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Rats A two-year rat inhalation toxicity/carcinogenicity study (Hazleton Europe, 1981) was also evaluated. Groups of 100 per sex/dose were exposed to 0, 1,000, or 8,000 ppm butadiene for 6 hours/day, 5 days/week for 105-111 weeks. Unlike the mouse I study, survival of treated animals was not adversely affected in the first year of the study, but during the second year there was a statistically significant relationship between mortality and air concentration of butadiene. The published incidences (Owen, 1987) are slightly different form those given by U.S. EPA (1985). The total significant tumor incidences (number of animals bearing one or more significant tumors) in males based on U.S. EPA criteria and 1987 published incidences are 4/100, 5/100 and 20/100 for the control, low, and high dose groups (Leydig cell tumors, pancreatic exocrine tumors, and Zymbal gland tumors). Total female significant tumor incidences in the control, low and high dose groups were: 18/100, 19/100, and 41/100 (mammary carcinoma, thyroid follicular cell tumors, and Zymbal gland tumors). Tumor incidence data are shown in Table 3. Table 3: Incidence of Primary Tumors in Rats Exposed to Butadiene a (<strong>OEHHA</strong>, 1992) Site / Lesion Sex Nominal Dose (ppm) in Air 0 1000 8000 Mammary / Fibroadenoma F 32 64 55 Mammary / Carcinoma F 18 15 26 TOTAL 50 b 79 c 81 c Thyroid / Follicular cell adenoma F 0 2 10 Thyroid / Follicular cell carcinoma F 0 2 1 TOTAL 0 b 4 11 c Uterus / Cervical stromal sarcoma F 1 4 5 Testis / Leydig cell adenoma or carcinoma M 0 d 3 8 c Pancreas / Exocrine adenoma M 3 d 1 10 e Zymbal gland adenoma M 1 1 1 F 0 0 0 Zymbal gland carcinoma M 0 0 1 F 0 0 4 TOTAL M 1 1 2 F 0 d 0 4 a Data of Hazleton Europe (1981) as published by Owen et al., 1987. Number of rats examined: 100 males and 100 females. b Increasing trend (p < 0.01); c Increase compared to control (p < 0.01) d Increasing trend (p < 0.05); e Increase compared to control (p < 0.05) 143
IV. DERIVATION OF CANCER POTENCY Basis for Cancer Potency OSHA (1990) has classified butadiene as a “potential occupational carcinogen”. U.S. EPA (1985) and IARC (1987) have concluded that the evidence for carcinogenicity of butadiene in animals is sufficient. These organizations have classified the chemical as Group B2 and 2B respectively in their schemes of ranking potential human carcinogens. With respect to quantitative risk assessment, the epidemiological data base is still considered inadequate for predicting risks of community exposure to butadiene. Thus, the quantitative risk assessment presented in this document relies on data from animal bioassays rather than epidemiologic studies. Cancer potencies were calculated using tumor incidence data from NTP (1984), Melnick et al. (1990), and Hazelton Europe (1981). Methodology Cancer potency estimates were made for mice and rats using total significant tumor incidences and individual site incidences, three measures of dose, and the linearized multistage procedure of low dose extrapolation. The most sensitive tumor site was the lung alveolar and bronchiolar neoplasms in female mice (mouse II bioassay data of Melnick et al., 1990). The continuous internal dose was considered to be the best measure of dose available. When interspecies equivalent units of mg/m 2 surface area were used, the resulting upper range of human cancer potency based on all rodent assays was 4.4 × 10 -6 to 3.6 × 10 -4 (µg/m 3 ) -1 . The range of upper bound risk is based on the two orders of magnitude difference between potency figures for the mouse and the rat. This difference has been the subject of much additional metabolic and kinetic investigation. In addition to a higher metabolic rate for butadiene in the mouse, limited detoxification and accumulation of the primary reactive genotoxic metabolite (BMO) may be a significant factor in the increased susceptibility of mice to butadiene-induced carcinogenesis. The most detailed evaluation of the carcinogenicity of butadiene has been conducted in the mouse. The staff of the Office of Environmental Health Hazard Assessment concluded that, for use in risk assessment, the quality of the mouse II bioassay data is superior to that of the rat data. The primary reasons for this conclusion are: 1) the use of lower, more relevant dose levels in the mouse II study; 2) the use of five dose levels in the mouse II study, compared to two in the rat study; 3) the presence of two mouse studies; 4) the fact that the rat study has not been replicated; 5) the consistency in sites of carcinogenicity between the two mouse studies; 6) the greater detail in the available mouse data which allows in-depth analysis; and 7) suggestions from limited epidemiological observations that butadiene exposure may be associated in humans with lymphatic and hematopoietic cancers, effects that were seen in mice. The analysis above using lung alveolar and bronchiolar neoplasm incidences in female mice (mouse II bioassay data of Melnick et al., 1990) resulted in a cancer potency of 6.0 (mg/kg-day) -1 , and a cancer unit risk of 1.7 × 10 -4 (µg/m 3 ) -1 . 144
