Philip Morris
'health Effects of Passive Smoking: Assessment of Lung Cancer in Adults and Respiratory Disorders in Children' Notes on the Meeting of the US Environmental Protection Agency (Epa) Science Advisory Board (Sab) to Consider the External Review Draft Held at Crystal City, Washington Dc on 901204 and 901205
Fields
- Author
- Lee, P.N.
- Area
- LEGAL DEPT/EEMA ARCHIVE
- Document File
- 2501073421/2501073557/Ets General 900000 - 910000 Eema Legal Dpt.
- Type
- REPT, REPORT, OTHER
- Named Organization
- Americans for Nonsmokers Rights
- American Cancer Society
- Centers for Disease Control
- Ciar, Center for Indoor Air Research
- Coalition on Smoking or Health
- Doctors Ought to Care
- Epa Board
- Epa, Environmental Protection Agency
- Harvard
- Hri, Health Research Inst,Roswell Park
- Iarc
- Nrc
- RJR, R.J.Reynolds
- Science Advisory Board
- TI, Tobacco Inst
- Washington Post
- Women Vs Smoking Network
- 1990 World Smoking + Health Conference
- American Cancer Society
- Site
- E35
- Named Person
- Aviado
- Axelrad
- Bayard, S.
- Benowitz
- Blot
- Brown, K.
- Burns, D.
- Butler, W.J.
- Clayton
- Crawfordbrown, D.
- Cummings
- Curvall
- Davis, D.L.
- Debethizy
- Dockery
- Doll
- Farland, W.H.
- Flaak, R.
- Flamm
- Fleiss, J.L.
- Garfinkel
- Gibbons, J.D.
- Giovani
- Glantz, S.A.
- Gori, G.
- Gross, A.J.
- Haley, N.
- Hammond
- Hiller
- Hirayama
- Hoffmann
- Hood
- Houston
- Howard, G.
- Huber, G.L.
- Humble, C.
- Idle
- Janerich
- Kabat, G.
- Katzenstein, A.W.
- Kilpatrick, S.J.
- Knudson
- Koppikar, A.
- Laties
- Layard, M.
- Lee, P.N.
- Levois, M.
- Lewtas, J.
- Lippmann
- Lopez
- Lowrey
- Makosky
- Mantel, N.
- Moolgavkar
- Okeeffe
- Parrish
- Peto
- Pettiti
- Poland, T.M.
- Reasor
- Repace
- Ritchie
- Robertson
- Rockette
- Rosenbaum, W.L.
- Sanet
- Schneider, B.
- Shimizu
- Sobue
- Springall, A.
- Sterling, T.D.
- Stewart
- Surgeon General
- Switzer, P.
- Thorslund, T.
- Trichopoulos
- Tweedie, R.
- Uberla, K.
- Varela
- Wald
- Weinkam, J.J.
- Wells, A.J.
- Will
- Williams
- Witorsch, P.
- Witorsch, R.
- Wu
- Wynder, E.
- Axelrad
- Attachment
- 2501073503/2501073556
- Master ID
- 2501073503/3556
Related Documents:- 2501073503
- 2501073529 U.S. Environmental Protection Agency Science Advisory Board Indoor Air Quality and Total Human Exposure Committee (Iaqthec) Environmental Tobacco Smoke Review
- 2501073530-3532 U.S. Environmental Protection Agency Science Advisory Board Indoor Air Quality and Total Human Exposure Committee Environmental Tobacco Smoke Review Final Draft Agenda
- 2501073533-3535 Science Advisory Board Review of the Draft Report 'health Effects of Passive Smoking: Assessment of Lung Cancer in Adults and Respiratory Disorders in Children.' Epa/600/6-90/006a
- 2501073536-3555 Draft Talk to Epa Sab
- 2501073556 Passive Smoke A Cause of Cancer, Panel Concludes Epa Told Risk of Respiratory Illness in Children Also Increased by Involuntary Exposure
- Litigation
- Stmn/Produced
- Date Loaded
- 31 Jan 1999
- UCSF Legacy ID
- xhi33e00
Document Images
Hiller's talk was aimed at clarifying confusion on estimates of
relative exposure in ETS exposed non-smokers and active smokers, but
was in fact rather unclear, partly because he never discussed
average exposure. He did, however, refer to his well known work
demonstrating that pulmonary retention of particles from ETS is
substantially less than that from mainstream smoke.
