Document dYbxjmxMmEVLOZ6E5dr9BQ1kB

/ 5 Xd 4Il'IO October 1, 1990 Bill McDonald Fort Saskatchewan, Alberta Canada As I agreed, I am sending you copies of information on health issue discussions regarding our Avon Lake facility. Both the dialogue and technical data should be relevant to some of the issues you face on VCM. This letter also reaffirms my offer to assist you in any future situations involving health issues. Please do not hesitate to call if you need anything further (Ext. 4534). 0926-1/jp cc: Carl Mattia BFG07573 2087Z001 September 17, 1990 Richard Hardesty ALGC SUBJECT: VCM I am enclosing some position papers on VCM dealing with birth defects, cancer and immunotoxicity. R. K. Hinderer 0917-1/jp BFG07574 20872002 September 13, 1990 Bob Hinderer: During my visit to the Edmonton plant, the issue that was foremost in the plant manager's mind was that of VCM risks, not only to the plant but more specifically to the local community, in the event of a VCM release. Since I do not have a wealth of information on VCM health effects, I suggest that you contact Bill McDonald to discuss with him the type of support that we could give him with respect to risk assessment of VCM. He could use that information with his local pollution control agency to minimize pressure being exerted upon him as one of the high-risk chemical industries in the community. A quote from the pollution control authority is "VCM is the most deadly chemical that currently exists in the Province." This is not an accurate statement and is probably a result of past history issues with VCM, i.e., the angiosarcoma issue. Follow-up and let me know where you come out with this issue. cc: Bill McDonald 7/ f Carl A. Mattia 20872003 BFG07575 September 13, 1990 R. Hardesty ALGC This is a follow-up note to restate some of the things I said at your "Health Effects Meeting" on 10 September, 1990 at the Avon Lake General Chemical plant. There are published data on cancer mortality (death rates) for all counties in the United States, but I am not aware of such data for smaller units, except where special studies have been done. Lorain County does not have the highest cancer death rate in Ohio and Ohio does not have the highest cancer death rate within the United States. Ohio is in the upper third of the States and Lorain County is probably in the upper third of Ohio Counties, whether this constitutes, "one of the highest cancer rates in the country", is debatable. I know of no good data source on cancer occurrence (morbidity) at other than the national level. BFG has had, since 1977, a data collection and analysis system which allows us to track cause of death and disease diagnosis of BFG employees and retirees. You have been sent separately, a list of the diagnoses we routinely review annually. We haven't seen a health problem in our Avon Lake Plant population with respect to excessive occurrences of any diagnosis. I know of no good data source on miscarriage and birth defects broken down with specific geographic areas. There have been many instances when an individual becomes interested and collects what appears to be a large number of causes of miscarriages and/or birth defects. When these searches have been followed by good scientific surveys with proper controls, no problem has been identified. This was most recently demonstrated in several counties in Louisiana. As indicated at the meeting, we in Department 0020, are prepared to supply you with specific figures and general answers relating to these subjects as best we can and as you identify the need. 20872004 0913-1/jp BFG07576 Dr. Hal Dietz R. D. Hardesty 7-26-90 HEALTH EFFECTS STUDY FOR AVON LAKE In almost every interaction situation we have with the Avon Lake community two themes come up for which we have no concrete evidence to refute or answer from. The two themes are: 1. Avon Lake has one of the highest cancer rates in the Country. Or highest "blank type" cancer rate. 2. Avon Lake has one of the highest miscarriage rates in the country. The Avon Lake Community Relations Committee would like someone to research both these areas and see if any data exists which would help us respond. We have copies of the Vinyl Institute's literature reviews, but would like a written report specific to Avon Lake, detailing available data. Here is what data I feel we are looking for: 1. What cancer rate data exists for Avon Lake? 2. What miscarriage or birth effects type data exists for Avon Lake? 3. If any data exists, how does it compare to the national average or other recognized norm? 4. If no Avon Lake specific data exists, what is the smallest unit such data is broken down into? Please respond in writing with details or a position we can cite when interacting with the community. Thanks, 20872005 RDH/ac cc: Bob Krebs Vic Goode Carl Mattia Bob Hinderer Con Nosal Chuck Bush Richard D. Hardesty BFG07577 HEALTH EFFECTS MEETINGS Please plan to attend the following meeting to be held Monday, September 10, 1990 - 2:00 P.M. B/431 Avon Lake General Chemical Plant in the Customer Conference Room. This meeting is the outgrowth of a letter I sent to Dr. Dietz. See attached letter. Two groups of people will be present: BFG Corporate Safety/Health personnel and the Avon Lake Community Relations Committee. My questions in the letter will serve as the meeting agenda. Richard D. Hardesty Corporate Safety/Health Carl Mattia, VP Safety/Health Harold Dietz, Consultant MD Bob Hinderer, Toxicologist Ray Gomez, PR GVD RDH/ac 8/22/90 CRC ALTC Bob Krebs, Facility Manager Bob Kissling, HR Manager Frank Konya, Plant Engineer Dennis Fisher, Coordinator ALGC Vic Goode, Plant Manager Bob Sandfry, HR Manager Don Barnicki, Plant Engineer Richard Hardesty, Environ. Mgr. Dan Collins, Environmental Tech. Nora Jacobs, PR Consultant BFG07578 September 18, 1990 Bill Patient CL-OTM SUBJECT: AVON LAKE COMMUNITY HEALTH ISSUES My staff is providing the information to Avon Lake Community Relations Committee. Bob Hinderer and Hal Dietz met with Avon Lake staff and Ray Gomez on September 10, 1990 to assist them in addressing community health issues/concerns which they frequently have to address. They discussed the information that they could provide showing that cancer rates are not unusually high and birth defects are not an issue for chemicals such as VCM. However, they did caution Avon Lake that we do not want to take ownership of this issue because we are not the only company releasing chemicals in AL, and because some questions regarding cancer occurrence would require major funding to answer. Bob and Hal specifically provided and/or agreed to supply the following: 1) Background information on what is involved in worker or community cancer, or birth defect assessments in order to help them better understand limitations in statements that are made; 2) Cancer rates for U.S. and various counties including AL; 3) VI position paper on VCM and birth defects, and; 4) A hazard analysis/comparison of 313 chemicals reported by BFG and other companies in the community. 