UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON. D.C, 20460
Jane 10» 1985
OFFICE OF
THE ADMINISTRATOR
Honorable Lee M. Thomas
Mrnini stra tor
U.S. Environmental Protection Agency
401 M Street, S.w.
Washington, D.C. 20460
Dear Mr. Thomass
The Environmental Health Conroittee of IPA's Science Advisory Board has
completed its review of the Agency's draft Mutaganicity and Carcinogenicity
Assessment of 1,3-Butadiene. The stated purpose of the document is primari-
ly to support decision making by the Office of Air Quality Planning and
Standards regarding possible regulation of butadiene as a hazardous air
pollutant.
The draft document is an improvement ever some recent drafts for other
substances and is a well written review of the current literature for buta-
diene. The final version should explain, however, the reasons for restrict-
ing this document to rautagenieity and carcinogenicity and **iy little or no
exposure information is presented. The final document also should contain
additional discussion to put the issue of reproductive effects into perspec-
tive. The Ccraraittee recommends that a separate chapter on pharmacokinetics
be written frcm information already in the draft document and that recent
information on the pharxnacokinetics of butadiene be incorporated into the
revised draft.
The Ccronittee concurs with the general conclusion that butadiene is
mutagenic for microbes and lower animals. However, the evidence for sub-
roammalian mutagenicity is not ccstfielling, given the lack of data from
whole animal studies. The Committee agrees that the animal evidence of
carcinogenicity is "sufficient" and that the epideiniological evidence
for carcinogenicity is "inadequate," according to the criteria of the
International Agency for Research on Cancer (IASC). This information
places butadiene into IARC category 2B. It is thought prudent for a regu-
latory Agency to presume a category 2B substance to be a probable human
1 V
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Hon. Lee M. Thonas
Page two
carcinogen* The Ccmmittee recommends that the quantitative estimate of
carcinogenicity be revised, as detailed in the attached technical report.
We cxnmend the cexrparison Of epldemiologlcal data with the quantitative
estimates derived frora animal data for its creative approach.
We appreciate the opportunity to ocument on this public health issue
and stand ready to provide any further scientific advice. Wfe request a
written response to our advice.
Sincerely,
Richard A. Grieseaner, D.V.M., Ki*D,
Chair, Environmental Health Ccnmittee
Norton Nelson, Ph.D.
Chair, Executive Ccraaittee
Enclosure
ccs A. James Barnes
Assistant Administrators
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TECHNICAL REPORT OF THE EWIIOMEOTAL HEALTH ODMMITIEE OP SPA'S
SCIENCE ADVISORY BOARD REGARDING A CRAFT MOTAGENICITY
CARCINOGIJIICITY ASSESSMENT OP 1,3 BUTADIENE
INTRODUCTICTI
On April 10-11, 1985, the Environmental Health Committee o£ the Science
Advisory Board reviewed a draft Mutagenicity and Carcinogenicity Assessment
of 1,3-Butadiene [EPA-600/8-85-004A; February, 1985? Review Draft]. The
document was prepared by the Office of Health and Environmental Assessment
(OHEA) in the Office of Research and Development, The Coimittee's major
conclusions and technical comments are presented below.
FOEMAT AND CONTENT
The draft document, like the recent Health Assessment Document for
Chloroform, Is an improvement over sane previous documents for other sub-
stances, in that (1) attention is given to the limitations of positive
data? (2) the quantitative assessment makes an attempt to compare the pre-
dictions of animl studies with the available human data, while pointing
out the inherent uncertainties and limitations? (3) the quantitative assess-
ment is described and interpreted more completely; and (4) in general, the
document is well written.
Although the draft document adequately reviews the current information
cm the carcinogenicity and mutagenicity of butadiene, given the few, scat-
tered data cxi which it had to rely, it is not surprising that the authors
had a difficult time integrating these data into a coherent conclusion.
The reasons for restricting this document to mutagenicity and carcinogenic-
ity should be stated in the preface. The preface does not make clear why
the objective of the document limits the review. The preface also should
explain why little or no exposure information is presented and, in general
terms, vhat exposure infonsation was reviewed by the staff.
Acknowledgment that butadiene produces non-neoplastie organ systans1
damage (for example, alveolar metaplasia, nephrcpathy, and testicular
atrophy) belongs either in the preface or in a separate chapter. The
Committee disagrees with the statement (in Section 4,2.3} viiich atterapts
to equate cardiac tumors, cardiac disease and cardiac malformations, as
these are unrelated pathological processes.
