Document M4Z5zp21y1vNNgwoo2N4Qd9ey

so Physic! Prop 9- *JS of Hydrocarbons bo literature data and Its surface tension at 20 C was calculated by the equation where -030' * * nrfare tension at 20 C IP) m Parachor, estimated from the molecular structure b liquid density' at 20 C M as molecular weight The anticipated error by this method is 3*3 percent. The data for all four compounds were extrapolated over a wide temperature range by Kharbanda's nomograph oi where Ob surface tension at temperature T Tt m critical temperature The accuracy for this estimation method Is very good, aweaging 1*2 percent error. Conductivity. Then are no experimental ut* for either the vapor or liquid thermal conductivity * vinyl chloride or vinylidene chloride. Mason1' has ex* pcrimcmally determined the liquid therein! r and his dam appear to be more reliable than :h<* earlier reported dnta.T** McOovem present* the vntmr M-.mnai conductivity of trichloroethylene and [vcn.i;!o:^ctWene but the estimation method usrd i not very reliaw<*. None of the present estimation methods cave a rcaw.ah;e ti-n- perature-thcrmal conductivity trend for the vapr t`ha*e. Hence, only die liquid thermal comlurtiviu is presented, here, and then only for Use experimentally tiri*rmined tri* ehlorocthylene and pcrchloroethyletic ainre rstimat5--*n inetiiods gave highly unreliable results for the liquid phase also. * Vapor Thermal Conductivity. The vapor thermal con-, ductivitiei have been estimated by the method of Owens and Thodos1', with an expected error of tis5%. LITERATURE CITED 1. Stull, D. B., Industrial and Engineering Chemhtry 39, pp. 517-550 (April 1947}. 2. Molfw/on Cat Data Book, The Maiheson Co., East Ruth* erford.N.J. (1961). 3. Timmermans, J,, Phytico-Chcmieal Constant/ of Putt Organic Compound/, Elsevier Publishing Co., Inc., New York (1950), 4. "Vinyl Chloride Product Bulletin," The Dow Chemical Co., Midland, Mich. (1934). AP00007605 PO Box No 9 Bessemer Road Welwyn Garden City ordshire AL7 1 HO Telephone Welwyn Garden 23400 (STD Code 07073) STD Code from London Area 60 Telex 264251 Iciplast Welwyn $ /// Imperial f/^ Chemical / (Z Industries ^ Limited Plastics Division ft* X A Hoeteehvender Director, ftibiic Affaire American Koechat Corporation Route 202-206 north SooerviUe KJT OS876 VBX Your ref. Our ref JtyfcEV/DSO-IO? CCi Dr R Adame - Air Products Hr R Harding - Society of Plastics Industry Tel ext 3162 orUye ~ Dioi RectivED >4. UtA JAN 2 41977 A ROSS ADAMS w9 December 1976 (Diet 6 December) Pear DR J C VAGNES - WC WJST C****J*%'4+, /WU,^ 1UA I tried to s*t in touch with yon today to follow up *y letter of 16 HoveSer^** ? concerning Dr J C Vagner of our Medical Research Council Pneumoconiosis Halt and hie work cn FVC dust* So far as I know, Dr Wagner* work baa not been <**& published in *Mature* but the publication could be iasiaent* Sr Vagner was In the USA laat week 1 believe and X have not heard of any repercussions* However, X have today had news of a diaeloaure ha baa made at a seal private eelloquiua on toxicological and environmental problems being held in Luxembourg on 7,8 and 9 Deceaber* During a discussion of a paper by Or. Bans Copper on the effect of toxic natoriala on the liver. Dr Wagner gave an account of bia work with FYC powder* Our informant tells ua that the report waa given in a lurid dramatic sensational way calculated to causa ths amount of worry and slara* Sob# delegates ware not taken in however, and cemented that it waa deplorable that research results should be presented in such an ill digested manner, but Or Wagner took the view that ha waa a aiaple researcher who waa reporting flnilnga and it- was up to otters to interpret hia work! V# have been privileged te have confidential discussions with Or Vagnsr is this country on 9 Xoveaber and to bare access to the draft letter te wae proposing to publish in 'Mature4* Dr Vagner ted sade us well aware that te sxpeeted us to respect the confidentiality of his draft submission to * Nature1 and up to now we have done Just as he wished* However, hia disclosure la tills Luxembourg seeting has changed things quite substantially* We felt that we could talk with our govemnont Health and Safety Executive and Medical Advisory Services today concerning his work sad we are sending then appropriate documentation* For your information, we enclose s copy of a draft precautionary brief we have drawn up for our own management sad f* people* AP00007606 3) pasta polymer to carry out a feasibility study for on inhalation experiment* In addition It would seem advisable to supply the unwashod and washed ICI product for 1) and 2) and to consider whether the product* of both firms need to be investigated by inhalation. Dr. Wagner should* if possible* be persuaded to accept the specimens coded so that he is