£% ["j'liJl United States
Environmental Protection
^J^lniiil M % Agency
EPA/690/R-02/001F
Final
4-30-2002
Provisional Peer Reviewed Toxicity Values for
Acrolein
(CASRN 107-02-8)
Derivation of an Oral Slope Factor
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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4-30-2002
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
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p-RfD
provisional oral reference dose
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
li

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PROVISIONAL PEER REVIEWED TOXICITY VALUES
FOR ACROLEIN (CASRN 107-02-8)
Derivation of an Oral Slope Factor
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
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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.
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
The CRAVE workgroup (U.S. EPA, 1992) assigned acrolein to weight-of-evidence
Group C, possible human carcinogen, on the basis of no evidence in humans and limited
evidence in animals (increased incidence of adrenal cortical adenomas in female rats in an oral
study, but no increased tumors in inadequate inhalation, skin painting, and subcutaneous
injection studies). Supporting evidence included the carcinogenic potential of an acrolein
metabolite, the mutagenicity of acrolein in bacteria, and the structural relationship of acrolein to
probable or known human carcinogens. This assessment is listed on IRIS (U.S. EPA, 2001). No
oral slope factor for acrolein is listed on IRIS (U.S. EPA, 2001), in the HEAST (U.S. EPA,
1997), or in the Drinking Water and Health Advisories list (U.S. EPA, 2000). Source documents
for the IRIS assessment were a Health Assessment Document (HAD) (U.S. EPA, 1986) and a
Health Effects Assessment (HEA) for acrolein (U.S. EPA, 1987). The CARA list (U.S. EPA,
1991, 1994) also includes a Health and Environmental Effects Profile (HEEP) on acrolein (U.S.
EPA, 1985). IARC (1979, 1985, 1995) assigned acrolein to Group 3, not classifiable as to
human carcinogenicity because of inadequate evidence in humans and animals. A Toxicological
Profile for acrolein (ATSDR, 1990), an Environmental Health Criteria document on acrolein
(WHO, 1992), a carcinogenicity review of low-molecular-weight aldehydes (NIOSH, 1991), and
a toxicity review on aldehydes (Morandi and Maberti, 2001) were consulted for relevant
information. The NTP (2001) health and safety report for acrolein was also examined. These
resources contained no additional studies of acrolein itself. However, a metabolite of acrolein,
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glycidaldehyde, yielded positive results for carcinogenicity in skin painting assays in mice and
subcutaneous injection assays in mice and rats. In addition, the reviews note that acrolein is a
metabolite of cyclophosphamide, an immunosuppressive drug that is associated with an increase
in bladder cancer in humans. The reviews report both positive and negative results for acrolein
in genotoxicity tests. Literature searches were conducted from 1988 to April 2001 for studies
relevant to the derivation of an oral slope factor for acrolein. The databases searched were:
TOXLINE, MEDLINE, CANCERLIT, RTECS, GENETOX, HSDB, CCRIS, TSCATS,
EMIC/EMICBACK, and DART/ETICBACK.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
Reviews by the U.S. EPA (1985, 1986, 1987) and other agencies (ATSDR, 1990;
NIOSH, 1991; WHO, 1992; IARC, 1979, 1985, 1995) reported that no relevant data were
available regarding carcinogenicity of acrolein in humans following oral exposure. No relevant
human studies were located in the literature search.
Animal Studies
Reviews by the U.S. EPA (1985, 1986, 1987) and other agencies (ATSDR, 1990; WHO,
1992; IARC, 1979, 1985, 1995) reported that the data regarding carcinogenicity in animals
following oral exposure to acrolein were limited. The cancer assessment on IRIS (U.S. EPA,
2001) is based on the increased incidence of adrenal cortical adenomas (5/20 vs 0/20 controls)
observed in female rats exposed to 625 ppm of acrolein in drinking water for 100 weeks
(Lijinsky and Reuber, 1987). The literature search located two additional oral carcinogenicity
assays for acrolein in rodents.
