United States
Environmental Protection
1=1 m m Agency
EPA/690/R-02/008F
Final
5-31-2002
Provisional Peer Reviewed Toxicity Values for
Fluorene
(CASRN 86-73-7)
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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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
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MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-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-observed-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
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
(.imol
micromoles
voc
volatile organic compound
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5-31-2002
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
FLUORENE (CASRN 86-73-7)
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.
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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.
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, 2001) reports a cancer weight-of-evidence classification for fluorene of
Group D-Not classifiable as to human carcinogenicity, based on no human data and inadequate
data from animal bioassays. Accordingly, fluorene was unsuitable for quantitative risk
assessment and an oral slope factor was not derived. The classification was verified by the
CRAVE Work Group on 2/7/90 (U.S. EPA, 1995). An oral slope factor for fluorene was not
listed in the HE AST (U.S. EPA, 1997). A Group D cancer classification was also designated for
fluorene in the following documents: Drinking Water Standards and Health Advisories list (U.S.
EPA, 2000), Drinking Water Criteria Document for Polycyclic Aromatic Hydrocarbons (PAHs)
(U.S. EPA, 1991b), and HEA for Fluorenes (U.S. EPA, 1987). IARC (1987) assigned fluorene
to Group 3 "not classifiable as to its carcinogenicity to humans". ACGIH (2000) has not
assessed the carcinogenicity of fluorene. The following were also consulted for relevant
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5-31-2002
information: NTP (2001), WHO (2001), Toxicological Profile for Polycyclic Aromatic
Hydrocarbons (ATSDR, 1995), Multimedia Document for Polycyclic Aromatic Hydrocarbons
(U.S EPA, 1992), Mouse Oral Subchronic Toxicity of Fluorene (U.S. EPA, 1989), HEA for
PAHs (U.S. EPA, 1984), and IARC (1983). No additional EPA documents pertinent to a cancer
assessment for fluorene were located in the CARA list (U.S. EPA, 1991a, 1994). Literature
searches of the following databases were conducted from 1989 to November 2000 for relevant
studies: TOXLINE, MEDLINE, TSCATS, GENETOX, HSDB, CANCERLIT, CCRIS, RTECS,
EMIC/EMICBACK and DART/ETICBACK.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
The available reviews (U.S. EPA, 1984, 1987, 1991b; IARC, 1983, 1987; ATSDR, 1995)
found no studies regarding carcinogenicity of fluorene in humans following oral exposure. The
literature search identified no new studies regarding carcinogenicity of fluorene in humans
following oral exposure.
Animal Studies
The available reviews (U.S. EPA, 1984, 1987, 1991b; IARC, 1983, 1987; ATSDR, 1995)
located no animal data appropriate for derivation of an oral slope factor for fluorene. Two
limited oral bioassays are described on IRIS (Morris et al., 1960; Wilson et al., 1947), but did not
show increased tumor incidence following fluorene administration. The literature search
identified no new studies regarding carcinogenicity of fluorene in animals following oral
exposure.
Other Studies
The literature search identified the following relevant data for carcinogenicity of fluorene
not included on IRIS. Fluorene, at doses that were not cytotoxic, had a slight dose dependent
inhibiting effect, assessed using an in vitro scrape loading/dye transfer bioassay, on the gap-
junction channel intercellular communication (GJIC) of rat liver epithelial cells (Upham et al.,
1994, 1998; Weis et al., 1998). In vitro DNA repair assays (unscheduled DNA synthesis) were
negative in rat hepatocytes treated with fluorene (Selden et al., 1994). The literature contains
conflicting reports for fluorene in the in vitro mouse lymphoma TK locus forward mutation
assay; positive and conflicting results were reported by Wangenheim et al. (1988) and Garberg et
al. (1988), respectively. Fluorene induced chromosomal aberrations in a Chinese hamster lung
cell line only in the presence of an exogenous metabolic activation system (Matsuoka et al.,
1991). Epidermal growth factor binding levels for liver microsomes isolated from rats fed a diet
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5-31-2002
of 0.06% fluorene for 3 weeks were comparable to basal levels (Ringer et al., 1997). Fluorene
suspended in corn oil, administered to male C57BL/6J mice as a single oral gavage at 0.1, 1.0, 10
or 100 mg/kg, did not suppress the antibody response to sheep erythrocyte immunization,
whereas other PAHs suppressed the response by up to 94% of control response (Silkworth et al.,
1995).
FEASIBILITY OF DERIVING A PROVISIONAL ORAL SLOPE FACTOR FOR
FLUORENE
A provisional oral slope factor for fluorene cannot be derived because adequate
human and animal oral cancer data are lacking.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2000. TLVsŪ and
BEIsŪ: Threshold Limit Values for Chemical Substances and Physical Agents, Biological
Exposure Indices. Cincinnati, OH.
ATSDR (Agency for Toxicological Substances Disease Registry). 1995. Toxicological Profile
for Polycyclic Aromatic Hydrocarbons. U.S. Department of Health and Human Services, Public
Health Service. August.
Garberg, P., E. Akerblom and G. Bolcsfoldi. 1988. Evaluation of a genotoxicity test measuring
DNA-strand breaks in mouse lymphoma cells by alkaline unwinding and hydroxyapatite elution.
