vvEPA
United States Oifice of Research and Office of Air and •
Environmental Protection Development Radiation December 1992
Agency Washington, DC 20460 Washington, DC 20460
Respiratory Health
Effects of Passive
Smoking:
Lung Cancer and
Other Disorders
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EPA/600/6-90/006F
December 1992
RESPIRATORY HEALTH EFFECTS
OF PASSIVE SMOKING:
LUNG CANCER AND OTHER DISORDERS
Major funding for this report has been provided by the Indoor Air Division,
Office of Atmospheric and Indoor Air Programs
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, D.C.
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DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental Protection Agency
policy and approved for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
u
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CONTENTS
Tables viii
Figures xiii
Foreword ; xv
Preface xvi
Authors, Contributors, and Reviewers xvii
1. SUMMARY AND CONCLUSIONS 1-1
1.1. MAJOR CONCLUSIONS 1-1
1.2. BACKGROUND 1-2
1.3. PRIMARY FINDINGS 1-4
1.3.1. ETS and Lung Cancer 1-6
1.3.1.1. Hazard Identification 1-6
1.3.1.2. Estimation of Population Risk 1-11
1.3.2. ETS and Noncancer Respiratory Disorders 1-12
2. INTRODUCTION 2-1
2.1. FINDINGS OF PREVIOUS REVIEWS 2-2
2.2. DEVELOPMENT OF EPA REPORT 2-5
2.2.1. Scope 2-5
2.2.2. Use of EPA's Guidelines 2-6
2.2.3. Contents of This Report 2-8
,3. ESTIMATION OF ENVIRONMENTAL TOBACCO SMOKE EXPOSURE 3-1
3.1. INTRODUCTION 3-1
3.2. PHYSICAL AND CHEMICAL PROPERTIES 3-2
3.3. ASSESSING ETS EXPOSURE 3-10
3.3.1. Environmental Concentrations of ETS 3-12
3.3.1.1. Markers for Environmental Tobacco Smoke 3-18
3.3.1.2. Measured Exposures to ETS-Associated Nicotine and RSP 3-22
3.3.2. Biomarkers of ETS Exposure 3-40
3.3.3. Questionnaires fof Assessing ETS Exposures 3-48
3.4. SUMMARY 3-51
4. HAZARD IDENTIFICATION I: LUNG CANCER IN ACTIVE SMOKERS.
LONG-TERM ANIMAL BIOASSAYS, AND GENOTOXICITY STUDIES 4-1
4.1. INTRODUCTION 4-1
ill
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CONTENTS (continued)
4.2. LUNG CANCER IN ACTIVE SMOKERS „ o
4.2.1. Time Trends ............... .......................... 4"2
4.2.2. Dose-Response Relationships .............................. ' t^
4.2.3. ffistological Types of Lung Cancer and Associations WithSmoking ....... 4-io
A a ™ ^P01*011 of R1-k AP-rutable to Active Smoking § ...... T „
4.3. LIFETIME ANIMAL STUDIES ........ ....... " .......... 3
4.3.1. Inhalation Studies ....... '.'.'.'.'.'. ............................. 4"23
4.3.2. Intrapulmonary Implantations of Cigarette Smoke Condensates .......... ' 4~25
4.4. GENOToScir?1. Paindng ° Cig^e Smoke Condensates ...... : .' : : : : .' : : : 4-26
4.5. SUMMARY AND CONCLUSIONS ......... i ...'.''.'.' .................
' S^S? IDENTIFICATION II: INTERPRETATION OF EPIDEMIOLOGIC
STUDIES ON ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER ...... 5-1
5.1. INTRODUCTION .......
5.2. RELATIVE RISKS USED IN STATISTICAL' INFERENCE ....... ' .......... <~!s
5.2.1. Selection of Relative Risks ............. .............. ^" ^
5.2.2. Downward Adjustment to Relative Risk for Smoker ............ "
Misclassification Bias
5.3. STATISTICAL INFERENCE '••-••; ......................... 5-22
5.3.1. Introduction .......... .'........' ............... ' ......... 5"25
5.3.2. Analysis of Data by Study and Country ........................ " ' 5/l5,
5.3.2.1. Tests for Association . . ........... ' .......... ,'^r
5.3.2.2. Confidence Intervals .......... ..... ................. '^
5.3.3 Analysis of Data by Exposure Level ....................... *%.
5.3.3.1. Introduction ............... .'.'.'.'.'.' ......... ' ........ 5~£
5.3.3.2. Analysis of High-Exposure Data ................... ' ..... ^
5.3.3.3. Tests for Trend ... ..................... I'6'
5.3.4. Conclusions ... ............................... 5'40
5.4. STUDY RESULTS ON FACTORS THAT MAY AFFECT ................... 5"51
LUNG CANCER RISK ...
5.4.1. Introduction .............. .' [\ ' ................ ; ...........
5.4.2. ffistory of Lung Disease ..'.'.'.'.'.'.'. ............................
5.4.3. Family ffistory of Lung Disease ...... ......................... '
5.4.4. Heat Sources for Cooking or Heating ........................... ;"„
5.4.5. Cooking With Oil ............. ....................... ^
5.4.6. Occupation ........ ................................ 5"54
5.4.7. Dietary Factors ....'] ....'. ....'.[[ [[ [ ........... ' ........... 5"54
5.4.8. Summary on Potential Modifying Factors ....................... •" ' /S
5.5. ANALYSIS BY TIER AND COUNTRY ......... ................ S,~^
5.6. CONCLUSIONS FOR HAZARD IDENTIHCATION ..................... clo
5.6.1. Criteria for Causality ........ ' ' ' .............. ^
5.6.2. Assessment of Causality ........................ ':.
5.6.3. Conclusion . . . . ...... ...................... ............. 5'^0
.................................. 5-68
IV
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CONTENTS (continued)
6. POPULATION RISK OF LUNG CANCER FROM PASSIVE SMOKING 6-1
6.1. INTRODUCTION 6-1
6.2. PRIOR APPROACHES TO ESTIMATION OF POPULATION RISK 6-1
6.2.1. Examples Using Epidemiologic Data 6-2
6.2.2. Examples Based on Cigarette-Equivalents 6-5
6.3. THIS REPORT'S ESTIMATES OF LUNG CANCER MORTALITY
ATTRIBUTABLE TO ETS IN THE UNITED STATES 6-8
6.3.1. Introduction and Background 6-8
6.3.2. Parameters and Formulae for Attributable Risk 6-10
6.3.3. U.S. Lung Cancer Mortality Estimates Based on Results of
Combined Estimates from 11 U.S. Studies 6-16
6.3.3.1. U.S. Lung Cancer Mortality Estimates for Female
Never-Smokers 6-17
6.3.3.2. U.S. Lung Cancer Mortality Estimates for Male
Never-Smokers 6-17
6.3.3.3. U.S. Lung Cancer Mortality Estimates for Long-Term
(5+ Years) Former Smokers 6-20
6.3.4. U.S. Lung Cancer Mortality Estimates Based on Results of the
Fontham et al. (1991) Study (FONT) 6-21
6.3.5. Sensitivity to Parameter Values 6-27
6.4. SUMMARY AND CONCLUSIONS ON POPULATION RISK 6-29
7. PASSIVE SMOKING AND RESPIRATORY DISORDERS
OTHER THAN CANCER 7-1
7.1. INTRODUCTION 7-1
j
1 7.2. BIOLOGICAL MECHANISMS 7-2
7.2.1. Plausibility 7-2
7.2.2. Effects of Exposure In Utero and During the First
Months of Life 7-3
7.2.3. Long-Term Significance of Early Effects on
Airway Function 7-6
7.2.4. Exposure to ETS and Bronchial Hyperresponsiveness 7-7
7.2.5. ETS Exposure and Atopy 7-9
7.3. EFFECT OF PASSIVE SMOKING ON ACUTE RESPIRATORY
ILLNESSES IN CHILDREN 7-10
7.3.1. Recent Studies on'Acute Lower Respiratory Illnesses 7-11
7.3.2. Summary and Discussion of Acute Respiratory Illnesses 7-20
7.4. PASSIVE SMOKING AND ACUTE AND CHRONIC
MIDDLE EAR DISEASES 7-21
7.4.1. Recent Studies on Acute and Chronic Middle Ear Diseases 7-22
7.4.2. Summary and Discussion of Middle Ear Diseases 7-28
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CONTENTS (continued)
7.5. EFFECT OF PASSIVE SMOKING ON COUGH, PHLEGM
AND WHEEZING . ; . 7_30
7.5.1. Recent Studies on the Effect of Passive Smoking on Cough,
Phlegm, and Wheezing ' 7_30
7.5.2. Summary and Discussion on Cough, Phlegm, and
Wheezing 1-41
7.6. EFFECT OF PASSIVE SMOKING ON ASTHMA . .......... . . . . . .' ' .' .'.' .' ' [ 7.43
7.6.1. Recent Studies on the Effect of Passive Smoking on
Asthma in Children 7.44
7.6.2. Summary and Discussion on Asthma 7 50
7.7. ETS EXPOSURE AND SUDDEN INFANT DEATH SYNDROME 7~5i
7.8. PASSIVE SMOKING AND LUNG FUNCTION IN CHILDREN '.'.'.'.'.'.'.'. 7-57
7.8.1. Recent Studies on Passive Smoking and Lung Function
in Children 7.57
7.8.2. Summary and Discussion on Pulmonary Function
in Children 7_g3
7.9. PASSIVE SMOKING AND RESPIRATORY SYMPTOMS AND
LUNG FUNCTION IN ADULTS 7.54
7.9.1. Recent Studies on Passive Smoking and Adult Respiratory
Symptoms and Lung Function 7.54
7.9.2. Summary and Discussion on Respiratory Symptoms and
Lung Function in Adults : 7_<5g
8. ASSESSMENT OF INCREASED RISK FOR RESPIRATORY ILLNESSES IN
CHILDREN FROM ENVIRONMENTAL TOBACCO SMOKE g-1
8.1. POSSIBLE ROLE OF CONFOUNDING g.j
8.2. MISCLASSEFICATION OF EXPOSED AND UNEXPOSED SUBJECTS ........ 8-2
8.2.1. Effect of Active Smoking in Children g_2
8.2.2. Misreporting and Background Exposure g_3
8.3. ADJUSTMENT FOR BACKGROUND EXPOSURE 85
8.4. ASSESSMENT OF RISK 8-9
8.4.1. Asthma ' \[\ g_10
8.4.2. Lower Respiratory Illness . 8-13
8.4.3. Sudden Infant Death Syndrome 8 15
8.5. CONCLUSIONS '.'.'.'.'.'.'.'.'.'.'.'.'." 8-15
ADDENDUM: PERTINENT NEW STUDIES ADD-1
APPENDIX A: REVIEWS AND TIER ASSIGNMENTS FOR EPIDEMIOLOGIC
STUDIES OF ETS AND LUNG CANCER A-l
APPENDIX B: METHOD FOR CORRECTING RELATIVE RISK FOR
SMOKER MISCLASSIFICATTON B_!
