if!;	United States
Environmental Protectioi
if % Agency
EPA/690/R-09/002F
Final
6-15-2009
Provisional Peer-Reviewed Toxicity Values for
Anthracene
(CASRN 120-12-7)
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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COMMONLY USED ABBREVIATIONS
BMD
Benchmark Dose
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
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
RfC
inhalation reference concentration
RfD
oral reference dose
UF
uncertainty factor
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
ANTHRACENE (CASRN 120-12-7)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (U.S. EPA) 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.	U.S. EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in U.S. 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 U.S. EPA's 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 U.S. EPA IRIS Program. All provisional toxicity values receive internal
review by two U.S. EPA scientists and external peer review by three independently selected
scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multiprogram consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all U.S. 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 5-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 documents 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 Resource Conservation and Recovery Act (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 document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA
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Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. 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 U.S. 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, 2008) reports a RfD of 0.3 mg/kg-day for anthracene based on a NOEL
of 1000 mg/kg-day in mice given gavage doses for 90 days (Wolfe, 1989). A UF of 3000 was
applied (10 for interspecies extrapolation, 10 for intraspecies variability, and 30 for both the lack
of a chronic toxicity study and also the lack of reproductive/developmental toxicity data or
adequate toxicity data in a second species). The Drinking Water Criteria Document (DWCD) for
Polycyclic Aromatic Hydrocarbons (PAHs) (U.S. EPA, 1990) includes the same chronic RfD of
0.3 mg/kg-day for anthracene as does the Drinking Water Standards and Health Advisories list
(U.S. EPA, 2006). The Health Effects Assessment Summary Tables (HEAST; U.S. EPA, 1997)
lists a subchronic RfD of 3 mg/kg-day based on the same principal study (Wolfe, 1989) as used
for the IRIS (U.S. EPA, 2008) chronic RfD; however, a UF of 300 (UF components were not
specified in HEAST but presumably include 10 for interspecies extrapolation, 10 for intraspecies
variability, and 3 for database deficiencies [including the lack of reproductive/developmental
toxicity studies]) was applied to the NOEL. The Chemical Assessments and Related Activities
(CARA) list (U.S. EPA, 1991, 1994) includes a Health and Environmental Effects Profile
(HEEP) for Anthracene (U.S. EPA, 1987) in addition to the previously mentioned DWCD. Due
to the lack of relevant toxicity data at that time, the HEEP (U.S. EPA, 1987) did not derive an
RfD. The Agency for Toxic Substances and Disease Registry (ATSDR) Toxicological Profile
for Polycyclic Aromatic Hydrocarbons (PAH; ATSDR, 1995) used the Wolfe (1989) study to
derive an intermediate-duration MRL for anthracene of 10 mg/kg-day by dividing the NOEL of
1000 mg/kg-day by a UF of 100 (10 for extrapolation from animals-to-humans and 10 for human
variability).
IRIS (U.S. EPA, 2008) and the HEAST (U.S. EPA, 1997) do not report a chronic RfC,
and the ATSDR (ATSDR, 1995) does not report an inhalation MRL for anthracene. No
standards or guidelines for occupational exposure to anthracene have been promulgated by the
American Conference of Governmental Industrial Hygienists (ACGIH, 2007), the National
Institute for Occupational Safety and Health (NIOSH, 2008), or the Occupational Safety and
Health Administration (OSHA, 2008).
Based on the lack of human data and inadequate animal data, IRIS (U.S. EPA, 2008)
identifies anthracene as a classification D carcinogen—"not classifiable as to human
carcinogenicityThe National Toxicology Program (NTP, 2008) has not assessed the
carcinogenicity of this compound (NTP, 2005, 2008). The International Agency for Research on
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Cancer (IARC) Monograph for Anthracene (IARC, 1983) categorizes anthracene as a Group 3
carcinogen—"available data provide no evidence that anthracene is carcinogenic to
experimental animals
To identify toxicological information pertinent to the derivation of provisional toxicity
values for anthracene, literature searches were conducted in December 2007 using the following
databases: MEDLINE, TOXLINE, and DART/ETIC (1960s-December 2007); BIOSIS
(January 2000-June 2007); Current Contents (prior 6 months); and TSCATS1/2, GENETOX,
CCRIS, HSDB, and RTECS (not limited by date). The Environmental Health Criteria for
Selected Non-Heterocyclic Polycyclic Aromatic Hydrocarbons (WHO, 1998) and the Priority
Substances List Assessment Report on Polycyclic Aromatic Hydrocarbons (Health Canada,
1994) were also consulted for relevant information. Finally, an updated search for recently
published studies was conducted for the period from January, 2008 thru March, 2009.
