TOXICOLOGICAL PROFILE FOR 

BROMOFORM AND DIBROMOCHLOROMETHANE 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 

Public Health Service 

Agency for Toxic Substances and Disease Registry 

August 2005 
BROMOFORM AND DIBROMOCHLOROMETHANE ii 

DISCLAIMER 

The use of company or product name(s) is for identification only and does not imply endorsement by the 

Agency for Toxic Substances and Disease Registry. 
BROMOFORM AND DIBROMOCHLOROMETHANE iii 

UPDATE STATEMENT 
 

A Toxicological Profile for Bromoform and Dibromochloromethane, Draft for Public Comment was 

released in September 2003. This edition supersedes any previously released draft or final profile. 

Toxicological profiles are revised and republished as necessary. For information regarding the update 

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology/Toxicology Information Branch 

1600 Clifton Road NE 

Mailstop F-32 

Atlanta, Georgia 30333 



BROMOFORM AND DIBROMOCHLOROMETHANE vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous 

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation 

of available toxicologic and epidemiologic information on a substance. Health care providers treating 

patients potentially exposed to hazardous substances will find the following information helpful for fast 

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating 

patients about possible exposure to a hazardous substance. It explains a substance’s relevant 

toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of 

the general health effects observed following exposure. 

Chapter 2: Relevance to Public Health: The Relevance to Public Health Section evaluates, interprets, 

and assesses the significance of toxicity data to human health. 

Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type 

of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length 

of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are 

reported in this section. 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. Please refer to the Public Health Statement to identify general health effects observed 

following exposure. 

Pediatrics: Four new sections have been added to each Toxicological Profile to address child health 

issues: 

Section 1.6 How Can (Chemical X) Affect Children? 

Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)? 

Section 3.7 Children’s Susceptibility 

Section 6.6 Exposures of Children 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-888-42-ATSDR or (404) 498-0110 Fax: (770) 488-4178 

E-mail: atsdric@cdc.gov Internet: http://www.atsdr.cdc.gov 

The following additional material can be ordered through the ATSDR Information Center: 

Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an 

exposure history and how to conduct one are described, and an example of a thorough exposure 

history is provided. Other case studies of interest include Reproductive and Developmental 
BROMOFORM AND DIBROMOCHLOROMETHANE viii 

Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide 

Toxicity; and numerous chemical-specific case studies. 

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene 

(prehospital) and hospital medical management of patients exposed during a hazardous materials 

incident. Volumes I and II are planning guides to assist first responders and hospital emergency 

department personnel in planning for incidents that involve hazardous materials. Volume III— 

Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care 

professionals treating patients exposed to hazardous materials. 

Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances. 

Other Agencies and Organizations 

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, 

injury, and disability related to the interactions between people and their environment outside the 

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, 

GA 30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015. 

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational 

diseases and injuries, responds to requests for assistance by investigating problems of health and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains 

professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue, 

SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch, 

Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998 

• Phone: 800-35-NIOSH. 

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, 

Research Triangle Park, NC 27709 • Phone: 919-541-3212. 

Referrals 

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics 

in the United States to provide expertise in occupational and environmental issues. Contact: 

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 

• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/. 

The American College of Occupational and Environmental Medicine (ACOEM) is an association of 

physicians and other health care providers specializing in the field of occupational and 

environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, 

Elk Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266. 
BROMOFORM AND DIBROMOCHLOROMETHANE ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

John Risher, Ph.D. 
 

Dennis Jones, D.V.M. 
 

ATSDR, Division of Toxicology, Atlanta, Georgia 
 

Michael H. Lumpkin, Ph.D. 
 

Lisa Ingerman, Ph.D., DABT 
 

Daniel Plewak, M.S. 
 

Lori Moilanen, Ph.D., DABT 
 

Dolores Beblo, Ph.D. 
 

Jennifer Walters, M.S., M.P.A. 
 

Syracuse Research Corporation, North Syracuse, New York 
 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

1. 	 Health Effects Review. The Health Effects Review Committee examines the health effects 

chapter of each profile for consistency and accuracy in interpreting health effects and classifying 

end points. 

2.	 Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to 

substance-specific Minimal Risk Levels (MRLs), reviews the health effects database of each 

profile, and makes recommendations for derivation of MRLs. 

3. 	 Data Needs Review. The Research Implementation Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

4. 	 Green Border Review. Green Border review assures the consistency with ATSDR policy. 

BROMOFORM AND DIBROMOCHLOROMETHANE xi 

PEER REVIEW 
 

A peer review panel was assembled for bromoform and dibromochloromethane. The panel consisted of 

the following members: 

1. 	 Bruce Jarnot, Ph.D., DABT, Senior Toxicologist, American Petroleum Institute, Washington DC; 

2. 	 Kannan Krishnan, Ph.D., Professor, Human Toxicology Research Group, University of Montreal 

Montreal Canada; and 

3.	 Clint Skinner, Ph.D., Consultant, Skinner Associates, Creston California 

These experts collectively have knowledge of bromoform and dibromochloromethane'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. 

The citation of the peer review panel should not be understood to imply its approval of the profile's final 

content. The responsibility for the content of this profile lies with the ATSDR. 

BROMOFORM AND DIBROMOCHLOROMETHANE xiii 

CONTENTS 
 

DISCLAIMER ..............................................................................................................................................ii 
 

UPDATE STATEMENT .............................................................................................................................iii 
 

FOREWORD ................................................................................................................................................ v 
 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS....................................................................vii 
 

CONTRIBUTORS ....................................................................................................................................... ix 
 

PEER REVIEW ........................................................................................................................................... xi 
 

CONTENTS...............................................................................................................................................xiii 
 

LIST OF FIGURES ..................................................................................................................................xvii 
 

LIST OF TABLES ..................................................................................................................................... xix 
 

1. PUBLIC HEALTH STATEMENT.......................................................................................................... 1 
 

1.1 	 WHAT ARE BROMOFORM AND DIBROMOCHLOROMETHANE? .................................. 1 
 

1.2 	 WHAT HAPPENS TO BROMOFORM AND DIBROMOCHLOROMETHANE WHEN 
 

THEY ENTER THE ENVIRONMENT? .................................................................................... 3 
 

1.3 	 HOW MIGHT I BE EXPOSED TO BROMOFORM AND 

 DIBROMOCHLOROMETHANE?............................................................................................. 3 
 

1.4 	 HOW CAN BROMOFORM AND DIBROMOCHLOROMETHANE ENTER AND 

 LEAVE MY BODY? .................................................................................................................. 4 
 

1.5 	 HOW CAN BROMOFORM AND DIBROMOCHLOROMETHANE AFFECT MY 
 

HEALTH? ................................................................................................................................... 4 
 

1.6 	 HOW CAN BROMOFORM AND DIBROMOCHLOROMETHANE AFFECT 

 CHILDREN? ............................................................................................................................... 6 
 

1.7 	 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO BROMOFORM AND 

 DIBROMOCHLOROMETHANE?............................................................................................. 6 
 

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

EXPOSED TO BROMOFORM AND DIBROMOCHLOROMETHANE?............................... 7 
 

1.9 	 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 
 

PROTECT HUMAN HEALTH?................................................................................................. 7 
 

1.10 	 WHERE CAN I GET MORE INFORMATION? ....................................................................... 8 
 

2. RELEVANCE TO PUBLIC HEALTH ................................................................................................. 11 
 

2.1 	 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO BROMOFORM AND 
 

DIBROMOCHLOROMETHANE IN THE UNITED STATES ............................................... 11 
 

2.2 	 SUMMARY OF HEALTH EFFECTS...................................................................................... 11 
 

2.3 	 MINIMAL RISK LEVELS (MRLs) ......................................................................................... 15 
 

3. HEALTH EFFECTS .............................................................................................................................. 21 
 

3.1 	 INTRODUCTION ..................................................................................................................... 21 
 

3.2 	 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE .................................. 21 
 

3.2.1 	 Inhalation Exposure .............................................................................................................. 22 
 

3.2.1.1 Death ............................................................................................................................ 22 
 

3.2.1.2 Systemic Effects ........................................................................................................... 23 
 

3.2.1.3 Immunological and Lymphoreticular Effects ............................................................... 23 
 

3.2.1.4 Neurological Effects ..................................................................................................... 24 
 

3.2.1.5 Reproductive Effects .................................................................................................... 24 
 

3.2.1.6 Developmental Effects ................................................................................................. 24 
 

3.2.1.7 Cancer........................................................................................................................... 24 
 
BROMOFORM AND DIBROMOCHLOROMETHANE	 xiv 

3.2.2 Oral Exposure........................................................................................................................ 24 
 

3.2.2.1 Death ............................................................................................................................ 24 
 

3.2.2.2 Systemic Effects ........................................................................................................... 56 
 

3.2.2.3 Immunological and Lymphoreticular Effects ............................................................... 63 
 

3.2.2.4 Neurological Effects ..................................................................................................... 63 
 

3.2.2.5 Reproductive Effects .................................................................................................... 65 
 

3.2.2.6 Developmental Effects ................................................................................................. 67 
 

3.2.2.7 Cancer........................................................................................................................... 68 
 

3.2.3 Dermal Exposure................................................................................................................... 69 
 

3.2.3.1 Death ............................................................................................................................ 69 
 

3.2.3.2 Systemic Effects ........................................................................................................... 69 
 

3.2.3.3 Immunological and Lymphoreticular Effects ............................................................... 69 
 

3.2.3.4 Neurological Effects ..................................................................................................... 69 
 

3.2.3.5 Reproductive Effects .................................................................................................... 70 
 

3.2.3.6 Developmental Effects ................................................................................................. 70 
 

3.2.3.7 Cancer........................................................................................................................... 70 
 

3.3 GENOTOXICITY ..................................................................................................................... 70 
 

3.4 TOXICOKINETICS.................................................................................................................. 78 
 

3.4.1 Absorption............................................................................................................................. 78 
 

3.4.1.1 Inhalation Exposure...................................................................................................... 78 
 

3.4.1.2 Oral Exposure ............................................................................................................... 79 
 

3.4.1.3 Dermal Exposure .......................................................................................................... 79 
 

3.4.2 Distribution ........................................................................................................................... 81 
 

3.4.2.1 Inhalation Exposure...................................................................................................... 81 
 

3.4.2.2 Oral Exposure............................................................................................................... 81 
 

3.4.2.3 Dermal Exposure .......................................................................................................... 82 
 

3.4.3 Metabolism............................................................................................................................ 82 
 

3.4.4 Elimination and Excretion..................................................................................................... 87 
 

3.4.4.1 Inhalation Exposure...................................................................................................... 87 
 

3.4.4.2 Oral Exposure............................................................................................................... 87 
 

3.4.4.3 Dermal Exposure .......................................................................................................... 88 
 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ............. 88 
 

3.5 MECHANISMS OF ACTION .................................................................................................. 91 
 

3.5.1 Pharmacokinetic Mechanisms............................................................................................... 91 
 

3.5.2 Mechanisms of Toxicity........................................................................................................ 91 
 

3.5.3 Animal-to-Human Extrapolations ......................................................................................... 94 
 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS .......................... 94 
 

3.7 CHILDREN’S SUSCEPTIBILITY ........................................................................................... 95 
 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT .................................................................... 98 
 

3.8.1	 Biomarkers Used to Identify or Quantify Exposure to Bromoform and 

 Dibromochloromethane......................................................................................................... 99 
 

3.8.2 	 Biomarkers Used to Characterize Effects Caused by Bromoform and 

 Dibromochloromethane....................................................................................................... 100
 

3.9 INTERACTIONS WITH OTHER CHEMICALS .................................................................. 100 
 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ............................................. 102 
 

3.11 METHODS FOR REDUCING TOXIC EFFECTS................................................................. 102 
 

3.11.1 Reducing Peak Absorption Following Exposure ............................................................ 103 
 

3.11.2 Reducing Body Burden................................................................................................... 103 
 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects ......................................... 103 
 

3.12 ADEQUACY OF THE DATABASE...................................................................................... 104 
 

3.12.1 Existing Information on Health Effects of Bromoform and Dibromochloromethane .... 104 
 
BROMOFORM AND DIBROMOCHLOROMETHANE xv 

3.12.2 Identification of Data Needs ........................................................................................... 107 
 

3.12.3 Ongoing Studies.............................................................................................................. 115 
 

4. CHEMICAL AND PHYSICAL INFORMATION.............................................................................. 117 
 

4.1 CHEMICAL IDENTITY......................................................................................................... 117 
 

4.2 PHYSICAL AND CHEMICAL PROPERTIES...................................................................... 117 
 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL .......................................................... 121 
 

5.1 PRODUCTION ....................................................................................................................... 121 
 

5.2 IMPORT/EXPORT ................................................................................................................. 122 
 

5.3 USE.......................................................................................................................................... 122 
 

5.4 DISPOSAL .............................................................................................................................. 122 
 

6. POTENTIAL FOR HUMAN EXPOSURE ......................................................................................... 125 
 

6.1 OVERVIEW............................................................................................................................ 125 
 

6.2 RELEASES TO THE ENVIRONMENT ................................................................................ 125 
 

6.2.1 Air ....................................................................................................................................... 128 
 

6.2.2 Water ................................................................................................................................... 130 
 

6.2.3 Soil ...................................................................................................................................... 133 
 

6.3 ENVIRONMENTAL FATE.................................................................................................... 134
 

6.3.1 Transport and Partitioning................................................................................................... 134 
 

6.3.2 Transformation and Degradation ........................................................................................ 135 
 

6.3.2.1 Air............................................................................................................................... 135 
 

6.3.2.2 Water .......................................................................................................................... 135 
 

6.3.2.3 Sediment and Soil....................................................................................................... 136 
 

6.3.2.4 Other Media................................................................................................................ 137 
 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ............................... 137 
 

6.4.1 Air ....................................................................................................................................... 137 
 

6.4.2 Water ................................................................................................................................... 139 
 

6.4.3 Sediment and Soil ............................................................................................................... 145 
 

6.4.4 Other Environmental Media................................................................................................ 145 
 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ..................................... 146 
 

6.6 EXPOSURES OF CHILDREN ............................................................................................... 149 
 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ........................................... 150 
 

6.8 ADEQUACY OF THE DATABASE...................................................................................... 151 
 

6.8.1 Identification of Data Needs ............................................................................................... 151 
 

6.8.2 Ongoing Studies .................................................................................................................. 154 
 

7. ANALYTICAL METHODS ............................................................................................................... 157 
 

7.1 BIOLOGICAL MATERIALS ................................................................................................. 157 
 

7.2 ENVIRONMENTAL SAMPLES............................................................................................ 158 
 

7.3 ADEQUACY OF THE DATABASE...................................................................................... 160 
 

7.3.1 Identification of Data Needs ............................................................................................... 160 
 

7.3.2 Ongoing Studies .................................................................................................................. 163 
 

8. REGULATIONS AND ADVISORIES ............................................................................................... 165 
 

9. REFERENCES .................................................................................................................................... 171 
 

10. GLOSSARY ...................................................................................................................................... 217 
 
BROMOFORM AND DIBROMOCHLOROMETHANE xvi 

APPENDICES 

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS .............................................................A-1 
 

B. USER'S GUIDE .................................................................................................................................. B-1 
 

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS...................................................................... C-1 
 

D. INDEX ................................................................................................................................................D-1 
 
BROMOFORM AND DIBROMOCHLOROMETHANE xvii 

LIST OF FIGURES 
 

3-1. Levels of Significant Exposure to Bromoform—Oral........................................................................ 35 
 

3-2. Levels of Significant Exposure to Dibromochloromethane—Oral .................................................... 51 
 

3-3. Proposed Pathway of Trihalomethane Metabolism in Rats................................................................ 83
 

3-4. Proposed Pathway of Trihalomethyl-radical-mediated Lipid Peroxidation ....................................... 85
 

3-5. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a
 

Hypothetical Chemical Substance ....................................................................................................... 90
 

3-6. Existing Information on Health Effects of Bromoform.................................................................... 105
 

3-7. Existing Information on Health Effects of Dibromochloromethane.................................................106
 

6-1. Frequency of NPL Sites with Bromoform Contamination ............................................................... 126
 

6-2. Frequency of NPL Sites with Dibromochloromethane Contamination ............................................ 127
 

BROMOFORM AND DIBROMOCHLOROMETHANE xix 

LIST OF TABLES 
 

3-1. Levels of Significant Exposure to Bromoform—Oral........................................................................ 25 
 

3-2. Levels of Significant Exposure to Dibromochloromethane—Oral .................................................... 39 
 

3-3. Genotoxicity of Bromoform In Vivo................................................................................................... 71
 

3-4. Genotoxicity of Bromoform In Vitro.................................................................................................. 72
 

3-5. Genotoxicity of Dibromochloromethane In Vivo ............................................................................... 75
 

3-6. Genotoxicity of Dibromochloromethane In Vitro .............................................................................. 76
 

3-7. Partition Coefficients for Bromoform and Dibromochloromethane................................................... 80
 

4-1. Chemical Identity of Bromoform and Dibromochloromethane........................................................118
 

4-2. Physical and Chemical Properties of Bromoform and Dibromochloromethane............................... 119
 

5-1. Facilities that Produce, Process, or Use Bromoform ........................................................................ 123
 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use Bromoform.................129
 

6-2. Occurrence of Bromoform and Dibromochloromethane in Finished Drinking Water ..................... 140
 

6-3. Summary of Typical Human Exposure to Bromoform and Dibromochloromethane....................... 147
 

6-4. Ongoing Studies on the Potential for Human Exposure to Bromoform ........................................... 155
 

7-1. Analytical Methods for Determining Bromoform and Dibromochloromethane in Biological 
 

Materials ............................................................................................................................................ 159
 

7-2. Analytical Methods for Determining Bromoform and Dibromochloromethane in Environmental 

 Samples.............................................................................................................................................. 161
 

8-1. Regulations and Guidelines Applicable to Bromoform and Dibromochloromethane ...................... 167
 

BROMOFORM AND DIBROMOCHLOROMETHANE 1 

1. PUBLIC HEALTH STATEMENT 
 

This public health statement tells you about bromoform and dibromochloromethane and the 

effects of exposure to them. 

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in 

the nation. These sites are then placed on the National Priorities List (NPL) and are targeted for 

long-term federal clean-up activities. Bromoform and dibromochloromethane has been found in 

at least 140 and 174 of the 1,662 current or former NPL sites. Although the total number of NPL 

sites evaluated for these substances is not known, the possibility exists that the number of sites at 

which bromoform and dibromochloromethane is found may increase in the future as more sites 

are evaluated. This information is important because these sites may be sources of exposure and 

exposure to these substances may harm you. 

When a substance is released either from a large area, such as an industrial plant, or from a 

container, such as a drum or bottle, it enters the environment. Such a release does not always 

lead to exposure. You can be exposed to a substance only when you come in contact with it. 

You may be exposed by breathing, eating, or drinking the substance, or by skin contact. 

If you are exposed to bromoform or dichlorobromomethane, many factors will determine 

whether you will be harmed. These factors include the dose (how much), the duration (how 

long), and how you come in contact with them. You must also consider any other chemicals you 

are exposed to and your age, sex, diet, family traits, lifestyle, and state of health. 

1.1 WHAT ARE BROMOFORM AND DIBROMOCHLOROMETHANE? 

Bromoform (also known as tribromomethane) and dibromochloromethane are colorless to 

yellow, heavy, nonburnable liquids with a sweetish odor. These chemicals are possible 

contaminants of drinking water that has been chlorinated to kill bacteria and viruses that could 

cause serious waterborne infectious diseases. Bromoform and dibromochloromethane may form 
BROMOFORM AND DIBROMOCHLOROMETHANE 2 

1. PUBLIC HEALTH STATEMENT 

when chlorine reacts with other naturally occurring substances in water, such as decomposing 

plant material. Plants in the ocean also produce small amounts of these chemicals. 

These chemicals are found mainly in water that originally came from surface sources, such as 

rivers and lakes. Springs and deep drilled wells usually contain very little of the substances that 

react with chlorine to form these chemicals; therefore, well and spring water is less likely a 

source of bromoform and dibromochloromethane than water from a reservoir (artificial lake). 

The amount of bromoform and dibromochloromethane in drinking water can change 

considerably from day to day, depending on the source, temperature, amount of plant material in 

the water, amount of chlorine added, and a variety of other factors. 

In the past, bromoform was used by industry to dissolve dirt and grease and to make other 

chemicals. 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. Dibromochloromethane was used in the 

past to make other chemicals such as fire extinguisher fluids, spray can propellants, refrigerator 

fluid, and pesticides. It is now only used on a small scale in laboratories. 

In the environment, bromoform and dibromochloromethane are not found as pure liquids, but 

instead, they are found either dissolved in water or evaporated into air as a gas. Both bromoform 

and dibromochloromethane are relatively stable in the air, but reactions with other chemicals in 

the air cause them to break down slowly (about 50% in 1 or 2 months). Bromoform and 

dibromochloromethane 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 chemical identity of bromoform and 

dibromochloromethane in the environment may be found in Chapters 4, 5, and 6. 
BROMOFORM AND DIBROMOCHLOROMETHANE 3 

1. PUBLIC HEALTH STATEMENT 

1.2 	 WHAT HAPPENS TO BROMOFORM AND DIBROMOCHLOROMETHANE 

WHEN THEY ENTER THE ENVIRONMENT? 

Bromoform and dibromochloromethane enter the environment through the disposal of water that 

has been disinfected with chlorine or as vapors emitted from chlorinated water. These chemicals 

are also made naturally by plant-like organisms called algae that are found in the oceans. Some 

part of bromoform and dibromochloromethane that enters the air is removed by rain. What is 

left in the air takes about 1–2 months for half of it to degrade. In water, bromoform and 

dibromochloromethane are slowly broken down at the water surface where oxygen is available, 

but break down much faster in deep water and in water that is underground where there is a lot 

less oxygen. Bromoform and dibromochloromethane are mobile in soils and may seep into 

groundwater. Bromoform and dibromochloromethane do not appear to concentrate in fish. 

1.3 	 HOW MIGHT I BE EXPOSED TO BROMOFORM AND DIBROMOCHLOROMETHANE? 

You are most likely to be exposed to bromoform and dibromochloromethane by drinking water 

that has been treated with chlorine. Usually, the levels in chlorinated drinking water are between 

1 and 10 parts of bromoform and dibromochloromethane per billion parts of water (ppb). These 

are levels that are known to be without adverse health effects. Bromoform and dibromochloromethane have also been detected in chlorinated swimming pools. Exposure can occur at a 

swimming pool, by breathing bromoform or dibromochloromethane that has evaporated into the 

air, or by uptake from the water through the skin. Neither dibromochloromethane nor 

bromoform are likely to be found in food. 

If you live near a factory or laboratory that makes or uses dibromochloromethane or bromoform, 

you might be exposed to dibromochloromethane or bromoform in the air. Currently, bromoform 

is only used for geological and electronics testing. Dibromochloromethane is used on a smallscale in laboratories. Since neither dibromochloromethane 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, exposure to bromoform or dibromochloromethane in the air is a minor route. 

Exposure may occur if you come into contact with water or soil at a chemical waste site where 
BROMOFORM AND DIBROMOCHLOROMETHANE 4 

1. PUBLIC HEALTH STATEMENT 

dibromochloromethane or bromoform has been disposed. Further information on how you might 

be exposed to these chemicals is given in Chapter 6. 

1.4 	 HOW CAN BROMOFORM AND DIBROMOCHLOROMETHANE ENTER AND 

LEAVE MY BODY? 

Studies in animals or humans indicate that both bromoform and dibromochloromethane can 

easily enter your body after swallowing them in water or breathing them in air. They can also 

enter your body through your skin (for example, by washing or showering in water containing 

these chemicals). Some portion of bromoform and dibromochloromethane entering your body 

may be broken down to other compounds. Bromoform, dibromochloromethane, and their 

breakdown products can be removed from the body by being exhaled from the lungs. These 

chemicals leave the body fairly rapidly. Bromoform and dibromochlormethane do not tend to 

build up in the body, 50–90% of the amount that enters the body is removed within 8 hours. 

Further information on how bromoform and dibromochloromethane enter and leave your body is 

given in Chapter 3. 

1.5 	 HOW CAN BROMOFORM AND DIBROMOCHLOROMETHANE AFFECT MY 

HEALTH? 

Scientists use many tests to protect the public from harmful effects of toxic chemicals and to find 

ways for treating persons who have been harmed. 

One way to learn whether a chemical will harm people is to determine how the body absorbs, 

uses, and releases the chemical. For some chemicals, animal testing may be necessary. Animal 

testing may also help identify health effects such as cancer or birth defects. Without laboratory 

animals, scientists would lose a basic method for getting information needed to make wise 

decisions that protect public health. Scientists have the responsibility to treat research animals 

with care and compassion. Scientists must comply with strict animal care guidelines because 

laws today protect the welfare of research animals. 
BROMOFORM AND DIBROMOCHLOROMETHANE 5 

1. PUBLIC HEALTH STATEMENT 

The effects of bromoform and dibromochloromethane on your health depend largely on the 

amount you take into your body and the duration of exposure. In general, the more you take in, 

the greater the chance that an effect will occur. The main effect of swallowing or breathing large 

amounts of bromoform is a slowing of normal brain activities, resulting in sleepiness or sedation 

occuring quickly after the chemicals enter your body. In humans, these effects tend to disappear 

within a day. Exposures capable of producing these effects include swallowing 1–4 drops of 

liquid bromoform, an amount much greater than is usually found in a glass of drinking water. At 

much higher amounts, a person may become unconsciousness or die. The amount of dibromochloromethane taken by mouth that would affect humans is not known, but is probably similar to 

bromoform. 

Some studies in animals indicate that exposure to high doses of bromoform or dibromochloromethane may also lead to liver and the kidney injury within a short period of time. Exposure to 

low levels of bromoform or dibromochloromethane do not appear to seriously affect the brain, 

liver, or kidneys. Other animal studies suggest that typical bromoform or dibromochloromethane 

exposures do not pose a high risk of affecting the chance of becoming pregnant or harming an 

unborn baby. However, studies in animals indicate that long-term intake of either bromoform or 

dibromochloromethane can cause liver and kidney cancer. Although cancer in humans cannot be 

definitely attributed to these chemicals, it is an effect of special concern, since many people are 

exposed to low levels of bromoform and dibromochloromethane in chlorinated drinking water. 

The International Agency for Research on Cancer (IARC) concluded that bromoform and 

dibromochloromethane are not classifiable as to human carcinogenicity. The EPA classified 

bromoform as a probable human carcinogen and dibromochloromethane as a possible human 

carcinogen. 

Further information on how bromoform and dibromochloromethane can affect the health of 

humans and animals is presented in Chapter 3. 
BROMOFORM AND DIBROMOCHLOROMETHANE 6 

1. PUBLIC HEALTH STATEMENT 

1.6 	 HOW CAN BROMOFORM AND DIBROMOCHLOROMETHANE AFFECT 

CHILDREN? 

This section discusses potential health effects in humans from exposures during the period from 

conception to maturity at 18 years of age. 

In the early 1900s, bromoform was given to children suffering from whooping cough, resulting 

in several deaths when children were accidentally overdosed. Children appeared drowsy, then 

lifeless, just before dying. 

There are no studies in humans or laboratory animals that examine whether the effects of 

bromoform and dibromochloromethane change with age. Based on current knowledge of body 

function, and metabolism in the body, there is no indication that children will be affected more 

than adults. 

1.7 	 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO BROMOFORM 

AND DIBROMOCHLOROMETHANE? 

If your doctor finds that you have been exposed to substantial amounts of bromoform and/or 

dibromochloromethane, ask whether your children might also have been exposed. Your doctor 

might need to ask your state health department to investigate. 

The chance of consuming bromoform or dibromochloromethane in chlorinated public drinking 

water varies with season, water temperature, water chemistry, disinfection method, and other 

factors. However, the health risks associated with drinking non-disinfected water when there is 

evidence of disease-causing contamination (i.e., bacteria, viruses, etc.) are much greater than the 

risk of adverse health effects from exposure to bromoform or dibromochloromethane. 

There are water treatment methods that people can be used in the home to reduce exposure to 

bromoform and dibromochloromethane from chlorinated tap water. These include simple do-ityourself methods such as connecting solid carbon black filters to faucets and shower taps. 

Homeowners may discuss other home water treatment methods, including filtering, aeration or 
BROMOFORM AND DIBROMOCHLOROMETHANE 7 

1. PUBLIC HEALTH STATEMENT 

boiling, distillation, and/or activated charcoal, with a professional plumber or water well 

contractor. The chance of exposure to bromoform and dibromochloromethane may be reduced 

by minimizing contact with water expected to have higher levels of these chemicals, such as 

chlorinated swimming pool water. When bathing or showering some portion of dibromochloromethane and/or bromoform may evaporate into the air. Opening bathroom windows, and 

taking shorter baths and showers may reduce the amount of chemical vapor that is inhaled or 

absorbed through the skin. 

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

EXPOSED TO BROMOFORM AND DIBROMOCHLOROMETHANE? 

If you are exposed to bromoform or dibromochloromethane, 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 

bromoform and dibromochloromethane are quickly eliminated from the body, these special 

laboratory tests are only effective in detecting recent exposures (within 1 or 2 days). Further 

information on how bromoform and dibromochloromethane can be measured in exposed humans 

is presented in Chapters 3 and 7. 

1.9 	 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

The federal government develops regulations and recommendations to protect public health. 

Regulations can be enforced by law. The EPA, the Occupational Safety and Health 

Administration (OSHA), and the Food and Drug Administration (FDA) are some federal 

agencies that develop regulations for toxic substances. Recommendations provide valuable 

guidelines to protect public health, but cannot be enforced by law. The Agency for Toxic 

Substances and Disease Registry (ATSDR) and the National Institute for Occupational Safety 
BROMOFORM AND DIBROMOCHLOROMETHANE 8 

1. PUBLIC HEALTH STATEMENT 

and Health (NIOSH) are two federal organizations that develop recommendations for toxic 

substances. 

Regulations and recommendations can be expressed as “not-to-exceed” levels, that is, levels of a 

toxic substance in air, water, soil, or food that do not exceed a critical value that is usually based 

on levels that affect animals; they are then adjusted to levels that will help protect humans. 

Sometimes these not-to-exceed levels differ among federal organizations because they used 

different exposure times (an 8-hour workday or a 24-hour day), different animal studies, or other 

factors. 

Recommendations and regulations are also updated periodically as more information becomes 

available. For the most current information, check with the federal agency or organization that 

provides it. Some regulations and recommendations for bromoform and dibromochloromethane 

include the following: 

OSHA has set a legally enforceable limit of 0.5 ppm for bromoform in workroom air to protect 

workers during an 8-hour shift over a 40-hour work week. 

EPA recommends that drinking water levels for bromoform should not be more than 0.7 parts 

per million (ppm) for bromoform and 0.7 ppm for dibromochloromethane. 

1.10 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns, please contact your community or state health or 

environmental quality department, or contact ATSDR at the address and phone number below. 

ATSDR can also tell you the location of occupational and environmental health clinics. These 

clinics specialize in recognizing, evaluating, and treating illnesses that result from exposure to 

hazardous substances. 
BROMOFORM AND DIBROMOCHLOROMETHANE 9 

1. PUBLIC HEALTH STATEMENT 

Toxicological profiles are also available on-line at www.atsdr.cdc.gov and on CD-ROM. You 

may request a copy of the ATSDR ToxProfilesTM CD-ROM by calling the toll-free information 

and technical assistance number at 1-888-42ATSDR (1-888-422-8737), by e-mail at 

atsdric@cdc.gov, or by writing to: 

Agency for Toxic Substances and Disease Registry 

 Division of Toxicology 
 

1600 Clifton Road NE 

 Mailstop F-32 

 Atlanta, GA 30333 

 Fax: 1-770-488-4178 
 

Organizations for-profit may request copies of final Toxicological Profiles from the following: 

National Technical Information Service (NTIS) 
 

5285 Port Royal Road 

 Springfield, VA 22161 

 Phone: 1-800-553-6847 or 1-703-605-6000 

 Web site: http://www.ntis.gov/ 
 

BROMOFORM AND DIBROMOCHLOROMETHANE 11 

2. RELEVANCE TO PUBLIC HEALTH 

2.1 	 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO BROMOFORM AND 

DIBROMOCHLOROMETHANE IN THE UNITED STATES 

Bromoform (CHBr3; CAS Number 75-25-2), also known as tribromomethane, and dibromochloromethane (CHClBr2; CAS Number 124-48-1) belong to a group of chemicals referred to as trihalomethanes; the other two chemicals in this group are chloroform (also known as trichloromethane) and 

dichlorobromomethane. Trihalomethanes are formed when raw source water is disinfected by 

chlorination. In the United States, over 280 million people are served by public water systems that apply 

chlorine or some of its compounds as disinfectants to water in order to provide protection against 

microbial contaminants that otherwise might cause serious water-borne diseases. While these chlorinecontaining disinfectants are effective in controlling many microorganisms, they react with natural organic 

or carbon-containing matter in the water to form disinfection byproducts. Therefore, the principal source 

of human exposure to bromoform and dibromochloromethane is chlorinated water supplied to homes, 

work, and public places. Bromoform and dibromochloromethane concentrations in public supply or tap 

water are in the low microgram/L range. Dibromochloromethane is often found more frequently than 

bromoform in samples from chlorinated water systems. 

In the past, it was thought that most of the human exposure to bromoform and dibromochloromethane 

occurred through consumption of chlorinated drinking water. However, because of their physical 

properties (see Henry’s law constants in Chapter 4), some bromoform and dibromochloromethane 

volatilize into the air from normal household use of water containing these chemicals. Recent models for 

residential exposure predict that exposure by the inhalation and dermal routes may be significant. Dermal 

exposure is expected from showering or bathing. Total administered doses of bromoform or dibromochloromethane for residential tap water having low microgram/L concentrations are predicted to be on the 

order of 10-4 mg/kg/day. 

2.2 	 SUMMARY OF HEALTH EFFECTS 

The general population is primarily exposed to bromoform and dibromochloromethane via tap water. The 

primary routes of exposure are ingestion and inhalation (from volatized compounds) and dermal exposure 

during showering and bathing. Bromoform and dibromochloromethane are readily absorbed from the 
BROMOFORM AND DIBROMOCHLOROMETHANE 12 

2. RELEVANCE TO PUBLIC HEALTH 

gastrointestinal tract and may be absorbed through the respiratory tract and skin. They are rapidly 

distributed throughout the body. In the liver, bromoform and dibromochloromethane are metabolized by 

the cytochrome P-450 mixed function oxidase system to a highly reactive metabolite, which is ultimately 

metabolized to carbon dioxide or carbon monoxide. 

Studies in animals, combined with limited observations in humans, indicate that the principal adverse 

health effects associated with inhalation or oral exposure to bromoform or dibromochloromethane are 

central nervous system depression and liver and kidney damage. Although limited dermal data were 

located, it is likely that similar adverse health effects would occur from dermal exposure. Based on the 

no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) values 

identified in animal studies, the liver appears to be the most sensitive target organ. Two types of liver 

effects have been observed in laboratory animals: lipidosis and hepatocellular necrosis. Lipidosis is an 

accumulation of lipids in the hepatocytes resulting in cellular vacuolization and swelling. Hepatocellular 

necrosis is observed at higher doses. It is not known if these effects represent a continuum of liver 

damage or are due to separate modes of action. Kidney effects are typically observed at higher doses than 

the hepatic effects; tubular cell degeneration and nephrosis are the most commonly reported effects in 

laboratory animals. Central nervous system depression, as evidenced by lethargy, ataxia, and shallow 

breathing, is typically observed at very high, often lethal, doses. High-dose exposure is also associated 

with decreases in body weight gain. There are limited data on the immunotoxicity of bromoform and 

dibromochloromethane. Impaired humoral and cell-mediated (only observed with dibromochloromethane) immunity were observed in a study of mice administered bromoform or dibromochloromethane 

via gavage for 14 days. For bromoform, the immune and liver effects occurred at the same dose level; for 

dibromochloromethane, the immune effects occurred at a lower dose than liver effects. 

The available data on the potential of bromoform and dibromochloromethane to induce reproductive 

and/or developmental effects are inconclusive. Human data primarily come from epidemiological studies 

of pregnancy outcomes in women exposed to trihalomethanes in drinking water. These studies involved 

mixed exposures to the trihalomethane compounds (chloroform, dichlorobromomethane, bromoform, and 

dibromochloromethane), and many did not analyze for possible risks associated with bromoform or 

dibromochloromethane water concentrations. These data are inadequate for establishing a causal 

relationship between trihalomethane exposure and reproductive and/or developmental toxicity. The 

animal data suggest that exposure to bromoform or dibromochloromethane does not cause histological 

damage to reproductive organs or impair reproductive function; although high-dose exposure may result 

in reduced fertility. The available developmental toxicity data suggest that bromoform and 
BROMOFORM AND DIBROMOCHLOROMETHANE 13 

2. RELEVANCE TO PUBLIC HEALTH 

dibromochloromethane may be toxic to the developing fetus, but these data are inadequate to establish 

firm conclusions. 

The carcinogenicity of bromoform and dibromochloromethane has been studied in both humans and 

laboratory animals. The human data consist of studies of trihalomethane exposure via tap water. As with 

the reproductive and developmental toxicity studies, these data are inconclusive and do not establish 

causal relationships. Carcinogenic effects have been observed in animals exposed to bromoform and 

dibromochloromethane. Chronic oral exposure to bromoform resulted in increases in the occurrence of 

intestinal tumors in female rats. Dibromochloromethane induced liver tumors in male and female mice. 

The Department of Health and Human Services (DHHS) has not categorized the human carcinogenic 

potential of bromoform or dibromochloromethane. The International Agency for Research on Cancer 

(IARC) concluded that there were inadequate human data and limited animal data and assigned 

bromoform and dibromochloromethane to weight of evidence category 3, not classifiable as to 

carcinogenicity in humans. EPA classified bromoform as a probable human carcinogen, group B2 and 

dibromochloromethane as a possible human carcinogen, group C. 

The primary targets of bromoform and dibromochloromethane toxicity—liver, kidney, and central 

nervous system—are discussed in greater detail below. The reader is referred to Section 3.2, Discussion 

of Health Effects by Route of Exposure, for additional information on other health effects. 

Liver Effects. Acute, intermediate-, and chronic-duration studies in laboratory animals provide strong 

evidence that the liver is the critical target of bromoform and dibromochloromethane toxicity. There are 

very limited human data on the toxicity of these two compounds; data for other trihalomethanes, 

particularly chloroform, suggest that the liver would also be a target of toxicity in humans. 

There is strong evidence that the hepatotoxicity of bromoform and dibromochloromethane is due to their 

metabolism to reactive intermediates and highly reactive trihalomethyl free radicals. At lower doses, the 

hepatotoxicity of bromoform and dibromochloromethane is characterized by fatty infiltration, cellular 

vacuolization and swelling, and increases in liver weight. Consistent with the accumulation of lipids is 

the observed decrease in serum triglyceride levels and alterations in serum cholesterol levels. At higher 

doses, focal centrolobular necrosis and increases in SGOT and SGPT levels have been observed. For 

bromoform, the LOAEL is 50 mg/kg (5 days/week; 36 mg/kg/day) for fatty changes observed in rats 

administered bromoform in corn oil via gavage for 13 weeks. Necrosis was observed in rats receiving 

gavage doses of 200 mg/kg (143 mg/kg/day), 5 days/week for 2 years, but not after 13 weeks of dosing. 
BROMOFORM AND DIBROMOCHLOROMETHANE 14 

2. RELEVANCE TO PUBLIC HEALTH 

For dibromochloromethane, the LOAEL is 40 mg/kg (5 days/week; 28 mg/kg/day) for fatty liver changes 

in rats receiving gavage doses of dibromochloromethane in corn oil for 2 years. Necrosis was observed at 

173 mg/kg/day in rats exposed via the diet for 1 month. 

