EPA's Response to Major Interagency Comments on the Interagency Science Consultation Drafts of

the IRIS Toxicological Review of Benzo[a]pyrene

August 2013

Purpose: The Integrated Risk Information System (IRIS) assessment development process of May 2009
includes two steps (Steps 3 and 6) where the Executive Office of the President and other federal agencies
can comment on draft assessments. The following information is in response to comments from
interagency reviewers that were received over several rounds of Step 3 review (prior to public comment
and external peer review) as discussed below.

History of Interagency Science Consultation (Step 3 of the IRIS Process) for the draft IRIS
Toxicological Review of Benzo[a]pyrene:

June 2011 -Under the May, 2009 IRIS process, the Interagency Science Consultation step for
benzo[a]pyrene was initiated in June 2011 and comments were received from Agency for Toxic Substances
and Disease Registry (ATSDR), Office of Management and Budget (OMB), National Aeronautics and Space
Administration (NASA), National Institute for Occupational Safety and Health (NIOSH), Council on
Environmental Quality (CEQ), and Department of Defense (DOD). The complete original comments are
posted on the IRIS website (www.epa.gov/iris). Comments on this draft (June 2011) were taken into
consideration in revising the June 2012 interagency science consultation draft Revisions to the draft
included increased discussion of the epidemiological data in support the weight of evidence descriptor;
increased discussion of alternative modes of action for cancer; clarification regarding the selection of
studies and endpoints for consideration in dose-response analysis and application of uncertainty factors.
EPA responses to these comments are not discussed in detail here. In addition to considering previous
interagency comments, the document was revised in response to the 2011 recommendations on IRIS
assessments from the National Research Council (NRC, 2011).

June 2012 - A revised interagency science consultation draft was provided to the Executive Offices of the
President and other federal agencies for further comment in June 2012. Comments on this draft (June
2012) were received from ATSDR, NASA, NIOSH, CEQ, and DOD. The complete original comments are
posted on the IRIS website (www.epa.gov/iris).

August 2013-The June 2011 and June 2012 interagency science consultation drafts of the Toxicological
Review of Benzo[a]pyrene and external peer review charge questions, interagency comments on these
draft documents, and EPA's Response to Major Interagency Comments on the Interagency Science
Consultation Drafts are posted on the IRIS website (www.epa.gov/iris).

For a complete description of the IRIS process, including Interagency Science Consultation step, visit the
IRIS website (www.epa.gov/iris).

Selected Major Interagency Science Consultation Comments and Responses:

Topic #1: Inclusion of toxicogenomic data in the Toxicological Review of Benzo[a]pyrene- DOD noted
that microarray data for benzo[a]pyrene is available but was not discussed in the benzo[a]pyrene assessment.
DOD requested that a discussion be included as to why genomics data are not useful, even in a supporting role,
at this stage.

EPA RESPONSE: An analysis of the available microarray data for benzo[a]pyrene has been conducted and

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added to the Supplemental Information to the Toxicological Review, and a summary of the findings has
been added to the Toxicological Review.

Topic #2: The development of reference values based on developmental studies -An overall RfD and
an RfC were derived for benzo[a]pyrene using developmental endpointsfor which the period of exposure
involved developmental windows which are shorter than the duration considered to be a chronic exposure
duration. DOD commented that this shorter exposure timeframe is not applicable in risk assessment of chronic
exposures. DOD recommended EPA reconsider using developmental endpoints as candidate RfCs and RfDs
and that these studies would be better suited for deriving specific developmental toxicity reference values.

EPA RESPONSE: The database for benzo[a]pyrene was considered sufficient to allow for the calculation of
organ/system-specific RfDs for reproductive toxicity, developmental toxicity, and immunotoxicity. The
organ/system specific RfDs derived for reproductive and immunotoxic effects were both based on a
chronic exposure inferred from subchronic exposure duration. The organ/system specific RfD based on
neurodevelopmental effects was based on an exposure during the early postnatal period which is a
heightened period of susceptibility for brain development. Of the organ/system-specific RfDs derived for
benzo[a]pyrene, the RfD based on neurodevelopmental effects was the most sensitive and therefore was
selected to serve as the proposed overall RfD to be protective of the general human population, including
sensitive lifestages.

