ENVIRONMENTAL POLICY ANALYSIS
RISK ASSESSMENT
Comparison of Hazardous Air Pollutant Health Risk Benchmarks SUSAN B. GOLDHABER, ROBERT L. CHESSIN Research hriangle Institute Center for Environmental Analysis Research hriangle Park, NC 27709
The Clean Air Act Amendments of 1990 identify hazardous air pollutants and require significant reductions in their release from major emissions sources. Relevant to control of these substances, governmental agencies and organizations rely on several different cancer and noncancer endpoint benchmarks, standards gauging the adequacy of measures taken to protect the public. A comparison of EPA's Reference Dose and Reference Concentration data with the U.S. Agency for Toxic Substances and Disease Registry's chronic Minimal Risk Level data shows agreement with health risk endpoint estimates for most chemicals, although benchmark variations of an order of magnitude or more are found for several others. Discrepancies arise because of different uncertainty factors and differences in the selection and interpretation of studies used to assess health risks. Government agencies should seek to further harmonize risk assessment guidelines, data, and their interpretations.
5 6 8 A • VOL. 3 1 , NO. 12, 1997 / ENVIRONMENTAL SCIENCE & TECHNOLOGY / NEWS
EPA recently published a list of major categories and area sources that emit hazardous air pollutants and is in the process of issuing Maximum Achievable Control Technology standards for each type of listed source (i). Eight years after the standards are applied, EPA will examine residual risk levels at regulated facilities and determine whether additional controls are necessary to further reduce risks associated with pollutant emissions (2). Examining risk levels, EPA gathers available information on the health effects of hazardous air pollutants. The 189 pollutants listed in the Clean Air Act Amendments include industrial chemicals, pesticides, and inorganic substances such as cadmium compounds. To facilitate the discussion of health and risk information, in this report hazardous air pollutants are divided into the following categories: aromatic compounds and halogenated aromatics, hydrocarbons and halogenated hydrocarbons, nitrogenated organics, oxygenated hydrocarbons, pesticides, inorganics, phthalates, and other chemicals. Noncancer benchmarks examined include EPA's Reference Doses (RfD) and Reference Concentrations (RfC), the Agency for Toxic Substances and Disease Registry's (ATSDR) Minimal Risk Levels (MRL), and the World Health Organization's (WHO) Acceptable Daily Intakes (ADI). Cancer benchmarks consist of cancer classifications and risk levels obtained from EPA's Integrated Risk Information System (IRIS) and cancer classifications obtained from the International Agency for Research on Cancer (IARC) and the U.S. Department of Health and Human Services (DHHS). Health risk benchmark information can be obtained from primary sources of literature, such as EPA's IRIS, an online database for carcinogenic and noncarcinogenic benchmarks and supporting information (3); ATSDR Toxicological Profiles for noncarcinogenic benchmarks (MRL) {4); WHO Toxicological Monographs for noncarcinogenic benchmarks (ADI) (5); IARC Monographs for carcinogenic benchmarks (6); DHHS Annual Report on Carcinogens for carcinogenic benchmarks (7); and EPA's Health Effects Assessment Summary Tables (HEAST) for unverified carcinogenic and noncarcinogenic benchmarks (8) Other documents that provide supporting health effects information include EPA health effects assessments, health and environmental effects documents, and drinking water criteria documents for cancer and noncancer information; the EPA document Hazardous Air Pollutants: Profiles sf Noncancer Toxicity from Inhalation Exposures s9); Hazardous Substances Data Bank, an online database for cancer and noncancer information; Registry of Toxic Effects of Chemical Substances, an online database 0013-936X/97/0931-568A$14.00/0 © 1997 American Chemical Society
