While it is genotoxic, methyl bromide has not been classified as a human carcinogen. In human poisoning, clinical management is supportive therapy.

Bromine and Methyl Bromide

Bromine is an irritant halogen. It is usually handled as a liquid rather than as a gas, but it vaporizes readily. Sources of bromine exposure other than environmental releases include chemical synthesis and water purification.69,328–331 Bromine is a more potent irritant than chlorine and is approximately 100 times more irritating than ammonia.332 In a murine model of bromine-induced lung injury, high heme levels, possibly released from dead inflammatory cells or sloughed epithelial cells, correlated with a spectrum of adverse sequelae, including lung edema, increased airway resistance, and lung inflammation. Therapeutic reduction of heme levels improved lung function and survival, thus suggesting a potential role for heme attenuation as a treatment for victims of bromine inhalation, although this has not been studied in humans.333

Methyl bromide is a major industrial fumigant with far-greater potential for public exposure. Methyl bromide is also a potent respiratory irritant, but the central nervous system may represent the more important target organ in typical exposures.334,335

105.2 Chemical Properties and Pesticidal Uses of Methyl Bromide

Methyl bromide (CH3Br, bromomethane, CAS no. 74-83-9) is a colorless, odorless gas at normal temperature and pressure, and is produced by the interaction of methanol (CH3OH) and hydrogen bromide (HBr). Methyl bromide is made commercially but also is produced naturally by marine algae and other plants and as a by-product of the combustion of plant materials (i.e., forest fires). Under increased pressure or below 3°C, methyl bromide is a clear to straw-colored liquid and is usually shipped as a liquified, compressed gas. Methyl bromide has a boiling point of 38.5°F and is nonflammable in air. Methyl bromide formulations contain chloropicrin, an irritant and lacrimator, as a warning agent.

Methyl bromide is a broad-spectrum pesticide primarily used for soil fumigation, commodity/quarantine treatment, and structural fumigation. It is also used as an intermediate in the manufacture of other chemicals. Methyl bromide has been used as a fumigant for more than 50 years and is strictly controlled by the U.S. Environmental Protection Agency (U.S. EPA) under the Federal Insecticide, Fungicide, and Rodenticide Act. Its application and use are also controlled by various state regulatory authorities.

For soil fumigation, methyl bromide is injected directly into the soil, which is then covered with a variety of tarping materials. The tarps are sealed, kept in place for several days, and then removed. Soil fumigation with methyl bromide enhances the quality of the crops and increases yield by eliminating fungal diseases, nematodes, weed seeds, and other soil-borne pests. The primary crops grown in methyl bromide-treated soil are peppers, strawberries, tomatoes, and grapes.

Methyl bromide is widely used for fumigating postharvest commodities, including wheat and cereals, spices, nuts, and dried or fresh fruits, to eradicate pest infestations. Fumigation typically occurs where the commodities are stored, such as in ship holds, grain elevators, warehouses, special fumigation chambers, and on shipping piers/docks. Commodity fumigation typically involves the use of specially designed and permanently installed chambers into which the methyl bromide is released. After treatment, mechanical ventilation continuously aerates the commodity until concentration of methyl bromide in the vented air is at established safety levels. Another type of commodity fumigation involves sealing the commodity under a tarpaulin followed by injection of methyl bromide. Aeration and ventilation occurs after the tarpaulin is removed. In structural fumigation, all openings in the structure are sealed.

All types of commercial and residential structures may be fumigated with methyl bromide to control or eradicate pests, such as termites. The structure is covered by a “tent” or tarpaulin, and methyl bromide gas is released inside the structure. After a specified period, the tarpaulin is removed and the structure is aerated until concentration of methyl bromide inside the structure reaches safe levels.

Methyl bromide may only be applied and used by professional, certified applicators. All persons working with methyl bromide are required to be knowledgeable about its hazards and trained in the use of required respiratory protection equipment, detector devices, and emergency procedures. Applicators and other persons in the fumigation area must wear appropriate personal protective equipment (PPE) as required by the label and U.S. EPA regulations. Such PPE typically includes full eye/face shields, safety shoes, and respirators. If the concentration of methyl bromide in the work area exceeds established safety levels, all persons in the fumigated area must wear an approved, self-contained breathing apparatus or evacuate the area. The placarding and posting of warning notices at all entrances to an area undergoing fumigation is required. No one is permitted in a structure or area undergoing fumigation, unless involved in the fumigation and wearing appropriate PPE. Re-entry into fumigated areas or structures is prohibited until the air concentration of methyl bromide is shown to be at safe levels. Individuals living in close proximity to fumigated fields, greenhouses, or structures are unlikely to be exposed to unsafe levels of methyl bromide because of the application restrictions and the rapid dissipation of methyl bromide in the atmosphere. Additional regulatory controls further limit this possibility. For example, in California, maximum air concentration levels have been established for state-mandated buffer zones surrounding fumigated areas.

