TOXICOLOGICAL PROFILE FOR
 

1,3-BUTADIENE
 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
	

Public Health Service
	

Agency for Toxic Substances and Disease Registry
	

September 2012 
 

 

1,3-BUTADIENE ii 

DISCLAIMER 

Use of trade names is for identification only and does not imply endorsement by the Agency for Toxic 

Substances and Disease Registry, the Public Health Service, or the U.S. Department of Health and Human 

Services. 
 

 

 

 

 

 


	


	


	


	


	


	


	


	


	


	

1,3-BUTADIENE iii 

UPDATE STATEMENT 

A Toxicological Profile for 1,3-Butadiene, Draft for Public Comment was released in September 2009. 

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 and Human Health Sciences (proposed)
	

Environmental Toxicology Branch (proposed)
	

1600 Clifton Road NE
	

Mailstop F-62 

Atlanta, Georgia 30333
	
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 1,3-BUTADIENE v 

FOREWORD
	

This toxicological profile is prepared in accordance with guidelines* developed by the Agency for Toxic 

Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The 

original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised 

and republished as necessary. 

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects 

information for the toxic substances each profile describes. Each peer-reviewed profile identifies and 

reviews the key literature that describes a substance's toxicologic properties. Other pertinent literature is 

also presented but is described in less detail than the key studies. The profile is not intended to be an 

exhaustive document; however, more comprehensive sources of specialty information are referenced. 

The profiles focus on health and toxicologic information; therefore, each toxicological profile begins with 

a public health statement that describes, in nontechnical language, a substance's relevant toxicological 

properties. Following the public health statement is information concerning levels of significant human 

exposure and, where known, significant health effects. A health effects summary describes the adequacy 

of information to determine a substance's health effects. ATSDR identifies data needs that are significant 

to protection of public health. 

Each profile: 

(A) Examines, summarizes, and interprets available toxicologic information and 

epidemiologic evaluations on a toxic substance to ascertain the levels of significant human 

exposure for the substance and the associated acute, subacute, and chronic health effects; 

(B) Determines whether adequate information on the health effects of each substance is 

available or being developed to determine levels of exposure that present a significant risk to 

human health of acute, subacute, and chronic health effects; and 

(C) Where appropriate, identifies toxicologic testing needed to identify the types or levels of 

exposure that may present significant risk of adverse health effects in humans. 

The principal audiences for the toxicological profiles are federal, state, and local health professionals; 

interested private sector organizations and groups; and members of the public. 

This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been 

peer-reviewed. Staff of the Centers for Disease Control and Prevention and other federal scientists also 

have reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel 

and was made available for public review. Final responsibility for the contents and views expressed in 

this toxicological profile resides with ATSDR. 

Christopher J. Portier, Ph.D. 

Assistant Administrator
	

Agency for Toxic Substances and Disease Registry
	
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 1,3-BUTADIENE vi 

*Legislative Background 

The toxicological profiles are developed under the Comprehensive Environmental Response, 

Compensation, and Liability Act of 1980, as amended (CERCLA or Superfund). CERCLA section 

104(i)(1) directs the Administrator of ATSDR to “...effectuate and implement the health related 

authorities” of the statute. This includes the preparation of toxicological profiles for hazardous 

substances most commonly found at facilities on the CERCLA National Priorities List and that pose the 

most significant potential threat to human health, as determined by ATSDR and the EPA. Section 

104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile 

for each substance on the list. In addition, ATSDR has the authority to prepare toxicological profiles for 

substances not found at sites on the National Priorities List, in an effort to “...establish and maintain 

inventory of literature, research, and studies on the health effects of toxic substances” under CERCLA 

Section 104(i)(1)(B), to respond to requests for consultation under section 104(i)(4), and as otherwise 

necessary to support the site-specific response actions conducted by ATSDR. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 


 


 


 


 


 

1,3-BUTADIENE 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: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) Fax: (770) 488-4178 

E-mail: cdcinfo@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 

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

Toxicity; and numerous chemical-specific case studies. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE viii 

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. 
 

 

 

 

 

 

 

 

 

 


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	

1,3-BUTADIENE ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Annette Ashizawa, Ph.D.
	

Nickolette Roney, M.P.H.
	

Pamela G. Tucker, M.D.
	

Carolyn Harper, Ph.D.
	

Diana Cronin
	

ATSDR, Division of Toxicology and Human Health Sciences (proposed), Atlanta, GA
	

Lisa Ingerman, Ph.D., DABT
	

Julie Klotzbach, Ph.D.
	

Gary L. Diamond, Ph.D. 

Mike Lumpkin, Ph.D. 

Daniel J. Plewak, B.S.
	

SRC, Inc., North Syracuse, NY
	

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 Environmental Toxicology Branch (proposed) 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. 
1,3-BUTADIENE x 

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1,3-BUTADIENE xi 

PEER REVIEW
 

A peer review panel was assembled for 1,3-butadiene. The panel consisted of the following members: 

1. Sherif Abdel-Rahman, Ph.D., Department of Preventative Medicine and Community Health, 

University of Texas Medical Branch, Galveston, Texas 

2. Genevieve Matanoski, M.D., Dr.PH, Bloomberg School of Public Health, The Johns Hopkins 

Univeristy, Baltimore, Maryland 

3. Amir Sapkota, Ph.D., Maryland Institute for Applied Environmental Health, University of 

Maryland, School of Public Health, College Park, Maryland 

These experts collectively have knowledge of 1,3-butadiene'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. 
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1,3-BUTADIENE 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 IS 1,3-BUTADIENE? ...................................................................................................... 1
	

1.2 WHAT HAPPENS TO 1,3-BUTADIENE WHEN IT ENTERS THE ENVIRONMENT?......... 2
	

1.3 HOW MIGHT I BE EXPOSED TO 1,3-BUTADIENE? ............................................................. 2
	

1.4 HOW CAN 1,3-BUTADIENE ENTER AND LEAVE MY BODY? .......................................... 3
	

1.5 HOW CAN 1,3-BUTADIENE AFFECT MY HEALTH? ........................................................... 3
	

1.6 HOW CAN 1,3-BUTADIENE AFFECT CHILDREN?............................................................... 4
	

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO 1,3-BUTADIENE?........... 4
	

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

TO 1,3-BUTADIENE?................................................................................................................. 5
	

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH?.................................................................................................. 5
	

1.10 WHERE CAN I GET MORE INFORMATION?......................................................................... 6
	

2. RELEVANCE TO PUBLIC HEALTH ................................................................................................... 7
	

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO 1,3-BUTADIENE IN 

THE UNITED STATES............................................................................................................... 7
	

2.2 SUMMARY OF HEALTH EFFECTS ......................................................................................... 8
	

2.3 MINIMAL RISK LEVELS (MRLs)........................................................................................... 10
	

3. HEALTH EFFECTS.............................................................................................................................. 19
	

3.1 INTRODUCTION ...................................................................................................................... 19
	

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE.................................... 19
	

3.2.1 Inhalation Exposure ............................................................................................................ 20
	

3.2.1.1 Death...............................................................................................................................20
	

3.2.1.2 Systemic Effects.............................................................................................................. 21
	

3.2.1.3 Immunological and Lymphoreticular Effects................................................................. 39
	

3.2.1.4 Neurological Effects ....................................................................................................... 40
	

3.2.1.5 Reproductive Effects....................................................................................................... 40
	

3.2.1.6 Developmental Effects.................................................................................................... 42
	

3.2.1.7 Cancer............................................................................................................................. 42
	

3.2.2 Oral Exposure ..................................................................................................................... 46
	

3.2.3 Dermal Exposure................................................................................................................. 47
	

3.3 GENOTOXICITY....................................................................................................................... 47
	

3.4 TOXICOKINETICS ................................................................................................................... 55
	

3.4.1 Absorption........................................................................................................................... 55
	

3.4.1.1 Inhalation Exposure ........................................................................................................ 55
	

3.4.1.2 Oral Exposure ................................................................................................................. 56
	

3.4.1.3 Dermal Exposure............................................................................................................. 56
	
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	

1,3-BUTADIENE xiv 

3.4.2 Distribution ......................................................................................................................... 56
	

3.4.2.1 Inhalation Exposure ........................................................................................................ 56
	

3.4.2.2 Oral Exposure ................................................................................................................. 57
	

3.4.2.3 Dermal Exposure............................................................................................................. 57
	

3.4.3 Metabolism ......................................................................................................................... 57
	

3.4.4 Elimination and Excretion .................................................................................................. 62
	

3.4.4.1 Inhalation Exposure ........................................................................................................ 62
	

3.4.4.2 Oral Exposure ................................................................................................................. 63
	

3.4.4.3 Dermal Exposure............................................................................................................. 63
	

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models........... 64
	

3.5 MECHANISMS OF ACTION.................................................................................................... 85
	

3.5.1 Pharmacokinetic Mechanisms............................................................................................. 85
	

3.5.2 Mechanisms of Toxicity...................................................................................................... 87
	

3.5.3 Animal-to-Human Extrapolations....................................................................................... 89
	

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ........................... 90
	

3.7 CHILDREN’S SUSCEPTIBILITY ............................................................................................ 91
	

3.8 BIOMARKERS OF EXPOSURE AND EFFECT...................................................................... 92
	

3.8.1 Biomarkers Used to Identify or Quantify Exposure to 1,3-Butadiene................................ 93
	

3.8.2 Biomarkers Used to Characterize Effects Caused by 1,3-Butadiene .................................. 95
	

3.9 INTERACTIONS WITH OTHER CHEMICALS...................................................................... 96
	

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ................................................ 97
	

3.11 METHODS FOR REDUCING TOXIC EFFECTS.................................................................... 98
	

3.11.1 Reducing Peak Absorption Following Exposure ................................................................ 98
	

3.11.2 Reducing Body Burden.......................................................................................................99
	

3.11.3 Interfering with the Mechanism of Action for Toxic Effects.............................................. 99
	

3.12 ADEQUACY OF THE DATABASE......................................................................................... 99
	

3.12.1 Existing Information on Health Effects of 1,3-Butadiene................................................. 100
	

3.12.2 Identification of Data Needs............................................................................................. 100
	

3.12.3 Ongoing Studies................................................................................................................ 108
	

4. CHEMICAL AND PHYSICAL INFORMATION.............................................................................. 111
	

4.1 CHEMICAL IDENTITY.......................................................................................................... 111
	

4.2 PHYSICAL AND CHEMICAL PROPERTIES ....................................................................... 111
	

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL.......................................................... 114
	

5.1 PRODUCTION......................................................................................................................... 115
	

5.2 IMPORT/EXPORT................................................................................................................... 119
	

5.3 USE........................................................................................................................................... 119
	

5.4 DISPOSAL ...............................................................................................................................120
	

6. POTENTIAL FOR HUMAN EXPOSURE ......................................................................................... 121
	

6.1 OVERVIEW ............................................................................................................................. 121
	

6.2 RELEASES TO THE ENVIRONMENT ................................................................................. 123
	

6.2.1 Air ..................................................................................................................................... 124
	

6.2.2 Water................................................................................................................................. 129
	

6.2.3 Soil.................................................................................................................................... 129
	

6.3 ENVIRONMENTAL FATE..................................................................................................... 130
	

6.3.1 Transport and Partitioning ................................................................................................ 130
	

6.3.2 Transformation and Degradation ...................................................................................... 131
	

6.3.2.1 Air ................................................................................................................................. 131
	

6.3.2.2 Water............................................................................................................................. 132
	
 

 

 

 

 

 

 

 


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	

1,3-BUTADIENE xv 

6.3.2.3 Sediment and Soil ......................................................................................................... 133
	

6.3.2.4 Other Media .................................................................................................................. 133
	

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ................................ 133
	

6.4.1 Air ..................................................................................................................................... 133
	

6.4.2 Water................................................................................................................................. 134
	

6.4.3 Sediment and Soil ............................................................................................................. 134
	

6.4.4 Other Environmental Media.............................................................................................. 137
	

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE....................................... 137
	

6.6 EXPOSURES OF CHILDREN ................................................................................................ 141
	

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES............................................. 142
	

6.8 ADEQUACY OF THE DATABASE....................................................................................... 142
	

6.8.1 Identification of Data Needs ............................................................................................. 143
	

6.8.2 Ongoing Studies................................................................................................................ 145
	

7. ANALYTICAL METHODS................................................................................................................ 146
	

7.1 BIOLOGICAL MATERIALS .................................................................................................. 147
	

7.2 ENVIRONMENTAL SAMPLES............................................................................................. 148
	

7.3 ADEQUACY OF THE DATABASE....................................................................................... 150
	

7.3.1 Identification of Data Needs ............................................................................................. 151
	

7.3.2 Ongoing Studies................................................................................................................ 152
	

8. REGULATIONS, ADVISORIES, AND GUIDELINES..................................................................... 153
	

9. REFERENCES .................................................................................................................................... 157
	

10. GLOSSARY ...................................................................................................................................... 185
	

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
	
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1,3-BUTADIENE xvii 

LIST OF FIGURES
 

3-1. Levels of Significant Exposure to 1,3-Butadiene – Inhalation........................................................... 32 

3-2. Metabolism of 1,3-Butadiene ............................................................................................................. 58
	

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

Hypothetical Chemical Substance ...................................................................................................... 66
	

3-4. Existing Information on Health Effects of 1,3-Butadiene ................................................................ 101
	

6-1. Frequency of NPL Sites with 1,3-Butadiene Contamination ........................................................... 122
	
1,3-BUTADIENE xviii 

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1,3-BUTADIENE xix 

LIST OF TABLES 

2-1. Summary of Available Chronic Risk Assessment Values for 1,3-Butadiene ..................................... 16
	

3-1. Levels of Significant Exposure to 1,3-Butadiene – Inhalation ........................................................... 22
	

3-2. Genotoxicity of 1,3-Butadiene In Vitro .............................................................................................. 48
	

3-3. Genotoxicity of 1,3 Butadiene In Vivo ............................................................................................... 49
	

3-4. Physiological and Chemical Parameters Used in the Johanson and Filser (1993) PBPK Model 

for 1,3-Butadiene................................................................................................................................ 68
	

3-5. Physiological Parameter Values Used in the Kohn and Melnick (2001) PBPK Model for
	

1,3-Butadiene ..................................................................................................................................... 70
	

3-6. Chemical Partition Coefficients Parameter Values Used in the Kohn and Melnick (2001) PBPK 

Model for 1,3-Butadiene .................................................................................................................... 71
	

3-7. Chemical Metabolism Parameter Values Used in the Kohn and Melnick (2001) PBPK Model for 

1,3-Butadiene ..................................................................................................................................... 72
	

3-8. Physiological and Chemical Parameters Used in the Brochot et al. 2007 PBPK Model for
	

1,3-Butadiene Humans ....................................................................................................................... 75
	

3-9. Physiological Parameters Used in Sweeney et al. (1997) 1,3-Butadiene PBPK Model ..................... 78
	

3-10. Partition Coefficients Used in Sweeney et al. (1997) PBPK Model for 1,3-Butadiene ................... 79
	

3-11. Nonenzymatic Reaction Rate Constants Used in Sweeney et al. (1997) PBPK Model for
	

1,3-Butadiene ................................................................................................................................... 80
	

3-12. Metabolism Rate Constants Used in the Sweeney et al. (1997) PBPK Model for 

1,3-Butadiene ................................................................................................................................... 81
	

3-13. Physiological Parameters Used in the Sweeney et al. (2010) PBPK Model for 1,3-Butadiene 

in Humans ........................................................................................................................................ 82
	

3-14. Chemical Partition Coefficients Used in the Sweeney et al. (2010) PBPK Model for 

1,3-Butadiene in Humans................................................................................................................. 83
	

3-15. Chemical Metabolism Parameters Used in the Sweeney et al. (2010) PBPK Model for 

1,3-Butadiene in Humans................................................................................................................. 84
	

4-1. Chemical Identity of 1,3-Butadiene .................................................................................................. 112
	

4-2. Physical and Chemical Properties of 1,3-Butadiene ......................................................................... 113
	

5-1. Companies that Produce 1,3-Butadiene in the United States and Annual Capacities During
	

2008.................................................................................................................................................. 116
	
 

 


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	

1,3-BUTADIENE xx 

5-2. Facilities that Produce, Process, or Use 1,3-Butadiene .................................................................... 117
	

6-1. Releases to the Environment from Facilities that Produce, Process, or Use 1,3-Butadiene............. 125
	

6-2. 1,3-Butadiene Emission Data for 2005............................................................................................. 127
	

6-3. 1,3-Butadiene Concentrations in Outdoor Air.................................................................................. 135
	

6-4. 1,3-Butadiene Concentrations in Indoor Air .................................................................................... 136
	

6-5. Air Concentrations of 1,3-Butadiene Corresponding to Typical Operations Within a StyreneButadiene Rubber (SBR) Plant ........................................................................................................ 140
	

7-1. Analytical Methods For Determining 1,3-Butadiene in Environmental Samples............................ 149
	

8-1. Regulations, Advisories, and Guidelines Applicable to 1,3-Butadiene............................................ 154
	
 

 

 

 

 

 

 

 

 

 

 

 

 

 


	

1,3-BUTADIENE 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about 1,3-butadiene and the effects of exposure to it. 

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. 1,3-Butadiene has been found in at least 13 of the 1,699 current or former 

NPL sites. Because not all NPL sites were tested for 1,3-butadiene, the number of sites where this 

chemical 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 this substance may be harmful. 

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 1,3-butadiene, 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 it. 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 IS 1,3-BUTADIENE? 

Description 1,3-Butadiene is a colorless gas with a mild gasoline-like 

odor. 

Uses About 60% of 1,3-butadiene is used to make man-made 

rubber, which is then used mostly for car and truck tires. 

1,3-Butadiene is also used to make certain types of 

plastics such as acrylics. 

See Chapters 4 and 5 for more information on the sources, properties, and uses of 1,3-butadiene.
	
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 2 

1. PUBLIC HEALTH STATEMENT 

1.2 WHAT HAPPENS TO 1,3-BUTADIENE WHEN IT ENTERS THE ENVIRONMENT? 

Sources Large amounts of 1,3-butadiene are released into the air 

by industrial sources. Industrial releases to water and soil 

are relatively low. 

Automobile exhaust is a constant source of 1,3-butadiene 

release into the air. Other sources of 1,3-butadiene 

include cigarette smoke and the smoke of wood fires. 

Forest fires are considered to be a natural source of 

1,3-butadiene in the air. 

Break-down 

• Air 

• Water and soil 

Half of the 1,3-butadiene in the air will likely be broken 

down in about 6 hours. 

1,3-Butadiene that is spilled onto water or soil will likely 

evaporate quickly into the air based on its physical and 

chemical properties. 

See Chapters 5 and 6 for more information on 1,3-butadiene in the environment. 

1.3 HOW MIGHT I BE EXPOSED TO 1,3-BUTADIENE? 

Air The primary way you can be exposed to 1,3-butadiene is by 

breathing air containing it. Releases of 1,3-butadiene into the air 

occur from: 

• vehicle exhaust 

• tobacco smoke 

• wood burning 

• burning of rubber and plastic 

• forest fires 

• accidental or intentional release at manufacturing plants 

The average amount of 1,3-butadiene in the air is between 

0.04 and 0.9 parts of 1,3-butadiene per billion parts of air (ppb) in 

cities and suburban areas. 

Workplace air Workers in the production of rubber, plastics, and resins are likely 

exposed to higher levels of 1,3-butadiene. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 


 
	


	


	


 

1,3-BUTADIENE 3 

1. PUBLIC HEALTH STATEMENT 

Food and drinking water 1,3-Butadiene has been measured at very low levels in plastic or 

rubber of food containers, but it has not been found often in food 

samples. 

Exposure to 1,3-butadiene through ingestion of food and drinking 

water is expected to be very low compared to exposure through 

breathing contaminated air. 

Gasoline People may be exposed to small amounts of 1,3-butadiene if 

gasoline gets on their skin or by breathing air that contains gasoline 

fumes. 

1.4 HOW CAN 1,3-BUTADIENE ENTER AND LEAVE MY BODY?
 

Enter your body 1,3-Butadiene in air can be absorbed from the lungs and enter the 

blood stream. 

Leave your body 1,3-Butadiene is broken down to other chemicals in the liver. 

About half of inhaled 1,3-butadiene is broken down and exhaled, 

while most of the remaining chemical is broken down and excreted 

in the urine. 1,3-Butadiene typically leaves the body by 10 hours. 

For more information on how 1,3-butadiene enters and leaves the body, see Chapter 3. 

1.5 HOW CAN 1,3-BUTADIENE AFFECT MY HEALTH? 

This section looks at studies concerning potential health effects in animal and human studies. 

Noncancer
 In laboratory animals, 1,3-butadiene causes inflammation of nasal
	

tissues, changes to lung, heart, and reproductive tissues,
	

neurological effects, and blood changes.
	
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 

1,3-BUTADIENE 4 

1. PUBLIC HEALTH STATEMENT 

Cancer Studies of workers exposed to 1,3-butadiene suggest that workers 

may have an increased risk for cancers of the blood and lymphatic 

system. 

Laboratory animals have developed cancer in multiple body tissues 

after exposure to 1,3-butadiene for 13 weeks or longer. Animals 

appear to be most sensitive to blood and lymphatic system 

cancers. 

The International Agency for Research on Cancer (IARC), National 

Toxicology Program (NTP), and EPA all classify 1,3-butadiene as a 

human carcinogen. 

1.6 HOW CAN 1,3-BUTADIENE AFFECT CHILDREN? 

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

conception to maturity at 18 years of age. 

Effects in children It is likely that children would show the same health effects as 

adults. We do not know whether children are more sensitive to the 

effects of 1,3-butadiene. 

Birth defects We do not know whether 1,3-butadiene causes birth defects in 

people. Some studies have found decreases in fetal weight and 

skeletal defects in laboratory animals exposed to 1,3-butadiene. 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO 1,3-BUTADIENE?
 

Wood burning Take precautions to minimize the amount of smoke released into 

the home during wood burning. 

Vehicle engines Make sure vehicle engines are turned off when in an enclosed 

space such as a garage. 

Vehicle traffic Minimize time spent near areas of heavy vehicle traffic and avoid 

living very close to busy roads. 

Tobacco smoke Families can reduce exposure to 1,3-butadiene by avoiding tobacco 

smoke, particularly indoors. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 5 

1. PUBLIC HEALTH STATEMENT 

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

1,3-BUTADIENE? 

Development of blood 

tests 

We currently have no reliable medical test to determine if someone 

has been exposed to 1,3-butadiene. However, scientists are 

working on tests to show if 1,3-butadiene attaches to compounds in 

the blood, such as proteins or deoxyribonucleic acid (DNA). 

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 and Health (NIOSH) are two federal organizations that develop 

recommendations for toxic substances. 

Regulations and recommendations can be expressed as “not-to-exceed” levels. These are levels of a toxic 

substance in air, water, soil, or food that do not exceed a critical value. This critical value 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 1,3-butadiene include the following: 

Levels in breathing air 

set by EPA 

EPA has set a reference concentration in breathing air of 0.9 ppb 

for 1,3-butadiene. 

Levels in drinking water 

set by EPA 

EPA has not set levels in drinking water for 1,3-butadiene. 

Levels in workplace air 

set by OSHA 

OSHA set a legal limit of 1 ppm for 1,3-butadiene in air averaged 

over an 8-hour work day. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


	


	


	


	


	


	


	


	

1,3-BUTADIENE 6 

1. PUBLIC HEALTH STATEMENT 

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. 

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 1-800-CDCINFO (1-800-232-4636), by e-mail at cdcinfo@cdc.gov, or by 

writing to: 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology and Human Health Sciences (proposed) 

1600 Clifton Road NE 

Mailstop F-62 

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/
	
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 

1,3-BUTADIENE 7 

2. RELEVANCE TO PUBLIC HEALTH
 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO 1,3-BUTADIENE IN THE 

UNITED STATES 

1,3-Butadiene is a highly volatile gas that is used in the production of synthetic rubber; the major end use 

of the synthetic rubber is automobile tires. 1,3-Butadiene is also used for the production of high impact 

polystyrene and acrylonitrile-butadiene-styrene (ABS) resin plastics The predominant source of 

1,3-butadiene in the atmosphere is industrial releases, which can occur during manufacturing, use, 

transport, and storage of the chemical. Automobile exhaust is a constant source of low levels of 

1,3-butadiene release to the atmosphere. Minor sources of 1,3-butadiene in the atmosphere include 

cigarette smoke, wood burning (including forest fires), and the burning of rubber and plastics. In the 

atmosphere, 1,3-butadiene is expected to undergo photo-initiated destruction with a half-life of 

approximately 6 hours. Relatively low levels of 1,3-butadiene are released to water and soil. 1,3-Butadiene in water or soil is expected to rapidly evaporate to the atmosphere. 

Inhalation is the predominant route of exposure for the general population. Mean concentrations of 

1,3-butadiene in the air in cities and suburban areas ranges from 0.1 to 2 μg/m3

 (0.04–1 ppb); the average 

background concentration of 0.13 μg/m3

 (0.59 ppb) has been estimated. Higher atmospheric 

concentrations have been measured in areas near oil refineries, chemical manufacturing plants, and plastic 

and rubber factories where 1,3-butadiene is manufactured or used; concentrations as high as 40 μg/m3 

(18 ppb) have been measured near industrial sites. Within the general population, smokers (and 

individuals exposed to secondhand smoke) and individuals inhaling smoke from wood fires are likely to 

be exposed to higher levels of 1,3-butadiene. Workers involved in the production of rubber, plastics, and 

resins are most likely to receive the largest exposures. No data are available to quantify general 

population exposure to 1,3-butadiene by other routes of exposure, but it is expected to be very low 

compared to breathing contaminated air. Low levels of 1,3-butadiene have been detected in U.S. drinking 

water supplies; however, specific quantitative data were not located. 1,3-Butadiene has also been 

measured at very low levels in the plastic or rubber of food containers and has been found in a few food 

samples. 

Several biomarkers of exposure have been identified for 1,3-butadiene; these include 1,3-butadiene 

urinary metabolites, M1 and M2, and three hemoglobin adducts, N-(2-hydroxy-3-butenyl)valine 

(MHB-Val), N-(2,3,4-trihydroxybutyl)valine (THB-Val), and N,N-(2,3-dihyroxy-1,4-butadyl)valine 

(pyr-Val), which are surrogate biomarkers for the 1,3-butadiene metabolites 1,2 epoxy-3-butene (EB), 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 8 

2. RELEVANCE TO PUBLIC HEALTH 

1,2-dihydroxy-3,4-epoxybutane (EBD), and 1,2:3,4-diepoxybutane (DEB), respectively. In workers, the 

levels of urinary metabolites and hemoglobin adducts have been shown to correlate with 1,3-butadiene 

exposure levels. However, background levels for the general population have not been established for 

these biomarkers of exposure. 

2.2 SUMMARY OF HEALTH EFFECTS 

The available data for 1,3-butadiene exposure and toxicity in humans and animals are limited to 

inhalation exposures; the effects from significant oral or dermal exposures are not known. Information on 

the toxicity of 1,3-butadiene in humans comes from case reports and epidemiology studies that primarily 

focused on the potential carcinogenicity of 1,3-butadiene. Slight eye irritation and difficulty in focusing 

on instrument scales were reported by two men exposed to 2,000 or 4,000 ppm 1,3-butadiene for 6– 

7 hours; however, this was not reported when the two men were exposed to 8,000 ppm for 8 hours. 

Psychomotor tests conducted in these subjects did not find alterations at 2,000–8,000 ppm. Numerous 

epidemiological studies of multiple occupational cohorts, including one encompassing 15,000 workers, 

have associated a higher incidence of hemato-lymphopoietic cancer mortality among exposed workers. 

Although most of these workers were co-exposed to other organic compounds, including styrene, 

benzene, and dithiocarbamates, multivariate analysis suggested that the estimates of 1,3-butadiene 

exposure provided the best correlation with the rates of lympho-hematopoietic cancers. 

Numerous target organs for 1,3-butadiene toxicity have been identified in well-conducted laboratory 

studies ranging from single episode to lifetime exposures. Observed effects include death, neurological 

dysfunction, reproductive and developmental effects, hematological and lymphoreticular effects, and 

cancer. Evaluation of the relevance of adverse health effects observed in laboratory animals to human 

health is encumbered by large species differences in the metabolism of 1,3-butadiene. The metabolism of 

1,3-butadiene in humans and laboratory animals involves the same enzymatic pathways; however, there 

are notable quantitative differences in the production and detoxification of several reactive metabolites, 

particularly, EB, DEB, and EBD; see Sections 3.4.2 and 3.5.3 for more information on species 

differences. Mice, the most sensitive species, are more efficient at converting 1,3-butadiene to EB and 

converting EB to DEB. Using pyr-Val hemoglobin adduct levels as a biomarker for blood DEB levels, an 

exposure to approximately 1 ppm 1,3-butadiene resulted in mouse DEB levels that were 50 times higher 

than rats and 1,000 times higher than humans. Although the mode of action has not been elucidated for 

all toxic end points, there are strong data to support the reactive metabolites as the causative agents for the 

ovarian atrophy, cancer, and genotoxic effects observed in laboratory animals. Without information on 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 9 

2. RELEVANCE TO PUBLIC HEALTH 

the mode of action, particularly the causative agent, the reader should use caution in evaluating the 

relevance of the animal data presented in this section to human health. 

Lesions of the respiratory tract (olfactory tissues and lungs), liver, kidney, stomach, and eyes have been 

seen in mice exposed to ≥200 ppm for intermediate durations, but these lesions are typically epithelial or 

endothelial hyperplasias and are precancerous in nature. Non-neoplastic lesions of the liver (necrosis) in 

rats and kidney (renal nephrosis) in mice occurred following intermediate-duration exposure to 625 or 

8,000 ppm, respectively. 

Although no biologically relevant alterations in hematological parameters have been observed in 

1,3-butadiene workers, changes in the blood and lymphoid tissues are common observations in rodents 

exposed for intermediate and chronic durations. Decreases in red blood cell counts and hemoglobin 

concentration occurred at 65 ppm in mice, progressing to macrocytic megaloblastic anemia from 

exposures of 200 ppm. These effects are likely associated with observed changes in normal bone marrow 

function, as indicated by reduced circulation of erythrocytes and leukocytes, and increased proliferative 

activity with no associated change in bone marrow cellularity. Lymphoreticular toxicity in mice was 

indicated by significant changes in thymus weight and lesions in lymphoid organs following intermediateduration exposures to 625–1,250 ppm in mice. A reversible suppression of cytotoxic T-lymphocyte 

generation to mastocytoma cells and a depression of spleen cellularity were observed at these exposures. 

The changes in spleen and thymus weights, lymphocytic differentiation, and appearance of lymphoid 

lesions comport with the onset of lymphoma in mice after chronic exposure to 1,3-butadiene. 

Reproductive and developmental effects are the most sensitive non-cancer effects observed in rodents. 

Wavy ribs and skeletal abnormalities occurred in offspring of rats exposed to 1,000–8,000 ppm during 

gestation days (GDs) 6–15. In mice, exposure of pregnant dams to 40 ppm on GDs 6–15 resulted in a 5% 

decrease in fetal body weight among male mice. Exposure of mice to ≥200 ppm resulted in ≥19% 

reductions in fetal weight. A possible dominant lethal effect was observed in mice in which increased 

fetal deaths occurred from exposure to 200 ppm. The lowest lowest-observed-adverse-effect level 

(LOAEL) identified for intermediate-duration exposures was 12.5 ppm in male mice mated with 

unexposed females, resulting in increased late fetal death, exencephaly, and skull abnormalities of fetuses. 

Serious lesions of reproductive tissues in male and female mice have arisen from intermediate- and 

chronic-duration exposures. Ovarian atrophy, including complete loss of oocytes, follicles, and corpora 

lutea, occurred in mice exposed to 200 ppm for 9 months and as low as 6.25 ppm for 2 years. Male mice 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 10 

2. RELEVANCE TO PUBLIC HEALTH 

were somewhat less sensitive, with testicular atrophy observed after 15-month exposures to 625 ppm 

1,3-butadiene. 

The consistent carcinogenic responses in rodent bioassays support the associations derived in 

epidemiological studies between hemato-lymphopoietic cancer and 1,3-butadiene exposure. In rats, 

2-year exposure to 1,000 or 8,000 ppm resulted in increased incidences of tumors of the testes, pancreas, 

uterus, mammary gland, Zymbal gland, and thyroid. In mice, exposure to 200 ppm for 40 weeks resulted 

in increased tumor incidences of lymphopoietic system, heart, lung, stomach, liver, and eye. These same 

tumors developed in mice in as little as 13 weeks after exposure to 625 ppm. Chronic exposure of mice to 

concentrations of 20 ppm (males) and 6.25 ppm (females) of 1,3-butadiene resulted in increased tumor 

development in the lymphopoietic system, heart, lung, stomach, liver, eye, mammary glands, and ovaries. 

2.3 MINIMAL RISK LEVELS (MRLs) 

Inhalation MRLs 

The toxicity of 1,3-butadiene following inhalation exposure has been examined in epidemiology studies, 

intermediate- and chronic-duration studies in rats and mice, reproductive toxicity studies in mice, and 

developmental toxicity studies in rats and mice. The epidemiological studies have primarily focused on 

carcinogenicity and have found increases in lympho-hematopoitic cancers. Observed effects found in 

animal studies include neurological dysfunction, reproductive and developmental effects, hematological 

and lymphoreticular effects, and cancer. Acute exposures have resulted in fetal effects (decreased growth 

and skeletal defects) (DOE/NTP 1987b; Irvine 1981) and reproductive effects (increased intrauterine 

death following male-only exposure) (DOE 1988b). Intermediate-duration exposures in mice resulted in 

precancerous lesions of the respiratory tract (olfactory tissues and lungs), liver, kidney, stomach, and eyes 

(NTP 1984, 1993). Non-neoplastic lesions of the liver (necrosis) in rats and kidney (renal nephrosis) in 

mice occurred following intermediate-duration inhalation exposure. In mice, intermediate-duration 

inhalation exposure also resulted in decreases in red blood cell counts and hemoglobin concentration, 

progressing to macrocytic megaloblastic anemia (NTP 1993), decreases in spleen and thymus weight 

(NTP 1993), and depressed splenic cellularity (Thurmond et al. 1986). Chronic-duration inhalation 

exposure studies identified a number of targets of toxicity in mice including, bone marrow, lungs, heart, 

forestomach, Harderian gland, testes, ovaries, and uterus (NTP 1984, 1993); neoplastic lesions were also 

observed in a number of tissues. In rats, chronic exposure resulted in histological alterations in the lungs 

and increased severity of nephropathy (Owen et al. 1987). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 11 

2. RELEVANCE TO PUBLIC HEALTH 

Comparison of rat and mouse data identifies large differences in sensitivity to 1,3-butadiene, which are 

due to metabolic differences between species. As discussed in Sections 3.4.2 and 3.5.3, quantitative 

differences between humans, rats, and mice in the rate of formation of reactive metabolites, particularly 

EB and DEB have been found. These differences result in higher tissue levels of reactive metabolites in 

rodents than in humans (Bond et al. 1993; Csanády et al. 1992; Dahl et al. 1991; Filser et al. 2001, 2007, 

2010; Henderson et al. 1996, 2001; Himmelstein et al. 1997; Kirman et al. 2010a; Krause and Elfarra 

1997; Schmidt and Loeser 1985; Thornton-Manning et al. 1995b). Following inhalation exposure to 

1,3-butadiene, blood EB levels were 2–8 times higher in mice as compared to rats (Filser et al. 2007) and 

the maximum butadiene-diol levels were 4 times higher in mice than rats (Filser et al. 2007). The DEB 

levels were >100-fold higher in mice as compared to rats (Filser et al. 2007). At a similar exposure level 

(1 ppm), mice produce approximately 1,000 times as much DEB as humans, as measured using pyr-Val 

hemoglogin adduct as a biomarker and 50 times as much DEB as rats (Swenberg et al. 2011). 

The Agency usually considers humans more sensitive than animals and makes an adjustment to the point 

of departure to account for species differences when deriving an MRL from an animal study. If possible, 

chemical-specific data, such as physiologically based pharmacokinetic (PBPK) modeling, is used to 

account for toxicokinetic differences between species. Although PBPK models for 1,3-butadiene have 

been developed in rodents (Johanson and Filser 1993; Kohn and Melnick 1993, 1996, 2000) and a 

preliminary model has been developed in humans (Brochot et al. 2007), the models are limited in their 

ability to predict internal doses for key metabolites (Kirman and Grant 2012). An alternative to using 

PBPK models would be to use a biomarker of exposure to reactive metabolites. Several biomarkers of 

exposure have been identified for reactive 1,3-butadiene metabolites including MHB-Val hemoglobin 

adducts, THB-Val hemoglobin adducts, and pyr-Val hemoglobin adducts, which have been shown to be 

good surrogate biomarkers for EB, EBD, and DEB, respectively (Georgieva et al. 2010; Slikker et al. 

2004). However, there are limited mechanistic data that would allow identification of the 1,3-butadiene 

metabolite(s) (or parent compound) that is responsible for the non-neoplastic effects, with the exception 

of ovarian atrophy observed in mice, which is likely due to DEB. 

In the absence of chemical-specific data, the Agency generally applies an uncertainty factor of 10 to 

account for interspecies differences in toxicokinetic and toxicodynamic properties. However, the 

toxicokinetic data for 1,3-butadiene indicate that mice are many-fold more sensitive than humans. Thus, 

the Agency can only use an uncertainty factor of 1 (or not apply an uncertainty factor [UF]), which in the 

case of 1,3-butadiene, may cause the MRL to overestimate the risk to humans. Therefore, in this instance, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 12 

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the Agency has elected to not derive inhalation MRLs for 1,3-butadiene. Brief discussions of the 

available literature for each duration period are presented below. 

Acute-Duration Inhalation MRL. Death and neurological effects have been observed in rats, mice, and 

rabbits exposed to 8,000–250,000 ppm from <1 to 4 hours (Carpenter et al. 1944; Shugaev 1969). Studies 

examining nonlethal effects were limited to three developmental toxicity studies and a reproductive 

toxicity study. Significant increases in the occurrence of major skeletal defects, predominantly wavy ribs, 

were observed in the offspring of Sprague-Dawley rats exposed to 1,000 or 8,000 ppm 1,3-butadiene 

6 hours/day on GDs 6–15 (Irvine 1981). Other non-concentration-related effects included an increase in 

minor skeletal defects at 200 ppm, but not at higher concentrations, and increases in the occurrence of 

minor external/visceral defects at 1,000 ppm, but not at 8,000 ppm. The study also found decreases in 

fetal growth (body weight and crown-rump length) at 8,000 ppm and decreases in maternal weight gain at 

≥200 ppm; at 8,000 ppm, maternal body weight gain was 45% lower than controls. The investigators 

noted that the increase in the occurrence of wavy ribs was likely secondary to the decrease in maternal 

weight gain. In a second rat developmental toxicity study, no developmental effects (including alterations 

in occurrence of skeletal defects, fetal body weight, or maternal body weight) were observed in SpragueDawley rats exposed to 40–1,000 ppm 6 hours/day on GDs 6–15 (DOE/NTP 1987a). In a mouse 

developmental toxicity study, decreases in fetal body weight were observed in the offspring of CD-1 mice 

exposed to ≥40 ppm 6 hours/day on GDs 6–15 (DOE/NTP 1987b). The male fetal body weights were 5, 

18, and 23% lower than controls and no significant alterations in female body weight were observed; 

interpretation of these results is limited by the lack of statistical adjustment for litter size. In the 

reproductive toxicity study, the mating of male CD-1 mice exposed to ≥200 ppm 6 hours/day for 5 days 

with unexposed females resulted in significant increases in dams with two or more intrauterine deaths 

(DOE/NTP 1988b). This effect was only observed when the mating occurred 1 week post-exposure, 

suggesting that the mature spermatozoa and/or spermatids were the targets. 

The limited available data on the toxicity of 1,3-butadiene following acute-duration inhalation exposure 

suggest that mice are more sensitive than rats for developmental effects. Exposures to 1,3-butadiene has 

resulted in decreases in fetal body weights in mice at ≥40 ppm (DOE/NTP 1987b) and rats at ≥200 ppm 

(Irvine 1981), dominant lethal effects in mice at ≥200 ppm (DOE/NTP 1988b), and increases in skeletal 

malformations in rat fetuses at ≥1,000 ppm (Irvine 1981). The no-observed-adverse-effect levels 

(NOAELs) were 40 ppm for dominant lethal effects in mice and 200 ppm for skeletal defects in rats. As 

noted previously, the Agency has elected to not derive an acute-duration inhalation MRL for 

1,3-butadiene due to the large species differences in the metabolism of 1,3-butadiene and the lack of 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 13 

2. RELEVANCE TO PUBLIC HEALTH 

chemical-specific data to adjust for these differences, which may result in the MRL overestimating the 

risk to humans. 