O'Keeffe, who represented Americans for Non-Smokers Rights,
added nothing to the science. Apart from encouraging the EPA to act
rapidly, she noted that grapes from Chile had been banned because
they contained 3 pg of hydrogen cyanide, which contrasted with 100
~Lg for ETS. (There seemed to be a problem with units here!)
Pettiti, an epidemiologist from California, discussed some
issues related to metaanalysis. She noted that exclusion of the
Varela study did not affect the conclusion regarding the statistical
significance of the overall meta-analysis relative risk. She also
noted that the study relative risks did not show statistically
significant evidence of heterogeneity. She did not, however,
mention the fact that global tests of heterogeneity are very weak in
power, and that in fact there was clear evidence that US studies
gave much lower relative risk estimates than Asian studies.
Houston, of "Doctors ought to Care", pointed to industry
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bringing in epidemiologists who claim epidemiology does not mean
anything. He cited the (totally bogus) consistency of the various
estimates of risk of lung cancer from ETS claimed by Repace and
Lowrey in their recent risk assessment.
Giovani, talking on behalf of the CDC (Centers for Disease
Control), said the draft report was excellent, comprehensive and
objective. This view, though patently absurd, is quite important,
as CDC have a reputation as being a strong base for good
epidemiology.
Makosky, of "Women vs Smoking Network",
the debate.
added nothing new to
Lowrey, Repace's well-known colleague, discussed briefly some
of the well-known claims of the two of them, since Repace, who was
at the meeting, being a member of EPA, could not talk. He
emphasised the point that they felt the evidence showed that
workplace exposure of women in the US, but not of women in Japan,
was higher than that at home. This increased background exposure in
the US studies explained why Hirayama found a larger relative risk
for spouse smoking than in Japan.
2501073515
The final speaker was Judson Wells (neither Stewart nor
Hoffmann on the list attended). He discussed misclassification of
active smokers as never smokers. He was strongly critical of much
of my work, as he had been at Perth in the 1990 World Smoking and
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Health Conference, despite the fact that I had essentially answered
all his relevant criticisms in the work submitted to EPA. It was
notable that he presented estimates of the effect of
misclassification, study by study, that were substantially lower
than those he provided in his written submission (which I have
already commented on in detail). I will comment on his new material
at length separately, but for the moment it was clear that
(i) even he was coming up with estimates of bias in US studies that
were similar in magnitude to the relative risks observed, and
(ii) that he had no good data on misclassification in Asian
populations.
i. Comments of the SAB
The procedure was to go through the various sections of the
draft report, starting with detailed (clearly prepared) comments by
the members of the SAB best qualified to discuss particular areas,
and then to have comments from anyone else on the SAB that wanted to
comment. At intervals, the conclusions would be summarised for the
benefit of the EPA staff members, and on occasion Dr.Bayard asked
questions to clarify what the committee ment and he also at times
explained why EPA had taken the course they did. I do not intend to
go through all the points made in detail. Rather, in the rest of
this section I summarize general impressions and conclusions,
leaving discussion of some of the scientific points to the net
section. 2501073516
A number of general points came over very clearly. On the one
hand, it was evident that the SAB found
the document highly
unsatisfactory for numerous reasons and that it wanted to see it
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considerably rewritten - there seemed no likelihood of an approved
version appearing inside the next 6 months. On the other hand, it
was also evident that a document revised along the lines they
envisaged would be perhaps more damaging to the industry than the
current draft. Although it seemed quite likely that the 3800 deaths
per year from lung cancer may change substantially - in particular,
it may be given a much larger aura of uncertainty - the majority
opinion of the SAB was that ETS caused not only lung cancer but a
range of other effects. I suspect that there will be another
similar meeting in perhaps 9 months time to go through the next
draft, but, given the views of the SAB, I think that the broad
conclusions of the report will be along the lines predicted from the
conclusions in the Surgeon-General and NRC reports. It is
interesting to note that there appears to be a situation where the
public perceives the EPA as being more authoritative than the
Surgeon-General or NRC, despite the fact that the EPA staff and
consultants who prepare the report are clearly very inexperienced
and are of inadequate scientific stature to go against conclusions
of the Surgeon-General or NRC!
