Document GmgxN1y95Xo8QObdVRerkjoKv
Law Offices
Keller and Heckman llp
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Washington, D C 2oOOi Telephone 1202) 434-4100 Facsimile 1202) 434-44e
Bollevaid Louis Sohiot 87
B 1040 B*t**aei-s
Telephoxi OS() 732 5 SO FACfrHiLE 0(E) 73C 53 OS
February 19, 1997
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MOT AlWlTTIP IN OC 4HCHBCKT HuUtLl
WrTTJTl DIRECT DIAL HUMIC!*
(202) 434-4141 de la Cruz6khlaw.com
Hasmukh Shah, Ph.D. Chemical Manufacturers Association 1300 Wilson Boulevard Arlington, VA 22209
Dear Dr. Shah:
It was a pleasure to speak to you and Wendy Sherman on February 13 concerning EPA's carcinogen risk assessment project as well as the vinyl Institute's interest in changing the reportable quantity limit for vinyl chloride under the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA). Some background materials expanding on the points I made during our conversation are enclosed.
I appreciate your time and agree that you, Wendy, Frank Borrelli and I should meet in early March to update each other and explore these matters in more detail. Would the afternoon of March 5 be convenient? If not, would March 4 or 7 be agreeable?
We look forward to confirming a meeting date. In the interim, if you have any comments or questions or I can be of assistance, please do not hestitate to call.
Cordially yours
Enclosures
Peter L. de la Cruz
CMA 121594
vvERA,
United States Environmental Protection Agency
Research and Development
0HEA-C-073-194
June 1988 Final
EVALUATION OF THE POTENTIAL CARCINOGENICITY OF VINYL CHLORIDE (75-01-4)
IN SUPPORT OF REPORTABLE QUANTITY ADJUSTMENTS PURSUANT TO CERCLA SECTION 102
Prepared for
OFFICE OF EMERGENCY AND REMEDIAL RESPONSE OFFICE OF SOLID WASTE AND EMERGENCY RESPONSE
Prepared by
CARCINOGEN ASSESSMENT GROUP
Office of Health and Environmental Assessment Washington, D.C. 20460
CMA 121600
DISCLAIMER This document has been reviewed in accordance with U.S. Environmental Protection Agency policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.
ii
CMA 121601
PREFACE
This report sumnarizes and evaluates information on the potential carcinogenicity of a substance designated as hazardous under Section 101 (14) of the Comprehensive Environmental Response, Compensation and Liability Act of 19B0 (CERCLA). Pertinent epidemiologic and toxicologic data were obtained through on-line searches and from hard-copy sources. On-line searches were extended as far back as the data bases would allow. Retrieval of historical data was accomplished through searches of hard-copy sources and bibliographies of relevant publications. Every attempt has been made to rely upon primary publications as opposed to data sunnaries or abstracts contained in secondary sources such as monographs, surveys, review articles, criteria documents, etc. The on-line data bases that were searched included CHEMLINE (National Library of Medicine [NLM]), RTECS (NLM), Toxicology Data Bank (NLM), TOXLINE (NLM), CANCERLINE (NLM), and Chemical Abstracts (DIALOG Information Services). Unpublished data were not used in this evaluation.
The Agency's Methodology for obtaining, evaluating, and ranking CERCLA potential carcinogens is described in the Technical Background Document to Support Rulemaking Pursuant to CERCLA Section 102, Volume 3, April 26, 1988 (EPA/600/8-89/053). This document revises the previous methodology document of 1986 according to the public coimnents received on the March 16, 1987 Notice of Proposed Rulemaking (52 FR 8140). The Methodology for Adjusting reportable quantities is described in the Technical Background Document to Support Rulemaking Pursuant to CERCLA Section 102, Volume 1, March, 1985, and is also sussnarized in Volume 2, August, 1986, and Volume 3, December, 1986. The EPA's Office of Emergency and Remedial Response (OERR) has considered this evaluation in adjusting reportable quantities pursuant to CERCLA Section 102. This report is consistent with the revised methodology. It draws largely on information supplied by the Syracuse Research Corporation in 1984 under EPA Contract No. 68-03-3112. Due to the amount of time elapsed between the original work performed by Syracuse Research Corporation and the present
iii
\2A602
effort to produce this document. Environmental Monitoring' & Services, Inc., under EFA Contract No. 68~03~3182, has been involved in an extensive review of all the Syracuse documents. In some cases, this review involved updating the information provided but it was primarily a quality assurance effort. The present document is a result of this effort.
). , iv
CMA121603
ABSTRACT
Vinyl Chloride is a human carcinogen, classified as weight-of-evidence Group A under the EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a). Evidence on potential carcinogenicity from animal studies is "Sufficient," and the evidence from human studies is "Sufficient."
The potency factor (F) for vinyl chloride is estimated to be 18.1 (mg/kg/day)'^, placing it in potency group 2, according to the CAG's methodology for evaluating potential carcinogens (U.S. EPA, 1986b).
Combining the weight-of-evidence group and the potency group, vinyl chloride is assigned a "HIGH" hazard ranking for' the purpose of RQ adjustment.
>,
V
CMA 121604
TABLE OF CONTENTS
Page
1.0 WEIGHT OF EVIDENCE....................................................................................................................1-1
1.1 ANIMAL STUDIES.........................................................................................
1-1
1.2 HUMAN STUDIES............................................................................................................................ 1-3
1.3 WEIGHT-OF-EVIDENCEASSESSMENT . . . ............................................................................. 1-4
2.0 POTENCY.......................................................................................................................................... 2-1 3.0 HAZARD RANKING.............................................................................................................................3*1
4.0 REFERENCES........................................................................................................................................