The information on reproductive effects raises concerns, but the major
study on this subject is not published and will not be easily available to
the general public. Therefore, the document should contain additional
discussion to put reproductive concerns into perspective as much as pos-
sible. The information on teratogenicity should either be placed in the
preface or enlarged into a separate diapter. in particular, the brief
description of teratogenicity data was ambiguous, difficult to interpret
and is inappropriately located in the carcinogenicity chapter. A consultant
to th«-Cotftuttee, Dr. taiald Hood, undertook a fuller review 1 of reproductive
effects issues. His comments have been cotrounicated separately to Oi|EA.
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The Agency should place the information an metabolism (found in the
mutagenieity chapter) and the information on elimination rates (found in
the carcinogenieity chapter) into a separate pharmaeokinetics chapter. In
the current draft the discussion of pharmacokinetics is fragmented and
partially duplicated.
EXPOSURE
In the recent past the Committee has relied on separate memoranda from
the Office of Mr Quality Planning and Standards (QA0PS) fee summary infor-
mation on exposure. However, OAOES did not supply exposure information on
butadiene. TJie exposure infoznetion in the draft document is inadequate
to form an impression of either risk or critical hazards.
The draft should review the dimerization of butadiene to 4-vinyleyclo-
hexene, because the variable presence of dimer in the material administered
to laboratory animals may affect the results of toxicology studies. Hie
National Ibxicolcgy Program (NTP) Technical Reports Review Subeonmittee
found that a recent N1F study of the carcinogenesis of 4-vinylcyclohexene
(Report Ho. 303} was inadequate to draw conclusions regarding effects on
rats or male mice because extensive mortality occurred in the treated
groups.2 A majority of the Subcommittee concluded that 4-vinyleyelchexene
caused cancer in female mice. Ihe health assessment document also should
provide a reference to support the statement that butadiene has been detected
in cigarette siroke, fossil fuels, and the incineration products of fossil fuels.
Ihe statement that "concentrations ranging frcm 1 to 5 ppb have been detected
in urban air" is in error. The concentration range is actually 1 to 9
ppb.3
PHARMACOKINSTICS
It is essential that recent information on the pharmacokinetics of
butadiene be incorporated into the revised draft since they indicate that
rats can metabolize butadiene to butadiene monoxide and that this route of
metabolism is saturable. Studies by Bolt and co-workers* and by Filser
and Bolt^ are particularly important in this regard.
itie section on metabolism is incomplete. Ttie document adequately
discusses the in vitro aspects of butadiene metabolism in mawnalian tissues,
but a report by Malvoisin and co-workers was not included in this discus-
sion,® Ihe paper discusses the enzymatic hydration of butadiene monoxide
and its importance in the overall metabolism of butadiene. This report
should be cited and the results incorporated into the discussion of the
metabolic activation and detoxication of butadiene metabolites. Ihe draft
document states that there is no information available on the mutagenicity
of 3-butene-lt2-diol and 3f4-epo3cy-l,2-butanediol. However, Halvosin and
Roberfroid indicate that their unpublished results show that these two
metabglites are not mutagenic.? ^
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3 -
The potential role of glutathione in the metabolic inactivation of
butadiene monoxide should be mentioned. Wiile there are no data at present
to support the hypothesis that glutathione is involved in the metabolic
detoxication of butadiene monoxide, Malvoisin and co-workers indicate that
a glutathione conjugate of butadiene monoxide is formed both chemically
and enzymatieally.6 (This was mentioned in the discussion of the paper
as an unpublished result)*
A recent abstract presented at the Society of Toxicology annual meet-
ing by Bolt and eoworkers showed that B6C3F1 mice are capable of metaboliz-
ing butadiene at rates approximately twice that observed in Sprague Dawley
rats, and that this metabolism was saturated at high exposure concentra-
tions.8 Furthermore, this study provided data on binding of radiolabel to
DNA and total protein following inhalation exposure. These observations
suggest a possible explanation for some of the species difference in the
incidence of cancer following inhalation of butadiene.