Species and possible gender differences in the hepatotoxicity of bromoform and dibromochloromethane 

have been identified. Rats appear to be more sensitive than mice to the liver effects. Under similar 

exposures scenarios, respective NOAEL and LOAEL values of 25 and 50 mg/kg (5 days/week) for fatty 

changes were identified in rats exposed to bromoform for 13 weeks; the NOAEL and LOAEL values in 

mice were 100 and 200 mg/kg (5 days/week), respectively. For dibromochloromethane, the NOAEL and 

LOAEL values for fatty changes following a 13-week gavage exposure (5 days/week) were 30 and 

60 mg/kg for rats and 125 and 250 mg/kg for mice. 

Kidney Effects. Renal effects have not been consistently found in studies of laboratory animals, 

particularly in the case of bromoform exposure. One study reported mesangial nephrosis in mice exposed 

to 145 mg/kg/day bromoform via gavage for 14 days and identified a NOAEL of 37 mg/kg/day. 

Comprehensive intermediate- and chronic-duration studies in rats and mice did not find significant renal 

effects at doses as high as 400 mg/kg (5 days/week; 286 mg/kg/day). In contrast, exposure to 

dibromochloromethane resulted in mesangial hyperplasia in mice exposed to ≥37 mg/kg/day via gavage 

for 14 days. Toxic nephropathy was observed in rats and mice exposed to 250 mg/kg (179 mg/kg/day) 

for 13 weeks and in mice receiving gavage doses of 100 mg/kg (71 mg/kg/day) for 2 years. 

Central Nervous System Depression. In children, oral doses of around 60 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. The onset of 

sedation after ingestion is rapid, reportedly minutes in children and about an hour in mice. In 

intermediate and chronic oral studies in animals, doses of bromoform ≥100 mg/kg (5 days/week; 

71 mg/kg/day) caused lethargy. Airborne concentrations of bromoform leading to central nervous system 

depression in humans are not known, but brief exposures of laboratory animals to high concentrations 

(7,000 ppm) leads to deep sedation within minutes. Central nervous system effects were also observed in 

laboratory animals at a concentration of 240 ppm in a short-term, repeated dose study. 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. 
BROMOFORM AND DIBROMOCHLOROMETHANE 15 

2. RELEVANCE TO PUBLIC HEALTH 

2.3 MINIMAL RISK LEVELS (MRLs) 

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for bromoform and 

dibromochloromethane. An MRL is defined as an estimate of daily human exposure to a substance that is 

likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of 

exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of 

effect or the most sensitive health effect(s) for a specific duration within a given route of exposure. 

MRLs are based on noncancerous health effects only and do not consider carcinogenic effects. MRLs can 

be derived for acute, intermediate, and chronic duration exposures for inhalation and oral routes. 

Appropriate methodology does not exist to develop MRLs for dermal exposure. 

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), 

uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional 

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

example, acute inhalation MRLs may not be protective for health effects that are delayed in development 

or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic 

bronchitis. As these kinds of health effects data become available and methods to assess levels of 

significant human exposure improve, these MRLs will be revised. 

The details regarding calculations of the MRLs for bromoform and dibromochloromethane are described 

in Appendix A. 

Inhalation MRLs 

MRLs for acute- (≤14 days), intermediate- (15–364 days), and chronic-duration (≥364 days) inhalation 

exposure to bromoform or dibromochloromethane have not been derived because quantitative data were 

not available to determine NOAELs or LOAELs. 

Information on the toxicity of bromoform or dibromochloromethane in humans following inhalation 

exposure was not available. Brief summaries of adverse effects in laboratory animals following 

inhalation exposure to bromoform, reported in abstract form, do not provide sufficient basis for MRL 

derivation. No studies were located regarding effects of dibromochloromethane in animals exposed via 

inhalation. Therefore, inhalation MRLs were not derived for either bromoform or dibromochloromethane. 
BROMOFORM AND DIBROMOCHLOROMETHANE 16 

2. RELEVANCE TO PUBLIC HEALTH 

Oral MRLs 

Bromoform 

•	 An MRL of 0.7 mg/kg/day has been derived for acute-duration oral exposure (14 days or less) to 

bromoform. 

The acute toxicity of bromoform has been investigated in a number of animal studies. These studies have 

identified several targets of toxicity. The available data suggest that the liver is the most sensitive target. 

The threshold for liver effects appears to be between 50 and 125 mg/kg/day. Increases in absolute and 

relative liver weights were observed in mice exposed to 125 mg/kg/day bromoform in emulphor in water 

for 14 days (Munson et al. 1982). Centrilobular pallor, considered to be indicative of hepatocellular 

degeneration, was observed at 145 mg/kg/day in mice receiving gavage doses of bromoform in corn oil 

for 14 days (Condie et al. 1983). Hepatocellular vacuolization and/or swelling was observed at 

200 mg/kg (9 days/11 days) and higher (Coffin et al. 2000). Other effects observed in acute-duration 

animal studies include mesangial nephrosis in mice exposed to 145 mg/kg/day via gavage for 14 days 

(Condie et al. 1983), central nervous system depression, as evidenced by lethargy, labored and shallow 

breathing, and ataxia in rats and mice at ≥600 mg/kg/day for 1–14 days (Balster and Borzelleca 1982; 

Bowman et al. 1978; NTP 1989a), and developmental effects (increases in the occurrence of skeletal 

anomalies) in the offspring of rats exposed to 200 mg/kg/day on gestational days 6–15 (Ruddick et al. 

1983). 

The Condie et al. (1983) and Munson et al. (1982) studies identify the lowest LOAELs for liver effects. 

The Condie et al. (1983) study identified a NOAEL of 72 mg/kg/day and LOAEL of 145 mg/kg/day for 

centrilobular pallor in mice receiving daily gavage doses of bromoform in corn oil for 14 days. Focal 

inflammation and increase in SGPT levels were observed at 280 mg/kg/day. The Munson et al. (1982) 

study identified a NOAEL of 50 mg/kg/day and LOAEL of 125 mg/kg/day for increases in absolute and 

relative liver weights in mice receiving daily gavage doses of bromoform in a 10% emulphor/de-ionized 

water solution for 14 days. At 250 mg/kg/day, increases in SGOT and SGPT levels were also observed. 

The Condie et al. (1983) study was selected as the basis of the MRL because it identified a higher 

NOAEL for liver effects than the Munson et al. (1982) study and included histopathological examination 

of the liver which was not included in the Munson et al. (1982) study. The NOAEL of 72 mg/kg/day was 

divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human 

variability) to yield an acute-duration oral MRL of 0.7 mg/kg/day. 
BROMOFORM AND DIBROMOCHLOROMETHANE 17 

2. RELEVANCE TO PUBLIC HEALTH 

•	 An MRL of 0.2 mg/kg/day has been derived for intermediate-duration oral exposure (15–
 

364 days) to bromoform.
 

The oral toxicity database in animals provides strong evidence that the liver is the most sensitive target of 

bromoform toxicity. Several intermediate-duration studies have reported liver effects, typically at the 

lowest dose level. At lower doses, fatty changes, characterized as hepatocellular vacuolization and 

swelling, were observed in rats and mice. Focal necrosis was observed at higher oral doses. The lowest 

LOAEL for liver effects identified in an intermediate-duration study is 50 mg/kg in rats receiving gavage 

doses of bromoform in corn oil 5 days/week for 13 weeks (NTP 1989a); this study identified a NOAEL of 

25 mg/kg. The intermediate-duration oral MRL of 0.2 mg/kg/day for bromoform was derived by 

applying an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human 

variability) to the duration-adjusted NOAEL of 18 mg/kg/day. 

•	 An MRL of 0.02 mg/kg/day has been derived for chronic-duration oral exposure (365 days or 

more) to bromoform. 

Three studies have examined the chronic toxicity of bromoform in animals. Rat and mouse studies 

conducted by NTP (1989a) are comprehensive studies that found fatty liver changes (hepatocellular 

vacuolization) at the lowest dose tested, 100 mg/kg (5 days/week; 71 mg/kg/day). The third study (Tobe 

et al. 1982) identified a similar LOAEL (140 mg/kg/day) in rats exposed to bromoform in the diet for 

2 years; this study also identified a NOAEL of 35 mg/kg/day. At 140 mg/kg/day, yellowing of the liver 

and increased absolute and relative liver weights were observed. The NTP (1989a) rat study was selected 

as the basis of the chronic-duration oral MRL for bromoform. Even though the Tobe et al. (1982) study 

identified a NOAEL for liver effects, this study was not selected as the critical study because no 

histological examination of the liver was conducted and the results were poorly reported. The durationadjusted LOAEL of 71 mg/kg/day was divided by an uncertainty factor of 300 (3 for use of a minimal 

LOAEL, 10 for animal to human extrapolation, and 10 for human variability) and a modifying factor of 

10 to account for the identification of a lower LOAEL in a 13-week study (NTP 1989a) resulting in an 

MRL of 0.02 mg/kg/day. 

Dibromochloromethane 

•	 An MRL of 0.1 mg/kg/day has been derived for acute-duration oral exposure (14 days or less) to 

dibromochloromethane. 
BROMOFORM AND DIBROMOCHLOROMETHANE 18 

2. RELEVANCE TO PUBLIC HEALTH 

The available data on the oral toxicity of dibromochloromethane in animals strongly suggest that the liver 

is the most sensitive target of toxicity. In most studies, liver effects are observed at lower doses than 

kidney effects (the next most sensitive end point). The study of Condie et al. (1983) was selected as the 

basis for the acute-duration oral MRL for dibromochloromethane because it showed dose-related 

incidences of liver and kidney lesions and identified the lowest LOAEL for liver effects among the 

available studies. A LOAEL of 37 mg/kg/day, the lowest dose tested, was identified for liver damage 

(hepatocellular vacuolization) in mice administered dibromochloromethane in corn oil for 14 consecutive 

days. A reliable NOAEL for liver or kidney effects could not be determined from the available acute 

data. Applying an uncertainty factor of 300 (3 for use of a minimal LOAEL, 10 for extrapolation from 

animals to humans, and 10 for human variability) to the LOAEL of 37 mg/kg/day yields an acute-duration 

oral MRL of 0.1 mg/kg/day for dibromochloromethane. 

No data were located regarding the toxicity of dibromochloromethane following intermediate-duration 

oral exposure in humans. A number of intermediate-duration studies of rats and mice were located. The 

liver was identified as the most sensitive target. Hepatocellular vacuolization was observed at 

43 mg/kg/day (60 mg/kg, 5 days/week) and higher (Aida et al. 1992; Daniel et al. 1990; NTP 1985); the 

highest NOAEL for liver effects is 21 mg/kg/day (30 mg/kg, 5 days/week) (NTP 1985). At higher doses 

(≥100 mg/kg/day), proximal tubular degeneration and nephropathy were observed (Daniel et al. 1990; 

NTP 1985). Impaired humoral immune function was observed in mice administered 125 mg/kg/day via 

gavage for 14 days (Munson et al. 1982). Several animal studies also reported neurological effects: 

decreases in brain weight and decreases in operant behavior at ≥100 mg/kg/day (Balster and Borzelleca 

1982; Daniel et al. 1990). Borzelleca and Carchman (1982) found decreases in fertility at high 

dibromomochloromethane doses (685 mg/kg/day). 

Derivation of an intermediate-duration oral MRL for dibromochloromethane based on the NTP (1985) rat 

study, which identified NOAEL and LOAEL values of 21 and 43 mg/kg/day, was considered. However, 

the resultant MRL would be higher than the acute-duration oral MRL. 

•	 An MRL of 0.09 mg/kg/day has been derived for chronic-duration oral exposure (365 days or 

less) to dibromochloromethane. 

Studies of dibromochloromethane consistently indicate that the liver is a target organ. The NTP (1985) 

study, in which rats received gavage doses of 0, 40, or 80 mg/kg of dibromochloromethane in corn oil, 

5 days/week, for 104 weeks, was selected as the basis for the chronic-duration oral MRL. This study 

(NTP 1985) was selected because it showed dose-related incidences of microscopic hepatic lesions and 
BROMOFORM AND DIBROMOCHLOROMETHANE 19 

2. RELEVANCE TO PUBLIC HEALTH 

also identified the lowest LOAEL of 40 mg/kg (duration-adjusted LOAEL of 28 mg/kg/day) for hepatic 

effects in chronic studies (NTP 1985; Tobe et al. 1982) of dibromochloromethane toxicity. A chronicduration oral MRL of 0.09 mg/kg/day was derived by applying an uncertainty factor of 300 (3 for use of a 

minimal LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability) to the 

LOAEL of 28 mg/kg/day. 

BROMOFORM AND DIBROMOCHLOROMETHANE 21 

3. HEALTH EFFECTS 

3.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of bromoform and 

dibromochloromethane. It contains descriptions and evaluations of toxicological studies and 

epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and 

toxicokinetic data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons living or working near 

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, 

oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, 

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure 

periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). 

Levels of significant exposure for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-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. "Serious" effects are those that 

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress 

or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, 

or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a 

considerable amount of judgment may be required in establishing whether an end point should be 

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be 

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the 

Agency has established guidelines and policies that are used to classify these end points. ATSDR 

believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between 
BROMOFORM AND DIBROMOCHLOROMETHANE 22 

3. HEALTH EFFECTS 

"less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is 

considered to be important because it helps the users of the profiles to identify levels of exposure at which 

major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not 

the effects vary with dose and/or duration, and place into perspective the possible significance of these 

effects to human health. 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and 

figures may differ depending on the user's perspective. Public health officials and others concerned with 

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

associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no 

adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans 

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. 

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of bromoform or 

dibromochloromethane are indicated in Tables 3-1 and 3-2 and Figures 3-1 and 3-2. Because cancer 

effects could occur at lower exposure levels, Figures 3-1 and 3-2 also shows a range for the upper bound 

of estimated excess risks, ranging from a risk of 1 in 10,000 to 1 in 10,000,000 (10-4 to 10-7), as developed 

by EPA. 

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in 

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 

3.2.1 Inhalation Exposure 

No studies were located regarding health effects of bromoform or dibromochloromethane in humans 

following inhalation exposure. In animals, there are limited data from several older studies on the effects 

of inhalation exposure to bromoform; no studies were located regarding effects of dibromochloromethane. 

3.2.1.1 Death 

Inhalation of very high concentrations (56,000 or 84,000 ppm) of bromoform vapor for 1 hour has been 

reported to cause death in dogs (Merzbach 1928). The chief symptoms noted were initial excitation 
BROMOFORM AND DIBROMOCHLOROMETHANE 23 

3. HEALTH EFFECTS 

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. 

3.2.1.2 Systemic Effects 

No studies were located regarding respiratory, cardiovascular, gastrointestinal, hematological, 

musculoskeletal, endocrine, dermal, ocular, or body weight effects in animals or humans following 

inhalation exposure to bromoform or dibromochloromethane. 

Hepatic Effects. Two studies (Dykan 1962, 1964; published in Russian and available only as the 

English abstract) indicate that inhalation exposure of animals to high concentrations of bromoform leads 

to hepatic injury. Exposure of rats to 240 ppm of bromoform for 10 days resulted in dystrophic and 

vascular changes in the liver, with altered hepatic metabolism (Dykan 1964). Longer-term exposure 

(2 months) to concentrations of 24 ppm also led to hepatic changes (decreased blood clotting and 

impaired glycogenesis) (Dykan 1962). No significant alterations were observed after exposure to 4.8 ppm 

(Dykan 1964). These changes appear to resemble the changes produced after oral exposure to bromoform 

(see Section 3.2.2.2), suggesting that the hepatotoxicity of bromoform is not route-specific. 

Renal Effects. Similar to the hepatic effects, exposure to 240 ppm bromoform for 10 days resulted in 

dystrophic and vascular changes in the kidney with altered renal filtration (Dykan 1964). A 2-month 

exposure to 24 ppm resulted in proteinuria and decreased creatinine clearance (Dykan 1962). A 

concentration of 4.8 ppm was estimated to be without significant effects on the kidney (Dykan 1964). 

These changes appear to resemble the changes produced after oral exposure to bromoform (see 

Section 3.2.2.2). 

3.2.1.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological effects in humans or animals after inhalation exposure 

to bromoform or dibromochloromethane. 
BROMOFORM AND DIBROMOCHLOROMETHANE 24 

3. HEALTH EFFECTS 

3.2.1.4 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 

bromoform or dibromochloromethane: 

3.2.1.5 Reproductive Effects 

3.2.1.6 Developmental Effects 

3.2.1.7 Cancer 

3.2.2 Oral Exposure 

Most information on the health effects of bromoform and dibromochloromethane 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 dibromochloromethane in humans. Summaries of studies that provide reliable quantitative toxicity 

data are presented in Table 3-1 and Figure 3-1 for bromoform and in Table 3-2 and Figure 3-2 for 

dibromochloromethane. The main conclusions from these studies are discussed below. 

3.2.2.1 Death 

Bromoform. 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; Kobert 1906; Roth 1904 as cited in von Oettingen 1955). The principal clinical signs 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). If death could be 

averted, recovery was generally complete within several days (Benson et al. 1907; Burton-Fanning 1901; 
Table 3-1 Levels of Significant Exposure to Bromoform 

Exposure/ 

- Oral 

LOAEL 

a

Key to 

Figure 

ACUTE EXPOSURE 

Species 

(Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

Serious

(mg/kg/day) 

Reference Chemical Form 

Death 

1 Human 1 d 445 F (single child died due to overdose) Dwelle 1903 2 Rat 1 day (Sprague- (GO) 1147 F (LD50) Chu et al 1982a Dawley) 3 Rat (G) 

(SpragueDawley) 

1388 M 

b 

1147 F 

(LD50) (LD50) 

Chu et al. 1980 

4 Rat 1 d 

(Fischer- 344) (GO) 933 (LD50) 

NTP 1989a 5 Rat 14 d (Fischer- 344) 1x/d 600 (100% mortality) NTP 1989a 

(GO) 

6 Mouse 1 d 

(ICR) (GW) 

b 

1400 M (LD50) Bowman et al 1978 1550 F (LD50) 

7 Mouse 1 d 

(B6C3F1) (GO) 

b 

707 M (LD50) NTP 1989a 

1072 F (LD50) 
Table 3-1 Levels of Significant Exposure to Bromoform - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

Systemic 

8 Rat 

(Fischer- 344) 

14 d 1x/d (GO) 

Endocr 600 800 (enlarged thyroid gland) 

NTP 1989a 

Bd Wt 200 M 400 M (14% decreased body 

weight gain) 

9 Rat 1 d 

(G) Hepatic 1440 

Plaa and Hewitt 1982a 

10 Rat 

(Fischer- 344) 

7 d (GW) Endocr 190 M 380 M (decreased serum testosterone) 

Potter et al 1996 

Bd Wt 380 M 

11 Mouse 

(B6C3F1) 

9 doses in 11 

days(GO) 

Hepatic 200 F (hepatocellular 

ballooning andproliferation) 

Coffin et al 2000

12 Mouse 

(B6C3F1) 

11 days (W) Hepatic 300 F (hepatocellular ballooning) Coffin et al 2000 

13 Mouse 

(CD-1) 

14 d 1x/d (GO) 

Hepatic 

c 

72 M 145 M (centrilobular pallor) Condie et al 1983 

Renal 72 M 145 M (mesangial nephrosis) Bd Wt 289 M 
Table 3-1 Levels of Significant Exposure to Bromoform - Oral (continued) 

Exposure/ LOAEL 

a

Key to 

Figure 

Species 

(Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

14 Mouse 

(CD-1) 

14 d 1x/d (GW) 

Hepatic 50 M 125 M (increased absolute and 

relative liver weights) 

Munson et al 1982 

15 Mouse 

(B6C3F1) 

14 d 1x/d (GO) 

Gastro 200 M 400 M (stomach nodules) 

NTP 1989a 

Immuno/ Lymphoret 

16 Mouse 

(CD-1) 

14 d 1x/d (GW) 

125 M 250 M (impaired humoral 

immune function) 

Munson et al 1982 

Neurological 

17 Rat 

(Fischer- 344) 

14 d 1x/d (GO) 

400 600 (lethargy, labored and 

swallowing breathing, ataxia) 

NTP 1989a 

18 Rat 

(Fischer- 344) 

1 d (GO) 500 1000 (shallow breathing) NTP 1989a 

19 Mouse 

(ICR) 

14 days daily (GW) 

9.7 M Balster and Borzelleca 

Bromoform 

20 Mouse 

(ICR) 

1 d (GW) 431 M (ED50 for impaired motor performance) 

Balster and Borzelleca 
Table 3-1 Levels of Significant Exposure to Bromoform - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

21 Mouse 1 d 

(ICR) (GW) 1000 (ataxia, sedation, anesthesia) 

Bowman et al 1978 22 Mouse 14 d 1x/d (B6C3F1) 400 600 (lethargy and ataxia) NTP 1989a 

(GO) 

Developmental 

23 Rat 9 d 

Gd 6-15 (Sprague- 100 200 (skeletal anom.) 

Ruddick et al 1983 

Dawley) (GO) 

INTERMEDIATE EXPOSURE Systemic 

24 Rat 30 d 

(Wistar) (F) Hepatic 56.4 F (hepatocellular vacuolization and 

Aida et al 1992 swelling) 

Bd Wt 187.2 M 617.9 M (24% decreased body 

weight) 

25 Rat 28 d 

(Sprague- (W) Hemato 14 M Chu et al 1982a 

Dawley) 

Hepatic 14 M Renal 14 M Bd Wt 14 M 
Table 3-1 Levels of Significant Exposure to Bromoform - Oral (continued) 

Exposure/ LOAEL

a

Key to Species 

Figure (Strain) 

Duration/

Frequency

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

26 Rat 13 wk 

(Fischer- 344) 5d/wk Resp 200 

NTP 1989a (GO) 

Cardio 200 

Gastro 200 

d 

Hepatic 25 M 50 M (hepatocellular

vacuolization)

Renal 200 Endocr 200 Dermal 200 Bd Wt 200 

27 Mouse 3 wk 5 d/wk (B6C3F1) 

(GO) 

Hepatic 200 F 500 F (hepatocyte hydropic 

degeneration; increased SGPT and sorbitol 

Melnick et al 1998 

dehydrogenase) 

Bd Wt 500 F 
Table 3-1 Levels of Significant Exposure to Bromoform - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

28 Mouse 

(B6C3F1) 

13 wk 5d/wk Resp 400 

NTP 1989a (GO) 

Cardio 400 

Hepatic 100 M 200 M (minimal to moderate 

heptocellular vacuoles) 

Renal 400 Endocr 400 Dermal 400 Bd Wt 400 

29 Mouse 

(Swiss) 

102 d 1x/d Resp 200 

NTP 1989b (GO) 

Hepatic 200 (hepatocullular vacuoles) Renal 200 

Endocr 200 

Neurological 

30 Rat 

(Fischer- 344) 

13 wk 5d/wk 50 M 100 M (lethargy) NTP 1989a 

(GO) 

31 Mouse 

(ICR) 

90 d 1x/d(GW) 

0.9 M 9.2 M (decreased exploratory 

activity) 

Balster and Borzelleca Bromoform
Table 3-1 Levels of Significant Exposure to Bromoform - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

32 Mouse 60 d 

1x/d (ICR) (GW) 

100 M (decreased response 

rate in operant behavior test) 

Balster and Borzelleca Bromoform 33 Mouse 30d 1x/d (ICR) 100 M Balster and Borzelleca 

(GW) Reproductive 

34 Rat 13 wk 

5d/wk (Fischer- 344) 200 NTP 1989a (GO) 

35 Mouse 13 wk 

5d/wk (B6C3F1) 400 

NTP 1989a 

(GO) 

36 Mouse 105 d 

1x/d (Swiss) 200 

NTP 1989b 

(GO) 

CHRONIC EXPOSURE Death 

37 Rat 103 wk 

5d/wk (Fischer- 344) 200 M (decreased survival) NTP 1989a 

(GO) 
Table 3-1 Levels of Significant Exposure to Bromoform - Oral (continued) 

Exposure/ LOAEL 

a

Key to

Figure 

Species 

(Strain) 

Duration/

Frequency

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

Systemic 

38 Rat 103 wk 

(Fischer- 344) 5d/wk Cardio 200

NTP 1989a 

(GO) 

Gastro 100 M 200 M (forestomach ulcer) 

Hemato 100 F 200 F (spleen pigmentation) 

e 

Hepatic 100 (hepatocellular 

vacuolization) 

Renal 200 

Endocr 100 M (pituitary gland 

hyperplasia) 

Dermal 200 Bd Wt 100 200 (>10% decrease in body 

weight gain) 

39 Rat 2 year 

(Wistar) (F) Hepatic 35 F 140 F (yellowing of liver; increased absolute and Tobe et al 1982 

relative liver weight) 

Bd Wt 90 M 590 M (40% decrease in body 

weight gain) 
Table 3-1 Levels of Significant Exposure to Bromoform - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

40 Mouse 103 wk 

5d/wk (B6C3F1) Resp 100 M 

NTP 1989a (GO) 

Cardio 100 M 

Gastro 50 M 100 M (hyperplasia in glandular 

stomach) 

Musc/skel 100 M Hepatic 100 F (hepatocellular 

vacuolization) 

Renal 100 M Endocr 100 F 200 F (follicular cell hyperplasia in thyroid) Dermal 100 M 

Bd Wt 100 M 

Neurological 

41 Rat 103 wk 

(Fischer- 344) 5d/wk 100 (lethargy) NTP 1989a 

(GO) 

Reproductive 

42 Rat 103 wk 

(Fischer- 344) 5d/wk 

(GO) 

b 

100 M 200 F 

200 M (squamous metaplasia in 

prostate) 

NTP 1989a 
Table 3-1 Levels of Significant Exposure to Bromoform - Oral (continued) 

Exposure/ LOAEL
 

a

Key to Species 

Figure (Strain) 

Duration/

Frequency 

(Route)


 

System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

43 Mouse 

(B6C3F1) 

103 wk 5d/wk 

b

100 M 

NTP 1989a 

(GO) 200 F 

Cancer 

44 Rat 103 wk 

5d/wk (Fischer- 344) (GO) 

200 F (CEL: adenomatous NTP 1989a polyps and adenocarcinoma in large 

intestine) 

a The number corresponds to entries in Figure 3-1. 

b Differences in levels of health effects and cancer effects between male and females are not indicated in Figure 3-1. Where such differences exist, only the levels most sensitive gender are presented. c Used to derive an acute-duration oral MRL of 0.7 mg/kg/day; dose divided by an uncertainty factory of 100 (10 for extrapolation from animals to humans and 10 fovariability). d Used to derive an intermediate-duration oral MRL of 0.2 mg/kg/day; dose adjusted for intermittent exposure and divided by an uncertainty factor of 100 (10 for extanimals to humans, and 10 for human variability). e Used to derive a chronic-duration oral MRL of 0.02 mg/kg/day; dose adjusted for intermittent exposure and divided by an uncertainty factory of 300 (3 for extrapolminimal LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability) and a modifying factor of 10 to account for the identification of a lower Lsubchronic study (NTP 1989a). d = day(s); F = female; (F) = food; (G) = gavage; Gastro = gastrointestinal; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; no-observed-adverse-effect level; (W) = water; wk = week(s); x = time(s) 
Death Gastrointestinal Hepatic Renal Endocrine Body Weight Immuno/Lymphor Neurolog

Figure 3-1. Levels of Significant Exposure to Bromoform - Oral 

Acute (≤14 days) 

Systemic 

mg/kg/day 

10000 

6m 9r

2r 3r 1000 4r 21m 

8r 7m 5r 8r 22m 17r 

1 15m 10r 8r 10r 20m 22m 

12m 13m 

15m 11m 10r 8r 16m 

13m 13m 14m 16m 

100 

13m 13m 

14m 

10 19m 

1 

0.1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Respiratory Cardiovascular Gastrointestinal Hematological Renal Endocrine Dermal Body Weight Ne

Figure 3-1. Levels of Significant Exposure to Bromoform - Oral (Continued) 

Intermediate (15-364 days) 

Systemic 

mg/kg/day Hepatic 

1000 

24r 

27m 27m 

28m 28m 28m 28m 28m 28m 

29m 26r 26r 26r 27m 28m 29m 29m 26r 29m 26r 26r 24r 26r 

100 28m 32m 

24r 26r 

26r 

25r 25r 25r 25r 

10 3

1 3

0.1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Death Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal 

Figure 3-1 Levels of Significant Exposure to Bromoform - Oral
 

Chronic (≥365 days)
 

Systemic 

mg/kg/day 

1000 

37r 38r 38r 38r 

100 40m 40m 40m 38r 38r 40m 

40m 

10 

1 

0.1 

0.01 

0.001 

0.0001 

1E-5 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Renal Endocrine Dermal Body Weight Neurological Reproductive 

Figure 3-1 Levels of Significant Exposure to Bromoform - Oral
 

Chronic (≥365 days)
 

Systemic 

mg/kg/day 

1000 

39r 

100 

38r 40m 38r 38r 43m 42r 42r 

40m 40m 38r 40m 40m 38r 39r 41r 43m 42r

10 

1 

0.1 

-4 0.01 10 

-5 0.001 10 

*Doses represent the lowest dose tested per study that produced a tumorigenic -6 0.0001 10 

response and do not imply the existence of a threshold for the cancer endpoint. 

-7 1E-5 10 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Table 3-2 Levels of Significant Exposure to Dibromochloromethane - Oral 

Exposure/ LOAEL 

Duration/ a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

ACUTE EXPOSURE Death 

1 Rat 1 d 848 F (LD50) Chu et al 1982a (Sprague- (GO) 

Dawley) 

2 Rat (G) 1186 M (LD50) Chu et al. 1980 (Sprague- b Dawley) 848 F (LD50) 

3 Rat 1 d 3700 M (100% mortality) Hewitt et al 1983 (Sprague- (GO) 

Dawley) 

4 Rat 1 d 1250 M (4/5 died) NTP 1985 (Fischer- 344) (GO) 

5 Rat 14 d 500 (8 of 10 died) NTP 1985 1x/d (Fischer- 344) 

(GO) 

6 Mouse 1 d b 800 M (LD50) Bowman et al 1978 (ICR) (GW) 

1200 F (LD50) 

7 Mouse 1 d 630 M (3/5 died) NTP 1985 (B6C3F1) (GO) 

8 Mouse 14 d 500 (7 of 10 died) NTP 1985 1x/d (B6C3F1) 

(G) 
Table 3-2 Levels of Significant Exposure to Dibromochloromethane - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a Frequency Reference Key to Species NOAEL Less Serious Serious (Route) Figure (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

9 Hamster 

(Golden Syrian) 

Systemic 

10 Rat 

(SpragueDawley) 

1 d (G) 1 d (GO) Hepatic 2500 M (increased SGPT and OCT levels) 

145 M (LD50) Korz and Gatterman 19

Hewitt et al 1983 

Renal 2500 M 

11 Rat 

(Fischer- 344) 

14 d 1x/d (GO) 

Hepatic 250 500 (mottled liver) NTP 1985 Renal 250 500 (darkened renal 

medullae) 

Bd Wt 125 M 250 M (45% decrease body 

weight gain) 

12 Rat 1 d 

(G) Hepatic 1220 Plaa and Hewitt 1982a 

13 Rat 

(Fischer- 344) 

7 d (GW) Endocr 160 M 310 M (decreased serum testosterone) Potter et al 1996 

Bd Wt 160 M 310 M (14% decrease in body 

weight) 
Table 3-2 Levels of Significant Exposure to Dibromochloromethane - Oral (continued) 

Exposure/ LOAEL 

a

Key to 

Figure 

Species 

(Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

14 Mouse 

(B6C3F1) 

9 doses in 11 day period (GO) 

Hepatic 100 F (hepatocellular 

ballooning and proliferation) 

Coffin et al 2000 15 Mouse (B6C3F1) 11 days (W) Hepatic 170 F (hepatocellular ballooning) Coffin et al 2000 

16 Mouse 

(CD-1) 

14 d 1x/d (GO) 

Hepatic 

c 

37 M (hepatocellular 

vacuolization) 

Condie et al 1983 

Renal 37 M (mesangial hyperplasia) 

Bd Wt 147 M 17 Mouse 

(CD-1) 

14 d 1x/d (GW) 

Hepatic 125 F 250 F (increased relative and 

absolute liver weight, decreased serum glucose, and increased SGPT and SGOT) 

Munson et al 1982 

18 Mouse 

(B6C3F1) 

14 d 1x/d (GO) 

Renal 250 500 (reddened renal 

medullae) 

NTP 1985 

Immuno/ Lymphoret 

19 Mouse 

(CD-1) 

14 d 1x/d (GW) 

50 F 125 F (impaired humoral 

immunity) 

Munson et al 1982 
Table 3-2 Levels of Significant Exposure to Dibromochloromethane - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

Neurological 

20 Rat 14 d 

1x/d (Fischer- 344) 250 500 (lethargy, ataxia) 

NTP 1985 

(GO) 

21 Rat 1 d 

(Fischer- 344) (GO) 160 310 (lethargy) 

NTP 1985 

22 Mouse 14 days 

daily (ICR) 10 M 

Balster and Borzelleca 

(GW) 

23 Mouse 1 d 

(ICR) (GW) 454 M (ED50 for impaired motor performance) 

Balster and Borzelleca Chlorodibromomethane 

24 Mouse 1 d 

(ICR) (GW) 500 (sedation, anesthesia) 

Bowman et al 1978 

25 Mouse 14 d 

1x/d (B6C3F1) 

(GO) 

250 500 (lethargy, ataxia, and 

labored breathing)

NTP 1985

Developmental 

26 Rat 9 d 

Gd 6-15 (Sprague- 200 Ruddick et al 1983 

Dawley) (GO) 

INTERMEDIATE EXPOSURE Death 

27 Rat 13 wk 

5d/wk (Fischer- 344) 250 (18/ 20 died) NTP 1985 

(G) 
Table 3-2 Levels of Significant Exposure to Dibromochloromethane - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

Systemic 

28 Rat 

(Wistar) 

30 d (F) Hepatic 18.3 M 56.2 M (heptocellular vacuolation) 

Aida et al 1992 

Bd Wt 173.3 M 

29 Rat 

(Sprague28 d (W) Hemato 12 M 

Chu et al 1982a 

Dawley) 

Hepatic 12 M Renal 12 M Bd Wt 12 M 
Table 3-2 Levels of Significant Exposure to Dibromochloromethane - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

30 Rat 

(Sprague90 d (GO) Resp 200 

Daniel et al. 1990 Dawley) 

Cardio 200 

Gastro 200 Hemato 200 Hepatic 50 (hepatocellular 

vacuolization) 

Renal 50 100 (tubular degeneration) Endocr 200 Dermal 200 Ocular 200 Bd Wt 50 200 (55% decrease in body 

weight gain) 
Table 3-2 Levels of Significant Exposure to Dibromochloromethane - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

31 Rat 13 wk 

(Fischer- 344) 5d/wk Resp 250 

NTP 1985 (GO) 

Cardio 250 

Gastro 250 Musc/skel 250 Hepatic 30 M 60 M (hepatocellular 

vacuolization) 

Renal 125 250 (toxic nephropathy) Endocr 250 Dermal 250 Bd Wt 125 M 250 M (47% decreased body weight gain) 

Other 250 (salivary gland 

hyperplasia) 

32 Mouse 3 wk 

5 d/wk (B6C3F1) (GO) 

Hepatic 50 F 192 F (hepatocyte hydropic 

degeneration) 

Melnick et al 1998 

b 

100 F (increased relative liver 

weight) 

Bd Wt 417 F 
Table 3-2 Levels of Significant Exposure to Dibromochloromethane - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

33 Mouse 

(B6C3F1) 

13 wk 5d/wk (GO) 

Resp 250 

NTP 1985 Gastro 250 

Hepatic 125 M 250 M (hepatocellular 

vacuolization) 

Renal 125 M 250 M (toxic nephropathy) Endocr 250 Dermal 250 

Bd Wt 250 

Immuno/ Lymphoret 

34 Rat 

(SpragueDawley) 

90 d (GO) 100 200 (34-40% decr. in thymus wt.) 

