TOXICOLOGICAL PROFILE FOR
 

1,2-DIBROMOETHANE
 

Agency for Toxic Substances and Disease Registry
 

U.S. Public Health Service
 

July 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.
 
iii
 

FOREWORD
 

The Superfund Amendments and Reauthorization Act (SARA) of 1986
 

(Public Law 99-499) extended and amended the Comprehensive Environmental
 

Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).
 

This public law directed the Agency for Toxic Substances and Disease
 

Registry (ATSDR) to prepare toxicological profiles for hazardous
 

substances which are most commonly found at facilities on the CERCLA
 

National Priorities List and which pose the most significant potential
 

threat to human health, as determined by ATSDR and the Environmental
 

Protection Agency (EPA). The lists of the 250 most significant
 

hazardous substances were published in the Federal Resister on April 17,
 

1987; on October 20, 1988; on October 26, 1989; and on October 17, 1990.
 

A revised list of 275 substances was published on October 17, 1991.
 

Section 104(i)(3) of CERCLA, as amended, directs the Administrator
 

of ATSDR to prepare a toxicological profile for each substance on the
 

lists. Each profile must include the following content:
 

(A) An examination, summary, and interpretation of available
 

toxicological information and epidemiological evaluations on the
 

hazardous substance in order to ascertain the levels of significant
 

human exposure for the substance and the associated acute,
 

subacute, and chronic health effects.
 

(B) A determination of whether adequate information on the health
 

effects of each substance is available or in the process of
 

development to determine levels of exposure which present a
 

significant risk to human health of acute, subacute, and chronic
 

health effects.
 

(C) Where appropriate, an identification of toxicological testing
 

needed to identify the types or levels of exposure that may present
 

significant risk of adverse health effects in humans.
 

This toxicological profile is prepared in accordance with
 

guidelines developed by ATSDR and EPA. The original guidelines were
 

published in the Federal Register on April 17, 1987. Each profile will
 

be revised and republished as necessary.
 

The ATSDR toxicological profile is intended to characterize
 

succinctly the toxicological and adverse health effects information for
 

the hazardous substance being described, Each profile identifies and
 

reviews the key literature (that has been peer-reviewed) that describes
 

a hazardous substance's toxicological properties. Other pertinent
 

literature is also presented but described in less detail than the key
 

studies. The profile is not intended to be an exhaustive document;
 

however, more comprehensive sources of specialty information are
 

referenced.
 









1
 

1. PUBLIC HEALTH STATEMENT
 

This Statement was prepared to give you information about
 

1,2-dibromoethane (ethylene dibromide, EDB) 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).
 

1,2-Dibromoethane has been found at 9 of these sites. However, we do not know
 

how many of the 1,177 NPL sites have been evaluated for 1,2-dibromo-ethane.
 

As EPA evaluates more sites, the number of sites at which 1,2-dibromoethane is
 

found may change. The information is important to you because
 

1,2-dibromoethane may cause harmful health effects and because these sites are
 

potential or actual sources of human exposure to 1,2-dibromoethane.
 

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 the chemical.
 

If you are exposed to a hazardous substance such as 1,2-dibromoethane,
 

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 1,2-DIBROMOETHANE?
 

1,2-Dibromoethane is a pesticide and gasoline additive. It is mostly
 

man-made, but it may occur naturally in the ocean in very small amounts. In
 

the 1970s and early 1980s, it was used in soil to kill insects and worms that
 

get on fruits, vegetables, and grain crops. It was also used in soil to
 

protect grass, such as on golf courses. Another use was to kill fruit flies
 

on citrus fruits, mangoes, and papayas after they were picked. EPA stopped
 

most of these uses in 1984. 1,2-Dibromoethane is added to leaded gasoline to
 

produce better fuel efficiency. Because use of leaded gasoline has fallen,
 

less 1,2-dibromoethane is made for this use. The chemical is a colorless
 

liquid with a mild, sweet odor. It evaporates easily and can dissolve in
 

water. 1,2-Dibromoethane stays in groundwater and in soil for a long time but
 

breaks down quickly in the air. More information on the chemical and physical
 

properties of 1,2-dibromoethane can be found in Chapter 3 and on its
 

occurrence and fate in the environment in Chapter 5.
 
2
 

1. PUBLIC HEALTH STATEMENT
 

1.2 HOW MIGHT I BE EXPOSED TO 1,2-DIBROMOETHANE?
 

You can be exposed to low levels of 1,2-dibromoethane in drinking water
 

(especially well water) and in air. Before EPA stopped the use of
 

1,2-dibromoethane as a pesticide, the most common way you would have been
 

exposed was by eating food that had very small amounts of this chemical in it.
 

You could still be exposed to low levels of 1,2-dibromoethane, particularly
 

from groundwater (well water), in areas where the chemical was used in farming
 

or from hazardous waste sites. Most of the 1,2-dibromoethane that enters the
 

soil will get into the groundwater or evaporate into the air. Small amounts
 

can remain in very tiny particles in soil near hazardous waste sites or in
 

areas once used as farmland. The compound may be released from these
 

particles slowly over time or if the soil is crushed or disturbed. You can be
 

exposed to 1,2-dibromoethane in the air near production plants. Background
 

levels in the environment are very low. The air most people breathe contains
 

between 0.01-0.06 parts of 1,2-dibromoethane per billion parts of air (ppb).
 

Because 1,2-dibromoethane easily evaporates, most surface waters do not
 

contain detectable amounts. Groundwater is more likely to contain
 

1,2-dibromoethane with an average concentration of about 0.9 ppb. In foods,
 

1,2-dibromoethane has recently been found in 2 out of 549 samples at
 

concentrations of 2 and 11 ppb. There is no information on background levels
 

in surface water or soil. If you applied 1,2-dibromoethane on a farm or golf
 

course, if you worked to pack fruits gassed with 1,2-dibromoethane, or if you
 

worked in a factory that made 1,2-dibromoethane, you could be exposed to much
 

higher than background levels. For more information on human exposure to
 

1,2-dibromoethane, see Chapter 5.
 

1.3 HOW CAN 1,2-DIBROMOETHANE ENTER AND LEAVE MY BODY?
 

1,2-Dibromoethane can enter your body after you eat or drink
 

contaminated food and water. It can also enter your body through your skin
 

when you bathe or swim in contaminated water. The 1,2-dibromoethane inside
 

tiny soil particles may enter your body if you crush or eat contaminated soil.
 

The chemical can enter your nose and lungs when you breathe air that contains
 

1,2-dibromoethane or when you shower with water that is contaminated. Near
 

hazardous waste sites or near areas that once were farmed, the most likely way
 

that you will be exposed is by drinking contaminated groundwater.
 

1,2-Dibromoethane will be rapidly taken into your bloodstream by any method of
 

exposure. Most of it builds up in your liver and kidneys where it is rapidly
 

broken down to different substances. These substances leave your body quickly
 

in the urine, and smaller amounts are passed in liver bile into the stool.
 

Small amounts of 1,2-dibromoethane that are not broken down can be breathed
 

out of your lungs. Chapter 2 has more information on how 1,2-dibromoethane
 

enters and leaves the body.
 
3
 

1. PUBLIC HEALTH STATEMENT
 

1.4 HOW CAN 1,2-DIBROMOETHANE AFFECT MY HEALTH?
 

The effects of breathing high levels of 1,2-dibromoethane in humans are
 

unknown. Studies in animals show that they can die from breathing high
 

concentrations of 1,2-dibromoethane for a short time while lower
 

concentrations can cause liver and kidney damage. You can die if you swallow
 

or have skin contact with large quantities of 1,2-dibromoethane. A woman who
 

drank 40 milliliters (mL) of pure liquid 1,2-dibromoethane died within a day.
 

Changes in the liver and kidney are reported in humans that died of ingestion
 

of 1,2-dibromoethane. People who tried to commit suicide by swallowing
 

concentrated 1,2-dibromoethane got ulcers inside their mouth and stomach.
 

Laboratory rats and mice fed less-concentrated 1,2-dibromoethane for as little
 

as 2 weeks had damage to the lining of their stomach. If you spill liquid
 

1,2-dibromoethane on your skin, you can get blisters.
 

Breathing 1,2-dibromoethane for moderately long periods damages the
 

lining of the nose in rats. This effect has not been seen in humans. Animals
 

that breathed or ate food containing 1,2-dibromoethane for short or long
 

periods were less fertile or had abnormal sperms. Changes in the brain and
 

behavior have occurred in young rats whose male parents had breathed 1,2­

dibromoethane.
 

A worker who breathed 1,2-dibromoethane for several years developed
 

bronchitis, headache, and depression, but his health improved after he stopped
 

breathing air contaminated with 1,2-dibromoethane. 1,2-Dibromoethane is not
 

known to cause birth defects in people. It can impair reproduction in males
 

by damaging sperms in testicles. This type of damage has been seen in workers
 

exposed to 1,2-dibromoethane for several years. Pregnant animals that are
 

sick from exposure to 1,2-dibromoethane have had pups with birth defects.
 

There are no reports of cancer in workers or other people exposed to 1,2­

dibromoethane for several years. Rats and mice that repeatedly breathed,
 

swallowed, or had skin contact with 1,2-dibromoethane for long periods had
 

cancer in many organs. The Department of Health and Human Services has
 

determined that 1,2-dibromoethane may reasonably be anticipated to be a
 

carcinogen.
 

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


 EXPOSED TO 1,2-DIBROMOETHANE?
 

There is no known reliable medical test to determine whether you have
 

been exposed to 1,2-dibromoethane. For more information, see Chapters 2
 

and 6.
 
4
 

1. PUBLIC HEALTH STATEMENT
 

1.6 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO


 PROTECT HUMAN HEALTH?
 

The federal government has set standards and guidelines to protect
 

people from the potential health effects of 1,2-dibromoethane in drinking
 

water, food, and air. EPA recommends that no more than 0.008 ppm of
 

1,2-dibromoethane should be present in drinking water that is consumed for up
 

to 10 days. EPA does not allow any 1,2-dibromoethane to be in food.
 

Companies must report to EPA if they spill 1,000 pounds or more of
 

1,2-dibromoethane.
 

The Occupational Health and Safety Administration (OSHA) has limited
 

workers' exposure to 1,2-dibromoethane in air to an average of 20 ppm for an
 

8-hour workday. According to OSHA, short-term exposure of 15 minutes to
 

1,2-dibromoethane should not be more than 0.5 ppm. The National Institute for
 

Occupational Safety and Health (NIOSH) has set an average limit for
 

1,2-dibromoethane of 0.045 ppm in workroom air during an 8-hour day.
 

According to NIOSH, short-term exposure of 15 minutes to 1,2-dibromoethane
 

should not be more than 0.13 ppm.
 

For more information on guidelines and standards for 1,2-dibromoethane
 

exposure, see Chapter 7.
 

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 illness 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 1,2-dibromoethane 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 1,2-dibromoethane 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 (less than 15 days), 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-observedadverse-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.
 

Levels of exposure associated with the carcinogenic effects of
 

1,2-dibromoethane are indicated in Figures 2-l and 2-2. Because cancer
 

effects could occur at lower exposure levels, the figures also show a range
 

for the upper bound of estimated excess risks, ranging from a risk of one in
 

10,000 to one in 10,000,000 (10m4

 to 10m7), as developed by EPA.
 
6
 

2. HEALTH EFFECTS
 

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 and to extrapolate from laboratory animal data to humans.
 

Although methods have been established to derive these levels (Barnes et
 

al. 1988; EPA 1989a), 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
 

2.2.1.1 Death
 

No studies were located regarding death in humans after inhalation
 

exposure to 1,2-dibromoethane. However, inhalation exposure as well as dermal
 

exposure may have played a role in the deaths of two pesticide workers exposed
 

to 1,2-dibromoethane. For a discussion of this report by Letz et al. (1984),
 

see Section 2.2.3.1.
 

Older studies have established lethal concentrations of inhalation
 

exposure to 1,2-dibromoethane for experimental animals. Groups of rats were
 

exposed to 1,2-dibromoethane at concentrations of l00-10,000 ppm and durations
 

of 0.02-16 hours (Rowe et al. 1952). For each exposure concentration tested,
 

several exposure durations were selected that were expected to encompass
 

0%-100% mortality. A total of 40 combinations of exposure concentration and
 

duration were tested, using a total of 711 rats. Plots were constructed of
 

concentration versus exposure duration expected to produce 99.99%, 50%, and
 

0.01% mortality. Selected points from the 50% plot are illustrated in
 

Figure 2-l and recorded in Table 2-l.
 

Deaths in rats resulting from single-exposure concentration/duration
 

combinations expected to produce 50%-90% mortality usually occurred within
 

24 hours. These deaths were attributed to cardiac or respiratory failure and
 

were probably a direct effect of 1,2-dibromoethane toxicity. Deaths resulting
 

from exposure concentration/duration combinations expected to produce
 

0.01%-50% mortality occurred as long as 12 days after exposure and were due to
 

pneumonia. The authors attributed pneumonia to 1,2-dibromoethane-induced lung
 

injury, but this lesion could also have been due to intercurrent bacterial or
 

mycoplasmal pulmonary infection. Rats free of enzootic respiratory infections
 

were not available in 1952. More contemporary inhalation studies of
 








15
 

2. HEALTH EFFECTS
 

1,2-dibromoethane using commercially produced rats (Nitschke et al. 1981; NTP
 

1982) did not report pneumonic lesions or pneumonia-related mortality.
 

As the duration of exposure of the rats increased, the LC50 (lethal
 

concentration, 50% kill) value decreased. Maximum nonfatal single exposures
 

for rats were 1.2 minutes at 10,000 ppm, 2.4 minutes at 5,000 ppm, 6 minutes
 

at 3,000 ppm, 12 minutes at 1,600 ppm, 36 minutes at 400 ppm, 2 hours at
 

200 ppm, and 16 hours at 100 ppm, the longest exposure tested. In other
 

species exposed to 1,2-dibromoethane by Rowe et al. (1952), maximum nonfatal
 

single exposures for guinea pigs were 2 hours at 400 ppm and 7 hours at
 

200 ppm, the longest exposure tested.
 

A group of albino rats heterogenous for weight (range of 190-604 grams)
 

was exposed in a fumigation chamber to 1,040 ppm of 1,2-dibromoethane until
 

death occurred (Akamine 1952). Clinical signs of toxicity were reddened nasal
 

mucous membranes, epistaxis, ptyalism, anorexia, weight loss, and weakness.
 

The lethal exposure times ranged from 5 to 165 minutes.
 

Deaths occurred in pregnant female Crl:CD rats and CD mice exposed to
 

1,2-dibromoethane for 23 hours per day over a 10-day period. Female rats and
 

mice had increased mortality when exposed to 80 ppm of 1,2-dibromoethane while
 

female mice also had significant mortality when exposed to concentrations of
 

38 ppm 1,2-dibromoethane (Short et al. 1978). Twenty percent mortality
 

occurred in female Crl:CD rats exposed to 80 ppm 1,2-dibromoethane over a
 

3-week period; mortality did not occur at lower concentrations of 20 or
 

39 ppm. Male rats exposed to 89 ppm 1,2-dibromoethane over a 10-week period
 

had 21% mortality but mortality did not occur at lower concentrations of 19 or
 

39 ppm (Short et al. 1979). There was no gross necropsy or histopathologic
 

examination to establish the cause of death as related to chemical toxicity in
 

either of these studies, which were focused primarily on development and
 

reproduction.
 

Rats and mice exposed chronically to 1,2-dibromoethane by inhalation had
 

high mortality (NTP 1982; Wong et al. 1982). The majority of deaths were
 

related to cancer rather than direct toxic effects of 1,2-dibromoethane. Both
 

studies are discussed further in Section 2.2.1.8.
 

The highest NOAEL value and the reliable lethal concentrations for each
 

species for the acute-duration category, in rats for the intermediate-duration
 

category and in rats and mice for the chronic-duration/category are recorded
 

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

2.2.1.2 Systemic Effects
 

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.
 
16
 

2. HEALTH EFFECTS
 

No studies were located regarding cardiovascular, gastrointestinal, or
 

musculoskeletal effects in humans or animals after inhalation exposure to
 

1,2-dibromoethane.
 

Respiratory Effects. The respiratory tract, particularly the nasal
 

cavity, is the point-of-contact target organ affected by inhalation of
 

1,2-dibromoethane.
 

A possible case of chronic intoxication by 1,2-dibromoethane occurred in
 

a worker involved in 1,2-dibromoethane production (Kochmann 1928). Symptoms
 

were nonspecific. Upper respiratory symptoms consisted of pharyngitis and
 

bronchitis; other symptoms were lymphadenopathy, conjunctivitis, anorexia,
 

headache, and depression. The worker's condition improved upon cessation of
 

exposure. No other studies were located regarding respiratory effects in
 

humans after inhalation exposure to 1,2-dibromoethane.
 

Rats were exposed repeatedly to inhalation of 1,2-dibromoethane (Rowe et
 

al. 1952). Of 10 female rats exposed to 100 ppm of 1,2-dibromoethane over a
 

9-day period, 30% did not survive. Survivors had increased lung weights and
 

increased number of leukocytes in pulmonary septa. There was no description
 

of nasal lesions; therefore, it is likely that the nasal cavity was not
 

examined microscopically.
 

There have been several subchronic studies of 1,2-dibromoethane. In
 

one, rats and guinea pigs were exposed to 50 ppm of 1,2-dibromoethane daily
 

for as many as 63 (rats) or 57 (guinea pigs) exposures (Rowe et al. 1952).
 

Experimental findings were complicated by upper respiratory infection and
 

pneumonia.
 

To determine doses to be used in chronic inhalation studies, F344 rats
 

and B6C3F1 mice of both sexes were exposed to 0, 3, 15, or 75 ppm
 

1,2-dibromoethane for 13 weeks (NTP 1982; Reznik et al. 1980). Lesions
 

occurred in respiratory turbinates in the dorsal portion of the nasal cavity
 

of rats and mice exposed to 75 ppm. Respiratory epithelium was affected with
 

cytomegaly of basal cells, focal hyperplasia, loss of cilia, and squamous
 

metaplasia. Rats exposed to 15 ppm 1,2-dibromoethane had similar lesions but
 

at lower incidence and with less severity; mice exposed to 15 ppm had no nasal
 

lesions. Lung lesions were not described for rats; mice exposed to 75 ppm.
 

developed megalocytic bronchiolar epithelial cells (NTP 1982).
 

A study was conducted to examine proliferative nasal epithelial lesions
 

in F344 rats following subchronic inhalation of 1,2-dibromoethane at
 

concentrations of 0, 3, 10, or 40 ppm (Nitschke et al. 1981). The study
 

incorporated serial sacrifices and sacrifices after an 88-89-day postexposure
 

period. Rats in the mid- and high-dose groups had hyperplasia of nasal
 

turbinate epithelium; rats at the highest dose also exhibited nonkeratinizing
 

squamous metaplasia of respiratory epithelium of the nasal turbinates.
 
17
 

2. HEALTH EFFECTS
 

Lesions in both dose groups reverted to normal after the postexposure
 

interval. Although lesions did not progress and were essentially reversible
 

during the recovery period, it is possible that such effects could progress in
 

severity and result in neoplasia following long-term inhalation of
 

1,2-dibromoethane.
 

In a chronic inhalation study conducted by NTP (1982), carcinogenic end
 

points were nasal tumors in rats and mice and pulmonary tumors in mice (see
 

Section 2.2.1.8). A nonneoplastic lesion of epithelial hyperplasia occurring
 

throughout the respiratory tract was a prominent histologic feature in the
 

1,2-dibromoethane-exposed mice.
 

Hematological Effects. No studies were located regarding hematologic
 

effects in humans after inhalation exposure to 1,2-dibromoethane.
 

Female rats exposed acutely to 100 ppm 1,2-dibromoethane for up to seven
 

exposures (see Section 2.2.1.1) had splenic congestion and hemosiderosis; no
 

changes in hematopoietic or lymphoid elements were described (Rowe et
 

al. 1952).
 

Hematologic evaluation was performed on Sprague-Dawley rats that
 

received 20 ppm 1,2-dibromoethane by inhalation and were fed either a control
 

diet or a diet containing 0.05% disulfiram for 18 months (Wong et al. 1982).
 

Hematologic evaluation of control rats with no exposure to 1,2-dibromoethane
 

was not done. This study is discussed in Section 2.2.1.8. Moribund animals
 

(males and females) that had exposure to the inhalation and dietary regimens
 

for 10-12 months were evaluated. Rats exposed to 1,2-dibromoethane and fed 'a
 

control diet had hematologic parameters within normal ranges. Atrophy of the
 

spleen occurred in male rats. Both sexes of rats exposed to 1,2-dibromoethane
 

and fed the 0.05% disulfiram diet had total erythrocyte counts, hematocrit,
 

and hemoglobin values significantly lower than rats exposed to
 

1,2-dibromoethane and fed the control diet, with females most severely
 

affected. Both sexes of rats on this latter regimen had splenic atrophy.
 

Because there was no description of this splenic lesion, it is unclear whether
 

atrophy referred to decreased extramedullary hematopoiesis in the red pulp,
 

lymphoid depletion of the white pulp, or both changes.
 

Hepatic Effects. Two workers collapsed after entering a pesticide
 

storage tank containing residues of 1,2-dibromoethane (Letz et al. 1984).
 

Clinical chemistry prior to death for both men revealed acute hepatic failure
 

along with other symptoms of toxicity. As with dermal exposure, inhalation
 

exposure was also postulated to play a potentially important role. However,
 

the exposure levels were not quantified.
 

The iiver is a target organ for toxic effects of 1,2-dibromoethane in
 

experimental animals following exposure by a variety of routes.
 
18
 

2. HEALTH EFFECTS
 

Acute toxic hepatic effects of 1,2-dibromoethane consisting of
 

hepatocellular cloudy swelling, centrilobular fatty change, and patchy
 

necrosis were reported in animals after a single inhalation exposure (Rowe et
 

al. 1952). Repeated inhalation exposures of rats and rabbits to 100 ppm
 

1,2-dibromoethane induced diffuse hepatocellular cloudy swelling in rats and
 

centrilobular hepatocellular fatty change and necrosis in rabbits.
 

Rats in a subchronic inhalation study exposed to 50 ppm
 

1,2-dibromoethane had intercurrent infectious disease that severely
 

complicated experimental results (see the discussion in this section on
 

Respiratory Effects). No liver lesions were reported in surviving rats (Rowe
 

et al. 1952). Guinea pigs exposed to 50 ppm 1,2-dibromoethane did not develop
 

respiratory disease. Their liver lesions consisted of minimal centrilobular
 

hepatocellular fatty change (Rowe et al. 1952). Liver lesions were not
 

induced in F344 rats or B6C3F1 mice following subchronic exposure to any
 

concentrations of 1,2-dibromoethane used including the highest dose (75 ppm.)
 

(NTP 1982).
 

In the chronic inhalation bioassay of 1,2-dibromoethane conducted by NTP
 

(1982) (discussed in Section 2.2.1.8), increased incidence of focal and
 

centrilobular hepatocellular necrosis occurred in male and female F344 rats
 

exposed to the highest dose (40 ppm) of 1,2-dibromoethane. Compound-related
 

degenerative or necrotizing hepatocellular lesions did not occur in B6C3F1
 

mice following exposure to any concentration used. Liver lesions were not
 

reported in rats after chronic inhalation exposure to 20 ppm 1,2-dibromoethane
 

with or without 0.05% disulfiram in the diet; however, hepatocellular tumors
 

(not otherwise classified) were induced in exposed rats fed dietary disulfiram
 

(Wong et al. 1982). Also see Section 2.2.1.8.
 

Renal Effects. The clinical chemistry prior to death of two men who
 

entered a pesticide tank that contained residues of 1,2-dibromoethane revealed
 

acute renal failure (Letz et al. 1984). The exposure levels were not
 

reported.
 

Renal effects have been reported in laboratory animals. Slight renal
 

congestion, edema, and cloudy swelling of tubular epithelium (mild and
 

nonspecific lesions) occurred in rats exposed acutely by inhalation (single
 

exposure) to toxic concentrations greater than,100 ppm. Rats receiving
 

several inhalation exposures to 100 ppm 1,2-dibromoethane had elevated kidney
 

weights but no renal lesions. No evidence of kidney damage occurred in
 

rabbits on a somewhat similar exposure regimen (Rowe et al. 1952). Blood urea
 

nitrogen levels were not elevated in either species, indicating that renal
 

function was not compromised.
 