Intermediate-Duration Inhalation MRL. Intermediate-duration exposures resulted in death in mice 

exposed to 5,000 ppm, 6 hours/day for 5 weeks (NTP 1984) and 200 ppm, 6 hours/day for 40 weeks 

(NTP 1993). No systemic effects were seen in rats or mice exposed to 8,000 ppm, 6 hours/day for 13– 

14 weeks, with the exception of a 13% body weight reduction in mice exposed to 2,500 ppm (NTP 1984). 

Exposure of mice to 625 ppm, 6 hours/day for 40 weeks resulted in pre-cancerous hyperplasia of the 

respiratory and gastrointestinal systems (epithelial hyperplasia), as well as a 19% reduction in thymus 

weight. Multi-site cancer was observed in mice after 13–52 weeks of exposure to 200 ppm for 

6 hours/day (NTP 1993). Hematological effects included decreased erythrocyte counts, hemoglobin 

concentration, and red blood cell volume in mice at 62.5 ppm and macrocytic megaloblastic anemia at 

200 ppm, administered 6 hours/day for 40 weeks (NTP 1993). Reproductive effects in mice were the 

most sensitive effects observed, with ovarian atrophy occurring at exposures of 200 ppm, 6 hours/day for 

40 weeks (NTP 1993). The most sensitive developmental effects observed were exencephalies, skull 

abnormalities, and late fetal death in the offspring of unexposed female mice mated with male mice 

exposed to 12.5 ppm for 10 weeks (Anderson et al. 1996). 

The Agency has elected to not derive an intermediate-duration inhalation MRL for 1,3-butadiene due to 

the large species differences in the metabolism of 1,3-butadiene and the lack of chemical-specific data to 

adjust for these differences, which may result in the MRL overestimating the risk to humans. 

Chronic-Duration Inhalation MRL. Chronic-duration exposures resulted in increased mortality in rats 

and mice exposed to 8,000 or 20 ppm, 6 hours/day for 2 years. Rats exposed to 8,000 ppm, 6 hours/day 

for 2 years exhibited increased lung weight and metaplasia and kidney nephrosis (Owen and Glaister 

1990; Owen et al. 1987). In mice, exposure to 1,250 ppm for 65 weeks resulted in nasal olfactory 

epithelial atrophy in mice (NTP 1984). Hepatic necrosis, forestomach epithelial hyperplasia, 

megaloblastic anemia, and endothelial hyperplasia of the heart were observed in mice exposed to 

625 ppm (6 hours/day, 5 days/week) for 61–65 weeks (NTP 1984, 1993); testicular atrophy and preputial 

gland hyperplasia were observed in mice exposed to 625 ppm for 2 years (NTP 1993). Ovarian atrophy 

was observed in mice exposed to 62.5 ppm for 65 weeks or 6.25 ppm for 2 years (NTP 1993); complete 

destruction of oocytes, follicles, and corpora lutea was also observed. Alveolar epithelial hyperplasia was 

observed in mice following a 2-year exposure to 6.25 ppm (NTP 1993). In addition to the noncancerous 

effects, mammary gland tumors developed in rats exposed to 1,000 ppm, 6 hours/day for 2 years (Owen 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 14 

2. RELEVANCE TO PUBLIC HEALTH 

and Glaister 1990; Owen et al. 1987), while multi-site cancer was observed in mice at 625 ppm, 

6 hours/day for 61 weeks (NTP, 1984) and lung cancer occurred in mice following exposure to 6.25 ppm, 

6 hours/day for 2 years (NTP 1993). 

Considerable species differences were observed in the chronic-duration studies in terms of observed 

effects and sensitivity. The lowest LOAEL in rats is 8,000 ppm for lung and kidney effects and the 

lowest LOAEL in mice is 6.25 ppm for ovarian and lung effects. Renal effects have not been observed in 

mice exposed to up to 625 ppm for 2 years (NTP 1993) and ovarian effects were not observed in rats 

exposed to concentrations as high as 8,000 ppm for 2 years (Owen et al. 1987). The differences in 

sensitivity and possibly critical targets are most likely related to species differences in 1,3-butadiene 

metabolism. As noted previously, mice produce substantially more DEB than rats; one study (ThorntonManning et al. 1995b) found that peak tissue levels of DEB were 40–160-fold greater in mice than rats. 

A comparison of blood DEB levels estimated from pyr-Val hemoglobin adduct levels found that at 

similar exposure levels (approximately 1 ppm), mouse DEB levels were 50 times higher than in rats and 

1,000 times higher than in humans (Swenberg et al. 2011). In the absence of human data for 

noncarcinogenic effects following chronic exposure, the species differences in metabolism necessitate 

estimating human equivalent concentrations for each end point and comparing these values in order to 

identify the most likely critical target in humans. The available data provide strong evidence that the 

1,3-butadiene metabolite, DEB, is the causative agent of the ovarian atrophy observed in mice (Doerr et 

al. 1996). Mechanistic data that could be used to identify relevant internal dose metrics for other sensitive 

end points in rats and mice were not identified, which precludes a comparison of human equivalent 

concentrations for each sensitive target. Thus, the Agency has elected to not derive a chronic-duration 

inhalation MRL for 1,3-butadiene; the lack of chemical-specific data to adjust for the large species 

differences in metabolism may result in the MRL overestimating the risk to humans. 

Although ATSDR considers that the lack of data that can be used to evaluate the most sensitive target of 

chronic toxicity in humans precludes derivation of a chronic-duration inhalation MRL, the U.S. EPA 

(IRIS 2012), the Texas Commission on Environmental Quality (TCEQ) (Grant et al. 2010), and Kirman 

and Grant (2012) have derived chronic risk assessment values based on ovarian atrophy in mice. These 

three approaches share several commonalities, but also have several differences. All three approaches use 

a time-to-response benchmark dose (BMD) model; EPA and TCEQ used incidence data from the National 

Toxicology Program (NTP 1993) chronic mouse study and Kirman and Grant (2012) used incidence data 

from intermediate- and chronic-duration rat and mouse studies. The EPA approach did not make any 

adjustments for chemical-specific differences in metabolism. TCEQ derived chemical-specific 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 15 

2. RELEVANCE TO PUBLIC HEALTH 

uncertainty factors to account for species differences in DEB formation, whereas Kirman and Grant 

(2012) ran the BMD modeling using an internal dose metric for DEB. A summary of these risk 

assessment values are presented in Table 2-1 and a more detailed discussion of the three approaches 

follows. 

EPA (IRIS 2012). In 2002, EPA derived a reference concentration (RfC) of 0.0009 ppm based on a 

BMCL10 of 0.88 ppm using the concentration-response data for ovarian atrophy in mice exposed to 

1,3-butadiene for 2 years (NTP 1993) and an uncertainty factor of 1,000 (3 for interspecies extrapolation 

with dosimetric adjustments, 10 for intraspecies variability, 3 for incomplete database, and 10 for 

extrapolation to a level below the 10% effect level). The BMD modeling used the Weibull time-toresponse model and incorporated the incidence data from the interim and final sacrifices; the data were 

modeled to include extra risk only until age 50 years. Human equivalent concentrations were calculated 

by adjusting the BMCL10 for intermittent exposure (6 hours/day, 5 days/week) and multiplying the 

adjusted BMCL10 by an RGDR (ratio of blood:gas partition coefficients) of 1. 

Texas Commission on Environmental Quality (Grant et al. 2010). The TCEQ (Grant et al. 2010) 

derived a chronic reference value of 0.0154 ppm based on a BMCL05 of 0.462 ppm for ovarian atrophy in 

mice (NTP 1993) and a total uncertainty factor of 30. Similar to EPA, the Weibull time-to-response 

model was used for BMD analysis of the ovarian atrophy incidence data for mice exposed to 

1,3-butadiene for 2 years (9- and 15-month interim sacrifice data were also included in the model). The 

component uncertainty factors were 1 for animal to human extrapolation, 10 for intraspecies variability, 

and 3 for database deficiencies (lack of a multigenerational reproductive study). Both the intraspecies and 

the interspecies uncertainty factors were divided into toxicokinetic and toxicodynamic components. For 

the intraspecies uncertainty factor, a default value of 3 was used to account for toxicodynamic factors 

because data are lacking on the key sequence of events and how DEB interacts in different subpopulations 

to produce ovarian atrophy; a toxicokinetic factor of 3 was used because metabolic genetic 

polymorphisms may account for differences in susceptibility of 2–3.5-fold in humans. For the 

interspecies uncertainty factor, 3 was used for toxicodynamic differences because data are not available 

on possible differences on how DEB would react in different species to produce ovarian atrophy; a 

toxicokinetic factor of 0.3 was selected to account for species differences in 1,3-butadiene metabolism. 

The basis of this 0.3 factor was: (1) a comparison of the levels of DEB-specific hemoglobin adduct (pyrVal adduct) formation in mice and humans; (2) a comparison of total 1,3-butadiene metabolite levels in 

the blood; and (3) comparisons of DEB blood concentrations, DEB tissue levels, and blood area-under-
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	


	

1,3-BUTADIENE 16 

2. RELEVANCE TO PUBLIC HEALTH 

Table 2-1. Summary of Available Chronic Risk Assessment Values for 

1,3-Butadiene 

Source of data for UF (UFL, 

benchmark UFA, UFH, 

Source analysis POD UFDB) Issues and considerations 

EPA 

(IRIS 2012)
	

TCEQ
	

(Grant et al.
	

2010)
	

Kirman and 

Grant 2012
	

2-Year mouse 

study (including 

interim sacrifices) 

2-Year mouse 

study (including 

interim sacrifices) 

Intermediate and 

chronic rat and 

mouse studies 

BMCL10: 1,000 

0.88 ppm (10, 3, 10, 3) 

BMCL05: 30 

0.462 ppm (NA, 1, 10, 3) 

BMCL01: 10 

1.5 ppm (NA, 3, 1, 3) 

The RfC does not have a chemical-specific 

adjustment for the increased production of 

DEB (reactive metabolite) in mice, as 

compared to humans. 

Does not take into consideration that ovarian 

atrophy may not be the most sensitive target 

in humans and that effects due to exposure 

to other reactive metabolites may occur at 

lower doses. 

Accounts for species differences by 

quantifying toxicokinetic differences between 

mice and humans and selecting the low end 

of the range as an uncertainty factor to 

account for interspecies toxicokinetic 

differences. 

Does not take into consideration that ovarian 

atrophy may not be the most sensitive end 

point in humans and that effects due to 

exposure to other reactive metabolites may 

occur at lower doses. 

Accounts for species differences by 

including rat incidence data in BMD model 

and using pyr-Val hemoglobin adduct levels 

as a biomarker of DEB levels. 

Does not take into consideration that ovarian 

atrophy may not be the most sensitive end 

point in humans and that effects due to 

exposure to other reactive metabolites may 

occur at lower doses. 

BMCL = 95% lower confidence limit of the benchmark concentration; BMD = benchmark dose;
	

DEB = 1,2:3,4-diepoxybutane; LOAEL = lowest-observed-adverse-effect level; NA = not applicable;
	

NOAEL = no-observed-adverse-effect level; POD = point of departure; RfC = reference concentration;
	

UF = uncertainty factor: UFL = extrapolation from NOAEL to LOAEL; UFA = extrapolation from animals to humans;
	

UFH = human variability; UFDB = database limitations
	
 

1,3-BUTADIENE 17 

2. RELEVANCE TO PUBLIC HEALTH 

the-curve levels in rats and mice; these comparisons resulted in a range of toxicokinetic uncertainty 

factors of 0.01–0.2 and the value of 0.3 was selected. 

Kirman and Grant (2012). Kirman and Grant (2012) based their RfC of 0.2 ppm on a BMCL01 of 

1.5 ppm for ovarian atrophy and an uncertainty factor of 10 (3 for extrapolation from animals to humans 

and 3 for database deficiencies [lack of a multigenerational study and lack of dose-response data for 

follicle depletion]). A multi-stage Weibull time-to-response BMD model was applied to the combined 

dose-response data for ovarian atrophy in mice exposed for 2 years (including 40- and 65-week interim 

sacrifices (NTP 1993), mice exposed for 61 weeks (NTP 1984), mice exposed for 13 weeks (Bevan et al. 

1996), rats exposed for 2 years (Owen et al. 1987), and rats exposed for 13 weeks (Bevan et al. 1996). To 

account for species differences in the metabolism of 1,3-butadiene, the BMD model was run using blood 

DEB levels as the internal dose metric. Blood DEB levels were estimated using a multistep process that 

used pyr-Val adduct burden as a biomarker for DEB levels. Pyr-Val adduct burdens were estimated using 

data on pyr-Val adduct efficiency (amount of adducts formed per ppm of 1,3-butadiene in air) in rats and 

mice as a function of 1,3-butadiene exposure concentration following a 4-week exposure (6 hours/day, 

5 days/week). The estimated pyr-Val adduct burden were then used to calculate blood DEB 

concentrations using species-specific rate constants for the reaction of DEB with the terminal valine of 

hemoglobin and erythrocyte lifespan. For the time-to-response model, the exposure duration of interest 

was set equal to the window of susceptibility for ovotoxicity. Since the window of susceptibility is 

dependent on the number of follicles present at birth, the model was run for three scenarios: an average 

number of follicles at birth, the lower bound of central tendency for number of follicles, and the upper 

bound of the central tendency for the number of follicles; the range of susceptibility for depletion of 

follicle reserves for 95% of the population ranges from 8.5 higher and 8.5 lower than the average 

individual. The BMD model also included a 3-fold shift to account for toxicokinetic variation among 

humans. Since the model accounts for toxicokinetic and toxicodynamic differences in humans, no 

additional uncertainty factors were added to account for human variability. 

Oral MRLs 

There are no data available for effects in humans or animals exposed orally to 1,3-butadiene. For this 

reason, no acute-, intermediate-, or chronic-duration oral MRLs could be derived. 
 

1,3-BUTADIENE 18 

2. RELEVANCE TO PUBLIC HEALTH 

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1,3-BUTADIENE 19 

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 1,3-butadiene. 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 

"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 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 20 

3. HEALTH EFFECTS 

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 1,3-butadiene 

are indicated in Table 3-1 and Figure 3-1. Because cancer effects could occur at lower exposure levels, 

Figure 3-1 also shows a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 

10,000 to 1 in 1,000,000 (10-4 to 10-6), 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 

3.2.1.1 Death 

Information on the lethality of 1,3-butadiene in humans is limited. A number of occupational exposure 

studies have examined mortality ratios in 1,3-butadiene workers, the results of these studies are discussed 

in subsequent sections on the primary effects. 

No deaths were seen in B6C3F1 mice exposed to ≤8,000 ppm 1,3-butadiene 6 hours/day, 5 days/week, for 

2 weeks (NTP 1984). The majority of rabbits died when exposed to 250,000 ppm 1,3-butadiene for an 

average of 23 minutes (Carpenter et al. 1944). The LC50 values calculated for mice and rats exposed for 

2 and 4 hours, respectively, was 122,000 and 129,000 ppm, respectively (Shugaev 1969). 

Intermediate-duration exposures produced no deaths in rats exposed for 6 hours/day, 5/days/week, for 

13 weeks to 8,000 ppm (Crouch et al. 1979), or in rats, guinea pigs, rabbits, and dogs during 8 months of 

exposure to 6,700 ppm (Carpenter et al. 1944). Increased mortality was seen in mice exposed to 

5,000 ppm, but not 2,500 ppm, for 6 hours/day, 5 days/week, for 14 weeks (NTP 1984). The lowest 
 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 21 

3. HEALTH EFFECTS 

intermediate-duration exposure resulting in death was observed in mice receiving 200 ppm for 

6-hours/day, 5 days/week, for 40 weeks (NTP 1993), ostensibly from the early development of 

neoplasms. 

During chronic exposure to 625 and 1,250 ppm of 1,3-butadiene for 61 weeks, significantly increased 

mortality, primarily due to cancer, was found in B6C3F1 mice (NTP 1984). Similar results were obtained 

in another study using a much lower concentration (20 ppm) (NTP 1993). Exposure of rats to 8,000 ppm 

1,3-butadiene resulted in statistically significant increased mortality from cancer when compared with 

controls (Owen et al. 1987). The LC50 values and all reliable LOAEL values for death in each species and 

duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.2 Systemic Effects 

Respiratory Effects. Workers exposed to 1,3-butadiene gas during the manufacture of rubber 

complained of irritation of the eyes, nasal passages, throat, and lungs (Wilson 1944). In some, coughing, 

fatigue, and drowsiness developed. All symptoms disappeared on removal from the gas. The associated 

exposure levels were not reported. 

No effects in respiratory tissues were observed in rats, guinea pigs, rabbits, or dogs inhaling up to 

6,700 ppm 1,3-butadiene for 7.5 hours/day, 6 days/week, for 8 months (Carpenter et al. 1944) or in rats or 

mice exposed to 8,000 ppm 1,3-butadiene for 6 hours/day, 5 days/week, for 13–14 weeks (Crouch et al. 

1979; NTP 1984). No effects were observed in lungs of mice exposed to concentrations as high as 

625 ppm for 6 hours/day, 5 days/week, for 9 months (NTP 1993). 

An increase in chronic inflammation of the nasal cavity, fibrosis, cartilaginous metaplasia, osseous 

metaplasia, atrophy of the sensory epithelium, and hyperplasia of the respiratory epithelium were 

observed in mice exposed to 1,250 ppm for 2 years (NTP 1984). Lungs of rats exposed chronically to 

8,000 ppm 1,3-butadiene exhibited metaplasia (Owen and Glaister 1990; Owen et al. 1987). Atrophy of 

the nasal olfactory epithelium was observed in mice exposed to concentrations as high as 1,250 ppm 

1,3-butadiene for 6 hours/day, 5 days/week, for 61 weeks (NTP 1993), while alveolar epithelial 

hyperplasia (a possible precancerous lesion) occurred in mice exposed to 6.25 ppm 6 hours/day, 

5 days/week for 2 years (NTP 1993). 
97

129000

96

122000

67

250000

159

200

8000

71

8000

68

250000

154

1000

158

200

Table 3-1 Levels of Significant Exposure to 1,3-butadiene - Inhalation 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 1 d 

4 h/d 

System 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

LOAEL 

Serious 

(ppm) 

129000 (LC50) 

Reference Chemical Form 

Shugaev 1969 

2 Mouse 1 d 

2h/d 122000 (LC50) Shugaev 1969 

3 Rabbit 

Systemic 

4 Rat 

1 d 23 min/d 10 d 6 hr/d Gd 6-15 

Bd Wt 200 F (decreased maternal 

body weight gain) 

250000 

8000 F (45% decreased 

maternal body weight gain) 

Carpenter et al. 1944 Irvine 1981 

Neurological 

5 Human 1 d 

6-8 hr/d 8000 Carpenter et al. 1944 

6 Rabbit 

Reproductive 

7 Mouse 

(B6C3F1) 

1 d 23 min/d 5 d 6 h/d 

250000 

1000 M (73% increase in number 

of abnormal sperm heads) 

(anesthesia) Carpenter et al. 1944 

DOE/NTP 1988a 

8 Mouse 

CD-1 

6 hr/day 5 days 200 M (increased intrauterine death) DOE/NTP 1988b 
74

1000

72

200 8000

1000

100

40

23

5000

144

200

Table 3-1 Levels of Significant Exposure to 1,3-butadiene - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

Developmental 

9 Rat 

(SpragueDawley) 

10 d 6 hr/d Gd 6-15 

1000 DOE/NTP 1987a 

10 Rat 10 d 

6 hr/d Gd 6-15 

200 8000 

1000 

(decreased fetal growth) (major skeletal 

malformations) 

Irvine 1981 

11 Mouse 

(CD-1) 

10 d 6 hr/d GD 6-15 

40 M (decreased fetal BW in 

males) 

DOE/NTP 1987b 

INTERMEDIATE EXPOSURE Death 

12 Mouse 14 wk 

5 d/wk 6 hr/d 

5000 (increased mortality) NTP 1984 

13 Mouse 

(B6C3F1) 

13-52 wk 6 hr/d 5 d/wk 

200 (increased mortality from 

40 weeks of exposure) 

NTP 1993 
57

80008000800080008000800080008000

7

1250

Table 3-1 Levels of Significant Exposure to 1,3-butadiene - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species 

Figure (Strain) 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) Serious (ppm) 

Systemic 

14 Rat 13 wk 

5 d/wk 6 hr/d 

Resp 8000 

Cardio 8000 Hemato 8000 Musc/skel Hepatic Renal 

8000 8000 8000 

Dermal 8000 Ocular 8000 

15 Mouse 3-24 wk 

6 d/wk 6 hr/d 

Hemato 1250 M (macrocytic 

megaloblastic anemia starting at 6 weeks) 

Reference Chemical Form 

Crouch et al. 1979 

Irons et al. 1986a, b 
24

80008000800080008000800080001250

2500

146

200200

200

625

Table 3-1 Levels of Significant Exposure to 1,3-butadiene - Inhalation (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

16 Mouse 14 wk 

5 d/wk 6 hr/d 

17 Mouse 

(B6C3F1) 

13-52 wk 

6 hr/d 

5 d/wk 

System 

Resp 

Cardio Gastro Musc/skel Hepatic Renal Dermal Bd Wt Resp Cardio Ocular 

NOAEL 

(ppm) 

8000 

8000 

8000 

8000 8000 8000 8000 

1250 

200 M 

LOAEL 

Less Serious Serious Reference 

(ppm) (ppm) Chemical Form 

NTP 1984 

2500 M (13% decreased body 

weight) 

200 M (alveolar epithelial NTP 1993 

hyperplasia after 40 weeks) 

200 M (endothelial hyperplasia 

after 40 weeks) 

625 M (Harderian gland 

hyperplasia after 26 weeks) 
147

200

625

625200

62562.5

200

625625625

152

625

3

1250

86

8000

Table 3-1 Levels of Significant Exposure to 1,3-butadiene - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form 

18 Mouse 

(B6C3F1) 

40 wk 6 hr/d 5 d/wk 

Resp 200 M 625 M (alveolar epithelial 

hyperlasia) 

NTP 1993 

Cardio 625 Gastro 200 625 (forestomach epithelial 

hyperplasia) 

Hemato 62.5 M (decreased erythrocyte 

counts, hemoglobin concentration, and red cell volume) 

200 F (macrocytic 

megaloblastic anemia) 

Immuno/ Lymphoret 

19 Mouse 

(B6C3F1) 

40 wk 6 hr/d 5 d/wk 

Musc/skel Hepatic Bd Wt 

625 625 F 625 

625 F (19% reduction in relative 

thymus weight) 

NTP 1993 

20 Mouse 6-24 wk 

5 d/wk 6 hr/d 

1250 (lymphoid organ 

histopathology) 

Thurmond et al. 1986 

Neurological 

21 Rat 13 wk 

5 d/wk 6 hr/d 

8000 Crouch et al. 1979 
89

8000

136

12.5

137

12.5

65

150

62.5 200

143

200

Table 3-1 Levels of Significant Exposure to 1,3-butadiene - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

22 Mouse 

Reproductive 

23 Mouse 

(CD) 

24 Mouse 

(CD) 

25 Mouse 

(B6C3F1) 

Cancer 

26 Mouse 

(B6C3F1) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

14 wk 5 d/wk 6 hr/d 

8000 NTP 1984 

10 wk 6 h/d 5 d/wk 

12.5 M (increase in late fetal 

deaths, exencephalies, and skull abnormalities) 

Anderson et al. 1996 

4 wk 6 h/d 5 d/wk 

12.5 M 65 M (increases in early fetal 

deaths) 

Anderson et al. 1998 

40 wk 6 hr/d 5 d/wk 

62.5 F 200 F (ovarian atrophy) NTP 1993 

13-52 wk 6 hr/d 5 d/wk 

200 M (CEL:lymphocytic 

lymphoma, histiocytic sarcoma, cardiac hemangiosarcoma, alveolar/bronchiolar adenoma/carcinoma, forestomach squamous cell papilloma/carcinoma, hepatocellular adenoma, Harderian gland adenoma/adenocarcinoma 

preputial gland carcinoma) 

NTP 1993 
15

1000 8000

125

625

140

20

14

1000

8000

80008000800080001000 800080008000

Table 3-1 Levels of Significant Exposure to 1,3-butadiene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

CHRONIC EXPOSURE Death 

27 Rat 105-111 wk 

5 d/wk 6 hr/d 

1000 8000 (increased mortality) Owen et al. 1987, Owen 

Glaister 1990 

28 Mouse 61 wk 

5 d/wk 6 hr/d 

625 (increased mortality) NTP 1984 

29 Mouse 

(B6C3F1) 

2 yr 6 hr/d 5 d/wk 

20 (increased mortality) NTP 1993 

Systemic 

30 Rat 105-111 wk 

5 d/wk 6 hr/d 

Resp 1000 8000 (increased organ weight, 

metaplasia) 

Owen et al. 1987, Owen Glaister 1990 

Cardio 8000 Gastro 8000 Hemato 8000 Hepatic 8000 Renal 1000 8000 (nephrosis) 

Dermal 8000 Ocular 8000 
26

625

1250

625625

1250

625

12501250

142

6.25

200 625

625200

625

62.5

625

Table 3-1 Levels of Significant Exposure to 1,3-butadiene - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference (Route) Figure (Strain) System (ppm) (ppm) (ppm) Chemical Form 

31 Mouse 61 wk 

5 d/wk 6 hr/d 

Resp 625 1250 (atrophy of nasal 

olfactory epithelium) 

NTP 1984 

Cardio Gastro Musc/skel Hepatic Renal 

1250 1250 

625 (endothelial hyperplasia) 

625 (epithelial hyperplasia) 625 (hepatic necrosis) 

Dermal 1250 

32 Mouse 

(B6C3F1) 

2 yr 6 hr/d 5 d/wk 

Resp 6.25 M (alveolar epithelial 

hyperplasia) 

NTP 1993 

Cardio Gastro 

200 625 (endothelial hyperplasia) 

625 F (forestomach epithelial 

hyperplasia) 

200 F (forestomach epithelial 

hyperplasia) 

Musc/skel Hepatic Bd Wt 

625 625 

62.5 (liver necrosis) 
145

200

625

625

73

8000

127

1250

84

8000

27

625

151

6.25

153

20 62.5

Table 3-1 Levels of Significant Exposure to 1,3-butadiene - Inhalation (continued) 

a 

Key to Species 

Figure (Strain) 

33 Mouse 

(B6C3F1) 

Neurological 

34 Rat 35 Mouse 

Reproductive 

36 37 38 39 

Rat Mouse Mouse (B6C3F1) Mouse (B6C3F1) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

65 wk 6 hr/d 5 d/wk 

Hemato 200 625 (macrocytic 

megaloblastic anemia) 

NTP 1993 

Bd Wt 625 

105-111 wk 5 d/wk 6 hr/d 

8000 Owen et al. 1987, Owen 

Glaister 1990 

61 wk 5 d/wk 6 hr/d 

1250 NTP 1984 

105-111 wk 5 d/wk 6 hr/d 

8000 Owen et al. 1987, Owen 

Glaister 1990 

61 wk 5 d/wk 6 hr/d 

625 (gonadal atrophy) NTP 1984 

2 yr 6 hr/d 5 d/wk 

6.25 F (ovarian atrophy) NTP 1993 

65 wk 6 hr/d 5 d/wk 

20 F 62.5 F (ovarian atrophy) NTP 1993 
13

1000

25

625

133

6.25

Table 3-1 Levels of Significant Exposure to 1,3-butadiene - Inhalation (continued) 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

Cancer 

40 Rat 105-111 wk 

5 d/wk 6 hr/d 

Owen et al. 1987, Owen Glaister 1990 1000 (CEL: mammary gland adenoma and sarcoma) 

41 Mouse 61 wk 

5 d/wk 6 hr/d 

625 (CEL:alveolar/bronchiolar NTP 1984

adenoma or carcinoma, malignant lymphoma, hemangiosarcoma, forestomach squamous cell papilloma or carcinoma, mammary gland carcinoma, ovarian granulosa cell tumor) 

42 Mouse 

(B6C3F1) 

2 yr 6 hr/d 5 d/wk 

6.25 F (CEL: NTP 1993

alveolar/bronchiolar adenoma/carcinoma) 

a The number corresponds to entries in Figure 3-1. Bd Wt = body weight; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); F = Female; Gastro = gastrointestinal; Gd = gestational day; Hemato = hematohour(s); Immuno/Lymphoret = immunological; LC50 = lethal concentration, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; min = minute(s); Mumusculoskeletal; NOAEL = no-observed-adverse-effect level; Resp = respiratory; wk = week(s); yr = year(s) 
Death 

Body WeiNeurologiReproducDevelop

ppm
	

1E+6
	

3h 6h 

2m 1r

100000 

10000 

4r 5 10r 

1000 7m 9r 10r 

4r 8m 10r 

100 

11m 

10 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

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

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

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

q-Cow a-Sheep g-Guinea Pig Cancer 

ght cal 

tive 

mental 

Figure 3-1 Levels of Significant Exposure to 1,3-Butadiene - Inhalation 

Acute (≤14 days) 

Systemic 

1,3-BUTADIENE

3. HEALTH EFFECTS

32
Death 

RespiratoryCardiovascGastrointesHematologiMusculoskHepatic Renal Dermal Ocular Body WeigImmuno/LyNeurologic

ppm 

10000 

16m 14r 16m 14r 16m 14r 16m 14r 16m 14r 16m 14r 16m 14r 14r 22m 21r 

12m 

16m 

15m 16m 20m 

1000 

18m 18m 18m 18m 18m 17m 18m 19m 

13m 17m 18m 17m 18m 18m 17m 

100 

18m 

10 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

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

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

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

q-Cow a-Sheep g-Guinea Pig Cancer 

ular 

tinal 

cal 

eletal 

ht 

mphor 

al 

Figure 3-1 Levels of Significant Exposure to 1,3-Butadiene - Inhalation (Continued)

Intermediate (15-364 days) 

Systemic 

1,3-BUTADIENE

3. HEALTH EFFECTS

33
Reproductive 

Cancer * 

 

 

ppm 

10000 

1000 

25m 26m 

100 

24m 25m 

23m 24m *Doses represent the lowest dose tested per study that produced a tumorigenic 

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

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

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

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

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

q-Cow a-Sheep g-Guinea Pig Cancer 

Figure 3-1 Levels of Significant Exposure to 1,3-Butadiene - Inhalation (Continued)
 

Intermediate (15-364 days)
	 1,3-BUTADIENE

3. HEALTH EFFECTS

34
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Dermal Ocular Body Weight Neurological Reproductive Cancer * 

 

 

ppm 

10000 

27r 30r 30r 30r 30r 30r 30r 30r 30r 34r 36r 

31m 31m 31m 31m 35m 

1000 27r 30r 30r 40r 

28m 31m 31m 32m 31m 32m 33m 32m 31m 32m 33m 37m 41m 

32m 32m 33m 

100 

32m 39m 

29m 39m 

10 

32m 38m 42m 

*Doses represent the lowest dose tested per study that produced a tumorigenic 

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

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans LD50/LC50

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

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

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

q-Cow a-Sheep g-Guinea Pig Cancer 

Figure 3-1 Levels of Significant Exposure to 1,3-Butadiene - Inhalation (Continued)

Chronic (≥365 days) 

Systemic 

1,3-BUTADIENE

3. HEALTH EFFECTS

35
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 36 

3. HEALTH EFFECTS 

Cardiovascular Effects. In a retrospective epidemiological study of middle-aged workers in the 

rubber industry, excessive mortality was noted for certain types of cardiovascular diseases, mainly 

chronic rheumatic and arteriosclerotic heart diseases (McMichael et al. 1974). Furthermore, increased 

mortality for arteriosclerotic heart disease was reported among black males in the rubber industry 

(Matanoski and Schwartz 1987). This result was also reported in an update of the original study 

(Matanoski et al. 1988, 1990). However, increased mortality from cardiovascular disease was not 

observed in three other cohorts of SBR and 1,3-butadiene monomer workers (Cowles et al. 1994; Divine 

and Hartman 1996, 2001; Ward et al. 1995). Thus, it is unclear if cardiovascular disease is likely to be 

caused by 1,3-butadiene exposure. 

No cardiovascular lesions were found in mice or rats exposed to 8,000 ppm 1,3-butadiene 6 hours/day, 

5 days/week, for 13–14 weeks (Crouch et al. 1979; NTP 1984). Endothelial hyperplasia in the heart (an 

early preneoplastic lesion) was observed in mice after exposure to 200 ppm for 6 hours/day, 5 days/week 

for 40 weeks (NTP 1993) or 625 ppm 6 hours/day, 5 days/week for 61 weeks or 2 years (NTP 1984, 

1993). No exposure-related histopathological cardiac lesions were found in rats exposed chronically to 

up to 8,000 ppm for 2 years (Owen et al. 1987). 

Gastrointestinal Effects. No studies were located regarding noncancer gastrointestinal effects in 

humans after inhalation exposure to 1,3-butadiene. 

No significant incidences of gastrointestinal tract lesions were observed in mice following exposure to 

8,000 ppm 1,3-butadiene for 6 hours/day, 5 days/week, for 14 weeks (NTP 1984) or 200 ppm for 

6 hours/day, 5 days/week for 40 weeks (NTP 1993). In a chronic-duration study, high incidences of 

forestomach epithelial hyperplasia (a possible preneoplastic lesion) were observed in mice exposed to 

625 ppm for 6 hours/day, 5 days/week for 61 weeks (Melnick et al. 1990a; NTP 1984) and for 2 years 

(NTP 1993). No exposure-related nonneoplastic gastrointestinal lesions were found in rats exposed 

chronically to up to 8,000 ppm for 6 hours/day, 5 days/week for 2 years (Owen et al. 1987). 

Hematological Effects. A hematological survey of workers at a styrene-butadiene rubber plant 

revealed little indication of bone marrow toxicity among the workers (Checkoway and Williams 1982). 

Styrene and 1,3-butadiene were the most significant chemicals in the atmosphere; benzene and toluene 

were present in much lower concentrations. A group of eight tank farm workers (workers who load and 

unload chemicals from storage tanks; mean level exposure of 20 ppm) demonstrated slightly lower levels 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 37 

3. HEALTH EFFECTS 

of red blood cells, hemoglobin, platelets, and neutrophils compared with other workers, but these findings 

were within the normal range. Tsai et al. (2005) examined a number of hematological end points in a 

petrochemical production facility in which the current time-weighted average (TWA) 1,3-butadiene 

exposure level was 0.25 ppm; prior to 1997, the TWA concentration was 4.55 ppm. As compared to 

unexposed controls, no significant alterations in total or differential leukocyte levels, erythrocyte levels, 

hemoglobin levels, mean corpuscular volume, or platelet levels were found. An older study of workers 

from one of the facilities examined by Tsai et al. (2005) also found no significant alterations in total and 

differential leukocyte levels, erythrocyte levels, hemoglobin levels, platelet levels, or mean corpuscular 

volume (Cowles et al. 1994); the mean 1,3-butadiene concentration was 3.5 ppm. 

No signs of blood dyscrasias were found among 164 animals (rats, rabbits, guinea pigs, dogs) exposed to 

concentrations up to 6,700 ppm of 1,3-butadiene for 8 months (Carpenter et al. 1944). The results were 

supported by a 3-month study in which no effects on hematological indices were found in rats after 

exposure to 8,000 ppm of 1,3-butadiene (Crouch et al. 1979). 

A treatment-related macrocytic megaloblastic anemia was observed in B6C3F1 and NIH mice exposed to 

1,250 ppm 1,3-butadiene for 6 hours/day, 6 days/week for 6–24 weeks, but not after a 3-week exposure to 

the same concentration (Irons et al. 1986a, 1986b). The bone marrow damage was expressed as reduced 

numbers of red blood cells, decreased hemoglobin concentration and hematocrit, and increased mean 

corpuscular volume of circulating erythrocytes. The changes were observed in both strains, 

independently of the occurrence of murine leukemia viruses in the animals. Male mice exposed to 

≥62.5 ppm for 6 hours/day, 5 days/week for 40 weeks exhibited decreased red blood cell counts, 

hemoglobin concentration, and hematocrit (NTP 1993). Leukopenia and lymphopenia occurred at 

≥200 ppm. Females exhibited macrocytic megaloblastic anemia and bone marrow atrophy after exposure 

to 200 and 625 ppm, respectively, 6 hours/day, 5 days/week for 40 weeks (NTP 1993). 

Macrocytic megaloblastic anemia and bone marrow hyperplasia was also observed in mice exposed 

chronically to 625 ppm 1,3-butadiene 6 hours/day, 5 days/week for 65 weeks (NTP 1993). Surviving 

females, but not males, in this study exhibited increased bone marrow cellularity. 

In contrast to the findings in mice, no effects on hematology or blood chemistry of Sprague-Dawley rats 

were observed after exposure to 1,000 and 8,000 ppm of 1,3-butadiene for 105–111 weeks (Owen et al. 

1987). 
 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 38 

3. HEALTH EFFECTS 

Musculoskeletal Effects. No studies were located regarding musculoskeletal effects of 1,3-butadiene in humans after inhalation exposure. 

No musculoskeletal effects were observed in mice and rats exposed to 8,000 ppm 1,3-butadiene 

6 hours/day, 5 days/week for 13–14 weeks (Crouch et al. 1979; NTP 1984) or in mice exposed to 

625 ppm 6 hours/day, 5 days/week from 40 or 65 weeks or 2 years (NTP 1993). 

Hepatic Effects. No studies were located regarding hepatic effects of 1,3-butadiene in humans after 

inhalation exposure. 

No histopathological changes in livers of rats (Crouch et al. 1979) or mice (NTP 1984) were found after 

intermediate-duration exposure to 1,3-butadiene. The relative liver weights of both sexes of SpragueDawley rats were elevated after the chronic exposure to 1,3-butadiene (1,000 and 8,000 ppm); however, 

this finding was not associated with any pathological changes (Owen et al. 1987). Mice exposed to 

≥625 ppm 6 hours/day, 5 days/week for 61 weeks had a significant increase in liver necrosis (NTP 1984). 

Renal Effects. No studies were located regarding renal effects in humans after inhalation exposure to 

1,3-butadiene. 

The results of urinalysis in 164 animals, including rats, guinea pigs, rabbits, and dogs were all normal 

after an 8-month exposure to concentrations up to 6,700 ppm of 1,3-butadiene (Carpenter et al. 1944), but 

the methods were poorly described. These results were supported, however, in rats after 13 weeks of 

exposure to concentrations up to 8,000 ppm of 1,3-butadiene (Crouch et al. 1979). Nephrosis was found 

among male rats after 111 weeks of exposure to 8,000 ppm, but not 1,000 ppm, of 1,3-butadiene (Owen 

et al. 1987). No non-neoplastic renal lesions were observed in mice exposed to 8,000 ppm 6 hours/day, 

5 days/week for 14 weeks (NTP 1984) or 625 ppm 6 hrs/day, 5 days/week, for 40 weeks to 2 years. 

Dermal Effects. No studies were located regarding dermal effects in humans after inhalation exposure 

to 1,3-butadiene. 

No histopathological dermal changes were found in rats or mice after 13–14 weeks exposure to 

8,000 ppm 1,3-butadiene (Crouch et al. 1979; NTP 1984), in rats after 111 weeks exposure to 8,000 ppm 

(Owen et al. 1987), or in mice after 40 weeks to 2 years exposure to 625 ppm (NTP 1993). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 39 

3. HEALTH EFFECTS 

Ocular Effects. Two men reported slight irritation of the eyes and difficulty in focusing on instrument 

scales during 6–7 hours exposure to 2,000 and 4,000 ppm 1,3-butadiene (Carpenter et al. 1944). 

Ophthalmologic examination of the eyes of dogs and rabbits disclosed no signs of injury during the 

course of exposure to up to 6,700 ppm 1,3-butadiene for 8 months (Carpenter et al. 1944). After the 

termination of the experiment, histological examination revealed that the sclera, cornea, and ciliary body 

were normal. Sections of the optic nerve with adjacent retina showed no myelin sheath degeneration. 

Although the ophthalmological examination was described in detail, the study was limited by the small 

number of animals used. 

No histopathological ocular changes were found in rats or mice after 13–14 weeks exposure to 8,000 ppm 

(Crouch et al. 1979; NTP 1984) or in rats after 111 weeks exposure to 8,000 ppm 1,3-butadiene (Owen 

et al. 1987). Increased Harderian gland hyperplasia (a precancerous lesion) was observed in male mice 

exposed to ≥62.5 ppm 6 hours/day, 5 days/week for 65 weeks and 2 years (NTP 1993); this effect is not 

relevant to humans because they do not have Harderian glands. 

Body Weight Effects. Body weights were reduced by 13% in male mice exposed to 2,500 ppm 

1,3-butadiene 6 hours/day, 5 days/week for 14 weeks, but were not significantly different from controls 

when exposed to 1,250 ppm 6 hours/day, 5 days/week for 61 weeks or when exposed to 625 ppm 

6 hours/day, 5 days/week for 2 years (NTP 1993) 

3.2.1.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological effects of 1,3-butadiene in humans after inhalation 

exposure. 