Daniel et al. 1990 

Neurological 

35 Rat 

(SpragueDawley) 

90 d (GO) 50 F 100 F (decreased absolute brain weight) Daniel et al. 1990 

36 Mouse 

(ICR) 

60 d 1x/d(GW) 

100 M 400 M (decreased response 

rate in operant behaviortest) 

Balster and Borzelleca 

37 Mouse 

(ICR) 

30d 1x/d

(GW) 

100 M 

Balster and Borzelleca 

Chlorodibromomethane
Table 3-2 Levels of Significant Exposure to Dibromochloromethane - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

Reproductive 

38 Rat 90 d 

(Sprague- (GO) 100 

Daniel et al. 1990 

Dawley) 

39 Rat 13 wk 

(Fischer- 344) 5d/wk 250 

NTP 1985

(GO) 

40 Rat 15 d 

(Sprague- (W) 47.8 F 

NTP 1996 

Dawley) 

41 Rat 28-34 d 

(Sprague- (W) 28.2 M 

NTP 1996 Dawley) 46 F 

42 Mouse 2 generations 

(continuous) (ICR) 170 F 685 F (decreased fertility) Borzelleca and Carchm

1982 

(W) 

43 Mouse 13 wk 

5d/wk (B6C3F1) 250 NTP 1985 

(GO) 

Developmental 

44 Mouse 2 generations 

(continuous) (ICR) 685 Borzelleca and Carchm

1982 

(W) 
Table 3-2 Levels of Significant Exposure to Dibromochloromethane - Oral (continued) 

Exposure/ LOAEL 

a

Key to 

Figure 

Species 

(Strain) 

Duration/ 

Frequency

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day)

CHRONIC EXPOSUREDeath

45 Mouse 105 wk

5d/wk (B6C3F1) 100 M (decreased survival) 

NTP 1985 

(GO)

Systemic

46 Rat 2 yr

(Fischer- 344) 5d/wk Resp 80

NTP 1985 

(GO)

Cardio 80Gastro 80Musc/skel 80

d 

Hepatic 40 (fatty change)Endocr 80Dermal 80Bd Wt 80

47 Rat 2 year 

(Wistar) (F) Hepatic 20 M 85 M (yellowing of liver; hypertrophy) Tobe et al 1982 

Bd Wt 20 M 85 M (10% decrease in body 540 M (marked decrease in 

weight gain) body weight gain) 
Table 3-2 Levels of Significant Exposure to Dibromochloromethane - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

48 Mouse 105 wk 

5d/wk (B6C3F1) Resp 100 

NTP 1985 (GO) 

Cardio 100 

Gastro 100 Musc/skel 100 Hepatic 50 F (fatty metamorphosis) Renal 100 M (nephrosis) Endocr 50 F (thyroid follicular cell 

hyperplasia) 

Dermal 100 Bd Wt 50 100 (14-17% decreased 

terminal body weight) 

Reproductive 

49 Rat 2 yr 

(Fischer- 344) 5d/wk 80 NTP 1985 

(GO) 

50 Mouse 105 wk 

5d/wk (B6C3F1) 100 NTP 1985 

(GO) 
Table 3-2 Levels of Significant Exposure to Dibromochloromethane - Oral (continued) 

Exposure/ LOAEL 

a

Key to Species 

Figure (Strain) 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Reference Chemical Form Less Serious (mg/kg/day) Serious (mg/kg/day) 

Cancer 

51 Mouse 

(B6C3F1) 

105 wk 

5d/wk(GO) 

100 (CEL: hepatocellular NTP 1985 adenoma or carcinoma) a The number corresponds to entries in Figure 3-2. b Differences in levels of health effects and cancer effects between male and females are not indicated in Figure 3-2. Where such differences exist, only the levels 

most sensitive gender are presented. c Used to derive an acute-duration oral MRL of 0.1 mg/kg/day; dose divided by an uncertainty factory of 300 (3 for use of a minimal LOAEL, 10 for extrapolation frohumans, and 10 for human variability). 

d Used to derive a chronic-duration oral MRL of 0.09 mg/kg/day; dose adjusted for intermittent exposure and divided by an uncertainty factory of 300 (3 for use of a 10 for extrapolation from animals to humans, and 10 for human variability). Bd Wt = body weight; CNS = central nervous system; d = day(s); F = female; (F) = food; (G) = gavage; Gd = gestation day; Gastro = gastrointestinal; LD50 = lethaLOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observed-adverse-effect level; (W) = water; wk = week(s); x = time(s) 
10000 

Death Hepatic Renal Endocrine Body Weight Immuno/Lymphor Neurological 

Figure 3-2. Levels of Significant Exposure to Dibromochloromethane - Oral 

Acute (≤14 days) 

Systemic 

mg/kg/day 

3r 

10r 10r 

4r 12r

1000 

6m 1r 2r7m 8m 5r 11r 18m 11r 24m 25m 2

23m 

13r 13r 2

17m 11r 18m 11r 11r 25m 2

15m 13r 13r 2

9s 16m 17m 11r 19m 

100 14m

19m 

16m 16m 

10 22m 

1 

0.1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
1000 

Death Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal End

Figure 3-2. Levels of Significant Exposure to Dibromochloromethane - Oral (Continued

Intermediate (15-364 days) 

mg/kg/day 

Systemic 

27r 33m 31r 31r 33m 31r 31r 33m 33m 31r 33m 

30r 30r 30r 30r 30r 

33m 33m 31r 

100 32m 30r 

31r 28r 

32m 30r 30r 

31r 

28r 

29r 29r 29r 

10 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Ocular Body Weight Other Immuno/Lymphor Neurological Reproductive Developme

Figure 3-2. Levels of Significant Exposure to Dibromochloromethane - Oral (Continued) 

Intermediate (15-364 days) 

Systemic 

mg/kg/day 

1000 

42m 44m 

32m 36m 33m 31r 31r 43m 39r 

30r 30r 34r 

28r 42m 31r

100 34r 36m 37m 35r 38r 

30r 35r 40r 41r 

41r 

29r

10

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
Death Respiratory Cardiovascular Gastrointestinal Musculoskeletal Hepatic Renal Endocrine Dermal Body Weight 

Figure 3-2. Levels of Significant Exposure to Dibromochloromethane - Oral (Continue

Chronic (≥365 days) 

Systemic 

mg/kg/day 

1000 

47r 

100 45m 48m 48m 48m 48m 47r 48m 48m 48m 47r 

46r 46r 46r 46r 46r 46r 46r 

48m 46r 48m 48m

47r 47r

10

1 

0.1 

0.01 

0.001 

0.0001 

1E-5 1E-6 

*Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. 1E-7 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans 

d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans 

p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans 

q-Cow a-Sheep g-Guinea Pig 
BROMOFORM AND DIBROMOCHLOROMETHANE 55 

3. HEALTH EFFECTS 

Kobert 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 about 5 g had been fatal. For a 10–20-kg child, this 

corresponds to an approximate dose of 250–300 mg/kg. 

In animal studies, estimates of the acute oral LD50 for bromoform typically range between 707 and 

1,550 mg/kg (Bowman et al. 1978; Chu et al. 1982a; NTP 1989a). There does not appear to be much 

difference in the doses that cause death across species or between sexes. The LD50 values for a 1-day 

exposure to bromoform ranged from 933 to 1,388 mg/kg in rats (Chu et al. 1980; NTP 1989a) and from 

707 to 1,550 mg/kg in mice (Bowman et al. 1978; NTP 1989a). LD50 values ranged from 1,072 to 

1,550 for females and from 707 to 1,388 for males exposed to bromoform for 1 day (Bowman et al. 1978; 

Chu et al. 1980, 1982a; NTP 1989a). Acute, repeated oral exposure to 600 mg/kg/day resulted in 

100%mortality in rats (NTP 1989a). However, only 2/10 mice died from exposure to 800 mg/kg/day 

(NTP 1989a). No deaths were observed in rats and mice administered 200 or 400 mg/kg (5 days/week) 

via gavage for 90 days (NTP 1989a). However, significant reductions in survival were observed in rats 

administered 200 mg/kg via gavage (5 days/week) for 2 years (NTP 1989a). 

In animals, the cause of death following acute oral exposure to bromoform has not been thoroughly 

investigated. Prominent clinical signs include central nervous system depression (Bowman et al. 1978). 

While central nervous system depression is probably an important factor in rapid lethality, some studies 

report death occuring several days after an acute exposure (Bowman et al. 1978; NTP 1989a). This 

suggests that other effects (e.g., hepatic and/or renal injury) may also be important. 

Dibromochloromethane. No studies were located regarding death in humans after oral exposure to 

dibromochloromethane. The acute lethality of dibromochloromethane has been evaluated by several 

animal studies in rats and mice, with LD50 estimates ranging between 800 and 2,650 mg/kg (Bowman et 

al. 1978; Chu et al. 1980, 1982a; Hewitt et al. 1983; NTP 1985). Korz and Gatterman (1997) reported an 

LD50 of 145 mg/kg for a Golden Syrian hamster; however, the experimental details were not reported to 

validate the data. Deaths in animals have been reported from single oral doses as low 300–600 mg/kg 

(NTP 1985). 

In intermediate and chronic oral exposure studies, significant increases in mortality have been observed in 

mice and rats at 250 mg/kg (5 days/week) for exposures of 14–90 days (Chu et al. 1982a; Condie et al. 

1983; Daniel et al. 1990; NTP 1985) and in rats at 100 mg/kg (5 days/week) for exposures up to 2 years 

(NTP 1985). 
BROMOFORM AND DIBROMOCHLOROMETHANE 56 

3. HEALTH EFFECTS 

Gender-related differences in mortality have been observed in rats and mice acutely exposured to 

dibromochloromethane. In rats, females appear to be more sensitive than males; increases in mortality 

were observed at 848 mg/kg in females compared to 1,186 mg/kg in males (Chu et al. 1982a). In 

contrast, increases in mortality were observed at lower doses in males (800 mg/kg) than females 

(1,200 mg/kg) (Bowman et al. 1978). 

The cause of death following oral exposure of animals to dibromochloromethane has not been thoroughly 

investigated. Some of the chief clinical signs observed are those of central nervous system depression 

and other effects, such as hepatic and/or renal injury (Bowman et al. 1978; NTP 1985). 

3.2.2.2 Systemic Effects 

Respiratory Effects. Labored breathing has been observed in animals exposed to lethal doses of 

bromoform and dibromochloromethane (NTP 1985, 1989a); this is likely due to central nervous system 

depression rather than impaired lung function. 

Bromoform. No studies were located regarding respiratory effects in humans after oral exposure to 

bromoform. NTP (1989a) examined the respiratory tract of rats and mice receiving gavage doses of 

bromoform for 90 days or 2 years. No histological alterations were observed in the intermediate-duration 

studies or in female rats and male and female mice in the chronic-duration study. An increased incidence 

of chronic inflammation of the lungs was observed in male rats exposed to 100 or 200 mg/kg 

(5 days/week). 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 infection by the virus or slower to recover (NTP 1989a). 

Dibromochloromethane. No studies were located regarding respiratory effects in humans after oral 

exposure to dibromochloromethane. No histological alterations in the respiratory tract were observed in 

rats and mice administered gavage doses of up to 250 mg/kg (days/week) for 90 days or 80–100 mg/kg 

(5 days/week) (NTP 1985). 
BROMOFORM AND DIBROMOCHLOROMETHANE 57 

3. HEALTH EFFECTS 

Cardiovascular Effects. 

Bromoform. No studies were located regarding cardiovascular effects in humans after oral exposure to 

bromoform. Histological examination of rats and mice exposed to up to 100–200 mg/kg (5 days/week) 

bromoform by gavage for up to 2 years revealed no evidence of adverse effects upon the heart (NTP 

1989a). While this indicates that cardiac tissue is not directly injured by bromoform, indirect effects on 

cardiovascular functions might occur as a consequence of the central nervous system depressant activity 

of these compounds. 

Dibromochloromethane. No studies were located regarding cardiovascular effects in humans after oral 

exposure to dibromochloromethane. Decreased heart rates and increased blood pressure were observed in 

male rats following the administration of a single gavage dose (83–667 mg/kg) of dibromochloromethane 

(Müller et al. 1997). However, a dose-related trend was not exhibited for these. While this suggests that 

cardiac function may be impaired by dibromochloromethane exposure, it is unclear if effects are caused 

by the direct action on cardiac function or if they are indirectly caused as a result of central nervous 

system depression. No histological alterations to cardiac tissue were observed in intermediate- and 

chronic-duration studies of dibromochloromethane administered to rats and mice via gavage (NTP 1985). 

Gastrointestinal Effects. 

Bromoform. No studies were located regarding gastrointestinal effects in humans after oral exposure to 

bromoform. NTP (1989a) examined the esophagus, stomach, and intestines of rats and mice orally 

exposed to bromoform. Stomach nodules were observed in male and female mice following 14 days of 

exposure to 400 and 600 mg/kg/day, respectively (NTP 1989a). The biological significance of these 

nodules is not certain, but it is likely that they are a response to a direct irritant effect of bromoform on the 

gastric mucosa. In chronic-duration studies, histological alterations were observed in male rats and male 

mice. Forestomach ulcers were observed in male rats at 200 mg/kg (5 days/week) (NTP 1989a) and 

hyperplasia of the glandular stomach was observed in male mice at 100 mg/kg (5 days/week) (NTP 

1989a). No stomach lesions were observed in female rats or mice exposed to bromoform at doses up to 

200 mg/kg. The histological observations in NTP (1989a) suggest that males may be more sensitive to 

gastrointestinal effects from acute and chronic bromoform exposures than females. In acute studies, the 

onset of stomach nodules occurred at a lower dose level in males (400 mg/kg) than in females 

(600 mg/kg). In chronic studies, gastrointestinal effects were only observed in males. While these 
BROMOFORM AND DIBROMOCHLOROMETHANE 58 

3. HEALTH EFFECTS 

observations clearly indicate that the stomach may be affected by bromoform, it is possible that the 

exposure regimen (bolus administration) leads to irritant effects in the stomach that might not occur if 

exposure were continuous at lower concentrations in food or drinking water. 

Dibromochloromethane. No studies were located regarding gastrointestinal effects in humans after oral 

exposure to dibromochloromethane. No histological changes of the esophagus, stomach, or intestines 

were observed in mice or rats administered dibromochloromethane via gavage at doses up to 100 mg/kg 

(5 days/week) for up to 2 years (NTP 1985). 

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 bromoform and 

dibromochloromethane. 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 

bromoform or dibromochloromethane on hemoglobin, hematocrit, red blood cells, or white blood cells. 

Musculoskeletal Effects. No studies regarding musculoskeletal effects in humans or animals after 

oral exposure to bromoform or dibromochloromethane. 

Hepatic Effects. The liver is the primary target organ for bromoform and dibromochloromethaneinduced toxicity. Oral exposure to these compounds results in an accumulation of fat in the liver, 

manifested as increased liver weight, appearence of hepatocyte vacuoles, alterations in serum cholesterol 

levels, and decreases in serum triglyceride levels. In addition to fatty liver changes, exposure to 

bromoform and dibromochloromethane results in focal hepatocellular necrosis. The necrosis is typically 

observed at higher doses than the fatty liver. The toxicity of both compounds is greater following gavage 

administration compared to exposure via the diet or drinking water. This is probably due to the large 

bolus dose overwhelming the liver’s ability to detoxify reactive metabolites and the oil vehicle, which 

likely increases absorption. 

Bromoform. Several animal studies have examined the hepatotoxicity of bromoform in rats and mice 

following gavage, drinking water, or dietary exposure. The most sensitive hepatic end point appears to be 

fatty degeneration as indicated by centrilobular pallor observed in mice at 145 mg/kg/day for 14 days 

(Condie et al. 1983) and hepatocellular vacuolization and/or swelling, which has been observed following 

acute gavage exposure to 200 mg/kg (9 days in an 11-day period) (Coffin et al. 2000), acute drinking 

water exposure to 300 mg/kg/day (Coffin et al. 2000), intermediate-duration gavage exposure to 50 mg/kg 
BROMOFORM AND DIBROMOCHLOROMETHANE 59 

3. HEALTH EFFECTS 

(5 days/week) (NTP 1989a), dietary exposure to 56.4 mg/kg/day (Aida et al. 1992), and chronic gavage 

exposure to 100 mg/kg (5 days/week) (NTP 1989a). Increases in relative and/or absolute liver weights, 

although not always consistently found, occur at similar doses (Munson et al. 1982; Tobe et al. 1982). 

Alterations in clinical chemistry parameters associated with the fatty changes (alterations in serum 

triglyceride and cholesterol levels) are typically observed at higher doses. Decreases in serum 

triglyceride levels were observed at 207.5 and 590 mg/kg/day in rats exposed via the diet for 1 or 

24 months, respectively (Aida et al. 1992; Tobe et al. 1982); the no effect levels for this end point are 

56.4 and 90 mg/kg/day, respectively. An increase in serum total cholesterol was observed in rats exposed 

to ≥187.2 mg/kg/day in the diet for 1 month (Aida et al. 1992) and a decrease was found in rats exposed 

to 590 mg/kg/day in the diet for 24 months (Tobe et al. 1982). The data are inadequate to assess whether 

the difference in the direction of change was related to exposure duration or was an inconsistent finding. 

Higher doses of bromoform result in hepatocellular necrosis. Necrosis was observed in rats exposed to 

200 mg/kg (5 days/week) for 2 years (NTP 1989a); focal inflammation has also been observed in mice 

receiving gavage doses of 280 mg/kg for 14 days (Condie et al. 1983). Significant increases in SGPT 

and/or SGOT, which is indicative of hepatocellular damage, were observed in mice at 250– 

289 mg/kg/day for 14 days (Condie et al. 1983; Munson et al. 1982), mice at 500 mg/kg (5 days/week) 

for 3 weeks (Melnick et al. 1998), and rats at 720 mg/kg/day for 24 months (Tobe et al. 1982). A 

decrease in serum glucose levels observed in rats exposed to ≥61.9 mg/kg/day for 1 month (Aida et al. 

1992) or ≥40 mg/kg/day for 24 months (Tobe et al. 1982) and an increase in hexabarbital sleep time 

observed in mice at 125 mg/kg/day for 14 days (Munson et al. 1982) are also indicative of liver damage. 

There are limited data to assess species differences. The results of the NTP intermediate-duration study 

(NTP 1989a) suggest that rats may be more sensitive to the hepatotoxicity of bromoform than mice. The 

NOAEL and LOAEL values for hepatocellular vacuolization were 25 and 50 mg/kg (5 days/week) in rats 

and 100 and 200 mg/kg in mice. Liver damage was the critical end point used for the derivation of acute-, 

intermediate-, and chronic-duration oral MRLs for bromoform, as described in the footnotes for 

Table 3-1 and in Appendix A. 

Dibromochloromethane. A variety of hepatic effects have been observed in rats and mice orally 

exposed to dibromochloromethane. Hepatocellular vacuolization and/or swelling were observed at the 

lowest adverse effect levels. The LOAEL values for this end point are ≥37 mg/kg in acutely exposed 

mice (Coffin et al. 2000; Condie et al. 1983), ≥50 mg/kg in rats and mice exposed for an intermediate 

duration (Aida et al. 1992; Daniel et al. 1990; NTP 1985), and ≥40 mg/kg in rats and mice following 
BROMOFORM AND DIBROMOCHLOROMETHANE 60 

3. HEALTH EFFECTS 

chronic exposure (NTP 1985). Clinical chemistry alterations, which are associated with the fatty changes 

in the liver, include increases in serum cholesterol after a single gavage dose of 1,500 mg/kg (Chu et al. 

1982a) or after a 1-month dietary exposure to 56.2 mg/kg/day (Aida et al. 1992), decreases in serum 

cholesterol at 540 mg/kg/day after a 24-month dietary exposure (Tobe et al. 1982), and decreases in 

serum triglycerides at 173.3 and 20 mg/kg/day following 1- or 24-month dietary exposures, respectively 

(Aida et al. 1992; Tobe et al. 1982). Additionally, increases in liver weight were observed in mice 

administered gavage doses of 250 mg/kg/day for 14 days (Munson et al. 1982) or 100 mg/kg 

(5 days/week) for 3 weeks (Melnick et al. 1998). The increased incidences of hepatocellular vacuoles 

observed at 37 mg/kg/day following acute exposure and 40 mg/kg following chronic exposure (NTP 

1985) were used to derive acute- and chronic-duration oral MRLs for dibromochloromethane, as 

described in the footnotes to Table 3-2 and in Appendix A. 

At higher doses, oral exposure to dibromochloromethane resulted in hepatocellular necrosis. Necrosis 

was found in rats and mice exposed to ≥100 mg/kg (Aida et al. 1992; Daniel et al. 1990; NTP 1985) for 

intermediate durations. Necrosis was not reported following acute-duration exposure; however, increases 

in SGOT and/or SGPT (indicative of hepatocellular damage) were found in rats and mice exposed to 

≥145 mg/kg (Condie et al. 2000; Hewitt et al. 1983; Munson et al. 1982). Necrosis was not found 

following chronic exposure in rats and mice exposed to 80 or 100 mg/kg (5 days/week), respectively 

(NTP 1985). Other liver effects include bile duct hyperplasia in rats exposed to 250 mg/kg (5 days/week) 

for 13 weeks (NTP 1985), hepatocyte hydropic degeneration in mice exposed to 192 mg/kg (5 days/week) 

for 3 weeks (Melnick et al. 1998), and decreased serum glucose levels in rats exposed to 540 mg/kg/day 

for 24 months (Tobe et al. 1982). 

Renal Effects. 

Bromoform. There is some evidence that oral exposure to bromoform can induce kidney damage. 

Condie et al. (1983) noted minimal to slight nephrosis and mesangial hypertrophy in male mice exposed 

to repeated oral doses of 145–289 mg/kg/day of bromoform. In contrast, no significant histopathological 

alterations were detected by NTP (1989a) in rats or mice receiving gavage of 200 mg/kg (5 days/week) of 

bromoform for 2 years. 

Dibromochloromethane. Histological studies performed by NTP (1985) indicate that oral exposure to 

dibromochloromethane 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 
BROMOFORM AND DIBROMOCHLOROMETHANE 61 

3. HEALTH EFFECTS 

7 of 10 animals died. Of greater toxicological concern were effects on the nephron that develop after 

intermediate or chronic exposure to doses of 50–250 mg/kg/day (NTP 1985). These effects were usually 

much more apparent in males than females, and were 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), which found that ingestion of dibromochloromethane tended to impair uptake of para-amino hippuric acid in renal slices prepared from male 

mice exposed to 37–147 mg/kg/day for 2 weeks. 

Endocrine Effects. 

Bromoform. Several endocrine effects have been observed in animals exposed to bromoform; however, 

none of the effects were consistently found. The observed endocrine effects included enlarged thyroid 

gland in rats administered a lethal dose of 800 mg/kg/day for 14 days (NTP 1989a), decreased thyroid 

follicular size and colloid density 90 days after termination of exposure to 360 mg/kg/day (Chu et al. 

1982b), thyroid follicular cell hyperplasia in mice administered 200 mg/kg (5 days/week) for 2 years 

(NTP 1989a), pituitary gland hyperplasia in rats administered 100 mg/kg (5 days/week), but not 

200 mg/kg (NTP 1989a), and decreased serum testosterone levels in rats exposed to 380 mg/kg/day for 

7 days (Potter et al. 1996). 

Dibromochloromethane. Several studies have examined the potential of dibromochloromethane to 

induce histological alterations in endocrine glands following longer-term exposure. No alterations in 

endocrine glands were observed following intermediate-duration exposure of rats to 200 or 

256 mg/kg/day (Chu et al. 1982b; Daniel et al. 1990) or rats or mice to 250 mg/kg for 5 days/week (NTP 

1985). Administration of dibromochloromethane via gavage for 2 years resulted in thyroid follicular cell 

hyperplasia in mice exposed to 50 or 100 mg/kg (5 days/week). No effects were observed in rats 

administered 40 or 80 mg/kg (5 days/week) (NTP 1985). No effects on serum testosterone levels were 

observed in rats given gavage doses of 160 mg/kg/day for 7 days. However, a decrease in levels resulted 

from doses of 310 mg/kg/day (Potter et al. 1996). 

Dermal Effects. No histological alterations were found in the skin of rats and mice exposed to 

bromoform or dibromochloromethane by gavage for up to 2 years (NTP 1985, 1989a). 

Ocular Effects. No histological alterations were found in the eyes of rats and mice exposed to 

bromoform or dibromochloromethane by gavage for up to 2 years (NTP 1985, 1989a). 
BROMOFORM AND DIBROMOCHLOROMETHANE 62 

3. HEALTH EFFECTS 

Body Weight Effects. 

Bromoform. In animals, treatment with bromoform is associated with significant decrements in body 

weight, without concurrent reductions in food intake. The threshold for body weight effects appears to be 

duration-related, as generally observed in the oral exposure studies. In acute repeated-dose oral gavage 

studies (Condie et al. 1983; Munson et al. 1982, NTP 1989a), 4 and 14% decreases in body weight were 

observed in female and male rats, respectively, given 400 mg/kg. No significant, consistently-observed 

effects on body weight were seen in mice administered up to 800 mg/kg. Intermediate-duration studies of 

bromoform appear to present a similar dose-response relationship for body weight effects as the acute 

studies. Body weights of rats were unaffected by bromoform doses of ≤200 mg/kg administered by 

gavage, in feed, or in drinking water (Aida et al. 1992; Chu et al. 1982a; NTP 1989a). Body weights of 

mice treated with 400 mg/kg of bromoform by gavage were slightly (8%) reduced (NTP 1989a). Lower 

adverse effect levels were observed in chronic studies. Body weights were decreased by 4–10% in rats 

and female mice treated with 100 mg/kg of bromoform by gavage, whereas 16–25% decreases in body 

weight gain were noted at 200 mg/kg (NTP 1989a). A chronic feeding study in rats (Tobe et al. 1982) 

showed a dose-response similar to the gavage studies. Body weight reductions of 15% were observed at 

90–150 mg/kg, while reductions of 30–40% were observed at doses above 365 mg/kg. 

Dibromochloromethane. Treatment with dibromochlormethane is also associated with decreased body 

weight gain in animals. Rats appear to be more sensitive than mice to body weight effects. The doseresponse relationship seemed to be sensitive to exposure duration, but was similar for varoius 

adminstration routes (gavage, feed, drinking water). The greater sensitiviy of rats to dibromochloromethane compared with mice was appearent in both acute and intermediate duration exposures (Chu et al. 

1980; Condie et al. 1983; Daniel et al. 1990; Munson et al. 1982; NTP 1985). Rats experienced 20% 

(400 mg/kg/day) and 47% (250 mg/kg/day) decreases in body weight gain from acute and intermediate 

gavage exposures, respectively. In contrast, no effect was seen in mice for these dose levels and 

durations. Duration-related changes to the dose-response were indicated in both species for body weight 

gain decreases of 10% or more. These effects on body weight gain occurred in the range of 250– 

500 mg/kg (acute), 200–250 mg/kg (intermediate), and 70–200 mg/kg (chronic) (Aida et al. 1992; Daniel 

et al. 1990; NTP 1985; Tobe et al. 1982). In chronic exposure studies (NTP 1985; Tobe et al. 1982), 

neither species nor administration route seemed to affect the dose response. 
BROMOFORM AND DIBROMOCHLOROMETHANE 63 

3. HEALTH EFFECTS 

3.2.2.3 Immunological and Lymphoreticular Effects 

There are limited data on the immune and lymphoreticular system toxicity of bromoform and dibromochloromethane. Munson et al. (1982) examined immune function following exposure to both compounds. 

Other studies (Daniel et al. 1990; NTP 1985, 1989a) monitored organ weights or examined tissues for 

histological damage. 

Bromoform. Impaired humoral immune function, as indicated by the response to sheep red blood cells, 

was observed in rats and mice exposed to 125 or 250 mg/kg/day bromoform for 14 days (Munson et al. 

1982), though no adverse effect on cell-mediated immunity was noted. Additionally, male rats exposed to 

bromoform for 2 years appeared to have decreased resistance to a common viral infection (NTP 1989a), 

suggesting functional impairment of the immune system. No histological alterations were observed in 

tissues of the immune or lymphoreticular systems in rats and mice exposed to 200 and 400 mg/kg 

(5 days/week), respectively, for 90 days (NTP 1985) or 100–200 or 200 mg/kg (5 days/week), 

respectively, for 2 years (NTP 1985). 

Dibromochloromethane. Exposure of mice to doses of 125 or 250 mg/kg/day of dibromochloromethane 

for 14 days resulted in impaired humoral immunity (splenic IgM response to sheep red blood cells) 

(Munson et al. 1982). Impaired cellular immunity (popliteal lymph node response to sheep red blood 

cells) was also observed at 250 mg/kg/day. A significant decrease in thymus weight was observed in rats 

exposed to 300 mg/kg/day for 90 days (Daniel et al. 1990). No histological alterations were observed in 

immune or lymphoreticular tissues of rats and mice following intermediate or chronic duration to 250 or 

80–100 mg/kg (days/week), respectively (NTP 1985). 

3.2.2.4 Neurological Effects 

Bromoform. 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 

1900s and was commonly administered to children for relief from whooping cough. Several poisonings 

and a few deaths resulted from accidental overdoses or separation of the emulsion (Benson 1907; BurtonFanning 1901; Dwelle 1903; Stokes 1900; von Oettingen 1955). In mild cases of accidental overdose, 

clinical signs included rapid breathing, constricted pupils, and tremors; more severe cases were 

accompanied by a drunken-like stupor, cyanosis, shallow breathing, and erratic heart rate (Benson 1907; 

Kobert 1906). Actual doses associated with these neurological symptoms are not known with certainty. 
BROMOFORM AND DIBROMOCHLOROMETHANE 64 

3. HEALTH EFFECTS 

Based on experiences with seven cases of accidental bromoform poisonings in children with whooping 

cough, Burton-Fanning (1901) advised initial treatment volumes of 0.03 mL for children under 1 year, 

0.06 mL for those 1–4 years old, and 0.13 mL for children 4–8 years of age, or approximately 25– 

60 mg/kg. Dwelle (1903) reported the case of a 33-month-old girl who was prescribed bromoform for 

relief of whooping cough-induced coughing and vomiting. It is estimated that the girl ingested 

approximately 700 mg bromoform (60 mg/kg/day) and slept undisturbed that night, suggesting the 

occurrence of sedative effects. 

As with humans, high doses of bromoform result in central nervous system depression in animals. 

Impaired performance on neurobehavioral tests is observed at lower doses,. The severity of the central 

nervous system depression is dose-related, with anesthesia and shallow breathing occurring at very high, 

often lethal, doses and ataxia, lethargy, and sedation at lower doses. In rats, lethargy, shallow breathing, 

and ataxia were observed at 600 and 1,000 mg/kg/day (NTP 1989a) following acute exposure. Lethargy 

was also observed at 100 mg/kg (5 days/week) during a 13-week or 2-year exposure (NTP 1989a). In 

mice, anesthesia, ataxia, and sedation were observed following a single dose of 1,000 mg/kg (Bowman et 

al. 1978) and lethargy and ataxia were observed following doses of 600 mg/kg/day for 14 days (NTP 

1989a). No overt signs of neurotoxicity were observed at 100 or 400 mg/kg following gavage 

administration, 5 days/week, for 13 weeks or 2 years (NTP 1989a). 

A series of experiments conducted by Balster and Borzelleca (1982) assessed neurobehavioral 

performance in mice following acute- or intermediate-duration exposures. The ED50 for impaired motor 

performance was 431 mg/kg following a single dose. A decrease in exploratory behavior was observed 

following 9.2 mg/kg/day for 90 days and a decrease in response rate in an operant behavior test following 

doses of 100 mg/kg/day for 60 days. No effect on swimming endurance was observed (9.7 mg/kg/day for 

14 days) or on passive-avoidance learning (100 mg/kg/day for 30 days). 

Dibromochloromethane. No human data on the neurotoxicity of dibromochloromethane were located. 

In animals, central nervous system depression occurs at relatively high doses, as evidenced by lethargy, 

ataxia, and sedation. An acute exposure to 500 mg/kg/day resulted in lethargy, ataxia, sedation, and 

shallow breathing in rats and mice (Bowman et al. 1978; NTP 1985). Lethargy was also observed in rats 

receiving a single gavage dose of 310 mg/kg (NTP 1985). No overt signs of neurotoxicity were observed 

following intermediate-duration exposure to 250 mg/kg (5 days/week) or chronic exposure to 80– 

100 mg/kg (5 days/week) (NTP 1985). Daniel et al. (1990) found a significant decrease in brain weights 

in rats exposed to 100 or 200 mg/kg/day for 90 days. However, no alterations in brain weight or 
BROMOFORM AND DIBROMOCHLOROMETHANE 65 

3. HEALTH EFFECTS 

histopathology were observed at doses as high as 250 mg/kg (5 days/week) for 13 weeks (NTP 1985) or 

80 mg/kg (5 days/week) for 2 years (NTP 1985). 

Some alterations in neurobehavioral performance were observed in mice (Balster and Borzelleca 1982). 

An ED50 of 454 mg/kg was calculated for impaired motor performance following a single dose exposure 

and a decrease in response rate in operant behavior test during a 60-day exposure to 400 mg/kg/day. No 

alterations were observed in swimming endurance (10 mg/kg/day for 14 days), exploratory behavior 

(10 mg/kg/day for 90 days), or passive avoidance learning tests (100 mg/kg/day for 30 days). 

3.2.2.5 Reproductive Effects 

The reproductive toxicity of bromoform and dibromochloromethane has been assessed in a small number 

of human and animal studies. A number of studies have examined the potential association between 

adverse reproductive outcomes (spontaneous abortions, stillbirths, and preterm delivery) and consumption 

of municipal drinking water containing triholomethanes (bromoform, dibromochloromethane, dichloromethane, and chloroform) (Bove et al. 1992, 1995, 2002; Dodds et al. 1999; Kramer et al. 1992; Mills et 

al. 1998; Nieuwenhuijsen et al. 2000; Savitz et al. 1995; Waller et al. 1999). These studies involved 

mixed exposures to trihalomethane compounds and most did not provide bromoform or dibromochloromethane exposure data. Two pregnancy outcome studies (Kramer et al. 1992; Waller et al. 1999) have 

examined risks associated with levels of bromoform or dibromochloromethane in drinking water. A third 

study (Windham et al. 2003) examined the association of altered menstrual cycle function in women 

exposed to trihalomethanes in drinking water. Collectively, the studies provide insufficient evidence for 

establishing a causal relationship between exposure to trihalomethane compounds and adverse 

reproductive outcome. 

The Kramer et al. (1992) study is a population case-control study of pregnant white, non-Hispanic women 

living in communities in Iowa where all drinking water was supplied from a single source. No significant 

associations were found between bromoform or dibromochloromethane levels in the drinking water and 

the risk of prematurity. The odds ratios were 1.1 (95% confidence limit of 0.8–1.4) for communities with 

bromoform levels of 1 μg/L and higher and 1.1 (95% confidence limit of 0.7–1.4) for communities with 

dibromochloromethane levels of 1–3 μg/L. No cases were found in communities with dibromochloromethane levels of 4 μg/L and higher. Similar results were found in the Waller et al. (1999) study. In this 

study, pregnancy health outcomes were examined in pregnant women living in communities with 

groundwater, surface water, or mixed sources of drinking water. The risk of spontaneous abortion was 
BROMOFORM AND DIBROMOCHLOROMETHANE 66 

3. HEALTH EFFECTS 

not significantly associated with bromoform or dibromochloromethane water levels; the percentage of 

pregnancies ending with spontaneous abortions were 9.2, 9.8, and 10.3% in communities with bromoform 

drinking water levels of 0, 1–15, and ≥16 μg/L, respectively, and 9.7, 9.6, and 10.4% for dibromochloromethane levels of 0, 1–30, and ≥31 μg/L, respectively. 

Windham et al. (2003) examined the possible association between trihalomethanes in drinking water and 

menstrual cycle function. Menstrual parameter values in premenopausal women were determined based 

on hormone levels in urine collected during an average of 5.6 menstrual cycles (n=403). Estimates of 

bromoform and dibromochloromethane levels for each cycle were based on residential data (individual 

trihalomethane concentrations measured within a relatively narrow time period around the menstrual 

cycle start date) and utility measurements (quarterly measurements made by water utilities during a 

90-day period beginning 60 days before the cycle start date). Significant associations were found 

between exposure to the top quartile of bromoform (≥12 μg/L) and decreasing menstrual cycle and 

follicular phase length. The age, race, body mass index, income, pregnancy history, and caffeine and 

alcohol consumption-adjusted differences were -0.79 days (95% confidence interval [CI] of -1.4 to -0.14) 

for cycle length and -0.78 days (95% CI -1.4 to -0.14) for follicular phase length. For dibromochloromethane, the differences for the 2–3 quartile (level not reported) and highest quartile (≥20 μg/L) were 

-0.69 days (95% CI of -1.4 to -0.02) and -1.21 days (95% CI of -2.0 to -0.38), respectively, for menstrual 

cycle length and -0.62 days (95% CI of -1.3 to 0.05) and -1.1 days (95% CI of -1.9 to -0.25), respectively, 

for follicular phase length. No associations between bromoform or dibromochloromethane concentration 

and luteal phase length, menses length, or cycle variability were found. Interpretation of the study results 

is limited due to coexposure to other trihalomethanes. 

Bromoform. Data on the reproductive toxicity of bromoform in humans are limited to the trihalomethane 

studies described above. Animal studies have examined the potential of bromoform to induce histological 

alterations (NTP 1989a) and impair reproductive function (NTP 1989b). No histological alterations were 

observed in rats and mice exposed to 200 or 400 mg/kg, respectively, 5 days/week for 13 weeks (NTP 

1989a). Dose related incidences of squamous metaplasia of the prostate gland were observed in male rats 

exposed to 200 mg/kg (5 days/week) for 2 years (NTP 1989a). This lesion may represent a chemical 

effect associated with concurrent inflammatory lesions in this gland, which occurred at similar rates in all 

groups of male rats tested, including vehicle controls. Chronic exposure of mice to 200 mg/kg 

(5 days/week) resulted in no detectable noncancerous histological effects in male reproductive tissues 

(testes, prostate, and seminal vesicles) (NTP 1989a). No nonneoplastic histological alterations were 

observed in female rats or mice receiving gavage doses of 200 mg/kg (5 days/week) for 2 years (NTP 
BROMOFORM AND DIBROMOCHLOROMETHANE 67 

3. HEALTH EFFECTS 

1989a). No adverse effects on reproductive performance or fertility were observed in male and female 

mice receiving gavage doses of 200 mg/kg/day (NTP 1989b). 

Dibromochloromethane. Human data on the reproductive toxicity of dibromochloromethane are limited 

to the trihalomethane studies described above. No histological alterations (testes, prostate, seminal 

vesicles, ovaries, uterus, and mammary gland examined) were observed in rats or mice receiving gavage 

doses of up to 250 mg/kg 5 days/week for 13 weeks (Daniel et al. 1990; NTP 1985) or 80 or 100 mg/kg, 

respectively, 5 days/week for 2 years (NTP 1985). In contrast to these negative findings, female mice 

exposed to dibromochloromethane 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 effects 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 dibromochloromethane on reproduction, but it appears that reproductive tissues and functions are not markedly impaired 

at doses that do not cause frank maternal toxicity. This is supported by a reproductive toxicity study 

conducted by NTP (1996). No alterations in reproductive or fertility indices were observed in female rats 

exposed to 40.3 mg/kg/day dibromochloromethane in drinking water for 35 days (13 days prior to mating, 

during mating, and gestation). 

3.2.2.6 Developmental Effects 

There are limited data on the developmental toxicity of bromoform or dibromochloromethane in humans 

and animals. Several human studies have examined the potential association between exposure to 

trihalomethanes in drinking water and birth outcomes (Dodds et al. 1999; Kramer et al. 1992; Savitz et al. 

1995). However, only one study (Kramer et al. 1992) examined the exposure to individual 

trihalomethanes. In this population-based case control of pregnant white, non-Hispanic women living in 

communities in Iowa where all drinking water was supplied from a single source, no significant 

association between exposure to ≥1 μg/L of bromoform or ≥4 μg/L of dibromochloromethane in tap water 

and increased risk of low birth weight babies and intrauterine growth retardation were found. 

Interpretation of this study is limited by the co-exposure to other trihalomethane compounds. 
BROMOFORM AND DIBROMOCHLOROMETHANE 68 

3. HEALTH EFFECTS 

Bromoform. Human data on the developmental toxicity of bromoform are limited to the trihalomethane 

studies discussed above. One animal study (Ruddick et al. 1983) was identified. No significant 

alterations in the number of resorption sites, fetuses per litter, fetal body weights, fetal malformations, or 

visceral anomalies were observed in the offspring of rats administered up to 200 mg/kg/day bromoform in 

corn oil on gestational days 6–15. Increases in several skeletal anomalies were found in the offspring of 

rats exposed to bromoform, including the presence of a 14th rib, wavy ribs, interparietal deviations, and 

sternebra aberrations. The study authors did not conduct a statistical analysis of the data. However, an 

independent analysis of the data using Fisher Exact test revealed a significant increase in the incidence 

(per fetus and number of affected litters) in sternebra aberrations. 

Dibromochloromethane. Human data on the developmental toxicity of dibromochloromethane are 

limited to the trihalomethane studies discussed above. Two animal studies examined the potential of 

dibromochloromethane to induce developmental effects. In a study by Ruddick et al. (1983) of rats 

receiving gavage doses of up to 200 mg/kg/day on gestational days 6–15, no alterations in the number of 

resorption sites, fetuses per litter, fetal body weights, fetal gross malformations, or skeletal or visceral 

anomalies were found. Borzelleca and Carchman (1982) exposed mice to 685 mg/kg/day of 

dibromochloromethane in drinking water for several generations and detected no significant effect on the 

incidence of gross, skeletal, or soft-tissue anomalies. 

3.2.2.7 Cancer 

No studies were located regarding carcinogenic effects in humans following oral exposure to bromoform 

or dibromochloromethane. There are a number of epidemiological studies that indicate that there may be 

an association between chronic ingestion of chlorinated drinking water (which typically contains 

trihalomethanes including bromoform and dibromochloromethane) 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 

bromoform, dibromochloromethane, or to one or more of the hundreds of other byproducts that are also 

present in chlorinated water. 