Recent studies sponsored by the National Toxicology Program (KIP)
should confirm and extend the quantitative observations of Bolt and his
collegues. In both rats and mice the absorption of butadiene decreases
significantly as the exposure concentration increases. These studies also
show that metabolism of butadiene by the rat is saturated at concentra-
tions that were used in the chronic toxicity study (8000 ppn). The spe-
cific details of this study should be available soon in the NTP quarterly
report.
ABSORPTION
The statement that the absorption fraction is "assumed the same for
all species" for butadiene is not warranted, and the attempt to support
the assumption of equivalent absorption fraction by a citation to the text-
book by Dripps and coworkers is not justified. The fact that the minimum
alveolar concentration necessary to produce a given stage of anesthesia
is similar in man and animals does not mean that all chemicals will have
similar absorption characteristics across species.
MUTJ^SNICITY AND CLASTOGENICITY
The Ccmmittee agrees with the general conclusion of this chapter that
butadiene is mutagenic for microbes and animals. However, the evidence
for sub-mammalian mutagenicity is not compelling, given the lack of data
from whole animal studies. The emphasis of the chapter has been placed on
studies with presumed animal metabolites because of the lack of data on the
parent compound, and this supporting information frcm mutagenesis studies
on the major metabolites has been well-developed*
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The draft document suggests that butadiene is a mutagen by virtue of
its metabolism to diepoxybutane. One study develops the hypothesis that
butadiene is metabolized to diepoxybutane, but this pathway is not proven.^
The data do not show that this metabolite is responsible for observed muta-
genicity with butadiene, "fte statements in the text therefore require
some qualification. Also diepoxybutane also is unlikely to reach the gonads
of mammals as such following inhalation. Wiile it increased the rate of
sex-linked recessive lethal mutations in Drosophila, in the experiment the
diepoxide was administered "by feeding .* Following absorption frcro the
gut* diepoxybutane probably was biotransformed to other metabolites.
The conclusion that diepoxybutane is a powerful clastogenic agent is
questionable. Fewer cells were examined at the mid-dose and high-dose levels*
suggesting that correction for cytotoxicity and non-specific toxic damage
might be in order. At the dose of one microgrant per milliliter of diepoxy-
butane, chremosames were not affected. Diepoxybutane is clsistogenie, but
if comparative adjectives such as "powerful" are applied, the basis for
the oonparison must be given. The draft document also concludes that die-
poxybutane is responsible for producing a dose-dependent , sister chromatid
exchange response. Again, in mammals, the diepoxide is reactive and un-
likely to be transported to bone marrow following intraperitoneal injections
without undergoing further modification.
Several additional reports should be discussed in the document. A study
by de ffeester and ecworkers indicates that butadiene is a direct mutagen in
several strains of S, typhimuriuiru^ However, a study published by the same
grcup in 1980 contradicts this observation and suggests that the observations
reported earlier regarding the direct mutagenic aspects may have been due to
an "artifact. "^ Analysis of the data from both studies suggest that the re-
sults from the 1978 study may have been due to a volatile metabolite of buta-
diene. A paper by Citti and coworkers has not been incorporated into the
discussion of DNA alkylation.H In that paper, the authors demonstrate that
butadiene monoxide can react with Ctft in vitro. This paper also characterizes
the CNA adducts formed with butadiene monoxide. The draft document states that
"alkylation activity correlated with mutagenieity in E. Coli WP2 wvrA," but the
discussion is not clear, since no data are presented on which to base this state-
ment. A paper by De Meester and co-workers describes the mutagenicity of buta-
diene monoxide in bacteria. ^
ANIMAL STODIBS OF
The Garanittee agrees with the apparent conclusion of the document,
which is not clearly stated, that the animal evidence of careinogenicity
is "sufficient" according to the criteria of the International Agency for
Itesearch on Cancer (IARC)* An increased incidence of malignant tumors of
several histological types and one rare type occurred in more than one
species. The incidence of malignant tumors was especially high for mice.
Genoboxieity information (see above) is consistent with this categorization.
