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Benzo[a]pyrene (BaP)
CASRN 50-32-8
Contents
0136
Benzo[a]pyrene (BaP); CASRN 50-32-8
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR BaP
File On-Line 03/31/1987
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 11/01/1994
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Benzo[a]pyrene (BaP)
CASRN -- 50-32-8
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Benzo[a]pyrene (BaP)
CASRN -- 50-32-8
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Benzo[a]pyrene (BaP)
CASRN -- 50-32-8
Last Revised -- 11/01/1994
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
NOTE: At the June 1992 CRAVE Work Group meeting, a revised risk estimate for
benzo[a]pyrene was verified (see Additional Comments for Oral Exposure). This
section provides information on three aspects of the carcinogenic risk
assessment for the agent in question; the U.S. EPA classification, and
quantitative estimates of risk from oral exposure and from inhalation
exposure. The classification reflects a weight-of-evidence judgment of the
likelihood that the agent is a human carcinogen. The quantitative risk
estimates are presented in three ways. The slope factor is the result of
application of a low-dose extrapolation procedure and is presented as the risk
per (mg/kg)/day. The unit risk is the quantitative estimate in terms of
either risk per ug/L drinking water or risk per ug/cu.m air breathed. The
third form in which risk is presented is a drinking water or air concentration
providing cancer risks of 1 in 10,000 or 1 in 1,000,000. The Carcinogenicity
Background Document provides details on the rationale and methods used to
derive the carcinogenicity values found in IRIS. Users are referred to the
Oral Reference Dose (RfD) and Reference Concentration (RfC) sections for
information on long-term toxic effects other than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- B2; probable human carcinogen
Basis -- Human data specifically linking benzo[a]pyrene (BAP) to a
carcinogenic effect are lacking. There are, however, multiple animal studies
in many species demonstrating BAP to be carcinogenic following administration
by numerous routes. BAP has produced positive results in numerous
genotoxicity assays.
___II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate. Lung cancer has been shown to be induced in humans by various
mixtures of polycyclic aromatic hydrocarbons known to contain BAP including
cigarette smoke, roofing tar and coke oven emissions. It is not possible,
however, to conclude from this information that BAP is the responsible agent.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Sufficient. The animal data consist of dietary, gavage, inhalation,
intratracheal instillation, dermal and subcutaneous studies in numerous
strains of at least four species of rodents and several primates. Repeated
BAP administration has been associated with increased incidences of total
tumors and of tumors at the site of exposure. Distant site tumors have also
been observed after BAP administration by various routes. BAP is frequently
used as a positive control in carcinogenicity bioassays.
BAP administered in the diet or by gavage to mice, rats and hamsters has
produced increased incidences of stomach tumors. Neal and Rigdon (1967) fed
BAP (purity not reported) at concentrations of 0, 1, 10, 20, 30, 40, 45, 50,
100 and 250 ppm in the diets of male and female CFW-Swiss mice. The age of
the mice ranged from 17-180 days old and the treatment time from 1-197 days;
the size of the treated groups ranged from 9 to 73. There were 289 mice
(number of mice/sex not stated) in the control group. No forestomach tumors
were reported in the 0-, 1- and 10-ppm dose groups. The incidence of
forestomach tumors in the 20-, 30-, 40-, 45-, 50-, 100- and 250-ppm dose
groups were 1/23, 0/37, 1/40, 4/40, 23/34, 19/23 and 66/73, respectively. The
authors felt that the increasing tumor incidences were related to both the
concentration and the number of doses administered. Historical control
forestomach tumor data are not available for CFW-Swiss strain mice. In
historical control data from a related mouse strain, SWR/J Swill, the
forestomach tumor incidence rate was 2/268 and 1/402 for males and females,
respectively (Rabstein et al., 1973).
Brune et al., (1981) fed 0.15 mg/kg BAP (reported to be "highly pure") in
the diet of 32 Sprague-Dawley rats/sex/group either every 9th day or 5
times/week. These treatments resulted in annual average doses of 6 or 39
mg/kg, respectively. An untreated group of 32 rats/sex served as the control.
