BROMOFORM
CHLORODIBROMOMETHANE
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry
TP-90-05
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TOXICOLOGICAL PROFILE FOR
BROMOFORM AND CHLORODIBROMOMETHANE
Prepared by:
Life Systems, Inc.
Under Subcontract to:
Clement Associates, Inc.
Under Contract No. 205-88-0608
Prepared for:
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
December 1990
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DISCLAIMER
The use of company or product name(s) is for identification only
and does not imply endorsement by the Agency for Toxic Substances ancj
Disease Registry.
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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 Register on April 17, 1987, on
October 20, 1988, on October 26, 1989, and on October 17, 1990.
Section 104(i)(3) of CERCLA, as amended, directs the Administrator of
ATSDR to prepare a toxicological profile for each substance on the list.
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, and
(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, but no less often than every three years, as
required by CERCLA, as amended.
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.
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Foreword
Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the public health statement is
information concerning significant health effects associated with exposure
to the substance. The adequacy of information to determine a substance's
health effects is described. Data needs that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program (NTP) of the Public Health Service, and EPA. The focus
of the profiles is on health and toxicological information; therefore, we
have included this information in the beginning of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested private
sector organizations and groups, and members of the public.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been reviewed
by scientists from ATSDR, the Centers for Disease Control, the NTP, and
other federal agencies. It-has also been reviewed by a panel of
nongovernment peer reviewers and is being made available for public
review. Final responsibility for the contents and views expressed in this
toxicological profile resides with ATSDR.
Wi i.
Administrator
Agency for Toxic Substances and
Disease Registry
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CONTENTS
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT ARE CHLORODIBROMOMETHANE AND BROMOFORM? 1
1.2 HOW MIGHT I BE EXPOSED TO CHLORODIBROMOMETHANE OR
BROMOFORM? 2
1.3 HOW CAN CHLORODIBROMOMETHANE AND BROMOFORM ENTER AND
LEAVE MY BODY? 3
1.4 HOW CAN CHLORODIBROMOMETHANE AND BROMOFORM AFFECT
MY HEALTH? 3
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 3
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE
BEEN EXPOSED TO CHLORODIBROMOMETHANE OR BROMOFORM? 8
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH? 9
1.8 WHERE CAN I GET MORE INFORMATION? 9
2. HEALTH EFFECTS 11
2.1 INTRODUCTION 11
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 11
2.2.1 Inhalation Exposure 12
2.2.1.1 Death 12
2.2.1.2 Systemic Effects 12
2.2.1.3 Immunological Effects 13
2.2.1.4 Neurological Effects • 13
2.2.1.5 Developmental Effects 13
2.2.1.6 Reproductive Effects 13
2.2.1.7 Genotoxic Effects ...... 13
2.2.1.8 Cancer 13
2.2.2 Oral Exposure 14
2.2.2.1 Death 14
2.2.2.2 Systemic Effects 28
2.2.2.3 Immunological Effects 30
2.2.2.4 Neurological Effects 31
2.2.2.5 Developmental Effects 32
2.2.2.6 Reproductive Effects 32
2.2.2.7 Genotoxic Effects 33
2.2.2.8 Cancer 33
2.2.3 Dermal Exposure 35
2.2.3.1 Death 35
2.2.3.2 Systemic Effects 35
2.2.3.3 Immunological Effects 35
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2.2.3.4 Neurological Effects 35
2.2.3.5 Developmental Effects 35
2.2.3.6 Reproductive Effects 35
2.2.3.7 Genotoxic Effects 35
2.2.3.8 Cancer 35
2.3 TOXICOKINETICS 35
2.3.1 Absorption 35
2.3.1.1 Inhalation Exposure 35
2.3.1.2 Oral Exposure 36
2.3.1.3 Dermal Exposure 36
2.3.2 Distribution 36
2.3.2.1 Inhalation Exposure 36
2.3.2.2 Oral Exposure 36
2.3.2.3 Dermal Exposure 37
2.3.3 Metabolism 37
2.3.4 Excretion 39
2.3.4.1 Inhalation Exposure 39
2.3.4.2 Oral Exposure 41
2.3.4.3 Dermal Exposure 41
2.4 RELEVANCE TO PUBLIC HEALTH 41
2.5 BIOMARKERS OF EXPOSURE AND EFFECT 47
2.5.1 Biomarkers Used to Identify or Quantify Exposure
to Chlorodibromomethane and Bromoform 48
2.5.2 Biomarkers Used to Characterize Effects Caused by
Chlorodibromomethane and Bromoform 49
2.6 INTERACTIONS WITH OTHER CHEMICALS 49
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 50
2.8 ADEQUACY OF THE DATABASE 50
2.8.1 Existing Information on the Health Effects of
Chlorodibromomethane and Bromoform 51
2.8.2 Identification of Data Needs 51
2.8.3 On-going Studies 58
3. CHEMICAL AND PHYSICAL INFORMATION 61
3.1 CHEMICAL IDENTITY 61
3.2 PHYSICAL AND CHEMICAL PROPERTIES 61
4. PRODUCTION, IMPORT, USE AND DISPOSAL 65
4.1 PRODUCTION 65
4.2 IMPORT 65
4.3 USE 65
4.4 DISPOSAL 66
5. POTENTIAL FOR HUMAN EXPOSURE 67
5.1 OVERVIEW 67
5.2 RELEASES TO THE ENVIRONMENT 67
5.2.1 Air 67
5.2.2 Water 67
5.2.3 Soil 70
5.3 ENVIRONMENTAL FATE 70
5.3.1 Transport and Partitioning 70
5.3.2 Transformation and Degradation 71
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5.3.2.1 Air 71
5.3.2.2 Water 72
5.3.2.3 Soil 72
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 72
5.4.1 Air 72
5.4.2 Water 73
5.4.3 Soil 75
5.4.4 Other Media 75
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 75
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 77
5.7 ADEQUACY OF THE DATABASE 77
5.7.1 Identification of Data Needs 77
5.7.2 On-going Studies 80
6. ANALYTICAL METHODS 81
6.1 BIOLOGICAL MATERIALS 81
6.2 ENVIRONMENTAL SAMPLES 82
6.3 ADEQUACY OF THE DATA BASE 82
6.3.1 Identification of Data Needs 85
6.3.2 On-going Studies 86
7. REGULATIONS AND ADVISORIES 87
8. REFERENCES 91
9. GLOSSARY 117
APPENDIX 122
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LIST OF FIGURES
2-1 Levels of Significant Exposure to Chlorodibromomethane - Oral ... 20
2-2 Levels of Significant Exposure to Bromoform - Oral 26
2-3 Proposed Pathway of Trihalomethane Metabolism in Rats 38
2-4 Proposed Pathway of Trihalomethyl-Radical-Mediated Lipid
Peroxidation 40
2-5 Existing Information on Health Effects of Chlorodibromomethane ... 52
2-6 Existing Information on Health Effects of Bromoform 53
5-1 Frequency of Sites with Chlorodibromomethane Contamination 68
5-2 Frequency of Sites with Bromoform Contamination 69
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LIST OF TABLES
1-1 Human Health Effects from Breathing Chlorodibromomethane
or Broraoform 4
1-2 Animal Health Effects from Breathing Chlorodibromomethane
or Bromoform 5
1-3 Human Health Effects from Eating or Drinking Chlorodibromomethane
or Bromoform 6
1-4 Animal Health Effects from Eating or Drinking Chlorodibromomethane
or Bromoform 7
2-1 Levels of Significant Exposure to Chlorodibromomethane - Oral ... 15
2-2 Levels of Significant Exposure to Bromoform - Oral 22
2-3 Summary of Lifetime Carcinogenicity Bioassay Findings 34
2-4 Genotoxicity of Bromoform In Vitro . . . . ¦ 44
2-5 Genotoxicity of Chlorodibromomethane In Vitro 45
2-6 Genotoxicity of Chlorodibromomethane and Bromoform In Vivo 46
2-7 Summary of On-going Research on the Health Effects of
Chlorodibromomethane or Bromoform 59
3-1 Chemical Identity of Bromoform and Chlorodibromomethane 62
3-2 Physical and Chemical Properties of Bromoform and
Chlorodibromomethane 63
5-1 Occurrence of Bromoform and Chlorodibromomethane in Finished
Drinking Water 74
5-2 Summary of Typical Human Exposure to Chlorodibromomethane
and Bromoform 76
6-1 Analytical Methods for Determining Bromoform and
Chlorodibromomethane in Biological Materials 83
6-2 Analytical Methods for Determining Bromoform and
Chlorodibromomethane In Environmental Samples 84
7-1 Regulations and Guidelines Applicable to Chlorodibromomethane
and Bromoform 88
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1. PUBLIC HEALTH STATEMENT
This Statement was prepared to give you information about
chlorodibromomethane and bromoform (tribromomethane) and to emphasize
the human health effects that may result from exposure to these
chemicals. These two chemicals are considered together in this report
because they are similar in their properties and in the health effects
which they cause, and because they are often found together in the
environment. The Environmental Protection Agency (EPA) has identified
1,177 sites on its National Priorities List (NPL). Chlorodibromomethane
and bromoform have been found at 14 of these sites. However, we do not
know how many of the 1,177 NPL sites have been evaluated for chlorodi-
bromomethane and bromoform. As EPA evaluates more sites, the number of
sites at which chlorodibromomethane and bromoform are found may change.
The information is important for you because chlorodibromomethane and
bromoform may cause harmful health effects and because these sites are
potential or actual sources of human exposure to chlorodibromomethane
and bromoform.
When a chemical is released from a large area, such as an
industrial plant, or from a container, such as a drum or bottle, it
enters the environment as a chemical emission. This emission, which is
also called a release, does not always lead to exposure. You can be
exposed to a chemical only when you come into contact with the chemical.
You may be exposed to it in the environment by breathing, eating, or
drinking substances containing the chemical or from skin contact with
it.
If you are exposed to a hazardous substance such as
chlorodibromomethane and bromoform, 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 ARE CHLORODIBROMOMETHANE AND BROMOFORM?
Chlorodibromomethane and bromoform (also known as tribromomethane)
are colorless, heavy, nonburnable liquids with a sweetish odor. In the
past, bromoform was used by industry to dissolve dirt and grease and to
make other chemicals, and it was also used in the early part of this
century as a medicine to help children with whooping cough get to sleep.
Currently, bromoform is only produced in small amounts for use in
laboratories and in geological and electronics testing. Chlorodibromo-
methane was used in the past to make other chemicals such as fire
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1. PUBLIC HEALTH STATEMENT
extinguisher fluids, spray can propellants, refrigerator fluid, and
pesticides. Currently it is produced only in small amounts for use in
laboratories.
Another source of chlorodibromomethane and bromoforin is drinking
water. When chlorine is added to drinking water to kill any disease-
causing organisms which might be present, the chlorine reacts with
natural substances found in the water, producing low levels of
chlorodibromomethane and bromoform as undesired byproducts. Small
amounts are also produced by plants in the ocean.
In the environment, chlorodibromomethane and bromoform are not
found as pure liquids, but rather they are found either dissolved in
water or evaporated into air as a gas. Both chlorodibromomethane and
bromoform are relatively stable in the air, but reactions with other
chemicals in the air cause them to break down slowly (about 'jO* in one
or two months). Any chlorodibromomethane or bromoform in water or soil
may also be broken down by bacteria, but the speed of this process is
not known.
Further information on the properties, uses, and behavior of
chlorodibromomethane and bromoform in the environment may be found in
Chapters 3, 4, and 5.
1.2 HOW MIGHT I BE EXPOSED TO CHLORODIBROMOMETHANE OR BROMOFORM?
You are most likely to be exposed to chlorodibromomethane and
bromoform by drinking water that has been treated with chlorine
Usually the levels in chlorinated drinking water are between 1 and
10 parts of chlorodibromomethane and bromoform per billion parts of
water (ppb). Chlorodibromomethane and bromoform have also been detected
in chlorinated swimming pools. When you are at a pool, you could be
exposed by breathing chlorodibromomethane or bromoform that have
evaporated into the air, or by uptake from the water through the skin
Neither chlorodibromomethane nor bromoform arc likely to be found in
food.
If you live near a factory or laboratory that makes or uses
chlorodibromomethane or bromoform, you might be exposed to chlorodi-
bromomethane or bromoform in the air. However, since neither
chlorodibromomethane nor bromoform have widespread use in this country
they are usually present in outside air at very low levels (less than
0.01 ppb). Therefore, this sort of exposure is not likely for most
people. Another place where you might be exposed is near a chemical
waste site where chlorodibromomethane or bromoform has been allowed to
leak into water or soil. In this case, you could be exposed if you
drank the water or got the soil on your skin. Further information on
how you might be exposed to these chemicals is given in Chapter 5.
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1. PUBLIC HEALTH STATEMENT
1.3 HOW CAN CHLORODIBROMOMETHANE AND BROMOFORM ENTER AND LEAVE MY BODY?
Studies in animals and humans indicate that both chlorodibromo-
methane and bromoform can readily enter your body after you drink them
in water or breathe them in air. It is likely that these chemicals
would also enter your body if you got them on your skin, but this has
not been studied. The main way that chlorodibromomethane and bromoform
are removed from the body is by being breathed out through the lungs.
Elimination is fairly rapid and complete (from 50% to 90% in 8 hours),
so they do not tend to build up in the body. Further information on how
chlorodibromomethane and bromoform enter and leave your body is given in
Chapter 2.
1.4 HOW CAN CHLORODIBROMOMETHANE AND BROMOFORM AFFECT MY HEALTH?
The effects of chlorodibromomethane and bromoform on your health
depend on how much you take into your body. In general, the more you
take in, the greater the chance that an effect will occur. Studies In
animals and humans indicate that the main effect of eating or breathing
large amounts of these chemicals is a slowing down of normal brain
activities. This occurs quite quickly, and tends to go away within a
day. In humans exposed to large amounts of bromoform, the usual effect
is only sleepiness. However, unconsciousness or death can occur in
extreme cases. Studies in animals indicate that exposure to high doses
of bromoform or chlorodibromomethane may also lead to injury to the
liver and the kidneys within a short period of time. Studies in animals
also suggest that neither chlorodibromomethane nor bromoform has a high
risk of harming an unborn baby, but this has not been studied in humans.
Exposure to low levels of chlorodibromomethane or bromoform do not
appear to seriously affect the brain, liver, or kidneys, but studies in
animals indicate that long-term intake of either chlorodibromomethane or
bromoform can cause cancer. Although no cases of cancer in humans can
be definitely attributed to these chemicals, this is an effect of
special concern, since many people are exposed to low levels of
chlorodibromomethane and bromoform in chlorinated drinking water.
Further information on how chlorodibromomethane and bromoform can
affect the health of humans and animals is presented in Chapter 2.
1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
In general, chlorodibromomethane and bromoform tend to produce
similar effects at comparable dose levels, although chlorodibromomethane
may be slightly more potent. Tables 1-1 to 1-4 summarize information on
the lowest doses that have been shown to cause observable changes. The
levels of chlorodibromomethane or bromoform in air that affect humans
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1. PUBLIC HEALTH STATEMENT
TABLE 1-1. Human Health Effects from Breathing
Chlorodibromomethane or Bromoform*
Short-term Exposure
(less than or equal to 14
days)
Levels
i n
Air
Length of Exposure
Description of Effects
The health effects
resulting from short-term
exposure of humans to air
containing specific
levels of chlorodibromo-
methane or bromoform are
not: known.
Long-term Exposure
(greater than 14 days)
Levels
in
Air
Length of Exposure
Description of Effects
The health effects
resulting from long-term
exposure of humans to air
containing specific
levels of chlorodibromo-
methane or bromoform are
not known.
*See Section 1.2 for discussion of exposures encountered in daily life
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1. PUBLIC HEALTH STATEMENT
TABLE 1-2. Animal Health Effects from Breathing
Chlorodibromomethane or Bromoform
Short-term Exposure
(less than or equal to 14
days)
Levels in Air
( ppb )
Lenpth of Exposure
Description of Effects*
240,000
10 days
Injury to the liver and
kidney in rats exposed
to bromoform.
The health effects
resulting from short-term
exposure of animals to
air containing specific
levels of chlorodibromo-
methane are not known.
Long-term Exposure
(greater than 14 days)
Levels in Air
(ppb)
Length of Exposure
Description of Effects*
24,000
2 months
Injury to the liver and
kidney in rats exposed
to bromoform.
The health effects
resulting from long-term
exposure of animals to
air containing specific
levels of chlorodibromo-
methane are not known.
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-3. Human Health Effects from Eating or
Drinking Chlorodibromomethane or Bromoform*
Short-term Exposure
(less than or equal to 14 days)
Lenpth of Exposure
Description of Effects**
The health effects resulting
from short-term exposure of
humans to food containing
specific levels of chlorodi-
bromome thane or bromoform
are not known.
Levels in Water
(DDb)
Estimated Minimal Risk Level
for chlorodibromomethane
(based on studies in
animals; see Section 1.5 for
discuss ion).
Estimated Minimal Risk Level
for bromoform (see Section
1.5 for discussion).
Sleepiness in children
given bromoform.
1,300
21,000
2,100,000
1 day
Long-term Exposure
(greater than 14 days)
Levels in Food
Lfinpth of Exoosure
Descriotion of Effects**
The health effects resulting
from long-term exposure of
humans to food containing
specific levels of chloro-
dibromomethane or bromoform
are not known.
Lpvels in Water
(DDb)
Estimated Minimal Risk Level
for chlorodibromomethane
(based on studies in
animals; see Section 1.5
for discussion)
Esimated Minimal Risk Level
for bromoform (based on
studies in animals; see
Section 1.5 for discussion).
1,000
6,900
*See Section 1.2 for a discussion of exposures encountered in daily life.
**These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
TABLE 1-4. Animal Health Effects from Eating or
Drinking Chlorodlbromomethane or Bromoform
Short-term Exposure
(less than or equal to 14 days)
Levels in Food
Leneth of Exposure
Description of Effects*
Levels in Water
(ppb)
The health effects resulting
from short-term exposure of
animals to food containing
specific levels of chloro-
dibromomethane or bromoform
are not known.
190,000
660,000
2,600,000
2,900,000
14 days
14 days
14 days
14 days
Mild effects on liver and
kidney in mice given chloro-
dibromomethane.
Mild liver injury in mice
given bromoform.
Death in mice given chlorodi-
bromomethane.
Death in rats given bromoform.
Long-term Exposure
(greater than 14 days)
Levels in Food
(pob)
Leneth of
ExDosure
Description of Effects*
880,000
1,600,000
2
2
yr
yr
Liver injury in rats given
chlorodibromomethane.
Liver injury in rats given
bromoform.
Levels in Water
(oob)
290,000
530,000
1,300,000
2
2
13
yr
yr
wk
Mild liver and kidney injury
in rats given chlorodibromo-
me thane .
Mild liver and kidney injury
in mice given bromoform.
Mild liver and kidney injury
in mice given chlorodi-
bromome thane .
*These effects are listed at the lowest level at which they were first
observed. They may also be seen at higher levels.
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1. PUBLIC HEALTH STATEMENT
are not known (Table 1-1), but levels of around 1,000 to 2,000 ppb in
air can be detected by smell. Levels of 24,000 ppb or higher of
bromoform in air have been found to cause liver or kidney injury in
animals (Table 1-2), but the levels of chlorodibromonnethane in air that
affect animals are not known. Swallowing one or two drops of bromoform
causes sleepiness in children. This is about equal to the amount of
bromoform that would be swallowed in one day from drinking water
containing 2,100,000 ppb of bromoform (Table 1-3).