Rats exposed subchronically to 50 ppm 1,2-dibromoethane had increased
 

kidney weights but unremarkable kidney histology (Rowe et al. 1952). Guinea
 

pigs similarly exposed had elevated absolute and relative kidney weights.
 
19
 

2. HEALTH EFFECTS
 

Histologically, the guinea pig kidneys had slight congestion, edema, and
 

tubular epithelial degeneration (Rowe et al. 1952). Neither species exposed
 

to 1,2-dibromoethane had elevated blood urea nitrogen levels.
 

Renal lesions did not occur in rats or mice exposed by inhalation to 0.,
 

3, 15, or 75 ppm of 1,2-dibromoethane in a subchronic study to determine
 

concentrations to be used for the chronic inhalation bioassay (NTP 1982).
 

Renal changes were not reported in rats, guinea pigs, or rabbits exposed
 

to 25 ppm 1,2-dibromoethane over 205-214 days (Rowe et al. 1952). In the NTP
 

chronic inhalation study (NTP 1982), toxic nephropathy (not otherwise
 

characterized) was present in 4 low-dose (10 ppm) and 28 high-dose (40 ppm)
 

male and 8 high-dose female F344 rats but was not present in any of the
 

control animals. Compound-related renal lesions were not found in B6C3F1
 

mice, although ascending suppurative urinary tract infections may have masked
 

renal lesions as a result of early mortality and/or pyelonephritis.
 

Because neoplastic changes were emphasized in the study of Wong et
 

al. (1982), (see Section 2.2.1.8), it is unclear whether nonneoplastic lesions
 

were recognized by the investigators.
 

Dermal/Ocular Effects. No studies were located regarding dermal or
 

ocular effects in humans after inhalation exposure to 1,2-dibromoethane:
 

No studies were located regarding dermal effects in animals after
 

inhalation exposure to 1,2-dibromoethane.
 

In the subchronic inhalation study of 1,2-dibromoethane in rodents
 

conducted by NTP (1982), eye irritation was noted at study conclusion (weeks
 

12 and 13) in mice receiving the highest concentration (75 ppm).
 

Other Systemic Effects. Mild nonspecific endocrine lesions were
 

observed after inhalation exposure to 1,2-dibromoethane. After subchronic
 

exposure to 75 ppm, rats had adrenal lesions consisting of swelling and/or
 

cytoplasmic vacuolization of cells in the zona fasciculata of the cortex and
 

thyroid lesions consisting of slight decreases in follicular size.
 

Degenerative changes in the adrenal cortex occurred at elevated incidence in
 

female Fischer 344 rats after chronic exposure to 40 ppm 1,2-dibromoethane.
 

This may represent a secondary, stress-related effect because there was poor
 

survival at this high dose with the majority of rats dying or sacrificed when
 

moribund during the study (NTP 1982).
 

2.2.1.3 Immunological Effects
 

No studies were located regarding immunologic effects in humans after
 

inhalation exposure to 1,2-dibromoethane. Lymphoid neoplasia putatively
 
20
 

2. HEALTH EFFECTS
 

associated with exposure of grain milling workers to various chemicals
 

including 1,2-dibromoethane is discussed in Section 2.9.3.
 

As discussed in Section 2.2.1.2, splenic atrophy occurred in rats
 

exposed by inhalation to 20 ppm 1,2-dibromoethane and fed diets with or
 

without 0.05% disulfiram. Whether atrophy referred to lymphoid or
 

hematopoietic tissue was not specified (Wong et al. 1982).
 

2.2.1.4 Neurological Effects
 

In an old case report by Kochmann (1928), a worker exposed by inhalation
 

during 1,2-dibromoethane production had nonspecific neurologic signs of
 

headache and depression; these signs resolved after cessation of exposure.
 

Also, see Section 2.2.1.2,
 

There are no studies in animals focusing specifically on the nervous
 

system. In the lethality studies of Rowe et al. (1952) discussed in
 

Section 2.2.1.1, rats and guinea pigs exposed by inhalation to higher
 

concentrations of 1,2-dibromoethane had central nervous system depression
 

(exact clinical signs not specified). Brain tissue apparently was not
 

examined histologically.
 

2.2.1.5 Developmental Effects
 

No studies were located regarding developmental effects in humans after
 

inhalation exposure to 1,2-dibromoethane.
 

1,2-Dibromoethane can induce developmental effects in rodents (Short et
 

al. 1978, 1979; Smith and Goldman 1983). The results of these studies
 

indicate that 1,2-dibromoethane is more toxic to pregnant mice than pregnant
 

rats (Short et al. 1978). It produces maternal toxicity as evidenced by
 

decreases in food consumption, body weight gain, and survival (Short et
 

al. 1978, 1979). Developmental effects observed include anatomical and
 

skeletal defects and reduced survival of fetuses. However, these adverse
 

developmental effects have been observed in animals at doses that induce
 

maternal toxicity.
 

Inhalation exposure of pregnant Sprague-Dawley (Crl:CD) rats to
 

1,2-dibromoethane for 10 days during gestation resulted in significant
 

reduction in food consumption at 20 ppm, weight loss at 32, 38, and 80 ppm,
 

and 50% mortality at 80 ppm (Short et al. 1978). A significant reduction in
 

the viability of embryos and fetuses was also evident at 80 ppm, Skeletal
 

anomalies, primarily incomplete ossification, were common in the fetuses at
 

concentrations as low as 20 ppm. Using the same protocol, the authors
 

reported similar observations in CD-1 mice, although the maternal effects were
 

more pronounced (Short et al. 1978). The maternal mortality was 100% in the
 

80-ppm exposure group. Reduction in food consumption and maternal body weight
 

were noted at concentrations as low as 20 ppm. Fetotoxic effects consisted of
 
21
 

2. HEALTH EFFECTS
 

significantly increased resorptions and reduced fetal body weight. The
 

skeletal anomalies, primarily incomplete ossification, observed in fetuses may
 

have been the result of malnourishment rather than the direct effect of
 

1,2-dibromoethane-induced toxicity. However, the number of fetal mice was
 

insufficient to draw this conclusion.
 

The reliable LOAEL values for developmental effects in rats and mice for
 

the acute-duration category are reported in Table 2-l and plotted in
 

Figure 2-l.
 

2.2.1.6 Reproductive Effects
 

Antispermatogenic effects of 1,2-dibromoethane have been observed in
 

humans occupationally exposed to 1,2-dibromoethane (Ratcliffe et al. 1987;
 

Takahashi et al. 1981; Ter Haar 1980). These effects include changes in sperm
 

velocity and count. Whether or not these effects are associated with reduced
 

fertility in humans cannot be totally addressed, since the epidemiologic study
 

(Wong et al. 1979) was not capable of detecting such a sensitive effect.
 

Although this study had several limitations, it indicates a potential for
 

adverse effects of 1,2-dibromoethane on fertility.
 

Two types of human studies have been reported in the literature: one
 

that assessed fertility differences between groups of workers (Wong et
 

al. 1979) and others that assessed the potential antispermatogenic effects in
 

male workers (Ratcliffe et al. 1987; Ter Haar 1980). These studies provided
 

little or equivocal evidence that 1,2-dibromoethane exposure was associated
 

with adverse fertility or antispermatogenic effects in exposed workers. All
 

studies lacked sufficient statistical power to detect an association due to
 

small sample size, inadequate exposure assessment or histories, inappropriate
 

control groups, and a general methodological weakness in assessing fertility
 

status and antispermatogenic effects. Nevertheless, they do provide some
 

indication of potential adverse effects of 1,2-dibromoethane on fertility and
 

sperm production.
 

A decrease in male fertility to 49% below expected values (significant
 

at p=0.05) was reported in one of four 1,2-dibromoethane manufacturing plants
 

(Wong et al. 1979). After adjustment for workers who had vasectomies and one
 

whose wife had a hysterectomy, the reduction in fertility was 29% and no
 

longer significant at that level.
 

Occupational exposure to 1,2-dibromoethane has been reported to produce
 

adverse effects both on spermatogenesis (sperm concentration) and seminal
 

fluid production (semen volume) in human males (Ratcliffe et al. 1987;
 

Takahashi et al. 1981, Ter Haar 1980).
 

The study by Ter Haar (1980) examined the relationship between sperm
 

count and 1,2-dibromoethane exposure of 59 men employed at a production plant
 

for antiknock compounds in Arkansas. In the low-exposure group (less than
 
22
 

2. HEALTH EFFECTS
 

0.5 ppm 1,2-dibromoethane in air), 20% of the individuals had sperm counts
 

below 40 million while 42% of the high-exposure group (between 0.5 and 5 ppm
 

1,2-dibromoethane in the air) had sperm counts below 40 million. As discussed
 

by Dobbins (1987), there was no concurrent unexposed control group; sperm
 

counts were compared to several published values for the U.S. population.
 

While the differences between the low- and high-exposure groups were
 

significant, the absence of a control group was a serious defect.
 

The semen quality of 46 papaya workers with chronic exposure to
 

1,2-dibromoethane was examined (Ratcliffe et al. 1987). These men were
 

employed for an average of 5 years and worked in six plants as sorters,
 

packers, forklift drivers, and fumigators. The time-weighted average
 

1,2-dibromoethane exposure level was estimated at 0.088 ppm, with peak
 

exposures as high as 0.226 ppm. After adjusting data for several variables,
 

statistically significant decreases in sperm count, decreases in the
 

percentages of viable and motile sperm, and increases in sperm abnormalities
 

were evident when compared with a control population of unexposed sugar
 

refinery workers. Chronic exposure to 1,2-dibromoethane affected sperm
 

motility, but not velocity.
 

A significant reduction in sperm count of agricultural workers was also
 

reported in earlier studies by Takahashi et al. (1981). They examined sperm
 

counts, volume, morphology, and motility in a small sample of agricultural
 

workers in Molokai, Hawaii. Agricultural worker exposure to 1,2-dibromoethane
 

could not be estimated. A significant reduction in sperm count occurred in
 

the workers as compared to reference controls and to fertile controls.
 

Confounding factors were additional worker exposure to dibromochloropropane
 

and marijuana use.
 

The direct effect of inhalation exposure to 1,2-dibromoethane on
 

spermatogenesis in animals has not been studied. Nonetheless, the available
 

data from animal studies indicate that the male reproductive system in rats is
 

affected by exposure to 1,2-dibromoethane at high doses. In all studies
 

discussed below, however, rats had high mortality associated with chemical
 

toxicity and/or chemically-induced neoplasia. It is therefore difficult to
 

attribute effects on the reproductive organs to a direct result of
 

1,2-dibromoethane toxicity. Male Sprague-Dawley (Crl:CD) rats exposed by
 

inhalation to 1,2-dibromoethane at concentrations as high as 89 ppm in air for
 

10 weeks developed atrophy of the testis, epididymis, prostate, and seminal
 

vesicles (Short et al. 1979). None of the rats from the 89-ppm exposure group
 

were able to impregnate female rats during a 2-week mating period following
 

termination of exposure. Mortality and morbidity also occurred among rats
 

exposed at the high concentration. Testicular degeneration and testicular
 

atrophy in dosed F344 rats in NTP's chronic inhalation study (NTP 1982)
 

occurred in association with spontaneous interstitial cell tumors and
 

chemically-induced mesotheliomas. In the study by Wong et al. (1982),
 

testicular atrophy occurred in Sprague-Dawley rats exposed to
 
23
 

2. HEALTH EFFECTS
 

1,2-dibromoethane (20 ppm) in combination with disulfiram in the diet, a
 

regimen that resulted in 100% mortality by 14 months.
 

The highest NOAEL and reliable LOAEL values for reproductive effects in
 

rats for intermediate durations and a LOAEL value for chronic duration are
 

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

2.2.1.7 Genotoxic Effects
 

The incidence of sister chromatid exchange and chromosomal aberrations
 

in lymphocytes from workers occupationally exposed to 1,2-dibromoethane was
 

investigated by Steenland et al. (1985, 1986). Neither study revealed any
 

genotoxic effect. In a study conducted on workers involved in spraying
 

1,2-dibromoethane on fallen pine trees, the estimated average exposure level
 

of 1,2-dibromoethane was 0.06 ppm (Steenland et al. 1985). The rates of
 

sister chromatid exchange measured in vitro in lymphocytes obtained from these
 

workers soon after 1,2-dibromoethane exposure were not higher than those
 

observed in lymphocytes taken from the same individuals before the exposures.
 

In a subsequent study (Steenland et al. 1986), lymphocytes were taken from
 

60 workers in a papaya processing plant where 1,2-dibromoethane was used to
 

fumigate fruit. The estimated average exposure level was 0.088 ppm
 

1,2-dibromoethane for an average of 5 years. This study did not detect an
 

increase in the rate of sister chromatid exchange or the frequency of
 

chromosomal aberrations in vitro in lymphocytes obtained from these workers.
 

1,2-Dibromoethane did not induce dominant-lethal mutations in rats exposed by
 

inhalation to 1,2-dibromoethane vapor at exposure levels as high as 39 ppm
 

(Short et al. 1979).
 

Other genotoxicity studies are discussed in Section 2.4.
 

2.2.1.8 Cancer
 

There have been two epidemiological studies regarding carcinogenic
 

effects in workers exposed occupationally to 1,2-dibromoethane, primarily by
 

the respiratory route (Ott et al. 1980; Turner and Barry 1979).
 

Cancer mortality and mortality due to respiratory disease were studied
 

in 161 male employees exposed to 1,2-dibromoethane in two 1,2-dibromoethane
 

manufacturing plants located in Texas and Michigan (Ott et al. 1980). Because
 

the Texas and Michigan plants ceased operations in 1969 and 1976,
 

respectively, environmental assessments were based on existing records and
 

discussions with workers formerly associated with the plants. No
 

statistically significant increase in deaths was observed when data were
 

examined in terms of duration of exposure or interval since first exposure.
 

Although there was an increase in cancer mortality among employees with more
 

than 6 years of exposure to 1,2-dibromoethane in both plants, this increase
 

was not statistically significant. The authors suggested that the observed
 

incidence of cancer in the study population was lower than that which would be
 
24
 

2. HEALTH EFFECTS
 

predicted from animal studies. They concluded that there was a need for
 

continued surveillance of the cohort of 161 employees and an industry-wide
 

study of mortality among workers in 1,2-dibromoethane manufacturing plants.
 

Although this study has a number of limitations, results of the study neither
 

confirm nor refute the possibility that 1,2-dibromoethane is a human
 

carcinogen. Study limitations include not controlling for confounding factors
 

such as smoking, incomplete identification of exposure levels of
 

1,2-dibromoethane, concomitant exposure of workers to other chemicals, lack of
 

a matched control group, and lack of completeness of report data.
 

In another epidemiological study, the mortality of workers exposed to
 

1,2-dibromoethane in two manufacturing plants in Britain was evaluated (Turner
 

and Barry 1979). The manufacturing operation of each plant involved the
 

extraction of bromine from sea water and its subsequent reaction with ethylene
 

to form 1,2-dibromoethane. Although the size of the group studied was too
 

small to analyze mortality rates on a year-by-year basis, a comparison of
 

rates was done by grouping person-years of follow-up into four age ranges over
 

the period of the study (23 years). No increase in mortality from any cause,
 

including neoplasia, was identified in the 1,2-dibromoethane workers.
 

Chronic inhalation exposure of rodents to 1,2-dibromoethane has been
 

associated with neoplasms in the respiratory tract, as well as in other organ
 

systems. Two studies have examined the carcinogenic potential of
 

1,2-dibromoethane in rodents after inhalation exposure (NTP 1982; Wong et
 

al. 1982). There was also an A strain mouse assay (Adkins et al. 1986).
 

A chronic inhalation study (18 months) in Sprague-Dawley (Crl:CD) rats
 

examined the carcinogenicity of 20 ppm 1,2-dibromoethane alone and with
 

simultaneous exposure to 0.05% disulfiram in the diet (Wong et al. 1982).
 

Male rats exposed to 1,2-dibromoethane had significantly higher incidences of
 

splenic hemangiosarcomas and subcutaneous mesenchymal tumors. Female rats
 

exposed to 1,2-dibromoethane had significantly higher incidences of splenic
 

hemangiosarcomas and mammary tumors (combined adenoma, fibroadenoma,
 

carcinoma, or adenocarcinoma). In both sexes of rats, the combination of
 

1,2-dibromoethane and disulfiram resulted in significantly higher incidences
 

of hepatocellular tumors (percentage of adenoma or carcinoma not identified);
 

splenic hemangiosarcoma; kidney adenoma and adenocarcinoma; thyroid follicular
 

epithelial adenoma; and hemangiosarcoma of the omentum or mesentery. It was
 

unclear whether hemangiosarcoma of the mesentery (omentum) and of the lung.
 

were primary sites or metastatic from spleen. Female rats had increased
 

incidence of mammary gland tumors.
 

Because the nasal cavity of the animals was not examined histologically,
 

it cannot be determined whether nasal cavity tumors were induced. Also,
 

because the authors tested animals at only one concentration, the doseresponse
 

cannot be characterized.
 
25
 

2. HEALTH EFFECTS
 

The carcinogenicity of 1,2-dibromoethane in F344 rats and B6C3F1 mice was
 

examined in an inhalation bioassay (NTP 1982). Doses tested were 0, 10, and
 

40 ppm; study duration was 79-103 weeks. Mortality related to chemicallyinduced
 

malignant tumors and to toxic lesions was high in high-dose rats of
 

both sexes. Both sexes of rats had significant compound-related increases in
 

nasal epithelial tumors. EPA (IRIS 1991) has derived a unit risk value of.
 

2.2x10-4 μg/m3

 for cancer risk associated with inhalation exposure to 

1,2-dibromoethane from this study based on the incidence of nasal tumors in 

male rats. EPA also estimated that 1,2-dibromoethane concentrations of -1 -2 -3 3 -5 -6 -7
 5x10 , 5x10 , and 5x10 μg/m (6.5x10 , 6.5x10 , and 6.5x10 ppm) in air 

are associated in humans with excess lifetime cancer risks of 10-4, 10-5, and 

10-6, respectively. These values correspond to 1 excess cancer death in 

10,000, 100,000, or 1 million persons exposed continuously for their lifetime 

(estimated as 70 years) to these respective levels of 1,2-dibromoethane by 

inhalation. These estimated concentrations associated'with cancer risk were 

converted into ppm and plotted in Figure 2-l. 

Exposed rats also had elevated incidences of splenic hemangiosarcomas
 

(both sexes), mesothelioma of the tunica vaginalis (males), pulmonary
 

alveolar/bronchiolar adenoma or carcinoma (females), and fibroadenoma of the
 

mammary gland (females).
 

Exposed female mice had significant compound-related increases in nasal
 

carcinomas (NTP 1982; Stinson et al. 1981). The incidences of combined
 

alveolar/bronchiolar carcinoma and adenoma were significantly increased in the
 

lungs of high-dose male and female mice as compared with control animals. In
 

addition to these tumors, adenomatous polyps were present in tracheal,
 

bronchial, and bronchiolar lumens (NTP 1982).
 

There was a statistically significant compound-related increase in
 

incidence of several other tumors in female mice: hemangiosarcoma of the
 

abdominal retroperitoneum, particularly involving the area of the ovaries,
 

uterus, kidneys, and adrenal; subcutaneous fibrosarcomas; and mammary
 

adenocarcinoma (NTP 1982). A limitation of the study was poor survival in
 

male mice from ascending suppurative urinary tract infections.
 

A/J strain mice exposed by inhalation to 20 and 50 ppm 1,2-dibromoethane
 

for 6 months had a significant increase in the frequency and incidence of
 

alveolar-bronchiolar adenomas (Adkins et al. 1986).
 

In summary, two epidemiological studies have not identified an increased
 

risk of cancer in people occupationally exposed by inhalation to
 

1,2-dibromoethane. In experimental animals exposed by the inhalation route,
 

1,2-dibromoethane is a potent carcinogen, producing cancer at the point-of-contact-­

the upper respiratory tract--as well as in numerous organs and
 

tissues throughout the body.
 
26
 

2. HEALTH EFFECTS
 

2.2.2 Oral Exposure
 

2.2.2.1 Death
 

There are two case reports of death in humans following oral
 

administration of 1,2-dibromoethane in suicide attempts.
 

A white 43-year-old female died 54 hours after ingestion of 9 "Fumisoil"
 

capsules each containing 4.5 mL 1,2-dibromoethane (140 mg/kg/day) (Olmstead
 

1960). Clinical signs prior to death were emesis, diarrhea, oliguria
 

progressing to anuria, tachypnea, and agitation. Pathologic findings were in
 

liver and kidney. The liver had extensive centrilobular hepatocellular
 

necrosis with sinusoidal dilatation and a minimal cellular reaction. The
 

kidney had patchy areas of either acute tubular necrosis or autolysis, mild
 

cytoplasmic vacuolization of proximal cortical tubules, and proteinaceous
 

casts in tubules near the cortico-medullary junction.
 

Ingestion of one ampule of commercial 1,2-dibromoethane occurred in six
 

additional human cases of attempted suicide (Saraswat et al. 1986). The
 

patients were all teenagers or young adults; two out of six died. One female
 

patient was admitted in a moribund condition and died approximately 36 hours
 

after admission. Pathologic findings were oropharyngeal ulceration, gastric
 

mucosal erosions, massive hepatocellular necrosis, icterus, and renal lesions
 

(hemorrhage, tubular swelling, and occasional necrosis). A second female was
 

admitted with nausea, emesis, and a burning sensation in her throat. She
 

became hypotensive, unconscious, and died approximately 15 hours after
 

admission. Pathologic findings were oropharyngeal ulcers, gastric hyperemia,
 

and centrilobular hepatocellular necrosis. Four other patients who survived
 

after ingesting 1,2-dibromoethane (three female, one male) had nausea and
 

emesis and three out of four had labial and oral erosions and ulcers.
 

In a study using large domestic animals because of concern over soil
 

nematocide residues in treated forage, 1,2-dibromoethane was administered
 

orally in a gelatin capsule to a small number of animals (Schlinke 1969).
 

1,2-Dibromoethane at 50 mg/kg body weight caused mortality in one calf, while
 

one calf given 25 mg/kg body weight and one calf given 10 mg/kg body weight
 

survived. Sheep were similarly treated; one given 50 mg/kg body weight died,
 

one out of two given 25 mg/kg died, and one given 10 mg/kg survived.
 

Interpretation of these studies was complicated by use of a ruminant species,
 

a very small number of animals, and lack of necropsy data.
 

Single-dose oral LD50 values in rats, guinea pigs, rabbits, and mice were
 

determined by Rowe et al. (1952) in a gavage study using 1,2-dibromoethane in
 

olive oil. All reliable LD50 values (lethal dose, 50% kill) for each species
 

for the acute-duration category are recorded in Table 2-2 and plotted in
 




31
 

2. HEALTH EFFECTS
 

2.2.2.2 Systemic Effects
 

No studies were located regarding respiratory, cardiovascular,
 

hematological, musculoskeletal, or dermal/ocular effects in humans or animals
 

after oral exposure to 1,2-dibromoethane.
 

The highest NOAEL and all reliable LOAEL values for systemic effects in
 

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

Figure 2-2.
 

Gastrointestinal Effects. Oral and/or pharyngeal ulceration occurred in
 

five out of six humans who ingested commercial 1,2-dibromoethane ampules
 

(Saraswat et al. 1986). This report was discussed in detail in
 

Section 2.2.2.1.
 

Because 1,2-dibromoethane given chronically by gavage induced a high
 

incidence of squamous cell tumors of the forestomach of rodents, a short-term
 

study was conducted to identify forestomach lesions following 2-week repeated
 

gavage administration of 40 or 80 mg/kg/day 1,2-dibromoethane to F344 rats
 

(Ghanayem et al. 1986). A significant increase in forestomach mucosal cell
 

proliferation and hyperkeratosis occurred in rats exposed to 80 mg/kg/day.
 

These proliferative lesions, which in themselves are not preneoplastic, could
 

suggest the potential for development of neoplastic lesions. The authors
 

concluded that forestomach mucosal hyperplasia resulting from chronic gavage
 

of 1,2-dibromoethane may provide a favorable environment for tumor
 

development.
 

