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3.«   ftppaadix.. C-~pos_iina£ry  ojCLJBTg  The Committee agreed with EPA
staff that Appendix C should be deleted.,in its present form.  Soae
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 now 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 janerlch 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 BUBDENS FOR THE LUHG, "
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-bronchial  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.11   However, the calculated half-times  (Ct 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 traeheobronchial  clearance in humans, and one study by
Wanner et al,  (1973)  on the  effects of chronic smoke  escposure 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 traeheobronehial tree.  It is curious to note that
 the C2  value calculated for the second "fast-phase" component in
 smokers is  1400 rain (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 O—*M tentative Approaches., for Estimating the Yearly.

 poa«-R«apoase  Modf^j.ng  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 carcinogenic ity 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 ITS  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]-pvrene 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 ait 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 epidemic!ogic 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 sane 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 be discussed
 rather than relying solely  on bioraarkers,  where the exposures are
 not  known.   A few caveats  are required regarding the  use of DNA
 adducts  to estimate  dose.   DNA  adducts  are  subject to repair
mechanism*,  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  adducta  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 benzofajpyrene (BaP)
 DNA  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
 epidemiolofic 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 £> might be  useful in
 estimating the  importance of  ETS  in  respiratory  diseases  in
 children.  Appendix D has information which is supportive of the
 pain  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.
3,1   i^jinaiaL_l-*gtptgarf  Pe3g£i|>tlQpT9 o< : ^fveaty-si*.. studies _OB
Environ»«ntal Tobacco Smofce ana Respiratory Disorders in Children
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  Rgyiltt	pJMfgjJL.EQErCY GtflDE         •       -  '

     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 a$f«*d to
examine whether  the Guide's statements on, health contained within
the  first 20 pages vere 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 EfS
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 the 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
          Caacsr ia_jk
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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 nonsmoker  (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)i (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  nonsaoker
 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;

     l.  Spousal smoking may account for a relatively  small propor-
        tion of lifetime  ETS exposure.  Janerich et al. (3,990) 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 nore general  indication of ETS exposure than

                                29
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      expected on the basis  of  exposure  in the home eer.  se, but
      sensitivifi*y%or total ETS.: .eaqapsure may vary,,.among different
      study populations.

 2.   The results of' comparing  ETS  household  exposure  to ETS
      household plus other exposures may vary in different coins-
      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 newsmakers within the home.
      Non-domestic background exposure varies with the nature of
      their workplace exposures, the extent of sacking 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»,
      19S9).  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 "exposed11 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 guantitating 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  sacking 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
         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 gtatas 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

                                31
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 increases  risk of lung cancer,   -i-t is appropriate to examine the
 totality of evidence from all the case-control and cohort studies,
 regardless of  where they were conducted.  "The Committee coatnented
 that the text  of Chapter'3 of the report seemed to overemphasize
 the  Japanese cohort  study,  but felt that this and'other non-tJ.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.

 S.I,4  Os« of Kata-Anslv3ia  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 ITS 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-analysis; 2} precise definition of criteria

                               32
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                                          * '
 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 meta-analysis.  In regard to general
 methodology, there  are several  roles a  meta-analysis might play.
 Bangert-Drowns  (1§86) distinguishes five different types of meta-
 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 pj^ior 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-mimber of
studies rejecting out  of n11  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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' S.I, 5   <3onf minders/MJacl as a i f ieat lea   Important potential  con-
 founders of the ETS-lung  cancer'relationship were.addressed in the
 report mainly by  carrying  out a separate meta-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 exposure, and  diet as confounders of  the ETS-lunf  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 eonfounders.

   ' •  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 SR 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,11  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.

5.1.6   Characterization  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:  (l) 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
epidemiologlc evidence on the relationship between exposure to ETS
and  lung  cancer appears  to argue  for a  positive effect.   With
exposure levels that are  usually guite 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,  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  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 smokingfs 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 resemblance  to mainstreamtobacco snoke.  The age-
          ing of tobacco snoke 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 content, of o-Cher complex  mixtures,  e.g.,  coke oven
           emissions,'  and "diesel".;exhaust  (The vork^of.Levtas'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.

      Epidemioloqi,c_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.

    .  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 ITS should be  justified  more adequately
 than is now the ease.  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 SR 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 particulate 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  tine.   Misre-
 po'rting  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 the 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 not 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 imfiltered  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 Quaatitativf Ria* 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 aany
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-snokers
     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  fron   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-
                               39
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      thermore, there are no relevant epidemiological  data concern-
      ing such  interactions.    '•"'•••;•:•    .   •    •..  ,

 5.1,7  Hon« va . WorXplacg  Exposure  The Committee recognizes that
 there is little epidemiologic  literature on the health effects of
 ETS  in the workplace, and  its  importance in relation to total ETS
 exposure.   However, the report should review  and  coaanent 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.

      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
     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 ITS  on respiratory health  in .children may  have much
 greater public health significance than the impacts of ETS on lung
 cancer  in  nonsmofcers.

     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 I, 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 19S6.

