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4. The linearized multistage polynomial procedure can be used to extrapolate potency outside the range of experimental observations to yield estimates of "low" dose potency. 5. Cancer hazard increases with the third power of age. The Carcinogenic Potency Database of Gold et al. (1984, 1986, 1987, 1989, 1990) contains the results of more than 4000 chronic laboratory animal experiments on 1050 chemicals by combining published literature with the results of Federal chemical testing programs (Technical Reports from the Carcinogenesis Bioassay Program of the National Cancer Institute (NCI)/National Toxicology Program (NTP) published prior to June 1987). The published literature was searched (Gold et al., 1984) through the period December 1986 for carcinogenicity bioassays; the search included the Public Health Service publication “Survey of Compounds Which Have Been Tested for Carcinogenic Activity” (1948-1973 and 1978), monographs on chemical carcinogens prepared by the International Agency for Research on Cancer (IARC) and Current Contents. Also searched were Carcinogenesis Abstracts and the following journals: British Journal of Cancer, Cancer Letters, Cancer Research, Carcinogenesis, Chemosphere, Environmental Health Perspectives, European Journal of Cancer, Food and Cosmetics Toxicology, Gann, International Journal of Cancer, Journal of Cancer Research and Clinical Oncology (formerly Zeitschrift fur Krebsforschung und Klinische Onkologie), Journal of Environmental Pathology and Toxicology, Journal of Toxicology and Environmental Health, Journal of the National Cancer Institute, and Toxicology and Applied Pharmacology. Studies were included in the database if they met the following conditions: 1. The test animals were mammals. 2. Chemical exposure was started early in life (100 days of age or less for hamsters, mice and rats). 3. Route of administration was via the diet, drinking water, gavage, inhalation, intravenous injection or intraperitoneal injection. 4. The test chemical was administered alone (not in combination with other chemicals). 5. Chemical exposure was chronic, with not more than 7 days between exposures. 6. The experiment duration was at least half the standard lifespan for the species used. 7. The study design included a control group and at least 5 animals/exposure group. 8. No surgical interventions were performed. 9. Pathology data were reported for the number of animals with tumors (not total number of tumors). 10. All results reported were original data (not analysis of data reported by other authors). Included in their data set tabulations are estimates of average doses used in the bioassay, resulting tumor 15
incidences for each of the dose levels employed for sites where significant responses were observed, dosing period, length of study and histopathology. Average daily dose levels were calculated assuming 100% absorption. Dose calculations follow procedures similar to those of Cal/EPA and US EPA; details on methods used and standard values for animal lifespans, body weights, and diet, water and air intake are listed in Gold et al. (1984). RCHAS (1992) reviewed the quality assurance, literature review, and control procedures used in compiling the data and found them to be sufficient for use in an expedited procedure. Cancer potency estimates were derived by applying the mathematical approach described in the section below to dose response data in the Gold et al. database. The following criteria were used for data selection: 1. Data sets with statistically significant increases in cancer incidence with dose (p ≤ 0.05) were used. (If the authors of the bioassay report considered a statistically significant result to be unrelated to the exposure to the carcinogen, the associated data set was not used.) 2. Data sets were not selected if the endpoint was specified as "all tumor-bearing animals" or results were from a combination of unrelated tissues and tumors. 3. When several studies were available, and one study stood out as being of higher quality due to numbers of dose groups, magnitude of the dose applied, duration of study, or other factors, the higher quality study was chosen as the basis for potency calculation if study results were consistent with those of the other bioassays listed. 4. When there were multiple studies of similar quality in the sensitive species, the geometric mean of potencies derived from these studies was taken. If the same experimentalists tested two sexes of the same species/strain under the same laboratory conditions, and no other adequate studies were available for that species, the data set for the more sensitive sex was selected. 5. Potency was derived from data sets that tabulate malignant tumors, combined malignant and benign tumors, or tumors that would have likely progressed to malignancy. Cancer potency was defined as the slope of the dose response curve at low doses. Following the default approach, this slope was estimated from the dose response data collected at high doses and assumed to hold at very low doses. The Crump linearized multistage polynomial (Crump et al., 1977) was fit to animal bioassay data: Probability of cancer = 1- exp[- (q 0 + q 1 d + q 2 d 2 + ...)] Cancer potency was estimated from the upper 95 % confidence bound on the linear coefficient q 1 , which is termed q 1 * . For a given chemical, the model was fit to a number of data sets. As discussed in the section above, the default was to select the data for the most sensitive target organ in the most sensitive species and sex, unless data indicated that this was inappropriate. Deviations from this default occur, for example, when 16
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: exposure to a concentration of 1 µ
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 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
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
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
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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
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-
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Table 1. Bis(chloromethyl)ether-ind
Page 147 and 148:
Drew RT, Laskin S, Kuschner M and N
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ates for the 1968 U.S. male populat
Page 151 and 152:
Table 1: Incidence of primary tumor
Page 153 and 154:
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.