VI
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CONTENTS (continued)
APPENDIX C: LUNG CANCER MORTALITY RATES ATTRIBUTABLE TO
SPOUSAL ETS IN INDIVIDUAL EPIDEMIOLOGIC STUDIES ....... C-l
APPENDIX D: STATISTICAL FORMULAE
SELECTED BIBLIOGRAPHY ...
u 1
K.-1
VU
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TABLES
3-1 Distribution of constituents in fresh, undiluted mainstream smoke and
diluted sidestream smoke from nonfilter cigarettes 3-5
3-2 Example sidestream cigarette smoke deliveries . . . 3-8
• o ~
3-3 Tobacco-specific //-nitrosamines in indoor air (ng/mj) ! 3-17
3-4 Weekly average concentrations of each measure of exposure by parental
smoking status in the cross-sectional study, Minnesota, 1989 3-36
3-5 Studies measuring personal exposure to airborne nicotine associated
with ETS for nonsmokers 3-37
3-6 Studies measuring personal exposure to paniculate matter associated
with ETS for nonsmokers 3-38
3-7 Approximate relations of nicotine as the parameter between
nonsmokers, passive smokers, and active smokers 3-4-3 ,
4-1 Main characteristics of major cohort studies on the
relationship between smoking and cancer 4-6,
4-2 Lung cancer mortality ratios-prospective studies 4-8
4-3 Lung cancer mortality ratios for men and women, by current
number of cigarettes smoked per day-prospective studies . 4-9
4-4 Relationship between risk of lung cancer and duration of smoking in
men, based on available information from cohort studies 4-11
4-5 Lung cancer mortality ratios for males, by age of
smoking initiation-prospective studies 4-12
4-6 Relationship between risk of lung cancer and number of years
since stopping smoking, in men, based on available information
from cohort studies 4-13
4-7 Relative risks of lung cancer in some large cohort studies among
men smoking cigarettes and other types of tobacco 4-15
4-8 Age-adjusted liing cancer mortality ratios for males and females,
by tar and nicotine (T/N) in cigarettes smoked 4-17
4-9 Relative risk for lung cancer by type of cigarette smoked (filter vs.
nonfilter), in men, based on cohort and case-control studies 4-17
viii
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TABLES (continued)
4-10 Main results of studies dealing with the relationship between
smoking and different histological types of lung cancer 4-18
4-11 Lung cancer deaths attributable to tobacco smoking in certain countries 4-24
5-1 Epidemiologic studies on ETS and lung cancer in this report and
tier ranking 5_4
5-2 Studies by location, time, size, and ETS exposure 5-6
5-3 Case-control studies of ETS: characteristics 5-8
5-4 Diagnosis, confirmation, and exclusion of lung cancer cases 5-12
5-5 Estimated relative risk of lung cancer from spousal ETS
by epidemiologic study (crude and adjusted for cofactors) 5-16
5-6 Effect of statistical adjustments for cofactors on risk estimates
for passive smoking 5-20
5-7 Alternative estimates of lung cancer relative risks associated
with active and passive smoking 5-23
5-8 Estimated correction for smoker misclassification . . . 5-26
5-9 Statistical measures by individual study and pooled by country,
corrected for smoker misclassification 5-28
5-10 Statistical measures for highest exposure categories only 5-39
5-11 Exposure response trends for females .. . 5-41
5-12 Reported p-values of trend rests for ETS exposure by study 5-44
5-13 P-values of tests for effect and for trend by individual study 5-46
5-14 Other risk-related factors for lung cancer evaluated in selected studies 5-52
5-15 Dietary effects in passive smoking studies of lung cancer in females 5-57
5-16 Classification of studies by tier 5-62
5-17 Summary data interpretation by tiers within country 5-64
IX
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TABLES (continued)
6-1 Definition and estimates of relative risk of lung cancer for 11 U.S. studies
combined for various exposure sources and baselines; population parameter
definitions and estimates used to calculate U.S. population-attributable
risk estimates for ETS -....' 6-11
6-2 Estimated female lung cancer mortality by attributable sources
for United States, 1985, using the pooleu relative risk estimate
from 11 U.S. studies 6-18
6-3 Female and male lung cancer mortality estimates by attributable
ETS sources for United States, 1985, using 11 U.S. studies
(never-smokers and former smokers who have quit 5+ years) 6-22
6-4 Female lung cancer mortality estimates by attributable sources
for United States, 1985, using both the relative risk estimates
and Z values from the Fontham et al. (1991) study 6-24
6-5 Female and male lung cancer mortality estimates by attributable
ETS sources for United States, 1985, using the Fontham et al. (1991) study
(never-smokers and former smokers who have quit 5+ years) 6-25
6-6 Effect of single parameter changes on lung cancer mortality due to
ETS hi never-smokers and former smokers who have quit 5+ years 6-28
7-1 Studies on respiratory illness referenced in the Surgeon General's
and National Research Council's reports of 1986 7-11
7-2 Recent epidemiologic studies of effects of passive smoking on
acute lower respiratory tract illnesses (LRIs) 7-12
7-3 Studies on middle ear diseases referenced in the Surgeon
General's report of 1986 7-22
7-4 Recent epidemiologic studies of effects of passive smoking on
acute and chronic middle ear diseases 7-23
7-5 Studies on chronic respiratory symptoms referenced in the Surgeon
General's and National Research Council's reports of 1986 7-31
7-6 Recent epidemiologic studies of effects of passive smoking on
cough, phlegm, and wheezing 7.32
7-7 Recent epidemiologic studies of effects of passive smoking on
asthma in childhood 7-45
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TABLES (continued)
7-8 Epidemiologic studies of effects of passive smoking on
incidence of sudden infant death syndrome (SIDS)' 7.53
7-9 Studies on pulmonary function referenced in the Surgeon General's
and National Research Council's reports of 1986 7-58
7-10 Recent epidemiologic studies on the effects of passive smoking
on lung function in children 7.59
7-11 Recent epidemiologic studies on the effects of passive smoking
on adult respiratory symptoms and lung function 7-65
8-1 Adjusted relative risks for "exposed children." Adjusted or background
exposure based on body cotinine ratios between "exposed" and "unexposed"
and equation 8-1 8-8
8-2 Behavior variations in adjusted relative risks from equation 8-1 when the
observed relative risks and Z ratios are uose together 8-9
8-3 Range of estimates of adjusted relative risk and attributable
risk for asthma induction in children based on both threshold
and nonthreshold models 8-11
A-l Study scores for tier assignments A-8
A-2 Total scores and tier assignment A-18
B-l Observed ratios of occasional smokers to current smokers
(based on cotinine studies) B-4
B-2 Examples, using five U.S. studies, of differences in smoker misclassifican'on
bias between EPA estimates and those of P.N. Lee regarding passive smoking
relative risks for females B-5
B-3 Misclassification of female current smokers . B-7
B-4 Misclassification of female former smokers reported as never-smokers
based on discordant answers B-l 1
B-5 Misclassification of female lung cancer cases B-12
B-6 Deletions from the "never" columns in Tables B-13 and B-16 and
corrected elements ! B-13
B-7 Notation for distribution of reported female lung cancer cases and
controls by husband's smoking status B-15
xi
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TABLES (continued)
B-S Notation for distribution of subjects by observed and true smoking status B-15
B-9 Observed ratios of female former smokers to ever-smokers in the U.S., U.K.,
and Swedish studies: populations or controls (numbers or percentage) B-16
B-10 Notation for observed lung cancer relative risks for exposed (k=l) and