APPENDIX: SUMMARY OF SIGNIFICANT HUMAN AND/OR ANIMAL STUDIES
TABLES
Table 2-1. DERIVATION OF POTENCYFACTOR (F)......................................................................... 2-2
1.
vi
CMA 121605
1.0 WEIGHT OF EVIDENCE
1.1 ANIMAL STUDIES
There are many reports on the carcinogenicity of vinyl chloride in animals (Maltoni, 1977a; IARC, 1979; U.S. EPA, 1980; Feron et al., 1981). Due to the limitations of this project, only the most substantial studies will be emphasized and used as a basis for evaluating carcinogenic risk.
A report by Viola et al. (1971) indicated an increased risk of skin carcinoma, lung carcinoma, and osteochondromas in Vistar rats treated with 30,000 ppm vinyl chloride by inhalation. Since then, studies by Maltoni (1977b), Maltoni et al. (1981), Lee et al. (1978), Hong et al. (1981), and Feron et al. (1981) have been the predominant sources of information on the carcinogenicity of vinyl chloride in animals.
Maltoni (1977b) reported an Increased incidence of hepatic angiosarcoma and renal nephroblastoma in Sprague-Dawley rats treated by inhalation or gavage. Kidney nephroblastomas were seen in animals treated with 10,000 and 6,000 ppm by inhalation, and 50 and 16.65 mg/kg vinyl chloride by gavage. An increased incidence of liver angiosarcoma was reported in groups treated with as little as 100 ppm vinyl chloride by inhalation and at both dose levels by gavage. Maltoni et al. (1981) reported kidney nephroblastomas in groups treated with 25 ppm vinyl chloride, while control groups had none. Liver angiosarcomas were evident in groups treated with 10 ppm by inhalation. No similar tumors were reported in rats treated with 5, 1, or 0.0 ppm vinyl chloride. In groups of Swiss mice treated with 50, 250. 500, 2,500, 6,000, and 10,000 ppm vinyl chloride, Maltoni et al. (1981) reported a dose-related incidence of liver angiosarcomas and lung tumors. In Golden Hamsters treated at the same levels by inhalation, papillomas and acanthomas of the forestomach were produced by vinyl chloride exposure.
1-1
CMA 121606
In groups of 36 male and 36 female CD rats, lung and liver hemangiosarcomas were produced in groups treated with 250 and 1,000 ppm vinyl chloride (Lee et
1., 1978). This study showed that females of this strain were more susceptible to the carcinogenic effect of vinyl chloride. Rats treated with 50 or 0.0 ppm vinyl chloride developed no similar tumors. Lee et al. (1978) also reported an increased incidence of bronchioloalveolar adenoma and hepatic hemangiosarcoma in male and female CD-I mice treated with 50, 250, and 1..000 ppm vinyl chloride by inhalation for six hours/day, five days/week.
In a study examining the carcinogenic effect of vinyl chloride at.various doses (50, 250, and 1,000 ppm) by inhalation for various durations of treatment (six or ten months treatment period for rats; one, three, or six months treatment period for mice), Hong et al. (1981) reported elevated numbers of liver and lung hepatocellular carcinomas, hemangiosarcomas, and bronchioloaveolar.tumors in rats treated with 250 ppm vinyl chloride for six to ten month duration. All four tumor types showed a significant dose-related response in rats. In mice, only hemangiosarcomas showed a dose-related response. One month of treatment at 250 or 1,000 ppm vinyl chloride for six hours/day, five days/week, followed by a 12 month latency period, was sufficient to produce an increase incidence of bronchioloalveolar tumors in mice.
In a study completed by Feron (1981), groups of 60 to 80 female Wistar rats were exposed to a target dose of 0, 20, 60, or 200 ppm vinyl chloride in the diet. The exposure period and the study length were both 144 weeks. The incidences of tumors from the four dose levels were 2/57 (control), 26/58, 42/59, 56/57. At the three exposure levels, there were 4, 8, and 32 multiple tumors in a single animal at each of the respective levels. None of the control had multiple tumors at a single site. The presence of multiple tumors at a single site adds to the weight of evidence that vinyl chloride is carcinogenic.
i.
1-2
CMA 121607
1.2 HUMAN STUDIES
Many case reports and epidemiology studies on the carcinogenicity of vinyl chloride are reported in recent reviews (IARC, 1979,; U.S. EPA, 1980; Infante, 1981). For this document, only those studies presenting sufficient data on the exposed population and a substantial number of cancer cases will be reviewed for the assessment of carcinogenic risk.
Infante (1981) reviewed epidemiological data that indicates an association between liver cancer, brain cancer, lung cancer, and hematopoietic and lymphatic cancers, and vinyl chloride exposure. Waxweliler et al. (1976) reported seven of 136 deaths were due to biliary and liver cancer in 1,287 workers exposed to vinyl chloride for >5 years. All seven occurred following a 15 year latency period. The expected number of cases in this group was 0,4 (P<0.01). Similarly, three brain and central nervous system cancers were reported after a 15 year latency, while only 0.6 were expected (PC0.05). Respiratory system cancer deaths numbered 11, while 5.7 were expected (P<0.05). Lymphatic and hematopoietic system cancer occurred in three vinyl chlorideexposed workers, which is suggestive of an increased incidence (1.7 expected), but is not statistically significant.
A cohort study of 750 workers exposed to vinyl chloride found 4 liver/ pancreatic cancers, two of which were confirmed liver angiosarcomas, compared to 0.68 expected for the group exposed for <10 years (P-0.005) (Bryen et al., 1976). An additional case of hepatic hernangiosarcoma that had occurred after the data were complied and was, therefore, not included in the reported cases, was reported in this study. Two cases of brain cancer were reported, compared to 0.33 expected (P<0.05). The increased incidence of lung cancer (3 observed versus 1.78 expected) was not statistically significant.