Bromoform. A significant increase in the incidence of adenomatous polyps or adenocarcinomas was 

observed in female rats receiving gavage dose of 200 mg/kg, 5 days/week for 2 years (NTP 1989a); a 

nonstatistically significant increase was observed in male rats. The incidences of this relatively rare 

tumor (combined incidences of adenomatous polyps and adenocarcinoma) were 0/50, 0/50, and 3/50 for 
BROMOFORM AND DIBROMOCHLOROMETHANE 69 

3. HEALTH EFFECTS 

males administered 0, 100, or 200 mg/kg and 0/50, 1/50, and 8/50 for females. No significant alterations 

in neoplastic lesions were observed in mice administered up to 100 (males) or 200 (females) mg/kg, 

5 days/week for 2 years (NTP 1989a). The International Agency for Research on Cancer (IARC) 

concluded that there were inadequate human data and limited animal data and assigned bromoform to 

weight of evidence category 3, not classifiable as to carcinogenicity in humans (IARC 1991a, 1999a) and 

EPA classified bromoform as a probable human carcinogen, group B2 (IRIS 2004a). Based on the 

increased occurrence of neoplastic lesions in the large intestines of female rats, EPA derived an oral slope 

factor of 7.9x10-3 (mg/kg/day)-1 (IRIS 2004a). 

Dibromochloromethane. In mice administered gavage doses of 100 mg/kg, 5 days/week for 2 years, 

increases in the incidences of hepatocellular adenomas and carcinomas were observed (NTP 1985). The 

incidence was significantly elevated for hepatocellular adenomas in females (2/50, 4/49, and 11/50 for 0, 

50, and 100 mg/kg), hepatocellular carcinoma in males (10/50 and 19/50 for 0 and 100 mg/kg) and 

combined incidences for hepatocellular adenoma or carcinoma (23/50 and 27/50 for males at 0 and 

100 mg/kg and 6/50, 10/49, and 19/50 for females at 0, 50, and 100 mg/kg). No significant alterations in 

the incidence of neoplastic lesion were observed in male or female rats administered up to 80 mg/kg 

5 days/week for 2 years (NTP 1985). The IARC considered the available data on dibromochloromethane 

carcinogenicity to be not classifiable as to carcinogenicity in humans (group 3) (IARC 1991b, 1999b). 

EPA classified dibromochloromethane as a possible human carcinogen, group C (IRIS 2004b). Based on 

the increased combined incidence of hepatocellular adenoma or carcinoma in female mice, EPA derived 

an oral slope factor of 8.4x10-2 (mg/kg/day)-1 (IRIS 2004b). 

3.2.3 Dermal Exposure 

No studies were located regarding the following health effects in humans or animals after dermal 

exposure to bromoform or dibromochloromethane: 

3.2.3.1 Death 

3.2.3.2 Systemic Effects 

3.2.3.3 Immunological and Lymphoreticular Effects 

3.2.3.4 Neurological Effects 
BROMOFORM AND DIBROMOCHLOROMETHANE 70 

3. HEALTH EFFECTS 

3.2.3.5 Reproductive Effects 

3.2.3.6 Developmental Effects 

3.2.3.7 Cancer 

3.3 GENOTOXICITY 

Bromoform. The in vivo and in vitro genotoxicities of bromoform are examined in numerous studies, the 

results of which are summarized in Tables 3-3 and 3-4, respectively. 

The potential of bromoform to induce gene mutations have reported have shown mixed results in in vitro 

assays. Increases (LeCurieux et al. 1995; Simmon and Tardiff 1978; Simmon et al. 1977) and no effect 

(Kubo et al. 2002; NTP 1989a; Rapson et al. 1980; Varma et al. 1988) on the occurrence of reverse 

mutations have been found in Salmonella tymphimurium; an increase in forward mutations was also 

found in S. tymphimurium (Roldan-Arjona and Pueyo 1993). The clastogenic activity of bromoform has 

been tested in one study (Galloway et al. 1985; NTP 1989a) that found no significant alterations with 

S9 metabolic activation and negative and weakly positive results without metabolic alteration. A 

significant alteration in mitotic aneuploidy was observed in Aspergillus nidulans (Benigni et al. 1993). 

Other tests of genotoxicity included an increase in sister chromatid exchange in human lymphocytes 

(Morimoto and Koizumi 1983) and rat erythroblastic leukemia K3D cells (Fujie et al. 1993), but not in 

Chinese hamster ovary cells (Galloway et al. 1985; NTP 1989a) or oyster toadfish leukocytes (Maddock 

and Kelly 1980); SOS induction in Escherichia coli (Lecurieux et al. 1995); trifluorotymidine resistance 

in mouse lymphoma cells (NTP 1989a). DNA strand breaks were observed in human lymphocytes 

(Landi et al. 1999) and lymphoblastic leukemia cells, but not in primary rat hepatocytes (Geter et al. 

2003a). 

The potential for bromoform to induce chromosome aberrations, micronuclei, sister chromatid exchange, 

and DNA damage was investigated in several in vivo studies, often with conflicting results. An increase 

in chromosome aberrations, in particular chromatid and chromosome breaks, was observed in rats 

receiving five daily gavage doses of 253 mg/kg/day or a single intraperitoneal dose of 25.3 or 253 mg/kg 

(Fujie et al. 1990), but not in mice administered up to 800 mg/kg via intraperitoneal injection (NTP 

1989a). A significant increase in sister chromatid exchange was observed in the bone marrow cells of 

mice receiving 25 mg/kg/day gavage doses for 4 days (Morimoto and Koizumi 1983) and mice receiving 
BROMOFORM AND DIBROMOCHLOROMETHANE 71 

3. HEALTH EFFECTS 

Table 3-3. Genotoxicity of Bromoform In Vivo 

Exposure 

End point Species (test system) route Results Reference 

Nonmammalian systems: 

 Sex-linked recessive Drosophilia melanogaster Feeding + Woodruff et al. 1985; 

lethal NTP 1989a Injection – 

 Reciprocal translocation D. melanogaster Feeding – Woodruff et al. 1985; 

NTP 1989a 

 Micronuclei Pleurodeleswaltl larvae + LeCurieux et al. 1995 

Mammalian systems: 

 Sister chromatid Mouse (bone marrow cell) IP + NTP 1989a 

exchange Mouse (bone marrow cell) oral + Morimoto and Koizumi 

1983 

Chromosomal aberrations Mouse (bone marrow cell) IP – NTP 1989a 

Rat (bone marrow cell) IP + Fujie et al. 1990 

Rat (bone marrow cell) Oral + Fujie et al. 1990 

Micronuclei Mouse (bone marrow cell) IP + NTP 1989a 

Mouse (bone marrow cell) Oral – Stocker et al. 1996 

Mouse (bone marrow cell) IP – Hayashi et al. 1988 

Repairable DNA damage Rat (liver cells) Oral – Stocker et al. 1996 

DNA strand breaks 	 Rat (kidney cells) Oral – Potter et al. 1996 
 

Rat (liver, kidney, Oral – Geter et al. 2003a 
 

duodenum) 
 

+ = positive result; – = negative result; IP = intraperitoneal 
BROMOFORM AND DIBROMOCHLOROMETHANE 72 

3. HEALTH EFFECTS 

Table 3-4. Genotoxicity of Bromoform In Vitro 

Resultsa 

With Without 

End point Species (test system) activation activation Reference 

Prokaryotic organisms: 

Reverse gene mutation Salmonella tymphimurium Simmon and Tardiff 1978; 

Simmon et al. 1977 

TA100 No data + 

TA1535 No data + 

S. typhimurium	 LeCurieux et al. 1995 

TA100 – + 

S. typhimurium – – Kubo et al. 2002 

TA100 

TA98 – – 

S. typhimurium

 TA98 – 

TA100 – 

TA1535 – 

TA1537 – 

Varma et al. 1988 

– 

(+) 

– 

– 

S. typhimurium	 Rapson et al. 1980 

TA100 No data – 

S. typhimurium 

(preincubation assay)

 TA97 

TA98 

TA100 

TA1535 

TA1537 

Forward gene mutation S. typhimurium 

 SOS induction Escherichia coli 

(+) – NTP 1989a 
 

–, –, (+) –, –, – 
 

–, –, – (+), –, – 
 

–, –, – –, –, – 
 

–, –, – –, –, – 
 

No data (+) Roldan-Arjona and Pueyo 
 

1993 

+ + LeCurieux et al. 1995 

Eukaryotic organisms: 

Fungi: 

 Mitotic aneuploidy Aspergillus nidulans No data + Benigni et al. 1993 

Fish: 

 Sister-chromatid Oyster toadfish No data – Maddock and Kelly 1980 

exchange leukocytes 

Mammalian cells: 

Sister-chromatid Human lymphocytes No data + Morimoto and Koizumi 

exchange 1983 

Chinese hamster ovary –, – –, (+) Galloway et al. 1985; 

cells NTP 1989a 
BROMOFORM AND DIBROMOCHLOROMETHANE 73 

3. HEALTH EFFECTS 

Table 3-4. Genotoxicity of Bromoform In Vitro 

Resultsa 

With Without 

End point Species (test system) activation activation Reference 

Rat erythroblastic + + Fujie et al. 1993 

leukemia K3D cells 

 Chromosomal Chinese hamster ovary –, – –, (+) Galloway et al. 1985; 

aberrations cells NTP 1989a 

 Trifluorothymidine Mouse lymphoma cells + + NTP 1989a 

resistance 

DNA strand breaks Human lymphocytes No data + Landi et al. 1999 

Human lymphoblastic + + Geter et al. 2003a 

leukemia cells 

Primary rat hepatocyte – – Geter et al. 2003a 

a

Results from two or more different contract laboratories are separated by commas 

+ = positive result; – = negative result; (+) = marginally positive result 
BROMOFORM AND DIBROMOCHLOROMETHANE 74 

3. HEALTH EFFECTS 

intraperitoneal doses of 800 mg/kg (NTP 1989a). Increases in micronuclei induction were observed in 

mice exposed to 800 mg/kg via intraperitoneal injection (NTP 1989a) and newt larvae following a 6-day 

exposure to 2.5 mg/L (LeCurieux et al. 1995), but not in mice receiving a single intraperitoneal dose of 

175–1,400 mg/kg (Hayashi et al. 1988) or 250–1,000 mg/kg via gavage (Stocker et al. 1997). No 

alterations in unscheduled DNA synthesis were observed in mice administered 324 or 1,080 mg/kg via 

gavage (Stocker et al. 1997). No alterations in DNA strand breaks were observed in the kidneys of rats 

administered 380 mg/kg for 1 day via gavage (Potter et al. 1996) or in the liver, kidney, or duodenum of 

rats administered 152 mg/kg either as a single oral bolus or on drinking water for 2 weeks (Geter et al. 

2003a). An increase in sex-linked recessive mutations was observed in Drosophila melanogaster 

following feeding, but not injection exposure (NTP 1989a); no effect on reciprocal translocations was 

found. 

Dibromochloromethane. The genotoxicity of dibromochloromethane has been assessed in a number of 

in vivo and in vitro assays. The results of these studies are presented in Tables 3-5 and 3-6, respectively. 

Mixed results were found in in vitro bacterial assays for reverse gene mutations, with some studies 

finding significant alterations (Landi et al. 1999; Simmon and Tardiff 1978; Simmon et al. 1977; Varma 

et al. 1988) and others not finding an effect (Kubo et al. 2002; LeCurieux et al. 1995; NTP 1985; Zeiger 

et al. 1987). A significant increase in forward gene mutations was found in mouse lymphoma cells 

(McGregor et al. 1991). An increase in gene conversion, but not gene reversion, was observed in 

Saccharomyces cervisiae (Nestman and Lee 1985). An increase in mitotic aneuploidy was observed in 

A. nidulans and sister chromatid exchange was observed in human lymphocytes (Morimoto and Koizumi 

1983; Sobti 1984), rat liver cells (Sobti 1984), and rat erythroblastic leukemia K3D cells (Fuije et al. 

1993). DNA strand breaks were observed in human lymphoblastic leukemia cells, but not in primary rat 

hepatocytes (Geter et al. 2003a). Additionally, increases in chromosomal aberrations were observed in 

mouse lymphoma cells (Sofuni et al. 1996) and Chinese hamster lung cells (Matsuoka et al. 1996). 

In vivo, oral exposure to 25–200 mg/kg/day for 4 days resulted in dose-related increases in the frequency 

of sister chromatid exchanges in mouse bone marrow cells (Morimoto and Koizumi 1983). An increase 

in the occurrence of chromosomal aberrations was also observed in bone marrow cells of rats receiving a 

single intraperitoneal injection of 20.8 mg/kg (Fujie et al. 1990); a weak positive response was observed 

following gavage administration of 10.5–1,041.5 mg/kg/day for 5 days (Fujie et al. 1990). No significant 

alterations in micronuclei induction (Hayashi et al. 1988), repairable DNA damage (Stocker et al. 1996), 
BROMOFORM AND DIBROMOCHLOROMETHANE 75 

3. HEALTH EFFECTS 

Table 3-5. Genotoxicity of Dibromochloromethane In Vivo 

Exposure 

End point Species (test system) route Results Reference 

Nonmammalian systems: 

 Micronuclei Pleurodeleswaltl larvae – 	 LeCurieux et al. 1995 

Mammalian systems: 

 Sister chromatid Mouse (bone marrow cell) Oral + 	 Morimoto and Koizumi 

exchange 1983 

Chromosomal aberrations Rat (bone marrow cell) IP + Fujie et al. 1990 

Rat (bone marrow cell) Oral (+) Fujie et al. 1990 

 Micronuclei Mouse (bone marrow cell) IP 
 – Hayashi et al. 1988 

Repairable DNA damage Rat (liver cells) Oral 
 – Stocker et al. 1996 

DNA strand breaks Rat (kidney cells) Oral 
 – Potter et al. 1996 

Rat (liver, kidney, Oral – Geter et al. 2003a 

duodenum) 

+ = positive result; – = negative result; (+) = weak positive; IP = intraperitoneal 
BROMOFORM AND DIBROMOCHLOROMETHANE 76 

3. HEALTH EFFECTS 

Table 3-6. Genotoxicity of Dibromochloromethane In Vitro 

Resultsa 

Species (test With Without 

End point system) activation activation Reference 

Prokaryotic organisms: 

Reverse gene mutation 	 Salmonella 
 Simmon and Tardiff 1978; 

typhimurium
 Simmon et al. 1977 

(desiccator sytstem) 
 

TA100 No data + 

S. typhimurium	 LeCurieux et al. 1995 

TA100 – – 

S. typhimurium Kubo et al. 2002 

TA100 – – 

TA98 – – 

S. typhimurium (plate Varma et al. 1988 

incorporation assay) 

TA98 + – 

TA100 + – 

TA1535 + + 

TA1537 + + 

S. typhimurium NTP 1985; Zeiger et al. 

(preincubation assay) 1987 

TA98 – – 

TA100 – – 

TA1535 – – 

TA1537 – – 

S. typhimurium	 Landi et al. 1999 

TPT100 + + 

 RSJ100 – – 

Eukaryotic organisms: 

Fungi: 

 Mitotic aneuploidy Aspergillus nidulans No data + Benigni et al. 1993 

 Gene conversion Saccharomyces – + Nestman and Lee 1985 

cervisiae 

 Gene reversion S. cerevisiae – – Nestman and Lee 1985 

Mammalian cells: 

Forward gene mutation Mouse L5178Y No data + McGregor et al. 1991 

lymphoma cells 

Sister-chromatid exchange	 Human lymphocytes No data + Morimoto and Koizumi 1983 

Human lymphocytes No data + Sobti 1984 

Rat liver cells No data (+) Sobti 1984 

Rat erythroblastic + + Fujie et al. 1993 

leukemia K3D cells 
BROMOFORM AND DIBROMOCHLOROMETHANE 77 

3. HEALTH EFFECTS 

Table 3-6. Genotoxicity of Dibromochloromethane In Vitro 

Resultsa 

Species (test With Without 

End point system) activation activation Reference 

Chromosomal aberrations 	 Mouse L5178Y +,+ (+),– Sofuni et al. 1996 

lymphoma cells 

Chinese hamster lung No data + Matsuoka et al. 1996 

cells 

DNA single strand breaks 	 Human lymphoblastic + + Geter et al. 2003a 

leukemia cells 

Priamry rat hepatocyte – – Geter et al. 2003a 

a

Results from two or more different contract laboratories are separated by commas 

+ = positive result; – = negative result; (+) = marginally positive result 
BROMOFORM AND DIBROMOCHLOROMETHANE 78 

3. HEALTH EFFECTS 

or DNA strand breaks (Potter et al. 1996) were observed in mouse bone marrow cells (intraperitoneal 

injection of 62.5–1,000 mg/kg), rat liver cells (gavage dose of 135 or 450 mg/kg), or rat kidney cells 

(gavage dose of 310 mg/kg), respectively. Likewise, no DNA strand breaks were observed in the liver, 

kidney, or duodenum of rats administered 125 mg/kg either as a single oral bolus or on drinking water for 

2 weeks (Geter et al. 2003a). 

3.4 TOXICOKINETICS 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

There are limited data on inhalation absorption of bromoform or dibromochloromethane. Based on the 

physical-chemical properties of these compounds, and by analogy with other related halomethanes such 

as chloroform (Agency for Toxic Substances and Disease Registry 1997), it is expected that bromoform 

and dibromochloromethane would be well-absorbed across the lung. The occurrence of systemic and 

neurological effects following inhalation exposure of animals to bromoform (see Section 3.2.1) supports 

this view. Aggazzotti et al. (1998) examined the uptake of trihalomethanes in five swimmers exposed to 

trihalomethanes via chlorinated pool water. Although bromoform was detected in the pool water, it was 

only detected in one of four indoor air samples. Dibromochloromethane was detected in the pool water 

(0.8 μg/L) and in air samples before swimming (5.2 μg/m3

) and after swimming (11.4 μg/m3). After 

sitting near the pool for 1 hour, the mean alveolar air level was 0.8 μg/m3

. After swimming, alveolar air 

levels were 1.4 μg/m3

; however, oral and percutaneous exposure also influenced this level. Estimated 

dibromochloromethane uptake during the 1 hour of sitting near the pool ranged from 1.5 to 2.0 μg/hour; 

after 1 hour of swimming, the estimated uptake rate ranged from 14 to 22 μg/hour. 

Several studies have examined the impact of showering with water contaminated with trihalomethanes on 

the absorption of individual trihalomethane compounds. Showering involves inhalation exposure to 

volatilized trihalomethanes, percutaneous exposure, and possibly oral exposure. Several studies have 

found elevated blood bromoform and/or dibromochloromethane levels following showering (Backer et al. 

2000; Lynberg et al. 2001; Miles et al. 2002). A comparative study by Backer et al. (2000) found the 

highest blood levels of dibromochloromethane after a 10-minute shower, compared to bathing for 

10 minutes or drinking 1 L of water in 10 minutes. This difference may be due to differences in total 

exposure levels, metabolism, or excretion rather than differences in absorption efficiencies. 
BROMOFORM AND DIBROMOCHLOROMETHANE 79 

3. HEALTH EFFECTS 

Several studies have estimated the blood:air partition coefficients for bromoform and dibromochloromethane in humans and rats, these values are summarized in Table 3-7. 

3.4.1.2 Oral Exposure 

There are limited data on the absorption of bromoform and dibromochloromethane following oral 

exposure. Most of the available data (Backer et al. 2000; da Silva et al. 1999; Mink et al. 1986) involved 

exposure to a mixture of trihalomethanes. Elevated blood concentrations of dibromochloromethane were 

also observed in humans ingesting drinking water containing trihalomethanes (Backer et al. 2000). 

da Silva et al. (1999) examined bromoform and dibromochloromethane absorption in rats following a 

single gavage dose. Both compounds were rapidly absorbed with peak plasma levels occurring <1 hour 

postexposure. Oral absorption constants of 0.412 and 0.55 per hour were reported for bromoforom and 

dibromochloromethane, respectively. A nonlinear relationship between dose (0.25 and 0.50 mmol/kg; 

63 and 126 mg/kg bromoform and 52 and 104 mg/kg dibromochloromethane) and areas under the blood 

concentration versus time curves (AUCs) were found, suggesting metabolism saturation. The AUCs (20– 

360 minutes postexposure) for 63 and 126 mg/kg bromoform were 48.6 and 190.4 μM/hour; for 52 and 

104 mg/kg dibromochlormethane, the AUCs (20–360 minutes) were 31.2 and 85.6 μM/hour. When 

bromoform and dibromochloromethane were administered along with chloroform and dichlorobromomethane (0.25 mmol/kg of each trihalomethane), the AUC was significantly higher than when 

administered singly. 

Mink et al. (1986) found that 60–90% of the bromoform and dibromochloromethane administered in a 

mixture of trihalomethanes in corn oil to rats (100 mg trihalomethane/kg) or mice (150 mg trihalomethane/kg) were recovered in expired air, urine, or in internal organs. This indicates that gastrointestinal 

absorption was at least 60–90% complete. This is consistent with the ready gastrointestinal absorption 

observed for other halomethanes such as chloroform (Agency for Toxic Substances and Disease Registry 

1997). 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. 

3.4.1.3 Dermal Exposure 

No studies were located regarding dermal absorption of bromoform. A single study was found to 

quantitatively demonstrate dermal absorption of dibromochloromethane in human volunteers exposed for 
Table 3-7. Partition Coefficients for Bromoform and Dibromochloromethane 

Chemical 

Bromoform 

Dibromochloromethane 

Bromoform 

Dibromochloromethane 

Bromoform 

Dibromochloromethane 

Bromoform 

Dibromochloromethane 

Blood:Air 

Fat:Air 

Liver:Air 

Muscle:Air 

Partition coefficient 

102.3 

161 

187 

198.1 

52.7 

49.2 

116 

97.5 

4,129 

1,919 

210.3 

126 

115.1 

55.6 

Species 

Human 

Rat 

Rat 

Rat 

Human 

Human 

Rat 

Rat 

Rat 

Rat 

Rat 

Rat 

Rat 

Rat 

Reference 

Batterman et al. 2002 

Beliveau and Krishnan 

2000 

Beliveau et al. 2000b 

da Silva et al. 1999 

Gargas et al. 1989 

Batterman et al. 2002 

Gargas et al. 1989 

Beliveau et al. 2000b 

da Silva et al. 1999 

Gargas et al. 1989 

da Silva et al. 1999 

Gargas et al. 1989 

da Silva et al. 1999 

Gargas et al. 1989 

BROMOFORM AND DIBROMOCHLOROMETHANE 80 

3. HEALTH EFFECTS 
BROMOFORM AND DIBROMOCHLOROMETHANE 81 

3. HEALTH EFFECTS 

60 minutes to tap water having a temperature similar to that of bathing water (Prah et al. 2002). The 

sealed exposure apparatus was designed to permit the exposure of a single hand and lower arm by 

immersion while preventing an inhalation exposure. The mean tap water concentration of dibromochloromethane was 1.4 ng/mL. Dibromochloromethane levels in the blood increased constantly from the start 

to 5 minutes after the end of the exposure. At 15 minutes after cessation of exposure, blood levels 

appeared to fall slightly slower than the rate of appearance. These data have limited use since rates of 

dermal absorption or appearance in the blood were not reported. 

As discussed under Inhalation Exposure, showering, which involves both inhalation and dermal exposure 

with water contaminated with trihalomethanes, can result in significantly elevated blood bromoform and 

dibromochloromethane levels. Xu et al. (2002) reported dermal absorption coefficients of 0.21 and 

0.20 cm/hour for aqueous solutions of bromoform and dibromochloromethane, respectively. These 

values were determined in vitro using excess breast skin tissues at two temperature settings (20 and 

25 °C). 

3.4.2 Distribution 

Several studies have estimated the tissue:air partition coefficients for bromoform and dibromochloromethane in humans and rats; these values are summarized in Table 3-7. In vitro data, suggest that 

hemoglobin is the primary ligand for bromoform, and presumably dibromochloromethane, in the blood 

(Béliveau and Krishnan 2000b). 

3.4.2.1 Inhalation Exposure 

No studies were located regarding the distribution of bromoform or dibromochloromethane in humans or 

animals following inhalation exposure. However, adverse effects involving several organs (liver, kidney, 

central nervous system) indicate distribution to these sites. 

3.4.2.2 Oral Exposure 

The distribution of bromoform and dibromochloromethane 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 10–40 mg/kg tissue in intestine, liver, kidney, and brain, 
BROMOFORM AND DIBROMOCHLOROMETHANE 82 

3. HEALTH EFFECTS 

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. 

In animals, Mink et al. (1986) found that only about 1–2% of a single oral dose of 14C-labeled dibromochloromethane or bromoform as part of a trihalomethane mixture was retained in the soft tissues of rats 

8 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 3.4.3). 

3.4.2.3 Dermal Exposure 

No studies were located regarding the distribution of bromoform or dibromochloromethane in humans or 

animals following dermal exposure. 

3.4.3 Metabolism 

The metabolism of bromoform, dibromochloromethane, and other trihalomethanes 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 3-3. The first step in 

the metabolism of trihalomethanes 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 

the 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 
X 

OH R-H 

X C X 

GSSG+CO 

HX 

X O
 

cytochrome P-450
 

X C X
 

OH
 

C 

X X 

X C X 

X X CO2 

2HX 

H2O 

2HX 

2GSH 

H COOH 2 H 

C C 

cysteine 

S NH 

C 2HX 

O 

OZT 

*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 

BROMOFORM AND DIBROMOCHLOROMETHANE 83 

3. HEALTH EFFECTS 

Figure 3-3. Proposed Pathway of Trihalomethane Metabolism in Rats* 
BROMOFORM AND DIBROMOCHLOROMETHANE 84 

3. HEALTH EFFECTS 

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 CO2. The 

amount of trihalomethane metabolized by each of these pathways has not been studied in detail, but it 

appears that conversion to CO2 is the main route. However, this depends on the species, the trihalomethane being metabolized, and metabolic conditions (cellular glutathione levels). Mink et al. (1986) 

found that mice oxidized 72% of an oral dose of dibromochloromethane and 40% of an oral dose of 

bromoform to CO2. In contrast, rats oxidized only 18% of dibromochloromethane and 4% of bromoform 

to CO2. 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 that 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 trihalomethanes 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 dibromochloromethane. 

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 

dibromochloromethane and bromoform. Figure 3-4 shows how free radical generation can lead to an 

autocatalytic peroxidation of polyunsaturated fatty acids (PLJFAs) 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 carbon tetrachloride (Agency for Toxicological Substances and Disease Registry 1994), but the significance of this 

pathway in the toxicity of dibromochloromethane and bromoform remains to be determined. 

Development of the general metabolic scheme for trihalomethanes shown in Figure 3-3 relied primarily 

on the use of chloroform and bromoform as model substrates. However, some metabolic data specific to 

dibromochloromethane are available from a series of experiments conducted in rats by Pankow et al. 

(1997). Increased levels of the metabolites bromide (in plasma) and carbon monoxide (as detected by 
cytochrome P-450 

O2 

CHX CX3OO + PUFA PUFA + CX3OOH 3 CX3 NADPH 

O2 PUFAOOH 

PUFAOO 

PUFA 

*Adapted from O’Brien 1988 

X = halogen atom (chlorine, bromine, iodine); PUFA = polyunsaturated fatty acid 

BROMOFORM AND DIBROMOCHLOROMETHANE 85 

3. HEALTH EFFECTS 

Figure 3-4. Proposed Pathway of Trihalomethyl-radical-mediated Lipid 

Peroxidation* 
BROMOFORM AND DIBROMOCHLOROMETHANE 86 

3. HEALTH EFFECTS 

formation of carboxyhemoglobin in blood) and dependence of their rate of production on hepatic GSH 

concentration in rats treated with dibromochloromethane are consistent with the metabolic scheme for the 

oxidative pathway shown in Figure 3-3. Observation of increased hepatic levels of GSSG in dosed rats 

by Pankow et al. (1997) is also consistent with the proposed scheme. The observation of (1) partial 

inhibition of bromide and carboxyhemoglobin production in dosed rats co-administered diethyldithiocarbamate (a potent inhibitor of P-450 isoform CYP2E1) and (2) stimulation of production in rats 

pretreated with isoniazid (a potent inducer of CYP2E1) indicates that cytochrome P-450 isoform 

CYP2E1 is at least partially responsible for oxidative metabolism of dibromochloromethane. 

Pretreatment with phenobarbital (an inducer of CYP2B1/2 in the rat) increased the concentration of 

bromide in plasma, suggesting that CYP2B1/2, as well as CYP2E1, catalyzes metabolism of 

dibromochloromethane in the rat. 

Recent studies suggest that brominated trihalomethanes, including bromoform and dibromochloromethane, may be metabolized by one or more pathways dependent on glutathione conjugation catalyzed 

by glutathione S-transferase (De Marini et al. 1997; Pegram et al. 1977) in addition to the oxidative and 

reductive pathways described above. Transfection of Salmonella typhimurium test strain TA1535 with 

the gene for rat glutathione S-transferase theta 1-1 increased the mutagenicity of bromoform and 

dibromochloromethane (by 95- and 85-fold, respectively) in reverse mutation assays when compared to 

mutagencity in TA1535 transfected with a nonfunctional form of the gene (De Marini et al. 1997). The 

mutational spectra and site specificity for bromoform, dibromochloromethane, and bromodichloromethane (a structurally-related brominated trihalomethane) were closely similar, suggesting bioactivation 

of all three compounds via common metabolic intermediates. The mutagenic metabolites were not 

identified in this study, but S-(1-halomethyl)glutathione, S-(1,1-dihalomethyl) glutathione, or their further 

metabolites were presumed on the basis of data reported for other halomethanes to be capable of reacting 

with DNA to produce the observed mutations (De Marini et al. 1997). 

The formation of reactive metabolites by conjugation of bromoform or dibromochloromethane via 

glutathione S-transferase theta-mediated pathways has not been examined in mammalian test systems. 

However, the metabolism of bromodichloromethane via glutathione conjugation has been investigated in 

vitro using cytosols prepared from human, rat, and mouse liver (Ross and Pegram 2003). Conjugation of 

bromodichloromethane with glutathione in mouse liver cytosol was time- and protein-dependent, was not 

affected by an inhibitor of alpha-, mu-, and pi-class glutathione S-transferases, and was correlated with 

activity toward 1,2-epoxy-3-(4'-nitrophenoxy)propane (a substrate specific for theta-class glutathione 

S-transferases). Conjugation activity toward bromodichloromethane in hepatic cytosols isolated from 
BROMOFORM AND DIBROMOCHLOROMETHANE 87 

3. HEALTH EFFECTS 

different species followed the rank order mouse, followed by rat, then human. The initial conjugate 

formed was S-chloromethyl glutathione. This compound was unstable and degraded to multiple 

metabolites including S-hydroxymethyl glutathione, S-formyl glutathione, and formic acid. These data 

demonstrate that glutathione conjugation of bromodichloromethane occurs in mammalian liver cytosols 

and is likely catalyzed by glutathione S-transferase theta. These findings are significant because 

production of reactive glutathione conjugates from bromodichloromethane may result in formation of 

DNA adducts and thus cause genotoxicity. Because there is structural similarity among the brominated 

trihalomethanes and evidence for common pathways of bioactivation (De Marini et al. 1997), the findings 

of Ross and Pegram (2003) support the idea that glutathione conjugation of bromoform and dibromochloromethane leading to formation of reactive metabolites also occurs in the liver of rodents and 

humans. 

Comparison of catalytic efficiencies for recombinant rat CYP2E1 and glutathione S-transferase theta 1-1 

using bromodichloromethane as a substrate (data on bromoform or dibromochloromethane are not 

available) suggest that glutathione conjugation is likely to be a quantitatively minor hepatic pathway in 

vivo (Ross and Pegram 2003). Although metabolism via this pathway may be minor from the standpoint 

that only a small fraction of the total dose is converted, it might be an important component of the 

mechanism for dibromochloromethane and/or bromoform toxicity in extrahepatic tissues where 

GSTT1-1 is expressed in conjunction with lower levels of CYP2E1. 

3.4.4 Elimination and Excretion 

3.4.4.1 Inhalation Exposure 

No studies were located regarding excretion of bromoform or dibromochloromethane by humans or 

animals following inhalation exposure. 

3.4.4.2 Oral Exposure 

In rats and mice given a single oral dose of 14C-labeled bromoform or dibromochloromethane as part of a 

trihalomethane mixture (100 mg/kg in rats and 150 mg/kg in mice), excretion occurred primarily by 

exhalation of bromoform or dibromochloromethane or of CO2 (Mink et al. 1986). In mice, 39.68 and 

71.58% of the administered radiolabelled bromoform and dibromochloromethane, respectively, were 

exhaled as CO2 and 7.18 and 12.31% as unmetabolized compound, respectively. In contrast, 4.3 and 
BROMOFORM AND DIBROMOCHLOROMETHANE 88 

3. HEALTH EFFECTS 

18.2% of bromoform and dibromochloromethane were exhaled as CO2 in rats and 66.9 and 48.1% of 

parent compound. Only 1–5% of the dose was excreted in urine (the chemical form in urine was not 

determined). The elimination half-times of bromoform and dibromochloromethane were 0.8 and 

1.2 hours, respectively, in rats at 8 or 2.5 hours, respectively, in mice. 

3.4.4.3 Dermal Exposure 

No studies were located regarding excretion of bromoform or dibromochloromethane by humans or 

animals following dermal exposure. 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen et al. 

1987; Andersen and Krishnan 1994). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parametrization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 
BROMOFORM AND DIBROMOCHLOROMETHANE 89 

3. HEALTH EFFECTS 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The 

numerical estimates of these model parameters are incorporated within a set of differential and algebraic 

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-5 shows a conceptualized representation of a PBPK model. 

PBPK models have not been developed for bromoform or dibromochloromethane. da Silva et al. (1999) 

developed a model to simulate the venous blood concentration of each trihalomethane after simultaneous 

exposure to the four trihalomethanes. This model, which simulates competitive inhibition of hepatic 

metabolism, is discussed in Section 3.9. Although da Silva et al. (1999) also described models in rats 

following single administration of bromoform or dibromochloromethane, these models involved 

optimizing metabolic parameters across the dose range used in the study and were not developed as standalone models. 
Fat 

ly 

ly 

K i 

S k in 

V 

E 

N 

O 

U 

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BROMOFORM AND DIBROMOCHLOROMETHANE 90 

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Figure 3-5. Conceptual Representation of a Physiologically Based 

Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance 

Source: adapted from Krishnan et al. 1994 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 
BROMOFORM AND DIBROMOCHLOROMETHANE 91 

3. HEALTH EFFECTS 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Bromoform and dibromochloromethane can be absorbed by inhalation (Graham 1915; Merzbach 1928), 

ingestion (Backer et al. 2000; Mink et al. 1986), and dermal (Backer et al. 2000; Xu et al. 2002) routes of 

exposure. In humans and laboratory animals, bromoform and dibromochloromethane are generally 

absorbed quickly (Backer et al. 2000). Although bromoform and dibromochloromethane are lipophilic, 

they do not appear to accumulate in adipose tissue (Stanley 1986). Bromoform and dibromochloromethane are thought to be metabolized by at least two route-independent pathways: oxidation by 

cytochrome P-450 mixed function oxidase system (Ahmed et al. 1977; Anders et al. 1978) and 

conjugation via glutathione S-transferase (DeMarini et al. 1997; Pegram et al. 1977). Bromoform and 

dibromochloromethane are primarily excreted via exhalation as the parent compound or carbon dioxide 

(Mink et al. 1986). 

3.5.2 Mechanisms of Toxicity 

The mechanisms by which bromoform and dibromochloromethane cause damage in target tissues is not 

fully understood, but there is strong evidence that metabolism to reactive intermediates is a prerequisite 

for toxicity. Subsequent interaction of the reactive intermediates with key cellular molecules leads to 

impaired function and/or cell death. 

Several mechanisms for cell injury by trihalomethanes have been proposed based on the combined 

experimental database for chloroform and the brominated trihalomethanes. These include: (1) oxidative 

metabolism by CYP2E1 to produce dihalocarbonyls, which deplete glutathione content, and alkylate 

cellular macromolecules to produce necrosis; (2) reductive dehalogenation under conditions of low 

physiological oxygen tension to produce highly reactive dihalomethyl free radicals that covalently bind to 

proteins or lipids; and (3) glutathione-dependent metabolism to DNA-reactive intermediates, which 

results in adduct formation and mutation. Toxicity of bromoform and dibromochloromethane may result 

from metabolism by one or more of these pathways. Bromine is generally a better leaving group than 

chlorine, suggesting that the degree of bromine substitution will influence the rate of metabolism among 

chlorinated and brominated trihalomethanes and the flux through specific pathways. 
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Although mechanistic data on bromoform and dibromochloromethane are lacking, the requirement for 

metabolism of these compounds to toxic intermediates is supported by studies of chloroform and 

bromodichloromethane. In a representative study, Ilett et al. (1973) observed covalent binding of 

radiolabeled material to proteins in the liver and kidney following administration of [14C]chloroform to 

mice. The amount of binding was correlated with the extent of renal and hepatic necrosis both in normal 

animals and in male mice pretreated with an inhibitor or inducer of microsomal enzymes. Autoradiograms showed that the bound radioactivity was located mainly in necrotic lesions. In other studies, 

Brown et al.(1974) reported that pretreatment of rats with phenobarbital (a cytochrome P-450 inducer) 

resulted in increased formation of covalent adducts and increased hepatic toxicity following chloroform 

exposure. Pohl et al. (1980) reported that the level of covalent binding correlated directly with injury to 

the liver tissue and concluded that phosgene was the metabolite responsible for the covalent binding to 

liver macromolecules. Tyson et al. (1983) confirmed that covalent binding to proteins in rats was more 

prevalent in areas of necrosis than in less damaged areas. More recently, Constan et al. (1999) evaluated 

toxicity in male B6C3F1, SV/129 wild-type (CYP2E1 +/+), and SV/129 null (CYP2E1 -/-) mice exposed 

to chloroform by inhalation. Parallel groups of control and treated mice (B6C3F1 and wild-type SV/129) 

were also treated with an irreversible cytochrome P-450 inhibitor. Extensive hepatic and renal necrosis 

occurred in B6C3F1 and SV/129 mice exposed to chloroform. Chloroform-exposed animals that received 

the inhibitor were completely protected against hepatic and renal toxicity and pathological changes were 

absent in null mice, demonstrating that metabolism is necessary for toxicity. 

The data linking metabolism of brominated trihalomethanes to toxicity are less extensive than those for 

chloroform. No data were located specifically for bromoform or dibromochloromethane. Pretreatment of 

female rats and mice with inhibitors of CYP2E1 metabolism reduced the acute renal and hepatic toxicity 

of bromodichloromethane (Thornton-Manning et al. 1994). Depletion of glutathione by pretreatment of 

male F344 rats with butathione sulfoximine (BSO) increased the incidence and severity of hepatic and 

renal lesions (Gao et al. 1996). Addition of glutathione to hepatic microsomal and S9 preparations and 

renal microsomes under aerobic conditions decreased covalent binding of [14C]bromodichloromethane to 

proteins. Addition of glutathione to hepatic or renal microsomes under anaerobic conditions decreased 

binding of [14C]bromodichloromethane to lipids (Gao et al. 1996). These data demonstrate a protective 

role of glutathione that is consistent with metabolism of bromodichloromethane to one or more reactive 

species. 

Studies in animals indicate that bromoform and dibromochloromethane have carcinogenic potential (NTP 

1985, 1989a). The mechanism of action for tumor induction by these chemicals is unknown and may 
BROMOFORM AND DIBROMOCHLOROMETHANE 93 

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involve contributions from more than one of the proposed pathways described above. Pathway 1 

(oxidative metabolism to dihalocarbonyl) may not be directly genotoxic, but may lead to increased risk of 

cancer as a result of cytotoxicity and subsequent regenerative hyperplasia, as observed for chloroform 

(ILSI 1997). Pathways 2 (reductive metabolism) and 3 (glutathione-dependent metabolism) may lead to 

direct DNA damage in vivo. The relative contribution of these pathways to the carcinogenic potential of 

bromoform and dibromochloromethane has not been determined. 