After 3–21 weeks of exposure to 1,250 ppm 1,3-butadiene, an increased expression of murine leukemia 

virus (MuLV) was observed in hematopoietic tissues of B6C3F1 mice, but not in NIH mice (Irons et al. 

1987a). Furthermore, altered regulation of the stem cell development in B6C3F1 mice was reported after 

a similar exposure (Leiderman et al. 1986). 

Intermediate-duration exposure of female mice to 62.5 ppm 1,3-butadiene 6 hours/day, 5 days/week for 

40 weeks resulted in a 17% reduction in relative spleen weight, while exposure to 625 ppm for the same 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 40 

3. HEALTH EFFECTS 

duration resulted in a 19% reduction in thymus weight (NTP 1993). By 65 weeks, relative spleen weights 

in 625 ppm females had increased to 57% higher than controls. 

Immunological changes were detected after evaluation of specific humoral and cell-mediated immunity in 

B6C3F1 mice exposed to 1,250 ppm 1,3-butadiene for 6, 12, or 24 weeks (Thurmond et al. 1986). 

Suppression of cytotoxic T-lymphocyte generation to mastocytoma cells was observed after 6 weeks, but 

recovered after 12 weeks of exposure. The histological examination of lymphoid organs showed 

depressed spleen cellularity after 24 weeks of exposure; this value is recorded as a LOAEL for 

immunological effects in Table 3-1 and plotted in Figure 3-1, although it is not known how these changes 

affect immunocompetency. 

3.2.1.4 Neurological Effects 

Psychomotor responses of two men inhaling 2,000, 4,000, or 8,000 ppm 1,3-butadiene for 6–8 hours/day 

on different days were evaluated by Carpenter et al. (1944). At the two higher concentrations, the 

subjects performed a steadiness test; at the highest concentration, a tapping rate test was also performed. 

Results after 1,3-butadiene exposure were identical to those obtained before exposure. 

Rabbits exposed to 250,000 ppm of 1,3-butadiene went through all stages of anesthesia to death in the 

average time of 23 minutes (Carpenter et al. 1944). Less than 2 minutes of exposure was required for loss 

of motor and labyrinth reflexes. 

No effects on erythrocyte or brain cholinesterase or on neuromuscular function tests were found in rats 

exposed to up to 8,000 ppm for 13 weeks (Crouch et al. 1979). In intermediate and chronic exposure 

studies in mice and rats, no treatment-related histopathological lesions were found in organs and tissues of 

the nervous system (brain, spinal cord, sciatic nerves) (Crouch et al. 1979; NTP 1984; Owen and Glaister 

1990; Owen et al. 1987). Tests results for neurological function (i.e., loss of balance on a rotating cone) 

were possibly confounded by the mammary tumors interfering with the mobility of rats (NTP, 1984). 

The highest NOAEL values and all reliable LOAEL values for neurological effects in each species and 

duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans after inhalation exposure to 1,3-butadiene. A concentration-related increase in the incidence of sperm-head abnormalities occurred in 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 41 

3. HEALTH EFFECTS 

B6C3F1 mice after exposure to 1,000 (73% increase) and 5,000 ppm (129% increase) of 1,3-butadiene 

6 hours/day for 5 days (DOE/NTP 1988a). No impairment of fertility was noted when groups of male 

and female rats, rabbits, or guinea pigs were exposed to ≤6,700 ppm 1,3-butadiene (Carpenter et al. 

1944). 

No treatment-related histopathological effects were seen in reproductive organs of rats or mice exposed to 

8,000 ppm 1,3-butadiene 6 hours/day, 5 days/week for 13–14 weeks (Crouch et al. 1979; NTP 1984). 

Reduction in the number of round and elongated sperm heads was seen in mice exposed to 130 ppm 

6 hours/day, 5 days/week for 4 weeks, but this was not associated with changes in fertility (Anderson et 

al. 1998). Ovarian and uterine atrophy occurred in female mice exposed to 200 ppm 6 hours/day, 

5 days/week for 40 weeks (NTP 1993), while testicular atrophy was seen in male mice exposed to 

625 ppm for the same duration. Exposure of female mice to 62.5 or ≥6.25 ppm 1,3-butadiene 

6 hours/day, 5 days/week for 65 weeks or 2 years, respectively, resulted in an increased incidence of 

ovarian atrophy (NTP 1993). Affected females had no evidence of oocytes, follicles, or corpora lutea. 

An increase in testicular atrophy and preputial gland hyperplasia was observed in males only after 

exposure to 625 ppm 6 hours/day, 5 days/week for 2 years (NTP 1993). In contrast, no histological 

alterations were observed in the gonads of rats exposed to up to 8,000 ppm 6 hours/day, 5 days/week for 

2 years (Owen et al. 1987). 

In untreated female mice mated with males exposed to ≥200 ppm 6 hours/day for 5 days, a significant 

increase in the number of females with two or more intrauterine deaths were observed (DOE/NTP 1988b). 

This effect was only observed in animals mated during the first week post-exposure. Additional effects 

included increases in early implantation loss at 1,000 ppm during the first post-week of exposure and at 

200 and 1,000 ppm during the second week post-exposure; implantation losses were not significantly 

increased in the mice exposed to 5,000 ppm. Early fetal death was also observed in untreated female 

mice mated to males exposed to 65 ppm for 6 hours/day, 5 days/week for 4 weeks (DOE/NTP 1988a). 

Fetal toxicity was observed following the mating of untreated female mice with males exposed to 

12.5 ppm 1,3-butadiene 6 hours/day, 5 days/week for 10 weeks (Anderson et al. 1996). Observed effects 

included an increase in late fetal death, exencephaly, and skull abnormalities. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 42 

3. HEALTH EFFECTS 

3.2.1.6 Developmental Effects 

No studies were located regarding developmental effects in humans after inhalation exposure to 1,3-butadiene. 

When exposed to concentrations up to 8,000 ppm 1,3-butadiene for 6 hours/day, 5 days/week during 

GDs 6–15, Sprague-Dawley rats showed signs of dose-related maternal and fetal toxicity (Irvine 1981). 

Depressed body weight gain among dams was observed at ≥200 ppm, and fetal growth (body weight and 

crown-rump length) was significantly decreased in the 8,000 ppm group. A significant increase in the 

number of litters with fetuses showing minor skeletal defects was observed at 200 ppm, but not at 

1,000 or 8,000 ppm; however, an increase in the number of fetuses with irregular ossification was 

observed at 8,000 ppm. Significant increases in the number of litters with fetuses showing major skeletal 

defects were observed at 1,000 and 8,000 ppm. The majority of the major skeletal defects were wavy 

ribs; abnormalities of the skull, spine, sternum, long bones, and ribs were also observed at 8,000 ppm. A 

significant increase in the number of litters with fetuses showing minor external/visceral defects was 

observed at 1,000 ppm, but not at 8,000 ppm. In a study in which female Sprague-Dawley rats were 

exposed to 40–1,000 ppm during GDs 6–15 (DOE/NTP 1987a), some skeletal abnormalities and 

ossification reductions were found in the fetuses, but were not statistically significant and were not 

considered to be treatment-related. In mice, a 5–23% decrease in fetal body weight gain, primarily 

among male mice, was observed after exposure of dams during GDs 6–15 to 40–1,000 ppm 1,3-butadiene. The magnitude of the decreased fetal body weight in males was 5, 18, and 23% in the 40, 200, and 

1,000 ppm groups, respectively. The investigators reported that the decreased fetal body weight was 

statistically significant in males at all dose levels; however, the statistical method used (ANOVA) did not 

account for differences in litter size. Increased incidences of extra ribs and reduced ossification of 

sternebrae were found in fetuses from groups exposed to 200 ppm and 1,000 ppm, respectively 

(DOE/NTP 1987b). 

The highest NOAEL value and all reliable LOAEL values for developmental effects in rats for the acute 

duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.7 Cancer 

Retrospective epidemiological studies of mortality among workers in the rubber industry were conducted 

in SBR (polymer) production workers and 1,3-butadiene monomer workers. For SBR workers, the 

primary cohort is comprised of largely overlapping cohorts from multiple SBR facilities in the United 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 43 

3. HEALTH EFFECTS 

States and Canada examined by investigators at John Hopkins (Matanoski and Schwartz 1987; Matanoski 

et al. 1989b, 1990) and the University of Alabama at Birmingham (Cheng et al. 2007; Delzell et al. 1996; 

Graff et al. 2005; Macaluso et al. 1996; Sathiakumar et al. 2005, 2007). Mortality among three 

independent cohorts of male 1,3-butadiene monomer production workers has been studied and updated on 

several occasions, including cohorts from Union Carbide (Ward et al. 1995), Texaco (Divine 1990; 

Divine et al. 1993), and Shell (Cowles et al. 1994). 

Matanoski et al. 1990 (in an update of the Matanoski and Schwartz 1987 cohort) found increased 

standardized mortality ratios (SMRs) of 532 (1 case), 656 (95% confidence interval [CI]=135–1,906), and 

482 (95% CI=59–1,762) for lymphosarcoma, leukemia, and other lymphatic neoplasms, respectively, in 

black SBR production workers; white workers exhibited an SMR of 230 (95% CI=92–473) for other 

lymphatic neoplasms. In white maintenance workers, SMRs of 144 (95% CI=53–314) and 166 (95% 

CI=93–275) were observed for esophageal and stomach cancer, respectively. An odds ratio of 9.4 for 

leukemia was observed in SBR workers in a nested case-control study of the Matanoski and Schwartz 

(1987) cohort of SBR workers (Matanoski et al. 1989b). No such association was found for exposure to 

styrene. Several investigators at the University of Alabama at Birmingham examined cancer mortality in 

a cohort of over 15,000 North American SBR workers (Cheng et al. 2007; Delzell et al. 1996; Graff et al. 

2005; HEI 2006; Macaluso et al. 1996; Sathiakumar et al. 2005, 2007). Delzell et al. (1996) found 

increased SMRs for leukemia of 265 (95% CI=141–453) for maintenance and 431 (95% CI=207–793) for 

laboratory workers. Macaluso et al. (1996) derived a relative rate value of 4.5 for leukemia development 

(no confidence interval reported) associated with a cumulative exposure of 80 ppm-years. In an update of 

these studies (Sathiakumar et al. 2005), an increase in deaths from all types of leukemia (SMR of 258; 

95% CI=156–403) was found among hourly employees with 20–29 years since hire and >10 years of 

employment. Increases in leukemia deaths were also found among workers in the polymerization (SMR 

of 204; 95% CI=121–322), maintenance labor (SMR of 326; 95% CI=178–456), and laboratory (SMR of 

326; 95% CI=178–546) operations. However, no increases in a specific type of leukemia were found. 

Similarly, Graff et al. (2005) reported increased relative risks for leukemia of 2.9 (95% CI=1.4–6.4) and 

3.7 (95% CI=1.7–8.0) among workers with cumulative 1,3-butadiene exposures of 184.7–<435.0 and 

425.0 ppm-years. When the relative risks were adjusted for exposure to styrene and dimethyldithiocarbamate, age, and years since hire, only the highest cumulative exposure group had a confidence 

interval that included 1 (relative risk of 3.0, 95% CI=1.0–9.2). When workers were divided into two 

categories based on exposure to >100 and ≤100 ppm, associations between 1,3-butadiene cumulative 

exposure and leukemia were found for both groups, although the association was weaker at the lower 

concentration (relative risk of 2.0; 95% CI=0.6–6.0 for cumulative exposure to >124.7 ppm-years) than at 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 44 

3. HEALTH EFFECTS 

the higher concentration (relative risk of 3.7; 95% CI=1.3–11.1 for cumulative exposure of >247.6 ppmyears) and the trend was only statistically significant in the >100 ppm workers (HEI 2006). A more 

recent paper by Graff and associates (Graff et al. 2009) used uncertainty analysis to evaluate the impact of 

potential exposure estimate inaccuracies on the leukemia relative risks. The investigators concluded that 

analysis of the complete probability distribution of 1,3-butadiene exposure estimate supported the 

association between 1,3-butadiene cumulative exposure and increased leukemia risk. Using personal 

monitoring device data collected from 1977 to 1991, Sathiakumar et al. (2007) compared measured 

1,3-butadiene levels with estimated levels. The mean measured 1,3-butadiene level (across all years and 

job categories) was 5.2 ppm and the mean estimated concentration was 4.7 ppm; the estimated 

1,3-butadiene levels tended to underestimate concentrations that were greater than 7 ppm. Cheng et al. 

(2007) found a significant trend for the association of leukemia in SBR workers and increasing 

cumulative exposure or number of “peak” exposures (>100 ppm). They also reported a minimal 

association (relative rate of 1.03) of leukemia in SBR workers receiving an estimated 5 ppm 

1,3-butadiene exposure for 20 years (100 ppm-years). Examination of possible associations between 

1,3-butadiene exposure and increased deaths from other cancer types, including non-Hodgkin’s 

lymphoma, Hodgkin’s lymphoma, and multiple myeloma were not found in this cohort (HEI 2006). 

Increases in the risk of colorectal and prostate cancer were observed in some subgroups of SBR workers; 

however, no consistent exposure-response trends were found (HEI 2006). 

These results in SBR workers with 1,3-butadiene exposure are supported by studies in 1,3-butadiene 

monomer production workers. Downs et al. (1987) calculated an SMR of 235 (no CI reported) for 

lymphosarcoma and reticular cell sarcoma. No increase in mortality from cancer of gastrointestinal, 

respiratory, urinary, and skeletal systems was associated with monomer exposure. Divine (1990) and 

Divine et al. (1993) reported similar results in a follow-up study of this cohort (SMR of 452 [95% 

CI=165–984]) for lymphosarcoma. Divine and Hartman (2001) followed this cohort for an additional 

5 years and found a statistically significant increase in SMR (141; 95% CI=105–186) for all 

lymphohematopoietic cancer. Subcohort analyses showed that increases in lymphohematopoietic cancers 

appear to be restricted to monomer workers employed before 1950 and for the shortest duration (Divine 

and Hartman 1996, 2001). Elevations were also seen for leukemia (SMR of 129; 95% CI=77–204) and 

non-Hodgkin’s lymphoma (SMR of 148; 95% CI=89–231), but the elevation was not statistically 

significant. Additionally, higher SMRs for leukemia and non-Hodgkin’s lymphoma were found in 

workers with shorter employment durations. No significant associations were found between cumulative 

1,3-butadiene exposure (defined as a combination of job exposure class, calendar time, and length of time 

in job) and the relative risk for lymphohematopoietic cancers, leukemia, or non-Hodgkin’s lymphoma 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 45 

3. HEALTH EFFECTS 

(Divine and Hartman 2001). Analysis of another cohort of 364 monomer workers, 277 of which worked 

in a U.S. Rubber Reserve plant during World War II, found an SMR of 577 (95% CI=157–1,480) for 

lymphosarcoma and reticulosarcoma (Ward et al. 1995). No significant association was found between 

1,3-butadiene monomer exposure and all, lung, or lympho-hematopoietic cancers in a cohort of 

614 monomer workers employed between 1948 and 1989 who were exposed to a relatively low mean 

concentration of 3.5 ppm, with many measurements below 1 ppm (Cowles et al. 1994). 

The major limitations of the epidemiological studies described so far include the lack of precise historic 

exposure data to 1,3-butadiene, lack of adjustment for smoking, and possible exposure to other chemicals. 

Irons and Pyatt (1998) suggest that dithiocarbamates, such as dimethyldithiocarbamate (DMDTC), used 

in the SBR vulcanization process from 1950 to 1965, may have played a significant role in leukemia 

development that was concentrated in workers employed during this period. However, Santos-Burgoa et 

al. (1992) and Delzell et al. (2001) and HEI (2006) used multivariate analysis to suggest that the estimates 

of 1,3-butadiene exposure provided the best correlation with the rates of leukemia, even in the presence of 

styrene and DMDTC. 

Several investigators have evaluated associations between childhood leukemias and ambient 

1,3-butadiene emissions. Knox et al. (2005, 2006) associated the occurrence of childhood cancer with 

proximity of birthplace to industrial 1,3-butadiene and benzene emissions, and roads, railways, 

waterways, and bus, ferry, or train stations in Great Britain; however, no actual exposure data or estimates 

were available. Reynolds et al. (2003) calculated leukemia rate ratios (RR), adjusted for age, ethnicity, 

and sex, of 1.21 (95% CI=1.03–1.42) and 1.32 (95% CI=1.11–1.57) for children in California census 

tracts ranked highest for combined exposure to 25 hazardous air pollutants (HAPs, including 

1,3-butadiene) and highest for point-source HAP exposures, respectively. Likewise, Whitworth et al. 

(2008) reported a significant association of childhood leukemia incidence with residence in census tracts 

close to the ship channel (which is in close proximity to petrochemical and chemical manufacturing 

facilities) in Houston, Texas. These studies do not indicate strong causality between 1,3-butadiene 

exposure and childhood leukemia, as many chemicals may have contributed to exposure and the actual 

exposure to 1,3-butadiene, if any, is unknown. 

The rodent bioassay database corroborates the association of lympho-hematopoietic neoplasms and 

occupational exposure to 1,3-butadiene reported in the epidemiology literature. Mice were clearly more 

sensitive to 1,3-butadiene-mediated tumor development than rats. In rats, increased tumors were not 

observed following intermediate-duration exposures of up to 8,000 ppm 1,3-butadiene 6 hours/day, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 46 

3. HEALTH EFFECTS 

5 days/week for 13 weeks (Crouch et al. 1979). Two-year exposure of rats to 1,000 or 8,000 ppm 

6 hours/day, 5 days/week resulted in increased incidences of Leydig cell adenoma, pancreatic exocrine 

adenoma, uterine sarcoma, mammary gland adenoma and carcinoma, Zymbal gland carcinoma, and 

thyroid follicular cell tumors (Owen and Glaister 1990; Owen et al. 1987). In mice, exposure to 200 ppm 

for 40 weeks resulted in increased incidences of lymphocytic lymphoma, histiocytic sarcoma, cardiac 

hemagiosarcoma, alveolar/bronchiolar adenoma/carcinoma, forestomach squamous cell papilloma/ 

carcinoma, hepatocellular adenoma, hardarian gland adenoma/adenocarcinoma, and preputial gland 

carcinoma (NTP 1993). These same tumors developed in mice in as little as 13 weeks after exposure to 

625 ppm 6 hours/day, 5 days/week (NTP 1993). Chronic exposure of mice to lower concentrations of 

1,3-butadiene also resulted in multi-target organ neoplasm development. Two-year 6-hour/day, 

5-day/week exposures of 20 ppm for male mice and 6.25 ppm (the lowest exposure level tested) for 

female mice resulted in increased incidences of lymphocytic lymphoma, histiocytic sarcoma, cardiac 

hemagiosarcoma, alveolar/bronchiolar adenoma/carcinoma, forestomach squamous cell papilloma/ 

carcinoma, hepatocellular adenoma, hardarian gland adenoma/adenocarcinoma, mammary gland 

carcinoma, adenocanthoma, malignant mixed tumor, and malignant ovarian granulosa cell tumor. 

The cancer effect levels (CELs) are recorded in Table 3-1 and plotted in Figure 3-1. 

Using the Poisson regression analysis by Health Canada (2000) of the leukemia risk data from a cohort of 

15,000 SBR production workers (Delzell et al. 1996), EPA derived a unit risk for inhalation exposure of 

0.08 ppm-1 (IRIS 2012). This unit risk corresponds to upper bound individual lifetime cancer risks at 

10-4–10-6 for exposure levels of 1x10-3–1x10-6 ppm, which are plotted in Figure 3-1. It should be noted 

that EPA derived the cancer risk levels in 2001, and thus, these values may not reflect the results of more 

recent studies of SBR workers. 

The International Agency for Research on Cancer (IARC) has classified 1,3-butadiene as a Group 1 

carcinogen (carcinogenic to humans) (IARC 2009). EPA has classified 1,3-butadiene as carcinogenic to 

humans (EPA 2002; IRIS 2012). The Department of Health and Human Services (NTP 2005) also 

identified 1,3-butadiene as a “known human carcinogen”. 

3.2.2 Oral Exposure 

No studies were located regarding health effects in humans or animals after oral exposure to 1,3-butadiene. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 47 

3. HEALTH EFFECTS 

3.2.3 Dermal Exposure 

Dermal contact with liquid 1,3-butadiene causes a sensation of cold followed by a sensation of burning, 

which is the result of rapid expansion of pressurized 1,3-butadiene from liquid to gas states (NIOSH, 

2005). Although this may cause frostbite, it is specific to an unusual exposure scenario and is not a toxic 

endpoint. However, the possible toxic effects from dermal absorption of such a concentrated amount of 

1,3-butadine are unknown. High gas concentrations may cause mild skin irritation as well (NIOSH, 

2005). No other studies were located regarding health effects in humans or animals following dermal 

exposure to 1,3-butadiene. 

3.3 GENOTOXICITY 

1,3-Butadiene has been tested for genotoxicity in a number of in vitro and in vivo studies (Tables 3-2 and 

3-3). Positive results have been found in the reverse mutation assay in Salmonella typhimurium TA1530 

and TA1535 in the absence or in the presence of metabolic activation system (de Meester et al. 1978; 

Madhusree et al. 2002). However, the interpretation of these results was confounded by the fact that the 

Petri dishes not containing S-9 mix were contaminated by volatile active metabolites. It was concluded 

that S-9 mix was necessary to activate 1,3-butadiene into mutagen(s) (De Meester 1988). TA1530 was 

the most sensitive strain, but 1,3-butadiene mutagenicity was detectable only with metabolic activation in 

the subsequent study (de Meester et al. 1980). No significant mutagenic effect on S. typhimurium strain 

TA100 with metabolic activation was observed (Victorin and Stahlberg 1988). A weak genotoxic activity 

was detected in strain TA1535 with rat S-9 (Arce et al. 1989). A weak increase in sister chromatid 

exchanges was observed in Chinese hamster ovary cells, but only with metabolic activation (Sasiadek et 

al. 1991). Increased mutations occurred in the hypoxanthione-guanine phosphoribosyl transferase (hprt) 

and tk gene loci of human TK6 lymphoblastoid cells (Cochrane and Skopek 1993). On the basis of these 

data, 1,3-butadiene appears to require metabolic activation to produce genotoxicity. 

The genotoxicity of 1,3-butadiene has been examined in several occupational exposure cohorts. Ward et 

al. (1994) reported a significant increase in hypoxanthine-guanine phosphoribosyltransferase (hprt) 

mutant frequency (measured in peripheral lymphocytes) among eight workers at a Texas 1,3-butadiene 

production plant working in the area of the plant where the highest 1,3-butadiene exposure occurred, as 

compared to levels in five workers in an area with low 1,3-butadiene exposures or in six controls who did 

not work at the 1,3-butadiene production plant. The mean area and personal 1,3-butadiene levels were 

3.5 ppm (although most individual samples were <1 ppm) in the high-exposure area and 0.03 ppm in the 
 

 

 

 

 

 

1,3-BUTADIENE 48 

3. HEALTH EFFECTS 

Table 3-2. Genotoxicity of 1,3-Butadiene In Vitro 

Results 

With Without 

Species (test system) End point activation activation Reference 

Prokaryotic organisms: 

Salmonella typhimurium 

TA1530 Gene mutation + – de Meester et al. 1980 

TA100 Gene mutation – – Victorin and Stahlberg 1988 

TA1535 Gene mutation + – Arce et al. 1989; Madhusree 

et al. 2002 

Eukaryotic organisms: 

Chinese hamster ovary SCE + – Sasiadek et al. 1991 

Human TK6 lymphoblastoid hprt and tk loci NA NA Cochrane and Skopek 1993 

cells mutations 

– = negative result; + = positive result; NA = not applicable; SCE = sister chromatid exchange 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 49 

3. HEALTH EFFECTS 

Table 3-3. Genotoxicity of 1,3 Butadiene In Vivo 

Species (test system) End point		 Results Reference
	

B6C3F1 mice (inhalation)		Bone marrow: Dose-dependent increase 

in SCEs 

Sprague-Dawley rats 

(inhalation) 

B6C3F1 mice (inhalation)		Bone marrow: increase in CAs, SCEs, 

and AGT, and depression of MI 

Swiss mice (inhalation)		 Peripheral blood erythrocytes: induction 

of micronuclei 

B6C3F1 mice (inhalation)		Bone marrow: alteration of 

hematopoietic stem cell development 

B6C3F1 mice (inhalation) Peripheral blood erythrocytes: induction 

of micronuclei
	

B6C3F1 mice (inhalation) Induction of MN; induction of SCEs; CAs
	

B6C3F1 mice (inhalation)		Sperm abnormalities; dominant lethality 

C57B1/6 mice Bone marrow increase in CAs and SCEs 

(intraperitoneal injection) 

B6C3F1 mice (inhalation)		lacZmutant frequency in lung 

B6C3F1 mice (inhalation)		lacZmutant frequency in liver and bone 

marrow 

B6C3F1 mice and F344 hprt loci mutations in splenic 

rats (inhalation)		 T lymphocytes 

B6C3F1 mice (inhalation)		Peripheral blood erythrocytes and bone 

Wistar rats 

C3H mice (inhalation) 

C3H mice (inhalation) 

CD-1 mice (inhalation) 

CAST/EiJ, NOD/LTj, A/J, 

WSB/EiJ, PWK/PhJ, 

129S/SvlmJ, C57BL/6J 

mice (inhalation) 

C57BL/6J mice 

(inhalation) 

Humans (inhalation) 

Humans (inhalation) 

Humans (inhalation) 

Humans (inhalation) 

Humans (inhalation) 

marrow: induction of micronuclei 

Peripheral blood erythrocytes and bone 

marrow: induction of micronuclei 

Heritable spermatid chromosomal 

translocations; dominant lethality 

Spermatocytes: induction of micronuclei 

Dominant lethality 

DNA adduct formation 

DNA adduct formation 

CA; SCE 

CA; SCE 

hprt loci in peripheral lymphocytes 

hprt loci in peripheral lymphocytes 

hprt loci in peripheral lymphocytes 

+ Cunningham et al. 1986
	

-

+		 Tice et al. 1987
	

+		 Irons et al. 1986b 

+		 Leiderman et al. 1986
	

+		 Jauhar et al. 1988
	

+		 Tice et al. 1988
	

+		 DOE/NTP 1988a 

+		 Sharief et al. 1986
	

+ Recio et al. 1992
	

- Recio et al. 1992
	

+		 Cochrane and Skopek
	

1993; Meng et al. 1999,
	

2000, 2004, 2007
	

+ Autio et al. 1994
	

- Autio et al. 1994
	

+		 Adler et al. 1998
	

+ Xiao and Tates 1995
	

- Brinkworth et al. 1998
	

+		 Koturbash et al. 2011a 

+		 Koturbash et al. 2011b 

+ Sram et al. 1998
	

- Lovreglio et al. 2006
	

- Hayes et al. 1996, 2000
	

- Tates et al. 1996
	

- Albertini et al. 2001,
	

2007; HEI 2003
	
 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 50 

3. HEALTH EFFECTS 

Table 3-3. Genotoxicity of 1,3 Butadiene In Vivo 

Species (test system) End point Results Reference
	

Humans (inhalation) hprt loci in peripheral lymphocytes - Liu et al. 2008 

hprt exon deletion + Liu et al. 2008 

Humans (inhalation) hprt loci in peripheral lymphocytes + Ward et al. 1994 

Humans (inhalation) hprt loci in peripheral lymphocytes + Abdel-Rahman et al. 

2001, 2003, 2005; Ma et 

al. 2000; Ward et al. 

1996, 2001 

Humans (inhalation) hprt loci in peripheral lymphocytes + Wickliffe et al. 2009 

C3H mice (inhalation) Induction of spermatid micronuclei + Tommasi et al. 1998 

B6C3F1 mice (inhalation) H- and K-ras mutation frequency + Sills et al. 2001 

NMRI mice (inhalation) Bone marrow: induction of micronuclei + Vodicka et al. 2006 

– = negative result; + = positive result; AGT = average generation time; CA = chromosomal aberration; MI = mitotic 

index; MN = micronucleated cell; SCEs = sister chromatid exchange 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 51 

3. HEALTH EFFECTS 

low-exposure area. A significant correlation between hprt variant frequency and urinary levels of the 

1,3-butadiene-specific metabolite, M1, was also found. No significant correlations between hprt variant 

frequency and age or employment length were found. A subsequent study of these workers reported 

2.5-fold higher hprt mutation frequencies in workers exposed to airborne concentrations of 0.3 ppm 

1,3-butadiene as compared to workers exposed to mean levels of 0.12 ppm (Ward et al. 1996), indicating 

good correlation between exposure and mutation frequency. Unlike the earlier study, no correlation 

between hprt variant frequency and urinary metabolite levels were found. A follow-up study of the 

southeast Texas SBR workers found a 3-fold increase in hprt mutation frequency in workers exposed to 

1.7 ppm, compared to workers exposed to 0.07 ppm (Ward et al. 2001). A re-analysis of the blood 

samples from the Ward et al. (1996) study using a cloning assay, rather than the autoradiographic assay 

used in the Ward analyses, confirmed the significant difference in hprt variant frequency between highexposure workers and the outside controls and found a significant difference in hprt mutation frequency 

between the groups (Ma et al. 2000). However, the investigators did not examine the possible association 

between 1,3-butadiene exposure level and mutation frequency. Neither Ma et al. (2000) nor Ward et al. 

(1994, 1996) provided demographic information on the outside control group, which consisted of workers 

in the Department of Preventive Medicine and Community Health at the University of Texas Medical 

Branch; thus, the appropriateness of this comparison group to the SBR workers cannot be evaluated. A 

more recent study of these SBR workers did not find a significant association between 1,3-butadiene 

exposure level and hprt variant frequency, after removal of an outlier (Wickliffe et al. 2009). The current 

1,3-butadiene exposure levels of the 30 subjects examined were low with only six subjects having levels 

of >0.1 ppm. A significant association between employment length and hprt mutant frequency was 

found. Another study conducted by this group (Ammenheuser et al. 2001) at a different SBR facility 

found a 3-fold increase in hprt mutation frequency in 22 workers in the high-exposure group (mean 

1,3-butadiene exposure level was 1.48 ppm) compared to low-exposure workers (mean exposure level of 

0.15 ppm). Significant correlations between hprt variant frequency and 1,3-butadiene levels and urinary 

M1 levels were found. Abdel-Rahman et al. (2001, 2003, 2005) examined the association between 

polymorphisms, 1,3-butadiene exposure, and hprt variant frequency among workers at the two Texas 

SBR facilities. Individuals with a polymorphism for microsomal epoxide hydrolase (EH), an enzyme 

important for the hydrolysis of epoxide metabolites of 1,3-butadiene (see Section 3.4.3), exhibited a 

3-fold higher hprt mutation frequency than workers without the polymorphism (Abdel-Rahman et al. 

2001). Further, polymorphisms in the glutathione-S-transferase (another important enzyme in epoxide 

metabolite metabolism) genotypes GSTM1 or GSTT1 did not impact hprt mutation rates, but a 

combination of EH and GST polymorphism did result in an increase in hprt mutation frequency (AbdelRahman et al. 2001, 2003, 2005). Several studies that examined the possible association between 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 52 

3. HEALTH EFFECTS 

1,3-butadiene exposure and the frequency of chromosomal aberrations and/or sister chromatid exchanges 

among Texas 1,3-butadiene workers have not found significant associations (Au et al. 1995; Hallberg et 

al. 1997; Kelsey et al. 1995). 

Unlike the results of Texas cohorts, studies of Chinese rubber production workers have not found 

alterations in hprt mutation frequency. No significant difference in hprt gene mutation frequency was 

observed in male and female Chinese polybutadiene rubber production workers exposed to an average of 

1.0–3.5 ppm (median of 2.0 ppm) and unexposed controls (Hayes et al. 1996, 2000, 2001). Additionally, 

no exposure-related significant associations between hprt mutation frequency and 1,3-butadiene exposure 

(as assessed by exposure levels, urinary metabolite levels, or hemoglobin adducts) were found. Similarly, 

no significant alterations in glycophorin A variant frequencies were observed (Hayes et al. 2000). In 

another Chinese study, hprt mutation frequencies in petrochemical workers exposed to mean levels of 

10 ppm were higher, but were not significantly different than unexposed controls, while the percentage of 

workers exhibiting hprt exon deletions (27%) was significantly higher than levels found in controls (13%) 

(Liu et al. 2008). 

Several investigators have examined hprt mutation frequency in cohorts of 1,3-butadiene workers in the 

Czech Republic. Tates et al. (1996) did not find significant alterations in hprt mutation frequency among 

male workers from a 1,3-butadiene production plant exposed to a mean concentration of 1.76 ppm, as 

compared to unexposed workers at the plant. However, a significant increase in the percentage of 

lymphocytes with chromosomal aberrations was observed in the exposed workers; increases in DNA 

damage (as assessed using the comet assay) and micronuclei frequency were observed in exposed 

smokers, as compared to unexposed smokers (Šrám et al. 1998; Tates et al. 1996). A significant increase 

in the frequency of sister chromatid exchanges was also observed (Šrám et al. 1998). When the exposed 

workers and unexposed workers were subdivided based on glutathione-S-transferase polymorphism for 

M1 gene (GSTM1) and glutathione-S-transferase polymorphism for T1 gene (GSTT1) genotypes, a 

significant increase in the frequency of chromosomal aberrations were observed in exposed workers with 

the GSTM1-positive genotype, as compared to exposed workers with GSTM1-null genotype; no effects 

was observed for the GSTT1 genotype. Multifactorial analysis (accounting for 1,3-butadiene exposure, 

smoking, GSTM1, GSTT1, and age) showed a significant association between the frequency of 

chromosomal aberrations and the number of cells with a high frequency of sister chromatid exchanges 

(Šrám et al. 1998). However, when 1,3-butadiene exposure was evaluated using N-1-(2,3,4-trihydroxybutyl)adenine adduct levels, there were no significant associations between chromosomal aberration 

frequency, micronuclei formation, or sister chromatid exchange (Zhao et al. 2001). In another study of 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 53 

3. HEALTH EFFECTS 

Czech 1,3-butadiene workers, no alterations in chromosome aberrations, sister chromatid exchanges, or 

micronuclei formation were observed in 1,3-butadiene production workers or workers in 1,3-butadiene 

polymer production (Sorsa et al. 1994). However, when workers were subdivided based on GSTM1 and 

GSTT1 genotypes, a significantly higher frequency of chromosomal aberrations were observed in 

1,3-butadiene workers lacking the GSTT1 gene (Sorsa et al. 1996). In a larger-scale study of 24 workers 

at a 1,3-butadiene production facility (mean exposure level of 0.64 mg/m3

 [0.29 ppm]) and 34 workers at 

a polymerization facility (mean exposure level of 1.76 mg/m3

 [0.79 ppm]), no significant association 

between 1,3-butadiene exposure (as assessed using air concentrations, urinary metabolites, or hemoglobin 

adducts) and hprt mutation frequency (assessed using cloning assay) were found; no associations were 

found when workers divided by a number of genotypes including GSTM1 or GSTT1 (Albertini et al. 

2001; HEI 2003). No significant alterations in the frequency of chromosomal aberrations or sister 

chromatid exchanges were found. In a follow-up study at the polymerization facility, male and female 

workers were examined. The mean 1,3-butadiene exposure levels were 0.397 mg/m3

 (0.18 ppm) and 

0.808 mg/m3

 (0.36 ppm) in the females and males, respectively (Albertini et al. 2007). No significant 

associations between 1,3-butadiene exposure and hprt mutation frequency were found; similarly, there 

were no significant associations between exposure and sister chromatid exchanges or chromosomal 

aberrations. 

In a cohort of workers at an Italian petrochemical plant exposed to very low levels of 1,3-butadiene (mean 

concentration of 0.0115 mg/m3

 [0.005 ppm]), no significant relationship between 1,3-butadiene exposure 

and alterations in the frequency of chromosomal aberrations or sister chromatid exchanges was observed 

Fustinoni et al. 2004; Lovreglio et al. 2006). 

In summary, studies of workers at Texas 1,3-butadiene production facilities or SBR facilities have found 

significantly higher frequencies of hprt variants in the lymphocytes in men working in areas of the facility 

with high 1,3-butadiene exposure levels (Ammenheuser et al. 2001; Ma et al. 2000; Ward et al. 1996, 

2001) However, no significant associations were found in Czech cohorts (Albertini et al. 2001, 2007; 

HEI 2003; Tates et al. 1996) or Chinese cohorts (Hayes et al. 1996, 2000, 2001). The reasons for 

dissimilar outcomes in lymphocyte hprt gene mutation frequency between the different cohorts are not 

clear, but may be the result of varying exposure levels, experimental techniques in exposures assessment 

(active vs. passive sampling) and mutation analysis (autoradiography vs. cloning hprt assays). The mean 

exposure levels in the Texas cohort studies tended to be higher than other cohorts; the mean levels in the 

Chinese cohort are elevated due to intermittent high exposures rather than a high TWA level. This is 

supported by a study conducted by Wickliffe et al. (2009) that did not find significant increases in hprt 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 54 

3. HEALTH EFFECTS 

frequency in a Texas cohort with low 1,3-butadiene exposure levels (only six subjects were exposed to 

levels >0.1 ppm). 

A number of rodent inhalation studies report genotoxic effects. Mice and rats exhibited increased hprt 

locus mutations in splenic T cells (Cochrane and Skopek 1993; Meng et al. 1999, 2000, 2004, 2007). 

Inhaled 1,3-butadiene also induce an increase in micronucleus induction in erythrocytes (Irons et al. 

1986b; Jauhar et al. 1988; Tice et al. 1987; Vodicka et al. 2006), spermatocytes (Tommasi et al. 1998; 

Xiao and Tates 1995), and bone marrow cells (Autio et al. 1994), increased frequency of sister chromatid 

exchanges (Tice et al. 1987) and chromosomal aberration frequencies (Cunningham et al. 1986; Tice et al. 

1987) in mice. Transgenic B6C3F1 mice exhibited an increased lacZ- mutant frequency in the lungs 

(Recio et al. 1992). Increased percentages of H- and K-ras proto-oncogene mutations were found in 

forestomach neoplasms from mice inhaling 1,3-butadiene for 2 years (83% in exposed mice compared to 

24% in spontaneous neoplasms from controls) (Sills et al. 2001). Increases in N-7-(2,3,4-trihydroxybut1-yl) guanine adduct formation in liver DNA were found in various mouse strains exposed to 

1,3-butadiene (Koturbash et al. 2011a, 2011b); the increase DNA adduct formation was concentrationrelated (Koturbash et al. 2011b). No genotoxic effects (micronucleus induction, chromosomal 

aberrations, or sister chromatid exchanges) were found in bone marrow of rats or liver of mice exposed by 

inhalation to 1,3-butadiene (Autio et al. 1994; Cunningham et al. 1986; Recio et al. 1992). 

In a dominant lethal study in which male CD-1 mice inhaled 1,3-butadiene for 5 days and were mated to 

nonexposed females, an increased number of dead implantations per pregnancy occurred at 200 and 

1,000 ppm, but not at 5,000 ppm during the first 2 weeks postexposure (DOE/NTP 1988b). These results 

were considered to be inconclusive because of the lack of a strict dose-response relationship. Increased 

numbers of dead fetuses were also observed in offspring of CH3 males inhaling 130 ppm (Adler et al. 

1998), but not in CD-1 mice exposed to 125 ppm (Brinkworth et al. 1998). Heritable spermatid 

chromosomal translocations occurred in F1 offspring of male CH3 mice inhaling 1,3-butadiene (Adler et 

al. 1995a, 1998). 

Although cytogenetic monitoring of 1,3-butadiene rubber workers for chromosomal aberrations revealed 

no or slight differences between exposed and control groups (Lovreglio et al. 2006; Sram et al. 1998; 

Zhou et al. 1986), 1,3-butadiene is clearly genotoxic in mice. As discussed in Section 3.4.3, species 

differences exist in the metabolism of 1,3-butadiene, and data suggest that humans may metabolize this 

compound at different metabolic rates than do rodents. If the genotoxic and clastogenic response of 

1,3-butadiene requires activation to an active metabolite that is formed more slowly or deactivated more 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 55 

3. HEALTH EFFECTS 

rapidly in humans than in rats and mice, the genotoxicity observed in animals may only be observed after 

much higher exposures in humans. The data in humans are too limited, however, to rule out the 

possibility of a genotoxic potential in humans exposed to 1,3-butadiene. 

3.4 TOXICOKINETICS 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

In human volunteers inhaling 2 ppm 1,3-butadiene for 20 minutes, the absorbed fraction varied from 18 to 

74% (Lin et al. 2001). Neither sex nor age (30±8 years for males, 29±9 years for females) were factors in 

this variation. Fractional absorption in Asian volunteers was about 20% greater than in Caucasians, 

African-Americans, or Hispanics. Blood triglyceride levels may influence absorption, as blood:air 

partition coefficients increased 20–40% in humans having borderline higher triglyceride levels after 

ingestion of fat in the diet (Lin et al. 2002). 