 5.2.2   Confonndera  h number of confounders were mentioned by the
 report,  but addressed improperly.  These include in uterg exposure,
                                41
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 parental  reporting  bias,  and active 'smoking.
 siders  the  following  factors to fee. critical:
            The Committee con-
 Unreported Smoking
 Other  Indoor Pollutants
 Biological Precursors
  & Medical Characteristics
 Exposure to Biological
  Agents
Other Exposures (outdoor)
Parental Symptoms
Socio-Economic" Factors
Other Sources of Reporting Bias
(includes Annoyance Responses)
     One  must stress the biological precursors  important to the
effects of ETS in childhood.   These  include genetic predisposition
(physiological, immunological and biochemical), jji 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  (res resistance), familial crowding, and
other contacts (especially day care)» medical attitudes and medical
care, etc.   Socio-economic  status  (SES)  and day care  have been
shown to modify the effects of ETS.

     .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., Galley, 1974;  Cederlof and Colley, 1974).   The  second is
thought to  occur because the  respondent becomes annoyed by £TS
(e.g., Weber 1984;  Hugod  19 84? NCHS 1976j  NIOSH 1971), and/or have
anger/ aggress ion reactions (e.g., Jones and Bogat 3.97B).

     Effects  of  active/self-smoking  interacting  with  passive
smoking should be  discussed  (Bland  et  al,  19 78j Lebowitz et al.
1987 and 1988)

     Other exposures which have similar effects  (e.g., wood smoke,
other particulate matter, NQ2, formaldehyde)  may be confounding the
effects of ETS (Hammer et al. 1976; Anderson 1979,* Speizer et al.
1980 (with update),*  ComstocK et  al.  1981?  Melia 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
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Including children may  have^ ifultiple micro-environaents in which
they are exposed, so insufficient information would tend to yield
incorrect exposure-response curves.

     Thus,  there  are many  possible eo-variates  and confounders
which should still be considered (Lebowitz 1990),

5,2.3  tJt>»  of  Mata-Analyais  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  SOMMARY ANP CONCMTSIONa

      In conducting its review of  the ETS  Risk Assessment
 and policy Guide, the Coiwnittee 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 tooth  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}
                in AdttlM  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 UTS.  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,   Carcinoganieitv  of ETS  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 epidemiologic studies

                                44.
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 of  sucking 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  careinogenicity,  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 smoke'rs  represents  a risk that is much  snailer 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.  apouaal Smoking-  All of the  studies cited in the report 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
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    l.    Spousal sraoking may account for a   relatively small  pro-
         portion 'of lifetime ETS  exposure.

    2,   The difference in ETS exposure comparing household exposure
         versus  household plus background  exposure  may differ in
         different countries and  different  regions within the U.S.

    3,    A major source of  ETS  exposure  is  that  incurred in child-
         hood/   which  could contribute to  increased lung cancer
         risk in an adult.

    4.   The use  of spousal smoking as an indicator of exposure may
         amplify the risk of misclassificmtion  of smokers as non-
         smokers.  p                                   '

   '• 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  ITS  exposure,
spousal smoking status is a reasonable method of  identifying people
with greater, versus lesser, ETS exposure.
     3.  q^|^«C8jkat_«araj^^^                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.   Pa» of Mota-xnalyais   Meta-analysis is an appropriate
tool to summarize  the epidemiological  studies investigating the
risk of ETS.   However, the priority given the me-ta-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 BTS, 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
a small elevated risk.
                                46
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     5.   CoBjfounders/Miaclassifigatign   Important potential con-
founders of the ETs-lung cancer relationship were  addressed in the
Report  mainly  by carrying out  a  separate  meta-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 eonfounders.

      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 misselassification should not be restricted to
misclassification of current  and  ex-smokers as "never smokers."
It should also  be mentioned that miselassification of diagnosis
(diagnoses other than lung cancer being incorrectly classified as
lung cancer; or vice versa) will cause a biasing of the RJR toward
the null.

     Not enough  attention  was given to  possible non~differential
miselassification of ETS  exposure.   TMs 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 miselas-
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,

     **  Charactarj^atiort of Pqcertainti«»   The  draft risJc  as-
sessment document's findings on the ETS/adult lung  cancer relation-
ship is based, on two main arguments;  (1) biological plausibility;
and  (2) eDidemioJ.ocrlg: 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 "a carcinogenicity
consists mainly of studies of exposure levels  produced by spousal
smoking, the biological plausibility argument  assumes great impor-
                                47
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 tance.   Each  step in that argument should therefore be carefully
 addressed,  with -the uncertainties encountered  bejlng  spelled out
 explicitly.

     7 *   Quantitative Rislc  Agaaaaajent   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*  Hon« va. Workplace Exposure  The Committee recognizes that
there is little epidemiclogic literature on the health effects of
ITS  in the workplace.    However,  the  report  should  review  and
comment on the data that do exist.

B.   Respiratory  Dioordarg 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 ITS 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  with 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 nonsjaokers.

      The earlier chapters on lung dosiwetry 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.   might of Hvidenca   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.  C.pqfounders  A  number of confounders were mentioned by  the
 report, but  addressed improperly,  such as j,u utero exposure, par-
 ental  reporting  bias, and active smoking.

     The biological precursors important to the effects of ETS  in
childhood  include  genetic predisposition (physiological,  iurauno-
 loglcal and  biochemical),  in  utero  exposure, and breast  feeding.
These  also include environmentally-induced atopy and  residua  of

                    •' '  - "•       49
-------
infections.    Pre-existing  aedical . 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.  Og« _of Kata-Analysia  The staff should five 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.   If 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   REg_BRS»CES  CUSP

 American Lung Association. "Maternal Smoking and Health Effects on
 Fetus an
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 Hammer D.I., Miller F.J., Stead A.G., and Hayes C.G. "Air Pollution
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