Turning to more specific issues, a number of conclusions were
evident from listening
to what the SAB had to say:
(i) The report should follow its own published recommended
procedures for hazard identification.
(ii) The report should extend the list of diseases considered, to
consider all those to which an association with ETS has been
claimed. In that context, Lippmann suggested that because
ETS may be deposited proportionately less in the lung than is
2501073517
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active smoke, other organs may be more affected by ETS.
(iii) When reviewing evidence, the report should discuss the merits
of each study and not only rely on the Surgeon-General or NRC
for pre-1986 studies.
(iv) The report should carefully discuss sources of potential bias
relevant to each association considered.
(v) The report should present an argument that the associations
seen with effects in children are cause and effect, the SAB's
view being that they were.
(vi) the report should clearly state, discuss and justify all
assumptions made.
(vii) The report should quantify the effect of all sources of
uncertainty - confidence limits resulting merely from
sampling variation are an inadequate expression of this.
(viii) For all diseases where a causal relationship is demonstrated,
the EPA should use risk assessment to quantify the effect on
the population.
(ix) Appendix C (Dosimetry of ETS), which was heavily criticised
by Lippmann (Constants used are "off the wall", "references
don't support statements", "A lot of nonsense"), should be
withdrawn. Instead, new sections on the chemistry and
physics of ETS should be included.
(x) Appendix D (Alternative approaches to risk assessment based
on dose-response modelling) was also heavily criticised. The
notion that polycyclic aromatic hydrocarbons (PAHs) could be
used as an adequate marker for ETS was strongly criticised,
it being noted that the epidemiology was not consistent with
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PAHs being a major source of the carcinogenicity of direct
smoking. Most of this Appendix was to be assigned to the
bin, though certain parts could be used elsewhere in the
revised report.
(xi) Appendix B (Mathematics of misclassification) would need
extensive editing, partly to make it
comprehensible, partly
to make the formulae correct.
(xii) Appendix A (Summary descriptions of eleven case-control
studies) should, as noted above, be extended to cover all
relevant studies, not just recent ones.
(xiii) There was considerable discussion, but no conclusion, about
the possibility of limiting attention (as IARC do) only to
publications in peer reviewed journals. Personally, I think
this a bad idea (especially with regard to publication bias).
EPA said it was not their general policy to limit data in
this way.
(xiv) The question of studies to be included or excluded in the
meta-analyses was given some thought. There seemed to be
fairly general agreement that EPA were wrong to exclude the
Varela thesis. Amazingly, Laties (an SAB member who was not
an epidemiologist) said he had read Kilpatrick's submission
criticisinz the Hirayama study and could not see how EPA
justified including it in their meta-analysis!! No-one on
the SAB agreed or disagreed with him, though Blot had said
earlier EPA were wrong to argue Hirayama was a better study
than Garfinkel. 2501073519
(xv) In discussing the draft policy guide it was noted more than
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once that the comparison of sidestream and mainstream smoke
was misleading. As Hammond noted there were not higher
concentrations in ETS of any compound. lore attention needed
to be given to the massive dilation of sidestream smoke by
room air. Concentrations in sidestream smoke were of little
or no direct relevance.
Two very important points should be noted.
First, Bayard of the EPA made it clear a number of times that
the SAB were asking for so many changes and envisaged such a
dramatically different and more comprehensive document (really an
updated S-G report with multiple meta-analyses and risk assessments
thrown in for good measure) that their existing staff and available
funds would be unable to cope.