Methyl Bromide–Induced Bullae

A vesiculobullous eruption has been reported after occupational exposure to high concentrations of methyl bromide used in fumigation.2419

Toxicokinetics

Methyl bromide is rapidly absorbed by inhalation. Rats are more efficient than humans at absorbing methyl bromide following inhalation exposure, with absorption being directly proportional to air concentration up to ∼about 300 ppm. Absorption is also rapid and extensive (97%) in rats after oral administration. Methyl bromide is distributed in fat, lung, liver, adrenals, and kidney, with less distribution into brain. Methyl bromide is rapidly and extensively metabolized to methanol, bromide, and finally to CO2. After oral or inhalation exposure in rats, 85% was eliminated within 65–72 h. Most (30–50%) was recovered as expired CO2 and 4–20% as expired parent compound. About 16–40% was recovered in the urine and a small percentage was eliminated in the feces. Extensive enterohepatic circulation is possible. Tissue half-lives of methyl bromide range from 0.5 to 8 h.

9.5.1 Methyl Bromide

Methyl bromide is a colorless, nonflammable, low boiling point chemical with high vapor pressure (227 kPa at 25°C) and reasonable water solubility (13.4 g/l) (Yates et al., 1996). It is often applied by shank injection as a liquid (from pressurized cylinder), which quickly vaporizes and diffuses in soil. Without tarps, as much as 21–87% of the applied MeBr can be released to the atmosphere (Yagi et al., 1993, 1995; Yates et al., 1997). The Henry’s law (KH) constant for MeBr is 0.24 at 20°C (Table 9.1). The adsorption coefficient (Kd) in different soil types is negligible but could increase to 0.20 in soils with high organic matter content (e.g., potting mix). The predominant mechanism that induces the spreading of MeBr through the soil profile is vapor diffusion (Goring, 1962; Kolbezen et al., 1974; Reible, 1994). After injection, which may involve a short period where pressure-driven flow dominates, liquid MeBr vaporizes and moves throughout the soil in response to the phase-change expansion and the initially high gradients near the injection points.

Degradation of MeBr is mainly via chemical hydrolysis and methylation through a SN2 nucleophilic substitution with water and nucleophilic sites on soil OM as indicated in Eqs. 3 and 4 (Gan et al., 1994). Bacteria have also been implicated by the oxidation of MeBr (Miller et al., 1997; Oremland et al., 1994; Ou et al., 1997; Rasche et al., 1990). This reaction is catalyzed by monooxygenase (Dungan and Yates, 2003):

(5)CH3Br+1/2O2→H2CO+H++Br-

Rasche et al. (1990) found that two soil ammonia-oxidizing nitrifiers, Nitrosomonas europaea and Nitrosolobus multiformis, consumed MeBr only in the presence of ammonium chloride. Inhibition of biodegradation by allylthiourea and acetylene, specific inhibitors of the ammonia monooxygenase, suggests that the enzyme catalyzed MeBr degradation. Oremland et al. (1994) showed that a methanotrophic bacterium, Methyloccus capsulatus, was also capable of co-oxidizing MeBr when incubated in the presence of methane. Methyl bromide did not support growth of the methanotroph. Miller et al. (1997), however, isolated a gram-negative aerobic bacterium that was able to utilize MeBr as a sole carbon and energy source. Detailed information about MeBr degradation can be found in Dungan and Yates (2003).

For pre-plant soil fumigation, mechanized shank injection is the predominant application method (Yates et al., 2003). Tarping with either high- or low-density films (HDPE or LDPE) following fumigant injection is often used to retain fumigants for good efficacy and to reduce emissions. Deep injection (45 cm or deeper) with tarps is required under newly adopted environmental regulations (CDPR, 2008). Shank spacing varies from 25 cm to 2 m depending on injection depth that considers movement of MeBr in the soil profile. MeBr is often applied with a small amount of CP (e.g., 98:2 MeBr/CP). Application rates range from 240 to 480 kg/ha (United Nations Environment Programmes, 1995). Lower rates can be used for tarped treatments.

METHYL BROMIDE (CAS 74-83-9)

Methyl bromide is a colorless and odorless liquid that quickly volatilizes. The gaseous form is heavier than air. It is used for pest control in agriculture and home fumigation. A lacrimating agent, chlorpicrin, is usually added to provide some warning of exposure. Methyl bromide has a TLV of 5 ppm, and the concentration which is immediately dangerous to life and health (IDLH) is 2000 ppm. Aside from use as a fumigant, this chemical has also been used in the past in fire extinguishers. The primary route of exposure is by inhalation, although dermal absorption may also result in significant morbidity.