for acute noncancer information; National Toxicology Program Bioassay Reports for cancer and noncancer information; and TOXLINE, an online database for a survey of the open scientific literature on toxicity information. Estimating noncancer benchmarks The development of noncancer benchmarks is based on the premise that a threshold exists for adverse health effects other than cancer. The first observed adverse effect that occurs as dose increases is termed the critical effect. The Lowest Observed Adverse Effect Level (LOAEL) is the lowest exposure level at which significant increases in frequency or severity of adverse effects occur between the exposed population and an appropriate control group. The NoObserved Adverse Effect Level (NOAEL) is the exposure level cit which there 3xe no significant increases in observed adverse effects compared with a control group (10). EPA's risk assessment methodology for noncancer effects is based on the above principles and consists of calculating the inhalation RfC and the oral RfD. The RfC represents an estimate, with an orderof-magnitude uncertainty range, of the air concentration to which humans, including sensitive subpopulations, may be continually exposed over a lifetime without an appreciable risk of deleterious effects. The RfD, also with an order-of-magnitude uncertainty range, is an estimate of the human population daily ingestion exposure dose that is likely to be without appreciable risk of deleterious effects. Restriction of pollutant exposures in conformance with RfC and RfD values, is presumed protective against the critical effect, thus affording protection against other effects at higher doses (11) A quantitative estimate of the RfC is obtained by dividing the NOAEL (expressed as a human equivalent concentration, adjusted for dosimetric differences between animal species and humans) by the product of an uncertainty factor (UF) and a modifying factor (MF). The value of the latter parameter in producing a reliable risk estimate is based on professional judgment of the entire database's utility, that is, sample size. RfC = NOAEL / (UF x MF)
(1)
An estimate of the RfD is developed in the same way. Uncertainty factors, which range in value from 3 to 10, account for extrapolation from a subchronic to a chronic exposure scenario, use of a LOAEL when a NOAEL value is unavailable, database incompleteness, and interspecies and intraspecies variability. Intraspecies variability considerations protect for sensitive subpopulations within the general population. A composite uncertainty factor is calculated as the product of individual factors. However, its maximum size is limited to a numerical value of 10,000. The additional modifying factor used to address other uncertainties accounts for the quality of the overall database for the chemical being evaluated and the choice and interpretation of critical studies used in assessing potential healdi risks. EPA is also considering use of an additional modifying factor, if no developmental or reproductive data are available for a
chemical {10). Modifying factors depend on the specific case being examined, range in value from 1 to 10, and are assigned by professional judgment. Elsewhere, at ATSDR, toxicological profiles are developed and maintained for chemicals found at hazardous waste sites. Profile development of individual chemicals is prioritized based on a weighting of available health and exposure data for 250 chemicals. Although different criteria were used to develop ATSDR's list of 250 chemicals and EPA's hazardous air pollutants list, 97 chemicals are common to both inventories. ATSDR's toxicological profiles identify and review key literature that describes a chemical's toxicological properties. Profiles developed by ATSDR from reliable data present estimates of exposure levels that pose minimal risk to humans (MRLs). MRLs are designed to serve as advisories to physicians and public health officials that they can use when making recommendations to protect populations living in the vicinity of a hazardous waste site or substance emission {12). MRLs consider the most sensitive noncancer effect associated with oral and inhalation pathways. An MRL is defined as "an estimate of the daily human exposure to a substance that is likely to be without an appreciable risk of adverse, noncancer effects over a specified duration of exposure" {12). It is calculated for acute (14 days or less), intermediate (15-364 days), and chronic (365 days or more) exposures, using human or animal data. Similar to the EPA method, adjustments are made to reflect human response variability and extrapolation of data from laboratory animals to humans. In establishing MRL estimates, ATSDR uses an extensive peerreview process. Chronic inhalation MRLs and chronic oral MRLs are, respectively, similar to EPA's RfCs