Document Dvp1JG3x7aOp94a8zQVj0jnRB

CHEMICAL MANUFACTURERS ASSOCIATION October 18, 1984 To: Prom: Vinyl Chloride Program Panel C. Stack <Zi Dr. Brian Bennett of ICI England recently visited the U.S. and met with Maury Johnson and myself. Dr. Bennett left materials which are enclosed. Included are comments on the Keldaas paper which appeared in the British Journal of Industrial Medicine. /rds Enclosures ucc 000234 Formerly Manufacturing Chemists Association--Serving the Chemical Industry Since 1872 2501 M Street, NW Washington. DC 20037 Telephone 202/887-1100 Telex 89617 (CMA WSH) PO Box No 6 Bessemer Road Welwyn Carden City Hertfordshire AL7 ]HD Telephone Welwyn Garden 23400 (STD Code 07073) Telex 264251 from J Stafford Health & Environment Protection Imperial Chemical Industries PLC Petrochemicals and Plastics Division To Dr G M Paddle Dr K S Williamson Dr W C F Adams Dr B Bennett Dr J J O'Sullivan Dr A P Wright Dr J T Carter Dr P Mann Dr I Williams Dr D M J Williams Mr P N Anderson Mr J G Davies Mr A Moses Mr G Dupont Mr Per Rangnes Dr Heldaas Dr J P Tasslgnon Dr C Celia Dr T R Torkelson Your ref Our ref Tel ext Date JS/SEN/DSO-16 7535 9 February 1983 VCM 1- MALIGNANT MELANOMAS Dr I F H Purchase has just drawn my attention to a very useful paper "Tumours in Control Hamsters, Rats & Mice: Literature Tabulation** by Sanford P Sher In the March 1982 number of "CRC Critical Reviews in Toxicology", pages 49 to 79. Melanomas and melanoeytomas seem to occur spontaneously in hamsters and are not uncommon. Though they are mentioned in a number of the papers cited, the Important references would appear to be Fortner, J G \ Cancer Vol 10 page 1153 (1957) Fortner, J G Cancer Research Vol 21 page 1491 (1961) I have not read these papers but I shall obtain copies. In the 1961 Fortner paper, .4 melanomas were found in 94 male hamsters and 1 melanoma in 87 females. J Stafford ucc 000235 From G M Paddle To Dr B Bennett Works Medical Adviser Hillhouse Works Imperial Chemical* Industrial PLC Central Medical Group Alderley Park, Macdaifiald Cheshire. SK10 4TJ Telephone : Alderley Edge (0625) 582332 Telex : 669095/669388 Copies to Your ret BB/MO Our ref GMP/EJ Tel ext 248 Date 27 Oct 1983 "INCIDENCE OF CANCER AMONG VC AND PVC WORKERS" HELDAAS et al Thank you for sending me a copy of the long-awaited paper by Heldaas et al. This paper cannot, of course, be evaluated without taking into account all the previous literature on VCM/PVC. It is just not reasonable to regard every 'significant' finding in every new paper as an add-on effect of VCM/PVC. My issnediate reaction is that this paper on its own is an unconvincing demonstration of excess risk for lung, colon, skin and thyroid; and that in the context of the evidence accumulated to date it is even less convincing. I do not doubt the thoroughness of the project, nor the honesty of the presentation, but 1 do think that the interpretation is rather naive. Detailed comments which you may use or ignore as you think fit are attached. G M Paddle ucc 000236 DETAILED COMMENTS ON HELDAAS ET AL 1. The categorisation of jobs as high, medium and low exposure does not match the ICI pattern. Why are monomer production workers, maintenance workers and packaging/drying workers classified as high? 2. When the cases are classified by job, rather than exposure level, there is little or no pattern to be seen in the records of the cancer cases. 3. Several of the key latent periods and exposure times are very short. 4. Table 6 does not seem to be accurate because the 23 cases listed include 2 not in the 23 in Table 4. One case has both lung and thyroid but cannot have been analysed as both (or was it?) 5. Any study of this size will produce a mixture of cancer cases. Are the sites chat are in excess more causatively plausible than those which must have been low? Why are the low ones not listed in fact? it G M Paddle 27 10 83 ucc 000237 *w .> I Brtath Journal 0f idduan 1984;4t:23-30 ^Incidence of cancer among vinyl chloride and polyvinyl chlorid^ workers -& s storejvedtiHELDaas)1 $ l(langA.rd;* an a^ndersend Center , Non* Hydro a a Boagrunn rubniier,. 3900 Pongmnn. 7W* /nkdlmi. > 0"|*p`prIU'H( 1 VflfifTflf, , -i'P r-J--.-g-f.nw. |f ii brilft, fltfir JTTflTwwty. Umn abstract The results of a follow up study of the incidence of cancer and the mortality in a cohort of 454 male workers producing vinyl chloride and polyvinyl chloride are presented. The study population was restricted to employees with more than one year's work experience in the study plant between 1950 and 1969 and the cohort was followed up from 1953 to the end of 1979. w' Twenty three new cases of cancer were observed compared with 20*2 expected; one ease of liver angiosarcoma was found. Five cases of lung cancer were found (2*8 expected) and four cases of malignant melanoma of the skin were observed (0*8 expected). The possibility of a causal rela tionship between exposure to vinyl chloride and the development of malignant melanomas is discussed. Since 1974 when Creech and Johnson presented their report,1 human exposure to vinyl