The amount of chlorodibromomethane taken by mouth that would affect
humans is not known, but is probably about the same as for bromoform.
Studies in animals indicate that concentrations of around 190,000 ppb of
chlorodibromomethane or 660,000 ppb of bromoform In food or water can
lead to effects on liver or kidneys over a 2-week period (Table 1-4).
The amounts of chlorodibromomethane or bromoform that would cause
similar effects following skin contact are not known.
Minimal Risk Levels (MRLs) are also included in Table 1-3. These
MRLs were derived from animal and human data for both short-term and
long-term exposure, as described in Chapter 2 and in Tables 2-2 and 2-3.
The MRLs provide a basis for comparison with levels that people might
encounter either in the air or in food or drinking water. If a person
is exposed to chlorodibromomethane or bromoform at an amount below the
corresponding MRL, it is not expected that harmful (noncancer) health
effects will occur. Because these levels are based only on information
currently available, some uncertainty is always associated with them.
Also, because the method for deriving MRLs does not use any information
about cancer, an MRL does not imply anything about the presence,
absence, or level of risk for cancer.
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO
CHLORODIBROMOMETHANE OR BROMOFORM?
If you are exposed to chlorodibromomethane or bromoform, measurable
levels of the chemicals can sometimes be detected in samples of your
blood, breath, or fat. However, there is not enough information at
present to use the results of such tests to estimate the level of
exposure or to predict the nature or the severity of any health effects
that might result. Since special equipment is needed, these tests are
not routinely performed in doctors' offices. Because chlorodibromo-
methane and bromoform are eliminated from the body fairly quickly, these
methods are best suited to detecting recent exposures (within 1 or
2 days). Further information on how chlorodibromomethane and bromoform
can be measured in exposed humans is presented in Chapters 2 and 6.
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1. PUBLIC HEALTH STATEMENT
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT
HUMAN HEALTH?
The U.S. Environmental Protection Agency (EPA) has set a Maximum
Contaminant Level of 0.10 ppm (parts per million) for the combination of
chlorodibromomethane, bromoform, and a group of similar compounds
(trihalomethanes) in drinking water. As noted in Section 1.2, most
water samples in the United States have levels of chlorodibromomethane
and bromoform lower than this. The Food and Drug Administration (FDA)
has set the same limit for bottled water, but no rules have been set for
chlorodibromomethane and bromoform in food. In order to protect workers
from bromoform while on the job, the Occupational Safety and Health
Administration (OSHA) states that workers may not be exposed to
concentrations of bromoform in air greater than 0.5 ppm for an 8-hour
workday. There is no OSHA standard for chlorodibromomethane. Further
information on regulations concerning chlorodibromomethane and bromoform
are presented in Chapter 7.
1.8 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 give you information on the location of the
nearest occupational and environmental health clinics. Such clinics
specialize in recognizing, evaluating, and treating illnesses that
result from exposure to hazardous substances.
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2. HEALTH EFFECTS
2.1 INTRODUCTION
This chapter contains descriptions and. evaluations of studies and
interpretation of data on the health effects associated with exposure to
chlorodibromomethane and bromoform. Its purpose is to present levels of
significant exposure for chlorodibromomethane and bromoform based on
toxicological studies, epidemiological investigations, and environmental
exposure data. This information is presented to provide public health
officials, physicians, toxicologists, and other interested individuals
and groups with (1) an overall perspective of the toxicology of
chlorodibromomethane and bromoform and (2) a depiction of significant
exposure levels associated with various adverse health effects.
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 data in this section
are 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, intermediate, and chronic.
Levels of significant exposure for each exposure route and duration
(for which data exist) are presented in tables and illustrated in
figures. The points in the figures showing no-observed-adverse-effect
levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs)
reflect the actual doses (levels of exposure) used in the studies.
LOAELs have been classified into "less serious" or "serious" effects.
These distinctions are intended to help the users of the document
identify the levels of exposure at which adverse health effects start to
appear, determine whether or not the intensity of the effects varies
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 on 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 or with the identification of persons with the potential
to develop such disease may be interested in levels of exposure
associated with "serious" effects. Public health officials and project
managers concerned with response actions at Superfund sites may want
information on levels of exposure associated with more subtle effects in
humans or animals (LOAELs) or exposure levels below which no adverse
-------
12
2. HEALTH EFFECTS
effects (NOAELs) have been observed. Est: iinnt.es of levels posing minimal
risk to humans (Minimal Risk Levels, MRLs) are of interest to health
professionals and citizens alike.
For certain chemicals, levels of exposure associated with
carcinogenic effects may be indicated in the figures. These levels
reflect the actual doses associated with the tumor incidences reported
in the studies cited. Because cancer effects could occur at lower
exposure levels, the figures also show estimated excess risks, ranging
from a risk of one in 10,000 to one in 10,000,000 (10 ^ to 10~?) , as
developed by EPA.
Estimates of exposure levels posing minimal risk to humans (MRLs)
have been made, where data were believed reliable, for the most
sensitive noncancer end point for each exposure duration. MRLs include
adjustments to reflect human variability and, where appropriate, the
uncertainty of extrapolating from laboratory animal data to humans.
Although methods have been established to derive these levels (Barnes
et al 1987; EPA 1989), uncertainties are associated with the
techniques.
2.2.1 Inhalation Exposure
No studies were located regarding health effects of
chlorodibromomethane or bromoform in humans following inhalation
exposure. In animals, no studies were located regarding effects of
chlorodibromomethane, but limited data are available from several older
studies on the effects of inhalation exposure1 to bromoform. These
studies are discussed below.
2.2.1.1 Death
Inhalation of very high concentrations (56,000 or 8A,000 ppm) of
bromoform vapor for 1 hour has been reported to cause death in dogs
(Merzbach 1928). The chief symptoms noted were Initial excitation
followed by deep sedation. This indicates that central nervous system
depression is probably the chief cause of death in such acute exposures.
Because only two animals were used (one animal per dose) and only high
doses were administered, these data do not provide a reliable estimate
of the minimum lethal concentration in dogs or other animal species.
2.2.1.2 Systemic Effects
Hepatic and Renal Effects. Only two studies (Dykan 1962; Dykan
1964) were located on the systemic inhalation toxicity of bromoform.
These studies (published in Russia and available only as the English
abstract) indicate that inhalation exposure of animals to high
-------
13
2. HEALTH EFFECTS
concentrations of bromoform leads to hepatic and renal injury. Exposure
of rats to 240 ppra of bromoform for 10 days resulted in dystrophic and
vascular changes in both liver and kidney, with altered renal filtration
and hepatic metabolism (Dykan 1964). Longer-term exposure (two months)
to concentrations of 24 ppm also lead to hepatic changes (decreased
blood clotting and impaired glycogenesis) and renal injury (proteinuria
and decreased creatinine clearance) (Dykan 1962). A concentration of
4.8 ppm was estimated to be without significant effects on liver and
kidney (Dykan 1964). These changes in liver and kidney appear to
resemble the changes produced after oral exposure to bromoform (see
Section 2.2.2,2), indicating that bromoform produces similar systemic
effects by either route of exposure.
Other Systemic Effects. No studies were located regarding other
systemic effects (respiratory, cardiovascular, gastrointestinal,
hematological, musculoskeletal, dermal/ocular) in animals or humans
following inhalation exposure to chlorodibromomethane or bromoform.
2.2.1.3 Immunological Effects
No studies were located regarding immunological effects in humans
or animals after inhalation exposure to chlorodibromomethane or
bromoform.
2.2.1.4 Neurological Effects
Inhalation exposure to high levels (29,000 ppm or above) of
bromoform has been observed to lead to rapid and profound depression of
the central nervous system in dogs (Graham 1915; Merzbach 1928). This
is presumably due to a nonspecific anesthetic effect similar to that
produced by various other volatile halocarbons. Obvious clinical signs
included deep relaxation and sedation (Merzbach 1928). Clinical signs
of nervous system depression appeared quickly (within minutes), and
tended to disappear within a day after exposure ceased (Graham 1915) .
No studies were located regarding the following effects in humans
or animals after inhalation exposure to chlorodibromomethane or
bromoform.
2.2.1.5 Developmental Effects
2.2.1.6 Reproductive Effects
2.2.1.7 Genotoxic Effects
2.2.1.8 Cancer
-------
14
2. HEALTH EFFECTS
2.2.2 Oral Exposure
Most information on the health effects of chlorodibromomethane and
bromoform comes from studies in animals (rats and mice) exposed by the
oral route. For bromoform, there are some observations in humans
stemming from the past use of bromoform as a sedative, but no studies
were located on the effect of chlorodibromomethane in humans. Summaries
of studies that provide reliable quantitative toxicity data are
nresented in Table 2-1 and Figure 2-1 for chlorodibromomethane and in
Table 2-2 and Figure 2-2 for bromoform. The main conclusions from these
studies are discussed below.
2.2.2.1 Death
In the early part of this century, bromoform was often given as a
sedative to children suffering from whooping cough, and several deaths
due to accidental overdoses have been described (Dwelle 1903; Robert
1906- Roth 1904 as cited in von Oettingen 1955). The principal clinical
siens in fatal cases were those of severe central nervous system
depression (unconsciousness, stupor, and loss of reflexes), and death
was generally the result of respiratory failure (von Oettingen 1955) .
Tf death could be averted, recovery was generally complete within
several days (Benson et al. 1907; Burton-Fanning 1901; Robert 1906).
The dose needed to cause death in children is not known with
certainty but both Dwelle (1903) and Roth (1904) estimated that a dose
of about5 g had been fatal. For a 10 to 20-kg child, this corresponds
to a dose of around 250 to 500 mg/kg.
In animal studies, estimates of the acute oral LD50 for
chlorodibromomethane and bromofon. typically range between 800 and
1 600 me/kK (Bowman et al. 1978; Chu et al. 1982,,). Single oral doses
as low as 300 to 600 mg/kg can cause death in a tew animals (NTP 1985,
1988) quite close to the estimated lethal dose in humans (above),
nnco^'below 250 mg/kg usually do not cause death in animals, even when
exposure is continued for 14 to 90 days (Condie et al. 1983; Munson
et al. 1982; NTP 1985, 1988).
The cause of death following acute oral exposure of animals has not
been thoroughly investigated, but as in humans, the chief clinical signs
bserved are those of central nervous system depression (Bowman et al.
1978) While central nervous system depression probably is an important
factor in acute lethality, in some cases death did not occur until
several days after an acute exposure (Bow,„„n et al. 197B; NTP 1985.
1988) This suggests that other effects (e.g., hepatic and/or renal
injury) may also be important (see Section 2.2.2.2). This is supported
-------
TABLE 2-1. Levels of Significant: Exposure to Chlorodibroawcnetliaiie - Oral
Figure
Key
Exposure
Frequency/
LOAEL (Effect)
NOAEL Less Serious
Species Route Duration Effect (mg/kg/day) (tng/kg/day)
Serious
(mg/kg/day)
Reference
ACUTE EXPOSURE
Death
1 Rat
Rat
Rat
Rat
Mouse
Mouse
Systemic
8 Rat
9 Rat
(G) 1 d
(G)
(G)
1 d
14 d
lx/d
(G) 1 d
Mouse (G) 1 d
10
Rat
(G) 1 d
(G) 14 d
lx/d
(G) 14 d
lx/d
(G) 1 d
(G) 1 d
Renal
Hepatic
Hepatic
310
250
1220
160
250
250
1500
500 (darkened
medullae)
2450 finer, ser.
enz.)
1186 (LD50 male)
848 (LD50 female)
630 (1 of 10 died)
500 (8 of 10 died)
1840 (1/5 died)
2650 (LD50 male)
800 (LD50 males)
1200 (LD50 females)
310 (1 of 10 died)
500a (7 of 10 died)
Chu et al. 1982a
SIP 1985
NIP 1985
Hewitt et al.
1983
Bowman et al.
1978
NTP 1985
NTP 1985
NTP 1985
Hewitt et al.
1983
Chu et al. 1982a
X
M
>
f
H
X
p]
•n
m
o
H
co
li
Rat
(G) 1 d
Renal
1500
Chu et al. 1982a
12
Rat
(G) 1 d
Hepatic 1220
Plaa and Hewitt
1982a
13
Rat
(G) 14 d
lx/d
Hepatic
250 500 (mottled liver)
NTP 1985
-------
TABLE 2-1 (Continued)
Figure
Key
Exposure
Frequency/
LOAEL (Effect)
NOAEL Less Serious
Species Route Duration Effect (mg/kg/day) (mg/kg/day)
Serious
(mg/kg/day)
Reference
14
15
16
17
Rat
Mouse
Mouse
Mouse
(G) 1 d
(G) 14 d
Ix/d
(G) 14 d
Ix/d
(G) 14 d
lx/d
ReriaL
Renal
Hepat ic
Hepatic
2450
37b (minimal hlstolog.
changes)
37^ (minimal histolog.
changes)
50 125 (incr. liver wt.)
Hevitt et al.
1983
Condie et al.
1983
Condie et al.
1983
Munson et al.
1982
18
19
20
Mouse
Mouse
Iosaunological
21 Mouse
Neurological
22 Rat
(G) 14 d
lx/d
Renal
Mouse (G)
14 d
lx/d
(G) 14 d
lx/d
(G) 14 d
lx/d
(G) 14 d
lx/d
250 500 (reddened
medullae)
60 125 (stomach nodules)
Hepatic 250 500 (mottled liver)
250 5CC (lethargy, ataxia)
125 ;decr.
inrrunity)
NTP 1985
NTP 1985
NTP 1985
Munson et al
1982
se
>
r
H
•x
TJ
m
n
23
2*
Rat
Mous«
(C) 1 d
(G) 1 d
160 310 (lethargy)
500 (sedat ion)
NTP 1985
Bowman et al.
1978
25
Mouse (C) 1 d
454 (ED50,
coordlnatIon)
Balster and
Bortelleca 1982
26
Mouse (G) 14 d
lx/d
250 500 (CNS depression)
HTP 1985
-------
TABLE 2-1 (Continued)
Exposure LQAEL (Effect)
FLgure Ftequervcy/ NOAEL Less Serious
Key Species Route Duration Effect (mg/kg/day) (mg/kg/day)
Serious
(mg/kg/day)
Reference
Deve1oproent a1
27 Rat
(G)
9 d
Gd 6-15
200
Ruddick et al.
1983
INTERMEDIATE EXPOSURE
D*ath
28
29
30
Systemic
31
32
33
34
35
36
Rat
Rat
Mouse
Rat
Rat
Rat
Rat
Neurological
37 Rat
(G)
(W)
(0)
(W)
r
H
ac
in
~n
r>
H
oo
-------
TABLE 2-1 (Continued)
Exposure
Frequency/
LOAEL (Effect)
Figure Frequency/ NOAEL Less Serious
Key Species flour* Duration Effect (mg/kg/day) (mg/kg/day)
Serious
(mg/kg/day)
Reference
S8
*9
Mouse
Mouse
Developmental
AO Mouse
Reproduct ive
41 Mouse
42
wk
- wk
250
100
685
400 (deer, operant
behavior)
NTP 1985
Balster and
Borrelleca 1982
Borzelleca and
Carchman 1982
bS5 (deer, fertility) Borreli^ca and
Carchraan 1982
NTP 1985
CHROtflC EXPOSURI
Systemic
4 3 R*t
44 Rat
45
46
47
fUt
Nous*
Nmm«
IG? 2 yz R*n*l
3d 'vk
IT) ;•! >r Hepatic
(C) 2 yt
id/vk
-------
TABLE 2-1 (Continued)
Exposure LOAEL (Effect)
Figure Frequency/ NOAEL Less Serious Serious
Key Species Route Duration Effect (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference
Neurologicai
A 8 Rat
49
Mouse
Rep r oduc t ive
50 Rat
51
House
Cancer
52 Mouse
(G) 2 yr
5d/vk
(G) 105 wk
5d/wk
(G) 2 yr
5d/wk
(G) 105 wk
5d/wk
(G) 105 wk
5d/wk
80
100
80
100
NTP 1985
NTP 1985
NTP 1985
NTP 1985
100 (liver tumors) NTP 1985
•Converted to an equivalent concentration of 2,600,000 ppb in water for presentation in Table 1-4.
bUsed to derive acute oral MRL; dose divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation
from animals to humans, and 10 for human variability). Dose of 37 mg/kg/day also converted to an equivalent concentration
of 190,000 ppb in water for presentation in Table 1-4. MRL of 0.04 mg/kg/day converted to an equivalent concentration of
1,300 ppb in water for presentation in Table 1-3.
°Converted to an equivalent concentration of 1,300,000 ppb in water for presentation in Table 1-4.
^Used to calculate chronic oral MRL: Dose adjusted for interroittant exposure, and divided by an uncertainty factor of
1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). Dose of 40 mg/kg/day
also converted to an equivalent concentration of 290,000 ppb in water for presentation in Table 1-4. MRL of 0.03 mg/kg/day
converted to an equivalent concentration of 1,000 ppb in water for presentation in Table 1*3.
•Converted to an equivalent concentration of 880,000 ppb in food for presentation in Table 1-4.
LOAEL » lowest-observed-adverse-effect level; NOAEL * no-observed-adverse-effect level;
milligram; kg * kilograms;
G ™ gavage; d - day: LD^q = lethal dose, SOX mortality; et al. ¦* and others; x = time; incr, = increased; ser. - serum;
enz • enzymes; histolog. * histological; wt. = weight; deer. = decreased; ED^q = dose at which 50% of the maximal effect occurs;
CNS * central nervous system; Gd * gestation day; wk * week; U = water; yr * year; P = feed.
X
W
>
r*
H
0C
W
*3
m
o
H
1/5
-------
(mg/kg/day)
10,000 r
ACUTE
(<14 Days)
/
/ J?
/
/
/
/
r£>
1,000
100
10 -
V"
5s" ¦*
O*
¦ Sin Hlf
07m
• >
•Sm07m°J'
o*
Obit
Otk
®20m(J Mr
Oi0roO>*
O '*•" (
Ol>
O'*'
O"'
OnmO*
'8
17m
16m
0 1
001
• 24m I
O M">
921m
021m
>2Sm #*»® 22r
0231
Q27r
Key
r Rat
¦ LD50
m Mouse
• LOAEL for serious effects (animals)
The number next to
3 LOAEL for less serious effects (antmais)
each point corresponds
O NOAEL (animals)
to entries in Table 2-2
~ CEL Cancer Effect Level
j Minimal risk level for
1 effects other than cancer
\ls
FIGURE 2-1. Levels of Significant Exposure to Chlorodibromomethane - Oral
-------
(mg/kg/day)
10,000 r-
365 Days)
*
S&T ,V
/ / /
^ c?
1,000
100
10
fl9tm
0»K>C» 03C43,
Os1nU ~S2m
Q«ar Osor
tn
m
>
r
H
s
ra
ti
>n
m
ci
H
CO
0.01
Key
r Rat
¦ LD50
m Mouse
0 LOAEL for serious effects (animals)
The number next to
O LOAEL for less serious effects (animals)
each point corresponds
O NOAEL (animals)
to entries in Table 2-2
~ CEL-Cancer Effect Level
j Minimal risk level for
! effects other than cancer
\1/
FIGURE 2-1 (Continued)
-------
TABLE 2-2. Levels of Significant Exposure to Bramoform - Oral
Exposure LOAEL (Effecrl
Figure Frequency/ NOAEL Less Serious Serious
Key Species Route Duration. Effect (mg/kg/day) (mg/kg/day) (mg/kgMay)
Reference
ACUTE EXPOSURE
Death
1
2
3
4
Human
Rat
Rat
Rat
Mouse
Mouse
Mouse
Mouse
Mouse
1 d
W 1 d
(G)
(G)
CG)
1 d
14 d
lx/d
1 d
(G) 1 d
(G) 14 d
lx/d
(G) 14 d
lx/d
(G) 14 d
lx/d
500
200
250
289
400
250
270
1388 (LD50 males)
1147 (LD50 females)
1000 (6 of 10 died)
400a (I of 10 died)
1400 (LD50 males)
1550 (LD50 females)
500 (1 of 10 died)
Dwells 1903
Chu et al. 1982a
NTP 1988
NTP 1988
Bounan et al.
