HEALTH EFFECTS OF

EXPOSURE TO

ENVIRONMENTAL TOBACCO SMOKE

FINAL DRAFT
FOR SCIENTIFIC, PUBLIC, AND
SRP REVIEW

FEBRUARY 1997

Office of Environmental Health Hazard Assessment

California Environmental Protection Agency

Preface

Environmental tobacco smoke (ETS), also called second hand tobacco smoke, can affect nonsmokers in proximity to people smoking tobacco. The scientific and medical literature contains numerous investigations of the association between ETS exposure and a variety of adverse health impacts, including carcinogenicity as well as cardiovascular, developmental, reproductive, and childhood respiratory effects. Although not all studies have shown an association, authoritative reviews over the past two decades have presented scientific evidence linking ETS exposures to a number of adverse health outcomes.

Interest in the health effects of second hand tobacco smoke on the part of members of the Scientific Review Panel (SRP) on Toxic Air Contaminants of the Air Resources Board (ARB) led to a request by the SRP for a health assessment of ETS, and a collaborative agreement between the Office of Environmental Health Hazard Assessment (OEHHA) and the ARB in February 1992 to initiate such an assessment. Although not formally entered into the State's Assembly Bill 1807 toxic air contaminant identification program, the ARB, SRP and OEHHA agreed that a thorough assessment of risk similar to that done under the AB 1807 process was warranted. This was done to ensure a thorough review of the scientific data, frequent public input through public comment periods and workshops, and an independent scientific review by the SRP.

Because the ARB has determined that this assessment is not part of the AB 1807 process and ETS is not being considered for formal identification as a toxic air contaminant by the ARB, this report will not be presented at a public hearing of the members of the Air Resources Board. Following both public review and comment, and peer review by the SRP, the final assessment along with all comments will be forwarded to the Department of Health Services (DHS) Tobacco Control Program for appropriate action under their mandate as the State's lead agency for addressing health effects related to tobacco use.

OEHHA, with the assistance of scientists from the DHS, had primary responsibility for the preparation of this assessment. ARB provided assistance with the ETS-related exposure data as well as with report reproduction, workshop organization, and mailouts.

OEHHA and ARB sponsored a workshop in October 1992 to obtain public input early in the evaluation of ETS health effects and exposure in California. At the workshop, preliminary thoughts on the direction of the ETS assessment were discussed with participants, which included individuals from local, state and federal government agencies, universities and other research organizations, representatives of the tobacco industry, and public interest groups.

The development of the assessment involved extensive literature review, document development, public workshops, public comment and scientific peer review followed by document revision. Public release of reviews on each major area of health effects occurred as they were prepared. The first two documents (Respiratory Health Effects of ETS and The Role of ETS in Cancers Other Than Lung Cancer) were mailed in May 1994; subsequent documents were released in September 1994 (Cardiovascular Health Effects of Exposure to ETS), March 1995 (Developmental and Reproductive Effects of Exposure to ETS), September 1995 (ETS: Exposure Measurements and Prevalence), and January 1996 (Carcinogenic Effects of Exposure to ETS, Excerpt: ETS and Lung Cancer). Following a public comment period, each document was revised to respond to comments received and updated to include critical new studies; these revised documents have been compiled to form the current assessment. This most recent health assessment of ETS was extensively peer reviewed by Professor Stanton Glantz of the University of California at San Francisco and Professor Craig V. Byus of the University of California at Riverside, members of ARB's Scientific Review Panel, and Jennifer Jinot of U.S. EPA and co-author of U.S. EPA's 1992 report "Respiratory Health Effects of Passive Smoking: Lung Cancer and Other Disorders". The chapter on carcinogenic effects of exposure to ETS was peer reviewed by Dr. Gary D. Friedman of the Permanente Medical Group and member of ARB's Scientific Review Panel and Dr. Kathryn E. Osann of the Department of Medicine, University of California at Irvine. The comments and suggestions from these reviewers have been addressed in this version of the health assessment of ETS.