Second, there was likely to be quite a strong switch of tack
about how the case was put forward to try to demonstrate that ETS
was a Group A carcinogen. The actual panel discussion on ETS
started with a nervously delivered but very sound commentary on the
limitations of the epidemiological evidence on lung cancer by
Geoffrey Kabat. Among points he noted were:
(i) the draft did not acknowledge that one is dealing with a weak
association,
(ii) that confounders may matter,
(iii) that epidemiology as a science was being stretched to its
l imi ts , 2501073520
(iv) that his own new data showed results that were "unbelievably
flat",
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(v) that Garfinkel's case-control study found no association with
ETS unless someone other than the subject or the spouse
reported the data,
(vi) that one cannot overcome problems by meta-analysis,
(vii) that one cannot take the S-G and NRC reports as gospel!,
(viii) that even active smoke was a weak carcinogen compared with
such as BCME,
(ix) that ETS, even if it was a carcinogen, was not in the same
league as others on the group A list, e.g. asbestos and vinyl
chloride, and that
(1) he was happiest with the IARC conclusion which labelled the
epidemiological findings as consistent with both an effect
and with no effect. He noted the nature of the evidence had
not changed since 1986.
The following speaker, Rockette, who discussed meta-analysis,
also made it clear the epidemiology was not convincing and that
there was need to investigate why there
was an association with lung
cancer in other countries and not in the US.
After that, the next speakers made it clear they felt that a
major limitation of the EPA report was that they had not made it
clear that:
(i) active smoking caused lung cancer,
(ii) no threshold had been demonstrated for active smoking, and
(iii) ETS and active smoking contained the same carcinnogens and
were "more similar than different",
2501073521
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and that this argument alone justified the claim that ETS was
carcinogenic. Despite the fact that the EPA had highlighted the
differences between ETS and active smoking, and had pooh-poohed the
cigarette equivalent approach, there were some who seemed to be
implicitly arguing that they might be happier with a dosimetric
based risk assessment. It must be noted, however, that a number of
the SAB, probably the majority, felt the epidemiology did indicate a
risk. It is interesting to note whether, since the EPA Group 1
classification demands epidemiological evidence, evidence of risk
from active smoking is actually sufficient to satisfy the criteria
as defined.
8. Questions of interpretation
8.1 Misclassification
There was no technical discussion or criticism of the
presentations on Wells and myself on the extent of bias due to
misclassification. It was generally agreed that it would be
appropriate to adjust study by study. I gave Brown, who did the
misclassification adjustment work in the draft, a copy of my
document criticising Wells' submission. I think the point went home
to the board that there was a lack of good Asian data on
misclassification rates with which to conduct accurate corrections.
2501073522
8.2 "Backg,round correction"
Taking the lung cancer risk of a totally non ETS-exposed never
smoker as 1 unit, let us define 1 + x as the risk of an average
never smoker not married to a smoker and 1+ y as the risk of an
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average never smoker married to a smoker. Since we observe the
relative risk (RR) according to marriage to a smoker and since we
can estimate, via ETS marker uptake, relative exposure for the two
groups (RE), we can estimate x
and y via the formulae
RR ~ 1 ±~
1 + x
RE - y/x
to give x= RR - 1
RE - RR
and
y = RE (RR-1)
RE - RR
In the report this "background correction" applied to an RR
value of 1.28 (based on meta-analysis adjusted for smoker
misclassification) and an RE value of 3 (based on Wald and Ritchie
cotinine data) gave a value of 1+ x of 1.16
and of 1 + y of 1.48.
In other words 16/116 - 14% of lung cancer risk among never
smokers not married to a smoker was attributed to ETS as was 48/148
= 32% of risk among never smokers married to a smoker.
While the Wald and Ritchie RE figure of 3 was close to what I
got from the TAC Cotinine Study, Cummings cited much lower RE values
based on urinary cotinine from his study in New York, 1.55 for women
and 1.27 for men. Had one used 1.55, and the same RR value, one
would have got
l+x
- 2.04 N
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1 + 3x
= 4.11 O
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