Document J3eLKV4oqdKVryGYX16pKZgvZ

IMP33IAL CHTIICAI I.VDuSTSIIS LIMI7TD PLASTICS DIVISION 33333*33 SCAD '.vIL'./YN 3A3D3T CITY HT3T3D3DSHI3S ENGLAND T3AN5LATI0N 0? CI3TAIN PAHTS 0? THS PROCISDINGS 0; THZ 20T5 MISTING OF THI CH3IICAL CARCINOGZNZ5I3 CLUB IN PARIS, IOTP. NCV313S3 1979 SU3J3CT: ANIMAL AND HUMAN IPIDEMIOLCGY - TH3 VINYL CHLORIDE H3NCM3R CASS P32SIDSNT: PR0FIS303 3 LATARJHT The definitive text of the Proceedings of the 20th. Meeting of the Chemical Carcinogenesis Club Is written in French and will be published early in May 1980. Professor C Maltoni has kindly provided an English version of the original French paper ho gave on 10th. November 1979 and this is included in the Proceedings. So that the other papers and the record of the discussion can be understood by a wider audience, the following Inglish translations have been made. Translating technical papers is fraught with peril. The translator has made many qualifications to h3 Inglish text and these are documented. If tine had permitted, these problems and ambiguities would have been discussed with the authors and a solution agreed. In the interests of 3peed. however, it was decided to make the attached translation available simultaneously with the French Proceedings, /ill you please note however that the French text is the only definitive one and where there is any doubt or disagreement, the French text should be consulted. John Stafford Division Manager, Health L Tnvironnent Protection Imperial Chemical Industries Limited Plastics Division 25 April I960 R&S 108619 ( R&S 108620 n TA3LZ OF C0NT3NTS 1. Introduction by Prof. 3 Latarjet 2. Historical perspective of theVCM case (Paper 1 - Dr 3errod) 3. ANIMAL SPUCTIOLCG? A, Experimental plan, results, comaentary and conclusions (Paper 2 - Prof. CMaltonl) (please see Prof.Maltoni's text in Trench Proceedings^ 3. Methodology of handling data (Paper 3 - Dr J ? Tassignon) C. Discussion of papers 4. HUMAN ZPIDS-lIOtCG? A. The VCM and PVC Industry (Paper 4 -Mr M Honnefoy) 3. European studies (Paper 5 - Dr ? Lazard) C. Solvay study at Tavaux (Paper 6 - Dr Pierre) D. Discussion of A, 3 and C 3. Protocol for Trench National Study (Paper 7 - Prof.Tlaaant and Mite Timarche f T. Discussion of 3 5- Concluding discussion 0. Translator's notes 1 3 7 8 42 45 57 64 73 75 32 33 50 R&S 108621 SIESLANCS TRANSLATION languages Cui t/TB. 1 h. 4-11 /IMG-d/1/3/F3 23 April 1980 CLUB DE CANCER0GZN33S CHIMI3UE Meeting of 10.11.79 1. INTRODUCTION 31 PROP.R LATARJET Today's meeting organised by the Club de Cancerog&iese Chimique is evidence of the interest ve all have in genotoxic, mutagenic and possibly carcinogenic pollution problems. It is a sequel to the first meeting devoted to vinyl chloride which we organised at the Institut Curie in 1976- * On* of the great obstacles to the solution of the problems presented by this pollution is that experiments with low doses administered over very long periods are impossible. And if we wish to use experiments we must extrapolate, with all the risks which this involves. The most effective way of getting round thi3 difficulty is to have recourse to epidemiological surveys, which can cover large groups of people and sometimes tell us whether a given type of exposure, quantitatively defined, is or is not accompanied by a significant difference from the normal incidence of a given genetic or somatic lesion. 3efore calling on Dr 3errod to address the meeting I have to express our gratitude to the active members and organisers of the Club de Cancerogenese Chimique, a particularly lively scientific society even though it has no funds, no subscription and no enrolment, but complete freedom with all the flexibility this gives. I thank M.Jean-Claude Thomas and Dr Berrod, who have been the parti cularly efficient king-pins, and Prof.Coussement, who let us have the lecture room, and my friend Prof.Truhaut, nembre de 1'Institut, for honouring us with his presence; I thank certain foreigners, well known in this field, who have made the journey in spite of the transport difficulties with which we are -2- currently familiar, la particular Dr and Dr Hopkins, from London, Dr Robert Frois,from Louvain, Dr from Holland, and Frof.Viola from Rome, in whom I salute the father of the whole of this Ion; story. I call upon Dr Berrod to address the meeting. R&S 108622 R&S 108623 -3- 2. HISTORICAL PS3SPSCTIV3 or TH5 VCM CASS (Paper 1 - Jr Berrod) M la President, Mesdames, Messieurs, I should like, for this 20th. meeting of the Club de Cancerogenese Chimique, to make a rapid historical survey of the pathology of this vinyl chloride problem. Vinyl chloride or sonochloroethylene was known to chemists for over a century after its discovery by Segnault in 1835 It is a halogenated derivative of aliphatic hydrocarbons which the growth of the plastics industry since the 2nd.World War has developed for numerous uses. ?VC is obtained from the monomer, vinyl chloride, which polymerises very readily. ?VC has been the basis of numerous applications; it is probably the most used of current plasties, and used for numerous applications. To give only one figure, the Trench industry alone produces over 700,COO t.p.a. This polymerisation of vinyl chloride is effected by polyaddition of monomer molecules. The macromolecular chain grows almost spontaneously in an^1^ industrial process which means that in industrial hygiene human intervention is necessary much less often than in the past; but it is still necessary, and therefore necessitates extremely substantial precautions. To vary the properties of the base material, the resin, it is necessary to use several additives^^, in particular plasticisers which give flexibility and stabilisers which prevent degradation. `/hat did we know of the toxicological properties of VCM ? './e knew of its narcotic effects, which are due to its high solubility in lipids and its volatility, which is also high; we knew of several cases of coma from massive inhalation, and above all, we knew that it was a flammable and explosive product when mixed with air in proportions of 4-2C% v/v^. Consequently the industry was aware of certain characteristics, but that was all until 1963. the year in which very special bone conditions were observed for the first tine in certain workmen in polymerisation plants, with osteolytic bands on the ungual phalanges of several fingers, whence the i i i ! - 4- name of acro-osteolysi3 which was given to this syndrome; they were or were not accompanied by circulatory phenomena of the peripheral anoxia^ type, as in Paynaud's disease. This pathology was the subject of three papers at the International Congress of Industrial Medicine in Tokyo in 1969i and it wa3 there that I had the occasion to meet Prof. Viola, who is here today, the author of one of the first papers on aero-osteolysis. A year later, we still did not know whether it was VCM or one of the ingredients which was involved. V/e knew that the conditions affected the people who handled the product most and entered the autoclaves to scrane the walls free of build-up after each run, and in consequence could show these finger conditions. But what we also knew was that some of them had serious bone conditions without any skin lesions and it therefore seemed difficult to admit that there was only one, uniquely local cause. 'Ve tended more towards a systemic disease. I went to see Prof. Viola in Italy on these acro-osteolysis problems and he was kind enough to tell me confidentially of his anxiety. In carrying out animal experiments to examine the bone disorders he had found extremely substantial tumoral lesions at a variety of sites 15) . This led him shortly after, in 1970, to make a communication to the Cancer Research Congress in Houston which had a most resounding effect. The French and European industries reacted to this problem. The Italian industry then entrusted to Prof. I!altoni of the Bologna Cancer Peaearch Institute, who is with us today, a long-term animal research programme under extremely rigorous conditions. The author himself will be talking about this in a few minutes, and I believe it is at present the largest programme of animal experiments on chemical carcinogenesis which has been undertaken in the world. R&S 108624 R&s 108625 The French company Fechiney-St.Gobain, the Belgian company Solvay and the English company ICI decided to join the Italian company Montedison in participating in this programme of animal experiments by Prof.Maltoni, which began in 1971 and ended, as he will tell you, in 1977* This confirmed the preliminary findings of Prof.Viola, -le were justified in hoping that we should not, perhaps,, have the unpleasant surprise of finding that this animal carcinogen was also a human carcinogen. unfortunately, following Prof..'!altoni's experiments, the United States, knowing what the position was with animals, began, with their well known rigour and above all the relative facility which they had since they possessed cancer registers, an epidemiological study which resulted in the discovery of cases of human tumours of the hepatic angiosarcoma type. were therefore faced with an animal and human carcinogen. 1 difficult problem arose for industry and industrial hygiene in a climate which was emotional and, of course, as always, well politicised. "ihat has happened ? After the first measures taken in 1973 if was in 1974, on the announcement of this human epidemiology, that analytical, technical and medical committees began to be created. The original methods of analysis using an explosimeter were rapidly replaced by others, much more soohisticated, for atmospheric analysis by gas chromatography, finally, (o) extremely accurate environmental monitoring devices ` were set up on the plant which have now resulted in automatic industrial chromatography. There are ten or so points on the plant where probes give results every two minutes; thus, each point is analysed about every twenty minutes, making a total of the order of over 7CG analyses per day, requiring a computer for processing the data. This results in a knowledge of the mean ambient level for an S-hour shift every day, which 13 extremely important. ! may add that there is a pre-set alarm system to warn the personnel when a giver, dose is exceeded. The personnel is therefore perfectly kept completely up to date with its -6- (3) history of exposure , corresponding to the ambient level on the plant. I may also add that there are portable analysis units, for use purely in emergency, which are placed in contentious areas and which consequently, at (ql present, enable access if the standard individual precautions in similar cases,eg the wearing of respirators (10) , are taken. Various precautions were taken by the technical sub-committee , 37 which followed the development of analytical methods /with CO a much more thorough checking of the sealing of the vessels, a reduction in the time for which the apparatus was open and, above all, the introduction in 0 00 01 1974 of prolonged hydraulic de-scaling which has enabled us to minimise the K> O) exposure of cleaners; prolonged stripping (11) ha3, moreover, made the levels found today really insignificant. At the same time, the personnel were educated; as we know, the supervisory staff and key-workers (12) in a firm have been given more responsibility. As to the medical problem, a committee of Trench doctors for vinyl chloride has tried to take the problem in hand. 'I** all know the limitations and the great difficulties that we have in finding parameters for the early biological monitoring of cancer; we still have practically no valid ones, but we have, even so, followed scientific developments and established a monitoring programme, in particular by hepatic eehotomograohyf ipidemiological surveys have also been undertaken, one a retrospective survey to recover the individual histories, which was very difficult, and the other a prospective one which we are just starting,to know, from now on, what will eventually happen. (u) Ve have had numerous J meetings with staff, particularly those on the health and safety committees, to explain what was happening, and we have now told the staff that they can, with all the prudence appropriate in such cases, be relatively optimistic for the future and think that the cases^14^ which we now face and which, unfortunately, we are still likely . (15I to find because they are dependent on the past, are going to decrease , and, we hope, disappear in the near future.____________________________ * 3rey scale ultrasonography R&S 108627 -7- There, ver7 rapidly, is the story of vinyl chloride. In conclusion, I should like to say this. It was a model('16) problem, model because, faced with an unknown toxicity of a product in very widespread use the whole scientific, medical, industrial and even political world was mobilised. All the biologists, epidemiologists, anatorao-pathologists and fundamental research workers '' joined in; all the doctors concerned, French and European colleagues, met, and their discussions were very fruitful. The coopanies have been as one; following the four companies initially associated with Prof. Maltoni's work there were numerous' 7 contacts with other European companies and companies throughout the world, in spite of their competing interests. Professor Truhaut, my dear master, may I recall about the industry that one day in the summer of 1975, when we were editing a note for the INHS records, you said to me "We must be strict and give the industry standards which will perhaps be a constraint on them' , but we cannot do otherwise in view of what we know". I acquiesced completely in this proposal, of course, although I was a little worried about reporting it to the Head of the Polymers Department (197) of my firm, but faced with facts as serious as this he showed himself to be in complete agreement, already knowing, moreover, the precautions we had begun to take. Finally, from the political point of view, the vinyl chloride problem has enabled us to set up discussions with the authorities, with the trade unions kept informed, and shown that mare ideas of profit were not the thing compared with^^ the protection and health of the workmen^"^- Finally, I think that the joint efforts of everybody over the vinyl chloride problem have been, are and will remain a model for various studies of chemicals we are now handling in the chenical world we are living in. I thank you for your attention. J. ANIMAL EPIDEMIOLOGY Prof. Latarjet called upon Prof. Maltoni to address the meecing. A. Experimental clan, results, commentary and conclusions (Facer Z - Prof.D Maltoni [please see Prof. Maltoni's English text in French Proceedings]] JO CO o 00 O) NJ 00 i 8- - Prof. Latarlet. after having expressed his admiration for such a gigantic work, conducted so well and for such a long tine, called on Dr Tassignon to address the meeting. 