For inhalation exposure, the derivation of multiple organ/system-specific reference doses were considered
for effects observed and identified as potential hazards of benzo[a]pyrene (developmental and
reproductive toxicity). However, an organ/system-specific RfC to represent reproductive toxicity could not
be derived due to a high level of uncertainty, thus the overall RfC was selected based on the hazard of
developmental toxicity.

The overall RfD or RfC is derived to be protective of all types of effects for a given duration of exposure and
is intended to protect the population as a whole including potentially susceptible subgroups (U.S. EPA,
2002). For example, elevated exposures during developmental lifestages could potentially lead to an
appreciable risk, even if average levels over a longer exposure duration were less than or equal to the RfD
or RfC. However, certain exposure scenarios may require particular attention to the risk assessment
population of interest in order to determine whether a reference value based on toxicity following
developmental exposure should be used. For example, the use of an RfD or RfC based on developmental
effects may not be appropriate for a risk assessment in which the population of interest is post-
reproductive age adults.

Additional text was added to the document to clarify the intent of the proposed overall RfD and RfC (see
Section 2.1.5. and 2.2.5.). EPA has also included charge questions (question D4 and D9) which request
comment on the selection of the overall RfD and RfC based on developmental endpoints.

Topic #3: Adequacy of the inhalation database to derive a reference value for benzo[a]pyrene - DOD

commented that the inhalation studies in animals available for benzo[a]pyrene do not meet the "minimum
database criteria" described in EPA's 1994 Methods for Derivation of Inhalation Reference Concentrations
(RfCs) and Application of Inhalation Dosimetry. These guidelines state that a low confidence RfC requires "a
well conducted subchronic inhalation bioassay that evaluated a comprehensive array of endpoints, including
an adequate evaluation of portal of entry (respiratory tract) effects¦, and the establishment of an unequivocal
NOAEL and LOAEL." DOD stated that based on these guidelines, the inhalation developmental and
reproductive studies available for benzo[a]pyrene are insufficient to develop an RfC as lung effects were not
sufficiently monitored and the duration is too short. DOD further commented that only a single 4 week
inhalation study observed effects in the lungs and that the available chronic inhalation cancer bioassay by did

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not report a histological examination of the lung. Therefore, DOD recommended that an inhalation RfC not be
developed.

EPA RESPONSE: Both EPA's 1994 Methods for Derivation of Inhalation Reference Concentrations (RfCs) and
Application of Inhalation Dosimetry and 2002 A Review of the Reference Dose and Reference Concentration
Processes (referred to below as the RfD/RfC technical panel report) include discussions of minimum
datasets for the derivation of an RfD and RfC. In contrast to the 1994 Methods for Derivation of Inhalation
Reference Concentrations (RfCs) and Application of Inhalation Dosimetry described above, the 2002 RfD/RfC
technical panel report describes a minimum dataset for RfD or RfC derivation as a database with no human
data but dose-response toxicity data (specific to the route and duration being evaluated) with the
assessment of endpoints other than mortality.

Although lung effects were not specifically monitored in the reproductive and developmental study used as
the basis of the RfC (Archibong et al., 2002), the available body of evidence for benzo[a]pyrene indicates
that it is not a respiratory irritant. A 4-week inhalation study in rats assessed lung inflammation and
cytotoxicity through bronchoalveolar lavage and lung histolopathology at 1 day, 2 weeks, 2 months, 6
months, and 12 months after exposure. No lung or nasal injury was detected with benzo[a]pyrene average
daily exposure levels 100 times greater than the point of departure used for the RfC.

