Document 6wL25eaBZbm6Z7nmDdKpVXz14

R&S 113787 BIO-MEDICAL.RESEARCH oooirmDOCUMENT DESCRIPTION FORM 63 Duplicate in all cards: --> 68 69 1W 76 year as-1961- File number [Right justify ru._ Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space 77 78 t Sub-Index Code 60 61 62 11 ii i3 Title of Report: end with space-hyphen-hyphen-space. Follow with Index Terms. separated from each other with comma-space. Avoid other punctuation; Source (Journal, Vol., Number, Pages, Date ) 12__________________________________________ /f7f Brief Summary 1 2______ 10 SUMMARYi 61 62 ll 32 61 62 61 62 63 64 0 ^ i R. Tc-i^t^sc^ i IMPERIAL CHEMICAL INDUSTRIES LIMITED i PLASTICS DIVISION 1 0000422 1 NOTE FOR APME VCM COMMITTEE FETING. LONDON 27 FEBRUARY 1979 PVC DUST I hop* this note will bring you up to dote on what is happening on PVC dust in the UK. 1 Tripartite Medical Meeting 24 January 1979 So for as PVC dust is concerned, this was a auch happier Meeting than we have had for 1/2 years because the Health and Safety Executive (HSE) and in particular its Enployment Medical Advisory Service (EMAS) were satisfied that industry is giving serious attention to PVC dust. Industry nay not yet be doing everything HSE would like to see us do but we have made a start. Work already initiated was reviewed and possible further work programmes were discussed as follows. 2 Literature Survey Dr Greenberg of EMAS tabled the attached paper Appendix 1 noting work reported since we had met in May 1978. He included a personal communication from Dr 8urrows of ICl on a survey of workers in an ICI PVC Fabrication unit regrettably this paper has not been accepted for publication because of defects in its protocol. This Ctintrasts strangely with the ease with which Moppet al and others of our antagonists can publish. EMAS and HSE continue to note that industry has not been able to disprove that long term inhalation of PVC dust is harmful to man. Dr Pigott of ICI's Central Toxicology Laboratory has had a literature search done on PVC dust. We have pruned the list because it contained so much marginal material and we hope to have something better available soon. 3 Survey of PVC Dust Exposed Employees at ICI's Hillhouse Works When Dr W G F Adams reviewed the work we had done in 1975/6 on ICI's Hillhouse employees examined by the National Coal Board's Radiographic Unit, he found that he could not write a- paper acceptable to a scientific journal because of lack of adequate control populations. Having net a somewhat similar problem in Dr Burrows' study and still being criticised by the HSE that we commented adversely on already published papers but published nothing ourselves, ICI have asked an independent body, the Institute of Occupational Medicine (IOM) in Edinburgh to carry out a survey which could and would be published. This work is now under way. The IOM are surveying 750 people out of a 2,400 population who have been at some time employed at Hillhouse in the period since 1 January 1967. The IOM have been given a free hand in choice of exposed and unexposed, present and former employees. In addition to full chest x-rays, spirometry, gas transfer tests etc, the IOM's industrial hygiene team will survey environmental conditions in the plant. The IOM are free to publish their survey in the medical and scientific press and indeed ICI will expect them to do so. Already there are some criticisms emerging about sampling/selection of people for inclusion in the survey. Regrettably the IOM could not devote the resources to examine the total population. The entire matter of sampling/selsction has been left to the IOM and has not been influenced R&S 113788 R&S 113789 2 by ICl. It is hoped that the survey will be reported by mid-year though it may take longer than this to get into journals. We would plead that other companies who have done regular studies of their PVC dust exposed populations should publish their findings. If you hove negative information, it is worth publishing!I 4 Improvement in PVC Dust Hygiene At same PVC plants, capital expenditure has been authorised to improve dust hygiene and HSE are pressing us for details of results of monitoring in our plants. Visits by HSE and EMAS personnel have been made to emulsion PVC plants in particular to familiarise themselves with processes and conditions. They seem however more concerned about conditions in customers' premises and were pleased that the UK PVC producers have now revised their literature to re-emphasise to customers the need for gore in handling PVC dust and for keeping as far as possible below 10 mg/m . Though they did not say so explicitly, we believe- that the survey they had asked the Medical Research Council's (MRC) Pneumoconiosis Research Unit (PRU) to carry out at a customer's premises had not revealed any respiratory disorders despite allegedly high PVC emulsion dust concentrations in the working atmosphere. The survey was led by Dr J C Wagner himself who is reputed to take the view that the exposures had not been long enough to show any - physiological effect. 