3. Methodology of handling data (Pacer 3 - Dr J P Tassignon) 1. Plan of the statistical analysis Statistics will not give an interpretation differing from that given by Prof.Maltoni, but will enable the uncertainties to be more or less quantified. The statistical effort was applied largely to the inhalation and ingestion studies in Sprague-Dawley rats. I shall restrict myself to the inhalation studies (Fig.1). Biological statisticians work on paper, on the mountain of data from the laboratory note-books which give the condition of the rats on autopsy, but also the changes occurring (22) during the experiment, that is, the weight at various stages, the behaviour of the animals and certain palpable tumours. The present 3tudy comprised first (Fig.1) collecting data from the laboratory note-books but also from sections - where necessary - according to the coding^of the tumours. This enabled us to establish a standardised form for each rat. The data from this form were then transcribed onto punched card3, the set of thousands of punched cards giving us as a by-product, in plain language, the listing^24^ of the figures on the cards. These cards were then checked and it was then possible to start work on three lines of analysis (Fig.3)a) '.Velght curves The simplest is the analysis of the weights of the rats, since this was a factor which night be influenced by vinyl chloride. Ve have looked at the development of the weight curves for the animals with the standard deviations and analysed the deviation from the weight curve in the different groups exposed o various doses in relation to ;heir own control. -9- We did not obsei-re any effect of the long-term administration of vinyl chloride on the weight of the rats, b) Analysis of the ages at death and of the nunber of tumours We then drew up Tables showing the various rat3, starting at rat No.1 and going on to rat No. 3.000 or so, one to each line. We noted, in columns, the lesions which these rat3 could display in Prof. Maltoni'3 code, which covers over 16O different lesions. The age at death of the animals was noted in this Table. Prom the initial Tables we drew up second generation Tables having the lesions, eg hepatic angiosarcoma, on separate lines,and columns for the doses and sexes, for example a column for 30,000 ppm/ males. Prom these Tables we were able to compare the number of rata affected by a given lesion appearing at a given dose with the number of rats affected by the same lesion in other groups. 'When a positive effect appears statist!- eally i probable/ J we can then examine possible dose/effect relations. Ve developed this line of analysis by carrying out a correspondence^ analysis. The analysis of the ages at death enabled us to establish survival curves for the various groups. 'We observed that the survival of the animals as a function of time decreased progressively from 10CS& 'until the point when the last rat died, and we observed that the last rat died increasingly soon as a function of the dose. Such curves can be compared. W* compare the curve for a given dose with the survival curve for the controls to assess whether or not there is increased mortality which is due to the dose. We can examine whether the mortality increases in parallel with or in proportion to the dose and then establish actuarial-type analyses which take into account both the frequency of the tumours and the moment at which the rats die of the tumour when it is a lethal cancer or are affected by the first symptoms of the tumours (for example, for mammary cancers we might tell the moment when the cancer begins to be palpable). R&S 108629 R&S 108630 2. The target organa by the Fisher test 'That are the target organs, or what are the tumours specifically induced by vinyl chloride ? There are over 50 cancers in both the controls t and the exposed animals and over SO benign tumours in both the controls and the exposed animals, some in excess in the exposed aniaals, others possibly in excess in the controls, ft was necessary to distinguish by a simple test between what was probably due to the vinyl chloride and what was probably the effect of spontaneous carcinogenesis in the colony of rats studied, tfe used Fisher's exact probability test, which only retains what is statistically significant at a single dose and in a single sex. This enabled us to define the limit of what is acceptable to the biologists and significant with a probability of error of less than From the Fisher test (Fig.4) carcinomas of Cymbal's gland, hepatic angiosarcomas and mammary adenocarcinomas seem extremely significant. At the 5/ level, only neuroblastomas and papillomas need to be retained, '/e may wonder how far we can go in this probability scale. The answer is for the biologists to say. Effectively, Prof ..Maltoni, this morning, stressed hepatocaroinoma as significantly linked with vinyl chloride, contrary to what the Fisher test proposed for acceptance. There is, in fact, biological reasoning,.side by side with the statistics,which can only be described differently. This reasoning takes precedence, but statistics are helpful in enabling the uncertainty to be quantified. 'Is might also retain hepatic angiosarcomas from the biological point of view, but here the Fisher test indicates such a large probability of error that no statistician could accept it. The Fisher test is used in chronic, long-term, routine experiments at the US National Cancer Institute, but it is already coming up against (27) a first problem, which is that it .may very well be that the tumours which reach a statistically significant level, like mammary adenocarcinomas, are of no importance to a biologist. Others, like hepatocarcinomas, which do not reach a significant level, are of importance to the biologist, './e cannot, therefore, trust blindly in the simple Fisher test. R&S 108631 - 11 - 3. Apparent dose/affect relations fpR') 3y going into the^ " statistical techniques and examining each of the tumours which may be targets for vinyl chloride with greater precision, we have attempted to work out dose/effect relations, ''(hen we have an effect which increases continuously as a function of dose it is clear that the substance studied has on effect and that the carcinogenic effect is peculiar to thi3 substance. This type of curve is relatively rare, for it only applies to powerful carcinogenic effects. '<e shall now examine the profile for various tumours. Firstly, hepatic angiosarcoma (Jig.5). In the controls, the incidence is zero, and then the effect gradually becomes more and more pronounced, the curve rising continuously with the dose, which strengthens us in our conviction that angiosarcomas are definitely linked with vinyl chloride - there is a dose/effect relation. Another argument which enables us to attribute an effect to the substance studied is that the mean latency period of the cancer decreases with the dose, oepatic angiosarcomas are lethal tumours. The latency period is taken to be the time between the beginning of the exposure and the death of the animal. If we plot the logarithm of the dose along the abscissa and the logarithm of the age of the animal along the ordinate we have experimental points which are roughly on a straight line (Jig.6). Linear regression illustrates what happens. 7e find, as is standard in experimental carcinogene3is,a proportional decrease in survival of the animals which is a function of the dose. This was very simply because of the extraordinarily low spontaneous incidence of angio sarcomas in rats. Tor cancer of Zymhal gland (Jig.7) the incidence increases as a function of the dose. The curve is entirely typical, with a proportionality between effect and dose which increases up to 3C,CC0 ppm. R&S 108632 -12- N'e-ohroblastomas (Fig.8) have a different curve, which is hump backed; in fact, at 3C,0CQ ppn we return to a zero level of the effect, that is, comparable with what is observed in the controls* Nevertheless, from the fact that nephroblastomas are extremely rare in the controls, we can attribute this tumour to the effect of vinyl chloride. The difference between males and females can also be studied; it is not very large. Neuroblastomas (Fig.9) are also very rare tumours in the various control groups; they do not occur at medium doses and then very gently begin to appear only to disappear again at very high doses. V/hat are we to make of this dose/effect curve 1 Since the tumour is extrenely rare in the controls the effect is nevertheless attributed to the dose. Mammary carcinomas (Fig.10), which were put in parentheses by Prof. Maltoni, are tumours with a certain frequency in the controls. We know that they are tumours which fluctuate enormously in the same colonies. We observe an increased effect at very low doses of the order of 1 ppm, which is not significant. At 5 PP it is significant, and at 10 and 25 ppm. At 50 ppm we have a possihle control, 3ince two experiments used the 50 ppm dose. In one, there were few mammary adenocarcinomas, and in the other there were many, and this is significant. The dose/effect curve tails off and at very high doses we no longer see the appearance of an excess of mammary adeno carcinomas. row are we to interpret the third type of curve with a large excess at very, very low doses ? 3y having recourse to the second argument for a relation with the carcinogen, that is, the reduction in the mean survival of the rats ? In this particular case (Fig.11) this will not help us because the latency period between the first exposure and the death of an animal with mammary adenocarcinoma does not represent the true latency period of the tumour since it is not a lethal tumour. 1 - 13 - Let us tike the case of another type of tumour, a benign one, which from tine to tine appears in the controls and from time to tine also in the exposed groups, which only breaks away from the base line at 30,OCO ppm, the forestomach papillona^'' (Fig.12). There, we cannot even show the dose/ effect relation or the reduction in the mean survival tine of the animals because we have too few results, './hat, then, are we to think of an isolated dose at which a tumour appears in excess, without any dose/effect relation ? deoatoearelnomas (Fig.13) do not reach, in the Fisher test, the probability level currently accepted in biology, but here we see a curve wr.ich dies down''^^ very quickly and there is then no further effect at very high doses. The fact that we found hepatocarcinonas in massive excess in new-born animals exposed for 5 weeks and then observed for the rest of their life justifies us in thinking that this effect is due to vinyl chloride. The Fisher test showed that fore3tomach papillonas^^ were in excess in the exposed animals. This was the only benign tumour in excess. In thi3 exoeriment we could restrict ourselves in the quantitative analysis to malignant tumours. Malignant tumours as a group increase with the dose (Fig. 14) Actuarial analysis (Figs. 15 and IS) of the incidence of cancer in rats also shows that the do3e induces many more cancers than would be proportional to the increase(31) , for both males and females, de may conclude that the tumorigenic power of vinyl chloride increases with the dose. 4. Analysis of the survival of rats The median survival (Fig.17) of the animals as a function of dose gives a very large scatter in the controls, particularly with the males; on the other hand, we note a reduction in the median survival time in proportion to the increase in dose. This is a very important factor to remember for the overall interpretation of the phenomenon; not only, on the one hand, is there R&S 108633 I u to o 00 <J> CO - 14 - an increase in the cancers hut on the other hand an increasingly large increase in mortality. Je may wonder whether thi.3 increase in mortality is due to the fact that with increasing dose the animals are affected by more cancers; the more cancers there were the greater would be the mortality and consequently this reduction in median survival as a function of the dose Is a reflection of this. In reality, on examining the mean survival as a function of dose, taking all the malignant and all the benign tumours into account (Jig.lS) or one particular tumour, for example, a tumour clearly linked with vinyl chloride, hepatic angiosarcoma (?ig.19), we find a reduction in the mean survival time which is proportional to the dose. This phenomenon of the reduction in the median survival time of the animals is therefore independent of the tumours present in these animals at death, and must be attributed to ''systemic toxicity". There are, therefore, two phenomena which are acting: cancers arising in various tissues and an increased mortality of a chronic general toxicological order which we have not yet defined. i'e can establish the correlation (Tig.20) between the increased mortality and the increase in cancer from the mean number of tumours per exposed animal for a well-defined dose. I 5(j) p. Correspondence analysis between lesions and doses Only data-processing methods^^ can enable us to integrate so nany ideas (over 90 malignant tumours, over 60 benign tumours, and an intercurrent increase in mortality), which is why correspondence analysis brought in here. (Tigs. 21, 22, 23). has been This factorial analysis enables us to identify the underlying factors in the experiment of which two are relatively important and would constitute almost 73^ of the information contained in the contingency table. The first factor is probably linked to the dose and to the initiating power of vinyl chloride. Thu3 nephroblastomas appear at relatively low doses - 15 - (200, 250, 500 and 2,500 pp.i0 . Angiosarcomas a-e strongly induced at higher doses. Hepatic angiosarcomas are found at low doses but become more prominent^^ at high doses, "euroblastomas are most prominent at high doses, as are carctaoraas of -ynbal gland* Forestonach papillonas , being exclusively linked to the 50,000 ppm dose, also appear In the analysis very close to this 5,000 ppm dose. 'v'e might, perhaps, push this type of analysis further. from the biochemical kinetics side we have discovered that the liver enzymes resncnsihle for the detoxification of vinyl chloride operate with a threshold which is found to be of the order of 200 ppm; the primary metabolic cathways ars superseded (34) and other, secondary metabolic pathways are induced at that point. (See the great distance between TM and N'uB in Tig.23). The other factor is the increased mortality. ihen there is a large increase in mortality we do not see many nenhrohlastonas, which have a long latency period. In contrast, carcinomas of lyrabal glar.d become increasingly prominent with increasing dose. 'ie may conclude that the dose affects organs with increasingly high initiation thresholds, and the initiation threshold of lymfcal gland is higher than that of the kidney. But the increased mortality is also due to the systemic toxicity. 6. Conclusion A complete analysis must therefore be made by various statistical methods, some of which can be very powerful, to obtain a quantitative result R&S 108635 989801- S9U - 16 - STUDIES ANALYSED INHALATION BT I SD Hat BT 2 *n BT 6 BT 9 BT 15 it 10BOO ppm 6 000 2 500 500 250 50 0 200 150 100 0 30000 50 0. 