TOXICOLOGICAL PROFILE FOR
 

BROMOMETHANE
 

Agency for Toxic Substances and Disease Registry 

U.S. Public Health Service 

September 1992 
ii 

DISCLAIMER 

The use of company or product name(s) is for identification only and 

does not imply endorsement by the Agency for Toxic Substances and Disease 

Registry. 










1
 

1. PUBLIC HEALTH STATEMENT 

This Statement was prepared to give you information about bromomethane 

and to emphasize the human health effects that may result from exposure to it. 

The Environmental Protection Agency (EPA) has identified 1,177 sites on its 

National Priorities List (NPL). Bromomethane has been found in at least 12 of 

these sites. However, we do not know how many of the 1,177 NPL sites have 

been evaluated for bromomethane. As EPA evaluates more sites, the number of 

sites at which bromomethane is found may change. This information is 

important for you to know because bromomethane may cause harmful health 

effects and because these sites are potential or actual sources of human 

exposure to bromomethane. 

When a chemical is released from a large area, such as an industrial 

plant, or from a container, such as a drum or bottle, it enters the 

environment as a chemical emission. This emission, which is also called a 

release, does not always lead to exposure. You can be exposed to a chemical 

only when you come into contact with the chemical. You may be exposed to it 

in the environment by breathing, eating, or drinking substances containing the 

chemical or from skin contact with it. 

If you are exposed to a hazardous chemical such as bromomethane, several 

factors will determine whether harmful health effects will occur and what the 

type and severity of those health effects will be. These factors include the 

dose (how much), the duration (how long), the route or pathway by which you 

are exposed (breathing, eating, drinking, or skin contact), the other chemicals 

to which you are exposed, and your individual characteristics such as 

age, sex, nutritional status, family traits, life style, and state of health. 

1.1 WHAT IS BROMOMETHANE?
 

Bromomethane (also called methyl bromide) is a colorless gas without 

much smell. Some bromomethane is formed in the ocean, probably by algae or 

kelp. However, most is made by humans to kill various pests (rats, insects, 

fungus, etc.) that might be present in homes, foods, or soil. Some 

bromomethane is also used to make other chemicals. 

Bromomethane is usually stored in sealed containers to keep it from 

evaporating. If leaking containers of bromomethane are put in a waste site, 

most of the bromomethane will probably escape into the air. Small amounts 

might leak into the soil or pass through the soil and dissolve in underground 

water. Bromomethane has been found in underground water at two hazardous 

waste sites on the NPL. 

Bromomethane breaks down in the environment to other chemicals. In air, 

it usually takes about 11 months for half the bromomethane that was released 

to disappear. In underground water, it usually takes about 1 month for half 

the bromomethane to break down. 

More information on the properties and use of bromomethane and how it 

behaves in the environment may be found in Chapters 3, 4, and 5. 
2
 

1. PUBLIC HEALTH STATEMENT 

1.2 HOW MIGHT I BE EXPOSED TO BROMOMETHANE?
 

Because bromomethane is a gas, you are most likely to be exposed by 

breathing it in air. In most places around the world, levels in air are 

usually less than 0.025 parts of bromomethane per billion parts of air (ppb). 

Some cities have higher levels (up to about l-2 ppb) because of releases from 

chemical factories and automobile exhausts. You will probably not be exposed 

to high levels unless you are near a place where bromomethane is being used 

for fumigation. Workers who fumigate homes or fields may be exposed to very 

high levels if proper safety precautions are not followed. Because 

bromomethane evaporates so quickly, it is usually not found in food, surface 

water, or soil. 

More information on how you might be exposed to bromomethane is given in 

Chapter 5. 

1.3 HOW CAN BROMOMETHANE ENTER AND LEAVE MY BODY?
 

If bromomethane is present at a waste site, you are most likely to be 

exposed to it by breathing the vapors in contaminated air. You might also be 

exposed by drinking water from contaminated wells, although this is less 

likely. If you breathe in bromomethane, about half of it will pass through 

your lungs and enter your blood. Studies in animals suggest that if you 

swallow bromomethane in water, nearly all of it will pass through your stomach 

or intestines and enter your body. Bromomethane that enters your body either 

from your lungs or stomach is quickly spread throughout your body by your 

blood. Most bromomethane in your body is broken down into other chemicals, 

and these chemicals leave your body in the urine or in the air you breathe 

out. This usually begins happening within minutes, and is usually nearly 

complete within several days. We do not know how much bromomethane can enter 

your body through the skin, but the amount is probably small. 

More information on how bromomethane enters and leaves your body is 

given in Chapter 2. 

1.4 HOW CAN BROMOMETHANE AFFECT MY HEALTH?
 

If you breathe bromomethane, you may develop a headache and begin to 

feel weak and nauseated several hours later. If you breathe a large amount, 

fluid may build up in your lungs and it may be hard to breathe. You may have 

muscle tremors, and sometimes even seizures. Your kidneys may also be 

injured, and urine production may slow or stop. In severe cases, these 

effects can lead to death. In less serious cases, most of these effects 

usually disappear after several weeks, but some of the effects may never go 

away. 

Studies in animals suggest that if you swallow bromomethane, you might 

experience stomach irritation but would probably not experience lung, kidney, 

or brain injury. Bromomethane that gets on your skin can cause itching, 

redness, and blisters. 
3
 

1. PUBLIC HEALTH STATEMENT 

Studies in animals also suggest that bromomethane does not cause birth 

defects and does not interfere with normal reproduction except at high 

exposure levels. Animals that breathed bromomethane for 2 years did not 

develop cancer. Animals that swallowed bromomethane for 25 weeks had changes 

in their stomachs that could have been an early sign of cancer, but we do not 

know if swallowing bromomethane for a longer time would cause cancer. Both 

the International Agency for Research on Cancer and the EPA have determined 

that bromomethane is not classifiable as to its carcinogenicity in humans. 

More information on the health effects of bromomethane in humans and 

animals can be found in Chapter 2. 

1.5 	IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN


 EXPOSED TO BROMOMETHANE?
 

Several tests are available to tell whether you have been exposed to 

bromomethane, but ‘each has limitations. The most direct test measures 

bromomethane in your blood or in the air you breathe out. However, this test 

is not usually used because most bromomethane does not stay in the body very 

long (see Section 1.3) and special measuring equipment is needed. More often, 

the main breakdown product of bromomethane (bromide) is measured in blood 

samples. Bromide is normally present in the blood of all people, but the 

levels of bromide increase when people are exposed to bromomethane. The 

amount of increase depends on the level of exposure. Tests for bromide are 

only useful if done within 1-2 days following exposure, and are not very 

helpful in predicting if exposed persons will have health effects or how 

serious the effects will be, because not all people respond to bromomethane 

the same way. 

More information on how bromomethane can be measured in exposed humans 

is presented in Chapters 2 and 6. 

1.6	 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN
 

HEALTH?
 

Concentrated bromomethane can be very dangerous, so the EPA allows only 

licensed professional fumigators to buy or use bromomethane. The government 

does not have any regulations at present about how much bromomethane can be 

present in outdoor air or water, but EPA requires water companies to test for 

this chemical in their water. The Food and Drug Administration (FDA) has set 

limits of 125-400 parts of bromide per million parts of food (ppm) for how 

much bromide may remain in food after the food is treated with bromomethane. 

The Occupational Safety and Health Agency (OSHA) limits the average level of 

bromomethane in workplace air to 5 ppm, and recommends that exposures be 

reduced to the lowest level feasible. 

More information on government rules regarding bromomethane can be found 

in Chapter 7. 
4 

1. PUBLIC HEALTH STATEMENT 

1.7 WHERE CAN I GET MORE INFORMATION?
 

If you have any more questions or concerns not covered here, please 

contact your state health or environmental department or: 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology 

1600 Clifton Road, E-29 

Atlanta, Georgia '30333 

This agency can also provide you with information on the location of the 

nearest occupational and environmental health clinic. Such clinics specialize 

in recognizing, evaluating, and treating illnesses that result from exposure 

to hazardous substances. 
5 

2. HEALTH EFFECTS
 

2.1 INTRODUCTION
 

The primary purpose of this chapter is to provide public health 

officials, physicians, toxicologists, and other interested individuals and 

groups with an overall perspective of the toxicology of bromomethane and a 

depiction of significant exposure levels associated with various adverse 

health effects. It contains descriptions and evaluations of studies and 

presents levels of significant exposure for bromomethane based on 

toxicological studies and epidemiological investigations. 

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
 

To help public health professionals address the needs of persons living 

or working near hazardous waste sites, the information in this section is 

organized first by route of exposure--inhalation, oral, and dermal--and then 

by health effect--death, systemic, immunological, neurological, developmental, 

reproductive, genotoxic, and carcinogenic effects. These data are discussed 

in terms of three exposure periods--acute (14 days or less), intermediate 

(15-364 days), and chronic (365 days or more). 

Levels of significant exposure for each route and duration are presented 

in tables and illustrated in figures. The points in the figures showing 

no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect 

levels (LOAELs) reflect the actual doses (levels of exposure) used in the 

studies. LOAELs have been classified into "less serious" or "serious" 

effects. These distinctions are intended to help the users of the document 

identify the levels of exposure at which adverse health effects start to 

appear. They should also help to determine whether or not the effects vary 

with dose and/or duration, and place into perspective the possible 

significance of these effects to human health. 

The significance of the exposure levels shown in the tables and figures 

may differ depending on the user's perspective. For example, physicians 

concerned with the interpretation of clinical findings in exposed persons may 

be interested in levels of exposure associated with "serious" effects. Public 

health officials and project managers concerned with appropriate actions to 

take at hazardous waste sites may want information on levels of exposure 

associated with more subtle effects in humans or animals (LOAEL) or exposure 

levels below which no adverse effects (NOAEL) have been observed. Estimates 

of levels posing minimal risk to humans (Minimal Risk Levels, MRLs) may be of 

interest to health professionals and citizens alike. 

Estimates of exposure levels posing minimal risk to humans (MRLs) have 

been made, where data were believed reliable, for the most sensitive noncancer 

effect for each exposure duration. MRLs include adjustments to reflect human 

variability from laboratory animal data to humans. 
6 

2. HEALTH EFFECTS 

Although methods have been established to derive these levels (Barnes 

et al. 1988; EPA 1989d), uncertainties are associated with these techniques. 

Furthermore, ATSDR acknowledges additional uncertainties inherent in the 

application of the procedures to derive less than lifetime MRLs. As an 

example, acute inhalation MRLs may not be protective for health effects that 

are delayed in development or are acquired following repeated acute insults, 

such as hypersensitivity reactions, asthma, or chronic bronchitis. As these 

kinds of health effects data become available and methods to assess levels of 

significant human exposure improve, these MRLs will be revised. 

2.2.1 Inhalation Exposure
 

Bromomethane exists as a gas under ordinary temperature and pressure, so 

most studies of bromomethane toxicity have focused on the inhalation route of 

exposure. Studies with reliable quantitative exposure-response information 

are summarized in Table 2-l and Figure 2-1, and the adverse effects of 

inhalation exposure are discussed below. 

2.2.1.1 Death
 

There are many reports of humans who have died following acute 

inhalation exposure to bromomethane. Most cases have involved accidental 

exposures associated with manufacturing or packaging operations, use of fire 

extinguishers containing bromomethane, or fumigation activities (Alexeeff and 

Kilgore 1983). Death is not immediate, but usually occurs within l-2 days of 

exposure (Marraccini et al. 1983; Prain and Smith 1952). The cause of death 

is not certain, but is probably due to neurological and lung injury. Fatal 

exposure levels in humans are usually not known, but limited data suggest the 

value depends in part on exposure duration. For example, lethality has been 

reported in humans following exposure to 60,000 ppm for 2 hours (Wyers 1945) 

and 1,600-8,000 ppm for 4-6 hours (Holling and Clarke 1944; Miller 1943). 

Studies in animals indicate that acute exposures to levels of 

160-980 ppm may be lethal (Alexeeff et al. 1985; Eustis et al. 1988; Honma 

et al. 1985; Hurtt et al. 1987a; Irish et al. 1940; Kato et al. 1986). 

Several studies reveal there is an extremely narrow margin between lethal and 

nonlethal exposures. For example, Kato et al. (1986) found no deaths in rats 

exposed to 700 ppm for 4 hours, but 100% lethality in animals exposed to 

800 ppm. Similarly, Irish et al. (1940) found 100% survival in rats exposed 

to 100 ppm for 24 hours, and 100% lethality at 220 ppm. Longer-term exposures 

of animals can lead to death after exposure to levels as low as 66-120 ppm 

(Drew 1984; Haber 1987; Hardin et al. 1981; Irish et al. 1940; Reuzel et al. 

1987). 

The highest NOAEL values and all reliable LOAEL values for lethality in 

each species and duration category are recorded in Table 2-l and plotted in 

Figure 2-l. 













20
 

2.HEALTH EFFECTS 

2.2.1.2 Systemic Effects
 

No studies were located regarding musculoskeletal effects on humans or 

animals after inhalation exposure to bromomethane. Information on other 

systemic effects is presented below. The highest NOAEL values and all 

reliable LOAEL values for systemic effects in each species and duration 

category are recorded in Table 2-l and plotted in Figure 2-l. 

Respiratory Effects. Studies in humans indicate that the lung may be 

severely injured by inhalation exposure to bromomethane. Edema is the most 

common effect, and is often accompanied by focal hemorrhagic lesions 

(Greenberg 1971; Marraccini et al. 1983; Miller 1943; Prain and Smith 1952; 

Wyers 1945). This injury can severely impair respiratory function and lead to 

hypoxia, cyanosis, and complete respiratory failure (Greenberg 1971; Hine 

1969; O'Neal 1987). Similar edematous and hemorrhagic lesions are seen in 

lungs of several rodent species exposed to bromomethane (Irish et al. 1940; 

Kato et al. 1986; Reuzel et al. 1987; Sato et al. 1985) and severe damage can 

also occur to the nasal epithelium (Eustis et al. 1988; Hurtt et al. 1987a, 

1988a). As shown in Table 2-l and Figure 2-1, these effects occur mainly at 

acute exposure levels of 100 ppm or higher, but may occur at levels of 

3-10 ppm if exposure duration is extended (Reuzel et al. 1987; Sato et al. 

1985). 

Cardiovascular Effects. No studies were located regarding 

cardiovascular effects in humans after inhalation exposure to bromomethane, 

but several studies in mice and rats indicate that the heart is susceptible to 

injury. Effects which have been repor.ted at exposure levels of 90-160 ppm 

include cardiomyopathy (Eustis et al. 1988), myocardial degeneration and 

cardiac thrombi (Reuzel et al. 1987) and fibrosis (Kato et al. 1988). 

Gastrointestinal Effects. No studies were located regarding 

gastrointestinal effects in humans after inhalation exposure to bromomethane. 

Gastrointestinal effects have not been noted in most animal studies, but 

Alexeeff et al. (1985) reported an unusual increase in hemorrhagic lesions of 

the colon in mice exposed to high concentrations (1,490 ppm) of bromomethane, 

and Reuzel et al. (1987) noted an increased incidence of hyperkeratosis of the 

esophagus and stomach in rats exposed to 90 ppm. This effect is probably 

mediated by transport of bromomethane from the lungs to the throat by 

mucociliary clearance (Reuzel et al. 1987). 

Hematological Effects. Hematological effects have not been observed in 

humans exposed to bromomethane (Johnstone 1945; Kantarjian and Shasheen 1963; 

Longley and Jones 1965; O'Neal 1987; Viner 1945; Wyers 1945). In animals, 

decreased red and white blood cell counts were noted in one study of rats 

exposed to 160 ppm (Eustis et al. 1988), but hematological effects were not 

detected by others (Drew 1984; Haber 1987; Kato et al. 1986; Reuzel et al. 

1987). These studies indicate that blood and blood-forming cells are not 

important target tissues for bromomethane. 
21
 

2.HEALTH EFFECTS 

Hepatic Effects. Case reports of humans exposed to bromomethane vapors 

indicate the liver may become swollen and tender in some cases (Hine 1969; 

O'Neal 1987; Miller 1943; Prain and Smith 1952), but often no significant 

liver injury is detected (Greenberg 1971; Hine 1969; Marraccini et al. 1983). 

Similar results have been reported in animals, with mild signs of liver injury 

(edema, focal hemorrhages, minimal necrosis) being noted in some studies at 

levels of 150-600 ppm (Alexeeff et al. 1985; Eustis et al. 1988; Hurtt et al. 

1987a; Kato et al. 1986), with no significant injury at levels of 66 ppm 

(Irish et al. 1940). 

Renal Effects. Adverse renal effects are often reported in humans 

exposed to high levels of bromomethane vapor. Common effects include 

congestion, anuria or oliguria, and proteinuria (Hine 1969; Marraccini et al. 