20872007 Carl Mattia 0917-1/jp BFG07579 AVON LAKE COMMUNITY RELATIONS COMMITTEE SEPTEMBER 10, 1990 MINUTES ATTENDING: R. Kissling, D. Fisher, D. Barnicki, V. Goode, R. Krebs, R. Sandfry, D. Collins, N. Jacobs, R. Hardesty, B. Hinderer, H. Dietz, R. Gomez The focus of this meeting was on developing an informed medical basis for site spokespersons to respond to local community questions regarding cancer and reproductive health issues. The CRC is aware that BFG will not take all responsibility for community health issues. However, the Avon Lake site spokesperson must have responses to community concerns and questions. Dr. Dietz provided some cancer mortality data for Ohio counties, including Lorain. Cancer mortality data is available for every U.S. county by type of cancer, for the years 1950-1979. Data is not available for small cities such as Avon Lake. There is no similar cancer incident data available. Additionallly, reliable, reproductive related data (birth defects, miscarriages) does not exist. Internal health studies of BFG employees and retirees, using medical surveillance data, indicate no cancer problems at the Avon Lake site when compared to other BFG sites, including division and corporate headquarters. Corporate Health and Environmental Services offered to provide the CRC with various information. The CRC requested the following: o SARA Title III data on Lorain County emissions, o Comparison of Ohio County cancer mortality rates, o Background statement on mortality and incident rate, o Comparison of Lorain County cancer mortality vs BFG employee/retiree data. o Background statements on mortality and incidence rate for cancer and reproductive related data (or lack of same), o Relevant Louisiana Chemical Manufactures study data. After this material is received, the CRC position/response for members to address questions. will formulate a community health Attached are copies of recent letters to the editor in The Lorain Journal and The Avon Lake Press. 20872008 bFG07580 NEXT MEETING September 17, 1990 - Customer Conference Room, ALGC 2:00pm - 3:30 pm. Q-istrifrutiaa: Don Barnlcki - ALGC Dennis Fisher - ALTC Dan Collins - ALGC Vic Goode - ALGC Richard Hardesty - ALGC Nora Jacobs (E. Howard k Co.) Bob Kissling - ALTC Frank Konya - ALTC Bob Krebs - ALTC Bob Sandfry - ALGC cc: Bob Accarino - Cleveland Dave Bonner - BRDC Chuck Bush - Cleveland Chuck Daniels - ALTC Bob Hillstrom - BRDC Gene Rrcmar - Cleveland Con Nosal - Cleveland Bob Schlatzer - Cleveland Rob Jewell - Bath Paul Zakriski - BRDC Ray Gomez - Cleveland Carl Mattia - Bath Robert Hinderer - Bath Hal Dietz - Bath 20878009 (CRC.DLF) BFG07581 8Z,ODd0 20&72010 noDipoQ SiqpAae&aqv'i ooav . abuedjpqo POTBM031 XnH 'qvndmoosBOBp sdpqs, aatqrad ^pmnnzzoa/ssainsnq jvqM jo qdaraxasp^i* n 8o|Ajas aog noA^treip ^OTQas- je&xiq a nj -yoddns 8mo8no 3noA ,jror qpfipoooja *saej Jjtxj|nsq oq) sAad BCfB^ ^dAV jo Ajpaq^AioN.npnoui d0i$ JShpa&nijp; ppai ofq s.a^vq jJOAy SnjjUMJepim Aq poddns jjaq) panopnoa saq.qsppDO*)' -v** ' 5PiBPBv jaAadxaVaq) )*oo mom apApag ^jqsoa. ps pazosBods Apiqq| ub pnB qaypooo `penado nmzSoid *.q`3'aoAV'TOqM ' ****L.: -diqwoeuods Moisttq'pboi BApAtq aaoq) jo moj *A) DaAasan:ajaq)Z9)eicqiQoai.)i8epns. :y,..y /!,;&ifaomo&p&ofixoo jasigeneq* eq~:^b{(ia b) paa8? ptnrpAaiO'J'j^Bai8 amliq' muSoid 'Ano jnn ArtneiwKfB' n* 'flast^oftidv -ojd toTOjjliqj. *niw8did MojskapfcwH jj.eapn px&y jb tiotidns ppqvmj'.qaq) *?} I*Pfc V. ,thz. s'jLVtjry: t^ssctfr-' ate -t&IJpOOBjg Of SMUBUI 7 i1. nnv- .;75.,i'7:/ . i-w-.'t-;. ok/W* r< o/>*J s$rj i*n THE IQTTRTVAT Letters to the Editor f'3C-?0 Goodrich good deal To The Editor: A special "thank you" to BFGoodrich for its financial support ot Avon Lake's Recycle Now program. This pilot project was started in April 1989. It was ap parently the only program in the Greater Cleveland area to enjoy the benefits of corpo rate sponsorship. Six months later, there are seven Recycle Now programs in Lorain County. Four of those involve local business sponsorship. When Avon Lake's program opened, Goodi rich and BFI jointly sponsored all costs. Re cycle Now cost the taxpayer nothing for its first full year of operation. Goodrich has continued its support by un derwriting Avon Lake's binrentalcharges of $130 per month. Now the city of Avon Lake pays the hauling fees. Thank you, BFGoodrich for your ongoing support In a larger sense, thank you for serving as a fine example of what businesscommunity partnerships can accomplish. Holly Kowalski, Avon Lake 20872011 BFG07583 Vinyl chloride monomer (VCM) has become one of the most widely studied chemicals in use today. Animal and human studies have shown that it can cause carcinogenic and noncarcinogenic effects in the liver and acro-osteolysis, a softening of bones in the fingers. Although VCM has induced tumors at a number of different sites in animals, the only tumor that has been confirmed in man is angiosarcoma of the liver. Studies in animals, however, have shown that VCM is a transplacental carcinogen. Numerous studies have shown that VCM does not cause birth defects or reproductive effects. While some human studies have claimed that VCM causes birth defects and miscarriages, close examination by numerous experts have found these early reports to be seriously flawed and not supportive of an effect. Although some types of cancer are known or are believed to result from the failure of the immune system to destroy abnormal, neoplastic cells, there is no evidence that VCM is an immunosuppresive agent. In fact, immunotoxicological studies in animals and man show that VCM induces an immunologic response. Studies in animals also indicate that while VCM appears to enhance immune reactivity, it does not alter the immune response to other antigens administered simultaneously. BFG07584 20B72012 FEB-13-'90 09:32 ID:THE UINYL INSTITUTE TEL NO:201 S90-7029 85 A Division oi The Society of The Plastic* Industry, Inc. April 21, 1988 TO: The VI Health, Safety & Environment Committee Enclosed are the comments submitted on behalf of the Vinyl Institute in response to ATSDR's request for comment on the Toxicological Profile for Vinyl Chloride. I have not burdened you with the voluminous appendices. MNS/pmb enclosure cc: Dr. R. Hinderer Dr. Paul Gurba Dr. J. Drumwright Meredith N. Scheck Assistant Director 20872013 Wkvna Intmmhmnnm Pia-ra n a ** a-"*- ** BFG07585 FEB-13-'90 09:33 ID:THE UINYL INSTITUTE TEL NO:201 990-7029 8563 P03 BEFORE THE AGENCY FOR TOXIC SUBSTANCES AND DISEASE REGISTRY. DEPARTMENT OF HEALTH AND HUMAN SERVICES. AND ENVIRONMENTAL PROTECTION AGENCY COMMENTS OF THE VINYL INSTITUTE ON ATSDR'S TOXICOLOGICAL PROFILE FOR VINYL CHLORIDE Vinyl Chloride Toxicological Profile; ) Request For Comment: ) 52 Fed. Reg. 38340 (October 15, 1987) ) Docket No. ATSDR-2 April 18. 1988 THE VINYL INSTITUTE A Division of the Society of the Plastics Industry, Inc. Wayne Interchange Plaza II 155 Route 46 West Wayne, New Jersey 07470 BFg07586 20872014 EE8-13-'90 09:33 ID:THE UINYL INETITUTE TEL NO:201 890-7029 563 P04 COMMENTS ON EPA TOXICOLOGICAL PROFILE ON VINYL CHLORIDE General Comments As described in section 2.3.1., SARA directs EPA to prepare toxicology profiles that will include an examination of the data, a determination of adequacy, and, where appropriate, an identification of needed toxicology testing. Although the draft Toxicological Profile for vinyl chloride (January 1988) is intended to meet this requirement, it falls far short of both the letter and spirit of the Act in many ways for the following reasons: 1. This document fails to incorporate key data. 2. It fails to provide the critical review necessary to draw a conclusion. 