No increased tumor incidence was reported in rats exposed to acrolein by gavage for 2
years, but the complete tumor incidence data were not available for evaluation (Parent et al.,
1992). Groups of Sprague-Dawley rats (70 per sex per group) were gavaged with acrolein (94.9-
98.5% pure, stabilized with 0.25% hydroquinone) at doses of 0, 0.05, 0.5 or 2.5 mg/kg-day for 2
years. Rats were checked twice daily for signs of toxicity, morbidity and mortality. Detailed
physical examinations were carried out daily for the first 4 weeks and weekly thereafter; animals
were palpated weekly for masses. Body weight and food consumption were recorded weekly for
the first 14 weeks and once every 4 weeks thereafter. At 13 weeks, 5 animals of each sex in the
high-dose group were sacrificed and necropsied; only the stomach was examined for
histopathology. Ten rats of each group sacrificed at 1 year and all surviving rats at termination
were necropsied and organ weights were recorded. In the control and high-dose groups, 42
tissues and any gross lesions were examined by histopathological examination. In the low- and
mid-dose groups, the lungs, liver, kidneys and any gross lesions were examined microscopically;
additional organs were examined if lesions occurred in the high-dose rats. The frequency of
clinical signs (including masses; data not shown) was elevated in a dose-related manner in mid-
and high-dose rats. Treatment caused no significant effect on body weight. There were
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significant dose-related trends for increased mortality in high-dose males during the first year
and in mid- and high-dose females throughout the study. Nevertheless, survival was adequate to
allow for late-developing tumors in all groups. The incidence of tumors in the adrenal gland did
not exhibit any dose-relationship. Since no tumor incidence data were reported for any other
organ, there is no basis for evaluating the authors' statements that tumor incidences were within
historical control values and occurred independently of dose. One source of uncertainty is that
several of the references for historical control data are several decades out-of-date and are,
therefore, not an appropriate basis for evaluating background levels for tumor incidences.
Another source of uncertainty centers on the authors' definition of 'dose-related effects.' In the
context of the frequency of clinical signs, the authors stated that no dose-related effects were
observed, despite finding a dose-effect at the mid- and high-doses; in this instance, low-dose
animals showed fewer clinical signs than controls. Thus, it is not clear whether the authors may
have discounted significant tumor frequencies at higher doses if the incidences in the control
group were higher than in the low exposure group.
No increase in tumor incidence was observed in CD-I mice that were gavaged daily with
acrolein at doses of <4.5 mg/kg-day for 18 months (Parent et al., 1991). Groups of CD-I mice
(70-75 per sex per group) were gavaged with 0, 0.5, 2.0, or 4.5 mg/kg-day of acrolein (94.9-
98.5% pure, stabilized with 0.25% hydroquinone) daily for 18 months. Mice were checked
twice daily for signs of toxicity, morbidity and mortality. Detailed physical examinations were
carried out daily for the first 4 weeks and weekly thereafter; animals were palpated weekly for
masses. Body weight and food consumption were recorded weekly for the first 14 weeks and
once every 4 weeks thereafter. At termination, all mice were subjected to gross necropsy, during
which absolute and relative organ weights of liver, kidneys, brain, and testes were recorded.
Gross lesions from all animals were examined for histopathology; in addition, 44 tissues in the
control and high dose groups, and the lungs, liver, and kidneys of low and mid-dose groups,
were also examined microscopically. Survival was significantly reduced in high-dose males
throughout the study due to an excess of mortality during the first 50 days of exposure.
Nevertheless, survival was adequate to allow for late-developing tumors in all groups. Body
weights were significantly reduced in high-dose males after week 20 and in high- and mid-dose
females after week 30. There was no increase in the incidence of neoplastic lesions in the liver
or lung in mice treated with acrolein compared to controls; no tumor incidence data were
presented for other organs.
