x
. Www* Advbory ' EPA-SAB-IAaC-SI-007
Environmental - *- Board (A-101) " • April 1991
Ption
&EPA AN SAB REPORT: REVIEW
OF DRAFT ENVIRONMENTAL
TOBACCO SMOKE HEALTH
EFFECTS DOCUMENT
REVIEW, BY THE INDOOR AIR
QUALITY AND TOTAL HUMAN
EXPOSURE COMMITTEE, OF THE
OFFICE OF RESEARCH AND
DEVELOPMENT'S DRAFT REPORT:
"HEALTH EFFECTS OF PASSIVE
SMOKING: ASSESSMENT OF LUNG
CANCER IN ADULTS AND
RESPIRATORY DISORDERS IN
CHILDREN" (EPA/600/6-90/006A)
(Reprinted report - original document, new cover. Report number adjusted from EPA-SAB-IAQTHC-91-007)
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x
1 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON. D.C. 20460
EPA-SAB-IAQflfcC-91-007
April 19, 1991 ornctor
. • TUB ADMINISTRATOR
Honorable William K. Reilly
Administrator
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington,. D.C. 20460
Subject: Science Advisory Board's review of the Office of Research and
Development document Health Effects of Passive Smoking; Assessment of
Lung Cancer in Adults and Respiratory Disorders in Children. EPA/600/
6-90/006A, June 1990, and the Office of Air and Radiation's draft doc-
ument Environmental Tobacco Smoke; A Guide to Workplace Smoking Poli-
cies. (EPA/400/6-90/004), June 1990.
Dear Mr. Reilly:
On November 1, 1990, the Offices.of Research and Development and
Air and Radiation requested that the Science Advisory Board (SAB)'
review the above referenced draft reports. The first document (here-
after referred to as the risk assessment report) incorporates a health
risk assessment of the impact of passive smoking (i.e., exposure to
environmental tobacco smoke, or ETS) on adult lung cancer incidence,
and a discussion of the effects of exposure to ETS on the incidence
and prevalence of respiratory disorders in children. The risk as-
sessment report was prepared at the request of the Indoor Air Divis-
ion, Office of Air and Radiation, to provide information and guidance
on the potential hazards of indoor air pollutants. The.second doc-
ument (hereafter referred to as the policy guide), reflects and para-
llels the risk assessment report,, but was not developed as .a sci-
entific document
The Agency sought the advice of the SAB's Indoor Air Quality and
Total Human Exposure Committee (IAQTHEC) concerning the risk assess-
ment's accuracy and completeness, and the Committee's opinion on
whether the weight of available evidence supported the conclusions
drawn concerning ETS's roles in causing lung cancer in adults and res-
piratory disease in children. The SAB was also requested to review
that portion of the policy guide which presented a scientific database
on ETS. . . . .
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The IAQTHEC net on December 4 and 5, 1990, in Arlington, Virginia
to conduct its review of the ETS draft documents, in summary, the
committee found the risk assessment document to be a good faith effort
to address complex and difficult issues affecting public health. The
authors attempted to select and interpret the most relevant infor-
mation from an enormous and diverse scientific data base, most of
which was not designed or intended to yield the information needed for
this task, since the task is extremely difficult, it should come as
no surprise that the Committee also found the document to-be incom-
plete, in many respects. The situation is analogous to that for the
Criteria Air Pollutants, vherein.it has been necessary to prepare and
review two of more draft criteria documents prior to their endorsement
by the Clean Air Scientific Advisory Committee. The IAQTHEC has sug-
gested changes both in the organization and specific technical content
of the draft, that if followed, can result in an improved ETS risk
assessment document. The Committee also suggested changes that would
strengthen the use of the incorporated scientific database to support
the recommendations contained in the policy guide.
The Charge to the Committee, and associated findings of the
Committee are outlined below:
A. Carcinoqenicity Issues
1. Carcinoqenicitv of ETS Has EPA met the requirements stated
in its carcinogen guidelines for characterizing ETS in Category A,
i.e., is the evidence sufficient to conclude that ETS is causally
associated with lung cancer?
The Committee concurs with the judgment of EPA that environmen-
tal tobacco smoke should be classified as a Class A Carcinogen, but
notes that it. had some difficulty in applying the Guidelines for Car-
cinogen Risk Assessment (51 FR 33992), as they are currently formu-
lated, to this complex and variable mixture. We advise EPA to place
greater weight on the biological considerations and the extensive
experience with active human smoking to support the classification.
2. Spousal Smoking Is spousal smoking a proper measure of ETS
exposure to assess lung cancer risk?
Despite its various limitations as an indicator of ETS exposure,
spousal smoking status seems to be a feasible method for identifying
people with greater, versus lesser, ETS exposure. There are potential
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important,eonfounders related to spousal smoking status as a measure
of exposure, but such confounding concerns are present in other
surrogates of exposure as veil. .
3. united States and Foreign studies Are the differences in
relative risk observed between studies in the U.S. and those overseas
of concern, and if so, to what degree?
, The Committee believes that data from studies conducted in other
countries, .as well as in the United States should be utilized in eval-
uating whether exposure to ZTS increases risk of lung cancer, and does
not find the observed differences to be of concern. It is appropriate
to examine the totality of evidence from all the. case-control and
cohort studies, regardless of where they were conducted.
4. Use of Meta-AnalvBJa is Meta-Analysis an appropriate tool
to use in the document and has it been applied correctly? Have the
epidemiological studies been properly evaluated and combined using.
this technique?
Meta-analysis is a general term applied to a wide range of
techniques intended to synthesize findings across related studies.
Although it is an appropriate tool to summarize the epidemiological
studies investigating the risk of ETS, the emphasis given the
meta-analysis of ETS/lung cancer association in this report is not
justified. Biological considerations related to respiratory carcin-
ogenesis and extrapolations from human exposure via active smoking
provide compelling evidence that is consistent with the results of the
meta-analysis.
5. Confoundera/Misclassification Have the most. important con-
founders been properly addressed? Has the issue of misclassification
(classifying current and former smokers as "never smokers") been ade-
quately addressed and the proper adjustments made? Are there other
confounders which could be addressed in greater detail?
Important potential confounders of the ETS-lung cancer relation-
ship were addressed in the report mainly, by carrying out a separate
meta-analysis of those studies which included adjusted analyses. The
potential main confounders included in these adjusted analyses were
age and surrogates for confounding factors, including education, and
social class. comparison of relative risks in those studies which
analyze: both., factors suggests., that these- effects are'.not. important
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" ** «* ' • -
confounders. As for other potential confounders of the ETS-lung
cancer relationship, including occupation, radon exposure, and diet,
there is no way to evaluate their importance as confounders or to
adjust for them, since virtually none of the studies contains
information on them.
6. characterization of Uncertainties Does the document charac-
terize the uncertainties, both in the weight-of-evidence and the
number of attributable deaths, appropriately?
.Vis-a-vis weight of evidence, the draft document's conclusion
that exposure to ETS sometimes leads to the development of lung cancer
in humans rests upon two main arguments: (1) the biological plausi-
bility of such a causal association is high, given the known effects.
of active smoking and the known composition of ETS (e.g. the carcino-
genicity of ETS in some animal studies, and the presence of known
human carcinogens in ETS); and (2) the accumulating eoidemiolotyie
evidence on the relationship between exposure to ETS and lung cancer.
These together appear to argue for a positive effect. Because the
epidemioiogic evidentiary base for drawing conclusions regarding ITS' s~
carcinogenicity consists mainly of studies of exposure levels produced
by spousal smoking, the biological plausibility argument assumes great
importance. Each step in that argument should therefore be carefully
addressed, with the uncertainties encountered being spelled out
explicitly. _
7. Quantitative Risk Assessment Has the quantitative risk of
lung cancer been properly assessed? Would it be more properly as-
sessed by a dose response assessment using either cotinine or res-
pirable suspended particulate matter as surrogate measures of exposure
(Appendix C) ? Would it be more properly assessed with alternative
modeling approaches (Appendix D)? Should a dose-response model be
developed for ETS-radon interaction effects?
The Committee generally agreed that the quantitative assessment
of the risk of lung cancer due to exposures to ETS should be based on
the human epidemiology studies and that meta-analysis is a suitable
approach to combining the data. This approach is direct and makes the
fewest assumptions. It should be noted that this approach is fully
consistent with the risk assessments that have been done for many
other carcinogens. Given that the epidemiology studies should be the
basis of the risk assessment, some suggestions for refinements of the
:risk assessment are detailed in. our report.
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8. fleme vs. Worlcplace Exposure Should the Draft Report
attempt to distinguish between the effects of home vs. workplace
exposure to ETS?
The Committee recognizes that there is little epidemiologic
literature on the health effects of ETS in the workplace, and
therefore on the relative impacts of home and workplace exposure.
However, the report should review and comment on. the data that do
exist, if only to bring out the need for future research in this area.
1. weight of Evidence Has the weight of evidence for ETS re-
lated respiratory disorders in children been properly characterized?
.A draft report with a detailed description and analysis of 26 recent
studies has recently been prepared and is enclosed. It is in a form
similar to that of Appendix A. Should it be included in a revised
report as Appendix E?
In reviewing the weight of the evidence, the present Chapter 5
does not establish an appropriate framework for considering the data.
The alternative explanations for association of ETS exposure with
adverse respiratory effects need to be clearly listed. The .weight of
the evidence could then be judged to determine the causality of
associations.
The additional literature available since 1986 provides a basis
for increased concern about the effects of ETS exposure on respiratory
disorders. Thus, the Committee urges a thorough review of the entire
body of evidence, including earlier reports covered in the 1986 re-.
ports of the Surgeon General and National Research Council. This
review could be included in the revised risk document as Appendix E.
2. Confoundera Have confounders in the epidemiologic studies
been adequately addressed?
A number of confounders were mentioned by the report, but ad-
dressed improperly, including in utero exposure, parental reporting
bias, and.active smoking. One must stress both the biological pre-
cursors important to the effects of ETS in childhood, and the socio-
economic and behavioral factors.
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3. Use ofMeta-Analysip Should a Beta-analytic approach be
attempted as in the lung cancer analysis?
The Agency should give serious consideration to meta-analysis of
those studies of sufficiently similar design to warrant it. However,
it was not clear that there is a body of studies suitable for such an
analysis,
C. Review of the Policy Guide
The Committee found, with some exceptions detailed in our report,
that the scientific database incorporated in the policy guide is cor*
rect and appropriate. The policy guide should be revised to reflect
changes made to the risk assessment report.
We appreciate the opportunity to review these issues, and stand
ready to provide review comments on any significant revisions to the
subject documents. We look forward to your response on the major
points we have raised.
Or. Raymond Loehr, Chairman
Science Advisory Board
n-LJi* /rT>
_^ _
Dr. Morton Lippmann, Chairman
Indoor Air Quality and Total
Human Exposure Committee
ENCLOSURE
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ABSTRACT
The Indoor Air Quality and Total Human Exposure Committee
(IAQTHEC) met on December 4/5, 1990, to conduct its review of the
environmental tobacco smoke (ETS) draft documents. In summary, the
Committee found the risk assessment document to be a good faith
effort to address complex and difficult issues affecting public
health. Since the task is extremely difficult, it should come as
no surprise that the Committee also found the document to be incom-
plete in many respects. The IAQTHEC has suggested changes both in
the organization and specific technical content of the draft, that
if followed, can result.in en improved ETS risk assessment docu-
ment. The Committee also suggested changes that would strengthen
the use of the incorporated scientific database to support the
recommendations contained in the policy guide.
The Charge to the Committee, and associated findings .of the
Committee are outlined below:
A. Lung Cancer in Adults
1. Carcinogenicity of ETS The Committee concurs with the
judgment of EPA that environmental tobacco smoke should be
classified as a Class A Carcinogen.
2. Spousal Smoking Despite its various limitations as an
indicator of ETS exposure, spousal smoking status seems to be a
feasible method for identifying people with greater, versus lesser,
ETS exposure.
3. United States and Foreign Studies The Committee believes
that data from studies conducted in other countries, as well as in
the United States should be utilized in evaluating whether exposure
to ETS increases risk of lung cancer.
4. Use of Meta-Analysis It is an appropriate tool to
summarize the epidemiological studies investigating the risk of
ETS, but the emphasis given the meta-analysis of ETS/lung cancer
association in this report is not justified.
5. Confounders/Misclassification Important potential con-
founders of the ETS-lung cancer relationship were addressed in the
report. Comparison of relative risks (RRs) in those studies which
analyze relevant factors suggests that these effects are not
important.
6. Characterization of Uncertainties The draft document's
conclusion that exposure to ETS sometimes leads to the development
-.. of lung cancer in humans rests upon two main arguments: (l) the
biological plausibility of such a causal association is high; and
(2) the accumulating, epidemiolooic evidence on the relationship
-------
between exposure to ETS and lung cancer.. Because the epidemiologic
evidentiary base for Braving'conclusions regarding ETS's carcino-
genicity consists mainly of studies of exposure levels produced by
spousal smoking, the biological- plausibility argument assumes great
importance. Each step in that argument should therefore be
carefully addressed, with the uncertainties encountered being
spelled out explicitly.'
7. Quantitative Risk Assessment The Committee generally
agreed that the quantitative assessment of the risk .of lung cancer
due to exposures to ETS should be based on the human epidemiology
studies and that meta-analysis is a suitable approach to combining
the data.
8. Home vs. Workplace Exposure The Committee recognizes that
there is little epidemiologic literature on the health effects of
ETS in the workplace. However, the report should review and
comment on the data that do exist, if only to bring out the need
for future research in this area.