The material comprising Chapters 2 to 8 has received internal and extensive external review through public workshops, meetings and written public comment, and reflects a number of changes made in response to comments received. To aid the reader of the current report, revisions to the chapters made after the external release are briefly outlined below. In addition, Appendix A summarizes written comments received from the public during the formal comment periods, as well as responses to those comments.

Chapter 2 on exposure measurement and prevalence was developed to provide background information on exposure measurement, emphasizing investigation and monitoring methods used in epidemiological evaluations of health effects. Information on prevalence of ETS exposure was also provided. In response to comments received suggesting that the document was being mistaken for a comprehensive exposure assessment, various wording changes were made to clarify the scope of the document. Regarding other specific changes, a study on DNA adducts of tobacco smoke constituents and the p53 gene and recent studies on the prevalence of ETS exposure in California and the U.S. have been added. The current assessment takes the position that thiocyanate is not a very useful biomarker of ETS exposure. It also points out that while 3-ethenylpyridine, solanesol and ultraviolet particulate matter have been used by some researchers, they have not been widely adopted.

Chapters 3 to 5 were externally released as a single document, and many detailed changes were made to these three chapters in response to comments received. Several points of clarification were made to Chapter 3, on perinatal manifestations of developmental toxicity. Four additional published studies on fetal growth and home and work exposure to ETS, and two additional studies on fetal growth and biomarker measures were reviewed and described, and the discussion was expanded to reflect study findings. Attributable risk calculations for ETS exposure and low birthweight were made. An additional study was included in the section on spontaneous abortion and perinatal mortality. In Chapter 4, on postnatal manifestations of developmental effects, a major change concerns the conclusion regarding the relationship between ETS exposure and sudden infant death syndrome (SIDS). Recently published studies on SIDS have been added, and the document now indicates that ETS exposure is causally associated with SIDS. Attributable risk calculations were provided for SIDS. In Chapter 5, on male and female reproductive effects, a definition of fecundability ratio is now given. A study on female fertility has been added.

Chapter 6, on respiratory effects, has been considerably enlarged, and several points of clarification added in response to comments. Additional recent studies have been reviewed. Major additions have been made to sections on asthma, lung function in children and cystic fibrosis. Medical terms are now defined as they are first used. The chapter now includes an explicit summary statement that published investigations on ETS exposure and atopy have produced mixed results.

Regarding revisions made to Chapter 7, on carcinogenic effects, the section on breast cancer has been expanded to describe recently published studies and discuss their implications. Clarifications regarding the U.S. EPA review of lung cancer and ETS have been made. The current chapter extends or modifies the discussion of issues related to ETS exposure and cervical cancer (e.g., on confounders in epidemiological studies, active smoking, DNA adducts in cervical biopsies), nasal sinus cancer, and leukemia. Several studies on biomarkers of transplacental and early childhood exposure to ETS and two studies on brain cancer in children have been added.

A number of changes have been made to Chapter 8 on cardiovascular effects. Added material includes: a review of two recent analyses of the American Cancer Society CPS cohort, a discussion of a recent review and risk assessment on ETS exposure and cardiovascular effects, descriptions and a discussion of the implications of several additional case-control studies, sections on clinical observations regarding ETS exposure and internal and common carotid wall thickness and endothelial function, and description of findings from six additional laboratory studies on rodents and dogs.

Authors and Acknowledgements

This document was prepared by the Reproductive and Cancer Hazard Assessment Section (RCHAS) and the Air Toxicology and Epidemiology Section (ATES) within the Office of Environmental Health Hazard Assessment (OEHHA) of the California Environmental Protection Agency (Cal/EPA). Lauren Zeise was the project officer with overall responsibility for the contents of this report. Amy Dunn coordinated the development of the draft chapters and their revision, and the public workshops. James Donald played a key role in the planning and development of Chapters 3, 4 and 5. Amy Dunn and Lauren Zeise were the editors of this report.