1983; O'Neal 1987; Prain and Smith 1952; Viner 1945; Wyers 1945). However, 

there are many cases where renal effects are minimal or absent (Hine 1969; 

Johnstone 1945; Longley and Jones 1965). Similar signs of renal injury have 

been reported in several animal studies, including swelling, edema, nephrosis, 

and tubular necrosis (Alexeeff et al. 1985; Eustis et al. 1988). 

Dermal/Ocular Effects. Bromomethane vapor is irritating to the skin and 

eyes, and humans who are exposed to bromomethane in air may experience 

conjunctivitis, erythema, rashes, or even blisters (Marraccini et al. 1983; 

O'Neal 1987; Wyers 1945). The effects of direct dermal or ocular contact with 

bromomethane vapors are discussed more fully in Section 2.2.3.2. No studies 

were located regarding dermal or ocular effects following systemic absorption 

of bromomethane in animals or humans. 

2.2.1.3 Immunological Effects
 

No studies were located regarding immunological effects in humans or 

animals after inhalation exposure to bromomethane. 

2.2.1.4 Neurological Effects
 

Inhalation exposure to bromomethane frequently leads to a spectrum of 

neurological effects in humans. Initial symptoms typically include headache, 

nausea, confusion, weakness, numbness, and visual disturbances (Anger et al. 

1986; Hine 1969; Kantarjian and Shasheen 1963; Marraccini et al. 1983; O'Neal 

1987; Rathus and Landy 1961; Watrous 1942). In severe cases, these effects 

may progress to ataxia, tremor, seizures, paralysis, and coma (Behrens and 

Dukes 1986; Greenberg 1971; Longley and Jones 1965; Marraccini et al, 1983; 

O'Neal 1987; Prain and Smith 1952; Prockop and Smith 1986; Rathus and Landy 

1961; Viner 1945; Wyers 1945). In most cases of acute exposure, the effects 

do not occur immediately, but develop after a lag of several hours (Clarke 

et al. 1945). If death does not ensue, symptoms usually decrease in severity 

over the course of several weeks to several months, although frequently they 

do not disappear completely (Chavez et al. 1985; Greenberg 1971; Hine 1969; 

Johnstone 1945; Kantarjian and Shasheen 1963; Longley and Jones 1965; Prockop 

and Smith 1986). 
22
 

2.HEALTH EFFECTS
 

Quantitative data on the exposure levels leading to neurological effects 

in humans are limited. Early studies indicated that workplace exposure to 

concentrations of 100 ppm or even less for 1-2 weeks could lead to headache, 

nausea, numbness, and ataxia (Johnstone 1945; Watrous 1942). Longer-term 

exposure (8 years) to average levels of 2.3 ppm are suspected to be the cause 

of an increased incidence of neurological symptoms (muscle ache, .fatigue, 

ataxia) in a group of fumigators who used bromomethane (Anger et al. 1986). 

Based on this value, a chronic inhalation MRL of 0.005 ppm was calculated, as 

described in footnote "d" of Table 2-1. 

Inhalation studies in animals confirm that the central nervous system is 

injured by inhalation exposure to bromomethane. Clinical effects that have 

been detected include tremors, ataxia, paralysis, and seizures (Alexeeff 

et al. 1985; Anger et al. 1981; Breslin et al. 1990; Drew 1984; Haber 1987; 

Hurtt et al. 1987a; Irish et al. 1940; Kato et al. 1986). Histological 

lesions in the brain (focal necrosis and hemorrhage) have also been detected 

(Alexeeff et al. 1985; Eustis et al. 1988; Hurtt et al. 1987a). As shown in 

Table 2-l and Figure 2-1, neurological effects are typically observed at 

exposure levels ranging between 80 and 1,000 ppm, although longer-term 

(6 month to 2 year) exposure of rabbits, monkeys, or mice has led to 

functional neurological impairment at concentrations of 33-66 ppm (Haber 1987; 

Irish et al. 1940). As in humans, these effects tend to be at least partly 

reversible when exposure ceases (Irish et al. 1940). 

The most sensitive indicator of neurological effects in animals appears 

to be alterations in the levels of neurotransmitters in the brain. In rats 

exposed to bromomethane for 8 hours, there was a significant decrease in the 

hypothalamic concentration of norepinephrine and a decrease in the activity of 

tyrosine hydroxylase at an exposure level of 31 ppm, but not at 16 ppm (Honma 

1987). Based on this value (16 ppm), an acute inhalation MRL value of 

0.05 ppm was calculated as described in footnote "b" of Table 2-1. When 

exposure duration was extended to 3 weeks (24 hours/day), dramatic decreases 

in norepinephrine and 5-hydroxytryptamine were detected at exposure levels of 

10 ppm but not at 5 ppm (Honma et al. 1982). Based on this value (5 ppm), an 

intermediate inhalation MRL of 0.05 ppm was calculated as described in 

footnote "c" of Table 2-1. 

2.2.1.5 Developmental Effects
 

No studies were located regarding developmental effects in humans after 

inhalation exposure to bromomethane. Several studies in rats and rabbits 

indicate that inhalation exposure to levels up to 70 ppm during gestation does 

not result in any significant developmental effects, even when there is severe 

maternal toxicity (Hardin et al. 1981; Sikov et al. 1980). However, an 

increased incidence of anomalies.and malformations was observed in offspring 

from rabbits exposed to 80 ppm during gestation (Breslin et al. 1990), and 

decreased pup weights were noted in a multigeneration study in rats exposed to 

30 ppm (Enloe et al. 1986). The NOAEL and LOAEL values are recorded in 

Table 2-1 and plotted in Figure 2-l. 
23 

2. HEALTH EFFECTS 

2.2.1.6 Reproductive Effects
 

No studies were located regarding reproductive effects in humans after 

inhalation exposure to bromomethane. In male animals, effects on the testes 

(delayed spermiation, tubular degeneration, atrophy) have been observed in 

rats and mice exposed to 160-405 ppm for 1-6 weeks (Eustis et al. 1988; Hurtt 

et al. 1987a; Kato et al. 1988) or 120 ppm for 13 weeks (Drew 1984). However, 

exposure of male rats to 70 ppm for 5 days did not interfere with normal 

reproductive function and impregnation success (McGregor 1981). No effects on* 

reproductive function in females have been observed in rats or rabbits exposed 

to levels up to 70 ppm before and during gestation (Sikov et al. 1980), even 

though these levels produce maternal toxicity. The highest NOAEL values and 

all reliable LOAEL values for reproductive effects in each species and 

duration category are recorded in Table 2-l and plotted in Figure 2-l. 

2.2.1.7 Genotoxic Effects
 

No studies were located regarding genotoxic effects in humans after 

inhalation exposure to bromomethane. In animals, the frequency of bone marrow 

cells with chromosomal aberrations was not increased in rats exposed to 70 ppm 

for 5 days (McGregor 1981), but was increased several-fold in rats exposed to 

140 ppm for 14 days (Ikawa et al. 1986). Djalali-Behzad et al. (1981) found 

that inhalation exposure of mice to bromomethane for 4 hours led to alkylation 

of DNA in liver and spleen, although the levels were quite low. In contrast 

to these positive findings, no genotoxic effects could be detected in sperm 

from rats or mice exposed to 70 ppm bromomethane for 5 days, using either the 

dominant lethal or recessive lethal tests, or by direct examination of the 

sperm (McGregor 1981). These studies indicate that bromomethane does have 

genotoxic potential, but that effects may be minimal and difficult to measure 

following brief or low dose exposure. Other genotoxicity studies are 

discussed in Section 2.4. 

2.2.1.8 Cancer
 

The carcinogenic potential of bromomethane has not been formally 

investigated in epidemiological studies of occupationally-exposed workers. 

Wong et al. (1984) studied the incidence of cancer in a cohort of workers 

exposed to a wide variety of brominated chemicals, and noted that two men who 

died of testicular cancer had both been exposed to bromomethane. However, 

since there are numerous risk factors for testicular cancer, and since the 

workers may have been exposed to other chemicals, this observation is not 

sufficient to indicate that bromomethane is carcinogenic. No evidence of 

carcinogenic effects was detected in mice exposed to 33 ppm for 2 years (Yang 

1990), or in rats exposed to 90 ppm for 29 months (Reuzel et al. 1987). 

2.2.2 Oral Exposure
 

Because bromomethane is a gas under ordinary conditions, the oral 

toxicity of this compound has not been thoroughly studied. No information was 

located regarding health effects in humans after oral exposure to 
24 

2. HEALTH EFFECTS 

bromomethane. Available data from oral studies in animals are summarized in 

Table 2-2 and Figure 2-2, and this information is discussed below. 

2.2.2.1 Death
 

No studies were located regarding lethality in humans or animals after 

oral exposure to bromomethane. 

2.2.2.2 Systemic Effects
 

No studies were located regarding cardiovascular, musculoskeletal, 

renal, or dermal/ocular effects in humans or animals after oral exposure to 

bromomethane. Information on other systemic effects is presented below. The 

highest NOAEL values and all reliable LOAEL values for these systemic effects 

are recorded in Table 2-2 and plotted in Figure 2-2. 

Respiratory Effects. No studies were located regarding respiratory 

effects in humans after oral exposure to bromomethane. In animals, no 

histological evidence of lung injury was detected in rats exposed to oral 

doses of 50 mg/kg/day for 13 weeks (Danse et al. 1984). Slight atelectasis 

was observed in some animals exposed to oral doses of 10 or 50 mg/kg/day, but 

this was judged to be due to inadvertent inhalation exposure that occurred 

during oral dosing (Danse et al. 1984). 

Gastrointestinal Effects. No studies were located regarding 

gastrointestinal effects in humans after oral exposure to bromomethane. 

Several studies in animals have shown that repeated (90-day) administration of 

concentrated solutions of bromomethane (40-5,000 mg/L, dissolved in oil) by 

gavage to rats can result in irritation and hyperplasia of the epithelium in 

the forestomach (Boorman et al. 1986; Danse et al. 1984). No effects were 

observed in animals administered 0.4 mg/kg/day (Danse et al. 1984). Mild 

focal hyperemia was detected at concentrations of 200 mg/L (equivalent to a 

dose of 2 mg/kg/day), with hyperplasia, hyperkeratosis, and fibrosis 

developing after repeated administration of 1,000 mg/L (equivalent to a dose 

of 10 mg/kg/day) or higher. Repeated doses of 5,000 mg/L (50 mg/kg/day) 

caused frank ulcerations of the forestomach. These lesions appear to be the 

result of a direct irritant effect of bromomethane on the epithelium. The 

epithelial hyperplasia regresses when exposure is stopped, although fibrotic 

lesions or adhesions which developed during exposure remain (Boorman et al. 

1986). The possible relationship between this hyperplastic response and 

cancer of the forestomach is discussed below in Section 2.2.2.8. 

Based on the data of Danse et al. (1984), it is judged that doses up to 

0.4 mg/kg/day do not produce significant adverse effects on the stomach, and 

this dose has been used to derive an intermediate oral MRL of 0.003 mg/kg/day 

as described in footnote "b" of Table 2-2. 


27
 

2. HEALTH EFFECTS 

Hematological Effects. No studies were located regarding hematological 

effects in humans after oral exposure to bromomethane. Slight anemia was 

observed in rats exposed to doses of 50 mg/kg/day for 13 weeks, but this was 

judged to be secondary to the pronounced lesions of the forestomach (Danse 

et al. 1984). No evidence of other hematological effects was detected at 

doses up to 10 mg/kg/day. 

Hepatic Effects. No studies were located regarding hepatic effects in 

humans after oral exposure to bromomethane. In animals, histological signs of 

liver damage were not detected in rats given doses up to 50 mg/kg/day for 

90 days (Danse et al. 1984). 

Other Systemic Effects. Rats exposed to oral doses of 50 mg/kg/day for 

90 days did not gain weight normally (Boorman et al. 1986; Danse et al. 1984). 

This effect was probably secondary to decreased food intake, and was not 

observed at doses up to 10 mg/kg/day (Danse et al. 1984). 

2.2.2.3 Immunological Effects
 

No studies were located regarding immunological effects in humans or 

animals after oral exposure to bromomethane. 

2.2.2.4 Neurological Effects
 

No studies were located regarding neurological effects in humans or 

animals after oral exposure to bromomethane. 

2.2.2.5 Developmental Effects
 

No studies were located regarding developmental effects in humans or 

animals after oral exposure to bromomethane. 

2.2.2.6 Reproductive Effects
 

No studies were located regarding reproductive effects in humans or 

animals after oral exposure to bromomethane. 

2.2.2.7 Genotoxic Effects
 

Genotoxicity studies are discussed in Section 2.4. 

2.2.2.8 Cancer
 

No studies were located regarding carcinogenic effects in humans after 

oral exposure to bromomethane. Danse et al. (1984) exposed rats by gavage to 

bromomethane (in oil) for 90 days, and observed a dose-dependent increase in 

the incidence of forestomach lesions which were interpreted as squamous cell 

carcinomas. However, histological diagnosis of epithelial carcinomas in the 

presence of marked hyperplasia is difficult (Wester and Kroes 1988). After 

reevaluation of the histological slides, a panel of scientists from the 
28 

2. HEALTH EFFECTS 

National Toxicology Program (NTP) concluded that there was no evidence of a 

neoplastic response in this study, but rather only hyperplasia and 

inflammation (IRIS 1989). This is consistent with the observation that the 

hyperplasia of the forestomach produced by 13 weeks of exposure to 

bromomethane regresses when exposure is ended (Boorman et al. 1986). However, 

longer-term (25 week) oral exposure of rats to 50 mg/kg/day of bromomethane 

led to a forestomach lesion in one rat (out of 15 exposed) that was judged to 

be a very early carcinoma. Although this observation is not adequate to draw 

firm conclusions, these data suggest that the initial hyperplasia produced by 

bromomethane may occasionally lead to neoplasia after sufficient time. 

2.2.3 Dermal Exposure
 

The effects of dermal contact with bromomethane have been described in 

numerous case reports of humans who were exposed either to liquid bromomethane 

(mainly from fire extinguishers) or bromomethane vapors (mainly during 

fumigation activities). These studies are discussed below. No studies were 

located regarding dermal exposure of animals to bromomethane. 

2.2.3.1 Death
 

No cases were located in which dermal exposure to bromomethane led to 

death in humans. 

2.2.3.2 Systemic Effects
 

Adverse effects on the respiratory system, cardiovascular system, 

gastrointestinal tract, blood, musculoskeletal system, liver, or kidneys have 

not been observed in humans exposed to bromomethane by the dermal route (e.g., 

Butler et al. 1945; Hine 1969; Wyers 1945; Zwaveling et al. 1987). 

Dermal/Ocular Effects. Direct dermal contact with bromomethane can lead 

to severe injury to the skin. Symptoms usually do not appear immediately, but 

develop a few hours after exposure. Early signs typically include a burning 

or itching sensation, with erythema, edema, and large blisters that resemble 

second-degree burns developing somewhat later (Butler et al. 1945; HezemansBoer et al. 1988; Watrous 1942; Wyers 1945). Injury is usually mild on 

exposed skin areas where rapid evaporation can occur and is more severe in 

moist or covered regions where evaporation is retarded (Watrous 1942; 

Zwaveling et al. 1987). Effects generally begin to subside within 5-10 days 

after exposure (Watrous 1942), and recovery is usually complete within about 

1 month (Butler et al. 1945; Zwaveling et al. 1987). 

The exposure levels leading to dermal effects of this sort are rarely 

known. Most cases involve people doused with liquid bromomethane (Longley and 

Jones 1965; Watrous 1942) or exposed to very high vapor levels (Hezemans-Boer 

et al. 1988; Zwaveling et al. 1987) (see Table 2-3). Numerous case reports of 

humans exposed to lower levels of bromomethane fumes did not include 

30 

2. HEALTH EFFECTS 

descriptions of dermal effects, even though the level of inhalation exposure 

caused profound or even fatal neurological or respiratory effects (e.g., 

Greenberg 1971; Hine 1989; Marraccini et al. 1983). 

No studies were located regarding the following effects in humans or 

animals after dermal exposure to bromomethane: 

2.2.3.3 Immunological Effects
 

2.2.3.4 Neurological Effects
 

2.2.3.5 Developmental Effects
 

2.2.3.6 Reproductive Effects
 

2.2.3.7 Genotoxic Effects
 

Genotoxicity studies are discussed in Section 2.4. 

2.2.3.8 Cancer
 

No studies were located regarding cancer in humans or animals after 

dermal exposure to bromomethane. 

2.3 TOXICOKINETICS
 

2.3.1 Absorption
 

2.3.1.1 Inhalation Exposure
 

No studies were located regarding the amount of bromomethane absorbed by 

humans during inhalation exposure. Several studies in rats indicate that the 

rate of bromomethane uptake across the lung is directly proportional to the 

concentration in air, 1.6 (kg hr)-1 with estimated rate constants ranging from 

0.32 to (Gargas and Andersen 1982; Medinsky et al. 1985). Fractional 

absorption appears to be about 50% at exposure levels up to around 180 ppm 

(Medinsky et al. 1985). At high levels (310 ppm), the total amount absorbed 

appears to reach a maximum (62 mg/kg), suggesting that some aspect of uptake 

(perhaps glutathione availability) becomes limiting (see Section 2.3.3). 