3. There is no identification of toxicological testing and the detail of discussion of this subject is not ade quate tu draw any eonolusiono. 4. Referencing the data in tables and texts is inadequate. 5. There are some instances where reference books and computerized data bases are utilized instead of the original references. This procedure does not allow critical review and it presents the opportunity for perpetuating errors and misstatements. This has been a frequent problem or real concern for at least one of the reference books used. 6. The detail of information provided is insufficient to provide any confidence in the NOAEL, LOAEL, Minimal Risk levels or conclusions or a clear understanding of how they arrived at these. To this end, we would recommend the use of MAS guidelines for use of safety factors (MAS,1982). 7. The use of a number of terms is questionable. The term PEL is misused on page 42, paragraph 1. Increase in DNA synthesis is not a frank effect. Also, the de scriptor "minimal" (page 44, General Discussion) lacks specificity. Standardized terms such as "Adequate" (or "Clear"), "Some" (or "Limited"), "Equivocal"), "No Evidence" and "Inadequate" should be used because their meanings transcend the subject of carcinogenicity and are broadly applicable. Furthermore, it would be better if adequacy was assessed in these terms. BFG07587 20872015 FE3-13-'30 09:34 ID:THE UINYL INSTITUTE TEL NO:201 350-7029 8563 P05 -2- Specific Comments on Section 1 - Public Health Statement CONSUMER EXPOSURE IN CARS (Section 1.2, page 1. paragraph 1; Section 7.2.4, page 71, paragraph 3) The Toxicological Profile states "air inside new cars nay contain levels of vinyl chloride higher than expected background levels, because vinyl chloride nay seep into the air from the new plastic parts". Support for this sweeping statement is an EPA report referenced as (EPA 1985b) (Health and Environment Effects Profile for Chloroethene. Cincin nati, Ohio; Environmental Criteria and Assessment Office. ECAO-CIN-P155). The data on page 71 of the Toxicological Profile "gives the analysis of interior air for two new cars (underline added for emphasis) and shows ranges of 0.3 to 1.2 ppm of vinyl chloride. There is qs information on background levels, nor is there information concerning the accuracy of the analytical method employed. Since the OSHA standard has a permissible exposure limit (for employees in an occupational setting) of not greater than 1 ppm averaged over any 8-hour period, the significance of the levels of vinyl chloride found in these two cars is clearly questionable. Further, it would be important to have additional data and particularly analysis made after the car has been in use for a period of time. Vinyl chloride emissions would be expected to be considerably reduced from the initial emissions in a "new" car and therefore would not represent a continuing exposure source. PLASTIC PIPE LEACHING DRINKING WATER EXPOSURE (Section page 1, paragraph 2; Section 1.3, page 2; Section 2.2.3.2, page IS, paragraph 2; Section 2.3.3.3, page 24, paragraph 2; Section 7.2.4, page 71. 1.2. Currently, PVC pipe (per the National Sanitation Foundation standards) must be 2 ppm in the bulk wall so that vinyl chloride in the extraction test is mfiu l ppb. The U.S. Environmental Protection Agency limit is 2 ppb. Therefore, the leaching of vinyl chloride into drinking water from PVC pipe is inaccurate. Behrens and Daniels have determined that the principal factors controlling vinyl chloride migration from polyvinyl chloride pipe are the initial vinyl chloride monomer content, thickness of the PVC section, temperature and age of the pipe. Their experimental data indicates that PVC pipe containing ^ 1 ppm residual vinyl chloride will result in vinyl chloride concentrations of less than 0.002 mg/kg (0.2 ppb) under any expected service conditions. The Behrens and Daniels paper is provided as Appendix A. BFG07588 2087Z0IS FEB-13-'90 09:35 ID:THE UINYL INSTITUTE TEL NO:201 390-7029 -3- 8563 P06 Further, a study conducted at McKesson Environmental Sciences Inc., on Effects on Water Quality By Leachable 8ubatanca From Copper Tubing. CPVC Piping and Galvanized Pipe Fittings is provided as Appendix B. The study used chlorinated polyvinyl chloride pipe (CPVC) as a worst-case since CPVC could be expected to have more potentially leachable impuri ties. The McKesson study had as its objective quantifying the rate of leaching of organic contaminants into water as a result of passage through chlorinated polyvinyl chloride (CPVC). Full data can be found in the McKesson Report (Part Three, pg. III-l ff). The significant finding is that "no vinyl chlo ride" was detected (see pg. III-2) in these studies. CARCINOGENICITY AND OTHER DfSEASE (Section 1.4, page 2. para graph J; Section 2.2.1.J, page 14, paragraph 1; Section 4.3.6.4.). The discussion of the types of disease and cancer caused by vinyl chloride is very misleading. The document states that "lower concentrations" cause "vinyl chloride disease" but fails to note that these effects are not of concern at present in the workplace and under ambient concentrations due to the OSHA standard which strictly regulates occupa tional exposure (see Section 1910.1017 at 40 FR 23072, May 28, 1975). Furthermore, this section suggests that vinyl chloride can cause cancer of the "liver, brain, lung and possible other organs." IARC supplement 4 (1982) clearly states that "Vinyl chloride causes angiosarcoma of the liver". It distinguishes other tumor having a lesser weight of evidence as being "associated with" other cancers. A recent assessment of the data by the world-renowned epidemiologist Sir Richard Doll (1987) further supports this distinction. He note# that the evidence that vinyl chloride causes liver cancer, specifically angiosarcoma is strong. However, the combined data on respiratory cancer fail to support an association of vinyl chloride and lung cancer. In the case of brain and lymphatic and meopoietic cancers, he indicates that the excesses are not statistically signif icant and that there is nothing to suggest that they are occupationally related. EFFECTS ON OFFSPRING/DEVELOPMENT (Section 1.4, page 2. para graph 1; Section 2.2.11, pages 13-14; Section 4.3.3.1; Section 4.4). The Toxicological Profile on vinyl chloride fails to note that there is no evidence that vinyl chloride causes birth defects or reproductive effects. It is only a concern because of potential transplacental carcinogenicity. The absence .of a critical review has contributed to a misleading presentation. Such a review should include consideration of 0872017 BFG07589 fl-u- 3>id jo ii^: : nc jiNil itoi i iuic lfci_ Nu:<*kjl U'St!