United States Environmental Protection 1=1 m m Agency EPA/690/R-01/003F Final 11-30-2001 Provisional Peer Reviewed Toxicity Values for Chrysene (CASRN 218-01-9) Derivation of an Oral RfD 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 MTD maximum tolerated dose MTL median threshold limit 1 ------- 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 microgram (.imol micromoles voc volatile organic compound 11 ------- 11-30-2001 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR CHRYSENE (CASRN 218-01-9) Derivation of an Oral RfD 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 ------- 11-30-2001 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 An RfD for chrysene is not available on IRIS (U.S. EPA, 2001) nor in the HEAST (U.S. EPA, 1997). Chrysene is included on the Drinking Water Regulations and Health Advisory list as a B2 carcinogen; a noncancer health advisory is not available (U.S. EPA, 2000). The CARA database (U.S. EPA, 1991, 1994) lists a Health and Environmental Effects Profile (HEEP) (U.S. EPA, 1984), as well as a 1983 Reportable Quantity Document for Chrysene. The 1984 HEEP for Chrysene indicates that an Acceptable Daily Intake (ADI) was not estimated, due to the lack of chronic and subchronic data following exposure to chrysene by any route (U.S. EPA, 1984). The 1990 Drinking Water Criteria Document for PAH (U.S. EPA, 1990) did not contain information on the noncarcinogenic effects of chrysene. In 1995, ATSDR published a Toxicological Profile for PAHs in which only the carcinogenic effects of chrysene are discussed (ATSDR, 1995). NTP has not evaluated the noncarcinogenic toxicity of chrysene (NTP, 2001). ACGIH (2000) and WHO (1998) were searched for relevant information. Updated literature searches for oral noncancer data were conducted from 1989 to December 2000. The databases searched were: 2 ------- 11-30-2001 TOXLINE, MEDLINE, CANCERLIT, CCRIS, TSCATS, HSDB, RTECS, GENETOX, DART/ETICBACK, and EMIC/EMICBACK. REVIEW OF THE PERTINENT LITERATURE Human Studies Since the IRIS posting in 1990 (U.S. EPA, 2001), reviews by U.S. EPA (2000), ATSDR (1995), and WHO (1998) provided no data regarding the noncarcinogenic toxicity of chrysene in humans following oral exposure. The updated literature search identified no relevant studies regarding the noncarcinogenic toxicity of chrysene in humans following oral exposure. Animal Studies Since the IRIS posting in 1990 (U.S. EPA, 2001), reviews by U.S. EPA (2000), ATSDR (1995), and WHO (1998) provided no data regarding the noncarcinogenic toxicity of chrysene in animals following oral exposure. The updated literature search identified no relevant studies regarding the noncarcinogenic toxicity of chrysene in animals following oral exposure. FEASIBILITY OF DERIVING A PROVISIONAL RfD FOR CHRYSENE A provisional RfD for chrysene cannot be derived due to the lack of human data and animal data. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2000. Documentation of Threshold Limit Values and Biological Exposure Indices, 6th ed. Cincinnati, OH. 1: 292-293. ATSDR (Agency for Toxicological Substances Disease Registry). 1995. Toxicological Profile for PAH. U.S. Department of Health and Human Services, Public Health Service, Atlanta, GA. NTP (National Toxicology Program). 2001. Management Status Report. Examined April 4, 2001. http://ntp-server.niehs.nih.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html U.S. EPA. 1983. Reportable Quantity Document for Chrysene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for Office of Emergency and Remedial Response, Washington, DC. 3 ------- 11-30-2001 U.S. EPA. 1984. Health and Environmental Effects Profile for Chrysene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. EPA/600/X-84/186. NTIS PB88-131123. U.S. EPA. 1990. 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 Drinking Water, Washington, DC. NTIS PB92-173459. U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April 1991. U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. December 1994. U.S. EPA. 1997. Health Effects Assessment Summary Tables. 