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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
Page 101 and 102: a benign tumor of the kidney. No ba
Page 103 and 104: al. (1968) found no tumors in lifet
Page 105 and 106: following relationship, where C(t 1
Page 107 and 108: Miakawa M. and Yoshida O. 1975. Pro
Page 109 and 110: human population and that BPDE-DNA
Page 111 and 112: demonstrated the tumor initiating a
Page 113 and 114: Table 4: Bronchoalveolar tumors fro
Page 115 and 116: Table 5: IARC groupings of PAHs, mi
Page 117 and 118: Table 6 (continued): IARC Group 3 P
Page 119 and 120: Potency Equivalency Factors (PEF) f
Page 121 and 122: This was rounded to a PEF of 0.1. 1
Page 123 and 124: experiment (Takayama et al., 1985)
Page 125 and 126: Deutsch-Wenzel RP, Brune H, Grimmer
Page 127 and 128: Krewski D, Thorslund T and Withey J
Page 129 and 130: U.S. Environmental Protection Agenc
Page 131 and 132: Sorahan et al. (1983) studied cance
Page 133 and 134: Lijinsky W. 1986. Chronic bioassay
Page 135 and 136: the drinking water (Schroeder and M
Page 137 and 138: Table II. Effective dose, upper-bou
Page 139 and 140: BIS(2-CHLOROETHYL)ETHER CAS No: 111
Page 141 and 142: IV. DERIVATION OF CANCER POTENCY Ba
Page 143 and 144: BIS(CHLOROMETHYL)ETHER CAS No: 542-
Page 145 and 146: Table 1. Bis(chloromethyl)ether-ind
Page 147 and 148: Drew RT, Laskin S, Kuschner M and N
Page 149 and 150: ates for the 1968 U.S. male populat
Page 151: Table 1: Incidence of primary tumor
Page 155 and 156: National Institute of Occupational
Page 157 and 158: was less than 0.05 when controlling
Page 159 and 160: up period. The final cohort include
Page 161 and 162: If the cadmium-exposed workers incl
Page 163 and 164: on personnel records (20%); (3) eva
Page 165 and 166: were exposed to a continuous (23.5
Page 167 and 168: procedure (NLIN), the parameters we
Page 169 and 170: International Agency for Research o
Page 171 and 172: Two reports were published on cance
Page 173 and 174: Mendel rats, respectively), and sub
Page 175 and 176: Eschenbrenner A and Miller E. 1946.
Page 177 and 178: III. CARCINOGENIC EFFECTS Human Stu
Page 179 and 180: cancers, were less than expected. T
Page 181 and 182: and no cases of cancer (although cl
Page 183 and 184: There was a statistically significa
Page 185 and 186: NTP (1982a) also conducted an carci
Page 187 and 188: Several pathologists have independe
Page 189 and 190: hepatocellular adenoma/carcinoma tu
Page 191 and 192: carcinogenic potency may decline in
Page 193 and 194: Cochrane W, Singh J and Miles W. 19
Page 195 and 196: North Atlantic Treaty Organization,
Page 197 and 198: CHLORINATED PARAFFINS (average chai
Page 199 and 200: ased on dose-response data for beni
Page 201 and 202: 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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U.S. Environmental Protection Agenc
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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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IV. DERIVATION OF CANCER POTENCY Ba
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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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Page 395 and 396:
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
Page 423 and 424:
Table 1. P-Nitrosodiphenylamine-ind
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N-NITROSOMORPHOLINE CAS No: 59-89-2
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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
Page 465 and 466:
Figure 1: Estimates of Relative Ris
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q 1 * = Excess relative risk × CA
Page 469 and 470:
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
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
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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:
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
Page 519 and 520:
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
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Mortillaro PT and Schiavon M. 1982.
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male or female rats. Increases in h
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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
Page 541 and 542:
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
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
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experiment, animals were exposed to
Page 567 and 568:
Experiment BT1 Most previous risk a
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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
Page 593 and 594:
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
Page 599 and 600:
Chemical Exposure Route Study Type
Page 601 and 602:
Page 603 and 604:
Page 605 and 606:
Methyl tert-butyl ether p. 5: Added
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