25 10 5 1 0 4 h/d, 5 d/w, for 52 w 11 ti 1 , *ri Fifl* *1 Plan of lJrof *Hal toni * a inhalation studies on Sprague--Dawloy rats 1? - laboratory note books Z980i- SSd EV-2: Plan of tlie statistical analysis (data collection) 809801- S'SU f - 18 - 3 lines of analysis analysis of counts analysis of ages at death and ra ts) ; \ age at death /lealorn weight analysis rat age/ 1 or o f ruts ~]J group of lesion number of rats survival curves % iur fivors + analysis of deviations from the control^' -f- analysis of the deviations from the controls -+ examination of doso/effect relations t + analysis of the deviations from the controls correspondence analysis between doses and lesions -p examination of dose/effect relations + incidence curves Fig. 3: 1'lan of the statistical analysis (analysis of the data) - 19 - Fift.A: Viaher'n exact probability test.f'rpm what probability level is { V?) vinyl chloride involved ? f P at at leaiit one dose for nt least one Gex P$0,0 1 P40.0S 0,1<P40,15 0,15<P^0.I Carcinoma of Symbal'a gland Hepatic angiosarooma NephrobIan toma Mammary adenocarcinoma i Mcuroblaatomu Pre-gastrie jjapillgma { ?9l Hepatocarcinoma Adenoma of Symbol's gland Ifrlj-a-hapiitic angiosarcoma 69980i SSd f 0*9801. S9U HEPATIC ANGIOSARCOMA . - 20 - BT 9 I 21 a t death DOSE Uog10J K i g. 6: Huts with hepatic angiosarcoma. Reduction in mean survival time 1^9801- S9U zvaaoi ssd T CAHCINOHA OF ZYHBAL GLAHD - 22 - I HEPliBOHLASTOHA - 23 - et?98oi. ssa frfr98(U s?a T NKHliOOLASTOMA - 24 - BT.9 fr`i^ 9 Proportion of rata affected by nauroblastotna ua u function of the doae MAKI1AKY ADENOCARCINOMA - 25 - IQ) 23 Doae Inhaled ( lofl. 10 ^ Fi10: Proportion of ruts affected by mammary adenocarcinoma as a function of the done Sfc980J. S9U 9179801. s*a - zfy - Age a t death BOSE {tog jq} F1k.11: Female rntfi with mammary adenocarcinoma: no shortening of life F0HKSTOHACI1 PAPILLOMA t29) - 2? - Dose Inhaled t Proportion of rattj affected by forestomaclt papillomaas a function of the dose Oaf Zt980L ssu 8*980t S3H f HKPATOCARCINOMAI -28- STS u------------------ --------- cb------------e-->-qp6--fa-0:-------- a--------- ---------------------------o-^q--------- l--o------------------ 0 1 2345 Uosa inhaled i t tOP . _ ) 10 Onf * Proportion of rata affected by hepatocarcinoma aa a function of the doue I ALLCANCERS DI9 0 1.2 3 Dose Inhaled < l"8 ,0 > --Proportion of rats affected by all cancers as a function of the dose 4 g^98Qi $9tJ 5 m -f - 50 30 Age at death (weeks) W Tig.15: Actuarial Method. Survival without cancer in the* 1 00 Sprague-Dawley rat exposed by inhalation to various doses of VC (expressed in 10? ppm, 4 h/d, 5 d/w for oCJ1 1 year). Maltoni'3 data. R&S 108651 31 - Age at death (weeks) r'ig. 16: Actuarial method. Survival without qancer in the female Sprague-Dawley rat exposed by inhalation to various doses of VC (expressed in 10^ ppm, 4- h/d,* 5 d/w for 1 year)- flaltoni's data. f ZS980L S9U - 32 - Median age a t death (weeks) Dose inhaled (ppm) Fj t'* 1?: deduction in median life of the rate as a function of the dose e*m o-f I - 33 - f Pig. IS Mean age a t d e a th (w eeks) R&S 108653 log (dose) tog (dose) Seduction In the life of the Sprague-Dawley rats as a function of the dose. The systemic toxic effect is independent of the type of tumour(s) present at death. '<ote that the animals completely free from tumours have the shortest lives (significant only for the females, 0.05 p 0.01, one-way analysis of variance). animals dying without tumours animals dying with benign tumours only animals dying with benign and malignant tumours both present animal3 dying with malignant tumours only ?i. 19 37 Co (/> o 00 O) 01 A Changes, as a function of dose, in the mean survival tine of rats affected by o-------- o 0---------& C-------- n " hepatic angiosarcoma __ malignant tumours not specific to VC cancer of Cymbal gland benign tumours not specific to VC Che effect of the dose is very significant (one-way analysis of variano e1 I, - 55 - ?ig- 20 I In ( survival of exposed rata survival of control rats Correlation between increaseJ mortality ant increase in tumours due to VC (r = -0.94). is the mean number of tumours oer animal exposed to the dose d, ; m is the mean number of tumours in the controls. A straight line passing through the origin has been fitted. R&S 108655 f HAI.E SPBAflUB-DAWl.EV RATS (BT 1+6) 9S980I. ssa *p4* 04 * ASH s hepatic angiosarcoma* HZ = adenoma of Zymbal v gland. CZ * carcinoma of Zymbal rland: IIC s hepatocarcinoma; NpB nephroblastoma; NrB = neuroblastoma; PE .forestomach papll loath; ra = all other benign tumours; Tfl = all other malignant tunioura. 10^ ppm, 4 h/d, 5 d/w for 1 year. 't The doses are expressed in - 37 - t BT 1 + 6)FfflALE 3PHACIU&-PAWLEY RATS AH = mammary adenocarcinoma; ASH = hepatic angiosarcoma; AZ = adenoma of Zymbal gland; CZ = carcinoma of Zymbal i gland; HC = hepatocarcinoma; PE = forestomach papillona; NpB = nephroblastoma; NrS - neuroblastoma, Til = benign tumourst TM = malignant tumours. The doses ore expressed in 10^ ppm. A h/d, 5 d/w, for 1 year. ZS98CH S'Sd 7 is - 39 Pig. 24 Ixanples of models of dose incidence relation applicable to the data of Maltoni's study 37 1 on Sprasue-Dawley rats. The shaded area shows the 95;i confidence liniS for the proportion of rats with spontaneous cancers. R&S 108659 R&S 108660 I - 40 - ?iS. 25 n= a) T23 C u u Extrapolation from a regression line defined fbr an. incidence of 10 to-100S of animals with cancer. The shaded area shows the 95/ confidence limits. From Shubik and Clayson, 1976 - 41 Cases oJC cancer, So ^BBBSsusmsm 1-99801 S'? a " W2 C* Discussion of papers Prof. Latar.jet I am Tery interested in what has just been said, and, even, in what has not been said. We are touching on fundamental problems there, like that of the threshold mid the dose/effect relation - whether or not it is linear. This statistical analysis has enabled us to profit from Maltoni's exceptional (39) experimentv ' to come close to answering these questions which are fundamental because they go to the very root of any legislation, (sic 1 >) There is one concept here which is dear to me, the concept of dose. The "ppm" have never been doses, they are concentrations. The doses are proportional to the ppm when the exposure-time is constant aud the inhalation conditions are constant, but if the animal is exposed for its whole life and if survival varies with concentration, the dose is no longer parallel to the concentration. What we have seen, then, are eoncentration/effeet curves, not dose/effect curves; this is my main interest is this paper and it is absolutely necessary for cancer specialists, chemists and toxicologists to understand that there is a rigour of expression which is not always observed in the Anglo-Saxon literature but which has become indispensable. We must be extremely strict, because considerable philosophical, social and legal consequences are involved. Mae Hurst To try to make a comparison with other known carcinogens, I should like to ask 33 0> a definite qnestion : In ingestion experiments with rats, what is the dose which </> caused the highest percentage of malignant hepatic tumours, and, under these o00 conditions, what was the shortest latency period ? at at to R&S 108663 - 43 Prof. Haltoni The dose which gave us the greatest response is 50 mg/kg body weight. In ED aniaals we obtained 17 hepatic angiosarcomas, or an incidence of 2l. We also ohserved in animals not bearing angiosarcomas, 5 dysplasias and 7 hyperplasias of the sinusoidal cells. The mean latency period of the angiosarcomas waa 73 weeks, but tumours certainly appeared sooner. line Hurst 50 mg/kg body weight was the total dose? Prof, Maltoni No, once a day, 5 days a week for 52 weeks. Prof. Viola I should like to add that Maltoni's experiments are magnificent but that extrapolation from.animals to man is still, I think, difficult, for many reasons. At different concentrations there are different cellular responses. There are all sorts of enzymes which no one has properly studied yet. If we are speaking of quantitative extrapolation, 10 or 50 p|m in Maltoni's work, we obtain our answers from animal experiments which have nothing to do with human beings. If 50 ppn is significant for humans then I wonder why only 100 people have died up to now.I I am well aware of the exposure situation 20 or 30 years ago with 1,000 - 3,000 ppm every day. Outside these concentrations, there are thousands of people who breathed 100 ppm of vinyl chloride and 300,000 who breathed 3 or k ppm. So I a quantitative extrapolation from 1 ppm, from 1,000 ppm is a reflection of research restricted to animals. When, for the first time, I went to USA to discuss all the problems of vinyl chloride, I said : "there are fundamental principles we must, above all, study and investigate. Is there or is there not a safety threahold?" This was 10 years ago and research on vinyl chloride has todav become a research method in cancer research. I must say that the analysis of all Maltoni's work raises a series of very interesting problems. I - 44 ~ Dr Tasaignon I should like to reply to Prof. Viola because the questions he raises, the dose/ j effect relation in animals and extrapolation of the data from animals to man are very important for this afternoon's discussion. The choice of a model is already very difficult. There are thousands of them. (See the examples in Pig. 24). When you have this small dose/effect relation^1) (pig. 25) in the dose-range examined and you wish to extrapolate the doses which are very low but which correspond to the manner in which human beings are permanently exposed in the environment or in their food, you are taking a terrible leap, and since any regression set up has confidence limits your confidence limits become extremely wide insofar as yon leave the range of the experiments. Moreover, which of tho various animal species is the right model for man? (Fig. 26). Prof. Maltoni The neoplastic response depends on the basic tumorigram'(-42) , the enzyme profile, and, of coarse, the dose. Vc know that for both man and animals there is a relation between the dose and the neoplastic response. This dose/effect relation has certainly been verified in animals in the case of carcinogenesis by vinyl chloride. As to the exact extrapolation of the quantitative data from animals to man, it is necessary to have comparable information on the susceptibility of responae (of which the basic tumorigram^^ is an expression), and the enzyme profile for animals and man. Parallel experimental and epidemiological investigations on man might make an extraordinary contribution to the extrapolation of the data from animals to man JJ not only in the case of carcinogenesis by vinyl chloride but for carcinogenesis W& in general. o 00 CCTT>> 4* R&S 108665 4. HUMAN ZPIDXMICLOGY - 45 - M Latarjet called upon M Bonnefoy (Solvayi to address the meeting. A. The VCM and PVC Industry (Pauer 4 - Mr M Bonnefov) I shoald like, on the occasion of this meeting, to raise some ideas which seem to me to be important both on the industrial level and on the human level in the PVC industry. It may be useful, in the first place, briefly to recall the outline of PVC production (Slide l). - Two raw materials - ethylene of petrochemical origin - chlorine obtained by electrolysis of salt, an industrial operation which produces, in parallel, caustic soda, the basic alkali of the chemical industry. - The synthesis of VCM, a continuous process under pressure, which requires gas-tight circuits. The plants built in the open are of the petrochemical type. The staff is small. - The polymerisation of vinyl chloride to PVC. This is a discontinuous operation comprising numerous manual operations. It is there that there used to be the greatest hazard of exposure to vinyl chloride, in particular when the cleaning of the polymerisation reactors was effected manually. - Finally, downstream, the conversion of the PVC resin to finished products, either directly or by the intermediary of compounds ready for use. R&S 108666 -- 46 -- What is the importance of FVC in our present society? A society which is by nature technical, industrial, and based on the use of artificial materials, whether they are steel, cement, glass or plastics. The world consumption of FVC in 1976 was 9-2 million tonnes, that of Western Europe 3-4 million tonnes (Slide 2). To illustrate these figures let us express the consumption of FVC as a fraction of that of other materials which may be more widely known. In the EEC, FVC represents - of all plastics - as much as all rubbers, including car tyres - more than the primary consumption of aluminium. Upstream, it must be stressed that 30^ of Cl^ production is fixed in FVC, thus putting the same proportion of NfcOH at the disposal of industry. Xovfoa the market, if the Cl^ is in excess there is a shortage of caustic soda. FVC therefore plays an indispensible part in the balance of several industrial sectors which consume caustic soda, some of them being of strategic importance for our economy. Downstream, FVC turns up in numerous applications where its various properties mechanical properties, non-flammability, resistance to ageing, economic competitiveness make it a prized, often irreplaceable product. I shall quote two examples as an illustration. - In the building sector: half the plastics used are FVC, thus: - in France, half the pipes are of PVC - in Germany, half the window-frames are of FVC. r &S 108667 - 47 - - Another example, food packaging, particularly bottles: - in France, 2 wine-bottles in every 25 20 water-bottles in every 25 17 oil-bottles in every 25 20 vinegar-bottles in every 25 are of FVC. These few paints of reference are quoted to stress that PVC is not a trifling novelty but a btsic raw material. It is therefore socially inconceivable to ignore it, still less to prohibit it. If production presents risks, it is up to the social partners ..firms, workers, scientists, the authorities to take steps to master and eliminate them. Uhat is the population directly involved in the production of FVC? It is evidently difficult to make an exact census - those present at this meeting who are presenting epidemiological surveys will explain to yon the obstacles one runs into in this field - but it is possible to make an estimate. At present, in Western Europe, the personnel employed in the production of VCM and FVC is of the order of 16,000 people. On a world scale, extrapolation based on FVC production gives a figure of 40,000 people. To represent the total population employed or formerly employed in FVC production we need to take two further factors into account: - The increase in the number of people employed in FVC production with time - The turnover in the personnel. The graph (Slide 5) from a survey carried out in Great Britain by the Employment Medical Advisory Service is a good illustration of these two aspects. i - 48 1 Beginning of the FVC industry in the years 1940-1950; exponential growth of the personnel employed up to 1973-1974, and, not apparent here, a smaller increase in numbers during the last few years because of the economic crisis and the slowing down of FVC production which this has caused. 