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. EPA/540/R-97/036. NTIS PB 97-921199. U.S. EPA. 2000. Drinking Water Regulations and Health Advisories. Examined April 4, 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 4, 2001. Online, http://www.epa.gov/iris/ WHO (World Health Organization). 1998. Selected Non-Heterocyclic Polycyclic Aromatic Hydrocarbons. International Programme on Chemical Safety, Environmental Health Criteria Document No. 202. 4 ------- 11-30-2001 Provisional Peer Reviewed Toxicity Values for Chrysene (CASRN 218-01-9) 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 MTD maximum tolerated dose MTL median threshold limit 1 ------- 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 microgram (.imol micromoles voc volatile organic compound 11 ------- 11-30-2001 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR CHRYSENE (CASRN 218-01-9) 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 ------- 11-30-2001 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 A carcinogenicity assessment for chrysene is available on IRIS (U.S. EPA, 2001). This assessment, verified on 2/7/90, assigned chrysene to cancer weight-of-evidence group B2, probable human carcinogen, based on development of carcinomas and malignant lymphoma in mice after intraperitoneal injection, skin carcinomas in mice following dermal exposure, and chromosomal abnormalities in hamsters and mouse germ cells after gavage exposure. In support of these studies, positive responses in bacterial gene mutation assays and transformed mammalian cells exposed in culture have been observed with chrysene (U.S. EPA, 2001). Although there are no human data that specifically link exposure to chrysene with human cancers, chrysene is a component of PAH mixtures that have been associated with human cancer. These include coal tar, soots, coke oven emissions and cigarette smoke. Due to the lack of oral data, an oral slope factor was not derived (U.S. EPA, 2001). CRAVE Workgroup meeting notes provide no additional insight as to the potential for oral carcinogenicity of chrysene (U.S. EPA, 1990a, 1993a,b, 1994b). The HEAST (U.S. EPA, 1997) provides no other information. The B2 2 ------- 11-30-2001 cancer weight-of-evidence classification is listed in the Drinking Water Standards and Health Advisories list without a health advisory quantification of cancer risk (U.S. EPA, 2000). The CARA list (U.S. EPA, 1991, 1994a) includes a Health and Environmental Effects Profile for Chrysene (U.S. EPA, 1984), as well as two reportable quantity documents for carcinogenic effects of chrysene (U.S. EPA, 1983, 1988). In the 1984 HEEP (U.S. EPA, 1984), the lack of available data regarding the carcinogenic effects of chrysene following oral exposure precluded derivation of a cancer quantitative estimate. The 1990 Drinking Water Criteria Document for PAH also considered the potential for carcinogenicity following exposure to chrysene; however, the oral route was not assessed (U.S. EPA, 1990b). An ATSDR Toxicological Profile for PAHs (ATSDR, 1995) did not include any information regarding carcinogenicity of chrysene following oral exposure. The International Agency for Research on Cancer (IARC, 1987, 2001) lists chrysene as a group 3 carcinogen, not classifiable as to its carcinogenicity to humans; only limited animal evidence exists. Neither WHO (1998) nor NTP (2001) provided any relevant information regarding the carcinogenic potential of chrysene by oral route. ACGIH (2000) lists chrysene as a confirmed animal carcinogen with unknown relevance to humans, but does not recommend a TLV specifically for chrysene. Updated literature searches for cancer data were conducted from 1989 to December 2000. The databases searched were: TOXLINE, MEDLINE, CANCERLIT, CCRIS, TSCATS, HSDB, RTECS, GENETOX, DART/ETICBACK, and EMIC/EMICBACK. REVIEW OF THE PERTINENT LITERATURE Human Studies Since the IRIS posting in 1990 (U.S. EPA, 2001), reviews by U.S. EPA (1993a, 1993b, 1994b, 2000), ATSDR (1995), and WHO (1998) provided no data regarding the carcinogenicity of chrysene in humans following oral exposure. The updated literature search identified no relevant studies regarding the carcinogenicity of chrysene in humans following oral exposure. Animal Studies Since