Other Studies
Recent studies by other routes provide negative or only suggestive evidence for the
carcinogenicity of acrolein in animals. When doses of 1-2 mg/kg were administered by i.p.
injection into male F344 rats once or twice a week for 6 weeks, acrolein initiated urinary bladder
carcinogenesis promoted by dietary uracil, doubling the incidence of papilloma compared to
uracil treatment alone (Cohen et al., 1992). Papillary/nodular hyperplasia of the bladder
developed in a few rats treated with acrolein alone for 26 weeks, but no tumors developed. In an
acute study by Roemer et al. (1993), groups of 3-5 male Sprague Dawley rats were exposed
(head only) by inhalation to 0, 0.2 or 0.6 ppm of acrolein vapor for 6 hours/day for 1 or 3
successive days. Exposure to acrolein significantly increased cell proliferation in the trachea and
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lung at >0.2 ppm and in the nose at 0.6 ppm. However, the effect of 3 days of exposure was less
than in rats exposed a single time, which the authors considered an adaptive response.
The review documents cited above reported positive and negative results for acrolein in
genotoxicity assays. Varied results were also reported in the additional genotoxicity studies
located in the literature search. With or without metabolic activation with S9, acrolein was
mutagenic in Salmonella typhimurium strains TA100, TA2638, and TA98, and was not
mutagenic in strains TA102, TA104, TA1535, TA1537, or TA1538 (Parent et al., 1996; Eder et
al., 1990; Jung et al., 1992; Kato et al., 1989; Miiller et al., 1993; Watanabe et al., 1998).
Acrolein was mutagenic in the Bacillus subtilis rec-assay without, but not with, S9 activation
(Matsui et al., 1989), was not mutagenic in Escherichia coli WP2/pKM101 or WP2
mr^/pKM 101 without activation (Watanabe et al., 1998), but was marginally mutagenic to
strain WP2 uvrA, with or without activation (Parent et al., 1996). Mutagenicity of acrolein to E.
coli was increased in a strain that was deficient in glutathione (Nunoshiba and Yamamoto,
1999). Acrolein did not induce the expression of SOS-regulated genes in S. typhimurium
TA1535/pSK1002 (Benamira and Marnett, 1992) and E. coli strain PQ37 (Eder et al., 1993).
The formation of acrolein-DNA adducts has been reviewed (Marnett, 1994; Chung et al.,
1999). Endogenous acrolein-derived exocyclic adducts (1 ,N2-propanodeoxyguanosine adducts)
have been identified as common DNA lesions in human and rat liver (Nath and Chung, 1994;
Nath et al., 1996), and human lung and colon (Yang et al., 1999). Acrolein-DNA adducts have
been generated following reactions with deoxynucleotides (Chenna et al., 1992; Chenna and
Iden, 1993), purified eukaryotic DNA (Maccubbin et al., 1990, 1992; Kuchenmeister et al.,
1998), or bacterial cells (Hoffman et al., 1989). Acrolein has induced DNA cross-links in
plasmids (Kawanishi et al., 1998), and DNA-protein cross-links in cultured human lymphoma
cells (Costa et al., 1997), in mixtures of plasmid DNA and calf thymus histone (Kuykendall and
Bogdanffy, 1992), and in SV40 virus (Permana and Snapka, 1994). Acrolein-modified DNA
was identified in peripheral blood leukocytes of 6/12 cancer patients who were treated with
cyclophosphamide, compared to 0/15 patients not treated with the drug (McDiarmid et al.,
1991).
In studies on cultured human bronchial cells (reviewed in Grafstrom, 1990), acrolein
reduced colony forming efficiency, clonal growth rate, and cellular levels of glutathione, and
increased the frequency of DNA single-strand breaks, DNA-protein cross-links, and the percent
of cells synthesizing cross-linked envelopes. Acrolein induced single-strand breaks in DNA in
human skin fibroblasts (Dypbukt et al., 1993), in a human lymphoblastoid cell line (Eisenbrand
et al., 1995), and, at high cytotoxic doses (1 mmol), in Salmonella typhimurium (Eder et al.,
1993).