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The unusual multiplicity of tumor types and the production of extreme-
ly rare heart tumors deserve repeated emphasis here and in the Summary and
Conclusions Section. The draft document states that the heart was the
only organ in which hemangiosareomas occurred. A report prepared for H»A
could be cited appropriately at this point. ^ This report summarizes a
study by Ripp of several tissues, including the heart, following subchronic
exposure of rats to inhaled butadiene. Same of the early changes described
in that report may relate to the hemangiosareonas observed in mice following
long-term exposure*
Two lifetime inhalational bioassays establish the carcincgenicity of
butadiene for rodents, the two studies also show that rats and mice re-
spond differently. Although this difference is indicated in the document,
a fuller review, particularly of quality assurance aspects of the two
studies, seems justified. The absence of evidence of immuncsuppression
based on histologic examination of lymphoid and hematopoietic tissues also
could be mentioned, for each bioassay, additional paragraphs should note
the limitations or special considerations in the tests, as recognized by
NIP reviewers (such as early deaths, and individual housing of mice, and
for rats the eight-fold interval in gas concentrations, the large proportion
of dimer, the problem of sampling mammary and zymbal glands, the lack of
peer review, the high incidence of rhinitis that occurred in male mice at
high doses and so forth).
The discussion of diepoxybutane carcincgenicity could be expanded to
give enough details of the Van Durren and Shimkin experiments so that the
reader has a sense of the extent of the experimentation and the weight of
the evidence.13 As expected for epoxides, dermal or subcutaneous applica-
tion of diepoxybutane produced local tumors at the sites of application,
Intraperitoneal injection produced lung tumors in the typical lung tumor
assay (but not leukemias or angiosareonas in the short experiment).
EPlDEMIQIJOGlcaL STODIE5 OF ONCER
The Gonmittee agrees with the conclusion in the draft document that
the epidemiological evidence for carcirogenicity is "inadecjuate,* according
to the IASC criteria.
The review of the epidemiology of butadiene is thoughtful, systematic,
analytical and thorough. The draft document describes study design, the
composition of the study groups, the methods of ascertainment and analysis,
the role of bias and confounding factors, and most importantly, the nature
of knowledge about the exposure. Exposure is "most important," because
the exposure usually occurs at a job site of within an occupational category,
Multiple study designs were used, and several occupational environments
were chosen. Jfo strong, consistent or specific carcinogenesis results could
be documented* The review objectively analyzes the strengths and limita-
tions of each study, and concludes "Given the inconsistency of results
fron different studies, the possible confounding due to exposure to $51-
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vents, styrene, and possibly other chsnicals, and the potential biases in
seme of the studies, the epidemiological data would have to be considered
inadequate for evaluating Aether a causal association exists between
butadiene exposure and cancer in humans." The analysis provides a valid
basis for this conclusion.
Since the data available for humans all deal with workplace exposures
to the multiple substances found there, and since no data exist for hunjan
exposure to butadiene alone, this chapter might well be based on the XAHC
review of the rubber industry in which 12 types of cancer are evaluated
and tied to the presumed agent or job category.W jf one wished to go fur-
ther , one could review separately the experimental and epidemiological
evidence of styrene, benzene, etc. and estimate their contributions, if
any, to the workplace risks. The conclusion will still be reached, how-
ever, that the epidemiolcgic data do not permit an evaluation of the car-
cinogen icity of butadiene.
QUALITATIVE CARCINQGENICITY CONCLUSIONS
The Cenmittee agrees with the conclusion in the draft document that
butadiene can be classified in IARC category 2B. The document also de-
scribes a ranking of B2 under the proposed EPA Guidelines for Carcinogen
Risk Assessment.*5
The terminology of "inadequate for determining a causal association*
derives frcro the IAIC definitions of the "degrees of evidence for carcino-
genicity from studies in humans," They are categorized as:
i. Sufficient evidence,
ii. Limited evidence,..,
iii. Inadequate evidence, *hich indicates that one of three conditions
prevailed: (a) there were few pertinent data; (b) the available
studies, while showing evidence of association, did not exclude
chance, bias or confounding; (c) studies were available which do
not show evidence of carcincgeneity.
The evidence under consideration does not address the issue of infer-
ring the lack of carcincgenicity. Further, it may be noted that the lARC Work-
ing Group was unable to define criteria for "negative" evidence. Thus, the
IARC carcinogen assessment systen does not contain a Group jlvy %*deh might
have been defined as "noncarcinogenic in humans." Thus, the term "inade-
quate" does not have the oairan meaning of unsuitable. "Inadequate" can
mean iii (c) above, merely that the available studies do not show evi-
dence of carcinogenic!ty in humans. The judgment that it is prudent for
regulatory agencies to regard butadiene as a "probable" human carcinogen
rests on the evidence frcro studies in two species of rodents.