8." Respiratory Disorders in Children
1. Weight of Evidence In reviewing the weight of the evi-
dence, the present Chapter 5 does not establish an appropriate
framework for considering the data* The alternative explanations
for association of ETS exposure with adverse respiratory effects
need to be clearly listed. The weight of the evidence could then
be judged to determine the causality of associations.
2. Con founders A number of confounders were mentioned by the
report, but addressed improperly, including IB utero exposure,
parental reporting bias, and active smoking.
3- Use of Meta-Analysis The Agency should give serious
consideration to meta-analysis of those studies of sufficiently
similar design to warrant .it. However, it was not clear that
there is a body of studies suitable for such an analysis.
C. Policy Guide The Committee found, with some exceptions
detailed in the report, that the scientific database incorporated
in the policy guide is correct and appropriate.
KEYWORDS: Environmental Tobacco Smoke (ETS); Carcinogenicity;
Passive Smoking; Sidestrearn Smoke; Meta-analysis; Confounders; Lung
Cancer; Respiratory Disease
ii
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D. &. ENVIRONMENTAL PROTECTION AGENCY
NOTICE
This report has been written as a part of the activities of
the Science Advisory Board, a public advisory group providing
extramural scientific information and advice to the Administrator
and other officials of the Environmental Protection Agency. The
Board is structured to provide balanced, expert. assessment of
scientific matters related to problems facing the Agency. This
report has not been reviewed for approval by the Agency and, hence,
the contents of this report do not necessarily represent the views
and policies of the Environmental Protection Agency, nor of other
agencies in the Executive Branch of the Federal government, nor
does mention of trade names or commercial products constitute a
recommendation for use.
iii
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U.S. Environmental Protection Agency
Science Advisory Board
Indoor Air Quality and Total Human Exposure Committee
Chairman
Dr. Morton Lippmann, Professor, Institute of Environmental
Medicine, New York University Medical Center, Tuxedo,
New York 10987
vice chairman
Dr. Jan A.J. Stolwijk, Professor, School of Medicine, Department
of Epidemiology and Public Health, Yale University, P.O. Box
3333, 60 College Street, New Haven, Connecticut 06510
Mte of the IXQTHBC
Dr. Joan Daisey, Senior Scientist, Indoor Environment Program,
90-3058, Lawrence Berkeley Laboratory, one Cyclotron Road,
Berkeley, -California 94720
Dr. Victor 6. Laties, Professor of Toxicology, Environmental
Health Science Center-Box EHSC, University of Rochester
School of Medicine, Rochester, New York 14642
Dr. Jonathan M. Samet, Professor of Medicine, Department of
Medicine, The University of New Mexico School of Medicine, and
The New Mexico Tumor Registry, 900 Camino De Salud, NE, .
Albuquerque, New Mexico 87131
Dr. Jerome J. Hesolowski, Chief, Air and Industrial Hygiene
Laboratory, California Department of Health, Berkeley,
California 94704
Dr. James E.- Woods, Jr., Professor of Building Construction;
College of Architecture and Urban Studies, 117 Burress Hall,
Virginia Polytechnic Institute and State University,
Blacksburg, Virginia 24061-0156
Consultants to the IAQTHBC
Dr. Neal L. Benowitz, Professor of Medicine, Chief, Division
of Clinical Pharmacology and Experimental Therapeutics,
University of California, San Francisco, Building 30,
Fifth Floor, San Francisco General Hospital, 1001
Potrero Avenue, San Francisco, California 94110
IV
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Dr. William J. Blot, National Cancer institute, 9000 Rockville
Pike, Bethesda, Maryland 20892 (Federal Liasion to the
Committee;
Dr. David Burns, Associate Professor of Medicine, Department
of Medicine, H772-C, University of California, San Diego
Medical Center, 225 Dickenson street, San Diego,
California 92103-1990
Dr. Delbert Eatough, Professor of Chemistry, 276 FB Brigham
Young University, Provo, Utah 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, Massachusetts
06155
Dr. Geoffrey Kabat, Senior Epidemiologist, American Health
Foundation, 320 East 43rd Street, New York, Nev York 10017
Dr. Michael D. Lebovitz, Professor of Internal Medicine, University
of Arizona College of Medicine, Division of Respiratory
Sciences, Tucson, Arizona 85724
Dr. Howard Rockette, Professor of Biostatistics, School of Public
.Health, 318.Parran Hall, University of Pittsburgh, Pittsburgh,
Pennsylvania 15261
Dr. Scott T. Weiss, Channing Laboratory, Harvard University School
of Medicine, Boston, Massachusetts 02115
Science Advisory Board Staff
Mr. Samuel R. Rondberg, Designated Federal Official, Science
Advisory Board (A-101F), U.S. Environmental Protection
Agency, 401 M Street, SH, Washington, DC 20460
(202) 382-2552 FAX: (202) 475-9693
Mr. A. Robert Flaak, Designated Federal Official, Science
Advisory Board (A-101F), U.S. Environmental Protection
Agency, 401 M Street, SW, Washington, DC 20460
(202) 382-2552 FAX: (202) 475-9693
Ms. Carolyn Osborne, staff Secretary, Science Advisory Board
(A-101F), U.S. Environmental Protection Agency, 401 M
Street, SW, Washington, DC 20460
(202) 382-2552 FAX: (202) 475-9693
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TABLE OFF CONTENTS
1.0 EXECUTIVE SUMMARY .......... 1
2.0 INTRODUCTION 8
2.1 Background 8
2.2 Scope of Issues/Charge to the Committee 9
2.3 Conduct of The Review 10
3.0 REVIEW OF THE RISK ASSESSMENT DOCUMENT ........ 11
3.1 Chapter 3—Epidemiologic Evidence of Lung Cancer
from ETS 11
3.2 Chapter 4—Assessment of Lung Cancer Risk from
ETS . . . 14
3.3 Chapter S—Environmental Tobacco Smoke and
Respiratory Disorders in Children . 15
3.4 Appendix A—Summary Descriptions of Eleven Case-
Control Studies 20
3.5 Appendix B—Mathematical Formulas and
Relationships ..... 20
3.6 Appendix C—Dosimetry of ETS 22
3.7 Appendix D—Alternative Approaches .for Estimating
the Yearly Number of Lung Cancer Deaths in Non-
Smoke rs Due to ETS Based on Dose-Response
Modeling 23
3.8 Appendix E—Summary Descriptions of Twenty-Six
Studies on Environmental Tobacco Smoke and
Respiratory Disorders in Children ........ 25
4.0 REVIEW OF THE POLICY GUIDE 26
5.0 SPECIFIC REVIEW ISSUES 27
5.1 Lung Cancer in Adults 27
5.1.1 Carcinogenicity of ETS .......... 27
5.1.2 Spousal Smoking 28
5.1.3 United States and Foreign Studies .... 31
5.1.4 Use of Meta-Analysis 32
5.1.5 Confounders/Misclassification 33
5.1.6 Characterization of Uncertainties .... 35
5.1.7 Home vs. Workplace Exposure 40
5.2 Respiratory Disorders in Children 40
5.2.1 Weight of Evidence 41
5.2.2 Confounders 41
5.2.3 Use of Meta-Analysis . . 43
6.0 SUMMARY AND CONCLUSIONS 44
7.0 -REFERENCES. CITED 51
vi
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1.0 EXECUTIVE SUMMARY
The Committee's review of the environmental tobacco smoke
(ETS) Risk Assessment document and Policy Guide found them to be
good faith efforts to address complex and difficult issues
affecting public health. The authors attempted to select and
interpret the most relevant information from an enormous and
diverse scientific data base, much of which was not designed or
intended to yield the information needed for this task. Since the
task is extremely difficult, it should come as no surprise that the
Committee also found, the documents to be . incomplete in many
respects. The situation is analogous to that for the Criteria Air
Pollutants, where it has been necessary to prepare and review two
or more draft documents prior to their endorsement by the Clean Air
Scientific Advisory Committee (CASAC). This Committee has
suggested both organizational and specific technical changes and
additional analyses that, if followed, should result in improved
ETS Risk Assessment and Policy Guide documents. The Committee
stands ready to provide further review comments on the revised
drafts.
The SAB was asked to address the following issues in reviewing
the documents.
A. Luna Cancer in Adults
The Committee noted that Chapters 3 and 4 draft risk document
addressed only the issue of lung cancer risk for non-smoking women
due to spousal smoking. It is suggested that the revised document
be expanded to include the full range of cancer impacts of ETS.
The Committee also noted a number of areas where considerable
improvements could be made organizationally, and in terms of
substantive content—particularly regarding material that was not
adequately covered or not covered at all. We urge the EPA staff
to redraft those chapters as well. Furthermore, we recommend the
addition of a new chapter addressing addressing the physical,
chemical, and dose considerations of ETS in relation to the same
considerations for active smoking. '.'
Findings on specific issues within the broader context of lung
cancer in adults follow:
1. Carcinoaenicity of ETS Has EPA met the requirements
stated in . its carcinogen guidelines for characterizing ETS in
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Category A, i.e., is the 'evidence sufficient to conclude that ETS
is causally associated with lung- cancer?
The Committee concurs with the judgment of EPA that environ-
mental tobacco smoke should be classified as a Class A Carcinogen,
but notes that it had some difficulty in applying the Guidelines
for Carcinogen Risk Assessment (51 FR 33992) , as they are currently
formulated, to this complex and variable mixture. The draft risk
assessment document's conclusion that exposure to ETS sometimes
leads to the development of lung cancer in humans rests upon. two
main arguments: (1) the biological plausibility of such a causal
association is high, given the known effects of active smoking and
the known composition of ETS (e.g. the carcinogenicity of ETS in
some animal studies, and the presence of known human carcinogens in
ETS) ; and (2) the accumulating epidemioloaie evidence on the
relationship between exposure to ETS and lung cancer. These
together appear to argue for a positive effect. We advise EPA to
place greater weight on the biological considerations and the ex-
tensive experience with active human smoking to support the classi-
fication.
2. Spousal Smoking Is spousal smoking a proper measure of
ETS exposure to assess lung cancer risk?
Despite its various limitations as an indicator of ETS ex-
posure, spousal smoking status seems to be a feasible method for
identifying people with greater, versus lesser, ETS exposure. The
problems in not accounting for background exposure from other
sources would, if anything, bias against finding increased risk of
lung cancer. Bias related to misclassification associated with
smoking status has been, addressed and corrected for in this draft
report. There are possible con founders related to spousal smoking
status, but such confounding concerns are present in other surro-
gates of exposure as well. The potential importance of these
confounders has been determined not to be sufficient to alter the
conclusion that ETS increases the risk of lung cancer.
3. Unitefl Stages and Foreign studies Are the differences in
relative risk observed between studies in the U.S. and those
overseas of concern, and if so, to what degree?
The Committee believes that: data from studies conducted in
other countries, as well as. in the United States, should be
-------
utilized in evaluating whether exposure to ETS increases risk of
lung cancer. It is appropriate to examine-the totality of evi-
dence from all the case-control and cohort studies, regardless of
where they were conducted.
4. ?•• of Meta-Analya^f Is Meta-Analysis an appropriate
tool to use in the document and has it been applied correctly?
Have the epidemiological studies been properly evaluated and
combined using this technique?
Meta-analysis is a general.term applied to a wide range of
techniques whose objective is to synthesize findings across related
studies. Although, it is an appropriate tool to summarize the
epidemiological studies investigating the risk of ETS, the emphasis
given the meta-analysis in this report in attempting to demonstrate
that ETS is causally associated with lung cancer is not justified.
Biological considerations related to respiratory carcinogenesis
(e.g., biologic plausibility) are equally compelling. Given the
similarities in composition between mainstream smoke and ETS,
biological considerations related to respiratory carcinogenesis and
the extensive evidence on active smoking should receive greater
weight.
5. . Confounders/Misclassification Have the most important
confounders been properly addressed? Has the issue of misclas-
sification (classifying current and former smokers as "never'smo-
kers") been adequately addressed and the proper adjustments made?
Are there other confounders which could be addressed in greater
detail?
Important potential confounders of the ETS-lung cancer rela-
tionship were addressed in the report mainly by carrying out a
separate meta-analysis of those studies which Included adjusted
analyses. The potential main confounders: included in these ad-
justed analyses were age and surrogates for confounding factors,
including education, and social class. Comparison of unadjusted
and adjusted relative risks (RRs) in those studies which present
both factors suggests that these effects are not important
confounders.
As for other potential confounders of the ETS-lung. cancer
relationship, including occupation, radon exposure, and diet, there
is no way to evaluate their importance as confounders or to adjust
1
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for them, since virtually none of the studies contains information
on them.
The issue of misclassification should not be restricted to
misclassification of current smokers and ex-smokers as "never
smokers." It should also be mentioned that misclassification of
diagnosis (diagnoses other than lung cancer being incorrectly
classified as lung cancer; or vice versa) will cause a biasing of
the RR toward the null.
Hot enough attention was given to-possible non-differential
misclassification of ETS exposure. This is an important issue,
since marriage to a .smoking spouse is an imperfect proxy for total
ETS exposure. In the case of dichotomous exposure, such misclassi-
fication would have the effect of biasing the RR estimate toward
the null. .
6. Characterisation of uncertainties Does the document
characterize the uncertainties, both in the weight-of-evidence and
the number of attributable deaths, appropriately?
Vis-a-vis weight of evidence, the draft document's conclusion
that exposure to ETS sometimes leads to the development of lung
cancer in humans rests upon the two main arguments noted earlier:
(1) the bioloaical^plausibility of such a causal association; and
(2) the accumulating epidemioloaic evidence on the relationship
between exposure to ETS and lung cancer. With exposure levels that
are usually quite low, it is not surprising that the association is
likely to be weak although, given the size of the exposed popula-
tion, societally important. Because the epidemiologic evidentiary
base for drawing conclusions regarding ETS's carcinogenicity
consists mainly of studies of exposure levels produced by Spousal
smoking, the biological plausibility argument assumes great impor-
tance. Each step in that argument should therefore be carefully
addressed, with the uncertainties encountered being spelled out
explicitly.