Fox and Collier (1977) examined the mortality of 7,409 workers exposed to vinyl
chloride in the production of polyvinyl chloride (PVC). This study examined
eight factories involved in the production of PVC. A total of four deaths due
to liver cancer were reported, compared to 1.64 expected.
i,. *
1*3
Three of these
CMA 121608
cases occurred in a factory involved with FVC production since 1944 (the longest period of those factories examined), while only 0.13 would have been expected (P<0.01) (Infante, 1981). Infante (1981) notes that 75% of the study cohort in this report were employed for more that ten years.
Examining 161 deaths among . vinyl chloride workers, Monson et al. (1974) reported eight liver and biliary cancers (0.7 expected; 11.0 risk ratio) five brain cancers (1.2 expected; 42 risk ratio), 13 lung cancers (7.9 expected; 1.6 risk ratio), 13 digestive tract cancers (8.3 expected; 1.5 risk ratio), and five lymphatic and hematopoietic cancers (3.4 expected; 1.5 risk ratio). The authors did not report statistical comparisons of these data but note an excess frequency of liver, lung, and brain cancers. It is also reported that the frequency of all cancers is increasing with length df exposure and latency.
1.3 WEIGHT-OF-EVIDENCE ASSESSMENT
Vinyl chloride has been shown to be a carcinogen in rats, mice, and hamsters. It produced a high incidence of liver, kidney, lung, and brain tumors (Maltoni et al., 1982; Feron, 1981) in a dost-related response when administered by oral or inhalation routes. Similar carcinogenic effects have been shown,in vinyl chloride-exposed workers. The predominant target organs are the liver, brain, lung, and lympho-hematopoietic system, but a general non-specific carcinogenic effect has been suggested. Thus, using the EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a) criteria for evaluating the overall weight of evidence to humans is most appropriately classified as a Group A chemical. The appendix contains summaries of the significant human and/or animal studies cited in this review.
1-4
CMA 121609
2.0 POTENCY
The potency factor (F) for vinyl chloride is estimated to be 18.1 (mg/kg/day)'1, placing it in potency group 2 under the CAG's methodology for evaluating potential carcinogens (U.S. EPA,,1986b). Table 2-1 contains data from the selected study used to derive the potency factor ,(F) for vinyl chloride.
i.
2-1
CMA 121610
table 1-1. Derivation of Potency Factor(F)
Agent: Vinyl Chloride
REFERENCE:
Feron et al., 1981
EXPOSURE ROUTE:
oral
SPECIES: STRAIN:
rat Wfatar
SEX:
F
VEHICLE OR PHTSICAl STATE:
diet
BOOT HEIGHT:*
0.20 kg
DURATION OF TREATMENT:
1008 day*
DURATION OF STUDY: LIFE SPAN OF ANIMAL:6
1008 day* 1008 days
TARGET ORGAN:
liver and Lung
TUMOR TYPE:
angI osarcone and hepatocellular card
EXPERIMENTAL DOSES/EXPOSURE
200 ppm
60 ppm
20 ppm
0.0 |
TRANSFORMED DOSES:' (ng/kg/day)
14.1
5.0
1.7
0.0
TUMOR INCIDENCE:
ANIMAL POTENCY: tmg/kg/day)'1
HUMAN POTENCY:*1 (mg/kg/day)'1
O f
NJ CD --
56/57 2.565
18.1
42/59
26/58
2/57
* Estimated 6 Assumed e Data were taken directly from Table 1 on page 319 of the Feron et al., ** Hunan potency * animal potency * (70 kg/ 0.20 kg)1^
1981
reference. .
3.0 HAZARD RANKING
Based on the weight-of-evidence, Group A for vinyl chloride, and the potency factor (F) of 18.1 (mg/kg/day)**-, vinyl chloride receives a hazard ranking of HIGH."
).
3-1
CMA 121612
4.0 REFERENCES
Byren, D., G. Engholm, A. England and P, Wescerholm, 1976. Mortality and Cancer Morbidity in a Group of Swedish VCM and PVC Production Vorkers. Environmental Health Perspective. 17: 167-170.
Feron, V.J., C.F.M. Hendriksen, A.J. Speck, HiP. Til and B.J. Spit, 1981. Lifespan Oral Toxicity Study of Vinyl Chloride in Rats. Fd Cosmet. Toxicol. 19(3): 317-333.
Fox, A.J. and P.F. Collier, 1977. Mortality Experience of Workers Exposed to Vinyl Chloride Monomer in the Manufacture of Polyvinyl Chloride in Great Britain. Br. J. Ind. Med. 34: 1-10.
Hong, C.B,, J.M. Winston, L.P. Thornburg and J.S. Woods, 1981. Follow-up Study on the Carcinogenicity of Vinyl Chloride and Vinylidene Chloride Rats and Mice: Tumor Incidence and Mortality Subsequent to Exposure. J. Toxicol. Environmental Health. 7(6): 909-92^.
IARC (international Agency for Research on Cancer), 1979. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Lyon, France: WHO. IARC, Volume 19, Pages 377-438.
Infante, P.F., 1981. Observations of the Site-Specific Carcinogenicity of Vinyl Chloride to Humans. Environmental Health Perspective. 41: 89.
Lee, C.C., J.C. Bhandari, J.M. Winston, W.B. House, R.L. Dixon and J.S. Woods, 1978. Carcinogenicity of Vinyl Chloride and Vinylidene Chloride. J. Tox. Environmental Health. 4: 15*30.