2.3.1.2 Oral Exposure
 

No studies were located regarding bromomethane absorption after oral 

exposure of humans. In rats given a single oral dose of 14C-labeled 

bromomethane dissolved in corn oil, only about 3% of the label was excreted in 

the feces (Medinsky et al. 1984). This indicates that at least 97% of the 

dose was absorbed from the gastrointestinal tract. 

2.3.1.3 Dermal Exposure
 

No quantitative studies were located regarding bromomethane absorption 

across the skin of humans or animals. 
31
 

2. HEALTH EFFECTS 

2.3.2 Distribution
 

2.3.2.1 Inhalation Exposure
 

No studies were located regarding bromomethane distribution in humans 

after inhalation exposure. In rats exposed to 14C-bromomethane in air, 

radioactive label was widely distributed throughout the body (Bond et al. 

1985; Jaskot et al. 1988; Medinsky et al. 1985). Levels were somewhat higher 

in lung, adrenal, liver, and kidney than in other tissues (Bond et al. 1985; 

Jaskot et al. 1988). The form of the label was not studied by these 

researchers, but is probably mostly metabolites. However, Honma et al. (1985) 

showed that low levels of parent bromomethane can be detected for up to 

24 hours after exposure. 

2.3.2.2 Oral Exposure
 

No studies were located regarding bromomethane distribution in humans 

after oral exposure. In rats given oral doses of 14C-bromomethane, label was 

distributed widely throughout the body, with highest levels in liver and 

kidney (Medinsky et al. 1984). 

2.3.2.3 Dermal Exposure
 

No studies were located on bromomethane distribution in humans or 

animals after dermal exposure. 

2.3.3 Metabolism
 

Bromomethane undergoes initial metabolism primarily by nucleophilic 

displacement of the bromide ion. When the attacking species is water, the 

products are methanol and bromide ion: 

HOH + CH3Br -> CH3OH + H+ + BrThe amount of bromomethane broken down by this reaction in the body is not 

known, but increased levels of both methanol and bromide have been detected in 

exposed animals (Gargas and Andersen 1982; Honma et al. 1985). Bromomethane 

may also react with organic thiols (R-SH) to yield S-methyl derivatives: 

R-SH + CH3

Br -> R-SCH3 + H+ + BrThis has been shown to result in formation of S-methylcysteine derivatives in 

hemoglobin of mice exposed to bromomethane (Iwasaki 1988b), and by analogy 

with methyl chloride (Kornburst and Bus 1983), is likely to result in 

formation of S-methyl glutathione (Medinsky et al. 1985). Further metabolism 

of methanol or S-methyl derivatives such as those mentioned above then leads 

to the formation of carbon dioxide (generally accounting for 40%-50% of the 

administered dose) and other unidentified nonvolatile metabolites (generally 

accounting for about 20%-25% of the dose) (Bond et al. 1985; Jaskot et al. 

1988; Medinsky et al. 1985). 
32
 

2. HEALTH EFFECTS 

2.3.4 Excretion
 

2.3.4.1 Inhalation Exposure
 

No studies were located regarding excretion of bromomethane in humans 

after inhalation exposure. In animals exposed to bromomethane vapors, 

excretion occurs mainly by expiration of carbon dioxide or by urinary 

excretion of nonvolatile metabolites (Bond et al. 1985; Jaskot et al. 1988; 

Medinsky et al. 1985). Only small amounts are excreted in the feces. Very 

little parent bromomethane is exhaled (Jaskot et al. 1988; Medinsky et al. 

1985), and tissue levels of parent bromomethane decrease with a half-life of 

only about 15-30 minutes (Honma et al. 1985; Jaskot et al. 1988). Half-lives 

for clearance of metabolites from the body and most tissues range from 2 to 

10 hours (Honma et al. 1985; Jaskot et al. 1988). 

A significant fraction (about 25%-30%) of 14C-label remains in tissues 

after 24-72 hours and is excreted more slowly (Jaskot et al. 1988; Medinsky 

et al. 1985). This slow excretion of label presumably represents turnover of 

various intracellular metabolites or adducts, although this has not been 

established. 

2.3.4.2 Oral Exposure
 

No studies were located regarding excretion of bromomethane by humans 

after oral exposure. One study in animals indicates that the rate and pattern 

of excretion of 14C-label following oral exposure to 14C-bromomethane is 

similar to that following inhalation exposure: 32% was exhaled as carbon 

dioxide, 43% was excreted in the urine, 4% of unmetabolized parent compound 

was exhaled, 2% was excreted in the feces, and 14% remained in the body after 

72 hours (Medinsky et al. 1984). 

2.3.4.3 Dermal Exposure
 

No studies were located regarding excretion of bromomethane by humans or 

animals after dermal exposure. 

2.4 RELEVANCE TO PUBLIC HEALTH
 

Bromomethane exists as a gas at ordinary temperatures, so the most 

likely route of human exposure is by inhalation. The hazard of this compound 

is increased by the fact that it has very little odor at potentially toxic 

levels (Alexeeff and Kilgore 1983), and effects on the body are generally 

delayed. Thus, people may be exposed to hazardous levels without being aware 

that the exposure is occurring. 

There are a number of studies that provide good quantitative doseresponse 

data by the inhalation route, and inhalation MRLs have been derived 

for acute, intermediate and chronic inhalation exposure. The acute value is 

based on a study in rats in which exposure to 31 ppm for 8 hours caused 

altered levels of brain neurotransmitters, while 16 ppm had no effect (Honma 
33
 

2. HEALTH EFFECTS
 

1987). The MRL of 0.05 ppm was obtained by adjusting the NOAEL (16 ppm) for 

less than continuous exposure (8 hour/day) and dividing by an uncertainty 

factor of 100 (10 for extrapolation from animals to humans, and 10 for human 

variability). The intermediate-duration inhalation MRL is based on a 3-week 

study in rats in which exposure to 10 ppm resulted in decreased brain 

neurotransmitters, while 5 ppm did not (Honma et al. 1982). The intermediate 

MRL of 0.05 ppm was derived from the NOAEL (5 ppm) by dividing by an 

uncertainty factor of 100, as described above. The chronic inhalation MRL is 

based on an epidemiological study of workers who had an increased prevalence 

of muscle ache, fatigue, and ataxia following chronic exposure to average 

levels of 2.3 ppm (Anger et al. 1986). The MRL was derived by adjusting this 

LOAEL (2.3 ppm) to account for noncontinuous exposure (8 hr/day, 5 days/week), 

and by dividing by an uncertainty factor of 100 (10 for use of a LOAEL, and 10 

for human variability). 

Because bromomethane tends to volatilize and exists mainly as a gas at 

room temperature, only two oral toxicity studies have been performed (Boorman 

et al. 1986; Danse et al. 1984). Both studies were performed by administering 

bromomethane dissolved in oil to rats and both studies reported that 

irritation of the stomach was the chief effect. The 13-week study by Danse 

et al. (1984) identified a NOAEL of 0.4 mg/kg/day and a LOAEL of 2 mg/kg/day. 

An intermediate-duration oral MRL of 0.003 mg/kg/day was derived from the 

NOAEL (0.4 mg/kg/day) by adjusting for intermittent exposure (5 days/week) and 

dividing by an uncertainty factor of 100 (10 for extrapolation from animals to 

humans, and 10 for human variability). 

No dermal MRLs have been derived for bromomethane due to the lack of an 

appropriate methodology for development of dermal MRLs. 

More detailed information on the adverse effects associated with 

exposure to bromomethane is presented below. 

Death. Many people have died following accidental inhalation exposure 

to high levels of bromomethane (Alexeeff and Kilgore 1983). The exposure 

levels leading to death in humans are not precisely defined, with estimates 

ranging from 1,600 to 60,000 ppm, depending on duration of exposure (Holling 

and Clarke 1944; Miller 1943; Wyers 1945). Lethal exposure levels in animals 

also depend on duration of exposure, with mortality occurring in rats and 

rabbits after 24 hours exposure to 220 ppm (Irish et al. 1940), or after 

2 weeks to 2 years exposure to 66-100 ppm (Drew 1984; Haber 1987; Hardin 

et al. 1981; Ikeda et al. 1980; Irish et al. 1940; Reuzel et al. 1987). 

Exposure to a lethal concentration of bromomethane is only likely to occur in 

the immediate vicinity of fumigation activities or a major spill, and is not 

of concern under normal circumstances. 

Systemic Effects. 

Respiratory Effects. Acute inhalation exposure of humans and animals to 

bromomethane can result in marked lung irritation (edema, hemorrhagic 

lesions), and this may lead to moderate to severe impairment of respiratory 
34 

2. HEALTH EFFECTS 

function (Greenberg 1971; O'Neal 1987; Prain and Smith 1952). Dose-response 

data are limited for humans, but the effect range in animals is usually 

lo-1,000 ppm (see Figure 2-l). Exposures to concentrations of bromomethane 

this high are not likely near waste sites unless a major spill or accident 

occurs. Oral exposure does not appear to result in lung injury (Danse et al. 

1984). 

Renal Effects. The kidney also is sensitive to bromomethane. Anuria 

and proteinuria are common signs of renal injury in acutely exposed humans 

(O'Neal 1987; Prain and Smith 1952; Viner 1945), but dose-response data are 

not available. In animals, nephrosis has been noted in rats and mice exposed 

to 160 ppm for 2-6 weeks (Eustis et al. 1988). 

Hepatic Effects. Mild effects (congestion, focal hemorrhages) are 

sometimes observed in liver and other tissues (O'Neal 1987; Prain and Smith 

1952; Wyers 1945), but these effects do not appear to be as significant as the 

respiratory and renal injury. 

Gastrointestinal Effects. Although data are limited, the only systemic 

tissue that has been found to be affected following oral exposure is the 

epithelium of the stomach (Boorman et al. 1986; Danse et al. 1984). This is 

presumably a result of direct contact between bromomethane and the 

gastrointestinal epi,thelium. Based on this effect, an intermediate-duration 

oral MRL of 0.003 mg/kg/day has been derived. It is likely that this effect 

(which has only been observed in animals dosed with concentrated solutions of 

bromomethane dissolved in oil) would be much less pronounced if exposure 

occurred via ingestion of more dilute solutions of bromomethane in water. 

However, this has not been studied. 

Dermal/Ocular Effects. Direct dermal contact with bromomethane can 

cause mild to severe skin lesions such as erythema, itching, and blisters 

(Butler et al. 1945; Hezemans-Boer et al. 1988; Watrous 1942). These lesions, 

which normally heal within 2-4 weeks after exposure, have only been noted 

after exposure to liquid bromomethane or very high concentrations of vapor, 

and are unlikely to occur in persons exposed to bromomethane in the 

environment. 

Immunological Effects. No studies were located regarding immunological 

effects in humans or animals after exposure to bromomethane. In the absence 

of any data, it is not possible to predict whether this is an effect of 

concern in exposed humans. 

Neurological Effects. Humans acutely exposed to high concentrations of 

bromomethane vapor nearly always experience injury to the central nervous 

system. Initial effects, which usually occur within a few hours of exposure, 

include headache, weakness, and nausea (Marraccini et al. 1983; Wyers 1945), 

and may also include blurred or double vision (Chavez et al. 1985; Johnstone 

1945). Depending on exposure level, these symptoms may progress into ataxia, 

tremors, and clonic seizures (Prain and Smith 1952; Prockop and Smith 1986). 

These effects typically begin to wane after several days, but recovery may not 
35 

2. HEALTH EFFECTS 

be complete even after many months (Longley and Jones 1965; Rathus and Landy 

1961). In rats, brain neurotransmitter levels were decreased following an 

acute exposure to 31 ppm (Honma 1987). Based on the NOAEL of 16 ppm 

identified by this study, an acute inhalation MRL of 0.05 ppm has been 

derived. 

Only limited information is available on the effects of long-term 

inhalation exposure of humans to low levels of bromomethane. Headache, 

weakness, and increased prevalence of neurological signs such as muscle ache, 

fatigue, dizziness, and ataxia have been noted in workers exposed for extended 

periods in the workplace (Anger et al. 1986; Hine 1989; Kantarjian and 

Shasheen 1963; Kishi et al. 1988). No cases of severe neurological effects 

from long-term exposure to low levels have been noted in humans, but 

intermediate or chronic inhalation exposure of animals to bromomethane vapor 

is known to result in moderate to severe neurological injury. Rabbits and 

monkeys appear to be the most sensitive species, with convulsions and 

paralysis occurring at exposure levels of 33-66 ppm for 6 months (Irish et al. 

1940). Continuous exposure to concentrations of 10 ppm decreased 

neurotransmitter levels in rats (Honma et al. 1982). Based on the NOAEL of 

5 ppm identified by this study, an intermediate inhalation MRL of 0.05 ppm has 

been derived. The chronic exposure level leading to neurological effects in 

humans is not known precisely, but Anger et al. (1986) reported mild effects 

in workers exposed to an average of about 2.3 ppm. Based on this, a chronic 

inhalation MRL of 0.005 ppm has been derived. 

No studies were located regarding neurological effects in humans or 

animals following oral exposure to bromomethane. Based on the clear 

neurological effects produced by inhalation exposure, it seems likely such 

effects would also be of concern following acute or repeated oral intake of 

adequate doses. 

The mechanism of bromomethane-induced neurotoxicity is not known. It is 

generally agreed that effects are not the result of metabolic breakdown 

products such as methanol or bromide, since neither the characteristic effects 

nor the dose dependency correspond to those of the metabolites (Clarke et al. 

1945; Honma et al. 1985). Rather, it is more likely that bromomethane acts by 

alkylating key cellular components such as enzymes (Lewis 1948; Rathus and 

Landy 1961). 

Developmental Effects. No studies were located regarding developmental 

effects in humans after exposure to bromomethane. Several studies of animals 

exposed to bromomethane vapors up to 70 ppm did not detect developmental 

effects, even though these concentration levels resulted in maternal toxicity 

(Hardin et al. 1981; Sikov et al. 1980). However, exposure of rabbits to 

80 ppm during gestation resulted in increased incidence of several 

developmental anomalies in the off-spring (Breslin et al. 1990). These data 

suggest bromomethane may cause developmental effects, but only at high doses 

where other effects would also be of concern. 
36 

2. HEALTH EFFECTS 

Reproductive Effects. No studies were located regarding reproductive 

effects in humans after exposure to bromomethane. Inhalation exposure of male 

rats to high levels of bromomethane (120-400 ppm) has resulted in decreased 

sperm production along with testicular degeneration and atrophy (Drew 1984; 

Eustis et al. 1988; Kato et al. 1986). However, exposures up to 70 ppm do 

not appear to interfere with reproductive functions in male (McGregor 1981) or 

female rats (Hardin et al. 1981; McGregor 1981; Sikov et al. 1980). It is 

difficult to judge from these data whether adverse reproductive effects are 

likely to occur in exposed humans, but it seems probable that the respiratory, 

neurological, and renal effects will normally be of greatest clinical concern. 

Genotoxic Effects. Bromomethane has produced positive results in a 

number of mutagenicity test systems, both in vitro (Table 2-4) and in vivo 

(Table 2-5). This effect does not appear to require metabolic activation, 

which is consistent with the fact the bromomethane is a direct-acting 

alkylating agent which can methylate DNA (Ikawa et al. 1986; Starratt and Bond 

1988). This property suggests that bromomethane might be carcinogenic, but 

this has not been established (see below). 

Carcinogenic Effects. No epidemiological studies were located on cancer 

incidence in humans exposed specifically to bromomethane. One study of 

workers exposed to a variety of brominated chemicals noted that bromomethane 

was the only common exposure of two men who died of testicular cancer (Wong 

et al. 1984). However, this does not establish that bromomethane was the 

causative agent. Chronic inhalation studies performed in mice and rats 

revealed no evidence of carcinogenic effects at exposure levels of 33-90 ppm 

(Reuzel et al. 1987; Yang 1990). Rats given daily oral doses of 50 mg/kg/day 

for 90 days developed inflammation and keratosis of the forestomach, along 

with lesions that were onginally interpreted as squamous carcinomas (Danse 

et al. 1984). However, reevaluation of the histological specimens by NTP 

scientists indicated that the forestomach lesions in this study were 

hyperplastic but not neoplastic. A subsequent study also found hyperplasia 

but no neoplasia in rat forestomach (Boorman et al. 1986) after 13 weeks of 

exposure. After 25 weeks, one animal developed a lesion that was judged to be 

a very early carcinoma. These results are too limited (both in number of 

animals and exposure duration) to draw firm conclusions, but in view of the 

alkylating ability and positive mutagenicity finding for this chemical, it 

seems possible that longer-term exposure might lead to measurable increases in 

tumor frequency, EPA considers that the data currently available are 

inadequate to evaluate the carcinogenic potential of bromomethane, and has 

assigned this chemical to Group D (not classifiable as to human 

carcinogenicity) (IRIS 1989). 