2 The number of former employees is substantially equal to those currently employed. On this basis we may, as a crude approximation, estimate that the population haring worked or working in the VC and PVC production sector is of the order of 80,000 people for the whole world. I should like, and this is a delicate aspect, to talk of the cases of death from hepatic angiosarcoma, a condition whose relation to exposure to high doses of vinyl chloride is clearly established. This graph (Slide 4) shows the curve for the growth of the number of cases identified as a fraction of time. We see a rapid growth from the years 1967-1970, culminating in 1976, and what seems to be a stabilisation in 1977 and 1978.I I should like to make a few remarks on this subject illustrated by this other, strictly qualitative graph (Slide 5) - The first curve is that of the preceding graph. How is it going to develop in future years? - The seeoud curve is an attempt to answer this question. It shows the frequency of cases actually occur ring,that i3, the number of effective cases each year in relation to the population exposed. We can show: - in (l), an underestimate for the years 19M-1950, for detection was certainly incomplete - in (2), a more moderate increase in the 60s, having regard to the rapid increase in the population exposed - in (3), the hoped-for effect of the reduction in exposure-levels in the 60s R&S 108668 - 49 and beginning of the 70a, the first results of the efforts connected with the prevention of acro-osteoljsis, on vhich Dr Berrod said a few words to us this Djrning - finally, in (4), 15 to 0 years after the putting into operation of the drastic reductions in exposure since 197^-1975, a tailing off of the cases. Does the stabilisation of the number of cases observed in 1977 and 1978 justify the hope that we have now reached rone (3)7 That is the question. I wish to conclude by putting forward some ideas. - Animal experiments - the discoveries of Dr Viola and the remarkable work of Prof. Maltoni are an illustration of this - have played a fundamental part in the story of vinyl chloride toxicity. They have enabled us to demonstrate its carcinogenic effect, to identify, inanimals, its target organs, and to confirm the hypothesis of a relation between the dose and the effect. Animal experiments, unfortunately, possess their own limitations. - The animal populations exposed are too 3mall in numbers to permit statistical exploitationy,,, results at low doses. - Above all, quantitative extrapolation is impossible at present between different animal species; still less is it possible from animal to man. Human epidemiology - and I beg you to excuse this anticipation of this afternoon's topic - makes up for the weaknesses of animal experiments. In the case of vinyl chloride the fact is that unfortunately the papulations exposed have been large. But above all, human epidemiology analyses the behaviour of man - a complex being in a complex environment - directly. This study is, to my mind, basic. R&S 108669 R&S 108670 - 50 Animal experiments and human epidemiology are, however, only a posteriori methods of study. In both eases we analyse actual situations and discover results. As a former works engineer I ask the question: Is it not equally suitable to direct scientific research effort towards a better knowledge of the carcinogenic function of vinyl chloride, towards the study of the various stages of development of the turnouts : why and how does vinyl chloride act? Ve ore cruelly lacking in knowledge of how to detect the early symptoms of the development of the disease in those who have been exposed in the past and in therapeutic means when a case of angiosarcoma is confirmed. Pros a more industrial aspect, it is certain that the various forms of exposure to vinyl chloride have been reduced to very low levels by a considerable effort by the industry. At this stage it becomea important for the community to assess the reality of the hogard associated with exposure to vinyl chloride accurately in relation to other social risks, so that the resources of the community are used where the action will be most effective. From this point of view, also, fundamental research on the mechanisms of action of vinyl chloride must contribute to supplying an answer. These are the questions I ask the distinguished scientists of your Club de Caneerogenese Chimique. Fig. 1 Raw Materials - 51 - R&S 108671 Intermediates (0 Production of VC Production of FVC Proceaaiug of F7~C FVC producta n fio cn o - 52 - O)00 Fig. 2 PVC ro 1 Consumption (1976) Vorld 9.2 million tonnes Europe million tonnes EEC 2.9 million tonnes 2 Importance of PVC (EEC = 1976) Plastics PVC Rubber Primary aluminium 12 - 13 million tonnes 2.9 million tonnes 2.9 million tonnes 2.0 million tonnes 3 Industries upstream PVC = 3056 of the chlorine end NaOH k Industries downstream Examples* Building* 50% of the plastics used (EEC) 1 pipe in 2 (France, Germany, Holland) 1 window-frame in 2 (Germany) Bottling; Vine a 2 bottles out of 25 Vater = 20 bottles out of 25 Oil a 17 bottles out of 25 Vinegar = 20 bottles out of 25 Fi*. 3 - 53 (BEAT BRITAIN' } VC/pyc r &S 108673 Number of persons employed at present and total number of persons who have left this industry each year since 1940. r &S 108675 Pig. 5 -}-) - World production of VC and FVC Detection incomplete Increase in number of people exposed Reduction in exposure-levels in the 60's Effect of the application of new safety standards. A R&S 108676 - %- Prof. Trnhaut Yon have, M Bonnef oy, compared the data from animal experiments with the data obtainable from the.epidemiology of exposed groups of humans. You said that the limiting factor was uncertainty. I should like to draw your attention and the attention of our audience to the fact that where we are concerned with long term effects human epidemiology has a limiting factor which is the observation cycle. In the ease of vinyl chloride, we have an example where animal experiments and epidemiological surveys are mixed. It was said this morning, in fact, that there had been three main stages in the detection of the risks associated with exposure to vinyl chloride. At the beginning, we knew that it was a flammable, neuro-toxic substance, and consequently the toxicologists had fixed limits for industrial exposure. Then suddenly. In about 1963, there was the discovery by humau epidemiology of the vaao-motor effects at the ends of the upper limbs with perforations in the fingers - the acro-osteolysis syndrome. It is because Prof. Viola wished to try to establish by animal experiments the mechanisms of the production of this acro-osteolysis syndrome that, to his surprise, he demonstrated carcinogenic effects with various localisations at fairly large doaes. Then we went on to an experiment in depth, which is what Prof, Maltoni told us about this morning. All this is mixed, and it so happens that in this case the data on the carcinogenic effect from the animal experiments led the epidemiologists to have retrospective surveys mode and demonstrate the production, in particular,of very special tumours, hepatic haemangioaarcomaa('43) . See how, in the field of cancer research-- and I personally would not know how to separate the study of the carcinogenic hazards from the study of the toxicological hazards - there was necessarily a close liaison between the two disciplines of toxicology and cancer research as a result of experiments and epidemiological surveys. - 57 - Prof. Latarjet called upon Dr Lazard of Rhone-Pouleuc ' to address the meeting, stating that he was a works doctor, a rapporteur to the French Medical Committee on VCI and the French representative on the Commission Europeenne des Federations des Industries Chimiques. 3. European studies (Paper 5 - Dr Lazard) I shall be brief, particularly because after the volume of work on animal experiments we are going to pass on to the study of human epidemiology which is to be evaluated by Prof. Flamant who, as an epidemiologist, will also be able to criticise the data of the surveys now published. After the first animal experiments by Prof. Viola showing that vinyl chloride was capable of inducing cancerous tumours, many research workers thought it necessary to carry out epidemiological surveys to determine in what proportions (46) vinyl chloride could be responsible for the increased pathological hazard, in particular cancer hazard, in the exposed workmen. Prof. Maltoni's papers, in their preliminary conclusions, specified the target-organs, and, more particularly, the statistically significant occurrence of hepatic angiosarcomas in the animals observed. These results led to a more precise investigation (47) of the effect' ' of exposure to vinyl chloride on the number of hepatic angiosarcomas and, moreover, confirmed the necessity of statistical surveys of the populations exposed. These snrveys, carried oat in Western Europe, ran into numerons difficulties over ascertaining the duration of exposure, the years of exposure, the degree of exposure and each of them has been or may still be (48) the subject of lively(49) discussion. r &S 108677 - 53 - la the context of this meeting, we are proposing very simply to take stock of the epidemiological findings that a practising works doctor may come across , reporting for each of the European countries the essential published papers, paying particular attention to the conclusions of cancer mortality au'veys.. I must emphasise, in passing, the role of the medical qomaittee of CEFIC responsible for the study of the pathology of vinyl chloride which, under the chairmanship of Dr de Boer, has centralised most of the European information and drawn general conclusions from it, and that of the Centre International de Becherche snr le Cancer in the field of centralisation of international research. In certain countries, in fact, for exmnple Holland and Norway, the total population exposed to vinyl chloride hazards is too small for us to be reasonably able to draw statistically valid conclusions. The conclusions may differ greatly from survey to survey. The Swedish authors Byren et al published in 1976 a survey covering all the workers on a single polymerisation plant in the 40s. Of a total of 771 persons, 21 were lost for the investigations. The degrees of exposure, ss is often the case, conld not be accurately determined in the absence of systematic measurements of the TC content of the atmosphere such as we are fmailiar with in our plants today. The TC content of the atmosphere was at that time a rough estimate and not determined as it is now by gas-chromatographs which enable ns to know the monthly, weekly, dally end yearly average exposure levels. In the group examined 4 or 5 times as many pancreatic tumours were noticed than in the general population, with two cases of hepatic angiosarcoma in 1967. The number of cerebral tumours and suicides did not differ from what was found in the general population. In contrast, cordio--vascular and cerebro-vasculsr complaints were significantly raised. The authors note that in the group concerned no exact investigation of the ways of life and the factors favouring chronic degenerative or cardio-vascular conditions had been made. In connection withfw51)' this work we must mention the work done by Blinder and Cederlof directed to the investigation of the R&S 108678 - 59 possible effect of VC on the environment* A survey of cancer for the perioc 1961-1974 was carried out on the Swedish population near a PNC production plant compared with a population of the same size situated beyond risk of exposure. This work concluded with the finding of a 50f increase in standardised mortality ratio for cancers of the pancreas compared with the control population and the national population. No increase was found in other cancerous conditions and there had not, at that time, been any cases of hepatic angiosarcoma . No valid aetiological explanation can be given for this increase in pancreatic tumours. In 1979, Holmberg et al., also in Sweden, noted('52) a survey relating to the employees of four FVC processing plants who had been exposed to the monomers for at least 3 months over the period 19^5-197^. It was possible to follow up 1970 of the 2073 workmen, and this group was compared with the Swedish population in respect of the mortality for the various causes of illness and for cancerous conditions. Mortality as a result of coronary thrombosis was greater in the group considered and particularly in a sub-group of workmen exposed to the product for at least 2 years (ll cases, compared with 5 cases in the control population). We also note a tendency for an increase in illness and mortality caused by tumours of the digestive tract (although this finding is not statistically significant). This survey will have to be the subject of a follow-up by the authors in order to evaluate the changes in these percentages accurately for future years. In Great Britain, Duck and his co-workers published in 1975 a mortality survey on workers in a single polymerisation plant. In a population of 2,100 male workers exposed for a period of up to, in some cases, 27 year3, the survey shows no excess in the specific causes of mortality, and the authors conclude that the survey does not give any evidence for an increased frequency of deaths due to the most common cancerous conditions. But, in reviewing the evidence provided by this publication, we must note that Wagoner, Infante and Saracci at that time, in 1976, arrived at very different conclusions. They found an excess of deaths due to cancer, in R& s 108679 33 089'' - 60 particular of the digestive tract and lung, which was closely related to the increased duration of exposure. Baxter and Fox, at the beginning of 1976, published a survey of PVC processing workers. This survey, which related to the mortality associated with every cause found between 1970 and 1972, suggested that cancers of the stomach anduzogenital tract conditions were statistically responsible for a greater('93)' number of deaths. The total number of deaths due to cancers of all 3ites observed is slightly higher than expected. (54) We had to wait until 1977 for a very important' British paper by Fox and Collier giving the results of a largesurvey of over 7,000 workers, representing the whole of the personnel in Great Britain between 1940 and 1975 exposed for periods of some length. This survey is still, so far as we know, the largest in Europe in terms of the number of people concerned. It was possible to follow up about 99JS of the workers, and the conclusions of this paper suggest a significant reduction in standard mortality ratio compared with the national percentage for deaths due to cancer in general. The survey does not enable us to demonstrate a significant increase in the total number of cancers except for cancers of the liver and angiosarcomas. The authors insist, however, on the fact that the total impact of the effect of ! VCM will probably only be capable of a full evaluation if epidemiological [ surveys are carried out for several years. i In October 1978, Frentxel-Beyme, Sohutx and Thiess in the German Federal Republic published their observations