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Male and female CD-1 mice and Sprague-Dawley CD rats (120/sex/group) were exposed to 0, 0.05 or 0.15 ppm (0, 0.36 or 1.07 mg/m 3 ) industrial-grade TDI (approximately 80% 2,4 isomer, 20% 2,6 isomer) by inhalation for 6 hours/day, 5 days/week, for 104 (mice), 108 (female rats) or 110 (male rats) weeks (Loeser, 1983). No treatment-induced increase in tumor incidence was noted in rats or mice. However, the rat histopathological evaluation was incomplete. Also, NTP (1986) noted that the exposure levels used corresponded to daily gavage doses of less than 1 mg/kg, and may not have been adequate doses to detect a potential carcinogenic response. IV. DERIVATION OF CANCER POTENCY Basis for Cancer Potency The NTP carcinogenicity study (1986) demonstrated that TDI induced tumors in several species (rats and mice), in both sexes in at least one of those species, at multiple sites. The male rat subcutaneous fibroma/fibrosarcoma tumor data was chosen as the basis of a cancer potency factor because it was the most sensitive endpoint in the most sensitive of the responsive species and sexes tested. Methodology Expedited Proposition 65 methodology (with cross-route extrapolation) was used to derive a cancer potency factor. A unit risk factor was then calculated by <strong>OEHHA</strong>/ATES from the cancer potency factor using a reference human body weight of 70 kg and an inspiration rate of 20 m 3 /day. V. REFERENCES California Environmental Protection Agency (Cal/EPA) 1992. Expedited Cancer Potency Values and Proposed Regulatory Levels for Certain Proposition 65 Carcinogens. Office of Environmental Health Hazard Assessment, Reproductive and Cancer Hazard Assessment Section, Berkeley, CA. Gold L, Slone T, Backman G, Eisenberg S, Da Costa M, Wong M, Manley N and Ames B. 1990. Third chronological supplement to the Carcinogenic Potency Database; Standardized results of animal bioassays published through December 1986 and by the National Toxicology Program through June 1987. Environ Health Perspect 84:215-285. Hazardous Substance Data Bank (HSDB) 1994. National Library of Medicine, Bethesda MD (CD- ROM Version). Micromedix, Inc., Denver CO, Edition 22. International Agency for Research on Cancer (IARC) 1985. Toluene diisocyanate. In: IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man, Volume 39. IARC, Lyon, France, pp. 287-323. Loeser E. 1983. Long-term toxicity and carcinogenicity studies with 2,4/2,6-toluene diisocyanate (80/20) in rats and mice. Toxicol Lett 15:71-81. 517
Mortillaro PT and Schiavon M. 1982. One case of lung cancer that developed in the course of a bronchopulmonary disease due to isocyanates (Ital.). Med Lav 3:207-209. National Toxicology Program (NTP) 1980. NTP Technical Report on the Carcinogenesis Studies of Commercial Grade 2,4 (86%) and 2,6 (14%) Toluene Diisocyanate (CAS No. 26471-62-5) in F344/N rats and B6C3F 1 Mice (Gavage Studies) (Tech. Rep. No. 251). Research Triangle Park, NC. 518
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Air Toxics Hot Spots Program Risk A
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Prepared by: John D. Budroe, Ph.D.