Maltoni, C., 1977a. Vinyl Chloride Carcinogenicity: An Experimental Model for Carcinogenesis Studies. In: Origins of Human Cancer, Book A./H.H. Hiatt, J.D. Watson, and J.A. Winston, Eds. Cold Springs Harbor Laboratory, Cold Springs Harbor, New York. Pages 119-146.
4-1
CMA 121613
Maltoni, C., 1977b. Recent Findings on the Carcinogenicity of Chlorinated Olefins. Environmental Health Perspective. 21: 1-5.
Maltoni, C., G. Lefemine, A. Coloberti, G. Cotti and, D. Carretti, 1981. Carcinogenicity Bioassay of Vinyl Chloride Monomer: A Model of Risk Assessment on an Experimental Basis. Environmental Health Perspective. 41: 3-29.
Maltoni, C. , A. Clilbertl and D. Carretti, 1982. Experimental Contributions in Identifying Brain Potential Carcinogens In the Petrochemical Industry, Ann. NY Academy of Sciences. 381: 216-249.
Monson, R.R., J.M. Peters, and M.N. Johnson, 1974. Among Vinyl-Chloride Workers. Lancer. 2: 397-398.
Proportional Mortality
U.S. EPA (Environmental Protection Agency), 1986a. Guidelines for Carcinogen Risk Assessment, 51 HI 33992-34003, September 24, 1986.
U.S. EPA (Environmental Protection Agency), 1986b. Methodology for Evaluating Potential Carcinogenicity in Support of Reportable Quantity Adjustments Pursuant to CERCLA Section 102, 0HEA-C-073, December 1986. Available from CERCLA Docket 102RQ-273C, The public document for RQ rulemaking is located In room M2427, U.S. Environmental Protection Agency, 401 M Street, SW, Washington, DC 20460. It is available for inspection Monday through Friday excluding .Federal holidays, between the hours of 9:00 a.m. and 4:00 p.m.
U.S. EPA (Environmental Protection Agency), 1988.
Technical Background
Document to Support Rulemaking Pursuant to CERCLA Section 102, Volume Three,
Draft, Appendix A, April 26, 1988.
Viola, P.L., A. Bigotti, and A. Caputo, 1971. Oncogenic Response of Rat Skin, Lungs, and Bones to Vinyl Chloride. Cancer Research. 31: 516-522.
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CMA 121614
APPENDIX SUMMARY OF SIGNIFICANT HUMAN AND/OR ANIMAL STUDIES
>. CMA 121615
lable A. Animat Agent; Vinyl Chloride Reference: Feron et al. 1981
Exposure Route
Species/ Strain Sex
Dose or
Exposure
Duration of
Treatnent
Duration of
Study
Purity of
Compound
Vehicle or Physical State
target Organ
Tumor Type
Tumor Incidence (P value)
oral
rat/ Ulstar
N
20 pp (1.7 ng/kg/day)
135 weeks
135 weeks 99.7X
diet
oral
ret/ Ulster
H
*0 ppm (5.0 ng/kg/day)
135 weeks
135 weeks 99. 7X
diet
oral
rat/ Ulstar
H
200 ppM
135 weeks
(14.1 ng/kg/day).
135 weeks 99.7X
diet
oral V
rat/ yiatar
H
O.OppM (controls)
135 weeks
13S weeks 99.7X
diet
oral
rat/ Ulster
r
20 ppn (1.7 ng/kg/day)
144 weeks
144 weeks 99.7X
diet
oral
rat/ Ulster
f
*0 ppn (5.0 ng/kg/day)
144 weeks
144 weeks 99.7X
diet
oral
oral %a
rat/ Ulstar
F
200 ppM
144 weeks
(14.1 ng/kg/day)
rat/ Ulstar
F
O.Oppm (controls)
144 weeks
144 weeks 144 weeks
99.7X 99. 7X
O diet
J>
N) O) diet G>
liver l iver liver liver tiver liver 1 iver l iver
neoplastic nodule carctnom angiosarcoma
1/58 (MS) 1/58 (NS) 0/58 (NS)
neoplastic nodule earcinoM angiosarcoma
7/56 (P 0.007) 2/56 (NS) 6/56 (P 0.014)
neoplastic nodule carcinoma angiosarcoma
23/59 (P < 0.001) 8/59 (p 0.004)
27/59 (P < 0.001)
neoplastic nodule carcinoma angiosarcoma
0/55 0/55 0/55
iCnO
o***.
neoplastic nodule carcinoaM angiosarcoma
(P < 0.001) 4/58 (NS) 0/58 (NS)
neoplastic nodule card none angiosarcoma
39/59 (P < 0.001) 19/59 (P < 0.001)
2/59 (NS)
neoplastic nodule carcinoma angiosarcoma
44/57 (P < 0.001) 29/57 (P < 0.001}
9/57 (P < 0.0014}
neoplastic nodule c a reinoma an?!osarcona
2/57 0/57 0/57
Table A. Animal Agent: Vinyl Chloride Reference: Kong et al. 1961
Exposure Route
Species/ Strain Sex
Dose or
Exposure*
f
rat/CD tt.F
SO ppm
i
rat/CD H.F
250 ppm
i
rat/CD H.F
1000 ppm
i
rat/CD ,F
0 ppm
i
mouse/ M,F
50 ppm
CO-1
Duration of
Treatment
Duration of
Study
Purity of
Compound
Vehicle or Physical State
Target Organ
Tumor Type
Tumor Incidence (P value)
6 or 10 monthic
6 or 10 months0
6 or 10 months0
6 or 10 months0
1 month
16 or 22 months0
99.8X
air/vapor l iver lung
16 or 22 months0
99.8X
air/vapor
liver
lung
18 or 22 months0
99.8X
air/vapor 1 iver lung
18 or 22 months0
99. ex
a f r/vapor
liver
lung
13 months
99.8X
air/vapor
lung 1 iver
hepatocellular carcinoma
hemangiosarcoma bronchiot oa1veo tar
tumor hemangiosarcoma
0/66 0/66
0/66 0/66
hepatocellular
carcinoma
2/68
hemangiosarcoma
5/68
bronchioIoa1veolar
tumor
' 2/66
hemangiosarcoma
2/68
hepatocellular carcinoma
hemangiosarcoma bronchioloalveolar
tumor hemangiosarcoma
7/72 14/72
4/72 7/72
hepatocellular carcinoma
hemangiosarcoma bronchioloa1veolar
tumor hemangiosarcoma
1/72 0/72
0/72 0/72
bronchioloaIveo1ar tumor
hemangiosarcoma
3/32 1/32
CMA 121617
table A. Animal Agent: Vinyl Chloride Reference: Hong et al. 19S1 (cont.)