5 Animal Studies The UK PVC industry is divided oh- its view about the value of a dust inhalation study on animals. The cost would be at least 500,000 for an inhalation experiment and in ICl's experience- the technical difficulties would be enormous. Moreover the choice of which "PVC Dust or Dusts" would be far from easy when one considers the differing particle sizes, surfactant coatings etc; our critics would say that Product XYZ proved to be all right but Product " with a different surface area/structure might not! After 3 years work and 0.5m expenditure, we could be left with an equivocal result which would overshadow even the most negative findings in an epidemiological survey. The question arises whether this money would be better spent in improving works hygiene. The HSE are still clearly of the view that further animalwork is required here (but it is of interest to note their very firm view that enough animals had been sacrificed on VCM toxicity work). Some UK companies are in favour since this could be one way of rebutting Wagner's claims for his own work which he has not yet published in full and also it would obviate the criticism that industry experiments on humans rather than animals. In addition to the technical difficulties of the inhalation experiment, there are some cogent arguments against the need for inhalation experiments. (a) Only one alleged pneumoconiosis case has been reported in any detail (Arnaud). (b) Many companies have x-rayed employees regularly and found no cases of pneumoconiosis. Selikoff has x-rayed many US PVC workers and found no cases. (c) In the UK, suspected cases are referred to Pneumoconiosis Medical Panels - none attributable to PVC have been reported to our knowledge. R&S 113790 3 (d) Short torn tests ot ICI's CTL have not indicated fibrosis. (e) The NI05H work on inhalation exposure of Geon 121 to monkeys, guinea pigs ond rats gave no evidence of fibrosis. NIOSH say the experiment was designed to test for fibrosis -.they don't know hbw they would overcome the problems of design of such on experiment to test for carcinogenicity and indeed they say they would undertake such a study only if human-epidemiology gave an equivocal result. (f) On the subject of carcinogenicity, Wagner's work on rots does n t appear to indicate such an effect and neither Waxweiler nor any other epidemiologist has yet produced a well accepted study in this area. The UK industry is coming round to the view that they should ask a small group of experts to construct a protocol for a PVC Dust InhalationStudy to demonstrate whether PVC dust is carcinogenic and/or fibrogenic. The exercise of composing the protocol may help in deciding whether the study is practicable. This group has also proposed a protocol for studies to assess the validity of the intrapleural injection technique as a method for testing carcinogenicity of particulate matter but no decisions have yet been made whether to commission such a study or if we do, how widely to cast around "dusty" industries for financial support. Epidemiological Studies Like ourselves, the HSE have tried to have a dialogue with Waxweiler post-Dubrovnik but failed. Everyone seemed to be agreed that Waxweiler had done an interesting but complex piece of work which deserves further study by people competent to do so. The HSE epidemiologists would like to try out the Waxweiler approach as another potential tool. They proposed a mortality study of workers exposed to PVC dust in the UK - this would :be a natural extension of the VCM study done in 1974/5. However the mixed exposure to VCH and PVC dust could be difficult to disentangle in Job histories. HSE were adamant that a survey in PVC fabrication workers would be even-more difficult. A small group of Govemment/industry biostatisticians will meet to discuss the feasibility of such a study. The HSE seem keen to do it but some industry representatives doubted whether the vast amount of work involved could be Justified*Of it avoided a whole-life inhalation study on rats it could be a worthwhile ventured) Xn July 1978 we found from Ethyl Corporation that Dr Patricia A Buffler of University of Texas would be publishing a paper which alleged an excess of respiratory tumours in PVC workers. Though Dr Torkelson of Dow has asked that I should be given a pre-print, this has not yet been received. HSE didn't know Dr Buffler or of her work. However she is known to ICI's Dr Paddle who hopes he may meet her this month at Stanford. Medical Research Council ond University Research Dr Wagner of the MRC has been provided with samples of washed and unwashed emulsion PVC powders for his animal work, (Some samples have been washed to remove surfactants,) The samples are - from BP and ICl but have been supplied under Chemical Industry Association (CIA) Code Numbers. The MRC claim that they can distinguish between the CIA codes and tell whose material they are examining^ Dr Wagner and his Director, Dr Elmes, have visited ICI's plants and expressed disappointment that they had not been commissioned to carry out the Hillhouse study. i Dr Wagner does not disclose much about the progress of