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This document is one of five docume
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TABLE OF CONTENTS PREFACE i INTRODU
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N-Nitrosodimethylamine 401 N-Nitros
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Hot Spots Unit Risk and Cancer Pote
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Additional ATES and PETS documents
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data. If several data sets (dose an
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US EPA Calculation of Carcinogenic
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exposure to a concentration of 1 µ
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incidences for each of the dose lev
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computes the surface area of a sphe
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Comparison of Hot Spots Cancer Unit
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Gold, L., de Veciana, M., Backman,
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Animal Studies Rats Woutersen et al
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ased on sufficient evidence of carc
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ACETAMIDE CAS No: 60-35-5 I. PHYSIC
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Methodology Expedited Proposition 6
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cancer mortality. However, US EPA (
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Table 2. Lung adenoma incidence in
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Table 3 (continued). Acrylamide-ind
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Robinson M, Bull RJ, Knutsen GL, Sh
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Also, a trend was observed correlat
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eported. Cause-specific expected de
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Bio/Dynamics Inc. conducted a study
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examination. Interim sacrifices wer
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Table 8. Tumor incidence in male an
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Gaffey WR and Strauss ME. 1981. A m
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(technical grade; 98% pure) by gava
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International Agency for Research o
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still alive in the low-dose control
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ANILINE CAS No: 62-53-3 I. PHYSICAL
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fibrosarcomas, stromal sarcomas, ca
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ARSENIC (INORGANIC) CAS No: 7440-38
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elationship between arsenic exposur
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al. (1988) did not induce lung tumo
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A risk assessment was also conducte
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Chen C, Chuang Y, You S, Lin T and
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Schrauzer G, White D, McGinness J,
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Table 1: Summary of epidemiologic s
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had at least one animal demonstrati
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mesothelioma, recommended lifetime
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National Institute for Occupational
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BENZENE CAS No: 71-43-2 I. PHYSICAL
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Animal Studies Available experiment
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Table 3: Summary of NTP bioassay re
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Table 4: Summary of benzene low-dos
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Maltoni C, Conti B and Cotti G. 198
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a benign tumor of the kidney. No ba
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al. (1968) found no tumors in lifet
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following relationship, where C(t 1
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Miakawa M. and Yoshida O. 1975. Pro
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human population and that BPDE-DNA
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demonstrated the tumor initiating a
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Table 4: Bronchoalveolar tumors fro
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Table 5: IARC groupings of PAHs, mi
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Table 6 (continued): IARC Group 3 P
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Potency Equivalency Factors (PEF) f
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This was rounded to a PEF of 0.1. 1
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experiment (Takayama et al., 1985)
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Deutsch-Wenzel RP, Brune H, Grimmer
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Krewski D, Thorslund T and Withey J
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U.S. Environmental Protection Agenc
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Sorahan et al. (1983) studied cance
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Lijinsky W. 1986. Chronic bioassay
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the drinking water (Schroeder and M
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Table II. Effective dose, upper-bou
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BIS(2-CHLOROETHYL)ETHER CAS No: 111
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IV. DERIVATION OF CANCER POTENCY Ba
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BIS(CHLOROMETHYL)ETHER CAS No: 542-
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Table 1. Bis(chloromethyl)ether-ind
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Drew RT, Laskin S, Kuschner M and N
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ates for the 1968 U.S. male populat
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Table 1: Incidence of primary tumor
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National Institute of Occupational
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was less than 0.05 when controlling
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up period. The final cohort include
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If the cadmium-exposed workers incl
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on personnel records (20%); (3) eva
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were exposed to a continuous (23.5
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procedure (NLIN), the parameters we
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International Agency for Research o
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Two reports were published on cance
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Mendel rats, respectively), and sub
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Eschenbrenner A and Miller E. 1946.
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III. CARCINOGENIC EFFECTS Human Stu
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cancers, were less than expected. T
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and no cases of cancer (although cl
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There was a statistically significa
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NTP (1982a) also conducted an carci
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Several pathologists have independe
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hepatocellular adenoma/carcinoma tu
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carcinogenic potency may decline in
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Cochrane W, Singh J and Miles W. 19
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North Atlantic Treaty Organization,
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CHLORINATED PARAFFINS (average chai
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ased on dose-response data for beni
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chloroform in drinking water with k
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Overall, the present epidemiologica
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female dogs received toothpaste bas
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Calculated q 1 * values from the ab
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Hogan MD, Chi Py, Hoel DG and Mitch
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Table 1. Study design summary for N
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V. REFERENCES California Environmen
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toluidine. Followup of this subcoho
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feeding studies on by NCI (1979) us
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CHROMIUM (HEXAVALENT) CAS No: 18540
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expected rate may be inflated becau
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Oral Borneff et al. (1968) exposed
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CREOSOTE (COAL TAR-DERIVED) CAS No:
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from an inhalation exposure study (
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Table 1. Study design summary for N
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Table 1. Experimental design for ca
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Hazardous Substance Data Bank (HSDB
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Table 1: Tumor induction in Fischer
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Table 1. Experimental design of 2,4
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Additional analysis of these data b
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Jackson RJ, Greene CJ, Thomas JT, M
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Table 1. Tumor incidence in rats ex
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Girard R, Tolot F, Martin P and Bou
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exposed more than 16 years before t
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interpretation of dose extrapolatio
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1, 1-DICHLOROETHANE CAS No: 75-34-3
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Table 1b. Study design for carcinog
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National Cancer Institute (NCI) 197
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mice, hepatocellular carcinoma inci
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V. REFERENCES California Department
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DAB/day by gavage for the life of t
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2,4-DINITROTOLUENE CAS No: 121-14-2
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Ellis et al.(1979) (also reported b
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Final Statement of Reasons for OAL,
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to the small sample size and short
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In an inhalation study, Torkelson e
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V. REFERENCES American Conference o
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EPICHLOROHYDRIN CAS No: 106-89-8 I.