REVIEW OF PERTINENT DATA
Human Studies
No adequate human studies that address oral or inhalation exposures to anthracene were
located.
Badiali et al. (1985) reported melanosis of the rectum in patients taking laxatives
containing anthracene for chronic constipation. Eighty-four patients (25 males, 59 females)
seeking medical advice for constipation were examined for melanosis of the colon and rectum.
Melanosis was present in 73.4% of the patients consuming anthracene laxatives and in 26.6% of
patients not taking such laxatives (p < 0.01). Other possible effects of anthracene were not
reported.
There were three cases of epithelioma (hand, cheek, and wrist) that were reported in men
who routinely handled 40% crude anthracene in an alizarin factory (Kennaway, 1924a,b). Two
of these workers handled anthracene for 30-32 years and had never worked with any other
coal-tar product. Workers in the same factory who had contact with only purified anthracene did
not develop tumors or other skin lesions (i.e., acne, keratoses, telangiectases, and pigmentation)
that had been observed in the workers who had contact with the crude material. The crude
anthracene was not chemically characterized and additional information regarding these
observations was not reported.
Animal Studies
Oral Exposure
Subchronic Studies—In a subchronic study conducted by Hazleton Laboratories
America for the U.S. EPA (according to TSCA Guidelines, 40CFR 798.2650), Groups of CD-10
(ICR) BR mice (20/sex/dose) were administered anthracene (5 mL/kg; 100% purity) by gavage
(in corn oil), for 7 days/week, at doses of 0, 250, 500, or 1000 mg/kg-day for 90 days (Wolfe,
1989). In addition to ophthalmoscopic and physical examinations prior to testing, all mice were
observed daily for signs of toxicity and twice daily for mortality and morbidity. Body weight
and food consumption were recorded weekly. Ophthalmoscopic examinations were again made
during week thirteen of exposure. Clinical pathology examinations (hematology and clinical
chemistry) were conducted on an additional group of 10 randomly selected mice of each sex
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prior to initiation of the study and on 10 randomly selected mice of each sex from each of the
control and treatment groups during week thirteen of exposure. Hematology variables included
cell counts (red, white, platelets, reticulocytes, differential white) and determination of
hemoglobin, hematocrit, and cell morphology. Clinical chemistry variables included sodium,
potassium, chloride, total protein, albumin, calcium, phosphorus, total bilirubin, urea nitrogen,
creatinine, glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT), globulin,
alkaline phosphatase, cholesterol, albumin/globulin ratio, and lactate dehydrogenase. All
animals were necropsied after 13 weeks of exposure, along with animals that died—or were
sacrificed—prior to the end of the study. Organs, including the heart, liver, kidneys, spleen,
testis, brain, ovaries, and adrenal glands, were weighed at the terminal sacrifice of each animal.
Comprehensive histological examinations were conducted on all control and high-dose animals.
Histological evaluations of lung, liver, kidney, and any grossly observable lesions were made for
all low- and mid-dose animals.
There was no treatment-related mortality (Wolfe, 1989). Two control mice (one male,
one female) and one low-dose female died as a result of gavage errors. Very few clinical signs
were observed both during the weekly evaluations and the postdosing cage-side evaluations;
none appeared to be treatment related. Both males and females in the low-, mid-, and high-dose
groups gained weight that was comparable to the controls' throughout the study, and there were
no significant differences between any treatment groups during any weekly evaluation or at the
end of the study. Similarly, food consumption did not vary between treatment groups.