1978
Condie et al.
1983
NTP 1988
Munion et al.
1982
£
r
H
3C
M
*3
M
O
hJ
to
fo
to
Systemic
10
11
Rat
(0) 1 d
(G) 1 d
Hepatic
Hepatic
765 1071 (hiitolog.
changes)
1440
Chu et al. 1982a
Plaa and Hewitt
1982a
12
13
Rat
Rat
(G) 1 d
(G) 1 d
Renal
Hepatic
1500
29
Chu et al. 1982a
Klingensmith and
Mehendale 1981
14
Rat
(G) 1 d
Hepatic
1000 (altered enzymes)
Moody and
Smuckler 1986
-------
TART-E 2-2 (Continued)
Exposure LOAEL (Effect')
Figure Frequency/ NOAEL Less Serious Serious
Key Species Route Duration Effect (mg/kg/day) (mg/kg/day) (mg/kg/day)
Reference
15
16
Mouse
Mouse
(G) 14 d
lx/d
(G) 14 d
lx/d
Renal
Gastro
72 145 (minimal histolog.
changes)
200
Condie et al.
1983
400 (stom. nodules) NIP 1988
17
18
Mouse
Mouse
(G) 14 d
lx/d
(G) 14 d
lx/d
Hepatic 145 (histolog.
changes)
Hepatic 50 125^ (incr. liver vt.)
Condie et al.
1983
Munson et al.
1982
Immunol og ical
19 Mouse
Neurological
20 Human
21 Mouse
22
(G) 14 d
lx/d
(G)
1 d
14 d
lx/d
Mouse (G) 1 d
23 Mouse (G) 1 d
Deve1opmental
24 Rat
(G) 9 d
Gd 6-15
125
50
60° (sedation)
600 (ataxia)
250 (deer.
immunity)
Munson et al.
1982
270 (severe CNS depr.) Dvelle 1903
NTP 1988
431 (ED50,
coordination)
1000 (sedation)
Balster and
Borzelleca 1982
Bowman et al.
1978
100 (skeletal anom.) Ruddick et al.
1983
£
5
EC
M
•n
Tl
M
n
H
C/i
NJ
<_o
INTERMEDIATE EXPOSURE
Death
25 Rat
(G) 13 vk
5d/vk
200
NTP 1988
26
27
Rat
(W) 28 d
Mouse (G) 13 vk
5d/wk
70
400
Chu et al. 1982a
NTP 1988
-------
TABLE 2-2 (Continued)
Figure
Key
Exposure
Frequency/
NOAEL Less Serious
Species Route Duration Effect (mg/kg/day) (mg/kg/day)
LOAEL (Effect)
Serious
(mg/kg/day)
Reference
Systemic
28
29
30
31
Rat
Rat
Rat
Mouse
Neurological
32
33
34
Rat
Mouse
Mouse
Reproductive
35 Mouse
(W) 28 d
(W) 28 d
(G) 13 wk
5d/wk
(G) 13 wk
5d/wk
(G) 13 wk
5d/wk
(G) 13 wk
5d/wk
(G) 30-90 d
lx/d
(G) 105 d
lx/d
Renal
Hepatic
Hepatic
Hepatic
70
70
50 (vacuolization)
100 200 (vacuolization)
100 (lethargy)
400
9.2 100 (deer, operant
behavior)
200
Chu et al. 1982a
Chu et al. 1982a
NTP 1988
NTP 1988
NTP 1988
NTP 1988
Balster and
Borzelleca 1982
X
w
>
r
H
x
m
Ci
H
ro
•P*
NTP 1989
CHRONIC EXPOSURE
Systemic
36 Rat
37
38
39
Rat
Rat
Mouse
(G) 103 wk Hepatic
5d/vk
(G) 103 wk
5d/wk
(G) 103 wk
5d/vk
Gastro
(F) 1-2 yr Hepatic
Gastro
100^ (inflammation,
fatty change)
20® 80 (yellow,
enlarged liver)
50 (hyperplasia)
100 (ulcer)
NTP 1988
NTP 1988
Tobe et al. 1982
NTP 1988
-------
TABLE 2-1 (Continued)
Figure
Key
Exposure
FrequencyI
LOAEL (Effect)
NOAEL Less Serious
Species Route Duration Effect (nig/kg/day) (mg/kg/day)
Serious
(mg/kg/day)
Reference
AO
Mouse
(G) 103 wk
Sd/vk.
Hepatic
100d (fatty change)
NTP 1988
Neurological
41 Rat
(G) 103 vk
5d/vk
20Q
NTP 1988
42
(G) 103 wk
5d/wk
200
NTP 1988
Reproduct ive
4 3 Rat
44
Mouse
Cancer
45 Rat
(G) 103 wk
5d/vk
(G) 103 wk
5d/vk
(G) 103 wk
5d/wk
200
200
200 (intestinal
tumors)
NTP 1988
NTP 1988
NTP 1988
rn
pi
>
r*
H N3
ffi <-n
m
tn
o
H
CO
^Converted to an equivalent concentration of 2,900,000 ppb in water for presentation in Table 1-4.
^Converted to an equivalent concentration of 660,000 ppb in water for presentation in Table 1-4.
cUsed to derive acute oral MRL: dose divided by an uncertainty factor of 100 (10 for use of a LOAEL, and 10 for human
variability). Dose of 60 mg/kg/day and MRL of 0.6 mg/kg/day converted to an equivalent concentrations of 2,100,000 and
21,000 ppb in water for presentation in Table 1-3.
^Converted to an equivalent concentration of 530,000 ppb in water for presentation in Table 1-4.
®Used to derive chronic MRL; dose divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans, and
10 for human variability). MRL of 0.2 mg/kg/day converted to an equivalent concentration of 6,900 ppb in water for
presentation in Table 1-3.
^Converted to an equivalent concentration of 1,600,000 ppb in food for presentation in Table 1-4.
LOAEL ¦ lowest-observed-adverse-effect level; NOAEL ¦ no-observed-adverse-effe<5t level,- mg - milligram; kg » kilogram; d * day;
G 38 Gavage; LDjq = lethal dose, SOX mortality; x *» time; histolog. — histological; Gastro — gastrointestinal; F * feed;
stom. • stomach; incr. » increased; vt. » weight; deer. = decreased; CNS = central nervous system; depr, = depression; ED50 ¦ dose
at which 50X of the maximal effect occurs; Gd = gestation day; anom = anomaly; W * water; wk « week; yr = year.
-------
(mg/kg/day)
10,000
ACUTE
(s14 Days)
/
o*
J
»>
so"8
^ ~
/
/
1,000-
100
10-
0.1
•6m O*
..O*" „ •*'
«06m0Tm0®'^)4t
01Gm
0«m
J11r
110t ®14r
>10r
Ol7m (^gm
Ol8m
01»
®15m
Ol5m
• 1»m A20
Ol»«
~20
123m
®21m
• Z2m
OtJr
OM'
tU
m
>
tr1
H
a:
m
w
o
H
C/3
ro
o
0.1
Key
r Rat
¦ LD50
m Mouse
• LOAEL for serious effects (animals)
The number next to
® LOAEL for less serious effects (animals)
each point corresponds
O NOAEL (animals)
to entries in Table 2-3
A LOAEL for serious effects (humans)
: Minimal risk level for
A LOAEL for less serious effects (humans)
j effects other than cancer
~ CEL Cancer Effect Level
FIGURE 2-2. Levels of Significant Exposure to Bromoform - Oral
-------
INTERMEDIATE
(15-364 Days)
CHRONIC
(^365 Days)
(mg/kg/day) ^
10,CXX)r
t»y
.V ¦
r
H
rc
m
m
o
H
w
N>
Key
r Rat
¦ LD50
m Mouse
• LOAEL for serious effects (animals)
The number next to
3 LOAEL for less serious effects (animals)
each point corresponds
0 NOAEL (animals)
to entries in Table 2-3
A LOAEL for serious effects (humans)
! Minimal risk level tor
A LOAEL for less serious effects (humans)
i effects other than cancer
w
~ CEL-Cancer Effect Level
FIGURE 2-2 (Continued)
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28
2. HEALTH EFFECTS
by observations in long-term studies, where deaths in rats dosed with
250 mg/kg/day of chlorodibromomethane did not occur until exposure had
continued for 8 to 10 weeks (NTP 1985).
2.2.2.2 Systemic Effects
Respiratory Effects. Histological examination of larynx, trachea,
lungs, and bronchi of rats and mice exposed to chlorodibromomethane (80
to 100 mg/kg/day) or bromoform (100 to 200 mg/kg/day) by gavage for up
to two years revealed no evidence of adverse effects, except for an
increased incidence of chronic inflammation of the lungs in male rats
exposed to bromoform (NTP 1985, 1988). This inflammation was similar in
appearance to that caused by a sialodacryoadenitis (SDA) virus
infection, and antibodies to rat SDA virus were detected in study
animals. Thus, the inflammation observed was probably secondary to the
infection and was not a direct result of bromoform. However, the
absence of symptoms in control animals suggested that bromoform-treated
rats may have been more susceptible to reinfection by the virus or
slower to recover (NTP 1988).
Cardiovascular Effects. Histological examination of rats and mice
exposed to chlorodibromomethane or bromoform by gavage for up to two
years revealed no evidence of adverse effects upon the heart (NTP 1985,
1988). While this indicates that cardiac tissue is not directly injured
by these chemicals, indirect effects on cardiovascular functions might
occur as a consequence of the central nervous system depressant activity
of these compounds (see Section 2.2.2.3). However, this has not been
studied.
Gastrointestinal Effects. Effects of chlorodibromomethane and
bromoform on the gastrointestinal tract have not been widely studied,
but histological examinations of stomach and intestine from rats and
mice exposed to these chemicals by gavage have been performed by NTP
(NTP 1985, 1988). In mice, raised nodules were observed in the stomach
following 14 days exposure to 125 mg/kg/day of chlorodibromomethane or
400 mg/kg/day of bromoform. These nodules were not observed in rats
exposed to chlorodibromomethane for 14 days, and were not observed in
either rats or mice exposed to doses of 80 to 100 mg/kg/day of
chlorodibromomethane or 100 to 200 mg/kg/day of bromoform for 90 days to
2 years. The biological significance of these nodules is not
immediately apparent, but it is likely that they are a response to a
direct irritant effect of the chemicals on the gastric mucosa.
Another gastrointestinal effect of potential concern is the
occurrence of ulcers in the forestomach of male rats exposed to 100 or
200 mg/kg/day of bromoform for two years (NTP 1988). This effect was
-------
29
2. HEALTH EFFECTS
not observed in female rats or in mice exposed to bromoform, although
mice exposed to bromoform displayed a dose - dependent hyperplasia of the
glandular stomach.
While these observations clearly indicate that the stomach may be
affected by chlorodibromomethane and bromoform, it is possible that the
exposure regimen (bolus dosing, by gavage, in oil) leads to irritant
effects in the stomach that might not occur if exposure were continuous
at lower concentrations in food or drinking water. However, this has
not been investigated.
Hematological Effects. Several studies (Chu et al. 1982a, 1982b;
Munson et al. 1982; Tobe et al. 1982) have investigated the
hematological effects of oral exposure of rats and mice to
chlorodibromomethane and bromoform. With the exceptions of some minor
fluctuations in lymphocyte count following exposure to bromoform (Chu
et al. 1982a, 1982b), none of these studies detected any significant
effects of chlorodibromomethane or bromoform on hemoglobin, hematocrit,
red blood cells, or white blood cells.
Musculoskeletal Effects. None of the available studies on the oral
toxicity of chlorodibromomethane or bromoform have reported effects on
the musculoskeletal system. However, detailed electrophysiologic or
histopathologic studies on these tissues have not been performed.
Hepatic Effects. Nearly all studies of chlorodibromomethane and
bromoform toxicity in rats and mice indicate that the liver is a target
tissue for these chemicals. However, hepatic effects are usually not
severe, being characterized most often by increased vacuolization, fat
accumulation, increased liver weight, and altered serum enzyme levels.
Small changes of this sort have been detected in some experiments
following exposure for 2 to 13 weeks at doses as low as 30 to
50 mg/kg/day (Condie et al. 1983; NTP 1985; Tobe et al. 1982), and
hepatic effects are frequently reported after doses of 50 to
500 mg/kg/day (Condie et al. 1983; Munson et al. 1982; NTP 1985, 1988).
Occasionally centrilobular necrosis may develop (NTP 1985), but this is
rarely extensive.
Chlorodibromomethane and bromoform appear to be of approximately
similar hepatotoxicity (Condie et al. 1983; NTP 1985, 1988). Males tend
to be more sensitive to chlorodibromomethane and bromoform than females,
and mice tend to be more sensitive than rats (NTP 1985, 1988), but these
differences also are not large. The basis for the variability between
chemicals, species and sexes is probably related to differences in the
metabolism of these compounds (see Section 2.6), but this has not been
rigorously established.
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30
2. HEALTH EFFECTS
Based on a LOAEL of 40 mg/kg/day for hepatic injury from
chlorodibromomethane (NTP 1985), a chronic oral MRL of 0.03 mg/kg/day
was calculated as described in footnote d in Table 2-1. For bromoform,
a NOAEL value of 20 mg/kg/day (Tobe et al. 1982) was used to calculate a
chronic oral MRL of 0.2 mg/kg/day, as described in footnote c in
Table 2-2.
Renal Effects. Histological studies performed by NTP (1985)
indicate that oral exposure to chlorodibromomethane can cause kidney
injury in both rats and mice. The medullae appear to be reddened in
both males and females after a single oral dose of 500 mg/kg, but this
dose was so high that 7 of 10 animals died. Of greater toxicological
concern are effects on the nephron that develop after intermediate or
chronic exposure to doses of 50 to 250 mg/kg/day (NTP 1985). These
effects are usually much more apparent in males than females, and are
characterized by tubular degeneration and mineralization leading to
nephrosis (NTP 1985). These histological findings of nephrotoxicity are
supported by the kidney function studies of Condie et al. (1983), who
found that ingestion of chlorodibromomethane (37 to 147 mg/kg/day) for
2 weeks by male mice tended to impair uptake of para-amino hippuric acid
(PAH) in renal slices prepared from exposed animals. Based on a value
of 37 mg/kg/day, an acute oral MRL of 0.04 mg/kg/day was calculated for
chlorodibromomethane, as described in footnote b in Table 2-1.
Bromoform also has nephrotoxic potential. Condie et al. (1983)
noted minimal to slight nephrosis and mesangial hypertrophy in male mice
exposed to repeated oral doses of 145 to 289 mg/kg/day of bromoform.
However, in contrast to the findings for chlorodibromomethane (see
above), no significant histopathological effects were detected by NTP
(1988) in rats or mice exposed to doses up to 200 mg/kg of bromoform for
two years. This suggests that bromoform may be somewhat less
nephrotoxic than chlorodibromomethane, but the data are too limited to
draw a firm conclusion. The basis for the difference in nephrotoxicity
between chlorodibromomethane and bromoform has not been thoroughly
studied, but is possibly related to differences in the renal metabolism
of these two compounds.
Dermal/Ocular Effects. Histological studies of tissues from rats
and mice exposed to chlorodibromomethane or bromoform by gavage for up
to two years revealed no treatment-related effects on skin or eyes (NTP
1985, 1988).
2.2.2.3 Immunological Effects
Only one study (Munson et al. 1982) has formally investigated the
effect of chlorodibromomethane and bromoform ingestion on the immune
system. Exposure of mice to doses of 125 or 250 mg/kg/day of
-------
31
2. HEALTH EFFECTS
chlorodibromomethane for 14 days lead to decreases in several indices of
humoral and cell-mediated immunity in both males and females. Similar
effects were observed in male mice exposed to 250 mg/kg of bromoform,
but no effects were noted in females. These observations indicate that
several cell-types of the immune system are affected by chlorodibromo-
methane and bromoform, but the data do not reveal whether these changes
are accompanied by a significant decrease in immune system function
(e.g., decreased resistance to infectious disease). In this regard, it
should be recalled that male rats exposed to bromoform for two years
appeared to have decreased resistance to a common viral infection (NTP
1988), suggesting (but not proving) that bromoform may have led to
functional impairment of the immune system in these animals.
2.2.2.4 Neurological Effects
Both chlorodibromomethane and bromoform, like other volatile
halogenated hydrocarbons, can lead to marked central nervous system
depression. Because of this property, bromoform was used as a sedative
in the early part of this century. Doses of 1 to 2 drops (probably
about 15 to 20 mg/kg) given 3 to 6 times per day usually produced
sedation (the ability to sleep) in children with whooping cough (Burton-
Fanning 1901; Dwelle 1903). This dose (probably averaging around
60 mg/kg/day) has been used to calculate an acute oral MRL for bromoform
of 0.6 mg/kg/day, as described in footnote c of Table 2-2. In mild
cases of accidental overdose, clinical signs included rapid breathing,
constricted pupils, and tremors; more severe cases of overdose were
accompanied by a drunken-like stupor, cyanosis, shallow breathing, and
erratic heart rate (Benson 1907; Kobert 1906). Doses producing these
effects could only be estimated, but most were probably in the range of
20 to 40 drops (corresponding to doses of about 150 to 300 mg/kg).
Very similar effects on the nervous system are observed in animals
exposed to bromoform or chlorodibromomethane. Acute signs such as
labored breathing, ataxia, and sedation are generally observed only
after doses of 300 mg/kg or above (Balster and Borzelleca 1982; Bowman
et al. 1978; NTP 1985, 1988). These effects appear quickly (within one
hour) and persist for a number of hours. Following repeated exposure to
lower doses, lethargy is the main effect (NTP 1988). It is not known
whether high doses of chlorodibromomethane or bromoform lead to any
histopathological changes in the brain, but intermediate (13 week) or
chronic (2 year) exposure of rats and mice to subanesthetic doses
produced no histological changes in the brain (NTP 1985, 1988).
Balster and Borzelleca (1982) employed a series of behavioral tests
to investigate the neurological effects of chlorodibromomethane and
bromoform in mice. Doses of 9 or 10 mg/kg/day for 90 days did not have
any significant effects on performance in tests of strength, activity,
-------
32
2. HEALTH EFFECTS
or coordination. Exposure to higher doses (100 or 400 mg/kg/day) for 30
to 90 days had no effect on passive avoidance learning, but did cause a
transient decrease in response rate in a test of operant behavior. It
should be noted that a number of animals receiving the high dose died
during the study.
These studies suggest that the depressant effects of chlorodibromo-
methane and bromoform on the nervous system are probably not accompanied
by any lasting behavioral or histological alterations.
2.2.2.5 Developmental Effects
The developmental effects of oral exposure to chlorodibromomethane
and bromoform have not been extensively investigated, but limited data
suggest these chemicals have relatively low toxicity on the developing
fetus. Ruddick et al. (1983) dosed pregnant rats with up to
200 mg/kg/day of chlorodibromomethane or bromoform during gestation. An
increased incidence of minor skeletal anomalies was noted at doses of
100 and 200 mg/kg/day of bromoform, but no other significant
fetotoxicity or teratogenicity was detected. Borzelleca and Carchman
(1982) exposed mice to 685 mg/kg/day of chlorodibromomethane in drinking
water for several generations and detected no significant effect on the
incidence of gross, skeletal, or soft-tissue anomalies.