Epideaiolocric evidence on the relationship between exposure to
ETS and lung cancer should be described more completely, with the
deficiencies of individual studies used to weight their contribu-
tions to any conclusions that are drawn. The assumptions and un-
certainties associated with each step of the risk assessment pro-
cess ought to be explicitly stated.
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. 7.. ftuantitative Riak v«««««F»nt Has the quantitative risk of
lung cancer been properly assessed? Would it be more properly
assessed by a dose response assessment using either cotinine or
respirable suspended particulate matter as surrogate measures of
exposure (Appendix C)? Would it be more properly assessed with
alternative modeling approaches (Appendix D)? Should a dose-
response model be developed for ETS-radon interaction effects?
The Committee generally agreed that the quantitative asses-
sment of the risk of lung cancer due to exposures to ETS should be
based on the human epidemiology studies and that meta-analysis is
a suitable approach to combining the data. This approach is direct
and makes the fewest assumptions. It should be noted that this
approach is fully consistent with the risk assessments that have
been done for many other carcinogens and that those assessments are
generally based on fewer studies. -
Given that the epidemiology studies should be the basis of
the risk assessment, some refinements of the risk assessment are
recommended with respect to:
1. Criteria for Including Individual Studies in the Meta
Analysis
2. Adjustment for Smoker Misclassification
3. Misclassification of Exposure
4. Uncertainties in the Estimate of Annual Lung Cancer Deaths
Due to Passive Smoking . .
5. Dose-Response Estimation of Risk
8.- Home vs. Workplace Exposure Should the Draft Report
attempt to distinguish between the effects of home vs. workplace
exposure to ETS?
The Committee recognizes that there is little epidemiologic
literature on the health effects of ETS in the workplace, and
therefore on the relative impacts of home and workplace exposure.
However, the report should review and comment on the data that do
exist, if only to bring out the need for future research in this
area. The report should also review and comment on the data that
exist.on exposure to ETS in public places.
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B. frefpiratory Disorders in Children
Chapter 5 on respiratory disorders in children was a com-
mendable first effort for a very difficult task. Nevertheless, we
found that it could be substantially improved and that the conclu-
sions drawn in it could be made much stronger if the chapter vere
revised in the manner suggested in this report.
The Committee found the evidence for respiratory health ef-
fects in children to be stronger and more persuasive than that
stated in Chapter 5 of. the draft ETS rtisfc Assessment document, and
recommends that the new draft contain a more comprehensive discus-
sion on quantitative risk assessment for these effects.
* * *
Specific issues are addressed below:
1. Weight of Evidence Has the weight of evidence for ETS
related respiratory disorders in children been properly charac-
terized? A draft report with a detailed description and analysis
of 26 recent studies has recently been prepared and is enclosed.
It is in a form similar to that of Appendix A. Should it be
included in a revised report as Appendix E?
The additional literature available since 198$ provides a
basis for increased-concern about the effects of ETS exposure on
respiratory disorders. Thus, the Committee urges a thorough review
of the entire body of evidence, including earlier reports covered
in the 1986 reports of the Surgeon General and National Research
Council, and its incopbration as Appendix.E.
In reviewing the weight of the evidence, the present Chapter
.5 does not establish an appropriate framework for considering the
data. The alternative explanations for association of ETS exposure
with adverse respiratory effects need to be clearly listed. The
weight of the evidence could then be judged to determine the caus-
ality of associations.
2. Confeunders Have confounders in the epidemiologic studies
been adequately addressed?
A number of confounders were mentioned by the report, but.
addressed improperly. These include in utero exposure, parental
-------
^* •
reporting bias, and active smoking. One must al^o stress both the
biological precursors important to the effects of'ETS in childhood,
and socio-economic and behavioral .factors.
3. gpe of Meta-Aaalvaia Should a meta-analytic approach be
attempted as in the lung cancer analysis?
The Agency should give serious consideration to meta-analysis
of those studies of sufficiently similar design to warrant it.
However, it was not clear that there is a body of studies suitable
for such ah analysis. If one is warranted, it should be guided, to
the extent possible, by the same considerations outlined for meta-
analysis for lung cancer.
The Committee was also asked to examine whether the draft
Policy Guide's statements on health contained within the first 20
pages were scientifically defensible. With some exceptions, de-
tailed in the this report (section 4.0), the scientific data and
interpretations contained in the draft Policy Guide were appro-
priate. The Policy Guide draft will need to be revised to reflect
the changes being made in the Risk Assessment.
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2.0 INTRODUCTION
2.1 fflefrtygound On November 1, 1990/the Offices of Research and
Development and Air and Radiation requested that the Science
Advisory Board (SAB) review the draft report "Health Effects of
Passive Smoking: Assessment of Lung Cancer in Adults and
Respiratory Disorders in Children," which incorporated a health
risk assessment of the impact of passive smoking, on lung cancer
incidence. The document was prepared by the Human Health
Assessment Group, Office of Research and Development, at the
request of the Indoor Air Division, Office of Air and. Radiation,
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.
The draft risk report reviews and analyzes the data on the
respiratory effects of environmental tobacco smoke (ETS) with heavy
emphasis on the epidemiologic data and statistical (meta) analysis.
One major portion of the Report (Chapters 3 and 4) examines the
weight of evidence for lung cancer in adults. It concludes that
under EPAVs carcinogen assessment guidelines, ETS should be
classified as a Category A or known human carcinogen.
It also estimates from .epidemiology (not modeling) data that,
on average, 3,800 lung cancer deaths per year in U.S. nonsmokers
are attributable to ETS. The final chapter of the report examines
the epidemiological evidence for non-cancer respiratory disorders
in children and concludes that the detrimental respiratory effects
described are associated with exposure to ETS, but that a causal
association has not been established.
The draft report also contains four appendices. Appendix A
provides a detailed summary and analysis of eleven recent case-
control studies of ETS and lung cancer. Appendix B presents
pertinent mathematical formulae and relationships. Appendix C
describes the dosimetry of ETS, and Appendix D presents a potential
framework for dose-response modeling for ETS and lung cancer.
The draft risk report was made available for public review and
comment on June 25, 1990, with a 90-day comment period which closed
Oct. 1, 1990. Over 3,500 copies were distributed and 107 public
comments were received as_ of Oct 10, ,1990. A summary of those
comments were prepared and provided to the SAB Committee.
8
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2*2 scope ef Issues/Charge to the commit^* The Agency sought the
advice of the SAB on the draft risk document's accuracy and com-
pleteness. The Agency also wanted an opinion on whether the weight
of available evidence supported the conclusions drawn concerning
ETS's role in causing lung cancer and respiratory disease. In ad-
dition, the SAB was asked to address the following specific issues:
A. Lung Cancer in Adults
1. Has EPA met the requirements stated in its carcino-
gen guidelines for characterizing ETS in Category A,
i.e. is the evidence-sufficient to conclude that ETS is
causally associated with lung cancer?
2. Is spousal smoking a proper measure of ETS exposure to
assess lung cancer risk? .
3. Are the differences in relative risk observed between
studies in the U.S. and those overseas of concern, and
if so, to,what degree?
4. Is meta-analysis an appropriate tool to use in the doc-
ument and: has it been applied correctly? Have the epi-
demiological studies been properly evaluated and com-
bined using this technique?
5. Have the most important confounders been properly ad-
dressed? Has the issue of misclassification (classify-
ing current and former smokers as never smokers) been
adequately addressed and the proper adjustments made?
Are there other confounders which could be addressed in
greater detail?
6. Does the document characterize the uncertainties, both
in the weight-of-evidence and the number of attributa-
able deaths, appropriately?
7. Has the quantitative risk of lung cancer been properly
assessed? Would it be more properly assessed by a dose
response assessment using either cotinine or respirable
suspended particulates as surrogate measures of expos-
ure (Appendix C) ? Would it be more properly assessed
with alternative modeling approaches (Appendix D}?
Should a dose-response model be developed for ETS-radon
interaction effects?
8. Should the Draft Report attempt to distinguish between
the effects of home vs. workplace exposure to ETS?
-------
B-
enclosed. ** included m
A. S2£V . c studies been ade-
^endxxE. ^ ^cpi.demiologlcstu
.,
-
-- r'-c«-
MeiaJ>ers of ta« _
10
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3.0 REVIEW 07 THE RIBK XflflgaaMgHT DOCPMEMT
The preparation of a risk assessment document for ETS rep-
resents a formidable challenge, and the Committee recognizes the
quite considerable efforts put forth by EPA staff in preparing the
draft. The document contains some excellent summary materials on
a large and diverse set of relevant literature, as well as some
skillful and pertinent analyses that serve to address the critical
issues related to the public health impact of exposures to ETS.
Although ve commend EPA for its efforts, ve find that the document
could be substantially improved, and recommend.a series of specific
changes in organization and content that, if followed, would make
the revised document a much stronger basis for policy guidance on
ETS exposure and its health effects. Since the impact of ETS on
public health is comparable to that of some of the criteria air
pollutants, we recommend that the revised document follow more
closely the format of the Air Quality Criteria Documents. It
should include additional chapters addressing the physics and
chemistry of ETS, its relation to mainstream smoke, the exposures
of various populations of interest to ETS, and as appropriate to
the discussions of biological plausibility and weight of evidence,
those aspects of dosimetry which will be needed to support other
parts of the document. The contents of these additional chapters
should strengthen the basis for any actions or recommendations.
The Committee also reviewed the utility, format and adequacy
of the five appendices to the ETS Risk Assessment Document. We
found them to be of varying utility and quality, and made specific
suggestions for revisions and deletions.
3.1 Chapter ~3—gpiqemioloqie Evidence of Luna Canoer from ETS The
focus of this chapter is on hazard identification: that is, de-
termining if the available evidence on ETS warrants the conclusion
that exposure to ETS increases the incidence of lung cancer. As
described in the Agency's "Guidelines for Carcinogen Risk Assess-
ment," hazard identification is a qualitative process that involves
review "...of the relevant biological and chemical information
bearing on whether or not an agent may pose a carcinogenic hazard."
The scope of hazard identification is broad, involving review of
information on 1) physical-chemical properties and routes and pat-
terns of exposure; 2} structure-activity relationships; 3)
11
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metabolic and pharmacokinetic properties; 4) toxicologic effects;
5) short-term tests; 6} long-term animal studies; and 7) human
studies.
The present chapter, comprising the hazard identification step
of the risk assessment, seems limited in scope when measured
against the encompassing process set out by the Agency. Although
the appendixes do address exposure and toxicology to an extent,
this material needs more direct discussion in the chapter. The
components of ETS possibly relevant to this risk assessment should
be reviewed along with the characteristics of mainstream and side-
stream smoke, and similarities in composition and from In vitro
bioassay should be discussed. The complexity of ETS merits
emphasis; it is not a single chemical agent, but a mixture with
varying characteristics by place and time in relation to its for-
mation in the burning cigarette. The toxicologic effects of in-
dividual components merit further discussion. Exhaustive review is
not needed, since the Surgeon General's Reports provide comprehen-
sive documentation.
In reviewing the human evidence, the chapter fails to draw on
the voluminous evidence on active smoking and lung cancer. The
1986 Surgeon General's Report, for example, concluded that there
was enough toxicologic similarity between mainstream smoke and ETS
to justify using the evidence from active smoking in reaching
conclusions'concerning ETS and lung cancer. The evidence on active
smoking and lung cancer documents the consequences of a higher
level of exposure to a mixture, mainstream smoke, that resembles
ETS in composition. The epidemiologic evidence on ETS and lung
cancer in nonsmokers should be considered as addressing the risks
of lower levels of exposure. Thus, the evidence on active smoking
and lung cancer needs to be reviewed in this chapter. The causal
nature of the association between active smoking and lung cancer
should be described, as should exposure-response relations for
active smoking and lung cancer. The Surgeon General's Reports
could serve as the basis for developing this material.
The existing chapter reviews case-control and cohort studies
providing information on the association of ETS with lung cancer.
Characteristics of these studies are considered. Several statis-
tical approaches are used to assess the aggregate significance of
the evidence and a pooled relative risk estimate with associated
confidence, limits ..is-calculated. . .The..chapter concludes with a
12
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review of potential biases affecting interpretation of these
studies, with an*emphasis on misclassification.
The roster of studies selected represents those available
through the tine at which this draft report was released; in re-
vising the draft, consideration should be given to substituting the
data from the recent report by Janerich et al. (1990) .for the
earlier analysis of these same data (Varela, 1987). The features
of the individual studies are adequately reviewed.
The discussion of bias (Section 3.5) needs expansion and some
consideration of types of bias other than misclassification. The
types of bias potentially affecting any epidemiological study
include selection bias, information bias (which includes both
differential and non-differential misclassification), and con-
founding bias. Selection bias, particularly likely to affect case-
control studies based on cases and controls derived from specific
institutions, should be addressed. The possibility of confounding
bias merits review because of evidence that smokers are increas-
ingly distinct from nonsmokers in socioeconomic characteristics
that may have implications for health. Thus, those more highly
exposed to ETS may differ from those less exposed in other
relevant characteristics. Confounding, however, is an_ unsatis-
factory explanation for the general pattern of the reported stud-
ies, with the majority showing increased risk. These studies have
been conducted in a wide variety of locales with consistent find-
ings of positive association; this consistency weighs against con-
founding as an explanation for the increased risk associated with
marriage to a smoker. The discussion of misclassification should
be expanded to include studies that have addressed the quality of
information on passive smoking derived from questionnaires as well
as the relation between questionnaire-based measures of exposure
and biological markers of exposure. The 1990 Report of the Surgeon
General includes reviews of the quality of information on smoking
from surrogate respondents as well as of the validity of self-
report of smoking history; this recent report should be considered
and cited in the discussion of misclassification.