-i'IdeL'S Bbbd Kid',' -4- key documents which are described in "Potential Effects of Vinyl Chloride on Human Offspring" (1987). This document is included in its entirety as an appendix to these comments. It is also interesting to note that the discussion of developmental toxicity on page 13 appears to avoid the fact that "vinyl chloride did not cause significant embryonal or fetal toxicity and was not teratogenic in any of the species at the concentrations tested". (John et.al., 1977) Based on these results it is incongruous that the document would espouse any NOAEL, not to mention one at 50 ppm. Unfortu nately, there is no information provided to support the 0.7 ppm minimal risk level or the 50 ppm NOAEL. Such absence of detail and supporting rationals is a common deficiency in this document. A report reviewing "Potential Effects of Vinyl Chloride on Human Offspring" prepared by The vinyl institute Medical subcommittee and issued December 1987 is provided ae Appendix C. CANCER RTSK ESTIMATES (Section 1.6.2, page 4; Section 2.2.1.1, pages 14*15). Estimates of cancer risk are limited to those derived by EPA in 1985. Since risk estimates have been derived by others, these should be identified and discussed. This is particu larly important since some of these estimates (NHCH, 1987) differ by more than 2 orders or magnitude from that presented by EPA. Furthermore, EPA has recently revealed the fact that it is now using new risk assessment procedures which have dramatically lessened risk estimates for many chemicals (Chemical Regulation Reporter, 1988). An updated risk assess ment based on the newly-developed procedures being used by EPA is thus warranted. Specific Comments on Section 2 20872018 GENOTOXICTT-Y (Section 2.2.1.1; 4.3.5.1; 4.3.5.2) Numerous studies have evaluated the genotoxicity of vinyl chloride. Although vinyl chloride has been found to cause mutations in some non-reproductive cells, particularly in vitro, the in vivo evidence for sommatic and germinal mutations is far less convincing. The ability of vinyl chloride to induce sommatic mutations 1q vivo in human cells was examined in three separate, independent studies conducted by Funes-Craviato et.al. (1975), Ducatman et.al. (1975), and Purchase et.al. (1975). All of -the studies examined workplace exposure to vinyl chloride, but all suffer from a number of flaws including lack of exposure data, inappropriate statistice, and no descriptions of how control groups were selected. The studies show a slight association between potential vinyl chloride exposure and chromosomal BFG07590 FEB-13-'90 09:36 ID:THE UINYL INSTITUTE TEL NC:201 990-7029 5- SSbd breaks in lymphocytes. Two of tha studio*, Pun*-Craviato ct.al. (1975), Ducatman et.al. (1975), actually found that the number of chromosomal aberrations were often lower among workers as their length of employment increased. This last observation indicates that there is no evidence of a dose or compound-related response. Because of all of the information that is missing from these studies, it is hard to draw any conclusions on the relationship between vinyl chloride exposure and chromosomal aberrations. Workplace exposure and chromosomal aberrations among lymphocytes of male workers was also examined by Leonard et.al. (1977). The workers studied were employed in a vinyl chloride facility in Belgium where there was no record of exposure levels. The authors assumed that employment during early exposure years was initially 500 ppm which was eventually reduced to 10 ppm. Controls who were employed in the laboratory of the same facility and were assumed to be exposed to less than l ppm. An additional 10 controls were obtained from outside the factory and were assumed to never have been exposed. The average of the number of aberrations per 100 cells was approximately the same for each group. Even though some specific chromosomal aberrations were found in the exposed group, the significance of the finding is questionable since each of those workers received regular radiologic examinations which could produce the same observations. Consequently, the Leonard study does not support the premise that vinyl chloride causes mutations in human subjects. Fleig and Thiess (1978) studied aberrations of lymphocyte chromosomes among workers at a BASF plant in Germany. The actual plant exposures have not been documented in this study, but they were reported to be comparable to the German workplace standard which was around 1,000 ppm in 1945 and decreased to 150 ppm in 1973. The subjects chosen in this study had overt signs of vinyl chloride toxicity which included angiosarcoma of the liver, and the controls were carefully matched and took into account smoking, alcohol, vaccinations and other medical problems or treatment. Fleig and Thiess reported that they could find no difference between the exposed workers and controls with the exception of one exposed worker who was receiving chemotherapy for cancer. The Fleig and Thiess study was not able to demon strate an increase in chromosome aberrations as a result of high lvl vinyl <?hl<aridi* in the workplace. The ability of vinyl chloride to produce germinal mutations was examined by Anderson et.al. (1976) using tne aommant lethal assay. Male mice were exposed to vinyl chloride for 6 hours per day for 5 days to concentrations of 3,000, 10,000, and 30,000 ppm. This study employed two known mutagens as positive, controls (cyclophosphamide and ethyl methane sulphonate). No mutagenic effects were noted at any of the 20872019 BFG07591 FEB-13-'90 09:37 ID:THE UINYL INSTITUTE TEL NO:201 890-7029 -6- 8568 P09 stages of spermatogenesis in tha vinyl chloride-exposed animals. However, evidence of mutagenicity was observed in the positive controls. The dominant lethal mutations study was later repeated by Himeno et.al. 1983) in CD-I mice under two different exposure conditions. One group of mice was exposed for four hours per day during five consecutive days to 10,000 ppm of vinyl chloride and the second group of mice was exposed for four hours per day, five days per week over a 10-week period to 5,000 ppm vinyl chloride. This study, like the earlier study of Anderson et.al. (1976) discussed above, was not able to demonstrate any dominant lethal type of mutations as a result of vinyl chloride exposure, and this independently supports the observation that vinyl chloride is non-mutagenic. INHALATION EXPOSURE (Section 2.2.1.1, page 8, paragraph 1) Human deaths from high level occupational exposure should be put in proper perspective. Most if not all of those fatali ties were the result of workers performing in a confined atmosphere with poor or little ventilation and vinyl chloride concentrations in the range of tens of thousands of ppm. There is a long history of workplace fatalities from confined workspace environments for many other agents than vinyl chloride, and all have been controlled by either using supplied airline respirators or proper ventilation. As in Section 4.3.1.1, it should be pointed out that the most likely cause of death in the circumstances is due to narcosis. FDA REGULATIONS (Section J.7, page 6; Section 2.2.3.1, page 18) The statement regarding Food and Drug Administration regula tions is not accurate and as written, suggests that ingestion of vinyl chloride is a public health problem when in fact, FDA has concluded otherwise. On February 3, 1986, FDA proposed a new regulation (51 FR 4, 177) to "provide for the safe use of certain vinyl chloride polymers by establishing limits on the amount of residual vinyl chloride monomer (RVCM) they may contain". Specifical ly, FDA proposed: 1. A 5 part per billion (ppb) limit on RVCM for plasticized films, coatings, and plasticized applications. 