United States
Environmental Protection
1=1 m m Agency
EPA/690/R-07/032F
Final
9-05-2007
Provisional Peer Reviewed Toxicity Values for
Pyrene
(CASRN 129-00-0)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms and Abbreviations
bw
body weight
cc
cubic centimeters
CD
Caesarean Delivered
CERCLA
Comprehensive Environmental Response, Compensation and Liability Act

of 1980
CNS
central nervous system
cu.m
cubic meter
DWEL
Drinking Water Equivalent Level
FEL
frank-effect level
FIFRA
Federal Insecticide, Fungicide, and Rodenticide Act
g
grams
GI
gastrointestinal
HEC
human equivalent concentration
Hgb
hemoglobin
i.m.
intramuscular
i.p.
intraperitoneal
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
i.v.
intravenous
kg
kilogram
L
liter
LEL
lowest-effect level
LOAEL
lowest-observed-adverse-effect level
LOAEL(ADJ)
LOAEL adjusted to continuous exposure duration
LOAEL(HEC)
LOAEL adjusted for dosimetric differences across species to a human
m
meter
MCL
maximum contaminant level
MCLG
maximum contaminant level goal
MF
modifying factor
mg
milligram
mg/kg
milligrams per kilogram
mg/L
milligrams per liter
MRL
minimal risk level
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-ob served-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
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PBPK
physiologically based pharmacokinetic
ppb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
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9-5-2007
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
PYRENE (CASRN 129-00-0)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
IRIS (U.S. EPA, 1997a) provides a chronic RfD of 3E-2 mg/kg-day developed from a
NOAEL of 75 mg/kg-day with a combined uncertainty factor of 3000 (10 each for intra- and
interspecies variability, 10 for the use of a subchronic study for chronic RfD derivation, and an
additional 3 to account for the lack of both toxicity studies in a second species and
developmental/reproductive studies) using a 13 week gavage study in mice, conducted by
Toxicity Research Laboratories, Muskegon, MI (U.S. EPA, 1989) for the Office of Solid Waste,
Washington, DC. The critical effects were renal tubular pathology and decreased kidney
weights. IRIS (U.S. EPA, 2007) did not develop an RfC. IRIS (U.S. EPA, 2007) provided a
classification of D, not classifiable as to human carcinogenicity based on no human data and
inadequate data from animal experiments. A subchronic RfD is currently listed on HEAST of
3E-1 mg/kg-day which will be removed when this PPRTV is activated (U.S. EPA, 1997b). It
was based on the same study as this PPRTV.
A cancer classification for pyrene of Group D is listed in the Drinking water Standard
and Health Advisory lists (U.S. EPA, 2000) based on an assessment of pyrene from the Drinking
Water Criteria Document for polycyclic aromatic hydrocarbons (U.S. EPA, 1990). The CARA
lists (U.S. EPA, 1991, 1994) report a Health Effects Assessment (U.S. EPA 1984) and a Health
and Environmental Effects Profile (HEEP) U.S. EPA 1987) for pyrene. ATSDR (2001) has not
published a toxicological profile for pyrene, but it is included in the profile for polycyclic
aromatic hydrocarbons (ATSDR, 1995). IARC has assigned pyrene to Group 3, not classifiable
as to its carcinogenicity to humans, based on no human data and limited animal data (IARC,
1983, 1987). A multimedia document for polycyclic aromatic hydrocarbons (U.S. EPA, 1992)
and the NTP status reports (NTP, 2001) were also searched to identify relevant data. Literature
searches for all exposure routes and effects were conducted from 1989 to December 2000 and
updated to 2007. The databases searched were: TOXLINE, TSCATS, CANCERLIT,
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9-5-2007
MEDLINE, GENETOX, HSDB, EMIC/EMIC/EMICBACK, DART/ETICBACK, CCRIS AND
RTECS.
This document has passed the STSC quality review and peer review evaluation indicating
that the quality is consistent with the SOPs and standards of the STSC and is suitable for use by
registered users of the PPRTV system.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
No human studies were located regarding exposure of humans to pyrene.
Animal Studies
A U.S. EPA (1989) study conducted by Toxicity Research Laboratories, Muskegon MI
for the Office of Solid Waste, Washington DC was the basis of IRIS's chronic RfD or 3E-2
mg/kg-day. Male and female CD-I mice (20/sex/group) were gavaged with 0, 75, 125, or 250
mg/kg/day pyrene in corn oil for 13 weeks. The toxicological parameters examined in this study
included body weight changes, food consumption, mortality, clinical pathological evaluations of
major organs and tissues, and hematology and serum chemistry. Nephropathy, characterized by
the presence of multiple foci of renal tubular regeneration, often accompanied by interstitial
lymphocytic infiltrates and/or foci of interstitial fibrosis, was present in 4, 1, 1, and 9 male mice
in the control, low-, medium-, and high-dose groups, respectively. Similar lesions were seen in 2,
3, 7, and 10 female mice in the 0, 75, 125, and 250 mg/kg treatment groups. The kidney lesions
were described as minimal or mild in all dose groups. Relative and absolute kidney weights were
reduced in the two higher dosage groups. Based on the results of this study, the low dose (75
mg/kg/day) was considered the NOAEL and 125 mg/kg/day the LOAEL for nephropathy and
decreased kidney weights. The IRIS RfD of 3E-2 mg/kg-day was calculated using a composite
uncertainty factor of 3000, including 10 each for intra- and interspecies variability, and an
additional 3 to account for the lack of both toxicity studies in a second species and
developmental/reproductive studies and 10 for extrapolation from subchronic to chronic.