Two major cohort studies providing evidence on passive smoking
and lung cancer have been published; a lengthy discussion is
provided concerning the comparative findings of the two studies.
Unfortunately, we lack information on the comparative exposures to
ETS of subjects in the two populations. For both studies, follow-
11
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up periods began well before present methods for atmospheric moni-
toring or for assessing biological markers vere available. Thus,
arguments concerning the possibility that passive smoking is more
"direct" in Japan are speculative and the lack of data should be
cited and uncertainty added in drawing any conclusion concerning
the comparative levels of exposure in the U.S. and Japan. The
discussion of the two studies should be markedly shortened.
In summary, Chapter 3 of the Nay.1990 External Review Draft
provides a generally adequate review and assessment of the epi-
demiologic evide~.se on ETS and lung cancer in never smokers. A
complete hazard identification is not conducted, however. The
chapter needs to be expanded to address more fully the toxicology
of ETS and the evidence on active smoking and lung cancer. This
expanded review, coupling more closely the evidence on biological
plausibility that ETS is a carcinogen with the supporting epidemi-
ological evidence would adequately support the conclusion that ETS
is a Group A carcinogen, a determination that should be moved from
the quantitative risk assessment (current Chapter 4) to Chapter 3.
The Committee accepts this overall, conclusion, in spite of the
limitations of the current chapter; a more comprehensive review as
suggested by the Committee should strengthen the determination that
ETS is a Group A carcinogen.
3.2 Chapter 4—Assessment of Luna Cancer Risk from ETS In
reviewing published quantitative risk assessments, Chapter 4 of the
review draft properly dichotomizes the approaches that have been
taken — the cigarette-equivalent approach, and analyses of epi-
demiologic studies in which the excess lung cancer risk in non-
smokers is observed as a function of exposure to ETS. As indicated
in Chapter 4, there are serious difficulties in both of these ap-
proaches. The cigarette-equivalent approach has the great ad-
vantage that it is based on relatively abundant and consistent
relative risk (RR) determinations in active smokers, which can be
used to project the risk in non-smokers exposed to ETS in the form
of a percentage of the risk in active smokers.
The assessment of the cigarette-equivalent in non-smokers due
to exposure to ETS has a considerable level of uncertainty embedded
in it. The ratio of sidestream (SS) to mainstream (MS) emissions
is highly variable among the components of cigarette smoke, so that
the number of cigarette-equivalents to which a passive smoker is
exposed varies greatly with the compound used as a marker or expo-
14
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sure surrogate. Neither cotfinine concentration in body fluids nor
the measurement of tobacco smoke parttculate natter can be used
with great confidence for quantitative assessment of the carcino-
genic potential of ETS. There is a suggestion that the uncertainty
in exposure assessment for either approach is about an order of
magnitude (It should be noted here that the Guideline for Carcino-
genic Risk Assessment anticipates that numerical risk; estimates
vill have no more than one significant digit). Neither cotinine
nor smoke particulate matter levels are direct indicators of car-
cinogenic components.
The other type of assessment is based on inferences from the
epidemiologic studies of the association of exposure to ETS and
carcinogenic risk in non-smokers. Since spousal smoking is a very
important exposure proxy used in many studies, the utility of a
categorical classification (married to a smoker/not married to a
smoker} for quantitative exposure assessments needs to considered.
Physical proximity of smokers to non-smokers), daily length of
exposure, and exposure outside the home to ETS may be quite dif-
ferent in different cultures and over decades of time. Misre-
porting of smoking.status for cases and controls in these studies
may also introduce a bias. Various attempts have been made to
apply corrections for these sources of bias. These attempts re-
quire further assumptions and are based on limited data available
on misreporting rates and cotinine concentrations in various
groups.
The assessment presented in the last section in Chapter 4 of
the Review Draft does not appear to be in conflict with procedures
established in other reviews, and states all assumptions made in
the quantitative assessment with considerable care. The results
are given in "too many significant figures however.
3.3 Chapter 5*"Bttvirftp"t*>t*tal Tobacco Smoke and Respiratory
Disorders in children The Committee recommends that this chapter
be re-organized to reflect directly the biological effects of
Passive/Involuntary smoking (This terminology reverts to the orig-
inal discussion of exposure-response and its impact, as per the
Surgeon General reports of 1982-1986). The chapter should treat in
H££cg exposure as a precursor to extra uterine/post birth/childhood
effects, and not as a confounder. It should also be extended to
address effects in adults, since the sequelae of'effects in chil-
15
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dren, as well as direct effects in adults, naturally proceed from
the discussion of effects in children. 1
The Committee's recommendations as to the structure for a
revised chapter follow. In outline, the proposed sections would
be: an Introduction; 1) Biological Mechanisms; 2) Exposure and its
Assessment;' 3) Annoyance and Irritation; 4) Acute Illnesses (middle
ear, upper respiratory, lower respiratory); S) Chronic Respiratory
Systems and exacerbations of chronic obstructive pulmonary disease
(COPD); 6) Asthma; 7) Pulmonary Function; and 8) Kealth Hazard
Assessment.
The introduction of the Chapter should include some reference
to the overall problem of acute and chronic respiratory diseases,
and the potential attributable risk of ETS/passive smoking
(Chronic respiratory disease is the fifth leading cause of death,
with an age-adjusted death rate of 15.7/105 in 1985; it is
increasing still. Acute lower respiratory disease is the sixth
leading cause of death, with an age-adjusted death rate of 13.4/105
in 1985. The prevalence rates of related conditions are signifi-
cant—the rate for asthma, for example, is 4.1/102 (NCHS, 1986).
Acute respiratory disease is the leading cause of morbidity and'
disability in the U. S. (as per NCHS)).
The first section of the Chapter could be called Biological
Mechanisms (5.1). It should discuss the biological plausibility of
the respiratory responses (akin to the discussion of carcinogen-
icity), and a brief discussion of the comparable response to active
smoking. Such topics as irritant responses to pollutants (as are
found in STS) have been discussed at length in EPA Office of
Research and Development and Office of Air Quality Planning and
Standards (OAQPS) documents (e.g., National Ambient Air Quality
Standards (NAAQS) Criteria Documents and Staff Papers, and National
Emissions Standards for Hazardous Air Pollutants (NESHAP) Criteria
Documents.
It should start with the effects of in utero exposure effects
as precursors to childhood effects (5.1.2.): reduced fetal oxy-
genation, poorer lung (and brain) development, low birth weight,
immunological and biochemical effects (e.g., changes in T cells and
immunoglobulin levels, changes in prostaglandin regulation, pro-
16
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tease inhibitors) (Amer. Acad. Peds. J. Peds., 1976; ALK report,
1983; Wall et al., 198S; Rantakallio, 1978; Mclntosh, 1984; Tager,
1988). .
The next discussion (5.1.3) could be of the effects of lov
lung function at birth (due to genetics and in u£gr£ exposure) as.
a precursor of lower respiratory infections; poorer lung develop-
ment (disposing to greater effects of ETS on lung growths) (Mar-
tinez et al., 1989; Sherrill et al., 1990; Lebowitz, 1991), as
discussed at the Committee's meeting).
There should be a discussion (5.1.4) of the potential re-
duction in host defense mechanisms due to ETS (going further than
that induced by inutero passive smoking), which is of a similar
nature (though a different dose) to that induced by active smoking.
This topic relates to the.increased predisposition to and prev-
alence rates of acute illnesses (middle ear, upper respiratory,
lower respiratory, other exacerbations of chronic respiratory
disease/chronic obstructive pulmonary disorder/airway obstructive
disease (COPD/AOD)).
The next logical discussion (Section 5.1.5) could concern how
these .experiences could lead to chronic respiratory disease (e.g.,
chronic cough, persistent wheeze) in childhood, and how the se-
quelae of such would be chronic respiratory disease in adult life.
The pathophysiological and anatomical mechanisms would be featured,
and some discussion of biochemical mediators would occur.
There should be a discussion (5.1.6) of the biological reasons
why ETS would produce or exacerbate bronchial lability and respon-
siveness (BR) (coupled to the lower airway caliber, and possibly
genetics, discussed above), and how this BR, especially in
conjunction with increased Immunoglobulin E and lower respiratory
infections (both discussed above) could lead to childhood wheezy
bronchitis and asthma (Tager, ARRD, '88; 138:507; Burrows and
Martinez, ARRD, '89 140:1515). The role of atopy (also genetically
regulated) in this process should be discussed (ibid.).
The role of these above-mentioned conditions (BR, bronchitis,
asthma/persistent wheeze) on decreased lung growth (Sherrill, op
cit.) should be discussed. This could lead into a general
discussion (5.1.7.) of why lower lung ...function is related
pathophysiologically to ETS, starting with deceased lung growth
17
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(see above), and how this would lead to low lung
function/COPD in adults (Tager et al., 1987; Lebovitz et al.,.
1987). Appropriate biochemical and anatomic "mechanisms would be
discussed. • . > • •
Unless the relevant material is covered generically in. an
earlier chapter. Exposure and its Assessment could be covered in a
separate second section (5.2). Such a section would cover reported
exposures, measurements of indoor nicotine, other related pollu-
tants (PH, CO, etc.)* and biological markers such as cotinine
(Jarvis et al., 1987). Factors-associated with ETS (cf., Sandier
et al., 1989) should be presented as relevant. Other methods of
exposure estimation and assessment should also be discussed,
including utilization of models based on source characterization
from chamber studies. The relationships between reported exposures
and monitoring results, and biases in reporting (cf., 'Friedman et
al., 1983) could be discussed also. Confounding needs to be
discussed (Quackenboss et al., 1989; Lebowitz, 1990) as well (other
key references include National Research Council (NRC) 1981; World
Health Organization (WHO) 1982; NRC 1986, and WHO/EURO Proceedings
on Zndoor Air 1984, 1987, and 1990.) Further, exposure-dose'
estimation would be presented (Hiller et al., 1982). .
The third section (5.3) should address Annoyance and Irri-
tation. Annoyance is important per se. and annoyance also affects
subjective reports (Lebowitz, 1989; Department of Health, Educa-
tion, and Welfare 1971; National Institute of Occupational Safety
and Health 1971; National Clearinghouse on Smoking and Health 1976;
NRC 1981, Surgeon General's Report 1986) (Odor topics should be
included in this section, introducing the concept of sensitive
individuals). Irritation effects are well-documented* (Weber, and
Hugod, 1984), and occur more quickly at lower doses in those more
"sensitive" (ibid., op cit). Acute irritant symptoms should be a
major topic. This section should document such effects in children
and adults, and differentiate irritant from infectious and
allergenic effects.
The fourth section (5.4) should cover Acute Illnesses. This
includes middle ear effusions (5.4.1), upper and lower respiratory
illnesses (including such exacerbations of COPD) (5.4.2-.4), and
sequelae of lower respiratory illnesses. The effects of LRI's on
lung function (e.g., Yarnell and St. Leger 1979), and the possi-
bility of LRI's leading to asthma in children (Gregg, 1973) war-
18
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* . " • • .
rants discussion. The effects of LRIs leading to asthma in
children (Gregg, 1973) should also be discussed. .The effects of
LRIs also includes AOD in adults (the overall effects of childhood
respiratory troubles (CRT)), especially as documented in longi-
tudinal studies (Lebovitz et al. 1987, 1988; and Sherrill et al.
1990); this could be a separate section (5.4.6).
*
Airway obstructive disease should be addressed in a major
section because of the veil-documented effects of ETS on lover
respiratory tract illnesses, and the above-mentioned sequelae. The
SPA report did a reasonable job in this are-, and can be expanded
(by incorporating some of the comments included in the reviews by
Samet and Lebovitz). Further discussion of biases in reporting are
available (Colley 1974; Cederlof and Colley 1974), as well as for
confounding by other exposures (Hammer et al. 1976; Anderson, 1979;
Speizer et al. 1980; Comstock et al., 1981; Melia et al. 1982; Koo
et al. 1988), and interactions with other exposures (Lebovitz "et
al. 1989 and 1990). There should also be discussion of the
concurrent effects of breast feeding and socio-economic status
(Martinez et al., '89, '90).
The fifth section should cover Chronic Respiratory Symptoms
(and increases of symptomatology in COPD as exacerbations). Some
of this topic vas covered in the EPA report, but it could be
improved by clarification and expansion (see revievs provided).
Again, biases in reporting, confounding by other exposures, and
interactions of exposures producing responses (ibid., op cit.)
warrant discussion. Effects of active/self-smoking interacting
with passive smoking should be discussed (Bland et al., 1978;
Lebovitz et al. 1987 and 1988). Effects of family history (ibid.,
Schilling et al. 1977; Weiss et al. 1980) should also be covered.
Sequelae (op cit.) could be discussed as veil, and direct effects
in adults also (Comstock et al. and Schilling et al., ibid.;
Lebovitz and Burrows, 1976; Schwartz and Zeger, 1990).
The sixth section (5.6) should cover all the aspects of
Asthma. This section is one of the most important, and vas one
that vas insufficiently discussed (in all aspects) in the EPA
report. It needs to discuss genetic and in utero aspects, the
evidence for .bronchial responsiveness, high IgE and atopy related
to ETS (Weiss et al. 1983 and 1988; Tager 1988; Burrows 6 Martinez
1989; and Lebovitz et al. 1989 and 1990, op cit.). The effects of
social status, breast feeding, other exposures, and sequelae should
19
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be discussed as well top cit.; Rantakallio 1979; Sherman et-al.,
1990). Other studies, in press, could also be used (e.g., Martinez
et al., Feds.)* Exacerbations can be studied as veil, including
those seen in field studies (Quackenboss et al. and Lebovitz et al.