nonexposed (k=0) wives by the wife's smoking status, using average
never-smoking wives RR(a)Q as the reference category B-18
B-l 1 Prevalences and estimates of lung cancer risk associated with active
and passive smoking B-19
B-12 Observed ratios of current smoker lung cancer risk to ever-smoker
risk for females B-23
B-l3 Observed smoking prevalence among the controls-Correa example B-26
B-14 Observed relative risks—Correa example B-27
B-15 Crude case table, prevalence of cases by smoking status-Correa example B^27
B-16 Normalized case table, prevalence of cases by smoking status—
Correa example B-27
B-l7 Distribution of subjects by observed and true smoking status for wives
in Correa example B-28
C-l Female lung cancer mortality from all causes in case-control studies C-2
C-2 Parameter values used to partition female lung cancer mortality
into component sources . C-4
C-3 Female lung cancer mortality rates by attributable source C-6
Lung cancer mortality rates of female ever-smokers (ES) and never-smokers (NS)
by exposure status ..'..; C-8
XII
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FIGURES
3-1 Diagram for calculating the RSP mass from ETS emitted into any
occupied space as a function of the smoking rate and removal rate (N) 3-14
3-2 Diagram to calculate the ETS-associated RSP ^ass concentration in ug/m3
in a space as a function of total mass of ETS-generated RSP emiued in rag
(determined from Figure 3-1) and the volume of a space 3-15
3-3 Range of average indoor concentrations for notable ETS comaminants associated
with smoking occupancy of different indoor environments 3-16
3-4 Mean, standard deviation, and maximum and minimum nicotine values measured
in different indoor environments with smoking occupancy 3-23
3-5 Mean, standard deviation, and maximum and minimum concentrations
of RSP mass measured in different indoor environments for smoking and
nonsmoking occupancy 3-26
3-6 Weeklong RSP mass and nicotine measurements in 96 residences
with a mixture of sources 3-27
3-7 Range of average nicotine concentrations and range of maximum
and minimum values measured by different indoor environments
for smoking occupancy from studies shown in Figure 3-4 3-28
3-8 Range of average RSP mass concentrations and range of maximum
and minimum values measured by different indoor environments
for smoking occupancy from studies shown in Figure 3-5 3-29
3-9 Cumulative frequency distribution and arithmetic means of vapor-phase.
nicotine levels over a 1-week period in the main living aiea in itsidences
in Onondaga and Suffolk Counties in New York State between January and
April 1986 3.3!
3-10 Cumulative frequency distribution and arithmetic means of RSP mass levels by
vapor-phase nicotine levels measured over a 1-week period in the main living
area in residences in Onondaga and Suffolk Counties in New York State between
January and April 1986 3.31
3-11 Monthly mean RSP mass concentrations in six U.S. cities 3-32
3-12a Week-long nicotine concentrations measured in the main living area of '
96 residences versus the number of questionnaire-reported cigarettes smoked
during the air-sampling period 3.33
xni
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FIGURES (continued)
3-12b Week-long RSP mass concentrations measured in the main living area
of 96 residences versus the number of questionnaire-reported cigarettes
smoked during the air-sampling period 3-34
3-13 Cumulative frequency distribution of RSP mass concentrations from
central site ambient and personal monitoring of smoke-exposed and
nonsmoke-exposed individuals 3-39
3-14 Average cotinine t^ by age groups ' 3-41
3-15 Distribution of individual concentrations of urinary cotinine by degree
of self-reported exposure to ETS 3-44
3-16 Urinary cotinine concentrations by number of reported exposures to
tobacco smoke in the past 4 days among 663 nonsmokers, Buffalo,
New York, 1986 • • 3-45
3-17 Average cotinine/creatinine levels for subgroups of nonsmoking
women defined by sampling categories of exposure or by
self-reporting exposure to ETS from different sources during
the 4 days preceding collection of the urine sample 3-47
4-1 Age-adjusted cancer death rates for selected sites, males,
United States, 1930-1986 4-3
4-2 Age-adjusted cancer death rates for selected sites, females,
United States, 1930-1986 • 44
4-3 Relative risk of lung cancer in ex-smokers, by number of years
quit, women, Cancer Prevention Study n . . . . 4-14
5-1 Test statistics for hypothesis RR = 1, all studies 5-32
5-2 Test statistics for hypothesis RR = 1, USA only 5-32
5-3 Test statistics for hypothesis RR = 1, by country 5-33
5-4 Test statistics for hypothesis RR = 1, tiers 1-3 only - 5-33
5-5 90% confidence intervals,"by country 5-35
5-6 90% confidence intervals, by country, tiers 1-3 only 5-35
xiv
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FOREWORD 1/19/93
"Respiratory Health Effects. of Passive Smoking: Lung
Cancer and ^ther Disorders" is the most recent scientific
assessment' of the health effects associated with exposure to
InvSnmental tobacco smoke, and the first undertaken by the
U S. Environmental Protection Agency (EPA). It confirms and
strengthens the results of two 1986 reports by the U.S.
Surgeon General and -he National Research Council, and
provides important new documentation of the emerging
scientific consensus that tobacco smoke is not 3 ust a health
risk for smokers. It is, in fact, also a significant risk
for nonsmokers, particularly for children.
This report demonstrates conclusively that
environmental tobacco smoke increases the risk of lung
cancer in healthy ncnsmokers. The report estimates that
roughly 30 percent cf all lung cancers caused by ractors
other than smoking are attributable to exposure *=
environmental tobacco smoke. Put another way, a nonsmoker
IxpoSeS to environmental tobacco smoke during everyday
activities faces an increased lifetime risk of lung cancer
of roughly l-in-500 _o l-in-l,OQO. By comparison EPA
Generally sets its standards or regulations so that
inSretsed cancer risks are below i-in-10,000 to l-in-a-
nillion. in other words, estimated lung cancer risks
?irt^fg^ns^^
elicit an action by EPA.
Perhaps as alar-ing are the. report's findings on the
effects of environmental tobacco smoke on infants and
children. Children up to 18 months of age.are'at twice the
risk of bronchitis and pneumonia if their parents smoke; the
reSort estimates that 150,000 to 300,000 cases per year are
SSr!bu"ble to environmental tobacco smpke En vironmental
tobacco smoke also increases the risks of fluid in the
middle ear, asthmatic attacks, respiratory tract irritation,
and reduced lung function.
We hope that this report will prove a useful guide for
policy \akers and citizens everwhere. _ Environme;'^^^^°
Smoke is a rarity, ar.ong the major env^°nmental health r^sks
we face today in so far as it is something we can personally
take steps to prevent. In the end, .responsibility f of—-,
projecting tn^safetv of the indoor/environment belo
ever^ne.
CSs£.
XV
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PREFACE
This assessment of the respiratory health effects associated with passive smoking has been
prepared by the Human Health Assessment Group, Office of Health and Environmental Assessment,
Office of Research and Development, which is responsible for the report's scientific accuracy and
conclusions. The assessment was prepared at the request of the Indoor Air Division, Office of
Atmospheric and Indoor Air Programs, Office of Air and Radiation, which defined the assessment's
scope and provided funding.
The report has been developed under the authority of Title IV of Superfund (The Radon Gas
and Indoor Air Quality Research Act of 1986) to provide information and guidance on the potential
hazards of indoor air pollutants.