There were no treatment-related effects on ophthalmoscopic examination or on any of the
hematological variables reported (Wolfe, 1989). The only clinical chemistry variable that
differed from controls with statistical significance was decreased total protein in all
anthracene-treated males but not females. However, this effect was not dose related; values were
5.8 + 0.40, 5.2 + 0.28, 5.4 + 0.35, and 5.4 + 0.42 for male control, 250-, 500-, and
1000-mg/kg-day groups, respectively. Both absolute and relative ovary weights were
statistically significantly elevated among 500-mg/kg-day females relative to controls but not in
the low-dose or the higher 1000-mg/kg-day group. No other effects on absolute or relative organ
weights are evident from the data.
Cysts were observed in the mouse ovaries upon gross necropsy in 1/19, 3/19, 5/20, and
2/20 females in the control, 250-, 500-, and 1000-mg/kg-day treatment groups, respectively. Of
the cysts observed, histopathologic examinations confirmed the presence of ovarian cysts in 1, 0,
3, and 1 females examined in the control, low-, mid- and high-dose groups, respectively. The
uterus was distended and fluid-filled in 0/19, 1/19, 1/20, and 2/20 females in the control, 250-,
500-, and 1000-mg/kg-day groups, respectively. Cystic endometrial hyperplasia of the uterus
was histologically identified in 3/19, 0/1, 0/3, and 3/20 females examined in the control, low-,
mid- and high-dose groups. Wolf (1989) provided no explanation for examining fewer animals
in the middle dose groups. There were no other notable or treatment-related histopathologic
changes. None of the observations were statistically significant (p < 0.05) and no other grossly
observable pathological changes were remarkable or treatment related. Both Wolfe (1989) and
U.S. EPA (1990, 2008) identify 1000 mg/kg-day (highest dose tested) as the NOEL for the
study.
Chronic Studies—No adequate chronic oral studies were identified for anthracene. A
group of twenty-eight 14-week-old BDI or BDIII rats of unspecified sex were fed diets that
initially contained 5 mg and later (timing not specified) 15 mg of "highly purified" anthracene in
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oil, 6 days/week, for a total of 550 treatment days (Schmahl, 1955). The total dose administered
was 4.5 grams/rat (28 mg/kg-day per U.S. EPA, 2008). All rats were observed until natural
death. The authors noted no toxic symptoms during treatment or recovery and reported a mean
survival time of 700 days. The authors do not describe their postmortem procedures, but they
report that malignant tumors were observed in only two of the treated rats: a liver sarcoma
developed in one rat after 18 months of treatment and a uterine adenosarcoma with numerous
metastases developed in another rat after 25 months of treatment. The authors did not believe
these tumors were related to anthracene administration and reported a control incidence of 0.5%
(presumably historical controls, because no controls were used in the experiment). No other data
regarding oral exposure are presented by the authors. Effect levels cannot be determined from
this study.
Reproductive/Developmental Studies—No oral-route reproductive or developmental
toxicity studies were identified for anthracene. The observed changes on the ovaries and uteri of
mice in the Wolfe (1989) study were not statistically significant (p < 0.05) and do not appear to
be dose related. In the oral subchronic toxicity study, Wolfe (1989) noted no changes in the
reproductive tissues of the male mice.
Inhalation Exposure
No subchronic, chronic, reproductive, or developmental studies of anthracene conducted
by the inhalation route of exposure in animals were identified.
Other Studies
Immunotoxicity
In a study of structure-activity relationships (White et al., 1985), 10 PAHs—including
anthracene (160 |imol/kg-day)—were subcutaneously injected into female B6C3F1 mice (8 per
chemical) daily for 14 days. Immunosuppression in the mice was evaluated by determining the
ability of the PAHs to inhibit the induction of splenic antibody-forming cells (AFCs) 4 days after
immunization with sheep erythrocytes. The spleen weights of mice treated with anthracene were
not statistically significantly (p < 0.05) different from the vehicle-treated control mice. Further,
treatment with anthracene failed to significantly (p < 0.05) reduce the number of IgM-AFCs in
the mice spleens in comparison with the control mice. The study authors concluded that PAH
immunosuppression closely parallels the structure-activity relationship for carcinogenesis and
that simple PAHs, including anthracene, do not suppress the AFC response.