on a mortality survey of 1,618 workers ! exposed to VCM and PVC in a BASF works at Ludwigshafen. The methodology and analysis of this survey were based on the usual international methods, enabling comparisons to be made. Since insufficient details of the degree of exposure were obtainable the mortality of the group studied was determined by reference to exposure-periods of 5, 10, 15 and over 15 years. Two groups were set up, one comprising the workers exposed before I960 and the other the workers who had R&S 108681 - 61 their first exposure after i960 and up to the end of the survey. This ties up vith what M Bonnefoy has just shown us, I960 being the year of advances in manufacture and so corresponding to shorter exposure-periods, while the years preceding i960 could correspond to much longer exposure-periods. Control groups were also studied, comprising firstly the town of Ludwigshafen (180,000 inhabitants), and secondly, the population of a complete region totalling 34- million inhabitants. Finally, a third group of workers from the same works, 1,960 workers on a styrene plant. At the end of this survey, leas cirrhosis of the liver and less myocardiac infarction than expected were found. Wo hepatic angiosarcomas were found in this works. The number of cases of death from natural causes (international definition ICO 0796) is also smaller. The number of deaths from unnatural cauaes (ICD 800 999) is very close to mtpectationa. Three condi tions with a greater frequency were noted - pulmonary tuberculosis, malignant tumours of the colon and stomach and prostatic hypertrophy. The duration of exposure does not seem to have had a significant effect in increasing the percentage mortality after long periods of exposure. The authors, moreover, remark that the observations made in other surveys of a significant increase in cancerous tumours of the brain, lung and liver were not confirmed in theirsurvny. They put forward the hypothesis that these differences are, perhaps, due to a dose/response effect, seeing that the level of exposure to VCM in their works has always been relatively low compared with works where similar surveys have been carried out. Heinl and his co-workers finished, in 1977, a survey of all the vorks in NordrheinVestfalen, which was published the same year and presented, in particular, at the 19th International Congress, Dubrovnik, in September 1978. This survey comprised j groups - a group of exposed workers, a control group, and a group of workers from the processing industries. The duration of exposure and the age-classes were taken into consideration. The results of this survey show conclusions rather different from the other surveys, in particular the British surveys of Fox and - 62 - Collier. In March 1979. however, Drs Reinl and Grosser, the authors of this publication, in the course of a meeting with Dr De Boer of CEFIC and Drs Adams and Paddle, modified the published Tables, and these changes will need to be the subject of a fresh publication. After these corrections, the conclusions of the survey appear as follows i firstly, the standard mortality ratio for all tumours is not significantly increased in Group I of the exposed subjects; secondly, there is no longer a significant increase in the number of cancers compared with the male population of Germany; thirdly, the standard mortality ratio for the tumours of the lymphopoietic system is increased in a fairly significant manner; and finally, the standard mortality ratio for the tumours of the digestive tract is higher overall and more particularly for the gastric tumours. For the hepatic tumours ineluding angiosarcomas, it seems very definitely increased. A definite increase in cardiovascular attacks'3 1 is noted, but this increase is found almost identically in the three groups compared. For the control groups, moreove(5r'7^)'', a significant increase in standardised mortality ratio due to malignant tumours of the liver and cardio-vascular conditions is noted. The standardised mortality ratio for all the tumours of an organ was not increased; nor was any significant increase in the number of tumours of the brain and respiratory system found in the produetton workers group. It was also at the 19th International Congress of Industrial Hygiene that Bertazzi, Villa and Foa and their co-workers presented an Italian epidemiological survey published earlier and covering 4,777 workers in 9 production works in various regions of Italy. This group represented ca. 86^ of the personnel exposed to vinyl chloride. The population studied comprised workers employed at the time of the survey (1975-1977), workers who had been exposed in the post and transferred to other sectors and workers who had been previously exposed and had retired, having given up all activity in the industry. Three exposure levels were defined low, medium and high. One part of the survey related to the results of clinical R&S 108682 Irs - n R&S 108683 - 63 and biological examinations for 4,713 workers. As to the mnrtality survey, -the reference period considered is given by the date of start-op of production in the various works. In the absence of adequate official registers in Italy the data can only bo indicative. In the dead workers (64, rather over 1.3$ of the total) the malignant tumours appeared to be responsible for death in 48.3? of the cases, 30$ being tumours of the liver and bile ducts, 3 of which were angiosarcomas. This percentage, 48$, is about twice the expected percentage. On the occasion of a meeting of the Medical Committee of wtriC in Milan (29 May 1979) Or Foa was kind enough to give us some comments on this survey. With particular reference to the study of clinical and biological mortality he indicated that the data obtained must be handled with care in view of the absence of a suitable control group and possible differences in the methods of examination and diagnosis. In the mortality survey more particularly in relation to cancerous tumours, an increase in standardised mortality ratio appears in certain works although the differences are generally relatively slight. In France, nothing has so far been published, but it is a gap that is going to be filled. The works doctors in French VC/FVC production works have formed themselves into a study-group and are not letting this question slide but are patiently collecting, sometimes with great difficulty, the documents which will enable them to make a survey of the deaths occurring among vinyl chloride workers so as to make an assessment of incidence. They published, at the Dubrovnik Congress, in September 1978, the whole of the clinical information on the 10 French cases of angiosarcoma then known; they have contributed to the 3tudy material of which Prof Flamant and Mme Tirmarche are about to tell us; the mortality survey carried out by my friend Dr Pierre and Dr Tassignon at the Tavaux works is a good illustration of this effort. - 64 c. Solvav studv at Tavaux (Paper 6 - Dr. Pierre) At tbs Tavanx works in the Jura where the Solvay group have polymerised vinyl chloride since 1953t an epidemiological mortality survey was carried out on 1,482 workers exposed to monomers during their employment in the works between start-up in 1953w ' and 31 December 1976, The collection of data was carried out at the works by Personnel and Production Departments and the Medical Department. The object of our survey was to establish the effect which exposure to vinyl chloride in the course of employment could have on the health of the personnel exposed for 24 years of VC and PVC production in this works. The number of deaths appearing in the course of the period considered is compared with what would be expected in a control population having the same sex, the same age-group distribution and living in the seme historical epoch sad whose mortality-rate is judged to be normal. The most accurate('59)' approach was to choose for each subject exposed to VC a control of the same sex, age, job, smoking and eating habits and socio-professional class and living near the first. To speed up the survey and produce it before the end of 1976, however, we mode use, as in analogous surveys, of the mortality-rate of the French population published in the WHO world health statistics yearbook. The survey covered all male workers - manual workers, foremen, office-workers, salaried staff - who were exposed to the monomers in the course of their duties in the VC synthesis and polymerisation plant and in the compounding plant up to packaging and storing. (6o) The laboratory and polymerisation pilot plant were also included. The maintenance teams and the personnel involved in the production of vinyl chloride/ vinylideue chloride copolymers were also added. The works Personnel Department has records permitting an accurate statement of the persons exposed to be made. R&S 108684 1,482 persons were recorded in this way. An individual record was set up comprising the name, forename, date of birth, where relevant the date of death, the date and period of employment in the various departmentsof Plastics Division, the posts held, and, where relevant, the diagnosis of the cause of death. 6 persons whose job was insufficiently well known were discarded; no deaths had been - 65 observed in these cases. 5 women, including one death, were excluded from the statistical calculations because there were too few of them. Finally, 160 persons had to be rejected because it was impossible to discover whether they were alive or dead at the end of the survey (we shall return to these Later). The deductions therefore leave 1,311 records which were used. The exposure was characterised by its intensity. In the absence of exact data for the individual VC exposure levels in the past these exposure-levels were estimated from the jobs held while working in a polluted environment. A detailed career history to within a month or so^2^ was obtainable from the works Personnel Department. A study of the development of job-definitions resulted in the isolation of six typical jobs, from the most to the least exposed; 1 Autoclave cleaner and emptier and latex/slurry filtration charge-hand^^ 2 As above, on more modem plant 3 Autoclave maintenance worker k Foremen and workers other than as specified above, working in the polymerisation halls 5 All foremen and workers working in the halls for the synthesis and liquefaction of VC from acetylene or in the charging and discharging of vinyl chloride tankers and autoclave workers in the IXAN5 (copolymers) section. 6 Finally, all other jobs not specified above. In production, the task of reconstituting the exposure-levels that had existed in the past from 1953-1976 was undertaken, the technical development of the various shops was retraced with the dates marking changes in working procedures or R&S 108685 technology (air-blasts' ' in the autoclaves, automatic hydraulic washing, suetion^^ on the autoclaves etc), thus defining 5 different periods. By- taking account of these elements and of measurements carried out sporadically we were able to establish grids giving, by department and job, the probable changes in the mean VC content with course of time. The mean contents were subdivided into 3 degrees of intensity, grade 1 corresponding to a "slight1' exposure, grade 2 to a "medium" exposure and group 3 to "severe" exposure. For a given job, the degree of risk has changed in the course of time (in the 5 periods defined) as a result of the improvements resulting from the technical precautions. Exposure-index The exposure of every worker was characterised by an index as defined in the paper by Tabershav et al., 1974. This index has the dimensions of a time-weighted average which is not expressed in concentration-units but in degrees of intensity on a scale ranging from 1 (the lowest) to 3 (the highest level). This indexlater called the exposure-index - is calculated by multiplying the number of months spent in a given job by the degree of intensity attributed to this job at a given time, summing these products aud dividing the total by the number of months of exposure to VC in the course of the subject's eareer. Duration of exposure The exposure of each worker was characterised also by its total duration, defined as the sum of the partial durations of work in contaminated environments in the Division. The time in the individual's career which would be spent off production was systematically discounted. - 67 - The drawing up of the alive/dead record required a substantial effort in tracing those who had been discharged or had resigned, who had in some cases left the country. It was, nevertheless, carried out with remarkable efficiency by the works Medical and Personnel Departments. About 8% of the individuals were contacted by post, by means of a questionnaire. The vital status of l60 men who had been discharged or had resigned (10.3 % of the 1,482 individuals) could not be established. These "non-respondents" are apportioned as follows; Exposure-index <2 >2 Duration of exposure J 5 years 5<i '15 years >15 years U9 21 2 10 S 0 Analysis shoved that they had been, on average, exposed for a shorter period (3.1 years as against 9.5 years for the personnel studied). This group was excluded from the calculations, as in the epidemiological surveys already oublished. This "non-respondents" problem always turns up in this way in an epidemiological survey. Do they constitute a random sample indistinguishable from the personnel as a whole - and thus capable of inclusion therein - or is this group characterised by an ahnomally high mortality from the fact that sensitive individuals would be spontaneously removed from the hazard - possibly in vain? In this case, there might be a segregation of the deaths in the group of those who had been discharged or had resigned who could not be found. This question remains unanswered in any epidemiological survey. R&S 108687 List of data - 63 - The following information was known for each of the individuals involved in the survey : name, forename, vital status on 31 December 1976, date of birth, date of death (where relevant), date of fir3t exposure, date of final exposure known on 31 December 1976, duration of observation (in years and months), duration of exposure (in years and months) and the index representing the mean exposure-level in the course of the career of the person concerned, R&S 108688 TREATMENT OF THE DATA Man-years of observation and standardisation bv age, sex and year The presentation of the national mortality statistics necessitated transformation of the crude data collected at Tavaux. These statistics indicate the number of deaths occurring each year in the French male (or female) population taken as a whole or split into 10-year age-groups. Each man-year contributed by a given individual is independent of the other manyears he contributed to the survey, and is thus considered as the experience of a year of life by a man (the same one, of course) whose exposure to the toxic material outside the year considered is simply ignored. This hypothesis, on which for a given individual the years of exposure constitute a cumulative