Similarly, the International Agency for Research on Cancer has placed 

bromomethane in Group 3 (not classifiable as to carcinogenic potential). 


39
 

2. HEALTH EFFECTS 

2.5 BIOMARKERS OF EXPOSURE AND EFFECT
 

Biomarkers are broadly defined as indicators signaling events in 

biologic systems or samples. They have been classified as markers of 

exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989). 

A biomarker of exposure is a xenobiotic substance or its metabolite(s) 

or the product of an interaction between a xenobiotic agent and some target 

molecule(s) or cell(s) that is measured within a compartment of an organism 

(NAS/NRC 1989). The preferred biomarkers of exposure are generally the 

substance itself or substance-specific metabolites in readily obtainable body 

fluid(s) or excreta. However, several factors can confound the use and 

interpretation of biomarkers of exposure. The body burden of a substance may 

be the result of exposures from more than one source. The substance being 

measured may be a metabolite of another xenobiotic substance (e.g., high 

urinary levels of phenol can result from exposure to several different 

aromatic compounds). Depending on the properties of the substance (e.g., 

biologic half-life) and environmental conditions (e.g., duration and route of 

exposure), the substance and all of its metabolites may have left the body by 

the time biologic samples can be taken. It may be difficult to identify 

individuals exposed to hazardous substances that are commonly found in body 

tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, 

and selenium). Biomarkers of exposure to bromomethane are discussed in 

Section 2.5.1. 

Biomarkers of effect are defined as any measurable biochemical, 

physiologic, or other alteration within an organism that, depending on 

magnitude, can be recognized as an established or potential health impairment 

or disease (NAS/NRC 1989). This definition encompasses biochemical or 

cellular signals of tissue dysfunction (e.g., increased liver enzyme activity 

or pathologic changes in female genital epithelial cells), as well as 

physiologic signs of dysfunction such as increased blood pressure or decreased 

lung capacity. Note that these markers are often not substance specific. 

They also may not be directly adverse, but can'indicate potential health 

impairment (e.g., DNA adducts). Biomarkers of effects caused by bromomethane 

are discussed in Section 2.5.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired 

limitation of an organism's ability to respond to the challenge of exposure to 

a specific xenobiotic substance. It can be an intrinsic genetic or other 

characteristic or a preexisting disease that results in an increase in 

absorbed dose, biologically effective dose, or target tissue response. If 

biomarkers of susceptibility exist, they are discussed in Section 2.7, 

"POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE." 

2.5.1 Biomarkers Used to Identify and/or Quantify Exposure to


 Bromomethane
 

The most convenient biomarker of bromomethane exposure is the 

concentration of bromide ion in the blood or serum. The relationship between 

bromide ion concentrations and the severity of effects in exposed people was 
40
 

2. HEALTH EFFECTS
 

investigated by Alexeeff and Kilgore (1983), who assembled and evaluated data 

from a large number of case reports. Serum bromide levels are usually below 

15 ppm in unexposed people. In bromomethane-exposed people, levels up to 

80 ppm may occur without any obvious clinical signs, while levels of 

150-400 ppm are observed in people with moderate to severe symptoms. Bromide 

is cleared from blood with a half-life of about 12 days in healthy people, and 

half-lives of 3-15 days have been observed in bromomethane-exposed people 

(Alexeeff and Kilgore 1983). Consequently, the correlation between serum 

bromide levels and severity of effects is most apparent within the first 

l-2 days of exposure, and there may be little correlation later. Bromide ion 

is cleared mainly by excretion in the urine, but no studies were located on 

the use of urinary bromide levels as a biomarker of bromomethane exposure. 

Measurement of parent bromomethane (e.g., in expired air, blood, or 

urine) has not been investigated as a possible biomarker of exposure in 

humans, mainly because studies in animals suggest that bromomethane is cleared 

so rapidly (half-lives of 15-30 min) that this is unlikely to be useful for 

monitoring environmental exposures. Similarly, methanol and other organic 

metabolites are also cleared with short half-lives (Honma et al. 1985; Jaskot 

et al. 1988), so they are also unlikely to be useful in biomonitoring. 

Formation of stable methylated adducts such as S-methylcysteine in hemoglobin 

is known to occur in animals following inhalation exposure to bromomethane 

(Iwasaki 1988a, 1988b), but this has not been developed as a biomonitoring 

method for humans. 

Neither elevated serum bromide levels nor formation of methylated 

adducts are, by themselves, specific for bromomethane exposure. For example, 

increased bromide levels could result from exposure to bromide in the diet or 

ingestion of bromate- or bromide-containing medicines, and increased methyl 

adducts might result from exposure to other methyl halides, various methyl 

nitrosoamines, or other alkylating agents. However, the combination of these 

two methods (i.e., a finding of increased bromide and increased methylation) 

would strongly indicate that bromomethane exposure had occurred. 

2.5.2 Biomarkers Used to Characterize Effects Caused by Bromomethane
 

As discussed in Section 2.2, the effects that are most often observed in 

humans exposed to bromomethane vapor are central nervous system injury 

(disturbed vision, tremor, convulsions, coma), lung irritation (edema, 

impaired respiration), and renal injury (oliguria or anuria). Of these, 

neurological or neurobehavioral signs appear to be the most sensitive 

indication of effect, since preclinical symptoms can be observed in humans 

exposed to low levels of bromomethane in the workplace (Anger et al. 1986; 

Kishi et al. 1988; Verberk et al. 1979). Of course, positive findings for end 

points of this sort (headache, weakness, ataxia, nausea, double vision, 

abnormal electroencephalogram) are not specific indicators of bromomethane 

exposure, since other chemicals or diseases may produce similar neurological 

changes. Biomarkers that are useful in evaluating neurological effects have 

been discussed by Johnson (1987). 
41 

2. HEALTH EFFECTS 

2.6 INTERACTIONS WITH OTHER CHEMICALS
 

No studies were located regarding the interaction of bromomethane with 

other chemicals. Since it seems likely that cellular glutathione may serve a 

protective function by reacting with bromomethane (Kornburst and Bus 1983), 

other chemicals (electrophilic xenobiotics, reactive intermediates) that lead 

to decreases in glutathione levels might increase the toxicity of 

bromomethane, but this has not been investigated. Similarly, bromomethane 

might be expected to have additive or synergistic interactions with other 

alkylating agents, but this has not been investigated. 

2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
 

No studies were located to suggest that any specific human subpopulation 

may be more susceptible to bromomethane than average, although it may be 

expected that the young, the elderly, and people with lung, kidney, or 

neurological disease might be more readily affected than healthy adults. 

Studies in animals reveal that there are differences in sensitivity between 

species (e.g., Irish et al. 1940), and some studies have noted small 

differences in sensitivity between males and females (Eustis et al. 1988). It 

is not known if these differences apply to humans. 

2.8 MITIGATION OF EFFECTS
 

This section will describe clinical practice and research concerning 

methods for reducing toxic effects of exposure to bromomethane. However, 

because some of the treatments discussed may be experimental and unproven, 

this section should not be used as a guide for treatment of exposures to 

bromomethane. When specific exposures have occurred, poison control centers 

and medical toxicologists should be consulted for medical advice. 

Human exposure to bromomethane is most likely to occur by inhalation or 

dermal contact (see Chapter 5). Inhalation exposure may cause neurological, 

respiratory and renal damage. Dermal contact may cause skin lesions while 

oral exposure leads to digestive tract mucosal membrane irritation (see 

Section 2.2). 

Procedures that have been used to reduce absorption of bromomethane 

include the following. If dermal exposure to concentrated bromomethane 

occurs, contaminated clothing is removed and the skin thoroughly washed with 

soap or mild detergent and water (Bradford 1990; Ellenhorn and Barceloux 1988; 

Morgan 1982). General burn care may also be necessary in severe cases. If 

inhalation exposure is sufficient to cause lung damage, administration of 

oxygen, mechanical ventilatory support, and administration of diuretics and 

bronchodilators may be required to reduce the effects of pulmonary edema 

(Bradford 1990; Morgan 1982). If seizures occur, treatment with standard 

anticonvulsants may be required. It is unlikely that exposures near waste 

sites would be large enough to require interventions of this sort. 
42 

2. HEALTH EFFECTS 

Intramuscular administration of sulfhydryl agents such as dimercaprol 

has been recommended to improve elimination of bromomethane, since 

bromomethane reacts with sulfhydryl groups (Bradford 1990). However, this 

treatment may cause troublesome side effects, and there is no evidence that 

such agents are effective when administered after exposure has occurred 

(Alexeeff and Kilgore 1983; Ellenhorn and Barceloux 1988; Rathus and Landy 

1961). Treatment with N-acetylcysteine has been suggested, since this 

compound is a precursor to glutathione, and elevated glutathione levels may be 

protective against bromomethane toxicity (Bradford 1990). It is not expected 

that treatments of this sort would normally be required for low dose exposures 

that occur near waste sites. Additional details regarding treatment following 

bromomethane intoxication may be found in the cited references. 

2.9 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of 

ATSDR (in consultation with the Administrator of EPA and agencies and programs 

of the Public Health Service) to assess whether adequate information on the 

health effects of bromomethane is available. Where adequate information is 

not available, ATSDR, in conjunction with the National Toxicology Program 

(NTP), is required to assure the initiation of a program of research designed 

to determine the health effects (and techniques for developing methods to 

determine such health effects) of bromomethane. 

The following categories of possible data needs have been identified by 

a joint team of scientists from ATSDR, NTP, and EPA. They are defined as 

substance-specific informational needs that, if met, would reduce or eliminate 

the uncertainties of human health assessment. In the future, the identified 

data needs will be evaluated and prioritized, and a substance-specific 

research agenda will be proposed. 

2.9.1 Existing Information on Health Effects of Bromomethane
 

The existing data on health effects of inhalation, oral, and dermal 

exposure of humans and animals to bromomethane are summarized in Figure 2-3. 

The purpose of this figure is to illustrate the existing information 

concerning the health effects of bromomethane. Each dot in the figure 

indicates that one or more studies provide information associated with that 

particular effect. The dot does not imply anything about the quality of the 

study or studies. Gaps in this figure should not be interpreted as "data 

needs" information (i.e., data gaps that must necessarily be filled). 

As shown in the upper portion of Figure 2-3, there are numerous studies 

of humans exposed to bromomethane by the inhalation route. These have focused 

mainly on the systemic and neurological effects of exposure, and other 

endpoints (immunological, developmental, reproductive, genotoxic, cancer) have 

not been investigated. There are also numerous case reports on the direct 

effects of bromomethane vapor or liquid on skin, but other effects have not 

been studied. 

44
 

2. HEALTH EFFECTS 

Studies in animals (shown in the lower half of Figure 2-3) have also 

focused on inhalation exposure, and most endpoints (except immunotoxicity) 

have been investigated. In contrast, the effects of oral exposure have 

received only limited attention, focusing mainly on the inflammatory and 

possible carcinogenic effects in the stomach. No information was located on 

dermal exposure of animals. 

2.9.2 Data Needs
 

Acute-Duration Exposure. There is sufficient information from studies of 

humans (Holling and Clarke 1944; Johnstone 1945; Miller 1943; Wyers 1945) to 

identify the principal target tissues of bromomethane following acute 

inhalation exposure (lung, kidney, nervous system). Studies in animals 

(Alexeeff et al. 1985; Eustis et al. 1988; Honma 1987; Honma et al. 1985, 

1987; Hurtt et al. 1987a, 1988a; Hurtt and Working 1988) support and confirm 

these observations. These data are sufficient to derive an acute inhalation 

MRL (Honma 1987). Information is available on dermal effects following 

exposure of humans (but not animals) both to the vapor (Hezemans-Boer et al. 

1988; Zwaveling et al. 1987) and the liquid (Longley and Jones 1965; Watrous 

1942). While the dose-response curve for dermal effects is not well-defined, 

it is apparent that this is of concern mainly at high levels, and is unlikely 

to be of concern at exposure levels likely to be encountered in the 

environment or near waste sites. 

No information is available on acute oral exposure of humans or animals 

to bromomethane. Extrapolation from acute inhalation data is probably not 

appropriate, since some of the effects (both inhalation and oral) are due to 

point-of-contact irritation. However, acute oral toxicity studies are 

probably not essential, since oral exposure of humans to acutely toxic levels 

of bromomethane is not likely to occur due to the high volatility of the 

compound. 

Intermediate-Duration Exposure. Limited information is available on the 

effects of intermediate-duration inhalation exposure of humans to bromomethane 

(Kantarjian and Shasheen 1963; Viner 1945). It appears clear that the target 

tissues are the same as for acute-duration exposure, but dose-response data from 

intermediate-duration human studies are not available. However, there 

are a number of studies in animals that do provide quantitative data (Anger 

et al. 1981; Eustis et al. 1988; Haber 1987; Honma et al. 1982; Ikeda et al. 

1980; Irish et al. 1940; Kato et al. 1986), and are sufficient to derive an 

intermediate-duration inhalation MRL (Honma et al. 1982). Further data from 

an intermediate-duration (90-day) study in animals recently completed by the 

NTP will help strengthen this data set, and additional intermediate-duration 

inhalation studies may not be required. 

No information is available on the effects of intermediate-duration oral 

exposure in humans, but two animal studies (Boorman et al. 1986; Danse et al. 

1984) provide sufficient data to identify the main target tissue (the stomach 

epithelium) and to define the dose-response relationship for this effect. 

These studies are suitable for derivation of an intermediate oral MKL, but 
45 

2. HEALTH EFFECTS 

further studies would still be helpful to search more specifically for 

possible subclinical neurological effects. This is important since 

neurological effects appear to be the most sensitive effect by the inhalation 

route, and people may be exposed to low levels of bromomethane in drinking 

water drawn from contaminated groundwater sources. No information is 

available on intermediate-duration dermal exposure to bromomethane. However, 

humans are not likely to experience significant dermal exposures to 

bromomethane near waste sites, so research in this area does not appear to be 

essential. 

Chronic-Duration Exposure and Cancer. There are several studies of 

humans chronically exposed to bromomethane in air (Anger et al. 1986; Chavez 

et al. 1985; Hine 1969; Kishi et al. 1988). These studies indicate 

neurological effects are the most sensitive effect following chronic exposure. 

Quantitative exposure data are limited, but are sufficient for derivation of a 

chronic inhalation MRL. The human data are supported by chronic inhalation 

studies in animals (Anger et al. 1986; Haber 1987). Nevertheless, further 

studies of humans exposed to low levels of bromomethane in the workplace would 

be helpful in order to increase the confidence in the chronic MRL. This is 

important since humans could be exposed to low levels of bromomethane in air 

near some waste sites. No information is available on effects in humans or 

animals after chronic oral exposure. Extrapolation from the inhalation route 

may not be appropriate, since two intermediate-duration studies in animals 

(Boorman et al. 1986; Danse et al. 1984) indicate that the stomach and not the 

nervous system is the main target following oral exposure. Chronic oral 

studies in animals would be helpful in evaluating human health risk by this 

route. This is important since humans might be exposed to low levels of 

bromomethane in drinking water drawn from contaminated groundwater sources. 

No information is available from studies of humans on the carcinogenic 

effects of inhalation exposure to bromomethane, but chronic inhalation studies 

in mice and rats (Reuzel et al. 1987; Yang 1990)yielded no evidence of 

carcinogenic effect. Nevertheless, epidemiological investigations of the 

incidence of cancer in workers who use bromomethane would be helpful in 

assessing the cancer risk to humans who could be exposed to low levels of 

bromomethane in air near some waste sites. 

The carcinogenic effects of oral exposure to bromomethane have been 

studied in two intermediate-duration studies (Boorman et al. 1986; Danse 

et al. 1984), but not in any chronic studies. The results suggest that 

bromomethane might be carcinogenic, but the data are difficult to interpret 

with certainty. Extrapolation from inhalation studies would not be 

appropriate, since the response observed is at the portal of entry (the 

forestomach). This is consistent with the concept that bromomethane is a 

direct-acting alkylating agent. Chronic oral exposure studies in animals 

would be valuable for clarifying the cancer risk of ingested bromomethane. 

This is needed since some people could be exposed to low levels of 

bromomethane in drinking water drawn from contaminated groundwater sources. 
46
 

2. HEALTH EFFECTS 

Genotoxicity. Bromomethane is a direct-acting alkylating agent, and 

there are studies both in vivo (Djalali-Behzad et al. 1981) and in vitro 

(Starratt and Bond 1988) which establish that it can methylate DNA. Studies 

of mutagenic potential in bacterial test systems have been mostly positive 

(Djalali-Behzad et al. 1981; Kramers et al. 1985; Moriya et al. 1983), as have 

several in vitro tests using eukaryotic cell types (Kramers et al. 1985; 

Tucker et al. 1986) and several in vivo tests in animals (Ikawa et al. 1986; 

Katz 1987; Kramers et al. 1985). Investigation of possible sister chromatid 

exchange or chromosome aberrations in peripheral lymphocytes of humans exposed 

in the workplace would be helpful in confirming the genotoxic potential of 

bromomethane, although studies in animals suggest that this effect may only be 

measurable at high exposure levels. 