In male Sprague-Dawley rats and male B6C3F1 mice exposed to 20 ppm 14C-radiolabeled 1,3-butadiene 

for 6 hours in a dynamic system, the total absorbed radioactivity, as estimated by the sum of 14C in urine, 

feces, carcass, and expired air, was 2.2% in rats and 1.6% in mice (Swain et al. 2003). In close-chamber 

studies, the uptake of inhaled 1,3-butadiene in mice and rats was linear to 2,000 and 1,000 ppm, 

respectively, above which metabolism is saturated (Kohn and Melnick 2001). Absorption of 

1,3-butadiene was demonstrated by measurements of the metabolite, 1,2-epoxy-3-butene (EB), in the test 

chamber (due to exhaled air) and measurement of 1,3-butadiene metabolites in blood of male SpragueDawley rats exposed 1–10,000 ppm and male B6C3F1 mice exposed to 1–6,000 ppm for 6–8 hours in 

closed chambers (Filser et al. 2007). In rats, EB concentrations in the test chamber reached a plateau at 

all exposure concentrations. In mice, chamber concentrations of EB were higher than for rats; EB levels 

reached a plateau at exposure concentrations up to 1,000 ppm, but no plateau was observed at exposure 

concentrations of 2,000–6,000 ppm. The study authors suggest that this concentration-dependence is due 

to “breakdown” of hepatic glutathione-S-transferase mediated 1,3-butadiene conjugation. Filsner et al. 

(2007) did not report an absorption fraction for either species. Absorption of 1,3-butadiene was also 

demonstrated by measurement of metabolites (butadiene monoepoxide and butadiene diepoxide) in blood 

and tissues of male Sprague-Dawley rats and male B6C3F1 mice exposed (nose only) to 62.5 ppm 

1,3-butadiene for 2 or 4 hours (Thornton-Manning et al. 1995a). Similar results were observed in male 

and female rats exposed (nose only) to 62.5 ppm 1,3-butadiene for 6 hours (Thornton-Manning et al. 
 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 56 

3. HEALTH EFFECTS 

1995b). The distribution coefficient for 1,3-butadiene between rabbit blood and air was 0.603 in vitro and 

0.654 in vivo, suggesting simple passive diffusion of the gas from the alveoli to the blood (Carpenter et al. 

1944). After 9 minutes of exposure of rabbits to 250,000 ppm, the concentration of 1,3-butadiene was 

0.26 mg/mL in the femoral artery and 0.18 mg/mL in the femoral vein. Pulmonary absorption, therefore, 

appears to be rapid. Distribution studies in rats and mice following inhalation exposure to 1,3-butadiene 

indicate that it is absorbed from the lungs in these species as well (see Section 3.4.2.1). When Macaca 

fascicularis monkeys were exposed to radioactively labeled 1,3-butadiene, the uptake was calculated as 

16.40 μmol/hour/10 ppm of inhaled and 3.20 μmol/hour/10 ppm of retained 1,3-butadiene (Dahl et al. 

1990). 

3.4.1.2 Oral Exposure 

No studies were located regarding absorption in humans or animals after oral exposure to 1,3-butadiene. 

3.4.1.3 Dermal Exposure 

No studies were located regarding absorption in humans or animals after dermal exposure to 1,3-butadiene. 

3.4.2 Distribution 

In vitro measurements of tissue:blood equilibrium partition coefficients suggest that 1,3-butadiene 

distributes to a variety of tissues. Partition coefficients in humans were highest in fat (18.4) and were 

similar in well- and poorly-perfused tissues (0.69 and 0.72, respectively) (Brochot et al. 2007). In rats, 

partition coefficients were highest for fat (21.9), similar for liver, kidney, muscle, and spleen (0.87–0.94), 

and lowest in brain (0.43) (Johanson and Filser 1993). 

3.4.2.1 Inhalation Exposure 

In volunteers inhaling 2 ppm 1,3-butadiene for 20 minutes, blood levels approached equilibrium by 

5 minutes (Smith et al. 2001). In mice and rats inhaling up to 625 ppm 1,3-butadiene, equilibrium in 

blood concentrations was reached by 2 hours, with blood levels in mice being three- to 4-fold higher than 

in rats at all times (Himmelstein et al. 1994). The distribution of 1,3-butadiene in several tissues in rats 

was measured following a 1-hour inhalation exposure to 129,000 ppm (Shugaev 1969). Perinephric fat 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 57 

3. HEALTH EFFECTS 

contained 152 mg 1,3-butadiene/100 cc tissue, compared to levels of 36–51 mg 1,3-butadiene/100 mL in 

the brain, liver, septum, and kidney. 

Species differences in the distribution of inhaled 1,3-butadiene were studied in Sprague-Dawley rats and 

B6C3F1 mice (Bond et al. 1986, 1987). When normalized for amount of inhaled 14C-1,3-butadiene, 

molar tissue concentrations of radioactive material at 1 hour postexposure were 17-fold (thyroid) to 

80-fold higher (lung) in mice than in rats. In blood, the normalized radioactivity concentration was 

57-fold higher in mice than rats, while 110- to 120-fold more radioactivity was found in mouse intestine 

than in rat intestine. 

3.4.2.2 Oral Exposure 

No studies were located regarding distribution in humans or animals after oral exposure to 1,3-butadiene. 

3.4.2.3 Dermal Exposure 

No studies were located regarding distribution in humans or animals after dermal exposure to 1,3-butadiene. 

3.4.3 Metabolism 

1,3-Butadiene is metabolized by oxidation, hydrolysis, and conjugation reactions, with oxidation and 

hydrolysis reactions leading to the formation of several reactive epoxide intermediates (Figure 3-2). Of 

the reactive intermediates formed, EB (formed by oxidation of 1,3-butadiene), 1,2:3,4-diepoxybutane 

(DEB; formed by oxidation of EB), and 1,2-dihydroxy-3,4-epoxybutane (EBD; formed by hydrolysis 

reactions of DEB) are reactive electrophilic compounds. Metabolism of 1,3-butadiene appears to follow 

the same enzymatic pathways in all species, including humans, with production of the same reactive 

intermediates. However, important species differences exist in the rates of formation and detoxification 

of reactive metabolites (Kirman et al. 2010a). As a result, rodents, particularly mice, have much higher 

tissue levels of reactive metabolites than nonhuman primates and humans. Evidence for species 

differences in metabolism of 1,3-butadiene is available from in vitro studies, studies using isolated 

perfused livers, and in vivo studies measuring tissue and urine metabolite levels and blood hemoglobin 

adduct levels. Metabolism of 1,3-butadiene exhibits nonlinear kinetics (Kirman et al. 2010a), with both 

dose- and exposure duration-dependent effects. Several processes have been proposed as sources of 
 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 58 

3. HEALTH EFFECTS 

Figure 3-2. Metabolism of 1,3-Butadiene 

BD 

P450 

OH

O 

OH CH2

OH 

OH

OH 

O 

O 

O 

O 

CH2 

2CH

CH2 

GST 

EB* 

DEB** 

B-diol HMVK* 

EBD* 

Erythritol 

GST 

conjugates 

GST 

conjugates 

GST 

conjugates 

(M2) 

GST 

conjugates 

(M1) 

Hb Adducts 

(HBVal) 

Hb Adducts 

(pyrVal) 

Hb Adducts 

(THBVal) 

GST 

GST ADH P450 

P450 EH

EH 

EH GST 

CH2 

□ = boxes indicate biomarkers of exposure that have been measured in exposed workers (Albertini et al. 2003);
	

* = monofunctional alkylating agent; ** = bifunctional alkylating agent; ADH = alcohol dehydrogenase;
	

B-diol = butanediol; BD = 1,3-butadiene; DEB = diepoxybutane; EB = epoxybutene; EBD = epoxybutane diol;
	

EH = epoxide hydrolase; GST = glutathione S-transferase; HBVal = N-(2-hydroxy-3-butenyl)-valine;
	

HMVK = hydroxymethylvinyl ketone; M1 = 1,2-dihydroxy-4-(N-acetylcysteinyl)-butane (urinary metabolite); 

M2 = 1-(N-acetylcysteinyl)-2-hydroxy-3-butene (urinary metabolite); P450 = cytochrome P450;
	

pyrVal = N,N-(2,3-dihydroxy-1,4-butadiyl)-valine; THBVal = N-(2,3,4-trihydroxybutyl)-valine
	

Source: Kirman et al. 2010 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 59 

3. HEALTH EFFECTS 

nonlinear kinetics; these include inhibition, induction, and saturation of various metabolizing enzymes 

and depletion of glutathione. 

The metabolism of 1,3-butadiene has been observed in the liver, lung, and kidneys. The liver is the 

predominant site of 1,3-butadiene metabolism (Elfarra et al. 2001; Schmidt and Loeser 1985, 1986). 

1,3-Butadiene is initially oxidized (Figure 3-2) by cytochrome P450 (CYP) to 2-butenal or EB (Bolt et al. 

1983; Csanady et al. 1992; Duescher and Elfarra 1994; Himmelstein et al. 1994, 1995; Kirman et al. 

2010; Malvoisin and Roberfroid 1982; Malvoisin et al. 1979; Thornton-Manning et al. 1995b, 1997). 

Metabolism of EB is mediated by three competing oxidative, hydrolytic, or conjugation pathways. The 

flux of 1,3-butadiene through the various pathways is concentration- and species-dependent. Successive 

oxidation steps of EB result in DEB and 3,4-epoxy-1,2-diol (EBdiol). EB can also be conjugated to 

glutathione by glutathione-S-transferase (GST) to form 1-glutathionyl-3-buten-2-ol, or can be hydrolized 

via epoxide hydrolase (EH) to 3-butene-1,2-diol (BDdiol). BDdiol is metabolized via CYP or aldehyde 

dehydrogenase (ADH) to the ketone 1-hydrozy-3-buten-2-one (hydroxymethylvinyl ketone, or HMVK) 

or EBdiol. GST can conjugate glutathione to HMVK and EBdiol to form 4-glutathionyl-1-hydroxy2-butanone and 4-glutathionylbutane-1,2,3-triol. Several isoforms of CYP have been implicated in the 

oxidative metabolism of 1,3-butadiene and resulting epoxides in various tissues. In human liver 

microsomes, CYP2E1 dominates metabolism at low concentrations (i.e., 0.16 mM), while CYP2A6 

dominates at higher concentrations (i.e., 4.4 mM) (Elfarra et al. 1996). In mice, CYP2E1 and 2A5 are 

active in 1,3-butadiene oxidation in lung and liver microsomes, but CYP4B1 dominates metabolism in the 

kidneys (Elfarra et al. 2001). 

Examination of blood levels of 1,3-butadiene metabolites in male Sprague-Dawley rats exposed to 1– 

10,000 ppm and male B6C3F1 mice exposed to 1–6,000 ppm for 6–8 hours in closed chambers indicates 

species differences in the predominance of metabolic pathways (Filsner et al. 2007). In rats and mice, 

EB, EBD, and 3-butene-1,2-diol concentrations in blood increased with increasing exposure 

concentrations. Ratios of mouse:rat EB blood levels ranged from 2.0 to 8.6 over 1,3-butadiene exposure 

concentrations of 1–1,250 ppm. DEB was detected in blood of mice, but not in rats. Similar results were 

observed in male Sprague-Dawley rats and male B6C3F1 mice exposed (nose only) to 62.5, 625, or 

1,250 ppm 1,3-butadiene for 6 hours; DEB was detected in mouse, but not rat, blood, and higher levels of 

butadiene monoepoxide were present in mouse blood, compared to rat blood (Himmelstein et al. 1994). 

Results of these studies are consistent with enhanced formation and/or lower metabolism of DEB in mice 

compared to rats. Differences also were noted between rodents and monkeys in 1,3-butadiene 

metabolism (Dahl et al. 1990; Sun et al. 1989a). At 10 ppm, blood levels of EB, DEB, and EBdiol were 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 60 

3. HEALTH EFFECTS 

lower in monkeys inhaling 10 ppm than in rodents. The difference was not so great at 8,000 ppm (Sun et 

al. 1989a). Similar exposures of 10 ppm 1,3-butadiene resulted in blood concentrations of total 1,3-butadiene metabolites in monkeys that were about 5–50 times lower than in mice and about 4–14 times lower 

than in rats (Dahl et al. 1991). The results indicated possible lower susceptibility to toxic effects of low 

levels of 1,3-butadiene in primates. 

Species differences in metabolism are also supported by results of studies examining tissue levels of 

metabolites (Filser et a;. 2007; Himmelstein et al. 1995; Thorton-Manning et al. 1995a, 1995b). 

Comparison of butadiene epoxide levels in livers and lungs of male Sprague-Dawley rats and male 

B6C3F1 exposed (nose only) to 62.5, 625, 1,250, or 8,000 (rats only) ppm 1,3-butadiene shows higher 

levels of butadiene monoepoxide in mice compared to rats, and the presence of butadiene diepoxide in 

mice, but not rats (Himmelstein et al. 1995). In male Sprague-Dawley rats and male B6C3F1 mice 

exposed to 62.5 ppm 1,3-butadiene for 4 hours, tissue levels of butadiene monoepoxide were higher in 

tissues (blood, heart, lung, liver, fat, spleen, and bone marrow) of mice compared to rats, with mouse:rat 

ratios ranging from 3.0 (heart) to 11.5 (bone marrow); butadiene diepoxide was not detected in lung or 

liver of rats (Thorton-Manning et al. 1995a). In mice, butadiene diepoxide levels were similar to 

monoepoxide levels in blood, heart, thymus and bone marrow; diepoxide levels in mouse lung, liver, and 

spleen were higher than monoepoxide levels, but were lower in fat. Butadiene diepoxide levels in rats 

were very low compared to levels in mice, and diepoxide was not detected in liver or bone marrow. 

Comparison of butadiene epoxide levels in tissues of male and female Sprague-Dawley rats exposed to 

1,3-buradiene for 6 hours (nose only) suggests gender differences in metabolism (Thorton-Manning et al. 

1995b). Butadiene monoepoxide levels in lung were approximately 5-fold higher in males compared to 

females; whereas similar monoepoxide levels for males and females were observed for blood, femur, and 

fat. 

Results of studies using isolated perfused livers provide additional evidence of species differences in 

metabolism of 1,3-butadiene. Following single pass, isolated perfusion of livers from male SpragueDawley rats and male B6C3F1 mice with 1,3-butadiene (at concentrations that approached saturation of 

1,3-butadiene metabolism), differences were observed in 1,3-butadiene metabolites in liver effluent 

(Filser et al. 2001). In mice, three epoxides (EB, DEB, and EBD) and 3-butane-1,2-diol (B-diol) were 

detected, whereas only EB and B-diol were detected in effluent from rat livers. Furthermore, the 

concentration of EB in effluent from rat livers was approximately 8.5-fold less than that in effluent from 

mouse livers. Additional species differences were observed in a study evaluating single-pass perfusion of 

the 1,3-butadiene metabolites, EB, DEB and B-diol (Filser et al. 2010). For perfusion with EB, EBD, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 61 

3. HEALTH EFFECTS 

DEB, and B-diol were formed in rats and mice, with an approximately 4-fold higher percentage of DEB 

in mice compared to rats. The major metabolite of DEB in rats and mice was EBD. For perfusion with 

B-diol, EBD was detected in effluent of rats, but not in mice. Results of studies using hepatic 

microsomes from mice and rats indicate differences in stereochemistry of 1,3-butadiene metabolites 

(Nieusma et al. 1997). Mouse microsomes form more (S)-EB than (R)-EB; rat microsomes initially 

formed more (S)-EB than (R)-EB, although the S:R fell below 1.0 as incubation time increased to 

30 minutes. For DEB formation, mice microsomes formed more DEB when starting with (S)-EB 

compared to when starting with (R)-EB; the opposite was observed with rat microsomes. 

In vitro studies indicate that mouse lung and liver have a higher capacity than other species, including 

humans, to oxidize 1,3-butadiene to EB and DEB, but have much less ability to detoxify the epoxides via 

the EH pathway (Jackson et al. 2000b). Female mouse tissue homogenates resulted in higher EB 

generation than in males or in rat, human, or monkey tissues, while human and monkey tissues 

hydrolyzed the epoxides to diols approximately 20-fold more extensively than rodents (Schmidt and 

Loeser 1985, 1986). In studies of liver microsomes, mice had intrinsic clearance (Vmax/Km) values of 

57.5 and 0.77 minute-1 for oxidation of 1,3-butadiene to EB and EB to DEB, respectively. These values 

are 3–4-fold higher than the respective rat values of 1,637 and 0.21 minute-1 (Elfarra et al. 2001). 

Conversely, intrinsic clearance via EH-mediated hydrolysis of EB was 34.4 minute-1 in rats, compared to 

12.4 minute-1 in mice. Clearance by EB conjugation with GSH was similar (21.0 and 22.0 minute-1) in 

both species. These in vitro findings comport with metabolic differences observed between rats and mice 

after inhalation exposure to EB (Kreiling et al. 1987; Laib et al. 1990). A limited rate of EB removal and 

its subsequent accumulation was observed in mice at 500 ppm exposure, but not in rats at exposures up to 

5,000 ppm. This may partially account for the differing levels of toxicity and carcinogenicity between 

rats and mice in long-term studies. For additional information, see Section 3.5 (Mechanisms of Action). 

Based on evaluation of hemoglobin adduct biomarkers (adducts formed by interaction of 1,3-butadiene 

metabolites with hemoglobin), mice appear to have higher DEB levels than rats and much higher levels 

than humans (Swenberg et al. 2007). Analysis of hemoglobin adducts in mice and rats exposed to 

1,3-butadiene by inhalation show much higher levels of the hemoglobin adducts, pyr-Val and THB-Val 

(formed by interaction of DEB with hemoglobin), in mice than in rats (Boysen et al. 2004). Results are 

consistent with results of studies showing higher levels of DEB in tissues of mice compared to rats. In 

polymerization workers exposed to 0.81 ppm 1,3-butadiene, THB-Val was the predominant hemoglobin 

adduct, comprising 99.6% of the total; the mean percent of HB-Val was 0.33% and the mean percent of 

pyr-Val was 0.05% (Boysen et al. 2012). In monomer workers exposed to lower concentrations of 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 62 

3. HEALTH EFFECTS 

1,3-butadiene (0.29 ppm), lower levels of HB-Val (0.26%) and higher levels of pyr-Val (0.11%) were 

found; the decrease in pyr-Val levels was significantly related to the increasing 1,3-butadiene 

concentrations. The lower percentage of pyr-Val formed in the workers exposed to higher 1,3-butadiene 

levels may be suggestive of saturation of the formation of pyr-Val in humans (Boysen et al. 2012). 

As noted in the introduction to Section 3.4.3, metabolism of 1,3-butadiene exhibits nonlinear kinetics 

(Kirman et al. 2010a), with both dose- and exposure duration-dependent effects. Glutathione deletion and 

saturable kinetics have been proposed as possible sources of nonlinear kinetics. Studies evaluating effects 

of hepatic glutathione levels show that gluthione depletion exhibited concentration-dependence and was 

greater in mice than in rats (Deutschman and Laib, 1989; Kreiling et al. 1988). Glutathione depletion was 

also observed in livers and lungs of rats and mice exposed to 1,3-butadiene, with more extensive 

depletion in mice than in rats (Himmelstein et al. 1995). Regarding saturable kinetics, blood levels of EB 

reached a plateau in rats, but not mice (Filser et al. 2007). The study authors suggested that the results are 

consistent with competitive inhibition of CYP450 isozymes. 

3.4.4 Elimination and Excretion 

3.4.4.1 Inhalation Exposure 

The monoepoxide metabolite, EB, can be conjugated to glutathione by GST to form 

monohydroxybutenylmercaptic acid (MHBMA, or M2), a mixture of N-acetyl-S-([1-hydroxymethyl]-

2-propenyl)cysteine and N-acetyl-S-([2-hydroxymethyl]-3-propenyl)cysteine. EBdiol, formed by 

hydrolysis of EB, may also be conjugated by GST to glutathione to form N-acetyl-S-(3,4-dihydroxybutyl)cysteine (DHBMA, or M1). Both mercaptic acids are excreted in the urine (Boogaard et al. 2001a; 

McDonald et al. 2004). These excretion products have been used as biomarkers of 1,3-butadiene 

exposures in both environmental and occupational settings (Albertini et al. 2001, 2007; Ammenheuser et 

al. 2001; Boogaard et al. 2001a) (see Section 3.8). The relative abundance of MHBMA and DHBMA in 

urine indicates the flux of EB through the competing GST and EH metabolic pathways. In humans, 

>97% of urinary mercaptic acid measured following 1,3-butadiene inhalation is DHBMA, indicating that 

most EB proceeds to hydrolysis via EH rather than to formation of the diepoxide (Henderson et al. 1996). 

Albertini et al. (2007) showed that women excrete lower levels of both mercaptic acids than men per unit 

of 1,3-butadiene exposure; however, they maintain the ratio of M1 and M2, suggesting sex differences in 

metabolic activity, but not pathway flux. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 63 

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In rats exposed to 1,3-butadiene, 1,2-epoxybutene-3 and acetone were exhaled as suspected metabolites of 

the administered compound (Bolt et al. 1983). The pharmacokinetic profile of inhaled 1,3-butadiene was 

studied in mice (Kreiling et al. 1986b) and in rats (Bolt et al. 1984; Filser and Bolt 1984). Following 

exposure of mice and rats to 14C-1,3-butadiene, the elimination of radioactivity was rapid, and 77–99% of 

the initial tissue amount was eliminated with half-lives of between 2 and 10 hours (Bond et al. 1987). At 

concentrations of approximately ≤1,000 ppm, the elimination of 1,3-butadiene followed first-order 

kinetics in both species. The first-order metabolic clearance of inhaled 1,3-butadiene per kg body weight 

was 4,500 mL/hour for rats (Laib et al. 1988) and 7,300 mL/hour for mice (Kreiling et al. 1986b). The 

maximal metabolic elimination rate was calculated as 220 μmol/hour/kg for rats (Laib et al. 1988) and 

400 μmol/hour/kg for mice (Kreiling et al. 1986b). With increasing concentrations of 14C-1,3-butadiene, 

exhalation of radiolabeled carbon was a major pathway for elimination of 14C in mice and rats (Bond et al. 

1986). Similar results were observed in mice and rats following inhalation of 62.5 ppm 1,3-butadiene for 

6 hours (Himmelstein et al. 1996). Blood 1,3-butadiene concentrations in mice fell from about 3 μM at 

the end of exposure to 0.03 μM 15 minutes later. Rat elimination of 1,3-butadiene from blood was 

slower, falling from a post-exposure maximum of about 1.5–0.1 μM 30 minutes later. 

About 2% of the total inhaled amount of 1,3-butadiene was excreted as metabolites in Cynomolgus 

monkeys (Sun et al. 1989a). Carbon dioxide was the major exhalation product at 10 ppm, while epoxymetabolites (specific compounds not determined) were predominant in exhaled breath at 300 and 

8,000 ppm. Urinary excretion of total metabolites was not influenced by exposure levels. In Macaca 

fascicularis monkeys, about 39% of metabolite radioactivity (specific compounds not determined) were 

eliminated in the urine, 0.8% in feces, and 56% were exhaled as carbon dioxide during the first 70 hours 

postexposure (Dahl et al. 1990). 

3.4.4.2 Oral Exposure 

No studies were located regarding excretion in humans or animals after oral exposure to 1,3-butadiene. 

3.4.4.3 Dermal Exposure 

No studies were located regarding excretion in humans or animals after dermal exposure to 1,3-butadiene. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 64 

3. HEALTH EFFECTS 

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 and 

Krishnan 1994; Andersen et al. 1987). 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 parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

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 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 65 

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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 3-3 shows a conceptualized representation of a PBPK model. 

Literature on PBPK modeling of 1,3-butadiene is extensive (Beaudouin et al. 2010; Bois et al. 1999; 

Bond et al. 1996; Brochot et al. 2007; Csanady et al. 1996; Evelo et al. 1993; Filser et al. 1993; Johanson 

and Filser 1993, 1996; Kohn 1997; Kohn and Melnick 1993, 1996, 2000, 2001; Leavens and Bond 1996, 

Péry and Bois 2009; Seilken et al. 1996; Smith et al. 2001; Sweeney et al. 1996, 1997, 2001). Models 

have been developed to simulate 1,3-butadiene kinetics in mice (Bond et al. 1996; Csanady et al. 1996; 

Johanson and Filser 1993, 1996; Kohn and Melnick 1993, 1996, 2000, 2001; Leavens and Bond 1996; 

Sweeney et al. 1996, 1997, 2001), rats (Bond et al. 1996; Csanady et al. 1996; Johanson and Filser 1993, 

1996; Kohn and Melnick 1993, 1996, 2000, 2001; Sweeney et al. 1996, 1997, 2001), and humans 

(Beaudouin et al. 2010; Bond et al. 1996; Brochot et al. 2007; Csanady et al. 1996; Evelo et al. 1993; 

Johanson and Filser 1996; Péry and Bois 2009). Model structures differ with respect to the number of 

physiological compartments simulated, the extent to which secondary and tertiary metabolites are 

simulated, and in which tissue compartments metabolism is assumed to occur. Selected examples are 

described in greater detail in the sections that follow. 

Johanson and Filser 1996 

Description of the Model. The Johanson and Filser model (Filser et al. 1993; Johanson and Filser 

1993, 1996) model simulates absorption and disposition of 1,3-butadiene and the metabolite, 3,4-epoxy1-butene, in the mouse, rat, and human. The hepatic conjugation of 3,4-epoxy-1-butene to GSH is also 

simulated. Tissue compartments include the blood/lung, liver, fat, and muscle/richly-perfused tissues. 
 

 

 

 

 

1,3-BUTADIENE 66 

3. HEALTH EFFECTS 

Figure 3-3. Conceptual Representation of a Physiologically Based
 

Pharmacokinetic (PBPK) Model for a 

Hypothetical Chemical Substance
 

Inhaled chemical Exhaled chemical 

Lungs 

Liver 

Fat 

Slowly 

perfused 

tissues 

Richly 

perfused 

tissues 

Kidney 

Skin 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

Vmax 

Km 

Ingestion 

GI 

Tract 

Feces 

Urine

 Chemicals 

contacting skin 

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. 

Source: Adapted from Krishnan and Andersen 1994 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 67 

3. HEALTH EFFECTS 

Model parameters are presented in Table 3-4. Both the exchange of 1,3-butadiene and 3,4-epoxy1-butene between blood and tissue or lung air is assumed to be first-order and flow-limited. In vitro 

derivation of tissue:air and tissue:blood partition coefficients was performed by the model authors and 

reported in the study. Michaelis-Menten expressions were included for 1,3-butadiene oxidation, 

3,4-epoxy-1-butene hydrolysis, and 3,4-epoxy-1-butene conjugation to GSH, all occurring in the liver 

compartment. Values for physiological (alveolar, pulmonary, and tissue perfusion rates, organ weights) 

and metabolic parameters (Vmax, Km, and GSH content and elimination rates) were taken from the 

literature, except for the affinity constant (Km) for 1,3-butadiene oxidation, which was fit to chamber air 

1,3-butadiene timecourse data from rat and mouse closed chamber experiments. Elimination of 

1,3-butadiene and 3,4-epoxy-1-butene was represented as either metabolism or as exchange passage back 

to the lung air. 

Risk Assessment. This model has not been used in risk assessment. The model predicts that steadystate blood concentrations of 3,4-epoxy-1-butene resulting from continuous inhalation exposures to 

1,3-butadiene would be higher in mice compared to rats or humans. At non-saturating conditions (e.g., 

exposures <1,000 ppm), the ratio of blood 3,4-epoxy-1-butene concentrations predicted from the model 

were: 1.6:1.0:0.3 for mouse:rat:human (Johanson and Filser 1996). 

Validation of the Model. The Km for 1,3-butadiene oxidation and 3,4-epoxy-1-butene hydrolysis 

were the only parameters optimized against close-chamber gas uptake data for 1,3-butadiene or 

3,4-epoxy-1-butene (1,000–5,000 ppm) in rats (Filser and Bolt 1984) and mice (Kreiling et al. 1987). 

Model predictions were evaluated against the concentration of 3,4-epoxy-1-butene appearing in the 

chambers (due to metabolism and exhalation from the animals) during the 1,3-butadiene exposures, and 

were found to predict 3,4-epoxy-1-butene levels that were similar to observations. 

Target Tissues. The model simulates concentrations of 1,3-butadiene and 3,4-epoxy-1-butene in 

liver, a target tissue for 1,3-butadiene metabolites, as well as in blood, fat, and a lumped compartment for 

muscle and richly-perfused tissues. 

Species Extrapolation. The model has been developed for simulations of rats, mice, and humans. 

Extrapolation to other species would require species-specific physiological and metabolism parameter 

values and blood-tissue partition coefficients. 
 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 68 

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Table 3-4. Physiological and Chemical Parameters Used in the Johanson and 

Filser (1993) PBPK Model for 1,3-Butadiene 

Mouse Rat 

Physiological data 

Body weight (bw) Standard animal 25 250 

(g) Simulations 27.5 157.5–217.5 

Alveolar ventilation Standard animal 15 70.2 

(mL/minute) 

Simulations proportional to bw2/3 proportional to bw2/3 

Cardiac output Standard animal 17 83 

Simulations proportional to bw2/3 proportional to bw2/3 

Blood flows Muscle and vessel-rich group 66 66 

(percent of cardiac (VRG) 

output) Fat 9 9 

Liver 25 25 

Compartment Lung and arterial 1 1 

volumesa

 (percent Muscle and VRG 75 80 

of body weight) Fat 10 7 

Liver 5.5 4 

Tissue:air partition coefficients 

Butadiene Lung and arterial, muscle and 0.76 0.76 

VRG, liver 

Fat 21.9 21.9 

Blood 3.03 3.03 

Epoxybutene Lung and arterial, muscle and 58.9 58.9 

VRG, liver 

Fat 155 155 

Blood 83.4 83.4 

Water 43.0 43.0 

Metabolic constants 

30 

3.22 

Butadiene oxidation Microsomal protein (mg/g liver) 

Vmax (nmol·minute-1

·mg -1) 

30 

2.17 

Km (μmol/L air) 5 5 

30 

19 

Epoxybutene 

hydrolysis 

Microsomal protein (mg/g liver) 

Vmax (nmol·minute-1

·mg -1) 

30 

17 

Apparent Km (mmol/L) 1.5 0.7 

Intrinsic Km (percent of apparent 20% 20% 

Km) 

Epoxybutene Cytosolic protein (mg/g liver) 95 95 

conjugation Vmax/Km of epoxybutene 15

(μL·minute-1·mg-1) 

11 

Km towards epoxybutene 100 100 

(mmol/L) 

Km towards glutathione (mmol/L) 0.1 0.1 

Glutathione kinetics Initial steady-state concentration 5.5 4.2 

0.15

(mmol/L) 

Elimination rate constant (hour-1) 0.15 

a

Density was set to 1 for all organs 

Source: Johanson and Filser 1993 (although simulations from a human model were reported in Johanson and Filser 

1996, parameter values were not reported) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 69 

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High-low Dose Extrapolation. The model has been evaluated for simulating inhalation exposures in 

mice and rats ranging from 500 to 5,000 ppm. 

Interroute Extrapolation. The model simulates inhalation exposures only and would require 

additional parameterization to simulate exposures by other routes. 

Strengths and Limitations. Strengths of the model are that it simulates disposition and clearance of 

inhaled 1,3-butadiene, as well as production and clearance of 3,4-epoxy-1-butene, the major oxidative 

metabolite formed in rodents. Limitations include: (1) the model has not been evaluated for inhalation 

exposures below 500 ppm; (2) the model does not simulate the appearance and disposition of other 

metabolites, such as the diepoxide, diols, and GSH-conjugate products eliminated in the urine; and (3) the 

model does not simulate 1,3-butadiene disposition in humans. 

Kohn and Melnick 2001 

Description of the Model. The Kohn and Melnick model (Kohn and Melnick 1993, 1996, 2000, 

2001) simulates absorption of 1,3-butadiene and the disposition of 1,3-butadiene and the metabolite, 

3,4-epoxy-1-butene, in the mouse and rat. Model parameters are presented in Tables 3-5, 3-6, and 3-7. 

The body is represented by discrete compartments for venous and arterial blood, lung, liver, kidney, fat, 

the gastrointestinal tract, and lumped compartments for richly- and poorly perfused tissues (viscera and 

muscle, respectively). Values for physiological flow rates, tissue volumes, and tissue:blood partition 

coefficients were taken from the literature. 1,3-Butadiene is eliminated by exhalation to lung air or 

oxidative metabolism to 3,4-epoxy-1-butene and its oxidation metabolites (3,4-epoxy-1-butene, DEB, 

3,4-epoxy-1,2-diol, 3-butene-1,2-diol) and glutathione conjugates. All of these pathways are described as 

saturable Michaelis-Menten processes, with Vmax and Km values optimized against published closedchamber 1,3-butadiene and 3,4-epoxy-1-butene uptake data (Bolt et al. 1984; Filser and Bolt 1984; 

Kreiling et al. 1986b, 1987). Epoxide hydrolysis was modeled such that dissociation of the diepoxide 

from P450 in the microsome is followed by preferential binding of the epoxide hydrolase, replicating the 

so-called privileged access model for epoxide hydrolysis. The model simulates production and utilization 

of glutathione in kidney, liver, and lung, with the assumption that glutathione production is limited by 

availability of cysteine for the first step in glutathione synthesis (γ-glutamylcysteine synthetase). 

Risk Assessment. This model has not been used in risk assessment. 
 

1,3-BUTADIENE 70 

3. HEALTH EFFECTS 

Table 3-5. Physiological Parameter Values Used in the Kohn and Melnick (2001) 

PBPK Model for 1,3-Butadiene 

Mouse (percent) Rat (percent) 

Tissue compartment volumes, percent body weight 

Liver 5.5 3.7 

Lung 0.6 0.52 

Alveolar 0.5 0.515 

Kidney 1.67 1.48 

Gastrointestinal tract 7.5 7.5 

Viscera 3.93 14.3 

Fat 6 7 

Muscle and skin 64.5 54.2 

Blood 6 5.4 

Capillary blood volume, percent tissue volume 

Liver 11 13.8 

Lung 11 18 

Kidney 10.2 16 

Gastrointestinal tract 2.9 2.65 

Viscera 7.1 7.1 

Fat 3 2 

Muscle and skin 1.3 2 

Blood flow rate, percent cardiac output 

Liver (hepatic artery only) 4.4 3.9 

Kidney 16.3 13.3 

Gastrointestinal tract 18.1 18.1 

Viscera 22.4 24.8 

Fat 5 6.5 

Muscle and skin 33.8 33.4 

Source: Kohn and Melnick 2001 
 

 

1,3-BUTADIENE 71 

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Table 3-6. Chemical Partition Coefficients Parameter Values Used in the Kohn 

and Melnick (2001) PBPK Model for 1,3-Butadiene 

Butadiene Epoxybutane Butenediol Epoxybutanediol Diepoxybutane 

Blood:air 1.95 56.8 – – – 

Liver 0.595 0.984 1.04 0.903 1.41 

Lung 0.615 0.977 1.107 0.958 1.41 

Kidney 0.472 0.842 0.962 0.833 1.54 

Gastrointestinal tract 0.446 0.908 1.22 1.06 1.41 

Viscera 0.446 0.908 1.22 1.06 1.41 

Fat 10.8 2.25 0.573 0.496 2.19 

Muscle and skin 0.564 0.736 1.139 0.986 1.82 

Source: Kohn and Melnick 2001 
 

 

 

 

 

1,3-BUTADIENE 72 

3. HEALTH EFFECTS 

Table 3-7. Chemical Metabolism Parameter Values Used in the Kohn and Melnick 

(2001) PBPK Model for 1,3-Butadienea 

Liver Lung Kidney 

Butadiene metabolism 

V

P450 

max 155, 130 139, 9.6 1,430, 30 

KP450 

m 0.002, 0.00375 0.00501, 0.00775 0.00501, 0.00216 

Epoxybutene metabolism 

V

P450 

max 45.1, 24.3 10.2, 9.84 48.6, 12.6 

KP450 

m 0.0156, 0.145 0.0156, 0.145 0.0156, 0.145 

VEH 

m 347, 584 34.8, 42.8 113, 14.7 

KEH 

m 1.59, 0.26 1.59, 0.7 1.59, 0.7 

VGST 

max 6,420, 4,260 720, 196 960, 494 

Adjusted K GST 

mx 3.59, 2.59 3.59, 4.94 3.59, 4.39 

Butenediol metabolism 

VP450 

max 16.3, 67.1 1.0, 31.5 1.0, 85.0 

KP450 

m 0.0156, 0.145 0.0156, 0.145 0.0156, 0.145 

VGST 

max 3,480, 1,230 491, 276 1,070, 658 

KGST 

mx 34, 34 34, 34 34, 34 

Epoxybutanediol metabolism 

V

EH 

max 363, 1,150 69.5, 169 10.0, 152 

KEH 

m 8.1, 2.76 7.5, 7.1 7.5, 7.1 

VGST 

max 2,260, 271 50.0, 100 50.0, 138 

KGST 

mx 6.40, 4.17 6.40, 4.17 6.40, 4.17 

Diepoxybutane metabolism 

VEH 

max 1,920, 3,170 10.0, 1,160 35.2, 1,000 

KEH 

m 8.1, 2.76 7.5, 7.1 7.5, 7.1 

VGST 

max 9,720, 1,940 100, 100 100, 100 

Adjusted K GST 

mx 6.40, 4.17 6.40, 4.17 6.40, 4.17 

Cysteine metabolism 

Tissue cysteine 0.193, 0.195 0.171, 0.127 0.280, 0.326 

Vγ-GCS 

max 420, 396 54, 50 7,920, 6,080 

EH = epoxide hydrolase; γ-GCS = gamma-glutamylcysteine synthesase; GST = glutathione S-transferase 

a

Non-bold values for mouse; bold values for rat; values in italics were estimated by formal optimization; entries in 

italics indicate optimized parameter values; Vmax values in nmol/hour/mg of protein; Km values and tissue cysteine 

concentrations in mM. 

Source: Kohn and Melnick 2001 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 73 

3. HEALTH EFFECTS 

Validation of the Model. The model predicted similar profiles of 1,3-butadiene and 3,4-epoxy1-butene uptake data (100–4,000 ppm) in mice and rats against which it was optimized. Further, it 

predicted single time point concentrations of 1,3-butadiene in mice and rats similar to observations from 

nose-only exposures to 7–1,250 ppm (Bond et al. 1986; Himmelstein et al. 1994). Additionally, it 

predicted similar percentages of GSH depletion in mouse and rat lung and liver observed following 

7-hour 1,3-butadiene exposures of 50–2,000 ppm (Deutschmann and Laib 1989). 

Target Tissues. The model simulates concentrations of 1,3-butadiene and 3,4-epoxy-1-butene in 

lung, liver, and kidney, all target tissues for 1,3-butadiene metabolite intoxication, as well as in blood, fat, 

gastrointestinal tract, and lumped compartments for muscle and viscera. 

Species Extrapolation. The model has been developed for simulations of rats and mice. 

Extrapolation of predictions to humans would require additional species-specific values for physiology 

and metabolism, as well as human data to verify the accuracy of the predictions. 

High-low Dose Extrapolation. The model has been evaluated for simulating inhalation exposures 

ranging from 7 to 4,000 ppm. 

Interroute Extrapolation. The model simulates inhalation exposures only and would require 

additional parameterization to simulate exposures by other routes. 

Strengths and Limitations. Strengths of the model are that it simulates disposition and clearance of 

inhaled 1,3-butadiene, as well as production and clearance of the major oxidative metabolites of 

1,3-butadiene in kidney, liver, and lung, including 3,4-epoxy-1-butene, 1,2:3,4-diepoxybutane, 3,4-epoxy1,2-diol, and 3-butene-1,2-diol. It also simulates production and utilization of GSH in the kidney, lung, 

and liver, which allows prediction of glutathione depletion resulting from 1,3-butadiene metabolism. 