risk to health is the null-hypothesis which the epidemiological survey is supposed^^ to reject or accept. Up to 31 December 1976, each worker at Tavaux subjected to the survey contributed each year to the epidemiological survey by adding one year of life or one man-year. I Each year, these man-years were distributed into age-groups so that we could i compare the mortality in the population under observation and in the control population for equivalent age-groups. The age-group distribution is, in fact, very different in a working population from that which exist3 in the national population. So as not to reduce the numbers too much, we considered 10-year age-groups. - 69 - Exposure-nan-years The total man-years of actual exposure to vinyl chloride is less than the total man-years of observation. On 31 December 1976 a man could very veil have been "observed" to be alive, having ceased to be exposed to vinyl chloride for several years (discharge, resignation, transfer from the VC/PVC sector). During this period, while contributing to the man-years of observation he would not any longer have contributed to the man-years of exposure. Observed deaths, expected deaths and standardised mortality ratio Every year, the deaths in the national population were totalled and compared with the man-years of life contributed by the various age-groups of the population. These mortality ratios standardised by age and sex are considered as standards in this study. The man-years of observation contributed by the Tavaux group were distributed in Tables of which the columns represented the 10-year age-groups. If, for example, a worker entered the survey in 1968 at the age of 32 and is still alive on 31 December 1976 he will have contributed about 8 man-years to the survey, of which 3 will have been spent in the age-group 25-34 years and the column 1935-1944 for the years of birth and the rest in the age-group just above this column(''6a)1 . The general and specific mortality-tables we took as our standard were set up in the same way on the basis of the national statistics. The figures are specific to sex,age-groups, and the historical epoch defined by the conjunction of the birth-year groups and the age-groups^^. The statistics for 1936, 1961, 1968 and 1974 were selected. Multiplication, case by case, of these two types of Table gave the expected number of deaths, that is, the number there would be in the group of workers studied if the risk-factors threatening them were no different from those affecting the general population. The ratio of this value to the expected deaths, multiplied by 100,^"^ constitutes the standardised mortality ratio. R&S 108689 R&S 108690 i m* t - 70 - Sub-groups For better interpretation of the results as a fhnetim of risk due to employment. the group was sub-divided into sub-groups. - firstly, by considering groups of individuals of exposure-index less than or greater than (or equal to) 2 - secondly, by considering groups of individuals contributing durations of exposure less than or greater than 5 years, or less than or greater than 15 years. Statistical analysis The comparison between the observed and expected values was made by assuming a Poisson distribution whose mean is equal to the expected number of deaths. (Geigy scientific tables). Results Characteristics of exposure to vinyl chloride at Tavaux The results of the surrey covered 1,311 men, totalling 15,458 man-years of observation and 12,470 man-years of exposure to VC, at various degrees of intensity (81)J of the man-years of observation). The most-exposed jobs (1--3) contributed 11$ of the man-hours of exposure, and the least exposed jobs (4-6) contributed 89$. Job no. 6 above, which only ever involves minimal exposure to VC, contributes 69$ of the man-hours of exposure. The mean duration of exposure was 9.5 years, and we calculated for each standard job the distribution of these years of exposure for a hypothetical average worker. It emerged once again that the group examined at'Tavaux works was, as a whole, in essence made up of individuals holding low-or medium-risk jobs. According to the intensity of exposure we find that only 7$ of the exposure manyears are spent in highly contaminated environments (degree of intensity 3) against 18$ in a moderately polluted environment and 75$ at a low exposure-level (degree of intensity l). Degree 3 apparently corresponds to a time-weighted average - 71 concentration of 200-500 ppm in the air; degree 2 to concentrations of 50-200 ppm; degree 1 to concentrations- of less than 50 ppm and, more often, less than 10 ppm. These figures ore proposed as the order of magnitude of the mean concentrations representative of the 3 arbitrary degrees of intensity which had been selected for estimating the exposure-intensity. As the health hazard depends both on the duration of exposure and its mean intensity, ve distributed the group in accordance with these two paremeters. lie found again that the low exposnre-indices were preponderant (81% of the personnel had an exposure-index of less than 1.5). During the analysis of the observed mortality it will therefore be absolutely necessary for the mortality of distinct sub-groups to be specifically isolated so that the mortality specific to highly-exposed individuals can be assessed in isolation. R&S 108691 Causes of death and analysis of mortality 25 deaths were observed, including 3 cancers, one of which was a hepatic angiosarcoma. The Table sets ont the causes of death classified by the corresponding number of the International Disease Classification (Classification Internationale des Maladies, CIM), revised in 1965. Of the specific causes, 2 diagnoses were not analysed : septicaemia and acute food-poisoning. The reason is that the corresponding heading of the CIM, numbered B 18 in the 1965 edition, was defined differently before 1965, so that ' (71) statistics comparable at -different'. ' periods cannot be reconstituted. It is most improbable that the diseases of heading B 13, "all other infections and parasitic diseases" have any point in common with VC. The standardised mortality ratio for the complete personnel is only 51 (25 deaths observed, as against 49 expected), which is very significantly less than expected. The overall mortality due to cancer is within the normal limits : 3 R&S 108692 IB? T - 72 cuts observed as against 9 expected, but one of the cases is a hepatic angiosarcoma. The number of suicides is slightly greater in the personnel as a whole, but the difference is not significant. Mecrotic^2^ enteritis is such a rare cause of death that the case which occurred at Tavaux definitely deviates from the normal; it is unconnected with VC. If we take into account the sub-groups sub-divided in accordance with exposureindex and duration of exposure we see that the hepatic angiosarcoma occurred in the group most highly exposed (index ^ 2) for the longest time (^" 1? years). There is a slight excess of suicides in the group given a slight exposure for less than 5 years, but the difference is not significant at the 0.05 level. Firstly, the personnel are relatively young with a mean age of 34. There are only 25 deaths for over, 100 persons. In the survey by Siren et al, 1976 which my friend Lazard quoted, there were 58 deaths in an exposed group of 771 persons Ott et al., in 1975, found 88 deaths among 594 persons exposed to PVC^^. The age-structure of these populations was older and gave a greater number of deaths. Secondly, there is a low overall mortality. The standardised mortality ratio of 51 lor the Tavaux group is a familiar observation in industrial epidemiology. Several factors are combined in this result. Industrial work is selective, requiring more robust health and rejecting the handicapped and sick from the start; work in a potentially toxic environment, moreover, presupposes medical selection for the job. The mortality-deficit thus artificially created was called the "healthy worker effect" in 1976. It should be noted that the death due to hepatic angiosarcoma occurred in a 42 year old factory-worker employed directly in the autoclaves since 1957. As to the other cases of death, in one of the two cases of cerebral cancer observed the exposure to vinyl chloride was characterised by an index of 1, the lowest possible, and in the other case, in contrast, the exposure had been heavy. The two cases of Hodgkin's disease proved not to be related to the exposure-intensity either (exposure--index c&.l). Finally - 73 (74) in the Tavaux group, there is nothing to confirm the much discussed' ' idea that the VC would cause an excess of cancers other than hepatic angiosarcoma. This conclusion must he tempered by the fact that the population studied was relatively young. It is now evident, thanks to world-wide epidemiological surveys as well as those carried out in our group, that hepatic angiosarcoma is not a uniform threat to the whole personnel working on monomer synthesis or polymerisation. The risk is greater for personnel exposed for a long time to high doses in the past. D. Discussion of capers Prof, Truhaut My question is an extension of^^ the question I asked M Bonnefoy. I should like to know what you mean by "mean exposure index"/ Dr Pierre The mean exposure index was arbitrarilyfixed between 20 and 200 ppm, given that we did not analyse the atmosphere at that date. Prof. Truhaut Is it a time-integrated average? Dr Pierre It is a time-integrated average. Prof, Truhant Are the deviations from the mean likely to be very large, or not? Dr Pierre Unfortunately we were completely unable to study the deviations at this period. R&s 108693 - 74 Prof. Truhaut This morning we heard Prof. Maltoni lay down^*^ the exposure-levels for us in a very precise manner. It is evidently very important to try to determine the dose/effect relations in a quantitative context, and this is the principal object of the epidemiological surveys. Dr Pierre In historical surveys that was not possible, and the exposure-indices would only be established by a study of the jobs held at different periods. Dr Chalvay I have no experience with vinyl chloride, but I can give you a personal experience with tar. You take people in the same job, they have the same dirt on their feet, hands and face. Some of them clean their hands with moist earth, like peasants do, and others, more knowledgeable, wash their hands in petrol, which is the painting technique used for the experimental stimulation of skin cancers. The results are falsified. Vinyl chloride is a liquid when stored, but boils at -13C. It is extremely volatile, and we can estimate that the people who go to the cloakroom are completely free of it. Someone just spoke of cleaning the autoclaves. Are they ventilated, and how? And where do you send what comes out? Dr Pierre The autoclaves, before opening, are aubjected to reduced pressure to purge them as completely as possible of residual traces of vinyl chloride. Moreover, now we know of the toxicity of vinyl chloride, the people, as a supplementary precaution, enter for much shorter periods since cleaning has been automated, and they no longer enter without a self-contained mask. Question (?) - 75 - M, Pierre, yon skated over the problem of smoking habits. Given the dose of carcinogen absorbed annually by every smoker inhaling a packet a day, I ask you : Do you, in your statistics, make a distinction between smokers and non-smokers'? R&S 108695 Dr Pierre We did not do so in our first statistical work, but it is really necessary now, given the precautions taken for doses which are small in comparison with the enormous doses derived from cigarette smoke. I think drinking habits and the various stresses of industrial work would have to be taken into account. Dr Lazard As for France, all the cases of hepatic angiosarcoma have been collected as they are found at the Comite* Francais. A report is then made through M. J.-C. Thomas to ARE and at European level on the details relevant to duration of exposure, age, and the nature, causes and circumstances of the diagnosis. The ARE is the Association des Productsurs de Matieres Plastiques, which is affiliated to the Federation des Industries Chimiques Europeennes, which we have mentioned before. Dr Stafford, who is here, keeps a very accurate record of all cases of angiosarcoma in the world. He is in contact with correspondents in all parts of the world. S. Protocol for French National Study (Paper 7 - Prof.Flanant and Mme Tlrmarche) Prof. Flamant As an epidemiologist of long standing, I am delighted to hear it said that epidemiology is going to have to provide the solution to a whole series of problems, but at the same time, I am afraid there are numerous difficulties. The participation of >4ne. Tirmarehe and myself in this field of research is fairly recent - it goes back just over a year. I must tell you that our present contribution is extremely modest, being limited to the results of an historical survey, but it was built on our (78) plans and hopes for the future. - 76 I should like first to recall a fev principles of epidemiological surreys. Whatever the survey technique the result may always be summarised as in the following Table. Ill Sot ill Exposed A C Unexposed b d a+ b c +d a+ c b+d X= a+ b + c + d It is composed of four cases with four groups of individuals; 1 People who have been exposed to the hazard (here, vinyl chloride) 2 Dhexposed people 3 People we call "ill" 4 People we call "not ill", who do not hove the disease studied. It is tables of this type that statistical analysis eventually has to deal with, whatever the method used to collect the information. Every effort will be made, (79) with these data , to measure the exposure to the hazard with all the difficulties already mentioned and common to all surveys (when we make smoking surveys it is difficult to know how mnch people smoke, but still mo re difficult to know how much they drink). -1 certain imprecision is tolerable if there is no relation between this approximation and the pathological condition we are going to measure. If we measure the exposure to the hazard by the fact that the people are or are not ill, or if we say that they are ill because they have been exposed, we are going to have the result before we have even commented on the survey. That is when this great idea of bias comes in; bias is nothing more than a systematic error which associates a priori the exposure with the hazard and the pathological condition we are measuring, which obviously falsifies the results. - 77 - There are several ways of classifying surveys. The first way concerns the chronological aspect. The survey is retrospective if it is set up at a time when the pathological condition has come to light (this is the case with people who have a pathological condition of the liver which we compare with controls); itis prospective if it is set up before the disease is found (wo then take people of whom we do not know whether they are ill or not, measure this exposure to the hazard, and, eventually, they will separate of their own accord into ill and not ill). The other way of characterising surveys takes