Reproductive Toxicity. No information was located regarding 

reproductive effects in humans. Intermediate-duration inhalation studies in 

animals (Eustis et al. 1988; Kato et al. 1986) indicate that the testes may 

undergo degeneration and atrophy at high exposure levels, but the doseresponse 

curve is not well defined. Further studies in animals to identify 

the threshold for this end point would be helpful in confirming that 

neurological effects are the most sensitive endpoint of toxicity. Two studies 

in female animals (Hardin et al. 1981; Sikov et al. 1980) have not detected 

reproductive effects even at doses that produced maternal toxicity. 

Additional studies to confirm this in several different animal species would 

be helpful. 

No information exists on reproductive effects in humans or animals after 

oral exposure. Based on the inhalation studies in animals which indicate the 

testes are a target tissue, it would be valuable to include histological 

examination of the testes in any intermediate- or chronic-duration oral 

studies in animals. In addition, tests of male reproductive success would be 

valuable in assessing the functional significance of any testicular lesions. 

Developmental Toxicity. There is no information on developmental 

effects in humans exposed to bromomethane, but two inhalation exposure studies 

in animals (rats and rabbits) indicate that developmental or teratogenic 

effects do not occur even at doses that are toxic to the dam (Hardin et al. 

1981; Sikov et al. 1980). No information is available on developmental 

effects after oral exposure of animals to bromomethane, but the inhalation 

data suggest that is not likely to be of concern. 

Immunotoxicity. No information was located on the immunological effects 

of bromomethane in humans or animals exposed by any route. A battery of 

immune function tests in several animal species exposed to bromomethane by the 

inhalation and the oral routes would be valuable in determining if the immune 

system is adversely affected, and if so, in determining species and route 

specificity, as well as the threshold for those effects. 

Neurotoxicity. There is clear evidence from studies in humans and 

animals that the nervous system is adversely affected by inhalation exposure 

to bromomethane. This includes evidence of clinical neurological signs and 
47 

2. HEALTH EFFECTS 

behavioral changes (Anger et al. 1986; Behrens and Dukes 1986; Clarke et al. 

1945; Greenberg 1971; Hine 1969; Kantarjian and Shasheen 1963; Longley and 

Jones 1965; Marraccini et al. 1983; O'Neal 1987; Prain and Smith 1952; Prockop 

and Smith 1986; Rathus and Landy 1961; Viner 1945; Wyers 1945), as well as 

biochemical changes and histological lesions in the brain (Alexeeff et al. 

1985; Eustis et al. 1988; Honma 1987; Honma et al. 1982; Hurtt et al. 1987a). 

Although quantitative exposure information from humans is limited, the 

thresholds for acute, intermediate, and chronic inhalation exposures are known 

with reasonable precision. No information is available on humans exposed by 

the oral route, but two oral studies in rats (Boorman et al. 1986; Danse 

et al. 1984) did not produce any visible neurological signs. It is not known 

if this apparent route specificity is due simply to differences in dose, or to 

differences in absorption, distribution, or metabolism between routes. For 

this reason, additional oral dose-response studies in animals that focus 

specifically on histological, biochemical, or functional tests of nervous 

system injury would be valuable. If these tests indicate that the nervous 

system is not injured following oral exposure, additional toxicokinetic 

studies would be helpful in understanding the basis for the distinction 

between inhalation and oral effects. 

Epidemiological and Human Dosimetry Studies. As noted previously, there are 

many reports on the adverse effects of bromomethane in humans. Most 

studies involve people with accidental acute high-level exposures in air, but 

there are also several studies of workers with repeated low-level exposures 

(Anger et al. 1986; Kishi et al. 1988; Verberk et al. 1979). These studies 

are sufficient to identify the main health effects of concern and to estimate 

the exposure levels that lead to effects. However, further studies of workers 

who are exposed to low levels during manufacture or use of bromomethane would 

be helpful, if reliable current and past exposure data are available. These 

additional quantitative human data would be valuable in increasing the 

confidence in the estimated safe exposure levels in the workplace and the 

environment. This would improve the ability to evaluate potential risk to 

humans exposed to low levels of bromomethane in air near waste sites. 

Biomarkers of Exposure and Effect. The most common biomarker of 

exposure to bromomethane is serum bromide concentration. Studies in humans 

have established a correlation between bromide levels and severity of effect 

(Alexeeff and Kilgore 1983), although the quantitative relation between 

exposure level and bromide concentration has not been established. Since 

bromide is cleared from the blood with a half-life of 3-15 days, this test is 

best suited for detecting relatively recent exposures. Because bromide is a 

normal component of blood, and because bromide levels may be increased by 

other chemicals or drugs, increased serum bromide is not specific for 

bromomethane. Other possible biomarkers available include direct measurement 

of parent bromomethane or methanol in expired air or blood (Honma et al. 1985; 

Jaskot et al. 1988), and measurement of methylated adducts such as 

S-methylcysteine in hemoglobin (Iwasaki 1988a). Measurement of parent 

bromomethane or methanol are not likely to be helpful except in the interval 

immediately following an acute exposure, while measurement of stable methyl 

adducts could be useful for longer periods. Further studies in humans or 
48 

2. HEALTH EFFECTS 

animals would be helpful in determining the sensitivity of these biomarkers 

and evaluating their usefulness in monitoring people exposed to low levels of 

bromomethane near waste sites. 

The most sensitive biomarkers of bromomethane effect appear to be 

changes in the nervous system. These can be detected in groups of exposed 

people by measuring the incidence of signs and symptoms such as weakness, 

nausea, ataxia, and vision problems. However, it is obvious that these are 

not specific for bromomethane-induced effects, and because of the large 

variation between people, these tests are not reliable for identifying 

preclinical effects in potentially exposed individuals. Studies to develop 

more specific and more objective biomarkers of bromomethane-induced effects 

would be useful in assessing the potential health significance of low-level 

bromomethane exposure near waste sites. 

Absorption, Distribution, Metabolism, and Excretion. The toxicokinetics of 

bromomethane have not been thoroughly investigated in humans, but there is good 

information from studies in animals on uptake, distribution, and excretion 

following inhalation exposure (Bond et al. 1985; Gargas and Andersen 1982; Honma 

et al. 1985; Jaskot et al. 1988; Medinsky et al. 1985), and there is one study on 

toxicokinetics following oral exposure (Medinsky et al. 1984). Available data 

indicate that the toxicokinetics of bromomethane absorption are mainly firstorder except at very high doses. While the metabolism of related 

compounds such as chloromethane has been studied in detail (Kornburst and Bus 

1983), the metabolism of bromomethane has not been thoroughly investigated. 

Additional studies on the rate and extent of bromomethane hydrolysis and 

alkylation reactions in vivo would be valuable in understanding the basis of 

bromomethane toxicity, and in assessing the utility of various biomarkers of 

exposure (e.g., parent compound, bromide, methanol, adducts). 

Comparative Toxicokinetics. Available studies indicate that 

bromomethane affects the same target tissues in humans and animals, although 

there are apparent differences in sensitivity between species, with rabbits 

being more sensitive than rats or mice (Irish et al. 1940). However, 

quantitative toxicokinetic data on absorption, distribution, and excretion are 

available only for rats (Bond et al. 1985; Gargas and Andersen 1982; Honma 

et al. 1985; Jaskot et al. 1988; Medinsky et al. 1984, 1985). Additional 

toxicokinetic studies would be helpful in understanding the basis of the 

differences in species sensitivity, and in determining which animal species is 

the most appropriate model for human exposure. 

Mitigation of Effects. Recommended methods for the mitigation of acute 

effects of inhalation exposure to bromomethane include mechanical ventilatory 

support, administration of oxygen and supportive therapy for pulmonary edema 

(Bradford 1990; Morgan 1982). Administration of thiol compounds to react with

absorbed bromomethane has also been suggested (Bradford 1990). Further 

studies on the efficacy of post-exposure treatment with agents of this type 

would be valuable. No information was located concerning mitigation of 

effects of lower-level or longer-term exposure to bromomethane. Further 

information on techniques to mitigate such effects would be useful in 
49
 

2. HEALTH EFFECTS 

determining the safety and effectiveness of possible methods for treating 

bromomethane-exposed populations surrounding hazardous waste sites. 

2.9.3 On-going Studies
 

The NTP has recently completed a series of inhalation studies in rats 

and mice, including both noncancer and cancer evaluations. The results of 

these studies will provide valuable new data on the toxicity of this compound 

in animals. Dr. W. Kilgore (University of California, Davis) is studying 

methods for detecting exposure of field workers to bromomethane, and is 

obtaining data on health effects in these workers. 

51 

3. CHEMICAL AND PHYSICAL INFORMATION 

3.1 CHEMICAL IDENTITY
 

Table 3-l lists common synonyms, trade names, and other pertinent 

identification information for bromomethane. 

3.2 PHYSICAL AND CHEMICAL PROPERTIES
 

Table 3-2 lists important physical and chemical properties of 

bromomethane. 



55 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL
 

4.1 PRODUCTION
 

Bromomethane is produced by reaction of methanol with hydrobromic acid, 

followed by distillation of the product (HSDB 1989; IARC 1986; Windholz 1983). 

Table 4-1 summarizes information on U.S. companies that reported the 

manufacture or use of bromomethane in 1987 (TRI 1989). The quality of the TRI 

data must be viewed with caution since the 1987 data represent first-time, 

incomplete reporting by these facilities. Not all facilities that should have 

reported have done so. Of the companies that did report, only two facilities 

produced bromomethane for sale and distribution: the Ethyl Corporation 

production facility in Magnolia, Arkansas, and the Great Lakes Chemical 

Corporation production facility in El Dorado, Arkansas (HSDB 1989; SRI 1987, 

1988, 1989; TRI 1989). The current combined production volume of these two 

facilities is approximately 19,500 metric tons (43 million pounds) (HSDB 1989; 

IARC 1986). This is nearly a two-fold increase over the production volume of 

11,200 metric tons (25 million pounds) reported for 1972 (IARC 1986). 

4.2 IMPORT/EXPORT
 

Imports of bromomethane were 735 metric tons (1.6 million pounds) in 

1982, while exports were 2,130 metric tons (4.7 million pounds) in 1984 and 

4,135 metric tons (9 million pounds) in 1987 (HSDB 1989). More detailed data 

regarding the import and export of bromomethane were not located. 

4.3 USE
 

The primary use of bromomethane is as a soil or space fumigant for the 

control of insects, fungi, and rodents (EPA 1986b; HSDB 1989; IARC 1986). 

Space fumigation is usually performed by enclosing the structure in a sealed 

tent and releasing bromomethane gas inside, while soil fumigation is usually 

done by injecting bromomethane into the soil underneath a nonporous covering. 

Bromomethane is also used as a methylating agent in various chemical 

reactions, and as a solvent to extract oils from nuts, seeds, and wool. 

Bromomethane was also used in fire extinguishers in Europe from the 1920s 

through the 1940s (IARC 1986), but never gained widespread use as a fire 

extinguishing agent in the United States (Alexeeff and Kilgore 1983). 

4.4 DISPOSAL
 

Because bromomethane is a gas above 3.6°C (38°F), most disposal is by 

release to the atmosphere (see Section 5.2.1). Disposal of liquid or solid 

wastes that contain bromomethane is regulated by federal restrictions which 

apply to hazardous substances (see Chapter 7). 

57 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.1 OVERVIEW
 

Because bromomethane is a gas under ordinary conditions, humans are most 

likely to be exposed to bromomethane in air. Low levels can be detected in 

air around the globe, perhaps onginating from natural sources in the ocean. 

Somewhat higher levels occur in urban environments, due to release from 

industrial point sources and from use of leaded gasoline. Extremely high 

levels may be encountered in air where bromomethane is being used for 

fumigation. Trace levels have been detected in some groundwater samples, but 

levels in surface water and food are usually negligible. Bromomethane may 

also be generated in drinking water as the result of chlorination, but this 

has not yet been quantified. 

Bromomethane in air is quite stable, undergoing breakdown by reaction 

with hydroxyl radicals with a half-life of about 11 months. Bromomethane in 

other media (water, soil) volatilizes sufficiently rapidly that breakdown in 

these media (via hydrolysis or reaction with organic components) is usually 

minor. 

The EPA has identified 1,177 NPL sites. Bromomethane has been found at 

12 of the sites evaluated for the presence of this chemical (View 1989). 

However, we do not know how many of the 1,177 sites have been evaluated for 

bromomethane. As more sites are evaluated by the EPA, the number may change. 

The frequency of sites where bromomethane has been found within the United 

States can be seen in Figure 5-1. 

5.2 RELEASES TO THE ENVIRONMENT
 

5.2.1 Air
 

Since bromomethane is highly volatile, nearly all environmental releases 

of bromomethane are into the-air. The most important anthropogenic releases 

are from fumigation activities, since bromomethane is simply dispersed into 

the air after fumigation is completed. Based on current estimates that about 

80% of bromomethane production is used for fumigation (65% for soil fumigation 

and 15% for space fumigation), and assuming that nearly all of this is 

ultimately released to air, approximately 34 million pounds/year may be 

released to air by this practice (HSDB 1989; IARC 1986). Air releases may 

also occur in association with industrial production and processing of 

bromomethane, as shown in Table 5-l (TRI 1989). Based on the data reported, 

total releases to air from industrial activities in the United States were 

1.3 million pounds in 1987. However, the quality of the TRI data must be 

viewed with caution since the 1987 data represent first-time, incomplete 

reporting of estimated releases by these facilities. Not all sources of 

chemical wastes are included, and not all facilities that should have reported 

have done so. 


60
 

5. POTENTIAL FOR HUMAN EXPOSURE 

The ocean is another important source of bromomethane release to air. 

It seems likely that this is the result of bromomethane production by marine 

organisms, but the exact source is not known (IARC 1986). Singh et al. 

(1983b) calculated that the amount released from the ocean was large enough to 

account for most bromomethane in the atmosphere, but Penkett et al. (1985) 

showed that anthropogenic releases were the most important source. This is 

supported by the observation that atmospheric levels are about 40% higher in 

the northern hemisphere (0.015-0.026 ppb) than the southern hemisphere 

(0.011-0.019 ppb) (Penkett et al. 1985; Singh et al. 1983b). 

Use of bromine-containing additives (ethylene dibromide) in leaded 

gasoline results in the release of bromomethane in exhaust fumes (about 

70-220 μg/m3

 of exhaust) (Harsch and Rasmussen 1977), and this may have been a 

significant source of bromomethane release in the past. Combustion of 

unleaded gasoline releases much less bromomethane (about 4-5 μg/m3

), so 

current emissions from this source are presumably much lower than previously, 

and are likely to decrease further as leaded gasoline continues to be phased 

out. 

5.2.2 Water
 

Because of its volatility, very little bromomethane is released to 

water. As shown in Table 5-1, no surface water releases were reported in the 

United States from industrial producers or processors of bromomethane (TRI 

1989), although in one case about 2,000 pounds of bromomethane was released to 

groundwater through underground injection. Some bromomethane may leach from 

fumigated soil into surface water (EPA 1986b; IARC 1986). Most of this would 

be expected to quickly volatilize into air (see Section 5.3.1.), although some 

could migrate downward into groundwater where evaporation is not significant. 

Bromomethane has not been detected in surface waters near any of 405 

waste sites (including 99 NPL sites) where it was investigated, but it was 

detected in six groundwater samples from two locations (both NPL sites) (CLPSD 

1989). The geometric mean of six samples from these two sites was 17 μg/L. 

5.2.3 Soil
 

Soil fumigation is the primary use of bromomethane in the United States, 

accounting for approximately 65% of total consumption (EPA 1989c; IARC 1986). 

Based on reported production for 1984 (43 million pounds), this would be about 

28 million pounds/year. However, as discussed in Section 5.3.1, most 

bromomethane will tend to evaporate from the soil within l-2 days, so soil 

contamination is normally not persistent. No industrial releases of 

bromomethane to soil were reported for 1987 (TRI 1989; see Table 5-l), and 

bromomethane has not been detected in soils or sediments at 455 hazardous 

waste sites, including 99 NPL sites (CLPSD 1989). 
61
 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.3 ENVIRONMENTAL FATE
 

5.3.1 Transport and Partitioning
 

Bromomethane is a readily volatile compound, with a boiling point of 

3.6°C (Windholz 1983) and a vapor pressure at 20°C of 1,420 mmHg (Mabey et al. 

1982). Consequently, bromomethane has a strong tendency to volatilize into 

air from other media (soil, water). 

Because bromomethane is quite soluble in water (approximately 13-18 g/L) 

(EPA 1986b), some bromomethane in air may partition into clouds, rain, or 

surface waters. This tendency is described by the Henry's law constant (H), 

which for bromomethane has a value of 0.2 atm·m3

/mole (Mabey et al. 1982). 