2.2.2.6 Reproductive Effects
Chronic exposure of rats and mice to chlorodibromomethane (80 to
100 mg/kg/day) or bromoform (100 to 200 mg/kg/day) resulted in no
detectable histological effects in reproductive tissues of males
(testes, prostate, and seminal vesicles) or females (ovaries, uterus,
and mammary gland) (NTP 1985, 1988). In a detailed study of the effects
of bromoform on reproduction and fertility in male and female mice,
doses up to 200 mg/kg/day had no significant effect (NTP 1989).
In contrast to these negative findings, female mice exposed to
chlorodibromomethane in drinking water at a high dose (685 mg/kg/day)
experienced a marked reduction in fertility, with significant decreases
in litter size, gestational survival, postnatal survival, and postnatal
body weight (Borzelleca and Carchman 1982). These affects may have been
due to marked maternal toxicity, as evidenced by decreased weight gain,
enlarged and discolored livers, and decreased survival. Exposure to
lower doses (17 or 170 mg/kg/day) resulted in occasional decreases in
one or more of the reproductive parameters monitored, but the effects
were not large and were not clearly dose-related. These data are not
sufficient to draw firm conclusions about the effects of
chlorodibromomethane on reproduction, but it appears that reproductive
tissues and functions are not markedly impaired at doses that do not
cause frank maternal toxicity.
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33
2. HEALTH EFFECTS
2.2.2.7 Genotoxic Effects
No studies were located regarding genotoxic effects of
chlorodibromomethane or bromoform in humans exposed by the oral route.
Morimoto and Koizumi (1983) found an increased frequency of sister
chromatid exchange in bone marrow cells from mice given oral doses of
25 to 250 mg/kg/day of chlorodibromomethane or bromoform for four days.
Other in vivo and in vitro studies on the genotoxicity of
chlorodibromomethane and bromoform are presented and discussed in
Section 2.4.
2.2.2.8 Cancer
No studies were located regarding carcinogenic effects in humans
following oral exposure to chlorodibromomethane or bromoform. There are
a number of epidemiological studies that indicate there may be an
association between chronic ingestion of chlorinated drinking water
(which typically contains chlorodibromomethane and bromoform) and
increased risk of rectal, bladder, or colon cancer in humans (Cantor
et al. 1987; Crump 1983; Kanarek and Young 1982; Marienfeld et al.
1986), but these studies cannot provide information on whether any
effects observed are due to chlorodibromomethane, bromoform, or to one
or more of the hundreds of other byproducts that are also present in
chlorinated water.
Chronic oral studies in animals indicate that both chlorodibromo-
methane and bromoform have carcinogenic effects. The key findings are
summarized in Table 2-3. Chronic exposure to chlorodibromomethane
resulted in an increased incidence of liver tumors (adenomas or
carcinomas) in mice (but not in rats) (NTP 1985), and bromoform caused
an increased frequency of neoplasms of the large intestine (adenomatous
polyps or adenocarcinomas) in rats (but not in mice) (NTP 1988) . Even
though the absolute incidence of intestinal neoplasms in bromoform-
treated rats was relatively low, the data constitute clear evidence for
the tumorigenicity of bromoform, since these lesions are rare in control
animals. For chlorodibromomethane, the evidence is more limited, but
the data are still indicative of carcinogenic potential.
The mechanism of carcinogenicity of chlorodibromomethane, bromoform
and other related trihalomethanes (THMs) such as bromodichloromethane
and chloroform is not known, but might be related to the metabolic
generation of a reactive dihalocarbonyl intermediate (see Section 2.3).
If so, the differences noted between tissues, sexes, and species
regarding the carcinogenic effect of any given THM could be related to
differences in the rate of generation of this intermediate. Likewise,
differences in potency and specificity between different THMs could be
related not only to the relative rate of metabolism to the
dihalocarbonyl, but also to the reactivity of the resulting
-------
TABLE 2-3. S
of Lifetime Carcinogenicity Bioa^say Findings
Chemical
(Reference)
Test
Species
Sex
Tissues with
Increased Tumors
Tumor Type(s)
Chlorodibromomethane
(KTP 1985)
Rat
Mouse
"ftroooform
(STP 1988)
Rat
M
F
M
None
None
Liver
Liver
Large
Intestine
F Large
Intestine
Mouse M None
F None
Statistical
Significance
Adenoma
Carcinoma
Adenoma or Carcinoma
Adenoma
Carcinoma
Adenoma or Carcinoma
Adenomatous polyps
Adenocarcinoma
Polyps or Adenocarcinoma
Adenomatous polyps
Adenocarc inoma
Polyps or adenocarcinoma
NS
0.030
0.065
0.016
0.258
0 . 004
NS
NS
0.028
0.015
NS
0.004
Level of
Evidence Category®
No evidence
No evidence
Equivical evidence
Some evidence
Some evidence
Clear evidence
No evidence
No evidence
SC
W
>
r
H
33
pa
w
o
H
oo
¦P-
aThese are specific level-of-evidence categories assigned by NTP. Refer to the source documents (NTP 1985 or NTP 1988) for a
full description of the meaning of these categories.
M * male; F m female; NS * Not statistically significant (P>0.05 by life-table test or logistic regression test).
-------
35
2. HEALTH EFFECTS
dihalocarbonyl. The apparent carcinogenic potency in the liver appears
to be inversely related to the chemical reactivity of the dihalocarbonyl
(NTP 1988). That is, THMs such as chloroform and bromodichloromethane
which generate dichlorocarbonyl (the least chemically reactive) are more
potent than THMs such as iodoform or bromoform which generate the more
reactive diiodocarbonyl or dibromocarbonyl groups. This may be because
the most highly reactive dihalocarbonyls are more readily destroyed by
reaction with glutathione, while the less reactive species are more
likely to diffuse into the nucleus and react with DNA before they are
destroyed (NTP 1988).
2.2.3 Dermal Exposure
No studies were located regarding the following health effects in
humans or animals after dermal exposure to chlorodibromomethane or
bromoform.
2.2.3.1
Death
2.2.3.2
Systemic Effects
2.2.3.3
Immunological Effects
2.2.3.4
Neurological Effects
2.2.3.5
Developmental Effects
2.2.3.6
Reproductive Effects
2.2.3.7
Genotoxic Effects
2.2.3.8
Cancer
2.3 TOXICOKINETICS
2.3.1 Absorption
2.3.1.1 Inhalation Exposure
No studies were located regarding the rate or the extent of
chlorodibromomethane or bromoform absorption in humans or animals
following inhalation exposure. Based on the physical-chemical
properties of these compounds, and by analogy with other related
halomethanes such as chloroform (ATSDR 1989a), it is expected that both
chlorodibromomethane and bromoform would be well-absorbed across the
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36
2. HEALTH EFFECTS
lung. The occurrence of systemic and neurological effects following
inhalation exposure of animals to bromoform (see Section 2.2.1) supports
this view.
2.3.1.2 Oral Exposure
Only one study was located which provides quantitative data on
gastrointestinal absorption of chlorodibrontomethane and bromoform. Mink
et al. (1986) found that 60% to 90% of single oral doses of these
compounds given in corn oil to rats or mice were recovered in expired
air, urine, or in internal organs. This indicates that gastrointestinal
absorption was at least 60% to 90% complete. This is consistent with
the ready gastrointestinal absorption observed for other halomethanes
such as chloroform (ATSDR 1989a) or carbon tetrachloride (ATSDR 1989b)
As noted by Withey et al. (1983), the rate of halocarbon uptake from the
gastrointestinal tract may be slower when compounds are given in oil
than when they are given in water.
2.3.1.3 Dermal Exposure
No studies were located regarding dermal absorption of
chlorodibromomethane or bromoform in humans or animals. The dermal
permeability constant for chloroform in aqueous solution has been
estimated to be 0.125 cm/hr (Beech 1980). Assuming that chlorodibromo-
methane and bromoform have similar permeability constants, flux rates of
around 10 ng/cm2/hr could occur during dermal contact with water
containing 100 A*g/L of these chemicals (Beech 1980).
2.3.2 Distribution
2.3.2.1 Inhalation Exposure
No studies were located regarding the distribution of chloro-
dibromomethane or bromoform in humans or animals following inhalation
exposure. However, adverse effects involving several organs (liver,
kidney, central nervous system) indicates distribution to these sites.
2.3.2.2 Oral Exposure
The distribution of chlorodibromomethane and bromoform in tissues
following oral exposure has not been thoroughly investigated. Analysis
of bromoform levels in the organs of a child who died after an
accidental overdose revealed concentrations of 10 to 40 mg bromoform
per kg tissue in intestine, liver, kidney, and brain, with somewhat
higher levels in lung (90 mg/kg) and stomach (130 mg/kg) (Roth 1904, as
cited in von Oettingen 1955). This suggests that bromoform is
distributed fairly evenly from the stomach to other tissues.
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37
2. HEALTH EFFECTS
In animals, Mink et al. (1986) found that only about 1 to 2% of a
single oral dose of 14C-labeled chlorodibromomethane or bromoform was
retained in the soft tissues of rats eight hours after dosing. The
tissues which contained measurable amounts of the radiolabel were the
brain, kidney, liver, lungs, muscle, pancreas, stomach (excluding
contents), thymus, and urinary bladder. The relative amount of
radiolabel in each tissue was not mentioned. Similar results were noted
in mice, except that blood also contained a significant fraction of the
total dose (10% in the case of bromoform). The chemical form of the
material in the tissues (parent, metabolite, or adduct) was not
reported. The form in blood also was not determined, but studies by
Anders et al. (1978) suggest that some or all may have been carbon
monoxide bound to hemoglobin (see Section 2.3.3).
2.3.2.3 Dermal Exposure
No studies were located regarding the distribution of
chlorodibromomethane or bromoform in humans or animals following dermal
exposure.
2.3.3 Metabolism
The metabolism of chlorodibromomethane, bromoform, and other THMs
has been investigated by Anders and colleagues (Ahmed et al. 1977;
Anders et al. 1978; Stevens and Anders 1979, 1981). The main reactions,
which are not believed to be route-dependent, are shown in Figure 2-3.
The first step in the metabolism of THMs is oxidation by the
cytochrome P-450 mixed function oxidase system of liver. This has been
demonstrated in vitro using isolated rat liver microsomes (Ahmed et al.
1977), and in vivo, where the rate of metabolism is increased by
cytochrome P-450 inducers (phenobarbital) and decreased by cytochrome
P-450 inhibitors (SKF-525A) (Anders et al. 1978). The product of this
reaction is presumed to be trihalomethanol, which then decomposes by
loss of hydrogen and halide ions to yield the dihalocarbonyl. Although
this intermediate has not been isolated, its formation has been inferred
by detection of 2-oxothiazolidine-4-carboxylic acid (OZT) in an in vitro
microsomal system metabolizing bromoform in the presence of cysteine
(Stevens and Anders 1979). The dihalocarbonyl molecule (an analogue of
phosgene) is highly reactive, and may undergo a number of reactions,
including: (a) direct reaction with cellular nucleophiles to yield
covalent adducts; (b) reaction with two moles of glutathione (GSH) to
yield carbon monoxide and oxidized glutathione (GSSG); and (c)
hydrolysis to yield C02.
The amount of THM metabolized by each of these pathways has not
been studied in detail, but it appears that conversion to C02 is the
main route. However, this depends on the species, the THM being
-------
X_L
i
x
OH '
x-c-x
I
X
HX
-Z.
0
1
c
/ \
X X
R-H
V
OH
¦* R-C-X
I
X
2GSH
-W-
¦* GSSG+CO
2HX
1°
-*
2HX
->co,
cysteine
—^"T[—" S
2HX
CH,— CH
/ \
COOH
NH
" C '
l
o
OZT
FIGURE 2-3. Proposed Pathway of Trihafomethane Metabolism in Rats*
'Adapted from Stevens and Anders 1981.
X = halogen atom (chlorine, bromine); R = cellular nucleophile (protein, nucleic acid); GSH = reduced
glutathione; GSSG = oxidized glutathione; OZT » oxothiazolidine carboxylic acid.
-------
39
2. HEALTH EFFECTS
metabolized, and metabolic conditions (cellular glutathione levels).
Mink et al. (1986) found that mice oxidized 72% of an oral dose of
chlorodibromomethane and 40% of an oral dose of bromoform to C02. In
contrast, rats oxidized only 18% of chlorodibromomethane and 4% of
bromoform to C02.
The fraction of the dose converted to carbon monoxide has not been
quantified, but dramatically increased levels of carboxyhemoglobin have
been reported following oral exposure of rats to bromoform (Anders
et al. 1978; Stevens and Anders 1981). Mink et al. (1986) reported
about 10% of a dose of bromoform was present in blood in mice; the form
of the label was not investigated, but it may have been
carboxyhemoglobin.
Metabolism of THMs by cytochrome P-450 can also lead to the
production of highly reactive trihalomethyl free radicals, especially
under hypoxic conditions (O'Brien 1988). Radical formation from
bromoform has been observed both in isolated hepatocytes incubated with
bromoform in vitro and in the liver of rats exposed to bromoform in vivo
(Tomasi et al. 1985). Although it has not been studied, it seems likely
that this pathway would also generate trihalomethyl radicals from
chlorodibromomethane.
While metabolism to free radicals is a minor pathway in the sense
that only a small fraction of the total dose is converted, it might be
an important component of the toxic and carcinogenic mechanism of
chlorodibromomethane and bromoform. Figure 2-4 shows how free radical
generation can lead to an autocatalytic peroxidation of polyunsaturated
fatty acids (PUFAs) in cellular phospholipids (O'Brien 1988).
Peroxidation of cellular lipids has been observed in rat kidney slices
incubated with bromoform in vitro, although lipid peroxidation was not
detectable in liver slices (Fraga et al. 1987). Lipid peroxidation is
considered to be a likely cause of cell injury for other halogenated
compounds such as CC14 (ATSDR 1989b), but the significance of this
pathway in the toxicity of chlorodibromomethane and bromoform remains to
be determined.
2.3.4 Excretion
2.3.4.1 Inhalation Exposure
No studies were located regarding excretion of chlorodibromomethane
or bromoform by humans or animals following inhalation exposure.
-------
CL
CYTO. P-450
CHXj ~ CX3.
NADPH
CXjOO- + PUFA
PUFAOOH
PUFA*+ CX3OOH
02
PUFAOO-
PUFA
FIGURE 2-4. Proposed Pathway of Trihalomethyl-Radical-Mediated
Lipid Peroxidation*
'Adapted from O'Brien 1988.
X = halogen atom (CI, Br, I); PUFA = Polyunsaturated Fatty Acid
-------
41
2. HEALTH EFFECTS
2.3.4.2 Oral Exposure
In rats and mice given a single oral dose of 14C-labeled
chlorodibromomethane or bromoform, excretion occurred primarily by
exhalation of parent THM or of C02 (Mink et al. 1986). The total
fraction of the administered dose excreted through the lungs ranged from
45% to 84%, mostly as C02 in mice and mostly as the parent THM in rats.
Only 1% to 5% of the dose was excreted in urine (the chemical form in
urine was not determined). Excretion was nearly complete within 8 hours
in all cases, indicating that there is a relatively rapid clearance of
the volatile species. However, significant levels (1 to 12%) of the
^C-label remained in tissues after 8 hours. The chemical form was not
determined, but this might be due to stable covalent adducts formed from
reactive metabolic intermediates (see Section 2.3.3).
2.3.4.3 Dermal Exposure
No studies were located regarding excretion of chlorodibromomethane
or bromoform by humans or animals following dermal exposure.
2.4 RELEVANCE TO PUBLIC HEALTH
Studies in animals, combined with limited observations in humans,
indicate that the principal adverse health effects associated with
short-term inhalation or oral exposure to high levels of chlorodibromo-
methane or bromoform are central nervous system depression, liver
injury, and kidney injury. Similar effects might be expected following
dermal exposure to concentrated liquid chlorodibromomethane or
bromoform, but this has not been studied. Because chlorodibromomethane
and bromoform have very low production and use (see Chapter 4) , doses
needed to cause these effects are not likely to be encountered by the
average person. However, many people are exposed to low levels of
chlorodibromomethane and bromoform in chlorinated water used for
drinking, bathing, or swimming, and studies in animals indicate that
chronic exposure to these chemicals may lead to increased risk of
cancer. These effects and others of possible concern are discussed in
greater detail below.
Death. Accidental overdoses of bromoform associated with the past
use of bromoform as a sedative for whooping cough resulted in the death
of a number of children in the early part of this century (Dwelle 1903;
Kobert 1906; Roth 1904). The cause of death in these cases was usually
marked depression of the central nervous system accompanied by
respiratory or cardiovascular collapse. The amount of bromoform needed
to cause death in humans is not known with certainty, but is probably
about 300 mg/kg (Dwelle 1903; Roth 1904). No cases of human death from
chlorodibromomethane are known, but studies in animals indicate that
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42
2. HEALTH EFFECTS
chlorodibromomethane and bromoform have roughly similar toxicity. On
this basis, it seems likely that a similar acute dose of chlorodibromo-
me thane (i.e. around 300 mg/kg) could also cause death in humans.
Opportunities for exposure to lethal doses of either chemical are now
remote.
Systemic Effects. The chief systemic effects recognized following
exposure to chlorodibromomethane or bromoform are injury to the liver
and the kidneys. These effects have been investigated mostly in animals
exposed by the oral route, but there is limited data indicating that
similar effects occur following inhalation exposure as well.
Typical effects in liver include increased liver weight,
vacuolization, and fat accumulation. Effects in kidney are usually
characterized by tubular degeneration and mineralization, leading to
nephrosis and decreased renal function.
Oral dose levels leading to renal and hepatic effects in animals
vary somewhat between chlorodibromomethane and bromoform, and also
between species and sexes. In general, renal and hepatic effects are
not apparent below doses of about 30 to 50 mg/kg/day, are rather mild at
doses of 50 to 200 mg/kg/day, and are not marked until doses reach
250 mg/kg/day. Although data on hepatotoxic and nephrotoxic doses in
humans are not available, it is reasonable to assume that the dose-
response relation in humans is roughly similar to that in animals.
Other systemic effects of chlorodibromomethane or bromoform appear
to be minor or absent. No direct effects of oral exposure of animals to
chlorodibromomethane or bromoform have been noted for the respiratory,
cardiovascular, hematological or musculoskeletal systems, or on the skin
or eyes. Some gastrointestinal effects (stomach nodules and ulcers)
have been noted in rats, but these are probably due to a direct irritant
action on the stomach, and are not likely to be of concern except at
high doses that also produce hepatic and renal lesions.
Immunological Effects. Only one study (Munson et al. 1982) has
investigated the effects of chlorodibromomethane and bromoform on the
immune system, but the findings of this study indicate that short-term
oral exposure of mice to doses of 125 mg/kg/day or higher can produce
significant changes in both the humoral and cell-mediated immune
systems. It is difficult to judge whether these changes are accompanied
by a significant impairment in the overall functioning of the immune
system, although data from one study (NTP 1988) indicated that chronic
exposure to bromoform might decrease resistance to viral infection. The
effect of chlorodibromomethane and bromoform on the immune system of
humans has not been studied, but the data of Munson et al. (1982)
indicate that this is an effect of potential concern.