Limitations include: (1) the model has not been evaluated against data for inhalation exposures in 

humans, and (2) the model does not simulate the appearance and disposition of other metabolites, such as 

the diepoxide, diols, and GSH-conjugate products eliminated in the urine. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 74 

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Brochot et al. 2007 

Description of the Model. The Brochot model (Brochot and Bois 2005; Brochot et al. 2007) 

simulates absorption of 1,3-butadiene and the disposition of 1,3-butadiene, 1,2-epoxy-3-butene, and 

1,2:2,3-diepoxybutane in the blood, fat, and lumped compartments for richly- and poorly-perfused tissues 

in humans. Model parameters are presented in Table 3-8. In addition, the disposition and clearance of 

3-butene-1,2-diol and 3,4-epoxy-1,2-butanediol was modeled for the blood and richly- and poorlyperfused tissues. Tissue:blood partition coefficients were taken from the literature. 1,3-Butadiene is 

eliminated by exhalation to lung air or oxidative metabolism, epoxide hydrolysis, or GSH conjugation in 

the richly-perfused tissues to mono- and diepoxide and the two diols. Since the model was intended to 

direct further study design for low-ppm human exposures, all of the metabolic steps are described as 

1st-order processes, governed by a rate constant for each pathway. The metabolic rate constants and 

physiological parameters were optimized using Bayesian techniques against 133 datasets from individual 

subjects inhaling 2 ppm 1,3-butadiene for 20 minutes (Lin et al. 2001). Several extensions of the Brochot 

et al. (2007) model have been reported. A 23-compartment model was developed for simulating 

1,3-butadiene and 1,2-epoxy-3-butene kinetics in humans (Péry and Bois 2009). The model simulates 

flow-limited distribution to each tissue with partitioning assumed to occur predominantly into tissue fat 

(estimated from the fat:blood partition coefficient and fat content of each tissue). Beaudouin et al. (2010) 

further extended this model to a generic human lifetime PBPK model that included growth and 

transplacental transfer to the fetus. 

Risk Assessment. This model has not been used in risk assessment. 

Validation of the Model. The model fit well against the human data from which it was calibrated. Its 

performance has not been evaluated against other independent human inhalation data. 

Target Tissues. The model predicts parent compound, mono- and diepoxide, and viscinal thiol 

(including the epoxydiol) concentrations in the blood, but not in other tissues. 

Species Extrapolation. The model was optimized for humans. Extrapolation of predictions to 

animals would require additional species-specific values for physiology and metabolism, as well as 

animal data (available in the literature) to verify the accuracy of the predictions. 
 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 75 

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Table 3-8. Physiological and Chemical Parameters Used in the Brochot et al. 

2007 PBPK Model for 1,3-Butadiene Humans 

Parameter Meana Standard deviationa 

Body weight (kg) 70 

Sex M 

Metabolic activity in liver (mg protein/kg liver) 

Microsomal protein 14,500 

Cytosolic protein 45,000 

Relative weight (percent of body weight) 

Liver 0.026 

Relative volumes (percent of body weight) 

Well-perfused tissues 0.10 0.02 

Fat 0.21 0.05 

Relative flows (percent of total blood flow) 

Poorly perfused tissues 0.26 0.06 

Fat 0.05 0.01 

Pulmonary characteristics 

Minute volume (L/minute) 7.5 1.87 

Ventilation perfusion ratio 1.0 0.25 

Dead space fraction 0.33 0.08 

Partition coefficients for BD 

Blood:air 1.22 0.30 

Poorly perfused tissues:blood 0.72 0.18 

Well-perfused tissues:blood 0.69 0.17 

Fat:blood 18.4 4.6 

Partition coefficients for EB 

Blood:air 93.3 23.3 

Poorly perfused tissues:blood 0.49 0.12 

Well-perfused tissues:blood 0.59 0.15 

Fat:blood 1.80 0.45 

Partition coefficients for DEB 

Poorly perfused tissues:blood 1.98 0.49 

Well-perfused tissues:blood 1.53 0.38 

Fat:blood 2.20 0.55 

Partition coefficients for BDD 

Poorly perfused tissues:blood 1.00 0.25 

Well-perfused tissues:blood 1.00 0.25 

Partition coefficients for EBD 

Poorly perfused tissues:blood 1.00 0.25 

Well-perfused tissues:blood 1.00 0.25 

Metabolic constants (minute-1) 

BD → EB 0.119 0.06 
 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 76 

3. HEALTH EFFECTS 

Table 3-8. Physiological and Chemical Parameters Used in the Brochot et al. 

2007 PBPK Model for 1,3-Butadiene Humans 

Parameter Meana Standard deviationa 

Metabolic constants 

EB → DEB 0.020 0.01 

EB → BDD 0.511 0.25 

DEB → EBD 0.471 0.23 

BDD → EBD 0.008 0.01 

Other transformations (L/kg liver/minute) 

EB by GSH 0.195 0.10 

DEB by GSH 0.113 0.06 

EBD by GSH 0.056 0.03 

EBD by hydrolysis 0.235 0.12 

BDD by ADH 0.045 0.02 

a

Mean and standard deviation of lognormal distributions, reflecting variability in the human population. 

ADH = alcohol dehydrogenase; BD = 1,3-butadiene; BDD = 3-butene-1,2-diol; DEB = 1,2:3,4-diepoxybutane; 

EB = 1,2-epoxy-3-butene; EBD = 3,4-epoxy-1,2-butanediol; GSH = glutathione 

Source: Brochot et al. 2007 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 77 

3. HEALTH EFFECTS 

High-low Dose Extrapolation. The model was calibrated for low (2 ppm) exposures in humans. 

Extrapolation to higher doses will require that the metabolic expression be modified to account for 

saturation of the oxidative, hydrolytic, and conjugating pathways described. 

Interroute Extrapolation. The model was designed to simulate inhalation exposures. Additional 

parameters and absorption expressions must be added (and optimized with oral or dermal data) in order to 

extrapolate internal dosimetry from inhalation exposures across other routes of exposure. Parameters for 

gastrointestinal absorption of 1,3-butadiene were reported for use in a generic lifetime model (Beaudouin 

et al. 2010). 

Strengths and Limitations. The model is the first PBTK model to simultaneously predict blood 

levels of 1,3-butadiene and its epoxide and viscinal diol metabolites in humans. Limitations include: 

(1) the model has not been evaluated against data for inhalation exposures in animals, and (2) the model 

does not account for saturation of metabolic pathways that may occur in humans (and have been observed 

in rodents) exposed to higher inhalation concentrations of 1,3-butadiene. 

Sweeney et al. 2001 

Description of the Model. The Sweeney et al. (1996, 1997, 2001) model simulates inhalation 

absorption of 1,3-butadiene and the disposition of 1,3-butadiene, 1,2-epoxy-3-butene, and 

1,2:2,3 diepoxybutane in mice, rats, and humans. Blood, fat, liver, and lumped compartments for richlyand poorly-perfused tissues are simulated. Model parameters are presented in Table 3-9, 3-10, 3-11, 3-12, 

3-13, 3-14, and 3-15. 1,3-Butadiene is eliminated by exhalation to lung air or oxidative metabolism to 

1,3-epoxide-3-butene or to other products (e.g., aldehydes) in liver. The monoepoxide (1,3-epoxide3-butene) undergoes further oxidative metabolism to the diepoxide (DEB) and both the mono- and 

diepoxide undergo epoxide hydrolysis, GSH conjugation, or nonenzymative degradation. Enzymatic 

reactions are simulated as saturable reactions (Km, Vmax) and non-enzymatic elimination reactions are 

simulated as first-order reactions. Production and utilization of glutathione in liver are simulated, which 

allows prediction of glutathione depletion resulting from 3,4-epoxy-1-butene metabolism. 

Risk Assessment. This model has not been used in risk assessment. 
 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 78 

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Table 3-9. Physiological Parameters Used in Sweeney et al. (1997) 1,3-Butadiene
 

PBPK Model
 

Parameter Rat Mouse
	

Alveolar ventilationa (Qpu) (L/hour/kg) 17 41 

Cardiac outputa (Qt) (L/hour/kg) 17 41 

Body weight (BW) (kg) 0.215–0.475 0.028–0.035 

Blood flowb (Qi) (fraction of cardiac output) (Fi) (dimensionless) 

Lung 1.0 1.0
	

Fat 0.09 0.09
	

Slowly perfused tissues 0.15 0.15
	

Richly perfused tissues 0.51 0.51
	

Liver 0.25 0.25
	

Organ volumesc (Vi) (fraction of body weight) (dimensionless) 

Lung 0.0053 0.005 

Fat 0.09 0.10 

Slowly perfused tissues 0.71 0.7 

Richly perfused tissues 0.0347 0.0226 

Liver 0.05 0.0624 

a

Alveolar ventilation and cardiac output are given for a hypothetical 1-kg animal. In the model simulations, the 

parameter is multiplied by the body weight of the animal (in kg) to calculate the ventilation rate and cardiac output (in 

L/hour) for that individual animal.

b

Tissue blood flows are calculated by multiplying the total cardiac output by the fractional flow: Qi = Fi x Qt.
	 c

Tissue volumes are calculated by multiplying the body weight by the fractional volume: Vi = Fi x BW.
	

Source: Sweeney et al. 1997 
 

 

 

 

 

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Table 3-10. Partition Coefficients Used in Sweeney et al. (1997) PBPK Model for 

1,3-Butadiene 

Butadienea Epoxybutenea Diepoxybutaneb 

Tissue Rat Mouse Rat Mouse Mouse 

Blood 1.49 1.34 50.4 36.6 0.437 

Liver 1.19 1.35 72.0 42.1 0.615 

Lung 0.92 1.47 54.7 56.3 ND 

Kidney ND ND ND ND ND 

Muscle 1.47 4.01 19.8 23.6 0.795 

Fat 22.2 19.2 138.0 91.2 0.959 

Saline 0.088 44.3 0.723 

Oil 23.2 164 ND 

a

Tissue:air partition coefficients.

b

Tissue:hexane partition coefficient.
	

ND = not determined
	

Source: Sweeney et al. 1997
	
 

 

 

1,3-BUTADIENE 80 

3. HEALTH EFFECTS 

Table 3-11. Nonenzymatic Reaction Rate Constants Used in Sweeney et al. (1997)
 

PBPK Model for 1,3-Butadiene
 

Epoxybutene Diepoxybutane 

Tissue Rat Mouse Rat Mouse 

Blood 0.582 0.558 ND 0.189 

Liver 4.94 4.14 ND 3.15 

Lung 6.07 2.70 ND 4.1 

Fat 1.72 1.56 ND 2.8 

Muscle 0 0 ND 0 

ND = not determined 

Source: Sweeney et al. 1997 
 

 

1,3-BUTADIENE 81 

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Table 3-12. Metabolism Rate Constants Used in the Sweeney et al. (1997) PBPK
 

Model for 1,3-Butadiene
 

Parameter value 

Substrate Tissue Pathway Units Rat Mouse 

Butadiene Liver Oxidation μmol/kg/hour 62 338 

(to all products) μmol/L 3.75 2.0 

Oxidation μmol/kg/hour 8.2 97 

(to epoxybutene only) μmol/L 1.54 0.88 

Oxidation μmol/kg/hour 54 243 

(to other volatiles) μmol/L 4.36 2.72 

Lung Oxidation μmol/kg/hour 1.01 21.6 

(to all products) μmol/L 7.75 5.01 

Oxidation μmol/kg/hour 0.13 6.4 

(to epoxybutene only) μmol/L 3.18 1.6 

Oxidation μmol/kg/hour 0.88 16.1 

(to other volatiles) μmol/L 9.14 9.5 

Epoxybutene Liver Oxidation μmol/kg/hour 57.1 176.6 

(one enzyme) μmol/L 141 145 

Oxidation μmol/kg/hour 10 32.5 

(two enzymes) μmol/L 141 15.6 

μmol/kg/hour 47.1 144.1 

μmol/L 141 145 

Hydrolysis μmol/kg/hour 260 754 

μmol/L 260 1,590 

Glutathione conjugation μmol/kg/hour 78,100 154,000 

μmol/L 13,800 35,300 

μmol/L 100 100 

Lung Glutathione conjugation μmol/kg/hour 819 4,088 

μmol/L 17,400 36,500 

Diepoxybutane Liver Hydrolysis μmol/kg/hour 5,555 4,193 

μmol/L 2,700 8,100 

Glutathione conjugation μmol/kg/hour 60,264 50,342 

μmol/L 24,000 6,400 

Lung Hydrolysis μmol/kg/hour 122.7 466.1 

μmol/L 7,100 7,500 

Glutathione conjugation μmol/kg/hour 332 577 

μmol/L 4,170 1,700 

Source: Sweeney et al. 1997 
 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 82 

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Table 3-13. Physiological Parameters Used in the Sweeney et al. (2010) PBPK
 

Model for 1,3-Butadiene in Humans
 

Parameter Value Units Comment
	

Alveolar ventilation rate (QPC) 4.3 L/hour/kg body weight QP = QPC x BW 

Cardiac output (QCC) 4.5 L/hour/kg body weight QC = QCC x BW 

Fractional blood flow to liver 0.227 Dimensionless QR = 0.76 x QC−QL 

Fractional blood flow to fat 0.052 Dimensionless QS = 0.24 x QC−QF 

Fractional weight of liver 0.027 Dimensionless 

Fractional weight of lung 0.0076 Dimensionless VR = 0.09−VL−VLU 

Fractional weight of fat 0.2142 Dimensionless VS = 0.81−VF 

Body weight 70 kg 

Cytosolic protein content of liver 89,000 mg protein/kg liver Rat value 

Microsomal protein content of liver 77,000 mg protein/kg liver Human value 

Source: Sweeney et al. 2001 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 83 

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Table 3-14. Chemical Partition Coefficients Used in the Sweeney et al. (2010)
 

PBPK Model for 1,3-Butadiene in Humans
 

Parameter Value Comment 

1,3-Butadiene 

Blood:air 1.22 Average of individual values for humans 

Liver:air 0.68 Human tissue 

Fat:air 22.5 Human tissue 

Lung:air 0.48 Human tissue 

Slowly perfused tissue:air 0.88 Value for human muscle 

Richly perfused tissue:air 0.84 Values for human kidney, brain, and 

liver weighted by contribution to body 

weight 

Butadiene monoepoxide 

Blood:air 93.3 Human tissue 

Liver:air 55.3 Human tissue 

Fat:air 168 Human tissue 

Lung:air 55.3 Value measured for human liver 

Slowly perfused tissue:air 45.8 Value measured for human muscle 

Richly perfused tissue:air 55.3 Value measured for human liver 

Butene diol 

Liver:blood 1 Volume of distribution=0.87 L/kg in 

mouse; mouse model has perfused 

tissues=0.9 kg/kg total body weight 

Rest of body:blood 1 Volume of distribution=0.87 L/kg in 

mouse; mouse model has perfused 

tissues=0.9 kg/kg total body weight 

Butadiene diepoxide 

Liver:blood 1.53 Rat tissue 

Fat:blood 2.2 Rat tissue 

Lung:blood 1.53 Rat liver value 

Slowly perfused tissue:air 1.82 Rat muscle value 

Richly perfused tissue:air 1.41 Rat kidney value 

Epoxybutane diol 

Liver:blood 1 Assumption based on butene diol and 

butadiene diepoxide partition 

coefficients 

Rest of body:blood 1 Assumption based on butene diol and 

butadiene diepoxide partition 

coefficients 

Source: Sweeney et al. 2001 
 

 

 

 

 

 

 

 

 

 

 

 

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Table 3-15. Chemical Metabolism Parameters Used in the Sweeney et al. (2010)
 

PBPK Model for 1,3-Butadiene in Humans
 

Parameter (units) Baseline valuea 

Vmax for epoxidation of 1,3-butadiene to butadiene monoepoxide (μmol/mg 0.0132
	

protein/hour)
	

Km for epoxidation of 1,3-butadiene to butadiene monoepoxide (μM) 0.7
	

Vmax for epoxidation of butadiene monoepoxide to butadiene diepoxide (μmol/mg 0.031
	

microsomal protein/hour)
	

Km for epoxidation of butadiene monoepoxide to butadiene diepoxide (μM) 880
	

Vmax for hydrolysis of butadiene monoepoxide to butene diol 1.4
	

Km for hydrolysis of butadiene monoepoxide to butene diol 540
	

Vmax for conjugation of butadiene monoepoxide and glutathione (μmol/mg cytosolic 2.7
	

protein/hour)
	

Km for conjugation of butadiene monoepoxide and glutathione (μM) 10,400
	

Vmax for conjugation of butadiene diepoxide and glutathione (μmol/mg cytosolic 0.4
	

protein/hour)
	

Km for conjugation of butadiene diepoxide and glutathione (μM) 3,390
	

Vmax for epoxidation of butene diol to epoxybutane diol (μmol/mg microsomal 0.031
	

protein/hour)
	

Km for epoxidation of butene diol to epoxybutane diol (μM) 880
	

Vmax for hydrolysis of butadiene diepoxide to epoxybutane diol (μmol/mg microsomal 9.2
	

protein/hour)
	

Km for hydrolysis of butadiene diepoxide to epoxybutane diol (μM) 4,605
	

Vmax for metabolism of butene diol by alcohol dehydrogenase (μmol/mg cytosolic 0.64
	

protein/hour)
	

Km for metabolism of butene diol by alcohol dehydrogenase (μM) 10,600
	

Vmax for hydrolysis of epoxybutane diol to erythritol (μmol/mg microsomal protein/hour) 4.6
	

Km for hydrolysis of epoxybutane diol to erythritol (μM) 4,605
	

Vmax for conjugation of epoxybutane diol and glutathione (μmol/mg cytosolic 0.2
	

protein/hour)
	

Km for conjugation of epoxybutane diol and glutathione (μM) 3,390
	

a

Median or average parameter values. 

Source: Sweeney et al. 2001 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Validation of the Model. The model was calibrated and evaluated against data from intravenous 

studies in rats and inhalation exposures of mice and rats (Sweeney et al. 1997) and humans (Sweeney et 

al. 2001). 

Target Tissues. The model has been used to predict parent compound, monoepoxide, and diepoxide 

concentrations in the blood. 

Species Extrapolation. Mouse, rat, and human models have been developed. Extrapolation of 

predictions to animals would require additional species-specific values for physiology and metabolism, as 

well as animal data (available in the literature) to verify the accuracy of the predictions. 

High-low Dose Extrapolation. The model has been evaluated for simulating inhalation exposures in 

mice and rats ranging from 60 to 1,250 ppm in rodents and 5 ppm in humans. 

Interroute Extrapolation. The model was designed to simulate inhalation exposures. Additional 

parameters and absorption expressions must be added (and optimized with oral or dermal data) in order to 

extrapolate internal dosimetry from inhalation exposures across other routes of exposure. 

Strengths and Limitations. Strengths of this model include simulation of an alternative oxidative 

pathway for 1,3-butadiene (other than leading to 1,2-epoxy-3-butene); simulations of both enzymatic and 

nonenzymatic elimination of 1,3-butadiene metabolites; and simulation of production and utilization of 

glutathione. 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Formation of Reactive Metabolites. The role of metabolism of 1,3-butadiene to reactive metabolites and 

the importance of species differences in metabolism of 1,3-butadiene to human health risk assessment 

were recently reviewed by Kirmam et al. (2010a). As discussed in Section 3.4.3 (Toxicokinetics/ 

Metabolism; also see Figure 3-2), 1,3-butadiene is metabolized by oxidation, hydrolysis, and conjugation 

reactions, with oxidation and hydrolysis reactions leading to the formation of several reactive epoxide 

intermediates. Of the reactive intermediates formed, EB (formed by oxidation of 1,3-butadiene), DEB 

(formed by oxidation of EB), and EBD (formed by hydrolysis reactions of DEB) are reactive electrophilic 
 

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compounds that have been shown to interact with DNA. The order of genotoxic potency of the epoxide 

metabolites is DEB >> EB > EBD. The higher genotoxic potency of DEB may be due to its ability to 

bind to two molecules or two places in the molecule at the same time (e.g., DNA-protein cross-links or 

DNA cross-links) (see discussion below in Section 3.5.2 on mechanisms of genotoxicity) (Albertini et al. 

2010). Thus, the formation of reactive metabolites is critical to the genotoxic activity of 1,3-butadiene. 

Although little information was identified regarding the role of reactive metabolites in the development of 

other adverse effects of 1,3-butadiene (e.g., nongenotoxic, noncancer), given their reactive nature, it is 

likely that reactive epoxide metabolites play an important role in the development of other adverse 

effects. 

Species Differences in Metabolism. Metabolism of 1,3-butadiene appears to follow the same enzymatic 

pathways in all species, including humans, with production of the same reactive intermediates. However, 

as discussed below, important species differences exist in the rates of formation and detoxification of 

reactive metabolites (Bond et al. 1993; Csanády et al. 1992; Dahl et al. 1991; Filser et al. 2001, 2007, 

2010; Himmelstein et al. 1997; Henderson et al. 1996, 2001; Kirman et al. 2010a; Krause and Elfarra 

1997; Schmidt and Loeser 1985; Thornton-Manning et al. 1995a). As a result, rodents, particularly mice, 

have much higher tissue levels of reactive metabolites than nonhuman primates and humans. Therefore, 

based on the assumption that the same mechanism of action is involved in the development of 1,3-butadiene-induced toxicity (i.e., interaction of the reactive metabolites with DNA and other cellular 

macromolecules) is the same for all species, mice are expected to be much more sensitive to 1,3-butadiene than other rats, nonhuman primates, and humans. 

As reviewed by Kirman et al. (2010a), evidence for species differences in metabolism of 1,3-butadiene is 

available from in vitro studies, studies using isolated perfused livers, and in vivo studies measuring tissue 

and urine metabolite levels and blood hemoglobin adduct levels. Results of in vitro studies using hepatic 

microsomal fractions isolated from mice, rats, and humans show that conversion of EB to DEB in mice is 

3.3-fold greater than in rats and 2.4–61-fold greater than in humans. Studies in isolated perfused livers 

show differences in metabolism of 1,3-butadiene in mice and rats. In livers perfused with 1,3-butadiene, 

three epoxide metabolites (EB, DEB, and EBD) were identified in perfusion effluent in mice, whereas 

only one epoxide metabolite (EB) was identified in rats. Effluent concentrations of EB in mice were 

8.5-fold greater than in rats. For perfusion studies with EB (which is oxidized to form DEB), DEB 

formation was greater in mice than in rats. Metabolite levels in tissues following inhalation exposure of 

mice and rats to 1,3-butadiene also provide evidence of species differences. Compared to rats, EB and 

DEB levels in blood and tissues of mice were from approximately 2–15- and >100-fold higher, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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respectively, with levels exhibiting dose- and time-dependence (see discussion below on nonlinear 

kinetics) (Filser et al. 2007). Based on evaluation of hemoglobin adduct biomarkers (adducts formed by 

interaction of 1,3-butadiene metabolites with hemoglobin), mice appear to have higher DEB levels than 

rats and much higher levels than humans (Swenberg et al. 2011). However, quantitative measurements of 

differences in hemoglobin adduct profiles show considerable variability, possibly due to differences in 

exposure conditions. Comparison of urinary excretion profiles of 1,3-butadiene metabolites in mice, rats, 

and humans also shows that species differences exist in the detoxification pathways. Findings suggest 

that humans and rats are more “efficient” at detoxification of reactive metabolites than mice. Taken 

together, results of in vitro and in vivo studies showing that mice have higher levels of reactive 

metabolites, particularly the highly reactive DEB, than other species suggest that mice may be uniquely 

sensitive to toxic effects of 1,3-butadiene and, therefore, may not be an appropriate animal model for use 

in human health risk assessment of 1,3-butadiene. 

Nonlinear Toxicokinetics (Metabolism). Metabolism of 1,3-butadiene exhibits nonlinear kinetics 

(Kirman et al. 2010a), with both dose- and duration-dependent effects (see discussion in Section 3.4.3 

Toxicokinetics/Metabolism). Because the formation of reactive metabolites are critical in the 

development of 1,3-butadiene toxicity, nonlinearity in metabolic processes has the potential to affect 

dose-response extrapolation from animals to humans. Several processes have been proposed as sources 

of nonlinear kinetics; these include inhibition, induction and saturation of various metabolizing enzymes 

and depletion of glutathione (as reviewed by Kirman et al. 2010a). 

3.5.2 Mechanisms of Toxicity 

Genotoxicity. The genotoxicity of 1,3-butadiene and its electrophilic metabolites have been extensively 

studied. A comprehensive review of the genotoxicity of 1,3-butadiene metabolites, focusing primarily on 

EB, DEB, and EDB, was recently published (Albertini et al. 2010). The weight of evidence strongly 

suggests that 1,3-butadiene metabolites, rather than 1,3-butadiene itself, are responsible for genotoxic 

effects, due to their highly reactive nature. Of these metabolites, the order of potency for mutagenicity is 

DEB >> EB > EDB. Results of in vitro studies in bacterial and mammalian cells (including human cells) 

show that the electrophilic metabolites of 1,3-butadiene form DNA adducts, induce DNA strand breaks, 

increase unscheduled DNA synthesis and DNA excision repair, induce sister-chromatid exchange, induce 

micronucleus formation, and produce mutations, chromosome aberrations (including breaks), and 

aneuploidy (as reviewed by Albertini et al. 2010). Results of in vivo studies in animals show that 

1,3-butadiene metabolites form adducts with DNA (Koturbash et al. 2011a, 2011b). Other studies 

evaluating genotoxicity following inhalation exposure to 1,3-butadiene provide indirect evidence of 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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genotoxicity of 1,3-butadiene metabolites (Cunninham et al. 1986; Jauhar et al. 1988; Lovreglio et al. 

2006; Sharief et al. 1986; Sram e tal. 1998; Tice et al. 1987). 

Carcinogenicity. As discussed in Section 3.2.1.7, chronic exposure to 1,3-butadiene is associated with an 

increased risk of mortality due to leukemia in styrene-butadiene workers and the development of multisite 

cancers in laboratory rodents. The mode of action for carcinogenicity of 1,3-butadiene was recently 

assessed by Kirman et al. (2010b). As discussed above (Mechanism of Toxicity, Genotoxicity), the 

genotoxicity of electrophilic metabolites of 1,3-butadiene (DEB, EB, and EBD) have been extensively 

studied. Results show that DEB, EB, and EBD react with DNA and are mutagenic. Based on the weight 

of evidence for genotoxicity, it is likely that the carcinogenic mode of action of 1,3-butadiene is 

mutagenic activity of the electrophilic 1,3-butadiene metabolites. 

Ovarian atrophy. Intraperitoneal studies in mice suggest that 1,3-butadiene metabolites are the causative 

agent for the ovarian effects observed in intermediate- and chronic-duration inhalation studies (NTP 

1993). Dose-related decreases in ovarian and uterine weights, number of small (primordial) ovarian 

follicles, and number of growing (primary to pre-antral) ovarian follicles were observed following a 

30-day intraperitoneal exposure to EB or DEB (Doerr et al. 1996). The ED50 (i.e., the effective dose that 

reduces the number of follicles to 50% of controls) values for small and growing follicles were 0.29 and 

0.40 mmol/kg, respectively, for EB and 0.10 and 0.14 mmol/kg, respectively, for DEB. Similarly, 

decreases in ovarian or uterine weight and the number of ovarian follicles were also observed in rats 

similarly exposed to DEB (Doerr et al. 1996). However, no alterations were observed in rats 

administered EB at doses as high as 1.43 mmol/kg. These data strongly suggest that DEB is the causative 

agent of the ovarian atrophy. 

Although similar effects were observed in rats and mice administered DEB, mice appear to be more 

sensitive to its toxicity than rats. Administration of 0.14 mmol/kg resulted in 83 and 52% depletion of 

small and growing follicles, respectively, in mice and only 31 and 40% reductions in rats. When the 

dose-response plot for ovarian weight is based on area under the blood EB or DEB concentration-time 

curve (estimated using PBPK modeling), the curves are similar for both species (Sweeney et al. 2001). 

Sweeney et al. (2001) also used PBPK modeling to estimate the blood area under the DEB concentrationresponse curve using the data from the NTP (1993) study, which found ovarian effects in mice exposed to 

≥6.25 ppm, and from the Owen study (Owen and Glaister 1990; Owen et al. 1987), which did not find 

ovarian effects in rats exposed to ≤8,000 ppm. In mice, the blood area under the DEB curve was 

consistent with the results of the Doerr et al. 1996) intraperitoneal study. The blood DEB area under the 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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curve for rats exposed to 8,000 ppm 6 hours/day, 5 days/week for 105 weeks would be 189 μM-hour; this 

value lies between the predicted NOAEL and LOAEL for ovarian effects in rats administered DEB via 

intraperitoneal injection. 

3.5.3 Animal-to-Human Extrapolations 

Comparison of rat and mouse data identify large differences in sensitivity to 1,3-butadiene, which are due 

to metabolic differences between species. Humans, rats, and mice metabolize 1,3-butadiene using the 

same enzymatic pathways resulting in the production of the same reactive metabolites, in particular, EB, 

DEB, and EBD. However, quantitative differences in the rate of formation and detoxification of reactive 

metabolites have been found that result in higher tissue levels of reactive metabolites in rodents, 

particularly mice, than in humans (Bond et al. 1993; Csanády et al. 1992; Dahl et al. 1991; Filser et al. 

2001, 2007, 2010; Henderson et al. 1996, 2001; Himmelstein et al. 1997; Kirman et al. 2010a; Krause and 

Elfarra 1997; Schmidt and Loeser 1985; Thornton-Manning et al. 1995b). In vitro and perfusion data 

show that mice are more efficient than rats at oxidizing 1,3-butadiene to form EB, and the conversion of 

EB to DEB in mice is 3.3-fold greater than in rats and 2.4–61-fold greater than in humans (Kirman et al. 

2010a). In addition, mice have a higher ratio of 1,3-butadiene activation to detoxification than rats or 

humans; the ratio of activation to detoxification was 74:1 in mouse, 6:1 in rat, and 6:1 in human liver 

tissues (Bond et al. 1993). 

Following inhalation exposure to 1,3-butadiene, blood and tissue levels of EB and DEB were 2–15- and 

>100-fold higher, respectively, in mice as compared to rats (Filser et al. 2007). At equivalent inhalation 

concentrations, the total amount of 1,3-butadiene metabolites were 5–50 times lower in cynomolgus 

monkeys than in mice and 4–14 times lower in monkeys compared to rats (Dahl et al. 1991). Swenberg et 

al. (2011) estimated DEB blood levels measured 1,3-butadiene-derived hemoglobin adducts levels in rats, 

mice, and humans exposed to approximately 1 ppm 1,3-butadiene. The estimated DEB doses were 0.02, 

0.42, and 24 nM-hour/ppm-hour in humans, rats, and mice, respectively. Thus, the extrapolation of 

rodent data to humans would require the use of an internal dose metric to account for these species 

differences in the metabolism of 1,3-butadiene. Although PBPK models have been developed in rodents 

(Johanson and Filser 1993; Kohn and Melnick 1993, 1996, 2000) and a preliminary model has been 

developed in humans (Brochot et al. 2007), the models are limited in their ability to predict internal doses 

for key metabolites (Kirman and Grant 2012). An alternative approach to using PBPK models would be 

to use a biomarker of exposure to the reactive metabolites. Several biomarkers of exposure have been 

identified for reactive 1,3-butadiene metabolites including MHB-Val hemoglobin adducts, N-(2,3,4-tri-
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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hydroxybutyl)valine (THB-Val) hemoglobin adducts, and pyr-Val hemoglobin adducts, which have been 

shown to be good surrogate biomarkers for EB, EBD, and DEB, respectively (Georgieva et al. 2010; 

Slikker et al. 2004). 

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 Thomas and Colborn (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 

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). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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No in vivo or in vitro studies were located regarding endocrine disruption in humans and/or animals after 

exposure to 1,3-butadiene. 

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 

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 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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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. 

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). 

No human data are available to determine whether children are more sensitive than adults to 1,3-butadiene toxicity. Mechanistic data in animals suggest that the ratio of 1,3-butadiene oxidation:epoxide 

hydrolysis may be a significant determinant of 1,3-butadiene sensitivity (see Sections 3.5.1 and 3.5.2). It 

is not known if the ratio of 1,3-butadiene oxidation:epoxide hydrolysis is different in children than adults. 

Unborn children may be more sensitive to 1,3-butadiene toxicity than adults, as changes in fetal body 

weight and developmental effects have been identified at the lowest LOAELs in mice exposed to acuteand intermediate-duration inhalation exposures (Anderson et al. 1996; DOE/NTP 1987b). Several studies 

have associated the development of childhood leukemia to close proximity of birthplace to industrial 

point sources of 1,3-butadiene (and other high-volume industrial chemicals, including benzene) (Knox et 

al. 2005, 2006; Reynolds et al. 2003; Whitworth et al. 2008). Although these study authors suggest that 

in utero exposure to 1,3-butadiene may have significantly contributed to cancer risks in these populations, 

there are no estimates of actual prenatal or postnatal exposures of mothers or children, respectively. 

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). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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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, 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 1,3-butadiene 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 

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 1,3-butadiene 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 1,3-Butadiene 

Two urinary metabolites of 1,3-butadiene have been identified in tollbooth workers. Sapkota et al. (2006) 

measured 258–378 ng/mL 1,2-dihydroxy-4-(N-acetylcysteinyl)-butane and 6–9.7 ng/mL of the isomeric 

mixture of 1-hydroxy-2-(N-acetylcysteinyl)-3-butene and 1-(N-acetylcysteinyl)-2-hydroxy-3-butene in 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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workers’ urine following average ambient 1,3-butadiene exposures of 0.4–1 ppb. These biomarkers are 

quite specific to 1,3-butadiene exposure, but the measured levels were not significantly associated with 

exposure, although this may have been due to the small sample size used or the low (0.0005 ppm) 

exposure levels studied. N-acetyl-S-((1-hydroxymethyl)-2-propenyl)cysteine and N-acetylS-((2-hydroxymethyl)-3-propenyl)cysteine, the isomeric mixture known as MHBMA (or M2), are the 

GST conjugation products of EB found in human urine following 1,3-butadiene exposure. Another 

urinary metabolite, N-acetyl-S-(3,4-dihydroxybutyl)cysteine, or DHBMA (M1), is formed by EBdiol 

conjugation with glutathione via GST (Boogaard et al. 2001a; McDonald et al. 2004). These urinary 

metabolites have been used as biomarkers of 1,3-butadiene exposures in several human studies (Albertini 

et al. 2001, 2007; Ammenheuser et al. 2001; Boogaard et al. 2001a; Fustinoni et al. 2004). 

Protein adducts have been widely used to monitor the formation of alkylating metabolites and can be used 

as dose metrics to compare species differences in metabolism. Hemoglobin adducts accumulate over the 

lifespan of the erythrocyte and they represent cumulative exposure since they are not removed by 

enzymatic repair systems (Georgieva et al. 2010). Three N-terminal valine hemoglobin adducts have 

been identified for 1,3-butadiene: MHB-Val, THB-Val, and pyr-Val. MHB-Val, THB-Val, and pyr-Val 

are formed when EB, DEB, and EB-diol, respectively, react with hemoglobin (Georgieva et al. 2010; 

Slikker et al. 2004). A linear accumulation of MHB-Val and THB-Val was observed in B6C3F1 mice 

and Sprague-Dawley rats after intraperitoneal (Sun et al. 1989b) and inhalation (HEI 2000) exposures. 

Species differences have been detected in the amount of adducts formed at a given 1,3-butadiene 

concentration. Higher levels of MHB-Val and pyr-Val adducts were found in mice compared to rats 

(Albrecht et al. 1993; Boysen et al. 2004). Concentration-response studies have shown that the formation 

of pyr-Val hemoglobin adducts is saturable. In rats, the formation of pyr-Val adducts plateaus at 

inhalation exposures of ≥200 ppm (Georgieva et al. 2010). In mice, the formation of pyr-Val adducts did 

not plateau; however, the rate of formation decreased below 1.5 ppm (Georgieva et al. 2010). MHB-Val 

and THB-Val hemoglobin adduct levels were well correlated with 1,3-butadiene exposure in 

1,3-butadiene monomer workers (Albertini et al. 2001, 2007; Begemann et al. 2001a, 2001b; OstermanGolkar et al. 1996) and Chinese polymer workers (Hayes et al. 2000; HEI 2000). Pyr-Val was not 

detected in blood of male and female Czech workers exposed to 0.2–0.4 ppm (Albertini et al. 2007). 

Pyr-Val adducts were detected in the blood of workers not occupationally exposed to 1,3-butadiene, in 

monomer workers and polymerization workers (Boysen et al. 2012); the levels in the polymerization 

workers (mean 1,3-butadiene exposure level of 0.81 ppm) were significantly higher than in the control 

and monomer workers (mean 1,3-butadene exposure levels of 0.01 and 0. 29 ppm, respectively). When 

the three groups of workers were combined, a significant association between pyr-Val adduct levels and 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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individual 1,3-butadiene exposure levels was found. Using levels of these hemoglobin adducts, 

Swenberg et al. (2011) estimated metabolite levels in rats, mice, and humans, which allowed for a species 

comparison of reactive metabolite levels at a given 1,3-butadiene concentration. 

Zhao et al. (2000) found a significant linear relationship of DNA adduction and 1,3-butadiene exposure 

between 1,3-butadiene workers and controls. The levels of N1-(2,3,4-trihydroxybutyl)adenine adduct in 

lymphocytes of 1,3-butadiene workers (mean exposure: 0.3 ppm; range: <0.005–7.7 ppm) were 5-fold 

higher than controls (mean exposure: 0.01 ppm; range: <0.001–0.07 ppm). 1,3-Butadiene-specific 

urinary metabolites and hemoglobin and DNA adducts have also been observed in animals. Excretion of 

1,3-butadiene metabolites was reported to be high in the urine of exposed monkeys (Dahl et al. 1990). 

DNA adducts were detected in the livers of mice and rats exposed to radiolabeled 1,3-butadiene (Kreiling 

et al. 1986b). In mice exposed to 1,3-butadiene by nose-only inhalation, the N7-guanine adduct 

(N7-(1-(hydroxymethyl)-2,3-dihydroxypropyl)guanine) from interaction with 3,4-epoxy-1,2-diol, was the 

major DNA adduct measured (Boogaard et al. 2001b). 

1,3-Butadiene has been measured in expired air of forestry workers living in mountain villages (Perbellini 

et al. 2003); however, the levels measured (median of 1.2 ng/L) were not correlated with any exposure to 

1,3-butadiene. 

3.8.2 Biomarkers Used to Characterize Effects Caused by 1,3-Butadiene 

Dermal, ocular, and/or upper respiratory irritation can occur following 1,3-butadiene exposure (NIOSH 

2005) and may alert the exposed individual. However, the effects are not specific for 1,3-butadiene 

exposure and may be caused by several other chemicals. 

Given the genotoxic (Section 3.3) and carcinogenic (Section 3.2.1.7) activity of 1,3-butadiene, a useful 

biomarker of effect would correlate a quantifiable measure of genetic mutation with 1,3-butadiene 

exposure. 1,4-Bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) and 1-(guan-7-yl)-4-(aden-1-yl)-

2,3-butanediol (N7G-N1A-BD) are DEB-specific DNA-DNA cross-links identified in rats and mice 

inhaling up to 625 ppm 1,3-butadiene (Goggin et al. 2009, 2011). Mice exhibited 4–10-fold higher levels 

than rats of these cross-links. Further, higher levels of bis-N7G-BD were measured in females, compared 

to males. The sensitivity of female mice to these biomarkers and to 1,3-butadiene-induced 

carcinogenicity suggests that: (1) DEB is the putative carcinogenic metabolite of 1,3-butadiene, and 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 96 

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(2) bis-N7G-BD and N7G-N1A-BD levels may quantitatively inform on genotoxicity leading to tumor 

development. 

Another biomarker of genetic change is the mutation frequency of the hprt gene locus in human 

peripheral lymphocytes, which has been used in multiple studies of 1,3-butadiene SBR, monomer, and 

polymer workers in the United States, China, and Czech Republic. These studies are discussed in detail 

in Section 3.3. Several of these studies demonstrated good correlation between the increase in hprt 

mutation frequency and 1,3-butadiene exposure (Abdel-Rahman et al. 2001, 2003, 2005; Ammenheuser et 

al. 2001; Ma et al. 2000; Ward et al. 1994, 1996, 2001), as well as correlation with urinary and 

hematological biomarkers of exposure. Others did not find a significant correlation between exposure 

and mutation frequency (Albertini et al. 2001, 2007; Hayes et al. 1996, 2000; HEI 2003; Liu et al. 2008; 

Tates et al. 1996). The reasons for the differences in sensitivity of the hprt mutation as a biomarker may 

include the very low exposures that were studied and differences in assay procedures (as discussed in 

Section 3.3). It is unclear at this time which hprt mutation frequency assay is most adequate for risk 

assessment. 