Rats were treated until moribund or dead; survival was similar in all groups.
Histologic examinations were performed on each rat. The combined incidence of
tumors of the forestomach, esophagus and larynx was 3/64, 3/64 and 10/64 in
the control group, the group fed BAP every 9th day and the group fed BAP 5
times/week, respectively. A trend analysis showed a statistically significant
tendancy for the proportion of animals with tumors of the forestomach,
esophagus or larynx to increase steadily with dose (Knauf and Rice, 1992).
As part of the same study, Brune et al. (1981) administered BAP ("highly
pure") orally to Sprague-Dawley rats by caffeine gavage. The rats were
treated until moribund or dead; all rats were subjected to terminal
histopathologic examination. Gavaged rats were divided into 3 dose groups of
32 rats/sex/group; the groups received 0.15 mg/kg per gavage either every 9th
day (Group A), every 3rd day (Group B) or 5 times per week (Group C); these
treatments resulted in annual average doses of 6, 18 or 39 mg/kg,
respectively. Untreated and gavage (5 times/week) controls (32
rats/sex/group) were included. The median survival times for the untreated
control group; the gavage control group; and groups A, B and C were 129, 102,
112, 113 and 87 weeks, respectively. The survival time of Group C was short
compared with controls and may have precluded tumor formation (Knauf and Rice,
1992). The combined tumor incidence in the forestomach, esophagus and larynx
was 3/64, 6/64, 13/64, 26/64 and 14/64 for the untreated control group, gavage
control group, group A, group B and group C, respectively. There was a
statistically significant association between the dose and the proportions of
rats with tumors of the forestomach, esophagus or larynx. This association is
not characterized by a linear trend. The linearity was affected by the
apparently reduced tumor incidence that is seen in the high-dose group (Knauf
and Rice, 1992).
Intratracheal instillation and inhalation studies in guinea pigs, hamsters
and rats have resulted in elevated incidences of respiratory tract and upper
digestive tract tumors (U.S. EPA, 1991a). Male Syrian golden hamsters
(24/group) were exposed by inhalation to 0, 2.2, 9.5 or 46.5 mg BAP/cu.m in a
sodium chloride aerosol (Thyssen et al., 1981). (Greater than 99% of the
particles had diameters between 0.2 and 0.5 um.) For the first 10 weeks of
the study, the hamsters were exposed to BAP daily for 4.5 hours/day;
thereafter, daily for 3 hours/day. Animals dying within the first year of the
study were replaced; the effective number of hamsters in the control, low-,
mid- and high-dose groups was 27, 27, 26 and 25, respectively. (The total
time of treatment, although over 60 weeks, was not stated.) During the first
10 weeks, animals in the 3 dose groups reportedly lost weight. After week 10,
however, the body weights in all groups were similar until week 60 when the
body weights of hamsters in the high-dose group decreased and the mortality
increased significantly. The incidence of respiratory tract tumors (including
tumors of the nasal cavity, larynx and trachea) in the control, low-, mid- and
high-dose groups was 0/27, 0/27, 9/26 and 13/25, respectively; the incidences
of upper digestive tract tumors (including tumors of the pharynx, esophagus
and forestomach) were 0/27, 0/27, 7/26 and 14/25, respectively. Trend
analysis for incidences of both respiratory tract tumors and upper
gastrointestinal tract tumors showed a statistically significant tendancy for
the proportion of animals with either tumor type to increase steadily with
increased dose (Knauf and Rice, 1992).
Intraperitoneal BAP injections have caused increases in the number of
injection site tumors in mice and rats (reviewed in U.S. EPA, 1991a).
Subcutaneous BAP injections have caused increases in the number of injection
site tumors in mice, rats, guinea pigs, hamsters and some primates (IARC,
1983; U.S. EPA, 1991a). BAP is commonly used as a positive control in many
dermal application bioassays and has been shown to cause skin tumors in mice,
rats, rabbits and guinea pigs. BAP is both an initiator and a complete
carcinogen in mouse skin (IARC, 1983). Increased incidences of distant site
tumors have also been reported in animals as a consequence of dermal BAP
exposure (reviewed in U.S. EPA, 1991a).