into account the methods of setting up the groups we are going to study. - Firstly, there is the representative sample of a population. For example, in surveys of smoking, the whole body of English doctors was taken, accepting that if a relation between smoking and cancer is found in doctors this relation holds for the rest of the population. In an American survey, a million people were taken, the smokers and non-smokers being distinguished, and they were followed Up far several years to see if they were ill or not. In the particular case of a survey on vinyl chloride the trouble is that there will probably be very few people exposed to the hazard. - There is another way of tackling the problem, which is to take exposed and onexpoaed people, providing we can define "exposed" and "unexposed", and either consider them retrospectively or pick up the pathological condition prospectively. - The final, well-known type is the type of the control-case survey where we take people who have, for example, a pathological condition of the liver, whether they are hospitalised or not, and look for controls, with all the difficulties which that involves. R&S 108697 R&S 108698 - 78 - Mme. Tirmarche ia going to tell ua in a moment about investigations of documents of the hiatorical type. Theae are not surveys, properly speaking. The subjects being already dead, we cannot anyhow try to reconstitute their history. But we never know why any given person drops out of sight. It ia very difficult to investigate past events, and, in addition, information noted in a file can never have been completely independent of the event we are studying. There may be an association between the exposure to the hazard and the pathological condition. These are therefore tasks which are booby-trapped at the start and may give indications but must be examined with great care. We are therefore going to begin there and lime. Tirmarche is going to give us some indications of the analysis of the filea that she has been able to make. Mne, Tirmarche We are faced with the causes of death collected by the works doctors at di 1 -ent works. These dead people had all, in the past, been exposed to vinyl chlor We had their duration and degree of exposure, but it was impossible to wei$; the exposure aa a function of the number of years. In fact, it often happe , that a person haa had a job with a high exposure-level for a very short time and s therefore coded 3 + (maximum exposure) while for the rest of the time he has been subject to much lower exposure. I attempted to make two separate studies, taking either degree of exposure or duration of exposure into account. We were then faced with two groups of people; those who died of cancer and those who died of other causes. I have classified the two groups by age-group, and I have picked at random from within the groups of people dying from causes other than cancer one person of the same age-group (+ 5 years) as the person having a cancer of known localisation. R&S 108699 - 19 - STUDY OF THE CONNECTION' BETWEEN DEATH FROM CANCER AND EXPOSURE TO VCM/PVC Each subject dying of cancer is matched according to age with a subject dying of another cause. - Liver cancers Significant difference pc.0.05 - Hepatic angiosarcomas Significant difference pc.0.05 - Lung cancers Significant difference p^.0.05 - Cancers of the digestive tract Difference not significant (stomach, intestine, rectum) - Cancer of the upper respiratory/digestive tract Difference not significant (larynx, oesophagus) (Wilcoxon test on matched series) Of the 6 cancers of the liver, I was able to observe a significant difference in the duration of exposure; the liver canc.er cases had been exposed for significantly longer than the group serving as their control. The same results were obtained for the hepatic angiosarcomas (ll at that time) and, a rather surprising thing, we also observed a significant difference for the lung cancers. In contrast, for the cancers of the digestive tract, including the stomach, intestine and rectum, I was unable to show any significant difference from the controls, and the same was true for the cancers of the larynx and oesophagus combined. Cancers located elsewhere were not studied because the cases were too few. These results it is true, have only an indicative value which must be open to dispute^^ because we know nothing of the other aetiologieal factors for these cancers. We do not know whether the distribution of smokers was the same between the controls and the cancer cases, what was the quantity smoked, or the alcohol consumption. Moreover, since all these people were from an industrial environment they had certainly been exposed to other products which may also have a carcinogenic action of which we are unaware. I should like to say that we have here a type of "ultimate'1 retrospective survey, given that we are trying to recover simultaneously l 00 CO o 00 -4 o o - 80 - the duration and degree of exposure. Aa for the degree of exposure. I observed no significant difference between the concer-caaes and the controls, whatever the localisation. I repeat that this study can have only an indicative value and give us lines of research for a later survey. The biases of a retrospective survey may be very large. Faced with a person dying from hepatic angiosarcoma we are forcibly led to a thorough investigation of the duration and degree of exposure of this person. Are things the same for the person killed in a road accident or dying from some other cause? I think this type of study never gives an exact answer to the questions we may ask, and it would now be advisable to launch a prospective survey, which M. Flamant is going to talk to you about. Prof. FI amant Our plan is to conduct a survey, the draft of which, now being edited, will have to be the subject of discussions at the end of Ibis month, the intention being to start the survey at the beginning of 1980. This survey will, in principle, be carried out in 10 or so works currently handling vinyl chloride as the monomer or polymer, in very close collaboration with all the works doctors of these works. The first major problem discussed was the choice of ths population on which to carry out the survey. We had to find a population which was or had been exposed relatively severely (whereas now the exposure is reduced to very low levels) so as not to have to wait many years for the results. We had to try to profit from this unfortunate circumstance which led to people having suffered relatively severe exposure and so take a rather older age-group which had the advantage of being close to the age-groups for which the incidence of cancer is greatest. For the moment, we have chosen to work on a population of men aged 40-55, not too near retirement, to avoid the difficulties of tracing people who have left the works or left the area. Of the three survey methods ve are moving towards('82)' a study of the "exposed/unexposed" type. What we should like is to find, as controls, healthy people of the same ajje-group who would be - 81 interrogated and examined under the some conditions by the same doctor. It would also be necessary for these people to be employed in the same works as the people exposed. We think these controls would be better than people taken at random from the general population. There is a whole series of important factorsi apart from these studied, which a priori differentiate a factory population, often very localised in a given region, from the general population as a whole. There will be the problem of exposure to chemicals other than vinyl chloride which it would be better to try and avoid insofar as ve want to find an unexposed control population, but we must not deceive ourselves too much; I believe the simplest thing will be to note this exposure carefully if it exists, and takeit into account in the statistical analysis. Here, in outline, is the problem of the choice of the population to he studied. As to the collection of the pathological data, there will, of course, be the possible deaths and their causes, but the survey would need to apply itself to specifying a certain number of morbidity data with the co-operation and active assistance' of the works doctors. The examinations will be mode, as is already the case, by the works doctors, with precisely the seme^8^ attitude whether they are dealing with exposed or unexposed people. A questionnaire will be filled in at each examination with - 1 general information of the type! age, civil status, place of residence. -2a measure of the exposure to the hazards, that is, the different stages of the industrial career, making every effort to take the chronology, the duration and intensity of this type of exposure into account in the hope that (85) it will be possible with, ail the seme' , maximum precision for past exposure, to arrive at a valid codification^8*^ of this exposure to vinyl chloride; R&S 108701 R&S 108702 - 82 - 3 * standard questionnaire on the consumption of tobacco and alcohol; there, again, we shall have to wait and see how things turn out, it is not always easy; - 4 The various pathological events which may occur with each of these individuals. All in all, we shall need to continue, in spite of the difficulties this may cause, to follow up the people even if they leave the works for any reason. . Only a trial period will be able to tell us whether we can eventually meet these objectives or not. To conclude, I feel that we can only accept the results of the work on this subject (st) which has already been done as being of indicative type ' . Apart from tha special case of angiosarcomas nothing is yet settled one way or the other. If we now wish to make a substantial contribution which marks a decisive step we shall inevitably have to proceed by way of this type of survey which is very difficult to conduct, which is probably why there have not been many of this type dane^^. 7. Discussion of preceding eager X think we can say that the great difficulty of epidemiological surveys is to group all the factors which may be involved, if only for the question of exposure. Tou are, perhaps, going to have information on the possible content of the airbreaided, but I believe that that will not be enough, and this morning, our attention waa sharply drawn to the difference between dose and concentration. We hod arrived at the dose/effect concept and it would have been interesting to calculate from the inhalation what was the weekly dose which bad no effect. 3y taking the air consumed by the animals into account we might, perhaps, have calculated that. In the case of man, we know that he consumes about 15--20 ni? of air per hour, but when at work on an intensive job he greatly exceeds this quantity, so we have to allow for a much larger consumption. i> Prof. Latarjet - 83 - When I presented proposals to the Conseil Superieur d'Hygiene to limit the dose of ethylene 1 distinguished a bracket ranging from the individual working in an office to one doing a physical job whose pulmonary ventilation is increased. That is why the doses proposed allowed a factar^"^ of 2^ so as to give reasonable coverage of the conditions obtaining. This is a factor to take into consideration. 5. concluding discussion I think it is the Chairman's j0b to open this discussion; if you will allow- me, I wish to begin the questions by recalling a phrase Prof. Maltoni used this morning which I consider very important. He said that in these problems of chemical carcinogenesis the qualitative aspect becomes less and less important and that it ia the quantitative aspect wo must consider. It^^ is certain that the qualitative aspect retains some importance, for example when we produce new substances and have to know if they are or are not carcinogenic. You are aware of the proliferation of methods based on simple microbiological testa designed to give rapid presumptive evidence of any carcinogenic capacity, but it is very evident that what matters is not to know in this way whether a contaminant is carcinogenic but to know the quantity already present and, above all, what are the additional quantities allowable when it is an indispensable contaminant, that is, a contaminant whose benefits seem to outweigh the hazards. One of the reasons why this quantitative aspect is becoming more and more important is the increasing accuracy of the methods for detecting carcinogens. These methods are becoming so sensitive that practically everything becomes carcinogenic. We now know how to detect benzpyrene in a puff of cigarette smoke. I do not think that if the whole population were forced to take a single puff at a cigarette iu the course of their lives we should have lung cancer. Squally, we find benzpyrene in bread; ve are not going to ban bread. This stress on the importance of the quantitative was repeated this evening by M. Bonnefoy, who insisted on the R&S 108703 i i - 84 - importance and even the necessity of comparing a given hazard with other hazards. Quantitative comparison becomes indispensable so as both to obtain the maximum protection for a given effort and to be in a position to study the total hazards resulting from joint exposure to several geno-toxic substances, that is, mixed exposure. In this connection I should like to contribute very rapidly to the discussion a finding which results from a different approach and again raises problems of extrapolation. R&S 108704 You will know that in certain laboratories, including ours (Dr Averbeck), attempts ore being made to determine on the basis of the lesions produced equivalences between a dose of ionising radiation expressed in rads and a dose of a geno-toxic chemical. Substantial studies of VCM have been made. It is evident that the equivalence found is baaed on various tests which are always genetic tests, in particular the induction of mutations in bacteria, yeasts and human cells in vitro. The equivalence found depends greatly on the system considered, but by comparing the values found for these various systems we arrive at an average value, a sort of centre of gravity. Appendix^*^. (Please refer to Averbeck's report in the If we adopt this equivalence as an approximation('192)' we come to the conclusion that a worker exposed for 8 hours a day, 40 hours a week and 40 weeks a year to an atmosphere limited to 5 ppm (which is a-currently accepted rule), or 5 ppm for 1,600 h, receives the equivalent of 40 rods. I remind yon that the law allows 30 rads per annnm for workers exposed part-time^ (94) and 3 rads when continuously' ' exposed. You see that the permitted annual dose of 40 rad-equivalents for VCM is close to what is currently allowed for radiation. We may say, then, that the limit of 5 ppm which the workers are permitted appears reasonable in practice and scarcely open to criticism. If we vent down to 1 ppm, or 8 rad-equivalents per annum, we should be able to consider ourselves completely safe on the basis of what is allowed for radiation. Let us R&S 108705 - S3 recall that the doses allowed for radiation have been the subject of detailed discussion for 25 years and that they currently correspond to a