Parenteral Carcinogenicity
Groups of 60 female 3- to 6-month-old Osborne-Mendel rats were observed for
55-81 weeks after receiving a single lung-implanted pellet of anthracene (0.5 mg/rat,
approximately 2 mg/kg by injection) dissolved in a 1:1 by volume (v/v) mixture of beeswax and
trioctanoin (0.1 mL) (Stanton et al., 1972). Controls received an implant of the vehicle. No
tumors were observed.
Dermal Carcinogenicity
Anthracene has been tested for carcinogenicity by skin application with and without
ultraviolet radiation in mice, in skin initiation-promotion assays with mice, by subcutaneous and
intraperitoneal injection in rats, and by implantation into the brain or eyes in rabbits (U.S. EPA,
1987). The results of the skin application studies with anthracene do not provide evidence of
carcinogenicity, but contradictory results were obtained when anthracene was applied to skin
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together with exposure to ultraviolet radiation. Initiating activity was not indicated in the mouse
skin initiation-promotion assays.
Skin-painting experiments were conducted on groups of 20 male C3H/HeJ mice
(Warshawsky et al., 1993). Anthracene dissolved in toluene was applied to areas of shaved skin
twice weekly for 6 months at a dose of 0.05 mg. Tumor incidence was determined at the end of
the study. In 14 treated animals, anthracene administered alone produced no tumors (0%). With
coadministration of 0.05 mg benzo[a]pyrene, 1/13 (8%) had a papilloma, with a mean latency
period of 85 weeks. Anthracene was negative as a complete carcinogen following chronic
dermal exposure (Habs et al., 1980). Swiss mice receiving 10% anthracene in acetone topically
applied to their backs three times a week throughout their lifetime did not develop any skin
tumors after 20 months of exposure (Wynder and Hoffmann, 1959).
No tumors were observed in an assay of initiating activity in which Crl:CD/l (ICR)BR
female albino mice were exposed to 1 mg anthracene in acetone and then treated with
12-0-tetradecanoyl-phorbol-13 acetate (TPA) as the promoting agent three times/week for
20 weeks (LaVoie et al., 1985). In another study with TPA (Scribner, 1973), a single dermal
application of 10 |iM anthracene (purity not stated) in benzene was administered to 30 female
CD-I mice; this initial application was followed 7 days later by twice-weekly applications of
5 |iM TPA for 35 weeks. Survival in the group was 93% after 35 weeks. By week 20 of the test,
2/28 (7%>) mice had developed skin tumors; this increased to 4/28 (14%) by week 35. In the
control group, in which 30 mice received only the TPA applications, a mouse developed a skin
tumor at week 25.
Kennaway (1924a) administered anthracene (purity unknown) as a 40% solution
dissolved either in lanolin or as an ether extract to two groups of 100 mice each (sex and strain
not stated). In the lanolin-group, 44% of the mice survived 131 days and in the ether-extract
group only 6% survived until day 160. In the lanolin-group, 1/44 (2%) surviving mice
developed a papilloma by day 131; no mice developed tumors in the ether-extract group by day
160. No information pertaining to the use of a control group was given.
Genotoxicity
With a single exception (Sakai et al., 1985), anthracene did not cause mutations or
chromosomal damage in bacteria, yeast, or mammalian cells. Most of the available studies
employed metabolic activation. Anthracene was negative in mutagenicity assays with
Salmonella typhimurium (McCann et al., 1975; Simmon, 1979a; LaVoie et al., 1978, 1985;
Kaden et al., 1979; Salamone et al., 1979; Ho et al., 1981; DeFlora et al., 1984); and was
negative in mutation assays with Chinese hamster V79 cells (Knapp et al., 1981;
Langenbach et al., 1983), rat liver epithelial cells (Ved Brat et al., 1983), human lymphoblastoid
TK6 cells (Barfknecht et al., 1981), and mouse lymphoma cells (Amacher and Turner, 1980;
Amacher et al., 1980). Sakai et al. (1985) reported positive results in a mutation assay with
Salmonella typhimurium strain TA97 at concentrations of 5 and 10 [j,g/plate in the presence of rat
liver S9. No other studies tested this strain. Anthracene did not induce sister chromatid
exchange in Chinese hamster D6 cells (Abe and Sasaki, 1977) or rat liver epithelial cells
(Tong et al., 1981; Ved Brat et. al., 1983), nor did it cause strand breakage in DNA from rat liver
hepatocytes (Sina et al., 1983). Anthracene did not cause DNA damage in Escherichia coli
(Rosenkrantz and Poirier, 1979; DeFlora et al., 1984) or Bacillus subtilis (McCarroll et al.,
1981), and it did not induce mitotic combination in Saccharomyces cerevisiae (Simmon, 1979b).