Nonneoplastic proliferative lesions of the forestomach were observed i.n
 

high-dose Osborne-Mendel rats in the chronic gavage study of 1,2-dibromoethane
 

conducted by the National Cancer Institute (NCI 1978). These consisted of
 

acanthosis and hyperkeratosis of forestomach squamous epithelium. Similar
 

lesions occurred in high-dose B6C3F1 mice. These dose levels are not plotted
 

and recorded in Figure 2-2 and Table 2-2, respectively, since these doses also
 

caused forestomach squamous cell tumors.
 

Hepatic Effects. Severe liver necrosis occurred in three humans who
 

ingested commercial 1,2-dibromoethane in order to commit suicide (Olmstead
 

1960; Saraswat et al. 1986). Necrosis was massive in one of these
 

individuals; the other two had centrilobular hepatocellular necrosis.
 

1,2-Dibromoethane is considered to be a weak hepatotoxin in animals.
 

Hepatocellular fatty change (degeneration) is one of the common lesions in
 

experimental animals associated with acute oral exposure to 1,2-dibromoethane
 

(Botti et al. 1986). When administered to rats by gavage at a dosage of
 

110 mg/kg/day, this lesion is corroborated by an increase in liver
 
32
 

2. HEALTH EFFECTS
 

triglyceride levels that begins within 8 hours of treatment (Nachtomi and
 

Alumot 1972).
 

Using light microscopy, Broda et al. (1976) did not observe
 

hepatocellular fatty change in livers of rats exposed by gavage to 110 mg/kg
 

1,2-dibromoethane in olive oil. Rats developed centrilobular dilatation
 

within 8 hours after exposure, hepatocellular degeneration within 17 hours
 

after exposure, and frank centrilobular necrosis 22 hours after
 

1,2-dibromoethane exposure.
 

Following gavage administration of 107 mg/kg 1,2-dibromoethane to rats,
 

1,2-dibromoethane depleted both cytosolic and mitochondrial glutathione;
 

ultrastructurally, some mitochondria had abnormal shapes (Botti et al. 1986).
 

When rats were pretreated 30 minutes prior to 1,2-dibromoethane administration
 

with diethylmaleate, a cytoplasmic glutathione-depleting agent, hepatocytes
 

had generalized vacuolization due to mitochondria with severe ultrastructural
 

abnormalities and swelling. These findings demonstrated the importance of
 

glutathione in maintenance of mitochondrial membrane integrity. With reduced
 

glutathione levels and the concomitant formation of glutathione disulfides,
 

the mitochondrial membrane became altered and permeable to calcium ions (Botti
 

et al. 1986).
 

Liver was not examined histologically in the subchronic study used to
 

set concentrations for the NCI chronic gavage bioassay of 1,2-dibromoethane
 

(NCI 1978). In the NCI (1978) gavage bioassay (discussed in detail in Section
 

2.2.2.8), a nonneoplastic hepatic lesion, peliosis hepatis, occurred in a
 

small number of treated male and female Osborne-Mendel rats and had an
 

equivocal relationship to 1,2-dibromoethane exposure.
 

Renal Effects. Renal lesions have been reported in humans dying acutely
 

after acute oral exposure to 1,2-dibromoethane. In the case report by
 

Olmstead (1960), the patient's kidneys had equivocal necrotizing tubular
 

lesions, proximal convoluted tubular cytoplasmic vacuolization, and
 

proteinaceous casts in tubules near the corticomedullary junction. In the
 

report of Saraswat et al. (1986), one of two fatalities had renal hemorrhage,
 

tubular swelling, and occasional necrotic tubular cells.
 

Cell proliferation, predominantly in the proximal tubules, occurred in
 

Wistar rats following a single oral dose of 100 mg/kg 1,2-dibromoethane in
 

corn oil. Mitotic activity peaked at 30 hours. Lack of any histologic
 

evidence of tubular necrosis between 8-48 hours after treatment indicates that
 

such proliferation was not a regenerative response (Ledda-Columbano et
 

al. 1987b).
 

Toxic nephropathy of the type seen after inhalation exposure of rats
 

(see Section 2.2.1.2) was not identified in rats or mice in the NCI (1978)
 

gavage bioassay of 1,2-dibromoethane.
 
33
 

2. HEALTH EFFECTS
 

Other Systemic Effects. Endocrine lesions related to 1,2-dibromoethane
 

exposure were reported in the NCI (1978) gavage bioassay. These consisted of
 

adrenal cortical cell degeneration in a small number of exposed male and
 

female Osborne-Mendel rats. The possibility exists that this adrenal change
 

represents a secondary (stress-related) effect rather than a primary effect of
 

1,2-dibromoethane exposure.
 

2.2.2.3 Immunological Effects
 

No studies were located regarding immunologic effects in humans or
 

animals after oral exposure to 1,2-dibromoethane.
 

2.2.2.4 Neurological Effects
 

No clinical signs specific to primary neurologic effects were described
 

in humans following ingestion of 1,2-dibromoethane (Saraswat et al. 1986) (see
 

Section 2.2.2.1). One of the patients who became unconscious and died after
 

ingestion of 1,2-dibromoethane had nonspecific brain lesions--meningeal
 

congestion and interstitial cortical edema. Of the four patients who
 

survived, three had symptoms of confusion upon admission although they were
 

conscious.
 

Sheep and calves dying after toxic oral doses of 1,2-dibromoethane
 

(Schlinke 1969) had nonspecific clinical signs of stiffness, prostration, and
 

anorexia.
 

2.2.2.5 Developmental Effects
 

No studies were located regarding developmental effects in humans and
 

animals after oral exposure to 1,2-dibromoethane.
 

2.2.2.6 Reproductive Effects
 

No studies were located regarding reproductive effects in humans,
 

although oral exposure via drinking water and contaminated food has been
 

documented in the literature.
 

Reproductive effects from oral exposure to 1,2-dibromoethane have been
 

investigated in various animals including bulls, rats, and mice over
 

intermediate and chronic exposure durations (Amir 1973; Amir and Ben-David
 

1973; Amir and Lavon 1976; Amir and Volcani 1965; Amir et al. 1983; NCI 1978).
 

These studies indicate species differences in sperm damage resulting from
 

exposure to 1,2-dibromoethane.
 

A high percentage (up to 79%) of abnormal spermatozoa in bull ejaculates
 

was reported as early as two weeks following oral administration of 10 doses
 

of 4 mg/kg 1,2-dibromoethane on alternate days (Amir and Ben-David 1973).
 
34
 

2. HEALTH EFFECTS
 

Radioactivity (3

H or 14C-1,2-dibromoethane) was detected in spermatozoa
 

collected approximately 1 week following the initial oral dose (Amir 1973).
 

These results indicate that 1,2-dibromoethane exerts spermicidal action during
 

the process of spermiogenesis and sperm maturation. This conclusion was
 

supported by the evidence that the percentage of sperm abnormalities was
 

highest when little 1,2-dibromoethane radioactivity could be detected in
 

sperm. In addition, reduction in sperm concentration was more pronounced in
 

adult bulls than in young bulls, and the period of recovery was longer in
 

adult animals (Amir 1975). In another study, bulls were fed 2 mg/kg/day
 

1,2-dibromoethane for 12 months followed by 4 mg/kg 1,2-dibromoethane every
 

other day ,until they reached the age of 14-16 months. The semen samples
 

examined revealed low sperm density, structural abnormalities, and low
 

mobility (Amir and Volcani 1965). Sperm production returned to normal as
 

early as 10 days postexposure (Amir and Lavon 1976; Amir et al. 1977).
 

In the chronic gavage study of 1,2-dibromoethane conducted by NCI
 

(1978), high-dose male Osborne-Mendel rats and B6C3F1 mice developed
 

testicular atrophy. Because study animals had high compound- and gavagerelated
 

mortality and early onset of forestomach squamous cell carcinomas, it
 

is difficult to determine from these results whether testicular atrophy
 

(degeneration) was a primary (compound-induced) or secondary (nonspecific)
 

event.
 

The highest NOAEL values for reproductive effects in rats and mice for
 

acute exposure duration and a reliable LOAEL in bulls for the intermediate-duration
 

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

2.2.2.7 Genotoxic Effects
 

No studies were located regarding genotoxic effects in humans after oral
 

exposure to 1,2-dibromoethane. Repeated oral administration of
 

1,2-dibromoethane to rats at 100 mg/kg/day (Epstein et al. 1972) and to mice
 

at doses as high as 150 mg/kg/day (Teramoto et al. 1980) did not induce
 

dominant lethal mutations. Females mated to these males did not show a
 

significant increase in the number of dead implants, indicating a lack of
 

genotoxic effect. Liver and sperm cells from rats gavaged once with
 

1,2-dibromoethane at doses ranging from 10 to 100 mg/kg were not found to have
 

higher rates of unscheduled DNA synthesis than those from untreated rats
 

(Working et al. 1986). In contrast, oral administration of approximately
 

3 mg/kg to rats resulted in the formation of DNA adducts in all tissues
 

examined (kidney, liver, spleen, intestine, stomach, testes, heart, brain, and
 

muscle, listed in decreasing order of amount detected) (Hill et al. 1978).
 

1,2-Dibromoethane induced DNA damage in rat liver cells when administered as a
 

single dose by gavage at doses ranging from 75-220 mg/kg (Nachtomi and Sarma
 

1977). Hepatocellular DNA damage caused at the 75-mg/kg dose level was
 

completely repaired 96 hours after administration.
 

Other genotoxicity studies are discussed in Section 2.4.
 
35
 

2. HEALTH EFFECTS
 

2.2.2.8 Cancer
 

No studies were located regarding carcinogenic effects in humans
 

following oral exposure to 1,2-dibromoethane.
 

The rat liver foci assay is a short-term in vivo test to predict
 

carcinogenic potential of a chemical. In this assay, 1,2-dibromoethane has
 

both initiating and promoting activity, which correlates well with its
 

carcinogenic effects in animals.
 

1,2-Dibromoethane was administered orally in corn oil to Sprague-Dawley
 

rats in doses up to 120 mg/kg body weight in an initiation protocol that
 

included partial hepatectomy (Milks et al. 1982). This treatment did not
 

cause an increase in γ-glutamyl transpeptidase (GGT) positive foci after 

2 months. When 1,2-dibromoethane was orally administered in corn oil at doses 

of 10 or 30 mg/kg in a promotion protocol with N-nitrosodiethylamine as an 

initiator, there was a significant increase in production of GGT positive foci 

after 2 months. Based on their results, the authors speculated that 

1,2-dibromoethane had epigenetic (promoter) activity, which could contribute 

to the compound's carcinogenic effect. Promotion effects may have been 

related to hepatocellular mitogenesis. Such a promotional effect was not 

detected when 1,2-dibromoethane was used to induce hepatocellular mitogenesis 

in the absence of partial hepatectomy following initiation by 

diethylnitrosamine (Ledda-Colwnbano et al. 1987a). 

In another liver foci study using Sprague-Dawley (Crl:CD) rats,
 

1,2-dibromoethane in corn oil given by gavage was used as an initiator. Two
 

dose regimens were used: 75 mg/kg 1,2-dibromoethane at 0 and 24 hours or corn
 

oil at 0 hours and 75 mg/kg 1,2-dibromoethane at 24 hours. Partial
 

hepatectomies and phenobarbital in drinking water also were part of the
 

protocol. With this system, at 16 months, 1,2-dibromoethane-exposed rats had
 

increased numbers of foci of hepatic cellular alteration. Rats that received
 

the two doses of 1,2-dibromoethane had increased numbers of nodules on
 

hematoxylin and eosin-stained sections as well as increased number and size of
 

GGT positive foci (Moslen 1984). These results indicate that
 

1,2-dibromoethane can act as an initiator.
 

Oral exposure of rodents to 1,2-dibromoethane either via gavage or
 

drinking water has resulted in neoplasms of the forestomach and other organs.
 

The carcinogenicity of 1,2-dibromoethane by the oral route has been
 

examined in a chronic bioassay conducted by NCI (1978). The chemical was
 

administered by gavage in corn oil to rats and mice. Because of dose
 

adjustments during the study, doses were expressed as time-weighted average
 

(TWA) as follows: high doses for rats were 41 mg/kg/day (males) and
 

39 mg/kg/day (females); low doses for rats were 38 mg/kg/day (males) and
 

37 mg/kg/day (females); the high dose for male and female mice was
 

107 mg/kg/day; and the low dose for male and female mice was 62 mg/kg/day.
 
36
 

2. HEALTH EFFECTS
 

Under test conditions, 1,2-dibromoethane was carcinogenic to Osborne-


Mendel rats and B6C3F1 mice resulting in squamous cell carcinomas of the
 

forestomach in rats and mice of both sexes and lung adenomas in male and
 

female mice. There were also two equivocal endpoints in rats: hepatocellular
 

tumors in females and hemangiosarcomas in males. It should be noted that
 

there were a number of problems associated with this study. High mortality as
 

a result of incorrect determination of the maximum tolerated dose necessitated
 

discontinuation of dosing from weeks 17 to 30 in the high-dose rats. Periodic
 

adjustments of dose were made for male and female mice. There may have been
 

errors in laboratory gavage procedures. Finally, the rat and mouse studies
 

were terminated early. However, these limitations do not diminish the
 

conclusion that 1,2-dibromoethane is carcinogenic to rats and mice following
 

chronic gastric intubation exposure.
 

EPA (1987a) has derived a q1* value of 85 (mg/kg/day)-1 for cancer risk
 

associated with oral exposure to 1,2-dibromoethane based on the study by NCI
 

(1978) in rats. IRIS (1991) also estimated that 1,2-dibromoethane
 -2 -3 -4 -6 -7 -8
 concentrations of 4x10 , 4x10 , and 4x10 μg/L (5x10m , 5x10 , and 5x10

mg/kg/day) in water are associated in humans with excess lifetime cancer risks -4 -5 -6
 of 10 , 10 , and 10 , respectively. These values correspond to 1 excess
 

cancer death in 10,000, 100,000, or 1 million persons, exposed continuously.
 

for their lifetime (estimated as 70 years) to these respective levels of
 

1,2-dibromoethane by ingestion. These estimated concentrations associated
 

with cancer risk were converted into mg/kg/day and plotted in Figure 2-2.
 

There are two drinking water studies of 1,2-dibromoethane that further
 

support the conclusion that oral exposure to 1,2-dibromoethane results in
 

forestomach tumors in mice.
 

A dose of 103 mg/kg/day for females and 116 mg/kg/day for males of
 

1,2-dibromoethane in drinking water induced squamous cell tumors (primarily
 

carcinomas) of the forestomach in male and female B6C3F1 mice (Van Duuren et
 

al. 1985). It should be noted that the male and female mice were sacrificed
 

before the completion of the chronic study because of excessive morbidity.
 

Because only one dose of 1,2-dibromoethane was used, a dose-response could not
 

be characterized.
 

In another drinking water study, 50 mg/kg/day 1,2-dibromoethane was used
 

as a positive control for a study on humic acids (Van Duuren et al. 1986).
 

Both sexes of B6C3F1 mice exposed to 1,2-dibromoethane had statistically
 

significant increases in squamous cell tumors of the forestomach: squamous
 

cell carcinomas in males and papillomas or carcinomas in females. Male
 

1,2-dibromoethane-treated mice also had a significant increase over control
 

animals in the incidence of papilloma and squamous carcinoma of the esophagus.
 

Animals were tested at only one dose; therefore, dose-response could not be
 

characterized.
 
37
 

2. HEALTH EFFECTS
 

2.2.3 Dermal Exposure
 

2.2.3.1 Death
 

Two fatal cases of occupational exposure to 1,2-dibromoethane were
 

reported by Letz et al. (1984). A worker collapsed shortly after entering a
 

pesticide storage tank containing residues of 1,2-dibromoethane; he remained
 

in the tank for 45 minutes. A supervisor attempting to rescue the worker also
 

collapsed and was exposed for 20-30 minutes prior to rescue. Both men died 12
 

and 64 hours after collapse, respectively. The primary route of exposure was
 

postulated to be dermal, with inhalation also playing a potentially important
 

role. Neither worker had been wearing protective clothing or respirators.
 

Clinical chemistry prior to death for both men revealed metabolic
 

acidosis, acute renal and hepatic failure, skeletal muscle necrosis, and
 

damage to other organ systems. Autolysis of viscera prevented complete
 

characterization of lesions associated with mortality from these
 

1,2-dibromoethane exposures.
 

Lethal amounts of topically applied 1,2-dibromoethane were rapidly
 

absorbed through the intact skin of rabbits. When evaporation was prevented
 

for 24 hours by occlusive dressing, mortality occurred within 4 days (Rowe et
 

al. 1952).
 

The reliable LOAEL for death in rabbits from acute dermal exposure to
 

1,2-dibromoethane is recorded in Table 2-3.
 

2.2.3.2 Systemic Effects
 

No studies were located regarding hematologic effects in humans or
 

animals after dermal exposure to 1,2-dibromoethane.
 

Respiratory Effects. In the case report of Letz et al. (1984) (see
 

Section 2.2.3.1), one patient had bilateral pulmonary edema and cyanosis at
 

necropsy. These lesions, however, are nonspecific and can occur with any type
 

of agonal death. No studies were located regarding respiratory effects in
 

animals after dermal exposure to 1,2-dibromoethane.
 

Cardiovascular Effects. One of the patients described by Letz et al.
 

(1984) (see Section 2.2.3.1) who had a terminal cardiopulmonary arrest had
 

acute myocardial interstitial edema, myocardial inflammation, and Grampositive
 

sporulating rods at necropsy. The second patient initially had a
 

39
 

2. HEALTH EFFECTS
 

normal electrocardiogram, but as his renal and hepatic function deteriorated,
 

eventually developed supraventricular tachycardia and asystole.
 

No studies were located regarding cardiovascular effects in animals
 

after dermal exposure to 1,2-dibromoethane.
 

Gastrointestinal Effects. Both patients described by Letz et al. (1984)
 

(see Section 2.2.3.1) vomited shortly after removal from the tank; one
 

complained of a burning throat. Both patients later developed diarrhea.
 

No studies were located regarding gastrointestinal effects in animals
 

after dermal exposure to 1,2-dibromoethane.
 

Musculoskeletal Effects. Both patients described by Letz et al. (1984)
 

(see Section 2.2.3.1) had greatly elevated levels of serum creatinine
 

phosphokinase after 1,2-dibromoethane exposure; this enzyme increases in the
 

event of skeletal muscle necrosis. There was no report of skeletal muscle
 

being examined at necropsy or histologically in either individual.
 

No studies were located regarding musculoskeletal effects in animals
 

after dermal exposure to 1,2-dibromoethane.
 

Hepatic Effects. Both patients described by Letz et al. (1984) (see
 

Section 2.2.3.1) had elevated serum aspartate aminotransferase and lactic
 

dehydrogenase, indicating severe hepatic damage. These enzymes were elevated
 

5 hours after exposure in one man who died 12 hours after exposure and
 

24 hours after exposure in the second patient who died 64 hours following
 

exposure. Liver from the patient dying first had intrasinusoidal nuclear
 

fragmentation consistent with Kupffer cell damage; autolysis precluded
 

examination of the second patient's liver.
 

No studies were located regarding hepatic effects in animals after
 

dermal exposure to 1,2-dibromoethane.
 

Renal Effects. The patient described by Letz et al. (1984) (see Section
 

2.2.3.1) who lived for 64 hours after exposure to toxic levels of
 

1,2-dibromoethane had acute renal failure as evidenced by severe oliguria
 

24 hours after exposure and abnormal clinical chemistry values (blood urea
 

nitrogen, creatinine, and serum uric acid). Severe metabolic acidosis was
 

present despite two hemodialysis procedures.
 

No studies were located regarding renal effects in animals after dermal
 

exposure to 1,2-dibromoethane.
 

Dermal/Ocular Effects. Volunteers including the report's author were
 

exposed topically to liquid from a remote water gauge; this liquid contained
 

1,2-dibromoethane as well as other chemicals (Pflesser 1938). Follow-up tests
 
40
 

2. HEALTH EFFECTS
 

were formed with 1,2-dibromoethane. No dermal changes occurred when the
 

liquid or 0.5 cc of 1,2-dibromoethane was applied to uncovered skin. A
 

burning sensation, inflammation and vesiculation occurred when a cloth
 

dressing saturated with the liquid was applied for 1-2 hours. Skin lesions
 

resolved with treatment after 7-13 days.
 

Erythema and blisters developed within 24 hours on the trunk and legs of
 

a worker exposed to residues of 1,2-dibromoethane in a pesticide tank (Letz et
 

al. 1984). This patient, immediately after rescue, complained of burning
 

eyes, but ocular lesions did not develop.
 

When rabbits were exposed topically to 1,2-dibromoethane, all animals
 

with occlusive dressings, irrespective of concentration, had moderate to
 

severe cutaneous erythema, edema, and necrosis with sloughing (Rowe et
 

al. 1952). When evaporation was not inhibited, slight erythema but no
 

additional damage occurred. Lethality associated with this exposure was
 

discussed in Section 2.2.3.1.
 

Undiluted 1,2-dibromoethane applied topically to rabbit eyes caused
 

pain, conjunctival irritation, and superficial cornea1 necrosis. A 10%
 

solution of 1,2-dibromoethane in propylene glycol applied topically produced
 

more ocular damage to rabbit eyes than undiluted 1,2-dibromoethane.
 

Conjunctival irritation and cornea1 damage were more pronounced and
 

persistent. Healing was complete 2 and 12 days after exposure to the
 

undiluted 1,2-dibromoethane and the 10% solution, respectively (Rowe et
 

al. 1952).
 

The LOAEL for dermal effects in rabbits from acute dermal exposure to
 

1,2-dibromoethane is recorded in Table 2-3.
 

2.2.3.3 Immunological Effects
 

No studies were located regarding immunologic effects in humans or
 

animals after dermal exposure to 1,2-dibromoethane.
 

2.2.3.4 Neurological Effects
 

Two male workers collapsed very shortly after entering a storage tank
 

that contained toxic 1,2-dibromoethane residues (Letz et al. 1984). After
 

45 minutes of exposure prior to rescue, one patient was comatose then became
 

combative and incoherent in the ambulance. One hour later, he was lethargic;
 

as metabolic acidosis developed, he became semicomatose. When the second
 

patient was rescued from the tank after 20-30 minutes of exposure; he became
 

delirious and combative. His neurological symptoms then ameliorated until he
 

developed hepatorenal failure.
 
41
 

2. HEALTH EFFECTS
 

In the study of Rowe et al. (1952) discussed in Section 2.2.3.1, rabbits
 

exposed dermally to 1,2-dibromoethane at all dosage levels had central nervous
 

system depression (not otherwise specified).
 

The reliable LOAEL for neurological effects in rabbits from acute dermal
 

exposure is recorded in Tible 2-3.
 

No studies were located regarding the following health effects in humans
 

or animals after dermal exposure to 1,2-dibromoethane:
 

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 carcinogenic effects in humans
 

following exposure to 1,2-dibromoethane by the dermal route alone. However,
 

occupational exposures to 1,2-dibromoethane are likely to involve dermal as
 

well as respiratory exposure. Two epidemiologic studies concerning
 

occupational exposure are discussed in Section 2.2.1.8 and an abstract is
 

discussed in Section 2.9.3.
 

Dermal exposure of mice to 1,2-dibromoethane has resulted in cutaneous
 

neoplasms and increased incidences of primary lung tumors.
 

Repeated topical application of 1,2-dibromoethane (0, 833, or
 

1,666 mg/kg/day) to Ha:ICR Swiss mice resulted in a statistically significant
 

increase in skin papillomas at the high dose (Van Duuren et al. 1979). In
 

addition, the number of mice with distant tumors (lung tumors) was
 

significantly higher at both doses applied. Because the mice in the study
 

were housed six to a cage with no restraining collars to prevent licking the
 

application site, aspiration to the lungs could have occurred during grooming.
 

1,2-Dibromoethane did not initiate skin tumors after a single topical
 

application, even when treatment by phorbol myristate (a potent tumor
 

promoter) followed the dermal application of 1,2-dibromoethane (Van Duuren et
 

al. 1979). The cancer effect level causing lung tumors in mice from chronic
 

dermal exposure is reported in Table 2-3.
 