Exposure Route
Species/ Strain Sea
Dose or
Exposure*
Duration of
Treatment
Duration of
Study
Purity of
Compound
Vehicle or Physical State
Target Organ
,
mouse/ n.t
250 ppm
CO-1
i
mouse/ H.T
1000 ppm
CD-I
1
mouse/ H,F
0 ppm
CO-1
i
aiouse/ M,F
50 ppm
"CD-I
i
mouse/ M,F
250 ppm
CO-1
i
mouse/ N.F
1000 ppm
CO-1
i . mouse/ N, f 0 ppm CD-I
1 month
13 months
99. ex
1 month
13 months
99. OX
1 month
13 months
99. SX
3 months
15 months
99.8X
3 months
15 months
99. ex
3 months
15 months
99. SX
3 months
15 months
99. ex
-
air/vapor
lung
liver
air/vapor lung
l iver
air/vapor lung
liver
alr/vapor lung
liver
air/vapor lung
liver
air/vapor lung
liver
a 1 r/vapor lung
liver
Tumor Type
Tumor Incidence (P value)
bronchioloalveolar tumor
hemangiosarcoma
bronchioloa1veolar tumor
hemangiosarcoma
bronchioloalveolar tumor
hemangiosarcoma
bronchioloa1veolar tumor
hemangiosarcoma
bronch f oloa1veola r tumor
hemangiosarcoma
bronch i o l oa 1 veol a r tuor
hemangiosarcoma
bronch t oloa1veolar tunor
hemangiosarcoma
19/32 0/32
20/32 0/32
3/32 0/32
12/32 0/32
21/32 A/32
5/20 ` 16/20
2/32 0/32
*.
'A
Table A. Animal Agent: Vinyl Chloride Reference: Hong et al. 1981 (cont.)
Exposure Species/
Route
Strain Sex
Dose or
Exposure***
Duration of
Treatment
Duration of
Study
Purity of
Compound
Vehicle or Physical State
Target Organ
i
mouse/ h,f
SO pp.
CD-I
i
mouse/ H,F
250 ppm
CD-I
1
mouse/ H,F
1000 ppm
CD-I
.i
amuse/ H,F
0 ppm
CO-1
6 months
18 months
99.8X
6 months
18 months
99.8X
6 months
18 months
99. BX
6 months
18 months
99.8X
air/vapor lung
air/vapor
l iver lung
1 iver
air/vapor lung
liver
air/vapor
lung
liver
Tumor Type
Tumor Incidence (P value)
bronchioloalveolar tumor
hemangiosarcoma
bronchioloalveolar tumor
hemangiosarcoma
bronchio1oa1veotar tumor
hemangiosarcoma
bronchioloalveolar tumor
hemangiosarcoma
3/16 1/16
12/20 9/20
14/24 13/24
11/56 1/56
QUALITY Of EVIDENCE
Strengths of Study:
Tvo animal apeclea were tested. Dose and exposure levels were varied to show a dose-response. Statistics of tumor incidence with respect to dose are reported.
Weaknesses of Study: The duration of treatment was too short in all cases.
Overall Adequacy:
Adequate
Consents:
This study uas conducted to enhance that reported by Lee et at., 1976.
* Exposure for 6 hours/day, 5 days/veek ** Shoved dose-related response; significant at P<0.0S c Duration of exposure uas for 6 months or 10 months, folloved by a 12-month latency period.
treetment-durstion group.
The results presented are for the combined
CMA 121619
Exposure Route
Species/ Strain Sex
Dose or
Exposure*
Agent: Vinyl Chloride Reference: Lee et at. 1978 (cont.)
Duration of
Treatment
Ouratfon of
Study
Purity of
Compound
Vehicle or Physical State
Target Organ
Tumor Type
Tumor Incidence (P value)
'
atouse/
H
50 ppai
CO-1
12 mnths
12 months
99. ax
vapor/air
respiratory tract
liver
bronchioloalveolar adenoma
hemanglosarcoma
8/29 3/29
l
muse/ F
50 ppm
CD-1
12 mnths
12 months
99.8X
vapor/air
respiratory tract
liver
bronchioloalveolar adenoma
hemangiosarcoma
4/34 0/34
1
muse/
N
250 ppm
CD-I
1
souse/
F
250 ppm
CO-1
12 awnths
12 months
99. 8X
12 mnths
12 mnths
99. SZ
vapor/afr vapor/air
respiratory tract
liver
bronchioloalveolar adenoma
hemangiosarcoma
respiratory tract.
liver
bronchioloalveolar adenoma
. hemsngiosarcoma
10/29 7/29 <P<0.05)
12/34 16/34 (P<0.05)
1 muse/ H 1000 ppm CD-I
12 mnths
12 months
99.8X
vapor/atr
respiratory tract
1 iver
bronchioloa1veolar adenoata
hemanglosarcoma
22/33 13/33 (P<0.05)
l RMHISC/ F 1000 ppm CD-I
12 mnths
12 months 99.6X
vapor/elr
DUAL ITT OF EVTDEUCE
respiratory tract
liver
bronchioloa1veo1ar adenoma
hemengloaareoma
26/36 18/36 (P<0.05)
Strengths of Study:
Three different levels of vinyl chlorfde were tested in tuo species of animals. Some statistics were reported. Vinyl chloride was quite pure. An extensive examination of organs and tissues uas performed.
weaknesses of Study: The significance of bronchioloalveolar adenoma in mice is not reported. The duration of study uas short (due t o mortality).