chloride (VCM) has been associated with the occurrence of angiosarcoma of the liver. Several studies have confirmed these initial results as reviewed by Spinas and `Kaminski.1 In animal studies where VCM was given to mice. rats, and hamsters by different routes of administration neoplasms have also been induced in other organs.1 Whether VCM has the potency to induce cancer in man in organs other than the liver has not yet been confirmed. Lung cancer,'*1 brain tumours,4-* and cancer in the digestive system, primarily angiosarcoma of the Itver,*4* have been suggested to be in excess in workers producing VCM and polyvinyl chloride (PVC), and the prime purpose of the present investigation was to study the incidence of cancer in workers exposed to VCM. with special emphasis on cancers other than liver tumours. Material and method tion of VCM and PVC was started in 1950. VCM was produced from acetylene in the room where the polymerisation reactors were located. In 1967 the VCM production was partly altered, and cracking of ethylenedichloridc (EDC) was introduced as one of two production methods. The production of VCM was discontinued in 1971 after which time the plant was operated as a polymerisation unit. From 1955 onwards VCM and PVC were produced in separate rooms; table 1 shows the volume of VCM and PVC production and the number of employees over time. STUDY POPULATION A list containing the names of employees who had started work before the end of 1974 and whose period of employment had exceeded one month was constructed from the personnel register provided by the plant. The health department of the company has kept the health records of all present and previ ous workers employed from 1940 and onwards. These records also contain some information on the place of work of cadi employee. By combining these PLANT DESCRIPTION The study plant is located in the county of Telemark in south east Norway. In addition to VCM and PVC the company produces fertilisers, magnesium, and chlorine in adjacent plant complexes. The produc Received 20 AufWS 1902 Accepted 14 October 1982 Table 1 Annual vinyl Moridt and polyvinyl ehlorid* production and number oftmpbyMa in the study plant Warit poind 1950-35 1956-60 1961-70 19Tl VCtilmml 1000- 1300 2300- 3000 N50o0m0-30000 rvciumi 1000- 2300 2300- 5000 5000-30000 30000-60000 Ne of tmpiayn 4435-- 50 90 90-130 120-130 25 ucc 000238 26 Heldaas, Ltngtrd, and Andersen two sources of information a lin of names wai eon- ufaetunng plant before 1970 may have contained strutted which wai presumed to be complete. The 500-ppm VCM or even higher concentrations." individual record contained the following informa- The plant was doted for reconstruction in tion on each worker: full name, date of binh. iden- October 1974 and sinee 1975 the VCM in the work- tity number, lest known address, dates for beginning ing atmosphere has been monitored continuously and terminating employment, departments in the with automatic measuring devices, including alarm plant at which each person had worked, and the systems that warn the workers during even minor duration of work in each department. Data were leakages. Sinee 1975 the VCM wxpoeura level in obtained for 1233 workers. the production units has been below ] ppm most of It was dedded to restrict the analyses to male the time. workers who had been employed for at least one year and who had first been employed at the plant joa classifications before 1970. These limitations reduced the number lobs considered to have been assodated with high of subjects to 454, VCM exposure include production, autoclave dean- i ing. maintenance, and upping. Owing to the great estimation of EXPOSURE amounts of surplus monomer in the PVC, one may As a consequence of the technical design of the also assume that the exposure level in the packing plant and the process operation, the level of expos- unit may have been high until 1970. Those working ure to VCM in the pasi must have been high but no in the development laboratory which contained industrial hygiene survey had been performed small autoclaves in small rooms, in the control before 1974. Estimates of the pverage atmospheric laboratory, and at processing in the customers' ser- concentration in the past were based on sporadic vice laboratory, may also have been heavily measurements that had been carried out with an exposed, but no information about VCM levels in "explosion-meter" which was graded from 0% to these working places is available. Nine different 100% of the estimated lower explosion limit; 1%, exposure categories were defined (table 2), a equivalent to 400 ppm of VCM. Two sources of number of the workers having been employed in supplementary information for estimating the VCM more than one exposure category. Membership of concentration were used: interviews with workers, an exposure category was defined as that categoty in some of whom had been employed in the plant since which the longest time had been spent. If an indi- the start of production, and a suggested odour vidual had been a production worker for some years, threshold of about 500 ppm VCM. Based on this and subsequently spent a greater number of years at information, we have assumed that the VCM eon- a job that clearly entailed minimal exposure, he cemration was about 2000 ppm from 1950 to 1954, would by definition belong to a low exposure categ- about 1000 ppm from 1955 to 1959. about 500 ppm ory. from 1960 to 1967, and about 100 ppm from 1968 As the exposure level was high in the early 1950s, to 1974. During autoclave cleaning the exposure an attempt was also made to classify the jobs as level may have been as high as 3000 ppm.'