Two drafts of this report were made available for public review and comments, the first in June
1990 (reviewed by the Agency's Science Advisory Board [SAB] in December 1990) and a significantly
revised draft in May 1992 (reviewed by the SAB in July 1992). This report reflects the comments
received from those reviews.
A comprehensive search of the scientific literature for this report is complete through September
1991. In addition, pertinent studies published through July 1992 have been included in the analysis in
response to recommendations made by reviewers.
Due to both resource and time constraints, the scope of this report has been limited to an
analysis of respiratory effects, primarily lung cancer in nonsmoking adults and noncancer respiratory
illnesses in children, with emphasis on the epidemiologic data. Further, because two thorough reviews
on passive smoking were completed in 1986 (by the U.S. Surgeon General and the National Research
Council), this document provides a summary of those reports with a more comprehensive analysis of the
literature appearing subsequent to those reports and an integration of the results.
xvi
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
This document was prepared by the Office of Health and Environmental Assessment (OHEA)
within the Office of Research and Development, with major contract funding provided by the Indoor Air
Division within the Office of Air and Radiation's Office of Atmospheric and Indoor. Air Programs.
Steven P. Bayard1 was the OHEA project manager with overall responsibility for the contents of this
report and its conclusions. Other OHEA staff members responsible for the scientific content of sections
of this document are Jennifer Jinot1 and Apama M. Koppikar.1 Jennifer Jinot and Steven Bayard were
the scientific editors.
AUTHORS
Major portions of this revised report were prepared by ICF Incorporated, Fairfax, Virginia,
under EPA Contract No. 68-00-0102. While OHEA staff provided technical editing and incorporated
reviewers' comments into each chapter in an attempt to develop a comprehensive and consistent
document, the following people were the primary authors:
Chapter 1: Steven P. Bayard
Chapter 2: Jennifer Jinot
Chapter 3: Brian P. Leaderer^. -
Chapter 4: Jennifer Jinot
Chapters 5/6: Kenneth G. Brown3
Chapter 7: Fernando D. Martinez4
Chapter 8: Fernando D. Martinez and Steven P. Bayard
Appendix A: Kenneth G. Brown, Neal R. Simonsen,3 and A. Judson Wells3
Appendix B: A. Judson Wells
Appendix C: Kenneth G. Brown
Appendix D: Kenneth G. Brown and Neal R. Simonsen
1Human Health Assessment Group, Office of Health and Environmental Assessment, U.S. EPA,
Washington, DC 20460.
2J.B. Pierce Foundation Laboratory, Department of Epidemiology and Public Health, Yale
University School of Medicine, New Haven, CT 06520. Subcontractor to ICF, Inc.
3Kenneth G. Brown, Inc., P.O. Box 16608, Chapel Hill, NC 27516. Subcontractor to ICF, Inc.
4Division of Respiratory Sciences, University of Arizona Medical Center, Tucson, AZ 85724.
Subcontractor to ICF, Inc.
xvii
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CONTRIBUTORS .
Numerous persons have provided helpful discussions or responded to requests for preprints,
data, and other material relevant to this report. The authors are grateful to W.J. Blot, N. Britten, R.C.
Brownson, ^.A. Buffler, T.L. Butle-, D.B Coultas, K.M. Cummings, J. Fleiss, E.T.H. Fontham, Y.T.
Gao, L. Garfinkel, S. Glantz, NJ. Haley, T. Hirayama, D.J. Hole, C. Humble, G.C. Kabat, J.C.
Kleinman, GJ. Knight, L.C. Koo, M. Layard, M.D. Lebowitz, P.N. Lee, P. MacaskiU, G.E. Palomaki,
J.P. Pierce, J. Repace, H. Shimizu, W.F. Stewart, D. Trichopoulos, R.W. Wilson, and A. Wu-Williams.
REVIEWERS
This final report was preceded by two earlier drafts: an External Review Draft (EPA/600/6-
90/006A) published in May 1990, and an SAB Review Draft (EPA/600/6-90/006B) published in May
1992. The External Review Draft was released for public review and comment on June 25, 1990, and
was subsequently reviewed by the EPA Science Advisory Board (SAB) on December 4 and 5, 1990.
The SAB Review Draft incorporated many of the public comments and especially the valuable advice
presented in the SAB's April 19, 1991, report to the Agency. In addition, many reviewers both within
and outside the Agency provided assistance at various internal review stages.
The second Review Draft also was reviewed by the SAB on July 21 and 22, 1992, which
provided its report to the Agency on November 20, 1992. The authors wish to thank all those who
sought to improve the quality of this report with their comments and are particularly grateful to the SAB
for its advice.
The following members of the SAB's Indoor Air Quality and Total Human Exposure Committee
(IAQTHEC) participated in the reviews of the two Review Drafts.
Chairman
Dr. Morton Lippmann, Professor, Institute of Environmental Medicine, New York University
Medical Center, Tuxedo, NY 10987
Vice Chairman
Dr. Jan A.J. Stolwijk, Professor, School of Medicine, Department of Epidemiology and Public
Health, Yale University, 60 College Street, New Haven, CT 06510
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Members of the IAQTHEC
Dr. Joan Daisey, Senior Scientist Indoor Environment Program, Lawrence Berkeley Laboratory,
One Cyclotron Road, Berkeley, CA 94720 ' .
Dr Timothy Larson, Environmental Science and Engineering Program, Department of Civil
Engineering, University of Washington, Seattle, WA 98195 (1992 review only)
Dr. Victor G. Laties, Professor of Toxicology, Environmental Health Science Center, Box EHSC,
University of Rochester School of Medicine, Rochester, NY 14642
Dr Paul Lioz, Department of Environmental and Community Medicine, Robert Wood Johnson
School of Medicine, Piscataway, NJ 08854 (1992 review only)
Dr Jonathan M. Samet, Professor of Medicine, Department of Medicine, University of New
Mexico School of Medicine, and New Mexico Tumor Registry, 900 Camino De Salud, NE,
Albuquerque, NM 87131
Dr. Jerome J. Wesolowski, Chief, Air and Industrial Hygiene Laboratory, California Department
of Health, Berkeley, CA 94704
Dr. James E. Woods, Jr., Professor of Building Construction, College of ArcWtecUire and Urban
Studies, 117 Burress Hall, Virginia Polytechnic Institute and State University, Blacksburg, VA
24061-0156
Consultants to the IAQTHEC
Dr. Neal L. Benowitz, Professor of Medicine, Chief, Division of Clinical Pharmaco_logy and
Experimental Therapeutics, University of California-San Francisco, Building ,C Fifth Floor,
San Francisco General Hospital. 1001 Potrero Avenue, San Francisco, CA 94110
Dr. William J. Blot, National Cancer Institute, 9000 Rockville Pike, Bethesda. MD 20892 (Federal
Liaison to the Committee)
Dr. David Bums, Associate Professor of Medicine, Department of Medicine University of
California, San Diego Medical Center, 225 Dickenson Street, San Diego, CA 92103-1990
Dr. Delbert Eatough, Professor of Chemistry, Brigham Young University, Provo, UT 84602
Dr S Katharine Hammond, Associate Professor, Environmental Health Sciences Program,
Department of Family and Community Medicine, University of Massachusetts Medical School,
55 Lake Avenue, North, Worcester, MA 06155
Dr. Geoffrey Kabat, Senior Epidemiologist, American Health Foundation, 320 East 43rd Street,
New York, NY 10017
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Dr. Michael D. Lebowitz, Professor of Internal Medicine, University of Arizona College of
Medicine, Division of Respiratory Sciences, Tucson, AZ 85724
Dr. Howard Rockette, Professor of Biostatistics, School of Public Health, 318 Parran Hall,
University of Pittsburgh, Pittsburgh, PA 15261
Dr. Scott T. Weiss, Charming Laboratory, Harvard University School of Medicine,
Boston, MA 02115
Acknowledgments
The authors would like to acknowledge the contributions of several people who have made this
report and the previous two drafts possible. Foremost is Robert Axelrad, Chief of the Indoor Air
Division, Office of Air and Radiation, who provided the foresight, funding, and perseverance that made
this effort possible. We also would like to thank the following people:
Individuals from the Office of Health aud Environmental Assessment's Technical
Information Staff who were responsible for the overall quality, coordinaiion, organization,
printing, and distribution of these reports: Linda Bailey-Becht, Terri Konoza, Marie Pfaff,
Michele Ranere, and Judy Theisen. Also, Karen Sandidge from the Human Health
Assessment Group for the typing support that she provided.
Staff from R.O.W. Sciences, Inc., under the direction of Kay Marshall, who were
responsible for editing, word processing, and proofreading the final report.