Authors

While OEHHA staff provided technical editing and incorporated reviewers' comments into each chapter to develop a comprehensive and consistent document, the following people were the primary authors:

Chapter 1: Lauren Zeise and Amy Dunn

Chapter 2: Lynne Haroun¹

Chapter 3: Gayle Windham² and Mari Golub

Chapter 4: Kirsten Waller²

Chapter 5: Gayle Windham and Mari Golub

Chapter 6: Michael Lipsett, Dennis Shusterman³, and Jennifer Mann

Chapter 7: Anna Wu⁴

Chapter 8: Anna Wu

¹ Previously with OEHHA, currently with PRC Environmental Management, Inc., San Francisco, CA.

² Reproductive Epidemiology Section, Environmental Health Investigations Branch, California Department of Health Services.

³ Previously with OEHHA, currently with the Department of Medicine, Division of Occupational & Environmental Medicine, University of California at San Francisco.

⁴ Previously with OEHHA, currently with University of Southern California, Norris Comprehensive Cancer Center, Department of Preventive Medicine, Los Angeles, CA.

Contributors and Reviewers

The authors are grateful to the following people for help in the development of this report: Peggy Jenkins, Susan Lum and other staff of the Indoor Exposure Assessment Section, Research Division, Air Resources Board; staff of OEHHA and of the Division of Epidemiologic and Occupational Disease Control of California Department of Health Services, for review of preliminary drafts; Mary Ann Mahoney of the Occupational and Environmental Health Library; William Lockett in the Ombudsman's Office, and Robert Krieger and other staff in the Toxic Air Contaminants Section of the Air Resources Board for guidance and assistance throughout the many phases of report development. In addition to the editors and primary authors, the following OEHHA staff contributed text to the document: Marlissa Campbell, Gerald Chernoff, James Donald, James Morgan, and David Ting.

As described in the preface, this draft was preceded by External Review Drafts of each topic area which were released for public review and comment. The authors wish to thank those who sought to improve the quality of this report with their comments, and are particularly grateful to the members of the Scientific Review Panel, especially the leads on ETS, Stanton Glantz, Gary Friedman, Craig Byus, and Charles Becker (former panel member), who provided guidance and detailed suggestions. Special thanks to Jennifer Jinot and Steven Bayard of U.S. EPA, and Ira Tager, Kathy Hammond, Neil Benowitz, John Balmes and John Pierce. Thanks also go to James Collins, John Faust, Jeff Fowles, Martha Sandy and David Ting, for assistance with the response to public comments.

Acknowledgements

The authors and editors would like to acknowledge the assistance of several people: Maria Patricia Aguilar, Julie Christiansen, Susan Davis, Eydie Duggan, Kathy Elliott, Michael MacIntosh, Laurie Monserrat, Susan Royo, and Joyce Smylie.

Table of Contents

Preface.........................................................…................................................................. i

Authors and Acknowledgements.................................................................................. iv

Executive Summary...................................................................................................... ES-1

1 Introduction

1.0 Impact of ETS on the Health of Californians....................................................... 1-1

1.1 Organization of the Report.................................................................................... 1-1

1.2 Definition of ETS.................................................................................................... 1-2

1.3 Methodology............................................................................................................ 1-2

1.4 Weight-of-Evidence Evaluations........................................................................... 1-5

Table............................................................…............................................................... 1-7

References......................................................…........................................................... 1-8

2 Exposure Measurements and Prevalence

2.1 Introduction............................................................................................................. 2-1

2.2 Properties of ETS and Its Constituents.................................................................. 2-2

2.3 Exposure Measurement: ETS Concentrations in Indoor Environments.............. 2-5

2.4 Exposure Measurement: Biological Markers...................................................... 2-11

2.5 Exposure Measurement: Use of Questionnaires.................................................. 2-19

2.6 Exposure Prevalence and Determinants.............................................................. 2-23

2.7 Chapter Summary and Conclusions....................................................................... 2-35

Figures.........................................................…............................................................. 2-37

