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IV. DERIVATION OF CANCER POTENCY Basis for Cancer Potency 4, 4'-Methylenedianiline The potency for this compound was derived from the potency for the dihydrochloride using a molecular weight conversion: q (anhydrous) = q (hydrate) h h × MW (hydrate) MW (anhydrous) where q h is the human potency and MW is the molecular weight. This conversion assumes that the intake of equivalent moles of the two forms of the chemical (e.g. the anhydrous and hydrate forms) results in equivalent concentrations of the active species in vivo. 4, 4'-Methylenedianiline didihydrochloride Results are listed for the drinking water studies by NTP (1983) in male and female B6C3F 1 mice and F344 rats. Significant increases in tumors of the liver or thyroid or both are observed for all sex/species combinations tested, with male mice the most sensitive. The cancer potency listed is based on the combined incidence of benign and malignant liver tumors in male mice (Cal/EPA, 1992). Methodology Expedited Proposition 65 methodology (with cross-route extrapolation) was used to derive a cancer potency factor. Analysis of the data set using the computer program TOX_RISK (Crump et al., 1991) indicated that inclusion of the high dose group resulted in a p-value of = 0.05 based on the chi-square goodness-of-fit test, indicating non-linearity. Following procedures described by US EPA (Anderson et al., 1983), the high dose group was excluded from the analysis to correct for the poor fit (Cal/EPA, 1992). 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 Anderson EL and the Carcinogen Assessment Group of the U.S. Environmental Protection Agency 1983. Quantitative approaches in use to assess cancer risk. Risk Anal 3:277-295. 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. 371
Crump KS, Howe RB, Van Landingham C and Fuller WG. 1991. TOXRISK Version 3. TOXicology RISK Assessment Program. KS Crump Division, Clement International Division, 1201 Gaines Street, Ruston LA 71270. Gold L, Sawyer C, Magaw R, Backman G, de Veciana M, Levinson R, Hooper N, Havender W, Bernstein L, Peto R, Pike M and Ames B. 1984. A Carcinogenic Potency Database of the standardized results of animal bioassays. Environ Health Perspect 58:9-319. Griswold Jr DP, Casey AE, Weisburger EK and Weisburger JH. 1968. The carcinogenicity of multiple intragastric doses of aromatic and heterocyclic nitro or amino derivatives in young female Sprague- Dawley rats. Cancer Res 28:924-933. Hazardous Substance Data Bank (HSDB) 1994. National Library of Medicine, Bethesda MD (CD- ROM Version). Micromedix, Inc., Denver CO, Edition 22. National Toxicology Program (NTP) 1983. Carcinogenesis Studies of 4,4'-Methylenedianiline (CAS No. 13552-44-8) in F344/N Rats and B6C3F 1 Mice (Drinking Water Studies). Technical Report Series No. 248. NIH Publication No. 83-2504. U.S. Department of Health and Human Services, NTP, Research Triangle Park, NC. 372
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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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Hazardous Substance Data Bank (HSDB
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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
Page 329 and 330: Table 1. Hexachlorobenzene-induced
Page 331 and 332: 50 pups (F 1 ) of each sex were ran
Page 333 and 334: Ertürk E, Lambrecht RW, Peters HA,
Page 335 and 336: Table 1. Liver hepatoma incidence i
Page 337 and 338: 1988). An airborne unit risk factor
Page 339 and 340: HYDRAZINE CAS No: 302-01-2 I. PHYSI
Page 341 and 342: Methodology Inhalation A linearized
Page 343 and 344: LEAD AND LEAD COMPOUNDS (INORGANIC)
Page 345 and 346: and other occupational carcinogens
Page 347 and 348: y inhalation is similar for rats an
Page 349 and 350: Goyer RA. 1992. Nephrotoxicity and
Page 351 and 352: LINDANE (g-Hexachlorocyclohexane) C
Page 353 and 354: Using these relationships, a human
Page 355 and 356: METHYL TERT-BUTYL ETHER (MTBE) CAS
Page 357 and 358: Tumor incidences according to the r
Page 359 and 360: kidney changes indicative of chroni
Page 361 and 362: Interspecies scaling for oral doses
Page 363 and 364: Table 4 (continued): Dose Response
Page 365 and 366: Experimental Pathology Laboratories
Page 367 and 368: Animal Studies Male and female HaM/
Page 369 and 370: Gold L, Sawyer C, Magaw R, Backman
Page 371 and 372: Using the statistical tests (one-ta
Page 373 and 374: Table 1: Methylene chloride-induced
Page 375 and 376: Significant treatment-related incre
Page 377 and 378: National Toxicology Program (NTP) 1
Page 379: noted; however, the study duration
Page 383 and 384: Table 1. Michler’s ketone-induced
Page 385 and 386: NICKEL AND NICKEL COMPOUNDS CAS No:
Page 387 and 388: the high exposure group was 14.0. A
Page 389 and 390: male and 121 female rats, was expos
Page 391 and 392: 2.1 - 2.6 × 10 -4 (µg/m 3 ) -1 .