DERIVATION OF A PROVISIONAL ORAL SLOPE FACTOR
FOR ACROLEIN
The cancer bioassays by Parent et al. (1991, 1992) provide no evidence for increased
tumor incidence in rats or mice following chronic oral exposure to acrolein. In both studies, an
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adequate number of animals of both sexes was tested and evaluated comprehensively, and
survival was long enough for tumors to have been detected. Based on survival and/or body
weight effects at the highest doses, the dosing levels appear to have been adequate for both
species. A limitation of both studies is that reporting of tumor incidence data was restricted to
the adrenals for rats and the lung and liver for mice. Thus, the complete data sets were not
available for evaluation. Older studies provided at best marginal evidence of acrolein
carcinogenicity and were not considered suitable for derivation of an oral slope factor in prior
assessments (U.S. EPA, 2001). On the basis of the available information, it is not possible to
derive a provisional oral slope factor for acrolein.
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Cohen, S.M., E.M. Garland, M. St. John et al. 1992. Acrolein initiates rat urinary bladder
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Dypbukt, J.M., L. Atzori, C.C. Edman and R.C. Grafstrom. 1993. Thiol status and
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Eder, E., S. Scheckenbach, C. Deininger and C. Hoffman. 1993. The possible role of a,P-
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Kawanishi, M., T. Matsuda, A. Nakayama et al. 1998. Molecular analysis of mutations induced
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Kuchenmeister, F., P. Schmezer and G. Engelhardt. 1998. Genotoxic bifunctional aldehydes
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Lijinsky, W. and M.D. Reuber. 1987. Chronic carcinogenesis studies of acrolein and related
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Maccubbin, A.E., L. Lee, R.F. Struck and H.L. Gurtoo. 1992. 32P-postlabeling of acrolein-
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McDiarmid, M.A., P.T. Iype, K. Kolodner et al. 1991. Evidence for acrolein-modified DNA in
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http://ntp-server.niehs.nih.gov/htdocs/Chem H&S/NTP Cheml/Radianl07 02 8.html
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Nunoshiba, T. and K. Yamamoto. 1999. Role of glutathione on acrolein-induced cytotoxicity
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April 2001. Online, http://www.epa.gov/iris/
Watanabe, K., K. Sakamoto and T. Sasaki. 1998. Comparisons on chemically-induced mutation
among four bacterial strains, Salmonella typhimurium TA102 and TA2638, and Escherichia coli
WP2/pKM101 and WP2 wvM/pKM101: Collaborative study II. Mutat. Res. 412: 17-31.
WHO (World Health Organization). 1992. Acrolein. Environ. Health Criteria. 127. Geneva,
Switzerland.
Yang, K., J.-L. Fnag, D. Li et al. 1999. 32P-postlabelling with high-performance liquid
chromatography for analysis of abundant DNA adducts in human tissues. IARC Sci. Publ. 150:
205-217.
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Jffl;	United States
iPilfEnvironmental Protectioi
if % Agency
EPA/690/R-01/000F
Final
11-30-2001
Provisional Peer Reviewed Toxicity Values for
Acrolein
(CASRN 107-02-8)
Derivation of an Inhalation Unit Risk
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
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p-RfD
provisional oral reference dose
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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11-30-2001
PROVISIONAL PEER REVIEWED TOXICITY VALUES
FOR ACROLEIN (CASRN 107-02-8)
Derivation of an Inhalation Unit Risk
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
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11-30-2001
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.
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
The CRAVE workgroup (U.S. EPA, 1992) assigned acrolein to weight-of-evidence
Group C, possible human carcinogen, on the basis of no evidence in humans and limited
evidence in animals (increased incidence of adrenal cortical adenomas in female rats in an oral
study, but no increased tumors in inadequate inhalation, skin painting, and subcutaneous
injection studies). Supporting evidence included the carcinogenic potential of an acrolein
metabolite, the mutagenicity of acrolein in bacteria, and the structural relationship of acrolein to
probable or known human carcinogens. This assessment is listed on IRIS (U.S. EPA, 2001). No
inhalation unit risk factor for acrolein is listed on IRIS (U.S. EPA 2001) or in the HEAST (U.S.