42
 

2. HEALTH EFFECTS
 

2.3 TOXICOKINETICS
 

2.3.1 Absorption
 

2.3.1.1 Inhalation Exposure
 

No studies were located in humans regarding the inhalation absorption of
 

1,2-dibromoethane. The available animal toxicity data (see Section 2.2.1)
 

indicate that absorption of 1,2-dibromoethane occurs in rats, mice, rabbits,
 

guinea pigs, and monkeys exposed via inhalation for acute, intermediate, and
 

chronic durations (Rowe et al. 1952; Stott and McKenna 1984). Based on the
 

findings in animal studies, 1,2-dibromoethane is expected to be absorbed in
 

humans exposed via the inhalation route.
 

2.3.1.2 Oral Exposure
 

No studies were located in humans regarding the oral absorption of
 

1,2-dibromoethane. However, there is evidence to suggest that oral absorption
 

occurs in humans. Death and poisoning resulting from suicide attempts
 

(Olmstead 1960; Saraswat et al. 1986) and from consumption of contaminated
 

fruits, grains, and drinking water (EPA 1983), indicate that absorption
 

occurred.
 

Uptake of 1,2-dibromoethane readily occurs in rats following oral
 

intubation (Botti et al. 1982; Nachtomi 1981; Plotnick et al. 1979; Van
 

Bladeren et al. 1980). The presence of 1,2-dibromoethane residues in the
 

kidney, liver, and spleen of rats following ingestion is also evidence of its
 

absorption (Plotnick et al. 1979). It may be inferred that uptake from the
 

gastrointestinal tract of rats is extensive, since 73% of a radiolabeled


14C-1,2-dibromoethane dose was excreted in the urine (Plotnick et al. 1979;
 

Van Bladeren et al. 1980) and about 2% was excreted in the feces by
 

24-48 hours (Plotnick et al. 1979).
 

2.3.1.3 Dermal Exposure
 

No studies were located regarding the dermal absorption of 

1,2-dibromoethane in humans. However, two occupational case reports suggest 

that dermal absorption of 1,2-dibromoethane was the major route of exposure to 

1,2-dibromoethane that resulted in death (Letz et al. 1984). Dermal 

absorption does occur in animals but has not been quantified. Absorption of 

1,2-dibromoethane was demonstrated in guinea pigs whose blood levels were 

monitored during dermal exposure to 1 mL of 1,2-dibromoethane (Jakobson et 

al. 1982). Following dermal application, the blood level of 1,2-dibromoethane 

increased rapidly, reaching a maximum level of approximately 2.1 μg/mL at 

1 hour and 1.8 μg/mL at 6 hours. 
43
 

2. HEALTH EFFECTS
 

The available data suggest that 1,2-dibromoethane may be absorbed
 

dermally by humans. Thus, contact with water contaminated with
 

1,2-dibromoethane may result in absorption.
 

2.3.2 Distribution
 

2.3.2.1 Inhalation Exposure
 

No studies were located in humans or animals regarding the distribution
 

of 1,2-dibromoethane after inhalation exposure. Although occupational cases
 

of inhalation exposure of humans have been reported (Letz et al. 1984), there
 

were no data on 1,2-dibromoethane levels in tissues.
 

2.3.2.2 Oral Exposure
 

No studies were located in humans regarding the distribution of
 

1,2-dibromoethane after oral exposure. In humans intentionally ingesting
 

1,2-dibromoethane, kidney lesions and centrilobular necrosis of the liver were
 

found (Olmstead 1960; Saraswat et al. 1986). This is indirect evidence of
 

distribution of 1,2-dibromoethane. The tissue distribution of
 

1,2-dibromoethane has been studied in rats following exposure by the oral
 

route. Although retention was limited, the kidneys, liver, and spleen appear
 

to retain the highest amounts of the administered dose (Plotnick et al. 1979)
 

as illustrated in Table 2-4. Rats received an oral dose of 15 mg/kg/day of
 

labeled 1,2-dibromoethane in corn oil. Twenty-four hours later 3% of
 

radioactivity was detected in fat, brain, kidney, liver, spleen, testes,
 

blood, and plasma, 72.38% in the urine, and 1.65% in the feces (Plotnick et
 

al. 1979). By 48 hours after administration, 73% of the radiolabeled dose was
 

accounted for in the urine, 1.1% in the liver, and 2.4% in the feces. Total
 

recovery was 77.8% of the administered radioactivity. 1,2-Dibromoethane in
 

the expired air was not measured.
 

The retention of 1,2-dibromoethane in tissues and body fluids can be
 

altered by concurrent exposure to modifiers of enzyme activity, such as
 

disulfiram (Plotnick et al. 1979). The concentration of radiolabeled
 

1,2-dibromoethane in the liver, kidneys, spleen, testes, and brain increased
 

significantly in rats fed disulfiram in the diet for 12 days before an oral
 

dose of 15 mg 14C-1,2-dibromoethane/kg compared with rats not fed disulfiram.
 

Disulfiram, an inhibitor of P-450 metabolism (via action on acetaldehyde
 

dehydrogenase), was found to increase the uptake of 14C into liver nuclei.
 

These observations correlate well with the results of chronic studies (Wong et
 

al. 1982) that demonstrated enhanced tumorigenic effects in the liver and
 

testes following combined 1,2-dibromoethane and disulfiram exposure.
 

2.3.2.3 Dermal Exposure
 

No studies were available in humans or animals regarding the
 

distribution of 1,2-dibromoethane following dermal exposure. However, toxic
 

45
 

2. HEALTH EFFECTS
 

effects observed in humans and animals after dermal exposure indicate that the
 

compound is widely distributed throughout the body.
 

2.3.2.4 Other Routes of Exposure
 

Tissue distribution of 1,2-dibromoethane following intraperitoneal
 

administration was studied in mice (Edwards et al. 1970) and guinea pigs
 

(Plotnick and Conner 1976). The kidney, liver, and stomach retained the
 

highest amounts of the administered 1,2-dibromoethane dose across all the
 

observation periods (see Tables 2-5 and 2-6). Autoradiographic studies of
 

mice injected intraperitoneally with 14C-1,2-dibromoethane (40 mg/kg) revealed
 

radioactivity primarily in the intestines, kidneys, liver, blood, fat, and
 

spleen. Only 1% of the administered dose (per gram of wet tissue) was
 

detected in the kidney and in the stomach tissue, 6.2% in whole blood, and
 

2.6% in plasma 24 hours posttreatment (Edwards et al. 1970). Following a
 

single intraperitoneal injection of 30 mg/kg 14C-1,2-dibromoethane in corn oil
 

to guinea pigs, the majority of the dose was accounted for in the urine
 

(65.9%), liver (2.16%), and feces (3%) by the end of the 72-hour period.
 

Approximately 10%-12% of the administered dose was excreted via the lungs
 

(Plotnick and Conner 1976). Plotnick and Conner (1976) investigated tissue
 

distribution of 1,2-dibromoethane in guinea pigs because they found
 

similarities in metabolism and biotransformation pathways between guinea pigs
 

and humans. The authors reported that target organs for tissue distribution
 

in guinea pigs were the same as those in rats, although the percentage of dose
 

recovered was higher in guinea pig tissues.
 

These results are similar to those after oral administration and suggest
 

that 1,2-dibromoethane is rapidly absorbed and distributed but retained to
 

only a limited extent mainly in the kidneys, liver, and stomach, regardless of
 

the route of exposure and the species tested.
 

2.3.3 Metabolism
 

1,2-Dibromoethane is metabolized to active forms capable of inducing
 

toxic effects by either of two systems- -the microsomal monooxygenase system
 

(cytochrome P-450 oxidation) and the cytosolic activation system (glutathione
 

conjugation). Figure 2-3 provides an overview of the metabolism of
 

1,2-dibromoethane by the two systems, The pathway of biotransformation for
 

1,2-dibromoethane appears to be the controlling factor for its biological
 

activity. Two reactive intermediates, 2-bromoacetaldehyde and S-(2-bromoethyl)
 

glutathione, are formed. The 2-bromoacetaldehyde is responsible for
 

tissue damage caused by covalent binding to cellular macromolecules.
 

S-(2-bromoethyl)glutathione is responsible for 1,2-dibromoethane's proven
 

genotoxic effect and, perhaps, its carcinogenic effect observed in laboratory
 

animals. These two systems and their relative importance are discussed in
 

detail below.
 



49
 

2. HEALTH EFFECTS
 

1,2-Dibromoethane is metabolized in various tissues through microsomal
 

oxidation by cytochrome P-450 to form 2-bromoacetaldehyde (Tamura et al. 1986;
 

Van Duuren et al. 1985). This metabolite can produce histopathological
 

changes such as liver damage, by binding to cellular proteins (Hill et
 

al. 1978). 2-Bromoacetaldehyde can be metabolized further by aldehyde
 

dehydrogenase in the presence of nicotinamide adenine dinucleotide
 

dehydrogenase to 2-bromoethanol which is highly toxic and causes genotoxicity.
 

2-Bromoacetaldehyde can also be metabolized by aldehyde dehydrogenase in the
 

presence of nicotinamide adenine dinucleotide to bromoacetic acid which is
 

excreted in the urine. In addition, 2-bromoacetaldehyde can also be
 

conjugated with glutathione. The conjugated metabolite is reduced to
 

S-carboxymethylglutathione. This compound can form S-carboxymethylcysteine
 

which may be metabolized to thioglycolic acid and excreted in the urine or can
 

be metabolized to S-(β-hydroxyethyl) cysteine. The latter is excreted in the 

urine following action by N-acetyl transferase in the presence of acetyl CoA 

enzyme and subsequent sulfoxidation to form mercapturic acids (Nachtomi et 

al. 1966; Van Bladeren 1983). Mercapturic acids are the primary urinary 

metabolites of 1,2-dibromoethane. Tomasi et al. (1983) demonstrated that 

1,2-dibromoethane can form a free radical intermediate under a hypoxic 

condition suggesting a new metabolic pathway for 1,2-dibromoethane. 

As shown in Figure 2-3, 1,2-dibromoethane can be conjugated with
 

glutathione through the action of glutathione transferases to form
 

S-(2-bromoethyl) glutathione (Peterson et al. 1988). This reactive
 

intermediate can react to form ethylene and glutathione disulfide through
 

further action of glutathione transferases. These are detoxification
 

products. The ethylene is exhaled, and the glutathione disulfide is
 

eliminated in the feces via the bile.
 

S-(2-bromoethyl)glutathione is considered to be the genotoxic, and
 

probably the carcinogenic, intermediate of 1,2-dibromoethane metabolism (Van
 

Bladeren et al. 1981). This ion is a highly reactive alkylating agent that
 

can bind to DNA either through direct nucleophilic substitution (Van Bladeren
 

1983) or substitution through the ethylene-S-glutathionyl-episulfonium ion to
 

form S-[2-(N7

-guanyl)ethyl]glutathione (Ozawa and Guengerich 1983; Koga et
 

al. 1986; Peterson et al. 1988). A recent study suggests that S-(2-bromoethyl)
 

glutathione is the main genotoxic metabolite that binds to DNA to form
 

the complex S-[2-(N7

-guanyl)ethyl]cysteine (Bolt et al. 1986). The ethylene-


S-glutathionyl-episulfonium ion can also react with water and be detoxified to
 

form S-(β-hydroxyethyl)glutathione, or react with glutathione to form 

S,S'-ethylene-bis-(glutathione). The latter is excreted in the feces via the 

bile. S-(β-hydroxyethyl)glutathione can form S-(β-hydroxyethyl)-glutathioneS-oxide by sulfoxidation or react with peptidases to form 

S-(β-hydroxyethyl)cysteine. The former is excreted in the feces via the bile. 

The latter forms S-(β-hydroxyethyl)mercapturic acid by the action of N-acetyl 

transferase and is excreted in the urine (EPA 1985; Nachtomi 1970; Van 

Bladeren 1983). 
50
 

2. HEALTH EFFECTS
 

In animals, 1,2-dibromoethane is rapidly metabolized after oral
 

administration and is converted into mercapturic acid derivatives that appear
 

in urine (Kirby et al. 1980; Nachtomi 1970; Nachtomi et al. 1965). The
 

principal mercapturic acid derivative, N-acetyl-S-(2-hydroxyethyl-)L-cysteine,
 

and other related metabolites are derived from the conjugation reaction of
 

1,2-dibromoethane with glutathione, a molecule present in mammalian cells.
 

This suggests that the primary pathway of 1,2-dibromoethane metabolism (i.e.,
 

activation and detoxification) in rats is via the microsomal monooxygenase
 

system. An in vivo study (Van Duuren et al. 1985) provides evidence that
 

microsomal oxidation of 1,2-dibromoethane in rodents can produce adducts that
 

bind preferentially to protein. In a study using tetradeutero-1,2-dibromoethane,
 

only about 20% of the mercapturic acid excreted was formed via direct
 

glutathione conjugation (Van Bladeren 1983). The reactive metabolites formed
 

by these two systems may bind to protein (2-bromoacetaldehyde) or DNA (S-[2­

bromoethyllglutathione) producing either cytotoxicity or genotoxicity,
 

respectively. Adducts formed via cytosolic glutathione conjugation-­

identified as S-[2-(N7

-guanyl)ethyl]glutathione by Ozawa and Guengerich
 

(1983)--have been associated with genotoxic, and perhaps carcinogenic, effects
 

(Van Bladeren et al. 1982; White et al. 1983). Edwards et al. (1970) also
 

identified metabolites after oral administration.
 

Evidence from animal bioassays supports the hypothesis that it is the
 

cytosolic system and not the microsomal oxidative system that is responsible
 

for the carcinogenicity of 1,2-dibromoethane. Metabolism of 1,2-dibromoethane
 

by glutathione conjugation was demonstrated in vitro in rat hepatocytes
 

(Sundheimer et al. 1982). In the long-term drinking water study of Van Duuren
 

et al. (1985), mice were administered equimolar concentrations of
 

1,2-dibromoethane, bromoethanol, and bromoacetaldehyde. Bromoethanol and
 

bromoacetaldehyde, which are microsomal metabolites of 1,2-dibromoethane, were
 

far less potent carcinogens than 1,2-dibromoethane. The cytosol-induced
 

binding to isolated DNA was 5-10 times greater than that found in microsomal
 

oxidation in isolated rat hepatocytes. The preferential binding of
 

1,2-dibromoethane metabolites to DNA in tissues of the forestomach, nasal
 

mucosa, oral epithelium, and testis of mice and rats demonstrates the ability
 

of these tissues to metabolize 1,2-dibromoethane by conjugation with
 

glutathione (Kowalski et al. 1985a; Sipes et al. 1986a; Wiersma and Sipes
 

1983).
 

2.3.4 Excretion
 

2.3.4.1 Inhalation Exposure
 

No studies were located-in humans or animals regarding the excretion of
 

1,2-dibromoethane after inhalation exposure.
 
51
 

2. HEALTH EFFECTS
 

2.3.4.2 Oral Exposure
 

No studies were available in humans regarding the excretion of
 

1,2-dibromoethane after oral exposure. Oral administration of
 

1,2-dibromoethane to rats primarily results in mercapturic acid derivatives
 

excreted in the urine (approximately 74% of the administered dose) (Plotnick
 

et al. 1979) as shown in Table 2-4. Unmetabolized 1,2-dibromoethane may be
 

excreted via the lungs; fecal excretion of metabolites accounts for
 

approximately 3% of the administered dose (Plotnick et al. 1979).
 

Based on the rapid and extensive metabolism seen in all animals, the
 

fate of 1,2-dibromoethane in humans would be expected to be similar. Seventy
 

percent of the administered parent compound is excreted in the urine and feces
 

by 48 hours. The lack of persistence of metabolites in the tissues indicate
 

that 1,2-dibromoethane is readily removed from the body. Low-level exposure
 

would not be expected to result in accumulation of 1,2-dibromoethane or its
 

metabolites in human tissue. However, theoretically, acute high-level
 

exposure may saturate metabolic pathways and consequently allow
 

1,2-dibromoethane to accumulate in the tissues for a longer period of time.
 

2.3.4.3 Dermal Exposure
 

No studies were found regarding the excretion of 1,2-dibromoethane in
 

humans or animals after dermal exposure.
 

2.3.4.4 Other Routes of Exposure
 

Plotnick and Conner (1976) reported that 10%-12% of a dose is excreted
 

via the lungs 72 hours after intraperitoneal injection of 30 mg/kg


14C-1,2-dibromoethane to guinea pigs. The majority of the dose was accounted
 

for in the urine (65.9%), liver (2.16%), and feces (3%).
 

Intraperitoneal administration of 37.6, 75, or 113 mg 1,2-dibromoethane/
 

kg/day (0.2, 0.4, or 0.6 mmol/kg) to rats resulted in metabolic
 

biotransformation into mercapturic acid which was strongly indicative of
 

saturable metabolism (Goyal et al. 1989). Administration of
 

L-2-oxothiazolidine-4-carboxylic acid (OTCA) (4±5 mmol/kg) enhanced 

glutathione availability and increased excretion of urinary mercapturic acid 

at the higher doses. These results suggest that OTCA increases the capacity 

for detoxification via the glutathione pathway. 

2.4 RELEVANCE TO PUBLIC HEALTH
 

No MRLs were derived for 1,2-dibromoethane because of a lack of
 

quantitative exposure data.
 

Humans are susceptible to the acute toxic effects of 1,2-dibromoethane
 

from various routes of exposure. Except for adverse reproductive effects in
 
52
 

2. HEALTH EFFECTS
 

men after occupational exposure, chronic effects of 1,2-dibromoethane exposure
 

have not been documented in humans. Based on data derived from animal
 

studies, mechanisms of action of 1,2-dibromoethane at a cellular level,
 

toxicokinetics, and genotoxicity tests, there is a potential for certain
 

adverse health effects in humans exposed chronically to low environmental
 

levels of 1,2-dibromoethane that could exist near hazardous waste sites or
 

areas of former agricultural use.
 

Clinical signs in humans and animals related to acute toxic exposure to
 

1,2-dibromoethane are depression and collapse, indicative of neurologic
 

effects, and erythema and necrosis of tissue at the point of contact (oral and
 

pharyngeal ulcers for ingestion, skin blisters and sloughing for dermal
 

exposure). Neurologic signs are not seen in animals exposed to nonlethal
 

doses.
 

Target organs of 1,2-dibromoethane are of two types. The first is the
 

point of contact with the chemical, i.e., skin for dermal exposure (humans and
 

animals), oropharynx for ingestion (humans), stomach for gavage administration
 

(rodents), and upper respiratory tract for inhalation exposure (humans,
 

rodents). Although there is little information on toxicity of 1,2-dibromoethane
 

in humans after inhalation, the testis was a target organ in exposed
 

workers; the liver and kidney have been identified as target organs after
 

dermal and oral exposure in humans. The liver, kidney, and testis are target
 

organs in experimental animals irrespective of the exposure route.
 

Death. 1,2-Dibromoethane can be fatal to humans after oral or dermal
 

exposure. Acute deaths following toxic doses are related to cardiopulmonary
 

arrest or, if affected individuals survive for a period of time, to hepatic
 

and renal failure. These results are supported by animal studies in which
 

acute death occurred after oral, dermal, and inhalation exposure.
 

Doses that cause acute death in humans and animals are relatively large.
 

For humans, reports of death following oral exposure were a result of
 

intentional ingestion of a high concentration of 1,2-dibromoethane. Human
 

death following dermal and inhalation exposure occurred in two accidentally-exposed
 

workers. It is therefore highly unlikely that there would be a risk
 

to humans of death under conditions of low-level, long-term exposure from
 

contaminated food or water.
 
53
 

2. HEALTH EFFECTS
 

Systemic Effects
 

Respiratory Effects. Nonspecific respiratory symptoms were reported in
 

a worker involved in 1,2-dibromoethane production and presumably chronically
 

exposed by inhalation (Kochmann 1928). One of the workers exposed in a
 

storage tank by dermal and inhalation routes to 1,2-dibromoethane had
 

bilateral pulmonary edema, a nonspecific agonal finding, at necropsy (Letz et
 

al. 1984). Similar results occurred in rats exposed acutely to toxic
 

concentrations by inhalation (Rowe et al. 1952). Abnormal respiratory effects
 

have been well documented in experimental animals after inhalation exposure;
 

respiratory effects did not occur after dermal or oral exposure. Many of the
 

respiratory tract lesions in animal inhalation studies consist of
 

proliferation, particularly in the upper respiratory tract. Animal studies
 

also identify the upper respiratory tract as a site for 1,2-dibromoethane
 

binding and metabolism. These animal studies are relevant to humans because
 

they suggest a possibility for adverse effects in the human respiratory system
 

following low-level exposure to 1,2-dibromoethane by inhalation.
 

Cardiovascular Effects. Cardiovascular effects as terminal events were
 

reported in patients dying after dermal and inhalation exposure to
 

1,2-dibromoethane. One individual also had acute myocardial lesions (Letz et
 

al. 1984). Cardiovascular effects were not identified in humans who died
 

after 1,2-dibromoethane ingestion. These findings in humans were not
 

supported by studies in experimental animals exposed by inhalation, oral, or
 

dermal routes. It is unlikely that humans exposed to low levels of
 

1,2-dibromoethane will experience adverse cardiovascular effects.
 

Gastrointestinal Effects. Gastrointestinal effects of labial, oral, and
 

pharyngeal ulcers occurred in humans intentionally ingesting high
 

concentrations of 1,2-dibromoethane (Saraswat et al. 1986). Nausea and emesis
 

occurred in humans exposed to high concentrations by the oral or dermal and
 

inhalation routes; the latter patients also developed diarrhea (Letz et
 

al. 1984). Results of adverse gastrointestinal effects in humans were
 

supported by animal studies using the oral route of exposure (Ghanayem et
 

al. 1986; NCI 1978). No gastrointestinal effects were present in animals
 

exposed dermally or by inhalation. While adverse gastrointestinal effects are
 

not likely in humans exposed orally to low levels of 1,2-dibromoethane, the
 

upper gastrointestinal tract is a potential site of 1,2-dibromoethane binding
 

and metabolism (Kowalski et al. 1985a).
 

Hematologic Effects. Effects of 1,2-dibromoethane on the hematopoietic
 

system of humans exposed by inhalation, oral, or dermal routes have not been
 

described. Results of animal studies are equivocal except that, based on a
 

study in rats, individuals taking disulfiram for alcoholism might be a
 

susceptible human subpopulation at higher risk for adverse hematopoietic
 

effects (Wong et al. 1982) (See Sections 2.6 and 2.7).
 
54
 

2. HEALTH EFFECTS
 

Musculoskeletal Effects. Dramatic musculoskeletal effects as evidenced
 

by elevated muscle enzymes in serum occurred in two patients exposed by the
 

dermal and inhalation routes (Letz et al. 1984). No musculoskeletal effects
 

were reported in humans exposed by other routes or in experimental animals.
 

Risks appear to be negligible for adverse musculoskeletal effects in humans
 

exposed to low levels of 1,2-dibromoethane.
 

Hepatic Effects. Hepatic effects have been reported in humans exposed
 

orally or by the dermal and inhalation routes to toxic doses of
 

1,2-dibromoethane (Letz et al. 1984; Olmstead 1960; Saraswat et al. 1986).
 

These effects consist of hepatocellular and Kupffer cell necrosis. Results in
 

humans are supported by animal studies in which the liver is also a target
 

organ for toxic effects of 1,2-dibromoethane following exposure by a variety
 

of routes (Botti et al. 1986; Brandt et al. 1987; Broda 1976; NTP 1982; Rowe
 

et al. 1952). 1,2-Dibromoethane, as well as inducing necrosis, can also act
 

as a hepatocellular mitogen in rats (Ledda-Columbano et al. 1987a).
 

Liver toxicity related to 1,2-dibromoethane depends on the metabolic
 

pathway utilized and the amount of damage induced in cellular protein and
 

membrane structures. Humans exposed to low levels of 1,2-dibromoethane are at
 

potential risk of having toxic events occurring within hepatocytes; whether
 

these effects will be subcellular or result in cell necrosis may depend on
 

internal dose and a variety of factors. Liver damage that is severe enough to
 

cause clinical disease in humans from low-level exposure is unlikely.
 

Intraperitoneal administration of 1,2-dibromoethane to male B6C3F1 mice
 

induced hepatic DNA damage (genotoxicity) at doses lower than those that
 

caused other signs of acute toxicity such as increased liver weights, elevated
 

serum enzyme levels, or mortality (Storer and Conolly 1983). Thus, in vivo
 

and in vitro studies suggest that there is a potential for humans to develop
 

subcellular damage after exposure by various routes to low levels of
 

1,2-dibromoethane.
 