* Both determined by the exposure level, using the number emulsion PVC and suspension PVC were produced, of " years of 500 ppm" exposure. The procedure was The surplus monomer in the PVC leaving the man- as follows: one year of production work in 1951, Table 2 Observed (O) end expected (E) deaths Jmen til causer, end tit new easts ofeencer m the study population except non-meienoma stun cancer Cxpmen tetepenm Meef marine 01 Vinyl eMendt (anytea*) 02 Vinyl cMofidt <EDC> 03 Rewafth labentcn 0* Fotyvmyt cfclendt pntduaiea 0} Autoclave thuning 06 Muntentnee 07 FackinuCiyiaa Ot CinuMiery Krvwt labontecy 09 Vanout joM Tout 17 a at 117 17 43 *J 59 SO 434 At iea O \ 2 1* 3 4 3 7 7 30 t 1-41 030 4-32 1*42 3-04 7-64 **44 *77 7.10 59-14 OiE NC NC 0-44 1-16 1*94 0-12 039 0-80 09a OI4 At CM O 0 0 9 2 1 3 3 2 23 E Oil 020 1-69 H0 1-03 2-17 2-93 3-06 2-44 2016 OH NC NC NC 1-76 1-94 NC 1-99 09* OI2 114 Pmom /95J-79 3603 1100 912-0 23005 309-5 iaa-0 1742-5 1063-5 971-3 1676-0 *NC Noi calculated. t, 2 e ti n n rr * u a tt li h <' f T ir a c ii it r t> > h h t' r >r <' u it u i Incidence of cancer among vinyi chloride and polyvinyl chloride worker* 27 when the working atmosphere contained about 2000 ppm VCM on average, *>* classified as four "300 ppm-yearx." The same type of work in 1961, when the atmosphere was about 300 ppm, would give one 300 ppm-ycar. Thif additional categorisa tion of exposure could be given for VCM produc tion, PVC production, autoclave cleaning, mainte nance work, and PVC packing. Owing to the surplus monomer in the resin, one year of packing PVC would give about one 300 ppm-ycar for each year up to 1970, and it is even possible that this high level continued until 1974. In this way high exposure for short periods in workers categorised by jobs with low exposure level could be accounted for. All workers were placed in an exposure category before we had any knowledge of their state of health or diagnoses. FOLLOW UP The main element of the method is to identify those individuals who meet the criteria for membership of the study population and to compare this population with a constructed Norwegian population whose age distribution was identical with that of the study group. (The method has been described in more detail by Langlrd rr at.") Total mortality and cancer incidence from 1933 to the end of 1979 have been determined for the study population. The Cancer Registry in Norway has records of all new cases of cancer since 1933 and has access to information on all causes of death provided by the- Central Bureau of Statistics. This study is based on a comparison of observed and expected total mortality and incidence of cancer for the period 1933-79. To estimate the expected number of cases of cancer, the national five year age specific incidence rates were used. According to the data of the Cancer Registry, the rates of cancer incidence in the Telemark county are between 0-90 and 0-93 of the national figures." Consequently, the more rob ust national rates could be used for reference pur- poses and the expected number of deaths are based on the national rates. Remits Deaths from all causes and the number of new cases of cancer, excluding non-melanoma skin oncer, an presented in table 2. The number of person-years at risk is also shown together with a tabulation of the nine different exposure categories. Among 434 men there were 30 deaths from all causes (expected 59-3). During the 27 yean of follow up, 23 new cases of oncer were found against 20-2 expected. The nine exposure otegories have been combined into three groups reflecting high, medium, and low exposure (table 3); the increased incidence of oncer is accounted for almost entirely by the high exposure group. There was only one liver angiosarcoma, recruited from exposure otegory 04, and this case has been included in a previous survey.1 Table 3 presents the observed and expected figures for some malignant neoplasms of interest. Five cases of lung oncer were observed in the whole study population compared with 2-8 expected. The mean time between first exposure and the time of diagnosis (latent period) in these five cases was 17-2 years (range 3-26) (nor shown in the table). Four of the five cases were in the high exposure group (1-82 expected). Four malignant melanomas of the skin were identified in the study population whereas only 0-8 was expected; three of the cases were observed in the high exposure group (0-3 expected). The tumours were looted as follows; two on the trunk, one