White and White (1939) fed six male rats (unspecified strain) a diet containing 2000 mg
pyrene/kg for 40 days. The average reported food intake for two animals was 6.1 g/day, and the
average body weight for these two animals was 94.3 g. A decrease in body weight gain was
observed in two animals. The authors stated that this body weight gain was representative of the
whole group; although there was no change in food intake. White and White (1939) also
observed enlarged livers and increased hepatic lipid content in animals treated with pyrene,
benzpyrene or methylcholanthrene in the diet; however, incidence data were not reported and it
is unclear whether this effect occurred in the pyrene treated rats. Interpretation of this study is
further complicated by the lack of experimental controls and statistical analysis, small sample
size, and incomplete reporting of histopathology results.
No other useful studies are available that examine only pyrene exposure
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Other studies
Pyrene has been assayed for genotoxicity in a number of tests with both positive and
negative results. These have been extensively reviewed by EPA (U.S. EPA, 1984, 1987, 2000,
2001) and only those studies published since the most recent EPA review was performed are
included in the following text.
In vitro genotoxicity tests of pyrene in prokaryotic systems have produced mixed results.
The consensus conclusion on the WHO international collaborative study (which involved 20
bacterial test sets) was that protocol or evaluation criteria were critical factors in individual test
verdicts (WHO, 1990). Pyrene has been shown to bind to DNA (Chen, 1983) and to form DNA
adducts (Segerback and Vodicka, 1993), but was not mutagenic in DNA damage assays in
Escherichia coli and Bacillus subtilis (Hellmer and Bolcsfold, 1992; Kranendonk et al., 1994,
1996; Mersch-Sundermann et al., 1992, 1993; Rossman et al., 1991). Both positive (Johnson,
1992)	and negative (Rexroat et al., 1995; Rusina et al., 1992; Van der Lelie et al., 1997) results
have been reported in bacterial gene mutation tests. Pyrene induced increased incidence of
mitotic gene conversion but not other genetic endpoints in yeast (deSerres et al., 1981).
Most in vitro tests in mammalian cells have given negative results. Pyrene gave mixed
results in tests of unscheduled DNA synthesis (Heil and Reifferscheid, 1992; Selden et al., 1994)
and was mostly negative in tests for sister chromatid exchange and negative for chromosome
aberrations (Darroudi and Natarajan, 1993; Natarajan and Darroudi, 1991). Pyrene was
mutagenic in the L5178Y mouse lymphoma gene mutation assay when metabolically activated
(Oberly et al., 1993), but was not mutagenic in metabolically competent human lymphoblastoid
cells (Busby et al., 1994; Durant et al., 1996) and did not induce micronucleus formation in a
variety of mammalian cell types (Crofton-Sleigh et al., 1993; Fritzenschaf et al., 1993; Muller-
Tegethoff et al., 1995; Natarajan and Darroudi, 1991; Neslany and Marzin, 1999). Results of
mammalian cell transformation assays have also been negative (U.S. EPA, 2000).
In vivo genotoxicity tests of pyrene have also produced mostly negative results. Pyrene
produced no increase or only a slight increase in sex-linked recessive lethals in Drosophila and
was negative in the Drosophila eye mosaic assay (Fujikawa et al., 1993; Vogel and Nivard,
1993).	Application of pyrene to the skin of hairless mice produced no increase in micronucleus
induction in keratinocytes (He and Baker, 1991). Pyrene was positive in the newt micronucleus
test (Fernandez et al., 1989).
DERIVATION OF A PROVISIONAL SUBCHRONIC OR CHRONIC RfD
FOR PYRENE
A U.S. EPA (1989) study conducted by Toxicity Research Laboratories, Muskegon MI
for the Office of Solid Waste, Washington DC was utilized by IRIS for development of a chronic
RfD. This study was selected for development of a provisional subchronic RfD. Based on the
results of this study, the low dose (75 mg/kg/day) was considered the NOAEL and 125
mg/kg/day the LOAEL for nephropathy and decreased kidney weights.
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9-5-2007
A composite uncertainty factor of 300 was applied to the NOAEL of 75 mg/kg-day; 10
each for intra- and interspecies variability, and an additional 3 to account for the lack of both
toxicity studies in a second species and developmental/reproductive studies providing a
subchronic RfD of 0.25 mg/kg-day or 3E-1 mg/kg-day.
NOAEL/ Uncertainty Factors = 75/300 = 0.25 or 3E-1 mg/kg-day
Confidence in the principal study is medium, as it was a well-designed experiment that
examined a variety of toxicological endpoints and identified both a NOAEL and LOAEL for the
critical effect. Confidence in the database is low, due to the lack of supporting subchronic,
chronic, and developmental/reproductive studies. Accordingly, confidence in the provisional
subchronic RfD is low.
DERIVATION OF A PROVISIONAL SUBCHRONIC OR CHRONIC RfC
FOR PYRENE
No provisional RfC is developed due to lack of usable information.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR PYRENE
IRIS (U.S. EPA, 2007) provides no quantitative assessments (OSF or IUR) for pyrene
and classifies it as classification of D, not classifiable as to human carcinogenicity based on no
human data and inadequate data from animal experiments. Based on the U.S. EPA (2005)
Cancer Guidelines, pyrene can be classified as "not likely to be a human carcinogen".
No data is currently available and suitable for developing cancer values.
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Crofton-Sleigh, C., A. Doherty, S. Ellard et al. 1993. Micronucleus assays using cytochalasin-
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