2. A 10 ppb limit on RVCM for rigid and semi-rigid food containers. 3. A 50 ppb limit on RVCM for pipe used to carry water inside a food processing plant. 20872020 BFG07592 rcB-l^-'SU inline. iN3i i iuic i ci_ iNUJitu 03&- -7- 4. A 50 ppb limit on RVCM in vinyl chloride - vinylidene chloride copolymer films and coatings. 3. A recognition of prior sanctioned status of both homopolymer and copolymer PVC resins used as films, coatings, water pipe, flexible tubing, gaskets, bottle or jar liners and rigid sheet. The proposal contained FDA's analysis of migration from bottles used for food contact use and estimated that individ ual exposure to vinyl chloride from PVC packaging would not exceed 25 nanograms per day. FDA calculated an individual lifetime risk of less than 1 in 10 million. Based on these considerations, FDA tentatively concluded that the use of PVC as food-contact materials, with the rvcm limits as established, was safe. The Public Health Statement section should be revised to reflect this. EFFECTS ON OFFSPRINGSEPRODUCTIVE (Section 2.2.1.I, page 14) No reference is provided to indicate what animal data is being discussed. We assume this refers to the work of Bi et.al. (1985). The authors of the Toxicological Profile fail either here or on page 50 to question whether these observations are consistent with observations in other long-term studies. In fact, a review of the data indicates the results of this study are not consistent with those observed in other long-term studies. (Maltoni and Mehlman, 1984). More importantly, it should be noted that histopathologic organ changes are evidence of systemic changes even if they are found in reproductive tissues. Although observations of toxic effects in reproductive tissues could lead one to question whether the reproductive capacity of an animal might be compromised, it does not provide any evidence that a chemical is a reproductive toxin. In the case of vinyl chloride, the data indicates that vinyl chloride does not affect reproduction. BIOLOGICAL MONITORING (Section 2.2.2, page 16, paragraph 3) The authors note observations of elevated urinary coproporphyrin as a common finding associated with vinyl chloride-related liver disease and suggest it might be useful in population monitoring. What is not pointed out, however, is that while this finding is indicative of liver disease, it is not specific to vinyl chloride or chemical-induced liver disease.- 208720Z1 BFG07593 FEB-13-'30 09:39 ID:THE ylNYL iNbiiiuic itL ,-^5 H3DO r _ j. -8- LEVELS FOUND IN THE ENVIRONMENT (Section 1.2.3.1, page IS, paregraph 1) The discussion of vinyl chloride associated with landfills suggests that all the vinyl chloride is the result of disposal of vinyl chloride-containing materials. Information is available which shows that vinyl chloride can also result from the biodegradation of l,1,1-trichloroethane which is found in many household products commonly deposited at waste sites and landfills. Thus, the finding of vinyl chloride over landfills may not at all be related to disposal of vinyl chloride or polyvinyl chloride. ADEQUACY OF DATA (Section 2.3.2.I, page 20) Item 2 should note that while a potency factor or potency factors can be derived, the precision of those estimates is unknown. The health effect and exposure route referred in Item 4 are unclear. Specific Comments on Section 4 - Toxicological Data INTERACTIONS WITH OTHER CHEMICALS (Section 4.4, page 60) The document fails to discuss the interaction of vinyl chlo ride and alcohol (i-e., metabolism and cancer in workers). John et.al. (1977) in a study on tetratogenicity in mice, rabbits and rats found that co-administration of ethyl alcohol with vinyl chloride exaggerated all aspects of maternal toxicity. References References cited in this submission that do not appear on the list of references in the Toxicological Profile on Vinyl Chloride (January 1988) are the following: - Drinking Water and Health, Volume 4, National Academy Press, Washington, D.C., page 153. - Fleig,- I., and Thiess, A.M., 1978. "Mutagenicity of Vinyl Chloride", J. occuoat Med. 20 (8), S57-361 20872022 BFG07594 EB-lJ-'90 09:40 ID: Irih viNrL iNbinui'e (l NOi201 890-7029 -9- 8568 P12 - "Prediction of Vinyl Chloride Monomer Migration From Rigid PVC Pip*", A.R. Berens and C.A. Daniel*, Polymer Engineering and Science. Volume 16, 8, August 1976. - Leonard, A., Decat, G., and Leonard, E.D., 1977. "Cytogenetic Investigations on Lymphocytes From Workers Exposed to Vinyl Chloride", J. Tox. Bnv. Health. 2, 1135-1141. - Himeno, S., okuda, H., and suauki, T., 1983 "Lack of Dominant Lethal Effects in Male CD-l Mice After Short-Term and Long-Term Exposures to vinyl Chloride Monomer", Tox Letter. 16 (1-2), 47-53. - Maltoni, C., and Mehlman, M.A. Experimental Research on Vinyl Chloride carcinogenesis, Volume II, Princeton Scientific Publishers, Inc., Princeton, New Jersey 1984. - "Effects of Exposure To Vinyl Chloride: An Assessment of the Evidence", Doll, Sir Richard, FRS (Consultant To Imperial Cancer Research Fund, Cancer Epidemiology and Clinical Trials unit, Radcliffe Infirmary, Oxford, April 1987 (tfNPVBLISHfiC) 20872023 BFG07595 f\tJ-3aoi POTENTIAL EFFECTS OF VINYL CHLORIDE ON HUMAN OFFSPRING Prepared by THE VINYL INSTITUTE Medical Subcommittee of the Technical Committee 20872024 ISSUED: DECEMBER 1987 This report has been prepared by the Medical Subcommittee of the Technical Committee of the Vinyl Institute as a service to its members and their customers and is based on literature information believed to be accurate. No warranty or guaranty, expressed or implied, is made for the accurancy or completeness of the information provided herein and neither the Vinyl Institute nor its members or contributors assume any responsibility for the accuracy or completeness of the information contained in this document The Vinyl Institute. A Division of Tne Society of the Plastics industry. Inc. Wayne Interchange Plaza II. 155 Route 46 Wesr. Wayne. New Jersey 07470. (201) 890-9299 BFG07596 POTENTIAL EFFECTS OF VINYL CHLORIDE ON HUMAN OFFSPRING SUMMARY Vinyl chloride monomer (VCM) is one of the most intensely studied chemicals that is used in industry today. Although it is a known human and animal carcinogen, many other alleged health concerns are not supported by animal or human data. Early or preliminary studies of offspring by some investigators have suggested that VCM causes birth defects and miscarriages. However, critical peer review and subsequent research have shown that there is no basis for such fears. What we do know from decades of research on VCM is that studies with pregnant animals have shown that VCM can undergo placental transfer and, at high levels, cause cancer in their offspring. Other animal studies have indicated that VCM does not produce any mutations in subsequent generations. Furthermore, numerous animal and human studies have shown that VCM does not cause birth defects or reproductive effects. While some human studies have claimed that VCM causes birth defects and miscarriages, close examination by numerous experts have found these early reports to be seriously flawed and not supportive of an