Overall Adequacy:
Adequate
a \kposure was for 6 hours/day, 5 days/week M/A * Not Applicable
Table A. Animat Agent: Vinyl Chloride Reference: Naltoni, 1977b
Exposure Route
Specie*/ Strain
Sex
Dose or
Exposure*
Duration of
Treetaent
Duration of
Study
Purity of
Compound
Vehicle or Physical
State
Target Organ
i rat/
Spregue- NR
10,000 ppm
52 weeks
15S ueeks
NR
vapor/eir
liver
Dauley
kidney
i rat/
Sprague- NR
6,000 ppai
52 ueeks
155 ueeks
HR
vapor/air liver
Dauley
kidney
i rat/
SpragueDauley
HR
200 ppm
52 ueeks
HI weeks
NIT
vapor/air
l iver
i rat/ "Spregue- NR Oauley
ISO ppai
52 ueeks
HI ueeks
NR
vapor/air
liver
' rat/
Sprague- NR
100 pp
52 ueeks
HI weeks
HR
vapor/eir liver
Dautey
1 rat/ Sprague- NR Oauley
HI
0 ppm
52 ueeks
155 ueeks
NA
air only
l iver
kidney
i ret/
Sprague- NR
50 aig/kg
52 ueeks
116 ueeks
NR
olive oil
liver
Dauley
kidney
rat/
Sprague- NR
0.0 mg/kg
52 ueeks
116 ueeks
NA
olive oil
liver
Dauley <-
kidney
Tumor Type
angiosarcoma nephroblastoma
angiosarcoma nephroblastoma
angiosarcoma
angiosarcoma
angiosarcoma
angiosarcoma nephroblastoma
angiosarcoma nephroblastoma
angiosarcoma nephroblastoma
Tumor Incidence <P value)
9/60 5/60
11/60 A/60
12/120
5/120
1/120
0/500 0/120
9/80 1/80
0/150 0/150
CM A121622
table A. Animat Agent: Vinyl Chloride Reference: Haltoni, 1977b (cont.)
Exposure Route
Species/ Strain
Sex
Dose or
Exposure*
Duration of
Treatment
Duration of
Study
Purity of
Compound
Vehicle or Physical
State
Target Organ
Tumor Type
Tumor Incidence (P value)
(KIAUTT OF EVIDEHCE
Strength! of Study:
A broad range of dose levels Here tested. Carcinogenic response was shown by two routes of administration. Duration of study was long in all cases.
Weaknesses of Study:
Ho statistics Hero reported. The sex of test animals uas not reported. Data for the control group for the gavage studies Is reported in Haltoni et al., 1981. Some animals Here treated by gavage. The purity of vinyl chloride is not reported.
Overall Adequacy:
Adequate
CoMaents: ~
This study focused on different factors affecting the carcinogenic effect (animat species, strain and age, treatment duration, and exposure levels.)
* Exposure.to vinyl chloride Has for 4 hours/day, 5 days/week for 52 weeks; by gavage, once daily in olive oil 4*5 days/week. HR > Hot Reported HA Hot Applicable
O
>
to CD to CO
table A. Animal Agent: Vinyl Chloride Reference: Hattoni, et !., 1901
Exposure Route
Spec 1es/ Strain
Sex
Dose or
Exposure*
Duration of
Treatment
Duration of
Study
Purity of
Compound
Vehicle or Physical
State
Target Organ
Tumor Type
Tumor Incidence (P value)
i rat/
SpragueOawley
30,000 ppm
52 weeks
60 ueeks >99.9*
air/vapor
liver kidney
angiosarcoma nephroblastoma
10/60 HR
i rat/
Sprague- H.f 10,000 ppm Dswtey
52 ueeka . 155 ueeks >99.9X
air/vapor
liver kidney
angiosarcoma - nephroblastoma
7/60 5/60
1 rat/
Sprague- M,F 6,000 ppm
52 ueeka
135 ueeks *99.9X
air/vapor
liver
angiosarcoma
13/59
Oawley
kidney
nephroblastoma
5/59
J rat/
fsprague- ",r
2,S00 ppm
52 weeks
135 ueeks >99.9X
air/vapor
liver
angiosarcoma
13/60
Oawley
kidney
nephroblastoma
6/60
i rat/
Spregue- n,r
500 ppM
52 ueeka
135 ueeks >99.9%
air/vapor
liver
anglosarcosia
6/60
Dsuley
kidney
nephroblastoma
6/60
1 rat/
Sprague- . n.t
250 ppM
52 ueeka
135 ueeks *99.9X
alr/vapor
liver
angiosarcoma
3/59
Paul ay
kidney
nephroblastoma
5/59
, i rat/
Spregue- H.f
200 ppm
52 ueeks
143 ueeks >99.9X
air/vapor
1 iver
angiosarcoma
12/120
Dawtey
kidney
nephroblastoma
7/20
i rat/
Sprague* H.F
150 ppm
52 ueeks
143 ueeks >99.9X
air/vapor
l iver
angiosarcoma
6/119
Dawley **
kidney
nephroblastoma
11/119
CMA 121624
Table A. Animal Agent: Vinyl Chloride Reference: Haltoni, et al., 1961 (Cont.)