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espiratory tumors were noted in the
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Table 4. Epichlorohydrin-induced fo
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Konishi Y, Kawabata A, Denda A, Ike
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exposed to arsenicals for 20 months
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espectively (all statistically sign
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ETHYLENE DICHLORIDE CAS No: 107-06-
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Several factors have been suggested
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myelogenous leukemias (4 and 8 year
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statistically significant. CDHS not
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combined with the incidence in the
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incidence of primary brain tumors.
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Table 6 (continued): Organ/Sex Mali
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An Upper 95% Confidence Limit (UCL)
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ETHYLENE THIOUREA (ETU) CAS No: 96-
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male and female rats. Tumor inciden
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FORMALDEHYDE CAS No: 50-00-0 I. PHY
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presented an extension of a previou
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Methodology In developing a spectru
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Casanova M, Morgan KT, Steinhagen W
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Tobe M, Kaneko T, Uchida Y, Kamata
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Table 1. Hexachlorobenzene-induced
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50 pups (F 1 ) of each sex were ran
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Ertürk E, Lambrecht RW, Peters HA,
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Table 1. Liver hepatoma incidence i
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1988). An airborne unit risk factor
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HYDRAZINE CAS No: 302-01-2 I. PHYSI
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Methodology Inhalation A linearized
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LEAD AND LEAD COMPOUNDS (INORGANIC)
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and other occupational carcinogens
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y inhalation is similar for rats an
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Goyer RA. 1992. Nephrotoxicity and
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LINDANE (g-Hexachlorocyclohexane) C
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Using these relationships, a human
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METHYL TERT-BUTYL ETHER (MTBE) CAS
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Tumor incidences according to the r
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kidney changes indicative of chroni
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Interspecies scaling for oral doses
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Table 4 (continued): Dose Response
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Experimental Pathology Laboratories
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Animal Studies Male and female HaM/
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Gold L, Sawyer C, Magaw R, Backman
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Using the statistical tests (one-ta
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Table 1: Methylene chloride-induced
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Significant treatment-related incre
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National Toxicology Program (NTP) 1
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noted; however, the study duration
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Crump KS, Howe RB, Van Landingham C
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Table 1. Michler’s ketone-induced
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NICKEL AND NICKEL COMPOUNDS CAS No:
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the high exposure group was 14.0. A
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male and 121 female rats, was expos
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2.1 - 2.6 × 10 -4 (µg/m 3 ) -1 .
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The increased incidence of bladder
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A linearized multistage procedure w
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N-NITROSO-N-METHYLETHYLAMINE CAS No
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propylamine in drinking water at 0.