BAP has also been reported to be carcinogenic in animals when administered
by the following routes: i.v.; transplacentally; implantation in the stomach
wall, lung, renal parenchyma and brain; injection into the renal pelvis; and
vaginal painting (U.S. EPA, 1991a).
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Benzo[a]pyrene has been shown to cause genotoxic effects in a broad range
of prokaryotic and mammalian cell assay systems (U.S. EPA, 1991a). In
prokaryotes, BAP tested positive in DNA damage assays and in both reverse and
forward mutation assays. In mammalian cell culture assays, BAP tested
positive in DNA damage assays, forward mutation assays, chromosomal effects
assays and cell transformation assays.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
NOTE: The range of oral slope factors calculated was: 4.5E+0 to 11.7E+0 per
(mg/kg)/day.
___II.B.1. SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 7.3E+0 per (mg/kg)/day
Drinking Water Unit Risk -- 2.1E-4 per (ug/L)
Extrapolation Method -- Risk estimate based on a geometric mean of four slope
factors obtained by differing modeling procedures. Derived from the
combination of multiple data sets from two different reports using more than
one sex and species.
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- -------------
E-4 (1 in 10,000) 5E-1 ug/L
E-5 (1 in 100,000) 5E-2 ug/L
E-6 (1 in 1,000,000) 5E-3 ug/L
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Tumor Type -- forestomach, squamous cell papillomas and carcinomas
Test Animals -- CFW mice, sex unknown
Route -- oral, diet
Reference -- Neal and Rigdon, 1967
a) Conditional upper bound two-stage model with terms for promotion
(modification of Moolgavkar-Venson-Knudson, generalized forms of two-stage
model)
Administered
Dose (ppm) Tumor Incidence
------------ ---------------
0 0/289
1 0/25
10 0/24
20 1/23
30 0/37
40 1/40
45 4/40
50 24/34
100 19/23
250 66/73
Tumor Type -- squamous cell carcinoma of the forestomach
Test Animals -- SWR/J Swill mice
Route -- oral, diet
Reference -- Rabstein et al., 1973
Administered
Dose (ppm) Tumor Incidence
------------ ---------------
0 2/268* male
0 1/402* female
*See additional comments concerning the use of control data from other studies
that utilized similar mouse strains.
b) Same data as above. Upper bound estimate by extrapolation from 10%
response point to background of empirically fitted dose-response curve.
(Procedure using two-stage model described in (a)).
c) Same data as above except the additional 2 control groups (Rabstein et al.,
1973) were excluded. Generalized Weibull-type dose-response model.
d) Tumor Type -- forestomach, larynx and esophagus, papillomas and carcinomas
(combined). Linearized Multistage Model, Extra Risk.
Test Animals -- Sprague-Dawley rats, males and females
Route -- oral, diet
Reference -- Brune et al., 1981
Dose Tumor
(mg/kg diet/year) Incidence
----------------- ---------
0 3/64
6 3/64
39 10/64
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
At the June 1992 CRAVE Work Group meeting, it was noted that an error had
been made in the 1991 document "Dose-Response Analysis of Ingested
Benzo[a]pyrene" which is quoted in the Drinking Water Criteria Document for
PAH. In the calculation of the doses in the Brune et al. (1981) study it was
erroneously concluded that doses were given in units of mg/year, whereas it
was in fact mg/kg/year. When the doses are corrected the slope factor is
correctly calculated as 11.7 per (mg/kg)/day, as opposed to 4.7 per
(mg/kg)/day as reported in the Drinking Water Criteria Document. The correct
range of slope factors is 4.5 to 11.7 per (mg/kg)/day, with a geometric mean
of 7.3 per (mg/kg)/day. A drinking water unit risk based on the revised slope
factor is 2.1E-4 per (ug/L). Therefore, these values have been changed on
IRIS and an Erratum to the Drinking Water Criteria Document is being prepared.