Renal Effects. The kidney is a target organ in humans for
 

1,2-dibromoethane toxicity (Letz et al. 1984; Olmstead 1960). In humans
 

exposed acutely to toxic concentrations of 1,2-dibromoethane either by oral or
 

dermal routes, renal damage was described, with one of the exposed individuals
 

dying of acute renal failure despite attempts at hemodialysis. Results in
 

humans are supported by animal studies. Renal effects occurred in male
 

Fischer 344 rats exposed to 1,2-dibromoethane by intraperitoneal injection.
 

Lesions were evenly distributed among renal proximal tubules and consisted of
 

cellular swelling and cytoplasmic vacuolization but not necrosis (Kluwe et al.
 

1982). Nonprotein sulfhydryl levels were initially reduced, then increased;
 

this is suggestive of changes in tubular glutathione levels.
 

1,2-Dibromoethane also acts as a renal mitogen in rats in the absence of
 

tubular cell necrosis (Ledda-Columbano et al. 1987b).
 
55
 

2. HEALTH EFFECTS
 

Renal lesions or changes in renal function in humans chronically exposed
 

to 1,2-dibromoethane have not been identified. Following chronic inhalation
 

exposure to 1,2-dibromoethane, rats developed toxic nephropathy (NTP 1982).
 

1,2-Dibromoethane can be activated in the kidney of rodents by a
 

glutathione-dependent pathway to toxic metabolites, as well as having such
 

metabolites reach the kidney via the enterohepatic circulation (Rush et
 

al. 1984; Working et al. 1986). Because similar metabolic pathways exist in
 

humans, animal studies suggest that there is a possibility for adverse renal
 

effects at a subcellular level to occur in humans exposed to low levels of
 

1,2-dibromoethane such as might occur near areas of former agricultural use or
 

hazardous waste sites. Such low-level exposure is very unlikely to result in
 

clinically detectable renal damage.
 

Dermal/Ocular Effects. Adverse dermal effects occur in humans following
 

topical exposure of relatively high concentrations of 1,2-dibromoethane.
 

These effects consist of inflammation, blister formation, and necrosis (Letz
 

et al. 1984; Pflesser 1938). Effects were most severe when 1,2-dibromoethane
 

applied to the skin was not allowed to evaporate (Pflesser 1938). Rapid
 

absorption of 1,2-dibromoethane through the skin can also result in systemic
 

toxicity (Letz et al. 1984). These results in humans are supported by studies
 

in animals (Rowe et al. 1952). Humans exposed to low levels of
 

1,2-dibromoethane in contaminated water such as during bathing or swimming,
 

are unlikely to have any local irritant effects but may be susceptible to
 

absorption of the compound.
 

Ocular effects have not been reported in humans exposed dermally or
 

orally to toxic doses of 1,2-dibromoethane. Animal studies have identified
 

adverse ocular effects such as irritation and cornea1 damage after exposure to
 

relatively high concentrations (NTP 1982; Rowe et al. 1952). While it appears
 

that humans would be susceptible to development of ocular damage if a high
 

concentration of 1,2-dibromoethane were splashed in the eyes, adverse ocular
 

effects of exposure to low levels of environmental 1,2-dibromoethane would not
 

be expected.
 

Immunological Effects. No studies were located that specifically
 

investigated immunological effects in humans or animals after exposure to
 

1,2-dibromoethane.
 

Neurological Effects. Depression, disorientation, and collapse have
 

been reported in humans with acute exposure to toxic doses of
 

1,2-dibromoethane by oral (Saraswat et al. 1986) or dermal (Letz et al. 1984)
 

routes. Residues of 1,2-dibromoethane were detected in the brain tissue of
 

one fatality (Letz et al. 1984). The fact that the nervous system is at risk
 

when humans are acutely exposed to lethal doses is supported by animal studies
 

(Rowe et al. 1952).
 
56
 

2. HEALTH EFFECTS
 

No neurological effects have been described in humans exposed in an
 

occupational setting except for one report of nonspecific signs of headache
 

and depression (Kochmann 1928). Neurologic signs were not reported in animals
 

exposed by various routes and for intermediate and chronic durations. It is
 

therefore unlikely that neurologic effects will occur in humans chronically
 

exposed to low levels of 1,2-dibromoethane.
 

Neurological effects as evidenced by alterations in brain
 

neurotransmitter enzymes occurred in the F1 progeny of male Fischer 344 rats
 

exposed to 1,2-dibromoethane by intraperitoneal injection (Hsu et al. 1985).
 

Choline acetyltransferase and acetylcholinesterase levels had reversible
 

changes in various parts of the brain while glutamic acid decarboxylase levels
 

remained depressed at 90 days post-partum. This study raises some concerns
 

about the progeny of men with occupational exposure since adverse effects of
 

1,2-dibromoethane on spermatogenesis have been reported in humans. In
 

addition, testicular binding and sperm damage in animals can occur by various
 

routes of exposure.
 

Developmental Effects. Adverse effects on fetal development have not
 

been documented in humans.
 

In rats and mice exposed to 1,2-dibromoethane by inhalation, most
 

developmental effects have been observed at doses that produced maternal
 

toxicity. This raises the possibility that the fetuses of pregnant women who
 

were exposed to doses high enough to cause clinical illness would be at risk
 

for development toxicity, depending on the trimester when exposure occurred.
 

Since overt toxicity would not be expected in pregnant women exposed to
 

low environmental levels of 1,2-dibromoethane, fetuses would not appear to be
 

at serious risk of developmental effects. However, the remote possibility
 

that behavioral effects in the fetus could occur as a result of exposure of
 

either the female or male parent to 1,2-dibromoethane should be considered.
 

Although the possibility of behavioral effects has not been investigated in
 

humans, this is a sensitive effect and would require a large study population
 

to detect. One animal study suggesting this possibility is the previously
 

discussed study of Hsu et al. (1985) in which the progeny of exposed male rats
 

had alterations in brain neurotransmitter enzymes. Another study (Fanini et
 

al. 1984) investigated the behavioral effects of paternal exposure to
 

1,2-dibromoethane in rat progeny. Male F344 rats injected intraperitoneally
 

daily for 5 consecutive days with doses of 1,2-dibromoethane in saline ranging
 

from 1.25 to 10 mg/kg were mated with untreated females 4 or 9 weeks following
 

exposure. Pups fathered by males from the dosed groups and conceived at 4 or
 

9 weeks post-exposure showed dose-dependent impairment in an open-field
 

activity test. Although the swimming performance of pups was significantly
 

impaired, it was dependent upon the time of breeding and the particular
 

component of swimming behavior analyzed.
 
57
 

2. HEALTH EFFECTS
 

Reproductive Effects. Antispermatogenic effects and possible effects on
 

fertility have been reported in humans occupationally exposed to
 

1,2-dibromoethane (Heinrichs 1983; Ratcliffe et al. 1987; Ter Haar 1980; Wong
 

et al, 1979). However, many of these studies lacked sufficient statistical
 

power to detect an association between parameters measured and exposure.
 

Adverse reproductive effects are supported by animal studies. However,
 

in some of the oral and inhalation studies in animals, chemical toxicity
 

and/or neoplasia made it difficult to ascribe testicular lesions to direct
 

toxicity. In other studies, antispermatogenic effects of 1,2-dibromoethane
 

were documented directly in bovines exposed via feed; these effects were
 

reversible after chemical withdrawal (Amir and Ben-David 1973; Amir and
 

Volcani 1965). Effects were more severe in adult bulls compared to young
 

bulls (Amir 1975).
 

The effects on reproduction of 1,2-dibromoethane administered to animals
 

by parenteral routes corroborate the findings of other investigations in
 

animals conducted via inhalation and oral routes. Sperm damage occurred in
 

rams after a single intratesticular injection of 1,2-dibromoethane (Amir et
 

al. 1983). A dose-response was observed with less acute effects on spermatids
 

noted at doses as low as 6.37 mg/kg. Some effects on morphology of sperm were
 

reversible. Transient sperm abnormalities were reported in Columbian rams
 

that received 12 consecutive, daily subcutaneous injections of
 

1,2-dibromoethane at various doses ranging from 7.8 to 13.5 mg/kg (Eljack and
 

Hrudka 1979a). A dose-related decline in sperm motility and acrosome
 

abnormalities were evident during the 5th week following initiation of
 

treatment.
 

The mechanism of action for the antispermatogenic effects of
 

1,2-dibromoethane may be related to covalent binding of metabolites of
 

1,2-dibromoethane with thiol groups of nucleoproteins in nuclei of
 

spermatozoa. Such adduct formation interferes with DNA, causing improper
 

packing of the chromatin (Amir and Lavon 1976; Amir et al. 1977).
 

Antispermatogenic effects in exposed workers and this preferential binding of
 

1,2-dibromoethane in the testis of rodents and ruminants suggest that similar
 

effects on spermatozoa could occur in men exposed to low levels of
 

1,2-dibromoethane.
 

Genotoxic Effects. 1,2-Dibromoethane has been tested extensively to
 

assess its genotoxic potential in prokaryotic, eukaryotic, and mammalian
 

systems. Tables 2-7 and 2-8 present the results of in vivo and in vitro
 

genotoxicity studies, respectively. The results of these studies indicate
 

that 1,2-dibromoethane is a potent mutagen, producing a broad spectrum of
 

mutations in various test systems.
 

In bacterial systems, 1,2-dibromoethane is a direct-acting mutagen and
 

primarily causes mutations of the base-pair substitution type (Barber et
 
58
 

2. HEALTH EFFECTS
 

al. 1981; McCann et al. 1975; Moriya et al. 1983; Principe et al. 1981;
 

Rosenkranz 1977). The mutagenicity of 1,2-dibromoethane in bacteria was not
 

influenced by mammalian metabolizing systems in four out of five studies
 

(Barber et al. 1981; Moriya et al. 1983; Principe et al. 1981; Stolzenberg and
 

Hine 1980). However, detection of its mutagenic activity is influenced by the
 

amount of glutathione present (Kerklaan et al. 1985; Zoetemelk et al. 1987).
 

1,2-Dibromoethane tested positive for mutagenicity with or without metabolic
 

activation in fungi and mammalian cell lines in in vitro assay systems (Brimer
 

et al. 1982; Clive et al. 1979; Crespi et al. 1985; Ferreri et al. 1983;
 

Malling 1969; Principe et al. 1981; Tan and Hsie 1981). It has been tested
 

for its ability to induce heritable mutations in vivo using fruit flies
 

(Drosophila melanogaster), mice, and rats. 1,2-Dibromoethane caused heritable
 

mutations in male fruit flies (Kale and Baum 1979, 1981, 1982, 1983; Vogel and
 

Chandler 1974) but not in mice (Epstein et al. 1972; Teramoto et al. 1980) or
 

rats (Teramoto et al. 1980).
 

Chromosomal abnormalities and sister chromatid exchanges have been
 

observed in mice following intraperitoneal administration of 1,2-dibromoethane
 

(Krishna et al. 1985). Such chromosomal aberrations were also detected in
 

vitro using human lymphocytes (Tucker et al. 1984); however, in studies which
 

use cells from animals and humans with prior exposure to 1,2-dibromoethane,
 

these abnormalities were unreliable or were not detected (Krishna et al. 1985;
 

Steenland et al. 1985, 1986).
 

1,2-Dibromoethane has been shown to bind covalently to DNA both in vitro
 

(Banerjee and Van Duuren 1979, 1983; DiRenzo et al. 1982; Inskeep and
 

Guengerich 1984; Koga et al. 1986; Ozawa and Guengerich 1983; Prodi et
 

al. 1986) and in vivo (Hill et al. 1978; Inskeep et al. 1986; Koga et
 

al. 1986; Prodi et al. 1986), forming a stable adduct. Such adducts have been
 

observed in rat testicular cells following in vivo exposure to 1,2-dibromoethane
 

(Hill et al. 1978) and DNA repair activity was increased in rat
 

spermatocytes treated in vitro with 1,2-dibromoethane (Working et al. 1986).
 

Preincubation of rat hepatocytes or spermatocytes with inhibitors of
 

cytochrome P-450-mediated oxidation did not affect 1,2-dibromoethane-induced
 

unscheduled DNA synthesis (UDS) in vitro. In contrast, depletion of cellular
 

glutathione inhibited 1,2-dibromoethane-induced UDS in both cell types in
 

vitro (Working et al. 1986). This observation indicates that conjugation of
 

1,2-dibromoethane to glutathione and its subsequent metabolism results in the
 

formation of genotoxic metabolites.
 

Thus, interaction of 1,2-dibromoethane with DNA can result in a mutation
 

that is passed on to offspring. In conclusion, sufficient evidence exists to
 

indicate that 1,2-dibromoethane presents potential genotoxic risks for humans.
 

These effects may occur in humans living in areas surrounding hazardous waste
 

sites or areas of former agricultural use where they may be exposed to
 

1,2-dibromoethane.
 



62
 

2. HEALTH EFFECTS
 

Cancer. There are no reports of cancer in humans associated with
 

occupational exposure to 1,2-dibromoethane, although the negative
 

epidemiologic studies have some limitations.
 

1,2-Dibromoethane has been positive in short-term tests in animals used
 

to predict carcinogenic potential of a chemical (Milks et al. 1982; Moslen
 

1984). In addition, there is dramatic tissue-specific binding of metabolites
 

in experimental animals. Radiolabeled 1,2-dibromoethane was administered
 

parenterally (intravenously or intraperitoneally) to C57BL mice, Sprague-


Dawley rats and F344 rats. Both species had binding of high levels of
 

1,2-dibromoethane metabolites in the epithelium of the entire respiratory
 

tract, the upper gastrointestinal tract, the vagina, and subepithelial glands
 

of the nasal olfactory mucosa. .Lower levels of metabolites were bound in the
 

liver, kidney, adrenal cortex, and testicular interstitium (Kowalski et
 

al. 1985a). DNA synthesis in the nasal mucosa of mice was inhibited (Hellman
 

and Brandt 1986). This tissue-specific metabolism correlates well with toxic
 

and/or carcinogenic lesions observed in experimental studies of inhalation and
 

oral exposure to 1,2-dibromoethane. The possibility exists that similar
 

binding and metabolism could occur in humans.
 

1,2-Dibromoethane is a potent carcinogen in rats and mice, causing
 

malignant and benign neoplasms of epithelial and mesenchymal origin in
 

multiple organ systems when administered by inhalation, oral, or dermal
 

routes. Cancer was also induced at initial point of contact with
 

1,2-dibromoethane--nasal cavity for inhalation exposure, forestomach for oral
 

(gavage and drinking water) exposure, and skin for dermal exposure.
 

The weight of evidence for carcinogenicity of 1,2-dibromoethane includes
 

induction of malignant neoplasms in two species of rodents and in multiple
 

organ systems by inhalation', oral, and dermal exposure. In addition,
 

1,2-dibromoethane and a number of its metabolites are electrophiles, and form
 

adducts with cell proteins and nucleic acid. Of two potential
 

1,2-dibromoethane metabolites tested in a drinking water study in mice,
 

bromoethanol induced squamous papillomas of the forestomach in male and female
 

mice while bromacetaldehyde did not induce a significant incidence of tumors.
 

Based on these findings, Van Duuren et al. (1985) determined that it was
 

unlikely that bromoethanol or bromoacetaldehyde were the active carcinogenic
 

metabolites of 1,2-dibromoethane. 1,2-Dibromoethane is a potent mutagen in
 

numerous in vitro test systems. Based on these findings, exposure of humans
 

to levels of 1,2-dibromoethane such as found in agricultural areas or near
 

hazardous waste sites presents a potentially serious public health risk.
 

EPA has classified 1,2-dibromoethane in the Carcinogen Assessment
 

Group's Group B2 (EPA 1987a). Group B2 includes chemicals for which evidence
 

for carcinogenicity is adequate in animals but inadequate in humans. The q1*
 
63
 

2. HEALTH EFFECTS
 

value developed by EPA for humans exposed orally is 85 (mg/kg/day)-1 based on
 

data from the NCI (1978) gavage bioassay. For humans exposed by inhalation, 

the unit risk value is 2.2x10-4 

μg/m3 based on data from the NTP (1982) 

inhalation bioassay (IRIS 1991). 

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 1,2-dibromoethane 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
 

1,2-dibromoethane 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
 
64
 

2. HEALTH EFFECTS
 

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


 1,2-Dibromoethane
 

Primary biomarkers of exposure are the presence of 1,2-dibromoethane in
 

blood or exhaled breath or excretion of specific metabolites in urine. In
 

humans exposed to toxic levels of 1,2-dibromoethane (Letz et al. 1984), the
 

parent compound was not measured in blood samples collected before death.
 

However, two exposed individuals had elevated levels of serum bromide ions.
 

This elevation is likely to have resulted from debromination of 1,2-dibromoethane
 

during its metabolism. Elevated serum bromide is not specific to
 

1,2-dibromoethane exposure, but, rather, it is indicative of exposure to
 

classes of brominated chemicals.
 

Because a proportion of unmetabolized 1,2-dibromoethane is excreted from
 

the lungs of guinea pigs (Plotnick and Conner 1976), measurement of the
 

chemical in exhaled breath of humans is another potential method of monitoring
 

human exposure. This has been done in a study using university student
 

volunteers from a petrochemical plant area and a nonindustrial area.
 

1,2-Dibromoethane in exhaled breath was not found in either group of
 

volunteers (Wallace et al. 1982).
 

Rats exposed acutely by gavage to 110 mg/kg of 1,2-dibromoethane in
 

olive oil had elevated concentrations of the parent compound in the blood up
 

to 30 minutes after exposure. At 2 and 4 hours postexposure, only trace
 

amounts were detected and by 13 hours after exposure, 1,2-dibromoethane
 

concentrations were not detected in the blood. Serum bromide levels were not
 

measured (Nachtomi and Alumot 1972). Metabolites of 1,2-dibromoethane in
 

urine from rats receiving a comparable dose were characterized chromatographically
 

(Nachtomi et al. 1965). Urine had increased concentrations of
 

bromide ion, S(β-hydroxyethyl) mercapturic acid, and S(β-hydroxyl)cysteine. 

These latter two metabolites are formed via the cytosolic rather than the 

microsomal pathway and, therefore, may not be present as biomarkers for humans 

of 1,2-dibromoethane exposure. However, urine of exposed humans has not been 

tested for the metabolites listed, including bromide ion. 

Two DNA adducts of 1,2-dibromoethane metabolites have been found in in
 

vitro studies (Bolt et al. 1986; Ozawa and Guengerich 1983; Peterson et ­

al. 1988). These adducts are S-[2-(N7

-guanyl)ethyl]glutathione and
 

S-[2-N7

-guanyl)ethyl] cysteine. These adducts are potential biomarkers of
 

exposure to 1,2-dibromoethane and could be tested for in biopsy or autopsy
 

tissue specimens.
 

A less invasive procedure that could provide a indication of DNA adduct
 

formation is measurement in the urine of the mercaptic acid S-[2-N7

­

guanl)ethyl]-N-acetylcysteine. Excretion of this metabolite into the urine of
 
65
 

2. HEALTH EFFECTS
 

rats occurs in a dose-dependent, linear manner after intraperitoneal
 

administration of 1,2-dibromoethane (Kim and Guengerich 1989). This biomarker
 

has not been looked for to date in humans suspected to have exposure to
 

1,2-dibromoethane.
 

2.5.2 Biomarkers Used to Characterize Effects Caused by 1,2-Dibromoethane
 

The liver, kidney, and testis are the major visceral target organs for
 

toxic effects of 1,2-dibromoethane.
 

Hepatocellular necrosis related to covalent binding of metabolites to
 

cell and plasma proteins and to mitochondrial membrane damage results in
 

release of intracellular enzymes into the bloodstream, providing biomarkers of
 

liver cell damage. Biomarkers of hepatocellular necrosis are not specific to
 

1,2-dibromoethane but are a general indication of damage. Increased serum
 

enzymes include aspartate aminotransferase (AST), glutamate oxalacetic
 

transaminase (GOT), alanine aminotransferase (ALT), glutamate pyruvate
 

transaminase (GPT), and lactic dehydrogenase (LDH) (Botti et al. 1986; Letz
 

1984) in humans and rats as well as leakage of LDH from exposed, isolated
 

rodent hepatocytes (Albano et al. 1984; Van Iersel et al. 1988). Plasma
 

prothrombin time was also measured by Rowe et al. (1952) in rodents exposed to
 

1,2-dibromoethane; this test, however, is of minimal diagnostic value in
 

detection of mild hepatocellular dysfunction (Berkow 1987).
 

Kidney effects can range from mild tubular damage to life-threatening
 

renal damage, i.e., tubular nephropathy. Severe toxic renal lesions can
 

result in compromised renal function with changes in urinalysis, oliguria, or
 

anuria (renal shutdown) and increases in blood urea nitrogen, serum
 

creatinine, and uric acid. While biomarkers of renal damage have been
 

identified in humans exposed to toxic doses of 1,2-dibromoethane by oral or
 

dermal routes, these findings have not been duplicated in animal experiments.
 

Chemically-induced testicular damage can be recognized by changes in
 

sperm concentration, sperm motility, and sperm morphology (Wyrobek 1984).
 

Reduced fertility, a highly sensitive biomarker, may also be associated with
 

chemical exposure of humans. For example, Ratcliffe et al. (1987) evaluated
 

spermatogenic parameters in papaya fumigation industry employees exposed for
 

an average length of 5 years to 1,2-dibromoethane and unexposed workers in the
 

sugar industry. The route of exposure to 1,2-dibromoethane was primarily
 

inhalation. They identified decreased sperm count per ejaculate, decreases in
 

the percentage of viable and motile sperm, and increases in numbers of sperm
 

with abnormal morphology in 1,2-dibromoethane-exposed workers. For additional
 

discussion of the study, see Section 2.2.1.6.
 

An epidemiological study on 1,2-dibromoethane has identified equivocal
 

effects of reduced fertility in exposed workers (Wong et al. 1979).
 
66
 

2. HEALTH EFFECTS
 

2.6 INTERACTIONS WITH OTHER CHEMICALS.
 

Disulfiram is the generic name for Antabuse, a drug used in the
 

treatment of chronic alcoholism. Disulfiram potentiates the toxic and
 

carcinogenic effects of 1,2-dibromoethane in experimental animals.
 

Presumably, this occurs by blocking conversion of the aldehyde metabolite as
 

with acetaldehyde from ethanol. There is no evidence that similar effects
 

occur in humans. Based on animal data, however, Ayerst Laboratories,
 

producers of Antabuse (disulfiram), recommended the following in the package
 

insert: "Patients taking Antabuse tablets should not be exposed to ethylene
 

dibromide or its vapors" (PDR 1991).
 

In rats treated with disulfiram prior to oral dosing with 1,2-dibromoethane
 

(Plotnik et al. 1979), there was decreased clearance of radiolabeled 1,2­

dibromoethane from the body with increased concentration in tissues (liver, kidney,
 

spleen, testis, and brain). In the liver of the disulfiram-1,2-dibromoethane. group,
 

there was preferential uptake of labeled
 

1,2-dibromoethane in hepatocyte nuclei, indicative of DNA binding.
 

The mechanism of synergism between the compounds is not known. Slower
 

clearance of 1,2-dibromoethane or increased tissue levels of a toxic
 

intermediate metabolite (likely the aldehyde) in disulfiram-exposed
 

individuals may be responsible for enhancement of toxic and neoplastic lesions
 

in exposed rodents (Plotnik et al. 1979).
 

As discussed in Section 2.2.1 under the various systemic effects and
 

cancer, rats exposed by inhalation to 1,2-dibromoethane and fed a diet
 

containing 0.05% disulfiram (Wong et al. 1982), compared to rats exposed to
 

1,2-dibromoethane alone, had significantly elevated incidences of certain
 

neoplastic and toxic lesions. Neoplasms elevated in the disulfiram1,2-dibromoethane group were hepatocellular tumors, renal adenoma and
 

adenocarcinoma, and thyroid follicular cell adenoma. Toxic lesions were
 

testicular degeneration (atrophy) and splenic atrophy. Rats receiving the
 

1,2-dibromoethane-disulfiram regimen also had high mortality at a
 

significantly earlier date compared to control rats, rats exposed to
 

disulfiram alone, or rats exposed to 1,2-dibromoethane alone.
 