This value is sufficiently large to indicate that partitioning of bromomethane 

from air into water will be quite small. Conversely, the rate of bromomethane 

volatilization from water into air will be quite high, depending on mixing, 

temperature, and depth. The measured rate constant for volatilization is 

22.5 cm/hr, which corresponds to a volatilization half-life of 3.1 hours for 

water 1 meter deep (Lyman et al. 1982). Half-lives of volatilization for 

lakes and deeper rivers range from 1 to 5 days (EPA 1986b). Rapid 

volatilization into indoor air would also be expected if contaminated water 

were used for showering, bathing, or cooking, but this has not been studied. 

Bromomethane, either as a gas or dissolved in water, has relatively low 

affinity for soils. This has been established by direct observation (Brown 

and Rolston 1980; Chisholm and Koblitsky 1943; Fuhr et al. 1948), and is also 

expected on the basis of the relatively small Koc (measured values range from 

1 to 10) for this chemical (EPA 1986b; Roy and Griffin 1985). Volatilization 

of bromomethane from soil is also relatively rapid, with half-lives ranging 

from 0.2 to 0.5 days, depending on depth (Jury et al. 1984). 

Bromomethane is not expected to bioconcentrate in aquatic organisms 

because of its low octanol/water partition coefficient (Kow) (estimated to be 

about 13) (Callahan et al. 1979). The bioconcentration factor (BCF) for 

bromomethane has not been measured experimentally. However, based on an 

empirical relation between the BCF and the Kow (Neely et al. 1974), the 

estimated BCF for bromomethane is about 3. This low estimated BCF indicates 

that bromomethane should not significantly bioconcentrate (EPA 1986b). 

5.3.2 Transformation and Degradation
 

5.3.2.1 Air
 

The main degradation pathway for bromomethane in air is reaction with 

photochemically-generated hydroxyl radicals. The rate constant for this 

reaction has been measured to be 4.14x10-14

 cm3·molecule-1·sec-1 at 25°C, and 

2.7x10-14

 cm3·molecule-l·sec-l at -8°C (the average temperature of the 

troposphere) (Davis et al. 1976). Assuming a concentration of atmospheric 

hydroxyl radicals of 9x105

 molecules/cm3, this corresponds to a tropospheric 

half-life of about 11 months. Thus, breakdown is relatively slow, and 
62
 

5. POTENTIAL FOR HUMAN EXPOSURE 

bromomethane will tend to become widely dispersed in the atmosphere. 

Molecules that diffuse upward and reach the stratosphere may undergo direct 

photolytic degradation by ultraviolet radiation (Robbins 1976), but this 

degradation pathway accounts for only a small fraction (about 3%) of 

atmospheric bromomethane degradation (EPA 1986b). 

5.3.2.2 Water
 

Bromomethane tends to undergo slow hydrolysis in water, yielding 

methanol, bromide ion, and hydrogen ion. The rate constant of this reaction 

has been measured to be about 3x10-7/second at 25°C (Castro and Belser 1981), 

and hydrolytic half-lives may range between 20 and 38 days, depending on 

temperature and pH (Castro and Belser 1981; Ehrenberg et al. 1974; Mabey and 

Mill 1978). It should be noted that these hydrolysis half-lives are 

considerably longer than typical volatilization half-lives (see 

Section 5.3.1). Thus, most bromomethane will volatilize from water before 

extensive hydrolysis occurs. 

5.3.2.3 Soil
 

The principal fate of bromomethane in soil is volatilization, but some 

may react with organic soil constituents to yield nonvolatile end products, 

including bromide ion (Brown and Rolston 1980; Goring et al. 1975; Shiroishi 

et al. 1964). There is little evidence that bromomethane in soil is degraded 

by microorganisms (EPA 1986b). 

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
 

5.4.1 Air
 

As shown in Table 5-2, bromomethane has been detected in air samples 

from regions all around the globe. Concentrations over the oceans and in 

rural areas are typically less than 0.025 ppb (0.1 μg/m3

), while 

concentrations in suburban and urban areas may range up to 1.2 ppb (5 μg/m3

). 

These values are all much lower than may be encountered near places where 

bromomethane is being used for fumigation (25 ppm or 100,000 μg/m3

) (Bond and 

Durnas 1987). 

5.4.2 Water
 

Bromomethane occurs in ocean waters at a concentration of about l-2 ng/L 

(Lovelock 1975; Singh et al. 1983b), but is not a common contaminant in fresh 

waters in the United States. It was not detected in storm water runoff from 

15 U.S. cities (Cole et al. 1984) or in influents to sewage treatment plants 

in four cities (Levins et al. 1979), and was detected in only 1.4% of over 900 

surface water samples recorded in the STORET database (Staples et al. 1985). 

The median concentration in these positive samples was less than 10 μg/L. 

64
 

5. POTENTIAL FOR HUMAN EXPOSURE 

Bromomethane has been detected (but not quantified) in drinking water supplies 

of several U.S. cities (Coleman et al. 1976; EPA 1975; Kool et al. 1982; 

Kopfler et al. 1977; Shackelford and'Keith 1976). Bromomethane in drinking 

water is presumably generated as an inadvertent byproduct following 

chlorination. 

Occurrence of bromomethane in groundwater is somewhat more likely than 

in surface water, since evaporation is restricted. Bromomethane has been 

detected in groundwater in New Jersey (Greenberg et al. 1982) but not in 

Wisconsin (Krill and Sonzogni 1986). 

5.4.3 Soil
 

No data were found on bromomethane levels in soil. Bromomethane is not 

expected to be a stable constituent of soil, since it either .evaporates or 

reacts.with organic soil components (see Section 5.3.2.3). However, bromide 

ion may be retained in fumigated soil (IARC 1986). Bromomethane was not 

detected in 353 sediment samples from STORET stations in the United States 

(Staples et al. 1985). 

5.4.4 Other Environmental Media
 

Although bromomethane is used extensively as a fumigant for grains and 

other food products, it is rarely detected unchanged as a residue in foods. 

Most of the fumigant is rapidly lost to the atmosphere, and the remaining 

portion reacts with the food components, producing residues of inorganic 

bromide (IARC 1986; NAS 1978). Daft (1987, 1988, 1989) and Cova et al. (1986) 

reported that bromomethane was not detected in hundreds of food products, and 

Duggan et al. (1983) found-bromomethane in only 3 of 5,631 samples of 

vegetables. The tolerances for residues on agricultural commodities and 

processed foods that have been set by EPA and FDA are for bromide ion, not 

bromomethane (21 CFR 193; 40 CFR 180). 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
 

Inhalation of bromomethane in ambient air is the predominant exposure 

route for most people in the United States. Singh et al. (1981b) calculated 

that average daily doses of bromomethane from air in 3 U.S. cities ranged from 

4.5 to 24.5 μg/person, based on total air intake of 23 m3

/day by an adult. 

These estimates were based on 1979 monitoring data in urban areas. It is 

likely that urban bromomethane levels are currently lower than in the past, 

due to decreased emissions from automobiles using leaded gasoline (see 

Section 5.2.1). Based on the very low levels of bromomethane in water and the 

negligible levels in food, it appears that exposure of the general population 

to bromomethane from sources other than air is likely to be insignificant 

under normal circumstances. 

Exposure of workers to bromomethane is highly variable, depending on 

conditions. Exposure levels inside factories are regulated by OSHA, and the 

8-hour average concentration is not permitted to exceed 5 ppm (OSHA 1989). 
65
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

Highest exposures are most likely to occur during fumigation activities, 

especially when bromomethane is first released to the environment after 

fumigation ends. Exposure levels under these conditions could reach from 25 

to 2,500 ppm (IARC 1986; NIOSH 1984a; Van Den Oever et al. 1982), which would 

correspond to a dose of 100-10,000 mg/hour for an exposed worker. NIOSH 

estimated that about 105,000 workers in the United States were potentially 

exposed to bromomethane in the workplace in 1980 (NIOSH 1984a). 

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
 

Members of the general population are not likely to be exposed to high 

levels of bromomethane except in the immediate vicinity of industrial 

facilities that release the gas into air, or near locations where bromomethane 

is being used as a soil or a space fumigant. This includes individuals 

returning to work or live in locations that have recently been fumigated, 

especially if insufficient time has been allowed for the chemical to disperse. 

Individuals living near waste sites that contain bromomethane might also be 

exposed, although the level of exposure is not known. Individuals involved in 

the production of bromomethane and those licensed to use it as a fumigant may 

be exposed to high levels if proper safety precautions are not followed. 

5.7 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of 

ATSDR (in consultation with the Administrator of EPA and agencies and programs 

of the Public Health Service) to assess whether adequate information on the 

health effects of bromomethane is available. Where adequate information is 

not available, ATSDR, in conjunction with the NTP, is required to assure the 

initiation of a program of research designed to determine the health effects 

(and techniques for developing methods to determine such health effects) of 

bromomethane. 

The following categories of possible data needs have been identified by 

a joint team of scientists from ATSDR, NTP, and EPA. They are defined as 

substance-specific informational needs that, if met, would reduce or eliminate 

the uncertainties of human health assessment. In the future, the identified 

data needs will be evaluated and prioritized, and a substance-specific 

research agenda will be proposed. 

5.7.1 Data Needs
 

Physical and Chemical Properties. The physical and chemical properties 

of bromomethane are sufficiently well known to allow estimation of 

environmental fate. Although there is some disparity in reported values for 

the solubility in water and Henry's law constant for bromomethane (see 

Table 3-l), further studies to define these parameters more precisely do not 

appear essential, since volatilization from water is so rapid. 
66
 

5. POTENTIAL FOR HUMAN EXPOSURE 

Production, Import/Export, Use, and Disposal. Large quantities of 

bromomethane are produced and used in this country (TRI 1989), and there is 

significant opportunity for humans to be exposed to both during production and 

use (IARC 1986). Information is available on current volumes, and available 

data suggest production is increasing (IARC 1986). The main use of 

bromomethane is as a fumigant for soil, agricultural produce, and structures 

(IARC 1986), but data on the amount of bromomethane used for each type of 

fumigation were not located. Due to its volatility, nearly all releases from 

fumigation are to air (TRI 1989), and this is the medium most likely to be 

contaminated. Currently there are no regulations which restrict this release. 

According to the Emergency Planning and Community Nght-to-Know Act of 

1986, 42 U.S.C. Section 11023, industries are required to submit chemical 

release and off-site transfer information to the EPA. The Toxics Release 

Inventory (TRI), which contains this information for 1987, became available in 

May of 1989. This database will be updated yearly and should provide a list 

of industrial production facilities and emissions. 

Environmental Fate. The fate of bromomethane in the environment is 

dominated by rapid evaporation into air, where it is quite stable (EPA 1986b). 

The rates of volatilization from soil and water have been studied and are 

known with reasonable precision (although such rates are typically sitespecific) 

(Jury et al. 1984; Lyman et al. 1982). The rates of breakdown by 

hydrolysis, reaction with hydroxyl radical, and direct photolysis in the 

stratosphere have also been estimated (Castro and Belser 1981; Davis et al. 

1976; Robbins 1976). Further studies to improve the accuracy of available 

rate constants for these processes would be helpful, but do not appear to be 

essential in understanding the basic behavior of bromomethane in the 

environment. 

Bioavailability from Environmental Media. Bromomethane is known to be 

well absorbed following inhalation and oral contact (Gargas and Andersen 1982; 

Medinsky et al. 1984). Small amounts may also be absorbed across the skin, 

but this has not been quantified. No information was located regarding the 

relative bioavailability of bromomethane from media such as food or soil. 

However, since bromomethane has a low Koc value (Mabey et al. 1982), it is not 

likely that bioavailability would be much reduced by these matrices. 

Moreover, since bromomethane is rarely found in these media, research on this 

subject does not appear essential. 

Food Chain Bioaccumulation. Although the bioconcentration, 

bioaccumulation, and biomagnification of bromomethane have not been formally 

investigated, it seems clear that these are not of significant concern. This 

is the result of several factors, including the high volatility and high water 

solubility of the compound, its low Kow, and its relatively rapid metabolism 

by reaction with organic materials (Mabey et al. 1982; Medinsky et al. 1985). 

On this basis, it does not appear that research in this area is essential. 
67 

5. POTENTIAL FOR HUMAN EXPOSURE 

Exposure Levels in Environmental Media. Several studies are available 

documenting bromomethane concentrations in ambient air (Brodzinsky and Singh 

1983; Harsch and Rasmussen 1977), but data for bromomethane in water are rare. 

Bromomethane has been analyzed for, but rarely detected, in foods (Daft 1987, 

1988, 1989). Human exposure levels of bromomethane by inhalation of urban air 

have been calculated (Singh et al. 1981b). However, these levels are based on 

monitoring data more than 10 years old. Since urban air concentrations of 

bromomethane may have decreased due to reduced emissions from automobiles, 

exposure levels calculated from past data should be taken as an upper limit, 

and new levels calculated from current monitoring data would be useful. 

Additional monitoring data on levels in air near sites where bromomethane is 

being made or used would also be valuable in defining environmental levels. 

Exposure Levels in Humans. Bromomethane is not normally measured in 

human tissues such as blood or urine, even in people exposed to high levels. 

This is because bromomethane is removed from the body very quickly after 

exposure ceases. Consequently, this is not likely to be a useful means of 

monitoring exposure of humans to low levels of bromomethane. Increased levels 

of bromide have been detected in blood of persons exposed to bromomethane in 

accidents or in the workplace, but no studies were located regarding bromide 

levels in persons potentially exposed to bromomethane near waste sites. Since 

bromide is a normal component of serum, and since the serum bromide level is 

quite variable, it does not seem that broad surveys of blood bromide levels in 

persons living near waste sites would be useful. However, site-specific 

studies at locations where bromomethane exposure is likely might prove 

helpful. 

Exposure Registries. No exposure registries for bromomethane were 

located. This compound is not currently one of the compounds for which a 

subregistry has been established in the National Exposure Registry. The 

compound will be considered in the future when chemical selection is made for 

subregistries to be established. The information that is amassed in the 

National Exposure Registry facilitates the epidemiological research needed to 

assess adverse health outcomes that may be related to the exposure to this 

compound. 

5.7.2 On-going Studies
 

No information was located on any on-going studies on the fate and 

transport of bromomethane. However, two studies related to human exposure to 

bromomethane are being supported by the U.S. Department of Agriculture and 

conducted at the University of California, Davis. One project will analyze 

bromomethane residues on foods, and the second will quantitate exposure levels 

of field workers to bromomethane and develop appropriate procedures to 

minimize exposure from this source. Remedial investigations and feasibility 

studies at NPL sites that contain bromomethane will provide further 

information on environmental concentrations and human exposure levels near 

waste sites. 

69 

6. ANALYTICAL METHODS
 

The purpose of this chapter is to describe the analytical methods that 

are available for detecting and/or measuring and monitoring bromomethane in 

environmental media and in biological samples. The intent is not to provide 

an exhaustive list of analytical methods that could be used to detect and 

quantify bromomethane. Rather, the intention is to identify well-established 

methods that are used as the standard methods of analysis. Many of the 

analytical methods used to detect bromomethane in environmental samples are 

the methods approved by federal agencies such as EPA and the National 

Institute for Occupational Safety and Health (NIOSH). Other methods presented 

in this chapter are those that are approved by groups such as the Association 

of Official Analytical Chemists (AOAC) and the American Public Health 

Association (APHA). Additionally, analytical methods are included that refine 

previously used methods to obtain lower detection limits, and/or to improve 

accuracy and precision. 

As a volatile material, bromomethane is readily determined by gas 

chromatographic analysis. The selectivity and sensitivity of detection are 

increased by the use of an electron capture detector or a halide-specific 

detector, both of which are very sensitive for organohalides such as 

bromomethane. Specificity in detection is achieved with mass spectrometric 

detectors. 

6.1 BIOLOGICAL MATERIALS
 

Bromomethane may be isolated from biological materials either by 

extraction into an organic solvent, or simply by collecting headspace vapors. 

Table 6-l summarizes several methods used by researchers for measuring parent 

bromomethane in blood or tissues. Detection limits are sufficiently low that 

levels in blood or tissue associated with health effects can easily be 

measured. However, as discussed in Section 2.3.4, parent bromomethane is 

cleared from blood and tissues quite rapidly, so detection of bromomethane 

exposure in humans is typically performed by measuring serum bromide levels 

instead. Several methods for measuring bromide ion in serum are also 

presented in Table 6-l. These methods are also sufficiently sensitive that 

detection limits (0.5-2.5 ppm) are lower than typical levels of bromide in 

serum of unexposed people (5-15 ppm), and increases due to bromomethane 

exposure can easily be measured (Alexeeff and Kilgore 1983). 