unaware ,, of their origin and whether or not they have been washed. It would probably also be best if he was unaware of the origin of the powder he uses for his inhalation experiment. In relation to c) findings in other studies may be of great importance* In an investigation carried out In a similar way to the PVC study* Dr* Wagner found that a high percentage of rats receiving crystalline silica developed a reticuloendothelial tumours. Most of these were composed of malignant'histiocytes* many of which In the early stages appeared . localised as reticulum cell sarcomas* The description of the tumours in silica-treated animals is somewhat similar to that found in the PVC treated animals; clearly full pathological examination of the animals already dead and of further animals will need to be completed before comparisons can be 'properly made. There is* of course* ample evidence that sillea is not a carcinogenic hazard to man. There la well documented evidence that inplantation of millipore filters or I,P, injection of mineral oils can produce tumours of the lympho-retlcular type in mice. For example* medicinal quality oil when injected into BALB/C mice can induce, as well as granulomatous nodules* myelomonocytic leukaemia* The formation of plasma cell tumours has also been described. . DBA./2 and CBA mice also develop reticulosarcocatous tumours and leukaemia with this treatment. These experiments suggest that in mice and rats reticulosarcomata may develop secondarily from granulomatous type lesions. The effect on the rat of particulate matter and tissue-damaging chemicals (including surfactants) when injected subcutaneously has been f studied In great detail by Golberg and Grasso. There is little doubt j that many such substances which are not # carcinogenic hazard to man do I produce a sarcomatous reaction in the rat* this reaction being dependent * on the physico-chemical properties rather chan the lnate carcinogenic 4 property of the materials. It might he that PVC with a strongly held coating of surfactant could behave in a similar way as a "secondary" carcinogen rather than a primary carcinogen* In other words the development of the tumours may be secondary to the formation of a primary lesion which la either unlikely to be produced in men or* if it is produced* will not necessarily lead on to eaneer induction, ' This possibility is well worth further study since Wagner's findings might at present be taken as indicative chat PVC is causing reticulum eell sarcomas* Evidence on die mechanism by which the lesion develops in rats may be essential In the interpretation of bis findings* The need for a suitable programme of work should be discussed by the scientists of the } I CIA. The_<leslrabllitv of someone other than Wagner carrying out the I studies ahmild ftlan H* -Considered. The persori Probably the most interested in this field in the UK is Dr* Paul Grasso of BXBILA* i The need for the radioactive tracer study suggested by Wagner should be given careful consideration* Particles will almost certainly Continued,** **00007607 L -4- enter the body when given by inhalation since they will probably be . swallowed and taken into the gut (by persorption). From the gut they could travel to the liver. It is doubtful whether the study will be* helpful in answering the main question, which, is what the development^ of reticulum cell sarcomas might moan to man. 41 The need was discussed at the meeting for the occupational I^ histories of those who have developed angiosarcoma attributable to I/ vinyl chloride to be re-examined to see'whetlier or not evidence exists! 0 of a relationship of tumour incidents with exposure to paste polymer. I It is probable that this has already been looked into. f t Consideration should also be given to the need to formulate a scientifically based reply to Wagner's letter to 1'Nature". M, Sharratt (Dictated but not signed by Dr. Sharratt) t Dahm(a)/Dahm,4(a)/(b) - MS/BU 23rd November 1976._ AP00007608 Ird PRATT IMPERIAL CHEMICAL INDUSTRIES LIMI^O) L PLASTICS DIVISION J CONFIDENTIAL PRECAUTIONARY BRIEF RELATING TO PROPOSED LETTER TO 'NATURE* BY DR J C VAGNER Introduction Sine* the discovery 3 years ago that the rare csaeerf angiosarcoma of the liver could be caused in man by exposure for long period# (normally more than 10 years) to high levels of vinyl chloride monomer (probably veil in excess of 500 ppm), a great deal of attention has been paid to occupational health in the PVC` industry. In particular great advances have been made in improving factory hygiene and reducing exposures to VCM. A tripartite working group consisting of Government, Uni one and Industry drev up an Interim Code of Practice for handling VCM based on exposure to 25 ppm over a time weighted average of 8 hours. This Code of