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QUANTITATIVE ESTIMATION OF CANCER INCIDENCE
The Oonmittee recommends that the quantitative estimate of carcino-
genic potency for humans be revised beyond the changes recommended by CUBA
staff at the meeting.
In brief, the situation is unusual in several respects. These include
CD markedly different quantitative results for incidence and tvmor site were
obtained in rats than in mice? (2) the epidemiological studies show very little,
if any, evidence of a carcinogenic effect? (3) the mortality rates for mice
were greater than expected f ran the subchronic study used to estimate the max-
imally tolerated dose? and (4) the incidence data for carcinogenicity in mice
suggests a "plateau effect" for the two exposure concentrations of butadiene.
The latter observation and the results outlined above on pharmaco-
kinetics suggest that nonlinear kinetics may play a role in the tumor
incidence in mice. Hie information about kinetics was not utilized in
the potency estimate in extrapolating between animals and man. As data
are available which relate absorbed dose to administered dose for the
mouse, this information should be factored into the potency assessment.
AS a first step, the dose levels in the mouse experiments should be
adjusted to reflect Heffective dose" before being used in the statistical
models. Since the Agency's objective is to use animal data at higher buta-
diene exposures to infer possible human effects at low exposures, it is
not necessary to have data on the phaimacokinetics of humans at high buta-
diene exposures for this exercise. The available mouse .data, for example,
are adequate to correct for internal dose at high exposures. Hie internal
doses can be extrapolated to low doses, and then the same standard factors
as those used in the draft document can be applied to achieve an estimate
for humans.
Bams cownent could be made on the lower frequency of mice with tumors
at tile higher dose, Ihis may have certain implications regarding metabol-
ism (i.e. metabolic saturation) of butadiene at these high concentrations.
Similar observations are found in the data presented in Tables 8 and 9 of
the draft document. The data frati Bolt and his collegues also suggest
that dose-dependent kinetics cones into play at these higher concentrations.
As a second step, a time to tumor approach should be employed. A
multistage model that includes time of death is available. Hie adjustment
factor used in the draft document is based on the assumption that time-of-
tumor increases as the third power of time. Ihis adjustment is in the
range observed for maraf cancers in humans, but in those cases the exposure
levels are not so high as to produce a carcinogenic response in about half
of the expected lifespan. One third power of time is observed because in-
cidence increases gradually over time and then much more markedly in the
latter part of life. She situation with butadiene is reminiscent o£. a
studjf-of mammary carcinomas induced in female mice by vinylidene ehleride.
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In this study more susceptible mice die sooner. Apparently, the mice in
the butadiene study were not authentic hybrids of inbred strains, so that
a heterogeneous population response is a distinct possibility.
As a third step, the Committee recommends that an upper bound calcu-
lation be made using the rat data and that this estimate be presented as a
sensitivity analysis case for comparison with the estimate based on mouse
data. The conceptual approach suggested here differs only slightly from
that used to conpare the estimate based on mouse data to the human epidem-
iological data. In addition, absorption and elimination studies suggest
marked species differences in pharmacokinetics, as do the metabolism studies
by Bolt and his colleagues. It would appear that metabolism of butadiene
may be the key to interpreting the tumor response. IMs is particularly
noteworthy since the non-linear kinetics noted above for butadiene may
have a profound impact on the relative carcinogenic response in rats and
mice.
Since carcinogenic!ty results are available for rats and mice with
varying results, it would be desirable to have comparative pharmacokinetie
data to know vliicn species are more relevant to man. in the absence of
human data, the Agency probably will have to use the higher incidence
mouse data for an upper bound estimate of potency because of policy and
quality assurance considerations. However, EPA should not ignore the rat
to mouse difference as it reflects on the uncertainty inherent in the ex-
trapolation from the mouse to humans.
Data regarding human metabolism would enhance our ability to extra-
polate from the animal data, and it is unfortunate that none are available
to EPA. Although such human data may be difficult or impossible to obtain
in the U.S., due to low domestic exposures, this may not be true of all
areas of the world. It is likely that there are countries where human
exposure to butadiene is such that adequate samples could be obtained and
analyzed for metabolites. The draft document should cite this and other
research needs.
The possible quantitative effects from the presence of the dimers in
the Moassay material on the experimental outcomes should be discussed
because complete conversion to dimers would halve the effective concen-
tration of active material, and the potency of 4-vinylcyclohexene also may
differ from the potency of moncmer,
Quantitative estimates of risk for non-carcinogenic effects should be
displayed in terms of an "acceptable daily intake" or "margin of safety."