Tables............................................................…............................................................ 2-44

References......................................................….......................................................... 2-60

3 Developmental Toxicity I: Perinatal Manifestations

3.1 Introduction.........................................................…............................................... 3-1

3.2 Fetal Growth.......................................................................................................... 3-1

3.3 Spontaneous Abortion and Perinatal Mortality.................................................... 3-24

3.4 Congenital Malformation...................................................................................... 3-30

3.5 Chapter Summary and Conclusions...................................................................... 3-35

Figures.........................................................…............................................................. 3-36

Tables............................................................…............................................................ 3-38

References......................................................….......................................................... 3-47

4 Developmental Toxicity II: Postnatal Manifestations

4.1 Introduction.........................................................…............................................... 4-1

4.2 Sudden Infant Death Syndrome........................................................................... 4-2

4.3 Cognition and Behavior in Children.................................................................... 4-12

4.4 Postnatal Physical Development........................................................................ 4-23

4.5 Respiratory Development and Function............................................................. 4-28

4.6 Chapter Summary and Conclusions...................................................................... 4-29

Tables............................................................….......................................................... 4-30

References......................................................….......................................................... 4-40

5 Reproductive Effects

5.1 Introduction........................................................................................................... 5-1

5.2 Female Fertility and Fecundability................................................................... 5-1

5.3 Other Female Reproductive Effects.................................................................... 5-8

5.4 Male Reproductive Toxicity................................................................................ 5-10

5.5 Chapter Summary and Conclusions.................................................................. 5-11

Tables............................................................…........................................................... 5-13

References......................................................…......................................................... 5-15

6 Respiratory Health Effects

6.0 Introduction.........................................................….............................................. 6-1

6.1 Acute Health Effects............................................................................................ 6-1

6.2 Chronic Health Effects........................................................................................ 6-32

6.3 Susceptible Populations...................................................................................... 6-52

6.4 Chapter Summary and Conclusions.................................................................. 6-60

References......................................................….......................................................... 6-61

Figures

7 Carcinogenic Effects

7.0 Introduction.........................................................…............................................... 7-1

7.1 All Cancers (combined)....................................................................................... 7-1

7.2 ETS and Lung Cancer......................................................................................... 7-12

7.3 ETS and Cancer Sites Other Than Lung that are Associated with
Active Smoking: Nasal Sinus, Cervical and Bladder............................................. 7-26

7.4 ETS and Cancer Sites Where the Role of Active Smoking is Equivocal:
Breast, Stomach, Brain, Leukemia, Lymphomas and Non-Hodgkin's
Lymphomas, Other Rare Childhood Cancers......................................................... 7-35

7.5 Chapter Summary and Conclusions.................................................................. 7-52

Tables............................................................…........................................................... 7-54

References......................................................…......................................................... 7-76

8 Cardiovascular Effects

8.0 Introduction.........................................................….............................................. 8-1

8.1 Description of Epidemiologic Studies................................................................ 8-4

8.2 Discussion of Epidemiologic Studies................................................................. 8-22

8.3 Other Supportive Evidence................................................................................. 8-26

8.4 Chapter Summary and Conclusions.................................................................. 8-36

Tables............................................................…........................................................... 8-37

References......................................................…......................................................... 8-63

Appendix A: Summary of Public Comments and Responses................................ A-1

List of Tables and Figures by Chapter

Executive Summary

Table ES.1 Health Effects Associated with Exposure to Environmental Tobacco Smoke

Table ES.2 Estimated Annual Morbidity and Mortality in Nonsmokers Associated with ETS Exposure

1 Introduction

Table 1.1 Estimated Annual Morbidity and Mortality in Nonsmokers Associated with ETS Exposure

2 Exposure Measurements and Prevalence

List of Figures:

Figure 2.1 Plasma Cotinine Concentrations in Self-Reported Smokers and Nonsmokers