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43
2. HEALTH EFFECTS
Neurological Effects. Animal studies indicate that both
chlorodibromomethane and bromoforra possess anesthetic properties, and
bromoform was previously used as a sedative in the treatment of whooping
cough in children. In children, oral doses of around 15 mg/kg/day of
bromoform typically produced only mild sleepiness, while doses of
150 mg/kg sometimes produced stupor or deep narcosis, usually
accompanied by depressed respiration and erratic heartbeat. Airborne
concentrations of bromoform leading to nervous system depression in
humans are not known, but brief exposures of animals to high
concentrations (^29,000 ppm) leads to deep sedation within minutes (Sax
1984) . These depressant effects on the nervous system appear to be
fully reversible both in animals and humans, but it is difficult to rule
out the possibility of subtle but enduring neurological changes
following narcotizing doses.
Developmental Effects. Studies in animals indicate that neither
chlorodibromomethane nor bromoform have significant fetotoxicity or
teratogenicity in animals exposed to oral doses up to 200 mg/kg/day,
although some minor skeletal anomalies were noted at doses of 100 or
200 mg/kg/day (Ruddick et al. 1983). No studies of developmental
effects in humans have been performed, but the animal data suggest that
effects of this sort are not likely to be of concern at the levels
typically encountered in the environment.
Reproductive Effects. Studies in animals indicate that oral
exposure to either chlorodibromomethane or bromoform does not result in
significant damage to reproductive organs in males or females (NTP 1985,
1988, 1989). Continuous exposure of mice to high doses of
chlorodibromomethane in water caused a marked reduction in fertility
(Borzelleca and Carchman 1982), but this was probably due to marked
maternal toxicity. Lower doses (those that did not produce maternal
toxicity) did not result in significant impairment of reproduction.
While the effects of chlorodibromomethane or bromoform on reproduction
have not been studied in humans, the data from animal studies suggest
that this is not likely to be major concern at typical human exposure
levels.
Genotoxic Effects. The genotoxicity of chlorodibromomethane and
bromoform has been investigated in a number of studies, both in vitro
(Tables 2-4 and 2-5) and in vivo (Table 2-6). The results of these
studies are generally mixed and are occasionally inconsistent, perhaps
because of variations in the efficiency of extrinsic or intrinsic
metabolic activation of the parent compounds under test conditions.
Still, a number of studies found evidence for both mutagenic and
cytogenetic effects by both chlorodibromomethane and bromoform. The
-------
TABLE 2-4. Genotoxicity of Brocaoform In Vitro
Results
End Point
Species (Test System)
Strain
With
Activation
Without
Activation
Reference
Prokaryotic organisms :
Gene mutation
Salmonella typhimurium
(desiccator system)
S. typhlmurium
(plate incorporation
assay)
TA100
TA1535
TA98
TA100
TA1535
TA1537
No data
No data
(+)
Simmon et al. 1977
Varma et al. 1988
Eukaryotic organisms:
Fish:
S ister-chromat id
exchange
Mammalian cells:
Sister-chromatid
exchange
S. typhimurium
(preincubation procedure)
Oyster toadfish leukocytes
Chinese hamster ovary cells
Human lymphocytes
TA100
TA97
TA98
TA100
TA1535
TA1537
CH0-W-B1
No data
( + )
(+)
No data
No data
( + ).
( + )
Rapson et al. 1980
NTP 1988
Maddock and
Kelly 1980
Galloway
et al. 1985
Morimoto and
Koizumi 1983
SC
P3
>
H
5G
M
m
o
H
oo
4>
Chromosomal
aberrations
Trifluorothymidine
resistance
Chinese hamster ovary cells
Mouse lymphoma cells
CHO-W-B1
L1578Y
( + )
Galloway
et al. 1985
NTP 1988
+ « positive result; - - negative result; (+) = marginally positive result. Results from two or more different contract
laboratories are separated by commas.
-------
TABLE 2-5. Genotoxicity of Chlorodlbromomethane In Vitro
End Point
Species (Test System)
Strain
Results
With
Activation
Without
Activation
Reference
Prokaryot ic organisms:
Gene mutation
Eukaryotic organisms:
Fungi:
Gene conversion
Gene reversion
Mammalian cells:
S i s te r-chromatid
exchange
Chromosomal
aberrations
Salmonella typhimurium
(desiccator system)
S. typhimurium
(plate incorporation
assay)
S. typhimurium
(preincubation
assay)
Saccharomyces cerevlslae
S. cerevlsiae
Human lymphocytes
Human lymphocytes
Rat liver cells
Chinese hamster ovary cell
Chinese hamster ovary cell
TA100
TA98
TA100
TA1535
TA1537
TA98
TA100
TA1535
TA1537
D7
XV185-14C
CCRF-CEM
rla
No data
No data
No data
No data
(+)
+
Simmon et al. 1977
Varma et al. 1988
Zeiger et al. 1987
Nestman and Lee 1985
Nestman and Lee 1985
Morimoto and
Koizumi 1983
Sobti 1984
Sobti 1984
NTP 1988
NTP 1988
OS
n
>
r
H
a
Dd
~n
n
o
H
CO
-p-
Ui
+ * positive result; - * negative result; (+) = marginally positive result.
-------
TABLE 2-6. Genotoxicity of Chlorodib:
ithane and Bronofonn In Vivo
Chemical
End Point
Species (Test System)
Exposure
Route Results
Reference
Chiorodibromomethane Mammalian systems:
Sister chromatid exchange Mouse (bone marrow cell)
Broosof orm
Chromosomal aberrat ions
Mouse (bone marrow cell)
Mouse (bone marrow cell)
Nonmammaliam systems:
Sex-linked recessive lethal Drosophila melanogaster
Reciprocal translocation Drosophila melanogaster
Mammaliam systems:
Sister chromatid exchange Mouse (bone marrow cell)
Mouse (bone marrow cell)
Chromosomal aberrat ions
Micronucleus test
Mouse (bone marrow cell)
Mouse (bone marrow cell)
PO
IP
IP
Feeding
Injection
Feeding
IP
PO
IP
IP
Morimoto and Koizumi 1983
NTP 1988
NTP 1988
Woodruff et al. 1985
Woodruff et al. 1985
Woodruff et al. 1985
NTP 1988
Morimoto and Koizumi 1983
NTP 1988
NTP 1988
SC
PI
>
t-
H
X
W
M
O
H
W
PO * oral: IP = intraperitoneal; + - positive result; - - negative result.
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47
2. HEALTH EFFECTS
significance of these data are difficult to interpret with respect to
human health risk, except that positive genotoxicity findings are
consistent with a carcinogenic potential for these chemicals.
Cancer. Studies in animals indicate that both chlorodibromomethane
and bromoform have carcinogenic potential. Chlorodibromomethane was
found to increase the incidence of liver tumors (adenomas and/or
carcinomas) in mice (NTP 1985), and bromoform was found to increase the
frequency of intestinal tumors (adenomatous polyps and adenocarcinomas)
in rats (NTP 1988). These findings are of special concern since many
people are chronically exposed to low levels of these chemicals in
chlorinated drinking water, and some epidemiological studies suggest
that consumption of chlorinated drinking water may increase risk of
cancer of the stomach, rectum, colon, and bladder (Cantor et al. 1987;
Crump 1983; Kanarek and Young 1982; Marienfeld et al. 1986).
On the other hand, it should be noted that most of the carcinogenic
responses in rats and mice exposed to chlorodibromomethane and bromoform
were rather small, and that the weight of evidence for carcinogenicity
was considered to be clear in only one case (intestinal tumors in female
rats given bromoform). Also, the weight of epidemiological evidence for
an association between ingestion of chlorinated water and increased
cancer risk is not definitive (Cantor 1983; Crump 1983), and such an
association (even if it were definitive) cannot provide direct evidence
that either chlorodibromomethane or bromoform is carcinogenic in humans,
since chlorinated water contains hundreds of other chemicals besides
chlorodibromomethane and bromoform. Consequently, while exposure to low
levels of chlorodibromomethane or bromoform in drinking water or from
any other source is cause for concern, the relative contribution of
these chemicals to human cancer risk remains to be resolved.
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 or cell 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 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
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48
2. HEALTH EFFECTS
metabolite of another xenobiotic (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
chlorodibromomethane and bromoform 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 chlorodibromomethane and bromoform 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. It can be an intrinsic genetic or
other characteristic or a preexisting disease that results in an
increase in absorbed dose, biologically effective dose, or target tissue
response. If biomarkers of susceptibility exist, they are discussed in
Section 2.7, "POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE."
2.5.1 Biomarkers Used to Identify or Quantify Exposure to
Chlorodibromomethane and Bromoform
The most straightforward means of identifying exposure to
chlorodibromomethane or bromoform in a person is measurement of parent
compound in blood or expired air. Sensitive and specific gas
chromatographic-mass spectrophotometry methods available for this
purpose are described in Section 6.1. Quantification of exposure is
complicated by the relatively rapid clearance rate of these compounds
from the body, both by exhalation and metabolic breakdown. Data are not
available on clearance rates in humans, but in animals clearance of
parent is nearly complete within 8 hours (see Section 2.3.A).
Consequently, this approach is best suited for detecting recent
exposures (within 1 to 2 days).
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49
2. HEALTH EFFECTS
No data are available on blood or breath levels of
chlorodibromomethane or bromoform in acutely exposed individuals.
Background concentrations in people not exposed to chlorodibromomethane
or bromoform except through chlorinated drinking water (see
Section 5.4.2) are about 0.6 ppb (Antoine et al. 1986), while levels in
expired breath are undetectable (Wallace et al. 1986a, 1986b). Although
chlorodibromomethane and bromoform are lipophilic, they do not appear to
accumulate in adipose tissue (Stanley 1986), so measurement of parent
levels in this tissue is not likely to be valuable as a bioraarker of
exposure.
The principal metabolites of chlorodibromomethane and bromoform are
C02l CO, CI" and Br". None of these metabolites are sufficiently
specific to be useful as a biomarker of exposure. It is suspected that
reactive intermediates formed during metabolism may produce covalent
adducts with proteins or other cellular macromolecules (see
Section 2.3.3), but these putative adducts have not been identified nor
has any means for their quantification been developed.
2.5.2 Biomarkers Used to Characterize Effects Caused by
Chlorodibromomethane and Bromoform
The most sensitive clinical sign of exposure to bromoform in humans
appears to be sedation, and it is likely the same is true for
chlorodibromomethane. However, generalized central nervous system
depression is too nonspecific to be useful as a biomarker of effects
from low-level exposure to chlorodibromomethane or bromoform. Studies
in animals indicate the liver and the kidneys are also affected,
resulting in fatty liver, increased serum enzyme levels, and nephrosis.
Effects on liver and kidney can be evaluated using a variety of
laboratory and clinical tests (CDC/ATSDR 1990), but these are also too
nonspecific to be valuable in recognizing early effects caused by low-
level exposure to these two chemicals.
2.6 INTERACTIONS WITH OTHER CHEMICALS
It is well-known that exposure to alcohols, ketones, and a variety
of other substances can dramatically increase the acute toxicity of
halomethanes such as carbon tetrachloride (ATSDR 1989b) and chloroform
(ATSDR 1989a). Several studies have been performed to determine if the
toxic effects of chlorodibromomethane and bromoform are similarly
affected by these agents.
Hewitt et al. (1983) found that pretreatment of rats with a single
oral dose of acetone resulted in a 10- to 40-fold potentiation of the
hepatotoxic effects of a single oral dose of chlorodibromomethane given
18 hours later. Similarly, pretreatment of rats for one to three days
with chlordecone resulted in a 7- to 60-fold potentiation of the
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50
2. HEALTH EFFECTS
hepatotoxic effects of a single oral dose of chlorodibromomethane (Plaa
and Hewitt 1982a, 1982b). In contrast, cblordecone pretreatraent had
relatively little potentiating effect on the hepatotoxicity of bromoform
(Agarwal and Mehendale 1983; Plaa and Hewitt 1982a).
The mechanism by which chemicals such as acetone and chlordecone
potentiate halomethane toxicity is not known, but it is generally
considered that at least some of the effect is due to stimulation of
metabolic pathways that yield toxic intermediates. If so, the findings
above support the hypothesis that the toxicity of chlorodibromomethane
is mediated at least in part by metabolic generation of reactive
intermediates, but that metabolism is relatively less important in
bromoform toxicity.
Harris et al. (1982) found that exposure of rats to a combination
of bromoform and carbon tetrachloride resulted in more liver injury
(judged by release of hepatic enzymes into serum) than would be
predicted by the effects of each chemical acting alone. The mechanism
of this interaction is not certain, but may be related to dihalocarbonyl
formation and lipid peroxidation (Harris et al. 1982).
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
Studies of chlorodibromomethane and bromoform toxicity in animals
reveal that there may be some quantitative and qualitative differences
in susceptibility between sexes and between species (see Section 2.2),
The basis for these differences is not known, but one likely factor is
sex and species-dependent differences in metabolism (see Section 2.3.3).
On this basis, it is reasonable to assume that there could be some
differences in susceptibility between humans as a function of sex, race,
or age. However, there are no studies that provide data on this point.
Studies in animals (discussed in Section 2.6) also suggest that humans
exposed to alcohols, ketones, or other drugs (e.g., barbiturates,
anticoagulants) that influence halomethane metabolism might be more
susceptible to the toxic effect of chlorodibromomethane and perhaps
bromoform as well. Persons with existing renal or hepatic disease might
also be more susceptible, since these organs are adversely affected by
exposure to chlorodibromomethane and bromoform.
2.8 ADEQUACY OF THE DATABASE
Section 104(1)(5) of CERCLA, 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 chlorodibromomethane and bromoform is available.
Where adequate information is not available, ATSDR, in conjunction with
the National Toxicology Program (NTP), is required to assure the
initiation of a program of research designed to determine the health
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51
2. HEALTH EFFECTS
effects (and techniques for developing methods to determine such health
effects) of chlorodibromomethane and bromoform.
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.
2.8.1 Existing Information on the Health Effects of
Chlorodibromomethane and Bromoform
The existing data on health effects of inhalation, oral, and dermal
exposure of humans and animals to chlorodibromomethane and bromoform are
summarized in Figures 2-5 and 2-6, respectively. The purpose of these
figures is to illustrate the existing information concerning the health
effects of chlorodibromomethane and bromoform. 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.
As shown in Figure 2-5, the toxicity of chlorodibromomethane has
been reasonably well studied in animals exposed by the oral route, but
there are no data in animals on inhalation or dermal toxicity, and there
are no data in humans by any route. As shown in Figure 2-6, the oral
toxicity of bromoform in animals has also been well studied. In
addition, because of its use as an oral sedative in the early part of
this century, there are some human data on the depressant effect of
bromoform on the nervous system and on lethal doses, and there are also
a few inhalation studies in animals. The dermal toxicity of bromoform
has not been studied.
2.8.2 Identification of Data Needs
Acute-Duration Exposure. Limited data from humans indicate that
one of the primary acute effects of ingestion of bromoform is sedation.
This is supported by studies in animals, where both chlorodibromomethane
and bromoform produced central nervous system depression following oral
or inhalation exposure. Studies in animals indicate that hepatic and
renal injury may also occur following acute oral or inhalation exposure,
and these effects occur at lower doses than measurable central nervous
system depression. Inhalation data are too sparse to define the
threshold for these effects, but oral data are more extensive and do
permit derivation of an acute MRL. Comparable data on hepatic or renal
-------
52
2. HEALTH EFFECTS
SYSTEMIC 7 7 7~Z1 7 7"
/ / /# /., ///# / /
/ Q> f J? / ^ / ^ / & / ^ / &
/£ /$/i /i/<$/# /#/ <$
Inhalation
Oral
Dermal
HUMAN
SYSTEMIC
Inhalation
Oral
Dermal
ANIMAL
Existing Studies
FIGURE 2-5. Existing Information on Health Effects of
Chlorodibromomethane
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53
2. HEALTH EFFECTS
SYSTEMIC
Inhalation
Oral
Dermal
HUMAN
SYSTEMIC
Inhalation
Oral
Dermal
ANIMAL
Existing Studies
FIGURE 2-6. Existing Information on Health Effects of Bromoform
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54
2. HEALTH EFFECTS
injury in humans are not available, but there is no evidence to suggest
the same effects would not occur in humans. Additional studies on the
short-term toxicity of chlorodibromomethane and bromoform would be
valuable to further clarify the relative sensitivity of the nervous
system, the liver, and the kidneys, and to define inhalation as well as
oral dose-response curves more precisely. These data would be helpful
since humans may be exposed to chlorodibromomethane and bromoform in air
or water for brief periods following spills or releases at hazardous
waste sites.
No data are available in humans or animals following dermal
exposure to chlorodibromomethane or bromoform. Contact with
concentrated solutions of these chemicals might be expected to produce
effects similar to those following Ingestion or inhalation, and might
also result in skin or eye irritation. Studies on this would be useful,
although contact with concentrated chlorodibromomethane or bromoform is
considered extremely unlikely for members of the general population or
residents near waste sites. Studies on the effects of dermal contact
with lower levels of the compounds in water or soil would be valuable,
since people might be exposed by these routes near waste sites.
Intermediate-Duration Exposure. The effects of intermediate -
duration oral exposure of animals to chlorodibromomethane and bromoform
have been investigated in a number of studies, and the dose - response
relation for the principal adverse effects (hepatic and renal toxicity)
is fairly well defined. The data suggest the threshold for
intermediate-duration renal and hepatic effects is similar to that for
chronic exposure (see below), so an intermediate oral MRL has not been
derived. Limited data indicate that intermediate-duration inhalation
exposure to bromoform also leads to renal and hepatic injury in animals,
but the data are too sparse to derive a reliable inhalation MRL. No
intermediate-duration inhalation exposure data are available for
chlorodibromomethane. Further studies on the intermediate-duration
inhalation toxicity of these compounds would be valuable in assessing
human health risks from airborne exposures near waste sites, although
available data suggest exposures in air near such sites are likely to be
low. As noted above, there are no data on dermal exposure, and studies
on intermediate-duration dermal exposure to the compounds in water or
soil would be useful in evaluating human health risk at waste sites.
Chronic-Duration Exposure and Cancer. The chronic oral toxicity of
chlorodibromomethane and bromoform has been investigated in several
studies, and the data are sufficient to identify hepatotoxicity as the
most sensitive end point and to derive MRL values for both chemicals.
However, in both cases, chronic oral MRLs are based on LOAELs for
hepatotoxicity so further studies to define the NOAELs would be helpful
in reducing uncertainty in the MRL calculations. Chronic inhalation
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55
2. HEALTH EFFECTS
data are not available for either chemical, and would be useful,
especially for chlorodibromomethane, since it is significantly more
volatile (vapor pressure =76 ramHg) than bromoform (vapor pressure -
5 mmHg). In the absence of such data, extrapolation of observations
from the oral route might be possible using appropriate toxicokinetic
models. As noted above, no data exist for dermal exposure, and further
studies (focusing on exposure in water or soil) would be valuable.
The carcinogenic effects of chronic oral exposure to
chlorodibromomethane and bromoform have been investigated in well-
designed studies in both rats and mice, and the data suggest that both
chemicals have carcinogenic potential. However, effects were limited or
equivocal in some cases, so additional studies to strengthen the weight
of evidence would be valuable. Of particular interest would be studies
of the carcinogenic effects when exposure is via drinking water rather
than by gavage, since drinking water is the most likely route of human
exposure, and exposure by gavage (especially using oil as a medium) may
not be a good model for this. Also of value would be studies on the
mechanism of carcinogenicity, and the identity of carcinogenic
metabolites. For example, studies on methylene chloride and other
volatile halocarbons indicate that metabolism via a glutathione pathway
may be important in carcinogenicity (e.g., Anderson et al. 1987; Reitz
et al. 1989). Studies to determine if chlorodibromomethane or bromoform
are metabolized by a similar pathway would be helpful in evaluating
carcinogenic mechanism and risk.