Quantitative results are displayed in the draft document for carcinogenic
incidence at exposures from 10 ppb to 10 ppm in comparing female mouse
data with three different models. Wien these documents are used by dif-
ferent regulatory agencies, "safe" levels are derived from q+ or qh by
the use of a preselected risk level. Important information is provided by
knowpig both the cancer risk and the margin of safety for noncareinegemc
effects at different exposure levels. However, butadiene may be difficult
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to address in this manner because of the apparent limitations of the toxi-
cological data. The document also will be worn useful if the models weed
to derive qj_ for butadiene are given* as well as the results obtained fron
the models at different exposures. Then the user will not have to inter-
polate between exposure levels at higher exposures.
Relative potency comparisons should either be avoided or their uncer-
tainties explained. itie relative potency table in the draft document is
calculated from data sets of various quality through the use of different
methods, and it reflects different degrees of uncertainty. However, the
table does not reflect important qualifying biological information, such
as time to tumor, degree of malignancy, and so forth. Such a summary sta-
tistic can be greatly misinterpreted, the upper bound nature of the poten-
cy estimates should be clearly stated. One improvement might be the pre-
sentation of a range of estimates of potency for each chemical. Another
might be the addition of information on the weight of evidence, and so
forth. The exposure cited in the text for a unit risk of one gram per
cubic meter is in error. The appropriate value is one microgram per cubic
meter.
COMPARISQtf OF ANIMAL ESTIMATES AND EPIDEMICffflG!f
The Committee commends the Agency staff for comparing the epidemiologi-
cal data with the quantitative estimates derived from animal data. It is
an imaginative endeavor to integrate all available data, and it tends to
validate the aniroal-to-man extrapolation of potency for doses in the range
of human exposures. Further, the calculation of "power to detect predicted
deaths" makes the argument more cogent. This effort is the best seen by
the Cemnittee so far to check the consistency of human and animal data.
The method used in the draft document has the potential to overcome the
problem of relying exclusively on animal data for potency estimates. For
butadiene, the poor exposure data and confounding factors severely limit
the extent to which the upper bound potency estimate from the animal data
can be compared to an upper bound estimate from the epideraiological data.
Yet, the comparison of animal and epidemiological data does provide feed-
back on the reasonableness of the animal models and the uncertainty in
the estimate.
Some problems with the application of the comparison should be noted,
however. These include i (1) the calculations need to be explained more
clearly in the documentj (2) as much as possible, the comparison should
be extended to the rat data; (3) the comparison should attanpt to further
explain inconsistent results by reviewing individual epidemiology studies
for their alignment with the animal estimate. Confounding exposures,
latency, mistaken estimates of exposure, and so forth, may provide a basis
to understand discrepancies. (4) The epidemiological investigations are,
as the document notes, "inadequate for determining a causal association
between butadiene exposure and cancer in humans.* This statement is super-
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f icially inconsistent with the ecnf>ariscm of epidemiologie data with the
potency estimate from the mouse experiments. The text should anticipate
and respond to this issue. (5) It diminishes the scientific cogency of
the document to assert that, "based on the comparisons between the predict-
ed and observed human response, the extrapolated value from the animal
data speared high by a factor of about 3..." The document would carry
greater infsact if it pointed out the implications of the cotfarison in
general terms, since emphasis on a point estimate is unwarranted, in view
of the poor quality of the exposure data. Rather, a wide range of uncer-
tainty exists.
Industry representatives have stated that the actual human exposures en-
countered in the epidsniological studies were lower than those estimated
in the document because of both the olfactory threshold and the possibility
of an explosion. Thus, the human potency estimate derived with more realis-
tic exposure values will be closer to the potency estimate for humans
derived fron the mouse data. A question remains as to whether many of
the workers included in the epidemiological studies received enough
exposure to warrant their study.
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10 — , --- _
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14 — y, --- „ -- IARC Monographs; The Rubber Industry* Vol. 28,
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15 u.S. Environmental Protection Agency, "Proposed Guidelines for Carcinogen
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46294-46301. Uiese proposed guidelines were reviewed by a special panel
of the Executive Garni ttee of the Science Advisory Board on April 22-23, 1985.
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