Two biomarkers for carcinogenic effect have been consistently found in multiple tumors sites in rodent 

chronic bioassays. A number of malignant gliomas and neuroblastomas in mice chronically inhaling 

1,3-butadiene exhibited mutations of the p53 gene and H- and K-ras oncogenes (Kim et al. 2005), which 

have also been observed in forestomach tumors (Sills et al. 2001), hemagiosarcomas (Hong et al. 2000), 

and lymphomas (Zhuang et al. 1997) of chronically exposed mice. 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

In addition to 1,3-butadiene, workers in the rubber industry are exposed to other chemicals, including 

styrene and its mutagenic metabolite, styrene oxide (Loprieno et al. 1978; Norppa et al. 1980; Pohlova 

et al. 1985; Watabe et al. 1978), as well as dithiocarbamates (Irons and Pyatt 1998). It is unclear whether 

these other chemicals or their active metabolites have a synergistic harmful effect in humans, but a 

multivariate analysis of an SBR worker cohort (HEI 2006) did not detect interactive effects of coexposure to 1,3-butadiene, styrene, and dimethyldithiocarbamate (DMDTC). Animal studies have found 

that DMDTC can qualitatively and quantitatively effect the metabolism of 1,3-butadiene. In vitro studies 

show that DMDTC treatment decreases the metabolism of 1,3-butadiene to EB and the metabolism of 

epoxybutene to DEB in rats and mice (Green et al. 2001). Styrene has been shown to inhibit the 

metabolism of 1,3-butadiene in rats simultaneously exposed to both compounds (Laib et al. 1992; 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Leavens et al. 1996). The inhibition was only observed at 1,000 ppm 1,3-butadiene concentration and not 

at 100 ppm (Leavens et al. 1996). However, blood levels of EB increased and the blood levels of DEB 

were unaffected by styrene co-exposure, as compared to exposure to 1,3-butadiene only (Leavens et al. 

1996). Thus, co-exposure to styrene may not affect the toxicity of 1,3-butadiene. Inhalation exposure to 

1,3-butadiene and styrene did not affect the genotoxic potential of 1,3-butadiene in mice (Leavens et al. 

1997). 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to 1,3-butadiene than will most 

persons exposed to the same level of 1,3-butadiene 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 1,3-butadiene, or compromised function 

of organs affected by 1,3-butadiene. Populations who are at greater risk due to their unusually high 

exposure to 1,3-butadiene are discussed in Section 6.7, Populations with Potentially High Exposures. 

The human and animal data do not identify a gender-specific susceptibility to 1,3-butadiene. Human in 

vivo data do not identify specific populations that may be sensitive to the effects of 1,3-butadiene. 

Polymorphisms in metabolic enzymes may affect the toxicokinetics of 1,3-butadiene and render some 

individuals more sensitive to toxicity, based on increased sensitivity to genetic changes seen in these 

groups. Lymphocytes from GSTT1-null 1,3-butadiene workers in Texas had higher induction of sister 

chromatid exchange following in vitro DEB exposure (Kelsey et al. 1995), while GSTT1-null Czech 

workers exhibited higher rates of chromosomal aberrations (Sorsa et al. 1996). However, no such effects 

were observed in other Czech (Sram et al. 1998) or Chinese (Hayes et al. 2000) workers that were GSTT1 

or GSTM1 deficient. Increased hprt mutation frequencies have been reported in U.S. 1,3-butadiene 

workers with various polymorphisms in EH (Abdel-Rahman et al. 2001, 2003, 2005). In in vitro studies 

with human lymphocytes, EB induced higher levels of sister chromatid exchanges in GSTM1-null 

samples, as compared to GSTM1 samples (Uusküla et al. 1995), suggesting that the clastogenic change 

may the result of less EB being detoxified via GSTM1-mediated glutathione conjugation. Similarly, EB 

induced higher levels of sister chromatid exchanges in lymphocytes from GSTT1-null individuals, as 

compared to GSTT1-positive individual (Bernardini et al. 1998). 

The relationship between polymorphisms and the urinary excretion of M1 and M2 metabolites has been 

exposed in studies of Czech 1,3-butadiene workers. GST polymorphisms resulted in shifts in the mean 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 98 

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ratio of M2/(M1 + M2) (indicative of the activity of EB glutathione conjunction pathway), which was 

significantly lower in GSTM1-null workers, as compared to GSTM1-positive workers (HEI 2003); a 

lower ratio was also found in the GSTT1-null workers, but it was not significantly different from the 

GSTT1-positive workers. No significant alterations in M1 or M2 concentrations or the ratio were found 

for workers genotyped for CYP2E1, EH, and ADH polymorphisms. Regression analysis revealed that the 

slopes of the 1,3-butadiene concentration-M2 levels and concentration-M2/(M1+M2) was significantly 

different in CYO2E1 D/D intron 6 polymorphism compared to workers who were heterozygous for C/D 

(HEI 2003). In a subsequent study by this group, a significant difference in M2/(M1+M2) ratio was 

observed in the GSTT1-null workers (Albertini et al. 2007). When different EH genotypes were 

combined into high, intermediate, and low activity phenotypes, significantly higher M2 levels were 

observed in the low activity genotype group (Albertini et al. 2007). 

Animals studies indicate that the predominant factor in species sensitivity is related to the toxicokinetics 

of 1,3-butadiene, specifically, the ratio of P450-mediated oxidation:epoxide hydrolase activity (see 

Section 3.4.3). Human populations that have a higher ratio of 1,3-butadiene oxidation:hydrolysis 

metabolism may also be more sensitive, although such populations have not been identified. In terms of 

absorption capacity, Asian volunteers had about 20% greater fractional absorption of inhaled 

1,3-butadiene than did Caucasians, African-Americans, or Hispanics (Lin et al. 2001). However, it is not 

known if this results in higher internal doses of the putative epoxide toxicants. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to 1,3-butadiene. However, because some of the treatments discussed may be experimental and 

unproven, this section should not be used as a guide for treatment of exposures to 1,3-butadiene. When 

specific exposures have occurred, poison control centers and medical toxicologists should be consulted 

for medical advice. 

3.11.1 Reducing Peak Absorption Following Exposure 

No specific antidotes for 1,3-butadiene are available; however, recommendations have been made for 

general treatment of intoxicated persons (Bronstein and Currance 1988; Stutz and Janusz 1988). First, the 

exposed individual should be removed from the contaminated area and contaminated clothing should be 

taken away (Currance et al. 2007; Leikin and Paloucek 2002). It has been suggested that exposed skin 

should be washed with soapy water and contaminated eyes should be flushed with water. Inhalation 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 99 

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exposure to high 1,3-butadiene concentrations may result in narcosis leading to respiratory paralysis and 

death. Data have shown that neurological effects, including anesthesia have been observed in animals 

exposed to 250,000 ppm (Carpenter et al. 1944). Therefore, administration of oxygen has been used and 

ventilation has been assisted as needed in cases of 1,3-butadiene poisoning. 

3.11.2 Reducing Body Burden 

No information is available regarding displacing or removing absorbed 1,3-butadiene prior to metabolism 

to reactive metabolites. 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

Toxicity studies found mice to be extremely sensitive (DOE/NTP 1987b; Melnick et al. 1989, 1990b; 

NTP 1993). Studies on the metabolism of 1,3-butadiene demonstrated that the chemical is converted to 

its epoxy derivatives by P450 isoforms in lung, liver, kidney (see Section 3.4.3), and possibly other 

tissues. The epoxides may be responsible for most toxic and carcinogenic effects caused by 1,3-butadiene 

exposure. The epoxides are detoxified by hydrolysis or conjugation with glutathione (Kreiling et al. 

1988). A higher rate of epoxide formation and a greater depletion of hepatic nonprotein sulfhydryl 

content in mice is probably responsible for their higher susceptibility to 1,3-butadiene toxicity. Since the 

macromolecular covalent binding is enhanced only after a substantial decrease of glutathione levels 

(Kreiling et al. 1988), sufficient availability of glutathione should mitigate the effects of 1,3-butadiene 

exposure. 

Interference with the oxidative metabolism of 1,3-butadiene may also be effective in allowing pulmonary 

clearance of the parent compound to occur before reactive epoxides are formed. In mice, a 30–56% 

reduction in induction of erythrocyte micronuclei was observed in mice pretreated with various P450 

inhibitors (Jackson et al. 2000b). However, the side effects of systemically inhibiting P450s in humans 

are unknown. 

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 1,3-butadiene is available. Where adequate information is 

not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 100 

3. HEALTH EFFECTS 

the initiation of a program of research designed to determine the health effects (and techniques for 

developing methods to determine such health effects) of 1,3-butadiene. 

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 1,3-Butadiene 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

1,3-butadiene are summarized in Figure 3-4. The purpose of this figure is to illustrate the existing 

information concerning the health effects of 1,3-butadiene. 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 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 seen from Figure 3-4, information regarding acute systemic effects (respiratory tract irritation and 

narcotic effect), chronic systemic effects (respiratory irritation), genotoxicity, and cancer exists for 

inhalation exposure in humans. No information was located regarding oral or dermal exposure of humans 

to 1,3-butadiene. 

Inhalation studies in animals provide data on death, systemic effects, immunologic effects, neurologic 

effects, reproductive and developmental effects, genotoxicity, and carcinogenicity. No information was 

located regarding effects in animals after oral or dermal exposure to 1,3-butadiene. 

3.12.2 Identification of Data Needs 

No studies were located regarding effects following oral or dermal exposure, and no pharmacokinetic 

studies by the oral or dermal routes were located; therefore, it is not possible to predict if effects 
 

1,3-BUTADIENE 101 

3. HEALTH EFFECTS 

Figure 3-4. Existing Information on Health Effects of 1,3-Butadiene 

Inhalation 

Oral 

Dermal 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Human 

Inhalation 

Oral 

Dermal 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Animal 

Existing Studies 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 102 

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following oral or dermal exposure would be similar to those observed after inhalation exposure. Because 

1,3-butadiene exists primarily as a gas and has been detected in soil off-gases at hazardous waste sites, 

inhalation exposure appears to be the greatest concern. However, it is not known if 1,3-butadiene is 

present in groundwater or soil at these hazardous waste sites because it is difficult to analyze these media 

for the compound. 1,3-Butadiene has been detected in industrial waste water and drinking water, and is 

poorly soluble in water (735 ppm). Therefore, oral and dermal routes of exposure cannot be ruled out. 

Information concerning 1,3-butadiene toxicity by these routes of exposure would be useful. 

Acute-Duration Exposure. Acute inhalation exposure to very high concentrations (>25,000 ppm) of 

1,3-butadiene may lead to narcosis and death by respiratory paralysis in animals (Carpenter et al. 1944). 

Data in humans are limited to a study of two men exposed to various concentrations of 1,3-butadiene for 

6–8 hours that examined clinical signs and psychomotor function (Carpenter et al. 1944). No studies 

were located that correlated the level of exposure with the first signs of toxicity in humans or animals. 

Developmental effects were seen in mice after exposure to concentrations as low as 40 ppm (DOE/NTP 

1987b; Irvine 1981). Although the available animal data identify critical targets of toxicity following 

acute-duration inhalation exposure, the database lacks adequate toxicokinetic and PBPK modeling data, 

which could be used to account for species differences in the metabolism of 1,3-butadiene; thus, an acuteduration MRL was not derived. Additionally, there are limited data on the potential effects of the parent 

compound, such as neurotoxicity, which may be a more sensitive target of toxicity in humans. Because 

people living at or near these hazardous waste sites may be exposed for brief periods of time, more doseresponse data for acute exposures by oral and inhalation routes is considered to be important. 

Intermediate-Duration Exposure. No information is available regarding effects of 1,3-butadiene 

during intermediate-duration exposure in humans. No studies were located regarding effects in humans 

or animals following oral or dermal exposure to 1,3-butadiene, and pharmacokinetic data for these routes 

of exposure are insufficient to predict whether the disposition or toxicity of 1,3-butadiene following oral 

or dermal exposure would be similar to that following inhalation exposure. Therefore, information 

regarding the toxicity of 1,3-butadiene by the oral route of exposure would be useful. Several studies on 

intermediate-duration inhalation exposure to 1,3-butadiene have been conducted in animals (Anderson et 

al. 1996, 1998; Crouch et al. 1979; Irons et al. 1986a; NTP 1984, 1993; Thurmond et al. 1986). Atrophy 

of reproductive organs, anemia, precancerous hyperplasia in multiple organs, and cancer occurred in mice 

exposed to ≥200 ppm (Irons et al. 1986a; NTP 1984, 1993). The observed hematological changes 

(macrocytic megaloblastic anemia) were similar to those found in human preleukemic syndrome (Biemer 

1983), suggesting that 1,3-butadiene exposure might interfere with normal bone marrow cell 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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development. Further investigation of this topic could be valuable since epidemiological studies in 

humans indicate that hematopoietic tissue may be a possible target for 1,3-butadiene toxicity (Checkoway 

and Williams 1982). Several studies have identified potential targets of toxicity following intermediateduration exposure; however, the available toxicokinetic and PBPK modeling data do not allow for 

adequate adjustment for species differences in the metabolism of 1,3-butadiene. Thus, intermediateduration inhalation MRLs were not derived. 

Chronic-Duration Exposure and Cancer. Possible risk for hematological disorders was reported 

in humans after chronic inhalation exposure to 1,3-butadiene in occupational settings, but exposure levels 

are lacking, and exposure to other chemicals occurs in these settings (Checkoway and Williams 1982). 

However, other studies (Cowles et al. 1994; Tsai et al. 2005) that monitored 1,3-butadiene levels have not 

found hematological alterations. Well-conducted inhalation studies identified respiratory effects, liver 

necrosis, gonadal atrophy, multi-site cancer, and increased mortality in mice at exposures as low as 

6.25 ppm (Melnick et al. 1989, 1990a; NTP 1984, 1993), while renal pathology, cancer, and increased 

mortality were observed in rats exposed to ≥1,000 ppm (Owen et al. 1987). Because a serious LOAEL of 

severe ovarian atrophy (with complete destruction of oocytes, follicles, and corpora lutea) was found at 

6.25 ppm, with no associated NOAEL, no chronic MRL has been derived. Chronic-duration studies are 

needed that identify a NOAEL in mice for gonadal atrophy. Oral studies are lacking, and toxicokinetic 

data are insufficient to predict toxicity across routes of exposure. Therefore, information concerning the 

possible toxicity of 1,3-butadiene by this route would be useful to identify the target organs and the 

thresholds for toxic effects. 

Epidemiological studies in humans indicate a possible increase in risk of leukemia from occupational 

exposure to 1,3-butadiene (Cheng et al. 2007; Delzell et al. 1996; Divine 1990; Divine and Hartman 

2001; Divine et al. 1993; Downs et al. 1987; Macaluso et al. 1996; Matanoski and Schwartz 1987; 

Matanoski et al. 1982, 1989a, 1989b, 1990; McMichael et al. 1974, 1975, 1976; Meinhardt et al. 1982; 

Ward et al. 1995). This is supported by the information about mutagenic activity of 1,3-butadiene 

metabolites (de Meester 1988) and by well-conducted chronic inhalation studies that provide information 

on carcinogenic effects of 1,3-butadiene in mice and rats (Melnick et al. 1989; NTP 1984, 1993; Owen et 

al. 1987). IARC (2009) and EPA (EPA 2002; IRIS 2012) concluded that there is sufficient evidence for 

the carcinogenicity of 1,3-butadiene in animals. IARC has classified 1,3-butadiene in group 1, 

carcinogenic to humans. EPA has classified 1,3-butadiene as a human carcinogen. The Department of 

Health and Human Services (NTP 2011) also identified 1,3-butadiene as a “known human carcinogen”. 

Further epidemiological investigations that examined additional potential targets of 1,3-butadiene toxicity 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 104 

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would be useful. Also, data are needed on 1,3-butadiene exposure to urban populations living in close 

proximity to major roadways and intersections, as well as on long-term follow-up of health effects, 

particularly the detection of diminishment in reproductive capability and prevalence of lymphohematopoietic cancers. 

No chronic oral or dermal carcinogenicity studies in animals were located, and pharmacokinetic data are 

insufficient to predict a carcinogenic potential of 1,3-butadiene by these routes. 

Genotoxicity. Studies of chromosomal aberrations, sister chromatid exchanges, and hprt mutation 

frequencies among petrochemical and 1,3-butadiene monomer workers exposed to low levels (≤2 ppm) 

provide conflicting results (Albertini et al. 2001, 2007; Ammenheuser et al. 2001; Hayes et al. 1996, 

2000; HEI 2003; Lovreglio et al. 2006; Sram et al. 1998; Tates et al. 1996; Ward et al. 1996, 2001; Zhou 

et al. 1986). 1,3-Butadiene has caused increases in micronuclei induction, chromosomal aberration 

frequency, and mutations of proto-oncogenes in in vivo studies of rats and mice following inhalation 

exposure (Autio et al. 1994; Cochrane and Skopek 1993; Cunningham et al. 1986; Irons et al. 1987b; 

Jauhar et al. 1988; Meng et al. 1999, 2000, 2004, 2007; Recio et al. 1992; Sills et al. 2001; Tice et al. 

1987; Vodicka et al. 2006). Information on the genotoxic effects of 1,3-butadiene was also obtained from 

in vitro studies in prokaryotic (Arce et al. 1989; de Meester 1988, de Meester et al. 1980; Victorin and 

Stahlberg 1988) and eukaryotic (Cochrane and Skopek 1993; Sasiadek et al. 1991) organisms. These data 

sufficiently characterize the mutagenic potential of 1,3-butadiene metabolites. 

Reproductive Toxicity. The atrophy of gonads in mice after chronic inhalation exposures as low as 

6.25 ppm 1,3-butadiene was reported (Melnick et al. 1989; NTP 1984, 1993). The fertility of rats, guinea 

pigs, or rabbits was reported to be unaltered by acute- and intermediate-duration inhalation exposure to 

1,3-butadiene (Anderson et al. 1996, 1998; Carpenter et al. 1944). Sperm head abnormalities were found 

in male mice exposed to 1,3-butadiene by inhalation (DOE/NTP 1988b). Further information regarding 

the reproductive effects of 1,3-butadiene in animals such as multigeneration studies would be useful to 

estimate the possible risk for reproductive effects in humans. An epidemiological study among exposed 

populations concentrating on reproductive effects would be useful. 

No studies were located regarding reproductive toxicity of 1,3-butadiene by the oral or dermal routes in 

humans or animals, and pharmacokinetic data were insufficient to suggest the potential for 1,3-butadiene 

to cause reproductive effects by these routes of exposure. The potential for exposure of humans by the 

oral and dermal routes, however, is not known. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Developmental Toxicity. No information on developmental toxicity in humans was located. A 

developmental study by the inhalation route indicated growth retardation in rat fetuses and an increase in 

major skeletal abnormalities at a concentration of 1,000 ppm of 1,3-butadiene (Irvine 1981). 

Furthermore, fetotoxicity was observed in mice at acute-duration exposures of 40 ppm and intermediateduration exposures of 12.5 ppm 1,3-butadiene (DOE/NTP 1987b). More data on developmental toxicity 

in other species (at least one of them nonrodent) would be useful to identify the possible developmental 

risk for humans. The developmental effects following other routes of exposure have not been studied, 

and pharmacokinetic data are insufficient to predict that responses would be similar to those by the 

inhalation route. Therefore, studies of oral exposures in animals to determine the possible developmental 

effects of 1,3-butadiene and the thresholds for these effects would be useful. 

Immunotoxicity. Reduction in thymus weight and lymphoid histopathology was seen after the 

intermediate-duration exposure of mice to ≥625 ppm 1,3-butadiene (NTP 1993; Thurmond et al. 1986). 

The indications of disturbances in hemato- and lymphatopoietic stem cell regulations were observed after 

inhalation exposure of mice to 1,3-butadiene (Liederman et al. 1986). The high incidence of lymphoma 

among mice after the chronic exposure (NTP 1984, 1993) also indicates that the immune system is a 

target. A battery of immune function tests has not been performed in humans or animals. More data 

regarding humans and animals would be useful for determining potential human immunotoxicity of 

1,3-butadiene. Studies regarding skin sensitization with 1,3-butadiene are lacking. 

Neurotoxicity. Narcosis has been demonstrated in animals after acute inhalation exposure to very high 

levels of 1,3-butadiene (250,000 ppm) (Carpenter et al. 1944). No reliable information was located 

regarding neurotoxicity due to chronic inhalation exposure or to oral or dermal exposure for any duration. 

Information regarding early, subtle signs of possible neurological effects with correlation to the exposure 

levels is lacking. A battery of neurological and neurobehavioral tests would be useful to better define the 

neurological end points. 

Epidemiological and Human Dosimetry Studies. Several epidemiological studies on health 

effects of 1,3-butadiene have been conducted (Case and Hosker 1954; Fox et al. 1974; Matanoski and 

Schwartz 1987; Matanoski et al. 1989a, 1989b; McMichael et al. 1974, 1975, 1976; Meinhardt et al. 

1982). The limitation of these studies is that the cohorts of exposed workers were recruited from the 

rubber industry, in which the people were exposed to a mixture of various chemicals. Some genotoxicity 

studies have been conducted among 1,3-butadiene manufacturing workers and petrochemical workers 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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exposed to low (≤2 ppm) exposures, but have reported conflicting results (Albertini et al. 2001, 2007; 

Ammenheuser et al. 2001; Hayes et al. 1996, 2000; HEI 2003; Kelsey et al. 1995; Lovreglio et al. 2006; 

Tates et al. 1996; Ward et al. 1996, 2001; Wickliffe et al. 2009; Zhou et al. 1986). Reliable dosimetry 

data on the exposed populations would be useful for good epidemiological comparisons. Efforts to 

improve estimates of past exposures and to more accurately define current exposure levels to 1,3-butadiene would be valuable. Epidemiological studies should concentrate on the possible carcinogenic effect 

of 1,3-butadiene in humans and on changes in hemato- and lymphatopoietic systems as possible targets 

for 1,3-butadiene induced toxicity. The data obtained from workers exposed occupationally to low 

concentrations of 1,3-butadiene could possibly be extrapolated to populations living near hazardous waste 

sites. 

Biomarkers of Exposure and Effect. 

Exposure. The determination of 1,3-butadiene-derived urinary metabolites (Albertini et al. 2001, 2007; 

Ammenheuser et al. 2001; Bechtold et al. 1994; Dahl et al. 1990; Hayes et al. 1996, 2000; Sapkota et al. 

2006; Ward et al. 1994, 1996), DNA adducts (Kreiling et al. 1986b; Sun et al. 1989b; Zhao et al. 2001), 

and hemoglobin adducts (Albertini et al. 2001, 2007; Begemann et al. 2001a, 2001b; Boogaard et al. 

2001b; Hayes et al. 2000; HEI 2000; Osterman-Golkar et al. 1996) of rats, mice, and humans exposed to 

1,3-butadiene has been performed. Data are needed that accurately correlate the level of biomarkers 

measured in the body, particularly for pyr-Val hemoglobin adducts with the exposure to 1,3-butadiene, as 

well as the variability in this correlation between sexes and ethnicity. 

Effect. Conflicting data exist for the sensitivity of human lymphocyte hprt mutation frequencies resulting 

from occupational exposures (Albertini et al. 2001, 2007; Ammenheuser et al. 2001; Hayes et al. 1996, 

2000; HEI 2003; Kelsey et al. 1995; Lovreglio et al. 2006; Tates et al. 1996; Ward et al. 1996, 2001; 

Wickliffe et al. 2009; Zhou et al. 1986). In mice and rats, levels of DEB-specific DNA-DNA cross-links 

correlated well with 1,3-butadiene inhalation and relative sensitivity of female mice to toxicity (Goggin et 

al, 2009). Two biomarkers for carcinogenic effect have been consistently found in multiple tumors sites 

in rodent chronic bioassays. A number of malignant gliomas and neuroblastomas in mice chronically 

inhaling 1,3-butadiene exhibited mutations of the p53 gene and H- and K-ras oncogenes (Kim et al. 

2005), which have also been observed in forestomach tumors (Sills et al. 2001), hemagiosarcomas (Hong 

et al. 2000), and lymphomas (Zhuang et al. 1997) of chronically exposed mice. Data for reliable and 

specific biomarkers indicating onset of developmental effects in animals would be useful to determine if 

comparable exposure may lead to these effects in humans. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 107 

3. HEALTH EFFECTS 

Absorption, Distribution, Metabolism, and Excretion. The timecouse of 1,3-butadiene and its 

primary metabolite, EB, in human blood has been investigated in volunteers inhaling 2 ppm for 

20 minutes (Lin et al. 2001). In vitro studies have characterized some of the metabolism dynamics of 

1,3-butadiene in animals (Bolt et al. 1983; Csanady et al. 1992; Duescher and Elfarra 1994; Elfarra et al. 

1996, 2001; Himmelstein et al. 1994, 1995; Jackson et al. 2000a; Kreiling et al. 1987; Laib et al. 1990; 

Malvoisin and Roberfroid 1982; Malvoisin et al. 1979; Schmidt and Loeser 1985, 1986; ThorntonManning et al. 1995b, 1997). Several toxicokinetic studies on 1,3-butadiene metabolism in vivo have 

been conducted in rats and mice following inhalation exposure (Bolt et al. 1983; Bond et al. 1987; 

Himmelstein et al. 1994; Kohn and Melnick 2001; Kreiling et al. 1986b; Shugaev 1969), but not 

following exposure by other routes. Thus, further studies in animals by the oral route to determine 

possible target organs by this route could be useful. Ethical considerations limit the testing of humans, 

but the development of methods to determine urinary and breath excretion of 1,3-butadiene and its 

metabolites by humans with known exposure to 1,3-butadiene may provide a means of monitoring 

humans for exposure. 

Comparative Toxicokinetics. The study by Schmidt and Loeser (1985) indicated that there is a 

difference between the capability of mouse and rat liver postmitochondrial fractions to produce 

1,2-epoxybutene-3 after incubation with 1,3-butadiene. Furthermore, monkey and human postmitochondrial liver preparations catalyzed the formation of only a small amount of the epoxide. Higher levels 

of the toxic epoxides were found in blood of mice following 1,3-butadiene exposure as compared to 

monkeys (Bolt et al. 1983; Csanady et al. 1992; Dahl et al. 1990; Duescher and Elfarra 1994; Elfarra et al. 

1996, 2001; Jackson et al. 2000a; Sun et al. 1989a). Species differences in the toxicokinetics of a 

chemical may account for differences in toxic responses. Analysis of the blood, breath, and urine of 

humans exposed to 1,3-butadiene for parent compound and metabolites over time would provide a greater 

knowledge of the human metabolic pathways. Qualitative and quantitative comparison of human 

metabolites with those of animals could help identify the most appropriate species to serve as a model for 

predicting toxic effects and mechanisms of action in humans. 

Methods for Reducing Toxic Effects. 

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. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 108 

3. HEALTH EFFECTS 

The sensitivity of children to 1,3-butadiene toxicity, if any, is unknown. In mice, acute- and intermediateduration inhalation exposures resulted in in utero fetal effects at exposure levels of 21.5–40 ppm 

(Anderson et al. 1996; DOE/NTP 1987b). No information is available for interfering with effects of 

1,3-butadiene toxicity in utero. 

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 

The following ongoing studies were identified in the Federal Research in Progress database (FEDRIP 

2009). 

E. Struble is being funded by EPA National Health and Environmental Effects Research Laboratory 

(HEERL) to use environmental irradiation chambers (smog chambers) to induce the natural 

photochemically stimulated transformations of environmental pollutants. The synthetic urban smog 

mixture is composed of 55 hydrocarbon species representative of the ambient air of an average city in the 

United States. In this study, A549 cells were exposed simultaneously to irradiated and non-irradiated 

chamber mixtures for 5 hours. Post exposure, adverse health effects were determined by measures of 

increased cellular stress cytokine release and cytotoxicity. Exposure to the photochemically-generated 

products of 1,3-butadiene, toluene, and methanol induced increases in both cytotoxicity and IL-8 gene 

expression compared to 1,3-butadiene, toluene, or methanol alone. The exposure design was used to 

investigate the toxicity of chemicals after photochemical reactions and interactions with the urban 

atmosphere on healthy and susceptible individuals using representative in vitro samples. This research 

informs the toxicity from exposures to multiple environmental pollutants found in urban settings. 

James A. Swenberg is being funded by the National Institute of Environmental Health Sciences (NIEHS) 

to examine the molecular dose of previously unexplored DNA adducts in rodents exposed to 

1,3-butadiene and 3-butene-1,2-diol (BD-diol). The data will be compared with mutation frequencies and 

mutational spectra to determine (1) if a particular adduct could be used as a mutagenic indicator, and 

(2) to determine the effects of exposure on gene expression. First, it will be determined if 

hydroxymethylvinyl ketone (HMVK) is formed in vivo during exposure to 1,3-butadiene and BD-diol in 

a sex-, species-, and exposure concentration-dependent manner, resulting in mutagenicity. Secondly, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 109 

3. HEALTH EFFECTS 

promutagenic N1 adenine adducts will be observed to see if they are converted to more stable inosine 

adducts, which may accumulate in tissues during chronic exposures. Several specific aims will be 

accomplished while addressing these questions. Specific Aim 1 is to examine the formation of potentially 

mutagenic DNA adducts (specifically 1, N2-propanodeoxyguanosine) by HMVK in vivo. Specific Aim 2 

is to determine the utility of the N-terminal valine adduct of HMVK (HMVK-Val) as a biomarker of 

HMVK formation by BD and BD-diol. Specific Aim 3 is to develop methods for detecting N1- inosine, 

N1- and N6-adenine adducts derived from BD metabolites in vivo. Specific Aim 4 is to determine the 

mutagenic responses induced by BD exposures and characterize the impact of BD-diol-derived 

metabolites on the spectra of mutations induced by BD exposure in the B6C3F1 mouse and F344 rat to 

identify which adducts studied in Aims 1 and 3 are quantitative indicators of mutagenesis. Specific Aim 

5 will examine the effects of exposure to BD and BD-diol on gene expression and DNA repair pathways. 

Collectively, these experiments have been designed to inform on adduct formation, DNA repair, 

mutagenicity, and genomic alterations in rodents exposed to 1,3-butadiene and BD-diol, as well as the 

impact of glutathione depletion and DNA repair deficiency. 

Elaine Symanski is being funded by the National Cancer Institute (NCI) to evaluate an association 

between lymphohematapoietic (LH) cancer incidence and air pollution in the Houston metropolitan area, 

with particular emphasis on three compounds: benzene, 1,3-butadiene, and styrene. Data from the Texas 

Cancer Registry (TCR) from 1995 to 2005 and the Texas Commission on Environmental Quality (TCEQ) 

from 1992 to 2003 will be analyzed to: (1) investigate the spatial and temporal distribution of LH cancer 

incidence in Harris and surrounding counties; (2) evaluate the association between distance from 

industrial sources and LH cancer incidence; (3) identify optimal methods for assessing ambient levels of 

benzene, 1,3-butadiene, and styrene using existing TCEQ monitoring data; and (4) evaluate the 

association between ambient levels of benzene, styrene, and 1,3-butadiene and LH cancer incidence using 

Poisson regression in single and multi-pollutant models. This will be the first study to examine this 

association in Harris and seven surrounding counties (Texas) and is among the first to utilize monitored 

levels of HAPs to assess increased risks of LH cancer associated with air pollution. This work will also 

correlate cancer rates with proximity to industrial facilities as well as ambient levels of benzene, styrene, 

and 1,3-butadiene. This study will address a gap in the literature by examining the association between 

HAPs and cancer incidence in Harris County, Texas and will further explore innovative methods to 

evaluate this association utilizing existing data sources. 

Natalia Y. Tretyakova is being funded by the National Cancer Institute to evaluate the role of DNA-DNA 

cross-linking in the genotoxicity of diepoxybutane and 1,3-butadiene. DEB-DNA cross-links will be 
 

 

 

 

 

1,3-BUTADIENE 110 

3. HEALTH EFFECTS 

structurally characterized and formation sequence preferences will be determined. The hydrolytic 

stability of DEB-DNA cross-links will be evaluated for their recognition by the E. coli UvrABC repair 

complex. DEB-DNA cross-links in rodent tissues will be quantified by capillary high performance liquid 

chromatography-electrospray tandem mass spectrometry (HPLC-ESI-MS/MS) methods. This research 

will provide valuable information on the molecular mechanisms underlying the genotoxic activity of 

diepoxybutane. 
 

 

1,3-BUTADIENE 111 

4. CHEMICAL AND PHYSICAL INFORMATION
 

4.1 CHEMICAL IDENTITY
 

Information regarding the chemical identity of 1,3-butadiene is located in Table 4-1. This information 

includes synonyms, chemical formula and structure, and identification numbers. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Information regarding the physical and chemical properties of 1,3-butadiene is located in Table 4-2. 
 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 112 

Table 4-1. Chemical Identity of 1,3-Butadienea 

Characteristic Information 

Chemical name 1,3-Butadiene 

Synonyms and trade names Butadiene; buta-1,3-diene; biethylene; bivinyl; divinyl; 

vinylethylene; erythrene; alpha,-gamma-butadiene; pyrrolyleneb 

Chemical formula C4H6 

Chemical structure 

H2C 

CH2 

Identification numbers: 

CAS registry 106-99-0 

NIOSH RTECS EI9275000c 

EPA hazardous waste R0377-0754d 

DOT/UN/NA/IMDG shipping 1010 

EINECS 203-450-8 

HSDB 181 

NCI C50602 

a

All information obtained from HSDB 2009 and ChemID Plus Advanced 2009 except where noted.

b

O’Neil et al. 2006.
	 c

NIOSH 2005.
	 d

Miller 1978.
	

CAS = Chemical Abstracts Service; DOT/UN/NA/IMDG = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EINECS = European Inventory of Existing Commercial
	

chemical Substances; EPA = Environmental Protection Agency; HSDB = Hazardous Substances Data Bank;
	

NCI = National Cancer Institute; NIOSH = National Institute for Occupational Safety and Health; RTECS = Registry
	

of Toxic Effects of Chemical Substances
	
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 113 

Table 4-2. Physical and Chemical Properties of 1,3-Butadiene 

Property 1,3-Butadiene Reference 

Molecular weight 54.09 O’Neil et al. 2006 

Color Colorless Lewis 2007 

Physical state Gas Lewis 2007 

Melting point -108.966 °C O’Neil et al. 2006 

Boiling point -4.5 °C O’Neil et al. 2006 

Density: 

at 25 °C (g/cm3) 0.6149 Lide 2008 

Vapor density 1.88 (air=1) NIOSH 2005 

Odor Mildly aromatic; gasoline-like Lewis 2007 

Water Not applicablea Amoore and Hautala 1983 

Air 1.6 ppm Amoore and Hautala 1983 

Odor threshold 

Solubility: 

Water at 25 °C 735 mg/L McAuliffe 1966 

Organic solvent(s) Soluble in ether, ethanol and Lide 2008 

benzene; very soluble in acetone 

Partition coefficients: 

Log Kow 1.99 Hansch et al. 1995 

Koc 288 (estimated)b HSDB 2009 

Vapor pressure at 25 °C 2.11x103 mm Hg AIChE 2000 

Henry's law constant at 25 °C 7.4x10-2 atm-m3/mol (estimated)c HSDB 2009 

Autoignition temperature 414 °C Lewis 2007 

Flashpoint -76 °C Lewis 2007 

Explosive limits 2.0-11.5% O’Neil et al. 2006 

Conversion factors 1 ppm=2.21 mg/m3 

1 mg/m3=0.452 ppm 

NIOSH 2005 

a

Amoore and Hautala (1983) reported an odor threshold of 0.0014 ppm for 1,3-butadiene in water; however, these
	

authors state that this solution lacks enough persistence for this value to be used for reference purposes.

b

This Koc value was estimated using the measured log Kow value (1.99) and a regression derived equation.
	 c

This Henry’s Law constant value was calculated from the measured vapor pressure (2.11x103 mm Hg at 25 °C) and 

water solubility (735 mg/L).
	
1,3-BUTADIENE 114 

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1,3-BUTADIENE 115 

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

5.1 PRODUCTION 

1,3-Butadiene was discovered in the nineteenth century and its use in the development of rubber-like 

polymers was explored during the early 1900s (Grub and Loser 2005; Sun and Wristers 2002). Large 

volume production of 1,3-butadiene in the United States began during World War II as a result of the 

nation’s synthetic rubber program (American Chemical Society 2007; Dolnick and Potash 1948). 

U.S. production rose to 2.7 billion pounds in 1965 as new plants were started to meet the increasing 

butadiene-rubber demand of the auto industry (Chemical Market Reporter 2006; Grub and Loser 2005; 

Kirshenbaum 1978). Production reached 3.7 billion pounds (1,674 metric tons) by 1974 and then 

fluctuated through the 1980s as a response to market pressures (Grub and Loser 2005; Kirshenbaum 

1978; Sun and Wristers 2002). Production growth resumed during the 1990s, reaching 4.5 billion pounds 

(2,020 metric tons) in 1998 (Grub and Loser 2005). Actual production volumes of 1,3-butadiene 

manufactured in the United States during more recent years are not available; however, the annual 

U.S. production capacity was reported to be 6 billion pounds (2,800 metric tons) during 2008 (Chemical 

Week 2008; SRI 2008). 

The 1,3-butadiene market is heavily dependent on the synthetic rubber demand of the auto industry, 

which accounts for approximately 60% of the total consumption of this substance (Chemical Market 

Reporter 2006). Also, since most 1,3-butadiene is produced through steam cracking, the supply of this 

chemical has been largely influenced by the demand for ethylene, the primary product from steam 

cracking (Sun and Wristers 2002). 

The companies that produced 1,3-butadiene in the United States, their production sites, and their annual 

capacities during 2008 (the most recent year for which figures are available) are shown in Table 5-1 (SRI 

2008). Table 5-2 summarizes the number of facilities in each state that manufactured or processed 

1,3-butadiene in 2007, the ranges of maximum amounts on site, if reported, and the activities and uses as 

reported in the Toxics Release Inventory (TRI) (TRI09 2011). The data listed in this table should be used 

with caution since only certain types of facilities are required to report. This is not an exhaustive list. 

Except for a small amount of 1,3-butadiene produced by the oxydehydrogenation of n-butene, all the 

1,3-butadiene produced in the United States is a co-product of ethylene manufacture (Chemical Market 

Reporter 2006; Sun and Wristers 2002). In this process, feed streams ranging from light hydrocarbons to 

heavy gas oils are cracked in the presence of steam at 700–900 °C (Grub and Loser 2005; Kirshenbaum 
 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 116 

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

Table 5-1. Companies that Produce 1,3-Butadiene in the United States and 

Annual Capacities During 2008
 

Capacity (million Capacity 

Company Location pounds/year) (metric tons) 

Equistar Chemicals, LP Alvin, Texas 150 68,060 

Channelview, Texas 865 392,500 

Corpus Christi, Texas 200 90,740 

ExxonMobil Chemical Company Baton Rouge, Louisiana 385 

Baytown, Texas 325 147,500 

INEOS Americas, LLC 

INEOS Olefins & Polymers USA Alvin, Texas 235 106,600 

Sabina Petrochemicals LLC Port Arthur, Texas 900 

Shell Chemical LP Deer Park, Texas 360 163,300 

Norco, Louisiana 575 260,900 

Texas Petrochemicals, Inc. Houston, Texas 1,080 490,000 

Port Neches, Texas 925 419,700 

Total 6,000 2,722,000 

Source: SRI 2008 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 117 

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

Table 5-2. Facilities that Produce, Process, or Use 1,3-Butadiene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AL 8 0 9,999,999 1, 3, 5, 6, 8, 13, 14 

AR 6 1,000 999,999 1, 2, 3, 6, 9, 12 

AZ 1 10,000 99,999 9 

CA 73 0 999,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 

CO 13 0 9,999,999 1, 3, 5, 6, 8, 12, 13 

CT 3 1,000,000 9,999,999 2, 3, 6 

DE 11 1,000 9,999,999 1, 2, 3, 5, 6, 7, 9, 12, 13 

GA 4 100,000 9,999,999 1, 5, 6 

HI 7 1,000 99,999 1, 3, 5, 6, 13, 14 

IA 5 100,000 9,999,999 1, 3, 4, 5, 6 

IL 39 0 49,999,999 1, 2, 3, 5, 6, 7, 8, 9, 11, 12, 13, 14 

IN 24 0 9,999,999 1, 3, 4, 5, 6, 7, 8, 12, 13, 14 

KS 11 0 499,999,999 1, 3, 6, 10, 13 

KY 16 10,000 9,999,999 1, 3, 4, 5, 6, 7, 9, 12, 13 

LA 106 0 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14 

MI 28 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13 

MN 10 0 9,999,999 1, 2, 3, 5, 6, 7, 12, 13 

MO 6 0 9,999 1, 5, 7, 12, 14 

MS 12 1,000 499,999,999 1, 2, 3, 4, 5, 6, 7, 9, 13, 14 

MT 19 100 999,999 1, 3, 5, 6, 8, 12, 13, 14 

NC 9 0 49,999,999 2, 3, 6, 7, 8, 10 

ND 4 0 9,999 1, 2, 3, 4, 6 

NE 2 0 9,999 3, 8, 11, 12 

NH 1 1,000 9,999 6 

NJ 16 0 99,999 1, 3, 4, 5, 6, 7, 12, 13 

NM 2 0 9,999 1, 3, 5, 7, 11 

NY 7 10,000 999,999 2, 3, 4, 6, 8, 11 

OH 33 0 49,999,999 1, 2, 3, 4, 5, 6, 7, 8, 9, 12, 13, 14 

OK 21 0 9,999,999 1, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13 

PA 20 0 9,999,999 1, 2, 3, 5, 6, 7, 8, 12, 13, 14 

PR 1 10,000,000 49,999,999 1, 5, 7 

SC 3 0 99,999 1, 5, 6, 13, 14 

TN 21 0 9,999,999 1, 2, 3, 5, 6, 7, 8, 9, 10, 12, 13, 14 

TX 234 0 10,000,000,000 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 

UT 15 100 999,999 1, 3, 4, 5, 6, 7, 8, 9, 12 

VA 7 0 9,999 1, 3, 4, 5, 6, 13 

VI 5 100 99,999 1, 2, 3, 6, 13 

WA 27 0 9,999,999 1, 2, 3, 4, 5, 6, 7, 11, 12, 13, 14 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 118 

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

Table 5-2. Facilities that Produce, Process, or Use 1,3-Butadiene 

Minimum Maximum 

Number of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

WI 2 100,000 9,999,999 6 

WV 10 0 99,999,999 1, 5, 6, 7, 8, 12 

WY 5 0 99,999 1, 3, 4, 6 

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 

Source: TRI09 2011 (Data are from 2009) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 119 

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

1978; Sun and Wristers 2002). The fraction of 1,3-butadiene produced by this process varies widely with 

the type of feedstock used and is lowest with low-boiling input streams (Grub and Loser 2005; 

Kirshenbaum 1978). 