1,2-Dibromoethane did not potentiate the hepatotoxic effects of carbon
 

tetrachloride in rats (Danni et al. 1988).
 
67
 

2. HEALTH EFFECTS
 

2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
 

Certain populations may have a higher risk for developing toxic effects
 

from low-level 1,2-dibromoethane exposure.
 

A biological difference that could increase susceptibility of fetuses
 

and premature or perinatal infants to 1,2-dibromoethane toxicity is
 

developmental immaturity of the P-450 (microsomal enzyme) system.
 

Biotransformation of xenobiotics occurs predominantly by glutathione
 

conjugation (Benet and Sheiner 1985; Sipes and Gandolfi 1986). This pathway
 

is known to generate a number of toxic intermediate metabolites of
 

1,2-dibromoethane. In addition, fetal mice have selective binding of
 

1,2-dibromoethane metabolites in epithelial lining of the upper alimentary
 

tract and the entire respiratory tract after 1,2-dibromoethane was
 

administered parenterally to pregnant females (Kowalski et al. 1986).
 

As discussed in Section 2.6, chronic alcoholics receiving Antabuse
 

(disulfiram) therapy are potentially more susceptible to toxic and neoplastic
 

effects of 1,2-dibromoethane. It also follows that individuals with compromised
 

liver or renal function or with asthma or other chronic respiratory
 

diseases may have increased susceptibility to the toxic effects of 1,2-dibromoethane;
 

however, chemical-specific effects have not been identified.
 

2.8 MITIGATION OF EFFECTS
 

This section will describe clinical practice and research concerning
 

methods for reducing toxic effects of exposure to 1,2-dibromoethane. 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 1,2­

dibromoethane. When specific exposures have occurred, poison control centers
 

and medical toxicologists should be consulted for medical advice.
 

Human exposure to 1,2-dibromoethane may occur by inhalation, ingestion or
 

by dermal contact. Mitigation approaches to reduce absorption of 1,2­

dibromoethane have included general recommendations of separating contaminated
 

food, water, air, clothing from the exposed individual. Externally, exposed
 

eyes and skin are flushed with a clean neutral solution such as water or
 

normal saline. Water or milk is administered after ingestion of 1,2­

dibromoethane to wash residual chemical through the esophagus if the patient
 

can swallow (Bronsten and Currance 1988). Residual chemical remaining in the
 

stomach is removed by gastric lavage after precautions have been taken to
 

protect the respiratory tract from aspiration of gastric contents. Activated
 

charcoal is administered to bind unabsorbed chemical that has passed out of
 

the stomach and into the lower gastrointestinal tract. Administration of a
 

cathartic is thought to be unnecessary since diarrhea frequently follows
 

ingestion of this agent.
 
68
 

2. HEALTH EFFECTS
 

Once absorbed, 1,2-dibromoethane is rapidly metabolized. Its metabolism
 

may induce effects by either of two systems, the microsomal monooxygenase
 

system or the cytosolic activation system. Animal research has shown that
 

seventy percent of 1,2-dibromoethane is excreted in the urine and feces within
 

48 hours. The lack of persistent metabolites in the tissues indicate that
 

1,2-dibromoethane is readily removed from the body. Methods for reducing body
 

burden were not found.
 

Two reactive intermediates are formed through 1,2-dibromoethane
 

metabolism, 2-bromoacetaldehyde and S-(2-bromoethyl) glutathione. The 2­

bromoacetaldehyde causes tissue damage by covalent binding to cellular
 

macromolecules. The S-(2-bromoethyl) glutathione is responsible for genotoxic
 

effects and possibly its carcinogenic effect observed in laboratory animals.
 

No specific antidote has been shown to be effective in treating 1,2­

dibromoethane intoxication once absorption into the bloodstream has occurred
 

(Ellenhorn and Barceloux 1988). Intravenous infusions of glucose may limit
 

the hepatotoxicity of 1,2-dibromoethane (EPA 1989b). During the recovery
 

phase, a diet rich in vitamin B and carbohydrates may limit liver damage
 

(Dreisbach and Robertson 1987; Lawrence and Michaels 1984). Hemodialysis may
 

be needed to regulate extracellular fluid and electrolyte balance and to
 

remove metabolic waste products if renal failure occurs (EPA 1989b).
 

Clinical or experimental methods to interfere with the mechanisms of
 

action for 1,2-dibromoethane are not well understood. Using P-450 inhibitors
 

may be possible to prevent the formation of the reactive metabolites, however
 

this may not be feasible since it would not be specific for 1,2-dibromoethane
 

and it would also affect the detoxification of other substances. Also, for
 

this approach to work the glutathione pathway must also be inhibited.
 

Otherwise, carcinogenicity would be increased due to the diversion of 1,2­

dibromoethane from the oxidative pathway to the conjugative pathway, which
 

forms S-(2-bromoethyl) glutathione, a more potent mutagen and carcinogen (EPA,
 

1985).
 

The carcinogenic and mutagenic effects of 1,2-dibromoethane is due to
 

its ability to bind to DNA and RNA with metabolic activation. The mechanism
 

of action for the antispermatogenic effects is probably related to the removal
 

of sulphur from cysteine in the nucleus of the spermatozoa. Clinical
 

intervention to interfere with these mechanisms has yet to be developed.
 

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 1,2-dibromoethane 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
 
69
 

2. HEALTH EFFECTS
 

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

determine such health effects) of 1,2-dibromoethane.
 

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 1,2-Dibromoethane
 

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

exposure of humans and animals to 1,2-dibromoethane are summarized in
 

Figure 2-4. The purpose of this figure is to illustrate the existing
 

information concerning the health effects of 1,2-dibromoethane. '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).
 

Figure 2-4 graphically depicts the information that currently exists on
 

the health effects of 1,2-dibromoethane in humans and animals by various
 

routes of exposure. The vast majority of literature reviewed concerning the,
 

health effects of 1,2-dibromoethane in humans described case reports and
 

longer-term studies of pesticide workers and case reports of accidental or
 

intentional ingestion of 1,2-dibromoethane. The predominant route of exposure
 

in the occupational studies is believed to be inhalation, with dermal exposure
 

also implied. In a case report of fatalities, dermal exposure was considered
 

the primary route (Letz et al. 1984). The information on human exposure is
 

limited in that the possibility of concurrent exposure to other pesticides or
 

other toxic substances cannot be excluded, and the duration and level of
 

exposure to 1,2-dibromoethane generally cannot be quantified from the
 

information presented in these reports.
 

The database for the health effects of 1,2-dibromoethane after
 

inhalation and ingestion in experimental animals is substantial. However, as
 

can be seen in Figure 2-4, only limited information is available on the
 

effects of dermal exposure to 1,2-dibromoethane in animals. Furthermore, the
 

health effects associated with intermediate and chronic exposure durations are
 

more fully characterized than those associated with acute exposure.
 

71
 

2. HEALTH EFFECTS
 

2.9.2 Data Needs
 

Acute-Duration Exposure. The toxic effects of inhalation exposure to
 

1,2-dibromoethane have been investigated in various species of animals but no
 

data are available in humans. Acute inhalation of 1,2-dibromoethane has been
 

shown to cause lethal effects in rats, rabbits, guinea pigs, and monkeys which
 

result primarily from respiratory and cardiac failure (Akamine 1952; Short et
 

al. 1978; Rowe et al. 1952). The lungs, liver, kidney, and spleen are the
 

target organs of inhaled 1,2-dibromoethane (Rowe et al. 1952). Central
 

nervous system (CNS) effects are more pronounced at high vapor concentrations
 

(Rowe et al. 1952). However, behavioral effects have been reported in rats
 

and mice at lower exposure concentrations (Rowe et al. 1952). Acute oral
 

exposures have. resulted in death in humans and animals (Olmstead 1960; Rowe et
 

al. 1952; Saraswat et al. 1986; Schlinke 1969). Hepatotoxicity has been the
 

primary effect in both humans and animals (Olmstead 1960; Rowe et al. 1952;
 

Saraswat et al. 1986). The limited data from human studies show that dermal
 

exposure causes blisters and death (Letz et al. 1984); similar effects occur
 

in animals (Rowe et al. 1952). Thus, acute effects of 1,2-dibromoethane in
 

animals have been characterized, and additional studies do not appear to be
 

necessary at this time.
 

Intermediate-Duration Exposure. Effects of repeated exposures in humans
 

have not been investigated. The animal studies described predominantly renal,
 

respiratory, hepatic, gastrointestinal tract, developmental, and reproductive
 

or dermal/ocular effects (Amir 1975; Amir et al. 1977; Nitschke et al. 1981;
 

NTP 1982; Rowe et al. 1952; Short et al. 1979). Little or no reliable
 

information on cardiovascular, hematological, musculoskeletal, neurological,
 

and immunological effects in animals is available. Since all three routes
 

(inhalation, oral, and dermal) are significant means of exposure for
 

individuals living near hazardous waste sites, more information on the health
 

effects (specifically neurological, immunological, hematological, and cardiac
 

effects) associated with repeated-dose, low-level exposure to
 

1,2-dibromoethane would be useful.
 

Chronic-Duration Exposure and Cancer. Limited epidemiological studies
 

have been conducted involving occupational exposure in workers, primarily by
 

the respiratory route (Ratcliffe et al. 1987; Takahashi et al. 1981; Ter Haar
 

1980; Wong et al. 1979). These studies did not identify chronic adverse
 

effects in organ systems other than the male reproductive system (refer to the
 

subsequent discussion on reproductive toxicity). Chronic bioassays have been
 

conducted in animals via the inhalation, oral, and dermal routes of exposure
 

(NCI 1978;'NTP 1982; Van Duuren et al. 1979, 1985, 1986; Wong et al. 1982).
 

These studies have found predominantly respiratory, forestomach, hepatic,
 

renal, and testicular effects. Thus, the chronic effects of 1,2-dibromoethane
 

in animals appear to be characterized, and additional studies do not appear to
 

be necessary. Because the use of 1,2-dibromoethane has diminished
 
72
 

2. HEALTH EFFECTS
 

dramatically since its registration was canceled in 1984, there is lower
 

potential for additional long-term exposure. However, based on the Wong et
 

al. (1982) study, additional chronic studies on the interactions between
 

1,2-dibromoethane and other chemicals may be warranted.
 

Limited epidemiological studies have been conducted involving
 

occupational exposure in workers, primarily by the respiratory route
 

(Ratcliffe et al. 1987; Takahashi et al. 1981; Ter Haar 1980; Wong et al.
 

1979). These studies neither confirm nor refute the possibility of
 

1,2-dibromoethane as a human carcinogen. Carcinogenicity bioassays have been
 

conducted in animals via the inhalation, oral, and dermal routes of exposure
 

(NCI 1978; NTP 1982; Van Duuren et al. 1979, 1985, 1986; Wong et al. 1982).
 

These studies have found cancer in multiple organ systems in two species of
 

rodents. Thus, the carcinogenic effects of 1,2-dibromoethane appear to be
 

well characterized, and additional studies are not necessary. Because the use
 

of 1,2-dibromoethane has diminished considerably since its registration was
 

canceled in 1984, the potential for additional long-term exposure is lower.
 

Genotoxicity. 1,2-Dibromoethane has been tested for mutagenic activity
 

in a battery of in vitro and in vivo assay systems. It is mutagenic in
 

bacteria, fungi, fruit flies, and cultured mammalian cells (Ames and Yanofasky
 

1971; Barber 1981; Brimer et al. 1982; Crespi et al. 1985; Moriya et al. 1983;
 

NTP 1989; Principe et al. 1981; Shiau et al. 1980). In the dominant lethal
 

assay, 1,2-dibromoethane failed to elicit a positive response (Epstein et al.
 

1972; Short et al. 1979; Teratomoto et al. 1980). In addition, there is
 

limited evidence that it may cause sister chromatid exchanges and chromosomal
 

aberrations (Ellingham et al. 1986; NTP 1989; Tezuka et al. 1980; Tucker et
 

al. 1984). However, conflicting results have been reported for chromosomal
 

aberration studies in human lymphocytes from exposed workers and in human and
 

animal cell lines treated with 1,2-dibromoethane in vitro (Krishna et al.
 

1985; Steenland et al. 1985, 1986). A number of in vitro and in vivo studies
 

demonstrate that 1,2-dibromoethane can interact with DNA resulting in
 

genotoxic events (Bentley and Working 1988; Meneghini 1974; Peroco and Prodi
 

1981; Williams et al. 1982; Working et al. 1986). In view of the limited and
 

somewhat conflicting evidence for the carcinogenicity of 1,2-dibromoethane in
 

exposed human populations, data on the clastogenic and genotoxic effects in
 

humans could offer insight into potential human health risks from
 

1,2-dibromoethane.
 

Reproductive Toxicity. Epidemiologic evidence concerning
 

antispermatogenic and antifertility effects of inhalation exposure to
 

1,2-dibromoethane has been documented in the literature (Heinrichs 1983;
 

Ratcliffe et al. 1987; Ter Haar 1980; Wong et al. 1979). However, results of
 

these studies are limited by the small sample size and confounding factors.
 

In rats, inhalation exposure results in impaired reproductive performance (NTP
 

1982; Short et al. 1979). Although no information on the reproductive
 

toxicity of 1,2-dibromoethane is available in humans by oral exposure,
 
73
 

2. HEALTH EFFECTS
 

antispermatogenic effects have been well demonstrated in various animal
 

species including the bull, rat, and mouse following oral exposure (Amir 1973;
 

Amir and Ben-David 1973; Amir and Lavon 1976; Amir and Volcani 1965; Amir et
 

al. 1983; NCI 1978). No studies are available in humans or animals to assess
 

reproductive toxicity resulting from the dermal route of exposure. The
 

toxicokinetic data indicate that 1,2-dibromoethane is absorbed through the
 

skin (Jakobson et al. 1982; Letz et al. 1984). Therefore, additional
 

information on the effects via the dermal route of exposure would be useful.
 

Developmental Toxicity. The developmental effects of inhalation
 

exposure to 1,2-dibromoethane have not been investigated in humans. The
 

studies in animals clearly indicate that fetotoxic and behavioral effects
 

occur in mice and/or rats at concentrations that are toxic to maternal welfare
 

as well (Fanini et al. 1984; Hsu et al. 1985; Short et al. 1978). No data are
 

available for humans or animals regarding developmental toxicity resulting
 

from oral and dermal routes of exposure. Since human exposure to
 

1,2-dibromoethane can occur via inhalation and dermal exposures at hazardous
 

waste sites and also from ingestion of contaminated drinking water, additional
 

epidemiological studies in populations around hazardous waste sites to
 

investigate the developmental hazard posed by 1,2-dibromoethane would be
 

useful. Such studies would also be useful in areas where groundwater was
 

contaminated by 1,2-dibromoethane from prior use of the pesticide in
 

agriculture.
 

Immunotoxicity. No information on specific immunological effects of
 

1,2-dibromoethane is available for humans or animals exposed via inhalation,
 

oral, or dermal routes. Some effect on the immune system can be inferred from
 

a report of lymphoid neoplasia associated with exposure of workers to various
 

chemicals including 1,2-dibromoethane (Alavanja et al. 1988). Epidemiological
 

and animal studies would be useful to investigate the immunotoxic potential of
 

1,2-dibromoethane. Furthermore, if 1,2-dibromoethane proves to be a potential
 

immunosuppressant, further research into this area could help identify
 

populations at higher risk because of pre-existing permanent
 

immunosuppression.
 

Neurotoxicity. Evidence for neurological effects in humans and
 

experimental animals after oral or inhalation exposure is limited. Acute
 

inhalation exposure of a worker resulted in transient depression (Kochmann
 

1928). Animal data show that acute inhalation of high concentrations causes
 

CNS depression in animals (Rowe et al. 1952). Behavioral effects have been
 

reported in offspring following inhalation exposure of rats during gestation
 

(Fanini et al. 1984; Hsu et al. 1985). Acute oral exposures have been
 

reported to cause death and brain lesions in humans (Saraswat et al. 1986) and
 

stiffness, prostration, and anorexia in animals (Schlinke 1969). No
 

information is available to assess neurological effects resulting from dermal
 

exposure to 1,2-dibromoethane in humans and animals. Further studies of
 
74
 

2. HEALTH EFFECTS
 

neurological effects following inhalation and/or dermal exposure in both the
 

newborn and adult would be valuable, as there are so few data available.
 

Epidemiological and Human Dosimetry Studies. Most of the available
 

information on the effects of 1,2-dibromoethane in humans comes from cases of
 

acute poisoning following accidental or intentional ingestion and from
 

occupational exposures in agricultural industries (Alavanja et al. 1988;
 

Kochmann 1928; Letz et al. 1984; Olmstead 1960; Ott et al. 1980; Ratcliffe et
 

al. 1987; Saraswat et al. 1986; Takahashi et al. 1981; Ter Haar 1980; Turner
 

and Barry 1979; Wong et al. 1979). Limitations inherent in these studies
 

include unquantified exposure concentrations and durations, small sample size,
 

as well as concomitant exposure to other pesticides and marijuana use. In
 

addition, developmental and systemic effects following inhalation, oral, and
 

dermal exposures in humans have not been studied. Well-controlled
 

epidemiological studies that focused on exposure levels and health effects
 

(e.g., systemic effects, developmental and immunological effects,
 

genotoxicity, and cancer) of persons living in areas near hazardous waste
 

sites would be useful in monitoring other affected populations. A common
 

problem in such studies is acquisition of reliable dosimetry data on the
 

exposed populations. For this reason, efforts to improve estimates of past
 

exposure and to define more accurately current exposure levels to
 

1,2-dibromoethane would be valuable. Follow-up of exposed workers would be
 

useful.
 

Biomarkers of Exposure and Effect. There appears to be no biological
 

indicator for 1,2-dibromoethane toxicity that is entirely adequate when
 

considered alone. Biomarkers of acute exposure to potentially toxic levels
 

are residues of 1,2-dibromoethane in target tissues such as liver and brain,
 

elevated serum bromide levels, and the presence of bromide ions and certain
 

metabolites of 1,2-dibromoethane in urine (Letz et al. 1984; Nachtomi et al.
 

1965). Tissue specimens also could be examined for the presence of
 

1,2-dibromoethane metabolites covalently bound to protein or DNA (Bolt et al.
 

1986; Ozawa and Guengerich 1983; Peterson et al. 1988).
 

Results of studies in humans and animals suggest that sperm
 

abnormalities, evidence of DNA damage such as chromosomal anomalies, and tests
 

for liver and kidney dysfunction may serve as biomarkers of the effects of
 

1,2-dibromoethane (Ellingham et al. 1986; Heinrichs 1983; NTP 1982, 1989;
 

Ratcliffe et al. 1987; Rowe et al. 1952; Ter Haar 1980; Wong et al. 1979).
 

More quantitative data on chronically exposed individuals would provide a good
 

database for use with screening protocols. These data could include tests of
 

urine for 1,2-dibromoethane metabolites, monitoring of serum and urinary
 

bromide ions, periodic monitoring of semen samples for abnormalities in sperm
 

concentration, motility and morphology, and serum aspartate aminotransferase
 

for liver cell damage.
 
75
 

2. HEALTH EFFECTS
 

Absorption, Distribution, Metabolism, and Excretion. Quantitative
 

evidence on the absorption of 1,2-dibromoethane in humans is not available.
 

However, it is known that workers,exposed to 1,2-dibromoethane experience
 

toxic effects following inhalation, oral, and dermal exposure (Alavanja et al.
 

1988; Kochmann 1928; Letz et al. 1984; Ott et al. 1980; Ratcliffe et al. 19.87;
 

Takahashi et al. 1981; Ter Haar 1980; Turner and Barry 1979; Wong et al.
 

1979). Animal studies clearly indicate that 1,2-dibromoethane is absorbed
 

(Botti et al. 1982; Jakobson et al. 1982; Letz et al. 1984; Rowe et al. 1952).
 

Reports that specifically evaluate the compound's rate or extent of absorption
 

would be useful.
 

No studies were located regarding the distribution of 1,2-dibromoethane
 

in humans. Animal studies regarding its distribution following oral
 

absorption are available (Plotnick et al. 1979; Wong et al. 1982). Based on
 

similar pathologic findings in humans and animals, the distribution in humans
 

seems to be similar. Studies that investigate the distribution of
 

1,2-dibromoethane following inhalation or dermal exposures would be useful in
 

order to evaluate whether 1,2-dibromoethane behaves similarly across all
 

routes of exposure. Information was not available regarding the metabolism of
 

1,2-dibromoethane following inhalation, oral, or dermal exposure in humans.
 

Its metabolism in humans probably occurs via the microsomal monooxygenase
 

system because glutathione conjugation is less prominent in man. Metabolism
 

of 1,2-dibromoethane in animals has been investigated via oral exposure
 

(Lawrence and Michaels 1984; Tamura et al. 1986; Van Duuren et al. 1985).
 

Mercapturic acids are identified as the primary metabolites of microsomal
 

oxidation (Kirby et al. 1980; Nachtomi 1970; Nachtomi et al. 1965). The
 

reactive metabolites formed by the microsomal oxidation or glutathione
 

conjugation of 1,2-dibromoethane may bind to protein or DNA, producing either
 

cytotoxicity or genotoxicity, respectively (Ozawa and Guengerich 1983; Van
 

Bladeren 1983; White et al. 1983). Quantitative information regarding the
 

metabolites formed would suggest which biodegradation pathways are favored and
 

would also provide insight into the enzyme kinetics. Information regarding
 

the overall rate of metabolism and rates of specific reaction following
 

inhalation and dermal exposures would be useful, as well as how metabolism is
 

affected by chemical interactions.
 

No studies in humans were found regarding excretion of 1,2-dibromoethane.
 

Animal studies regarding the excretion of 1,2-dibromoethane following
 

inhalation and dermal exposures are unavailable, but information is available
 

for excretion following oral exposures (Plotnick et al. 1979). Since
 

metabolites may contribute to the toxic effects attributed to
 

1,2-dibromoethane, it would be beneficial to conduct studies that would
 

establish elimination rates for each metabolite or similar metabolic products.
 

In addition, such studies may also provide information to facilitate the rapid
 

removal of 1,2-dibromoethane and its metabolites in exposed people.
 
76
 

2. HEALTH EFFECTS
 

Comparative Toxicokinetics. Generally, target organs and adverse
 

effects of 1,2-dibromoethane exposure are similar across species.
 

Toxicokinetic studies have been performed in rats, mice, and guinea pigs.
 

There are no major differences in distribution patterns. Humans would be
 

expected to metabolize 1,2-dibromoethane in a manner qualitatively similar to
 

animals. However, the disposition of 1,2-dibromoethane in humans remains to
 

be determined.
 

Mitigation of Effects. Data are needed on mechanisms that may be used
 

to decrease the effects of 1,2-dibromoethane once it has entered the
 

bloodstream. Currently, the only available data are regarding treatment of
 

clinical effects of 1,2-dibromoethane intoxication. Data are also needed on
 

the chronic effects of low-level exposure to 1,2-dibromoethane to assess its
 

long-term effects in humans.
 

2.9.3 On-going Studies
 

A recent abstract reported an excessive mortality from non-Hodgkin's
 

lymphoma during the 1970s and 1980s in grain millers in the grain processing
 

industry (Alavanja et al. 1988). Such workers had been exposed to
 

1,2-dibromoethane as well as aluminum phosphide, ethylene dichloride,
 

malathion, and methyl bromide.
 

Additional on-going studies regarding the health effects of 1,2-dibromoethane
 

were reported in the Directory of On-Going Research in Cancer
 

Epidemiology (Parkin and Wahrendorf 1987). T. Meinhardt (NIOSH, Cincinnati,
 

Ohio) is conducting epidemiological studies to investigate carcinogenic and
 

cytogenetic changes in two separate populations exposed occupationally to
 

1,2-dibromoethane. J. Ratcliffe, formerly of NIOSH, was investigating
 

cytogenetic and reproductive effects of exposure to 1,2-dibromoethane during
 

occupational exposure to workers engaged in fumigating papaya.
 
77
 

3. CHEMICAL AND PHYSICAL INFORMATION
 

3.1 CHEMICAL IDENTITY
 

The chemical formula, structure, synonyms, and identification numbers
 

for 1,2-dibromoethane are listed in Table 3-1.
 

3.2 PHYSICAL AND CHEMICAL PROPERTIES
 

Important physical and chemical properties of 1,2-dibromoethane are
 

listed in Table 3-2.
 