Genotoxicity. There have been a number of studies that indicate
chlorodibromomethane and bromoform are genotoxic, both in prokaryotic
and eukaryotic organisms. However, a number of other studies have
failed to detect significant genotoxic potential for these compounds.
The basis for this inconsistency is not entirely obvious, but might be
related to the efficacy of the test system to activate the parent
compound to genotoxic metabolites. Further studies to define conditions
under which these compounds are and are not genotoxic in vitro and
in vivo may help clarify both the mechanism of genotoxicity and the
relevance of this to human health risk. Studies on the genotoxic
effects of chlorodibromomethane and bromoform on germ cells (sperm or
ova) would also be valuable.
Reproductive Toxicity. No data are available on reproductive
effects of chlorodibromomethane or bromoform in humans. However,
chronic oral studies in rats and mice indicate that reproductive organs
are not targets for either chlorodibromomethane (NTP 1985) or bromoform
(NTP 1988). This is supported by direct studies showing no significant
reproductive effects in mice following oral exposure to bromoform for 2
generations (NTP 1989). However, high doses that produce frank maternal
toxicity may impair reproductive success (Borzelleca and Carchman 1982).
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2. HEALTH EFFECTS
No data are available on reproductive effects following inhalation
exposure. Based on the oral studies, it does not seem likely that
effects would occur except at very high levels, but inhalation exposure
studies to confirm this important point would be valuable.
Developmental Toxicity. Several studies in animals exposed by the
oral route indicate that neither chlorodibromomethane nor bromoform have
marked teratogenic potential (Borzelleca and Carchman 1982; Ruddick
et al. 1983). However, ingestion of bromoform did appear to increase
the frequency of several skeletal abnormalities in fetuses. Additional
oral studies on the developmental effects of both bromoform and
chlorodibromomethane in animals would be valuable to determine whether
these skeletal abnormalities are produced consistently, and whether they
lead to significant adverse effects in the neonate. If so, then similar
studies by the inhalation route would also be valuable to define safe
inhalation levels for developmental effects.
Immunotoxicity. The immunotoxic effects of chlorodibromomethane
and bromoform have been investigated in one 14-day oral study (Munson
et al. 1982). That study indicated both chemicals can lead to changes
in several immune cell-types in mice. Similar studies in other species
would be valuable in determining if this is a common response. In
addition, longer duration studies and tests of the functional
consequence of these changes (e.g., resistance to infectious disease)
would be especially valuable in assessing the biological significance of
these effects. If these studies indicate the immune system is a target,
then similar studies by inhalation exposure would also be valuable.
Neurotoxicity. Numerous studies, both in humans and animals,
reveal that central nervous system depression is a rapid effect
following either oral or inhalation exposure to bromoform, and more
limited data indicate that chlorodibromomethane also causes this effect
While central nervous system depression appears to be reversible within
a short time after exposure ceases, the possibility of permanent
neurological damage from high doses has not been thoroughly studied.
Histological studies by NTP (1985, 1988) indicate that sub-depressant
doses of chlorodibromomethane and bromoform do not lead to detectable
histological changes in the brain, but similar data are not available
following narcotizing doses. In addition to histological studies,
functional studies capable of detecting lasting neurological changes
would be valuable. One study of this sort (Balster and Borzelleca 1982)
indicates that both chlorodibromomethane and bromoform can cause some
behavioral changes at high doses. Further studies along these lines,
perhaps employing more sensitive tests of electrophysiological or
neurobehavioral changes, would be helpful in determining if this is an
effect of concern to exposed humans.
-------
57
2. HEALTH EFFECTS
Epidemiological and Human Dosimetry Studies. No epidemiological or
human dosimetry studies are currently available for chlorodibromomethane
or bromoform. Since only very small quantities of these chemicals are
produced or used in this country (see Chapter A), it does not seem
likely that a sufficiently large subpopulation of exposed workers exists
to serve as the basis for a meaningful epidemiological study.
Epidemiological studies of populations exposed to low levels of
chlorodibromomethane and bromoform in chlorinated drinking water cannot
provide specific data on the human health risks of chlorodibromomethane
or bromoform, since chlorinated drinking water contains hundreds of
different contaminants.
Biomarkers of Exposure and Effect. The only known biomarker of
exposure to chlorodibromomethane or bromoform is the level of parent
compound in blood or in expired air. However, data on blood or breath
levels in humans following acute exposure are lacking, due to the rarity
of such events. Since both chlorodibromomethane and bromoform are
rapidly cleared from the body by exhalation or metabolism, measurements
of parent compounds in blood or breath are likely to be useful only for
a short-time (1-2 days) after an exposure. Monitoring of humans
continuously exposed to the trace levels normally present in chlorinated
water reveal very low to nondetectable levels in blood or expired air.
The main metabolites of these compounds (C02, CO, CI", Br") are not
sufficiently specific to be useful for biomonitoring of exposure.
Identification of stable and specific biomarkers of exposure (e.g.,
halomethyl adducts) would be valuable in evaluating the exposure history
of people around waste sites and other sources where above-average
levels might be encountered.
No specific biomarkers of chlorodibromomethane or bromoform-induced
effect are known. Neurological, hepatic and renal effects caused by
these chemicals can be detected by standard clinical or biochemical
tests, but abnormal function in these tissues can be produced by a
number of common diseases in humans, so detection of abnormal function
is not proof that the effect was caused by chlorodibromomethane or
bromoform. Efforts to identify more specific and sensitive biomarkers
of chlorodibromomethane and bromoform-induced effects would be useful,
especially biomarkers (e.g., specific DNA adducts) that might be
predictive of carcinogenic risk.
Absorption, Distribution, Metabolism, Excretion. Limited data
indicate that chlorodibromomethane and bromoform are rapidly and
efficiently taken up from the gastrointestinal tract, but further
studies to confirm and refine available estimates would be valuable.
Toxicokinetic studies to date have generally employed exposure by gavage
in corn oil, so studies involving exposure via an aqueous vehicle would
be especially valuable. No toxicokinetic data exist for inhalation
-------
58
2. HEALTH EFFECTS
exposure, so quantitative estimates of the inhalation absorption
fraction, tissue distribution, and excretion rate would be beneficial.
Also, data on dermal absorption would be helpful, especially from soil
or from dilute aqueous solutions, since this is how humans are most
likely to experience dermal contact near waste sites.
The pathways of chlorodibromomethane and bromoform metabolism have
been investigated in several laboratories, but quantitative data on the
amount of chemical passing through each pathway are limited, and the
chemical identity of products appearing in urine has not been studied.
Of particular interest would be studies which seek to clarify the role
of metabolism in toxicity, the mechanism by which metabolites and
adducts lead, to toxic effects, and the importance of protective
mechanisms such as cellular antioxidants. This would include careful
dose-response studies to determine if either activating or protective
pathways are saturable.
Comparative Toxicokinetics. Available toxicity data indicate that
target tissues of chlorodibromomethane and bromoform are similar in
humans, rats arid mice. Limited data suggest that effect levels are
generally similar across species, but some distinctions are apparent.
Toxicokinetic studies have revealed differences between rats and mice
regarding metabolic patterns and clearance rates and these might
underlie the differences in toxicity between tissues, sexes, and
species. Additional comparative studies in animals, with special
emphasis on differences in metabolism, would be useful in understanding
these differences, and in improving inter-species extrapolation. In
addition, in vitro studies of metabolism by human liver cells would be
valuable in determining which animal species has the most similar
pattern of metabolism and is the most appropriate model for human
toxicity. Data from studies of this sort could then be used to support
physiologically-based toxicokinetic models.
2.8.3 On-going Studies
Table 2-7 summarizes two on-going research projects on the health
effects of chlorodibromomethane or bromoform. When completed, these
studies may be expected to provide valuable new data on several topics ,
including reproductive, developmental, and carcinogenic effects of
chlorodibromomethane and bromoform. In addition, the U.S. Department of
Human Health Services is sponsoring an on-going study (the National
Health and Nutrition Examination Survey) which will provide data on
levels of bromoform and chlorodibromomethane in blood of humans at
numerous locations across the United States.
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59
2. HEALTH EFFECTS
TABLE 2-7. Summary of On-going Research on
the Health Effects of Chlorodibromomethane or Bromoform
Principal Spons.
Investigator Affiliation Research Description Agency
H. Lilja Mason Research
Inst., Worcester,
Massachusetts
Subchronic and chronic NIEHS
toxicity and
carcinogenicity of
chlorodibromomethane
in mice and rats,
using various
routes of exposure
Division of
Toxicology
National Inst,
of Hygienic
Sciences
Tokyo, Japan
Carcinogenicity
study on
chlorodibromomethane
and bromoform
Government
of Japan
NIEHS = National Institute of Environmental Health Sciences.
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61
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Table 3-1 lists common synonyms, trade names, and other pertinent
identification information for bromoform and chlorodibromomethane.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Table 3-2 lists important physical and chemical properties of
bromoform and chlorodibromomethane.
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62
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-1. Chemical Identity of Bromoform and Chlorodlbromomethane
Chemical name
Synonyms
Trade name
Chemical formula
Chemical structure
Value Value
Bromoform Chlorodlbromomethane Reference
Bromoform
Tribromomethane;
methenyltri-
bromide;
methane,
tribromo-
No data
CHBr3
Br
I
Br™ C — Br
I
H
Chlorodlbromomethane NIM 1988
Dibromochloromethane; NLM 1988
methane, dibromochloro-
No data
CHBr2Cl
Br
i
CI —C — Br
H
NLM 1988
Identification numbers:
CAS Registry
NIOSH RTECS
EPA Hazardous Waste
OHM/TADS
DOT/UN/NA/IMCO
Shipping
HSDB
NCI
75-25-2
PB5600000
U225
8100034
UN 2515
IMCO 6.1
2517
C55130
124-48-1
PA6360000
No data
No data
No Data
2763
C55254
NLM 1988
HSDB 1988
NLM 1988
HSDB 1988
NLM 1988
HSDB 1988
NLM 1988
NLM 1988
CAS - Chemical Abstracts Service; NIOSH - National Institute for
Occupational Safety and Health; RTECS - Registry of Toxic Effects of
Chemical Substances; EPA - Environmental Protection Agency; OHM/TADS - oil
and Hazardous Materials/Technical Assistance Data System; DOT/UN/NA/IMCO
Department of Transportation/United Nations/North America/International "
Maritime Dangerous Goods Code; HSDB - Hazardous Substances Data Bank' NfT
National Cancer Institute. ' "
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63
3. CHEMICAL AND PHYSICAL INFORMATION
TABLE 3-2. Physical and Chemical Properties of Bromoform and
fThl nrtwl 1 Krflmnnwthan*
Value
Bromoform
Value
Chi o rod ibromome thane
Reference
Molecular weight
Color
Physical state
Melting point
Boiling point
Density at 20°C
Odor
Odor threshold:
Water
Air
Solubility:
Water at 20°C
Organic solvents
Partition coefficients:
Log octanol/water
Log K0c
Vapor Pressure at 20°C
Henry's law constant
Autoignition temperature
Flashpoint
Flammability limits
Conversion factors
252.75
Colorless
Liquid
8. 3 °C
149.5°C
2.8899
Sweet, similar
to chloroform
0.51 mg/L
13 .45 mg/nv*
3.01x10 mg/L
Soluble in
alcoholt ether,
benzene, chloro-
form, ligroin
2. 38a
2, 06a
5 mmHg
5.6x10"^ atm-m^/mol
No data
No data
Non-flammable
1 ppm = 10 mg/m^
1 mg/m^ * 0.097 ppm
208.29
Colorless to
pale yellow
Liquid
<-20°C
119-120°C
2.451
No data
No data
No data
4.OOxlO3 mg/La
Soluble in
alcohol, ether,
benzene, chloro-
form
2.24a
1.92a
76 mmHg
9.9xl0~^ atm-m"*/mol
No data
No data
Non-flammable
1 ppm « 8.5 mg/m^
1 mg/m3 * 0.12 ppm
Ueast 1985
Verschueren 1983
Verschueren 1983
Weast 1985
Verschueren 1983
Weast 1985
Weast 1985
Verschueren 1983
Amoore and
Hautala 1983
Amoore and
Hautala 1983
Mabey et al. 1982
Weast 1985
Mabey et al. 1982
Mabey et al. 1982
Mabey et al. 1982
Mabey et al. 1982
Sax and Lewis 1987
Verschueren 1983
^Calculated value.
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65
4. PRODUCTION, IMPORT, USE AND DISPOSAL
4.1 PRODUCTION
Bromoform may be prepared from acetone and sodium hypobromite, by
treating chloroform with aluminum bromide, or by electrolysis of
potassium bromide in ethyl alcohol (HSDB 1988; Stenger 1978).
Available information indicates that bromoform is not currently
produced commercially in the United States (SRI 1985, 1986, 1987, 1988).
Past bromoform producers included Dow Chemical Company, Midland,
Michigan, and Geoliquids, Inc., National Biochemical Company, Chicago,
Illinois. In 1975, production of bromoform in the United States was
estimated to be less than 500 kkga and the 1977 production was
estimated at 50 to 500 kkg (NTP 1988; Orrell and Mackie 1988; Perwak
et al. 1980).
Chlorodibromomethane is produced only in small quantities for sale
to laboratories by Columbia Organic Chemical Company, Cowden, South
Carolina, and Aldrich Chemical Company, Milwaukee, Wisconsin (HSDB 1988;
Perwak et al. 1980).
Both bromoform and chlorodibromomethane are inadvertently generated
during water chlorination when chlorine reacts with endogenous organic
materials such as humic and fulvgic acid (Rook 1977). It is estimated
that 17 kkg of bromoform and 204 kkg of chlorodibromomethane were
generated in this way in 1978 (Perwak et al. 1980).
4.2 IMPORT
Orrell and Mackie (1988) estimate that 6 to 9 kkg of bromoform are
currently imported by Freeman Industries. No information was located on
the import of chlorodibromomethane, but it is considered likely that
little, if any, is imported.
4.3 USE
Currently, bromoform has only limited uses, including: (1) as a
fluid for mineral ore separation in geological tests, (2) as a
laboratory reagent, and (3) in the electronics industry in quality
assurance programs (Orrell and Mackie 1988). Formerly, bromoform was
used as a solvent for waxes, greases, and oils (HSDB 1988; NTP 1988),
and as an ingredient in fire-resistant chemicals and gauge fluids, as an
intermediate in chemical syntheses, and as a sedative and antitussive
agent (HSDB 1988; Perwak et al. 1980).
1 kkg - 1,000 kg (1 metric ton)
-------
66
4. PRODUCTION, IMPORT, USE AND DISPOSAL
Chlorodibromomethane is used in laboratory quantities only and
there is no current commercial use for this compound (Perwak et al.
1980). Chlorodibromomethane was formerly used as a chemical
intermediate in the production of fire extinguishing agents, aerosol
propellants, refrigerants, and pesticides (HSDB 1988).
4.4 DISPOSAL
Because bromoform and chlorodibromomethane are listed as hazardous
substances, land disposal of wastes containing these compounds is
controlled by a number of federal regulations (see Chapter 7). Wastes
containing chlorodibromomethane or bromoform may be incinerated by
rotary kiln, liquid injection, or fluidized bed methods.
The amount of bromoform and chlorodibromomethane released or
disposed of through industrial and/or laboratory use of these chemicals
is not known, but is considered to be insignificant compared to the
amount inadvertently generated by water chlorination processes (EPA
1987c; HSDB 1988; Perwak et al. 1980).
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67
5. POTENTIAL FOR HUMAN EXPOSURE
5.1 OVERVIEW
The principal route of human exposure to chlorodibromomethane and
bromoform is from the consumption of chlorinated drinking water. These
chemicals are thought to form in the water as by-products from the
reaction of chlorine with dissolved organic matter and bromide ions.
Chlorodibromomethane and bromoform concentrations in water are quite
variable, but average levels are usually less than 5 /ig/L.
Most chlorodibromomethane and bromoform tend to volatilize from
water when exposed to the air. The fate of these chemicals in air has
not been investigated, but it is likely they are relatively stable, with
half-lives of about one to two months, Most measurements of the
concentration of these chemicals in air indicate that levels are quite
low (less than 10 ppt).
Neither chemical is strongly adsorbed from water by soil materials,
and it is likely that both readily migrate in groundwater. Neither
chemical appears to be easily biodegradable under aerobic conditions,
but they may readily biodegrade under anaerobic conditions, At this
time, chlorodibromomethane has been found at 14 of the 1,177 NPL
hazardous waste sites in the United States (VIEW Database 1989). The
frequency of these sites within the United States can be seen in
Figure 5-1. Bromoform has also been found at 14 sites, 13 within the
United States (Figure 5-2) and one in the Commonwealth of Puerto Rico.
5.2 RELEASES TO THE ENVIRONMENT
5.2.1 Air
No studies were located regarding the amount of bromoform and
chlorodibromomethane released into the atmosphere from laboratories,
chemical plants, or chemical waste sites. However, since neither
compound is produced or used in large quantities (Perwak et al. 1980),
atmospheric emissions from these sources are probably small.
5.2.2 Water
The principal source of bromoform and chlorodibromomethane in the
environment is chlorination of water containing organic materials
(Bellar et al. 1974; EPA 1980a; Rook 1977; Symons et al. 1975). It has
been estimated that the total amounts of bromoform and
chlorodibromomethane generated by chlorinating United States drinking
water in 1978 was 17 and 204 kkg, respectively (Perwak et al. 1980).
-------
FREQUENCY II 11 I 11 1 SITE SUB 2 SITES 4 SITES
FIGURE 5-1. Frequency of Sites with Chlorodibromomethane Contamination
-------
FREQUENCY II I I I II 1 SITE 2SITES BBH 3SITES
FIGURE 5-2. Frequency of Sites with Bromoform Contamination
-------
70
5. POTENTIAL FOR HUMAN EXPOSURE
Chlorodibromomethane and broraoform may also occur as a consequence of
chlorinating industrial waste waters (Perry et al. 1979). Staples
et al. (1985) reported that broraoform was detected in 60 of 1 346
samples of industrial waste effluent, at a median concentration of
< 5 ng/~L, and chlorodibromomethane was detected in 84 of 1,298 samples
at a median concentration of < 2.4 ng/L. These values are not
significantly higher than those for typical chlorinated water (see
Section 5.4.2), suggesting that industrial discharge may not be a major
source of release.
Class et al. (1986) observed trace levels of chlorodibromomethane
and bromoform and other halogenated methanes in seawater (0.1 to 6 np/T ^
and in the air (0.1 to 20 ppt) at several locations in the Atlantic
The presence of these compounds can be attributed to biosynthesis and
release of bromochloromethanes by macroalgae (Class et al. 1986-
Gschwend et al. 1985). Gschwend et al. (1985) estimated that marine
algae could be a major global source of volatile organobromides but
Class et al. (1986) concluded that this source accounts for < 1% of the
anthropogenic burden of bromomethanes in the atmosphere.
5.2.3 Soil
Soils and other unconsolidated surficial materials may become
contaminated with bromoform and chlorodibromomethane by chemical spills
the landfilling of halomethane-containing solid wastes, or the dischar '
of chlorinated water. However, no data were located to suggest that
land releases are a significant source of the chemicals in the
environment.