effect. Transplacental Carcinogenicity The carcinogenic potential of VCM is well recognized. Many studies have shown that it causes cancer in a number of differ ent animal species and conditions (Viola et al., 1971; Maltoni and Mehlman, 1984; Keplinger et al., 1975). The fact that VCM causes angiosarcoma in man is evidenced by numerous studies (Creech and Johnson, 1974; Delorme and Theriault, 1978; Fox and Collier, 1977; Noria et al., 1976). Studies by Maltoni (1974) and Maltoni and Mehlman (1984) also have shown that VCM is transplacental carcinogen. When pregnant rats were exposed to high levels of VCM, an increased incidence of cancer was observed in the offspring. Animal Studies of Developmental and Reproductive Effects The exposure of males and/or females to toxic chemicals prior to or following conception may provide an opportunity for BFG07597 20872025 -2- deleterious effects to occur. Because VCM has been found to cause mutation in some non-reproductive cells (Bartsch et al., 1976); McCann et al., 1975; Rannug, 1974; Drevon and Kuroki, 1979; Basler and Rohrborn, 1980), studies have been conducted to determine whether VCM can cause mutations in germ cells (egg, sperm) that could effect viability or produce body anomalies. In 1976, Anderson et al. examined VC mutagenicity in fertile male mice using the Dominant Lethal Assay. These investiga tions exposed mice to VC for 6 hours per day for 5 days in concentrations of 3,000, 10,000 and 30,000 ppm. To assure that their test system was functional, this study employed two known mutagens as positive controls (cyclophosphamide and ethyl methane sulphonate). No mutagenic effects were observed with VCM at any stage of spermatogenesis while dominant lethal effects were observed with the positive controls. This early work of Anderson et al. (1976) was later confirmed by Himeno et al. (1983) in a dominant lethal study using two different exposure conditions. One group of CD-I mice was exposed for four hours per day during five consecutive days to 10.000 ppm of VC, and the second group of mice was exposed four hours per day, five days per week over a 10 week period to 5.000 ppm VC. Again, no dominant lethal mutations were ob served following VC exposure. Using another approach, Peter and Ungvary (1980) studied the germinal mutation potential of VCM in the mammalian spot test. Following the mating of inbred females with rotated-bred males, they exposed groups of females on the 10th day of pregnancy to 0 or 4,600 ppm of VCM for 5 hours or to cyclophosphamide, the positive control. Cyclophosphamide caused a significant increase in the number of white or colored spots, while VCM did not cause an increase in color spots. Also, there was no effect on litter size at birth or at the end of the 3-5 week observation period. The authors concluded that although gene mutation had been reported in fruit flies exposed to VCM, there is no evidence that VCM causes mutations in mammals. Other studies have focused on the potential effects of mater nally inhaled VCM on embryonal and fetal development. In studies by John et al. (1977 and 1981) groups of rats and rabbits were exposed to 0, 50, 500 or 2,500 ppm VC for 7 hours per day during the critical development phase (organogenesis) for each species (days 6 to 15 for mice/rats and days 6 to 18 for rabbits). Additional groups of pregnant females were simultaneously exposed to VCM (2,500 ppm for rats and rabbits and 50 and 500 ppm for mice) plus 15% ethanol in their drinking water over the same period. Ethanol, a known reproductive toxin, was used because it is known to block the primary metabolic pathway for VCM. Although high levels of VCM caused Z0872026 BFG07598 frank maternal toxicity, no significant embryonal toxicity, fetal toxicity or teratogenic effects were observed. Greater maternal embryonal and fetal toxicity but not teratogenic effects were observed following exposure to ethanol and VCM. Because of the limited control data which was provided, it could not be determined whether this increase in toxic response was largely due to ethanol alone or the inhibition of VCM metabolism (detoxification) of VCM. However, these studies have further underscored the concerns associated with ethanol consumption during pregnancy. Ugvary et al. (1978) also carried out a detailed study in rats of the potential of VCM to cause birth defects. In their initial experiments, they exposed females on the 18th day of pregnancy to either 2,000, 7,000 or 12,000 ppm VCM for 2.5 hours. Analyses of the maternal blood, amniotic fluid, and fetal tissue demonstrated that VCM could be transferred across the placental barrier from the mother to the fetus. In subse quent experiments they exposed females to 1,500 ppm VCM 24 hours per day over three different periods of their pregnan cy and looked for fetal effects. No birth defects occurred as the result of VCM exposure. Fetal toxicity was evident in only one of the three groups. All of these studies cited above are remarkable in two ways. First, the exposure levels used in these experiments are for the most part several orders of magnitude above levels of VCM in the workplace and many orders of magnitude above that in the community. Such exposure would only be encountered under rare, catastrophic situations and would likely be short-lived rela tive to these studies. Secondly, even though the females were exposed to very high levels of VCM, the evidence indicates that VCM does not cause dominant lethal mutations or birth defects. Furthermore, these data indicate that the levels of VCM in the workplace and the ambient air are not of concern to the mother, embryo or developing fetus. Human Studies of Mutagenic. Developmental and Reproductive Effects Numerous studies of human populations have been conducted to evaluate the potential of VCM to cause birth defects or other reproductive effects. The studies in humans have been carried out with workers employed in polyvinyl chloride (PVC) produc tion or fabrication facilities, and other studies have examined communities in which a PVC production or fabrication facility is located. In contrast to the well controlled conditions of the animal studies in the laboratory, these human studies have had to contend with many confounding factors such as smoking, alcohol, maternal age, maternal infections, lack of exposure information, etc. The ability or inability of the author to deal with these variables has frequently affected the utility of the study and the validity of the authors' conclusions. Many of these problems have been encountered in studies of the effects of VCM on human reproductive outcome. BFG07599 20872027 -4 One of the earliest studies of the potential of VCM to influ ence human reproductive outcome was conducted by Infante et al. (1976a). Fetal loss among wives of VCM exposed workers was studied by interviewing husbands employed in VCM polymerization and PVC fabrication facilities in Ohio. No interviews were conducted with wives and no maternal age information was obtained. Among the workers potentially exposed to VCM, fetal loss was observed to be 15.8% compared to 8.8% among the unexposed controls. This effect was observed in men younger than 30 years old. The above study by Infante et al. (1976a) has been