Furthermore, the benzo[a]pyrene inhalation database includes human and animal data which informs
potential hazards. The available data of humans exposed to benzo[a]pyrene through PAH mixtures (using
biomarkers for benzo[a]pyrene) suggests thatbenzo[a]pyrene exposure may pose health hazards including
infertility, miscarriage, and reduced birth weight (Wu etal., 2010; Neal etal., 2008; Tang et al., 2006; Perera
et al., 2005b; Perera et al., 2005a) and cardiovascular effects (Friesen et al., 2010; Burstyn et al., 2005). The
human studies of PAH exposure are not currently sufficient to develop a non-cancer toxicity value for the
inhalation route. However, several inhalation studies using benzo[a]pyrene alone are available in animals
including several reproductive (not multi-generational) and developmental studies (Archibong et al., 2008;
Ramesh etal., 2008; Wormley etal., 2004; Archibong etal., 2002)(Inyang etal., 2003; Wu etal., 2003),
including one subchronic study (Ramesh et al., 2008).

The available studies of benzo[a]pyrene exposure in animals were considered sufficient to derive reference
values. While no human data are available following exposure to benzo[a]pyrene alone, toxicity
information including dose-response data applicable to the duration in question with assessment of
endpoints other than mortality are available by the inhalation route. However, recognizing the importance
of characterizing the strengths and limitations of the database, EPA has added text to describe more fully
the extent of the database for inhalation routes (see Section 2.1.1. and 2.2.1.). In addition, EPA has applied
a database uncertainty factor of 10 and has revised the draft to characterize the confidence in the RfC as
low. EPA has included a charge question (question D6) to address the selection of studies and relevant
endpoints for the derivation of candidate values for the RfC.

Topic # 4: Selection of studies and application of uncertainty factors associated with the derivation

of the RfD and RfC for benzo[a]pyrene - CEQ commented that the most appropriate studies and endpoints
appear to have been selected for the derivation of the reference values. NASA commented that although
benzo[a]pyrene has an extensive body of literature, EPA's choice of studies and application of composite
uncertainty factors of300 and 3000for the derivation of oral and inhalation reference values¦, respectively
raises questions as to the appropriateness of the chosen studies as the basis of these values. DOD commented
specifically on the database uncertainty factor ofl Ofor the RfC and stated that is an over application of the
uncertainty factor.

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EPA RESPONSE: The neurodevelopmental study by Chen et al. (2012) was selected as the basis of the
overall RfD. It was a well-designed and well-conducted study that evaluated multiple neurobehavioral
endpoints and measures of neurotoxicity in adolescent and adult rats. The candidate value from this study
was selected as the overall RfD because the observed neurobehavioral changes represent a sensitive effect
of benzo[a]pyrene exposure, with similar effects replicated across other studies (Bouayed etal., 2009;
Grova et al., 2008). In addition, the neurodevelopmental study by Chen et al. (2012) is associated with the
application of the smaller composite UF (300) compared to the organ/system-specific RfDs representative
of immunotoxicity and reproductive toxicity.

The study by Archibong et al. (2002) was selected as the study used for the derivation of the overall RfC, as
it was a well-designed and well-conducted study that observed biologically significant effects at the lowest
dose tested by the inhalation route. This study indicates that the developing fetus is a sensitive target
following inhalation exposure to benzo[a]pyrene and the observed decrease in fetal survival is the most
sensitive noncancer effects observed following inhalation exposure to benzo[a]pyrene. Additional support
for this endpoint is provided by a developmental/reproductive study conducted via the oral route
(Mackenzie and Angevine, 1981) and by a human study which associated benzo[a]pyrene exposure with
miscarriage (Wu et al., 2010). While the composite UF for the RfC of 3000 represents four areas of
uncertainty, the database identifies developmental toxicity as a hazard following BaP exposure.