Practice was modified in November 1975 to require an 8 hour personal TWA exposure of 10 ppm with which the industry is complying. *0 Careful medical screening and epidemiological surveys have discovered around 55 VCM related angiosarcoma cases in the Vorld, two of which vers la the US. In almost every authenticated case of angiosarcoma, the victim had been an autoclave cleaner; it is in this area that*the greatest advances have been made in minimising the health hazard. > I * Dr Wagner** Proposed Letter to 'Nature1 A copy of this letter is appended. Dr Vagner gives a factual report of work he has dene on one sample of PVC powder, paste polymer. In laymen's terms he injected suspension of PVC particles into the eavity between the lung's external covering and the rib cage in rats* About 1 year later (half the normal lifespan of a rat) four of the animals died. The animals had tumours mainly .../ AP00007609 -2- \ ( associated with the liver bat these were not liver angiosarcomas gauged by VCM. As Dr Vagner says this ia a preliminary report - 44 other rata are atill under observation. His.letter ia mainly concerned with identification of the varions tumours he has found in the 4 dead rats. Dr Vagner makes no comment to link the development of the tumours with' VCM in the PVC particles and indeed (ve repeat) the tumours are not the liver angiosarcomas typically related to VCM. The paper represents one portion of an overall programme Dr Vagner has been pursuing. Using another type of eoortonly inhaled, fine dust which has not been associated with cancer in he has discovered that somewhat similar tumours can be induced by this Unnatural process of injecting into the pleural cavity. Such a mode of entry into nan in any manufacturing process is inconceivable. This is no criticism of Dr Vagner's work which Is presumably aimed at studying carcinogenesis in the retlculo-endothelial system, the body's scavenging mechanism which involves among other things the generation of white blood cells and the removal of foreign bodies. Questions and"Answers . Q1 Vbat is new about Dr Vagner's work? , A1 This work involves the introduction of a suspension of dust into the pleural cavity, a normally inaccessible area betvoen the lung's external covering and the rib eage. * Q2 Vbat is be trying to prove? A2 Dr Vagner vorka for the MRC Pneumoconiosis Unit in South Vales* He is examining the posaibility that different types of industrial dust might have cancer causing properties; this work follows a number of studies he has carried out on asbestoe. He has found it possible to administer in one injection as much dust as can be inhaled by the rat in several years. He recognises that the route of administration is abnormal and AP00007610 3 1. f that positive result# in his tests will need to be investigated before their relevance to nan can be established* l Q3 Have any of these other dusts given rise to the sane effects as stated in the artiele? A3 The vork is in an early stage but ve believe that Dr Vagner baa bad similar results from other dusts not associated with eaacer formation in nan* Q4 What is the significance of Dr Vagner*a discovery? A4 The research is novel and the significance of the initial results is still being discussed by doctors and others* Q5 How does this development affect FVC manufacture? A3 Ve believe not at all* All operators wear dust Basks where they carry out jobs in areas where dust occurs* This is a standard precantioa adopted by the Industry over many years* FVC dust is classed as a nuisance* dust* ie it does not produce a significant toxic effect* Q6 Vhat further precautions will you institute? A Ve believe ve have adequate protection but industry is interested in anything In Dr Vagner'-a vork that might lead to further improvements in hygiene standards* Q7 This is a fine polymer - is it paste polymer? A7 Yss but vs understand that Dr Vagner's future vork vill embrace a range of FVC paste powders* * A. AP000076I1 3 it v C -4- . L Q8 You *ay that the fall significance of tho work haa yet to be assesaed by doctors and that the research la still in its early stages; supposing verst fears materialise? How could this then change the situation? A8 In till TJK.t the CIA Employment Medical Advisory Service health survey of the PVC industry in 1975 shoved no exeese disease or mortality of FVC workers against the general pattern of the population other than tho tvo loom cases of angiosarcoma. js/cjh/ds 0-107 6 December 1976 AP00007612 (, H' r ................. .<v& CM^e tti* production off sarcomas following the intrapleural inoculation of fine particles of polynweUad \tfi\ p'- vinyl chloride* , Vinyl chloride particle* of the finest commercial grade# Dean particle diameter 0*S06itm (range 0.07 - 1.56pm) were introduced into the pleural cavity of six-weak old Cesarean [derived wislar rats of the ZCZ Aldexley Park strain. The pax&cles were suspended in physiological saline and introduced into the right pleural cavity using the method described by Wagner end Berry# (1969). 