and RfDs, using the same basic methodology as described above. Unlike EPA, ATSDR does not apply an uncertainty factor for extrapolation from subchronic to chronic exposure, because ATSDR develops MRLs for three different time periods. Well-designed subchronic studies are used to develop intermediate MRL exposure estimates. Recently, ATSDR and EPA agreed that, on a case-by-case basis, use of uncertainty factors less than 10 is warranted; for example, MRL estimates, using uncertainty factors less than 10, are calculated in cases where the LOAELs tire based on minimal health effects, the experimental animal appears to be a sensitive species, or 3. large human database is accessible {12). WHO also collects and evaluates scientific data for various chemicals, recommending safe levels of use and estimating ADIs for several pesticides. ADIs estimate the amount of substances of concern in food or drinking water that can be ingested daily over a lifetime without appreciable risk. They are calculated using the same basic approach as EPA's RfDs and ATSDR's chronic oral MRLs {13)) Cancer benchmarks described ERA assumes that for carcinogenesis there is no doseresponse threshold, or if one does exist, it is very low and cannot be reliably identified. Consequently, any increase in dose is associated with an increased risk of developing cancer. This is an assumption, not a VOL. 3 1 , NO. 12, 1997 / ENVIRONMENTAL SCIENCE & TECHNOLOGY / NEWS • 5 6 9 A
TABLE 1 Health benchmark comparison Examples of information used by EPA and the Agency for Toxic Substances and Disease Registry in producing benchmark estimates. Variations in data and outcomes are discussed in the text. EPA
ATS0R Cook etal. (19741(77) Neurobehavioral effects (humans) 0.14 mg/m 3 (L) 100 10-use of LOAEL; 10-human variability
Benchmark
Roelsetal. (1987) (76) Neurobehavioral effects (humans) 0.15mg/m 3 (L) 1000 10-sensitive individuals; 10-use of LOAEL; 10-database limitations 0.00005 mg/m 3
Inorganic mercury Critical study Critical effect NOAEL or LOAEL Adjusted NOAEL or LOAEL Uncertainty factor Uncertainty factor basis Benchmark
Faweretal. (1983) (78) Neurological effects (humans) 0.025 mg/m 3 (L) 0.009 mg/m 3 (L) 30 10-sensitive individuals; 3-database limitations 0.0003 mg/m 3
Faweretal. (1983) (78) Neurological effects (humans) 0.026 mg/m 3 (L) 0.0014 mg/m 3 (L) 100 10-use of LOAEL; 10-human variability 0.000014 mg/m 3
Velsicol Chemical (1983) (79) Liver effects (rats) 0.055 mg/kg/day (N) 100 10-intraspecies differences; 10-human variability
Benchmark
Velsicol Chemical (1983) (79) Liver effects (rats) 0.055 mg/kg/day (N) 1000 100-inter- and intraspecies differences; 10-database limitations 0.00006 mg/kg/day
1,3-Dichloropropene Critical study Critical effect NOAEL or LOAEL Uncertainty factor Uncertainty factor basis Benchmark
Lomaxetal. (1989) (20) Hyperplasia nasal epithelium (mice) 20.9 mg/m 3 (N) 30 10-sensitive individuals; 3-interspecies differences 0.02 mg/m 3
Lomaxetal. (1989) (20) Hyperplasia nasal epithelium (mice) 20.9 mg/m 3 (N) 100 10-interspecies differences; 10-human variability 0.009 mg/m 3
Mobay, Inc. (1989) (27) Degeneration olfactory epithetium (rats) 0.035 mg/m 3 (N) 100 10-intraspecies differences; 3-interspecies differences; 3-absence of reproductive/ developmental studies 0.0001 mg/m 3
Mobay, Inc. (1989) (27) Degeneration olfactory epithelium (rats) 0.035 mg/m 3 (N) 90 3-use of minimal LOAEL; 3-intraspecies differences; 3-interspecies differences; 10-human variability 0.0007 mg/m 3
Chemical Manganese Critical study Critical effect NOAEL or LOAEL Uncertainty factor Uncertainty factor basis
Chlordane Critical study Critical effect NOAEL or LOAEL Uncertainty factor Uncertainty factor basis
Hexamethylene-1,6-diisocyanate Critical study Critical effect NOAEL or LOAEL Uncertainty factor Uncertainty factor basis
Benchmark Toluene Critical study Critical effect NOAEL or LOAEL Uncertainty factor Uncertainty factor basis Benchmark Hexachlorobenzene Critical study Critical effect NOAEL or LOAEL Uncertainty factor Uncertainty factor basis Benchmark
0.0003 mg/m 3
0.0006 mg/kg/day
' Fooetal. (1990) (22) Neurological effects (humans) 332 mg/m 3 (L) 300 10-intraspecies differences; 10-use of LOAEL; 3-database deficiencies 0.4 mg/m 3
Orback and Nise (1989) (23) Neurological effects (humans) 159 mg/m 3 (L) 30 3-use of minimal LOAEL; 10-human variability