Risk estimates were calculated from two different studies in two species
of outbred rodents (Neal and Rigdon, 1967; Brune et al., 1981). These studies
have several commonalities including mode of administration, tumor sites,
tumor types and the presumed mechanisms of action. The data sets were not
combined prior to modeling (the preferred approach) because they employed
significantly dissimilar protocols.
The geometric mean from several slope factors, each considered to be of
equal merit, was used to calculate a single unit risk. These four slope
factor estimates span less than a factor of three and each is based on an
acceptable, but less-than-optimal, data set. Each estimate is based on a low-
dose extrapolation procedure which entails the use of multiple assumptions and
default procedures.
Clement Associates (1990) fit the Neal and Rigdon (1967) data to a two-
stage dose response model. In this model the transition rates and the growth
rate of preneoplastic cells were both considered to be exposure-dependent.
(The functional form for the dose-dependence of preneoplastic cell growth rate
was simple saturation.) A term to permit the modeling of BAP as its own
promoter was also included. Historical control stomach tumor data from a
related, but not identical, mouse strain, SWR/J Swill (Rabstein et al., 1973)
and the CFW Texas colony (Neal and Rigdon, 1967) were used in the modeling. In
calculating the lifetime unit risk for humans several standard assumptions
were made: mouse food consumption was 13% of its body weight/day; human body
weight was assumed to be 70 kg and the assumed body weight of the mouse 0.034
kg. The standard assumption of surface area equivalence between mice and
humans was the cube root of 70/0.034. A conditional upper bound estimate was
calculated to be 5.9 per (mg/kg)/day (U.S. EPA, 1991a).
A U.S. EPA report (1991b) argued that the upper-bound estimate calculated
in Clement Associates (1990) involved the use of unrealistic conditions placed
on certain parameters of the equation. Other objections to this slope factor
were also raised. The authors of this report used the Neal and Rigdon (1967)
data to generate an upper-bound estimate extrapolated linearly from the 10%
response point to the background of an empirically fitted dose-response curve
(Clement Associates, 1990). Other results, from similar concepts and
approaches used for other compounds, suggest that the potency slopes
calculated in this manner are comparable to those obtained from a linearized
multistage procedure for the majority of the other compounds. The upper bound
estimate calculated in U.S. EPA (1991b) is 9.0 per (mg/kg)/day.
The authors of U.S. EPA (1991b) selected a model to reflect the partial
lifetime exposure pattern over different parts of the animals' lifetimes. The
authors thought that this approach more closely reflected the Neal and Rigdon
(1967) regimen. A Weibull-type dose-response model was selected to
accommodate the partial lifetime exposure; the upper-bound slope factor
calculated from this method was 4.5 per (mg/kg)/day.
Using the dietary portion of the Brune et al. (1981) rat data, a
linearized multistage procedure was used to calculate an upper bound slope
factor for humans. In the interspecies conversion the assumed human body
weight was 70 kg and the rat 0.4 kg. The slope factor calculated by this
method was 11.7 per (mg/kg)/day.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
The data are considered to be less than optimal, but acceptable. There
are precedents for using multiple data sets from different studies using more
than one sex, strain and species; the use of the geometric mean of four slope
factors is preferred because it makes use of more of the available data. The
use of the geometric means was based on arguments presented in a personal
communication (Stiteler, 1991).
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1991a,b
The 1991 Drinking Water Criteria Document for the polycyclic aromatic
hydrocarbons has received agency review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 01/07/1987, 12/04/1991, 06/03/1992, 08/05/1993, 02/02/1994,
06/09/1994
Verification Date -- 12/04/1991
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Benzo[a]pyrene (BaP)
CASRN -- 50-32-8
Last Revised -- 12/01/1993
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Brune, H., R.P. Deutsch-Wenzel, M. Habs, S. Ivankovic and D. Schmahl. 1981.