Purification of the crude C4 stream resulting from the steam cracking process cannot be achieved by a 

simple distillation due to the close boiling point of the various products and the fact that 1,3-butadiene 

forms an azeotrope with butane (Grub and Loser 2005; Kirshenbaum 1978). 1,3-Butadiene can be 

removed from the hydrocarbon stream by liquid-liquid extraction or extractive distillation. The selective 

solvents used in these processes include aqueous cupric ammonium acetate, acetonitrile, furfural, 

dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidinone (Grub and Loser 2005; Sun and 

Wristers 2002). 

The oxidative dehydrogenation of n-butene, used in the production of 1,3-butadiene, is a highly selective, 

irreversible process that involves heating the starting material, air, and a suitable catalyst together at 400– 

450 °C (Grub and Loser 2005; Kirshenbaum 1978; Sun and Wristers 2002). The hydrogen released in the 

dehydrogenation step combines with oxygen, producing large amounts of heat, which makes this process 

energy-efficient (Grub and Loser 2005; Kirshenbaum 1978; Sun and Wristers 2002). As indicated above, 

oxidative dehydrogenation of n-butene has not been competitive with the steam cracking process for 

manufacture of 1,3-butadiene (Chemical Market Reporter 2006; Grub and Loser 2005). Rather, this 

method has been used on a campaign basis when there is a large enough differential between feedstock 

and 1,3-butadiene prices (Grub and Loser 2005). 

5.2 IMPORT/EXPORT 

Large amounts of 1,3-butadiene are imported into the United States as consumption typically exceeds 

production (Chemical Market Reporter 2006; Chemical Week 2008; Sun and Wristers 2002). U.S. 

imports of 1,3-butadiene in 2005 were approximately 600 million pounds (Chemical Market Reporter 

2006). More recent import data are not available. U.S. Exports of 1,3-butadiene are considered to be 

negligible (Chemical Market Reporter 2006). 

5.3 USE 

1,3-Butadiene is used as a monomer in the production of rubber and plastics; approximately 60% of the 

1,3-butadiene consumed in the United States is used in the production of synthetic rubbers (Chemical 

Market Reporter 2006). 1,3-Butadiene uses can be broken down into the following categories: synthetic 
 

 

 

 

 

 

 

 

1,3-BUTADIENE 120 

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

rubber, 61% (styrene butadiene rubber [SBR], 30%; polybutadiene elastomer, 25%; polychloroprene 

elastomer, 4%; nitrile elastomer, 2%) adiponitrile/hexamethylene diamine (HMDA), 11%; styrenebutadiene latex, 12%; ABS resins, 5%; and other uses, 11% (Chemical Market Reporter 2006). 

Automobile tires are the major end-use product (Chemical Market Reporter 2006). Both styrene 

butadiene rubber and polybutadiene are used heavily for this purpose. 1,3-Butadiene is also used for 

other automotive applications such as high-impact polystyrene and ABS resin plastics (Chemical Market 

Reporter 2006). 1,3-Butadiene is a precursor in the production of adiponitrile (used to make nylon) and 

chloroprene (used to make neoprene) (Chemical Market Reporter 2006). 

5.4 DISPOSAL 

The recommended method of disposal of 1,3-butadiene is by incineration within a suitable combustion 

chamber or in a safe area (HSDB 2009). Gaseous 1,3-butadiene can be burned directly; however, 

liquefied 1,3-butadiene (in a compressed cylinder) must be atomized before burning (HSDB 2009). 

Kennedy et al. (2009) report that burning off 1,3-butadiene, also referred to as flaring, is commonly 

practiced at facilities where excess amounts of this substance need to be destroyed (Kennedy et al. 2009). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 121 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

1,3-Butadiene has been identified in at least 13 of the 1,699 hazardous waste sites that have been 

proposed for inclusion on the EPA National Priorities List (NPL) (HazDat 2007). However, the number 

of sites evaluated for 1,3-butadiene is not known. The frequency of these sites can be seen in Figure 6-1. 

1,3-Butadiene is a high-volume, volatile hydrocarbon used in the production of commercial plastics and 

synthetic rubbers (Chemical Market Reporter 2006). The chemical reactivity of this monomer is utilized 

in its transformation into polymeric materials (Sigsby et al. 1987). 

1,3-Butadiene may be released to the environment as an intentional or fugitive emission during its 

production, use, storage, transport, or disposal. Large amounts (1.17 million pounds) of this hydrocarbon 

are released to the atmosphere from commercial processes (TRI09 2011). Data on the detection of 

1,3-butadiene in soil and water are scarce. In the past, it has been qualitatively detected in drinking water 

(EPA 1978; Kraybill 1980); however, more recent measurements are not available. 

1,3-Butadiene is a highly volatile gas; therefore, it is expected to partition predominantly to the 

atmosphere. In the atmosphere, 1,3-butadiene is expected to undergo rapid destruction, primarily by 

photo-initiated reactions. The reaction with photochemically produced hydroxyl radicals has a calculated 

half-life of approximately 6 hours and is expected to be the dominant pathway for atmospheric removal 

(Atkinson 1989). Destruction of atmospheric 1,3-butadiene by the gas-phase reaction with tropospheric 

ozone and by the night-time reaction with nitrate radicals in urban areas is also expected to be significant 

(Atkinson and Carter 1984; Atkinson et al. 1984). 

Limited data have been located on the fate of 1,3-butadiene in soil or water. Based on its physical 

properties, rapid volatilization of 1,3-butadiene from either soil or water to the atmosphere is expected to 

dominate over all other potential environmental processes. Based on estimated soil adsorption coefficient 

values, 1,3-butadiene is not expected to adsorb significantly to soil or sediment, nor is it expected to 

bioconcentrate in fish or aquatic organisms based on estimated bioconcentration and bioaccumulation 

factors. 

Although 1,3-butadiene undergoes rapid photooxidation in the atmosphere, it is almost always present at 

very low concentrations in urban and suburban areas (Curren et al. 2006; Grant et al. 2007; Oguz et al. 
1,3-BUTADIENE 122 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with 1,3-Butadiene Contamination 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 123 

6. POTENTIAL FOR HUMAN EXPOSURE 

2003; Reiss 2006; Reiss and Griffin 2004; Sax et al. 2004). Automobile exhaust is a constant source of 

1,3-butadiene release to the atmosphere. Because of the compound's ubiquity in the urban/suburban 

atmosphere, the general population is exposed to low ppb levels of 1,3-butadiene through inhalation 

(Higashino et al. 2007; Hughes et al. 2003). Exposure to 1,3-butadiene may also occur from the 

inhalation of cigarette smoke or the smoke from wood fires (Adam et al. 2006; Bartle et al. 1969; 

Blomberg and Widmark 1975; Brunnemann et al. 1990; Carmella et al. 2009; Counts et al. 2006; 

Gustafson et al. 2007; Lofroth et al. 1989; Pankow et al. 2004, 2007; Penn and Snyder 2007; Stump et al. 

1989; Thweatt et al. 2007; Vainiotalo et al. 2008). Ingestion of contaminated food or drinking water may 

also lead to low levels of exposure, although current levels of this compound in food and water samples 

are not known, nor is there a good understanding of their frequency of detection (EPA 1978; Hughes et al. 

2003; Kraybill 1980; Leber 2001; McNeal and Breder 1987; Startin and Gilbert 1984). The levels of 

1,3-butadiene in soil are not known. Elevated levels of exposure for the general population may occur for 

those near its site of manufacture or facilities where it is made into polymeric materials. 

Occupational exposure to 1,3-butadiene is expected to be limited to those working at facilities that 

manufacture 1,3-butadiene or convert it into commercial polymers (Anttinen-Klemetti et al. 2006; 

Begemann et al. 2001a; Fustinoni et al. 2004; Jones and Harris 1983; Lovreglio et al. 2006; Meinhardt 

et al. 1982; Sathiakumar et al. 2007; Tsai et al. 2001, 2005; Ward et al. 2001). Exposure by inhalation is 

expected to be the dominant pathway for exposure. Dermal exposure to liquified 1,3-butadiene could 

occur during an explosion of a pressurized storage tank or some other catastrophic event. 

6.2 RELEASES TO THE ENVIRONMENT 

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005). This is not an exhaustive list. Manufacturing and processing 

facilities are required to report information to the TRI only if they employ 10 or more full-time 

employees; if their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011, 

1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the 

purpose of generating electricity for distribution in commerce), 4931 (limited to facilities that combust 

coal and/or oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to 

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 

5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities 

primarily engaged in solvents recovery services on a contract or fee basis); and if their facility produces, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 124 

6. POTENTIAL FOR HUMAN EXPOSURE 

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 2005). 

6.2.1 Air 

Estimated releases of 1.17 million pounds (530 metric tons) of 1,3-butadiene to the atmosphere from 

193 domestic manufacturing and processing facilities in 2009 accounted for about 99% of the estimated 

total environmental releases from facilities required to report to the TRI (TRI09 2011). These releases are 

summarized in Table 6-1. 

The dominant sources for the release of 1,3-butadiene to the atmosphere are fugitive or accidental 

emissions during its manufacture, use, transport, and storage. Low levels of 1,3-butadiene are 

continuously emitted to the atmosphere from many sources including exhaust from motor vehicle engines 

using petroleum-based fuels. 

EPA's National Emission Inventory database (NEI) contains detailed information about sources that emit 

criteria air pollutants and their precursors, and hazardous air pollutants for the 50 United States, 

Washington DC, Puerto Rico, and the U.S. Virgin Islands. Emission data for 1,3-butadiene in 2005 is 

presented in Table 6-2 and suggest that automobile usage accounts for approximately one-third of all 

emissions. 

1,3-Butadiene was measured in the exhaust of typical automobiles and light trucks using both winter and 

summer gasoline formulations and accounted for up to 0.12% of total hydrocarbon emissions (Stump 

et al. 1989). An earlier study determined that the concentration of 1,3-butadiene in automobile exhaust 

was 20–60 ppb (Neligan 1962). 1,3-Butadiene has also been detected in the exhaust of diesel engines 

(Hayano et al. 1985) and high-altitude jet aircraft engines operating under simulated conditions (Katzman 

and Libby 1975). 

There are several minor sources for the release of 1,3-butadiene to the atmosphere, all of which involve 

the thermal breakdown of other materials. 1,3-Butadiene has been detected as a component of the 

sidestream smoke from cigarettes (Adam et al. 2006; Bartle et al. 1969; Blomberg and Widmark, 1975; 

Carmella et al. 2009; Penn and Snyder 2007; Vainiotalo et al. 2008). The average amount of 1,3-butadiene in sidestream cigarette smoke is 205–361 μg/cigarette (Brunnemann et al. 1990), with an average 

airborne yield of 400 μg/cigarette (Lofroth et al. 1989). 
 

 

1,3-BUTADIENE 125 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or
 

Use 1,3-Butadienea
 

Reported amounts released in pounds per yearb 

Total release 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek On- and off-site 

AL 2 3,069 0 0 47 0 3,069 47 3,116 

AR 1 1,140 0 0 0 0 1,140 0 1,140 

AZ 1 1,460 0 0 0 0 1,460 0 1,460 

CA 17 6,116 0 0 8 0 6,116 8 6,124 

CO 3 776 0 0 0 0 776 0 776 

CT 1 32 0 0 0 0 32 0 32 

DE 1 534 0 0 0 0 534 0 534 

GA 2 3,732 0 0 0 0 3,732 0 3,732 

HI 1 401 0 0 0 0 401 0 401 

IA 1 4,766 0 0 0 0 4,766 0 4,766 

IL 7 43,415 10 0 44 0 43,425 44 43,469 

IN 5 3,859 5 0 0 0 3,864 0 3,864 

KS 3 120 0 0 0 0 120 0 120 

KY 5 15,246 0 0 726 0 15,246 726 15,972 

LA 23 110,511 574 0 65 0 111,085 65 111,150 

MI 2 3,585 0 0 0 0 3,585 0 3,585 

MN 1 3,983 2 0 0 0 3,985 0 3,985 

MS 1 809 0 0 0 0 809 0 809 

MT 3 903 0 0 0 0 903 0 903 

NC 3 858 0 0 0 0 858 0 858 

ND 1 89 0 0 0 0 89 0 89 

NJ 4 102 0 0 0 0 102 0 102 

OH 13 35,145 6 0 4,161 5 39,311 6 39,317 

OK 4 6,981 0 0 0 0 6,981 0 6,981 

PA 4 2,258 0 0 0 0 2,258 0 2,258 

SC 1 5,520 0 0 0 0 5,520 . 5,520 

TN 4 4,648 0 0 0 0 4,648 0 4,648 

TX 67 902,132 49 2,266 10 6 904,446 17 904,463 

UT 2 1,069 0 0 0 0 1,069 0 1,069 

VA 1 962 0 0 0 0 962 0 962 

VI 1 1,039 0 0 0 0 1,039 0 1,039 

WA 4 292 0 0 0 0 292 0 292 

WI 1 156 0 0 0 0 156 0 156 

WV 1 2,100 0 0 13 0 2,113 0 2,113 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 126 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or
 

Use 1,3-Butadienea
 

Reported amounts released in pounds per yearb 

Total release 

Statec RFd Aire Waterf UIg Landh Otheri On-sitej Off-sitek On- and off-site 

WY 2 500 0 0 0 0 500 0 500 

Total 193 1,168,307 646 2,266 5,074 11 1,175,391 913 1,176,304 

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 onsite 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 

Source: TRI09 2011 (Data are from 2009) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 127 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. 1,3-Butadiene Emission Data for 2005a 

Category name Type Annual emissions (tons) Percentage 

Fuel comb, residential fireplaces Nonpoint 3,352.17 6.35 

On-road vehicles, gasoline Onroad 16,008.77 30.32 

Miscellaneous sources Nonpoint 17,627.65 33.39 

On-road vehicles, diesel Onroad 1,058.86 2.01 

Agricultural field burning Nonpoint 339.31 0.64 

Fuel comb, residential woodstoves Nonpoint 315.31 0.60 

Graphic arts Point 0.00 0.00 

Gas stations Point 0.01 0.00 

Wildfires Nonpoint 3,340.53 6.33 

Bulk gasoline terminals Point 5.11 0.01 

Fuel comb, commercial/institutional Nonpoint 0.07 0.00 

Planes, trains, and ships Nonroad 109.07 0.21 

Prescribed fires Nonpoint 164.95 0.31 

Industrial process, storage and transfer Nonpoint 2.61 0.00 

Industrial process, NEC Point 129.88 0.25 

Surface coating, industrial Point 16.81 0.03 

Non-road equipment, diesel Nonroad 364.74 0.69 

Non-road equipment, gasoline Nonroad 8,062.72 15.27 

Industrial process, petroleum refineries Nonpoint 1.30 0.00 

Industrial process, petroleum refineries Point 22.15 0.04 

Industrial process, cement manufacturing Point 64.37 0.12 

Logging slash burning Nonpoint 211.34 0.40 

Fuel comb, electric utility Point 2.30 0.00 

Waste disposal, open burning Point 0.03 0.00 

Waste disposal, open burning Nonpoint 123.52 0.23 

Fuel comb, commercial/institutional Point 0.78 0.00 

Industrial process, oil and gas production Point 7.71 0.01 

Waste disposal Nonpoint 1.52 0.00 

Industrial process, chemical manufacturing Point 603.65 1.14 

Degreasing Point 0.01 0.00 

Industrial process, chemical manufacturing Nonpoint 1.44 0.00 

Solvent, NEC Point 0.24 0.00 

Planes, trains, and ships Point 323.90 0.61 

Fuel comb, industrial boilers, ICEs Nonpoint 2.86 0.01 

Fuel comb, industrial boilers, ICEs Point 111.72 0.21 

Waste disposal Point 37.16 0.07 

Industrial process, oil and gas production Nonpoint 0.18 0.00 

Industrial process, storage and transfer Point 217.59 0.41 
 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 128 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. 1,3-Butadiene Emission Data for 2005a 

Category name Type Annual emissions (tons) Percentage 

Industrial process, pulp and paper Point 0.30 0.00 

Industrial process, metals Point 161.81 0.31 

a

Emission estimates are subject to updates for subsequent revised versions of the 2005 National Emissions 

Inventory data. These numbers may be different than values published for previous versions of the 2005 data and 

may also be different than values for subsequent revisions of the data as generated by EPA. 

ICEs = internal combustion engines; NEC = not elsewhere classified 

Source: EPA 2008 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 129 

6. POTENTIAL FOR HUMAN EXPOSURE 

The burning of plastics or rubber has been shown to release small amounts of 1,3-butadiene (Miller 

1978). In a test designed to simulate a real-life electrical overload condition, 1,3-butadiene was detected 

when polyurethane coated wire was heated to 250 °C for 40 minutes (Rigby 1981). 1,3-Butadiene has 

also been measured as a component of the smoke from brush fire (Stephens and Burleson 1969), and as a 

stack emission from waste incinerators (Junk and Ford 1980). The concentrations of 1,3-butadiene were 

not presented in these studies. The mean, minimum, and maximum concentrations of 1,3-butadiene 

measured in the air of nine municipal structural fires were 1.03, 0.03, and 4.84 ppm, respectively (Austin 

et al. 2001). The sources of 1,3-butadiene were considered to be both the combustion of wood and the 

thermal degradation of polymeric materials. Forest fires are considered to be a natural source of 1,3-butadiene in the atmosphere (Curren et al. 2006). Detection of 1,3-butadiene while heating rapeseed oil 

indicates that the heating of cooking oils may be a source of 1,3-butadiene in indoor air (Pellizzari et al. 

1995). 

1,3-Butadiene has been identified in air samples collected at 8 of the 13 NPL hazardous waste sites where 

it was detected in some environmental media (HazDat 2007). 

6.2.2 Water 

Estimated releases of 646 pounds (0.29 metric tons) of 1,3-butadiene to surface water from 193 domestic 

manufacturing and processing facilities in 2009, accounted for about 0.05% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI09 2011). An additional 

913 pounds (0.08 metric tons) were transferred off-site which includes releases to publicly owned 

treatment works (POTWs) (TRI09 2011). These releases are summarized in Table 6-1. 

Additional information regarding the release of 1,3-butadiene to water was not located in the available 

literature. 1,3-Butadiene has been identified in groundwater samples collected at 1 of the 13 NPL 

hazardous waste sites where it was detected in some environmental media (HazDat 2007). It was not 

identified in surface water at any of the NPL sites. 

6.2.3 Soil 

Estimated releases of 5,074 pounds (2.3 metric tons) of 1,3-butadiene to soils from 193 domestic 

manufacturing and processing facilities in 2009, accounted for about 0.43% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI09 2011). An additional 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 130 

6. POTENTIAL FOR HUMAN EXPOSURE 

2,266 pounds (1.03 metric tons), constituting about 0.19% of the total environmental emissions, were 

released via underground injection (TRI09 2011). These releases are summarized in Table 6-1. 

Additional information regarding the release of 1,3-butadiene to soil was not located in the available 

literature. 1,3-Butadiene has been identified in soil samples collected at 2 of the 13 NPL hazardous waste 

sites where it was detected in some environmental media (HazDat 2007). It was not identified in 

sediment at any of the NPL sites. 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

1,3-Butadiene’s high volatility suggests that it will partition predominantly to the atmospheric 

compartment, where it is not expected to be adsorbed to particulate matter to any significant extent 

(Eisenreich et al. 1981). 

Based on the calculated Henry’s Law constant of 7.4x10-2 atm-m3

/mol, the half-life for volatilization of 

1,3-butadiene is 2.2 hours from a model river (1 m deep, flowing at 1 m/second, with a wind velocity of 

3 m/second) and 2.9 days from a model lake (1 m deep, flowing at 0.05 m/second, with a wind velocity of 

0.5 m/second) (Lyman et al. 1990). Based on an experimental log octanol/water partition coefficient of 

1.99 (Hansch et al. 1995), a calculated soil adsorption coefficient of 288 (Lyman et al. 1990) suggests that 

adsorption to sediment and suspended organic matter will not be a significant fate process. From the log 

octanol/water partition coefficient, a calculated bioconcentration factor of 19 (Lyman et al. 1990) 

indicates that 1,3-butadiene will not bioconcentrate in fish and aquatic organisms to any significant 

extent. However, no experimental data have been located to verify these theoretical values. 

If released to soil, 1,3-butadiene is expected to volatilize rapidly from either moist or dry soil to the 

atmosphere. This follows from the estimated lack of any appreciable adsorption to soil, and consideration 

of 1,3-butadiene's calculated Henry's law constant for moist soil or its vapor pressure, 2,100 mm Hg at 

25 °C (AIChE 2000), for dry soil. Both values suggest a rapid rate of volatilization from their respective 

media. 

The calculated soil adsorption coefficient of 288 (Hansch et al. 1995; Lyman et al. 1990) suggests that 

1,3-butadiene may display moderate mobility in soil (Swann et al. 1983). However, the expected rapid 

rate of volatilization and the possibility of rapid degradation in soil suggest that there is little potential for 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 131 

6. POTENTIAL FOR HUMAN EXPOSURE 

1,3-butadiene to leach into groundwater. But until adequate groundwater monitoring for 1,3-butadiene 

has been performed, the partitioning of 1,3-butadiene in soil cannot be adequately addressed. 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

Butadiene is a reactive, electron-rich chemical that is expected to undergo rapid reactions with the 

electrophilic oxidants typically present in the atmosphere: ozone, photochemically produced hydroxyl 

radicals, nitrate radicals, and molecular oxygen. Among these, the most rapid reaction in the atmosphere 

is with photochemically produced hydroxyl radicals. 

The atmospheric degradation of 1,3-butadiene by photo-initiated processes has been established 

empirically by early studies. These studies typically involved irradiating urban air samples in 

atmospheric chambers of varying complexity and monitoring the disappearance of each constituent. 

Using this technique, 1,3-butadiene, at an average concentration of 12.4 ppb, disappeared in 6 hours when 

irradiated with natural sunlight during October (Kopczynski et al. 1972). In another study, a half-life of 

2 hours was determined for the atmospheric removal of 1,3-butadiene using natural sunlight in October or 

November (Altshuller et al. 1970). In smog chamber studies, the sunlight oxidation of 1,3-butadiene led 

to the formation of fairly potent eye irritants, suggesting destruction of this compound with concomitant 

formation of oxygenated species (Dimitriades et al. 1975; Heuss and Glasson 1968). It is believed that 

the destruction of 1,3-butadiene occurs by photo-initiated bimolecular processes rather than direct 

photochemical degradation (Kopczynski et al. 1972). It is important to note that the rate of destruction of 

1,3-butadiene when it was irradiated with natural light depended on the time of day in which the 

irradiation occurred. Furthermore, these studies were performed in October and November, when the 

amount and the intensity of available sunlight is diminished over that of summer months; thus, these 

values probably represent the high end of the compound's atmospheric lifetime. The individual processes 

responsible for the destruction of 1,3-butadiene in the atmosphere are discussed below. 

Numerous studies have determined the rate constant for the gas-phase reaction of 1,3-butadiene with 

photochemically produced hydroxyl radicals (Atkinson 1985; Atkinson and Aschmann 1984; Atkinson 

et al. 1977, 1979; Maldotti et al. 1980). The experimental rate constant 6.85x10-11 cm3

/molecule-second 

at 26 °C (Atkinson et al. 1977) is representative. Given an average hydroxyl radical concentration of 

5x105 molecule/cm3

 (Atkinson 1985), the half-life for this second-order process is 5.6 hours. Major 

products of this reaction include acrolein and formaldehyde (Baker et al. 2005). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 132 

6. POTENTIAL FOR HUMAN EXPOSURE 

Gas-phase 1,3-butadiene also reacts with ozone in the atmosphere. Rate constants ranging from 

6.7x10-18 to 8.4x10-18 cm3

/molecule-second at 25 °C have been published in the literature (Atkinson and 

Carter 1984; Jaspar et al. 1974). Using an average atmospheric ozone concentration of 7x1011 molecules/ 

cm3

 (Atkinson and Carter 1984), half-lives ranging from 1.4 to 1.7 days can be calculated for this secondorder process. Therefore, the reaction of 1,3-butadiene with ozone is expected to contribute to the overall 

destruction of atmospheric 1,3-butadiene. The initial products from the reaction of 1,3-butadiene with 

ozone are acrolein, formaldehyde, acetylene, ethylene, and formic anhydride (Niki et al. 1983). All of 

these products are susceptible to secondary reactions with ozone and other atmospheric oxidants. 

The night-time degradation of 1,3-butadiene is also expected to occur via the gas-phase reaction with 

nitrate radicals; this tends to be significant in urban areas, where the concentration of this oxidant is 

typically higher than in rural areas (Altshuller and Cohen 1964; Gay and Bulfalini 1971; Maldotti et al. 

1980). A rate constant of 5.4x10-14 cm3

/molecule-second at 22 °C has been determined for this reaction. 

This corresponds to a half-life of 14.9 hours using an average atmospheric nitrate radical concentration of 

2.4x108 molecule/cm3

 (Atkinson et al. 1984), typical of mildly polluted urban centers. Acrolein has been 

identified as a primary product of this reaction. 

In summary, there are three gas-phase pathways that degrade 1,3-butadiene in the troposphere. 

Depending on local conditions, any one or all of these reactions may occur. Destruction of atmospheric 

1,3-butadiene by the gas-phase reaction with photochemically produced hydroxyl radicals is expected to 

be the dominant photo-initiated pathway. Degradation via nitrate radicals is expected to be a significant 

night-time process in urban areas. 

6.3.2.2 Water 

Data on the degradation of 1,3-butadiene in aquatic systems are limited. Experimental data are restricted 

to microbial degradation studies performed under aerobic conditions. The bulk of these data were 

obtained from isolated bacterial strains (pure cultures), not with mixed microbial populations typically 

found in natural systems, and are not considered to be representative of the biodegradation of 1,3-butadiene in the environment. However, results from these studies suggest that biodegradation of 1,3-butadiene proceeds through oxidation to form 3,4-expoxybutene (Hou et al. 1979, 1980, 1983; Patel et al. 

1982a; Watkinson and Somerville 1976). Watkinson and Somerville (1976) reported further degradation. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 133 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.3.2.3 Sediment and Soil 

As is the case for the degradation of 1,3-butadiene in water, very limited data on the destruction of this 

compound in soil could be located in the available literature. Results from pure culture studies suggest a 

similar aerobic biodegradation pathway for 1,3-butadiene in soil compared to the pathway in water (Hou 

et al. 1979; Patel et al. 1979, 1982a, 1982b; VanGinkel et al. 1987; Watkinson and Somerville 1976). 

6.3.2.4 Other Media 

Specific information regarding the transformation or degradation of 1,3-butadiene in other environmental 

media was not located. 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to 1,3-butadiene depends in part on the reliability 

of supporting analytical data from environmental samples and biological specimens. Concentrations of 

1,3-butadiene 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 1,3-butadiene 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 

1,3-butadiene in a variety of environmental media are detailed in Chapter 7. 

6.4.1 Air 

1,3-Butadiene is widely detected at low ppb levels in urban air samples. Reported average concentrations 

range from 0.1 to 2 μg/m3

 (0.04–0.9 ppb) (Curren et al. 2006; Grant et al. 2007; Oguz et al. 2003; Reiss 

2006; Reiss and Griffin 2004; Sax et al. 2004). A major source of 1,3-butadiene in urban air is 

automobile engine exhaust (Broderick and Marnane 2002; Sigsby et al. 1987; Stump and Dropkin 1985; 

Stump et al. 1989). Atmospheric emissions from industrial facilities that produce or use 1,3-butadiene are 

another major source of the compound in areas located near these facilities. Concentrations as high as 

40 μg/m3

 (18 ppb) have been measured in the air near industrial sites (highest 24-hour level measured 

downwind from a major industrial source) (Grant et al. 2007). Curren et al. (2006) analyzed 3,267 air 

samples collected at eight rural locations in Canada and reported a mean 1,3-butadiene concentration of 

0.02 μg/m3

 (0.009 ppb) at these sites. EPA (2003a) estimated that the average background concentration 

of 1,3-butadiene in the air of the United States is 0.13 μg/m3

 (0.058 ppb). McCarthy et al. (2006) 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 134 

6. POTENTIAL FOR HUMAN EXPOSURE 

provided a lower estimate (<0.02 μg/m3; 0.009 ppb) of 1,3-butadiene in the background air of North 

America. Table 6-3 lists reported concentrations of 1,3-butadiene measured in outdoor air. 

1,3-Butadiene has also been detected in indoor air samples. Mean concentrations of 1,3-butadiene 

measured in indoor air of homes in New York were 1.0 μg/m3

 (0.5 ppb) during the winter and 1.2 μg/m3 

(0.54 ppb) during the summer (Sax et al. 2004). In Los Angeles, mean concentrations were 0.5 μg/m3 

(0.2 ppb) during the winter and 0.2 μg/m3

 (0.09 ppb) during the fall. The concentrations of 1,3-butadiene 

measured in a tavern were 11 and 19 μg/m3

 (5.0 and 8.6 ppb) in two separate studies, while the outside air 

concentration was ≤1 μg/m3

 (0. 5 ppb) at the same time (Lofroth et al. 1989). The difference in the indoor 

versus outdoor concentration may be ascribed to the presence of 1,3-butadiene in cigarette smoke. The 

concentration of 1,3-butadiene in a smoke-filled bar was 2.7–4.5 μg/m3

 (1.2–2.0 ppb) (Brunnemann et al. 

1990). Higher 1,3-butadiene levels have been observed in air samples collected from the smoking areas 

of restaurants and pubs than in air samples collected from the nonsmoking areas of these buildings (Kim 

et al. 2001; Vainiotalo et al. 2008). Mean 1,3-butadiene concentrations measured in the indoor air of 

32 smoking homes and 32 nonsmoking homes were 1.7 and 0.5 μg/m3

 (0.77 and 0.23 ppb), respectively 

(Kim et al. 2001). Mean 1,3-butadiene levels were 0.31–0.38 μg/m3

 (0.14-0.17 ppb) in the air of wood 

burning homes and 0.114 μg/m3

 (0.0515 ppb) in non-wood burning homes in Hagfors, Sweden 

(Gustafson et al. 2007). Table 6-4 lists reported concentrations of 1,3-butadiene measured in indoor air. 

6.4.2 Water 

No current information on the occurrence of 1,3-butadiene in water was located in the available literature. 

1,3-Butadiene was found in 1 of 204 water samples taken in 1975–1976 from surface waters near known 

industrialized areas across the United States. The single positive sample was obtained in the Carquinez 

Strait, Posta Corta, California, at an approximate concentration of 2 ppb (Ewing et al. 1977). 

No specific data on its presence in drinking water, such as monitoring dates or concentration, were 

located; however, 1,3-butadiene has been qualitatively detected in U.S. drinking water in the past (EPA 

1978; Kraybill 1980). 

6.4.3 Sediment and Soil 

No data on the occurrence of 1,3-butadiene in soil were located in the available literature. 
 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 135 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. 1,3-Butadiene Concentrations in Outdoor Air 

Concentration (μg/m3) 

Location n >LOD LOD Mean Median Maximum Reference 

Urban 

New York City Sax et al. 2004 

Winter 31 14% 0.06 0.1 ND 0.7 

Summer 27 11% 0.06 0.1 ND 2.0 

Los Angeles Sax et al. 2004 

Winter 35 24% 0.06 0.2 ND 1.7 

Fall 32 3% 0.06 0.01 ND 0.3 

Houston Reiss 2006 

16 Locations 4,374 61% 0.02a 1.3 — 7.2 

Texas Grant et al. 2007 

47 Urban/ — <30–74% 0.61 0.5 — 40 

industrial sites 

Baltimore Sapkota and 

Toll booth 56 100% 0.46 — 2–13.5b 19 Buckley 2003 

Baltimore Kim et al. 2007 

Parking garage 24c — — — 0.2–0.5d 8 

Canada Curren et al. 

2006 

30 Locations 5,160 — 0.001–0.02 0.22 0.17 2.58 

Rural 

Canada Curren et al. 

2006 

8 Locations 3,267 — 0.001–0.02 0.02 — — 

Background estimate 

United States — — — 0.13 0.10 2.2 EPA 2003a 

North America — — — <0.02 <0.02 <0.02 McCarthy et al. 

2006 

a

Value is referred to as the reporting limit.

b

Lower and upper median values correspond to measurements taken during 12–3 a.m. and 6–9 a.m., respectively.
	 c

Seven-hour samples were collected on 18 week days and 6 weekend days. d

Lower and upper median values correspond to measurements taken on weekends and weekdays, respectively.
	

LOD = limit of detection; n = number of samples; ND = not detected 
 

 

 

 

 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. 1,3-Butadiene Concentrations in Indoor Air 

Concentration (μg/m3) 

Location n >LOD LOD Mean Median Maximum Reference 

New York City Sax et al. 2004 

Winter 36 64% 0.06 1.0 0.7 5.8 

Summer 30 44% 0.06 1.2 ND 12 

Los Angeles Sax et al. 2004 

Winter 40 60% 0.06 0.5 0.5 1.8 

Fall 32 38% 0.06 0.2 ND 1.5 

Arizona NHEXAS Gordon et al. 

Home indoor 24 4% 0.38 ND ND 0.6 1999 

Home outdoor 14 0% 0.38 ND ND ND 

Ottawa, Canada Graham et al. 

House background 17 65% 0.1 0.51 0.36 1.63 2004 

Cold-start housea 17 100% 0.1 5.76 2.69 28.6 

Cold-start garagea 17 100% 0.1 82.8 84.7 166 

Birmingham, United Kim et al. 2001 

Kingdom 

6 smoking homes 32 100% 0.11 1.7 0.7 10.8 

6 nonsmoking homes 32 <100% 0.11 0.5 0.4 1.1 

Restaurants 6 — 0.11 1.5 — — 

Pubs 6 — 0.11 3.0 — — 

Other indoorb 43 — 0.11 0.2–0.9 — — 

Helsinki, Finland Vainiotalo et al. 

10 Restaurants 2008 

Smoking area 20 100% 0.02 4.3 — 10.1 

Non-smoking area 20 100% 0.02 1.1 — 3.9 

Hagfors, Sweden Gustafson et 

Wood burning homes 14 NR 0.03–0.15 0.31–0.38 0.20–0.23 al. 2007 0.90–1.54c 

Reference homes 10 NR 0.03–0.15 0.11 0.10–0.11 0.18–0.24c 

Area outdoor 9 NR 0.03–0.15 0.12 0.11 — 

a

Concentrations measured in the house and garage after a cold vehicle engine was started in the attached garage.

b

Includes offices, department stores, cinemas, perfume shop, libraries, and laboratories.
	 c

90th percentile values.
	

LOD = limit of detection; n = number of samples; ND = not detected; NHEXAS = National Human Exposure
	

Assessment Survey; NR = not reported
	
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 137 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.4 Other Environmental Media 

1,3-Butadiene is used to manufacture synthetic rubber and plastics that are frequently used for food 

packaging. Because residual 1,3-butadiene may be present in the polymers used to make the containers, 

both the packaging and the food contained therein have been analyzed. In one study, 1,3-butadiene at a 

concentration of 8–9 ng/g (ppb) was detected in three of three brands of olive oil packaged in 1,3-butadiene rubber-modified acrylonitrile-acrylic bottles (McNeal and Breder 1987). Analysis of the bottles 

themselves found 1,3-butadiene residues as high as 6,600 ng/g (ppb). Soft-plastic packaging tubs used as 

containers for potato salad, cottage cheese, and yogurt had residual 1,3-butadiene levels in the range of 

21–1,700 ng/g (ppb). However, no 1,3-butadiene was detected in any of the food packed in these 

containers (detection limit 1 ppb). Chewing gum made with a 1,3-butadiene rubber base did not show 

residual traces of this diene (McNeal and Breder 1987). Soft-plastic margarine tubs from five major 

name brands in the United Kingdom contained 1,3-butadiene residues ranging from 5 to 310 μg/kg (ppb), 

but none of the monomer was detected in the margarine samples themselves (detection limit 0.2 μg/kg) 

(Startin and Gilbert 1984). The authors concluded that migration of the 1,3-butadiene monomer from 

plastic packaging to food is unlikely to present a problem. Residual levels of 1,3-butadiene in food 

containers are closely regulated by the Food and Drug Administration. 

Pellizzari et al. (1995) measured 0.1 mg of 1,3-butadiene in rapeseed oil emissions during 20 minutes of 

heating the oil in a wok at 260 °C. The presence of 1,3-butadiene was attributed to the pyrolytic 

decomposition of unsaturated fatty acids in the oil. 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

1,3-Butadiene is almost always present in the air at low levels due to its emission from motor vehicles. 

Therefore, the general population is probably routinely exposed to ppb levels of this compound. 

Exposure to 1,3-butadiene by the general population is expected to be dominated by inhalation 

(Higashino et al. 2007; Hughes et al. 2003). Reported mean concentrations of 1,3-butadiene measured in 

urban air generally range from 0.1 to 2 μg/m3

 (0.4–0.9 ppb) (Curren et al. 2006; Grant et al. 2007; Oguz et 

al. 2003; Reiss 2006; Reiss and Griffin 2004; Sax et al. 2004). Sapkota et al. (2006) measured mean 

1,3-butadiene personal air exposure levels of 1.22 μg/m3. (0.55 ppb) for suburban-weekend exposure, 

1.47 μg/m3

 (0.66 ppb) for urban-week day exposure, and 2.88 μg/m3 (1.3 ppb) for tollbooth worker 

exposure in the Baltimore, Maryland area. 
 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 138 

6. POTENTIAL FOR HUMAN EXPOSURE 

Inhalation of 1,3-butadiene by the general population may also occur due to other sources. 1,3-Butadiene 

has been identified in cigarette smoke; therefore, smokers and those nearby are exposed to this compound 

(Adam et al. 2006; Bartle et al. 1969; Blomberg and Widmark 1975; Brunnemann et al. 1990; Carmella et 

al. 2009; Counts et al. 2006; Lofroth et al. 1989; Pankow et al. 2004, 2007; Penn and Snyder 2007; 

Thweatt et al. 2007; Vainiotalo et al. 2008). Reported delivery levels of 1,3-butadiene in the mainstream 

smoke of cigarettes range from 1.3 to 100 μg/cigarette (Pankow et al. 2004; Thweatt et al. 2007). 

Nazaroff and Singer (2004) calculated a 1,3-butadiene inhalation intake of 16–37 μg/day for nonsmokers 

who live with a smoker. This value was based on an exposure relevant emission factor of 515 μg 

1,3-butadiene/cigarette and a 1,3-butadiene exposure concentration of 1.4–3.1 μg/m3 (Nazaroff and Singer 

2004). Counts et al. (2006) measured 1,3-butadiene concentrations ranging from 11.2 to 59.3 μg/cigarette 

in the mainstream smoke of 26 different commercial cigarettes sold in the United States. 

1,3-Butadiene is present in the smoke from brush fires, wood fires, and municipal structural fires (Austin 

et al. 2001; Gustafson et al. 2007; Stephens and Burleson 1969), suggesting that inhalation of the smoke 

from wood fires will lead to low-level exposure to 1,3-butadiene. Gustafson et al. (2007) reported a mean 

1,3-butadiene concentration of 0.33 μg/m3

 (0.15 ppb) in the personal air of individuals living in woodburning homes and 0.14 μg/m3

 (0.063 ppb) in the personal air of a reference group. Its presence in waste 

incinerator emissions (Junk and Ford 1980) suggests that exposure to the general population may occur 

for those living nearby. Small amounts of 1,3-butadiene are produced by the thermal degradation of 

polyurethane-coated wire, an event that may occur during an electrical overload (Rigby 1981). The 

thermal degradation of other 1,3-butadiene-based plastics or rubbers may produce 1,3-butadiene (Miller 

1978), also leading to low-level exposure of the general population by inhalation. 