the IRIS posting in 1990 (U.S. EPA, 2001), reviews by U.S. EPA (1993a, 1993b, 1994b, 2000), ATSDR (1995), and WHO (1998) provided no data regarding the carcinogenicity of chrysene in animals following oral exposure. The updated literature search identified no relevant studies regarding the carcinogenicity of chrysene in animals following oral exposure. Other Studies The Drinking Water Criteria Document for Polycyclic Aromatic Hydrocarbons (U.S. EPA, 1990b) indicated that chrysene produced mutations in Salmonella and chromosomal aberrations and morphologic transformation in mammalian cells (U.S. EPA, 1990b). Updated literature searches revealed no new information regarding the genetic toxicity of chrysene. 3 ------- 11-30-2001 FEASIBILITY OF DERIVING A PROVISIONAL ORAL SLOPE FACTOR FOR CHRYSENE A provisional oral slope factor for chrysene cannot be derived because human and animal oral cancer data are lacking. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2000. Documentation of Threshold Limit Values and Biological Exposure Indices. ATSDR (Agency for Toxicological Substances Disease Registry). 1995. Toxicological Profile for PAH. U.S. Department of Health and Human Services, Public Health Service, Atlanta, GA. IARC (International Agency for Research on Cancer). 1987. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Supplement 7. WHO Publications Center, Albany, NY. 7:60. IARC (International Agency for Research on Cancer). 2001. Cumulative Cross Index to IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs. Examined April 4, 2001. Online. http://l 93.51.164.11/htdocs/Monographs/V ol32/Chrysene.html NTP (National Toxicology Program). 2001. Management Status Report. Examined April 4, 2001. http://ntp-server.niehs.nih.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html U.S. EPA. 1983. Evaluation of the Potential Carcinogenicity of Chrysene. Prepared by the Office of Health and Environmental Assessment, Carcinogen Assessment Group, Washington, DC for the Office of Emergency and Remedial Response, Washington, DC. U.S. EPA. 1984. Health and Environmental Effects Profile for Chrysene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. EPA/600/X-84/186. NTIS PB88-131123. U.S. EPA. 1988. Evaluation of the Potential Carcinogenicity of Chrysene. Prepared by the Office of Health and Assessment, Carcinogen Assessment Group, Washington, DC for the Office of Emergency and Remedial Response, Washington, DC. EPA/600/8-91/094. NTIS PB93- 185155. 4 ------- 11-30-2001 U.S. EPA. 1990a. CRAVE Work Group Summary and Meeting Notes Dated 2/7/90. Office of Research and Development. Available from National Center for Environmental Assessment, Washington, DC. U.S. EPA. 1990b. 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 Drinking Water, Washington, DC. U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April. U.S. EPA. 1993a. CRAVE Work Group Summary and Meeting Notes dated 8/5/93. Office of Research and Development. Available from National Center for Environmental Assessment, Washington, DC. U.S. EPA. 1993b. CRAVE WorkGroup Summary and Meeting Notes Dated 9/21/93. Office of Research and Development. Available from National Center for Environmental Assessment, Washington, DC. U.S. EPA. 1994a. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. December. U.S. EPA. 1994b. CRAVE Work Group Summary and Meeting Notes dated 2/2/94. Office of Research and Development. Available from National Center for Environmental Assessment, Washington, DC. U.S. EPA. 1997. Health Effects Assessment Summary Tables. 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. EPA/540/R-97/036. NTIS PB 97-921199. U.S. EPA. 2000. Drinking Water Regulations and Health Advisories. Examined April 4, 2001. Online, http://www.epa.gov/ost/drinking/standards/ U.S. EPA. 2001. Integrated Risk Information System (IRIS). Online. Office of Research and Development, National Center for Environmental Assessment, Washington, DC. http ://www. epa. gov/ iris/ WHO (World Health Organization). 1998. Selected Non-Heterocyclic Polycyclic Aromatic Hydrocarbons. International Programme on Chemical Safety, Environmental Health Criteria Document No. 202. 5 ------- |