EPA, 1997). Source documents for the IRIS assessment were a Health Assessment Document
(HAD) (U.S. EPA, 1986) and a Health Effects Assessment (HEA) for acrolein (U.S. EPA, 1987).
The CARA list (U.S. EPA, 1991, 1994) also includes a Health and Environmental Effects
Profile (HEEP) on acrolein (U.S. EPA, 1985). IARC (1979, 1985, 1995) assigned acrolein to
Group 3, not classifiable as to human carcinogenicity because of inadequate evidence in humans
and animals. ACGIH (1998, 2000) lists an A4 notation for acrolein, indicating its status as not
classifiable as a human carcinogen. NIOSH (1991, 2001) notes that although carcinogenicity
testing is not complete for acrolein, enough studies report chemical reactivity and mutagenicity
to warrant efforts to reduce exposure. A Toxicological Profile for acrolein (ATSDR, 1990), an
Environmental Health Criteria document on acrolein (WHO, 1992), a carcinogenicity review of
low-molecular-weight aldehydes (NIOSH, 1991), and a toxicity review on aldehydes (Morandi
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11-30-2001
and Maberti, 2001) were consulted for relevant information. The NTP (2001) health and safety
report for acrolein was also examined. These resources contained no additional studies of
acrolein itself. However, a metabolite of acrolein, glycidaldehyde, yielded positive results for
carcinogenicity in skin painting assays in mice and subcutaneous injection assays in mice and
rats. In addition, the reviews note that acrolein is a metabolite of cyclophosphamide, an
immunosuppressive drug that is associated with an increase in bladder cancer in humans. The
reviews report both positive and negative results for acrolein in genotoxicity tests. Literature
searches were conducted from 1988 to April 2001 for studies relevant to the derivation of an
inhalation unit risk for acrolein. The databases searched were: TOXLINE, MEDLINE,
CANCERLIT, RTECS, GENETOX, HSDB, CCRIS, TSCATS, EMIC/EMICBACK, and
DART/ETICBACK.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
Reviews by the U.S. EPA (1985, 1986, 1987) and other agencies (ATSDR, 1990;
NIOSH, 1991; WHO, 1992; IARC, 1979, 1985, 1995) reported that no relevant data were
available regarding carcinogenicity of acrolein in humans following inhalation exposure. The
literature search uncovered a single case report in which acrolein was suggested as the cause of
alveolar cell carcinoma in a non-smoking cook (Wardle, 1988). The author argued that the
individual, who unavoidably inhaled the fumes of hot fat and oils in a confined space over many
years, was likely to have been exposed to acrolein as a common constituent of smoke. However,
exposure to acrolein was not established in this case, and in addition, the individual was likely to
have been exposed to other potential carcinogens as well.
Animal Studies
Reviews by the U.S. EPA (1985, 1986, 1987) and other agencies (ATSDR, 1990; WHO,
1992; IARC, 1979, 1985, 1995) report that the data regarding carcinogenicity in animals
following inhalation exposure to acrolein is limited. No tumors were found in hamsters
intermittently exposed to acrolein for one year, but the duration of the experiment was too short
to allow for latency (Feron and Kruysse, 1977). No additional studies were located in the
literature search regarding carcinogenicity in animals following chronic or subchronic inhalation
exposure to acrolein. The cancer assessment on IRIS (U.S. EPA, 2001) is based on the increased
incidence of adrenal cortical adenomas in female rats exposed to 625 ppm of acrolein in drinking
water for 100 weeks (Lijinsky and Reuber, 1987). However, in more recent studies, acrolein
administered by gavage did not increase the incidence of tumors in mice dosed with <4.5 mg/kg-
day for 18 months (Parent et al., 1991) or in rats dosed with <2.5 mg/kg-day for 2 years (Parent
etal., 1992).