reviewed by a number of investigators and has been found to be inadequate and misleading (Stallones, 1987; Clemmensen, 1982; Haas and Schottenfeld, 1979). This credibility and validity of the conclusions from this survey have been imposed by the absence of maternal interviews and information on maternal age, smoking or alcohol consumption and inappropriate statistical treatment of the data. Furthermore, it was presumed that all workers had a significant exposure to VCM. In addition to the above problems. Paddle (1977) asked for clarification of the age adjustment procedure used by Infante et al. (1976a). The response given by Infante et al. (1976b) tried to explain the age adjustment procedure, but the response also revealed that there were four different age-based catego ries in the original study. The alleged effect upon fetal loss could only be detected in the 25-29 year old age group. Such a specific response is hard to explain on any basis since one normally expects the overall incidence in fetal defects to increase with increasing observation for the presumed effect in the 25-29 year age group by pointing out that the fetal loss in the unexposed group was substantially lower than for any other age group within the unexposed population. The conclusion of Stallones was that the study was seriously flawed by the lack of internal consistency, and the study should be discarded on that basis alone. A recent study was conducted by Lindbohm et al. (1985) which examined spontaneous abortions among women employed in the plastics industry. The study was conducted in Finland during the years of 1973 to 1980 on workers who belonged to the Union of Chemical Workers, and whose potential exposure were to a variety of plastics materials including VC, styrenes, butadienes, acrylonitriles, and polyurethanes. Cases were selected from women who had been union members during their first trimester of pregnancy, and selections were done so that a given case was primarily exposed to only one type of plastic or monomer. Controls were selected from women not having a spontaneous, abortion. Exposure (yes or no only, no quantitation) was determined by having the physicians who treated a given patient fill out a questionnaire. 20872028 BFG07600 -5- When the data from Lindbohm et al. (1985) was examined, no difference in the rate of spontaneous abortions could be determined between the case and control populations for women working with PVC or PVC thermal degradation products. Although the number of women in the study was low, the statistical power of this study was sufficient to detect a two-fold increase in fetal wastage. Therefore, this study indicated that there was no association between VCM exposure and the occurrence of spontaneous abortion. In addition to these studies of workers, a number of investiga tors have examined the occurrence of birth defects in communi ties surrounding plants which use VCM to make PVC. Infante (1976) has published a study of birth defects in a number of communities in Ohio which contained PVC production facilities. He has reported that the rate of birth defects in the communi ties producing PVC was greater than in neighboring communities that did not produce PVC. One obvious problem with this Infante study was the total lack of any quantitative exposure data as in his previous study. Besides the lack of exposure data, no effort was made to correlate the rate of defects with distance from production facilities. If the defects were correlated with VC exposure, then one might expect a greater frequency of birth defects closer to the production sites with lower frequencies away from a given facility. When Edmonds (1976) examined the Infante data as frequency of defects vs. distance from a given facili ty, he could find no difference between the exposed and unex posed populations, and that observation weakens any putative link between observed birth defects and VC exposure. Bias is a major concern in the Infante (1976) study because of the way he examined and combined populations for analysis. There are three communities in the study which contained PVC plants, and those cities are Painesville, Ashtabula, and Avon Lake. For comparison communities without PVC plants, 10 cities were chosen for their proximity to the exposed communities. Of the 10 control communities, two of them (Geneva and North Ridgeville) had higher malformation rates than the exposed communities containing PVC facilities. Since North Ridgeville was proximate to Avon Lake, according to Infante, the North Ridgeville data were combined with data from Painesville, Ashtabula, and Avon Lake even though it did not contain any VC operations within its boundary. This combination of data made a more striking difference between the exposed and unexposed groups whereas the difference would have been diminished if North Ridgeville was properly placed with the unexposed data. This gerrymandering in the case of North Ridgeville is of particular concern since it is 10 miles from the nearest plant and since its southwest location is not in the line of typical prevailing winds. BFG07601 2087Z0Z9 -6- Another point to examine in the Infante study is the question of the CNS defects compared to the control population. Edmonds' (1976) examination of the data could not find an association between VC exposure and reported CNS defects. Edmonds also believes that localized increases can occur sporadically, but these localized increases do not always signal a potential problem. Moreover, Oakley (1981) examined CNS defects nationwide as part of an ongoing activity of the Center for Disease Control (CDC). Oakley found that the frequency of CNS defects has been decreasing in all regions of the country at a steady rate, and the decrease has been occur ring since the 1930's. Since CNS defects were a major concern of the Infante study, Edmonds et al. (1978) examined the presumed relationship of this defect to VC exposure in offspring of Hanawha County, West Virginia residents. In contrast to Infante et al. (1976a) and Infante (1976), Edmonds examined geographic distribution of CNS malformations in relationship to the PVC plant and attempted to quantitate ambient VC levels in the community. When Edmonds examined the malformation rates from matched pairs of exposed and unexposed residents, he could find no correlation with distance from the plant site. He did find some suggestive patterns in which more exposed were northeast and more unex posed south of the plant, but the correlation did not remain when wind and particulate deposition patterns were examined. VC was measured in the community after one large release, and levels of 0.1 to 0.2 ppm VC were found in grab samples to the northeast of the plant site. He was also able to determine emission data during his study period (1970-1974). He found that the rate of CNS malformations was declining during the study period, and the decline in CNS defects preceded the decrease in VCM emissions from the plant sites by about nine months. Edmonds concluded from his study that he could not find any correlation between any wind-borne pollutants and the incidence of CNS defects in Kanawha County, West Virginia. Theriault et al. (1981 and 1983) also examined the presumed