Three studies have examined cytotoxicity and regenerative hyperplasia in the liver of female B6C3F1 

mice (Coffin et al. 2000; Melnick et al. 1998) or the kidney of male F344 rats (Potter et al. 1996) 

following exposure to bromoform or dibromochloromethane. These studies are of limited use for 

understanding the mechanism of bromoform carcinogenesis because they do not address cytotoxicity or 

regeneration in the large intestine, the target tissue for tumor induction. Dibromochloromethane induced 

cytotoxicity and cell proliferation in the liver of female B6C3F1 mice, but the LOAEL values reported by 

Melnick et al. (1998) and Coffin et al. (2000) were inconsistent (400 vs. 100 mg/kg/day). Therefore, a 

threshold for induction of cellular proliferation cannot be clearly identified for comparison with the liver 

tumor incidence data in female B6C3F1 mice (NTP 1985). The reason for the discrepancy between 

studies is unknown, but might be related to the use of different techniques or different time points for 

measurement of labeling index (a method for estimating cell proliferation). These data do not allow a 

conclusion regarding the role of cytotoxicity and regenerative cell proliferation in the development of 

hepatic tumors in mice exposed to dibromochloromethane. Melnick et al. (1998) modeled dose response 

data for cell proliferation and serum enzyme activity (as a composite) and for tumor induction in the liver 

of B6C3F1 mice using an empirical Hill equation model. The dose-response curves for these processes 

had different shapes, suggesting that they were not causally associated. 

Positive results for mutagenicity and cytogenetic damage have been observed in some standard assays 

(see Section 3.3), suggesting that some metabolites of bromoform and dibromochloromethane interact 

directly with DNA. Reductive metabolism (Melnick et al. 1998) and glutathione conjugation of 

brominated trihalomethanes have been proposed as a source of DNA reactive intermediates (De Marini et 

al. 1997; Ross and Pegram 2003), but the available data are too limited to fully evaluate the contribution 

of these pathways to the genotoxicity and carcinogenicity of bromoform and dibromochloromethane. 

Studies of bromodichloromethane metabolism in hepatic cytosols prepared from rat, mouse, and liver 

microsomes suggest that metabolism of brominated trihalomethanes via a glutathione-dependent pathway 

is likely to be a minor pathway in the liver (Ross and Pegram 2003). It is unknown whether the small 

amounts formed in the liver are toxicologically significant. It is possible that glutathione-dependent 
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3. HEALTH EFFECTS 

pathways are of greater toxicological significance in extrahepatic tissues where concentrations of 

CYP2E1 are lower, such as the distal large intestine (Ross and Pegram 2003). 

3.5.3 Animal-to-Human Extrapolations 

Most of the available data on the toxicity and toxicokinetic properties of bromoform and dibromochloromethane come from studies in rats and mice. There are very limited human data, and the only end point 

that has been examined is neurotoxicity; high doses of bromoform result in central nervous system 

depression in humans and laboratory animals. Data from other trihalomethanes, particularly chloroform 

(Agency for Toxic Substances and Disease Registry 1997), suggest that the available laboratory animal 

toxicity and toxicokinetic data for bromoform and dibromochloromethane would also be applicable for 

humans. A potential difference between species is quantitative and qualitative differences in Phase I 

metabolism of trihalomethanes. In rats, trihalomethanes are substrates of cytochrome P-450 enzyme 

isoforms CYP2E1, CYP2B1, CY2B2, and CYP1A2 (Allis et al. 2001; Pankow et al. 1997). CYP2E1 and 

CPY1A2 are also expressed in human tissues; however, the relevance of metabolism by CYP2B1/2 to 

human health is presently uncertain, since these isoforms have not been reported in human adult or fetal 

tissues (Juchau et al. 1998; Nelson et al. 1996). CYP2B6 is the only active member of the CYP2B 

subfamily in man, although the CYP2B7 gene has also been found in the genome (Czerwinski et al. 

1994). 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine 

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals 

with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate 

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Colborn and Clement (1992), was also used in 1996 when Congress mandated the EPA 

to develop a screening program for “...certain substances [which] may have an effect produced by a 

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 

of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to 
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convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists 

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to 

the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active 

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist 

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens 

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are 

similar in structure and action to endogenous estrogen. Although the public health significance and 

descriptive terminology of substances capable of affecting the endocrine system remains controversial, 

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or 

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, 

development, and/or behavior (EPA 1997). Stated differently, such compounds may cause toxicities that 

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering, 

for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought 

to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994; 

Giwercman et al. 1993; Hoel et al. 1992). 

No in vitro studies were located regarding endocrine disruption of bromoform and dibromochloromethane. 

There is little evidence to suggest that bromoform or dibromochloromethane has the potential to distrupt 

the normal functioning of the neuroendocrine axis. There are some suggestive data that these chemicals 

have the potential to alter reproductive hormone levels. An ecological study found significant 

correlations between bromoform and dibromochloromethane concentrations in drinking water and 

alterations in menstrual cycle length (Windham et al. 2003); however, the women were exposed to a 

number of other potentially toxic compounds in the drinking water and the data are inadequate for 

establishing causality. In rats administered 310–380 mg/kg/day bromoform or dibromochloromethane, 

significant decreases in serum testosterone levels were observed (Potter 1996). 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 
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3. HEALTH EFFECTS 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 
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Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

There are limited data on the toxicity of bromoform and dibromochloromethane. In the early 1900s, 

bromoform was used as a sedative for the treatment of whooping cough (Benson 1907; Burton-Fanning 

1901; Dwelle 1903; Stokes 1900; von Oettingen 1955). Sedation was observed at the prescribed dosage; 

higher doses often resulted in central nervous system depression. Central nervous system depression has 

also been observed in adult animals following oral exposure to bromoform (Bowman et al. 1978; NTP 

1989a) or dibromochloromethane (Bowman et al. 1978; NTP 1985). There is no indication that children 

are more susceptible than adults to this effect. 

Animal data provide strong evidence that the liver is the critical target of bromoform and dibromochloromethane toxicity (Aida et al. 1992; Coffin et al. 2000; Condie et al. 1983; NTP 1985, 1989a; Tobe et al. 

1982). These animal studies were conducted in adults and no animal studies using juveniles were located. 

The available data suggest that the hepatotoxicity of bromoform and dibromochloromethane is due to 

tissue damage from reactive intermediates that are generated during metabolism. In rats, trihalomethanes 

are substrates for several cytochrome P-450 enzyme isoforms, including CYP2E1, CYP2B1, CYP2B2, 

and CYP1A2 (Allis et al. 2001; Pankow et al. 1997) in Phase I reactions and glutathione S-transferase 

theta (GSTT) (DeMarini et al. 1997; Pegram et al. 1987; Ross and Pegram 2003) in Phase II reactions. 

As discussed in EPA (2001a), CYP2E1 levels increase rapidly during the first 24 hours after birth and 

levels in children between 1 and 10 years of age are similar to those in adults. Similarly, GSTT levels in 

children older than 1 year are similar to adults. These data provide some suggestive evidence that 

exposure during early childhood would result in the formation of similar reactive intermediates and 

metabolites as in adults. 

The potential of bromoform and dibromochloromethane to induce developmental effects cannot be 

conclusively established from the existing database. A significant alteration in the occurrence of 

sternebra aberrations were observed in the offspring of rats administered 200 mg/kg/day bromoform in 

corn oil during gestation (Ruddick et al. 1983). A similar exposure to dibromochloromethane did not 

result in any significant alterations. Similarly, no developmental alterations were observed in mouse 
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offspring exposed to 685 mg/kg/day dibromochloromethane in drinking water for several generations 

(Borzelleca and Carchman 1982). 

There are no specific biomarkers of exposure or effect for bromoform or dibromochloromethane that have 

been validated in children or adults exposed as children. No studies were located regarding interactions 

of bromoform or dibromochloromethane with other chemicals in children. Additionally, there are no 

pediatric-specific methods of reducing peak absorption or reducing body burden following exposure to 

bromoform or dibromochloromethane. In the absence of these data, it is assumed that there are no agerelated differences in biomarkers, interactions, or mitigation of effects. 

3.8 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). 

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers 

as tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic 

substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target 

molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The 

preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in 

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

interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures 

from more than one source. The substance being measured may be a metabolite of another xenobiotic 

substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic 

compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental 

conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the 

body by the time 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 bromoform and dibromochloromethane are 

discussed in Section 3.8.1. 

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 
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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 not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused 

by bromoform and dibromochloromethane are discussed in Section 3.8.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.10 “Populations that are Unusually Susceptible.” 

3.8.1 	 Biomarkers Used to Identify or Quantify Exposure to Bromoform and 

Dibromochloromethane 

The most straightforward means of identifying exposure to bromoform or dibromochloromethane in a 

person is measurement of parent compound in blood or expired air. Sensitive and specific gas 

chromatographic-mass spectrophotometric methods available for this purpose are described in 

Section 7.1. 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 3.4.4). Consequently, this approach is best suited for detecting recent exposures (within 1– 

2 days). 

No data are available on blood or breath levels of bromoform or dibromochloromethane in acutely 

exposed individuals. However, studies involving exposure to trihalomethanes in water have found 

elevated alveolar air levels of dibromochloromethane following a 1-hour exposure to volatilized 

trihalomethanes from swimming pool water (Aggazzotti et al. 1998) and elevated blood bromoform and 

dibromochloromethane levels following a 10-minute shower or 10-minute bath (Backer et al. 2000). 

Background concentrations in people not exposed to bromoform or dibromochloromethane except 

through chlorinated drinking water are about 0.6 ppb (Antoine et al. 1986), while levels in expired breath 

are undetectable (Wallace et al. 1986a, 1986b). In a study of blood trihalomethane concentrations in 

women living in areas with trihalomethane in tap water (Miles et al. 2002), a simple linear relationship 
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3. HEALTH EFFECTS 

between blood levels and tap water levels of trihalomethanes was not found. For bromoform and 

dibromochloromethane, no significant correlations were found between tap water levels of these 

compounds and blood levels before showering. After showering, a significant correlation between 

bromoform levels in the tap water and blood levels were found; however, the correlation coefficient 

(0.450) is relatively low, suggesting that a number of variables affected blood bromoform levels. 

Although bromoform and dibromochloromethane 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 biomarker of exposure. 

The principal metabolites of bromoform and dibromochloromethane are CO2, CO, Cl-

, 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 3.4.3), but these putative adducts have not been identified nor has 

any means for their quantification been developed. 

3.8.2 	 Biomarkers Used to Characterize Effects Caused by Bromoform and 

Dibromochloromethane 

There are limited data on the toxicity of bromoform and dibromochloromethane in humans. Exposure to 

bromoform can result in sedation; it is likely that the same is true for dibromochloromethane. However, 

generalized central nervous system depression is too nonspecific to be useful as a biomarker of effects 

from bromoform or dibromochloromethane exposure. 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. 

3.9 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 (Agency for Toxic Substances 

and Disease Registry 1994) and chloroform (Agency for Toxic Substances and Disease Registry 1997). 
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Several studies have been performed to determine if the toxic effects of bromoform and dibromochloromethane 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 l0– 

40-fold potentiation of the hepatotoxic effects of a single oral dose of dibromochloromethane given 

18 hours later. Similarly, pretreatment of rats for one to three days with chlordecone resulted in a 7– 

60-fold potentiation of the hepatotoxic effects of a single oral dose of dibromochloromethane (Plaa and 

Hewitt 1982a, 1982b). In contrast, chlordecone pretreatment 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 dibromochloromethane 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). 

A PBPK model has been developed by da Silva et al. (1999) that examined the influence of exposure to a 

mixture of trihalomethanes (bromoform, dibromochloromethane, dichlorobromomethane, and chloroform) on the kinetics of individual compounds. When all four trihalomethanes were administered 

together (1.0 mmol/kg), the area under the blood concentration versus time curve was significantly higher 

as compared to the AUC after administration of a single compound (0.25 mmol/kg). For bromoform and 

dibromochloromethane, the AUCs after the single 0.25 mmol/kg dose were 48.6 and 31.2 μM/hour and 

after the 1.0 mmol/kg mixture of trihalomethanes, the AUCs were 127.3 and 128.6 μM/hour. These data 

suggest that there is metabolic interation between the trihalomethanes; likely competitive inhibition of 

hepatic metabolism. 
BROMOFORM AND DIBROMOCHLOROMETHANE 102 

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3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to bromoform or 

dibromochloromethane than will most persons exposed to the same level of bromoform or 

dibromochloromethane in the environment. Reasons may include genetic makeup, age, health and 

nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). These parameters result 

in reduced detoxification or excretion of bromoform or dibromochloromethane, or compromised function 

of organs affected by bromoform or dibromochloromethane. Populations who are at greater risk due to 

their unusually high exposure to bromoform or dibromochloromethane are discussed in Section 6.7, 

Populations with Potentially High Exposures. 

Studies of bromoform and dibromochloromethane toxicity in animals suggest that there may be some 

quantitative and qualitative differences in susceptibility between sexes and between species (see 

Section 3.2). The mechanistic basis for these differences is not known, but one likely factor is sex and 

species-dependent differences in metabolism (see Section 3.4.3). Thus, it is reasonable to assume that 

differences in susceptibility could exist between humans as a function of sex, age, or other metabolisminfluencing factors. Studies in animals (discussed in Section 3.9) 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 dibromochloromethane 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 bromoform and dibromochloromethane. The elderly 

may represent an unusually suseptible population because they may have age-related deficiencies of liver 

and kidney function. They may also be frequently exposed to metabolism-influencing medications. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to bromoform or dibromochloromethane. However, because some of the treatments discussed 

may be experimental and unproven, this section should not be used as a guide for treatment of exposures 

to bromoform or dibromochloromethane. When specific exposures have occurred, poison control centers 

and medical toxicologists should be consulted for medical advice. The following texts provide specific 

information about treatment following exposures to bromoform or dibromochloromethane: 
BROMOFORM AND DIBROMOCHLOROMETHANE 103 

3. HEALTH EFFECTS 

Haddad LM, Shannon MW, Winchester JF, eds. 1998. Clinimal management of poisoning and drug 

overdose. Philadelphia, PA: W.B. Saunders Co., 913-939, 992-1000. 

Viccellio P, ed. 1998. Emergency toxicology. Philadelphia, PA: Lippincott-Raven Publishers, 925-932. 

3.11.1 Reducing Peak Absorption Following Exposure 

Human exposure to bromoform or dibromochloromethane may occur by inhalation, ingestion, or dermal 

contact. General recommendations for reducing absorption of these chemicals include removing the 

exposed individual from the contaminated area and removing the contaminated clothing. If the eyes and 

skin were exposed, they should be flushed with water. In order to reduce absorption of ingested 

bromoform and dibromochloromethane, emesis may be considered unless the patient is comatose, is 

convulsing, or has lost the gag reflex. Controversy exists concerning use of emesis because of the rapid 

onset of central nervous system depression, the risk of aspiration of stomach contents into the lungs, and 

the relative ineffectiveness of this method. In comatose patients with absent gag reflexes, an endotracheal 

intubation may be performed in advance to reduce the risk of aspiration pneumonia. Gastric lavage may 

also be used. 

3.11.2 Reducing Body Burden 

Trihalomethanes levels in human blood have a short half-life of approximately 0.5 hours (Lynberg et al. 

2001). Bromoform or dibromochloromethane were not stored to any appreciable extent in the rat and 

were mostly metabolized to CO2 (see Section 3.4). The elimination half-life of bromoform was reported 

to be 0.8 hours in the rat and 8 hours in the mouse (Mink et al. 1986). The half-lives of dibromochloromethane were 1.2 and 2.5 hours in rats and mice, respectively (Mink et al. 1986). Despite an expected 

relatively fast clearance of from the body, toxic effects may develop in exposed individuals. No method 

is commonly practiced to enhance the elimination of the absorbed dose of bromoform or dibromochloromethane. 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

The primary targets of bromoform and dibromochloromethane are the liver, kidneys, and central nervous 

system. It is believed that the mechanism of bromoform and dibromochloromethane toxicity to the liver 

and kidneys involves metabolism to reactive intermediates. No methods for interfering with the 
BROMOFORM AND DIBROMOCHLOROMETHANE 104 

3. HEALTH EFFECTS 

mechanism of action have been developed for these compounds. Studies using two other trihalomethanes 

(chloroform and dichlorobromomethane) provide suggestive evidence that administration of agents which 

inhibit cytochrome P-450 decreases hepatotoxicity. Co-administration of chloroform and 1-aminobenzotriazole (an irreversible cytochrome P-450 inhibitor) (Constan et al. 1999) or dibromochloromethane and 

a CYP2E1 inhibitor (Thornton-Manning et al. 1994) resulted a reduction of acute hepatic and renal 

toxicity. 

3.12 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of bromoform or dibromochloromethane is available. Where 

adequate information is not available, ATSDR, in conjunction with the National Toxicology Program 

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

effects (and techniques for developing methods to determine such health effects) of bromoform or 

dibromochloromethane. 

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 the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

3.12.1 Existing Information on Health Effects of Bromoform and Dibromochloromethane 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

bromoform and dibromochloromethane are summarized in Figures 3-6 and 3-7, respectively. The 

purpose of this figure is to illustrate the existing information concerning the health effects of bromoform 

or dibromochloromethane. Each dot in the figure indicates that one or more studies provide information 

associated with that particular effect. The dot does not necessarily imply anything about the quality of the 

study or studies, nor should missing information in this figure be interpreted as a “data need”. A data 

need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs Related to 

Toxicological Profiles (Agency for Toxic Substances and Disease Registry 1989), is substance-specific 
BROMOFORM AND DIBROMOCHLOROMETHANE 105 

3. HEALTH EFFECTS 

Figure 3-6. Existing Information on Health Effects of Bromoform 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

System ic 

Inha ation l

Ora l 

Derma l 

Human 

Death

Acute

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

System ic 

Inhalat on i

Ora l 

Derma l 

Animal 

iExist ng Studies 
BROMOFORM AND DIBROMOCHLOROMETHANE 106 

3. HEALTH EFFECTS 

Figure 3-7. Existing Information on Health Effects of Dibromochloromethane 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

ic System

Inhalation 

Oral 

Dermal 

Human 

D

I

eath

Acute

Intermediate 

Chronic 

mmunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

System ic 

Inhalat on i

Ora l 

Derma l 

Animal 

Exist ng Studies i
BROMOFORM AND DIBROMOCHLOROMETHANE 107 

3. HEALTH EFFECTS 

information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a 

data gap more broadly as any substance-specific information missing from the scientific literature. 

As shown in Figure 3-6, there are limited data on the toxicity of bromoform following inhalation 

exposure. No human data were located and laboratory animal studies are limited to lethality studies, 

which found central nervous system depression, and acute and intermediate duration studies, which are 

only available as abstracts. Human data on the oral toxicity of bromoform are limited to reports of 

children taking bromoform for the treatment of whooping cough; effects are limited to death and central 

nervous system depression and the exposure levels are poorly characterized. A number of laboratory 

animal studies have examined the oral toxicity of bromoform, and data are available for all end points. 

However, in many cases, the available data for a particular end point are limited to a single study or use a 

route of administration (e.g., gavage) that may not be relevant to human environmental exposure to 

bromoform. The dermal toxicity of bromoform has not been studied in humans or animals. 

As shown in Figure 3-7, there are no human toxicity data for dibromochloromethane following inhalation, 

oral, or dermal exposure. Additionally, there are no laboratory animal data on dibromochloromethane 

following inhalation or dermal exposure. For the oral route of exposure, data are available for all end 

points. As noted for bromoform, information on a particular end point comes from a single study, and 

most studies used a gavage in oil administration route, which may not be relevant for human 

environmental exposure to dibromochloromethane. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. The available data on the acute toxicity of bromoform in humans are 

limited to reports of children prescribed bromoform for the treatment of whooping cough. Following 

ingestion, the children were said to sleep undisturbed through the night, suggestive of sedation (Dwelle 

1903); accidental overdoses resulted in symptoms of central nervous system depression (Benson 1907; 

Burton-Fanning 1901; Dwelle 1903; Stokes 1900; von Oettingen 1955). No human data were located 

discussing human toxicity following inhalation or dermal exposure to bromoform or after inhalation, oral, 

or dermal exposure to dibromochloromethane. Inhalation and oral exposure animal studies confirm that 

high oral doses of bromoform (Balster and Borzelleca 1982; Bowman et al. 1978; Graham 1915; 

Mertzbach 1928; NTP 1989a) or dibromochloromethane (Balster and Borzelleca 1982; NTP 1985) can 

result in central nervous system depression. At lower doses, the liver and possibly the kidney appear to 

be the primary targets of toxicity for both compounds. Nonlethal animal inhalation data are limited to a 
BROMOFORM AND DIBROMOCHLOROMETHANE 108 

3. HEALTH EFFECTS 

study published in Russian that found liver and kidney effects in rats (Dykan 1964). The inhalation data 

are inadequate to define the threshold for these effects or identify the critical target of toxicity; additional 

inhalation studies that examine a wide range of end points and exposure concentrations would be useful 

for establishing the critical targets of toxicity of bromoform and dibromochloromethane following 

inhalation exposure and establishing concentration-response relationships. There is a more extensive 

database following oral exposure, which allows for the derivation of acute-duration oral MRLs for 

bromoform and dibromochloromethane. Following oral exposure to bromoform, increases in liver weight 

(Munson et al. 1982), centrilobular pallor (Condie et al. 1983), and hepatocellular vacuolization and/or 

swelling (Coffin et al. 2000) have been observed. Other effects of bromoform observed in acute-duration 

animal studies include mesangial nephrosis (Condie et al. 1983), impaired humoral immune function 

(Munson et al. 1982), and developmental effects (Ruddick et al. 1983). As with bromoform, the most 

sensitive effects of dibromochloromethane following acute oral exposure are liver and kidney damage; 

the liver effects consisted of mottled liver, hepatocellular vacuolization and/or swelling, and increases in 

SGPT and SGOT levels (Coffin et al. 2000; Condie et al. 1983; Munson et al. 1982; NTP 1985) and 

kidney effects included mesangial hyperplasia and darkened renal medullae (Condie et al. 1983; NTP 

1985). At higher doses, impaired humoral immunity (Munson et al. 1982), decreased body weight gain 

(NTP 1985; Potter et al. 1996), and decreased serum testosterone levels (Potter et al. 1996) were 

observed. 

No data are available in humans or animals following dermal exposure to bromoform or dibromochloromethane. 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 bromoform or dibromochloromethane 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. No human data are available on the intermediate-duration 

toxicity of bromoform or dibromochloromethane following inhalation, oral, or dermal exposure. Animal 

data are limited to a study reporting liver and kidney effects in rats exposed to bromoform for 2 months 

(Dykan 1962); however, this study is currently only available as an abstract. No intermediate-duration 

animal inhalation exposure data are available for dibromochloromethane. 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 that exposures in air 
BROMOFORM AND DIBROMOCHLOROMETHANE 109 

3. HEALTH EFFECTS 

near such sites are likely to be low. The available intermediate-duration oral exposure animal studies 

strongly identify the liver as the most sensitive target for bromoform and dibromochloromethane. 

Hepatocellular vacuolization and/or swelling have been observed at the lowest adverse effect levels (Aida 

et al. 1992; Daniel et al. 1990; NTP 1985, 1989a). Other effects observed in animals exposed to higher 

doses of bromoform include lethargy (NTP 1989a), impaired performance on neurobehavioral tests 

(Balster and Borzelleca 1982), and decreased body weight gain (Aida et al. 1992). Exposure to higher 

doses of dibromochloromethane also resulted in kidney damage (tubular degeneration and nephropathy) 

(Daniel et al. 1990; NTP 1985), impaired performance on neurobehavioral tests (Balster and Borzelleca 

1982), and impaired fertility (Borzelleca and Carchman 1982). These animal data were considered 

adequate for derivation of an intermediate MRL for bromoform. An MRL was not derived for 

dibromochloromethane because the resultant MRL would be higher than the MRL for acute duration 

exposure. Additional studies using a number of dose levels would provide additional information on the 

threshold of hepatic toxicity and possible allow for the derivation of an intermediate-duration MRL for 

dibromochloromethane. 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. No human studies examining the chronic toxicity of 

bromoform or dibromochloromethane were located, although a number of studies examining health 

outcomes in areas with elevated trihalomethanes in tap water have been located. Chronic animal 

inhalation data are not available for either chemical, and would be useful, especially for 

dibromochloromethane, since it is significantly more volatile (vapor pressure=76 mmHg) than 

bromoform (vapor pressure=5 mmHg). Chronic-duration studies that identify the critical targets of 

toxicity and establish concentration-response relationships would be useful for deriving chronic-duration 

inhalation MRLs for bromoform and dibromochloromethane. In the absence of such data, extrapolation 

of observations from the oral route might be possible using appropriate toxicokinetic models. The 

chronic oral toxicity of bromoform (NTP 1989a; Tobe et al. 1982) and dibromochloromethane (NTP 

1985; Tobe et al. 1982) 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. No data exist for dermal 

exposure, and further studies (focusing on exposure in water or soil) would be valuable. 
BROMOFORM AND DIBROMOCHLOROMETHANE 110 

3. HEALTH EFFECTS 

The carcinogenic effects of chronic oral exposure to bromoform (NTP 1989a) and dibromochloromethane 

(NTP 1985) 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 on 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 dibromochloromethane 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 bromoform and dibromochloromethane are genotoxic, both in prokaryotic (LeCurieux et al. 1995; Roldan-Arjona and Pueyo 1993; 

Simmon and Tardiff 1978; Simmon et al. 1977; Varma et al. 1988) and eukaryotic (Benigni et al. 1993; 

Fujie et al. 1993; Landi et al. 1999; Matsuoka et al. 1996; McGregor et al. 1991; Morimoto and Koizumi 

1983; Nestman and Lee 1985; Sobti 1984; Sofuni et al. 1996) organisms. However, a number of other 

studies have failed to detect significant genotoxic potential for these compounds (Maddock and Kelly 

1980; NTP 1985, 1989a). 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. Several in vivo 

studies have also found genotoxic effects following exposure to bromoform (Fujie et al. 1990; Morimoto 

and Koizumi 1983; NTP 1989a) or dibromochloromethane (Fujie et al. 1990; Morimoto and Koizumi 

1983), although other studies have not found effects (Hayashi et al. 1988; Potter et al. 1996; Stocker et al. 

1996). 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 bromoform and dibromochloromethane on germ cells 

(sperm or ova) would also be valuable. 

Reproductive Toxicity. A number of ecological studies have examined the reproductive toxicity to 

women ingesting drinking water contaminated with trihalomethanes (Bove et al. 1992, 1995; Dodds et al. 

1999; Kramer et al. 1992; Mills et al. 1998; Nieuwenhuijsen et al. 2000; Savitz et al. 1995; Waller et al. 

1999). Three of these studies (Kramer et al. 1992; Waller et al. 1999; Windham et al. 2003) measured 

bromoform and dibromochloromethane levels; however, the contribution of the other trihalomethanes to 
BROMOFORM AND DIBROMOCHLOROMETHANE 111 

3. HEALTH EFFECTS 

the observed effects cannot be determined from the existing data. Collectively, the trihalomethane studies 

provide insufficient evidence to establish a causal relationship between exposure to trihalomethanes and 

adverse reproductive outcome. Animal data are limited to several studies that examined reproductive 

tissues for histological alterations or examined reproductive function following oral exposure to either 

compound. No histological alterations were observed in reproductive tissues following chronic exposure 

to bromoform (NTP 1989a) or dibromochloromethane (NTP 1985). No significant alterations in 

reproductive performance or fertility were observed in males or females exposed to bromoform (NTP 

1989b). For dibromochloromethane, one study found a marked reduction in fertility at a maternally toxic 

dose level (Borzelleca and Carchman 1982), but no effects on reproductive performance or fertility were 

observed at lower doses (NTP 1986). Multigeneration studies involving oral exposure to bromoform and 

dibromochloromethane would provide useful data on the reproductive potential of these chemicals. 

Based on the oral studies, it does not seem likely that effects would occur following inhalation or dermal 

exposure except at very high levels, but inhalation and dermal exposure studies to confirm this important 

point would be valuable. 

Developmental Toxicity. Several ecological studies have examined the relationship between 

exposure to trihalomethanes in tap water and the birth outcomes (Dodds et al. 1999; Kramer et al. 1992; 

Savitz et al. 1995). The Kramer et al. (1992) study reported levels for individual trihalomethanes, but this 

study, as well as the other studies, does not provide sufficient evidence for establishing a relationship 

between trihalomethane exposure and adverse birth outcomes. No other human studies were located for 

bromoform or dibromochloromethane. No inhalation or dermal exposure animal developmental toxicity 

studies were located. There are limited data on the developmental toxicity of bromoform and dibromochloromethane following oral exposure in animals. A minor skeletal abnormality was observed in the 

offspring of rats exposed to bromoform during gestation (Ruddick et al. 1983). No developmental effects 

were observed in studies of rat and mouse offspring exposed to dibromochloromethane (Borzelleca and 

Carchman 1982; Ruddick et al. 1983). Additional oral studies on the developmental effects of both 

bromoform and dibromochloromethane 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 and dermal routes would also be valuable to define 

safe inhalation levels for developmental effects. 

Immunotoxicity. The immunotoxic effects of bromoform and dibromochloromethane have been 

investigated in one 14-day oral study (Munson et al. 1982). That study indicated that both chemicals can 

lead to changes in several immune cell-types in mice. Similar studies in other species would be valuable 
BROMOFORM AND DIBROMOCHLOROMETHANE 112 

3. HEALTH EFFECTS 

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 and dermal exposure routes 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; more limited data 

indicate that dibromochloromethane 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 

indicate that sub-depressant doses of bromoform (NTP 1989a) and dibromochloromethane (NTP 1985) 

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 bromoform and dibromochloromethane can cause some behavioral changes (impaired motor 

performance, decreased exploratory behavior [bromoform only], and decreased response rate in tests of 

operant behavior) 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. 

Epidemiological and Human Dosimetry Studies. No epidemiological or human dosimetry 

studies are currently available for bromoform or dibromochloromethane. Since only very small quantities 

of these chemicals are produced or used in this country (see Chapter 5), 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 bromoform and 

dibromochloromethane in chlorinated drinking water cannot provide specific data on the human health 

risks of dibromochloromethane or bromoform, since chlorinated drinking water contains hundreds of 

different contaminants. 

Biomarkers of Exposure and Effect. 

Exposure. The only known biomarker of exposure to bromoform or dibromochloromethane 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 bromoform and 
BROMOFORM AND DIBROMOCHLOROMETHANE 113 

3. HEALTH EFFECTS 

dibromochloromethane 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 (CO2, CO, Cl-

, 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. 

Effect. No specific biomarkers of bromoform- or dibromochloromethane-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 

bromoform or dibromochloromethane. Efforts to identify more specific and sensitive biomarkers of 

bromoform and dibromochloromethane-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 bromoform and 

dibromochloromethane 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 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 bromoform and dibromochloromethane 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 that 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. 
BROMOFORM AND DIBROMOCHLOROMETHANE 114 

3. HEALTH EFFECTS 

Comparative Toxicokinetics. Available toxicity data indicate that target tissues of bromoform and 

dibromochloromethane are similar in humans, rats, and 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. 

Methods for Reducing Toxic Effects. Further research is needed to determine strategies designed 

to selectively inhibit the specific P-450 isozymes involved in the metabolism of bromoform or 

dibromochloromethane to reactive intermediates, and thus reduce the toxic effects. Because bromoform 

or dibromochloromethane are thought to be metabolized by glutathione conjugation (DeMarini et al. 

1997; Pegram et al. 1977; Ross and Pegram 2003), further research is needed to determine if 

administration of sulfhydryl compounds, such as L-cysteine, reduced GSH or N-acetylcysteine, as 

glutathione surrogates might provide protection against nephrotoxicity or hepatotoxicity induced due to 

depleted glutathione stores. Research on using dietary supplements for mitigating adverse effects of 

chronic exposure to bromoform or dibromochloromethane would be helpful, especially in the case of 

chronic exposure from chlorinated drinking water. 

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and 

developmental effects expressed either prenatally or during childhood, are discussed in detail in the 

Developmental Toxicity subsection above. 

The available human data for bromoform are mostly from case reports of accidental orally-administered 

overdose in children. No data exist on the toxicity of dibromochloromethane following oral 

administration in children, or of bromoform or dibromochloromethane following inhalation or dermal 

exposure in children. The developmental effects of oral exposure to bromoform and dibromochloromethane have not been extensively investigated, but limited data suggest that these chemicals have 

relatively low toxicity on the developing fetus (Borzelleca and Carchman 1982; Ruddick et al. 1983). 

However, these studies did not examine neurodevelopmental end points that may be a sensitive target. 

Additional animal studies assessing the neurodevelopmental toxicity of bromoform and dibromochloro­
BROMOFORM AND DIBROMOCHLOROMETHANE 115 

3. HEALTH EFFECTS 

methane would be useful. Toxicokinetic studies examining how aging can influence absorption rates 

would be useful in assessing children’s susceptibility to the toxicity of bromoform or dibromochloromethane. 

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: 

Exposures of Children. 

3.12.3 Ongoing Studies 

No ongoing studies on the health effects of bromoform or dibromochloromethane were listed in the 

Federal Research in Progress database (FEDRIP 2004). 

BROMOFORM AND DIBROMOCHLOROMETHANE 117 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Information regarding the chemical identity of bromoform and dibromochloromethane is located in 

Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Information regarding the physical and chemical properties of bromoform and dibromochloromethane is 

located in Table 4-2. 
BROMOFORM AND DIBROMOCHLOROMETHANE 118 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Bromoform and Dibromochloromethane 

Characteristic Bromoform Dibromochloromethane Reference 

Synonyms 

Registered trade 

name(s) 

Chemical formula 

Chemical structure 

Identification numbers: 

CAS registry 

 NIOSH RTECS 

 EPA hazardous 

waste 
 

OHM/TADS 

 DOT/UN/NA/IMCO 
 

shipping 
 

HSDB 
 

NCI 
 

Beilstein reference 
 

number 
 

Beilstein handbook 
 

reference 
 

Wisesser line 
 

notation 
 

Tribromomethane; 

methenyltribromide; 

methane, tribromoNo data 

CHBr3 

Br 

Br C Br 

H 

75-25-2 

PB5600000 

U225 

No data 

UN2515; IMCO 6.1 

2517 

C55130 

1731048 

4-01-00-00082 

EYEE 

Chlorodibromomethane 

dibromochloromethane; 

methane, dibromochloro-; 

methane, chlorodibromoNo data 

 CHBr2Cl 

Br 

Cl C Br 

H 

124-48-1 

PA6360000 

No data 

No data 

No data 

2763 

C55254 

1731046 

4-01-00-0081 

GYEE 

HSDB 2004a, 2004b 

O’Neil et al. 2001 

O’Neil et al. 2001 

RTECS 2003 

RTECS 2003 

HSDB 2004a, 2004b 

HSDB 2004a, 2004b 

HSDB 2004a, 2004b 

RTECS 2003 

RTECS 2003 

RTECS 2003 

RTECS 2003 

CAS = Chemical Abstracts Service; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North 
 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency;
 

HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for 
 

Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; 
 

RTECS = Registry of Toxic Effects of Chemical Substances
 
BROMOFORM AND DIBROMOCHLOROMETHANE 119 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Bromoform and 

Dibromochloromethane 

Property Bromoform Dibromochloromethane Reference 

Molecular weight 252.73 208.28 O’Neil et al. 2001 

Color Colorless Colorless to pale yellow Verschueren 2001 

Physical state Liquid Liquid Verschueren 2001 

Melting point 8.0 °C -20 °C Lide 2000 

Boiling point 149.1 °C 120 °C Lide 2000 

Density at 20 °C 2.899 2.451 Lide 2000 

Odor Sweet, similar to No data Verschueren 2001 

chloroform 

Taste Similar to chloroform No data Lewis 1997 

Odor threshold: 

Water 0.51 mg/L No data Amoore and Hautala 1983

 Air 13.45 mg/m3 No data Amoore and Hautala 1983 

Solubility: 

 Water 3.10x103

 mg/L (25 °C) 2.7x103 mg/L (20 °C) Horvath 1982; Heikes 

1987 

Organic solvents Miscible in ethanol, Soluble in ethanol, ether, Lide 2000 

benzene, petroleum acetone 

ether, acetone, oils 

Corrosivity Will attack some forms of No data HSDB 2004a 

plastics, rubber, and 

coatings. 

Partition coefficients: 

 Log octanol/water 2.4 2.16 CITI 1992; Sangster 1994

 Log Koc 2.06 1.92 Mabey et al. 1982 

Vapor pressure at 20 °C 5 mmHg 76 mmHg Mabey et al. 1982 

Vapor density 8.7 (air=1) No data IARC 1991a, 1991b 

Henry’s law constant 5.6x10-4 atm-m3

/mol 9.9x10-4 atm-m3/mol Mabey et al. 1982 

Surface tension 41.53 dynes/cm No data Lewis 1997 

Heat of vaporization 46.05 KJ/mol (25 °C) No data Lide 2000 

Autoignition No data No data 

temperature 

Flashpoint No data No data 

Flammability limits Non-flammable Non-flammable HSDB 2004a, 2004b 

Conversion factor 1 ppm = 10.34 mg/m3 1 ppm = 8.52 mg/m3 IARC 1999a, 1999b 

1 mg/m3

 = 0.097 ppm 1 mg/m3 = 0.12 ppm 

BROMOFORM AND DIBROMOCHLOROMETHANE 121 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.1 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 2004a; Stenger 

1978). 

Bromoform is currently produced by Geoliquids, Inc., Prospect Heights, Illinois and Sigma-Aldrich Fine 

Chemicals (SRI 2004). Bromoform was produced formerly by Dow Chemical Company, Midland, 

Michigan. In 1975, production of bromoform in the United States was estimated to be <500 metric tons 

(<1 million pounds) and the 1977 production was estimated at 50–500 metric tons (100,000–1 million 

pounds) (NTP 1989a; Orrell and Mackie 1988; Perwak et al. 1980). The production volume of 

bromoform reported by manufacturers in 1990, 1994, and 1998 was within the range of 10,000– 

500,000 pounds (5–230 metric tons) (IUR 2002). Production volume data were not listed for reporting 

year 2002. 

Dibromochloromethane can be prepared by the addition of dibromochloroacetone to 5N sodium 

hydroxide (IARC 1991b). It can also be prepared by reaction of a mixture of chloroform and bromoform 

with triethylbenzylammonium chloride and sodium hydroxide (IARC 1991a). Available information 

indicates that dibromochloromethane is no longer produced commercially in the United States (SRI 

2004). 

Both bromoform and dibromochloromethane are inadvertently generated during water chlorination when 

chlorine reacts with endogenous organic materials such as humic and fulvic acid (Rook 1977). When 

chlorine is added to water, hypochlorous acid is formed (Wallace 1997). Hypochlorous acid reacts with 

humic or fulvic acids in the water to produce chloroform or it can oxidize any bromide ion that is present 

to form hypobromous acid, which leads to the formation of bromoform, dibromochloromethane, or 

bromodichloromethane. It is estimated that 17 kkg of bromoform and 204 kkg of dibromochloromethane 

were generated in this way in 1978 (Perwak et al. 1980). According to a model generated by Clark et al. 

(1996), higher bromide to chloride ratios promote the bromine substitution reaction over the chlorine 

substitution reaction with organic matter in chlorinated water. At higher bromide concentrations, levels 

of chloroform decreased, while levels of bromoform increased. Dibromochloromethane was found to 
BROMOFORM AND DIBROMOCHLOROMETHANE 122 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

increase to a maximum level for bromide concentrations of 2.5 mg/L and then decline with increasing 

bromide concentration (Clark et al. 1996). 