Text in Sections 2.1 and 2.2 has been expanded to further describe the oral and inhalation databases
available for benzo[a]pyrene. Text was also added to further clarify the deficiencies in the benzo[a]pyrene
databases. Additional discussion was also added describing the uncertainty factors applied to help
extrapolate from a point of departure derived from less than chronic studies in laboratory animals to a
lifetime human exposure at which effects are not anticipated to occur. Charge questions have been
included (questions D3 and 8) requesting comment on the selection of the uncertainty factors in the
derivation of candidate values.

Topic #5: Use of toxicokinetic data to support a comparison between the RfD and RfC - DOD

commented that a direct mathematical comparison of the RfD and the RfC yields a 350-fold difference in dose.
DOD recommended that this difference be explicitly addressed in the document and that toxicokinetic
information to support or refute this difference should be discussed.

EPA RESPONSE: Additional information was added to the document to help describe what is known about
quantitative differences in route specific toxicokinetics (see the Supplemental Information to the
Toxicological Review). In the case of benzo[a]pyrene, absorption by the oral route is estimated to be
approximately 10-30%, whereas absorption by the inhalation route is likely >80% (see the Supplemental
Information to the Toxicological Review). First pass effects in the digestive tract, the liver, and the
respiratory tract are also expected, due to differential expression and activity of enzymes responsible for
the bioactiviation and neutralization of benzo[a]pyrene, which can greatly modify the systemically
available dose.

Simple route-to-route extrapolation, as presented by DOD, where an inhalation concentration is converted
to an oral dose (assuming an inhalation rate of 20 m3/day) is not preferable because differences in
toxicokinetics between exposure routes are not accounted for in this type of conversion (U.S. EPA, 2009,
2005, 2002,1994). This method relies on the implicit assumption that the route of administration is
irrelevant to the dose delivered to a target organ, an assumption considered quite uncertain and not
supported by the principles of dosimetry or toxicokinetics (U.S. EPA, 1994). The preferred method for
performing route-to-route extrapolation involves a validated pharmacokinetic model that describes the
disposition of the chemical for the routes of interest (U.S. EPA, 1994). Several pharmacokinetic models of

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benzo[a]pyrene have been developed for rodents, however, the models do not allow for cross-route
extrapolation because models are not available which simulate the typical inhalation exposure to
benzo[a]pyrene on poorly soluble carbonaceous particles (see the Supplemental Information to the
Toxicological Review).

Topic #6: Human relevance of benzo[a]pyrene-induced forestomach lesions and tumors - DOD

recommended the inclusion of a discussion about the human relevance of forestomach effects and tumors
observed in rodents following oral and inhalation exposure to benzo[a]pyrene given that humans do not have
a forestomach.

EPA RESPONSE: In addition to systemic tumors (liver, kidney, auditory canal, and mammary gland),
forestomach tumors have been observed in rats, mice, and hamsters following dietary, gavage, and
inhalation exposure to benzo[a]pyrene. The available data supports a mutagenic mode of action (MOA) for
induction of these tumors, and key events of this MOA have been observed in the forestomach of rodents.
In addition, benzo[a]pyrene-DNA adducts have been detected in oral and esophageal tissue obtained from
smokers (Phillips, 2002) and several epidemiological studies have identified increased exposure to PAHs as
an independent risk factor for esophageal squamous cell carcinoma (Abedi-Ardekani et al., 2010;

Szymanska etal., 2010; Gustavsson et al., 1998). While humans do not have a forestomach, they do possess
similar squamous epithelial tissue in their oral cavity (Wester and Kroes, 1988).

Additional text was added to the Toxicological Review to clarify that humans do not have a forestomach but
that, for the above reasons, the forestomach tumors observed in rodents following benzo[a]pyrene
exposure are supportive of a human hazard of carcinogenicity. In addition, EPA has included charge
questions requesting comment on the selection of studies and relevant endpoints for dose-response
analysis (questions Dll and 14).