Investigation of the tumorigenic response to benzo[a]pyrene in aqueous
caffeine solution applied orally to Sprague-Dawley rats. J. Cancer Res. Clin.
Oncol. 102(2): 153-157.
Clement Associates. 1990. Ingestion dose-response model to benzo(a)pyrene.
EPA Control No. 68-02-4601.
IARC (International Agency for Research on Cancer). 1983. Certain Polycyclic
Aromatic Hydrocarbons and Heterocyclic Compounds. Monographs on the
Evaluation of Carcinogenic Risk of the Chemical to Man, Vol. 3. Lyon, France.
Knauf, L. and G. Rice. 1992. Statistical Evaluation of Several
Benzo[a]pyrene Bioassays. Memorandum to R. Schoeny, U.S. EPA, Cincinnati, OH.
January 2.
Neal, J. and R.H. Rigdon. 1967. Gastric tumors in mice fed benzo[a]pyrene --
A quantitative study. Tex. Rep. Biol. Med. 25(4): 553-557.
Rabstein, L.S., R.L. Peters and G.J. Spahn. 1973. Spontaneous tumors and
pathologic lesions in SWR/J mice. J. Natl. Cancer Inst. 50: 751-758.
Stiteler, W. 1991. Syracuse Research Corporation, Syracuse, NY. Personal
communication with R. Schoeny, U.S. EPA, Cincinnati, OH.
Thyssen, J., J. Althoff, G. Kimmerle and U. Mohr. 1981. Inhalation studies
with benzo[a]pyrene in Syrian golden hamsters. J. Natl. Cancer Inst.
66: 575-577.
U.S. EPA. 1991a. Drinking Water Criteria Document for PAH. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Water Regulations and
Standards, Washington, DC.
U.S. EPA. 1991b. Dose-Response Analysis of Ingested Benzo[a]pyrene (CAS No.
50-32-8). Human Health Assessment Group, Office of Health and Environmental
Assessment, Washington, DC. EPA/600/R-92/045.
_VII. REVISION HISTORY
Substance Name -- Benzo[a]pyrene (BaP)
CASRN -- 50-32-8
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
08/01/1989 VI. Bibliography on-line
01/01/1992 II. Carcinogen assessment noted as pending change
01/01/1992 IV. Regulatory actions updated
04/01/1992 II. Summary revised; oral quantitative section added
04/01/1992 VI.C. Carcinogen assessment references revised
05/01/1992 II.D.2. Work group review and verification date corrected
07/01/1992 II. Text revised in NOTE
07/01/1992 II.B. Range of slope factors corrected
07/01/1992 II.B.1. Slope factor and risks corrected
07/01/1992 II.B.2. Data table heading corrected
07/01/1992 II.B.3. Slope factor corrected; last paragraph
07/01/1992 II.D.3. Secondary contact changed
09/01/1993 II. Carcinogenicity assessment noted as pending change
09/01/1993 II.D.2. Work group review date added
12/01/1993 VI.C. Reference revised - U.S. EPA, 1991b
02/01/1994 II.D.3. Primary contact's phone number changed
03/01/1994 II. Pending change note removed; no change
03/01/1994 II.D.2. Work group review date added
07/01/1994 II.D.2. Work group review date added
11/01/1994 II.B.1. Slope factor clarified; changed O to "0"
VIII. SYNONYMS
Substance Name -- Benzo[a]pyrene (BaP)
CASRN -- 50-32-8
Last Revised -- 03/31/1987
50-32-8
BaP
Benzo[a]pyrene
BENZO(d,e,f)CHRYSENE
3,4-BENZOPIRENE
3,4-BENZOPYRENE
6,7-BENZOPYRENE
BENZO(a)PYRENE
3,4-BENZPYREN
3,4-BENZPYRENE
3,4-BENZ(a)PYRENE
BENZ(a)PYRENE
3,4-BENZYPYRENE
BP
3,4-BP
B(a)P
RCRA WASTE NUMBER U022
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0136.HTM
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