Table 5-1 summarizes information on companies that reported the production, import, or use of 

bromoform for the Toxics Release Inventory in 2002 (TRI02 2004). The TRI data should be used with 

caution since only certain types of facilities are required to report. This is not an exhaustive list. 

5.2 IMPORT/EXPORT 

Orrell and Mackie (1988) estimated that 6–9 kkg of bromoform were imported by Freeman Industries in 

the late 1980s. No current information was located on the import of bromoform and dibromochloromethane, but it is likely that little, if any, is imported. 

5.3 USE 

Bromoform is used in geological assaying as a heavy liquid for mineral ore separations based on 

differences in specific gravity (Verschueren 2001). It is used in the electronics industry in quality 

assurance programs (Orrell and Mackie 1988). Bromoform has been used as a catalyst, initiator, or 

sensitizer in polymer reactions and in the vulcanization of rubber (HSDB 2004a). As a solvent, 

bromoform has been used for waxes, greases, and oils as well as for liquid-solvent extractions and nuclear 

magnetic resonance (NMR) studies (Lewis 1997; NTP 1989a). Former uses of bromoform include a fireresistant chemical ingredient, a gauge fluid ingredient, an intermediate in chemical syntheses, and a 

sedative and antitussive agent (HSDB 2004a; Perwak et al. 1980). 

Dibromochloromethane is used in laboratory quantities only and there is no current commercial use for 

this compound (Perwak et al. 1980). Dibromochloromethane was used formerly as a chemical 

intermediate in the production of fire extinguishing agents, aerosol propellants, refrigerants, and 

pesticides (IARC 1991b). 

5.4 DISPOSAL 

Because bromoform and dibromochloromethane are listed as hazardous substances, land disposal of 

wastes containing these compounds is controlled by a number of federal regulations (see Chapter 8). 
BROMOFORM AND DIBROMOCHLOROMETHANE 123 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Facilities that Produce, Process, or Use Bromoform 

Number of Minimum amount on site Maximum amount 

Statea facilities in poundsb on site in poundsb Activities and usesc 

AR 5 0 
 999,999 1, 2, 4, 9, 12, 13 

CA 1 100 
 999 12 

LA 2 0 
 999 1, 5, 13 

MS 1 0 
 99 12 

NE 1 10,000 
 99,999 12 

OH 1 1,000 
 9,999 12 

TX 2 1,000 
 999,999 12 

Source: TRI02 2004 (Data are from 2002) 

a

Post office state abbreviations used 

b

Amounts on site reported by facilities in each state 

c

Activities/Uses: 

1. Produce 6. Impurity 11. Chemical Processing Aid 

2. Import 7. Reactant 12. Manufacturing Aid 

3. Onsite use/processing 8. Formulation Component 13. Ancillary/Other Uses 

4. Sale/Distribution 9. Article Component 14. Process Impurity 

5. Byproduct 10. Repackaging 
BROMOFORM AND DIBROMOCHLOROMETHANE 124 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Wastes containing dibromochloromethane or bromoform may be incinerated by rotary kiln, liquid 

injection, or fluidized bed methods. CERCLA reportable quantities for bromoform and dibromochloromethane released to the environment are those quantities ≥100 pounds or 45.4 kg. 

The amount of bromoform and dibromochloromethane 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 2004a; Perwak et al. 

1980). 
BROMOFORM AND DIBROMOCHLOROMETHANE 125 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Bromoform has been identified in at least 140 sites while dibromochloromethane has been identified in at 

least 174 sites of the 1,662 hazardous waste sites that have been proposed for inclusion on the EPA 

National Priorities List (NPL) (HazDat 2005). However, the number of sites evaluated for bromoform 

and dibromochloromethane is not known. The frequency of these sites can be seen in Figures 6-1 and 

6-2, respectively. Of these sites, 137 of the 140 bromoform sites are located within the United States, 1 is 

located in the Virgin Islands (not shown), and 2 are located in the Commonwealth of Puerto Rico (not 

shown). For dibromochloromethane, 172 of the 174 sites are located within the United States, 1 is 

located in the Virgin Islands, and 1 is located in the Commonwealth of Puerto Rico. 

The principal route of human exposure to dibromochloromethane and bromoform is from the 

consumption of chlorinated drinking water. These chemicals are thought to form in the water as byproducts from the reaction of chlorine with dissolved organic matter and bromide ions. Dibromochloromethane and bromoform concentrations in water are quite variable, but average levels are usually 

<5 μg/L. 

Most dibromochloromethane 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 halflives of about 1–2 months. Most measurements of the concentration of these chemicals in air indicate that 

levels are quite low (<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. 

6.2 RELEASES TO THE ENVIRONMENT 

The TRI data should be used with caution because only certain types of facilities are required to report 

(EPA 1997). This is not an exhaustive list. Manufacturing and processing facilities are required to report 
BROMOFORM AND DIBROMOCHLOROMETHANE 126 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with Bromoform Contamination 

Frequency of 

NPL Sites 

1
 

2
 

3
 

4-7
 

Derived from HazDat 2005
 8-10
 

14-17
 
BROMOFORM AND DIBROMOCHLOROMETHANE 127 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-2. Frequency of NPL Sites with Dibromochloromethane Contamination 

Frequency of 

NPL Sites 

1
 

2-3
 

4-6
 

7-9
 

Derived from HazDat 2005
 10
 

15-18
 
BROMOFORM AND DIBROMOCHLOROMETHANE 128 

6. POTENTIAL FOR HUMAN EXPOSURE 

information to the Toxics Release Inventory only if they employ 10 or more full-time employees; if their 

facility is classified under Standard Industrial Classification (SIC) codes 20–39; and if their facility 

produces, imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds 

of a TRI chemical in a calendar year (EPA 1997). 

Bromoform and dibromochloromethane have been identified in a variety of environmental media (air, 

surface water, groundwater, soil, and sediment) collected at 140 and 174 of the 1,662 NPL hazardous 

waste sites, respectively (HazDat 2005). 

6.2.1 Air 

Estimated releases of 12 pounds (0.01 metric tons) of bromoform to the atmosphere from 3 domestic 

manufacturing and processing facilities in 2002, accounted for about 3% of the estimated total 

environmental releases (TRI02 2004). These releases are summarized in Table 6-1. 

Bromoform has been identified in air samples collected at 7 of the 140 NPL hazardous waste sites where 

it was detected in some environmental media (HazDat 2005). Dibromochloromethane has been identified 

in air samples collected at 1 of the 174 NPL hazardous waste sites where it was detected in some 

environmental media. 

The average concentration of dibromochloromethane in uncontrolled emissions from 40 medical waste 

incinerators in the United States and Canada was 0.96 μg/kg waste (Walker and Cooper 1992). The 

average concentration in controlled emissions was 536 μg/kg waste. 

Quack and Wallace (2003) estimated that the annual global flux of bromoform of 3–22 Gmol/year with 

the main source being sea-to-air emissions from macroalgal and planktonic bromoform production. 

Estimated anthropogenic emission rates for bromoform are 34 Mmol/year from coastal power plants, 

4 Mmol/year from inland nuclear power plants, 280 Mmol/year from coastal fossil fuel plants, 

14 Mmol/year from inland fossil fuel plants, 2 Mmol/year from desalination power plants, 12 Mmol/year 

from water disinfection processes giving a total of 346 Mmol/year from all anthropogenic sources (Quack 

and Wallace 2003). Emissions of bromoform from a commercial rice paddy in Houston, Texas were 

reported to range from 0.012 to 0.032 μg/m2

/hour with a median emission rate of 0.021 μg/m2/hour 

(Redeker et al. 2003). The mean annual concentrations of bromoform in air extracted from deep firn air 
BROMOFORM AND DIBROMOCHLOROMETHANE 129 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or 

Use Bromoforma 

Reported amounts released in pounds per yearb 

Total release 

Statec

 RFd Aire Waterf UIg Landh Otheri On-sitej

 Off-sitek On- and off-site 

AR 1 7 0 0 0 0 7 0 7 

LA 1 0 456 0 0 0 456 0 456 

NE 1 5 0 0 0 0 5 0 5 

Total 3 12 456 0 0 0 468 0 468 

Source: TRI02 2004 (Data are from 2002) 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number. 

b

Data in TRI are maximum amounts released by each facility. 

c

Post office state abbreviations are used. 

d

Number of reporting facilities. 

e

The sum of fugitive and point source releases are included in releases to air by a given facility. f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs)
 

(metal and metal compounds).
 g

Class I wells, Class II-V wells, and underground injection. 
 h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 
 

impoundments, other land disposal, other landfills. 
 i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for 
 

disposal, unknown 
 j

The sum of all releases of the chemical to air, land, water, and underground injection wells. 
 k

Total amount of chemical transferred off-site, including to POTWs. 
 

RF = reporting facilities; UI = underground injection 
 
BROMOFORM AND DIBROMOCHLOROMETHANE 130 

6. POTENTIAL FOR HUMAN EXPOSURE 

were 1.35 and 0.20 ppt at two Antarctic locations (Sturges et al. 2001). Mean annual concentrations of 

dibromochloromethane were 0.20 and 0.14 ppt. 

No other studies were located regarding the amount of bromoform and dibromochloromethane 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. 

6.2.2 Water 

Estimated releases of 456 pounds (0.21 metric tons) of bromoform to surface water and publicly owned 

treatment works from three domestic manufacturing and processing facilities in 2002, accounted for about 

97% of the estimated total environmental releases (TRI02 2004). These releases are summarized in 

Table 6-1. 

Bromoform has been identified in surface water samples and groundwater samples collected at 14 and 

103 of the 140 hazardous waste sites, respectively, where it was detected in some environmental media. 

Dibromochloromethane has been identified in surface water samples and groundwater samples collected 

at 15 and 146 of the 174 hazardous waste sites, respectively, where it was detected in some environmental 

media (HazDat 2005). 

The principal anthropogenic source of bromoform and dibromochloromethane in the environment is 

chlorination of water containing organic materials (Bellar et al. 1974; EPA 1980a; Peters et al. 1994; 

Rook 1977; Rodriguez et al. 2004; Symons et al. 1975, 1993). It has been estimated that the total 

amounts of bromoform and dibromochloromethane generated by chlorinating U.S. drinking water in 

1978 were 17 and 204 kkg, respectively (Perwak et al. 1980). Bromoform and dibromochloromethane 

were detected in the distribution systems of three water treatment plants that each use different methods 

of water chlorination (LeBel et al. 1997). Mean monthly concentrations of dibromochloromethane were 

0.2 μg/L in samples from the chlorine-chloramine treatment plant, 0.3 μg/L in samples from the chlorinechlorine treatment plant, and 0.1 μg/L in samples from the ozone-chlorine treatment plant. Mean monthly 

bromoform concentrations were <0.1 μg/L in samples from all three plants. 

Unlike the chlorination of low-bromide fresh water where chloroform is the trihalomethane produced in 

the largest amounts, bromoform is the trihalomethane usually produced in the largest amounts during the 
BROMOFORM AND DIBROMOCHLOROMETHANE 131 

6. POTENTIAL FOR HUMAN EXPOSURE 

chlorination of sea water or high-bromide fresh water (Khalanski 2003; Richardson et al. 2003). The 

concentrations of bromoform in the chlorinated cooling water at three European marine power stations on 

the English Channel were 25.16, 11.4, and 18.23 μg/L (Khalanski 2003). Richardson et al. (2003) 

measured bromoform concentrations of 23.3, 57, 59, 44, and 55 μg/L in high-bromide water from the Sea 

of Galilee in Israel after a pre-chlorination step during the months of December, May, September, 

November, and July, respectively. Concentrations of dibromochloromethanein these samples were 

reported only for the months of May, September, and July (9.39, 1.9, and 3.7 μg/L, respectively). 

Ozonation of water containing bromide ion has also been shown to be a source of bromoform in the 

environment (Glaze et al. 1989; Huang et al. 2003). Bromoform levels were 1.4, 3.7, and 2.1 mg/L in 

California State Project Water samples after ozonation at the Los Angeles Aqueduct Filtration Plant in 

1987 at ozone doses of 1.0, 2.0, and 4.0 mg/L, respectively (Glaze et al. 1989). Huang et al. (2004) 

reported that bromoform generation is greater in waters with higher organic matter content. 

Release of dibromochloromethane and bromoform into groundwater has been shown to occur as a 

consequence of the yearly aquifer storage and recovery (ASR) in the Las Vegas Valley. As an example, it 

is estimated that up to 16.3x106

 m3 water was injected into the underlying aquifer during the winter 

months of 1995–1996, when demand for water by neighboring Las Vegas was low (Thomas et al. 2000). 

Because the recharge water is chlorinated before injection, byproducts of this disinfection process are 

introduced into the groundwater at concentrations measured during the 1995–1996 ASR recharge seasons 

of 18 μg/L for dibromochloromethane and 2.6 μg/L for bromoform in the recharge water. During the 

water recovery phase beginning in the spring of 1996, initial concentrations of dibromochloromethane 

and bromoform in water recovered from one recharge well (#14) in the spring of 1996 were below 

detection limits (0.5 μg/L) but were much higher, 15 and 2.4 μg/L, respectively, in a second well (#51). 

Dibromochloromethane and bromoform levels in water recovered from the second well fell during the 

remaining spring and summer months decreasing to concentrations of 1.5 and 0.6 μg/L, respectively, in 

September of 1996. The differences in the concentrations of dibromochloromethane and bromoform 

between wells 14 and 51, and the decrease in concentrations observed in water recovered from well 

51 during the spring and summer recovery months of 1996, were attributed to both dilution of the 

recharge water in the aquifer with natural water from the surrounding aquifer basin and biotransformation 

of the trihalomethanes within the aquifer. 

Dibromochloromethane and bromoform may also occur as a consequence of chlorinating industrial waste 

waters (Perry et al. 1979). Staples et al. (1985) reported that bromoform was detected in 60 of 
BROMOFORM AND DIBROMOCHLOROMETHANE 132 

6. POTENTIAL FOR HUMAN EXPOSURE 

1,346 samples of industrial waste effluent, at a median concentration of <5 μg/L, and dibromochloromethane was detected in 84 of 1,298 samples at a median concentration of <2.4 μg/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. 

Bromoform and dibromochloromethane were detected in New York City municipal waste water samples 

taken from 1989 to 1993 (Stubin et al. 1996). Influent concentrations ranged from 7 to 40 μg/L for 

bromoform with a frequency of detection of 4% and 9 μg/L for dibromochloromethane with a frequency 

of detection of 1%. Effluent concentrations ranged from 3 to 11 μg/L for bromoform with a frequency of 

detection of 11% and from 2 to 15 μg/L for dibromochloromethane with a frequency of detection of 8%. 

Moschandreas et al. (1997) studied samples from 14 New York City waste water pollution control plants 

to determine the organic compound concentrations in the waste water at each of the plants. Bromoform 

was detected with concentrations of 0.4–10 μg/L in raw influent samples, 2.0–9.0 μg/L in primary 

influent samples, 1.0–10 μg/L in primary effluent samples, 0.3–11 μg/L in aeration tank samples, 0.4– 

12 μg/L in superficial of return activated sludge samples, and 0.2–12 μg/L in plant effluent samples. 

Only the plant effluent concentration range (0.3–5.0 μg/L) was reported for dibromochloromethane. 

Although most raw water samples collected from different points of the Great Lakes in 1990 contained 

trihalomethanes at concentrations <2 μg/L, mean concentrations in treated water samples from four of the 

six locations were above 25 μg/L (Henshaw et al. 1993). The low trihalomethane concentrations of the 

other two locations are attributed to the use of alternative methods of water treatment such as ammonia 

addition and potassium permanganate disinfection. 

The average concentration of dibromochloromethane in sewage treatment effluents in England and Wales 

in 1995 was 0.2007 μg/L with a frequency of detection of 30.4% (Stangroom et al. 1998a). The average 

concentration of dibromochloromethane in trade effluents in England and Wales in 1995 was 7.91 μg/L 

with a frequency of detection of 63%. 

Mean dibromochloromethane concentrations were determined to be 2 ng/L in water and sediment samples 

taken from the anoxic fjord Idefjorden between Norway and Sweden near the city of Halden, Norway 

(Abrahamsson and Klick 1989). Dibromochloromethane was detected in effluent water from a nearby 

paper pulp mill. 
BROMOFORM AND DIBROMOCHLOROMETHANE 133 

6. POTENTIAL FOR HUMAN EXPOSURE 

Class et al. (1986) observed trace levels of dibromochloromethane and bromoform and other halogenated 

methanes in sea water (0.1–6 ng/L) and in the air (0.1–20 ppt) at several locations in the Atlantic. Other 

studies have reported atmospheric bromoform concentration ranges of 1.0–22.7 pptv off the coast of 

Galway, Ireland, 0.7–8.0 pptv off the coast of northwestern Tasmania, 0.28–2.9 pptv in the West Pacific 

Islands, 0.32–7.1 pptv in the Asian Seas, and 1.0–37.4 pptv off the Antarctic Peninsula (Carpenter et al. 

1999, 2003). Dibromochloromethane was also detected off the coasts of Galway, Ireland and 

northwestern Tasmania with atmospheric concentrations of 0.13–1.8 and 0.1–1.4 pptv, respectively. The 

presence of these compounds can be attributed to biosynthesis and release of bromochloromethanes by 

macroalgae (Carpenter et al. 1999; Class et al. 1986; Gschwend et al. 1985; Marshall et al. 2003; Quack 

and Wallace 2003). Gschwend et al. (1985) estimated that marine algae could be a major global source of 

volatile organobromides. More recently, Carpenter and Liss (2000) estimated that macroalgae produce 

around 70% of the world’s bromoform, which is greater than what was previously estimated due to 

updated seaweed biomass estimates. However, Class et al. (1986) states that this source accounts for 

<1% of the anthropogenic burden of total organohalogens in the atmosphere. 

6.2.3 Soil 

There were no releases to the ground either through soil or underground injection from three domestic 

manufacturing and processing facilities in 2002 (TRI02 2004). This information is summarized in 

Table 6-1. 

Bromoform has been identified in soil and sediment samples collected at 26 and 3 of the 140 NPL 

hazardous waste sites, respectively, where it was detected in some environmental media. Dibromochloromethane has been identified in soil and sediment samples collected at 21 and 4 of the 174 NPL hazardous 

waste sites, respectively, where it was detected in some environmental media (HazDat 2005). 

Soils and other unconsolidated surficial materials may become contaminated with bromoform and 

dibromochloromethane by chemical spills, the landfilling of halomethane-containing solid wastes, or the 

discharge of chlorinated water. However, no data were located to suggest that land releases are a 

significant source of the chemicals in the environment. 
BROMOFORM AND DIBROMOCHLOROMETHANE 134 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

Bromoform and dibromochloromethane are slightly volatile liquids, and tend to exist primarily as vapors 

in the atmosphere. The vapor pressure of bromoform is 0.007 atm at 20 °C (Mabey et al. 1982), and the 

vapor pressure of dibromochloromethane at 20 °C is approximately 0.1 atm (Mabey et al. 1982). The 

half-time of evaporation from flowing, aerated water (e.g., rivers and streams) has been estimated to 

range from 1 to 581 hours for bromoform and from 0.7 to 398 hours for dibromochloromethane (Kaczmar 

et al. 1984; Mackay et al. 1982). 

Both dibromochloromethane and bromoform are moderately soluble in water (Callahan et al. 1979; 

Heikes 1987), 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 to partition between its vapor phase 

and water) for bromoform range from 4.3 to 5.6x10-4 atm-m3

/mole, and from 8.7 to 9.9x10-4 atm-m3/mole 

for dibromochloromethane (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 dibromochloromethane 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 57 has been estimated for dibromochloromethane, based on its measured water 

solubility (Heikes 1987). No studies were located on the adsorption of dibromochloromethane by soils or 
BROMOFORM AND DIBROMOCHLOROMETHANE 135 

6. POTENTIAL FOR HUMAN EXPOSURE 

soil materials, but it is likely that dibromochloromethane will have properties generally similar to those of 

bromoform. 

Bromoform and dibromochloromethane 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 dibromochloromethane (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 (BCF) for dibromochloromethane or bromoform, but based on measured BCFs for similar compounds (Kenaga 1980), the BCF of 

dibromochloromethane and bromoform may be on the order of 2–10. 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. 

The percent removal of dibromochloromethane measured at the outlet of a waste-water-dependent 

constructed wetland near Phoenix, Arizona was 86.5% (Keefe et al. 2004). The authors concluded that 

volatilization was the primary removal mechanism. 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

Based on the behavior of similar compounds, it seems likely that bromoform and dibromochloromethane 

may be degraded by photooxidative interactions with atmospheric OH radicals. Radding et al. (1977) 

proposed that the atmospheric half-life of bromoform and dibromochloromethane is approximately 1– 

2 months, but this has not been confirmed by direct experimental measurements. 

6.3.2.2 Water 

Both dibromochloromethane and bromoform are relatively stable in water, with estimated hydrolytic rate 

constants of 3.2x10-11 sec-1 and 8x10-11 sec-1 (Mabey and Mill 1978). These rate constants correspond to 

hydrolytic half-lives of 686 and 274 years for bromoform and dibromochloromethane, 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. 
BROMOFORM AND DIBROMOCHLOROMETHANE 136 

6. POTENTIAL FOR HUMAN EXPOSURE 

It has been found that dibromochloromethane and bromoform undergo only limited biodegradation (10– 

25%) under aerobic conditions, although the rate may increase somewhat after microbial adaptation 

(Bouwer et al. 1981; Tabak et al. 1981a). Bromoform, at initial concentrations ranging from 132 to 

177 μg/L, underwent >99% reduction in a continuous-flow biofilm column seeded with primary settled 

sewage with 1.5 hours packed-bed detention time (Cobb and Bouwer 1991). Under anaerobic conditions, 

dibromochloromethane and bromoform have been found to be readily biodegraded in the presence of 

methane-producing bacteria (Bouwer and McCarty 1983a; Bouwer et al. 1981), 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). Increased degradation rates were observed for bromoform and dibromochloromethane 

under conditions similar to those found inside ferrogenic aquifers, especially at higher pH (Kenneke et al. 

2003; Pecher et al. 2002). Bouwer and Wright (1986) reported that one degradation product of 

bromoform was dibromomethane, but there was no additional information on the identity or fate of 

environmental degradation by-products. Bromoform was not degraded in enriched sea water cultures 

taken from beds of the giant kelp, M. pyrifera off the coast of California after 40 days (Goodwin et al. 

1997). 

The concentration of bromoform decreased from 58 μg/L to <1 μg/L in water stored in an aquifer 7 days 

after recharge with chlorinated water (Nicholson et al. 2002). The concentration of dibromochloromethane decreased from 46 to 3 μg/L 28 days after recharge. The authors stated that the main attenuation 

processes were most likely adsorption and degradation under methanogenic conditions. McQuarrie and 

Carlson (2003) suggest that aquifer storage may be a potential method for the removal of disinfection 

byproducts such as bromoform and dibromochloromethane from treated water. 

6.3.2.3 Sediment and Soil 

No studies were located regarding the biodegradation of dibromochloromethane 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 rates in moist soils. 
BROMOFORM AND DIBROMOCHLOROMETHANE 137 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.3.2.4 Other Media 

No information was located on the transformation and degradation of bromoform or dibromochloromethane in other media. 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to bromoform and dibromochloromethane 

depends in part on the reliability of supporting analytical data from environmental samples and biological 

specimens. Concentrations of bromoform and dibromochloromethane in unpolluted atmospheres and in 

pristine surface waters are often so low as to be near the limits of current analytical methods. In 

reviewing data on bromoform and dibromochloromethane levels monitored or estimated in the 

environment, it should also be noted that the amount of chemical identified analytically is not necessarily 

equivalent to the amount that is bioavailable. The analytical methods available for monitoring 

bromoform and dibromochloromethane in a variety of environmental media are detailed in Chapter 7. 

6.4.1 Air 

Dibromochloromethane and bromoform are usually found in air only at very low concentrations. 

Brodinsky and Singh (1983) tabulated data on dibromochloromethane and bromoform levels in ambient 

air from five urban locations across the United States. For dibromochloromethane, 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). 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 dibromochloromethane concentration was 0.08 ppt (0.8 ng/m3

), but 54 of 

56 measurements were <0.05 ppt (0.5 ng/m3

). 

Fischer et al. (2000) found a nearly constant mixing ratio of bromoform at 0.5 parts per trillion by volume 

(pptv) in the marine troposphere of the Atlantic across 30 °W longitude. In the coastal region of South 

America, bromoform concentrations were 2.4 pptv. A high concentration of bromoform (2.0 pptv) was 

found in an air sample taken near Cape Verde Island. Air mixing ratios for bromoform in samples taken 

above the waters of the equatorial Pacific during the third joint Soviet-American Gases and Aerosols 
BROMOFORM AND DIBROMOCHLOROMETHANE 138 

6. POTENTIAL FOR HUMAN EXPOSURE 

(SAGA 3) experiment ranged from 0.68 to 3.28 pptv using the charcoal or Tenax adsorption method and 

from 0.5 to 6.7 pptv using the canister collection method (Atlas et al. 1993). Air mixing ratios for 

dibromochloromethane ranged from 0.09 to 0.49 pptv using the charcoal or Tenax adsorption method. 

Dibromochloromethane was not measured with the canister collection method. 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). 

During the Urban Air Toxics Monitoring Program, concentrations of bromoform and dibromochloromethane at 13 air monitoring sites located in Vermont, New Jersey, Louisiana, and Texas were <1 parts 

per billion by volume (ppbv) (no detection limit given) (Mohamed et al. 2002). Bromoform was not 

detected in air samples from three permanent sites in Arizona (Tucson, Payson, and Casa Grande) during 

the Arizona Hazardous Air Pollutants Monitoring Program, though the detection limit was not specified 

(Zielinska et al. 1998). Bromoform was detected at a fourth permanent site in Phoenix with a maximum 

concentration of 0.02 ppbv, although the average bromoform concentration at this site was below the 

detection limit. Bromoform was not detected (detection limit unspecified) in air samples collected from 

13 semi-rural to urban locations in Maine, Massachusetts, New Jersey, Pennsylvania, Ohio, Illinois, 

Louisiana, and California (Pankow et al. 2003). However, dibromochloromethane was detected at 

Kettering, Ohio at a concentration of 0.007 ppbV. This concentration was below the lowest daily 

standard of 0.057 ppbV. Neither bromoform nor dibromochloromethane were detected (detection limit 

not specified) in air samples from 13 locations in Texas, Louisiana, New Jersey, and Vermont (Mohamed 

et al. 2002). 

The mean, minimum, and maximum concentrations of dibromochloromethane in air samples taken during 

the Southern California Ozone Study in 1997 were 0.02 ppbv (210 ng/m3

), 0.04 ppbv (420 ng/m3), and 

0.01 ppbv (105 ng/m3

), respectively at a residential/industrial site in Mexicali, Mexico (Zielinska et al. 

2001). Dibromochloromethane was not detected at a residential site in Rosarito, Mexico (no detection 

limit given). Dibromochloromethane was detected at 24 ppb (0.210 mg/m3

) in Finnish industrial air 

samples medical industry preparing solutions and at 1.6 ppb (0.014 μg/m3

) in suburban air from Turku, 

Finland (Kroneld 1989a, 1989b). Dibromochloromethane was not detected in countryside air samples 

taken from the Islands of Inio at the southwest coast of Finland. Mean concentrations of bromoform 

detected in air samples collected at two locations in the city of Kaohsiung, Taiwan during the spring of 

2002 were 0.25 and 1.00 μg/m3

 (Lai et al. 2004). 
BROMOFORM AND DIBROMOCHLOROMETHANE 139 

6. POTENTIAL FOR HUMAN EXPOSURE 

Bromoform was detected with an occurrence rate of 54% in indoor air samples taken from 26 houses, 

although actual concentrations were not given (Kostiainen 1995). Air from 13 houses in Katusushika 

Ward, Tokyo, Japan were sampled during a survey of indoor pollution by volatile organohalogen 

compounds in February 1995 (Amagai et al. 1999). Thirty houses were sampled in July 1995. 

Bromoform was detected in all 13 houses during the February survey. In July, it was detected in 22 out 

of 30 houses. Dibromochloromethane was detected in all houses during both the February and July 

surveys. Mean concentrations of dibromochloromethane in February 1995 were 0.016 μg/m3 in outdoor 

air, 0.095 μg/m3 in living room air, 0.122 μg/m3 in kitchen air, 0.096 μg/m3 in bedroom air, and 

0.701 μg/m3 in bathroom air. Mean concentrations of dibromochloromethane in July 1995 were 

0.007 ug/m3 in outdoor air, 0.050 μg/m3 in living room air, 0.065 μg/m3 in kitchen air, 0.042 μg/m3 in 

bedroom air, and 0.372 μg/m3 in bathroom air. Mean concentrations of bromoform in February 

1995 were 0.009 ug/m3 in outdoor air, 0.016 μg/m3 in living room air, 0.018 μg/m3 in kitchen air, 

0.015 μg/m3

 in bedroom air, and 0.091 μg/m3 in bathroom air. Mean concentrations of bromoform in July 

1995 were 0.010 μg/m3

 in outdoor air, 0.013 μg/m3 in living room air, 0.013 μg/m3 in kitchen air, 

0.012 μg/m3

 in bedroom air, and 0.034 μg/m3 in bathroom air. 

Kerger et al. (2000) evaluated airborne concentrations of common trihalomethane compounds in 

bathrooms during showering and bathing in three urban homes supplied with chlorinated tap water. 

Samples were collected prior to, during, and after the water-use event for 16 shower and 7 bath events. 

The increases in average airborne concentration of dibromochloromethane were 0.5 μg/m3

 per μg/L 

during showers and 0.15 μg/m3

 per μg/L during baths. 

No studies were located regarding atmospheric concentrations of bromoform or dibromochloromethane in 

the workplace. Dibromochloromethane was detected in air samples at two hazardous waste sites, but the 

amounts were not quantified (LaRegina et al. 1986). 

6.4.2 Water 

Dibromochloromethane and bromoform are rarely measurable in nonchlorinated 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 dibromochloromethane in finished (chlorinated) drinking water have been 

investigated in several studies (see Table 6-2). Except for a few cases, the concentrations of bromoform 

and dibromochloromethane in drinking water were <100 μg/L, with mean concentrations generally 

<10 μg/L. 
BROMOFORM AND DIBROMOCHLOROMETHANE 140 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Occurrence of Bromoform and Dibromochloromethane in Finished 

Drinking Water 

 Concentration (μg/L) 

Frequency of detection 

percent Range Mean Location Reference 

Bromoform 

10 

27 

34 

67 

NR 

100 

26 

NR 

8 

NR 

Dibromochloromethane 

86 

NR 

37 

85 

65 

86 

99 

NR 

100 

42 

NR 

75 

NR 

NR 

ND–92 

ND–3.0 

NR 

NR–4.4 

ND–258 

4–17 

NR–110 

1–10 

ND–1.6 

NR 

<0.1–2 

3-32 

ND–110 

ND–15.0 

ND–9.0 

NR 

NR–33 

ND–128 

11–31 

NR–63 

1–28 

ND–40 

NR 

NR 

≈0.4 

≈0.5 

12 

0.4 

≈7 

9 

NR 

NR 

0.1 

0.8–8 

0.9 

NR 

2.7 

≈0.4 

2.9 

14 

5.6 

≈20 

20 

NR 

NR 

4.1 

1–2 

8–28 

National 

13 Cities 

National 

Midwest 

Texas 

Texas 

National 

Iowa 

Michigan 

California 

Ohio 

5 Cities 

National 

13 Cities 

Iowa 

National 

Midwest 

Texas 

Texas 

National 

Iowa 

Michigan 

New Jersey 

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’Itri 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 et al. 1985 

Furlong and D’Itri 1986 

Wallace et al. 1986a 

Wallace et al. 1986b 

μg = microgram; L = liter; ND = not detected; NR = not reported 
BROMOFORM AND DIBROMOCHLOROMETHANE 141 

6. POTENTIAL FOR HUMAN EXPOSURE 

Bromoform and dibromochloromethane were detected in approximately 90% of samples from 5,320 wells 

in 21 states from 1985 to 1995 according to data collected by the United States Geological Survey 

(USGS) National Water-Quality Assessment Program, although actual concentrations were not given 

(Lapham et al. 2000). Bromoform and dibromochloromethane were detected in 27 and 39 out of 

7,712 California drinking water wells, respectively, during monitoring studies conducted from 1984 to 

1990 (Lam et al. 1994). Maximum concentrations were 78 μg/L for bromoform and 30 μg/L for 

dibromochloromethane. Dibromochloromethane was detected in 5 out of 6 samples from 178 active 

public supply wells in the Los Angeles physiographic basin, California above the laboratory reporting 

limit of 0.18 μg/L in August through September 2000 (Shelton et al. 2001). Bromoform was detected in 

four out of four samples above the laboratory reporting limit of 0.06 μg/L. Clark et al. (1994) collected 

drinking water samples from different points along the North Marin Water District, which serves the 

greater Novato area in California. Bromoform and dibromochloromethane were detected in the samples 

with concentrations ranging from 2.4 to 11.4 μg/L and from <0.1 to 7.5 μg/L, respectively. The 

concentrations of bromoform and dibromochloromethane were below their detection limits of 0.06 and 

0.18 μg/L, respectively, in samples collected from 30 groundwater monitoring wells in Wichita, Kansas 

(USGS 2002). The wells were located in areas of recent residential and commercial development. 

The State of California’s Water Quality Monitoring Database contains data for public drinking water 

systems that use either groundwater or surface water sources (Storm 1994). Analysis of these data shows 

that bromoform was detected in 145 out of 11,765 samples (1.2%) and dibromochloromethane was 

detected in 171 out of 11,782 samples (1.5%). Mean concentrations in samples with detected dibromochloromethane and bromoform were 8.95 and 7.63 μg/L, respectively. Occurrence data from 

approximately 22,000 public water systems (source water: 88% groundwater and 12% surface water) 

from a cross-section of 24 states were selected from the Unregulated Contaminant Information System 

database (Round 1 monitoring data) (EPA 2001a). Dibromochloromethane and bromoform were detected 

in these systems with 99th percentile values of 12.7 and 7.3 μg/L, respectively. Occurrence data from 

approximately 27,000 public water systems (source water: 89% groundwater and 11% surface water) 

from a cross-section of 22 states were selected from the Safe Drinking Water Information System 

database (Round 2 monitoring data). Dibromochloromethane and bromoform were detected in these 

systems with 99th percentile values of 9.7 and 6.5 μg/L, respectively. 

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 
BROMOFORM AND DIBROMOCHLOROMETHANE 142 

6. POTENTIAL FOR HUMAN EXPOSURE 

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. 

The mean concentration of dibromochloromethane was 0.74 μg/L in cold season samples from the 

Elizabethtown, New Jersey water distribution system (Chen and Weisel 1998). Dibromochloromethane 

levels rose to 1.7 μg/L in warm season samples. Bromoform was not found above the detection limit 

(0.10 μg/L) in cold season samples from the distribution system, but it was detected in warm season 

samples with a mean concentration of 0.27 μg/L. Summer concentration ranges in treated water 

immediately prior to distribution in a 1993 national Canadian survey conducted by Health Canada were 

<0.1–19.8 μg/L for dibromochloromethane and <0.1–4.2 μg/L for bromoform (Ritter et al. 2002). Winter 

concentration ranges were <0.1–9.0 μg/L for dibromochloromethane and <0.1–3.3 μg/L for bromoform. 

Bromoform was detected in the influent, treated, and distribution stages from 47 municipal water 

treatment plants in Ontario, Canada at concentrations of 0.5, 0–7.0, and 0.2–8.5 μg/L, respectively. 

Dibromochloromethane was detected in samples from plant effluents of 35 Finnish waterworks with 

concentrations ranging from <0.05 to 3 μg/L (Nissinen et al. 2002). One exception was a comparatively 

high concentration of 43 μg/L measured at one of the plants. Bromoform concentrations were <0.05 μg/L 

in samples from all plants except for three (0.48, 0.31, and 27 μg/L). Concentrations of bromoform and 

dibromochloromethane in samples from two Finnish waterworks rose in the spring, changed little over 

summer and fall, and then dropped during winter. Campillo et al. (2004) detected bromoform in tap water 

samples collected in Spanish cities at concentrations ranging from 1.8 to 24.7 μg/L (mean=13.5 μg/L). 

The concentrations of dibromochloromethane in these samples ranged from 2.0 to 66.5 μg/L 

(mean=30 μg/L). Mean concentrations of dibromochloromethane and bromoform were 0.5 μg/L and 

below the detection limit (0.3 μg/L), respectively, in tap water from the city of Cherepovets, Russia 

(Egorov et al. 2003). Dibromochloromethane was detected in tap water samples collected from the 

19 districts of Hong Kong at concentrations ranging from 0.830 to 4.15 μg/L (Lee et al. 2004b). 

Bromoform was detected (detection limit 0.03 μg/L) in tap water samples from only 4 of the 19 districts 

at concentrations ranging from 0.040 to 0.920 μg/L. 

Bromoform and dibromochloromethane were detected in water samples from seven out of nine household 

residences in the Lower Rio Grande Valley during the spring of 1993 with concentrations ranging from 

1.0 to 14.1 μg/L and from 3.3 to 17.3 μg/L, respectively (Berry et al. 1997). These compounds were 
BROMOFORM AND DIBROMOCHLOROMETHANE 143 

6. POTENTIAL FOR HUMAN EXPOSURE 

detected in water samples from five out of nine residences in the same region during the summer of 

1993 with concentrations ranging from 1.6 to 31.7 μg/L and from 1.8 to 49.9 μg/L, respectively. 

In order to reduce trihalomethane and related disinfection byproduct concentrations in treated water, 

communities have begun employing treatment methods that remove disinfection byproduct precursors 

such as natural organic carbon from the water prior to chlorination (Dey et al. 2001; Peltier et al. 2002; 

Shetty and Chellam 2003; Weiss et al. 2003; Westerhoff et al. 2004). Some processes employ a 

coagulation step to aid in filtration or adsorption (Dey et al. 2001; Drikas et al. 2003). Disinfection 

byproduct removal was studied in the two trains of the Mery-sur-Oise treatment plant, which feeds the 

northern Parisian Suburbs (Peltier et al. 2002). The newer train uses nanofiltration technology while the 

older train employs conventional treatment. Trihalomethane concentrations in water treated by the 

nanofiltration train were 50% less than trihalomethane concentrations in water treated by the conventional 

train. Weiss et al. (2002, 2003) observed that levels of total organic carbon and dissolved organic carbon 

in water from the Ohio, Wabash, and Missouri Rivers were reduced by 35–67% after riverbank filtration. 

However, the brominated trihalomethane precursors were not removed as efficiently as the chlorinated 

trihalomethane precursors (<40% compared to 80%). This was attributed to the increase in the bromide 

to total organic carbon ratio as the water traveled from the rivers to the collection wells. 

Trihalomethanes may also form in chlorinated swimming pools (Beech et al. 1980). For fresh water 

pools, chloroform and dichlorobromomethane were usually the predominant THM species present, with 

dibromochloromethane and bromoform averaging 3–15 and 1–2 μg/L, respectively. However, in saline 

pools (which have a higher bromide ion content than fresh water pools), bromoform was the major THM 

present (average concentration of 650 μ/L), with lower concentrations (5–27 μg/L) of dibromochloromethane, bromodichloromethane, and chloroform. Concentrations of bromoform and dibromochloromethane were 1.8–2.9 and 3.5–17 μg/L, respectively, in samples taken from three chlorinated sandy 

bottom swimming areas in September (Mansour et al. 1999). The concentrations of dibromochloromethane were below 40 μg/L in water samples from eight swimming pools in Nagpur, India (Thacker and 

Nitnaware 2003). Bromoform was detected in samples from only one of the pools at a concentration 

below 10 μg/L. 