Arnold et al. (1985) (24) Liver effects (rats) 0.08 mg/kg/day (N) 100 10-intraspecies differences; 10-interspecies differences 0.0008 mg/kg/day
Arnold etal. (1985) (24) Developmental effects (rats) 0.016 mg/kg/day (L) 1000 10-intraspecies differences; 10-interspecies differences; 10-use of LOAEL 0.00002 mg/kg/day
5 7 0 A • VOL. 31, NO. 12, 1997 / ENVIRONMENTAL SCIENCE & TECHNOLOGY / NEWS
3.8 mg/m 3
final conclusion, that EPA makes to be conservative for policy purposes. EPA's recently released Proposed Guidelines for Carcinogen Risk Assessment suggests a revised method to characterize hazards from carcinogens {14). These guidelines propose mat all available evidence should be weighed, including tumor findings in animals or humans, structure-activity relationships to other carcinogenic agents, and activities in other carcinogenic processes; and a narrative, with risk descriptors, should be developed that summarizes the weight of evidence. The descriptors should characterize risk as: "known/likely," "cannot be determined" or "not likely." The narrative should explain the kind of evidence available indicate how it fits together in drawing conclusions and point out significant strengths and limitations of data and conclusions (14) If these oroposed guidelines are finalized this Drocedure will replace EPA's' current method in which chemicals are assigned a letter classification indicating trip direction and strength nf evi riVnrp nf h C
' i
1
i n n p p n i r risk
FIGURE 1 Health risk benchmark comparison For 14 of the 19 hazardous air pollutants analyzed, health risk endpoint estimates agree within an order of magnitude when, expressed as ratios, EPA's RfC and RfD benchmarks are, respectively, compared with ATSDR's chronic inhalation and oral dose MRLs.
Tnrrpntlv
HassifipH as A ["Human ) Rl
R? (P
h hi
H
man Carcinogen), C (Possible Human Carcinogen), D (Not Classifiable), or E (Evidence of Noncarcinogemcity) (15). The agency establishes quantitative risk estimates using mathematical models to extrapolate results from high-dose animal studies to lower dose levels that are more characteristic of human exposures. Existing guidelines use the "linearized multistage" procedure as a default, although there are several other models that could also be justified and used to make quantitative risk estimates. In the future, EPA's proposed cancer guidelines will use straight-line extrapolation as a linear default. The change in the default extrapolation procedure was proposed because of the unwarranted appearance of specific knowledge and sophistication implied by default use of the "linearized multistage" procedure (14) EPA presents quantitative risk estimates in three ways: a cancer slope factor, calculated as the risk per milligram per kilogram (mg/kg) per day; unit risk, the risk per microgram per liter (pg/L) of drinking water ingested or the risk per ug per m3 of air breathed; and risk presented as contaminant drinking water or air concentration levels that provide cancer risks of 1 in 10,000,1 in 100,000, or r in n million (3). These risk estimates present a plausible upper bound estimate of risk and, as such, do not give a realistic prediction of actual risk, that is, an estimate reflecting the influence of uncertainties on risk values (15). Upper bound risk estimates are calculated to be protective of public health and are extremely conservative values.
Elsewhere, IARC and DHHS's Public Health Service also evaluate and interpret available chemical carcinogenicity data. Both agencies assign chemicals into Groups 1, 2A, 2B, or 3 based on their evaluations (6, 7). Quantitative risk estimates for chemicals are not presented. Analysis of health information Table Al in Appendix A (included with Table A2 as supporting information to the article) presents available benchmark data for the 189 hazardous air pollutants cited in the Clean Air Act Amendments based on systemic effects: EPA's RfDs and RfCs, ATSDR's MRLs, and WHO's ADIs. EPA has derived RfDs for 86 chemicals and RfCs for 43 chemicals, ATSDR has derived 1 or more MRLs for 64 chemicals, and WHO has derived ADIs for 11 chemicals. Seven of the RfCs reported in the table are based on human data; the remaining 35 RfCs are based on VOL.31, NO. 12, 1997/ENVIRONMENTAL SCIENCE S TECHNOLOGY/NEWS " 5 7 1 A
TABLE 2 Health information for chemicals lacking benchmarks Health information documents are available for 21 of the 189 hazardous air pollutants. EPA Documents
Chemical (CAS No.)