hit own animal work where he must either be finding zero results or encountering problems he won't admit to us. Oddly enough in Appendix 1 Dr Greenberg does not refer to the paper Dr Wagner gave to the Pathological Society of Great Britain and Ireland in Southampton on 5 July 1978* The synopsis of the paper was as follows " the biological effects from fine polyvinyl CHLORIDE PARTICLES J C Wagner MRC Pneumoconiosis Unit, Llandough Hospital, Penarth Attention has been focussed, both in man and experimental animals, on the effects of inhalation of the gas monomer, vinyl chloride. Recently, note is being taken of the passible effects of the inhalation of the polymer in man. The particles in question are those produced commercially as 'paste polymer', having an average diameter of 0.15 microns, and accounting for. more than IQjS of the production in Britain. There are now strict regulations for the control of the monomer gas, but the particles are regarded as nuisance dust and their emission is not covered by specific legislation. Our studies on rats where both inhalation and implantation methods of exposure have been used, and examination of tissue from human cases exposed to 'paste polymers', indicate that these small particles are not as benign as has been supposed. Techniques have been developed by which these particles can be demonstrated in ordinary histological preparations, and by transmission electronmicroscopy. " R&S 113791 This is a fairly guarded statement which didn't attract any attention.. The CIA samples mentioned above will be used by Dr Wagner in injection (presumably intro-pleural) experiments early 1979. He would lik to do more PVC dust inhalation studies and it is rumoured that he is trying to get a university team (with no previous inhalation experience!) involved. Clearly progress is slow and this could in large part be related to. the immense methodological problems in this area. My own layman's view is that Wagner seems to be trying to correlate intra-pleural or intra-tracheal injection with inhalation and set up say IP injection as a quick r, cheaper test for carcinogenicity of particulates. The CIA are doing everything possible to provide Wagner and university researchers with materials and information. Is there any comparobl activity going on in European universities or research institutes? 8 Italian Epidemiological Study It is interesting that neither the HSE nor the Trade Union Congress Medical Adviser is pressing us for an explanation of Foa et al or Mapp et al papers. Like ourselves, they seem to have concluded that if there had in fact been so many PVC attributable pneumoconiosis cases in Italy, w would have had much more information from the Italian companies concerned and the press/scientific literature would have publicised the cases. 7 vv;.;, .. / '.yy-";'.":r'.;':-;v>:'.::y -^J^Y-sr:=yrv^V.`-- i *-'-. R&S 113792 5 9 PVC Staining Technique Some time ago my colleagues Pigott ond Wilson in our Control Toxicology Laboratory developed a staining technique for PVC particles. This technique has been made available to Wogner, Arnaud, Dr Torkelsorv of Dow and more recently to Dr Kammuller to be given to ClVO. We hope this technique will be subject of a paper in the Journal of Stain Technology and prove useful in identifying PVC particles in path slides. J J Stafford Circulation APME VCM Committee UK CIA VCM Committee PVC Dust file JS (10) Mr G J Sleddon Dr B Bennett, Hillhouse Dr F W Best, Millbank Dr T R Torkelson, Dow Dr W Davis, Goodyear Mr R N Wheeler, UCC Dr M N Johnson, BFG Mr A G Wheeler Dr J Conbere ICl Americas Mr M J S Gibbons JS/MJE/DS0-107 6 February 1979 ' , . 'T'O'-Vy^. " "" ' v :C%p; V^:'-y - ^ ' ' ' 7: r r VoLMQNARY DISEASE IN THE VC^/PVC INDUSTRIES - I . , 1 Some Further Reports Studied Since yny !` Vi Some Biochemical and Histopathological- Changes Induced by PVC Duet /5eon-l2i7in J .-:! * t ' `j<1 ' Ret Lung, Agarwal, D.K. et nl (197ft). Environmental Research, 16, 353-314. ------------------------------------------------------ -------------------- ------------------------- "Enzymatic and pathanorphologic alterations in rat lungs were studied at different time intervals un* to ifiO daysi after a singl,e intratracheal admi'nistration of 25 mg of polyvinylchloride dust. The activities of two energy-linked enzymes, succinic dehydrogenase (SDH) and adenosine triphosphatase (ATPase), and three lysosomal enzymes, acid phosphatase, glucuronidase, and ribonuclease, were significantly increased in the early period and then started to decline, nie activities of SDH and ATPase reached control values at 150 days, while those of the lysosomal enzymes remained significantly higher- up to this period. Hiatopathologically, the pulmonary response was in the form of acute inflammatory changes- during the early stages of dust burden, followed by the development of granulomatous lesions containing small amounts of stromal elements." No significant difference was stated to have been observe^ in the rate of mortality of control and PVC/Administored rats, no details are given of population sizes, pattern