in the face-neck area, and one on a foot. After the observation period one more ose has been diagnosed in the medium exposure group; this was in the face-neck area. We are aware of one case of incipient malignant melanoma looted on the trunk Tibi* 3 Broad categories ofwork indicating exposure level. Observed (Ot end expected IE) deaths from all causes, cases ofcancer (all sites), colon cancer (ICD I$3), bronchial canter (ICO 163/163). malignant mtianoma ofdieskin IlCD 190). and cancer ofthe thyroid gland (ICD 194). for work label, see table 3 Lxpmutr W Croup 3 Total No of mockery 297 107 SO 434 AU concert ICD 133 ICO 1911163 ICD 190 ICD 19* Pcetomycon /9JJ-79 O OtE O OH O OiC O on O on ISJ 12-96 1*4 4-7J 06 3 0 0-92 3-3 4 034 W 0 2 2-44 0-1 0 ota nc 1 1(3 2-2 067 NC 31 03S NC 0 OJl Oil 3-9 NC 2 0 OIO NC 0 on 102 3727*0 004 NC 1977-3 002 NC 971-S 23 20-16 II 3 1-44 2-1 i 2-14 l-t 'V 0-79 3-1 2 0>14 12 5 16760 Group 1 IHith -nnvl cMande owwl * Work kbek Ot. 02. OX, OS, 06. OS. Croup : < medium vinyl chlonde npMurt) Work kbeb 03.01. Croup 3 (low Vinyl chioodr txpnuurt) Work kbel 09. SC Sol calculated. 28 Heldaas, Langird, and Andersen Table 4 Observed lOland expected tE) cases ofcancer (all am), lung cancer (/CD 16211631. tad malignantmelanoma of the lit* (ICO 160) I" relation to ame offirst employment it the plant Years af fm rmptnymn4 No at 1950-4 1955-9 1960-4 1965-9 105 129 123 99 TmI 454 NC - Nm circulated. AMeateen O Jt * 3 21 a 631 * 4-33 3 2-12 25 2(51* QIC 61 12 1-4 1-4 159 ICO 1621103 0 2 1-01 2 (564 0 (55* 1 0-29 3 2-64 on 20 1-1 NC NC t- ICD 190 0X Pwnm Oi jianms-Yt 1 0-23 NC 26100 1 0-25 NC 1717-0 2 (51* 111 30*3-3 0 (512 NC 11465 4 0-79 5-1 16760 Table 5 Observed (O) and expected (E) eases ofcancer, all sites, ofdir colon (ICD 133). ofdie lung (ICD 16211631, malignant melanoma of tht thin (/CO 160). and etnerr of the dlyroid gland (ICD 194), by 300 ppm-year exposure index Nn of $00 Nq 9f AM cmtrot ICD IS3 /CD 1621163 ICD 190 ICD 194 ftww i--n o OH 0 Ot 0 Old 0 <1 169 6 TOft 0-* 0 (531 NC 1 1-05 20 1 1*5 124 3 3-10 1-0 1 <521 NC 0 (540 NC 0 5 161 14 9-93 1-4 2 (574 27 3 1-44 2-1 3 TiMal 454 23 20-16 II 3 1-44 2-1 5 2-64 1 1 4 NC Nm calculated. "For dMufttatiAA ciputurr for thcic eur vt material and mttHodi on 0 0-29 NC 0 <516 NC 0 0-33 9-1 2 0-79 5-1 2 e on 0-06 NC 3074-0 903 NC 20*63 (50ft 33-3 35465 016 125 (6760 Table 6 Distribution of exposure categories among workers in whom cancer has been diagnosed (all eases ofcancerf Figures five duration of exposure under differtnt categories in years Art H-hen mrrr Time rifftnt kw diafnorrd tmphvmetn Year af jpiara ICD Ne` Expature eaargontti -- 0/ 02 03 04 05 06 07 06 09 *3 1962 1979 151 2 *7 1964 1967 131 3 62 1956 1972 133 5 67 1962 1973 153 ii 55 1966 1977 153 6 5* 1950 1971 155 22 63 1950 1963 162 4 67 1952 197* 162/177 33 5* 1955 1977 162/194 7 ft 10 34 1951 1977 162 11 10 56 1966 1971 162 29 TO 1930 1973 177 2 IS 2ft 1961 1967 171 It 45 1952 1979 1t1 14 3* 1953 1957 190 4 451 1953 1911 1*0 2 40 1951 I960 190 4 4) 1961 1974 190 13 411 1961 1977 1*0 13 ft* 1964 197* 190 14 *: I960 1972 1*3 3 jj 1959 I960 194 II 35 1953 1*66 1*9 2 ICO 151 (umnftcbanefrb ICD 153 (colon cwuf). ICO 155 lam af id* Mun puufn and heat). ICO 1*2/143 (hutf tint bronchial altar). ICD ITT (onor at the irateie). ICO ITI (term cuw*r). ICD III (bUddtf canar). ICO 190 (auli|iuM neienona at th* OuaI, ICD I'M ((Mint at tlw thyiaid eland). tEepowte caicponcs ootriipondmg with ita ntunben hi table 2. fP an nectirred ibn tb* end a) obaervinsn penad. IlncipMin an. and grot. The the: hot wen T the case bot) T of ft all t also cant the shoamc high thar abo cate tabl inch It r. *or ppr one thar indi met T whe sue are met also pen Dis< The inci can pvi acc but mal PVi is o the can of t fror inc v Incidence of cancer among vinyl chloride and polyvinyl chloride worken 29 and diagnosed in 1977 from the medium exposure cancer, is compared with 5*7 expected, in VCM group. This ease has not been indudcd m the study. workers with at least five years' exposure who also The latent period for the four cases occurring during had been observed for 15 years or more after first the follow up period was 1-8 yean (range 2-28) (not exposure.* They also noted an unusual distribution shown in table 3). When the two additional cases in the histological type of lung eancer. Of the eight were included the latent period was 13-1 yean. histologically confirmed cases, five were classified as Three cases of colonic cancer were observed in large cell undifferentiated. In our study two of the the high exposure group against 09 expected. Two cates of lung cancer were classified as oat cell car cases of cancer in the thyroid gland were observed; cinomas (small cell undifferentiated). Both occurred both were medullary cardnomas. in the high exposure group, end both patients had Table 4 shows the relationship between the date suited work before 1959. As the numbers are small, of first employment in the plant and the incidence of no conclusions should be drown, but in Norway,14 as all cancers and of some specific tumour sites. We in other countries.'