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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
Page 203 and 204:
Overall, the present epidemiologica
Page 205 and 206:
female dogs received toothpaste bas
Page 207 and 208:
Calculated q 1 * values from the ab
Page 209 and 210:
Hogan MD, Chi Py, Hoel DG and Mitch
Page 211 and 212:
Table 1. Study design summary for N
Page 213 and 214:
V. REFERENCES California Environmen
Page 215 and 216:
toluidine. Followup of this subcoho
Page 217 and 218:
feeding studies on by NCI (1979) us
Page 219 and 220:
CHROMIUM (HEXAVALENT) CAS No: 18540
Page 221 and 222:
expected rate may be inflated becau
Page 223 and 224:
Oral Borneff et al. (1968) exposed
Page 225 and 226:
CREOSOTE (COAL TAR-DERIVED) CAS No:
Page 227 and 228:
from an inhalation exposure study (
Page 229 and 230:
Page 231 and 232:
Table 1. Study design summary for N
Page 233 and 234:
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
Page 255 and 256:
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
Page 261 and 262:
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
Page 267 and 268:
mice, hepatocellular carcinoma inci
Page 269 and 270:
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
Page 277 and 278:
Final Statement of Reasons for OAL,
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to the small sample size and short
Page 281 and 282:
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.
Page 287 and 288:
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
Page 293 and 294:
exposed to arsenicals for 20 months
Page 295 and 296:
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
Page 305 and 306:
statistically significant. CDHS not
Page 307 and 308:
combined with the incidence in the
Page 309 and 310:
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)
Page 315 and 316:
ETHYLENE THIOUREA (ETU) CAS No: 96-
Page 317 and 318:
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
Page 323 and 324:
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,
Page 335 and 336:
Table 1. Liver hepatoma incidence i
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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 and 380:
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
Page 389 and 390:
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
Page 397 and 398:
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
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:
Page 429 and 430:
N-NITROSOPIPERIDINE CAS No: 100-75-
Page 431 and 432:
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
Page 447 and 448:
Table 1 (continued): Reference Damb
Page 449 and 450:
Table 1 (continued): Reference Burn
Page 451 and 452:
Table 1 (continued): Reference Raff
Page 453 and 454:
Table 1 (continued): Epidemiologica
Page 455 and 456:
Table 1 (continued): Epidemiologica
Page 457 and 458:
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
Page 467 and 468:
q 1 * = Excess relative risk × CA
Page 469 and 470:
Table 3: Number of Workers in the E
Page 471 and 472:
u nexposed workers at zero concentr
Page 473 and 474:
for each µg/m 3 of diesel exhaust
Page 475 and 476:
Table 4: Values from Unit Risk for
Page 477 and 478:
their findings that a reasonable es
Page 479 and 480:
Garshick E, Schenker M, Woskie S an
Page 481 and 482:
Lewis T, Green, FH MW, Burg J and L
Page 483 and 484:
Rothman K. 1986. Modern epidemiolog
Page 485 and 486:
PENTACHLOROPHENOL CAS No: 87-86-5 I
Page 487 and 488:
The default lifespan for mice is 10
Page 489 and 490:
documented. An excess risk from ski
Page 491 and 492:
B6C3F 1 mice and F344/N rats were e
Page 493 and 494:
This model, rather than a time depe
Page 495 and 496:
POLYCHLORINATED BIPHENYLS (PCBs) CA
Page 497 and 498:
several benign adenomatous lesions
Page 499 and 500:
Ito et al. (1973) exposed groups of
Page 501 and 502:
could not be characterized by chlor
Page 503 and 504:
exposure (all pathways and mixtures
Page 505 and 506:
National Toxicology Program 1993. T
Page 507 and 508:
Table 1. Potassium bromate-induced
Page 509 and 510:
1,3-PROPANE SULTONE CAS No: 1120-71
Page 511 and 512:
Page 513 and 514:
PROPYLENE OXIDE CAS No: 75-56-9 I.
Page 515 and 516:
oxide. In the NTP carcinogenicity s
Page 517 and 518:
1,1,2,2-TETRACHLOROETHANE CAS No: 7
Page 519 and 520:
assumed a body weight of 70 kg and
Page 521 and 522:
total); an untreated control group
Page 523 and 524:
TOLUENE DIISOCYANATE CAS No: 26471-
Page 525 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
Page 533 and 534:
A mortality analysis of a cohort of
Page 535 and 536:
elative to that of the controls whi
Page 537 and 538:
applied or metabolized. The range o
Page 539 and 540:
Katz RM and Jowett D. 1981. Female
Page 541 and 542:
10,000 ppm 2,4,6-trichlorophenol in
Page 543 and 544:
Page 545 and 546:
Bionetics Research Laboratories. 19
Page 547 and 548:
control; females: 6/10 exposed, 0/1
Page 549 and 550:
over controls (p < 0.04). Other tum
Page 551 and 552:
was increased (100/314 exposed vs.
Page 553 and 554:
Table 3. Cancer potency estimates f
Page 555 and 556:
Crouch E. 1983. Uncertainties in in
Page 557 and 558:
VINYL CHLORIDE CAS No: 75-01-4 I. P
Page 559 and 560:
Table 1 (continued): A Summary of E
Page 561 and 562:
al., 1983). Histopathology of all o
Page 563 and 564:
Table 3: Tumor incidences in 100 pp
Page 565 and 566:
experiment, animals were exposed to
Page 567 and 568:
Experiment BT1 Most previous risk a
Page 569 and 570:
No statistical analyses of mortalit
Page 571 and 572:
Table 11 gives unit risk estimates
Page 573 and 574:
Bertazzi PA, Villa A, Foa V, Saia B
Page 575 and 576:
Nicholson WJ, Hammond EC, Seidman H
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
Page 595 and 596:
TECHNICAL SUPPORT DOCUMENT FOR DESC
Page 597 and 598:
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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