Figure 2.2 Urinary Cotinine of Breast-Fed Infants in Relation to Maternal Cigarette Smoking

Figure 2.3 Percent of Nonsmokers in California Reporting ETS Exposure

Figure 2.4 Reported Average Daily ETS Exposure Duration in California

Figure 2.5 Relative Person-Minutes of ETS Exposure in Different Environments

Figure 2.6 Adult Smoking Prevalence: California and U.S. (Without California)

Figure 2.7 Per Capita Consumption of Cigarettes: California and All Other States

List of Tables:

Table 2.1 Influence of Puff Volume and Filter Ventilation on Deliveries of Particulate Matter and Carbon Monoxide in Mainstream and Sidestream Smoke

Table 2.2 Chemical Constituents of Tobacco Smoke that Have Been Identified or Classified as to Their Carcinogenicity, Reproductive Toxicity or Other Health Hazard

Table 2.3 Mean Concentrations of Nicotine and Cotinine in the Saliva, Plasma, and Urine of ETS-Exposed Volunteers

Table 2.4 Comparison of Biomarkers in Unexposed and ETS-Exposed Nonsmokers, and Active Smokers

Table 2.5 Cut-Off, Sensitivity, and Specificity of Biomarkers for Discriminating True Smoking Status

Table 2.6 Studies of Cotinine Measurements in Self-Reported Nonsmokers and Criteria Used for Distinguishing Smokers and Nonsmokers

Table 2.7 Concentrations of Nicotine and Cotinine in Mothers' Milk

Table 2.8 Studies with Information on ETS Exposure Prevalence in California and the U.S.: Adults and Adolescents

Table 2.9 Studies with Information on ETS Exposure Prevalence in California and the U.S.: Infants and Children

3 Developmental Toxicity I: Perinatal Manifestations

List of Figures:

Figure 3.1: Summary of Differences in Mean Birthweight and 95% Confidence Intervals Between
ETS Exposed and Unexposed Pregnancies, by Definition of ETS and Study Size

Figure 3.2: Odds Ratio (Log Scale) and 95% Confidence Interval for the Association of
Low Birthweight and ETS, by Definition of ETS and Study Size

List of Tables:

Table 3.1: Studies of Birthweight and ETS Exposure Defined by Paternal Smoking Status

Table 3.2: Studies of Fetal Growth and ETS Exposure Defined by Paternal Smoking Status

Table 3.3: Studies of Fetal Growth and ETS Exposure from Multiple Sources, in Nonsmokers

Table 3.4: Studies of Fetal Growth and ETS Exposure Determined by Biomarkers

Table 3.5: ETS Exposure in Relation to Spontaneous Abortion and Perinatal Death

Table 3.6: ETS Exposure and Congenital Malformations

Table 3.7: Animal Studies of Tobacco Smoke Exposure and Fetal Growth

4 Developmental Toxicity II: Postnatal Manifestations

Table 4.1: Sudden Infant Death Syndrome: Studies that Assessed Some Source of Postnatal ETS Exposure

Table 4.2: Cognition in Children: Studies that Assessed Some Source of Postnatal ETS Exposure

Table 4.3: Behavior in Children: Studies that Assessed Some Source of Postnatal ETS Exposure

Table 4.4: Height Growth in Children: Studies that Assessed Some Source of Postnatal ETS Exposure

5 Reproductive Effects

Table 5.1: ETS Exposure and Infertility or Fecundability: Adult Exposure

Table 5.2: ETS Exposure and Infertility or Fecundability: Childhood Exposure

6 Respiratory Health Effects

List of Tables

Table 6.1: Studies Cited by the U.S. Environmental Protection Agency (1993) as Evidence
Supporting a Causal Relationship Between ETS Exposure and Increased Episodes
and Severity of Asthma in Children

Table 6.2: Controlled Exposure Studies of Asthmatic Subjects to ETS

Table 6.3: Studies of Middle Ear Effusion (MEE) and Otitis Media (OM) vs.
ETS Exposure Reviewed by the Surgeon General (1986), NRC (1986),
or U.S. EPA (1992).