If the mean daily urban air concentration of 1,3-butadiene is 0.29 ppb (0.64 μg/m3

), as determined in an 

analysis and compilation of experimental reports of ambient monitoring data obtained from 1970 to 1987 

(Shah and Heyerdahl 1988), a nonoccupational daily intake of 12.8 μg per person can be obtained based 

on an average human intake of 20 m3 air/day. Marshall et al. (2006) calculated a 1,3-butadiene intake rate 

of 7.3 μg/day based on an exposure concentration of 0.55 μg/m3 and a mean breathing rate of 

13.1 m3

/day. Kim et al. (2002) measured mean personal air exposure concentrations of 1.1 μg/m3 

(0.50 ppb) during the night time and 0.8 μg/m3

 (0.36 ppb) during the day time for 12 residents of 

Birmingham, United Kingdom who were nonsmokers. 

No data are available that quantify general population exposure to 1,3-butadiene by other routes of intake, 

such as ingestion of contaminated drinking water. Low-level exposure by ingestion of contaminated 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 139 

6. POTENTIAL FOR HUMAN EXPOSURE 

drinking water may occur as 1,3-butadiene has been qualitatively detected in U.S. drinking water supplies 

(EPA 1978; Kraybill 1980). Given that residues of 1,3-butadiene have been found in plastic and rubber 

food containers and in a few samples of the food contained in these containers (McNeal and Breder 

1987), very low-level exposure to the general population may occur by ingestion of contaminated foods 

packaged in these containers (Hughes et al. 2003; Leber 2001). Leber (2001) estimated an upper-bound 

1,3-butadiene intake of 44 ng/day from food contact sources which include styrene butadiene rubbercontaining chewing gum, polymeric coatings, closures with sealing gaskets, and other indirect additives. 

According to the National Occupational Exposure Survey (NOES) conducted by NIOSH between 

1980 and 1983, 9,456 workers, of which 286 are women, were estimated to be exposed to 1,3-butadiene 

(NIOSH 1989). The NOES database does not contain information on the frequency, concentration, or 

duration of exposure of workers to any chemicals listed therein. These surveys provide only an estimate 

of the number of workers potentially exposed to chemicals in the workplace. During a study involving 

13,130 men who had been employed for at least 1 year at any of eight synthetic rubber plants in the 

United States or one in Canada between 1943 and 1992, it was estimated that 10,429 (79%) of these 

individuals had occupational exposure to 1,3-butadiene (Delzell et al. 2001; Macaluso et al. 2004). 

Occupational exposure to 1,3-butadiene is expected to be limited to inhalation of this compound, although 

dermal contact with liquified 1,3-butadiene may occur during a large spill, tank explosion, pipeline 

rupture, or similar catastrophic event. Specific industrial classifications or job descriptions involving 

exposure to 1,3-butadiene are provided below. 

Levels of 1,3-butadiene measured in the air at styrene-butadiene rubber (SBR) plants have been reported 

(Anttinen-Klemetti et al. 2006; Jones and Harris 1983; Meinhardt et al. 1982; Sathiakumar et al. 2007; 

Ward et al. 2001). Table 6-5 lists 1,3-butadiene air concentrations associated with typical SBR 

operations. These concentrations were measured in air samples collected at different times between 1977 

and 1991 at a synthetic rubber plant in Canada (Sathiakumar et al. 2007). These data show that 

individuals directly involved in the production of styrene-butadiene rubber have the greatest exposure to 

1,3-butadiene at these facilities, although high concentrations were also associated with some equipment 

maintenance and control technician operations as well. Air concentrations associated with tank farm and 

transfer pumphouse operations (mean, 103 mg/m3

; 56.6 ppm) were at least an order of magnitude greater 

than those of any of the other operations. Maximum concentrations measured at this facility were as high 

as 1,490 mg/m3

 (673 ppm). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 140 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Air Concentrations of 1,3-Butadiene Corresponding to Typical
 

Operations Within a Styrene-Butadiene Rubber (SBR) Planta
 

Concentration (mg/m3) 

Operation n Mean Median Minimum Maximum 

SBR production 

Polymerization 

Tank farm, transfer pumphouse 231 103 33.1 0.13 1,490 

Reactor, blowdown, panel board 261 9.9 2.2 0.04 146 

Recovery, compressor house, high 333 22.5 3.5 0.04 1,200 

solids recovery 

Unspecified operative 35 2.4 0.91 0.00 34.3 

Coagulation, blending, solutions prep 314 2.1 0.44 0.04 42.0 

Finishing 

Baler, packager, reclaim 111 0.64 0.33 0.07 4.2 

Dryer, baler dryer 134 2.9 0.44 0.11 271 

Unspecified operative 39 0.29 0.15 0.04 1.5 

Maintenance, production, maintenance field 

Foreman, engineer 15 0.44 0.40 0.04 1.5 

Instrument worker, meter person, 56 4.9 0.42 0.04 108 

electrician, maintenance inspector 

Pipefitter, oiler, mechanic, blacksmith, 250 9.7 1.8 0.04 234 

boilermaker, outside machinist 

Cleanup crew, laborer, work pool, utility 74 3.1 1.1 0.11 40.0 

person 

Technical/lab 

Rubber control, technician 210 30.1 2.1 0.00 1,150 

Butadiene control, hydrocarbon control, 41 4.9 0.15 0.00 67.4 

technician 

Shipping/distribution 

Labor, utility person, service person 24 0.20 0.15 0.00 0.66 

Utilities 

Copolymer effluent operative 103 1.3 0.88 0.00 17.5 

Unspecified/miscellaneous operative 114 0.42 0.22 0.00 4.2 

a

Air samples were collected at different times at a Canadian synthetic rubber plant between 1977 and 1991. 

Source: Sathiakumar et al. 2007 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 141 

6. POTENTIAL FOR HUMAN EXPOSURE 

1,3-Butadiene has been measured in the air of petrochemical facilities (Begemann et al. 2001a; Fustinoni 

et al. 2004; Lovreglio et al. 2006; Tsai et al. 2001, 2005). Mean time-weighted average concentrations of 

1,3-butadiene were 10.23 mg/m3

 (4.55 ppm) between 1979 and 1996 and 0.56 mg/m3 (0.25 ppm) between 

1997 and 2003 at the Deer Park and Norco Manufacturing complexes owned by Shell Oil Company (Tsai 

et al. 2005). Short-term exposures to this substance were as high as 987 mg/m3

 (439 ppm) in 1979–1996 

and 337 mg/m3

 (150 ppm) in 1997–2003. The decline in 1,3-butadiene levels in air at these facilities in 

recent years is attributed to the implementation of new health standards in 1996 (Tsai et al. 2001, 2005). 

A walk-through survey of 11 monomers, 17 polymers, and 2 end-user plants found that personal 

exposures ranged from <0.006 ppm to 374 ppm ( 0.013-827 mg/m3

) (Fasen et al. 1990). 

Two studies have reported levels of 1,3-butadiene measured in human blood, breath, and urine. Perbellini 

et al. (2003) measured average 1,3-butadiene concentrations of 1.0, 1.9, and 1.0 ng/L in the alveolar air, 

blood, and urine, respectively, of 46 forestry workers who were nonsmokers and 3.6, 11.4, and 3.9 ng/L 

in the alveolar air, blood, and urine, respectively, of 15 forestry workers who were smokers. The 

individuals had not been involved in forestry work for 2 months; therefore, occupational exposure was not 

considered to be a contributing factor. Fustinoni et al. (2004) measured end-shift 1,3-butadiene levels of 

2.4, 3.8, and 4.3 ng/L in the exhaled air, urine, and blood, respectively, of 42 workers with a mean 

personal exposure of 11.5 μg/m3

 (5.20 ppb) and levels of 2.3, 3.1, and 5.9 ng/L in the exhaled air, urine, 

and blood, respectively, of 43 workers with a mean personal exposure of 0.9 μg/m3

 (0.4 ppb). Pre-shift 

levels in exhaled air and urine were 2.4 and 3.8 ng/L, respectively, for the higher exposed workers and 

below detection for the lower-exposed workers. 

Other occupations where exposures to 1,3-butadiene may occur include petroleum refinery workers, 

professional bus, truck, and taxi drivers, parking garage attendants, tollbooth workers, and employees 

working in areas where smoking is permitted. 

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. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

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, 

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). 

Children are expected to be exposed to 1,3-butadiene primarily through inhalation of low levels in air. 

Children who live near areas of heavy vehicle traffic or near industrial facilities where 1,3-butadiene is 

produced or used may be exposed to higher levels of 1,3-butadiene. The available data indicate that 

exposure to 1,3-butadiene through ingestion of food and drinking water is expected to be low relative to 

inhalation exposure. Biomonitoring data for children, including levels of 1,3-butadiene and its 

metabolites measured in breast milk, neonatal blood, cord blood, and meconium fluid have not been 

located in the available literature. 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

High levels of exposure to 1,3-butadiene are likely to be limited to those resulting from an occupationally 

related use of this compound. Inhalation is the most likely route of high exposure to 1,3-butadiene. 

1,3-Butadiene is stored and transported in pressurized tanks, and it is possible that high levels of exposure 

by inhalation or dermal contact with the liquified gas may occur during the loading and unloading of 

these tanks, or by the accidental rupture of these tanks. Occupations where potentially high exposures to 

1,3-butadiene may occur include those in styrene-butadiene rubber facilities, those in petroleum 

refineries, professional bus, truck, and taxi drivers, parking garage attendants, tollbooth workers, and 

employees working in areas where smoking is permitted. Individuals who live near facilities where 

1,3-butadiene is produced or used have the potential for high exposure to this substance. Individuals who 

are frequently exposed to smoke from combustion sources, such as firefighters, may have high exposures 

to 1,3-butadiene (Austin et al. 2001). Individuals living very close to high traffic roads may be exposed 

to higher levels of butadiene. 

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 1,3-butadiene is available. Where adequate information is 

not available, ATSDR, in conjunction with NTP is required to assure the initiation of a program of 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

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

such health effects) of 1,3-butadiene. 

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 1,3-butadiene are well 

documented (Amoore and Hautala 1983; Hansch et al. 1995; HSDB 2009; Lewis 2007; Lide 2008; 

McAuliffe 1966; O’Neil et al. 2006; NIOSH 2005), and its environmental fate can be estimated from 

these properties (Lyman et al. 1982). No data needs are identified. 

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 2009, became available in February of 2011. This database is updated yearly and should provide a list 

of industrial production facilities and emissions. 

The trends in the production and use of 1,3-butadiene are well documented (Chemical Market Reporter 

2006; Chemical Week 2008; Grub and Loser 2005; Kirshenbaum 1978; SRI 2008; Sun and Wristers 

2002), and there do not appear to be any critical information gaps. 1,3-Butadiene monomer does not 

occur in most products used in the home, although residues of this compound in commercial packages, 

especially food containers (McNeal and Breder 1987), are not well described. It is clear that the majority 

of 1,3-butadiene is released to the atmosphere (TRI09 2011). The disposal of 1,3-butadiene appears to be 

a straightforward process (HSDB 2009). No data needs are identified. 

Environmental Fate. The fate of 1,3-butadiene in the atmosphere is well understood (Atkinson 1985; 

Atkinson and Carter 1984; Atkinson et al. 1984; Kopczynski et al. 1972). The fate of 1,3-butadiene in 

soil and water is not well understood, and partitioning from these media has to be determined from the 

physical and chemical properties of this compound (Lyman et al. 1982). A reliable method capable of 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 144 

6. POTENTIAL FOR HUMAN EXPOSURE 

detecting 1,3-butadiene in soil and water was not located in the available literature, and it is not clear 

whether 1,3-butadiene is absent from these media or simply not yet detected. The persistence of 1,3-butadiene in soil and water is not known, and the degree of partitioning from one environmental compartment 

to another can only be estimated. Exposure via ingestion or dermal contact to populations surrounding 

hazardous waste sites cannot, therefore, be accurately determined. Experimental data that address the 

partitioning of 1,3-butadiene in the environment, its potential to enter drinking water supplies, and its 

lifetime in soil and water are necessary to completely characterize the environmental fate of this 

compound. 

Bioavailability from Environmental Media. Numerous toxicokinetic and toxicity studies in 

humans and animals have demonstrated the bioavailability of 1,3-butadiene from air. No data on the 

bioavailability of 1,3-butadiene from other sources (water or soil, for example) were located in the 

available literature. In conjunction with the data needs for determining 1,3-butadiene in environmental 

media, bioavailability studies from environmental media would be useful. 

Food Chain Bioaccumulation. In theory, 1,3-butadiene is not believed to bioconcentrate 

significantly in fish and aquatic organisms; thus, it is not expected to biomagnify in the food chain 

(Hansch and Leo 1995; Lyman et al. 1982). No data addressing this point, however, were located in the 

available literature. Validation of these theories by valid experimental studies will aid in establishing a 

quantitative determination of 1,3-butadiene exposure to the general public. 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of 1,3-butadiene in contaminated media at hazardous waste sites are needed so that the information obtained on 

levels of 1,3-butadiene in the environment can be used in combination with the known body burden of 

1,3-butadiene to assess the potential risk of adverse health effects in populations living in the vicinity of 

hazardous waste sites. 

Data on the levels of 1,3-butadiene in environmental media are limited. Extensive data on the occurrence 

of 1,3-butadiene in ambient air samples are available (Curren et al. 2006; Grant et al. 2007; Oguz et al. 

2003; Reiss 2006; Reiss and Griffin 2004; Sax et al. 2004), but more data would be helpful. Data on the 

occurrence of 1,3-butadiene in water samples are very limited (Ewing et al. 1979). The presence of 

1,3-butadiene in drinking water has been noted in the literature, but no concentrations or frequency of 

detection are available (EPA 1978; Kraybill 1980). The development of reliable analytical techniques for 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 145 

6. POTENTIAL FOR HUMAN EXPOSURE 

the analysis of 1,3-butadiene in soil and water will establish unambiguously the levels at which this 

compound is found in environmental media. 

Exposure Levels in Humans. Limited data on levels of occupational exposure to 1,3-butadiene 

were available in the literature; however, occupational exposure to this compound appears to be limited to 

a readily definable group of industrial classifications (NIOSH 1989; Sathiakumar et al. 2007). Exposure 

levels for the general population are not well defined. Studies that correlate personal exposure with daily 

activities are necessary to adequately establish exposure levels for 1,3-butadiene. Biological monitoring 

studies cannot be performed until acceptable experimental techniques are developed. Exposure levels for 

those living near hazardous waste sites are not available and should be established. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. No information regarding exposures of children to 1,3-butadiene are 

currently available. Biomonitoring data for children, including levels of 1,3-butadiene and its metabolites 

measured in breast milk, neonatal blood, cord blood, and meconium fluid have not been located in the 

available literature. Studies are needed to help determine if there are differences between childhood and 

adult exposure to 1,3-butadiene. 

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 1,3-butadiene were located. This substance is not currently one of the 

compounds for which a sub-registry has been established in the National Exposure Registry. The 

substance 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 

Ongoing studies related to the potential for human exposure to 1,3-butadiene were not located. 
 

1,3-BUTADIENE 146 

6. POTENTIAL FOR HUMAN EXPOSURE 

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1,3-BUTADIENE 147 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring 1,3-butadiene, its metabolites, and other biomarkers of exposure and effect 

to 1,3-butadiene. 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. 

7.1 BIOLOGICAL MATERIALS 

No standardized method to test for the presence of 1,3-butadiene in biological materials presently exists. 

Only a limited number of techniques have been employed to measure this compound in biological 

materials. 

Perbellini et al. (2003) have developed a method to measure unmetabolized 1,3-butadiene concentrations 

in human blood, urine, and exhaled air. Breath samples were collected by expiration into headspace vials. 

Venous blood samples with EDTA added as an anticoagulant or urine samples were injected into a glass 

tube. Samples were analyzed using gas chromatography-mass spectrometry (GC-MS). Reported 

detection limits for 1,3-butadiene were 0.5 ng/L in blood, 1 ng/L in urine, and 0.8 ng/L in alveolar air. 

A technique for the determination of 1,3-butadiene in margarine samples was reported by Startin and 

Gilbert (1984). The margarine sample is placed in a vial, sealed, and heated to 70 °C where it is allowed 

to equilibrate for 1 hour. The amount of 1,3-butadiene in the sample is determined by withdrawing a 

headspace sample, and injecting it directly into a GC equipped with a MS detection system. Quantitation 

is obtained by comparison of the peak height to that of a standard of known concentration. The 

sensitivity of this method allows quantitation down to 0.001 mg/kg (1 ppb). A similar headspace 

technique was used to test for the presence of butadiene in olive oil, vegetable oil, and yogurt samples 

(McNeal and Breder 1987). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 148 

7. ANALYTICAL METHODS 

7.2 ENVIRONMENTAL SAMPLES 

Standardized methods for determining 1,3-butadiene in environmental samples are limited to air samples, 

as no methodology has been described for analyzing this compound in water or soil samples (EPA 1982, 

1986). A representative list of the methods available for the determination of 1,3-butadiene in air samples 

can be found in Table 7-1. The determination of 1,3-butadiene in personal air can be obtained using the 

procedures outlined in NIOSH Method 1024 (NIOSH 1994) and OSHA Method 56 (OSHA 2009a) or 

EPA Methods TO-14A and TO-15 (EPA 1999a, 1999b). 

For NIOSH Method 1024, the air sample is obtained by passing a known volume of air (5–25 L) through 

a set of tandem coconut charcoal tubes, which adsorb 1,3-butadiene and remove it from the air stream 

(NIOSH 1994). The collected 1,3-butadiene is then removed from the adsorption tube by extraction with 

methylene chloride. Injection of the methylene chloride solution into a GC equipped with a flame 

ionization detector (FID) separates 1,3-butadiene from any interfering compounds that may be present. 

The choice of chromatography column for this determination is not crucial, as long as it cleanly separates 

1,3-butadiene from other compounds. 

The estimated quantitation limit (LOQ) of this method is 0.02 ppm, with an applicable range of 0.04– 

220 μg per sample (approximately 0.04–100 ppm) for a 25 L sample. The precision of this method 

appears to change as a function of the concentration being measured, due to desorption efficiencies 

changing as a function of sample concentration. With increasing concentration, the preparation of a 

standard becomes more difficult. A limitation of this study is the relatively high LOQ (20 ppb), since 

concentrations observed in environmental settings are often <1 ppb. 

In NIOSH Method 1024, quantitation of 1,3-butadiene is accomplished by comparing the area under the 

sample's response signal to that of a known amount of 1,3-butadiene. The preparation and injection of a 

gaseous 1,3-butadiene standard is a difficult procedure; it must be performed carefully or erroneous 

results will occur. Sample storage appears to dramatically affect the results of the measurement. Samples 

stored at -4 °C displayed an average recovery of 93–98% over a 21-day period, while samples stored at 

room temperature ranged from 61 to 95%. 

OSHA Method 56 for analyzing 1,3-butadiene in air samples is similar to the NIOSH method described 

above. Air is drawn through sampling tubes containing charcoal absorbent coated with 4-tert-butylcatechol. The samples are then desorbed with carbon disulfide and analyzed using gas chromatograph-
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 149 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods For Determining 1,3-Butadiene in Environmental
 

Samples
 

Analytical Sample Percent 

Sample air Preparation method method detection limit recovery Reference 

Personal air Pass air through GC/FID 0.04– 61–98 NIOSH 1994 

(Method 1024) charcoal tube followed 220 μg/sample 

by desorption with (25L sample) 

methylene chloride 

Personal air Pass air through GC/FID 200 μg/m3 77–94 OSHA 2009a 

(Method 56) charcoal tube coated (90 ppb) 

with 4-tertbutylcatechol followed 

by desorption with 

carbon disulfide 

Air Pressurized container GC/MS/SIM or No data No data EPA 1999a 

(Method TO-14A) sampling followed by SCAN 

cryogenic 

concentration 

Air Pressurized container GC/MS/SIM or No data No data EPA 1999b 

(Method TO-15) sampling followed by SCAN 

multisorbent 

concentration and 

thermal desorption 

Air Collect air in Tedlar GC/FID No data No data Stump and 

bag concentrate on Dropkin 1985 

Tenax cartridge, 

thermal desorption 

Air Pass air through GC/MS No data No data Texax Air 

charcoal tube solvent Control 

desorption Board 1990 

Air Draw air into 12-foot GS/MS No data No data Texax Air 

(real time) sampling loop, direct Control 

injection Board 1990 

Air Pass air through GC/MS 0.11–0.16 μg/m3 >95% Kim et al. 

sorbent tubes 1999 

containing Carbopack 

B/Carbosieve SIII 

followed by thermal 

desorption 

FID = flame ionization detector; GC = gas chromatography; MS = mass spectrometry; SCAN = wide range of mass 

to charge ratio scanning; SIM = select ion monitoring 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 150 

7. ANALYTICAL METHODS 

flame ionization detector (GC-FID). The recommended air volume and sampling rate is 3 L at 

0.05 L/minute. The detection limit is 200 μg/m3

 and the quantitation limit is 343 μg/m3. As with NIOSH 

Method 1024, the usefulness of OSHA Method 56 for analysis of 1,3-butadiene in environmental media is 

limited since the reported detection and quantitation limits are much higher than levels often observed in 

environmental settings. 

1,3-Butadiene, along with other volatile hydrocarbons, has been found in ambient air samples by a 

technique that uses cryogenic concentration before GC analysis. This technique is performed by 

collecting a large volume of air in a specially designed bag or other sampling container and concentrating 

the volatile components by condensation at low temperatures. The sample is separated into its 

components by GC and quantified with an internal standard. Numerous variations of this method were 

found in the literature (Curren 2006; Graham et al. 2004; Lonneman et al. 1979; Neligan 1962; Stephens 

and Burleson 1967, 1969; Stump and Dropkin 1985). 

EPA Methods TO-14A and TO-15 describe procedures for the analysis of volatile organic compounds 

(VOCs) in air (EPA 1999a, 1999b). Method TO-14A calls for cryogenic concentration of the air sample 

as described above. Method TO-15 calls for pressurized air sampling using a stainless steel canister. The 

sample is then passed through a solid multisorbent concentrator and the concentrator is finally dry-purged 

with helium. The sample is thermally desorbed prior to analysis. For both of these methods, analysis is 

performed using GC followed by either a specific or nonspecific detector. However, the use of a specific 

detector is recommended, such as linear quadrupole mass spectrometer operating in either select ion 

monitoring (SIM) mode or a mode that scans a wide range of mass to charge ratios (SCAN). Precision 

and recovery data for 1,3-butadiene are not specified in these methods. Kim et al. (1999) developed an 

improved method by using a combination Carbopack B/CarbosieveSIII sorbent as a collection material. 

Sample collection was followed by thermal desorption and GC/MS analysis. These authors reported a 

precision of 2.4–13%, recoveries of >95%, and a detection limit of 0.11–0.16 μg/m3

 for this method. 

Therefore, this method is useful for measuring 1,3-butadiene concentrations in the low ppb (μg/m3

) range 

in environmental air samples. 

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 1,3-butadiene is available. Where adequate information is 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 151 

7. ANALYTICAL METHODS 

not available, ATSDR, in conjunction with NTP is required to assure the initiation of a program of 

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

such health effects) of 1,3-butadiene. 

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. No standardized method for 

the determination of biomarkers of exposure and effect for 1,3-butadiene was located. 

Exposure. Biomarkers that have been proposed as indicators of exposure to 1,3-butadiene include the 

urinary metabolites 1,2-dihydroxybutyl mercapturic acid (DHBMA or M1) and 1- and 2-monohydroxy3-butenyl mercapturic acid (MHBMA or M2) and the hemoglobin adducts 1- and 2-hydroxy-3-butenyl 

valine (MHB-Val) and N-(2,3,4-trihydroxy-butyl)valine (THB-Val) (Albertini et al. 2001; Boogaard et al. 

2001a; Carrieri et al. 2009; McDonald et al. 2004; Sapkota et al. 2006; Schettgen et al. 2009; Shen et al. 

2009). Measurement of unmetabolized 1,3-butadiene in human blood and urine may be preferable for 

assessing very low levels of exposure to this substance (0.4 μg/m3 median concentration in personal air) 

(Fustinoni et al. 2004; Perbellini et al. 2003; Schettgen et al. 2009). 

Both the urinary metabolites and the hemoglobin adducts have been well correlated with exposure to 

1,3-butadiene (Albertini et al. 2001; Preston 2007). Methods developed to measure these biomarkers 

have utilized either HPLC or GC followed by tandem MS (Boogaard et al. 2001a; Carrieri et al. 2009; 

Sapkota et al. 2006; Schettgen et al. 2009). Shen et al. (2009) has developed a method based on liquid 

chromatography/electrospray ionization-mass spectrometry to measure 3-butene-1,2-diol, a 1,3-butadiene 

urinary metabolite intermediate. 

Effect. Biomarkers of effect resulting from 1,3-butadiene exposure, such as gene mutation and 

chromosomal changes, have been explored; however, no clear associations have been observed (Albertini 

et al. 2001; Preston 2007). 
 

 

 

 

 

 

 

 

1,3-BUTADIENE 152 

7. ANALYTICAL METHODS 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Data on the determination of 1,3-butadiene in environmental media were limited. 1,3-Butadiene in air samples has been detected by techniques routinely used for detecting volatile hydrocarbons 

(Kim et al. 1999; Stump and Dropkin 1985; Texas Air Control Board 1990; EPA 1999a, 1999b). 

Improvements to these methods have made possible the detection of 1,3 butadiene concentrations in the 

low ppb (μg/m3

) range in environmental air samples (Kim et al. 1999). Procedures accepted for the 

determination of volatile hydrocarbons in other environmental media (soil, water, sediment, plants, etc.) 

may also be suitable for 1,3-butadiene. This question can be answered only by the data obtained from 

properly designed experiments. The information will assist in determining the prevalence of this 

compound in the environment and aid in a quantitative determination of human exposure to 1,3-butadiene. 

7.3.2 Ongoing Studies 

Ongoing studies related to the development of analytical methods for 1,3-butadiene were not located. 
 

 

 

 

 

 

 

 

1,3-BUTADIENE 153 

8. REGULATIONS, ADVISORIES, AND GUIDELINES
 

EPA (IRIS 2012) has established an inhalation reference concentration (RfC) for 1,3-butadiene of 0.9 ppb 

based on a BMCL10 of 0.88 ppm for ovarian atrophy in female B6C3F1 mice exposed to 1,3-butadiene by 

inhalation for 6 hours/day, 5 days/week for up to 103 weeks. 

EPA has not established an oral reference dose (RfD) for 1,3-butadiene (IRIS 2012). 

OSHA has required employers of workers who are occupationally exposed to 1,3-butadiene to institute 

engineering controls and work practices to reduce and maintain employee exposure at or below 

permissible exposure limits (PELs) (OSHA 2009b). The employer must use engineering and work 

practice controls to reduce exposures to not exceed 1 ppm for 1,3-butadiene at any time (OSHA 2009b). 

EPA has designated 1,3-butadiene as a hazardous air pollutant (HAP) under the Clean Air Act (CAA) 

(EPA 2009b). 1,3-Butadiene is on the list of chemicals appearing in “Toxic Chemicals Subject to 

Section 313 of the Emergency Planning and Community Right-to-Know Act of 1986” and has been 

assigned a reportable quantity (RQ) limit of 100 pounds (EPA 2009d). The RQ represents the amount of 

a designated hazardous substance which, when released to the environment, must be reported to the 

appropriate authority. 

The international and national regulations, advisories, and guidelines regarding 1,3-butadiene in air, 

water, and other media are summarized in Table 8-1. 
 

 

 

 

 

 

 

1,3-BUTADIENE 154 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to 1,3-Butadiene 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification Group 1a IARC 2009 

WHO Air quality guidelines No guideline value is 

recommended at this 

time 

WHO 2000 

Drinking water quality guidelines No WHO 2006 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH 

AIHA 

TLV (8-hour TWA) 

ERPG-1b 

ERPG-2b 

ERPG-3b 

2 ppm 

10 ppm 

200 ppm 

5,000 ppm 

ACGIH 2008 

AIHA 2008 

EPA 

EPA 

RfC 

Inhalation unit risk 

AEGL-1c 

0.9 ppb 

3×10-5 per μg/m3 

IRIS 2012 

EPA 2009a 

10 minutes 670 ppm 

30 minutes 670 ppm 

60 minutes 670 ppm 

4 hours 670 ppm 

8 hours 

AEGL-2c 

670 ppm 

10 minutes 6,700 ppm 

30 minutes 6,700 ppm 

60 minutes 5,300 ppm 

4 hours 3,400 ppm 

8 hours 

AEGL-3c 

2,700 ppm 

10 minutes 27,000 ppm 

30 minutes 27,000 ppm 

60 minutes 22,000 ppm 

4 hours 14,000 ppm 

8 hours 6,800 ppm 

Level of distinct odor awareness 3.7 ppm 

Hazardous air pollutant Yes EPA 2009b 

42 USC 7412 
 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 155 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to 1,3-Butadiene 

Agency Description Information Reference 

NATIONAL (cont.) 

Regulated flammable substances and 

threshold quantities for accidental 

release preventiond 

10,000 pounds EPA 2009c 

40 CFR 68.130 

NIOSH REL (10-hour TWA) Potential occupational 

carcinogens 

NIOSH 2005 

IDLH (10% LEL) 2,000 ppm 

Target organs Eyes, respiratory 

system, central 

nervous system, and 

reproductive system 

OSHA PEL (8-hour TWA) for general industry 

STEL (15-minutes) 

1 ppm 

5 ppm 

OSHA 2009b 

29 CFR 1910.1051 

b. Water 

EPA Drinking water standards and health 

advisories 

No EPA 2006a 

National primary drinking water 

standards 

No EPA 2003b 

National recommended water quality 

criteria 

No EPA 2006b 

c. Food 

FDA EAFUSe No FDA 2008 

d. Other 

ACGIH Carcinogenicity classification A2f ACGIH 2008 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 156 

8. REGULATIONS, ADVISORIES, AND GUIDELINES 

Table 8-1. Regulations, Advisories, and Guidelines Applicable to 1,3-Butadiene 

Agency Description Information Reference 

EPA Carcinogenicity classification Carcinogenic to 

humans by inhalation 

IRIS 2012 

RfD No data 

Superfund, emergency planning, and 

community right-to-know 

Designated CERCLA hazardous 

substance 

Yesg EPA 2009d 

40 CFR 302.4 

Reportable quantity 100 pounds 

Effective date of toxic chemical 

release reporting 

01/01/1987 EPA 2009e 

40 CFR 372.65 

NTP Carcinogenicity classification Known to be a human 

carcinogen 

NTP 2005 

a

Group 1: carcinogenic to humans

b

ERPG-1 is the maximum airborne concentration below which nearly all individuals could be exposed for up to 1 hour
	

without experiencing other than mild, transient health effects; ERPG-2 is the maximum airborne concentration below
	

which nearly all individuals could be exposed for up to 1 hour without experiencing irreversible or other serious
	

adverse effects; and ERPG-3 is the maximum airborne concentration below which nearly all individuals could be 

exposed for up to 1 hour without life-threatening health effects (AIHA 2008).
	 c

AEGL-1 is the airborne concentration of a substance above which it is predicted that the general population,
	

including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic nonsensory
	

effects, however, the effects are not disabling and are transient and reversible upon cessation of exposure; AEGL-2 

is the airborne concentration of a substance above which it is predicted that the general population, including 

susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an 

impaired ability to escape; and AEGL-3 is the airborne concentration of a substance above which it is predicted that
	

the general population, including susceptible individuals, could experience life-threatening health effects or death 

(EPA 2009a).

d

Basis for listing: flammable gas
	 e

The EAFUS list of substances contains ingredients added directly to food that FDA has either approved as food 

additives or listed or affirmed as GRAS.
	 f

A2: suspected human carcinogen
	 g

Designated CERCLA hazardous substance pursuant to Section 112 of the Clean Air Act
	

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline levels;
	

AIHA = American Industrial Hygiene Association; CERCLA = Comprehensive Environmental Response,
	

Compensation, and Liability Act; CFR = Code of Federal Regulations; EAFUS = Everything Added to Food in the 

United States; EPA = Environmental Protection Agency; ERPG = emergency response planning guidelines;
	

FDA = Food and Drug Administration; GRAS = Generally Recognized As Safe; IARC = International Agency for
	

Research on Cancer; IDLH = immediately dangerous to life or health; IRIS = Integrated Risk Information System;
	

LEL = lower explosive limit; NIOSH = National Institute for Occupational Safety and Health; NTP = National
	

Toxicology Program; OSHA = Occupational Safety and Health Administration; PEL = permissible exposure limit;
	

REL = recommended exposure limit; RfC = inhalation reference concentration; RfD = oral reference dose;
	

STEL = short-term exposure limit; TLV = threshold limit values; TWA = time-weighted average; USC = United States
	

Code; WHO = World Health Organization
	
 

 

 

 

 

 

 

 

 

 

 

 

_______________________ 

 

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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. 

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. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 186 

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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. 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 187 

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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. 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 188 

10. GLOSSARY 

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. 

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 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 189 

10. GLOSSARY 

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. 

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. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 190 

10. GLOSSARY 

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. 

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. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 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. 

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 
 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE A-2 

APPENDIX A 

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 and Human Health Sciences (proposed), expert panel peer reviews, and agencywide 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 

and Human Health Sciences (proposed), Agency for Toxic Substances and Disease Registry, 1600 Clifton 

Road NE, Mailstop F-62, Atlanta, Georgia 30333. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 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 

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. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE B-2 

APPENDIX B 

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. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 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. 

(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"). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE B-4 

APPENDIX 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). 

(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. 
 

 

 

 

1,3-BUTADIENE B-5 

APPENDIX B 

(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. 
1 2 3 4 12 

→

SAMPLE 

Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

→→

Exposure frequency/ 

Species duration 

Key to figurea INTERMEDIATE EXPOSURE 

↓6 

↓

5 

Systemic 

System ↓7 

NOAEL (ppm) ↓8 

LOAEL (effect) Less serious (ppm) 

↓

9 

Serious (ppm) 

Re

↓

10 

→→

Nit

CHRONIC EXPOSURE 

WoNTNT

(CEL, multiple organs) (CEL, lung tumors, nasal tumors) (CEL, lung tumors, hemangiosarcomas) 

10 (hyperplasia) 

11 ↓20 10 10 

3b 13 wk Resp 

5 d/wk 6 hr/d 18 mo 5 d/wk 7 hr/d 89–104 wk 5 d/wk 6 hr/d 79–103 wk 5 d/wk 6 hr/d 

Rat Rat Rat Mouse 

18 Cancer 38 39 40 a The number corresponds to entries in Figure 3-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3 ppm; dose adjusted for intermittent exby an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

1,3-BUTADIENE B-8 

APPENDIX B 

This page is intentionally blank. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 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 

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 aminotransferase 

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/C benchmark dose or benchmark concentration 

BMDX dose that produces a X% change in response rate of an adverse effect 

BMDLX 95% lower confidence limit on the BMDX 

BMDS Benchmark Dose Software 

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 
 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE C-2 

APPENDIX C 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMDG North America/Intergovernmental 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 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 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 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1,3-BUTADIENE 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 

SGPT serum glutamic pyruvic transaminase 

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 
 

 

1,3-BUTADIENE 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 
1,3-BUTADIENE C-6 

APPENDIX C 

This page is intentionally blank. 
 

1,3-BUTADIENE D-1 

APPENDIX D. INDEX 

absorbed dose.............................................................................................................................................. 93 

adenocarcinoma .......................................................................................................................................... 46 

adsorbed.................................................................................................................................................... 130 

adsorption.................................................................................................................................. 121, 130, 148
	

aerobic............................................................................................................................................... 132, 133
	

ambient air ................................................................................................................................ 108, 144, 150
	

anemia................................................................................................................................. 9, 10, 13, 37, 102
	

bioaccumulation........................................................................................................................................ 121 

bioavailability ........................................................................................................................................... 144 

bioconcentration factor ............................................................................................................................. 130 

biodegradation................................................................................................................................... 132, 133
	

biomarker .......................................... 7, 8, 11, 16, 17, 58, 61, 62, 87, 89, 93, 94, 95, 96, 106, 109, 147, 151
	

blood cell count................................................................................................................................. 9, 10, 37
	

body weight effects..................................................................................................................................... 39 

breast milk......................................................................................................................................... 142, 145
	

cancer........................................................ 4, 8, 9, 10, 13, 14, 20, 21, 43, 44, 45, 46, 92, 100, 102, 103, 109
	

carcinogen............................................................................................................................... 4, 46, 103, 156
	

carcinogenic ...................................................................... 10, 19, 20, 46, 88, 95, 96, 99, 103, 104, 106, 156
	

carcinogenicity.............................................................................................. 8, 10, 61, 88, 95, 100, 103, 104 

carcinoma .................................................................................................................................................... 46 

cardiovascular ............................................................................................................................................. 36 

cardiovascular effects.................................................................................................................................. 36 

cholinesterase.............................................................................................................................................. 40 

chromosomal aberrations.................................................................................................. 52, 53, 54, 97, 104
	

clearance ....................................................................................................................... 61, 63, 69, 73, 74, 99
	

death........................................................................................ 8, 9, 10, 13, 19, 21, 40, 41, 99, 100, 102, 156
	

deoxyribonucleic acid (see DNA)................................................................................................................. 5 

dermal effects.............................................................................................................................................. 38 

developmental effects ................................................................. 8, 9, 10, 12, 13, 42, 92, 100, 105, 106, 107
	

DNA (see deoxyribonucleic acid)......................................... 5, 49, 52, 54, 86, 87, 88, 93, 95, 106, 108, 109
	

elimination rate ..................................................................................................................................... 63, 67
	

endocrine............................................................................................................................................... 90, 91
	

fetus....................................................................................................................................................... 74, 91
	

fractional absorption ................................................................................................................................... 98 

gastrointestinal effects ................................................................................................................................ 36 

general population............................................................................................. 7, 8, 123, 137, 138, 145, 156 

genotoxic............................................................................................. 8, 19, 47, 54, 86, 87, 95, 97, 104, 110
	

genotoxicity........................................................................................... 47, 55, 86, 87, 88, 96, 100, 105, 109
	

groundwater .............................................................................................................................. 102, 129, 131
	

growth retardation..................................................................................................................................... 105 

half-life.................................................................................................................... 7, 93, 121, 130, 131, 132
	

hematological effects .................................................................................................................................. 36 

hematopoietic.............................................................................................................. 8, 39, 45, 49, 103, 104
	

hepatic effects ............................................................................................................................................. 38 

hydrolysis................................................................ 51, 57, 61, 62, 67, 68, 69, 74, 76, 77, 84, 85, 92, 98, 99
	

hydroxyl radical ........................................................................................................................ 121, 131, 132
	

immune system ......................................................................................................................................... 105 

immunological ................................................................................................................................ 19, 39, 40
	

immunological effects........................................................................................................................... 39, 40
	
 

1,3-BUTADIENE D-2 

APPENDIX D 

Kow ............................................................................................................................................................ 113 

leukemia.................................................................................................... 37, 39, 43, 44, 45, 46, 88, 92, 103
	

lymphatic ................................................................................................................................................ 4, 43
	

lymphopoietic ......................................................................................................................................... 8, 10
	

lymphoreticular....................................................................................................................................... 8, 10
	

micronuclei ....................................................................................................................... 49, 50, 52, 99, 104
	

musculoskeletal effects...............................................................................................................................38 

neonatal............................................................................................................................................. 142, 145
	

neoplasm ..................................................................................................................................................... 46 

neoplastic .................................................................................................................................... 9, 10, 11, 38
	

neurobehavioral................................................................................................................................... 90, 105
	

neurological effects............................................................................................................. 3, 12, 40, 99, 105
	

non-Hodgkin’s lymphoma .......................................................................................................................... 44 

ocular effects............................................................................................................................................... 39 

odds ratio..................................................................................................................................................... 43 

partition coefficients ................................................................................... 15, 55, 56, 67, 68, 69, 74, 79, 83
	

pharmacodynamic ....................................................................................................................................... 64 

pharmacokinetic............................................................................ 11, 63, 64, 65, 66, 91, 100, 102, 104, 105
	

rate constant .................................................................................................................... 17, 68, 74, 131, 132
	

renal effects................................................................................................................................................. 38 

reproductive effects....................................................................................................................... 10, 40, 104
	

respiratory effects................................................................................................................................ 21, 103
	

sarcoma ................................................................................................................................................. 44, 46
	

solubility ................................................................................................................................................... 113 

spermatozoa ................................................................................................................................................ 12 

systemic effects............................................................................................................................. 13, 21, 100
	

T3................................................................................................................................................................ 22 

thyroid............................................................................................................................................. 10, 46, 57
	

toxicokinetic............................................................................ 11, 15, 16, 17, 19, 97, 98, 102, 103, 107, 144
	

tumors ......................................................................................................................... 10, 13, 40, 45, 96, 106
	

vapor pressure ................................................................................................................................... 113, 130
	

volatility.................................................................................................................................................... 130 

volatilization ..................................................................................................................................... 121, 130