Robert Flaak, Assistant Staff Director of the SAB, whose efforts and professionalism hi
organizing and coordinating the two SAB reviews led to an improved and more useful
product
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1. SUMMARY AND CONCLUSIONS
1.1. MAJOR CONCLUSIONS
Based on the weight of the available scientific evidence, the U.S. Environmental
Protection Agency (EPA) has concluded that the widespread exposure to environmental
tobacco smoke (ETS) in the United States presents a serious and substantial public health
impact.
In adults:
• ETS is a human lung carcinogen, responsible for approximately 3,000 lung
cancer deaths annually in U.S. nonsmokers.
In children: - ' >
• ETS exposure is causally associated with an increased risk of lower
respiratory tract infections (LRIs) such as bronchitis and pneumonia. This
report estimates that 150,000 to 300,000 cases annually in infants and young
children up to 18 months of age are attributable to ETS.
• ETS exposure is causally associated with increased prevalence of fluid in the
middle ear, symptoms of upper respiratory tract irritation, and a small but
significant reduction in lung function.
• ETS exposure is causally associated with additional episodes and increased
severity of symptoms in children with asthma. This report estimates that
200,000 to 1,000,000 asthmatic children have their condition worsened by
exposure to ETS.
• ETS exposure is a risk factor for new cases of asthma in children who have
not previously displayed symptoms.
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1.2. BACKGROUND
Tobacco smoking has long been recognized (e.g., U.S. Department of Health, Education, and
Welfare [U.S. DHEW], 1964) as a major cause of mortality and morbidity, responsible for an
estimated 434,000 deaths per year in the United States (Centers for Disease Control [CDC], 1991a).
Tobacco use is known to cause cancer at various sites, in particular the lung (U.S. Department of
Health and Human Services [U.S. DHHS], 1982; International Agency for Research on Cancer
[IARC], 1986). Smoking can also cause respiratory diseases (U.S. DHHS, 1984, 1989) and is a
major risk factor for heart disease (U.S. DHHS, 1983). In recent years, there has been concern that
nonsmokers may also be at risk for some of these health effects as a result of their exposure ("passive
smoking") to the tobacco smoke that occurs in various environments occupied by smokers. Although
this ETS is dilute compared with the mainstream smoke (MS) inhaled by active smokers, it is
chemically similar, containing many of the same carcinogenic and toxic agents.
In 1986, the National Research Council (NRC) and the Surgeon General of the U.S. Public
Health Service independently assessed the health effects of exposure to ETS (NRC, 1986;
U.S. DHHS, 1986). Both of the 1986 reports conclude that ETS can cause lung cancer in adult
nonsmokers and that children of parents who smoke have increased frequency of respiratory
symptoms and acute lower respiratory tract infections, as well as evidence of reduced lung function.
More recent epidemiologic studies of the potential associations between ETS and lung cancer
in nonsmoking adults and between ETS and noncancer respiratory effects more than double the size of
the database available for analysis from that of the 1986 reports. This EPA report critically reviews
the current database on the respiratory health effects of passive smoking; these data are utilized to
develop a hazard identification for ETS and to make quantitative estimates of the public health
impacts of ETS for lung cancer and various other respiratory diseases.
The weight-of-evidence analysis for the lung cancer hazard identification is developed in
accordance with U.S. EPA's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a) and
established principles for evaluating epidemiologic studies. The analysis considers animal bioassays
and genotoxicity studies, as well as biological measurements of human uptake of tobacco smoke
components and epidemiologic data on active and passive smoking. The availability of abundant and
consistent human data, especially human data at actual environmental levels of exposure to the
specific agent (mixture) of concern, allows a hazard identification to be made with a high degree of
certainty. The conclusive evidence of the dose-related lung carcinogenicity of MS in active smokers
(Chapter 4), coupled with information on the chemical similarities of MS and ETS and evidence of
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ETS uptake in nonsmokers (Chapter 3), is sufficient by itself to establish ETS as a known human lung
carcinogen, or "Group A" carcinogen under U.S. EPA's carcinogen classification system. In
addition, this document concludes that the overall results of 30 epidemiologic studies on lung cancer
and passive smoking (Chapter 5), using spousal smoking as a surrogate of ETS exposure for female
never-smokers, similarly justify a Group A classification.
The weight-of-evidence analyses for the noncancer respiratory effects are based primarily "on a
review of epidemiologic studies (Chapter 7). Most of the endpoints examined are respiratory
disorders in children, where parental smoking is used as a surrogate of ETS exposure. For the
noncancer respiratory effects in nonsmoking adults, most studies used spousal smoking as an exposure
surrogate. A causal association was concluded to exist for a number of respiratory disorders where
there was sufficient consistent evidence for a biologically plausible association with ETS that could
not be explained by bias, confounding, or chance. The fact that the database consists of human
evidence from actual environmental exposure levels gives a high degree of confidence in this
conclusion. Where there was suggestive but inconclusive evidence of causality, as was the case for
asthma induction hi children, ETS was concluded to be a risk factor for that endpoint. Where data
were inconsistent or inadequate for evaluation of an association^ as for acute upper respiratory tract
infections and acute middle ear infections in children, no conclusions were drawn.
This report also has attempted to provide estimates of the extent of the public health impact,
where appropriate, hi terms of numbers of ETS-attributable cases in nonsmoking subpopulations.
Unlike for qualitative hazard identification assessments^ where information from many sources adds to
the confidence in a weight-of-evidence conclusion, for quantitative risk assessments, the usefulness of
studies usually depends on how closely the study population resembles nonsmoking segments of the
general population. For lung cancer estimates among U.S. nonsmokers, the substantial epidemiology
database of ETS and lung cancer among U.S. female never-smokers was considered to provide the
most appropriate information. From these U.S. epidemiology studies, a pooled relative risk estimate
was calculated and used in the derivation of the population risk estimates. The large number of
studies available, the generally consistent results, and the condition of actual environmental levels of
exposure increase the confidence hi these estimates. Even under these circumstances, however,
uncertainties remain, such as in the use of questionnaires and current biomarker measurements to
estimate past exposure, assumptions of exposure-response linearity, and extrapolation to male never-
smokers and to ex-smokers. Still, given the strength of the evidence for the lung carcinogenicity of
tobacco smoke and the extensive human database from actual environmental exposure levels, fewer
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assumptions are necessary than is usual in EPA quantitative risk assessments, and confidence in these
estimates is rated medium to high.
Population estimates of ETS health impacts are also made for certain noncancer respiratory
endpoints in children, specifically lower respiratory tract infections (i.e., pneumonia, bronchitis, and
bronchiolitis) and episodes and severity of attacks of asthma. Estimates of ETS-attributable cases of
LRI in infants and young children are thought to have a high degree of confidence because of the
consistent study findings and the appropriateness of parental smoking as a surrogate measure of
exposure in very young children. Estimates of the number of asthmatic children whose condition is
aggravated by exposure to ETS are less certain than those for LRIs because of different measures of
outcome in various studies and because of increased extraparental exposure to ETS in older children.
Estimates of the number of new cases of asthma in previously asymptomatic children also have less
confidence because at this time the weight of evidence for asthma induction, while suggestive of a
causal association, is not conclusive.
Most of the ETS population impact estimates are presented in terms of ranges, which are
thought to reflect reasonable assumptions about the estimates of parameters and variables required for
the extrapolation models. The validity of the ranges is also dependent on the appropriateness of the
extrapolation models themselves.
While this report focuses only on the respiratory health effects of passive smoking, there also
may be other health effects of concern. Recent analyses of more than a dozen epidemiology and
toxicology studies (e.g., Steenland, 1992; National Institute for Occupational Safety and Health
[NIOSH], 1991) suggest that ETS exposure may be a risk factor for cardiovascular disease. In
addition, a few studies in the literature link ETS exposure to cancers of other sites; at this time, that
database appears inadequate for any conclusion. This report does not develop an analysis of either
the nonrespiratory cancer or the heart disease data and takes no position on whether ETS is a risk
factor for these diseases. If it is, the total public health impact from ETS will be greater than that
discussed here.
1.3. PRIMARY FINDINGS
A. Lung Cancer in Nonsmoking Adults
1. Passive smoking is causally associated with lung cancer in adults, and ETS, by the
total weight of evidence, belongs in the category of compounds classified by EPA as
Group A (known human) carcinogens.
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2. Approximately 3,000 lung cancer deaths per year among nonsmokers (never-
smokers and former smokers) of both sexes are estimated to be attributable to ETS
in the United States. While there are statistical and modeling uncertainties in this
estimate, and the true number may be higher or lower, the assumptions used in this
analysis would tend to underestimate the actual population risk. The overall
confidence in this estimate is medium to high.