5,3 ENVIRONMENTAL FATE
5,3.1 Transport and Partitioning
Bromoform and chlorodibromomethane are slightly volatile liquids
and tend to exist primarily as vapors in the atmosphere. The vapor '
pressure of bromoform is 0.007 atm at 25°C (Mackay et al. 1982), and th
vapor pressure of chlorodibromomethane at 20°C is approximately'0 1 atm6
(Mabey et al. 1982). The half-time of evaporation from flowing, aerat
water (e.g., rivers and streams) has been estimated to range from 1 to6
581 hours for bromoform and from 0.7 to 398 hours for
chlorodibromomethane (Kaczmar et al. 1984; Mackay et al. 1982)
Both chlorodibromomethane and bromoform are moderately soluble in
water (Callahan et al. 1979; Mabey et al. 1982), and so each may be
removed from the air by being dissolved into clouds or raindrops.
Estimates of the Henry's law constant (H) (the tendency of a chemical
partition between its vapor phase and water) for bromoform range from °
4.3 to 5.6 x 10"* atm-m3/mole, and from 8.7 to 9.9 x 10"4 atm-m3/mole fQ
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71
5. POTENTIAL FOR HUMAN EXPOSURE
chlorodibromomethane (Mabey et al. 1982; Mackay and Shiu 1981; Munz and
Roberts 1987; Nicholson et al. 1984). The magnitude of these values
suggest that the two halomethanes will tend to partition to both water
and air.
It is not known if either compound can be adsorbed by airborne
particulate matter that is subject to atmospheric dispersion,
gravitational settling, or wash-out by rain. Particle adsorption is
probably not an important transport mechanism because these chemicals
occur at such low concentrations in the atmosphere.
Bromoform and chlorodibromomethane have a minor tendency to be
adsorbed by soils and sediments. Calculated and measured values of Koc
(the organic carbon/water partition coefficient, an index of the
relative mobility of a material in water-soil systems) for bromoform
range from 62 to 126 (Hassett et al. 1983; Hutzler et al. 1986; Mabey
et al. 1982). These relatively low values imply that bromoform will
exhibit only a minor affinity for soil materials and will tend to be
highly mobile (Roy and Griffin 1985) . This low tendency for adsorption
to soil has been confirmed in laboratory studies by Curtis et al. (1986)
and in field studies by Roberts et al. (1986).
A similar Koc value of 83 has been estimated for chlorodibromo-
methane, although this value is uncertain because its solubility in
water has not been measured. No studies were located on the adsorption
of chlorodibromomethane by soils or soil materials, but it is likely
that chlorodibromomethane will have properties generally similar to
those of bromoform.
Bromoform and chlorodibromomethane may be slightly bioconcentrated
by aquatic organisms. The octanol/water partition coefficient (Kow) (an
index of the partitioning of a compound between octanol and water) is
approximately 240 for bromoform and 170 for chlorodibromomethane (Mabey
et al. 1982). The magnitudes of these values suggest that the chemicals
will tend to partition to fat tissues of aquatic organisms. No studies
were located regarding the bioconcentration factor for chlorodibromo-
methane or bromoform, but based on measured BCFs for similar compounds
(Kenaga 1980), the bioconcentration factor of chlorodibromomethane and
bromoform may be on the order of 2 to 10. It is not known if these
chemicals can be transferred through food chains to higher trophic
levels, but this seems unlikely to be of major concern.
5.3.2 Transformation and Degradation
5.3.2.1 Air
Based on the behavior of similar compounds, it seems likely that
bromoform and chlorodibromomethane may be degraded by photooxidative
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72
5. POTENTIAL FOR HUMAN EXPOSURE
interactions with atmospheric OH radicals. Radding et al. (1977)
proposed that the atmospheric half-life of bromoform and chlorodibromo-
methane is approximately one to two months, but this has not been
confirmed by direct experimental measurements.
5.3.2.2 Water
Both chlorodibromomethane and bromoform are relatively stable in
water, with estimated hydrolytic rate constants of 3.2 x 10"11 sec"1 and
8 x 10"11 sec"1 (Mabey and Mill 1978) . These rate constants correspond
to hydrolytic half-lives of 686 and 274 years for bromoform and
chlorodibromomethane, respectively.
No information was located on oxidation or photolysis of these
chemicals in water, but it is not expected that either is a significant
degradative pathway.
It has been found that chlorodibromomethane and bromoform undergo
only limited biodegradation (10 to 25%) under aerobic conditions,
although the rate may increase somewhat after microbial adaptation
(Bouwer et al. 1981; Tabak et al. 1981a). Under anaerobic conditions,
chlorodibromomethane and bromoform have been found to be readily
biodegraded in the presence of methane-producing bacteria (Bouwer et al
1981; Bouwer and McCarty 1983a), and under denitrifying and sulfate-
reducing conditions in batch and column experiments (Bouwer and
McCarty 1983b; Bouwer and Wright 1986). There is also some field
evidence that trihalomethanes degrade in anaerobic groundwater (Bouwer
et al. 1981), with half-lives estimated to be between 21 and 42 days
(Bouwer and McCarty 1984). Bouwer and Wright (1986) reported that one
degradation product of bromoform was dibromethane, but there was no
additional information on the identity or fate of environmental
degradation by-products.
5.3.2.3 Soil
No studies were located regarding the biodegradation of
chlorodibromomethane or bromoform in soil. It is expected that
observations regarding biodegradation rates in aerobic and anaerobic
aqueous media (above) will be generally applicable to degradation rat-
in moist soils. es
5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
5.4.1 Air
Chxoro^o—e ™
and bromoform level, In ambient air from tlve urban
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73
5. POTENTIAL FOR HUMAN EXPOSURE
locations across the United States. For chlorodibromomethane, 63 of 89
samples were below the detection limit, the mean value was 3.8 ppt
(32 ng/m3) , and the highest value was 27 ppt (230 ng/m3) . For
bromoform, 60 of 78 samples were below the detection limit, the mean
value was 3.6 ppt (37 ng/m3) and the highest value was 71 ppt
(730 ng/m3). The mean concentration of bromoform in ambient air samples
collected in the Arctic Circle was 5.1 ppt (53 ng/m3) (Berg et al.
1984). Forty-six air samples collected near four chemical plants in
Arkansas contained a mean bromoform concentration of 0.9 ppt (9 ng/m3)
(Pellizzari 1978). The mean chlorodibromomethane concentration was
0.08 ppt (0.8 ng/m3), but 54 of 56 measurements were less than 0.05 ppt
(0.5 ng/m3) .
No studies were located regarding atmospheric concentrations of
bromoform or chlorodibromomethane in the workplace. Chlorodibromo-
methane was detected in air samples at two hazardous waste sites, but
the amounts were not quantified (LaRegina et al. 1986).
5.4.2 Water
Chlorodibromomethane and bromoform are rarely measurable in non-
chlorinated water (Cech et al. 1981; Staples et al. 1985; Varma et al.
1984), but both are very frequently found in chlorinated water. The
levels of bromoform and chlorodibromomethane in finished (chlorinated)
drinking water have been investigated in several studies (see
Table 5-1). Except for a few cases, the concentrations of bromoform and
chlorodibromomethane in drinking water were less than 100 ^g/L, with
mean concentrations generally less than 10 ^g/L.
It is usually found that halomethanes occur at higher
concentrations in drinking water derived from surface sources than those
from groundwater supplies because the former tends to contain more
dissolved organic matter (Bellar et al. 1974; Cech et al. 1981; Glaze
and Rawley 1979; Page 1981). The total trihalomethane content of
finished water from a given facility can be extremely variable as a
function of time (Arguello et al. 1979; Smith et al. 1980), with lower
levels of halomethanes usually occurring during the winter.
Trihalomethanes may also form in chlorinated swimming pools (Beech
et al. 1980). For freshwater pools, chloroform and dichlorobromontethane
were usually the predominant THM species present, with chlorodibromo-
methane and bromoform averaging 3 to 15 and 1 to 2 Mg/L, respectively.
However, in saline pools (which have a higher bromide ion content than
freshwater pools), bromoform was the major THM present (average
concentration of 650 vg/L), with lower concentrations (5 to 27 ng/V) of
chlorodibromomethane, bromodichloromethane, and chloroform.
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74
5. POTENTIAL FOR HUMAN EXPOSURE
TABLE 5-1. Occurrence of Bromoform and Chlorodibromomethane
in Finished Drinking Water
Frequency of Concentration (jig/L)
Detection % Range Mean Location Reference
Bromoform
10
ND- 92
27
ND-3.0
34
NR
67
NR-4.4
NR
ND-258
100
4-17
26
NR-110
NR
1-10
8
ND-1.6
NR
NR
Chlorodibromomethane
86
<0.1-2
NR
3-32
37
ND-110
85
ND-15. C
65
ND-9.0
86
NR
99
NR- 33
NR
ND-128
100
11-31
42
NR- 63
NR
1-28
75
ND-40
NR
NR
NR
NR
=0.4 national
=0.5 13 cities
12 national
0.4 midwest
=7 Texas
9 Texas
NR national
NR Iowa
0.1 Michigan
0.8-8 California
0.9 Ohio
NR 5 cities
2.7 national
=0.4 13 cities
2.9 Iowa
14 national
5.6 midwest
=20 Texas
20 Texas
NR national
NR Iowa
4.1 Michigan
1-2 New Jersey
8-28 California
Symons et al. (1975)
Keith et al. (1976)
Brass et al. (1977)
ORVWSC (1979)
Glaze and Rawley (1979)
Smith et al. (1980)
Westrick et al. (1984)
Kelley et al. (1985)
Furlong and D'ltri (1986)
Wallace et al. (1986b)
Bellar et al. (1974)
Coleman et al. (1975)
Symons et al. (1975)
Keith et al. (1976)
Morris and Johnson (1976)
Brass et al. (1977)
ORVWSC (1979)
Glaze and Rawley (1979)
Smith et al. (1980)
Westrick et al. (1984)
Kelley (1985)
Furlong and D'ltri (1986)
Wallace et al. (1986a)
Wallace et al. (1986b)
Hg — microgram; L — liter; ND — Not detected; NR - Not reported.
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75
5. POTENTIAL FOR HUMAN EXPOSURE
Chlorodibromomethane and bromoform have also been detected in water
near hazardous waste sites, although this is not common. Data from the
Contract Laboratory Program (CLP) Statistical Data Base (CLPSD 1988)
indicated that bromoform was detected in surface water at two of 862
hazardous-waste sites; the median concentration was 7 Mg/L.
Chlorodibromomethane was detected in only one sample (45 #ig/L).
Bromoform was detected in groundwater samples collected at 4 sites; the
median concentration was 26 /^g/L.
5.4.3 Soil
Staples et al. (1985) reported that bromoform was not detected in
any of 353 sediment samples analyzed. No data were available for
chlorodibromomethane. Data from the Contract Laboratory Program
Statistic Data Base (CLPSD 1988) indicated chlorodibromomethane and
bromoform were detected in soils in only 2 of 862 hazardous waste sites;
the median concentrations were 17 /ig/kg (bromoform) and 15 ^g/kg
(chlorodibromomethane).
5.4.4 Other Media
No studies were located regarding the occurrence of bromoform and
chlorodibromomethane in food or other media.
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
Because of the variability of chlorodibromomethane and bromoform
concentrations in water and air, it is not possible to derive precise
estimates of typical human exposure levels. However, based on the
typical ranges of chlorodibromomethane and bromoform concentrations
measured in water and air, it is likely that most individuals will be
exposed to average doses of less than 1 ^g/kg/day (Table 5-2), of which
nearly all is due to water. Limited data suggest that exposure levels
around chemical factories or waste sites are not likely to be much
higher, but this can only be evaluated on a site-by-site basis.
Exposure to chlorodibromomethane and bromoform may be above-average
for persons who swim in chlorinated swimming pools. Beech (1980)
estimated that the total dose for a six-year old boy who swam for
3 hours in a pool containing 500 //g/L of trihalomethanes could be as
high as 2.8 mg (130 /ig/kg) . About 60% of this dose was attributed to
dermal absorption, with about 30% resulting from inhalation. In
freshwater pools, only a small fraction of this would be
chlorodibromomethane or bromoform, but in a saltwater pool, a large
fraction would be expected to be bromoform (Beech et al. 1980).
No studies were located regarding human exposure levels in the
workplace.
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76
5. POTENTIAL FOR HUMAN EXPOSURE
TABLE 5-2. Summary of Typical Human Exposure to
Chlorodibromomethane and Bromoform
Parameter
Exposure Medium
Water
Air
Typical concentration
in medium
Assumed intake of medium
by 70-kg adult
Assumed absorption
fraction
Estimated dose to 70-kg
adult
1-20 £Jg/L
2 L/d
1.0
0-0.1 fj. g/m3
20 m3/d
0.5
0.03-0.6 A
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77
5. POTENTIAL FOR HUMAN EXPOSURE
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
The environmental medium most likely to be contaminated with
bromoform and chlorodibromomethane is chlorinated water. Therefore, any
person who is in frequent contact with such water could have above-
average exposures. This includes individuals who drink large quantities
of water, such as workers in hot climates, or individuals with swimming
pools or saunas, where contact could occur by inhalation or by dermal
contact. Since bromoform and chlorodibromomethane levels in water
depend on the organic content of the source water before chlorination,
individuals whose water source is high in organics are likely to have
finished water with higher-than-average bromoform and
chlorodibromomethane levels.
Workers in chemical production facilities or laboratories where
bromoform and chlorodibromomethane is made or used would also have
potentially high exposures to the chemicals, most likely by inhalation
or dermal exposure. Persons living near hazardous-waste sites may have
potentially high exposures to bromoform and chlorodibromomethane, but
this can only be evaluated on a case-by-case basis.
5.7 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, 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 chlorodibromomethane and bromoform 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 chlorodibromomethane and
bromoform.
The following categories of possible data needs have been
identified by a joint team of scientists from ATSDR, NTP, and EPA. They
are defined as substance-specific informational needs that, if met would
reduce or eliminate the uncertainties of human health assessment. In
the future, the identified data needs will be evaluated and prioritized,
and a substance-specific research agenda will be proposed.
5,7.1 Identification of Data Needs
Physical and Chemical Properties. Most of the physical-chemical
properties of chlorodibromomethane and bromoform have been measured, but
the solubility of chlorodibromomethane in water has only been estimated.
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78
5. POTENTIAL FOR HUMAN EXPOSURE
Direct measurement of this value would be valuable in improving
estimates of the fate and transport of chlorodibromomethane in aqueous
media.
Production, Use, Release and Disposal. Available data indicate
that neither broraoform nor chlorodibromomethane is produced or used in
significant quantities in the United States. Nevertheless, a listing of
laboratories or industries that use small amounts in research or testing
would be valuable in identifying locations where the potential for
environmental releases or human exposure exists. Also, information on
the means of disposal of waste chemicals would be valuable in
identifying environmental media likely to be affected at such sites.
Federal regulations do restrict disposal of chlorodibromomethane and
bromoform to land or in industrial effluents.
According to the Emergency Planning and Community Right to Know Act
of 1986 (EPCRTKA), (§313), (Pub. L. 99-499, Title III, §313), industries
are required to submit release information to the EPA. The Toxic
Release Inventory (TRI), which contains release information for 1987
became available in May of 1989. This database will be updated yearly
and should provide a more reliable estimate of industrial production and
emission.
Environmental Fate. The fate of chlorodibromomethane and bromoform
in the environment has not been thoroughly studied, although the
physical-chemical properties indicate that both are likely to partition
to air and water. Volatilization rates have been calculated for flowing
rivers and streams, but direct measurements of half-times of
volatilization would be useful, both for surface waters and for
household water (showers, baths, cooking, etc.). Adsorption of these
compounds to soils and sediments has been studied and does not appear to
be a significant factor. Consequently, transport in surface or
groundwater are likely to be important. Studies to confirm these
expectations and provide more precise descriptions of the environmental
behavior of these compounds would be valuable in assessing human
exposure near specific sources of release.
Degradation of chlorodibromomethane and bromoform in air has not
been studied, but is expected to occur by reaction with hydroxyl
radicals. Studies to measure the atmospheric half-times of these
compounds would be valuable in estimating long-term trends in
atmospheric levels, but such studies are probably not essential in
estimating exposure near specific sources. Neither chemical undergoes
chemical degradation in water, but both are subject to microbial
breakdown in water (especially anaerobic groundwater) or moist soils
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79
5. POTENTIAL FOR HUMAN EXPOSURE
Further data on the rate of microbial degradation of
chlorodibromomethane and bronioform in water and soil would be valuable,
with special attention to how these rates depend on environmental
conditions (oxygen level, pH, etc.).
Bioavailability from Environmental Media. Both chlorodibromo-
methane and bromoform are known to be absorbed following oral and
inhalation exposure. No data are available regarding dermal absorption,
but it seems likely that uptake across the skin may occur. No data were
located regarding the relative bioavailability of chlorodibromomethane
and bromoform in water, soil or air. Because of their physical and
chemical properties, it is expected that the bioavailability of
chlorodibromomethane and bromoform are not significantly reduced by
environmental media, but studies to substantiate this presumption would
be helpful.
Food Chain Bioaccumulation. There are few data on bioconcentration
of chlorodibromomethane or bromoform by plants or aquatic organisms, and
no data were located on the bioaccumulation of bromoform and
chlorodibromomethane in the food chain. This lack of data may not be a
major limitation because the general levels of the chemicals in water
and soil appear to be quite low, and based on the Koc of these
chemicals, there appears to be a low likelihood of food chain buildup.
Exposure Levels in Environment Media. There are several studies on
the atmospheric concentrations of bromoform and chlorodibromomethane in
urban and rural environments, but many of the samples did not have
detectable levels. No data on levels in air near waste sites were
located. More research in this area using more sensitive analytical
methods would be helpful, although it is anticipated that typical
atmospheric levels will usually be low enough that air is not the
principal route of exposure. Data are available on chlorodibromomethane
and bromoform in a number of chlorinated drinking water systems, and
these compounds have been detected in surface water and groundwater near
a few hazardous waste sites. Further studies on the levels of these
compounds in water and soil around waste sites would be valuable in
evaluating the risk to human health posed by these contaminants.
Exposure Levels in Humans. There are no data on levels of
chlorodibromomethane or bromoform in blood, breath or other tissues from
humans residing near waste sites. Low levels of bromoform have been
detected in blood of humans, presumably as the result of exposure
through ingestion of chlorinated drinking water. Levels in expired
breath and in adipose tissue appear to be too low to measure reliably
for the general population. Direct measurement of typical human intake
from water and air (especially indoor air) would be helpful in obtaining
more accurate estimates of typical human dose levels. Similar data on
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80
5. POTENTIAL FOR HUMAN EXPOSURE
inhalation and dermal doses would be useful for bromoform and
chlorodibromomethane in and around swimming pools (especially indoor
pools) .
Exposure Registries. No exposure registries for bromoform and
chlorodibromomethane were located. These compounds are not currently
among the compounds for which subregistries have been established in the
National Exposure Registry. These compounds 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 these
compounds.
5.7.2 On-going Studies
No information was located on any on-going studies on the fate and
transport of bromoform and chlorodibromomethane, or on the potential for
human exposures to these chemicals.
As part of the Third National Health and Nutrition Evaluation
Survey (NHANES III), the Environmental Health Laboratory Sciences
Division of the Center for Environmental Health and Injury Control,
Centers for Disease Control, will be analyzing human blood samples for
chlorodibromomethane, bromoform, and other volatile organic compounds.
These data will give an Indication of the frequency of occurrence arid
background levels of these compounds in the general population.