Topic #7: Consideration of additional modes of action (MOAs), including cytotoxicity and promotion,
other than mutagenicity for benzo[a]pyrene carcinogenicity - DOD commented that the benzo[a]pyrene
dose-response data for adducts and tumors in animal appear to suggest additional nonlinear MOAs may be
operational. DOD suggested additional cancer MOAs be considered in the document.

EPA RESPONSE: Animal bioassays are not, generally, designed to establish whether tumor responses have
thresholds; they have insufficient power to detect increases as large as 1 in 100. In addition, nonlinear
curves within the range of observation do not mean there is no risk at low exposures. Bioassay data cannot
indicate how many MOAs there are, but rather can provide a basis for evaluating consistency with possible
MOAs.

Cytotoxicity and mutation are not mutually exclusive modes of action; some observed effects can be
consistent with more than one mode of action. A mutagen at high doses can cause cytotoxicity and
regenerative proliferation that is a secondary response to massive DNA damage. Benzo[a]pyrene is a
complete carcinogen; the contributing roles of other processes involved in the promotion and progression
of benzo[a]pyrene-induced tumors, including cytotoxicity, inflammation, and regenerative cell proliferation,
are acknowledged within the MOA discussion. The text was also expanded to discuss other potential
contributors to benzo[a]pyrene-induced carcinogenicity, such as immune suppression, inflammatory
responses, and AhR binding (i.e. regulation of benzo[a]pyrene metabolism/upregulation of progression
related genes). However, there is not sufficient evidence that these mechanisms act independently of DNA
damage and mutation to produce benzo[a]pyrene-induced tumors. A discussion to this effect was added to
the cancer MOA section. In addition, EPA has included a charge question asking for comment on the
conclusion that a mutagenic mode of action is the primary mode of action of benzo[a]pyrene-induced
carcinogenicity (question C4).

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Topic #8: Consideration of data on biotransformation enzyme activity in infants and children and
the application of age-dependent adjustment factors (ADAFs) - DOD commented that due to the

decreased expression ofbioactivation enzymes in early lifestages, children may be less susceptible to
benzo[a]pyrene-induced carcinogenesis. DOD suggested that EPA include comparative data for age-specific
metabolic activity. In addition DOD requested that EPA provide a stronger rationale for EPA's assertion that
children are expected to be more susceptible to benzo[a]pyrene-induced carcinogenicity.

EPA RESPONSE: EPA acknowledges that infants are generally understood to have lower expression of
cytochrome p450 (CYP) enzymes (Ginsberg et al., 2004; Cresteil, 1998). Data in young animals indicate
that benzo[a]pyrene exposure shortly after birth results in induction CYP1A1 (Wu et al., 2003) and
increased carcinogenicity (Melikian et al., 1989; Vesselinovitch et al., 1975). However, studies in humans
which quantitatively inform early postnatal expression of CYP1A1, the primary phase I bioactivation
enzyme for benzo[a]pyrene, were not identified. While the degree of benzo[a]pyrene metabolism in the
infant is unclear, numerous studies have indicated that this metabolism occurs in the developing fetus and
in children, as indicated by the detection of benzo[a]pyrene specific DNA adducts, protein adducts, or
urinary metabolites (Naufal et al., 2010; Ruchirawat et al., 2010; Suter et al., 2010; Mielzynska et al., 2006;
Perera etal., 2005a; Tang et al., 1999; Whyatt et al., 1998). Other toxicokinetic differences in infants and
children may increase susceptibility to benzo[a]pyrene-induced carcinogenicity, such as decreased activity
of Phase II detoxifying enzymes, increased liver to body mass ratio, and increased blood flow to the liver
(Ginsberg et al., 2004; Pacifici et al., 1988).

An expanded discussion of age-related toxicokinetics of benzo[a]pyrene was added to the Populations or
Lifestages Particularly Susceptible to the Hypothesized Mode of Action section of the Toxicological Review
and the Toxicokinetics section (see the Supplemental Information to the Toxicological Review).

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