philosophy we can call conservative, meaning that whenever ve are in doubt we err on the safe side. The limits currently allowed for radiation are very safe; to take equivalent doses for a chemical is a philosophy of safety. I have one reservation, however, which is that all these philosophies have been accepted with the idea of exposure to radiation only. But it is quite evident that when we are dealing with mixed exposures we must consider the additive or potentiating effects, and sometimes antagonisms, for they do exist, but that is another problem. Messieurs, the discussion is open. Prof. Latarjet* I Ah well, if nobody is going to attack, I am going to continue on another topic. I was,very interested in the curves M. Tassignon presented this morning, particularly one showing a definite threshold, which is very important, then, at very large doses, a drop. This drop is a phenomenon which geneticists are familiar with and which caused much surprise at first. A bell-shaped curve was found for the first time in 19*0 in plotting curves for the induction of mutations in Neurospora by OV. I remember, also, obtaining a bell-shaped curve for the first virus mutation with OV, carried out in 19^*9* Since then these curves have become well known. Two phenomena may be involved. The mutant may be more sensitive to the agent than the original type and therefore be eliminated as soon as it is formed. Moreover, there may be inducible enzyme phenomena, with either the chemical inducing metabolic enzymes which transform it into an active form or the lesion produced in the nucleic acid inducing the synthesis of repair enzymes which make mistakes at thearig(9i5n) of the mutation. The bell-shaped curves found with vinyl chloride undoubtedly indicate chat this compound is involved in an inducible enzyme-system. - 86 - It seems today that we are moving towards legislation which seems to give guarantees of harmlessness, perhaps not total, but satisfactory in relation to the benefits expected from this industry. We must not look for zero risks, we must look for safety. Safety is never anything else but an accepted risk. I have seen curves stabilise, if not fall, from 1976. Do you think these reductions, which now are resulting in concentrations of the order of a few ppm, should be considered as satisfactory, or, on the contrary, no longer^^ convincing? Prof. Truhaut The fact is that we call risks socially acceptable which are not major risks in the context of the general benefit/risk concept, although, of course, the benefits are benefits to the community and not to one part of the community. M. Taasignon We have the epidemiological experience of another industry, the polymer processing industry, in very practical applications (PVC-insulated electric cables, polymer articles etc), this industry employing tens of thousands of people all over the world. Thus hundreds of thousands of people have, in fact, been exposed to vinyl chloride, because in the past the finished (qy\ contained a much higher concentration than now of residual VCM. Thi3 vinyl chloride contaminated the processing shops and the places where the bulk polymer or polymer already prepared for processing was stored, which meant that there were low concentrations of the order of 10 ppm in these shops, in spite of which no angiosarcomas have yet appeared in the personnel exposed in this way. Is this already a proof? We know that the latency-period is shorter for severe exposures, but in spite of that, there is this positive fact that we still have no angiosarcomas in processing workers. 13 (/) oo -vl o o> R&S 108707 - 87 Prof. Trahant This morning, if ve had had the time, I would have asked M. Tassignon and M. Maltoni some questions, stressing the biochemical aspects. I think, M, Tassignon, that you stressed the importance attached to the "toxification" phenomenon, and you were thinking, of course, of the formation of the epoxide (98) But besides this formation, which corresponds to the toxification of vinyl chloride, there are detoxification mechanisms, since the epoxides^^ themselves are, as you know, eventually destroyed, this destruction involving, inter alia, ' * (go) eompounta with ,'sulphydryl. groups , and M. Maltoni must certainly remember that work had been carried out in the OSA which tended to 3hov that vinyl chloride only began, to act on the receptors if at all, from the moment when the "scavengers", acting somewhat like raoppers-up of vinyl chloride, had exhausted their means of action and the vinyl chloride was free to act again. One important point was raised this morning, the choice of equivalent^11^ species for subjecting a given chemical to experiments for extrapolation to man, particularly substances having a long-term effect. Ve ore limited for observations on man by the fact that we need a certain observation-cycle , which means that of the parameters we take into consideration the biochemical parameters are of primary importance. They are primary in respect of the metabolic fate and also primary in respect of the mechanisms of action, for there are^101^ cases where animal species metabolise a ctmtpouid in exactly the same way as man although not themselves sensitive to the toxic action; this is the case for example, with tri-o-cresyl phosphate(*^, which in the rat is metabolised as in man, although the rat is not sensitive to its paralysing action, and, as you know, ve have to use hens as the equivalent species. Ve still discover equivalent species by lucky accident^10^ , but one day, we hope, we shall have parameters for selecting the equivalent species, and instead of experimenting with 6 or 7 species, we shall begin from the start by selecting, on the basis of biochemical parameters, the species most nearly equivalent for extrapolation to man under conditions which will no longer be conditions of such great uncertainty as at present. 88 Prof. Mai ton! Aa has just been said, it is essential for the planning of experimental studies in carcinogenesis to take metabolic parameters into consideration, but it is also necessary to evaluate the susceptibility of the animal expressed in a general way by the basic tnmorigram ('k2)'. Prof, Tmhant* I .Vothing prevents us thinking, my dear friend, that the basic tumorigram^2^ is itself conditioned by biochemical factors. Prof, Flamant I was struck this morning by the insistence with which Prof. Maltoni spoke of non-cancerous lesions which he has systematically investigated, saying that they could be pre-cancerous lesions. Is there a correspondence with human pathology7 Might one, on an epidemiological level, look for "infra-clinical" symptoms, if I may call them that, in any case well before the appearance of a cancer? Prof. Maltoni I think that the systematic search for precursors in the tests for carcinogenicity is an important source of information (104) which should always be determined and evaluated. This type of investigation depends on our knowledge of the pre-cancerous lesions. Many of these "precursor" lesions are known, both in animals and in man. I think we now need fundamental research in this sector. In the case of the vinyl chloride angiosarcoma we have identified pre-cancerous lesions which are, surprisingly, similar for animals and man, and of the same type as the cells we can observe in human liver after exposure to other agents (arsenical pesticides end thorotraat) which can cause hepatic angiosarcoma. - 89 - Prof. Latar.jet We have been exposed for over 6 hours to a very high concentration of VCM, I 1 do not know how many ppn there have been in this hall, but certainly a very high concentration. I do not think that the risk we have run is very high, but I am certain that the benefit/risk ratio is broadly positive. X thank all those who have contributed by their papers and their interventions in the discussions, and I thank the organisers for having given us the opportunity to take part in this very interesting meeting. R&S 108709 0U80V L - 88 - Prof. Maltoni As hoa juat been said, it is essential for the planning of experimental studies in carcinogenesis to take metabolic parameters into consideration, but it is also necessary to evaluate the susceptibility of the animal expressed in a general way by the basic tumorigram ('42) . Prof, Truhaut Nothing prevents us thinking, my dear friend, that the basic tumorigjmm^2^ is itself conditioned by biochemical factors. Prof. FI amant I was struck this morning by the insistence with which Prof. Maltoni spoke of non-caacerous lesions which he has systematically investigated, saying that they could be pre-cancerous lesions. Is there a correspondence with human pathology? Might one, on an epidemiological level, look for "infra-clinical" symptoms, if I may call them that, in any case well before the appearance of a cancer? Prof. Maltoni I think that the systematic search for precursors in the tests for carcinogenicity (104) is an important source of information which should always be determined and evaluated. This type of investigation depends on our knowledge of the pre-cancerous lesions. Many of these "precursor" leaious are known, both in animals and in man. I think we now need fundamental research in this sector. In the case of the vinyl chloride angiosarcoma we have identified pre-cancerous lesions which are, surprisingly, similar for animals and man, and of the same type as the cells we can observe in human liver after exposure to other agents (arsenical pesticides end thorotrast) which can cause hepatic angiosarcoma. R&S 108711 - 91 - 2b "analyse des correspondances" (On this first occasion, by a clerical error, this appears as "correspondantes"). In the Solvay report(TR 15925) this was translated "correspondence analysis". 27 "hnte ... snr" 23 "en avancant dans .." 29 "papillome dn pre^estomae". It is not clear what the "pre-estomac" is from the dictionaries consulted. 30 "tres rite emoussee" 31 This seems to be the sense, although the grammar is messy. 32 "infomatique" 33 "S'exprime nieux " 34 "depaasees" 35 "avoir des chilfres on ms quantification" 36 These seem to be blocks and sections of data, not of tissue, were it not for the reference to "sections" in para 4 of 1 on p8, and for what looks like a slide-tray in the drawing. 37 "S'agit-il" 33 The meaning of "bt" is not given, but is presumably Maltoni's "BT". 39 "experience", of course, can also mean "experience" 40 "je vous prie de voir lh tout lrintlret que j'ai porte a It is not clear what is meant. 41 What "small" means is not clear, unless it is "slight", possibly referring to the fact that quite different mathematical models give equally good fit. 42 "tumorigramme de base". 43 "agents sociaux". 44 "matieres premieres", strictly "raw materials", although this had already been used for "matieres de base" at the top of the Table. 45 Presumably not a special sub-class of angiosarcomas but a slip on the authorb part. 46 Whether this means "the extent to which vinyl chloride or is referring literally to the concentrations is not altogether clear. 47 "incidence", here used in a sense other than that used elsewhere in this document. 48 The grammar has somewhat collapsed here: " a ou pent encore faire", but the meaning is clear. i - 90 TRANSLATOR'S NOTES 1 "en processus industriel", What is meant here is completely obscure. 2 "Cette polymerisation ... doit s'accompagner", which suggests that the additives must be added to the reactor, which may not be what the author intended. 3 The French can only be rend as saying that the explosive limits for vinyl chloride are 4-20$ V/V of air in the vinvl chloride, which seems improbable. 4 "asphyxie des extremites" 5 "avec localisations diverses". 6 "quil en etait su point de vue animalier" 7 "meauxes d'ambiance" 3 "an courant du suiri qu'il a". 9 "intervention" 10 "masques a adduction d'air" 11 "degazage". Whether this refers to forced ventilation of the reactor or stripping of the polymer is not altogether clear in the context. 12 "cheville ouvriere" 13 "multiples" 14 "la pathologie" 15 "s'attenuer" 16 "exemplaire" 17 "foadamentalistes" IS "contraignantes" or "which will, perhaps, be binding on them" 19 "direction generale des polymeres" 20 "n'etaient pas de mise en regarde" 21 "des ouvriers et des travailleurs" 22 "deroulementde 1'expedience" 23 "code" 24 "listing" 25 "probable" seems to be required to make sense. R&S 108712 108713 (/) - 93 71 "different" inserted for clarity ("dans le temps"), 72 Or "necrosing" ("necrosaate") 73 "VC" may, of coarse, be meant. 74 Or "disputed" 75 "Ms question prolongs.." 76 "fixer", 77 "filer". 78 "elle est faite de projets .." 79 "Ces informations vont s'efforcer de mesurer.," How the data are going to make every effort to measure is not clear. 80 Simply "vinyle" in the French 81 "qui doit %tre discutes". Or "which must be discussed". 82 Or, perhaps more definitely, "we are preparing to undertake" ("nous nous somoes orientes vers"). 83 "activite" 84 "ideatique et parallels" 85 "quand memo". The force of this here is not clear. 86 "codifier". The meaning here seems to be "definition". 37 "as being"inserted forclarity. 88 "qu'il n'y en a pas en beaucoup de faites salon ce type". 89 "intervalle" 90 Or, perhaps, "He is certain". 91 Not supplied for translation. 92 "ordre de grandeur" ' 93 "portiellement") This may refer not to the time but to 94 "en totalite" ) parts of thebody and the whole body. 95 This is prestmably referring to the enzymes "mis-reading" the damaged nucleotide sequence, 96 "plus".' Presumably the negative is implied here. 97 "chlorure de vinyle" in the French. 93 "epoxine" f 33 : So J) 0o0 -N| -mk 11 ! i i i j - 92 49 "pasaionnees". The meaning here can be anything from "lively discussions" to "passionate disputes". 50 "percevoir". The meaning also includes the more active "collect, gather", bat apparently only in relation to taxes and the like. 51 "en correspondence avec". The question is whether this means the vague "in connection with" or "on a level with", the rather more definite "corresponding to" or the still more definite "in agreement with". 52 "font etat". The meaning here may be "reported". 53 In relation to what is not clear. 54 Or "large" 55 Or "important" 56 "accidents" 57 " par ailleurs" normally means "elsewhere, in another connection", and it seems that "d1ailleurs" was meant hers. 58 The French text has "1963", bnt in view of the "1953" earlier in the sentence and the reference to "24 years" this has been taken as a slip. 59 "fiddle". 60 "le hall d'essai des methodes de polymerisation" 6l "copolymeres du chlorure de vinyle et du chlorure de vinylidene". Although this could refer broadly to all VC copolymers and all VDC copolymers presumably the narrower meaning is intended here. 62 "au mois pres" 63 I"fpre^pose" 64 "soufflage dans led autoclaves" 65 "aspiration" 66 The "greater than" sign was missing in the French text. 67 "sensee". This has been read as "censee"# 68 This is not too clearly worded, but evidently the age-group column is meant and not the birth-year column. 69 '(hat is meant by "conjunction" here is not clear. 70 This, again, is badly worded and has been heavily revised. *