1989-1991, op cit.) and chamber studies (Shepherd et al. 1979;
Dahrns et al. 1981; Stankus et al. 1988; Oanuzer et al. 1991).
The seventh section (5.7) should .cover effects on Pulmonary
Function alluded to above, in the EPA report, including all the
previous effects (and confounders, etc.) discussed above. It
should be more precise, and,include,amount of.change found.
There could be a section at this point covering other,
miscellaneous topics, as in the.previous report. Alternatively,
these topics could be put into other sections.
The (eighth section (5.8) would be a Health Hazard Assessment.
vhich would include attributable risk and population impact.
Further discussion is needed concerning the initial aspects of the
section.
studies The Committee agreed that Appendix A made a valuable
contribution to the document, and that it should be included in the
final draft. Much of the information contained in the appendix
might be more useful however, if it was organized as a series of
tables rather than a running text description. For example, a
table that described the important characteristics of the study,
e.g., population size, number of lung cancers, measure of ETS
exposure used, characteristics of the control population and
criteria for selecting the cases. Other tables might include
potential biases addressed or not addressed in each of the studies
and smoking characteristics in the background and control
populations.
3.5 Appendix B—Mathematical Formulas and Relationships The
Committee agreed that Appendix B is important to the overall
report. However, in its present form, it contains several errors,
both typographical and substantive, which should be corrected.
Moreover, its format is difficult to read, and it is incomplete.
The Committee recommends that Appendix B be restructured and
rewritten in a more "reader friendly" style to include, as a
minimum, the following three sections:
20
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3.
a.
1. An introduction to describe the .purpose of the Appendix
and its objectives. -. ' - ;
2. An overview of the Mantei-naein»*.c^ .~~~ that was used
in this report for the meta-analysis. This section should
also include a rationale for the selection of this pro-
ceedure, rather than the method used in the previous NRC
report. Appendix B in the NRC report is suggested as a
guide for the presentation of this material.
>nd derivations of the risk asfc.
ttons used. A rationale for the specific equations, a
discussion of the validity of these equations for case-
control as well as cohort studies, and explicit, assump-
tions pertaining to the equations should be included in
this section. The Committee also suggests that the deri-
vations be presented in a systematic format for ease of
reader understanding: . .
A new section on the derivation of the unadjusted
relative risk equation. (This could be incorporated .
with item 2, above).
b. A revised section on the derivation of the relative
risk equation adjusted for misclassification (Bl).
A revised section on the derivation of the relative
risk equation adjusted for background exposure (B2).
A revised section on the derivation of the equation
to estimate the population-attributable risk (B3).
specific written comments pertaining to Appendix B were
submitted by several Committee members. These comments identified
several errors, typographical and substantial, in the equations.
The Committee therefore recommends that these errors be corrected
and that the results based on these equations be carefully reviewed
before final publication. For example, it was acknowledged at the
Committee meeting in December that the correction of one such error
resulted in a slight downward shift of the predicted annual lung
cancer deaths due to passive smoking.
c.
d.
21
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3.6 appendix c--Do8Jme.trv of BT8 The Committee agreed with EPA
staff that Appendix C should be deleted-in its present form. Some
of the issues that are addressed in Appendix C* should be addressed
in at least one or more of the new chapters/ but in a format appro-
priate to a chapter, rather than :a format considered appropriate to
an appendix. . .,
When incorporating the discussion nov located in Appendix C
into appropriate text chapters, it should be noted that the Ap-
pendix, as written, has serious technical errors and limitations.
It is seriously deficient in that it focusses entirely on carcino-
gens and their dosimetry in healthy adults. This is inadequate
even when .the endpoint of concern is lung cancer, as evidenced in
the recent report .of Janerich et al. (op. cit.) on the association
between lung cancer in adults and their childhood exposure to ETS.
It is even more inadequate in that it ignores the respiratory
disorders in children that are reviewed in great detail in Chapter
Five. ..
The whole section C-5, "INTERNAL ORGAN BURDENS FOR THE LUNG,"
is based upon a simplistic set of models and assumptions that
produce regional lung retention times and dose estimates that are
truly fanciful. It correctly states "that removal from the
tracheo-brbnchial region generally may be characterized by two
phases. The first is a rapidly cleared phase, dominated by par-
ticles deposited on the mucus of the upper passageways. The second
is dominated by particles deposited on the slowly moving mucus of
distal passageways." However, the calculated half-times (C, and C2)
of 450 and 710 minutes, respectively, for the fast and slow phases
of ETS particle clearance, differ considerably from• the actual
radio-aerosol study data on which the model is supposedly based,
and which show much faster rates. •
The literature on the effect of active smoking on particle
deposition and clearance rates is misinterpreted. One study of
Albert et al. (1975) concerning the short-term effects of smoking
on overall tracheobronchial clearance in humans, and one study by
Wanner et al. (1973) on the effects of chronic smoke exposure on
mucociliary transport velocity in the trachea of the dog are cited
as a basis for doubling the retention times of particles on the
tracheobronchial tree as a whole. . The conclusion was drawn that
smoking has no effect on the regional deposition of particles. The
reality..is quite different. Smokers have much greater tracheo-
22
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bronchial deposition than nonsmokers, and the short-term effect of
smoking is to greatly accelerate the ~clearance of particles
deposited on the tracheobronchial tree. It is curious to note that
the C2 value calculated for the second "fast-phase" component in
smokers is 1400 min (23.3 hours), while a 17 hour half-time was
used for the "slower" alveolar region half-time in the dose
calculations.
3.7 Appendix D--Alternative Approaches forEstimating the Yearly
Dose-Eesponse Modeling The major purpose of Appendix D is to
bolster the risk assessment document. Much of the data referenced
in this appendix provide further evidence of the carcinogenicity of
environmental tobacco smoke, and should be clearly presented in
this light. For instance, the Grimmer study clearly demonstrates
the lung carcinogenicity of ETS in animals. Other sections are
currently incomplete and point to future directions for research.
While interesting, these sections are not as supportive of the main
document and may be distracting.
The first two approaches for deriving ETS dose-response
models, the relative potency approach and the cigarette equivalent
approach, share an implicit assumption that particle phase com-
pounds, and polynuclear aromatic hydrocarbons in particular, are
the carcinogens of interest. Other carcinogens have been identi-
fied in ETS, and many of these are in the vapor phase, e.g., ben-
zene, vinyl chloride, formaldehyde, and several N-nitrosamines. To
the degree that vapor phase carcinogens have been ignored, or
incompletely collected or extracted for administration in animal
experiments, the potency of ETS has been underestimated. Further-
more, the use of benzo-[a]-pyrene as a reference standard of human
lung cancer is highly problematic and should be reconsidered.
The uncertainties in the relative potency approach are too
great to support the derivation .of an ETS dose-response model that
would be an improvement over any that can be calculated from epi-
demiologic data. The relative potency in animals is not neces-
sarily the same as the relative potency in humans, especially to
the degree that metabolism may be involved. Furthermore, the data
do not exist to support calculating the relative potency by a
straightforward comparison, e.g., ETS and compound X in animal
system A, compared with a known .dose-response relationship for
compound X in humans, so .other intermediate comparisons are re-
23
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quired, such as compound X and mixture Y with different routes of
exposure, on different animals, and with different tumors. The
uncertainties of each step quickly overwhelm the uncertainties in
the epidemiologic studies.
The complexities of tobacco emissions complicate the cigarette
equivalent approach. The referent mainstream emissions should be
those of unfiltered cigarettes, upon which most of the active smo-
king epidemiologic data is based. The variable ratios in side-
stream to mainstream emissions of toxins lead to differences in the
calculated cigarette equivalents to which a passive smoker is
exposed, and these may range over two orders of magnitude (see
Hammond, 1990). These different emission ratios are a source of
variability in the ratio of biomarkers in smokers and nonsmokers.
(Metabolism rates are another potential difference.) - Thus, co-
tinine in nonsmokers is typically less than 1% the level found in
smokers, while the median level of 4-aminobiphenyl hemoglobin ad-
ducts in nonsmokers was 14% the median in smokers (Hammond et al,
1990). This corresponds to the emission ratios of_these compounds,
which differ by a factor of 15. Russell and coworkers (1986) (page
4-19) based their estimates of the risk of premature death from
passive smoking on the ratio of cotinine in passive smokers to that
in active smokers, 0.007, and assumed the same ratio held between
premature deaths in passive and active smokers. The use of 4-
aminobiphenyl hemoglobin adducts instead of cotinine to estimate
relative exposures would have led to a higher predicted premature
death rate due to passive smoking.
Several studies have been conducted on the deposition of MS
and SS particles in the human lung. These should bis discussed
rather than relying solely on biomarkers, where the exposures are
not known. A few caveats are required regarding the use of DNA
adducts to estimate dose. DKA adducts are subject to repair
mechanisms, and the rate of repair may differ in smokers and
nonsmokers. Since nonsmokers have very different exposures to ETS,
one expects a wide range in the ratio of adducts in smokers and
nonsmokers. A disadvantage in the exclusive use of DNA and protein
adducts as biomarkers of dose is that such markers are available
for only a few suspected agents. The use of benzo[a]pyrene (BaP)
DMA adducts is further complicated by the many other sources of
BaP,-including diet and various combustion products.
24
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Determination of the dose-response effect of ETS based on the
epidemiologic studies of Hirayama would be most valuable. The data
gathered by Hirayama and colleagues could have been greatly enhan-
ced and more generalizable if measurements of ETS levels (especial-
ly respirable particle and nicotine concentrations) had been taken
in Japanese homes with varying amounts of smoking.
Some of the methods used in Appendix D might be useful in
estimating the importance of ETS in respiratory diseases in
children. Appendix D has information which is supportive of the
main document. Some of this information can be improved; some is
suggestive of .future research directions. - The release of the final
document should not be delayed for these data. Finally, the data
may be best incorporated into the relevant sections of the main
document, rather than exist as an independent appendix.
3.8. aooendlir E— Buiraiirv Descriptions ef Twenty-Six studies on
The Committee concluded that an Appendix E, similar to the Appendix
A, should be included in the revised document. As before, the
Committee recommends that the information by organized as a series
of tables rather than as a running text description with a similar
format.
25
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4.0 HEyjftt oy"
The Policy Guide was not prepared as a scientific document,
but its recommendations are based upon summary statements of
scientific knowledge. On this basis the Committee kas agreed to
examine whether the Guide's statements on health contained within
the first 20 pages were scientifically defensible. The Committee
did note that there is much technical content in other sections of
the Policy Guide, including technical statements on ventilation,
room and building ventilation.
For the most part, the scientific data and interpretations
contained in the draft Policy Guide were appropriate, but there
were some notable exceptions — an incorrect definition as to what
constitutes a small particle, an erroneous statement as to the
depth of penetration of mainstream smoke vs. sidestream smoke, and
a misstatement of the current particulate matter NAAQS, to cite a
few. Furthermore, there were statements about cardiovascular
mortality, cancers at other sites, and aggravation of cardiovas-
cular and respiratory disease that were not addressed in the ETS
Risk Assessment. Thus, without having any supporting documenta-
tion, the Committee could not endorse these statements.
The Policy Guide draft will need to be revised to reflect the
changes being made -n rhe Risk Assessment. If the Committee is to
review the Policy Guide again, it should be sent to the Committee
with a supporting document that explicitly states the technical
basis for each of its summary statements on the state of scientific
knowledge.
26
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s.o . ••Vteigic KsrxBE iotas.
S.I Tfflny cancer ia ftflqfrty The Committee noted that Chapters 3 and
4 addressed the issue of lung cancer risk due to spousal smoking
only for non-smoking women. It is suggested that the revised doc-
ument be expanded to include the full range of cancer impacts of
ETS. The Committee also noted a. number of areas where substantial
improvements could be made in the organization of the document, as
well as in its content — some material was not adequately covered
or not addressed at all. The Committee urges the EPA to redraft
-those ch-^ters as .well. Some specific suggestions follow.
5.1.1 Carcinoaeaicity of BTS The Indoor Air Quality and Total
Human Exposure Committee concurs with the finding of the draft
report that Environmental Tobacco Smoke (ETS) should be classified
as a Class A Carcinogen. The Committee believes, however, that the
case could be made more persuasively than does the current draft
document. Part of the difficulty nay be found in the language and
the rationale of the Guidelines for Carcinogen Risk Assessment as
they are currently formulated (51 FR 33992, August 22, 1986). The
Guidelines address the case of a single chemical compound which may.
contain contaminants or impurities. The process envisioned in the
Guidelines consists of Hazard Identification and ".. should include
a review.... to the extent that it is available" of:
1. Physical -Chemical Properties and Routes and Patterns of
Exposure :
2. Structure-Activity Relationships
3. Metabolic and Pharmacokinetic Properties
4. Toxicologic Effects
5. Short-Term Tests
6. Long-Term Animal Studies
7. Human Studies
In the Guidelines, the Long-Term Animal Studies section is
covered in 25 column- inches, and the Human Studies section takes up
about seven column-inches, an indication of the emphasis on long-
term animal toxicology studies.
i
The evidence for the carcinogenicity of tobacco smoke is not
based on long-term animal studies, which are negative. In this
case, the strongest evidence is that obtained in a large number of
'epidemiologic studies of active smoking and lung cancer. The
causality of the connection between inhalation of tobacco smoke and
excess .risk of lung cancer .cannot be in doubt. It has been
27
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demonstrated that cessation of inhalation of tobacco smoke leads to
a reduction of the excess lung cancer risk. The risk has been
shown to be proportional to the .amount of smoke inhaled. In terms
of overall impact it has been shown that a very high proportion of
the observed lung cancer incidence is due to inhalation of tobacco
smoke. If the Guidelines for Carcinogenic Risk Assessment can be
used to cast doubt on a finding that inhalation of tobacco smoke by
humans causes an increased risk of lung cancer, the situation
suggests a need to revise the Guidelines.