B. Noncancer Respiratory Diseases and Disorders
1. Exposure of children to ETS from parental smoking is causally associated with:
a. increased prevalence of respiratory symptoms of irritation (cough, sputum,
and wheeze),
b. increased prevalence of middle ear effusion (a sign of middle ear
disease), and
c. a small but statistically significant reduction in lung function as tested by
objective .measures of lung capacity.
2. ETS exposure of young children and particularly infants from parental (and
especially mother's) "smoking is causally associated with an increased risk of LRIs
(pneumonia, bronchitis, and bronchiolitis). This report estimates that exposure to
ETS contributes 150,000 to 300,000 LRIs annually in infants and children less than
18 months of age, resulting in 7,500 to 15,000 hospitalizations. The confidence in
the estimates of LRIs is high. Increased risks for LRIs continue, but are lower in
magnitude, for children until about age 3; however, no estimates are derived for
children over 18 months.
3. a. Exposure to ETS is causally associated with additional episodes and increased
severity of asthma in children who already have the disease. This report
estimates that ETS exposure exacerbates symptoms in approximately 20% of
this country's 2 million to 5 million asthmatic children and is a major
aggravating factor in approximately 10%.
b. In addition, the epidemiologic evidence is suggestive but not conclusive that
ETS exposure increases the number of new cases of asthma in children who
have not previously exhibited symptoms. Based on this evidence and the
known ETS effects on both the immune system and lungs (e.g., atopy and
airway hyperresponsiveness), this report concludes that ETS is a risk factor for
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the induction of asthma in previously asymptomatic children. Data suggest that
relatively high levels of exposure are required to induce new cases of asthma in
children. This report calculates that previously asymptomatic children exposed
to ETS from mothers who smoke at least 10 cigarettes per day will exhibit an
estimated 8,000 to 26,000 new cases of asthma annually. The confidence in
this range is medium and is dependent on the conclusion that ETS is a risk
factor for asthma induction.
4. Passive smoking has subtle but significant effects on the respiratory health of
nonsmoking adults, including coughing, phlegm production, chest discomfort, and
reduced lung function.
This report also has reviewed data on the relationship of maternal smoking and sudden infant
death syndrome (SIDS), which is thought to involve some unknown respiratory pathogenesis. The
report concludes that while there is strong evidence that infants whose mothers smoke are at an
increased risk of dying from SIDS, available studies do not allow us to differentiate whether and to
what extent this increase is related to in utero versus postnatal exposure to tobacco smoke products.
Consequently, this report is unable to assert whether or not ETS exposure by itself is a risk factor for
SIDS independent of smoking during pregnancy. Regarding an association of parental smoking
with either upper respiratory tract infections (colds and sore throats) or acute middle ear infections hi
children, this report finds the evidence inconclusive.
1.3.1. ETS and Lung Cancer
1.3.1.1. Hazard Identification
The Surgeon General (U.S. DHHS, 1989) estimated that smoking was responsible for more
than one of every six deaths in the United States and that it accounted for about 90% of the lung
cancer deaths in males and about 80% in females in 1985. Smokers, however, are not the only ones
exposed to tobacco smoke. The sidestream smoke (SS) emitted from a smoldering cigarette between
puffs (the main component of ETS) has been documented to contain virtually all of the same
carcinogenic compounds (known and suspected human and animal carcinogens) that have been
identified in the mainstream smoke (MS) inhaled by smokers (Chapter 3). Exposure concentrations of
these carcinogens to passive smokers are variable but much lower than for active smokers. An excess
cancer risk from passive smoking, however, is biologically plausible.
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Based on the firmly established causal association of lung cancer with active smoking with a
dose-response relationship down to low doses (Chapter 4), passive smoking is considered likely to
affect the lung similarly. The widespread presence of ETS in both home and workplace and its
absorption by nonsmokers in the general population have been well documented by air sampling and
by body measurement of biomarkers such as nicotine and cotinine (Chapter 3). This raises the
question of whether any direct evidence exists for the relationship between ETS exposure and lung'
cancer in the general population and what its implications may be for public health. This report
addresses that question by reviewing and analyzing the evidence from 30 epidemiologic studies of
effects from normally occurring environmental levels of ETS (Chapter 5). Because there is
widespread exposure and it is difficult to construct a truly unexposed subgroup of the general
population, these studies attempt to compare individuals with higher ETS exposure to those with
lower exposures. Typically, female never-smokers who are married to a smoker are compared with
female never-smokers who are married to a nonsmoker. Some studies also consider ETS exposure of
other subjects (i.e., male never-smokers and long-term former smokers of either sex) and from other
sources (e.g., workplace and home exposure during childhood), but these studies are fewer and
represent fewer cases, and they are generally excluded from the analysis presented here. Use of the
female never-smoker studies provides the largest, most homogeneous database for analysis to
determine whether an ETS effect on lung cancer is present. This report assumes that the results for
female never-smokers are generalizable to all nonsmokers.
Given that ETS exposures are at actual environmental levels and that the comparison groups
are both exposed to appreciable background (i.e., nonspousal) ETS, any excess risk for lung cancer
from exposure to spousal smoke would be expected to be small. Furthermore, the risk of lung cancer
is relatively low in nonsmokers, and most studies have a small sample size, resulting in a very low
statistical power (probability of detecting a real effect if it exists). Besides small sample size and low
incremental exposures, other problems inherent in several of the studies may also limit their ability to
detect a possible effect. Therefore, this report examines the data in several different ways. After
downward adjustment of the relative risks for smoker misclassification bias, the studies are
individually assessed for strength of association, both for the overall data and for the highest exposure
group when exposure-level data are available, and for exposure-response trend. Then the study
results are pooled by country using statistical techniques for combining data, including both positive
and nonpositive results, to increase the ability to determine whether or not there is an association
between ETS and lung cancer. Finally, in addition to the previous statistical analyses that weight the
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studies only by size, regardless of design and conduct, the studies are qualitatively evaluated for
potential confounding, bias, and likely utility to provide information about any lung carcinogenicity of
ETS. Based on these qualitative considerations, the studies are categorized into one of four tiers and
then statistically analyzed successively by tier.
Results from all of the analyses described above strongly support a causal association between
lung cancer ETS exposure. The overall proportion (9/30) of individual studies found to show an
association between lung cancer and spousal ETS exposure at all levels combined is unlikely to occur
by chance (p < 10~4). When the analysis focuses on higher levels of spousal exposure, every one of
the 17 studies with exposure-level data shows increased risk in the highest exposure group; 9 of these
are significant at the p < 0.05 level, despite most having low power, another result highly unlikely to
occur by chance (p < 10'7). Similarly, the proportion (10/14;
p < 10'9) showing a statistically significant exposure-response trend is highly supportive of a causal
association.
Combined results by country showed statistically significant associations for Greece
(2 studies), Hong Kong (4 studies), Japan (5 studies), and the United States (11 studies), and in that
order of strength of relative risk. Pooled results of the four Western European studies (three
countries) actually showed a slightly stronger association than that of the United States, but it was not
statistically significant, probably due to the smaller sample size. The combined results of the Chinese
studies do not show an association between ETS and lung cancer; however, two of the four Chinese
studies were designed mainly to determine the lung cancer effects of high levels of other indoor air
pollutants indigenous to those areas, which would obscure a smaller ETS effect. These two Chinese
studies do, however, provide very strong evidence on the lung carcinogenicity of these other indoor
air pollutants, which contain many of the same components as ETS. When results are combined only
for the other two Chinese studies, they demonstrate a statistically significant association for ETS and
lung cancer.
The heterogeneity of observed relative risk estimates among countries could result from
several factors. For example, the observed differences may reflect true differences in lung cancer
rates for never-smokers, in ETS exposure levels from nonspousal sources, or in related lifestyle
characteristics in different countries. For the time period in which ETS exposure was of interest for
these studies, spousal smoking is considered to be a better surrogate for ETS exposure in more
"traditional" societies, such as Japan and Greece, than in the United States. In the United States,
other sources of ETS exposure (e.g., work and public places) are generally higher, which obscures
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the effects of spousal smoking and may explain the lower relative risks observed in the United States.
Nevertheless, despite observed differences between countries, all showed evidence of increased risk.
Based on these analyses and following the U.S. EPA's Guidelines for Carcinogen Risk
Assessment (U.S. EPA, 1986a), EPA concludes that environmental tobacco smoke is a Group A
(known human) carcinogen. This conclusion is based on a total weight of evidence, principally:
• Biological plausibility. ETS is taken up by the lungs, and components are distributed
throughout the body. The presence of the same carcinogens in ETS and MS, along with
the established causal relationship between lung cancer and active smoking with the dose-
response relationships exhibited down to low doses, establishes the plausibility that ETS
is also a lung carcinogen.