Exposure Route
Species/ Strain
SCN
Dose or
Exposure*
Duration of
Treatment
Durst ion of
Study
Purity of
Compound
Vehicle or Physical
State
Target Organ
1 ret/
Sprague* H,F
100 ppm
Dawley
i rat/
Sprague* H,F
50 ppm
Dawley
l rat/
Sprague- H,F
25 ppm
Cawley
t rat /
7sprague -
H,F
10 ppm
Dawley
i rat/
Sprague- N,F
5 ppm
Cawley
i rat/
Sprague-
H.F
1 ppm
Dawley
i rat/
SpragueVJ
Dawley
>
1
rat/ Sprague-
o> K)
Dawley
Ch
H.F 0 ppm H.F 10,000 ppm
52 weeks
143 weeks >99.9X
52 weeks
135 weeks >99.9X
52 weeks
147 weeks
>99.9X
52 weeks
147 weeks
>99.9X
52 weeks
147 weeks
>99.9X
52 weeks
147 weeks
>99.9X
135 -
HA
147 weeks
HA
30 weeks
81 weeks >99.9X
air/vapor
l iver kidney
air/vapor
liver kidney
air/vapor
liver kidney
air/vapor
liver kidney
air/vapor
liver kidney
air/vapor
l iver kidney
air only
1 iver kidney
air/vapor
liver lung
Tumor Type
Tumor Incidence (P value)
angiosarcoma nephroblastoma
1/120 10/120
angiosarcoma nephroblastoma
1/60 1/60
angiosarcoma nephroblastome
5/120 1/120
angiosarcoma nephroblastoma
1/119 0/119
angiosarcoma nephroblastoma
0/119 0/119
angiosarcoma nephroblastoma
0/118 0/118
angiosarcoma nephroblastoma
0/363 0/363
angiosarcoma tumor
10/56 46/56
Table A. Animal Agent: Vinyl Chloride Reference: Haltoni, et al., 1901 (Cont.)
Exposure Route
Species/ Strain
Sex
Oose or
Exposure*
Duration of
Treatment
Duration of
Study
Purity of
Compound
Vehicle or Physical
State
Target Organ
Tumor Type
Tumor Incidence (P value)
f mouse/
Swiss
H.E 6,000 ppm
30 weeks
SI weeks >99.9%
air/vapor
liver
angfosarcoata
lung
tumor
f mouse/ Suiss
10,000 ppm
30 weeks
81 weeks >99.9%
air/vapor
liver lung
angiosarcoma tumor
i aiouse/
Swiss
M.f 2.SOO ppm
30 weeks
81 weeks >99.9X
air/vapor liver
angiosarcoma
lung
tumor
1 aiouse/
Suiss
H.f
500 ppm
30 weeks
Si weeks >99.9%
air/vapor liver
angiosarcoma
lung
tumor
13/60 47/60
10/56 46/56
16/59 40/59
14/60 50/60
i mouse/
Suiss
H,F
2S0 ppm
30 weeks
SI.weeks >99.9%
air/vapor liver
angiosarcoma
lung
tumor
18/60 41/60
i amuse/ Suiss
50 ppm
30 weeks
SI weeks >99.9%
air/vapor
liver lung
angiosarcoma tumor
1/60 6/60
l mouse/
Suiss
N.F
0 ppm
HA
SI ueeks
HA
air only
liver
angiosarcoma
0/150
lung
tumor
15/150
hamster/ h,F 10,000 ppm Syrian Golden
30 weeks
109 ueeks
>99.9%
air/vapor forestomach papi1loma/scanthome 10/30
CMA 121626
Table A. Animal Agent: Vinyl Chloride Reference: Maltoni, et al., 1981 (Cont.)
Exposure Route
Species/ Strain
Sex
Dose or
Exposure*
Duration of
Treatment
Duration of
Study
Purity of
Compound
Vehicle or Physical
State
larget Organ
Tumor Type
Tumor Incidence (P value)
i
hamster/ *.r 6,000 ppm
30 ueeks
109 ueeks >99.9*
air/vapor
fores tomach papf1loma/acanthoma 10/30
Syrian
Golden
1
hamster/ N.F
2,500 ppm
30 ueeks
109 ueeks >99.9*
air/vapor forestomach papilloma/acanthoma 17/30
Syrian
Golden
i
hamster/ H.f
500 ppm
30 ueeks
109 ueeks >99.9*
air/vapor
forestomach papilloma/acanthoma 9/30
Syrion
Golden
i
hamster/ H.F
250 ppm
30 ueeks
109 ueeks >99.9*
air/vapor
forestomach papi1loma/acanthoma 4/30
Syrian
Golden
1
hamster/ H.F
50 ppm
30 ueeks
109 ueeks >99.9*
alr/vapor forestomach papilloma/scanthome 3/30
Syrian
Golden
i
hamster/ H.F
0 ppm
HA
109 ueeks
HA
air only
forestomach papf1loma/acanthoma 3/60
Syrian
Golden
COAtlTT OF EVIDENCE
Strengths of Study:
Vinyl chloride uas administered by inhalation, gavage, or subcutaneous or intraperitoneal injection to rats, mice, and hamsters at a broad range of doses. Extensive examinations of animals were performed. The vinyl chloride uas quite pure. Duration of studies uas long.
Overall Adequacy: Comments:
Adequate This report uas extensive and ewch of the data uas not reported here due to the scope of this project.