relationship of community VC exposure and the appearance of a variety of birth defects. Their study was conducted in Shawinigan, Canada during the period of 1966 to 1979. In addition to examining the geographic distribution of defects and attempting to quantitate ambient VC levels in the air like Edmonds et al. (1978), this study also examined the seasonal variations in VC levels and malformation rates. Geographic distribution of malformation rates were examined in Shawinigan and comparison communities by using school district boundaries. The rate of defects was constant for each school district in.Shawinigan as well as the comparison areas, and the ratio of observed to expected defects was always close to one (1). The ratio of observed to expected defects was approxi mately one (1) for the school district with the PVC plant as well. Further comparisons were made between school districts BFG07602 2087Z030 -7with high and low VC levels, and no correlation could be found between the exposed and unexposed groups for CNS or any of the other malformations. One group, however, did show an increase in malformation rates, but it was located furthest from the plant and would have had the lowest degree of exposure. Consequently, no association was found between the geographic distribution of malformations and VCM exposure. Although Theriault et al. (1983) reported that seasonal varia tions in birth defects corresponded with variations in atmo spheric concentration, they concluded that a causal association between VCM and birth defects was not supportable. VCM concen tration did not correlate with the distribution of birth defects and malformation rates were not high near the plant or in areas where VCM levels were the highest. Furthermore, districts with the highest rates were farthest from the plant. BFG07603 20872031 -8- 71104-3 References Anderson, D., M.C. Hodge, and I.F. Purchase. 1976. "Vinyl Chloride: Dominant Lethal Studies in Male CD-I Mice", Mutat Res. 404. 359-370. Bartsch, H. , C. Malaveille, A. Barbin, H. Bresil, L. Tomatis and R. Montesano. 1976. "Mutagenicity and Metabolism of Vinyl Chloride and Related Compounds", Environ Health Perspect. 17. 193-187. (Cited in IARC, 1979). Basler, A. and G. Rohrborn. 1980. "Vinyl Chloride: An Example for Evaluating Mutagenic Effects in Mammals In Vivo after Exposure to Inhalation", Arch Toxicol. 45. 1-7. Clemmensen, J. 1982. "Mutagenicity and Teratogenicity of Vinyl Chloride Monomer", Mutat Res. 98. 97-100. Creech, J.L. and M.N. Johnson. 1974. "Angiosarcoma of Liver in the Manufacture of Polyvinyl Chloride", J Occup Med. 16, 150-151. Delorme, F. and G. Theriault. 1978. "Ten Cases of Angiosarcoma of the Liver in Shawinigan, Quebec", J Occup Med 20. 338-340. Drevon, C. and T. Koroki. 1979. "Mutagenicity of Vinyl Chlo ride, Vinylidene Chloride and Chloroprene in V79 Chinese Hamster Cells", Mutat Res. 67, 173-182. Edmonds, L. 1976. "Birth Defects and Vinyl Chloride", Soc Occup Env Health. Proceedings: Conference on Women and the Workplace. Washington, D.C., June 17-19, 1976, 114-129. Edmonds, L.D., C.E. Anderson, J.W. Flynt, Jr., and L.M. James. 1978. "Congenital Central Nervous System Malformations and Vinyl Chloride Monomer Exposure: A Community Study", Teratology. 17, 137-142. Fox, A.J. and P.F. Collier. 1977. "Mortality Experience of Workers Exposed to Vinyl Chloride Monomer in the Manufacturer of Polyvinyl Chloride in Great Britain", Brit J Ind Med. 34. 1-10. Garro, J.B. 1976. "Vinyl Chloride Dependent Mutagenesis: Effects of Liver Extracts and Free Radicals", Mutat Res. 36, 81-88. Haas, J.F. and D. Schottenfeld. 1979. "Risks to the Offspring from Parental Occupational Exposures", J Occup Med. 22.(9), 607-613. 20872032 BFG07604 -9- Himeno, W., H. Okuda, and T. Suzuki. 1983. "Lack of Dominant Lethal Effects in Male CD-I Mice after Short-Term and Long-Term Exposures to Vinyl Chloride Monomer", Tox Lett. 16(1-2), 47-53. Infante, P.F. 1976. "Oncogenic and Mutagenic Risks in Communi ties with Polyvinyl Chloride Production Facilities", Ann NY Acad Sci. 271. 49-57. Infante, P.F., J.K. Wagoner, A.J. McMichael, R.J. Waxweiler, and H. Falk. 1976a. "Genetic Risks of Vinyl Chloride", Lancet. 1, 734-735. Infante, P.F., J.K. Wagoner, A.J. McMichael, R.J. Waxweilder, and H. Falk. 1976B. "Genetic Risks of Vinyl Chloride", Lancet. I, 1289-1290. John, J.A., F.A. Smith, F.K.J. Leong, and B.A. Schwetz. 1977. "The Effects of Maternally Inhaled Vinyl Chloride on Embryonal and Fetal Development in Mice, Rats, and Rabbits:, Tox AppI Pharm. 39. 497-513. John, J.A., F.A. Smith, and B.A. Schwetz. 1981. "Vinyl Chlo ride: Inhalation Teratology Study in Mice, Rats and Rabbits", Evn Health Persoect 41. 171-177. Keplinger, M.L., J.W. Goode, D.C. Gordon and J.C. Calendra. 1975. "Interim Results of Exposure of Rats, Hamsters, and Mice to Vinyl Chloride, Ann NY Acad Sci, 246. 219-224. Lindbohm, M. L., K. Hemminki, and P. Kyyronen. 1985. "Spontane ous Abortions Among Women Employed in the Plastics Industry", Am J Med, S., 579-586. Maltoni, C. 1976. "Preductive Value of Carcinogenic Bioassays", Ann NY Acad Sci. 271. 431-443. Maltoni, C. and M.A. Mehlman. 1984. "Experimental Research on Vinyl Chloride Carcinogenesis", Archives of Research on Indus trial Carcinogenesis, Vol. II, Princeton Scientific Publishers, Inc., Princeton, New Jersey. McCann, J. , V. Simmon, D. Streitwieser and B.N. Ames. 1975. "Mutagenicity of Chloroacetaldehyde, a Possible Metabolic Product of 1,2-dichloroethane (Ethylene Dichloride), Chloroethanol (Ethylene Chlorohydrin), Vinyl Chloride, and Cyclophosphamide", Proc. Natl. Acad Sci (Wash.), 72., 3190-3192. (Cited in IARC, 1979) Noria, D.F., S. Ritchies, and M.D. Silver. 1976. "Angiosarcoma of the Liver after Vinyl Chloride Exposure: Report of a Case and Review of the Literature", (Abstract), Lab. Investigations. 34/ 346. 20872033 BFG07605 -10- Oakley, G.P. 1981, "Incidence and Epidemiology of Birth De fects", in: Kaback, M.M., ed. "Genetic Issues in Pediatric and Obstetric Practice". Chicago: Yearbook Medical Publishers, 25-34. Paddle, G.M. 1976. "Genetic Risks of Vinyl Chloride", Lancet. 1, 1079 (letter). Peter, S. and G. Ungvary. 1980. "Lack of Mutagenicity Effect of Vinyl Chloride Monomer in the Mammalian Spot Test", Mutat Rec. 72, 193-196. Rannug, U., A. Johanssen, C. Ramel and C. A. Wachmeister. 1974. "The Mutagenicity of Vinyl Chloride after Metabolic Activa tion", Ambio. 2/ 194-197. (Cited in IARC, 1979). Stallones, R.A. 1987. "The Use and Abuse of Subgroup Analysis in Epidemiological Research", Prevent Med. 16. 183-194. Theirault, G.P., H. Iturra, and s. Gingras. 1981. "Association Between Birth Defects and Exposure to Vinyl Chloride", EPA--600/1-81--075. Theriault, G.P., H. Iturra,and S. Gingras. 1973. "Evaluation of the Association Between Birth Defects and Exposure to Ambient Vinyl Chloride", Teratology. 27. 359-370. Ungvary, G. , A. Hudak, E. Tatrai, M. Lorincz, G. Folly. 1978. "Effects of Vinyl Chloride Exposure Alone and in Combination with Trypan Blue - Applied Systematically During All Thirds of Pregnancy on the Fetuses of CFY Rats", Toxicol. 111. 45-54. Viola, P.L., A. Bigotti, A. Caputo. 1971. "Oncogenic Response of Rat Skin, Lungs and Bones to Vinyl Chloride", Cancer Res. 31, 516-522. BFG07606 20872034