• Supporting evidence from animal bioassays and genotoxicity experiments. The
. carcinogenicity of tobacco smoke has been demonstrated in lifetime inhalation studies in
the hamster, intrapulmonary implantations in the rat, and skin painting in the mouse.
There are no lifetime animal inhalation studies of ETS; however, the carcinogenicity of
•., SS condensates has been shown in intrapulmonary implantations and skin painting
experiments. Positive results of genotoxicity testing for both MS and ETS provide
corroborative evidence for their carcinogenic potential.
• Consistency of response. All 4 of the cohort studies and 20 of the 26 case-control
studies observed a higher risk of lung cancer among the female never-smokers classified,
as ever exposed to any level of spousal ETS. Furthermore, every one of the 17 studies
with response categorized by exposure level demonstrated increased risk for the highest
exposure group. When assessment was restricted to the 19 studies judged to be of higher
utility based on study design, execution, and analysis (Appendix A), 17 observed higher
risks, and 6 of these increases were statistically significant, despite most having low
statistical power. Evaluation of the total study evidence from several perspectives leads
to the conclusion that the observed association between ETS exposure and increased lung
cancer occurrence is not attributable to chance.
• Broad-based evidence. These 30 studies provide data from 8 different countries, employ
a wide variety of study designs and protocols, and are conducted by many different
research teams. Results from all countries, with the possible exception of two areas of
China where high levels of other indoor air lung carcinogens were present, show small to
modest increases in lung cancer associated with spousal ETS exposure. No alternative
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explanatory variables for the observed association between ETS and lung cancer have
been indicated that would be broadly applicable across studies.
Upward trend in exposure-response. Both the largest of the cohort studies—the Japanese
study of Hirayama with 200 lung cancer cases—and the largest of the case-control studies-
-the U.S. study by Fontham and associates (1991) with 420 lung cancer cases and two
sets of controls-demonstrate a strong exposure-related statistical association between
passive smoking and lung cancer. This upward trend is well supported by the
preponderance of epidemiology studies. Of the 14 studies that provide sufficient data for
a trend test by exposure level, 10 were statistically significant despite most having low
statistical power.
Detectable association at environmental exposure levels. Within the population of
married women who are lifelong nonsmokers, the excess lung cancer risk from exposure
to their smoking husbands' ETS is large enough to be observed, even for all levels of
their spousal exposure combined. Carcinogenic responses are usually detectable only in
high-exposure circumstances, such as occupational settings, or in experimental animals
receiving very high doses. In addition, effects are harder to observe when there is
substantial background exposure in the comparison groups, as is the case here.
Effects remain after adjustment for potential upward bias. Current and ex-smokers may
be misreported as never-smokers, thus inflating the apparent cancer risk for ETS
exposure. The evidence remains statistically significant and conclusive, however, after
adjustments for smoker misclassification. For the United States, the summary estimate of
relative risk from nine case-control plus two cohort studies is 1.19 (90% confidence
interval [C.I.] = 1.04, 1.35; p < 0.05) after adjustment for smoker misclassification.
For Greece, 2.00 (1.42, 2.83), Hong Kong, 1.61 (1.25, 2.06), and Japan, 1.44 (1.13,
1.85), the estimated relative risks are higher than those of the United States and more
highly significant after adjusting for the potential bias.
Strong associations for highest exposure groups. Examining the groups with the highest
exposure levels increases the ability to detect an effect, if it exists. Nine of the sixteen
studies worldwide for which there are sufficient exposure-level data are statistically
significant for the highest exposure group, despite most having low statistical power.
The overall pooled estimate of 1.81 for the highest exposure groups is highly statistically
significant (90% C.I. = 1.60, 2.05; p < la6). For the United States, the overall pooled
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estimate of 1.38 (seven studies, corrected for smoker misclassification bias) is also highly
statistically significant (90% C.I. = 1.13, 1.70; p = 0.005).
• Confounding cannot explain the association. The broad-based evidence for an association
found by independent investigators across several countries, as well as the positive
exposure-response trends observed in most of the studies that analyzed for them, make
any single confounder highly unlikely as an explanation for the results. In addition, this
report examined potential confounding factors (history of lung disease, home heat
sources, diet, occupation) and concluded that none of these factors could account for the
observed association between lung cancer and ETS.
1.3.1.2. Estimation of Population Risk
The individual risk of lung cancer from exposure to ETS does not have to be very large to
translate into a significant health hazard to the U.S. population because of the large number of
smokers and the widespread presence of ETS. Current smokers comprise approximately 26% of the
U.S. adult population and consume more than one-half trillion cigarettes annually (1,5 papks per day,
on average), causing nearly universal exposure to at least some ETS. As a biomarker of tobacco
smoke uptake, cotinine, a metabolite of the tobacco-specific compound nicotine, is detectable in the
blood, saliva, and urine of persons recently exposed to tobacco smoke. Cotinine has typically been
detected in 50% to 75% of reported nonsmokers tested (50% equates to 63 million U.S. nonsmokers
age 18 or older).
The best estimate of approximately 3,000 lung cancer deaths per year in U.S. nonsmokers age
35 and over attributable to ETS (Chapter 6) is based on data pooled from all 11 U.S. epidemiologic
studies of never-smoking women married to smoking spouses. Use of U.S. studies should increase
the confidence in these estimates. Some mathematical modeling is required to adjust for expected bias
from misclassification of smoking status and to account for ETS exposure from sources other than
spousal smoking. The overall relative risk estimate of 1.19 for the
United States, already adjusted for smoker misclassification bias, becomes 1.59 after adjusting for
background ETS sources (1.34 for nonspousal exposures only). Assumptions are also needed to
relate responses in female never-smokers to those in male never-smokers and ex-smokers of both
sexes, and to estimate the proportion of the nonsmoking population exposed to various levels of ETS.
Overall, however, the assumptions necessary for estimating risk add far less uncertainty than other
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EPA quantitative assessments. This is because the extrapolation for ETS is based on a large database
of human studies, all at levels actually expected to be encountered by much of the U.S. population.
The components of the 3,000 lung cancer deaths figure include approximately 1,500 female
never-smokers, 500 male never-smokers, and 1,000 former smokers of both sexes. More females are
estimated to be affected because there are more female than male nonsmokers. These component
estimates have varying degrees of confidence; the estimate of 1,500 deaths for female never-smokers
has the highest confidence because of the extensive database. The estimate of 500 for male never-
smokers is less certain because it is based on the female never-smoker response and is thought to be
low because males are generally subject to higher background ETS exposures than females.
Adjustment for this higher background exposure would lead to higher risk estimates. The estimate of
1,000 lung cancer deaths for former smokers of both sexes is considered to have the lowest
confidence, and the assumptions used are thought to make this estimate low as well.
Workplace ETS levels are generally comparable with home ETS levels, and studies using
body cotinine measures as biomarkers demonstrate that nonspousal exposures to ETS are often greater
than exposure from spousal smoking. Thus, this report presents an alternative breakdown of the
estimated 3,000 ETS-attributable lung cancer deaths between spousal and nonspousal exposures. By
extension of the results from spousal smoking studies, coupled with biological measurements of
exposure, more lung cancer deaths are estimated to be attributable to ETS from combined nonspousal
exposures—2,200 of both sexes—than from spousal exposure—800 of both sexes. This spouse-versus-
other-sources partitioning depends on current exposure estimates that may or may not be applicable to
the exposure period of interest. Thus, this breakdown contains this element of uncertainty in addition
to those discussed above with respect to the previous breakdown.
An alternative analysis, based on the large Fontham et al. (1991) study, which is the only
study that provides biomarker estimates of both relative risk and ETS exposure, yields population risk
point estimates of 2,700 and 3,600. These population risk estimates are highly consistent with the
estimate of 3,000 based on the combined U.S. studies.
While there is statistical variance around all of the parameters used in the quantitative
assessment, the two largest areas of uncertainty are probably associated with the relative risk estimate
for spousal ETS exposure and the parameter estimate for the background ETS exposure adjustment.
A sensitivity analysis that independently varies these two estimates yields population risk estimates as
low as 400 and as high as 7,000. These extremes, however, are considered unlikely; the more
probable range is narrower, and the generally conservative assumptions employed suggest that the
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actual population risk number may be greater than 3,000. Overall, considering the multitude,
consistency, and quality of all these studies, the weight-of-evidence conclusion that ETS is a known
human lung carcinogen, and the limited amount of extrapolation necessary, the confidence in the
estimate of approximately 3,000 lung cancer deaths is medium to high.