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N-NITROSODIETHYLAMINE CAS No: 55-18
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Table 2. Treatment groups, concentr
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California Department of Health Ser
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animals and the second generation t
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ationale for selection of the OEHHA
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A unit risk value based upon air co
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N-NITROSODIPHENYLAMINE CAS No: 86-3
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Methodology Dosage estimates of NDP
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Crump KS, Howe RB. 1984. The multis
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Table 1. P-Nitrosodiphenylamine-ind
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N-NITROSOMORPHOLINE CAS No: 59-89-2
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N-NITROSOPIPERIDINE CAS No: 100-75-
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Table 3. N-Nitrosopiperidine-induce
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Crump KS, Howe RB, Van Landingham C
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testicular tumors were noted in the
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PARTICULATE MATTER FROM DIESEL-FUEL
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etired railroad workers who had had
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employment (χ 2 test for trend: p
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elevated smoking-adjusted risk esti
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Table 1 (continued): Reference Miln
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Table 1 (continued): Reference Damb
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Table 1 (continued): Reference Burn
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Table 1 (continued): Reference Raff
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Table 1 (continued): Epidemiologica
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Table 1 (continued): Epidemiologica
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Table 1 (continued): Reference Wegm
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Animal Studies Section 6.1 (Animal
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The variability, or heterogeneity,
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estimate for those studies for whic
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Figure 1: Estimates of Relative Ris
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q 1 * = Excess relative risk × CA
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Table 3: Number of Workers in the E
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u nexposed workers at zero concentr
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for each µg/m 3 of diesel exhaust
Page 475 and 476: Table 4: Values from Unit Risk for
Page 477 and 478: their findings that a reasonable es
Page 479 and 480: Garshick E, Schenker M, Woskie S an
Page 481 and 482: Lewis T, Green, FH MW, Burg J and L
Page 483 and 484: Rothman K. 1986. Modern epidemiolog
Page 485 and 486: PENTACHLOROPHENOL CAS No: 87-86-5 I
Page 487 and 488: The default lifespan for mice is 10
Page 489 and 490: documented. An excess risk from ski
Page 491 and 492: B6C3F 1 mice and F344/N rats were e
Page 493 and 494: This model, rather than a time depe
Page 495 and 496: POLYCHLORINATED BIPHENYLS (PCBs) CA
Page 497 and 498: several benign adenomatous lesions
Page 499 and 500: Ito et al. (1973) exposed groups of
Page 501 and 502: could not be characterized by chlor
Page 503 and 504: exposure (all pathways and mixtures
Page 505 and 506: National Toxicology Program 1993. T
Page 507 and 508: Table 1. Potassium bromate-induced
Page 509 and 510: 1,3-PROPANE SULTONE CAS No: 1120-71
Page 511 and 512: IV. DERIVATION OF CANCER POTENCY Ba
Page 513 and 514: PROPYLENE OXIDE CAS No: 75-56-9 I.
Page 515 and 516: oxide. In the NTP carcinogenicity s
Page 517 and 518: 1,1,2,2-TETRACHLOROETHANE CAS No: 7
Page 519 and 520: assumed a body weight of 70 kg and
Page 521 and 522: total); an untreated control group
Page 523 and 524: TOLUENE DIISOCYANATE CAS No: 26471-
Page 525: Animal Studies The National Toxicol
Page 529 and 530: male or female rats. Increases in h
Page 531 and 532: TRICHLOROETHYLENE CAS No: 79-01-6 I
Page 533 and 534: A mortality analysis of a cohort of
Page 535 and 536: elative to that of the controls whi
Page 537 and 538: applied or metabolized. The range o
Page 539 and 540: Katz RM and Jowett D. 1981. Female
Page 541 and 542: 10,000 ppm 2,4,6-trichlorophenol in
Page 543 and 544: IV. DERIVATION OF CANCER POTENCY Ba
Page 545 and 546: Bionetics Research Laboratories. 19
Page 547 and 548: control; females: 6/10 exposed, 0/1
Page 549 and 550: over controls (p < 0.04). Other tum
Page 551 and 552: was increased (100/314 exposed vs.
Page 553 and 554: Table 3. Cancer potency estimates f
Page 555 and 556: Crouch E. 1983. Uncertainties in in
Page 557 and 558: VINYL CHLORIDE CAS No: 75-01-4 I. P
Page 559 and 560: Table 1 (continued): A Summary of E
Page 561 and 562: al., 1983). Histopathology of all o
Page 563 and 564: Table 3: Tumor incidences in 100 pp
Page 565 and 566: experiment, animals were exposed to
Page 567 and 568: Experiment BT1 Most previous risk a
Page 569 and 570: No statistical analyses of mortalit
Page 571 and 572: Table 11 gives unit risk estimates
Page 573 and 574: Bertazzi PA, Villa A, Foa V, Saia B
Page 575 and 576: Nicholson WJ, Hammond EC, Seidman H
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immunotoxicity, reproductive toxici
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scheme. TEFs for two major noncance
Page 581 and 582:
NATO/CCMS (1988a) Pilot Study on In
Page 583 and 584:
Table 2 Toxicity Equivalency Factor
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Table 4 A Comparison of CTEF- and I
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Office of Environmental Health Haza
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Group 4: The agent is probably not
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TECHNICAL SUPPORT DOCUMENT FOR DESC
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US EPA IRIS Inhalation Unit Risk an
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TECHNICAL SUPPORT DOCUMENT FOR DESC
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as appropriate, and revise IRIS fil
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Chemical Exposure Route Study Type
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Page 603 and 604:
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Methyl tert-butyl ether p. 5: Added
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