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Table 1. Tumor incidence in male and female Sprague-Dawley rats exposed to acrylonitrile by inhalation (Maltoni et al., 1977) Tumor type Tumor incidence Acrylonitrile concentration (ppm) 0 5 10 20 40 mammary tumors (females) 5/30 10/30 7/30 10/30 7/30 mammary tumors (males) 1/30 0/30 1/30 4/30 4/30 nonglandular forestomach papillomas (males) 0/30 1/30 2/30 0/30 3/30 skin carcinomas (females) 0/30 4/30 1/30 1/30 1/30 The authors claimed that these results indicated a “border-line carcinogenic effect”. US EPA (1983) noted that low sensitivity of this study due to the low concentrations of acrylonitrile used and the short duration of acrylonitrile exposure (12 months). Additionally, male and female Sprague-Dawley rats (40/sex/group) were exposed to 0 or 5 mg/kg body weight acrylonitrile by gavage 3 times/week for 52 weeks. On spontaneous death, a moderate increase in the incidence of female rat mammary gland tumors and nonglandular forestomach tumors was noted. US EPA (1983) commented that although the observation period was relatively short (52 weeks) and only a single dose level was used, this study provides additional evidence for the carcinogenicity of acrylonitrile. A three-generation reproductive study on the effect of acrylonitrile exposure in male and female Charles River rats [CRL:COBS CD (SD) BR] was conducted by Litton-Bionetics, Inc. for the Chemical Manufacturers Association (Beliles et al., 1980; reviewed by US EPA, 1983). The rats and their offspring were exposed to drinking water containing 0, 100 or 500 ppm acrylonitrile starting 15 days post-weaning and were mated after 100 days. After delivery of two litters, the animals were exposed to acrylonitrile for approximately 45 weeks. After exposure, all animals in generations F 0 , F 1 b and F 2 b were sacrificed and examined histologically. Second-generation rats in the 500 ppm exposure group demonstrated a significant increase in the incidence of astrocytomas and Zymbal gland tumors. Tumor incidence data are listed in Table 2. Table 2. Tumor incidence data in Charles River rats during a three-generation reproductive study (Beliles et al., 1980) Tumor type Generation Tumor incidence Acrylonitrile dose (ppm) 0 100 500 astrocytomas F 0 0/19 1/20 2/25 F 1 b 0/20 1/19 4/17 F 2 b 0/20 1/20 1/20 Zymbal gland F 0 0/19 0/20 1/25 F 1 b 0/20 2/19 4/17 F 2 b 0/20 0/20 3/20 43
Bio/Dynamics Inc. conducted a study on the toxicity and carcinogenicity of acrylonitrile in Sprague- Dawley rats (Bio/Dynamics, 1980a) for the Monsanto Company (St. Louis, MO); the results of this study were subsequently submitted to the US EPA by the Monsanto Company on June 30, 1980. Male and female Sprague-Dawley rats (100/sex/treatment group) were exposed to acrylonitrile in drinking water at concentrations of 0,1, and 100 ppm. Interim sacrifices (10/sex/treatment group) were conducted at 6, 12 and 18 months. The study was terminated at less than 2 years because of low survival rates; males were sacrificed at 22 months and females were sacrificed at 19 months. Statistically significant increases were noted in the incidence of astrocytomas of the brain and spinal cord, adenomas and carcinomas of the Zymbal gland, and nonglandular forestomach squamous cell papillomas and carcinomas in males and females of the 100 ppm group. Tumor incidence data are listed in Table 3. Table 3. Tumor incidences in male and female Sprague-Dawley rats exposed to acrylonitrile in drinking water (Bio/Dynamics, 1980a) Tumor type Dose level (ppm) Tumor incidence males females brain astrocytomas 0 2/98 0/99 1 3/95 1/100 100 23/97 32/97 spinal cord astrocytomas 0 NA 0/96 1 NA 0/99 100 NA 7/98 Zymbal gland carcinomas 0 1/100 0/99 1 0/91 0/95 100 14/93 7/98 nonglandular forestomach papillomas/carcinomas 0 3/98 1/100 1 3/98 4/99 100 12/97 7/99 NA - not analyzed A similar study was conducted by Bio/Dynamics Inc. on the toxicity and carcinogenicity of acrylonitrile in Fischer 344 rats (Bio/Dynamics, 1980b) for the Monsanto Company (St. Louis, MO); the results of this study were subsequently submitted to the US EPA by the Monsanto Company on December 12, 1980. Male and female Fischer 344 rats (100/sex/acrylonitrile treatment group; 200/sex/control group) were exposed to acrylonitrile in the drinking water at concentrations of 0,1, 3, 10, 30 and 100 ppm. Interim sacrifices (10/sex/acrylonitrile treatment group; 20/sex/control group) were conducted at 6, 12 and 18 months. The study was designed to be 24 months in duration; however, because of poor survival, all females were sacrificed at 23 months. Males were continued on study until 26 months, when survival rates comparable to females were achieved. Statistically significant increases were noted in the incidence of astrocytomas of the brain and spinal cord in males (30 and 100 ppm groups) and 44
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 and 44: Table 2. Lung adenoma incidence in
Page 45 and 46: Table 3 (continued). Acrylamide-ind
Page 47 and 48: Robinson M, Bull RJ, Knutsen GL, Sh
Page 49 and 50: Also, a trend was observed correlat
Page 51: eported. Cause-specific expected de
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
Page 99 and 100: 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
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demonstrated the tumor initiating a
Page 113 and 114:
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
Page 129 and 130:
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
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International Agency for Research o
Page 171 and 172:
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
Page 183 and 184:
There was a statistically significa
Page 185 and 186:
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
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
Page 235 and 236:
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
Page 253 and 254:
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
Page 263 and 264:
Table 1b. Study design for carcinog
Page 265 and 266:
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
Page 283 and 284:
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
Page 289 and 290:
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
Page 297 and 298:
ETHYLENE DICHLORIDE CAS No: 107-06-
Page 299 and 300:
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
Page 319 and 320:
FORMALDEHYDE CAS No: 50-00-0 I. PHY
Page 321 and 322:
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
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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
Page 347 and 348:
y inhalation is similar for rats an
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Goyer RA. 1992. Nephrotoxicity and
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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
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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
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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
Page 399 and 400:
N-NITROSO-N-METHYLETHYLAMINE CAS No
Page 401 and 402:
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
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California Department of Health Ser
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animals and the second generation t
Page 413 and 414:
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
Page 435 and 436:
testicular tumors were noted in the
Page 437 and 438:
PARTICULATE MATTER FROM DIESEL-FUEL
Page 439 and 440:
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
Page 445 and 446:
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
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
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1,3-PROPANE SULTONE CAS No: 1120-71
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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
Page 521 and 522:
total); an untreated control group
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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
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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
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
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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
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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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