and causes of death or histopathology other than of lung tissue. Malignant Tumours of the Liver and Lungs in an Area with a PVC Industry. Saric,. M. et al (1976). Environmental Health Perspectives, 17, 189-192 "The incidence of malignant tumors of the- lung' and bronchus and of cytologically confirmed primary malignant tumor of the liver was analyzed for a 4-year period in a city with several factories, including a PVC industry. Prior to the study of two cases of angiosarcoma of the liver were diagnosed in workers employed in PVC production. The total incidence of analyzed tumors was only slightly higher than predicted. The tumors of the liver recorded did not show any dependence- on place of work or -! residence. During the period of observation, malignant tumors of the bronchus 'i .1 (lung) were not recorded in the PVC industry. Their rate in the area in which ; the PVC industry is situated was approximately the same as that for the entire city area. The study does not indicate that the occurrence of malignant tumors other than angioaarcoma is associated with exnosuro to vinyl chloride." 3D 0) CvOj CO CO -. - * * -2- The period of observation was too short for n !f'''initive conclusion to be reached: furthermore a substantial proportion of perse with lung cnncer could not be adequately investigated. An Epidemiological Investigation of an Excess Lung Cancer Bisk in a Synthetic Chemical Plant. Waxveiller, R.J. et al (1978) N'lOSK While this does not conclusively demonstrate a causal relationship between exposure to PVC dust and lung cancer, it indicates such a possibility and' merits further consideration. Works of Wagner, J.C. In a series of personal coanunieations, he has reported the presence of PVC particles in lung sections obtained from PVC workers. In his animal studies, intra,- pleural instillation has shown there to be dissemination with evidence of particles present in lung sections. His inhalation study on rats showed there to be pulmonary fibrosis and multiple granulomas. Pathology of Polyvinyl Reains. Broussard, 0. (1969) Folia,Medica 93, 102-108 This paper claims that PVC reain powder on inhalation accumulates in the lung with a consequent loss of alveolar surface. He considers the powder insoluble and inactive. He further considers that when mixed powders are inhaled pulmonary fibrosis msy develop with a restricted ventilation defect, alteration in the alveolar-capillary permeability, and as obstructive or combined type of defect in the- case of pulmonary fibrosis. The radiological appearance is said to be reticulation with enlargement of the hilar lymph nodes or a oicronodular appearance without enlargement of the hilar lymph nodes. Clinically, chronie bronchitis with progressive respiratory insufficiency alternating with periods of remission of the symptoms are said to occur. Unfortunately there aieno hard data to support these contentions and although several references are listed at the end of the paper . it is uncertain as to what support they give to the asseverations of this paper. Radiological and lung Function Studies of Workers Exposed to Polyvinyl Chloride Dust. Burrows, O.E. et al (19787) Personal Covmninicntion Summary The results of a number of studies on the effects cf PVC dust both in vitro and R&S 113795 -V in animals and man have been conflicting. The present studies performed in 1976 ^ smd 1977 consist of chest radiological nt:d Lung function assessment of male "j , workers exposed to HVC dust. In '976 Chest X-rays were taken on 179 men exposed | ahd SJ men not exposed to PVC dust. In "^77 r09 men; 104 exposed to PVC dust '] only, 11? exposed to solvents only and 39^ exposed to a mixture of both, app-eed ;)j to fill in the MRC questionnaire- on respiratory- function and performed simple spirometric tests. j The radiological survey showed no pneumoconiosis and the proportion of all j abnormalities was the same in the two grouos. Lung function, forced expiratory volume (FEV,, q) and forced vital capacity (7VC) were determined for members of each of the three groups. No differences were found after allowance was made for age, height and anoking. ; When service and smoking effects were separately considered, the latter is shown to be the dominant cause of reduced function. Ii Work with PVC dust has not produced deleterious effects on lung function in this | study." i There are a number of observations one might make on this study. Thus it would be helpful to know more about the background to the x-ray study in terms of response rate, turnover of employees etc.. Although the MRC questionnaire was employed, (the method of administration was not a standard one) the results are not discussed. The pulmonary function study reveals largo standard deviations-suggesting that'the study was not adequate for detecting moderate differences in lung function between the exposure groups even if these had been present. If pneumoconiosis under the circumstances of this particular study had a low prevalence, it would be easily be missed in a study of this nature. Ideally, one would have wanted a total population > study