Category
Naphthalene (91-20-3)
Aromatics
• O
Dibenzofuran (132-64-9)
Aromatics
•
Chloroprene (126-99-8)
Halogenated hydrocarbons
2,2,4-Trimethylpentane
Hydrocarbons
HS0B
IARC
ATSDR
IRIS
A
A
A
• o
Benchmark (Status) RfD (under review) RfC (under review)
A
RfC (under review)
A
RfC (inadequate data)
A
RfC and RfD (under review)
(540-84-1) Chlorine (7782-50-5)
Inorganics
Mineral fibers (N/A)
Inorganics
DA
2-Methyoxyaniline (90-04-0)
Nitrogenated organics
A
A
RfC (inadequate data)
4-Nitrobiphenyl (92-93-1)
Nitrogenated organics
A
A
RfC (under review)
4-Nitrophenol (100-02-7)
Nitrogenated organics
A
p-Phenylenediamine (106-50-3)
Nitrogenated organics
A
RfC (inadequate data) and RfD (under review)
O
A
Diethanolamine (11-42-2)
Nitrogenated organics
A
Ethyleneimine (151-56-4)
Nitrogenated organics
A
Calcium cyanamide (156-62-7)
Nitrogenated organics
A
Diazomethane (334-88-3)
Nitrogenated organics
Methyl isocyanate (624-83-0)
Nitrogenated organics
W-Nitroso-n-methylurea
Nitrogenated organics
A O
A A
RfC (inadequate data)
A
A A
A
RfC (inadequate data) A
(684-93-5) Phosgene (75-44-5)
Oxygenated hydrocarbons
Quinone (106-51-4)
Oxygenated hydrocarbons
•
A A
A
RfC (inadequate data) RfC (inadequate data)
Pyrocatechol (120-80-9)
Oxygenated hydrocarbons
A
A
RfC (under review)
Propionaldehyde (123-86-6)
Oxygenated hydrocarbons
A
Carbonyl sulfide (463-58-1)
Other
A
RfC (under review)
Legend: • = EPA Health Effects Assessment Document, O = EPA Health and Environmental Effects Profile, • = EPA Health and Environmental Effects Document, D = EPA Drinking Water Criteria Document, A = EPA Ambient Water Quality Criteria Document, and A = all other documents.
laboratory animal data. The most common endpoint used as a basis for estimating risk is nasal effects; 17 hazardous air pollutants have RfCs based on this endpoint. Neurological effects, used for estimating health risks of eight chemicals, are the next most prevalent endpoint. Other endpoints used as the basis for estimating RfCs are developmental effects; reproductive effects; and effects on the blood, liver, kidney, and spleen. The majority of RfC estimates is given a medium confidence rating. Figure 1 compares EPA's RfCs and RfDs to ATSDR's chronic inhalation MRLs and ATSDR's chronic oral MRLs, respectively, for chemicals where coexisting estimates are available. Table 1 (16-24) compares, ,n more detail, five EPA RfC and two RfD estimates witii ATSDR's chronic inhalation and chronic oral MRL estimates, respectively. For the limited number of chemicals analyzed in this report, the reasons for major differences between the health-risk benchmark estimates appear to be as follows. • Chosen uncertainty factor—EPA and ATSDR based benchmark estimates on the same study, but used different uncertainty factors, resulting in very different outcomes. Even though EPA and ATSDR follow similar uncertainty factor guidelines, the interpretation of these guidelines can differ, resulting in selection of different uncertainly factors. • Study selected—EPA and ATSDR selected different studies as the basis for performing risk assessments. The selection of studies involves a great deal of scientific judgment. General guidelines are 5 7 2 A • VOL. 31, NO. 12, 1997 / ENVIRONMENTAL SCIENCE & TECHNOLOGY / NEWS
followed, but people with varying scientific backgrounds may interpret studies differently and ultimately select different studies. The relatively small fraction of common chemical benchmarks that differ significandy, combined with the application of uncertainty factors or the absence of a pattern in selecting studies, suggests an EPA-ATSDR consistency not just in risk assessment approaches and development of benchmark values. Table A2 in Appendix A summarizes EPA cancer classifications and quantitative 1CT6 risk estimates for inhalation and drinking water exposures, and IARC and DHHS cancer classifications for the 189 hazardous air pollutants listed in the Clean Air Act Amendments. Chemicals ranked by EPA as Group A, by IARC as Class 1, and by DHHS as known carcinogens include benzene, vinyl