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11-30-2001
Other Studies
Recent short-term studies in animals provide negative or only suggestive evidence of the
carcinogenic potential of acrolein. When doses of 1-2 mg/kg were administered by i.p. injection
into male F344 rats once or twice a week for 6 weeks, acrolein initiated urinary bladder
carcinogenesis promoted by dietary uracil, doubling the incidence of papilloma compared to
uracil treatment alone (Cohen et al., 1992). Papillary/nodular hyperplasia of the bladder
developed in a few rats treated with acrolein alone for 26 weeks, but no tumors developed. In an
acute study by Roemer et al. (1993), groups of 3-5 male Sprague Dawley rats were exposed
(head only) by inhalation to 0, 0.2 or 0.6 ppm of acrolein vapor for 6 hours/day for 1 or 3
successive days. Exposure to acrolein significantly increased cell proliferation in the trachea and
lung at >0.2 ppm and in the nose at 0.6 ppm. However, the effect of 3 days of exposure was less
than in rats exposed a single time, which the authors considered an adaptive response.
The review documents cited above reported positive and negative results for acrolein in
genotoxicity assays. Varied results were also reported in the additional genotoxicity studies
located in the literature search. With or without metabolic activation with S9, acrolein was
mutagenic in Salmonella typhimurium strains TA100, TA2638, and TA98, and was not
mutagenic in strains TA102, TA104, TA1535, TA1537, or TA1538 (Parent et al., 1996; Eder et
al., 1990; Jung et al., 1992; Kato et al., 1989; Miiller et al., 1993; Watanabe et al., 1998).
Acrolein was mutagenic in the Bacillus subtilis rec-assay without, but not with, S9 activation
(Matsui et al., 1989), was not mutagenic in Escherichia coli WP2/pKM101 or WP2
mr^/pKM 101 without activation (Watanabe et al., 1998), but was marginally mutagenic to
strain WP2 uvrA, with or without activation (Parent et al., 1996). Mutagenicity of acrolein to E.
coli was increased in a strain that was deficient in glutathione (Nunoshiba and Yamamoto,
1999). Acrolein did not induce the expression of SOS-regulated genes in S. typhimurium
TA1535/pSK1002 (Benamira and Marnett, 1992) and E. coli strain PQ37 (Eder et al., 1993).
The formation of acrolein-DNA adducts has been reviewed (Marnett, 1994; Chung et al.,
1999). Endogenous acrolein-derived exocyclic adducts (1 ,N2-propanodeoxyguanosine adducts)
have been identified as common DNA lesions in human and rat liver (Nath and Chung, 1994;
Nath et al., 1996), and human lung and colon (Yang et al., 1999). Acrolein-DNA adducts have
been generated following reactions with deoxynucleotides (Chenna et al., 1992; Chenna and
Iden, 1993), purified eukaryotic DNA (Maccubbin et al., 1990, 1992; Kuchenmeister et al.,
1998), or bacterial cells (Hoffman et al., 1989). Acrolein has induced DNA cross-links in
plasmids (Kawanishi et al., 1998), and DNA-protein crosslinks in cultured human lymphoma
cells (Costa et al., 1997), in mixtures of plasmid DNA and calf thymus histone (Kuykendall and
Bogdanffy, 1992), and in SV40 virus (Permana and Snapka, 1994). Acrolein-modified DNA
was identified in peripheral blood leukocytes of 6/12 cancer patients who were treated with
cyclophosphamide, compared to 0/15 patients not treated with the drug (McDiarmid et al.,
1991).
