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 ------- 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 1 ------- 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 11 ------- 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. 1 ------- 5-31-2002 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 2 ------- 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 3 ------- 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. 4 ------- 5-31-2002 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. 5 ------- 5-31-2002 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 6 ------- 5-31-2002 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. 7 ------- |