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Table 3. Acrylamide-induced tumor incidences in male and female Fischer 344 rats (Johnson et al., 1986) Administered dose (mg/kg/day) Human equivalent dose 1 (mg/kg/day) Tumor type Tumor incidence males females 0 0 combined central nervous NA 13/60 0.01 0.001 system (CNS), mammary NA 18/60 0.1 0.015 gland, oral cavity, thyroid NA 14/60 0.5 0.076 gland, uterus 2 NA 21/60 2.0 0.305 NA 46/60 0 0 adrenal pheochromacytomas 3 3/60 NA 0.01 0.001 7/60 NA 0.1 0.015 7/60 NA 0.5 0.076 5/60 NA 2.0 0.305 10/60 NA 0 0 central nervous system 4 5/60 1/60 0.01 0.001 2/60 2/60 0.1 0.015 0/60 1/60 0.5 0.076 3/60 1/60 2.0 0.305 8/60 9/60 0 0 oral cavity 5 6/60 0/60 0.01 0.001 7/60 3/60 0.1 0.015 1/60 2/60 0.5 0.076 5/60 3/60 2.0 0.305 6/60 8/60 0 0 mammary gland 6 NA 2/60 0.01 0.001 NA 2/60 0.1 0.015 NA 1/60 0.5 0.076 NA 5/58 2.0 0.305 NA 8/61 0 0 scrotal mesotheliomia 3/60 NA 0.01 0.001 0/60 NA 0.1 0.015 7/60 NA 0.5 0.076 11/60 NA 2.0 0.305 10/60 NA 0 0 thyroid 7 1/60 1/58 0.01 0.001 0/58 0/59 0.1 0.015 2/59 1/59 0.5 0.076 1/59 1/58 2.0 0.305 7/59 5/60 0 0 uterine adenocarcinomas NA 1/60 0.01 0.001 NA 2/60 0.1 0.015 NA 1/60 0.5 0.076 NA 0/59 2.0 0.305 NA 5/60 35
Table 3 (continued). Acrylamide-induced tumor incidences in male and female Fischer 344 rats (Johnson et al., 1986) 1, 2. As calculated by US EPA (1988). 3. Benign and malignant. 4. Tumors of glial origin or glial proliferation suggestive of early tumor. 5. Squamous cell papillomas and carcinomas. 6. Adenomas and adenocarcinomas. 7. Males: follicular adenomas; females: follicular adenomas and adenocarcinomas. NA not available IV. DERIVATION OF CANCER POTENCY Basis for Cancer Potency The studies by Bull et al. (1984a, 1984b), Robinson et al. (1986) and Johnson et al. (1986) indicate that acrylamide is capable of acting as both an initiator and a complete carcinogen in animals. However, only the Johnson et al. (1986) study contained a data set suitable for generating a cancer potency factor. Female Sencar mice developing tumors after exposure to acrylamide in the study by Bull et al. (1984a) were also additionally exposed to TPA; animals not exposed to TPA did not develop skin tumors. Female A/J mice exposed in that study to acrylamide by either gavage or intraperitoneal injection developed an increased incidence of lung adenomas without requiring TPA exposure. However, the animals were not evaluated for tumor types other than lung adenomas, and numerical tumor incidence data for animals exposed to acrylamide by gavage was not listed. Also, the exposure and observation durations for animals exposed by gavage (8 weeks and 7 months, respectively) and by intraperitoneal injection (8 weeks and 6 months, respectively) were short. Female ICR-Swiss mice exposed to acrylamide by gavage in the study by Bull et al. (1984b) were generally also exposed to TPA; only one exposure group was included which received acrylamide (300 mg/kg) but not TPA. Additionally, the exposure duration was only 2 weeks and the exposure duration was less than lifetime (52 weeks). In the study by Robinson et al. (1986), all animals for which tumor incidence data was reported were exposed to TPA as well as acrylamide. Animals in the Johnson et al. (1986) study were exposed to acrylamide alone for the lifetime of the animals, and were comprehensively examined for tumors. For these reasons, tumor incidence data from the Johnson et al. (1986) study was used to derive a cancer potency factor for acrylamide. Methodology As recommended in the US EPA Guidelines for Carcinogen Risk Assessment (1986), US EPA (1988) pooled tumor incidence data from different tumor sites, under the consideration that risk numbers derived from site-specific tumor incidence data potentially may not be predictive of, and may in fact underestimate, “<strong>whole</strong>-body” risks that are determined using the pooled individual animal data. The dose-response curves for each sex based on the pooled tumor incidence (benign and malignant) constituted the data sets of choice for risk assessment. Tumors at a particular site were added into the 36
Page 1 and 2: Air Toxics Hot Spots Program Risk A
Page 3 and 4: Prepared by: John D. Budroe, Ph.D.