* Exposure uas for A hours/day, 5 days/ueek MA Not Applicable
CMA 121627
Table A. Animat Agent: Vinyl Chloride Reference: Viota, et al., 1971
Exposure Species/
Route
Strain
Sex
Dose or
Exposure*
Duration of
Treatment
Duration of
Study
Purity of
Compound
Vehicle or Physical
State
Target Organ
Tumor Type
Tumor Incidence <P value)
f
ret/Uister M
30,000 ppm 12 months
>12 months
99X
vapor/air
skin
(Ar/tRE)
lung
bone
i rat/Uistar H (Ar/IRE)
0 ppm
HA
>12 months
HA
air only
skin
lung
bone
epidenaoid carcinoma carclnoau osteochondroma
epidermoid carcinoma carcinoma osteochondroma
15/26 6/26 5/26
0/25 0/25 0/25
DUALITT OF EVIDENCE
StrengthsTof Study:
An appropriate route of administration uas used. The vinyl Chloride was irelatively pure. Appropriate controls were included for coa^tarison.
Weaknesses of Study: Only auile mice Here tested. The duration of the study could have been longer. No statistics were complied on incidences between treated and untreated animals.
Overall Adequacy:
Adequate
* Exposure was for A houra/day, 5 days/week for 12 months. HA * Hot Applicable
CMA 121628
Table A. Animat Agent: Vinyl Chloride Reference: Viola, et all, 1971
Exposure Species/
Route
Strain
Sex
Dose or
Exposure*
Duration of
Treatment
Duration of
Study
Purity of
Compound
Vehicle or Physical
State
Target Organ
Tumor Type
Tumor Incidence (P value)
i
rat/Uistar H
30,000 ppm 12 months
>12 months
99X
vapdr/air
skin
(Ar/IRE >
lung
bone
i rat/Uistar N <Ar/IRE)
0 ppm
HA
>12 months
MA
air only
skin
lung
bone
epidersnid carcinoma carcinoma osteochondroma
epidermoid carcinoma carcinoma osteochondroma
15/26 6/26 5/26
0/25 0/25 0/25
DUAL ITT OF EVIDENCE
Strength* Tbf Study:
An appropriate route of administration was used. The vinyl Chloride was irelatively pure. Appropriate control* were included.for comparison.
Weaknesses of Study: Only male mica were tested. The duration of the study could have been longer. Ho statistics were complied on incidences between treated and untreated animals.
Overall Adequacy:
Adequate
* Exposure uai for A hour*/day, 5 day*/week for 12 months. na Hot Applicable
CMA 121628
*.
Table B. Humans i
Agent: Vinyl Chloride
Reference: Bryen et el., 1976
Exposure Route
Size of Exposed Population
Site of Control Population
Level of
Sex Exposure
Duration of
Exposure
Target Organ
Tumor Type
Humber of Tumors
Observed
Humber of Tuanrs
Expected
Relative Risk
(P Value)
d*i+o
750
1969
N periodically >10 years
liver/
cancer
4
Swedish
up to 15,000
pancreas
Population
.PP"
<1 to >10 years <1 to >10 years
brain lung
cancer cancer
2 3
0.60
0.33 1.78
P<0.005
P<0.043 P<0.260
QUALITY Of EVIPERCE
Strengths of Study: The Exposed population was compared to the Swedish population. The Incidence of liver tumors was reported based on lengths of exposure. Statistics were compiled to show significant Increases In tumor Incidence.
Weaknesses of Study: Specific levels of exposure are not reported. A relatively small number of cancer deaths were examined.
Overall Adequacy:
Adequate
CMA 121629
a,
Table B. - Humana Agent: Vinyl Chloride Reference: Monson et al., 1974
Exposure Route
Site of Expoted Population
Site of Control Population
level of
Sex Exposure
d+i+o
161
161 M NR
Duration of
Exposure
NR
Target Organ
Tumor Type
Number of Tumors
Observed
liver and biliary tract cancer
brain
cancer
lung
cancer
digestive system
cancer
lymphatic and hematopoietic system
cancer
8 5 13 13
5
Humber of Tumors
Expected
Relative Risk
(P Value)
0.7 1.2 7.9
. 8.3
11.0 4.2 1.6
1.6
3.4 1.5
OUAIITT Of EVIDENCE
Strength* of Study:
Death* In vinyl chiorIds-exposed population were compared with a comparable age/time/cause-speclfIc reference population. The incidence of (everal cauae* of death were examined.
Weaknesses of Study: The level* of exposure and duration are not reported. Mo itatixtlca are reported.
Overall Adequacy:
Adequate
NR Not reported
CMA 121630
Table B. Humans Agent: Vinyl Chloride Reference: Uaxweiler et al., 1976
Expoture Route
Size of Exposed Population
Site of Control Population
Level of
Sex Exposure
O.S. death rates
n,r
HR
Duration of
Exposure
Target Organ
Tumor Type
Humber of Tumors
Observed
Humber of Tumors
Expected
Relative Risk
(P Value)
>5 years
tiver and bi1lary
brain and CNS
cancer cancer
lymphatic and cancer
hematopoietic
respiratory
cancer
7
3 3 11
0.4 16.0 fP<0.01)
0.6 5.0
1.7 1.8 CHS)
5.4 1.9
PURLITT OF EV1DEHCE
Strengths of Study:
Tumor Incidences were analyzed on the basis of latency period. Statistical analyses of different types of cancer compared to expected values Here performed. The study was of workers with >5 years exposure.
Weaknesses of Study: Levels of Exposure were not available.
Overall Adequacy:
Adequate
Incidence of tueore after 15-year latency HR Hot reported HS Hot significant
CMA 121631