81
 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL
 

4.1 PRODUCTION
 

1,2-Dibromoethane is a halogenated aliphatic hydrocarbon produced when
 

gaseous ethylene comes in contact with bromine. The mixing of ethylene and
 

bromine is accomplished in a variety of ways. One of the more common
 

manufacturing processes involves a liquid-phase bromination of ethylene at
 

35°-85°C. After the bromination of ethylene, the mixture is neutralized to 

free acid and then purified by distillation. Other methods of 

1,2-dibromoethane formation include the hydrobromination of acetylene and a 

reaction of 1,2-dibromoethane with water (Fishbein 1980; HSDB 1989). 

In the 1970s, production of 1,2-dibromoethane in the United States
 

remained stable, averaging 280 million pounds per year; production peaked in
 

1974 at 332.1 million pounds. In 1979, the production volume averaged to
 

285.9 million pounds (Santodonato et al. 1985). Since then, production has
 

consistently decreased. This decrease was primarily due to increased
 

government regulation and restriction on products using 1,2-dibromoethane.
 

Consequently, by 1982, the U.S. production of 1,2-dibromoethane reached a low
 

of 169.8 million pounds (Santodonato et al. 1985). Data on production of
 

1,2-dibromoethane are not available after 1984.
 

1,2-Dibromoethane production constitutes one of the largest single uses
 

of bromine; as a result, 1,2-dibromoethane production plants are generally
 

located near major sources of bromine, such as in Arkansas (Fishbein 1980).
 

Current facilities that manufacture or process 1,2-dibromoethane are listed in
 

Table 4-l.
 

4.2 IMPORT/EXPORT
 

The U.S. import levels of 1,2-dibromoethane fluctuated between 1977 and
 

1981, reaching a peak in 1980 of 0.861 million pounds and a low in 1979 of
 

0.079 million pounds (Santodonato et al. 1985). Worldwide producers of
 

1,2-dibromoethane include the United Kingdom, Benelux, France, Spain, Italy,
 

and Switzerland; collectively they produce lo-66 million pounds per year
 

(Fishbein 1980).
 

A major market for U.S. 1,2-dibromoethane production has been overseas,
 

although export levels have been declining. The U.S. export level of
 

1,2-dibromoethane in 1981 was 29.8 million pounds. This was substantially
 

lower than in 1978 when the U.S. export level was 84.8 million pounds
 

(Santodonato et al. 1985).
 

4.3 USE
 

1,2-Dibromoethane has been and is still used in a variety of ways. The
 

main use is as an additive in leaded gasoline where 1,2-dibromoethane acts as
 

a "scavenger" that converts lead oxides in cars to lead halides; these are
 


84
 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL
 

released more easily with engine exhaust (Fishbein 1980; Stenger 1978). In
 

1978, 90% of the 1,2-dibromoethane produced went into leaded gasoline for this
 

purpose (Santodonato et al. 1985). Due to the increased regulation of leaded
 

gasoline, the production and consumption of 1,2-dibromoethane has been and
 

will continue to decrease in the future (Fishbein 1980; Santodonato et
 

al. 1985).
 

In the 1970s and early 1980s, the second largest application of
 

1,2-dibromoethane was as a soil fumigant to protect against insects, pests,
 

and nematodes in citrus, vegetable, and grain crops and as a fumigant for
 

turf, particularly on golf courses (HSDB 1989). However, in 1984, EPA banned
 

the use of 1,2-dibromoethane as a soil and grain fumigant, thus eliminating
 

this market for 1,2-dibromoethane manufacturers (Santodonato et al. 1985).
 

Currently, other minor applications include treatment of felled logs for
 

bark beetles, termite control, control of wax moths in beehives, spot
 

treatment of milling machinery, Japanese beetle control in ornamental plants,
 

and as a chemical intermediate for dyes, resins, waxes, and gums (HSDB 1989).
 

4.4 DISPOSAL
 

Disposal methods of 1,2-dibromoethane fall under the general regulation
 

for organic pesticide disposal developed by EPA. The two main methods of
 

disposal are incineration and burial. Incineration is the preferred method;
 

disposal by burial, in a specially designated landfill, is used only if no
 

appropriate incineration facilities are available. All emissions of the
 

incineration process must meet the requirements of the Clean Air Act of 1970
 

relating to gaseous emissions. Similarly, combustible containers of organic
 

pesticides should be disposed of in a pesticide incinerator or be buried in a
 

specially designated landfill. The noncombustible containers should be
 

triple-rinsed and then returned to the manufacturer to be recycled. Residues
 

and rinse liquids should be used in conjunction with the 1,2-dibromoethanecontaining
 

product where possible, otherwise they should be disposed of as described above (HSDB
 

1989).
 
85
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.1 OVERVIEW
 

1,2-Dibromoethane has historically been released to .the environment
 

mainly as a result of its use as a gasoline additive and fumigant.
 

1,2-Dibromoethane partitions to the atmosphere and groundwater. The compound
 

can be transported over long distances in the atmosphere, and is very mobile
 

in soils. 1,2-Dibromoethane is transformed in the atmosphere by reaction with
 

hydroxyl radicals and in soils by biodegradation. As a result of its high
 

water solubility, the compound is not expected to bioconcentrate or biomagnify
 

in food chains. Residual 1,2-dibromoethane bound to soil micropores is
 

relatively immobile and resistant to degradation. This material is present in
 

ppb concentrations and may be slowly leached from soil micropores over years
 

to contaminate groundwater. If the micropores are disturbed and crushed,
 

there is a greater likelihood of releasing the bound 1,2-dibromoethane. The
 

compound persists in soils and groundwater.
 

The most important route of exposure to 1,2-dibromoethane for most
 

members of the general population is ingestion of contaminated drinking water.
 

Individuals living in the vicinity of hazardous waste sites contaminated with
 

1,2-dibromoethane may be exposed to higher concentrations of the compound.
 

EPA has identified 1,177 NPL sites. 1,2-Dibromoethane has been found at
 

9 of the total number of sites evaluated for that compound. We do not know
 

how many of the 1,177 sites have been evaluated for 1,2-dibromoethane. As
 

more sites are evaluated by EPA; this number may change (View 1989). The
 

frequency of these sites within the United States can be seen in Figure 5-1.
 

5.2 RELEASES TO THE ENVIRONMENT
 

1,2-Dibromoethane has been widely released to the environment mainly as
 

a result of the historical use of the compound as a gasoline additive and a
 

fumigant (Fishbein 1979). The compound has also been released from industrial
 

processing facilities. For example, 1,2-dibromoethane was found in air,
 

water, soil, and sediment samples taken near industrial bromine facilities in
 

El Dorado and Magnolia, Arkansas, in 1977 (Pellizzari et al. 1978).
 

According to the SARA Section 313 Toxics Release Inventory (TRI), an
 

estimated total of at least 152,634 pounds of 1,2-dibromoethane were released
 

to the environment from manufacturing and processing facilities in the United
 

States in 1987 (see Table 5-l). This total includes an estimated 44 pounds
 

that were released through underground injection. The TRI data should be used
 

with caution since the 1987 data represent first-time reporting by these
 

facilities. Only certain types of facilities were required to report. This
 

is not an exhaustive list.
 




90
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

Class and Ballschmitter (1988) suggested that 1,2-dibromoethane may be
 

produced naturally in sea water from a dibromomethane precursor via a halogen
 

exchange reaction. The dibromomethane is produced by brown algae via
 

haloperoxidase enzymes and released to sea water.
 

5.2.1 Air
 

1,2-Dibromoethane releases to the atmosphere historically have been due
 

to fugitive emissions from leaded gasolines, automobile exhaust, and the
 

former use of the compound as a fumigant (Fishbein 1979).
 

An estimated total of at least 149,854 pounds of 1,2-dibromoethane was
 

released to the atmosphere from manufacturing and processing facilities in the
 

United States in 1987 (TR187 1989) (see Table 5-l).
 

5.2.2 Water
 

The use of 1,2-dibromoethane as a solvent and chemical intermediate has
 

led to release of the compound to surface waters in industrial process
 

effluents (Fishbein 1979).
 

An estimated total of at least 1,034 pounds of 1,2-dibromoethane was
 

released to surface waters from manufacturing and processing facilities in the
 

United States in 1987 (TR187 1989) (see Table 5-l).
 

1,2-Dibromoethane has been detected in an estimated 0.23% of the
 

groundwater samples analyzed for the 2,783 hazardous waste sites participating
 

in the Contract Laboratory Program (CLP); a positive geometric mean
 

concentration value was not reported. 1,2-Dibromoethane has not been detected
 

in surface water samples taken at hazardous waste sites (CLPSD 1988). Note
 

that the CLP Statistical Database (CLPSD) includes data from both NPL and non-


NPL sites.
 

5.2.3 Soil
 

The main sources of 1,2-dibromoethane release to soils appear to be the
 

historical use of the compound as a soil fumigant and land disposal of wastes
 

containing the compound.
 

An estimated total of at least 1,702 pounds of 1,2-dibromoethane was
 

released to soils from manufacturing and processing facilities in the United
 

States in 1987 (TR187 1989) (see Table 5-l).
 

1,2-Dibromoethane has been detected in an estimated 0.12% of the soil
 

samples collected from the 2,783 hazardous waste sites that have had samples
 

analyzed by the CLP; a positive geometric concentration value was not reported
 

(CLPSD 1988). Note that the CLPSD includes data from both NPL and non-NPL
 

sites.
 
91
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.3 ENVIRONMENTAL FATE
 

5.3.1 Transport and Partitioning
 

The vapor pressure (11 mmHg at 25°C) of 1,2-dibromoethane suggests that
 

the compound readily partitions to the atmosphere following release to surface
 

water and soils. As the data in Section 5.4.1 indicate, 1,2-dibromoethane can
 

be transported for long distances in the atmosphere before removal in wet and
 

dry deposition or degradation.
 

Volatilization is the most important removal process for 1,2-dibromoethane
 

released to surface waters. Volatilization half-lives of 1-16 days
 

have been estimated for flowing and standing surface waters. Sorption to
 

sediment or suspended particulate material is not expected to be an important
 

process (EPA 1987a, 1987b; HSDB 1989).
 

As a result of its low sorption potential, high vapor pressure, and high
 

water solubility, 1,2-dibromoethane is rapidly lost from soils by
 

volatilization to the atmosphere or leaching to surface water and groundwater
 

(EPA 1987a). In studies with two silty clay loam soils and cation saturated
 

montmorillonite clays, a maximum of only 4% of applied 1,2-dibromoethane was
 

found to be sorbed to soil particulates; an experimental soil sorption
 

coefficient (Koc) value of 66 was reported (Rogers and McFarlane 1981).
 

However, Steinberg et al. (1987) have reported that a small fraction of
 

1,2-dibromoethane released to soils (that is not rapidly volatilized, leached,
 

or degraded) is sorbed strongly to soil micropores where it persists for long
 

periods of time, resistant to mobilization and degradation. This residual
 

1,2-dibromoethane may slowly leach (half-life = years) from micropore sites to
 

contaminate groundwater.
 

As a result of its high water solubility, 1,2-dibromoethane is not
 

expected to bioconcentrate or biomagnify in terrestrial and aquatic food
 

chains.
 

5.3.2 Transformation and Degradation
 

5.3.2.1 Air
 

Direct photolysis of 1,2-dibromoethane in the troposphere is not
 

expected to occur (Jaber et al. 1984). 1,2-Dibromoethane reacts with hydroxyl
 

radicals in the atmosphere; the half-life for the reaction has been estimated
 

to be about 40 days (EPA 1987a).
 

5.3.2.2 Water
 

Biotic and abiotic degradation of 1,2-dibromoethane in surface waters is
 

slow relative to volatilization of the compound to the atmosphere (EPA 1987b).
 

1,2-Dibromoethane is resistant to hydrolysis (Jaber et al. 1984); the
 
92
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

hydrolytic half-life of the compound has been reported to range from 2.5 years
 

(Vogel and Reinhard 1982) to 13.2 years (HSDB 1989). As a result of its
 

hydrolytic stability and the limited biological activity in subsurface soils,
 

1,2-dibromoethane leached to groundwater is expected to persist for years.
 

5.3.2.3 Soil
 

1,2-Dibromoethane undergoes biodegradation in aerobic surface soils; the
 

rate has been reported to decrease with increasing concentrations of the
 

compound (Pignatello 1986). Biodegradation appears to be limited under
 

anaerobic conditions (Bouwer and McCarty 1983). Residual 1,2-dibromoethane
 

sorbed to soil micropores is resistant to biodegradation, chemical
 

transformation, and mobilization; Steinberg et al. (1987) detected the
 

compound in a surface soil 19 years after 1,2-dibromoethane had been applied
 

for the last time as a fumigant.
 

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
 

As a result of its persistence in soil and groundwater, and past
 

Widespread use as a gasoline additive and fumigant, 1,2-dibromoethane has been
 

detected in ambient air, soils, groundwater, and food. However, most of the
 

monitoring data reported in this section, although the latest available, are
 

not current. Volatilization is the most important removal process for
 

1,2-dibromoethane released to surface waters. Since only a small fraction of
 

the compound is sorbed to soil, sorption to sediment and subsequent
 

persistence in sediment is not expected to be an important process in the
 

removal of 1,2-dibromoethane from the environment. The data may reflect
 

ambient concentrations of a decade or more ago, but because of the phaseout of
 

the use of leaded gasoline and the ban on fumigant uses of 1,2-dibromoethane,
 

current ambient media concentrations, with the potential exception of
 

groundwater concentrations, are expected to be much lower than the levels
 

reported here.
 

5.4.1 Air
 

1,2-Dibromoethane has been detected in ambient air samples collected at
 

a number of sites in the United States. In a review of available monitoring
 

data for volatile organic compounds, Brodzinsky and Singh (1983) reported the
 

following median concentrations of 1,2-dibromoethane in ambient air samples in
 

the United States: rural and remote areas--less than detection limit; urban
 

and suburban areas--2.6 parts per trillion (ppt); and source-dominated areas-­

1.9 ppt. Typical daily concentrations at four sites in the metropolitan Los
 

Angeles area in 1983 were reported to range from less than 5 ppt to 17 ppt
 

(Kowalski et al. 1985b). Ambient air concentrations for other metropolitan
 

areas in the United States in 1980 were reported by Singh et al. (1981) as
 

follows:
 
93
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

1,2-Dibromoethane (ppt)
 

Location Mean Range 

Houston, TX 59 10-368 

St. Louis, MO 16 8-26 

Denver, CO 31 10-78 

Riverside, CA 22 10-47 

1,2-Dibromoethane has also been detected in ambient air samples
 

collected at two hazardous waste sites in New Jersey at geometric mean
 

concentrations of 20-50 ppt; the maximum value reported was 6,710 ppt
 

(La Regina et al. 1986).
 

Long-range transport of 1,2-dibromoethane from industrialized areas may
 

have been the source of the compound found in ambient air samples collected in
 

the Arctic by Rasmussen and Khalil (1984). 1,2-Dibromoethane concentrations
 

in the 1983 study were reported to range from 1.0 to 1.9 ppt.
 

Natural production was speculated to be the source of 1,2-dibromoethane
 

found in ambient air samples collected from open areas of the North and South
 

Atlantic Ocean by Class and Ballschmitter (1988); concentration levels were
 

reported to be less than 0.001-0.003 ppt.
 

5.4.2 Water
 

As a result of its volatility, 1,2-dibromoethane has been detected at
 

only low levels in surface water samples collected in the United States.
 

Ewing et al. (1977) reported that 1,2-dibromoethane was detected (i.e.,
 

concentrations greater than 1,000 ppt) in only 2 of 204 surface water samples
 

collected near heavily industrialized sites throughout the country.
 

1,2-Dibromoethane was detected at a maximum concentration of 200 ppt in 11 of
 

175 surface water samples collected in New Jersey from 1977 to 1979 (Page
 

1981). However, the compound has been widely detected in groundwater samples
 

collected in the United States. States with reported 1,2-dibromoethane
 

groundwater contamination problems include Wisconsin (Krill et al. 1986),
 

Hawaii (Oki and Giambelluca 1987), New Jersey (maximum concentration of
 

48,800 ppt in 34 of 421 samples) (Page 1981), and Georgia (l,OOO-94,000 ppt)
 

(Marti et al. 1984). According to the interim data available in the
 

Pesticides in Ground Water Data Base, 1,2-dibromoethane detection in
 

groundwater has been confirmed in six states: California, Connecticut,
 

Georgia, Massachusetts, New York, and Washington. The median and maximum
 

concentrations reported were 900 and 14,000 ppt, respectively (Williams et al.
 

1988).
 
94
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

Class and Ballschmitter (1988) suggested that brown algae may be the
 

source of the <0.01-0.03 ppt of 1,2-dibromoethane found in the marine water
 

samples collected from the North and South Atlantic Oceans.
 

5.4.3 Soil
 

No information was found in the literature regarding current ambient
 

concentrations of 1,2-dibromoethane in surface soils in the United States.
 

5.4.4 Other Environmental Media
 

1,2-Dibromoethane residues in foods have decreased since the use of the
 

compound as a fumigant was banned by EPA. For example, Daft (1989) reported
 

finding 1,2-dibromoethane in only 2 of 549 samples of fatty and nonfatty foods
 

analyzed for fumigant residues in a recent survey. 1,2-Dibromoethane was
 

detected in samples of peanut butter and whiskey at a mean concentration of
 

7 μg/g (range 2-11 ng/g). Historical foodstuff residue levels have been 

reviewed by EPA (1983). 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
 

Current human exposure to 1,2-dibromoethane for most members of the
 

general population appears to be limited to ingestion of low levels of the
 

compound in contaminated drinking water. According to EPA (1985), daily
 

intake from drinking water has been estimated to range from 0 to 16 μg/kg/day. 

Ingestion of contaminated foodstuffs does not appear to be an important source 

of exposure; EPA (1983) estimated that the maximum intake of 1,2-dibromoethane 

from contaminated foods was 0.09 μg/kg/day. Average inhalation of ambient air 

also appears to be .of less importance than ingestion of groundwater, although 

the available data are not current and variable. Daily respiratory intake was 

estimated by EPA (1985) to range from 0 to 79 μg/kg/day. Average inhalation 

exposures in four metropolitan areas of the United States in 1980 were 

estimated by Singh et al. (1981) to range from 2.8 to 9.9 μg/day (or 

0.04-0.14 μg/kg/day for a 70-kg human). However, inhalation of 

1,2-dibromoethane released to indoor air from contaminated groundwater (e.g., 

during showering) may be an important source of human exposure. For example, 

McKone (1987) modeled the mass transfer of several volatile organic compounds, 

including 1,2-dibromoethane, from water to air and calculated a maximum 

concentration of 1,2-dibromoethane in household air of 2.4x10-4 mg/L, assuming 

a tap water concentration of 1 mg/L. 

Exposure of the general population to higher concentrations of
 

1,2-dibromoethane may result from contact with contaminated hazardous waste
 

site media, principally soils and groundwater. No information was found in
 

the available literature regarding the size of the human population
 

potentially exposed to 1,2-dibromoethane through contact with contaminated
 

waste site media.
 
95
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

In occupational settings, current exposures are expected to be
 

substantially reduced from historical levels (Santodonato et al. 1985). The
 

large numbers of people exposed to 1,2-dibromoethane in the workplace through
 

its manufacture and use as a gasoline additive and fumigant have decreased as
 

these uses of the compound have been limited. NIOSH (1977) estimated that as
 

many as 108,000 workers were potentially exposed to 1,2-dibromoethane during
 

production and fumigant related uses, and an additional 875,000 workers were
 

exposed to lower levels of the compound through its use in leaded gasoline.
 

Current exposure levels are also expected to be substantially reduced from the
 

historical inhalation and dermal exposures reported in manufacturing and
 

processing facilities by Rumsey and Tanita (1978) and in fumigation operations
 

reviewed by EPA (1983).
 

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
 

Members of the general population with potentially high exposure to
 

1,2-dibromoethane include individuals living near the nine NPL sites currently
 

known to be contaminated with the compound. The size of the population and
 

the concentrations of 1,2-dibromoethane in all of the contaminated media to
 

which these people are potentially exposed have not been completely
 

characterized. Other populations with potentially high exposures to
 

1,2-dibromoethane include individuals in the six states with confirmed
 

groundwater contamination, and workers involved in the manufacture and
 

continued use of 1,2-dibromoethane.
 

5.7 ADEQUACY OF.TIiE 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 1,2-dibromoethane 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 1,2-dibromoethane.
 

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.
 
96
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

5.7.1 Data Needs
 

Physical and Chemical Properties. The physical/chemical properties of
 

1,2-dibromoethane, described in Table 3-2, are sufficiently well characterized
 

to enable assessment of the environmental fate of the compound.
 

Production, Import/Export, Use, and Disposal. According to the
 

Emergency Planning and Community Right-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 Toxic 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.
 

Although 1,2-dibromoethane is currently produced and used in the United
 

States, increased government regulation and restriction on products containing
 

the compound probably have decreased the potential for exposure of the U.S.
 

population (Fishbein 1980; Santodonato et al. 1985). The most recent
 

information on the annual U.S. production of 1,2-dibromoethane is for 1982
 

(169.8 million pounds); this is lower than the average for the 1970s (280
 

million pounds) (Santodonato et al. 1985). The most recent import and export
 

data are for 1980 (0.861 million pounds) and 1981 (29.8 million pounds),
 

respectively; import volumes reportedly fluctuated between 1977 and 1981 and
 

the 1981 export volume is substantially lower than that for 1978 (84.8 million
 

pounds) (Santodonato et al. 1985). 1,2-Dibromoethane may be found in air and
 

water as a result of its use, e.g., as a chemical intermediate, although its
 

uses as a lead scavenger in gasoline and as a soil and grain fumigant have
 

been decreased or eliminated by governmental regulation (Fishbein 1979, 1980;
 

HSDB 1989; Santodonato et al. 1985; Stenger 1978). In addition, the general
 

regulations governing organic pesticide disposal developed by EPA are
 

applicable to 1,2-dibromoethane. It is disposed of mainly by incineration and
 

by burial; however, the amounts disposed of by each method are not reported
 

(HSDB 1989). Therefore, more recent production, import, export, use, and
 

disposal volumes of 1,2-dibromoethane would be useful in assessing the
 

potential for the release of, and exposure to, this chemical.
 

Information regarding the various modes of production, use, and disposal
 

of 1,2-dibromoethane is well documented. However, more recent data describing
 

present domestic production levels, the proportions of 1,2-dibromoethane
 

consumed by the various uses, as well as data on export levels and the
 

countries to which these exports are made would be helpful in providing a
 

broader, more up-to-date picture of the U.S. 1,2-dibromoethane industry as a
 

whole.
 

Environmental Fate. 1,2-Dibromoethane partitions to the atmosphere and
 

groundwater (Windolz 1983). It is transported in the atmosphere where it
 

undergoes degradation by hydroxyl radicals (EPA 1987a). 1,2-Dibromoethane is
 
97
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

mobile and biodegradable in soils, although 1,2-dibromoethane sorbed to soil
 

micropores is immobile and persistent (Pignatello 1986; Steinberg et al.
 

1987). 1,2-Dibromoethane is volatilized from surface waters before it can
 

undergo degradation (EPA 1987b). Additional information is needed on the
 

persistence of 1,2-dibromoethane in groundwater and sorbed to soil micropores.
 

This information will be helpful in establishing the half-life of the compound
 

in the media of most concern for human exposure.
 

Bioavailability from Environmental Media. 1,2-Dibromoethane can be
 

absorbed by inhalation of contaminated ambient air, dermal contact, and
 

ingestion of contaminated drinking water and foodstuffs (EPA 1983; Jakobson et
 

al. 1982; Letz et al. 1984; Rowe et al. 1952; Saraswat et al. 1986; Stott and
 

McKenna 1984). Ingestion of contaminated groundwater is the exposure route of
 

concern at hazardous waste sites. Additional information is needed on the
 

absorption of 1,2-dibromoethane from soil following ingestion or dermal
 

contact. This information will be useful in determining the abioavailability
 

of residual 1,2-dibromoethane in soils.
 

Food Chain Bioaccumulation. 1,2-Dibromoethane is not expected to
 

bioconcentrate in plants, aquatic organisms, or animals, or biomagnify in
 

terrestrial or aquatic food chains as a result of its high water solubility
 

(NIOSH 1978; Parrish 1983). Additional information is needed on
 

bioconcentration and biomagnification of the compound to confirm this
 

predicted environmental behavior.
 