chloride, benzidine, bis(chloromethyl)ether, asbestos, arsenic, and chromium VI. The Group B2 classification predominates for the majority of chemical categories. The exception to this is the inorganics grouping, where chemicals are split between Group D (26%) and Group A (22%). Halogenated hydrocarbons evenly split among cancer classifications than other chemical categories witii 10% in Group A 37% in GrouD B2 and B2/C 31% in Group C and 17% in Group D EPA has calculated the 10"6 risk-specific inhalation dose for 39 chemicals. This ranges from 0.000004 fibers/m3 for asbestos to 2 ug/L for metiiylene chloride. The 10"6 risk-specific oral exposure dose has also
been calculated for 39 chemicals and ranges from 0.00016 ug/L for bis(chloromethyl)ether to 40 ug/L for isophorone. Table 2 lists hazardous air pollutants for which no health benchmarks have yet been derived. Many of these hazardous air pollutants have RfCs or RfDs currendy under review by EPA, or were examined by EPA and determined to have inadequate data for development of an RfC or RfD estimate. Benchmark values developed byATSDR, EPA, and WHO are used differently by each agency, other organizations, and the public. ATSDR uses MRLs as advisories to public health officials and others making decisions about potential hazardous waste-site exposures. These values are used in a nonregulatory manner and are often interpreted differently on a case-by-case basis. EPA benchmarks, RfDs and RfCs, are used by specific EPA program offices as the basis for their regulations. For example, EPA's Office of Water uses RfDs in developing its "maximum contaminant level goal," defined as the "level at which no known or anticipated adverse effects on the health of individuals occur and which allows an adequate margin of safety." The drinking water regulatory numbers must be set "as close to the maximum contaminant level goal as feasible" EPA's Office of Solid Waste uses cancer risks that range from 10"4 to 10"6 in determining whether a waste stream is inherently hazardous. EPA benchmark values have been used to support state and local agency development of regulations and guidelines, evaluate and contribute to international public health efforts, and set targets for environmental monitoring and evaluation programs. Similarly, WHO benchmark advisory values are used by international and national regulatory authorities in developing decisions on food safety and environmental contamination. Despite differences in the way benchmarks are used by the various governmental organizations and the observation (albeit based on a limited number of chemicals) that only a fraction of common benchmarks differs significantly, government agencies should seek to further harmonize risk assessment guidelines and their interpretations. These efforts should aim to reduce problems that arise because of differing interpretations of supporting studies. They also should seek to create a framework within which the uncertainties in risk estimates can be clearly recognized and their significance easily understood. The establishment of interagency workgroups may provide a mechanism for review of benchmarks and development of new methods for producing reliable risk estimates. Moreover communication and sharing of validated health information through use of the Internet and electronically accessible databases mav increase oDDortunities for harmonizing risk information and its lisp
Supporting information available Ancillary material cited as Tables Al and A2 in this report will appear following these pages in the microfilm edition of this volume of the journal. Photocopies of supporting information from this paper, or microfiche (105 x 148 mm, 24 x reduction, negatives), can be obtained from the Microforms Office, American Chemical Society, 1155 16th St.,
NW, Washington, DC 20036. Full bibliogrrphic citation (journal, number, and issue number) and prepayment, check or money order, for $25.50 for a photocopy ($27.50 foreign) or $12.00 for microfiche ($13.00 foreign) are required. Canadian residents should add 7% GST.