Dibromochloromethane 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 2 of 862 hazardous-waste sites; 

the median concentration was 7 μg/L. Dibromochloromethane was detected in only one sample 
BROMOFORM AND DIBROMOCHLOROMETHANE 144 

6. POTENTIAL FOR HUMAN EXPOSURE 

(45 μg/L). Bromoform was detected in groundwater samples collected at four sites; the median 

concentration was 26 μg/L. Based on monitoring data from 479 disposal site groundwater investigations 

that were conducted across the United States, bromoform was detected in groundwater samples from 

10 hazardous waste disposal sites and dibromochloromethane has been detected in groundwater samples 

from 8 hazardous waste disposal sites (Plumb 1991). Actual concentrations of bromoform and 

dibromochloromethane were not given. 

In a random survey of 954 community water systems, bromoform and dibromochloromethane were 

detected (minimum reporting limit of 0.2 μg/L) in 3.4 and 5.5%, respectively, of source water samples 

(Delzer and Ivahnenko 2003). Both bromoform and dibromochloromethane were detected more 

frequently in groundwater sources than surface water sources. Concentrations of bromoform in 

groundwater ranged from 0.19 to 2.61 μg/L with a median value of 0.26 μg/L; in surface water, the 

concentrations ranged from 0.03 to 0.06 μg/L with a median value of 0.05 μg/L. For dibromochloromethane, concentrations in groundwater ranged from 0.02 to 2.43 μg/L with a median value of 0.04 μg/L; 

in surface water, the concentrations ranged from 0.02 to 0.15 μg/L with a median value of 0.03 μg/L. In a 

study of over 21 cities throughout the United States conducted between 1991–1995, dibromochloromethane was detected (minimum reporting limit of 0.2 μg/L) in 3.4% of storm water and 0.5% of shallow 

groundwater samples (Lopes and Bender 1998). The presence of dibromochloromethane in these samples 

was attributed to the irrigation of lawns, gardens, and parks with chlorinated water, the draining of 

swimming pools, and uses of chlorinated water that result in its introduction to storm water catchments. 

Dibromochloromethane has been detected at concentrations ranging from 1.1 to 36.3 ng/L in the Scheldt 

River estuary, Germany during May 1998; from 0.2 to 22.7 ng/L in Scheldt River estuary, Germany 

during October 1998; from below the detection limit to 39.0 ng/L in the Thames River estuary, England 

during February 1999; from below the detection limit to 7.7 ng/L in the Loire River estuary, France 

during September 1998; and from below the detection limit to 9.8 ng/L in the Rhine River estuary, 

Germany during November 1997 (Christof et al. 2002). Bromoform and dibromochloromethane were 

detected in water samples from the Southampton Water estuary at concentrations of 10–2,597 and 10– 

2,200 ng/L, respectively (Bianchi et al. 1991). 

Bromoform was not found above a detection limit of 0.08 μ/L in 644 samples from 46 surface water 

locations, including sea, estuarine, river, and industrial effluent, throughout Portugal (Martinez et al. 

2002). Concentrations of bromoform in the Belaya River, Russia were <0.0001 mg/L above an industrial 

zone and <0.0004 mg/L below the industrial zone (Safarova et al. 2004). The concentration of 
BROMOFORM AND DIBROMOCHLOROMETHANE 145 

6. POTENTIAL FOR HUMAN EXPOSURE 

bromoform in the waste water flowing into this river was measured as 0.0021 mg/L. The concentrations 

of bromoform and dibromochloromethane in finished water from the city of Hanoi, Vietnam ranged from 

1.2 to 8.5 μg/L (average, 6.6 μg/L) and from 0.3 to 22.3 μg/L (average, 6.3 μg/L), respectively, in high 

bromide finished water and from <0.2 to 3.7 μg/L (average, 0.5 μg/L) and from <0.2 to 3.8 μg/L (average, 

1.8 μg/L), respectively, in low bromide finished water (Duong et al. 2003). In high bromide finished 

water that also had high ammonia content, dibromochloromethane was detected at concentrations ranging 

from <0.2 to 3.7 μg/L (average, 0.3 μg/L), while the concentration of bromoform was <0.2 μg/L. 

Bromoform and dibromochloromethane have been detected in the Marta River, Italy at concentrations of 

2.39–3.35 and 0.04–0.11 μg/L, respectively (Russo et al. 2003). The concentrations of bromoform and 

dibromochloromethane in the Tiber River, Italy were 0.82–1.82 and <16–0.11 μg/L, respectively. 

6.4.3 Sediment and Soil 

Staples et al. (1985) reported that bromoform was not detected in any of 353 sediment samples analyzed. 

No data were available for dibromochloromethane. Data from the Contract Laboratory Program Statistic 

Data Base (CLPSD 1988) indicated dibromochloromethane and bromoform were detected in soils in only 

2 of 862 hazardous waste sites; the median concentrations were 17 μg/kg (bromoform) and 15 μg/kg 

(dibromochloromethane). Bromoform and dibromochloromethane were detected in sediment samples 

from the Southampton Water estuary at concentrations ranging from 75 to 62,609 and from 150 to 

27,350 ng/kg, respectively (Bianchi et al. 1991). During a monitoring study of volatile halogenated 

organic compounds in the Klosterhede State Forest District in Jutland, Denmark, bromoform was the only 

brominated compound detected in soil air samples and only in the upper soil layer with a concentration of 

0.25 ng/L (Laturnus et al. 2000b). 

6.4.4 Other Environmental Media 

The use of chlorinated water in the manufacture of commercially bottled drinks has raised concern over 

the presence of trihalomethanes in these drinks (McNeal et al. 1995). Levels of dibromochloromethane in 

bottled water and in carbonated soft drinks ranged from 0.5 to 2 ng/g in a survey of soft drinks, juices, 

beers, bottled water, and canned foods purchased from Washington, DC markets in 1991–1992. 

Bromoform was not found in any of the samples above a detection limit of 0.1 ng/g. Campillo et al. 

(2004) detected bromoform in pineapple juice, apple juice, and forest fruits juice at concentrations of 4.2, 
BROMOFORM AND DIBROMOCHLOROMETHANE 146 

6. POTENTIAL FOR HUMAN EXPOSURE 

3.5, and 2.5 μg/L, respectively. Dibromochloromethane was found in pasteurized milk from a suburban 

area of Turku, Finland (Kroneld and Reunanen 1990). 

Neither bromoform nor dibromochloromethane were detected in oyster, clam, or sediment samples from 

the Ariho and Yoshingaga Rivers in Japan (Gotoh et al. 1992). No detection limit was given. The mean 

concentrations of bromoform and dibromochloromethane in daily dietary samples collected from 

housewives in Nogoya and Yokohama, Japan were 0.2–0.6 and <0.1–0.2 ng/g, respectively (Toyoda et al. 

1990). 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

Because of the variability of dibromochloromethane 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 dibromochloromethane and bromoform concentrations measured in water and air, it is likely 

that most individuals will be exposed to average doses of <1 μg/kg/day (Table 6-3), nearly all of which is 

from 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. 

The range of dibromochloromethane concentrations in tap water, in blood samples before showering, and 

in blood samples after showering in Cobb County, Georgia were <1–4, 0.001–0.003, and 0.003– 

0.029 μg/L, respectively (Miles et al. 2002). Concentrations in tap water, in blood samples before 

showering, and in blood samples after showering samples from Corpus Christi, Texas were 5–20, 0.002– 

0.031, and 0.011–>0.093 μg/L, respectively. Bromoform was detected in the Cobb County, Georgia 

samples at concentrations of <1 μg/L in tap water, 0.001–0.0052 μg/L in blood before showering, and 

0.0001–0.0059 μg/L in blood after showering. Concentrations of dibromochloromethane in tap water, in 

blood samples before showering, and in blood samples after showering from Corpus Christi, Texas 

ranged from 2–17, 0.001–0.02, and 0.006–0.064 μg/L, respectively. Breath samples of individuals taken 

within 5 minutes after a shower with high dibromochloromethane and bromoform water concentrations 

contained dibromochloromethane at a mean concentration of 4.8 μg/m3 and bromoform at a mean 

concentration of 2.3 μg/m3 (Weisel 1999). Breath samples taken 5–20 minutes after a shower with high 

water concentration contained dibromochloromethane at a mean concentration of 2.8 μg/m3 and 

bromoform at a mean concentration of 1.2 μg/m3

. Breath samples taken >20 minutes after a shower with 

high water concentration contained dibromochloromethane at a mean concentration of 1 μg/m3 and 

bromoform at a mean concentration of 0.6 μg/m3

. Breath samples from individuals after a shower with 
BROMOFORM AND DIBROMOCHLOROMETHANE 147 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Summary of Typical Human Exposure to Bromoform and 

Dibromochloromethane 

 Exposure medium 

Parameter Water Air 

Typical concentration in medium 1–20 μg/L 0–0.1 μg/m3 

Assumed intake of medium by 70-kg adult 2 L/day 20 m3

/day 

Assumed absorption fraction 1.0 0.5 

Estimated dose to 70-kg adult 0.03–0.6 μg/kg/day 0.0–0.01 μg/kg/day 

μg = microgram; kg = kilogram; L = liter; m3 = cubic meters 
BROMOFORM AND DIBROMOCHLOROMETHANE 148 

6. POTENTIAL FOR HUMAN EXPOSURE 

low water concentration contained dibromochloromethane with a mean concentration of 1 μg/m3 at 

different collection times and bromoform with a mean concentration of 0.6 μg/m3 at different collection 

times. 

Blood samples taken from 16 individuals in the Lower Rio Grande Valley during the spring of 1993 had a 

maximum dibromochloromethane concentration of 0.05 μg/L (38% frequency of detection) and a 

maximum bromoform concentration of 0.07 μg/L (19% frequency of detection) (Buckley et al. 1997). 

Blood samples taken during the Third National Health and Nutrition Examination Survey, which included 

over 1,000 individuals, had a maximum dibromochloromethane concentration of 0.024 μg/L (14.5% 

frequency of detection) and a maximum bromoform concentration of 0.034 μg/L (9.9% frequency of 

detection) (Buckley et al. 1997; Needham et al. 1995). 

Dibromochloromethane was found in human kidney and lung tissue at 0.6 and 0.06 μg/kg, respectively, in 

samples taken in the city of Turku, Finland in 1987 (Kroneld 1989a). It was also detected in air samples 

from that region at a concentration of 0.31 mg/m3

. Polkowska et al. (2003) studied the relationship 

between concentrations of volatile organic halogens in drinking water and the concentrations of these 

substances in the urine of individuals living in Gdansk-Sopot-Gdynia Tri City area of Poland. 

Concentrations of dibromochloromethane in drinking water from three locations were 0.015–0.159, 

0.912–1.125, and 0.953–0.987 μg/L with corresponding urine concentrations ranging from not detected to 

0.003 μg/L, from 0.001 to 0.012 μg/L, and from not detected to 0.005 μg/L, respectively. Bromoform 

was only detected in drinking water from two locations at concentrations of 0.018–0.032 and 0.018– 

0.045 μg/L. It was not detected in any of the urine samples. Detection limits were not provided in this 

study. 

The mean concentrations of bromoform and dibromochloromethane in daily dietary samples collected 

from housewives in Nogoya and Yokohama, Japan were 0.2–0.6 and <1–0.2 ng/g, respectively (Toyoda 

et al. 1990). Based on these concentrations, the mean daily dietary intakes for housewives in these cities 

were calculated to be 0.5–1.2 μg for bromoform and 0–0.5 μg for dibromochloromethane. 

Exposure to dibromochloromethane and bromoform may be above average for persons who swim in 

chlorinated swimming pools. Beech (1980) estimated that the total dose for a 6-year-old boy who swam 

for 3 hours in a pool containing 500 μg/L of trihalomethanes could be as high as 2.8 mg (130 μg/kg). 

About 60% of this dose was attributed to dermal absorption, with about 30% resulting from inhalation. In 

fresh water pools, only a small fraction of this would be dibromochloromethane or bromoform, but in a 
BROMOFORM AND DIBROMOCHLOROMETHANE 149 

6. POTENTIAL FOR HUMAN EXPOSURE 

salt water pool, a large fraction would be expected to be bromoform (Beech et al. 1980). Aggazzotti et al. 

(1998) studied the exposure of competitive indoor swimmers to trihalomethanes. The mean 

concentrations of dibromochloromethane were 0.8 μg/L in the pool water, 5.2 μg/m3

 in the pool air prior 

to swimming, and 11.4 μg/m3

 in pool air during swimming. The mean concentration of bromoform was 

0.1 μg/L in the pool water. Bromoform was detected above 0.1 μg/m3

 in only one air sample. Mean 

concentrations of dibromochloromethane in the alveolar air sampled from five swimmers were 0.8 μg/m3 

before swimming and 1.4 μg/m3

 after 1 hour of swimming. Bromoform was not quantified in any of the 

alveolar air samples. Calculated dibromochloromethane intakes for the five swimmers were 1.5– 

1.9 μg/hour before swimming and 14–22 μg/hour after 1 hour of swimming. 

Individuals who work at indoor pool facilities are expected to be at risk for occupational exposure to 

trihalomethanes (Fantuzzi et al. 2001). Dibromochloromethane was detected in 24 out of 32 alveolar air 

samples collected from individuals who work at selected indoor swimming pools in Modena, Italy 

(Fantuzzi et al. 2001). The mean concentration was 0.5 μg/m3

. Bromoform was not detected in any of 

the alveolar air samples above the detection limit of 0.1 μg/m3

. The authors reported that the 

concentration of trihalomethanes in the alveolar air of poolside attendants was double that in alveolar air 

collected from employees working in the engine room and reception area (25.1 vs. 14.8 μg/m3

). Mean 

concentrations of dibromochloromethane measured in this study were 1.9 μg/L in pool water, 3.1 μg/m3 

in poolside ambient air, 1.5 μg/m3

 in reception area ambient air, and 1.6 μg/m3 in engine room ambient 

air. The mean concentration of bromoform was 0.4 μg/L in pool water. It was only detected in one 

ambient air sample (poolside) at a concentration of 0.8 μg/m3

. 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 
BROMOFORM AND DIBROMOCHLOROMETHANE 150 

6. POTENTIAL FOR HUMAN EXPOSURE 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

No information was located regarding the exposures of children to bromoform or dibromochloromethane. 

Exposures of children to bromoform and dibromochloromethane through inhalation are expected to vary 

depending on the length of time a child spends indoors and the concentrations of these compounds in 

indoor air. The concentrations of bromoform and dibromochloromethane will depend on the source of 

household water, exchange rate of indoor and outdoor air, frequency and duration of showers, and 

emission rates of these compounds from other household sources (e.g., dishwasher, washing machines, 

etc.). Dermal exposures of children to bromoform and dibromochloromethane are expected to be lower 

than, or similar to, those found for adults, depending on frequency and duration of bathing or showering. 

However, the primary routes of exposure to bromoform and dibromochloromethane are expected to be 

through drinking water or consumption of beverage or food products that contain water that has been 

disinfected through chlorination. It is expected that a child’s exposure to bromoform and dibromochloromethane will depend predominantly on the source and amount of drinking water consumed per day. 

Exposure of newborns and infants to bromoform and dibromochloromethane, whose diets are 

supplemented with human breast milk, cow’s milk, or infant formulas, is not known, since measurements 

of these compounds are not available in these media. Swimming is expected to provide an additional 

source of exposure for children who spend time in chlorinated swimming pools (Beech et al. 1980). 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

The environmental medium most likely to be contaminated with bromoform and dibromochloromethane 

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 dibromochloromethane 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 dibromochloromethane levels. 

Workers in chemical production facilities or laboratories where bromoform and dibromochloromethane 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 dibromochloromethane, but this can only be evaluated on a case-by-case basis. 
BROMOFORM AND DIBROMOCHLOROMETHANE 151 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.8 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of bromoform and dibromochloromethane is available. Where 

adequate information is not available, ATSDR, in conjunction with the National Toxicology Program 

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

effects (and techniques for developing methods to determine such health effects) of bromoform and 

dibromochloromethane. 

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 the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The physical and chemical properties of dibromochloromethane and bromoform have been well studied, and reliable values for key parameters are available for 

use in environmental fate and transport models. On this basis, it does not appear that further studies of 

the physical-chemical properties of dibromochloromethane and bromoform are essential. 

Production, Import/Export, Use, Release, and Disposal. According to the Emergency 

Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required 

to submit substance release and off-site transfer information to the EPA. The TRI, which contains this 

information for 2002, became available in May of 2004. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. 

Available data indicate that neither bromoform nor dibromochloromethane 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 
BROMOFORM AND DIBROMOCHLOROMETHANE 152 

6. POTENTIAL FOR HUMAN EXPOSURE 

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 dibromochloromethane and bromoform to land or in industrial 

effluents. 

Environmental Fate. The fate of dibromochloromethane 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 dibromochloromethane 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. Further data on the rate of microbial degradation of dibromochloromethane 

and bromoform 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 dibromochloromethane 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 dibromochloromethane and bromoform in water, soil or air. Because of their 

physical and chemical properties, it is expected that the bioavailability of dibromochloromethane 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 dibromochloromethane 

or bromoform by plants or aquatic organisms, and no data were located on the bioaccumulation of 
BROMOFORM AND DIBROMOCHLOROMETHANE 153 

6. POTENTIAL FOR HUMAN EXPOSURE 

bromoform and dibromochloromethane 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 Environmental Media. Reliable monitoring data for the levels of bromoform 

and dibromochloromethane in contaminated media at hazardous waste sites are needed so that the 

information obtained on levels of bromoform and dibromochloromethane in the environment can be used 

in combination with the known body burden of bromoform and dibromochloromethane to assess the 

potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites. 

There are several studies on the atmospheric concentrations of bromoform and dibromochloromethane 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 dibromochloromethane 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 dibromochloromethane 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 inhalation and dermal doses would be useful for bromoform and dibromochloromethane in and 

around swimming pools (especially indoor pools). 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. No formal studies of children’s inhalation, dermal, or oral exposures to 

bromoform and dibromochloromethane were located in the literature. Based on the concentrations of 

bromoform and dibromochloromethane measured in indoor air and in drinking water that has been 
BROMOFORM AND DIBROMOCHLOROMETHANE 154 

6. POTENTIAL FOR HUMAN EXPOSURE 

disinfected by chlorination, studies are needed to assess the inhalation, dermal, and oral exposures of 

children to these and other disinfection by-products. Data on inhalation and dermal doses would be 

useful for bromoform and dibromochloromethane in and around swimming pools (especially indoor 

pools). 

Child health data needs relating to susceptibility are discussed in Section 3.12.2, Identification of Data 

Needs: Children’s Susceptibility. 

Exposure Registries. No exposure registries for bromoform and dibromochloromethane were 

located. These compounds are not currently one of the compounds for which a sub-registry has been 

established in the National Exposure Registry. These compounds will be considered in the future when 

chemical selection is made for sub-registries 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 exposure to this substance. 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2004) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified in Section 6.8.1. These 

studies are summarized in Table 6-4. 
BROMOFORM AND DIBROMOCHLOROMETHANE 155 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Ongoing Studies on the Potential for Human Exposure to Bromoforma 

Investigator Affiliation Research description	 Sponsor 

Harrington, J;	 

Simpson WR 	 

Pennsylvania State 

University, University 

Park, Pennsylvania; 

University of Alaska 

Fairbanks Campus, 

Fairbanks, Alaska 

Development and testing of a radiation-transfer 

model for snow photochemistry. This will help 

quantify the extent of photochemical processing 

of trace compounds within snow and will help in 

interpreting ice core climate records and 

understanding atmospheric chemistry in snowcovered regions. The study will include 

measurements of photolysis rates for 

bromoform. 

National 

Science 

Foundation 

Meyer GJ	 Johns Hopkins 

University, Baltimore, 

Maryland 

Development of new reductive and oxidative 

dehalogenation chemistries and the elucidation 

of their fundamental mechanisms; application of 

these new findings to the sensing, remediation, 

and determination of the environmental fate of 

National 

Science 

Foundation 

organohalide pollutants. The study will provide a 

pedagogical platform that informs and educates 

the next generation of environmental chemists. 

Saltzman E 	 University of 

California-Irvine 	 

The degradation of natural halogenated 

compounds in coastal seawater will be studied. 

Measurements will be used to revise estimates 

National 

Science 

Foundation 

for the uptake of atmospheric halocarbons by the 

oceans, the extent to which the oceans can 

buffer atmospheric halocarbon conc entrations, 

and the production rate for these gases in the 

surface oceans. 

a

Source: CRIS 2003; FEDRIP 2003, 2004 

BROMOFORM AND DIBROMOCHLOROMETHANE 157 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring bromoform and dibromochloromethane, its metabolites, and other 

biomarkers of exposure and effect to bromoform and dibromochloromethane. The intent is not to provide 

an exhaustive list of analytical methods. Rather, the intention is to identify well-established methods that 

are used as the standard methods of analysis. Many of the analytical methods used for environmental 

samples are the methods approved by federal agencies and organizations such as EPA and the National 

Institute for Occupational Safety and Health (NIOSH). Other methods presented in this chapter are those 

that are approved by groups such as the Association of Official Analytical Chemists (AOAC) and the 

American Public Health Association (APHA). Additionally, analytical methods are included that modify 

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 dibromochloromethane and bromoform is gas chromatography (GC) (Ashley et al. 1996; Djozan and Assadi 1995; 

Fishbein 1985). A number of devices are suitable for detection and quantification of dibromochloromethane 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 

dibromochloromethane 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 dibromochloromethane 

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. 

7.1 BIOLOGICAL MATERIALS 

Separation of dibromochloromethane and bromoform from biological samples is most often achieved by 

headspace analysis, purge-and-trap collection, solvent extraction, or direct collection on adsorbent resins. 
BROMOFORM AND DIBROMOCHLOROMETHANE 158 

7. ANALYTICAL METHODS 

Headspace analysis offers speed, simplicity, and good reproducibility, but partitioning of the analyte 

between the headspace 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 (Ashley et al. 1996; 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. 

1987). 

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 dibromochloromethane in biological 

materials are summarized in Table 7-1. 

7.2 ENVIRONMENTAL SAMPLES 

Dibromochloromethane 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. Arthur et 

al. (1992) used solid phase micro extraction to separate volatile halogenated compounds from water 

samples. The organic analytes partition between the water sample and the stationary phase coating of a 

fused silica fiber before they are thermally desorbed in a GC injector. Djozan and Assadi (1995) 

introduced a gas stripping cryogenic trapping technique for separating volatile halogenated compounds 

from drinking water samples. In this method, a purified gas passes through the water sample in a 

stripping column where it removes volatile compounds from a water sample. The effluent from the 

column is dried, trapped in a cold trapping coil, and then released to the GC system by warming. 

Membrane inlet mass spectrometry (MIMS) is another technique for separating organohalogen 

compounds from drinking water (Bocchini et al. 1999). With this method, volatile organic compounds 
Table 7-1. Analytical Methods for Determining Bromoform and 

Dibromochloromethane in Biological Materials 

Sample Accuracy 

Sample Analytical detection (percent 

matrix Preparation method method limit recovery) Reference 

Adipose Extraction, bulk lipid HRGC/MS 0.1 μg/g NR Mack and Stanley 

tissue removal, Florisil 1985 

fractionation 

Adipose Heated dynamic HRGC/MS 1 ng/g NR Stanley 1986 

tissue headspace purge-and- (DBCM) 

trap 2 ng/g (TBM) 

Adipose Purge from liquified fat GC/HSD <2 μg/L 83–107 (TBM) Peoples et al. 1979 

tissue at 115 °C, trap on 90–118 (DBCM) Tenax/silica gel, thermal 

desorption 

Blood Purge from blood onto GC/MS ≈0.1 ng/mL NR Antoine et al. 1986 

Tenax, thermal 

desorption onto column 

maintained at -20 °C 

Blood Extract with n-pentane HRGC/ECD 0.1 μg/L NR Kroneld 1985 

(DBCM) 

Blood Purge from blood at GC/MS 0.021μg/L 102–108 (TBM) Ashley et al. 1992 

30 °C, trap onto Tenax, (TBM) 

thermal desorption 

Blood Purge from blood at GC/MS 0.017μg/L 91–104 (DBCM) Ashley et al. 1992 

30 °C, trap onto Tenax, (DBCM) 

thermal desorption 

Blood, Macerate tissue in GC/MS 3 ng/mL NR Pellizzari et al. 1985b 

tissue water, warm blood or (blood) 

tissue, pass inert gas 6 ng/g (tissue) through, trap on Tenax, 

thermal desorption 

Blood Purge from water-serum GS/HSD <2 μg/L 79–100 (TBM) Peoples et al. 1979 

serum mixture containing 78–100 (DBCM) antifoam reagent at 

115 °C, trap on 

Tenax/silica gel, thermal 

desorption 

Breath Trap on Tenax, dry over GC/MS 1–5 μg/m3 92±15 (TBM) Wallace et al. 1986b 

calcium sulfate, thermal 93±13 (DBCM) desorption 

μg = microgram; DBCM = dibromochloromethane; ECD = electron capture detector; g = gram; GC = gas 

chromatography; HRGC = high resolution gas chromatography; HSD = halide specific detector; L = liter; m3

 = cubic 

meters; mg = milligram; mL = milliliter; MS = mass spectrometry; ng = nanogram; NR = not reported; 

TBM = bromoform 

BROMOFORM AND DIBROMOCHLOROMETHANE 159 

7. ANALYTICAL METHODS 
BROMOFORM AND DIBROMOCHLOROMETHANE 160 

7. ANALYTICAL METHODS 

from the drinking water sample diffuse through a hollow-fiber membrane into a mass spectrometer. The 

advantages of this method are that sample pre-treatment is not required, response times are fast, and trace 

analysis of the pollutants can be preformed on-line. 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 (Pankow et al. 1998). 

Analytical methods for the determination of dibromochloromethane and bromoform in environmental 

samples are given in Table 7-2. 

7.3 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of bromoform and dibromochloromethane is available. Where 

adequate information is not available, ATSDR, in conjunction with the National Toxicology Program 

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

effects (and techniques for developing methods to determine such health effects) of bromoform and 

dibromochloromethane. 

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 the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. Sensitive and specific methods exist for the determination of dibromochloromethane and 

bromoform in blood, expired air, and adipose tissue. These methods are presumably sensitive enough to 
BROMOFORM AND DIBROMOCHLOROMETHANE 161 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Bromoform and 

Dibromochloromethane in Environmental Samples 

Sample Accuracy 

Sample Analytical detection (percent 

matrix Preparation method method limit recovery) Reference 

Drinking Solvent extraction with HRGC/ECD <0.5 μg/L NR Fayad and 

water pentane, direct injection of Iqbal 1985 

extract 

Drinking Gas stripping and cryogenic GC/FID 0.05 μg/L 75±7.7 Djozan and 

water trapping system (DBCM) (DBCM) Assadi 1995 

Drinking Adsorption to and diffusion MIMS 0.5 μg/L NR Bocchini et al. 

water through a polymeric hollow­ (TBM) 1999 

fiber membrane 

Drinking Adsorption to and diffusion MIMS 0.5 μg/L NR Bocchini et al. 

water through a polymeric hollow­ (DBCM) 1999 

fiber membrane 

Drinking Purge and trap, thermal GC/MS 0.1μg/L 89–90 (TBM) Eichelberger et 

water desorption al. 1990 

Drinking Purge and trap, thermal GC/MS 0.1μg/L 95–100 (TBM) Eichelberger et 

water desorption al. 1990 

Air Coconut shell charcoal GC/FID 10 μg/sample 14.0 (TBM) NIOSH 1994 

sorption, carbon disulfide (TBM) 

desorption 

Air Carbotrap/Carboxen filled GC/MS 0.02 ppbv 95–102 (TBM) Pankow et al. 

glass cartridge (TBM) 1998 

adsorption/thermal 

desorption 

Air Carbotrap/Carboxen filled GC/MS 0.04 ppbv 96–99 (DBCM) Pankow et al. 

glass cartridge (DBCM) 1998 

adsorption/thermal 

desorption 

Water Purge and trap GC/MS 10 μg/L NR EPA 1980b 

Water Purge and trap GC/HSD 0.20 μg/L 89±9 (TBM) EPA 1982a 

(TBM) 

0.09 μg/L 98±7 (DBCM) 

(DBCM) 

Water Purge and trap GC/MS 4.7 μg/L 105±16 (TBM) EPA 1982b 

(TBM) 

3.1 μg/L 104±14 

(DBCM) (DBCM) 

Water Purge and trap GC/HSD 0.5 μg/L 97 (DBCM) APHA 1985a 

101 (DBCM) 

Water Purge and trap GC/MS <2 μg/L 82 (TBM) APHA 1985b 

Water Solvent extraction GC/ECD 2 μg/L NR ASTM 1988 

(isooctane) 

Water Solid phase micro extraction GC/MS 4.7 μg/L Arthur et al. 

(TBM) 1992 
BROMOFORM AND DIBROMOCHLOROMETHANE 162 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Bromoform and 

Dibromochloromethane in Environmental Samples 

Sample Accuracy 

Sample Analytical detection (percent 

matrix Preparation method method limit recovery) Reference 

Water Solid phase micro extraction GC/MS 3.1 μg/L Arthur et al. 

(DBCM) 1992 

Contaminated Purge and trap GC/HSD 2 μg/kg (TBM) 96b

 (TBM) EPA 1986a 

soil 0.9 μg/kg 94b

 (DBCM) 

(DBCM) 

Wastes, Purge and trap GC/HSD 250 μg/kg 96b

 (TBM) EPA 1986a 

nonwater (TBM) 

miscible 113 μg/kg 94b

 (DBCM) 

(DBCM) 

Solid waste Purge and trap GC/MS 5 μg/kg 118b

 (TBM) EPA 1986b 

101b

 (DBCM) 

a

Value refers to both DBCM and TBM unless noted otherwise. 
 b

This recovery is typical at concentrations of around 100 μg/L or higher. Recoveries may deviate at lower 
 

concentrations. 
 

μg = microgram; DBCM = dibromochloromethane; ECD = electron capture detector; FID = flame ionization detector; 
 

g = gram; GC = gas chromatography; HRGC = high resolution gas chromatography; HSD = halide specific detector; 
 

kg = kilogram; L = liter; MS = mass spectrometry; NR = not reported; TBM = bromoform 
 
BROMOFORM AND DIBROMOCHLOROMETHANE 163 

7. ANALYTICAL METHODS 

measure levels in humans exposed to doses of the chemicals that produce sedation or cause injury to 

liveand 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 

halomethyl adduct) would be valuable. 

Effect. 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 dibromochloromethane 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 chemicalspecific cancer potency values are available for these components, this is not certain. 

7.3.2 Ongoing Studies 

No ongoing studies on analytical methods were identified in a search of the Federal Research in Progress 

database (FEDRIP 2004). 

BROMOFORM AND DIBROMOCHLOROMETHANE 165 

8. REGULATIONS AND ADVISORIES 

The international, national, and state regulations and guidelines regarding bromoform and dibromochloromethane in air, water, and other media are summarized in Table 8-1. 

An acute-duration oral MRL of 0.7 mg/kg/day has been derived for bromoform. This MRL is based on a 

NOAEL of 72 mg/kg/day and a LOAEL of 145 mg/kg/day for centrilobular pallor in mice receiving 

gavage doses of bromoform for 14 days (Condie et al. 1983). The MRL was derived by dividing the 

NOAEL by an uncertainty factor of 100 (10 for animal to human extrapolation and 10 for human 

variability). 

An intermediate-duration oral MRL of 0.2 mg/kg/day has been derived for bromoform. This MRL is 

based on a NOAEL of 50 mg/kg for hepatocellular vacuolization in rats administered gavage doses of 

bromoform in corn oil 5 days/week for 13 weeks (NTP 1989a). The MRL was derived by dividing the 

duration adjusted NOAEL of 18 mg/kg/day by an uncertainty factor of 100 (10 for animal to human 

extrapolation and 10 for human variability). 

A chronic-duration oral MRL of 0.02 mg/kg/day has been derived for bromoform. This MRL is based on 

a LOAEL of 100 mg/kg for hepatocellular vacuolization in rats administered gavage doses of bromoform 

in corn oil 5 days/week for 2 years (NTP 1989a). The MRL was derived by dividing the duration 

adjusted LOAEL of 71 mg/kg/day by an uncertainty factor of 300 (3 for use of a minimal LOAEL, 10 for 

animal to human extrapolation, and 10 for human variability) and a modifying factor of 10 to account for 

the identification of a lower LOAEL in a 13-week study (NTP 1989a). 

An acute-duration oral MRL of 0.1 mg/kg/day has been derived for dibromochloromethane. This MRL is 

based on a LOAEL of 37 mg/kg for hepatocellular vacuolization in mice administered gavage doses of 

dibromochloromethane in corn oil for 14 days (Condie et al. 1983). The MRL was derived by dividing 

the LOAEL by an uncertainty factor of 300 (3 for use of a minimal LOAEL, 10 for animal to human 

extrapolation, and 10 for human variability). 

A chronic-duration oral MRL of 0.09 mg/kg/day has been derived for dibromochloromethane. This MRL 

is based on a LOAEL of 40 mg/kg for fatty changes in the liver of rats administered gavage doses of 

dibromochloromethane in corn oil for 2 years (NTP 1985). The MRL was derived by dividing the 
BROMOFORM AND DIBROMOCHLOROMETHANE 166 

8. REGULATIONS AND ADVISORIES 

duration-adjusted LOAEL of 28 mg/kg/day by an uncertainty factor of 300 (3 for use of a minimal 

LOAEL, 10 for animal to human extrapolation, and 10 for human variability). 
BROMOFORM AND DIBROMOCHLOROMETHANE 167 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Bromoform and 

Dibromochloromethane 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

 IARC Carcinogenicity classification 

 Bromoform 

 Dibromochloromethane 

WHO Drinking water guideline 

 Bromoform 

 Dibromochloromethane 

NATIONAL 

Regulations and 

Guidelines: 

a. Air: 

ACGIH TLV (8-hour TWA) 

 Bromoformb 

NIOSH REL (10-hour TWA) 

 Bromoformc 

IDLH 

OSHA PEL (8-hour TWA) for general 

industry 

 Bromoformd 

PEL (8-hour TWA) for construction 

industry 

 Bromoformd 

PEL (8-hour TWA) for shipyard 

industry 

 Bromoformd 

USC Hazardous air pollutant 

b. Water 

EPA Drinking water health advisories 

 Bromoform 

1-day (10-kg child) 

10-day (10-kg child) 

DWELe 

10-4 Cancer riskf

 Dibromochloromethane 

1-day (10-kg child) 

10-day (10-kg child) 

DWELe 

Lifetimeg 

10-4 Cancer riskf 

Effluent guidelines and standards; 

toxic pollutants pursuant to 

Section 307 (a)(1) of the Clean 

Water Act 

IARC 1999a, 1999b 

Group 3a 

Group 3a 

WHO 1996 

100 mg/L 

100 mg/L 

ACGIH 2003 

0.5 ppm 

NIOSH 2003 

0.5 ppm 

850 ppm 

OSHA 2003a 

29 CFR 1910.1000, 

0.5 ppm Table Z-1 

OSHA 2003c 

29 CFR 1926.55, 

0.5 ppm Appendix A 

OSHA 2003b 

29 CFR 1915.1000 

0.5 ppm 

Bromoform USC 2003 

EPA 2002a, 2002b 

5.0 mg/L 

2.0 mg/L 

0.7 mg/L 

0.4 mg/L 

6.0 mg/L 

6.0 mg/L 

0.7 mg/L 

0.06 mg/L 

0.04 mg/L 

Bromoform EPA 2003c 

40 CFR 401.15 
BROMOFORM AND DIBROMOCHLOROMETHANE 168 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Bromoform and 

Dibromochloromethane 

Agency Description Information Reference 

NATIONAL (cont.) 

EPA National primary drinking water EPA 2003f 

regulations 40 CFR 141.12 

MCL for total trihalomethanesh 0.10 mg/L 

Pollutants of initial focus in the Bromoform and EPA 2003m 

Great Lakes Water Quality Initiative dibromochloromethane 40 CFR 132, Table 6 

c. Food 

FDA Bottled drinking water allowable 0.10 mg/L FDA 2003 

concentrations for total trihalo­ 21 CFR 165.110 

methanesi 

d. Other 

 ACGIH Carcinogenicity classification A3j

 ACGIH 2003

 EPA Carcinogenicity classification IRIS 2004a, 2004b 

 Bromoform B2k 

Cl Dibromochloromethane 

RfC No data IRIS 2004a, 2004b 

RfD IRIS 2004a, 2004b 

 Bromoform 2.0x10-2 mg/kg/day 

 Dibromochloromethane 2.0x10-2 mg/kg/day 

Community right-to-know; release EPA 2003i 

report; effective date of reporting 40 CFR 372.65 

 Bromoform 01/01/87 

Identification and listing of EPA 2003d 

hazardous waste; hazardous waste 40 CFR 261, 

number Appendix VIII 

 Bromoform U225 

Land disposal restrictions; universal Waste Non-waste EPA 2003e 

treatment standards water water 40 CFR 268.48 

(mg/L) mg/kg) 

 Bromoform 0.63 15 

 Dibromochloromethane 0.57 15 

Municipal solid waste landfills; Suggested EPA 2003a 

hazardous constituents method PQL (μg/L) 40 CFR 258, 

 Bromoform 8010 2 Appendix II 

8021 15 

8260 5 

 Dibromochloromethane 8010 1 

8021 0.3 

8260 5 

Reportable quantity of hazardous EPA 2003b 

substance in accordance with 40 CFR 302.4 

Section 307 (a) of the Clean Water 

Act, Section 112 of RCRA, and 

Section 112 of the Clean Air Act 

 Bromoform 100 pounds 
BROMOFORM AND DIBROMOCHLOROMETHANE 169 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Bromoform and 

Dibromochloromethane 

Agency Description 	 Information Reference 

NATIONAL (cont.) 