Page 393 and 394: U.S. Environmental Protection Agenc
Page 395 and 396: The increased incidence of bladder
Page 397 and 398: A linearized multistage procedure w
Page 399 and 400: N-NITROSO-N-METHYLETHYLAMINE CAS No
Page 401 and 402: Hazardous Substance Data Bank (HSDB
Page 403 and 404: propylamine in drinking water at 0.
Page 405 and 406: N-NITROSODIETHYLAMINE CAS No: 55-18
Page 407 and 408: Table 2. Treatment groups, concentr
Page 409 and 410: California Department of Health Ser
Page 411 and 412: animals and the second generation t
Page 413 and 414: ationale for selection of the OEHHA
Page 415 and 416: A unit risk value based upon air co
Page 417 and 418: N-NITROSODIPHENYLAMINE CAS No: 86-3
Page 419 and 420: Methodology Dosage estimates of NDP
Page 421 and 422: Crump KS, Howe RB. 1984. The multis
Page 423 and 424: Table 1. P-Nitrosodiphenylamine-ind
Page 425 and 426: N-NITROSOMORPHOLINE CAS No: 59-89-2
Page 427 and 428: IV. DERIVATION OF CANCER POTENCY Ba
Page 429 and 430: 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
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Table 4: Values from Unit Risk for
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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
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PENTACHLOROPHENOL CAS No: 87-86-5 I
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The default lifespan for mice is 10
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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
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several benign adenomatous lesions
Page 499 and 500:
Ito et al. (1973) exposed groups of
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could not be characterized by chlor
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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:
Page 513 and 514:
PROPYLENE OXIDE CAS No: 75-56-9 I.
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oxide. In the NTP carcinogenicity s
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1,1,2,2-TETRACHLOROETHANE CAS No: 7
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assumed a body weight of 70 kg and
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total); an untreated control group
Page 523 and 524:
TOLUENE DIISOCYANATE CAS No: 26471-
Page 525 and 526:
Animal Studies The National Toxicol
Page 527 and 528:
Mortillaro PT and Schiavon M. 1982.
Page 529 and 530:
male or female rats. Increases in h
Page 531 and 532:
TRICHLOROETHYLENE CAS No: 79-01-6 I
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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
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10,000 ppm 2,4,6-trichlorophenol in
Page 543 and 544:
Page 545 and 546:
Bionetics Research Laboratories. 19
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control; females: 6/10 exposed, 0/1
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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
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al., 1983). Histopathology of all o
Page 563 and 564:
Table 3: Tumor incidences in 100 pp
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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
Page 577 and 578:
immunotoxicity, reproductive toxici
Page 579 and 580:
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
Page 585 and 586:
Table 4 A Comparison of CTEF- and I
Page 587 and 588:
Office of Environmental Health Haza
Page 589 and 590:
Group 4: The agent is probably not
Page 591 and 592:
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:
Page 605 and 606:
Methyl tert-butyl ether p. 5: Added
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