The inhalation of ETS by children, by non-smokers or former
smokers represents a risk that is much smaller than that experi-
enced by active smokers, but it is an involuntary exposure. It is
not uncommon to derive quantitative risk assessments of exposures
to carcinogens from data obtained in more heavily exposed occupa-
tional populations, and in that sense smokers represent a more
heavily exposed population, providing data for extrapolation to the
lower exposures imposed on children and- adult non-smokers.
There are both differences and similarities in the charac-
teristics and the composition of mainstream smoke, sidestream
smoke, exhaled tobacco smoke and environmental tobacco smoke. It
is important to deal both with the differences and similarities as
they might affect the quantitative risk which is most accurately
known for mainstream smoke. The difference in carcinogenic po-
tential is not such that any one of these other categories could be
considered as non-carcinogenic in humans. The very clear carcino-
genicity of mainstream tobacco smoke directly implies carcinogen-
icity of ETS, particularly in view of the similarities in chemical
composition and sizes of particulates between mainstream and
sidestream smoke.
Meta-analyses of epidemiologic studies in non-smokers and for-
mer smokers are sensitive to decisions about exclusions and inclu-
sions, and are primarily oriented towards increasing the overall
statistical power and more precisely describing risk, such analy-
ses cannot effectively take into account any differences in quality
of the study, differences in the way exposures were determined or
classified, etc. Biases will be reduced only in that they will be
averaged.
5.1.2 apouaal Smoking All of the studies cited in the report on
ETS and risk of .lung cancer have made.observations on married women
28
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who have been classified as "never-smoking". Those married, to a
smoker are assumed to be exposed to greater levels of ETS than
those married to a nohsmoker (p.3-12). " As noted in the report,
this relative risk comparison implicitly compares women exposed to
both spousal and other ETS to those exposed to other ETS only.
The ideal measure of ETS exposure for lung cancer studies
would include all .sources of ETS with data on both dose of ETS and
exposure over time for a lifetime, or at a minimum over the past 20
to 30 years. Spousal smoking is believed to be a useful and valid
marker for ETS. exposure because (1) it often indicates many years
of exposure (this contrasts with biological markers such as urinary
cotinine, which indicate exposure at only one point in time); (2)
the level of ETS exposure in the home when the spouse smokes ap-
pears to be greater in magnitude than the exposure from other, non-
domestic, sources. Several studies exploring urinary cotinine as
a measure of ETS exposure have found higher levels in non-smokers
married to smoking spouses than to those married to nonsmoker
spouses. The statement that ETS in the home is greater than that
of other ETS exposures may be more or less true according to a
variety of factors as noted below. The use of spousal smoking data.
is highly attractive because such data are easy and inexpensive to
collect. For most studies spousal smoking is the only available
measure of ETS exposure.
There are potential limitations in the use of spousal smoking
as an indicator of ETS exposure that need to be considered:
1. Spousal smoking may account for a relatively small propor-
tion of lifetime ETS exposure. Janerich et al. (1990) est-
imated that spousal exposure accounted for only 30% of
lifetime exposure. These authors computed correlation co-
efficients of 0.37 and 0.51 between spousal smoking and
lifetime ETS exposure for men and women, respectively. In
this study childhood exposure was a major source of life-
time ETS exposure and correlated more highly with lifetime
exposure. Likewise, Cummings et al. (1989) found little
relationship between childhood, adult home and work place
ETS exposure. On the other hand, Thompson and co-workers
(1990) found that non-smokers who lived with a smoker re-
• ported more ETS exposure outside of the home than those who
.did not live with a smoker. In this way spousal smoking
could be a more general indication of ETS exposure than
29
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expected on the.basis of exposure in the home pey s&, but
sensitivity for total ETS exposure may vary among different
study populations.
2. The results of comparing ETS household exposure to ETS
household plus other exposures may vary in different coun-
tries and different regions within the U.S. Exposure
within the residence depends on size and the.type of con-
struction of the dwelling, the amount of ventilation, and
the proximity of smokers and nonsmokers within the home.
„.. Non-domestic background exposure varies with the nature of
their workplace exposures, the extent of smoking restric-
tions in the work place and public places, the climate
and the time of the year. With respect to the latter,
exposures as assessed by urinary cotinine concentrations
in Buffalo, New York were greater in the winter compared
to the summer, presumably due to more time spent indoors
. with less ventilation in cold weather (Cummings et al.,
1989). Such differences would be expected to be less mar-
ked in warmer regions of the country. For non-smoking peo-
ple in particular, the extent of exposure outside of the
, home may depend on whether the woman works and how many
other people in the population, who may be friends of
non-smoking women, smoke. Thus, in countries such as
Japan where fewer women work outside of the home, and
fewer women in general smoke, spousal smoking may indicate
differential exposure for women who are, and who are not
exposed to ETS, than in the U.S. In any case, bias due
to concerns (1) and (2) would decrease the difference in
true exposure between the "exposed" and "non-exposed" non-
smoking spouses, and would favor finding no difference in
relative risk. These issues may explain some of the vari-
ability found in relative risk for lung cancer with ETS
exposure in different countries around the world.
3. As noted previously, a major source of ETS exposure is. that
incurred in childhood, which could contribute to increased
lung cancer risk in an adult. Although not generally spe-
cified in quantitating the risk of having a smoking spouse,
it is possible that a person whose parent(s) smoked (and
therefore who was exposed to ETS as a child) is more li-
kely to marry a. smoker.. In this, case the risk of ETS might
30
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reflect the risk of combined childhood and spousal expo-
sure rather than just exposure to the spouse.
4. The use of spousal smoking as an indicator of exposure
may amplify the risk of misclassification of smokers as
non-smokers. There appears to be a concordance between
spousal smoking and false reporting of current or former
smoking status. The misclassification of smoking status
would falsely increase the relative risk of lung cancer in
1 non-smokers related to ETS exposure. The misclassifica-
tion issue is considered in detail in the report and appro-
priate corrections have been made for misclassification.
5. Spousal smoking status could be associated with several
sources of potential confounding. For example, it is pos-
sible (although not documented by specific studies) that
the presence of a smoking spouse is associated with an in-
creased likelihood of lower socio-economic class, dietary
differences, more alcohol or other drug exposure, more
exposure to air pollution, etc. Such factors could possi-
bly increase the risk of lung cancer, and published epi-
demiologic studies have addressed these factors to varying
degrees. The potential sources of confounding based on
spousal smoking status should be discussed in the report,
with a recommendation that future studies explicitly ad-
dress these issues.
In summary, considering its various limitations as an indi-
cator of ETS exposure, spousal smoking status seems to be a reason-
able method of identifying people with greater, versus lesser, ETS
exposure. The problems in not accounting for background exposure
would, if anything, bias against finding increased risk of lung
cancer. Bias related to misclassification associated with smoking
status has been addressed and corrected for in the draft report.
There are possible confounders related to spousal smoking status,
but such confounding concerns are present in other surrogates of
exposure as well study. The importance of these confounders has
not been determined to be sufficient to alter the conclusion that
ETS increases the risk of lung cancer.*
5*1.3 United states and Poreiern studies The Committee felt that
data . from studies conducted overseas as well as in the United
States should be utilized in evaluating whether exposure to ETS
31
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f
increases risk of lung cancer. -It is appropriate.to examine the
totality of evidence from all the case-control and cohort studies,
regardless of where they were conducted. 'The Committee commented
that the text of Chapter 3 of the report seemed to overemphasize
the Japanese cohort study, but felt that this and other non-U.S.
investigations were directly relevant to establishing that ETS is
a carcinogen for lung tissue.
Given the variety of study settings and the potential for
differences in exposure to ETS between (and even within) countries,
it is not surprising that relative risks vary from study to study.
"'The higher relative risks found in some studies outside the United
States may in part be related to differing characteristics of
exposure to spousal smoking, differences in background ETS levels,
or still other variables. The Committee believes that the report
should recognize such potential differences, although adjustment
for them may.be precluded by lack of detailed ETS exposure data in
the various studies. We do not disagree with the draft report's
approach of incorporating data from around the world in estimating
the numbers of lung cancer deaths in this country due to ETS, but
believe that the estimates should be interpreted cautiously. In
this regard, we recommend that the assumptions used, and their •
accompanying uncertainties in estimating numbers of lung cancer
deaths attributable to ETS, be underscored.
5.1.4 use of Meta-Analysis Meta-analysis is an appropriate tool
to summarize the epidemiological studies investigating the risk of
ETS. However, the priority given the meta-analysis in this report
in attempting to demonstrate that ETS is causally associated with
lung cancer is not justified. Evidence on the carcinogenic effect
of active smoking, the presence of carcinogens in ETS, and pre-
dicted lung cancer risk of low dose exposure to tobacco smoke from
appropriate models, are an important part of establishing a causal
relationship. The meta-analysis could then be interpreted as
showing the available epidemiologic evidence is consistent with a
— • _ •_
small elevated risk.
Meta-analysis is a general term applied to a wide range of
techniques whose objective is to synthesize findings across related
studies. Although, there is still considerable debate over many
aspects of conducting a meta-analysis, several criteria are usually
considered, essential. These include: 1) clear-statement of the
objective: of the meta-analysisr 2} .precise, definition of ..criteria
-------
t.'*
»•
used to include (or exclude) studies; 3) critical review of studies
included in the analysis; and 4) assessment of the effect of in-
dividual studies on the analysis. Many of these points were not
adequately addressed in the meta-analysis provided in the EPA.
document.
The authors of the draft report did not provide a precise
statement of the role of the Beta-analysis. In regard to general
methodology, there, are several roles a meta-analysis might play.
Bangert-Drowns (1986) distinguishes five different types of Beta-
analyses depending on the question to be addressed. In the EPA
draft report, the consistency of the various studies is addressed,
an attempt is made to estimate overall risk, the possibility of
heterogeneity of study results is considered, and geographic
variation is discussed as a possible source of heterogeneity.
Unfortunately, it is not clear which of these issues is the primary
target of the analysis. If it was intended to address all four
issues, they were inadequately covered. In regard to consistency
of findings (which is probably the most important issue), the
findings were not presented in the most appropriate way. Estimates
with corresponding confidence intervals are the most generally
acceptable method of presentation. If the intention was to*
investigate heterogeneity, then formal tests of heterogeneity
should have been provided. If it was intended to address .the
hypothesized U.S./foreign difference, it would have been useful to
test the difference in risk between the two sub-groups of studies.
Specific criteria for including studies was not provided. The
importance of this was reinforced at the Committee.meeting when a
reanalysis was presented on a different set of studies than those
in the report. This resulted in a change in the overall risk est-
imate. Decisions as to study inclusion should be made Etiojc to
analysis, based on clearly stated criteria. It is also desirable
to evaluate the impact on conclusions of closely related, but ex-
cluded, studies.
Finally, in testing the hypothesis of an elevated relative
risk across studies, the reliance on the measure of "x-number of
studies, reject ing out of n" as the basis for the p-values seems
.somewhat arbitrary and inefficient. It would be preferable to use
the sum of the S-statistics _given in the report as a test
statistic.
33
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5.1.5 qonfouaders/Misclasaifiieatioa Important potential con-
founders of the ETS-lung cancer relationship were addressed in the
report mainly by carrying out a separate aeta-analysis of those
studies which included adjusted analyses. The variables included
in these adjusted analyses were age, education, and social class.
Comparison of unadjusted and adjusted Rrs in those studies which
present both, suggests that these variables are relatively un-
important.
There is no way to evaluate the importance of occupation,
radon e: posure, and diet as confounders of the ETS-lung cancer
relationship, or to adjust for them, since virtually none of the
studies contain information on them. However, they could be
mentioned in the text as potential confounders.
The issue of misclassification should not be restricted to
misclassification of current and ex-smokers as "never, smokers.".
It should also be mentioned that non-differential misclassification
of diagnosis (diagnoses other than lung cancer being incorrectly
classified as lung cancer; or vice versa) will cause a biasing of
the RR toward the null.
The misclassification of smoking status is differential in
that current smokers and (particularly) ex-smokers are apt to be
reported as "never smokers,n whereas the reverse is unlikely.
The adjustment for misclassification of smokers as nonsmokers
in the Report makes use of the formula used by the National Re-
search Council for prospective studies, but no rationale or explan-
ation for the formula is given in either Chapter 4 or Appendix B
(Note also that several errors have been pointed out in the form-
ulae given in Appendix B). Also, no distinction is made between
prospective and case-control studies. In the latter, in order for
bias due to misclassification of active smoking status to occur,
there has to be differential misclassification between cases and
controls.
Finally, not enough attention is given in the draft report to
possible non-differential misclassification of ETS exposure. This
is an important issue, since marriage to a smoking spouse is an
imperfect proxy for total ETS exposure. In the case of dichotomous
exposure,.such misclassification would have the effect of biasing
the RR estimate toward the null. .
34
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Other potential biases which deserve mention include recall
bias (differential reporting of exposure status by cases compared
to controls) and bias due to the use of proxy respondents.
f-
5.1.6 character 1 «at Ion of uncertainties Vis-a-vis weight of
evidence, the draft document's conclusion that exposure to ETS
sometimes leads to the development of lung cancer in humans rests
upon two main arguments: (i) the biological plausibility of such
a causal association is high, given the known effects of active
smoking and the known composition of ETS; and (2) the accumulating
epidemiolegic evidence on the relationship between exposure to ETS
and lung cancer appears to argue . for a positive effect. With
exposure levels that are usually quite low, it is not surprising
that the association is weak in many studies and in the aggregate,
although, given the size of the exposed population, societal ly
important. Because the epidemiologic evidentiary base "for drawing
conclusions ' regarding ETS's carcinogenicity consists mainly of
studies of exposure levels produced by spousal smoking, the
biological plausibility argument assumes great importance. Each
step in that argument should therefore be carefully addressed, with
the uncertainties encountered being spelled out explicitly.