* only sbout 20% of all histologi also related the expected chance (risk) of developing cally classified lung tumours ire listed as oat cell or cancer to the estimated weighed level of exposure, small cell cardnomas. Studies on populations occu the 300 ppm-year indicator, and these results are pationally exposed to anenic. asbestos, chromium shown in table 3. The highest risk ratios were found VI, radiation from uranium, and chloro- among those workers who were characterised by methylether" indicate that the proportion of oat high exposure--that is. those accumulating more cell lung cancers in these groups is much higher than five 300 ppm-yearx. We have no information than expected, and this suggests that attention about the VCM exposure level for the exposure should be paid to oat cell lung cancer in categories 03 and 08 (table 2). which are classified in epidemiological studies on working populations. table 3 under the "less than one" index and which Buffler er at observed three deaths from lung cancer includes workers with less than one 500 ppm-year. (0-68 expected) in a subgroup of VCM exposed It may be assumed, however, that some of these workers with more than five years' exposure at high workers were exposed to VCM levels of about 500 exposure level and a long observation period.* Fox ppm. Therefore, the correct exposure category for and Collier, on the other hand, could not show an one of the two cases of lung cancer under the "less increased risk of lung eancer in members of a cohort than one" index (table 5) could be the "one to five" recruited from different plants.* They included all index. The same may be true for the one malignant exposed workers, laid down no requirements for melanoma under the "less than one" index. exposure minimum, and no minimum observation The plant employment history of all workers in period was accounted for. whom cancer has been diagnosed and the tumour In the present study the smoking habits of the sites, ranked according to ICD code (7th revision), members of eohort are not completely known. A are presented in table 6. The year of first employ smoking questionnaire survey in the plant in 1980 ment and the age when cancer was diagnosed are showed that 53% of the workers were smokeis, by also included. The previously mentioned latent contrast with 42% in the male population in the periods have been calculated from table 6. whole country in the same year.14 Consequently, it does not seem likely that smoking as a confounding Discussion factor can explain the differences in the incidence of cancer.14 The present investigation has shown an increased Maltoni er al have indicated that VCM is a mul incidence of malignant melanomas of the skin, lung tipatent earnnogen in mice, rats, and golden hams cancer, colonic cancer, and thyroid cancer in VCM/ ters.1 They also showed skin tumours in golden ham PVC workers. Our observation on lung cancers is in sters. some of which were malignant melanomas. In accordance with the results of several other studies a study of the kinetics and organ distribution of but to our knowledge, an increased incidence of VCM in which rets were exposed to ,4C-VCM by malignant melanomas in worken producing VCM/ inhalation. Duprat er al showed "a great deal of PVC has not been shown before. The present study labelled molecules probably both VCM and its is one on the incidence of cancer, by contrast with metabolite^' in the skin after three hours.1* In a the other investigations which refer to deaths from cancer. If the percentage survival in diagnosed cases of malignant melanoma is high, studies on deaths similar study Watnabc a al confirmed these results.'4 None of these authors discussed the significance of the distribution of VCM to the skin, from cancer may have masked a possible increased however. incidence of this tumour. Malignant melanoma of the skin is believed to be Waxweiler er al observed 11 deaths from lung associated with exposure to sunlight14 and few occu- I 30 pationi have been associated with the development of thetc tumours. Tear gas (a-dtioroaoctophcnone) and polychlorinated biphenyls* are chemicals that have been suggested as possible inducers. In our study population one more case of melanoma has been diagnosed after the closure of the study and before the increased incidence of tumour was known to us- This additional cate considerably strengthens the association between exposure to VCM and the development of malignant melanomas. As the medi cal services in the Telemark county have been of a high quality and easily accessible, we do not believe that there has been any bias due to the presence of the occupational health service in the company. In fact, none of the four cases was diagnosed by the occupational physicians. One of the five subjects with skin cancer had survived until June 1982. The incidence of malignant melanomas in the rural areas of Telemark county is slightly higher than tht national rate, while the incidence in urban areas is fairly equal to the national rate." All subjects with skin