References (1) Fed. Regist. 1992, 57, 31576. (2) The Clean Air Act Amendments of 1990, Summary Materials; U.S. Environmental Protection Agency, Office of Air and Radiation, U.S. Government Printing Office: Washington, DC, 1990. (3) Integrated Riik Information nystem; U.S. Environmental Protection Agency, Database, Environmental Criteria, and Assessment Office, U.S. Government Printing Office: Washington, DC, ,997. (4) Agency for Toxic Substances and Disease Registry. Minimal Risk Levels for Hazardous Substances, http:// atsdrl.atsdr.cdc.gov:8080/mrls.html (accessed November 1996). (5) World Health Organization. International Programme on Chemical Safety, WHH: Geneva, Switzerland. (6) International Agency for Research on Cancer. IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans: Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs s to o2. Supplement t; IARA Working Group on the Evaluation of Carcinogenic Risks to Humans, World Health Organization: Lyon, France, 1987. (7) U.S. Department of Healm and Human Services, Public Health Service. Seventh Annual Reporr on Carcinogens; Summary of report prepared for the National Institute of Environmental Health Sciences, U.S. Government Printing Office: Washington, DC, 1994. (8) Health Effects Assessment Summary Tables. Annual Update; U.S. Enviionmental Protectton Agency, Office oo Research and Development, U.S. Government Printing Office: Washhngton, DC, ,199; EPA 540/R-95-036. (9) Hazardous Air Pollutants: Profiles ofNoncancer Toxicity from Inhalation Exposures; EPA/600/R-93/142; U.S. Environmental Protection Agency, Office of Research and Development, U.S. Government Printing Office: Washington, DC, 1993. (10) Methods for Derivation nf Inhalation Reference Concentrations and Appllcation of Inhalation Dosimetry; EPA/ 600/8-90/066F; U.S. Environmental Protection Agency, Office of Research and Development, U.S. Government Printing Office: Washington, DC, 1994. (11) Jabarek, A. M. et al. Toxicol. Ind. Health 1990, 6(5), 2792 (12) Pohl, H. R.; Abadin, H. G. Regul. Toxicol. Pharmacol. 1995, 22, 180. (13) Dourson, M. L.; Lu, E C. Biomed. Environ. Sci. 1995, 8, 1. (14) Proposed Guidelines for Carcinogen Risk Assessment; EPA/ 600/P-92/003C; U.S. Environmental Protection Agency, Office of Research and Development, U.S. Government Printing Office: Washington, DC, 1996. (15) Fed. Regist. 1986, 51, 33992. (16) Roels, H.; Lauwerys, R.. Buchett ,-P.Am.J. Ind. Med. 1987, 11, 307. (17) Cook, D. C; Fahn, S.; Brait, K. A. Arch. Neurol. 1974, 30, 59. (18) Fawer, R. E; DeRibaupierre, Y.; Guillemin, M. Br. .. Ind. Med. 1983, 40, ,04. (19) Velsicol Chemical Company. MRID No. 00138591, 00144313, ,983; as cited in integrated Risk Information System (IRIS) on Chlordane; U.S. Environmental Protection Agency, Environmental Criteria and Assessment Office, U.S. Goveenment Printing Offfce: Washington, DC, 1995. (20) Lomax, G. G. et all Fundam.Appl. Toxicol. 1989,12, 4184 (21) Mobay, Inc. Chronic Inhalation Toxicity and Oncogenicity Study with 1,6-HexamethyleneDiisocyanate (HDI) in Rats; Final Report No. 83-241-01; TSCATS/405587; ;PA/ OTS Doc. No. 86-900000055; U.S. Environmental Protection Agency, U.S. Government Printing Office: Washington, DC, 1989. (22) Foo, S. C; Jeyaratnam, J.; Koh, D. Br. J. Ind. Med. 1990, 47(7), 480. (23) Orback, P.; Nise, G. Am.]. Ind. Med. 191989,, 6,. (24) Arnold, D. L.; Moodie, C. A.; Chaabonneau, S. M. Chem. Toxicol. 1985, 23(9), 779. VOL. 3 1 , NO. 12, 1997 /ENVIRONMENTAL SCIENCE S TECHNOLOGY / NEWS • 5 7 3 A