Page 5 and 6: This document is one of five docume
Page 7 and 8: TABLE OF CONTENTS PREFACE i INTRODU
Page 9 and 10: N-Nitrosodimethylamine 401 N-Nitros
Page 11 and 12: Hot Spots Unit Risk and Cancer Pote
Page 17 and 18: Additional ATES and PETS documents
Page 19 and 20: data. If several data sets (dose an
Page 21 and 22: US EPA Calculation of Carcinogenic
Page 23 and 24: exposure to a concentration of 1 µ
Page 25 and 26: incidences for each of the dose lev
Page 27 and 28: computes the surface area of a sphe
Page 29 and 30: Comparison of Hot Spots Cancer Unit
Page 31 and 32: Gold, L., de Veciana, M., Backman,
Page 33 and 34: Animal Studies Rats Woutersen et al
Page 35 and 36: ased on sufficient evidence of carc
Page 37 and 38: ACETAMIDE CAS No: 60-35-5 I. PHYSIC
Page 39 and 40: Methodology Expedited Proposition 6
Page 41 and 42: cancer mortality. However, US EPA (
Page 43: Table 2. Lung adenoma incidence in
Page 47 and 48: Robinson M, Bull RJ, Knutsen GL, Sh
Page 49 and 50: Also, a trend was observed correlat
Page 51 and 52: eported. Cause-specific expected de
Page 53 and 54: Bio/Dynamics Inc. conducted a study
Page 55 and 56: examination. Interim sacrifices wer
Page 57 and 58: Table 8. Tumor incidence in male an
Page 59 and 60: Gaffey WR and Strauss ME. 1981. A m
Page 61 and 62: (technical grade; 98% pure) by gava
Page 63 and 64: International Agency for Research o
Page 65 and 66: still alive in the low-dose control
Page 67 and 68: ANILINE CAS No: 62-53-3 I. PHYSICAL
Page 69 and 70: fibrosarcomas, stromal sarcomas, ca
Page 71 and 72: ARSENIC (INORGANIC) CAS No: 7440-38
Page 73 and 74: elationship between arsenic exposur
Page 75 and 76: al. (1988) did not induce lung tumo
Page 77 and 78: A risk assessment was also conducte
Page 79 and 80: Chen C, Chuang Y, You S, Lin T and
Page 81 and 82: Schrauzer G, White D, McGinness J,
Page 83 and 84: Table 1: Summary of epidemiologic s
Page 85 and 86: had at least one animal demonstrati
Page 87 and 88: mesothelioma, recommended lifetime
Page 89 and 90: National Institute for Occupational
Page 91 and 92: BENZENE CAS No: 71-43-2 I. PHYSICAL
Page 93 and 94: Animal Studies Available experiment
Page 95 and 96:
Table 3: Summary of NTP bioassay re
Page 97 and 98:
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
Page 107 and 108:
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
Page 137 and 138:
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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Page 155 and 156:
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
Page 169 and 170:
International Agency for Research o
Page 171 and 172:
Two reports were published on cance
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Mendel rats, respectively), and sub
Page 175 and 176:
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
Page 183 and 184:
There was a statistically significa
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NTP (1982a) also conducted an carci
Page 187 and 188:
Several pathologists have independe
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hepatocellular adenoma/carcinoma tu
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carcinogenic potency may decline in
Page 193 and 194:
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 (
Page 229 and 230:
Page 231 and 232:
Table 1. Study design summary for N
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Methodology Expedited Proposition 6
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Table 1. Experimental design for ca
Page 237 and 238:
Hazardous Substance Data Bank (HSDB
Page 239 and 240:
Table 1: Tumor induction in Fischer
Page 241 and 242:
Page 243 and 244:
Table 1. Experimental design of 2,4
Page 245 and 246:
Methodology Expedited Proposition 6
Page 247 and 248:
Additional analysis of these data b
Page 249 and 250:
Page 251 and 252:
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
Page 271 and 272:
DAB/day by gavage for the life of t
Page 273 and 274:
2,4-DINITROTOLUENE CAS No: 121-14-2
Page 275 and 276:
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
Page 283 and 284:
V. REFERENCES American Conference o
Page 285 and 286:
EPICHLOROHYDRIN CAS No: 106-89-8 I.
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espiratory tumors were noted in the
Page 289 and 290:
Table 4. Epichlorohydrin-induced fo
Page 291 and 292:
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
Page 297 and 298:
ETHYLENE DICHLORIDE CAS No: 107-06-
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Several factors have been suggested
Page 301 and 302:
Page 303 and 304:
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.
Page 311 and 312:
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
Page 325 and 326:
Casanova M, Morgan KT, Steinhagen W
Page 327 and 328:
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,
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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
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
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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
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noted; however, the study duration
Page 381 and 382:
Crump KS, Howe RB, Van Landingham C
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
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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 .
Page 393 and 394:
Page 395 and 396:
The increased incidence of bladder
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A linearized multistage procedure w
Page 399 and 400:
N-NITROSO-N-METHYLETHYLAMINE CAS No
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Page 403 and 404:
propylamine in drinking water at 0.
Page 405 and 406:
N-NITROSODIETHYLAMINE CAS No: 55-18
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Table 2. Treatment groups, concentr
Page 409 and 410:
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
Page 421 and 422:
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
Page 427 and 428:
Page 429 and 430:
N-NITROSOPIPERIDINE CAS No: 100-75-
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Table 3. N-Nitrosopiperidine-induce
Page 433 and 434:
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
Page 441 and 442:
employment (χ 2 test for trend: p
Page 443 and 444:
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
Page 459 and 460:
Animal Studies Section 6.1 (Animal
Page 461 and 462:
The variability, or heterogeneity,
Page 463 and 464:
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
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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:
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
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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
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elative to that of the controls whi
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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
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
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Experiment BT1 Most previous risk a
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No statistical analyses of mortalit
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Table 11 gives unit risk estimates
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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
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
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Table 4 A Comparison of CTEF- and I
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Office of Environmental Health Haza
Page 589 and 590:
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:
Page 605 and 606:
Methyl tert-butyl ether p. 5: Added
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