cancer had lived in the urban area. We observed two ancers of the thyroid gland (0*16 expected): both ases occurred in the high exposure group and were of the same histological type. We are not aware of other studies indiating an excess of this type of anar but as only two cases have been observed, no conclusions an be drawn. In a Canadian study on workers exposed to VCM for five years or more Theriault and Allard showed an excess of anar in the digestive system,* but the authors concluded that the exass is accounted for exclusively by anar of the liver. In the present study we found s slight exass of anar of the colon. Many of the other studies referred to include anar of the liver in digestive ancers, and they conclude that the excess risk is da to this tumour. There are few reports on occupationally induced anar of the colon and rectum although it has been indiated that asbestos workers, textile workers, and steel workers have an increased risk from these diseases.11 Watnabe er of in their kinetic study showed some faecal elimination of "C after the inhalation of "C-VCM. but they discuss only urinary and pulmonary elimi nation in their paper." The results presented in the present study, consdered with other epidemiological studies, seem to support the view that VQ4 may act as a multicar cinogen in man. This is in accordance with observa tions from animal studies.1 Some of our findings dif fer from those presented by other workers, and wiU be followed up later. The observation period is short for some of the members of the cohort, and the study group is small. Nevertheless, the fact that the excess of different cancers was seen in the group with the highest estimated exposure level streng- HMaas. LangM, and Anderten thens the suggested assodation between VCM exposure and these types of cuneem, in particular the malignant melanomas. We thank the Plastic Division of Nonfc Hydro a s for cooperation throughout the study. O C Bbckmsn's critical comments were of great helpL We thank Mrs P A Flor for linguistic help and Mrs U Daniclscn for typing the manuscript. Rifmani 1 Creech 1U Mmm MN. Aicmsiwm of *wt in Uw manuta*. twv af potynoyt dtlnrtita. lOM 1974;lfci50-l. * Sptnaa A Ifaninki A Aagiotwawiu at lha Int vmy\ ddoiidalpeiyvmyt cMeridt -ortar*. i7T apdau a( tbt NTOSH rt|mar. ION 1971.2* 427-9. * Makeni C Laftmint 0. Qkbertt A Cacti G. Canatti O. Carcutogawaty htoaaaayi af nnyt miandi unmir a node! ef nak iwiia an an tiptnmaaul bam. Liww MmM rVM 19*1:41:3-29. 4 Monaco RA hntn 1M. Taiwan MN. Praparaenal meruiny u*an| vtaylohlotida -erktn. Lmctt I974ji397-S ' Tabtnhaw IA Qalfay WA Monthly uady af -acton in lha maaulaaun af vinyl aMondt and b potymwv JOM 1974:1*509-11. * Wanwitar AT. Stringer W. Waconar JA lama J. Falk H. Caittr C. NittpUmc rnk amoa| work*n mpoaed w vmyt cManda. Anm Mr At* So t97*471:40-1. ' hlhi PA Wood S, Ei(tar C Scum L GKm 01. Monabiy espanan af-ofCan at a *myi dtlonda wsaonMf production plane. JOU 197941:195-202. * Paa kl. Collier PF. Monabiy aiperienw M -acton npoatd to vtnyt dUoridf monomer tht raiaidamav of peiyvtayl dtianda to Ofaat arnau. it J Ini Mti 197744:1-10. * TMnauh C, Altafd P. Caaatr mortality af a poop of Canadian -orken icpniad to vinyl ddondt aonontar. JOM 19(143:67]-*. * Barm AW. Vinyl dtianda and tht produmea of PVC. hetnf. f> of Plf Roynl Soatty of Melton* 197*49477-11. " Karatadt M PVC: haalth impbatione and production anidi. wn HaoM Renfro 1976;17:107-13. " Laoptd S. Andanta Aa. Oytaadt I. Inddtnm ef aneer among (trrochrocnium and hnaUiaen -orkan. it J Jnd Met 191047:114-20. * Cancer Ragrary of Not--ay. Tucdmr of aaaear in Nanay 1972-197* Olio: Th* Norwegian Cenett Sooaty. 1971, " Kvtlc 0. lehanaaa At. LtingckifitNorgt:taovnikt baaanpk Knftngmtrttt metarule. Ttdnkr Nor Lneftfom 1912:1*1:4*0-4. " Wfgmaa DH. Ptrtra 1M. Oa cell tans canon a lekaad aeruptMca: a mooMOomi eudy.JOM 19714*793-* -Aattaoo O. Aaptcs ao taiifnmtdiag ia aoaopadonal baabh tptdamielOBr. Semi J Want b-- iwp 1971:4:13-9. f'Popw P, Fthfy IP. Gcidnki D. Map Sac 1L. Macabalie ppcaach to mduarid powtag: Mood ktotoa and diunbutieo of "C-vmykhlondt eapcnaf (VCM). Atto Phan-amf TootoJ 1977:41. appl 1:142-3. * Wacanaba PC. McGowan OA Madfid CO. Oobring PI. Fact of 1"C] vtoyt mterida ledo-ing i-htlatoou aapnoirt a> nu. Torof Appf RRotmoto! 197*47:49-39. " Magma K. Hbbiu of not cipatuia and rtab of makgnani maianoaw: an analyte af ioddtna ratal in Nocway 19351977 by eohort. ms. ap and pnmary mm uu. Conewr 1911:41.2329-33. " Sober AJ. Fttmauick TB. Oananc and aavuenmamal factaca of malignant melanoma >* maa. h/ment Cttt 1979-.S.SA94 " lamaon B. Colonelal cancan--an oentpational dtaaaac? Cat* oornltroiofy 1971.75:321-3. ri: r. F'* AB1 hyc car car c%\ she of Hy uu (pa all* aC as > no car Go jnc pot on sal* t 45 inc cin da: leu tin ph. pc* adi dci t Me Re Ac HiiihouM Sin PO Sex No 4 Thornton -Clevtley* Blackpool FY84QO Talaphono: Cl*v*l*v (STD Coda 02531 856161 Ttlax 67483 IciplMt Clvlyt Industries PLC Dr Carol Stack Chemical Manufacturers' Association 2501 M Street MW WASHINGTON DC 20037 USA Medical Department Your