EPA Reportable quantity of hazardous EPA 2003b 

substance in accordance with 40 CFR 302.4 

Section 112 of RCRA 

 Dibromochloromethane 100 pounds 

Standards for the management of EPA 2003g 

specific hazardous waste and types 40 CFR 266, 

of hazardous waste management Appendix V 

facilities Risk specific doses 

 Bromoform 7.0x10-1 μg/m3 

Standards for owners or operators EPA 2003h 

of hazardous waste TSD facilities; 40 CFR 264, 

maximum concentration for Suggested Appendix IX 

groundwater protection method PQL (μg/L) 

 Bromoform 8010 2 

8240 5 

 Dibromochloromethane 8010 1 

8240 5 

TSCA; chemical information rules Effective Sunset EPA 2003k 

date date 40 CFR 712.30 

 Bromoform 03/11/94 05/10/94 

TSCA; health and safety data Effective Sunset EPA 2003j 

reporting date date 40 CFR 716.120 

 Bromoform 06/01/87 06/01/97 

 Dibromochloromethane 06/01/87 06/01/87 

TSCA; identification of specific EPA 2003l 

chemical substance and mixture 40 CFR 799.5055 

testing requirements for 

 Bromoform Hydrolysis testing 

STATE 

a. Air No data 

b. Water 

Arizona Drinking water guideline HSDB 2004a, 2004b 

 Bromoform 0.19 μg/L 

 Dibromochloromethane 0.19 μg/L 

Florida Drinking water guideline HSDB 2004a, 2004b 

 Bromoform 4.0 μg/L 

 Dibromochloromethane 1.0 μg/L 

Minnesota Drinking water guideline HSDB 2004a, 2004b 

 Bromoform 40 μg/L 

 Dibromochloromethane 10 μg/L 

New Hampshire Drinking water guideline HSDB 2004a 

 Bromoform 4.0 μg/L 

Wisconsin Drinking water guideline HSDB 2004a, 2004b 

 Bromoform 4.4 μg/L 

 Dibromochloromethane 
 60 μg/L 
BROMOFORM AND DIBROMOCHLOROMETHANE 170 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Bromoform and 

Dibromochloromethane 

Agency Description Information Reference 

STATE (cont.) 

c. Food No data 

d. Other No data 

a

Group 3: not classifiable as to its carcinogenicity to humans 

b

Skin notation: refers to the potential significant contribution to the overall exposure by the cutaneous route, including 

mucous membranes and the eyes, either by contact with vapors or, of probable greater significance, by direct skin 

contact with the substance. 

c

Skin designation: indicates the potential for dermal absorption; skin exposure should be prevented as necessary 

through the use of good work practices and gloves, coveralls, goggles, and other appropriate equipment. d

Skin designation 

e

DWEL: a lifetime exposure concentration protection of adverse, non-cancer health effects, that assumes all of the 

exposure to a contaminant is from drinking water. 

f

10-2 Cancer risk: the concentration of a chemical in drinking water corresponding to an excess estimated lifetime 

cancer risk of 1 in 10,000. 

g

Lifetime: the concentration of a chemical in drinking water that is not expected to cause any adverse 

noncarcinogenic effects for a lifetime of exposure. The Lifetime HA is based on exposure of a 70-kg adult 

consuming 2 L water/day. 

h

Total trihalomethanes (the sum of the concentrations of bromoform, dibromochloromethane, bromodichloromethane, and chloroform) applies to subpart H community water systems which serve a population of 10,000 people 

or more until December 31, 2001. This level applies to community water systems that use only groundwater not 

under the direct influence of surface water and serves a population of 10,000 people or more until December 31, 

2003. Compliance with the MCL for total trihalomethanes is calculated pursuant to 40 CFR 141.30. After 

December 31, 2003, this section no longer applies. 

i

Total trihalomethanes: sum of the concentration in mg/L of the trihalomethane compounds (bromoform, 
 

dibromochloromethane, bromodichloromethane, and chloroform), rounded to two significant figures. 
 j

A3: confirmed animal carcinogen with unknown relevance to humans 
 k

B2: probable human carcinogen 
 l

C: possible human carcinogen 

ACGIH = American Conference of Governmental Industrial Hygienists; CFR = Code of Federal Regulations; 

DWEL = drinking water equivalent level; EPA = Environmental Protection Agency; FDA = Food and Drug 

Administration; HSDB = Hazardous Substances Data Bank; IARC = International Agency for Research on Cancer; 

IDLH = immediately dangerous to life or health; IRIS = Integrated Risk Information System; MCL = maximum 

contaminant level; NIOSH = National Institute for Occupational Safety and Health; OSHA = Occupational Safety and 

Health Administration; PEL = permissible exposure limit; PQL = practical quantitation level; RCRA = Resource 

Conservation and Recovery Act; REL = recommended exposure limit; RfC = inhalation reference concentration; 

RfD = oral reference dose; TLV = threshold limit values; TSCA = Toxic Substances Control Act; TSD = treatment, 

storage, and disposal; TWA = time-weighted average; USC = United States Code; WHO = World Health 

Organization 
_______________________ 

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BROMOFORM AND DIBROMOCHLOROMETHANE 217 

10. GLOSSARY 

Absorption—The taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by 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. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Biomarkers—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. 

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen—A chemical capable of inducing cancer. 

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 
BROMOFORM AND DIBROMOCHLOROMETHANE 218 

10. GLOSSARY 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

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 occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (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. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 
BROMOFORM AND DIBROMOCHLOROMETHANE 219 

10. GLOSSARY 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

Immunological Effects—Functional changes in the immune response. 

Incidence—The ratio of individuals in a population who develop a specified condition to the total 

number of individuals in that population who could have developed that condition in a specified time 

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo—Occurring within the living organism. 

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population. 

Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals. 

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical 

is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus. 

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure. 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1. 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 
BROMOFORM AND DIBROMOCHLOROMETHANE 220 

10. GLOSSARY 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s 

DNA. Mutations can lead to birth defects, miscarriages, or cancer. 

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions. 

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not 

considered to be adverse. 

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution. 

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the 

exposed group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek. 

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests. 

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 
BROMOFORM AND DIBROMOCHLOROMETHANE 221 

10. GLOSSARY 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3

 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

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 no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 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. 
BROMOFORM AND DIBROMOCHLOROMETHANE 222 

10. GLOSSARY 

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort. 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed 

group compared to the unexposed group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population. 

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)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 
BROMOFORM AND DIBROMOCHLOROMETHANE 223 

10. GLOSSARY 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or 

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to 

account for (1) the variation in sensitivity among the members of the human population, (2) the 

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis, 3 being the approximate logarithmic 

average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system. 

BROMOFORM AND DIBROMOCHLOROMETHANE A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a 

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance 

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are 

used by ATSDR health assessors to identify contaminants and potential health effects that may be of 

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or 

action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level 

above the MRL does not mean that adverse health effects will occur. 
BROMOFORM AND DIBROMOCHLOROMETHANE A-2 

APPENDIX A 

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology, expert panel peer reviews, and agency-wide MRL Workgroup reviews, with 

participation from other federal agencies and comments from the public. They are subject to change as 

new information becomes available concomitant with updating the toxicological profiles. Thus, MRLs in 

the most recent toxicological profiles supersede previously published levels. For additional information 

regarding MRLs, please contact the Division of Toxicology, Agency for Toxic Substances and Disease 

Registry, 1600 Clifton Road NE, Mailstop F-32, Atlanta, Georgia 30333. 
BROMOFORM AND DIBROMOCHLOROMETHANE A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Bromoform 

CAS Number: 75-25-2 

Date: August 2005 

Profile Status: Final Draft of Post-Public Comment Toxicological Profile 

Route: [ ] Inhalation [X] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Key to Figure: 13 

Species: Mice 

Minimal Risk Level: 0.7 [X] mg/kg/day [ ] mg/m3 

Reference: Condie LW, Smallwood CL, Laurie RD. 1983. Comparative renal and hepatotoxicity of 

halomethanes: Bromodichloromethane, bromoform, chloroform, dibromochloromethane and methylene 

chloride. Drug Chem Toxicol 6:563-578. 

Experimental design: 

Groups of 5–16 male CD-1 mice received daily gavage doses of 0, 72, 145, or 289 mg/kg/day 

bromoform in corn oil for 14 days. Body weight was measured on days 1 and 14. Blood was collected 

for clinical chemistry at study termination. Renal cortical slices of kidney tissue were collected for 

measurement of para-aminohippurate (PAH) uptake, and samples of liver and kidney tissue were 

collected for histopathological examination. 

Effects noted in study and corresponding concentrations: 

No significant alterations in body weight gain were observed. PAH uptake by kidney slices was 

decreased by 30% in the 289 mg/kg/day group; a significant increase in SGPT was also observed at this 

dose. Minimal to moderate liver and kidney histological alterations were observed. Liver effects 

included centrilobular pallor at 145 and 289 mg/kg/day and focal inflammation at 289 mg/kg/day. 

Kidney effects consisted of epithelial hyperplasia at 289 mg/kg/day and mesangial nephrosis at 145 and 

289 mg/kg/day. 

Concentration and end point used for MRL derivation: 

The MRL is based on a NOAEL of 72 mg/kg/day and a LOAEL of 145 mg/kg/day for hepatice 

centrilobular pallor in mice. 

[ X ] NOAEL [ ] LOAEL 

Uncertainty Factors used in MRL derivation: 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent 

concentration: NA 
BROMOFORM AND DIBROMOCHLOROMETHANE A-4 

APPENDIX A 

Was a conversion used from intermittent to continuous exposure? No. 

Other additional studies or pertinent information that lend support to this MRL: 

Several acute-duration studies support the identification of the liver as the most sensitive target of 

bromoform toxicity. The observed effects include hepatocellular vacuolization and swelling (Chu et al. 

1982a; Coffin et al. 2000), centrilobular pallor (Condie et al. 1983), increased absolute and relative liver 

weights (Munson et al. 1982), alterations in serum chemistry enzymes such as SGPT (Munson et al. 

1982), and impaired liver function (Munson et al. 1982). The highest NOAEL for liver effects is 

72 mg/kg/day in mice (Condie et al. 1983); in this study, centrilobular pallor (Condie et al. 1983), which 

was considered to be indicative of liver degeneration, was observed at 145 mg/kg/day. At 

125 mg/kg/day, increases in liver weight were observed (Munson et al. 1982) and hepatocellular 

vacuolization and swelling were observed at 200 mg/kg (164 mg/kg/day) (Coffin et al. 2000). Other 

adverse effects that have been observed at similar or higher dose levels include mesangial nephrosis at 

145 mg/kg/day (NOAEL of 72 mg/kg/day) (Condie et al. 1983), impaired immune function at 

125 mg/kg/day (NOAEL of 50 mg/kg/day) (Munson et al. 1982), skeletal anomalies in the offspring of 

rats exposed to 200 mg/kg/day (NOAEL of 100 mg/kg/day) (Ruddick et al. 1983), and central nervous 

system depression at ≥600 mg/kg (Balster and Borzelleca 1982; Bowman et al. 1978; NTP 1989a). 

Although several adverse effects have been reported at 100–200 mg/kg/day, the liver was selected as the 

critical target because the adverse liver effects are consistently observed in animals following acute-, 

intermediate-, and chronic-duration exposure. 

Agency Contact (Chemical Managers): John Risher, Dennis Jones 
BROMOFORM AND DIBROMOCHLOROMETHANE A-5 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Bromoform 

CAS Number: 75-25-2 

Date: August 2005 

Profile Status: Final Draft of Post-Public Comment Toxicological Profile 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Key to Figure: 26 

Species: Rat 

Minimal Risk Level: 0.2 [X] mg/kg/day [ ] mg/m3 

Reference: NTP. 1989a. Toxicology and carcinogenesis studies of tribromomethane (bromoform) in 

F344/N rats and B6C3F1 mice (gavage studies). National Toxicology Program. Technical Report Series 

No. 350. Research Triangle Park, NC: U.S. Department of Health and Human Services. 

Experimental design: 

Groups of F344/N male and female F344/N rats (10/sex/group) received gavage doses of 0, 12, 25, 50, 

100, or 200 mg/kg bromoform in corn oil 5 days/week for 13 weeks. The rats were observed twice per 

day and weighed weekly. At sacrifice, all animals were necropsied and tissues from the vehicle control 

and high dose groups were examined histologically. 

Effects noted in study and corresponding concentrations: 

None of the rats died before the end of the study. Final mean body weights were similar in dosed and 

control groups. Lethargy was observed in all male rats exposed to 100 or 200 mg/kg and in all females 

exposed to 200 mg/kg. Hepatocellular vacuolization was observed in male rats (3/10, 6/10, 5/10, 8/10, 

8/10, and 10/10 in the 0, 12, 25, 50, 100, and 200 mg/kg groups, respectively); the response reached 

statistical significance (Fisher exact one-tailed p-value of 0.03) at 50 mg/kg/day. Severity data were not 

reported for this lesion, but the study authors noted that vacuoles were more numerous in the 200 mg/kg 

group. Corresponding hepatic effects were not observed in females. 

Concentration and end point used for MRL derivation: 

The MRL is based on a NOAEL of 25 mg/kg (duration-adjusted to 18 mg/kg/day) and a LOAEL of 

50 mg/kg (duration-adjusted to 36 mg/kg/day) for hepatic lesions (hepatocellular vacuolization). 

[X] NOAEL [ ] LOAEL 

Uncertainty Factors used in MRL derivation: 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent 

concentration: NA 
BROMOFORM AND DIBROMOCHLOROMETHANE A-6 

APPENDIX A 

Was a conversion used from intermittent to continuous exposure? 

The NOAEL was adjusted for intermittent exposure: 25 mg/kg x 5 days/7 days = 18 mg/kg/day 

Other additional studies or pertinent information that lend support to this MRL: 

A number of animal studies have identified the liver as the critical target of bromoform oral toxicity. An 

intermediate-duration study in rats (Aida et al. 1992) supports the identification of 50 mg/kg as the critical 

dose. In this study, a LOAEL of 56.4 mg/kg/day was identified for hepatocellular vacuolization and 

swelling in rats exposed to bromoform in the diet for 1 month. At a higher dose (207.5 mg/kg/day), a 

decrease in serum triglycerides and an increase in serum cholesterol levels were found; these findings are 

consistent with the liver histological alterations. Mice appear to be less sensitive to the toxicity of 

bromoform than rats. NOAEL and LOAEL values of 100 and 200 mg/kg (5 days/week) for 

hepatocellular vacuolization were identified in the intermediate-duration mouse NTP study (NTP 1989a). 

Melnick et al. (1998) found hydropic degeneration and increases in SGPT and sorbitol dehydrogenase 

levels in mice receiving gavage doses of 500 mg/kg, 5 days/week for 3 weeks. Acute- and chronicduration studies have also identified the liver as the most sensitive target of toxicity. 

Agency Contact (Chemical Managers): John Risher, Dennis Jones 
BROMOFORM AND DIBROMOCHLOROMETHANE A-7 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Bromoform 

CAS Number: 75-25-2 

Date: September 2005 

Profile Status: Final Draft of Post-Public Comment Toxicological Profile 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Key to Figure: 38 

Species: Rat 

Minimal Risk Level: 0.02 [X] mg/kg/day [ ] mg/m3 

Reference: NTP. 1989a. Toxicology and carcinogenesis studies of tribromomethane (bromoform) in 

F344/N rats and B6C3F1 mice (gavage studies). National Toxicology Program. Technical Report Series 

No. 350. Research Triangle Park, NC: U.S. Department of Health and Human Services. 

Experimental design: 

Groups of male and female F344/N rats (50/sex/group) were administered via gavage 0, 100, or 

200 mg/kg bromoform in corn oil 5 days/week for 103 weeks. Animals were observed for clinical signs 

throughout the study. Body weights were measured weekly for 12 weeks and monthly thereafter. At 

termination, all study animals were necropsied. Full histopathological examination was performed on all 

control and high dose animals and on low dose males. Selected tissues including esophagus, gross 

lesions, kidney, liver, lymph nodes, mammary gland, pancreas, pituitary gland, salivary glands, thyroid 

gland, trachea, and uterus were examined in low-dose females. 

Effects noted in study and corresponding concentrations: 

Significantly increased mortality was observed in male rats exposed to 200 mg/kg after week 91 (36–78% 

vs. 26–32%). Survival was comparable to vehicle controls in males exposed to 100 mg/kg and in females 

exposed to 100 or 200 mg/kg. Bromoform-related clinical signs included lethargy in both sexes and 

aggressiveness in males. After 15 weeks, the difference between control body weights and body weights 

of males exposed to 200 mg/kg males was consistently ≥10%; terminal body weights were 21% lower 

than controls. In the females exposed to 200 mg/kg, the difference in body weights was ≥10% after week 

41; terminal body weights were 25% lower than controls. Body weights in the 100 mg/kg groups were 

typically within 10% of controls. Bromoform-related hepatic lesions included fatty change (characterized 

as hepatocellular vacuolization) in 23/50, 49/50, and 50/50 males exposed to 0, 100, or 200 mg/kg, 

respectively, and 19/50, 39/49, and 46/50 females; chronic active inflammation (male: 0/50, 29/50, and 

23/50; female: 9/50, 8/49, and 27/50); and necrosis (male: 7/50, 3/50, and 20/50; female: 11/50, 3/49, 

and 2/50). Other lesions with significantly increased incidences included salivary gland duct squamous 

metaplasia at 100 and 200 mg/kg (males: 0/50, 15/50, and 31/48; females: 0/49, 10/49, and 16/50) and 

chronic active inflammation (male: 0/50, 14/50, and 22/48; female: 0/49, 9/49, and 18/50); ulcers of the 

forestomach in males at 200 mg/kg (1/49, 5/50, and 10/50); chronic active inflammation in the lungs in 

males at 100 and 200 mg/kg (1/50, 7/50, and 15/50); squamous metaplasia in the prostate gland at 

200 mg/kg (2/49, 6/46, and 12/50); hyperplasia of the anterior lobe of the pituitary gland in males at 

100 mg/kg (9/48, 26/50, and 15/50); and spleen pigmentation in females at 200 mg/kg (7/49, 6/28, and 

29/50), which was characteristic of hemosiderin. The occurrence of ulcers in the forestomach may have 

resulted from gavage bolus dose delivery. Lesions observed in the lungs and salivary glands were 

reported to be consistent with infection by sialodacryloadenitis (SDA) virus. However, since the 
BROMOFORM AND DIBROMOCHLOROMETHANE A-8 

APPENDIX A 

occurrence of these lesions was clearly dose-related, the study authors concluded that they were likely to 

represent a combination of viral and chemical-related effects. 

It should be noted that the study authors did not report statistical analysis data for nonneoplastic lesions. 

An independent statistical analysis was conducted; statistical significance was determined using a Fisher 

exact test, one tailed p<0.05). 

Concentration and end point used for MRL derivation: 

The MRL is based on a LOAEL of 100 mg/kg (duration-adjusted to 71 mg/kg/day) for histopathological 

changes (vacuolization) in the liver. 

[ ] NOAEL [X] LOAEL 

Uncertainty Factors used in MRL derivation: 

[X] 3 for use of a minimal LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Modifying Factors used in MRL derivation: 

[X] 10 to account for the identification of a lower LOAEL in the 13-week NTP (1989a) 

study. 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent 

concentration: NA 

Was a conversion used from intermittent to continuous exposure? Yes. 

The LOAEL was adjusted for intermittent exposure: 100 mg/kg x 5 days/7 days = 71 mg/kg/day 

Other additional studies or pertinent information that lend support to this MRL: 

Two studies have examined the chronic toxicity of bromoform (NTP 1989a; Tobe et al. 1982). Both 

studies identified the liver as the most sensitive target of toxicity. Both the NTP (1989a) rat and mouse 

studies identified LOAEL values of 100 mg/kg (5 days/week) for hepatocellular vacuolization. The rat 

study was selected over the mouse study because the effects were observed in both sexes. This study is 

supported by a 2-year dietary study conducted by Tobe et al. (1982). Yellowing of the liver and increases 

in absolute and liver weights were observed in female rats exposed to 140 mg/kg/day; histological 

examinations were not conducted. Alterations in several clinical chemistry parameters are also indicative 

of liver damage. Increases in SGOT and SGPT and decreases in serum triglycerides and cholesterol were 

observed at 590–720 mg/kg/day. A number of intermediate-duration studies (Aida et al. 1992; Chu et al. 

1982b; Melnick et al. 1998; NTP 1989a) support the identification of the liver as the critical target of 

bromoform toxicity. 

Agency Contact (Chemical Managers): John Risher, Dennis Jones 
BROMOFORM AND DIBROMOCHLOROMETHANE A-9 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Dibromochloromethane 

CAS Number: 124-48-1 

Date: August 2005 

Profile Status: Final Draft of Post-Public Comment Toxicological Profile 

Route: [ ] Inhalation [X] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Key to Figure: 16 

Species: Mouse 

Minimal Risk Level: 0.1 [X] mg/kg/day [ ] mg/m3 

Reference: Condie LW, Smallwood CL, Laurie RD. 1983. Comparative renal and hepatotoxicity of 

halomethanes: Bromodichloromethane, bromoform, chloroform, dibromochloromethane and methylene 

chloride. Drug Chem Toxicol 6:563-578. 

Experimental design: 

Groups of 5–16 male CD-1 mice received daily gavage doses of 0, 37, 74, or 147 mg/kg/day dibromochloromethane in corn oil for 14 days. Body weight was measured on days 1 and 14. Blood was 

collected for clinical chemistry at study termination. Renal cortical slices of kidney tissue were collected 

for measurement of para-aminohippurate uptake, and samples of liver and kidney tissue were 

histopathological examination. 

Effects noted in study and corresponding concentrations: 

No deaths or treatment-related clinical signs were reported. No significant alterations in body weight gain 

were observed. Para-aminohippurate uptake by kidney slices was decreased by approximately 30% in the 

147 mg/kg/day group; a significant increase in SGPT was also observed at this dose. Minimal to 

moderate liver and kidney histological alterations were observed. Liver effects included hepatocellular 

vacuolization at 37 mg/kg/day and higher (1/16, 3/5, 4/10, and 8/10 in the 0, 37, 74, and 147 mg/kg/day 

groups, respectively) and mitotic figures at 147 mg/kg/day (0/16, 0/5, 2/10, and 4/10). Kidney effects 

consisted of mesangial hypertrophy was observed at 37 mg/kg/day and higher (0/16, 4/5, 7/10, and 7/10). 

Concentration and end point used for MRL derivation: 

The MRL is based on a LOAEL of 37 mg/kg/day for hepatocellular vacuolization (Condie et al. 1983). 

[ ] NOAEL [X] LOAEL 

Uncertainty Factors used in MRL derivation: 

[X] 3 for use of a minimal LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 
BROMOFORM AND DIBROMOCHLOROMETHANE A-10 

APPENDIX A 

If an inhalation study in animals, list conversion factors used in determining human equivalent 

concentration: NA 

Was a conversion used from intermittent to continuous exposure? No. 

Other additional studies or pertinent information that lend support to this MRL: 

There are numerous studies that support the identification of the liver as the critical target of 

dibromochloromethane toxicity. Hepatocellular vacuolization and/or swelling were observed in mice 

exposed to 100 and 300 mg/kg (9 doses in an 11-day period) (Coffin et al. 2000), at ≥50 mg/kg in rats and 

mice exposed to dibromochloromethane for an intermediate duration (Aida et al. 1992; Daniel et al. 1990; 

NTP 1985) and in rats and mice exposed to ≥40 for 2 years (NTP 1985). At higher doses, hepatocellular 

necrosis is observed (Aida et al. 1993; Daniel et al. 1990; NTP 1985) in rats and mice exposed to 

≥100 mg/kg for intermediate durations. 

The Condie et al. study (1983) also identified the 37 mg/kg/day dose as a LOAEL for kidney effects, 

mesangial cell hyperplasia. Other animal studies have also found kidney lesions following oral exposure 

to dibromochloromethane. Nephropathy, characterized by tubular cell degeneration and tubular cast 

formation was noted in 80% of male rats and 100% of female rats, but was not found in the controls or 

other dose groups exposed to dibromochloromethane in corn oil for 13 weeks (NTP 1985). The liver was 

selected as the critical target because the results of other studies suggest that it may be the more sensitive 

target of toxicity. 

Agency Contact (Chemical Managers): John Risher, Dennis Jones 
BROMOFORM AND DIBROMOCHLOROMETHANE A-11 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Dibromochloromethane 

CAS Number: 124-48-1 

Date: August 2005 

Profile Status: Final Draft of Post-Public Comment Toxicological Profile 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Key to Figure: 46 

Species: Rat 

Minimal Risk Level: 0.09 [X] mg/kg/day [ ] mg/m3 

Reference: NTP. 1985. Toxicology and carcinogenesis studies of dibromochloromethane in F344/N rats 

and B6C3F1 mice (gavage studies). National Toxicology Program. Technical Report Series No. 282. 

Research Triangle Park, NC: U.S. Department of Health and Human Services. 

Experimental design: 

Groups of 50 male and 50 female F344/N rats received 0, 40, or 80 mg/kg gavage doses of 

dibromochloromethane in corn oil 5 days/week for 2 years. Clinical signs were recorded weekly. Body 

weights were recorded weekly for the first twelve weeks of the study and monthly thereafter. Necropsy 

was performed on all animals. Histopathological examination was conducted on tissues from all dose 

groups. 

Effects noted in study and corresponding concentrations: 

Survival was comparable in all study groups. Body weight gain was within 10% of controls throughout 

the study. In the liver, fatty change (male: 27/50, 47/50, and 49/50; female: 12/50, 23/50, and 50/50) 

and "ground glass" cytoplasmic changes (male: 8/50, 22/50, and 34/50; female: 0/50, 1/50, and 12/50) 

were observed. A dose-related increase in nephrosis was observed in female rats (7/50, 11/50, and 

14/50); however, the incidences in exposed rats was not statistically higher than in vehicle controls 

assessed using the Fisher exact test. 

It should be noted that the study authors did not report statistical analysis data for nonneoplastic lesions. 

An independent statistical analysis was conducted; statistical significance was determined using a Fisher 

exact test, one tailed p<0.05). 

Concentration and end point used for MRL derivation: 

The MRL is based on a LOAEL of 40 mg/kg (duration-adjusted to 28 mg/kg/day) for liver histopathology 

(fatty change) (NTP 1985). 

[ ] NOAEL [X] LOAEL 

Uncertainty Factors used in MRL derivation: 

[X] 3 for use of a minimal LOAEL 

[X] 10 for extrapolation from animals to humans 

[X] 10 for human variability 
BROMOFORM AND DIBROMOCHLOROMETHANE A-12 

APPENDIX A 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? No. 

If an inhalation study in animals, list conversion factors used in determining human equivalent 

concentration: NA 

Was a conversion used from intermittent to continuous exposure? 

The LOAEL was adjusted for intermittent exposure: 40 mg/kg x 5 days/7 days = 28 mg/kg/day 

Other additional studies or pertinent information that lend support to this MRL: 

The identification of the liver as the critical target is supported by numerous acute-duration studies in rats 

and mice exposed to ≥37 mg/kg (Chu et al. 1982a; Coffin et al. 2000; Condie et al. 1983; Hewitt et al. 

1983; Munson et al. 198; NTP 1985), 50 mg/kg for intermediate durations (Aida et al. 1992; Daniel et al. 

1990; Melnick et al. 1998; NTP 1985), and 40 mg/kg for chronic durations (NTP 1985; Tobe et al. 1982). 

The identification of the LOAEL of 40 mg/kg for fatty changes in the liver is supported by the NTP 

(1985) mouse study and a rat study by Tobe et al. (1982). Fatty metamorphosis was found in mice 

receiving gavage doses of 50 mg/kg, 5 days/week for 2 years (NTP 1985). Necrosis was observed at 

100 mg/kg. In the Tobe et al. (1982) study, groups of rats were exposed to dibromochloromethane in diet 

for 2 years. No histological examinations were conducted; however, hypertrophy and yellowing of the 

liver was found at 85 mg/kg/day. Alterations in a number of clinical chemistry parameters, which are 

indicative of liver damage, were also observed. Decreases in serum triglycerides were observed at 

20 mg/kg/day and decreases in serum cholesterol were observed at 540 mg/kg/day. 

Agency Contact (Chemical Managers): John Risher, Dennis Jones 
BROMOFORM AND DIBROMOCHLOROMETHANE B-1 

APPENDIX B. USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in non-technical language. Its intended 

audience is the general public, especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it would 

still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Relevance to Public Health 

This chapter provides a health effects summary based on evaluations of existing toxicologic, 

epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions: 

1.	 What effects are known to occur in humans? 

2. 	 What effects observed in animals are likely to be of concern to humans? 

3. 	 What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites? 

The chapter covers end points in the same order that they appear within the Discussion of Health Effects 

by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human 

data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). 

In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also 

considered in this chapter. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer 

potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if 

derived) and the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Chapter 3 Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 
BROMOFORM AND DIBROMOCHLOROMETHANE B-2 

APPENDIX B 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans. 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. 

MRLs are based largely on toxicological studies in animals and on reports of human occupational 

exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human 

variability to protect sensitive subpopulations (people who are most susceptible to the health effects 

caused by the substance) and for interspecies variability (extrapolation from animals to humans). In 

deriving an MRL, these individual uncertainty factors are multiplied together. The product is then 

divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used 

in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to 

locate data for a specific exposure scenario. The LSE tables and figures should always be used in 

conjunction with the text. All entries in these tables and figures represent studies that provide reliable, 

quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 
BROMOFORM AND DIBROMOCHLOROMETHANE B-3 

APPENDIX B 

LEGEND 

See Sample LSE Table 3-1 (page B-6) 

(1) Route of Exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. Typically 

when sufficient data exist, three LSE tables and two LSE figures are presented in the document. 

The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, 

and dermal (LSE Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each 

route of exposure and will not, therefore, have all five of the tables and figures. 

(2) Exposure Period. Three exposure periods—acute (less than 15 days), intermediate (15– 

364 days), and chronic (365 days or more)—are presented within each relevant route of exposure. 

In this example, an inhalation study of intermediate exposure duration is reported. For quick 

reference to health effects occurring from a known length of exposure, locate the applicable 

exposure period within the LSE table and figure. 

(3) Health Effect. The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the "System" column of the LSE table (see key number 

18). 

(4) Key to Figure. Each key number in the LSE table links study information to one or more data 

points using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the two "18r" data points in sample Figure 3-1). 

(5) Species. The test species, whether animal or human, are identified in this column. Chapter 2, 

"Relevance to Public Health," covers the relevance of animal data to human toxicity and 

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. 

Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent 

human doses to derive an MRL. 

(6) Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure 

regimens are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation 

for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen, 

refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 

1981). 

(7) System. This column further defines the systemic effects. These systems include respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and 

dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered 

in these systems. In the example of key number 18, one systemic effect (respiratory) was 

investigated. 
BROMOFORM AND DIBROMOCHLOROMETHANE B-4 

APPENDIX B 

(8) NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the 

organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 

(9) LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific end point used to 

quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key 

number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from 

Serious LOAELs. 

(10) Reference. The complete reference citation is given in Chapter 9 of the profile. 

(11) CEL. A CEL is the lowest exposure level associated with the onset of carcinogenesis in 

experimental or epidemiologic studies. CELs are always considered serious effects. The LSE 

tables and figures do not contain NOAELs for cancer, but the text may report doses not causing 

measurable cancer increases. 

(12) Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Sample Figure 3-1 (page B-7) 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13) Exposure Period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the acute and intermediate exposure periods are illustrated. 

(14) Health Effect. These are the categories of health effects for which reliable quantitative data 

exists. The same health effects appear in the LSE table. 

(15)	 Levels of Exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3

 or ppm and oral exposure is reported in 

mg/kg/day. 

(16) NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in 

the rat upon which an intermediate inhalation exposure MRL is based. The key number 18 

corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of 

0.005 ppm (see footnote "b" in the LSE table). 
BROMOFORM AND DIBROMOCHLOROMETHANE B-5 

APPENDIX B 

(17) CEL. Key number 38m is one of three studies for which CELs were derived. The diamond 

symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the 

LSE table. 

(18) Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upperbound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the 

cancer dose response curve at low dose levels (q1*). 

(19) Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 
SAMPLE 

1 →	 Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

LOAEL (effect) Exposure 

Key to frequency/ NOAEL Less serious Serious (ppm) 

figurea Species duration System (ppm) (ppm) Re

2 3 4 

→ INTERMEDIATE EXPOSURE 

5 6 7 8 9 10

→ Systemic ↓ ↓ ↓ ↓ ↓	 ↓

3b 18 Rat	 13 wk Resp 10 (hyperplasia) 

→	 5 d/wk Nit

6 hr/d 

CHRONIC EXPOSURE 

Cancer 11 

↓

38 Rat 18 mo 20 (CEL, multiple W

5 d/wk organs) 7 hr/d 

39 Rat 89–104 wk 10 (CEL, lung tumors, NT

5 d/wk nasal tumors) 6 hr/d 

40 Mouse 79–103 wk 10 (CEL, lung tumors, NT

5 d/wk hemangiosarcomas) 6 hr/d 

12 a → i 	 The number corresponds to entries in F gure 3-1. b Used to derive an intermediate inha ation Minimal Risk Level (MRL) of l 5x10-3 ppm; dose adjusted for intermittent ex

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 


BROMOFORM AND DIBROMOCHLOROMETHANE C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase (also known as SGPT) 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotranferase (also known as SGOT) 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD benchmark dose 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

DOE Department of Energy 

DOL Department of Labor 
BROMOFORM AND DIBROMOCHLOROMETHANE C-2 

APPENDIX C 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMCO North America/International Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 
BROMOFORM AND DIBROMOCHLOROMETHANE C-3 

APPENDIX C 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 
BROMOFORM AND DIBROMOCHLOROMETHANE C-4 

APPENDIX C 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase (also known as AST) 

SGPT serum glutamic pyruvic transaminase (also known as ALT) 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 
BROMOFORM AND DIBROMOCHLOROMETHANE C-5 

APPENDIX C 

> greater than ≥ greater than or equal to 

= equal to 

< less than ≤ less than or equal to 

% percent α alpha β beta γ gamma δ delta μm micrometer μg microgram q1 

* cancer slope factor 

– negative 

+ positive 

(+) weakly positive result 

(–) weakly negative result 

BROMOFORM AND DIBROMOCHLOROMETHANE D-1 

APPENDIX D. INDEX 

absorbed dose ......................................................................................................................................................99, 103 
 

adenocarcinoma ...........................................................................................................................................................68 
 

adenocarcinomas .........................................................................................................................................................68 
 

adipose tissue............................................................................................................................... 91, 100, 153, 160, 163 
 

adsorbed.............................................................................................................................................................125, 134 
 

adsorption .................................................................................................................. 134, 136, 138, 143, 158, 160, 161
 

aerobic .........................................................................................................................................................92, 125, 136 
 

ambient air .................................................................................................................................................137, 138, 149 
 

anaerobic..............................................................................................................................................92, 125, 136, 152 
 

bath ......................................................................................................................................................................99, 139 
 

bioaccumulation ........................................................................................................................................................152 
 

bioavailability ............................................................................................................................................................152 
 

bioconcentration factor ..............................................................................................................................................135 
 

biodegradation ...........................................................................................................................................................136 
 

biomarker.......................................................................................................................................98, 99, 100, 112, 163 
 

biomarkers .....................................................................................................................................98, 99, 113, 157, 163 
 

body weight effects................................................................................................................................................23, 62 
 

breast milk .........................................................................................................................................................149, 150 
 

cancer................................................................................................................................. 4, 5, 22, 68, 93, 96, 163, 170 
 

carcinogen......................................................................................................................................................13, 69, 170 
 

carcinogenic............................................................................................................. 13, 15, 21, 22, 68, 84, 92, 110, 113 
 

carcinogenicity ................................................................................................................................13, 69, 93, 110, 170 
 

carcinoma ....................................................................................................................................................................69 
 

carcinomas ...................................................................................................................................................................69 
 

cardiovascular........................................................................................................................................................23, 57 
 

cardiovascular effects ..................................................................................................................................................57 
 

chromatid exchange.......................................................................................................................70, 71, 72, 74, 75, 76 
 

chromosomal aberrations.............................................................................................................................................74 
 

clearance ................................................................................................................................................23, 99, 103, 114 
 

CYP2E1................................................................................................................................. 86, 87, 91, 92, 94, 97, 104 
 

cytochrome ................................................................................................................ 12, 82, 84, 86, 91, 92, 94, 97, 104 
 

death ...................................................................................................................................... 21, 22, 24, 55, 56, 91, 107 
 

dermal effects ..............................................................................................................................................................61 
 

dermal exposure....................................................... 11, 12, 15, 69, 81, 82, 88, 104, 107, 108, 109, 111, 112, 114, 150
 

DNA .......................................................................................... 70, 71, 73, 74, 75, 77, 78, 86, 87, 91, 93, 99, 113, 163
 

duodenum ..................................................................................................................................................71, 74, 75, 78 
 

elderly ........................................................................................................................................................................102 
 

elimination half-time ...................................................................................................................................................88 
 

endocrine ...................................................................................................................................................23, 61, 94, 95 
 

endocrine effects..........................................................................................................................................................61 
 

fetal tissue....................................................................................................................................................................94 
 

fetus .........................................................................................................................................................13, 68, 96, 114 
 

gastrointestinal effects ...........................................................................................................................................57, 58 
 

general population .........................................................................................................................11, 98, 108, 153, 163 
 

genotoxic .......................................................................................................................................................21, 93, 110 
 

genotoxicity .......................................................................................................................................70, 74, 87, 93, 110 
 

glutathione ......................................................................................................... 83, 84, 86, 87, 91, 92, 93, 97, 110, 114
 

groundwater ..................................................................... 3, 65, 125, 128, 130, 131, 136, 141, 144, 152, 153, 169, 170 
 

growth retardation........................................................................................................................................................67 
 

half-life ........................................................................................................................................................98, 103, 135 
 
BROMOFORM AND DIBROMOCHLOROMETHANE D-2 

APPENDIX D 

hematological effects ...................................................................................................................................................58 
 

hepatic effects ......................................................................................................................................12, 19, 23, 58, 59 
 

hydrolysis ....................................................................................................................................................................84 
 

hydroxyl radical.........................................................................................................................................................152 
 

immune system ....................................................................................................................................................63, 112 
 

immunological.......................................................................................................................................................21, 23 
 

immunological effects .................................................................................................................................................23 
 

Kow .............................................................................................................................................................................135 
 

LD50 .............................................................................................................................................................................55 
 

leukemia ..............................................................................................................................................70, 73, 74, 76, 77 
 

lymphoreticular............................................................................................................................................................63 
 

menstrual .........................................................................................................................................................65, 66, 95 
 

micronuclei ............................................................................................................................................................70, 74 
 

milk....................................................................................................................................................................146, 150 
 

musculoskeletal effects................................................................................................................................................58 
 

neoplastic.....................................................................................................................................................................69 
 

neurobehavioral ...............................................................................................................................64, 65, 95, 109, 112 
 

neurodevelopmental...................................................................................................................................................114 
 

nuclear ...............................................................................................................................................................122, 128 
 

odds ratio .....................................................................................................................................................................65 
 

oxidative metabolism.......................................................................................................................................86, 91, 93 
 

P-450 ................................................................................................................. 12, 82, 84, 86, 91, 92, 94, 97, 104, 114
 

partition coefficients ..............................................................................................................................................79, 81 
 

PBPK model ..................................................................................................................................................88, 89, 101 
 

pharmacodynamic........................................................................................................................................................88 
 

pharmacokinetic...............................................................................................................................................88, 89, 90 
 

pharmacokinetics .........................................................................................................................................................96 
 

photolysis...........................................................................................................................................................135, 155 
 

potentiation ................................................................................................................................................................101 
 

rate constant...............................................................................................................................................................135 
 

rate constants .............................................................................................................................................................135 
 

renal effects .............................................................................................................................................14, 23, 60, 113 
 

SGOT.................................................................................................................................................13, 16, 59, 60, 108 
 

shower ....................................................................................................................... 4, 6, 11, 78, 81, 99, 139, 146, 150
 

solubility ............................................................................................................................................................134, 157 
 

swimming .................................................................................. 3, 6, 64, 65, 78, 99, 143, 144, 148, 149, 150, 153, 154
 

tap water .................................................................................................. 6, 11, 13, 67, 81, 99, 109, 111, 139, 142, 146 
 

testosterone ....................................................................................................................................................61, 95, 108 
 

thyroid .........................................................................................................................................................................61 
 

toxicokinetic ..................................................................................................................................21, 94, 109, 113, 114 
 

tremors.........................................................................................................................................................................63 
 

tumors ....................................................................................................................................................................13, 93 
 

vapor phase................................................................................................................................................................134 
 

vapor pressure....................................................................................................................................................109, 134 
 

volatilization ......................................................................................................................................................135, 152 
 

whooping cough ..............................................................................................................................2, 6, 24, 63, 97, 107