The biological plausibility argument depends upon establish-
ing: (a) cigarette smoking' s known carcinogenic effects; and (b)
ETS's resemblance to mainstream tobacco smoke in terms of particle
size distribution and composition of carcinogens, co-carcinogens
and tumor promoters. ,
(a) Cigarette smoking' s known effects. The document would
benefit from a more complete presentation of the evi-
dence concerning mainstream tobacco smoke's role in
causing lung cancer. More detailed consideration of the
dose-effect relationship for inhaled tobacco smoke would
better set the stage for presenting evidence concerning
the biological plausibility that exposure to ETS has
similar, albeit lesser, health effects.
(b) ETS's r?ni?ffiMflTT70 to mainstream tobacco smoke. The age-
ing of tobacco smoke influences its uptake and deposition
in the lung and its potential carcinogenicity. Nonethe-
less, there are strong similarities in the chemical and
In vitro biological activity of ETS and mainstream to-
bacco smoke. .These. similarities .should be discussed in
35
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the context, of other complex mixtures, e.g., coke oven
emissions, and "diesel exhaust (The work of Lewtas at EPA
should be revisited for this purpose). The uncertain-
ties surrounding the evidence regarding changes in side-
stream smoke composition should be assessed and the im-
plications of such findings for the biological plausibil-
ity argument should be spelled out more thoroughly.
Epidemioloaic evidegcf on the relationship between exposure to
ETS and lung -cancer should be described more completely, with the
deficiencies of individual studies used to weight their contribu-
tions to any conclusions that- are drawn. The assumptions-and un-
certainties associated with each step of the risk assessment pro-
cess ought to be explicitly stated. .
Not all the factors that probably contribute to- the uncer-
tainties surrounding the estimates of deaths attributable to ETS
exposure are now considered. For example, it is important to
justify the use of the particular biological marker chosen to
estimate relative exposures (and, therefore, premature deaths) in
passive versus active smokers, since that choice can cause the
attributable deaths figure to vary over a twenty-fold range.'
Consequently, any estimate of the number of deaths to be expected
each year from exposure to ETS should be justified more adequately
than is now the case. A graphical presentation would clarify the
uncertainties associated with each step as well as those inherent
in the final estimate of attributable deaths.
As noted in Section 3.2, the cigarette-equivalent approach has
a great advantage in that it is based on relatively sturdy RR de-
terminations in active smokers, which can be used to 'project the
risk (in the -form of a percentage of the risk in active smokers) to
nonsmokers exposed to ETS. However, the assessment of the ciga-
rette-equivalent in non-smokers due to exposure to ETS has a con-
siderable level of uncertainty embedded in it, i.e., about an order
of magnitude. Neither cotinine nor smoke participate levels are
adequate direct indicators of carcinogenic components.
The other type of exposure assessment is based on inferences
from the epidemiologic studies. .Since spousal smoking is a very
important exposure proxy used in many studies, there is concern
about how usable this categorical classification is for quanti-
tative exposure assessments. Physical proximity, daily, length, of ,'
36
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exposure, and exposure outside the home to ETS may be quite dif-
ferent in different cultures and over decades of tiae. Misre-
porting of smoking . status in the cases in some studies also
introduces a bias. Various attempts have been made to apply
corrections for these biases.
Both the relative potency approach and the cigarette
equivalent approach share an implicit assumption that particle
phase compounds, and polynuclear aromatic hydrocarbons in par-
ticular, are tiae carcinogens of interest. However/; other-carcin-
ogens have been identified in ETS, and many of these are in the
vapor phase (refer back to Section 3.7 for a full description). To
the degree that vapor phase carcinogens have been ignored, or in-
completely collected or extracted for experiments, the potency of
ETS has been underestimated.
Another, consideration is that the relative potency in animals
is hot necessarily the same as the relative potency in humans. The
complexities of tobacco emissions complicate the cigarette equiv-
alent approach. The referent mainstream emissions should be those
of unfiltered cigarettes, upon which most of the active smoking
epidemiologic data is based. The variable ratios in sidestream to
mainstream emissions of toxins lead to differences in the .calcu-
lated cigarette equivalents to which a passive smoker is exposed.
These different emission ratios are one source of variability in
the ratio of biomarkers in smokers and nonsmokers. For example,
cotinine in nonsmokers is typically less than 1% of the level found
in smokers, while the median level of 4-aminobiphenyl hemoglobin
adducts in nonsmokers was 14% of the median in smokers. Further-
more, DNA adducts are subject to repair mechanisms, and-the rate of
repair may differ in smokers and nonsmokers* .
5.1.7 Qvfiatit«tive Rifk Assessment the Committee generally agreed
that the quantitative assessment of the risk of lung cancer due to
exposures to ETS should be based on the human epidemiology studies
and that meta-analysis was a suitable approach to combining the
data. This approach is the most direct and makes the fewest
assumptions. It should be noted that this approach is fully con-
sistent with the risk assessments that have been done for many
other carcinogens and that those assessments are generally based on
fewer studies.
37
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Given that the epidemiology studies should, be the basis of
the risk assessment, some refinements of the risk assessment are
recommended: . .
1. Criteria for Including Individual Studies in the Meta-analysis
Criteria to include or exclude individual studies from the
meta-analysis should be determined and explicitly stated (See
section 5.1.4, preceding). The effects of individual exclu-
ded studies on the quantitative risk assessment should be
evaluated and discussed. The power of the individual studies
should also be considered and discussed.
2. Adjustment for Smoker Misclassification
The rationale for the formula used to adjust.for smoker mis-
classification should be given. Appropriate distinctions
should be made in applying the misclassification formula to
the case-control and the cohort studies. Because of the mar-
~ riage aggregation factor — the greater tendency for smokers
to marry smokers — the misclassification of some smokers as
nonsmokers can artificially inflate the relative risk of lung
cancer associated with passive smoking in cohort studies. In
case control studies,, misclassification by itself is not
enough to inflate the relative risk. Differential misclassi-
fication, with cases mis-reporting more frequently than con-
trols, is needed. The assumptions used in adjusting for smo-
ker misclassification and their effect on. the adjustment
should be more fully discussed. If the approach taken is con-
servative, then it is noteworthy that the misclassification
adjustment only lowers the relative risk estimate from a lit-
tle over 1.4 to 1.3.
3. Misclassification of Exposure
Some unexposed women, classified as un-exposed (non-smokers
married to non-smokers) may in fact be exposed to relatively
high levels of ETS in the workplace or in other settings
outside of .the home. Some recent of non-smokers1 exposure to
nicotine indicate variations in exposures ranging over two
orders of magnitude. Correction for "background" exposure
does not adequately correct for this misclassification. Fur-
thermore, the use of spousal smoking habits to classify ETS
38
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exposure status is more likely to misclassify American wo-
men's exposure than Japanese women's exposure because of dif-
ferences in American and Japanese lifestyles. Non-smoking
American women married to non-smokers are more likely to be
exposed to ETS outside of the home than are Japanese women be-
cause more American women work outside the home and have
friends who smoke. Some evaluation of the effects of these
biases would be appropriate in the risk estimations.
4. Uncertainties in the Estimate of Annual Lung Cancer Deaths.Due
to Passive Smoking
{
The uncertainty in the relative risk estimate of lung cancer
due to passive smoking is based only on statistical consider-
ations. There are other uncertainties that influence this
estimate. A more critical analysis of the potential for
systematic bias should be done. Acknowledging such uncertain-
ties would provide greater balance to the report, while not
substantially altering its overall message.
5. Dose-Response Estimation of Risk
There are many more assumptions and uncertainties in any risk
estimation made on the basis of dose-response or dosimetry
than for epidemiologic data. Nonetheless, such an estimate
may be of value if the assumptions are fully stated and the
uncertainties in the estimate are quantitatively estimated.
with uncertainty estimates explicitly included, this approach
may well be consistent with that based on epidemiology. Ex-
posure estimates for ETS should include the exposures from
birth to age 15, not only from age 15 on up as* is done for
mainstream smoking. This can have a substantial impact on
the estimated risk. Complex dosimetry models should be con-
sidered the subject of research at this point in time, since
they require many more assumptions.
6. Dose-Response Model for ETS-Radon Interaction Effects
Development of a specific dose-response model for ETS-radon
interactions is not recommended. The interactions of ETS with
radon are numerous and involve both physical and biological
interactions which are not fully understood at present. Fur-
s'9
-------
J»
thermore, there are no relevant epideaiological data^ concern-
ing such interactions. "• ]
^t
S.I.7 ggM v»« Workplace Expoaujf The Committee recognizes that
there is little epideniologic literature on the health effects of
ETS.in the workplace, and its importance in relation to total ETS
exposure. However, the report should teviev and comment on the
data that do exist, if only to bring out the need for future re-
search in this area. The report should also review and comment on
the data that exists on exposure to ETS in public places.
N '
The Committee also recommends that EPA staff discuss possible
approaches for estimating the exposure of children to ETS in homes
with one or more smoking parents. This is recommended because of
the potentially large public health Impact of respiratory disorders
in children that may be caused by exposure to ETS.- Careful
consideration should be given to the differences in the exposure
parameters required for lung cancer as opposed to respiratory
disorder assessments. For example, cancer assessment may require
integrating exposures over longer time intervals than does the
assessment of respiratory disorders. Besides developing approaches .
for estimating average child population exposures, it is also
important to establish the shape of the exposure distribution,
particularly the tail of the distribution, in order to determine
whether a numerically significant subset of children is at high
risk.
5.2 Respiratory Disorders in Children
Chapter 5 on respiratory disorders in children was a com-
mendable first effort for a very difficult task. Nevertheless, we
found that it could be substantively improved and that the conclu-
sions drawn could be made much stronger if the chapter is revised
in the manner suggested in Section 3.3.
The Committee found the evidence for respiratory health
effects in children to be stronger and more persuasive than stated
in Chapter 5 of the draft ETS Risk Assessment document, and rec-
ommends that the new draft contain a chapter devoted to quanti-
tative risk assessment, in terms of the number of children at risk
for various outcomes. It would be analogous to Chapter 4, which
deals only with the evidence for lung cancer risk discussed in
Chapter 3. The risks are different, but it is possible that the
40
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impact of ETS on respiratory health in .children nay have much
greater public health significance than the impacts of ETS on lung
cancer in nonsmokers. . .
There will need to be new material in the earlier chapters on
lung dosimetry and the physical and chemical factors affecting it.
The difference in deposition and retention of ETS components be-
tween children and adults need to be recognized and considered in
a risk assessment.
5.2.1 Weight of Evidence The scope of Chapter 5 is limited to
selected studies published subsequent to the 1986 Surgeon General's
Report and the National Research Council Report. Neither of these
reports judged the associations of ETS exposure and children with
adverse respiratory effects to be causal; alternative explanations
for the associations including confounding and information bias
could not be-excluded., The additional literature available since
1986 provides a basis for increased concern. Thus, the Committee
urges a thorough review of the entire body of evidence. A consid-
ered judgment cannot be made concerning causality without assessing
the totality of the evidence including studies reviewed in the two
1986 reports and those published subsequently.
. In reviewing the weight of the evidence, the present Chapter
5 does not establish an appropriate framework for considering the
data. The alternative explanations for association of ETS exposure
with adverse respiratory effects need to be clearly listed
(causality, confounding, information bias) and the individual
studies reviewed for the approaches used to address confounding and
information bias. The weight of the evidence could then be judged
to determine the causality of associations.
With regard to including the reviews of the 26 new reports as
Appendix E, the scope of the review should be expanded to include
all studies not in the 1986 Surgeon General's Report. A more com-
prehensive search is needed since the 26 publications identified by
the chapter's authors do not represent all significant publications
on the effects of ETS on children published since 1986.
5.2.2 confounders A number of confounders were mentioned by the
report,- but addressed improperly.. These include In U&fi£& exposure,
41
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parental reporting baas, and active smoking. The Committee con-
siders the following factors to be critical: -.•.•?
Unreported Smoking Other Exposures (outdoor)
Other Indoor Pollutants Parental Symptoms
Biological Precursors Socio-Economic Factors
& Medical Characteristics Other Sources of Reporting Bias
Exposure to Biological (includes Annoyance Responses) „, ,
Agents _ *
One must stress the biological precursors important to the
effects of ETS in childhood. These include genetic predisposition
(physiological, immunologicar and biochemical); j,n, utero exposure,
and breast feeding. These also include environmentally-induced
atopy and residua of infections. Pre-existing medical conditions,
such as cystic fibrosis, congenital defects will also affect
responses to ETS. -...'.
The socio-economic and behavioral factors are important as
they relate to nutrition (re: resistance), familial crowding, and
other contacts (especially day care), medical attitudes and medical
care, etc. Socio-economic status (SES) and day care have been
care, etc.
shown to modify the effects of ETS.
, T.
Reporting bias is a critical issue for ascertaining exposure,
as has been documented by many previously. There are two major
components to this, the positive bias and the negative bias. The
first is thought to occur associated with parental conditions
(e.g., Col ley, 1974; Cederlof and Colley, 1974). The second is
thought to occur because the respondent becomes annoyed by ETS
(e.g., Weber 1984; Hugod 19 84; NCHS 1976; NIOSH 1971), and/or have
anger/ aggression reactions (e.g., Jones and Bogat 197B) .