6.2 ENVIRONMENTAL SAMPLES
 

Collection of bromomethane from environmental samples is nearly always 

achieved by trapping on a solid sorbent such as activated charcoal. For air 

samples, this is done simply by drawing the air through the sorbent. For 

water, soil, or solid wastes, bromomethane is purged from the sample by 

flushing with an inert gas, and this is then passed through the sorbent. 

Desorption may be achieved by extraction in a convenient solvent, or by 

heating. Table 6-2 summarizes a number of methods that have been developed 

for measuring bromomethane in various types of environmental media. In all 

cases, detection limits are much lower than levels of health concern. 


72
 

6. ANALYTICAL METHODS 

6.3 ADEQUACY OF THE DATABASE
 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of 

ATSDR (in consultation with the Administrator of EPA and agencies and programs 

of the Public Health Service) to assess whether adequate information on the 

health effects of bromomethane is available. Where adequate information is 

not available, ATSDR, in conjunction with the NTP, is required to assure the 

initiation of a program of research designed to determine the health effects 

(and techniques for developing methods to determine such health effects) of 

bromomethane. 

The following categories of possible data needs have been identified by 

a joint team of scientists from ATSDR, NTP, and EPA. They are defined as 

substance-specific informational needs that, if met, would reduce or eliminate 

the uncertainties of human health assessment. In the future, the identified 

data needs will be evaluated and prioritized, and a substance-specific 

research agenda will be proposed. 

6.3.1 Data Needs
 

Methods for Determining Biomarkers of Exposure and Effect. Exposure to 

bromomethane may be evaluated by measuring parent bromomethane, serum bromide, 

or methylated adducts. Existing methods can measure parent bromomethane in 

blood or expired air with excellent sensitivity (Honma et al. 1985; Pellizzari 

et al. 1985; Woodrow et al. 1988), but this is rarely done because 

bromomethane is cleared so quickly. Several sensitive methods exist for 

measuring serum bromide (Honma et al. 1985; Hunter 1955; Yamano et al. 1987), 

and this is the most common means for evaluating exposure. However, increased 

bromide is not specific for bromomethane exposure, and levels may vary widely 

between individuals. No routine methods have been established for measuring 

methyl adducts in DNA or protein (except those involving 14C-labeled 

bromomethane). Efforts to develop sensitive and specific immunoassays for 

these adducts would be valuable, since levels of these adducts may be directly 

proportional to tissue damage. In addition, combination of a method for 

detecting methyl adducts with a test for increased serum bromide would 

increase specificity in bromomethane exposure estimates. 

The characteristic markers of effect in people exposed to high levels of 

bromomethane are lung irritation, renal shut-down, and central nervous system 

injury (Clarke et al. 1945; O'Neal 1987; Prain and Smith 1952). In people 

exposed to low levels, only the neurological effects can be detected (Anger 

et al. 1986; Kishi et al. 1988; Verberk et al. 1979). Other than standard 

clinical neurological or neurobehavior tests, no specific biomarkers of 

bromomethane effects are known. Since parameters measured in these tests are 

highly variable among individuals, these tests are neither specific nor 

particularly sensitive. Efforts to identify and develop a more specific and 

objective biomarker of exposure would be valuable in evaluating the health 

significance of exposures that might occur in the environment or near waste 

sites. 
73 

6. ANALYTICAL METHODS 

Methods for Determining Parent Compounds and Degradation Products in 

Environmental Media. The medium of main concern for human exposure to 

bromomethane is air. Trace levels may occur in water or soil, but human 

exposures from these sources are not expected to be large enough to be of 

concern except in rare situations. Existing analytical methods can measure 

bromomethane in air (LeFevre et al. 1989; Mackenzie Peers 1985; Woodrow et al. 

1988) and other environmental media (APHA 1985a, 1985b; EPA 1982b, 1986c, 

1988d, 1988e, 19883) at levels considerably below those of health concern. 

The accuracy and precision of the methods are established, and adequate 

specificity may be achieved by use of mass spectrophotometric detectors. 

Nevertheless, further efforts to improve accuracy and ease of sample isolation 

and transfer to the analytical instrument would be helpful. 

6.3.2 On-going Studies
 

The Environmental Health Laboratory Sciences Division of the Center for 

Environmental Health and Injury Control, Centers for Disease Control, is 

developing methods for the analysis of bromomethane and other volatile organic 

compounds in blood. These methods use purge and trap methodology and magnetic 

mass spectrometry which gives detection limits in the low parts per trillion 

range. 

Research is underway at the Cooperative Institute for Research in 

Environmental Sciences (CIRES) at the University of Colorado, Boulder, to 

improve methods of analysis for bromomethane and related compounds in 

environmental samples. 

Examination of the literature suggests that studies are in progress to 

improve means for determining bromomethane, its metabolites, and related 

compounds in biological samples and environmental media. For example, a 

"Master Analytical Scheme" is being developed for organic compounds in water 

(Michael et al. 1988), which includes bromomethane as an analyte. The overall 

goal is to detect and quantitatively measure organic compounds at 0.1 μg/L in 

drinking water, 1 μg/L in surface waters, and 10 μg/L in effluent waters. 

Improvements continue to be made in chromatographic separation and detection. 

Problems associated with the collection of bromomethane on a sorbent trap, 

followed by thermal desorption may be overcome with direct purging to a 

capillary column with whole column cryotrapping (Pankow and Rosen 1988). 

Current research activities in supercritical fluid extraction (King 1989) and 

supercritical fluid chromatography (Smith 1988) include organohalide analytes 

such as bromomethane in biological samples and environmental media. 

75 

7. REGULATIONS AND ADVISORIES
 

Because of its potential to cause adverse health effects in exposed 

people, a number of regulations and guidelines have been established for 

bromomethane by various national and state agencies. These values are 

summarized in Table 7-l. 



________________ 

79
 

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analysis - method 20. IARC Sci Pub1 68:375-380.
 

Seiber JN, Woodrow JE. 1984. Airborne residues and human exposure. Studies
 

in Environmental Science 24:133-146.
 
95
 

8. REFERENCES 

*Shackelford WM, Keith LH. 1976. Frequency of organic compounds identified
 

in water. Athens, GA: Environmental Research Laboratory, Analytical
 

Chemistry Branch. EPA-600/4-76-062. NTIS No. PB-265470.
 

*Shah JJ, Heyerdahl EK. 1988. Project summary: National ambient volatile 

organic compounds (VOCs) data base update. Report to U.S. Environmental 

Protection Agency, Center for Environmental Research, Cincinnati, OH, by 

Atmospheric Sciences Research Laboratory, Research Triangle Park, NC. 

EPA/600/S3-88/010. 

Shah JJ, Singh HB. 1988. Distribution of volatile organic chemicals in 

outdoor and indoor air. Environ Sci Technol 22:1381-1388. 

*Shikiya J, Tsou G, Kowalski J, et al. 1984. Ambient monitoring of selected 

halogenated hydrocarbons and in the California South Coast Air Basin. 

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Association, 1-21. 

*Shiroishi M, Hayakowa A, Okumura K, et al. 1964. [Methyl bromide.]
 

Shokuryo Kenkyusho Kenkyu Hokoku 18:193-199. (Japanese) (Chem Abstr
 

66:36639s, 1967).
 

*Sikov MR, Cannon WC, Carr DB. 1980. Teratologic assessment of butylene 

oxide, styrene oxide and methyl bromide. Report to National Institute for 

Occupational Safety and Health, Division of Biomedical and Behavioral Science, 

U.S. Department of Health, Education and Welfare, Cincinnati, OH, by Battelle,
 

Pacific Northwest Laboratory, Richland, WA. NTIS No. PBSl-168510.
 

Simmon VF. 1978. Structural correlations of carcinogenic and mutagenic alkyl
 

Proceedings of the second FDA Office of Science Summer
 

Symposium on Structural Correlates of Carcinogenesis and Mutagenesis, U.S.
 

Naval Academy, August 31-September 2, 1977, 163-171.
 

*Simmon VF, Tardiff RG. 1978. The mutagenic activity of halogenated
 

compounds found in chlorinated drinking water. In: Water chlorination:
 

Environmental impact and health effects. Vol. 2. Ann Arbor, MI: Ann Arbor
 

Science, 417-431.
 

Simmon VF, Kauhanen K, Tardiff RG. 1977. Mutagenic activity of chemicals
 

identified in drinking water. Dev Toxicol Environ Sci 1:249-258.
 

Singh HB, Salas LY, Smith A, et al. 1979a. Atmospheric measurements of
 

selected toxic organic chemicals. Report to U.S. Environmental Protection
 

Agency, Environmental Sciences Research Laboratory, Atmospheric Chemistry and
 

Physics Department, Research Triangle Park, NC, by SRI International, Menlo
 

Park, CA, 3-4, 28, 33, 35.
 
96
 

8. REFERENCES
 

*Singh HB, Salas LJ, Shigeishi H, et al. 1979b. Atmospheric distributions,
 

sources, and sinks of selected halocarbons, hydrocarbons, SF6, and N2O.
 

Report to U.S. Environmental Protection Agency, Office of Research and
 

Development, Research Triangle Park, NC, by SRI International, Atmospheric
 

Sciences Center, Menlo Park, CA.
 

Singh HB, Salas LJ, Smith A, et al. 1980. Atmospheric measurements of
 

selected toxic organic chemicals. Report to U.S. Environmental Protection
 

Agency, Environmental Sciences Research Laboratory, Atmospheric Chemistry and
 

Physics Department, Research Triangle Park, NC, by SRI International, Menlo
 

Park, CA, 6.
 

Singh HB, Salas LJ, Smith A, et al. 1981a. Atmospheric measurements of
 

selected toxic organic chemicals. Report to U.S. Environmental Protection
 

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Physics Department, Research Triangle Park, NC, by SRI International,
 

Atmospheric Science Center. EPA-600/3-81-032.
 

*Singh HB, Salas LJ, Smith AJ, et al. 1981b. Measurements of some
 

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15:601-612.
 

*Singh HB, Salas LJ, Stiles RE, et al. 1982. Distribution of selected
 

gaseous organic mutagens and suspect carcinogens in ambient air. Environ Sci
 

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Singh HB, Salas LJ, Stiles RE. 1983a. Selected man-made halogenated
 

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*Singh HB, Salas LJ, Stiles RE. 1983b. Methyl halides in and over the 

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*Smith RM. 1988. Supercritical fluid chromatography. Letchworth, England:
 

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SRI. 1986. Directory of chemical producers: United States of America.
 

Menlo Park, CA: SRI International, 853.
 

*SRI. 1987. Directory of chemical producers: United States of America.
 

Menlo Park, CA: SRI International, 841.
 

*SRI, 1988. Directory of chemical producers: United States of America.
 

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*SRI. 1989. Directory of chemical producers: United States of America.
 

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*Staples CA, Werner AF, Hoogheem TJ. 1985. Assessment of priority pollutant
 

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*Starratt AN, Bond EJ. 1988. In vitro methylation of DNA by the fumigant
 

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Stenger VA. 1978. Kirk-Othmer encyclopedia of chemical technology. 3rd ed.
 

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Sturges WT, Harrison RM. 1986. Bromine in marine aerosols and the ongin,
 

nature and quantity of natural atmospheric bromine. Atmos Environ
 

20:1485-1496.
 

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prehospital care. 2nd ed. Beltsville, MD: Bradford Communications
 

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Thomas DA, Morgan KT. 1988. Olfactory toxicity: Studies of methyl bromide.
 

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olfactory epithelium of rats following inhalation exposure to methyl bromide
 

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methyl bromide-induced olfactory toxicity [Abstract]. Toxicologist 9:37.
 

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*TRI. 1989. Toxic Chemical Release Inventory. National Library of Medicine,
 

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Tucker JD, Xu J, Stewart J, et al. 1985. Development of a method to detect
 

volatile genotoxins using sister chromatid exchanges [Abstract]. Environ
 

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*Tucker JD, Xu J, Stewart J, et al. 1986. Detection of sister chromatid
 

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*Van Den Oever R, Roosels D, Lahaye D. 1982. Actual hazard of methyl bromide
 

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mutagenic potential of carbon disulfide, carbon tetrachloride,
 

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Environmental Protection Agency, Office of Health and Environmental
 

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*Viner N. 1945. Methyl bromide poisoning: A new industrial hazard. Can Med
 

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Vogel TM, Reinhard M. 1986. Reaction products and rates of disappearance of
 

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insecticides, their toxicity and potential dangers. Washington, DC: U.S.
 

Public Health Service. PHS Publication No. 414, 15-28.
 

Voogd CE, Knaap AGAC, Van Der Heijden CA, et al. 1982. Genotoxicity of
 

methyl bromide in short-term assay systems [Abstract]. Mutat Res 97:233.
 

*Watrous RM. 1942. Methyl bromide, local and mild systemic toxic effects.
 

Ind Med 11:575-579.
 

*Wester PW, Kroes R. 1988. Forestomach carcinogens: Pathology and relevance
 

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*Windholz M, ed. 1983. The Merck index: An encyclopedia of chemicals,
 

drugs, and biologicals. Rahway, NJ: Merck and Company, Inc, 865.
 
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*Wang 0, Brocker W, Davis HV, et al. 1984. Mortality of workers potentially
 

exposed to organic and inorganic brominated chemicals, DBCP, TRIS, PBB and
 

DDT. Br J Ind Med 41:15-24.
 

*Woodrow JE, McChesney MM, Seiber JN. 1988. Determination of methyl bromide
 

in air samples by headspace gas chromatography. Anal Chem 60:509-512.
 

Worthing CR, Walker SB, ed. 1983. Methyl bromide. In: The pesticide
 

manual: A world compendium. 7th ed. London, England: The British Crop
 

Protection, 372.
 

*Wyers H. 1945. Methyl bromide intoxication. Br J Ind Med 30:24-29.
 

*Yamano Y, Ito I, Nagao N, et al. 1987. [A simple determination method of
 

bromide ion in plasma of methyl bromide workers by head space gas
 

chromatography.] Sangyo Igaku 29:196-201. (Japanese)
 

*Yang RSH. 1990. Personal communication from Dr. Raymond Yang (NTP) to Dr.
 

William Cibulas, Jr. (ATSDR) regarding findings and publication status of
 

draft technical report on inhalation studies on methyl bromide.
 

*Zwaveling JH, De Kort WL, Meulenbelt J, et al. 1987. Exposure of the skin
 

to methyl bromide: A study of six cases occupationally exposed to high
 

concentrations during fumigation. Hum Toxicol 6:491-495.
 

101
 

9. GLOSSARY
 

Acute Exposure -- Exposure to a chemical for a duration of 14 days or less, as
 

specified in the Toxicological Profiles.
 

Adsorption Coefficient (KOC) -- The ratio of the amount of a chemical adsorbed per
 

unit weight of organic carbon in the soil or sediment to the concentration of the
 

chemical in solution at equilibrium.
 

Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or
 

soil (i.e., the solid phase) divided by the amount of chemical in the solution
 

phase, which is in equilibrium with the solid phase, at a fixed solid/solution
 

ratio. It is generally expressed in micrograms of chemical sorbed per gram of
 

soil or sediment.
 

Bioconcentration Factor (BCF) -- The quotient of the concentration of a
 

chemical in aquatic organisms at a specific time or during a discrete time
 

period of exposure divided by the concentration in the surrounding water at
 

the same time or during the same period.
 

Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or group
 

of studies, that produces significant increases in the incidence of cancer (or
 

tumors) between the exposed population and its appropriate control.
 

Carcinogen -- A chemical capable of inducing cancer.
 

Ceiling Value -- A concentration of a substance that should not be exceeded,
 

even instantaneously.
 

Chronic Exposure -- Exposure to a chemical for 365 days or more, as specified
 

in the Toxicological Profiles.
 

Developmental Toxicity -- The occurrence of adverse effects on the developing
 

organism that may result from exposure to a chemical prior to conception
 

(either parent), during prenatal development, or postnatally to'the time of
 

sexual maturation. Adverse developmental effects may be detected at any point
 

in the life span of the organism.
 

Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a
 

result of prenatal exposure to a chemical; the distinguishing feature between
 

the two terms is the stage of development during which the insult occurred.
 

The terms, as used here, include malformations and variations, altered growth,
 

and in utero death.
 

EPA Health Advisory -- An estimate of acceptable drinking water levels for a
 

chemical substance based on health effects information. A health advisory is
 

not a legally enforceable federal standard, but serves as technical guidance
 

to assist federal, state, and local officials.
 

Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental
 

concentration of a contaminant from which one could escape within 30 min
 

without any escape-impairing symptoms or irreversible health effects.
 
102
 

9. GLOSSARY
 

Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days
 

as specified in the Toxicological Profiles.
 

Immunologic Toxicity -- The occurrence of adverse effects on the immune system
 

that may result from exposure to environmental agents such as chemicals.
 

In Vitro -- Isolated from the living organism and artificially maintained, as
 

in a test tube.
 

In Vivo -- Occurring within the living organism.
 

Lethal Concentration(Lo) (LCLo) -- The lowest concentration of a chemical in air
 

which has been reported to have caused death in humans or animals.
 