Table 6.4: Studies of Middle Ear Effusion (MEE) or Otitis Media (OM) vs. ETS
Exposure Not Reviewed by the Surgeon General (1986), NRC (1986),
or U.S. EPA (1992).

Table 6.5 ETS Exposure Relationship with Pulmonary Function, Hospitalizations a
Disease Severity in Children with Cystic Fibrosis

List of Figures

Figure 6.1: Reported risk ratios and 95% confidence intervals for studies that used
clinically recognized asthma as an outcome

Figure 6.2: Reported risk ratios and 95% confidence intervals for studies that used "wheezing bronchitis or "chronic wheezing/whisting in chest" as an outcome

7 Carcinogenic Effects

List of Tables

Table 7.1 Exposure to Spouse's Smoking and Relative Risk (RR) of All Cancers in Adults

Table 7.2A Hair Concentrations of Nicotine and Cotinine in Women and
Their Newborn Infants

Table 7.2B 4-Aminobiphenyl Hemoglobin Adduct Concentrations in Pregnant Women
and Fetuses by Exposure to Tobacco Smoke

Table 7.2C Cotinine and PAH-Albumin Levels in Mothers and Their Preschool Children

Table 7.3 Maternal Smoking During Index Pregnancy and Risk of All Childhood
Cancers Combined

Table 7.4 The Study Designs of Four US Lung Cancer Studies Published since 1991

Table 7.5 Association Between Risk of Lung Cancer in Lifetime Nonsmoking Females
and Exposure to Spousal Smoking

Table 7.6 Association Between Risk of Lung Cancer and ETS Exposures From Parents
and Other Household Members

Table 7.7 Studies on ETS Exposure at the Workplace and Lung Cancer Among
Lifetime Nonsmoking Subjects

Table 7.8 Association Between Passive Smoke Exposure and Risk of
Nasal Sinus Cancers in Nonsmokers

Table 7.9 Relationship Between Active and Passive Smoke Exposure and Risk of
Cervical Cancer

Table 7.10 Nicotine and Cotinine Measured in the Cervical Mucus of Smokers,
Passive Smokers, and Nonsmokers

Table 7.11 Passive Smoking and Bladder Cancer Among Nonsmokers

Table 7.12 Mean Levels of Hemoglobin Adducts of 4- and 3-Aminobiphenyls in Nonsmokers

Table 7.13 Mean Levels of 4-ABP Hemoglobin Adducts (PG/G of Hemoglobin)
Among Smokers and Nonsmokers by Acetylator Phenotype

Table 7.14 Brain Tumors in Children and Exposure to Parents' Smoking

Table 7.15 Maternal or Parental Smoking During Pregnancy and Childhood Leukemia

Table 7.16 Association Between Exposure to Passive Smoking and Risk of Lymphoma
and Non-Hodgkins Lymphoma in Children

8 Cardiovascular Effects

List of Tables

Table 8.1 Cohort Studies on ETS Exposure and Heart Disease

Table 8.2 Case control Studies on ETS Exposure and Heart Disease

Table 8.3 Risks of Heart Disease and Active Smoking in Women

Table 8.4 Risks of Heart Disease and Active Smoking in Women By Age

Table 8.5 Effect of Exposure to ETS on Exercise Tolerance

Table 8.6 Effect of Exposure to ETS on Lipid Profile in Children

Table 8.7 Platelet Sensitivity to Anti-aggregatory Prostaglandins
Before and After Exposure to ETS

Table 8.8 Measures of Platelet Function in Relation to Exposure
to Active Smoking and Passive Smoking

Table 8.9 Carotid Artery Intimal-Medial Thickness (IMT) as Measured by
B-mode Ultrasound in Current Smokers, Exsmokers, Never Smokers

Table 8.10 Endothelium-Dependent Arterial Dilatation in Active Smokers,
Passive Smokers, and Nonsmokers