with standardised methods of observation (x-ray reading, symptomatic enquiry and lung function) and analyses admitting the most heavily exposed to be studied separately. This paper does not resolve the position vis-a-vis the respiratory effects of PVC inhalation. Various Studies of Meat Workers Asthma While these relate to emissions from heated labels and wrapping material, there is disease evidence in some cases that/nay be due to components such a phthalic anhydride, 2, 5 di-tert-amyl quinone and dicyclohexylphthnlate. Other irritant substances may also be formed. While these reports have no immediate bearing, they underline the importance of considering the composition- of compounded resin. -*; iT" - * NI03H Animal Studies - Rcnorts dated r'th "ny ''JTV (Rats), "'Oth May 1`)77 (Guinen LJi,gs) mill fit.li flnpl.rinlinr* 1'i`t" (Morikcvn) signed Clnudnri Kiiimnlnnnl This was A V month study only of rota exposed to RVC nt "'O mr/r ' for 6 hours/dny for 6 days/woek. exposed rata and 64 control mala rats ware used. It won concludad that there was no inflammatory or otherdd.eteri.OJa effects seen in-the lung of exposed animals that could he attributable to PVC inhalation. Male guinea pigs were similarly exposed for a 12 month period (36 exposed, control 39). As with the rata there were more macrophages nresent in the lungs of exposed other animals but it was concluded that no inflammatory or/deleterious effects seen in the lungs of these animals could be attributable to PVC inhalation. 10 male Cynomolgus monkeys were exposed to similar levels for almost 22 months. It wes concluded that the only contribution of the inhaled PVC dust deposition and retention to pulmonary tissue morphology, was numerous aggregations of PVC-eontaining macrophages. The report of plant material in the lungs of exposed animals could have affected interpretation in certain, circumstances. It ir s ,1'ficult1 to reconcile the results of these experiments with others reported. The studies were net set up to determine carcinogenic properties of PVC dust, which incidentally is not specified in the documents available. In a letter to the Chief of the Pathology section at NIOSH, B.F.Goodrich Chemical Company, both Goon 121 and Geon 92 are referred to. Which was used in these studies warn not specified in the papers available. PVC Chronic Inhalation Toxicology Study A document which is a photocopy of two pages of typescript and one table with no attribution is present on the department files. The clue to its origin lies in the following quotation: "In light of the relationship unequivocally established between ocoupationnl exposure to vinyl chloride monomer and liver angio-sarcoma and the concern expressed on potential risk to human health from exposure to polyvinyl chloride (PVC) dust manufactured and used from no1, vmerization of the vinyl chloride monomer, DBBS in FY'75 in its project n'-. ~ on "Chronic Exploratory Toxicology Studies and Tssts of Validity of Industrial Air Standards" proponed an inhalation exposure study with PVC dust. Actual exposures to a representative material (B.F. Goodrich Company ,(Geon 121) began in February 1976 utilising 3 species of animals - monkey, guinea nig and rat.................." -4- >!?- Although there are certain numeric.-i'. 'i-errnancies between this annarent summary paper and the 7 mamma' study renortr-J bv TIOSH, it is noasible that they refer to the same study, Nevrrt.hr': ,,s .e''.'.tract refers to further data not included in the NIOSH reports indue, -f nM'.monnry function of the monkeys and hiochemical/cl.inienl chemistry on p- noa nip and rat. Tests for liver damage were relatively insensitive so the* t is not possible to conclude that there was no liver damage but only that no ext .naive fynotion.-* liver damage occurred. The monkey pulmonary function testa sur~".nt -imr loss of lung recoil pressure probably as the result of ageing and there was sore v.iication Of small air-way obstruction of non-stntistical significance. At months 22 compared with pre-exposure data of lung function no significant differences were observed. j) Functional Respiratory Changes upon Chronic Exposure to Monomeric and Polymeric Vinylchloride. Mapp, C (1978) Istituto Medicina del Lavoro, 69, 191-162 --I 1 298 workers producing polyvinyl chloride were studied by respiratory symptom questionnaire, lung function radiography etc. In their conclusions the authors i i consider that vinylchloride monomer has adverse effect on lung function which is generally moderate in terms of prevalence and severity as distinct from a foreign body type reaction due to polymer. Thev raise the possibility of s potentiation of effects between monomers,oolymer nowders and tobacco which can lead to obstructive disease and symptoms of chronic bronchitis. CONCLUSIONS :- 1* The additional studies reviewed do not disprove t*^ suggestion that the long term inhalation of PVC dust ('pure' and compounded) mny be a hazard to man in terms of respiratory disease (malignant and non-malignnnt) or disease of other systems. .< 1 -j i .i R&S 113797 M GREENBERG i JANUARY 1979