13.2. ETS and Noncancer Respiratory Disorders
Exposure to ETS from parental smoking has been previously linked with increased respiratory
disorders in children, particularly in infants. Several studies have confirmed the exposure and uptake
of ETS in children by assaying saliva, serum, or urine for cotinine. These cotinine concentrations
were highly correlated with smoking (especially by the mother) in the child's presence. Nine to
twelve million American children under 5 years of age, or one-half to two-thirds of all children in this
age group,, may be exposed to cigarette smoke hi the home (American Academy of Pediatrics, 1986;
Overpeck and Moss, 1991).
With regard to the noncancer respiratory effects of passive smoking, this report focuses on
epidemiologic evidence appearing since the two major reports of 1986 (N£C and U.S. DHHS) that
bears on the potential association of parental smoking with detrimental respiratory effects, in their -
children. These effects include symptoms of respiratory irritation (cough, sputum production,, or- ;
wheeze); acute diseases of the lower respiratory tract (pneumonia, bronchitis, and bronchiolitis);. acute
middle ear infections and indications of chronic middle ear infections (predominantly .middle ear
effusion); reduced lung function (from forced expiratory volume and flow-rate measurements);
incidence and prevalence of asthma and exacerbation of symptoms in asthmatics; and acute upper
respiratory tract infections (colds and sore throats). The more than 50 recently published studies
reviewed here essentially corroborate the previous conclusions of the 1986 reports of the NRC and
Surgeon General regarding respiratory symptoms, respiratory illnesses, and pulmonary function, and
they strengthen support for those conclusions by the additional weight of evidence (Chapter 7). For
example, new data on middle ear effusion strengthen previous evidence to warrant the stronger
conclusion in this report of a causal association with parental smoking. Furthermore, recent studies
establish associations between parental smoking and increased incidence of childhood asthma.
Additional research also supports the hypotheses that in utero exposure to mother's smoke and
postnatal exposure to ETS alter lung function and structure, increase bronchial responsiveness, and
enhance the process of allergic sensitization, changes that are known to predispose children to early
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respiratory illness. Early respiratory illness can lead to long-term pulmonary effects (reduced lung
function and increased risk of chronic obstructive lung disease).
This report also summarizes the evidence for an association between parental smoking and
SIDS, which was not addressed in the 1986 reports of the NRC or Surgeon General. SIDS is the
most common cause of death in infants ages 1 month to 1 year. The cause (or causes) of SIDS is
unknown; however, it is widely believed that some form of respiratory pathogenesis is generally
involved. The current evidence strongly suggests that infants whose mothers smoke are at an
increased risk of dying of SIDS, independent of other known risk factors for SIDS, including low
birthweight and low gestational age, which are specifically associated with active smoking during
pregnancy. However, available studies do not allow this report to conclude whether that increased
risk is related to in utero versus postnatal exposure to tobacco smoke products, or to both.
The 1986 reports of the NRC and Surgeon General conclude that both the prevalence of
respiratory symptoms of irritation and the incidence of lower respiratory tract infections are higher hi
children of smoking parents. In the 18 studies of respiratory symptoms subsequent to the 2 reports,
increased symptoms (cough, phlegm production, and wheezing) were observed in a range of ages
from birth to midteens, particularly in infants and preschool children. In addition to the studies on
symptoms of respiratory irritation, 10 new studies have addressed the topic of parental smoking and
acute lower respiratory tract illness in children, and 9 have reported statistically significant
associations. The cumulative evidence is conclusive that parental smoking, especially the mother's,
causes an increased incidence of respiratory illnesses from birth up to the first 18 months to 3 years
of life, particularly for bronchitis, bronchiolitis, and pneumonia. Overall, the evidence confirms and
strengthens the previous conclusions of the NRC and Surgeon General.
Recent studies also solidify the evidence for the conclusion of a causal association between
parental smoking and increased middle ear effusion in young children. Middle ear effusion is the
most common reason for hospitalization of young children for an operation.
At the time of the Surgeon General's report on passive smoking (U.S. DHHS, 1986), data
were sufficient to conclude only that maternal smoking may influence the severity of asthma in
children. The recent studies reviewed here strengthen and confirm these exacerbation effects. The
new evidence is also conclusive that ETS exposure increases the number of episodes of asthma in
children who already have the disease. In addition, the evidence is suggestive that ETS exposure
increases the number of new cases of asthma in children who have not previously exhibited
symptoms, although the results are statistically significant only with children whose mothers smoke 10
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or more cigarettes per day. While the evidence for new cases of asthma itself is not conclusive of a
causal association, the consistently strong association of ETS both with increased frequency and
severity of the asthmatic symptoms and with the established ETS effects on the immune system and
airway hyperresponsiveness lead to the conclusion that ETS is a risk factor for induction of asthma in
previously asymptomatic children.
Regarding the effects of passive smoking on lung function in children, the 1986 NRC and '
Surgeon General reports both conclude that children of parents who smoke have small decreases in
tests of pulmonary output function of both the larger and smaller air passages when compared with
the children of nonsmokers. As noted in the NRC report, if ETS exposure is the cause of the
observed decrease in lung function, the effect could be due to the direct action of agents in ETS or an
indirect consequence of increased occurrence of acute respiratory illness related to ETS.
Results from eight studies on ETS and lung function in children that have appeared since
those reports add some additional confirmatory evidence suggesting a causal rather than an indirect
relationship. For the population as a whole, the reductions are small relative to the interindividual
variability of each lung function parameter. However, groups of particularly susceptible or heavily „
exposed children have shown larger decrements. The studies reviewed suggest that a continuum of
exposures to tobacco products starting in fetal life may contribute to the decrements in lung function
found in older children. Exposure to tobacco smoke products inhaled by the mother during
pregnancy may contribute significantly to these changes, but there is strong evidence indicating that
postnatal exposure to ETS is an important part of the causal pathway.
With respect to lung function effects in adults exposed to ETS, the 1986 NRC and Surgeon
General reports found the data at that time inconclusive, due to high interindividual variability and the
existence of a large number of other risk factors, but compatible with subtle deficits in lung function.
Recent studies confirm the association of passive smoking with small reductions in lung function.
Furthermore, new evidence also has emerged suggesting a subtle association between exposure to ETS
and increased respiratory symptoms in adults.
Some evidence suggests that the incidence of acute upper respiratory tract illnesses and acute
middle ear infections may be more common in children exposed to ETS. However, several studies
failed to find any effect. In addition, the possible role of confounding factors, the lack of studies
showing clear dose-response relationships, and the absence of a plausible biological mechanism
preclude more definitive conclusions.
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In reviewing the available evidence indicating an association (or lack thereof) between ETS
exposure and the different noncancer respiratory disorders analyzed in this report, the possible role of
several potential confounding factors was considered. These include other indoor air pollutants:
socioeconomic status; effect of parental symptoms; and characteristics of the exposed child, such as
low birthweight or active smoking. No single or combined confounding factors can explain the
observed respiratory effects of passive smoking in children.
For diseases for which ETS has been either causally associated (LRIs) or indicated as a risk
factor (asthma cases in previously asymptomatic children), estimates of population-attributable risk
can be calculated. A population risk assessment (Chapter 8) provides a probable range of estimates
that 8,000 to 26,000 cases of childhood asthma per year are attributable to ETS exposure from
mothers who smoke 10 or more cigarettes per day. The confidence in this range of estimates is
medium and is dependent on the suggestive evidence of the database. While the data show an effect
only for children of these heavily smoking mothers, additional cases due to lesser ETS exposure also
are a possibility. If the effect of this lesser exposure is considered, the range of estimates of new
cases presented above increases to 13,000 to 60,000. Furthermore, this report estimates that the
additional public health impact of ETS on asthmatic children includes more than 200,000 children
whose symptoms are significantly aggravated and as many as 1,000,000 children who are affected to
some degree.
This report estimates that ETS exposure contributes 150,000 to 300,000 cases annually of
lower respiratory tract illness in infants and children younger than 18 months of age and that 7,500 to
15,000 of these will require hospitalization. The strong evidence linking ETS exposure to increased
incidence of bronchitis, bronchiolitis, and pneumonia in young children gives these estimates a high
degree of confidence. There is .also evidence suggesting a smaller ETS effect on children between the
ages of 18 months and 3 years, but no additional estimates have been computed for this age group.
Whether or not these illnesses result in death has not been addressed here.
In the United States, more than 5,000 infants die of SIDS annually. It is the major cause of
death in infants between the ages of 1 month and 1 year, and the linkage with maternal smoking is
well established. The Surgeon General and the World Health Organization estimate that more than
700 U.S. infant deaths per year from SIDS are attributable to maternal smoking (CDC, 1991a,
1992b). However, this report concludes that at present there is not enough direct evidence supporting
the contribution of ETS exposure to declare it a risk factor or to estimate its population impact on
SIDS.
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