Lethal Concentration(50) (LC50) -- A calculated concentration of a chemical in air
 

to which exposure for a specific length of time is expected to cause death in 50%
 

of a defined experimental animal population.
 

Lethal Dose(Lo) (LDLo) -- The lowest dose of a chemical introduced by a route other
 

than inhalation that is expected to have caused death in humans or
 

animals.
 

Lethal Dose(50) (LD50) -- The dose of a chemical which has been calculated to cause
 

death in 50% of a defined experimental animal population.
 

Lethal Time(50) (LT50) -- A calculated period of time within which a specific
 

concentration of a chemical is expected to cause death in 50% of a defined
 

experimental animal population.
 

Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical in a
 

study or group of studies, that produces statistically or biologically
 

significant increases in frequency or severity of adverse effects between the
 

exposed population and its appropriate control.
 

Malformations -- Permanent structural changes that may adversely affect
 

survival, development, or function.
 

Minimal Risk Level -- An estimate of daily human exposure to a chemical that
 

is likely to be without an appreciable risk of deleterious effects
 

(noncancerous) over a specified duration of exposure.
 

Mutagen -- A substance that causes mutations. A mutation is a change in the
 

genetic material in a body cell. Mutations can lead to birth defects,
 

miscarriages, or cancer.
 

Neurotoxicity -- The occurrence of adverse effects on the nervous system
 

following exposure to chemical.
 
103
 

9. GLOSSARY
 

No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which
 

there were no statistically or biologically significant increases in frequency
 

or severity of adverse effects seen between the exposed population and its
 

appropriate control. Effects may be produced at this dose, but they are not
 

considered to be adverse.
 

Octanol-Water Partition Coefficient (Kow) -- The equilibrium ratio of the
 

concentrations of a chemical in n-octanol and water, in dilute solution.
 

Permissible Exposure Limit (PEL) -- An allowable exposure level in workplace
 

air averaged over an g-hour shift.
 

q1* -- The upper-bound estimate of the low-dose slope of the dose-response
 

curve as determined by the multistage procedure. The q1* can be used to
 

calculate an estimate of carcinogenic potency, the incremental excess cancer
 

risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3 for air). 

Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps an
 

order of magnitude) of the daily exposure of the human population to a
 

potential hazard that is likely to be without risk of deleterious effects
 

during a lifetime. The RfD is operationally derived from the NOAEL (from
 

animal and human studies) by a consistent application of uncertainty factors
 

that reflect various types of data used to estimate RfDs and an additional
 

modifying factor, which is based on a professional judgment of the entire
 

database on the chemical. The RfDs are not applicable to nonthreshold effects
 

such as cancer.
 

Reportable Quantity (RQ) -- The quantity of a hazardous substance that is
 

considered reportable under CERCLA. Reportable quantities are: (1) 1 lb or
 

greater or (2) for selected substances, an amount established by regulation
 

either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities are
 

measured over a 24-hour period.
 

Reproductive Toxicity -- The occurrence of adverse effects on the reproductive
 

system that may result from exposure to a chemical. The toxicity may be directed
 

to the reproductive organs and/or the related endocrine system. The
 

manifestation of such toxicity may be noted as alterations in sexual behavior,
 

fertility, pregnancy outcomes, or modifications in other functions that are
 

dependent on the integrity of this system.
 

Short-Term Exposure Limit (STEL) -- The maximum concentration to which workers
 

can be exposed for up to 15 min continually. No more than four excursions are
 

allowed per day, and there must be at least 60 min between exposure periods.
 

The daily TLV-TWA may not be exceeded.
 

Target Organ Toxicity -- This term covers a broad range of adverse effects on
 

target organs or physiological systems (e.g., renal, cardiovascular) extending
 

from those arising through a single limited exposure to those assumed over a
 

lifetime of exposure to a chemical.
 
104
 

9. GLOSSARY
 

Teratogen -- A chemical that causes structural defects that affect the
 

development of an organism.
 

Threshold Limit Value (TLV) -- A concentration of a substance to which most
 

workers can be exposed without adverse effect. The TLV may be expressed as a
 

TWA, as a STEL, or as a CL.
 

Time-weighted Average (TWA) -- An allowable exposure concentration averaged
 

over a normal 8-hour workday or 40-hour workweek.
 

Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a route
 

other than inhalation, which is expected to cause a specific toxic effect in
 

50% of a defined experimental animal population.
 

Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD
 

from experimental data. UFs are intended to account for (1) the variation in
 

sensitivity among the members of the human population, (2) the uncertainty in
 

extrapolating animal data to the case of human, (3) the uncertainty in
 

extrapolating from data obtained in a study that is of less than lifetime
 

exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data.
 

Usually each of these factors is set equal to 10.
 
A-l 

APPENDIX A
 

USER'S GUIDE
 

Chapter 1
 

Public Health Statement
 

This chapter of the profile is a health effects summary written in nontechnical 

language. Its intended audience is the general public especially people living in 

the vicinity of a hazardous waste site or substance release. If the Public 

Health Statement were removed from the rest of the document, it would still 

communicate to the lay public essential information about the substance. 

The major headings in the Public Health Statement are useful to find specific 

topics of concern. The topics are written in a question and answer format. The 

answer to each question includes a sentence that will direct the reader to 

chapters in the profile that will provide more information on the given topic. 

Chapter 2
 

Tables and Figures for Levels of Significant Exposure (LSE)
 

Tables (2-1, 2-2, and 2-3) and figures (2-l and 2-2) are used to summarize health 

effects by duration of exposure and endpoint and to illustrate graphically levels 

of exposure associated with those effects. All entries in these tables and 

figures represent studies that provide reliable, quantitative estimates of NoObserved-Adverse-Effect Levels (NOAELS), Lowest-Observed- Adverse-Effect Levels 

(LOAELs) for Less Serious and Serious health effects, or Cancer Effect Levels 

(CELs). In addition, these tables and figures illustrate differences in response 

by species, Minimal Risk Levels (MRLs) to humans for noncancer end points, and 

EPA's estimated range associated with an upper-bound individual lifetime cancer 

risk of 1 in 10,000 to 1 in 10,000,000. The LSE tables and figures can be used 

for a quick review of the health effects and to locate data 

for a specific exposure scenario. The LSE tables and figures should always be 

used in conjunction with the text. 

The legends presented below demonstrate the application of these tables and 

figures. A representative example of LSE Table 2-l and Figure 2-l are shown. The 

numbers in the left column of the legends correspond to the numbers in the 

example table and figure. 

LEGEND
 

See LSE Table 2-l
 

(1) Route of Exposure One of the first considerations when reviewing the

 toxicity of a substance using these tables and figures should be the

 relevant and appropriate route of exposure. When sufficient data exist, 
 

 

 

A-2
 

APPENDIX A

 three LSE tables and two LSE figures are presented in the document. The

 three LSE tables present data on the three principal routes of exposure,

 i.e., inhalation, oral, and dermal (LSE Table 2-1, 2-2, and 2-3,

 respectively). LSE figures are limited to the inhalation (LSE Figure 2-1)

 and oral (LSE Figure 2-2) routes. 

(2) Exposure Duration Three exposure periods: acute (14 days or less);

 intermediate (15 to 364 days); and chronic (365 days or more) are

 presented within each route of exposure. In this example, an inhalation

 study of intermediate duration exposure is reported. 

(3) 	 Health Effect The major categories of health effects included in 

LSE tables and figures are death, systemic, immunological, 

neurological, developmental, reproductive, and cancer. NOAELs and 

LOAELs can be reported in the tables and figures for all effects but 

cancer. Systemic effects are further defined in the "System" column 

of the LSE table. 

(4) Key to Figure Each key number in the LSE table links study information

 to one or more data points using the same key number in the corresponding

 LSE figure. In this example, the study represented by key number 18 has

 been used to define a NOAEL and a Less Serious LOAEL (also see the two

 "18r" data points in Figure 2-l). 

(5) Species The test species, whether animal or human, are identified in this

 column. 

(6) Exposure Freauencv/Duration The duration of the study and the weekly and

 daily exposure regimen are provided in this column. This permits

 comparison of NOAELs and LOAELs from different studies. In this case (key

 number 18), rats were exposed to [substance x] via inhalation for 13

 weeks, 5 days per week, for 6 hours per day. 

(7) System This column further defines the systemic effects. These systems

 include: respiratory, cardiovascular, gastrointestinal, hematological,

 musculoskeletal, hepatic, renal, and dermal/ocular. "Other" refers to any

 systemic effect (e.g., a decrease in body weight) not covered in these

 systems. In the example of key number 18, one systemic effect

 (respiratory) was investigated in this study. 

(8) NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure

 level at which no harmful effects were seen in the organ system studied.

 Key number 18 reports a NOAEL of 3 ppm for the respiratory system which

 was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm

 (see footnote "c"). 

(9) LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest

 exposure level used in the study that caused a harmful health effect.

 LOAELs have been classified into "Less Serious" and "Serious" effects.

 These distinctions help readers identify the levels of exposure at which

 adverse health effects first appear and the gradation of effects with

 increasing dose. A brief description of the specific end point used to 
A-3
 

APPENDIX A

 quantify the adverse effect accompani.es the MAEL. The "Less Serious"

 respiratory effect reported in key number 18 (hyperplasia) occurred at a

 LOAEL of 10 ppm. 

(10). Reference The complete reference citation is given in Chapter 8 of the

 profile. 

(11). CEL A Cancer Effect Level (CEL) is the lowest exposure level associated

 with the onset of carcinogenesis in experimental or epidemiological

 studies. CELs are always considered serious effects. The LSE tables and

 figures do not contain NOAELs for cancer, but the text may report doses

 which did not cause a measurable increase in cancer. 

(12). Footnotes Explanations of abbreviations or reference notes for data in

 the LSE tables are found in the footnotes. Footnote "c" indicates the

 NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.005 ppm. 

LEGEND
 

See LSE Figure 2-l
 

LSE figures graphically illustrate the data presented in the corresponding LSE 

tables. Figures help the reader quickly compare health effects according to 

exposure levels for particular exposure duration. 

(13). Exposure Duration The same exposure periods appear as in the LSE table.

 In this example, health effects observed within the intermediate and

 chronic exposure periods are illustrated. 

(14). Health Effect These are the categories of health effects for which 

reliable quantitative data exist. The same health effects appear in the 

LSE table. 

(15). Levels Of Exposure Exposure levels for each health effect in the LSE 

tables are graphically displayed in the LSE figures. Exposure levels are 

reported on the log scale "y" axis. Inhalation exposure is reported in 

mg/m3

 or ppm and oral exposure is reported in mg/kg/day. 

(16). NOAEL In this example, 18r NOAEL is the critical end point for which an 

intermediate inhalation exposure MRL is based. As you can see from the 

LSE figure key, the open-circle symbol indicates a NOAEL for the test 

species (rat). The key number 18 corresponds to the entry in the LSE 

table. The dashed descending arrow indicates the extrapolation from the 

exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005 

ppm (see footnote "b" in the LSE table). 

(17). CEL Key number 38r is one of three studies for which Cancer Effect Levels 

(CELs) were derived. The diamond symbol refers to a CEL for the test 

species (rat). The number 38 corresponds to the entry in the LSE table. 
A-4
 

APPENDIX A
 

(18). Estimated Upper-Bound Human Cancer Risk Levels This is the range 

associated with the upper-bound for lifetime cancer risk of 1 in 10,000 

to 1 in 10,000,000. These risk levels are derived from EPA's Human Health 

Assessment Group's upper-bound estimates of the slope of the cancer dose 

response curve at low dose levels (q1*). 

(19). Key to LSE Figure The Key explains the abbreviations and symbols used in 

the figure. 


A-7
 

APPENDIX A
 

Chapter 2 (Section 2.4)
 

Relevance to Public Health
 

The Relevance to Public Health section provides a health effects summary based 

on evaluations of existing toxicological, epidemiological, and toxicokinetic 

information. This summary is designed to present interpretive, 

weight-of-evidence discussions for human health end points by addressing the 

following questions. 

1. 	 What effects are known to occur in humans? 

2. 	 What effects observed in animals are likely to be of concern to 

humans? 

3. 	 What exposure conditions are likely to be of concern to humans, 

especially around hazardous waste sites? 

The section discusses health effects by end point. Human data are presented 

first, then animal data. Both are organized by route of exposure (inhalation, 

oral, and dermal) and by duration (acute, intermediate, and chronic). In vitro 

data and data from parenteral routes (intramuscular, intravenous, subcutaneous, 

etc.) are also considered in this section. If data are located in the 

scientific literature, a table of genotoxicity information is included. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, 

when appropriate, using existingtoxicokinetic, genotoxic, andcarcinogenic data. 

ATSDR does not currently assess cancer potency or perform cancer risk 

assessments. MRLs for noncancer end points if derived, and the end points from 

which they were derived are indicated and discussed in the appropriate 

section(s). 

Limitations to existing scientific literature that prevent a satisfactory 

evaluation of the relevance to public health are identified in the Identification 

of Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information was available, MRLs were derived. MRLs 

are specific for route (inhalation or oral) and duration (acute, intermediate, 

or chronic) of exposure. Ideally, MRLs can be derived from all six exposure 

scenarios (e.g., Inhalation - acute, -intermediate, -chronic; Oral - acute, ­

intermediate, - chronic). These MRLs are not meant to support regulatory action, 

but to aquaint health professionals with exposure levels at which adverse health 

effects are not expected to occur in humans. They should help physicians and 

public health officials determine the safety of a community living near a 

substance emission, given the concentration of a contaminant in air or the 

estimated daily dose received via food or water. MRLs are based largely on 

toxicological studies in animals and on reports of human occupational exposure. 
A-8 

APPENDIX A 

MRL users should be familiar with the toxicological information on which the 

number is based. Section 2.4, "Relevance to Public Health," contains basic 

information known about the substance. Other sections such as 2.6, "Interactions 

with Other Chemicals" and 2.7, "Populations that are Unusually Susceptible" 

provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are 

derived using a modified version of the risk assessment methodology used by the 

Environmental Protection Agency (EPA) (Barnes and Dourson, 1988; EPA 1989a) to 

derive reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the end point which, in its best 

judgement, represents the most sensitive humanhealth effect for a given exposure 

route and duration. ATSDR cannot make this judgement or derive an MRL unless 

information (quantitative or qualitative) is available for all potential effects 

(e.g., systemic, neurological, and developmental). In order to compare NOAELs 

and LOAELs for specific end points, all inhalation exposure levels are adjusted 

for 24hr exposures and all intermittent exposures for inhalation and oral routes 

of intermediate and chronic duration are adjusted for continous exposure (i.e., 

7 days/week). If the information and reliable quantitative data on the chosen 

end point are available, ATSDR derives an MRL using the most sensitive species 

(when information from multiple species is available) with the highest NOAEL that 

does not exceed any adverse effect levels. The NOAEL is the most suitable end 

point for deriving an MRL. When a NOAEL is not available, a Less Serious LOAEL 

can be used to derive an MRL, and an uncertainty factor (UF) of 10 is employed. 

MRLs are not derived from Serious LOAELs. Additional uncertainty factors of 10 

each are used for human variability to protect sensitive subpopulations (people 

who are most susceptible to the health effects caused by the substance) and for 

interspecies variability (extrapolation from animals to humans), In deriving an 

MRL, these individual uncertainty factors are multiplied together. The product 

is then divided into the adjusted inhalation concentration or oral dosage 

selected from the study. Uncertainty factors used in developing a 

substance-specific MRL are provided in the footnotes of the LSE Tables. 




C-l 

APPENDIX C 

PEER REVIEW 

A peer review panel was assembled for bromomethane. The panel consisted 

of the following members: Dr. Judith S. Bellin, Private Consultant, 

Washington, DC; Dr. Caroline Holsapple (formerly Caroline Kramer), Department 

of Pharmacology and Toxicology, Medical College of Virginia, Richmond, VA; 

Dr. Norman M. Trieff, Department of Preventive Medicine and Community Health, 

The University of Texas Medical Branch, Galveston, TX; and Dr. Nancy Reiches, 

Private Consultant, Columbus, Ohio. These experts collectively have knowledge 

of bromomethane's physical and chemical properties, toxicokinetics, key health 

end points, mechanisms of action, human and animal exposure, and 

quantification of risk to humans. All reviewers were selected in conformity 

with the conditions for peer review specified in the Comprehensive 

Environmental Response, Compensation, and Liability Act of 1986, Section 104. 

Scientists from the Agency for Toxic Substances and Disease Registry 

(ATSDR) have reviewed the peer reviewers' comments and determined which 

comments will be included in the profile. A listing of the peer reviewers' 

comments not incorporated in the profile, with a brief explanation of the 

rationale for their exclusion, exists as part of the administrative record for 

this compound. A list of databases reviewed and a list of unpublished 

documents cited are also included in the administrative record. 

The citation of the peer review panel should not be understood to imply 

its approval of the profile's final content. The responsibility for the 

content of this profile lies with the ATSDR.