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81
6. ANALYTICAL METHODS
The purpose of this chapter is to describe the analytical methods
that are available for detecting and/or measuring and monitoring
chlorodibromomethane and bromoform 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
chlorodibromomethane and bromoform. 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
chlorodibromomethane and bromoform 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 a trade
association such as the Association of Official Analytical Chemists
(AOAC) and the American Public Health Association (APHA). Additionally,
analytical methods are included that refine previously used methods to
obtain lower detection limits, and/or to improve accuracy and precision.
As is true for most volatile organic compounds, the preferred
analytical technique for chlorodibromomethane and bromoform is gas
chromatography (GC) (Fishbein 1985). A number of devices are suitable
for detection and quantification of chlorodibromomethane and bromoform
as they emerge from the GC, including flame ionization detection
(GC/FID), halogen-sensitive detection (GC/HSD) or electron-capture
detection (GC/ECD). In general, HSD or ECD are preferable because of
their high sensitivity for halogenated compounds. When absolute
confidence in compound identity is required, mass spectrometry (GC/MS)
is the method of choice.
The most variable aspect of analyses of this sort is the sample
preparation procedure used to separate chlorodibromomethane and
bromoform from the test medium in order to prepare a sample suitable for
GC analysis. As volatile organic compounds of relatively low water
solubility, both chlorodibromomethane and bromoform are easily lost from
biological and environmental samples, so appropriate care must be
exercised in handling and storing such samples for chemical analysis.
Brief summaries of the methods available for extraction and detection of
these compounds in biological and environmental samples are provided
below.
6.1 BIOLOGICAL MATERIALS
Separation of chlorodibromomethane and bromoform from biological
samples is most often achieved by headspace analysis, purge-and-trap
collection, solvent extraction, or direct collection on adsorbent
resins. Headspace analysis offers speed, simplicity, and good
reproducibility, but partitioning of the analyte between the headspace
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82
6. ANALYTICAL METHODS
and the sample matrix is dependent upon the nature of the matrix and
must be determined separately for each different kind of matrix (Walters
1986) .
Purge-and-trap collection is well suited to biological samples such
as blood or urine that are readily soluble in water (Peoples et al.
1979). This method consists of bubbling an inert gas through a small
volume of the sample and collecting the vapor in a trap packed with
sorbent. The analytes are then removed from the trap by heating it and
backflushing the analytes onto a gas chromatographic column. The two
materials most widely used for adsorption and thermal desorption of
volatile organic compounds collected by the purge and trap technique are
Carbotrap®, consisting of graphitized carbon black, and Tenax®, a porous
polymer of 2,6-diphenyl-p-phenylene oxide (Fabbri et al. 19B7).
For water-insoluble materials such as fat or other tissues, the
most common separation procedure is extraction with an organic solvent
such as diethyl ether (Zlatkis and Kim 1976). Homogenization of tissue
with the extractant and lysing of cells usually improves solvent
extraction efficiency.
Analytical methods for the determination of bromoform and
chlorodibromomethane in biological materials are summarized in
Tab 1e 6-1.
6.2 ENVIRONMENTAL SAMPLES
Chlorodibromomethane and bromoform may be isolated from
environmental samples using the same methods and principles as those
used for biological materials, followed by gas chromatographic analysis.
The most convenient procedure for most liquid and solid samples is the
purge-and-trap method. Halocarbons can also be removed from water by
adsorption on synthetic polymers contained in cartridges, followed by
thermal desorption of the analyte (Pankow et al. 1988). Among the
products used for this purpose are Tenax-GC® and Tenax-TA®. a similar
procedure is used for air, in which the air is passed through an
adsorbent canister, followed by thermal desorption.
Analytical methods for the determination of chlorodibromomethane
and bromoform in environmental samples are given in Table 6-2.
6.3 ADEQUACY OF THE DATA BASE
Section I04
-------
TABLE 6-1. Ana.l7t.ical Methods for Determining Bronoform and Ghlorodibromnenethane in Biological Materials
Sample
Detection Accuracy
Sample Matrix Sample Preparation Analytical Method Limit (X Recovery) Reference
Adipose tissue Extraction, bulk lipid removal,
Florisil fractionation
Adipose tissue Heated dynamic headspace
purge-and-trap
HRGC/MS
HRGC/MS
0.1 <^g/g NR
1 ng/g
(CDBM)
2 ng/g
(TBM)
Mack and Stanley 1985
Stanley 1986
Adipose tissue Purge from liquified fat at 115°C,
trap on Tenax/silica gel, thermal
desorption
GC/HSD
<2 v%IL
83-107(TBM) Peoples et al. 1979
90-118(CDBM)
Blood
Blood
Blood, tissue
Blood serum
Breath
Purge from blood onto Tenax,
thermal desorption onto column
maintained at -20°C
Extract vith n-pentane
Macerate tissue in water, warm
blood or tissue, pass inert gas
through, trap on Tenax,
thermal desorption
Purge from water-serum mixture
containing antifoam reagent at
115°C, trap on Tenax/silica gel,
thermal desorption
Trap on Tenax, dry over calcium
sulfate, thermal desorption
GC/MS
HRGC/ECD
GC/MS
GC/HSD
GC/MS
*0 .1 tig/mL NR
0.1 jjg/L
(CDBM)
3 ng/mL
(blood)
6 ng/g
(tissue)
<2 pg/L
NR
NR
Antoine et al. 1986
Kroneld 1985
Pelliszari et al.
1985b
79-100(TBM) Peoples et al. 1979
7B-100(CDBM)
1-5 vsim3 92*15 (TBM) Wallace et al. 1986b
93±13 (CDBM)
>
£
t-3
M OO
n oj
>
t-1
3:
m
H
X
o
©
00
HRGC - high resolution gas chromatography; MS - mass spectrometry; us " microgram; g c gram; NR « not reported; ng - nanogram;
CDBM » chlorodibromoaiethane; TBM = bromoform; GC « gas chromatography: HSD ¦ halide specific detector; L = liter; mL = milliliter;
ECD = electron capture detector; mg = milligram; m^ = cubic meters.
-------
TABLE 6-2- Arvalyr icval Methods for Dctemininc BroaofoiA uvd Chlorodlbrwnthane in EnvlramBntal Saaoples
Sample Matrix
Sample Preparation
Analytical Method
Sample
Detection
Limit*
Accuracy
(X Recovery)
Reference
Drinking Water
Air
Water
Hater
Water
Water
Water
Water
Contaminated
soil
Wastes, non-
vater mlscible
Solid waste
Solvent extraction with pentane,
direct injection of extract
Coconut shell charcoal sorption,
carbon disulfide desorption
Purge and trap
Purge and trap
Purge and trap
Purge and trap
Purge and trap
Solvent extraction (isooccane)
Purge and trap
Purge and trap
Purge and trap
HRGC/ECD
GC/FID
GC/MS
GC/HSD
GC/MS
GC/HSD
GC/MS
GC/ECD
GC/HSD
GC/HSD
GC/MS
<0.5 *ig/L
10 Mg per
sample (IBM)
10 ^g/L
0.20 pg/L (TBM)
0.09 mil (CDBM)
4.7 Mg/L (TBM)
3.1 ug.IL (CDBM)
0.5 /ig/L
<2 ug.IL (TBM)
2 us/L
2 ^g/kg (TBM)
0.9 Aig/kg (CDBM)
250 /kg (TBM)
113 wg/kg (CDBM)
5 ng/kg
NR
NR
NR
89*9(TBM)
98*7(CDBM)
105±16(TBM)
104*14(CDBM)
97(CDBM)
101(CDBM)
82 (TBM)
NR
96b(TBM)
94b(CDBM)
96b(TBM)
94b(CDBM)
118b(TBM)
101b(CDBM)
Fayad and Iqbal
1985
NIOSH 1984
EPA 1980b
EPA 1982a
EPA 1982b
APHA 1985a
APHA 1985b
ASTM 1988
EPA 1986a
EPA 1986a
EPA 1986b
>
£
H
M
o
>
r
s
w
H
a
o
c
w
00
aValue refers to both CDBM and TBM unless noted otherwise.
^Thts recovery is typical at concentrations of around 100 **g/L or higher. Recoveries may deviate at lover concentrations.
HRGC = high re$olution gas chromatography; ECD « electron capture detector; ^g * microgram,' L = liter; NR — not reported;
GC « gas chromatography? FID * flame ionization detector; TBM ¦ bromoform; MS = mass spectrometry; HSD « halide specific
detector; CDBM s chlorodibromomethane; kg = kilogram.
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85
6. ANALYTICAL METHODS
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 chlorodibromomethane and
bromoform.
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 Identification of Data Needs
Methods for Determining Biomarkers of Exposure and Effect.
Sensitive and specific methods exist for the determination of
chlorodibromomethane and bromoform in blood, expired air, and adipose
tissue. These methods are presumably sensitive enough to measure levels
in humans exposed to doses of the chemicals that produce sedation or
cause injury to liver and kidney. However, data on this are lacking due
to absence of cases. The methods are also suitable for measuring
background levels in the general population, although increased
sensitivity would be useful for analysis of expired air and adipose
tissue. The major limitation to these methods is that only recent
exposures can be detected, so work to identify and quantify a more
stable biomarker of exposure (e.g., a haloraethyl adduct) would be
valuable.
No chemical or biochemical biomarkers of effect are recognized,
aside from nonspecific indices of hepatic or renal dysfunction. Efforts
to identify a specific biomarker of effect (in particular, an effect
such as alkylation of DNA that may be related to cancer risk) would be
valuable in evaluating potential health risk to exposed humans.
Methods for Determining Parent Compounds and Degradation Products
in Environmental Media. Reliable and specific methods exist for
measuring parent chlorodibromomethane and bromoform in air, water, soil
and solid wastes. Humans could be exposed to these compounds by contact
with any of these media, although ingestion of or dermal contact with
contaminated water appears to be the most likely route near a chemical
waste site. Existing methods are readily able to detect concentration
values in environmental media that are likely to lead to significant
noncancer health effects, but might not be sensitive enough to measure
levels that pose low levels of cancer risks. However, since no
chemical-specific cancer potency values are available for these
components, this is not certain.
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86
6. ANALYTICAL METHODS
6.3.2 On-going Studies
As noted earlier, one difficulty is analyzing biological or
environmental samples for volatile halocarbons such as chlorodibromo-
methane and bromoform is the extraction and separation of the analytes
from the sample matrix. The development of supercritical fluid (SCF)
extraction holds great promise for analysis of nonpolar organic analytes
such as chlorodibromomethane and bromoform. Current research in this
area has been summarized by Hawthorne (1988).
The use of capillary column chromatography has markedly improved
both sensitivity and resolution of gas chromatographic analysis, but
because of the very small quantities of sample required, has also made
sample delivery more difficult. One of the more promising approaches to
sample introduction using capillary columns with purge-and-trap
collection is the use of cryofocusing. Basically, this procedure
consists of collecting purged analyte on a short section of the
capillary column cooled to a low temperature (e.g., -100°C), followed by
heating and backflushing of the sample onto the analytical column.
Bromoform, chlorodibromomethane and several closely related compounds
have been determined in water by this method (Washall and Wampler 1988) .
Methods are also being developed for in situ measurement of
organohalide levels in water. This has been demonstrated for
chloroform-contaminated well water using remote fiber fluorimetry (RFF)
and fiber optic chemical sensors (FOCS) (Milanovich 1986). With this
approach, fluorescence of basic pyridine in the presence of organohalide
(the Fujiwara reaction) is measured from a chemical sensor immersed in
the water at the end of an optical fiber. If conditions can be found
under which chlorodibromomethane or bromoform undergo a Fujiwara
reaction, it is likely that they could be determined by this approach.
The Environmental Health Laboratory Sciences Division of the Center
for Environmental Health and Injury Control, Centers for Disease
Control, is developing methods for the analysis of chlorodibromomethane,
bromoform, and other volatile organic compounds in blood. These methods
use purge and trap methodology and magnetic sector mass spectrometry
which gives detection limits in the low parts per trillion range.
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87
7. REGULATIONS AND ADVISORIES
Because of their potential to cause adverse health effects in
exposed people, a number of regulations and guidelines have been
established for bromoform and chlorodibromomethane by various
international, national and state agencies. These values are summarized
in Table 7-1.
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88
7. REGULATIONS AND ADVISORIES
TABLE 7-1. Regulations and Guidelines Applicable
to Chlorodlbroooaiethaiie and Bromoform*
Agency
Description
Value
Reference
Regulat ions:
a. Air:
OSHA
b. Water:
EPA ODW
EPA OWRS
Nonspecific
media:
EPA OERR
EPA OSW
EPA OTS
FDA
uidelines:
Air:
ACGIH
Water:
EPA ODW
EPA OWRS
National
PEL TWA (TBM)
MCL (Total trihaLomethanes)
Monitoring for unregulated
contaminants
General permits under NPDES
Criteria and Standards for NPDES
General pretreatment regulations for
existing and nev sources of pollution
Reportable quantity
Hazardous vaste constituent
(Appendix VIII)
Groundwater monitoring list
(Appendix IX)
Land disposal restrictions
Health and safety data reporting rule
Toxic chemical release reporting (TBM)
Bottled water (Total trihalomethanes)
TLV TWA (TBM)
RfD (oral)
Ambient water quality criteria*3
(Ha1ome t hane s)
Ingesting water and organisms
10-5
-1-6
0.5 ppm
(5 irig/ni3)
0.10 mg/L
NA
NA
NA
100 lb
NA
NA
NA
NA
NA
0. 10 mg/L
0.5 ppm
<5 mg/m3)
1-2
10"
10
-7
2x10 * rag/kg/day
3-3
1.9xl0"4 mg/L
1 .9xl0'5
OSHA 1989
29 CFR 1910.1000
Table Z-l-A
AO CFR HI. 12
EPA 1987a
(40 CFR 141.35,
141.40)
40 CFR 122
(Appendix D
Table II)
40 CFR 125
40 CFR 403
EPA 1985
(40 CFR 302.4)
EPA 1980a
(40 CFR 261)
EPA 1987b
(40 CFR 264)
EPA 1987c, 1988c
(40 CFR 268.32)
EPA 1988a
(40 CFR 716)
EPA 1988b
(40 CFR 372)
21 CFR 103.35
ACGIH 1986
IRIS 1988
EPA 1980b
mg/L
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89
7. REGULATIONS AND ADVISORIES
TABLE 7-1 (Continued)
Agency
Description
Value
Reference
NAS
Ingesting organisms oniy
10~5
10 '
SNARL (CDBM)
1 day
1.57x10 * mg/L
1.57x10
-2
-3
mg/L
1.57x10"J mg/L
18 mg/L
NAS 1980
State
Regulations:
a. Air:
Acceptable ambient air concentration (TBM)
Connecticut
Nevada
Virginia
North Dakota
Water:
Maryland (TBM)
Illinois (CDBM)
Drinking water
100 pg/m^ (8 hr)
0.1190 mg/m^ (8 hr)
80 pg/m^ (24 hr)
0.05 mg/m^ (8 hr)
1 vg/L
NATICH 1988
FSTRAC 1988
1 /ig/L
a All regulations listed apply to both chiorodibromomethane (CDBM) and bromoform (TBM), unless otherwise noted,
b Numerical values are provided in this column, when available. However, many regulations list
chemicals and/or involve requirements too complex for inclusion here. In these cases, NA (Not
Applicable is inserted in this column. The cited references provide details of the regulations.
c Because of the structural similarity of CDBM, TBM, and other trihalomethanes to chloroform, the criteria for
this class of compounds was set equal to the criteria for chloroform. Because of its carcinogenic potential,
the EPA-recommended concentration for chloroform In ambient water is zero. However, because attainment of
this level may not be possible, levels which correspond to upper bound incremental lifetime cancer risks of
10"^, 10"^, and 10"^ were estimated.
OSHA = Occupational Safety and Health Administration! PEL « Permissible Exposure Limit; TWA °= Time-Weighted
Average; TBM = bromoform; ppm = parts pr.r million; mg ¦ milligram; cubic meters; EPA « Environmental
Protection Agency; ODW * Office of Drinking Water; MCL - Maximum Contaminant Level; L « liter; NA = Not
Applicable; OWRS - Office of Water Regulations and Standards; NPDES - National Pollutant Discharge Elimination
Systems OERR = Office of Emergency and Remedial Response; lb « pound; OSW ® Office of Solid Wastes; OTS * Office
of Toxic Substances; FDA = Food and Drug Administration; ACGIH * American Conference of Governmental Industrial
Hygienists; TLV = Threshold Limit Value; RfD ¦ Reference dose; NAS * National of Sciences; SNARL ¦ Suggested-no-
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9. GLOSSARY
Acute Exposure -- Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Adsorption Coefficient (K^.) -- 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 time period.
Cancer Effect Level (CEL) -- The lowest dose of chemical in a study or
group of studies which produces significant increases in incidence of
cancer (or tumors) between the exposed population and its appropriate
control.
Carcinogen -- A chemical capable of inducing cancer.
Ceiling value (CL) -- 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 Recurrence 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.
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9. GLOSSARY
EPA Health Advisory --An estimate of acceptable drinking water levels
for a chemical substance based on health effects information. A health
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH) -- The maximum
environmental concentration of a contaminant from which one could escape
within 30 min without any escape-impairing symptoms or irreversible
health effects.
Intermediate Exposure -- Exposure to a chemical for a duration of 15-364
cays, 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^) (LClq) -- 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^) (LDlq) -- 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 Tlme(50) (LT30) -- 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 which produces statistically or
biologically significant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.
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9. GLOSSARY
Malformations -- Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level (MRL) - - An estimate of daily human exposure to a
chemical that is likely to be without an appreciable risk of deleterious
effects (noncancerous) over a specified duration of exposure.
Mutagen -- A substance that causes mutations. A mutation is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages, or cancer.
Neurotoxicity -- The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NOAEL) -- That dose of chemical at
which there are 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 (K^,) -- 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.
qx* -- The upper-bound estimate of the low-dose slope of the dose-
response curve as determined by the multistage procedure. The qx* can
be used to calculate an estimate of carcinogenic potency, the
incremental excess cancer risk per unit of exposure (usually ^g/L for
water, mg/kg/day for food, and ng/m3 for air).
t
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.
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9. GLOSSARY
Reportable Quantity (RQ) -- The quantity of a hazardous substance that
is considered reportable under CERCLA. Reportable quantities are: (1) 1
lb or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-hour period.
Reproductive Toxicity -- The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system.
Short-Term Exposure Limit (STEL) -- The maximum concentration to which
workers can be exposed for up to 15 min continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not be exceeded.
Target Organ Toxicity - - This term covers a broad range of adverse
effects on target organs or physiological systems (e.g., renal,
cardiovascular) extending from those arising through a single limited
exposure to those assumed over a lifetime of exposure to a chemical.
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 (TD5Q) -- 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 humans, (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.
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APPENDIX
APPENDIX
PEER REVIEW
A peer review panel was assembled for chlorodibromomethane and
bromoform. The panel consisted of the following members:
Dr. Joseph Borzelleca, Head, Division of Toxicology, Department of
Pharmacology and Toxicology, Medical College of Virginia;
Dr. Nancy Reiches, Private Consultant, Columbus, OH; Dr. James Withey,
Research Scientist, Environmental Health Center, Ottawa, Ontario,
Canada; Dr. John L. Egle, Jr., Associate Professor, Department of
Pharmacology and Toxicology, Medical College of Virginia; Dr. Joseph P.
Gould, Research Scientist, School of Civil Engineering, Georgia
Institute of Technology. These experts collectively have knowledge of
chlorodibronsomethane's and bromoform'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.
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 their approval of the profile's final content. The responsibility
for the content of this profile lies with the Agency for Toxic
Substances and Disease Registry.
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