Effects of active/ self -smoking interacting with passive
smoking should be discussed (Bland et al. 19 78; Lebowitz et al.
1987 and 1988)
Other exposures which have similar effects (e.g., wood smoke,
other particulate matter, N02, formaldehyde) may be confounding the
effects of ETS (Hammer et al. 1976; Anderson 1979; Speizer et al.
1980 (with update); Comstock et .al. 1981; Helia et al. 1982; and
Koo et al. 1988 ),, or may interact with ETS in producing effects
(Lebowitz et al. 1990, and in press). Of course, individuals
42
-------
including children may have%multiple micro-environments in which
they are exposed, so insufficient information would tend to yield
incorrect exposure-response curves. -
Thus, there are many possible co-variates and confounders
which should still be considered (Lebowitz 1990).
5.2.3 Use of Meta-Analysis The staff should give serious con-
sideration to meta-analysis of those studies of sufficiently sim-
ilar design to warrant it. However, it was not clear that there is
a body of suitable studies for such an analysis. If one is war-
ranted, it should be guided, to the extent possible, by the same
considerations outlined in Section 5.1.4.
.
43
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6.0 SUMMARY XNP CONCLUSIONS
In conducting its review of the ETS Risk Assessment document
and Policy Guide, the Committee found them to be good faith efforts
to address complex and difficult issues affecting public health.
The authors attempted to select and interpret the most relevant
information from an enormous and diverse scientific data base, most
of which was not designed or intended to yield the information
needed for this task, since the task is extremely difficult, it
should come as no surprise that the Committee also found the
.documents to. be incomplete in many respects. The situation is
analogous to that for the Criteria Air' Pollutants, where it has
been necessary to prepare and review two or more draft documents
prior to their endorsement by the Clean Air Scientific Advisory
Committee (CASAC). This Committee has suggested both organiza-
tional and specific technical changes and additional analyses that,
if followed;-can result in improved ETS Risk Assessment and Policy
Guide documents, and stands ready to provide further review
comments on the revised drafts.
The SAB was asked to address the following issues in reviewing
the documents:
A. Luna Cancer in Adults . The Committee noted that Chapters 3 and
4 addressed only the issue of lung cancer risk for non-smoking
women due to spousal smoking. The revised document should be
expanded to include the full range of cancer impacts of ETS. The
Committee also noted a number of areas where substantial improve-
ments could be made organizationally, and in terms of content of
material that was not adequately covered or not covered at all, and
urge the EPA staff to redraft those chapters as well. Comments on
specific issues within the broader context of lung cancer follow
below.
1. Careiaooenicitv of BTfl The Committee concurs with the
judgement of EPA that Environmental Tobacco Smoke should be
classified as a Class A Carcinogen. The Committee had some
difficulty with the use of the Guidelines for carcinogen Risk
Assessment as they are currently formulated (51 FR 33992 August 22,
1986) .
The strongest evidence for the carcinogenicity of tobacco
smoke is that obtained in a large number of epidemiclogic studies
44
-------
of smoking and lung cancer. The causality of the connection
between direct inhalation of tobacco smoke and excess risk of lung
cancer cannot be in doubt. It has been demonstrated that cessation
of inhalation of tobacco smoke leads to a reduction of the excess
lung cancer risk. The risk has been shown to be proportional to
the amount' of smoke inhaled. In terms of overall impact it has
been shown that a very high proportion of the current lung cancer
incidence is due to inhalation of tobacco smoke. The ageing of
sidestream tobacco smoke influences its uptake and deposition in
the lung and. its potential carcinogenicity, but there are strong
similarities in the chemical and In vitro biological activity of
ETS and mainstream tobacco smoke, and ETS resembles mainstream
tobacco smoke in terms of particle size distribution and compo-
sition of carcinogens, co-carcinogens and tumor promoters.
The inhalation of ETS by children, by non-smokers or
former smokers represents a risk that is much smaller than that
experienced by.smokers, but it is an involuntary exposure. It is
not uncommon to derive quantitative risk assessments of exposures
to carcinogens from data obtained in more heavily exposed occu-
pational populations, and in that sense smokers represent a more
heavily exposed population which can be used for extrapolation to
the lower exposures imposed on children and non-smokers.
2. Spousal Smoking All of the studies cited in the report1 on
ETS and risk of lung cancer have made observations on married women
who have been classified as "never-smoking." Those married to a
smoker are assumed to be exposed to greater levels of ETS than
those married to a nonsmoker. As noted in the report, this rel-
ative risk comparison.is implicitly a comparison of women exposed
to both spousal and other ETS to those exposed to other ETS only.
Spousal smoking is believed to be a useful maker for total ETS
exposure because (1) it often indicates many years of exposure:
this contrasts with biological markers such as urinary cotinine,
which indicate exposure at only one point in time; (2) the level of
ETS exposure in the home when the spouse smokes appears to be of
substantially greater magnitude than the background exposure.
There are potential limitations in the use of spousal smoking
as an indicator of ETS exposure, that need to be .considered:
45
-------
*. f^f A relatively small pro-
Spousal smoking may account for a
portion of lifetime ETS exposure.
hood,
risk in an adult.
The use of spousal smoking as an indicator of exposure may
amplify the risk of misclassification of smokers as non-
4.
smokers.
5.
Spousal smoking status could be associated .with several
sources of confounding, e.g., lower socio-economic class,
diet, alcohol, drugs, more exposure to air pollution, etc.,
factors that could possibly increase lung cancer risk.
Despite various limitations as an indicator of ETS exposure,
spousal smoking status is a reasonable method of identifying people.
with greater, versus lesser, ETS exposure.
3. ?ni,ted states and Foreign Studies The Committee felt that
data from studies conducted overseas as well as in the United
States should be utilized in evaluating whether exposure to ETS
increases risk of lung cancer. It is appropriate to examine the
totality of evidence from all the case-control and cohort studies,
regardless of where they were conducted.
4. Pse of Meta-xnalysis Meta-analysis is an appropriate
tool to summarize the epidemiological studies investigating the
risk of ETS. However, the priority given the meta-analysis in this
report in attempting to demonstrate that ETS is causally associated
with lung cancer is not justified. Evidence on the carcinogenic
effect of active smoking, the presence of carcinogens in ETS, and
predicted lung cancer risk of low dose exposure to tobacco smoke
from appropriate models are an important part of establishing a
causal relationship. The meta-analysis could then be interpreted
as showing the available, epidemiologic evidence is consistent with
--<• » _i«,1r
a small elevated risk.
46
-------
*'• Confounders/Hiselassif ieation Important potential con-
founders of the ETS-lung cancer relationship were addressed in the
Report mainly by carrying out a separate Beta-analysis of those
studies which included adjusted analyses. The main confounders
included in these adjusted analyses were: age, education, and
social class. Comparison of unadjusted and adjusted RRs in those
studies which present both, suggests that these variables are not
important confounders.
As for other potential confounders of _ the ETS-lung cancer
relationship, 'including occupation, radon exposure, and diet, there
is no way to evaluate their importance as confounders or to adjust
for them, since virtually none of the studies contains information
on them. However, they could be mentioned in the text as potential
confounders.
The issue of misclassification should not be restricted to
misclassif ieation of current and ex-smokers as "never smokers."
It should also be mentioned that misclassification of diagnosis
(diagnoses other than lung cancer being incorrectly classified as
lung cancer; or vice versa) will cause a biasing of the RR toward
the null.
Not enough attention was given to possible non-differential
misclassification of ETS exposure. This is an important issue,
since marriage to a smoking spouse is an imperfect proxy for total
ETS exposure. In the case of dichotomous exposure, such misclas-
sification would have the effect of biasing the RR estimate toward
the null. Other potential biases which deserve mention include
recall bias (differential, reporting of exposure status by cases
compared to controls) and bias due to the use of proxy respondents.
of Uncertainties The draft risk as-
sessment document's findings on the ETS/ adult lung cancer relation-
ship is based on two main arguments: .(1) biological plausibility;
and (2) epideniologic evidence. with exposure levels that are
usually quite low, it is not surprising that the association is
likely to be weak although, given the size of the exposed pop-
ulation, societally important. Because the epidemiologic eviden-
tiary base for drawing conclusions regarding ETS's carcinogenicity
consists mainly of studies of exposure levels produced by spousal
smoking, the biological plausibility argument assumes great impor-
47
-------
tance. Each step in that argument should therefore be carefully
addressed, with the uncertainties encountered being spelled out
explicitly.
7. QyfMfciNative Risk Assessment The Committee generally
agreed that the quantitative assessment of the risk of lung cancer
due to exposures to ETS should be based on the human epidemiology
studies and that meta-analysis was a suitable approach to combining
the data. It is direct and makes few assumptions. It should be
noted that this approach is fully consistent with the risk assess-
ments that have been done for many other carcinogens and that those
assessments are generally based on fewer studies. '
Given that the epidemiology studies should be the basis of
the risk assessment, some refinements of the risk assessment are
recommended with respect to:
1. Criteria for Including Individual Studies in the Meta-
analysis
2. Adjustment for Smoker Misclassification
3. Misclassification of Exposure •
4. Uncertainties in the Estimate of Annual Lung Cancer Deaths
Due to Passive Smoking
5. Dose-Response Estimation of Risk
8* froae vs. Workplace Exposure The Committee recognizes that
there is little epidemiologic literature on the health effects of
ETS in the workplace. However, the report should review and
comment on the data that do exist.
B. Respiratory Disorders in Children Chapter 5 on respiratory
disorders in children was a commendable first effort for a very
difficult task. Nevertheless, we found that it could be substan-
tially improved and that the conclusions drawn in it could be made
much stronger if the chapter was revised in the manner suggested in
this report.
The Committee found the evidence for respiratory health ef-
fects in children to be stronger and more persuasive than that
stated in Chapter 5 of the draft ETS Risk Assessment document, and
48
-------
recommends that the new draft contain a chapter devoted to quanti-
tative risk assessment. It would be analogous to Chapter 4, which
deals only vith the evidence for lung cancer risk discussed in
Chapter 3. The risks are different, but it is possible that the
impact of ETS on respiratory health in children may have much
greater public health significance than the impact of ETS on lung
cancer in nonsmokers.
The earlier chapters on lung dosimetry and the physical and
chemical factors affecting it should incorporate new material. The
difference in deposition and retention of ETS components between
children and adults need to be established and considered in a risk
assessment.
Comments om specific issues follow:
1. Weight of Evidence The scope of Chapter 5 is limited to
selected studies published subsequent to the 1986 Surgeon Gen-.
eral's Report and the National Research Council Report. The addi-
tional literature available since 1986 provides a basis for in-
creased concern. Thus, the Committee urges a thorough review of
the entire body of evidence. Judgment cannot be made concerning
causality without assessing the totality of the evidence including
studies reviewed in the two 1986 reports and those published
subsequently.
In reviewing the weight of the evidence, the present. Chapter
5 does not establish an appropriate framework for considering the
data. The alternative explanations for association of ETS exposure
with adverse respiratory effects need to be clearly listed (causal-
ity, confounding, information bias) and the individual studies re-
viewed for the approaches used to address confounding and informa-
tion bias. The weight of the evidence could then be judged to de-
termine the causality of associations.
2. Cenfouadera A number of confounders were mentioned by the
report, but addressed improperly, such as in ji£a£2 exposure, par-
ental reporting bias, and active smoking.
The biological precursors important to the effects of ETS in
childhood include genetic predisposition (physiological, immuno-
logical and biochemical), In utero exposure, and breast feeding.
These also include environmentally-induced atopy and residua of
••-'•' 49
-------
infections. Pre-existing medical . conditions, such as cystic
fibrosis, congenital defects will also affect responses to ETS.
The socio-economic and behavioral factors are important as
they relate to nutrition (re: resistance), familial crowding and
other contacts (especially day care), medical attitudes and medical
care, etc. SES and day care have been shown to modify effects of
ETS.
3. Use of Meta-Analysis The staff should give serious con-
sideration to meta-analysis of those studies of sufficiently sim-
ilar design to warrant it. However, it was not clear that there
was a body of suitable studies for such an analysis. Zf one is
warranted, it should be guided, to the extent possible, by the same
considerations outlined for meta-analysis for lung cancer.
50
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7.0 REFEREKq^a CITED .
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x
Anderson H.R. "Respiratory Abnormalities, Smoking Habits, and
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135 • •
Banqert-Drowns Psvchol Bull 19flfir pa. 388-399}
Bland M., Bewley B.R., Pollard V., and Banks M.H. "Effects of
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Burrows B., and Martinez P.O. "Bronchial Responsiveness, Atopy,
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Dahms T.E., Bolin M.D., and Slavin R.6. "Passive Smoking: Effects
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Hammer D.I., Miller F.J., Stead A.G., and Hayes C.G. "Air Pollution
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.Hammond, S.K., Gann, P.H., Coghlin, J., Tannenbaum, S.R., Skipper,
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Conference on Indoor Air Quality and Climate Toronto, Ontario,
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Hammond, S. Katharine. The Uses of Markers to Measure Exposures to
Complex Mixture, in, Exposure Assessment for Epidemiology and,
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Hammond, S. K., Lewtas, J., Mumford, J. and Henderson, F.W.
Exposures to environmental tobacco smoke in homes. Measurement of
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the Air and Waste Manangement Association, Pittsburgh, PA pp.
590-595, 1989.
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Helms, R.W., Forehand, L., Mumford, J., Lewtas, J., Haley, N.J.,
and Hammond, S.K. Home air nicotine levels and urinary cotinine
excretion in young children. Am Rev Respir Pis. 140: 197-201,
1989.
Henderson, R.W., Reid, H.F., Morris, R., Wang, Ou-Li, Hu, P.C.,
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