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DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR ANTHRACENE
Subchronic p-RfD
The subchronic toxicity study by Wolfe (1989) is the only oral toxicity study for
anthracene that is suitable for the basis of a subchronic p-RfD for anthracene because a variety of
toxicologic endpoints were examined in three dose groups and one control group of mice by
gavage dosing. This study defines a NOEL of 1000 mg/kg-day (highest dose tested) and is the
basis for U.S. EPA's verified chronic RfD of 0.3 mg/kg-day for anthracene on IRIS (U.S. EPA,
2008). The Benchmark Dose approach was not applied because a dose-response relationship
was not identified in the critical study. Using the NOEL from Wolfe (1989) as the point of
departure and a composite UF of 1000, a subchronic p-RfD of 1 mg/kg-day is derived as
follows:
Subchronic p-RfD = NOEL UF
= 1000 -H 1000
= 1 or 1 x 10° mg/kg-day
The composite UF of 1000 is composed of the following:
•	A full UF of 10 was applied for interspecies extrapolation to account for potential
pharmacokinetic and pharmacodynamic differences between rats and humans.
•	A full UF of 10 was applied for intraspecies differences to account for potentially
susceptible individuals in the absence of information on the variability of response in
humans.
•	A full uncertainty factor of 10 was applied to account for database uncertainty. The
database lacks developmental toxicity or multigeneration reproduction studies.
Confidence in the principal study is medium. The study examined a variety of
toxicological endpoints but the failure to identify a LOAEL precludes a higher level of
confidence. Confidence in the database is low because of the lack of adequate toxicity data in a
second species and developmental/reproductive studies. Low confidence in the subchronic
p-RfD follows.
Chronic p-RfD
IRIS (U.S. EPA, 2008) currently posts a verified (11/15/89) chronic RfD of
0.3 mg/kg-day for anthracene based on the study by Wolfe (1989). The basis for the chronic
RfD is a NOEL of 1000 mg/kg-day divided by a UF of 3000 (10 for interspecies extrapolation,
10 for intraspecies variability, and 30 for lack of a chronic toxicity study,
reproductive/developmental toxicity data or adequate toxicity data in a second species).
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION p-RfC VALUES FOR ANTHRACENE
There are no data available from which to derive p-RfC values for anthracene.
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PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
ANTHRACENE
Weight-of-Evidence Descriptor
Under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005),
"inadequate information is available to assess the carcinogenic potential" of anthracene. This is
reflected in IRIS (U.S. EPA, 2008) where anthracene is classified as a Group D carcinogen—
"not classifiable as to human carcinogenicitybased on a lack of human data and inadequate
data from animal bioassays. As discussed previously, oral, dermal, parenteral, and lung-injection
routes of exposure have failed to provide evidence of carcinogenicity, although some of the
studies are limited in terms of design and reporting. Numerous genotoxicity studies were
overwhelmingly negative.
Quantitative Estimates of Carcinogenic Risk
Due to the lack of adequate data, it is neither possible nor appropriate to derive
quantitative estimates of carcinogenic risk for anthracene for either oral or inhalation exposures.
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REFERENCES
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exchanges induced by chemicals. Proc. Jap. Acad. 53:46-49. (Cited by U.S. EPA, 1990).
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Amacher, D.E. and G.N. Turner. 1980. Promutagen activation by rodent-liver post
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Kaden, D.A., R.A. Hites and W.G. Thilly. 1979. Mutagenicity of soot and associated polycyclic
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