Mutat. Res. 203: 155-176.
IARC (International Agency for Research on Cancer). 1983. IARC Monographs on the
Evaluation of Carcinogenic Risk of Chemicals to Humans, Polynuclear Aromatic Compounds,
Part 1: Chemical, Environmental and Experimental Data. Lyon, France. Vol. 32, p. 365-371.
IARC (International Agency for Research on Cancer). 1987. IARC Monographs on the
Evaluation of Carcinogenic Risk to Humans, Overall Evaluations of Carcinogenicity: An
Updating of IARC Monographs Volumes 1 to 42. Lyon, France. Supplement 7, p. 63.
Matsuoka, A, T. Sofuni, N. Miyata and M. Ishidate, Jr. 1991. Clastogenicity of 1-nitropyrene,
dinitropyrenes, fluorene and mononitrofluorenes in cultured Chinese hamster cells. Mutat. Res.
259: 103-110.
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Morris, H.P., C.A. Velat, B.P. Wagner, M. Dahlgard and F.E. Ray. 1960. Studies of
carcinogenicity in the rate of derivatives of aromatic amines related to N-2-fluorenyl acetamide.
J. Natl. Cancer Inst. 24: 149-180.
NTP (National Toxicology Program). 2001. Management Status Report. Examined April 13,
2001. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ALL SRCH/iH ALL SRCH Frames.html
Ringer, D.P., P.L. Panzeter and L.A. DeCicco. 1997. Alterations in epidermal growth factor
binding to hepatic membranes following dietary exposure of rats to known hepatocarcinogens.
Toxicol. Lett. 91:7-12.
Selden, J.R., F. Dolbeare, J.H. Clair et al. 1994. Validation of a flow cytometric in vitro DNA
repair (UDS) assay in rat hepatocytes. Mutat. Res. 315: 147-167.
Silkworth, J.B., T. Lipinskas and C.R. Stoner. 1995. Immunosuppressive potential of several
polycyclic aromatic hydrocarbons( PAHs) found at a superfund site: New model used to evaluate
additive interactions between benzo[a]pyrene and TCDD. Toxicology. 105: 375-386.
Upham, B.L., S.J. Masten, B.R. Lockwood and J.E. Trosko. 1994. Nongenotoxic effects of
polycyclic aromatic hydrocarbons and their oxygenation by-products on the intercellular
communication of rat liver epithelial cells. Fund. Appl. Toxicol. 23:
470-475.
Upham, B.L., L.M. Weis and J.E. Trosko. 1998. Modulated gap junctional intercellular
communication as abiomarker of PAH epigenetic toxicity: Structure-function relationship.
Environ. Health Perspect. 106: 975-981.
U.S. EPA. 1984. Health Effects Assessment for Polycyclic Aromatic Hydrocarbons (PAHs).
Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response,
Washington, DC. September. EPA/540/1-86/013. NTIS PB86-134244.
U.S. EPA. 1987. Health Effects Assessment for Fluorenes. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH
for the Office of Emergency and Remedial Response, Washington, DC. EPA/600/8-88/040.
NTIS PB88-182860.
U.S. EPA. 1989. Mouse Oral Subchronic Toxicity of Fluorene. Prepared by Toxicity Research
Laboratories, Ltd., Muskegon, MI for the Office of Solid Waste, Washington, D.C. May. TRL
Study No. 042-010.
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U.S. EPA. 1991a. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1991b. Drinking Water Criteria Document for Polycyclic Aromatic Hydrocarbons
(PAHs). Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Water, Washington, DC. NTIS
PB92-173459INZ.
U.S. EPA. 1992. Multimedia Document for Polycyclic Aromatic Hydrocarbons. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH. January.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1995. Monthly Status Report of RfD/RfC and CRAVE Work Groups (as of
09/01/95). Office of Research and Development, National Center for Environmental
Assessment, Cincinnati, OH.
U.S. EPA. 1997. Health Effects Assessment Summary Tables (HEAST). FY-1997 Update.
Prepared by the Office of Research and Development, National Center for Environmental
Assessment, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington,
DC. July. EPA/540/R-97/036. NTIS PB 97-921199.
U.S. EPA. 2000. Drinking Water Regulations and Health Advisories. Summer 2000. Office of
Water, Washington, DC. Examined April 13, 2001. Online.
http://www.epa. gov/ ost/drinking/ standards/
U.S. EPA. 2001. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Examined
April 13, 2001. Online, http://www.epa.gov/iris/
Wangenheim, J. and G. Bolcsfoldi. 1988. Mouse lymphoma L5178Y thymidine kinase
Locus assay of 50 compounds. Mutagenises. 3:193-205.
Weis, L.M., A.M. Rummel, S.J. Masten et al. 1998. Bay or baylike regions of polycyclic
aromatic hydrocarbons were potent inhibitors of gap junctional intercellular communication.
Environ. Health Perspect. 106: 17-22.
WHO (World Health Organization). 2001. World Health Organization Publications. Examined
April 13, 2001. Online. http://www.who.int/dsa/cat97/zehc.htm#Alphabetical
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Wilson, R.H., F. DeEds and A J. Cox. 1947. The carcinogenic activity of 2-acetominofluorene.
IV. Action of related compounds. Cancer Res. 7: 453-458.
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