ref Our ref BB/MQ Tel ext 332 Date 8 Noe 84 Dear Carol, Thank you very ouch for meeting me in Washington and for giving me so much of your time. When we met, I promised to send you a copy of the OK VCM Code of Practice and the Guidance Note which goes with the Code of Practice, and the document "VCM and you", which is a document which will be given to each worker who works with VCM. The first two documents will be issued in the near future and, it is believed, in the present format. The latter document, "VCM and you", 1 anticipate will be altered, though the information will be in a similar vein. The changes I anticipate are on page 2, and the words, 'similar to Banti's Syndrome' will be removed, and on the penultimate page, health checks will not be offered to individuals if they cease to become a Registered worker. (In my area, we do offer medical examinations to individuals who remain within the Site perimeters, even though they are not registered. I am the only Works in the UK that offers this service). 1 am also enclosing, as promised, the IOM Vinatex full and published report, along with Geoff Paddle's critique for you to use in any way you see fit. I would like to mention the various surveys which are ongoing in the world at present with reference to VCM. I did mention these when we spoke, but feel it might be better to detail these for your information : 1) C.H.A. Z have written to Sir Richard Doll, asking about the possibility of he himself reviewing all the epidemiological data base, in order to perform a critical review for industry* I will forward the reply when 1 receive it. 2) Sir Richard Doll and myself are in the process of writing a Paper for publication with reference to the ASL Register. We are being helped by David Forman, who works for Sir Richard Doll, and therefore hie name will go on the Paper. I myself have insisted that John Stafford's name should also be included. /Over ucc 000244 JtoWfMme I" infWne No. 7IS0IS ftw<nr.d Offln - lmp*rl* OweXcS Han*, Mlltoflk, IsMSK SWIP 3JF. HB 2004 From Dr B Bennett To Dr C Stack 8 Nov 84 - 2- 3) I have been informed by Norsk Hydro that the Scandinavian countries, Norway, Sweden, Denmark and Finland, have asked Mdme. Heldaas to prepare a critique of all the Papers associated with VCM, in order that a Panel, the members of which we do not know at present, can prepare a document with reference to definite and possible VCMrelated diseases. Mdme Heldaas has been given only several weeks' to perform her task and the document is planned to be finished during 1985. (This is Mdme. Heldaas of melanoma fame). 4) Ecetoc (European Chemical Industry Ecology and Toxicology Centre) (Brussels) is setting-up a task force to write a review of the carcinogenicity of VCM. This will take into consideration human and animal data. This has been triggered-off by the fact that, in Holland, a study has been performed on animals, which were fed VCM by mouth in the diet, and this study showed liver cancer occurring at low levels, and much lower than had been suggested before* Holland is trying to convert this ingested animal dose into human dose terms. This task, I believe, is difficult, and it is virtually impossible to convert ingested animal dose into human terms. Holland are then moving a stage further, and suggesting - and even trying - to lower the hygiene standard (TLV) of VCM to an extremely low level. The Working Party has been set-up to combat this project. 5) Tax and Collier up-date. The Statistician who is now up-dating this study is called J. Hodgson. The Study is job related, rather than Site related, the jobs' relation meaning exposure related* They are 99* of the way towards completing the Study, and it is expected to be completed by the middle of 1985* I have heard, unofficially, that there is nothing coming out of this Study which is expected to cause us any anxiety. 6) Tabershaw and Cooper up-date, which you mentioned to me when we were talking. Tou also mentioned that the VCM workers are lumped together, irrespective of whether their exposure was of 1 ppm or 1000 ppm, whereas the Fox and Collier up-date is more exposure related. /Over ucc 000245 From Dr B Bennett To Dr C Stack 8 Nov 84 - 3- I hope to acquire the results of all this ongoing research when the various projects have been completed. I will therefore forward copies to you when I receive them. Likewise, I will send a copy of the Norsk Hydro Asbestos/Melanoma Paper, and the letter from the Chief Medical Officer of Norsk Hydro, refuting the Heldaas conclusions, when these are to hand. I have just received from Qeoff Paddle a copy of the letter from William R. Gaffey, Monsanto, with reference to the Heldaas Paper, which appears to be in line with the Geoff Paddle thinking. I should be grateful to receive any such documents which you feel will be of interest to me in the future. I am also enclosing, as promised, a copy of the ASL Register. Once again, I would like to thank you for meeting with me during my visit to the States, and if I can be of any help in the future, please do not hesitate to let me know. Kind regards. Yours sincerely, B BENNETT Site Medical Adviser enca PS I have spoken to aome of the UK PVC/VCM producers, and 1 am getting a positive response to funding of the CMA Study. (Similar correspondence to ; Dr M N Johnson Dr I 3 Torkelson) ucc 000246 Monsanto Montanto Company 800 N. Lindbargh Boulavard St. Louia. Mitioufi 03167 Phona: 1314) 094-1000 October 23, 1984 For Dif^rir-t'^n T'v . \| \ PrRC-.r. ;v - i' , t. x\ <> c iLc - JZV7 . 