Methyl bromide is a severe vesicant. Dermal exposure to the gas can result in severe blistering of the skin. It can irritate the mucosa of the oropharynx; coughing may be sufficiently intense to produce post-tussive emesis. The central nervous system is the most profoundly affected in cases of methyl bromide poisoning. Early neurologic symptoms of an acute exposure may vary from tremors, headache, ataxia, blurred or double vision, and vertigo to grand mal seizure, status epilepticus, and coma. The onset of symptoms after an acute exposure may be delayed up to 24 hours. Both acute and chronic exposures may result in psychosis, hallucinations, or delirium.21 Chronic exposures of methyl bromide are associated with extremity paresthesia, hearing or vision loss, balance disturbances, and syncopal episodes. One study found symmetric midbrain and cerebellar lesions on magnetic resonance imaging of a 30-year-old man who worked in a warehouse that was regularly fumigated with methyl bromide. His presenting complaints were foot paresthesia and a gait disturbance.22

Exposures to methyl bromide occur under a variety of circumstances. Some cases are the result of fumigators who did not follow proper procedures or had faulty protective equipment. Other reports involve use of the chemical in an area that had previously unknown venting sources. Underground sewer pipes and other similar conduits have been implicated in several deaths. In Norway, a newborn infant was killed when the methyl bromide that was used to fumigate a house in another part of the housing subdivision leaked into the victim's home through the sewer pipes.23 In the United States, there is a case report of a 36-year-old woman who died from methyl bromide exposure. This woman lived in a guesthouse that was connected to the main house by eight hidden conduit pipes of which the property owner was unaware. Aside from these abandoned pipes, the guesthouse was not structurally connected to the main house. The property owner had the main house fumigated with methyl bromide, and that evening, the woman told friends she felt ill. The next morning, she was found in status epilepticus, which persisted despite multiple anticonvulsants and being placed on a pentobarbital infusion. She remained in a persistent vegetative state until she died 19 days after fumigation. At autopsy, the heart showed areas of edema and hemorrhage, the lungs had severe edema with infiltrates of neutrophils and macrophages, the liver had areas of centrilobular necrosis, and the brain had bilateral hippocampal necrosis which was thought to be consistent with status epilepticus and anoxia. All tested tissue samples, blood, bile, liver, and adipose tissue had detectable levels of methyl bromide.24

Several mechanisms have been postulated for the severity of the neurotoxic effects of methyl bromide. Its overall toxicity is believed to be the result of alkylation of sulfhydryl groups of numerous enzymes involved in routine physiologic functioning. Methyl bromide is metabolized into methyl glutathione by the enzyme glutathione transferase. The methyl glutathione is then converted into the neurotoxic metabolites of methanethiol and formaldehyde. Animal studies have shown that those species with decreased glutathione stores manifest lesser neurotoxic effects when exposed to methyl bromide.25 This may be one of the few instances when treatment with N-acetylcysteine may be detrimental.

Treatment of methyl bromide exposure consists of thorough decontamination and supportive care. Seizures should be treated aggressively with anticonvulsants, benzodiazepines, and barbiturates if needed. Although it is possible to obtain blood and urine methyl bromide levels, these assays are not routinely used and have little bearing on the management of the patient. Serum bromide levels may be used as a marker for exposure. Methyl bromide is not listed as a possible carcinogen.

Under the Clean Air Act passed in 1993, methyl bromide was declared to be an ozone-depleting agent. Therefore, manufacture and importation of this substance was set to be phased out by 2001. However, in 2003, the EPA announced the phase-out would not be completed until 2005. Methyl bromide may still be used under a critical use exemption as alternative fumigants are still being investigated. Unfortunately, methyl bromide has been an effective agricultural fumigant for more than 30 years, and some of its uses have no good alternative treatments at this time. It is expected that total cessation of methyl bromide use will be met with some resistance, and the phase-out is expected to take longer than expected.26

11.4.2 Pesticides Exhibiting Genotoxicity with Limited or No Evidence of Carcinogenicity

In-transit Shipboard Fumigation

Methyl bromide is rarely, if ever, used for this type of fumigation. The weight of the gas makes it difficult to remove it from a ship's hold, and the duration of the treatment is the duration of the voyage, which can be up to a month or more. During long voyages, the methyl bromide is usually sorbed in the commodity, particularly if it is grain in bulk. This can result in unacceptable residues. The methodology of this fumigation treatment has been largely limited to bulk grain fumigation with hydrogen phosphide (phosphine).