Exposure Levels in Environmental Media. 1,2-Dibromoethane has been
 

detected in ambient air, groundwater, soils, and foodstuffs (Brodzinsky and
 

Singh 1983; EPA 1983; Ewing et al. 1977; Daft 1989; Page 1981; Pellizzari et
 

al. 1978; Singh et al. 1981; Williams et al. 1988). However, the monitoring
 

data for these media are not current. Estimates of human intake have been
 

made on the basis of these older data. Additional information is needed on
 

the current levels of 1,2-dibromoethane in ambient air, soils, and groundwater
 

and on human intake levels, particularly at the nine hazardous waste sites
 

known to be contaminated with the compound. This information will be helpful
 

in estimating human exposure to the compound via contact with contaminated
 

media.
 

Exposure Levels in Humans. 1,2-Dibromoethane can be measured in blood
 

and metabolites can be detected in urine (Letz et al. 1984; Nachtomi et al.
 

1965). However, since the compound is rapidly and extensively metabolized in
 

mammals, and 1,2-dibromoethane metabolites do not persist in tissues, these
 

biomarkers have not been useful in identifying or quantifying human exposure
 

to the compound.
 

Exposure Registries. No exposure registries for 1,2-dibromoethane were
 

located. This compound is not currently one of the compounds for which a
 

subregistry has been established in the National Exposure Registry. The
 
98
 

5. POTENTIAL FOR HUMAN EXPOSURE
 

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
 

As part of the Third National Health and Nutrition Evaluation Survey
 

(NHANES III), the Environmental Health Laboratory Sciences Division of the
 

National Center for Environmental Health and Injury Control, Centers for
 

Disease Control, will be analyzing human blood samples for 1,2-dibromoethane
 

and other volatile organic compounds. These data will give an indication of
 

the frequency of occurrence and background levels of these compounds in the
 

general population.
 

On-going remedial investigations and feasibility studies conducted at
 

the nine NPL sites known to be contaminated with 1,2-dibromoethane will add to
 

the available database on exposure levels in environmental media, exposure
 

levels in humans, and exposure registries.
 
99
 

6. ANALYTICAL METHODS
 

The purpose of this chapter is to describe the analytical methods that
 

are available for detecting and/or measuring and monitoring 1,2-dibromoethane
 

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 1,2-dibromoethane. 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 1,2-dibromoethane 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.
 

6.1 BIOLOGICAL MATERIALS
 

Gas chromatography (GC) equipped with a flame ionization detector has
 

been employed for measuring the concentration of 1,2-dibromoethane in the
 

tissues of two workers following exposure (Letz et al. 1984). A detection
 

limit of 0.5 μg of 1,2-dibromoethane per gram of tissue was achieved. In the 

same report, Letz et al. (1984) detected ppm (mg/L) levels of bromide ion (a 

metabolite of 1,2-dibromoethane) in the serum and whole blood before and after 

the death of two individuals, respectively. Detection limits of 50 mg of 

bromide ion per liter of serum and 8 mg of bromide ion per liter of whole 

blood were obtained using gold chloride calorimetry and high-performance 

liquid chromatography, respectively. GC has also been used for quantifying 

ppm levels of 1,2-dibromoethane in blood and liver of rats and chicks 

(Nachtomi and Alumot 1972). See Table 6-l for details. 

6.2 ENVIRONMENTAL SAMPLES
 

High-resolution GC equipped with an appropriate detector is the most
 

common analytical technique for determining the concentrations of
 

1,2-dibromoethane in air, water, wastewater, soil, leaded gasoline, and
 

various foods (e.g., grains, grain-based foods, beverages, and fruits). The
 

choice of a particular detector will depend on the nature of the sample
 

matrix, the detection limit, and the cost of the analysis. Because volatile
 

organic compounds in environmental samples may exist as complex mixtures or at
 

very low concentrations, concentrations of these samples prior to
 

quantification are usually necessary.
 

Gas purging and trapping is the most commonly used method for the
 

preconcentration of 1,2-dibromoethane from water, waste water, soil, and
 

various foods. This method also provides a preliminary separation of
 

1,2-dibromoethane from other less volatile and nonvolatile components in the
 

101
 

6. ANALYTICAL METHODS
 

samples, thereby alleviating the need for extensive separation of the
 

components by a chromatographic column prior to quantification.
 

The best sensitivity for 1,2-dibromoethane quantification is obtained by
 

either electron capture detector (ECD) or Hall electrolytic conductivity
 

detector (HECD) in the halide detection mode, since these detectors are
 

relatively insensitive to nonhalogenated species and very sensitive to
 

halogenated species. Another common detection device is a mass spectrometer
 

(MS) connected to a GC. The GC/MS combination provides unequivocal
 

identification of 1,2-dibromoethane in samples containing multiple components
 

having similar GC elution characteristics (see Table 6-2). To date, GC
 

equipped with either ECD or HECD has provided the greatest sensitivity for
 

detecting 1,2-dibromoethane. However, GC/MS employing the techniques of
 

selective ion monitoring and isotope dilution have produced sensitivities in
 

the parts-per-quadrillion range for some organic pollutants (Patterson et
 

al. 1987), and could be used for 1,2-dibromoethane analysis.
 

The primary method of analyzing 1,2-dibromoethane in air is by
 

adsorption on a solid phase (i.e., activated charcoal tube or Tenax adsorbent
 

followed by thermal or solvent elution for subsequent quantification. GC/ECD
 

and GC/MS are the most commonly used analytical techniques for
 

1,2-dibromoethane after elution from the solid phase (Clark et al. 1982;
 

Collins and Barker 1983; Erikson and Pellizzari 1978; Girish and Kumar 1975;
 

NIOSH 1987; Scott et al. 1987). NIOSH has recommended GC/ECD (method 1008)
 

for determining 1,2-dibromoethane in air (NIOSH 1987). The range of
 

quantification is 0.3-1,000 ppb for a 25-L air sample.
 

1,2-Dibromoethane is usually isolated from aqueous media by the purgeandtrap method or liquid-liquid extraction. GC/ECD or GC/MS is the technique
 

employed for measuring 1,2-dibromoethane in water and waste water at ppt
 

levels (Kroneld 1985; Marti et al. 1984; Simmonds 1984). GC/ECD is also the
 

technique (method 8011) recommended by the EPA Office of Solid Waste and
 

Emergency Response for determining 1,2-dibromoethane in drinking water and
 

groundwater at ppt levels (EPA 1987b).
 

1,2-Dibromoethane can be isolated from soil samples by liquid-liquid
 

extraction and subsequent quantification by GC/MS (Sawhney et al. 1988). Low
 

ppb levels of 1,2-dibromoethane in soil were reported using this technique.
 

Sample collection and preparation for the analysis of 1,2-dibromoethane
 

in foods includes the purge-and-trap method, headspace gas analysis, liquid-liquid
 

extraction, and steam distillation (Alleman et al. 1986; Anderson et
 

al. 1985; Bielorai and Alumot 1965, 1966; Cairns et al. 1984; Clower et
 

al. 1985; Pranoto-Soetardhi et al. 1986; Scudamore 1985). GC equipped with
 

either ECD or HECD is the technique used for measuring 1,2-dibromoethane in
 

foodstuffs at ppt levels (Clower et al. 1985; Entz and Hollifield 1982; Heikes
 

and Hopper 1986; Page et al. 1987; Van Rillaer and Beernaert 1985).
 


104
 

6. ANALYTICAL METHODS
 

A highly sensitive and specific liquid chromatographic method for
 

determining 1,2-dibromoethane in leaded gasoline has been developed by Colgan
 

et al. (1986). The method involves the reaction between silver picrate
 

adsorbed on silica gel and 1,2-dibromoethane to form 1-bromo-2-(picryloxy)­

ethane and/or 1,2-bis(picryloxy)ethane. The derivatives formed were analyzed
 

by high-performance liquid chromatography (HPLC) equipped with an oxidative
 

electrochemical detector (ED). A detection limit of 280 ppt of
 

1,2-dibromoethane was reported (Colgan et al. 1986).
 

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 1,2-dibromoethane 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 1,2-dibromoethane,
 

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. GC, HPLC,
 

and gold chloride calorimetry have been used for measuring low ppt levels of
 

1,2-dibromoethane and bromide ion. These techniques are sensitive for
 

measuring background levels of 1,2-dibromoethane in the population (Letz et
 

al. 1984). However, it is not known whether these techniques are sensitive
 

for measuring levels of 1,2-dibromoethane at which health effects may begin to
 

occur. Although analytical methods are available to detect exposures to
 

1,2-dibromoethane, it is difficult to monitor for exposure to
 

1,2-dibromoethane in humans. This is because 1,2-dibromoethane is volatile
 

and has a short half-life in biological materials (Plotnick et al. 1979;
 

Windholz 1983). Monitoring for bromide ion in biological media is also
 

problematic in that the presence of this metabolite may result from the
 

metabolism of other brominated hydrocarbons (see Chapter 2). Furthermore,
 

information on the precision and accuracy of the gas chromatographic technique
 

would be useful for interpreting monitoring data in biological tissues and
 

fluids.
 
105
 

6. ANALYTICAL METHODS
 

Biochemical assays have been employed to measure changes in enzyme
 

levels (e.g., aspartate aminotransferase, lactic dehydrogenase) as an
 

indication of exposure to 1,2-dibromoethane in humans and animals (Albano et
 

al. 1984; Botti et al. 1989; Letz et al. 1984; Van Iersel et al. 1988).
 

Decreased sperm counts per ejaculate and increased numbers of sperm with
 

abnormal morphology have also been identified in workers following exposure to
 

1,2-dibromoethane (Ratcliffe et al. 1987; Wyrobek 1984). In general, these
 

techniques are nonspecific for 1,2-dibromoethane exposure (see Chapter 2).
 

There are no data to indicate whether a biomarker, if available, would be
 

preferred over chemical analysis for monitoring exposure to 1,2-dibromoethane.
 

Methods for Determining Parent Compounds and Degradation Products in
 

Environmental Media. GC equipped with either ECD, HECD, or MS and HPLC/ED are
 

the analytical techniques used for measuring low levels of 1,2-dibromoethane
 

in air, water, waste water, soil, leaded gasoline, and foodstuffs (Colgan et
 

al. 1986; Daft 1988; EPA 1987b; Marti et al. 1984; Michael et al. 1988; NIOSH
 

1987; Sawhney et al. 1988; Simmonds 1984). The media of most concern for
 

potential human exposure to 1,2-dibromoethane are drinking water, air, and
 

foodstuffs. Gas chromatographic techniques are sensitive for measuring
 

background levels of 1,2-dibromoethane in these media and levels of
 

1,2-dibromoethane at which health effects might begin to occur. GC/ECD is the
 

technique (method 8011) recommended by EPA for measuring ppt levels of
 

1,2-dibromoethane in water (EPA 1987b). NIOSH has also recommended GC/ECD as
 

the method (method 1008) for measuring low-ppm to sub-ppb levels of
 

1,2-dibromoethane in air (NIOSH 1987). GC/HECD or ECD has been employed for
 

detecting 1,2-dibromoethane in various foodstuffs at low- to sub-ppb levels.
 

No additional analytical methods for measuring 1,2-dibromoethane in
 

environmental media appear to be necessary at this time.
 

6.3.2 On-going Studies
 

The Environmental Health Laboratory Sciences Division of the National
 

Center for Environmental Health and Injury Control, Centers for Disease
 

Control, is developing methods for the analysis of 1,2-dibromoethane and other
 

volatile organic compounds in blood. These methods use high resolution gas
 

chromatography and magnetic sector mass spectrometry which gives detection
 

limits in the low parts-per- trillion range.
 

107
 

7. REGULATIONS AND ADVISORIES
 

1,2-Dibromoethane is on the list of chemicals appearing in "Toxic
 

Chemicals Subject to Section 313 of the Emergency Planning and Community
 

Right-to-Know Act of 1986" (EPA 1987f).
 

The international, national, and state regulations and guidelines
 

regarding 1,2-dibromoethane in air, water, and other media are summarized in
 

Table 7-1.
 



____________________ 

111
 

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Schrag SD, Dixon RL. 1985. Occupational exposures associated with male
 

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Scott BR, Sparrow AJ, Schwemmer SS, et al. 1978. Plant metabolic activation
 

of 1,2-dibromoethane (EDB) to a mutagen of greater potency. Mutat Res
 

49:203-212.
 

*Scott DR, Dunn WJ III, Emery SL. 1987. Classification and identification of
 

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*Scudamore KA. 1985. Gas chromatographic determination of chloroform, carbon
 

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*Shiau SY, Huff RA, Wells BC, et al. 1980. Mutagenicity and DNA-damaging
 

activity for several pesticides tested with Bacillus subtilis mutants. Mutat
 

Res 71:169-179.
 

Shih TW, Hill DL. 1981. Metabolic activation of 1,2-dibromoethane by
 

glutathione transferase and by microsomal mixed function oxidase: Further
 

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Shikiya J, Tsou G, Kowalski J, et al. 1984. Ambient monitoring of selected
 

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Shirasu Y, Moriya M, Tezuka H, et al. 1984. Mutagenicity of pesticides.
 

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137
 

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*Short RD, Winston JM, Hong CB, et al. 1979. Effects of ethylene dibromide
 

on reproduction in male and female rats. Toxicol Appl Pharmacol 49:97-105.
 

*Simmonds PG. 1984. Analysis of trace halocarbons in natural waters by
 

simplified purge and cytotrap method. J Chromatogr 289:117-127.
 

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*Singh HB, Salas T.J, Shigeishi H. 1981. Atmospheric measurements of selected
 

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28.
 

*Steenland K, Carrano A, Clapp D, et al. 1985. Cytogenetic studies in humans
 

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1,2-dibromoethane by cytochrome P-450-linked hydroxylation systems as observed
 

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*Tan EL, Hsie AW. 1981. Mutagenicity and cytotoxicity of haloethanes as
 

studied in the CHO/HGPRT system. Mutat Res 90:183-191.
 

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*Ter Haar G. 1980. An investigation of possible sterility and health effects
 

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*Teramoto S, Saito R, Aoyama H, et al. 1980. Dominant lethal mutation
 

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77:71-78.
 

*Tezuka H, Ando N, Suzuki R, et al. 1980. Sister chromatid exchanges and
 

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*Tomasi A, Albano E, Dianzani MU, et al. 1983. Metabolic activation of
 

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*Tucker JD, Xu J, Stewart J, et al. 1984. Detection of sister-chromatid
 

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Vamvakas S, Elfarra AA, Dekant W, et al. 1988. Mutagenicity of amino-acid
 

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Pharmacol 29:2975-2982.
 

*Van Bladeren PJ, Breimer DD, Van Huijgevoort JA, et al, 1981. The metabolic
 

formation of N-acetyl-S-2-hydroxyethyl-L-cysteine from tetradeutero1,2-dibromoethane. Relative importance of oxidation and glutathione
 

conjugation in vivo. Biochem Pharmacol 30:2499-2502.
 

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chemically-induced somatic mutation and recombination in Drosophila
 

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pesticides in Drosophila melanogaster. Experientia 30:621-623.
 

*Vogel TM, Reinhard M. 1986. Reaction products and rates of disappearances
 

of simple bromoalkanes, 1,2-dibromopropane, and 1,2-dibromoethane in water.
 

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39:1022.
 

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the metabolism and toxicity of 1,2-dibromoethane. Toxicol Appl Pharmacol
 

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rat liver, forestomach, and glandular stomach [Abstract]. Tox Lett 18 (Suppl
 

1):155.
 

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primary culture/DNA repair test in testing of coded carcinogens and
 

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Inc.
 

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of 1,2-dibromoethane in rats treated with disulfiram [Abstract]. Toxicol Appl
 

Pharmacol 48:A25.
 

*Wang LC, Winston JM, Hong CB, et al. 1982. Carcinogenicity and toxicity of
 

1,2-dibromoethane in the rat. Toxicol Appl Pharmacol 63:155-165.
 

*Wang 0, Utidjian MD, Karten VS. 1979. Retrospective evaluation of
 

reproductive performance of workers exposed to ethylene dibromide (EDB). J
 

Occup Med 21:98-102.
 
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induction of unscheduled DNA synthesis by ethylene dibromide in rat
 

spermatocytes and hepatocytes. J Cell Bio. Vol. 101, 462A.
 

*Working PK, Smith-Oliver T, White RD, et al. 1986. Induction of DNA repair
 

in rat spermatocytes and hepatocytes by 1,2-dibromoethane: The role of
 

glutathione conjugation. Carcinogenesis 7:467-472.
 

*Wyrobek AJ. 1984. Identifying agents that damage human spermatogenesis:
 

Abnormalities in sperm concentration and morphology. Monitoring human
 

exposure to carcinogenic and mutagenic agents. Lyon, France: International
 

Agency for Research on Cancer, Scientific Publication No. 59. 387-402.
 

Zijlstra JA, Vogel EW. 1988. The ratio of induced recessive lethals to
 

ring-x loss has prognostic value in terms of functionally of chemical
 

mutagenesis in Drosophila melanogaster. Mutat Res 201:27-38.
 

*Zoetemelk CEM, Mohn GR, Van DerGen A, et al. 1987. 1,2-Dibromo compounds:
 

Their mutagenicity in Salmonella strains differing in glutathione content and
 

their alkylating potential. Biochem Pharmacol 36:1829-1835.
 

Zweidinger R, Erickson M, Cooper S, et al. 1982. Direct measurement of
 

volatile organic compounds in breathing-zone air, drinking water, breath,
 

blood, and urine. Washington, DC: US Environmental Protection Agency.
 

EPA 600/4-82-015.
 

145
 

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.
 
146
 

9. GLOSSARY
 

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.
 

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 (LC ) (Lo) Lo
 -- 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 (LD ) (Lo) Lo
 -- 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.
 
147
 

9. GLOSSARY
 

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.
 

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 8-hour shift.
 

q1* -- The upper-bound estimate of the low-dose slope of the dose-response 

curve as determined by the multistage procedure. The ql* 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 

pg/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.
 
148
 

9. GLOSSARY
 

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.
 

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 (2-1 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 No-ObservedAdverse-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 2-1 and Figure 2-1 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 

"181:" data points in Figure 2-l). 

(5). Species The test species, whether animal or human, are identified in this 

column. 

(6). Exposure Frenquency/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 MKL 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 accompanies the LOAEL. 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 2-1
 

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 existing toxicokinetic, genotoxic, and carcinogenic 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.
 
B-l
 

ACGIH
 

ADME
 

ATSDR
 

BCF
 

BSC
 

CDC
 

CEL
 

CERCLA
 

CFR
 

CLP
 

cm
 

CNS
 

DHEW
 

DHHS
 

DOL
 

ECG
 

EEG
 

EPA
 

EKG
 

FAO
 

FEMA
 

FIFRA
 

LD

LD

LC

LC

f1
 

fpw
 

ft
 

FR
 

g
 

GC
 

HPLC
 

hr
 

IDLH
 

IARC
 

ILO
 

In
 

Kd
 

kg
 

Koc
 

Kow
 

L
 

LC
 

Lo
 

50
 

Lo
 

50
 

American
 

APPENDIX B
 

ACRONYMS, ABBREVIATIONS, AND SYMBOLS
 

Conference of Governmental Industrial Hygienists
 

Absorption, Distribution, Metabolism, and Excretion
 

Agency for Toxic Substances and Disease Registry
 

bioconcentration factor
 

Board of Scientific Counselors
 

Centers for Disease Control
 

Cancer Effect Level
 

Comprehensive Environmental Response, Compensation,
 

and Liability
 

Act
 

Code of Federal Regulations
 

Contract Laboratory Program
 

centimeter
 

central nervous system
 

Department of Health, Education, and Welfare
 

Department of Health and Human Services
 

Department of Labor
 

electrocardiogram
 

electroencephalogram
 

Environmental Protection Agency
 

see ECG
 

Food and Agricultural Organization of the United
 

Nations
 

Federal Emergency Management Agency
 

Federal Insecticide, Fungicide, and Rodenticide Act
 

first generation
 

feet per minute
 

foot
 

Federal Register
 

gram
 

gas chromatography
 

high performance liquid chromatography
 

hour
 

Immediately Dangerous to Life and Health
 

International Agency for Research on Cancer
 

International Labor Organization
 

inch
 

adsorption ratio
 

kilogram
 

octanol-soil partition coefficient
 

octanol-water partition coefficient
 

liter
 

liquid chromatography
 

lethal concentration low
 

lethal concentration 50 percent kill
 

lethal dose low
 

lethal dose 50 percent kill
 
B-2
 

APPENDIX B
 

LOAEL
 

LSE
 

m
 

mg
 

min
 

mL
 

mm
 

mmol
 

mppcf
 

MRL
 

MS
 

NIEHS
 

NIOSH
 

NIOSHTIC
 

nm
 

ng
 

NHANES
 

nmol
 

NOAEL
 

NOES
 

NOHS
 

NPL
 

NRC
 

NTIS
 

NTP
 

OSHA
 

PEL
 

pg
 

pmol
 

PHS
 

PMR
 

ppb
 

ppm
 

ppt
 

REL
 

RfD
 

RTECS
 

sec
 

SCE
 

SIC
 

SMR
 

STEL
 

STORET
 

TLV
 

TSCA
 

TRI
 

TWA
 

U.S.
 

lowest-observed-adverse-effect level
 

Levels of Significant Exposure
 

meter
 

milligram
 

minute
 

milliliter
 

millimeters
 

millimole
 

millions of particles per cubic foot
 

minimal risk level
 

mass spectroscopy
 

National Institute of Environmental Health Sciences
 

National Institute for Occupational Safety and Health
 

NIOSH's Computerized Information Retrieval System
 

nanometer
 

nanogram
 

National Health and Nutrition Examination Survey
 

nanomole
 

no-observed-adverse-effect level
 

National Occupational Exposure Survey
 

National Occupational Hazard Survey
 

National Priorities List
 

National Research Council
 

National Technical Information Service
 

National Toxicology Program
 

Occupational Safety and Health Administration
 

permissible exposure limit
 

picogram
 

picomole
 

Public Health Service
 

proportional mortality ratio
 

parts per billion
 

parts per million
 

parts per trillion
 

recommended exposure limit
 

Reference Dose
 

Registry of Toxic Effects of Chemical Substances
 

second
 

sister chromatid exchange
 

Standard Industrial Classification
 

standard mortality ratio
 

short-term exposure limit
 

STORAGE and RETRIEVAL
 

threshold limit value
 

Toxic Substances Control Act
 

Toxic Release Inventory
 

time-weighted average
 

United States
 
B-3 

APPENDIX B 

UF uncertainty factor 

WHO World Health Organization 

> greater than ≥ greater than or equal to
 

=
 equal to


<
 less than
 ≤
 

%
 

less than or equal to
 

percent
 

αβδγ
 μm μg 

alpha
 

beta
 

delta
 

gamma
 

micron
 

microgram
 

C-l
 

APPENDIX C
 

PEER REVIEW
 

A peer review panel was assembled for 1,2-dibromoethane. The panel
 

consisted of the following members: Dr. Donald Hill, Southern Research
 

Institute, Birmingham, Alabama; Dr. Herbert Rosenkrantz, Professor and
 

Chairman of Department of Environmental Health Sciences, Case Western Reserve
 

University, Cleveland, Ohio; and Dr. John Egle, Jr., Associate Professor of
 

Pharmacology, Medical College of Virginia, Richmond, Virginia. These experts
 

collectively have knowledge of 1,2-dibromoethane'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
 

Section 104(i)(13) of the Comprehensive Environmental Response, Compensation,
 

and Liability Act, as amended.
 

A second peer review panel was assembled to review mitigation of effects
 

(Section 2.8) for 1,2-dibromoethane. The panel consisted of the following
 

members: Dr. Brent Burton, Medical Director, Oregon Poison Center, Oregon
 

Health Sciences University, Portland, Oregon; Dr. Alan Hall, Private
 

Consulting and Medical Translating Services, Evergreen, Colorado; and Dr. Alan
 

Woolf, Director of Clinical Pharmacology, and Toxicology, Massachusetts Poison
 

Control System, The Children's Hospital, Boston, Massachusetts. All reviewers
 

were selected under the same conditions mentioned above.
 

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.
 

U.S. Government Printing Offce: 1992- 636-281