In studies on cultured human bronchial cells (reviewed in Grafstrom, 1990), acrolein
reduced colony forming efficiency, clonal growth rate, and cellular levels of glutathione, and
increased the frequency of DNA single-strand breaks, DNA-protein cross-links, and the percent
4

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11-30-2001
of cells synthesizing cross-linked envelopes. Acrolein induced single-strand breaks in DNA in
human skin fibroblasts (Dypbukt et al., 1993), in a human lymphoblastoid cell line (Eisenbrand
et al., 1995), and, at high cytotoxic doses (1 mmol), in Salmonella typhimurium (Eder et al.,
1993).
FEASIBILITY OF DERIVING A PROVISIONAL INHALATION UNIT RISK
FOR ACROLEIN
The literature search disclosed no new information regarding carcinogenicity of acrolein
following inhalation exposure in humans or animals. Although acrolein is designated a possible
human carcinogen (Group C) on IRIS (U.S. EPA, 2001), there are no inhalation data upon which
to base an inhalation unit risk.
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Benamira, M. and L.J. Marnett. 1992. The lipid peroxidation product 4-hydroxynonenal is a
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Chenna, A., R.A. Rieger and C.R. Iden. 1992. Characterization of thymidine adducts formed by
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Chung, F.-L., L. Zhang, J.E. Ocando and R.G. Nath. 1999. Role of 1 ,N2-
propanodeoxyguanosine adducts as endogenous DNA lesions in rodents and humans. IARC Sci.
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Cohen, S.M., E.M. Garland, M. St. John et al. 1992. Acrolein initiates rat urinary bladder
carcinogenesis. Cancer Res. 52:3577-3581.
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Costa, M., A. Zhitkovich, M. Harris et al. 1997. DNA-protein cross-links produced by various
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Dypbukt, J.M., L. Atzori, C.C. Edman and R.C. Grafstrom. 1993. Thiol status and
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Eder, E., C. Hoffman, H. Bastian et al. 1990. Molecular mechanisms of DNA damage initiated
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Grafstrom, R.C. 1990. In vitro studies of aldehyde effects related to human respiratory
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Salmonella typhimurium TA102. Mutat. Res. 278: 265-270.
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Kato, F., A. Araki, K. Nozaki and T. Matsushima. 1989. Mutagenicity of aldehydes and
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Kawanishi, M., T. Matsuda, A. Nakayama et al. 1998. Molecular analysis of mutations induced
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Kuchenmeister, F., P. Schmezer and G. Engelhardt. 1998. Genotoxic bifunctional aldehydes
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Maccubbin, A.E., L. Caballes, F. Scappaticci et al. 1990. 32P-postlabeling analysis of binding of
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Maccubbin, A.E., L. Lee, R.F. Struck and H.L. Gurtoo. 1992. 32P-postlabeling of acrolein-
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Nath, R.G. and F.-L. Chung. 1994. Detection of exocyclic 1 ,N2-propanodeoxyguanosine
adducts as common DNA lesions in rodents and humans. Proc. Natl. Acad. Sci. USA. 91: 7491-
7495.
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Nath, R.G., J.E. Ocando and F.-L. Chung. 1996. Detection of 1 ,N2-propanodeoxyguanosine
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U.S. EPA. 1987. Health Effects Assessment for Acrolein. Prepared by the Office of Health and
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Wardle, E.N. 1988. Alveolar cell carcinoma in a cook. Br. J. Clin. Pract. 42:173-174.
Watanabe, K., K. Sakamoto and T. Sasaki. 1998. Comparisons on chemically-induced mutation
among four bacterial strains, Salmonella typhimurium TA102 and TA2638, and Escherichia coli
WP2/pKM101 and WP2 wvM/pKMlOl: Collaborative study II. Mutat. Res. 412: 17-31.
WHO (World Health Organization). 1992. Acrolein. Environ. Health Criteria 127. Geneva,
Switzerland.
Yang, K., J.-L. Fnag, D. Li et al. 1999. 32P-postlabelling with high-performance liquid
chromatography for analysis of abundant DNA adducts in human tissues. IARC Sci. Publ. 150:
205-217.
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