7 v.ii Carol Stack, Ph.D. CMA 2501 M Street NW Washington, D.C. 20037 Dear Carol: .. I just received your memo and copy of.the Heldass paper on cancer in VCM and PVC workers, together with Geoff Paddle's critique. As you know, I can be depended upon to bring up some obscure mathematicostatistical issue at the drop of a hat, and this case is no exception. ldass et al. state that they classified workers as having the posure level of the category in which the greatest time was spent. They should have classified person-years, not workers, on this basis. You may remember that this issue (should we classify persons or person-years) came up early on in the CMA benzene study, although in that case it didn't change the results in any important way. I'm not sure what would happen in the present case. Take the following example. Suppose a worker is hired into a high exposure job and works there for ten years. Then he switches to a low exposure job and works there for 11 years, at which time he dies. Heldass et al. would correctly classify the death as a low exposure death by their definition, but if I understand the paper correctly, they would also put all of his 21 person-years of observation into the low exposure category for the purpose of calculating expected deaths. In fact, for the first 20 years of his employment, this worker's longest period of employment was in the high exposure category. That is, if he had died in the first 20 years, his death would have been a high exposure death. Therefore, the first 20 years of his employment should be counted as 20 person-years of high exposure, and only the final single year should be counted as low exposure. If the data were analyzed with a ten year latency, the situation would not be so lopsided. Nevertheless, in that case there would be 11 years of observation, ten of which belong in the high exposure category and one in the low exposure category. ucc 000247 Carol Stack, Ph.D. October 23, 1984 Page 2 The above is an extreme example, still, if there were a tendency for new employees to be hired into high exposure jobs and then to graduate to low exposure jobs, the number of person-years in low exposure (and, consequently, the number of expected deaths) could be overestimated, while the number of expected high exposure deaths could be underestimated. I'm not sure that all of the above makes any practical difference in the present paper, but it could. I also share the concerns expressed by Geoff Paddle in his detailed comments on the paper. Yours sincerely, .u'o william R. Gaffey, Ph.D. Manager, Epidemiology /br CC: G. M. Paddle ICI Ltd. 3 The Drive Holmes Chapel Cheshire England UCC 000248 PO Bo* No * Thornton -0*vtl*yP.CEIVE.U N3\/ I 419M Blackpool FY54Q0 Ttltphont: Cltvtltyt (STD Coda 0353) 856161 Talas 67483 Mplan Clviyt Imperial Chemical Industries PLC Sir Richard Doll Imperial Cancer Research Fund University of Oxford Gibson Building Tho Radcllfft infirmary OXFORD 0X2 6HS Silent copies to : Dr K S Williamson b? ft fi nf^i^s Dr H N Johnson C Stack Dr T R Torkelson Medical Department Your raf Our rvf HE/MO Tal axt 332 Data 8 Nee 84 Dear Sir Richard, When I spoke with you at Newcastle recently, yon mentioned that David Forman was in the process of writing the article whioh we hope to publish with reference to the ASL Register. Z was wondering how it is proceeding, and whether or not Z could be of any help? It so, Z would be only too happy to sect to contribute in any way I can. When Z set you, 1 mentioned that Z was to visit the States. While in the 8tates I set Maurle Johnson of B. F. Goodrich, Carol Stack of the Chemical Manufacturers' Association, and spoke to Ted Torkelson of Dow. The Americans are exploring the possibility of an independent epidemiologist reviewing all the epidemiological data base in order to provide a critical review of the VCH literature. I was asked by the American doctors if someone like yourself would be prepared to take on such a task. The American VCM Industry agreed that they would be happy to fund such a project. If you feel you do not have the time to undertake such a project, I should be grateful if you could tell me of another world.respected individual whom you feel would be suitable for me to approach. I look forward to hearing from you in the near future, when 1 hope we can meet once again. Kind regards. Tours sinssrely, li/UL a auum1! Site Medical Adviser FS Z have spoken to some of the OK FVC/VCM producers, and I as getting a positive response to funding of the CNA Study. ucc 000249 fefintfie In CnfWnC N*. 2110It a*fl>Mre Offlw - InwrWI Omkal MuM. Mlltank, LonAn Wit lit. HR 2004