48 animals were inoculated# 24 of each sex# in August# 1975* [ ; Shis Is a preliminary report on the first four animals that have i died up* until the 1st November, 1976. - She first animal developed a large fibroadenoma of the breast# which, was causing discomfort# and was killed' in July# 1976. Histological examination of the liver showed the presence of enlarged hyperplastic Xupffer cells in the liver and hyperplastic histiocytes in the spleen* She second animal died of pyelonephritis in July# 1978# the liver was slightly enlarged# pals' in colour# and the spleen was grossly enlarged and ! firm in consistency* Sections from the liver showed the presence of clumps atypical histiocytes# some with feiaarre nuclei* Sections from the spleen demonstrated that the normal architecture is maintained# MT" dependent lymphocytes appear to be normal* No secondary germinal centres are seen - the marginal rone is indistinct and merges into the!zed pulp* The cells*in .the red pulp are large with dear cytoplasm* Nuclei and. cells vary in size end shape* There are more multinucleated cells titan usual and occasional nucleated red blood cells are seen* In addition# there are collections of small deeply steined cells# these may be artefact but tho possibility of monocytic cloning should be considered. ' . AP00007613 \ . *) The third animal.was found dead on the 10th October# 1976. The liver was grossly onlargod and pale with obvious yellow tumour nodules extending throughout the liver substance. The spleen was grossly enlarged and fins* The liver sections showed the normal hepatic cells to be replaced by a tumour consisting mainly of reticulua^like cells with occasional foci of grossly atypical histiocytic cells.; The spleon was similar in appearance to that seen in the previous animal. The atypical cells in the red pulp were clearly malignant giving the appearance of a tumour arising in situ. All three animals had small white granulomata at the sits of Inoculation and scattered through the right chest cavity with prominent nodules on the diaphragm. i . ( The fourth animal showed malignant histiocytic tumour nodules in the right pleural cavity# lung# spleen'and bone-marrow# with occasional foci of grossly atypical histiocytes in the.sinusoids of the liver. ' HRC. Pneumoconiosis Unit# Llandough Hospital# . . Penarth, S. Glamorgan. CF6 1XW J. C*. Wagner HD. me.Path Reference Vagner# J.C.# and,Berry, G# Brit. J. Cancer# 23,, 567-581# (1969). J AP00007614 l1 Sr % A Hochachvendar ) 2 9 December 1976 J Shis contains the drift of the proposed letter by Wagner to 'Mature1. Would 1 you please be careful what you do with this draft letter so that we do not cause any offence to fir Vagner. It would be better f he achieved his * 1 ambition of having it published first in 'Nature* We think it is important * that you should have this information because Z an pretty sure that Dr Popper will be reporting these very preliminary and preoature results to your government on his return. )fay X aay that we in XCX have done some "in vitro" and "in vivo" work on CTC powders. The "in. vitro" work has been completed and was the subject of a j paper to the American Chemical Society last spring by Dr Plggott of our Central Toxicological laboratory, fir Plggott is still doing his "in vivo" work Which involves the injection of FVC powders into the trachea and peritonaeal cavity of, X believe, rata. So far. no abnormal reactions of the histiocytes in liver or spleen has been observed, but the total duration of Dr Piggottfs work is nearly six months compared with the one year ' plus in Dr Wagner's work. She CTL work has, therefore, little bearing on Vagner's results except to indicate the need for Vegner to do further work to determine which components of the eaulainmaaie are responsible for the effeota he has observed. There ia also the need to investigate whether materials administered via the lungs are capable of producing such reactions, since only ] this route has aay relevance to possible industrial exposures. In other words, Dr Vagner has aome interesting data but we have a long way to go in interpreting the very preliminary findings in his work. X would hope that our scientific community will take the news calmly and logically and not jump to any premature conclusions. If I can be of any help in elucidating anything further, please do not hesitate to gat in touch with. me. ' With best wishes. Tours sincerely J Stafford Division Manager Health tc Environment Protection PSt X alee enclose a copy of the draft CXA report of our 9 Hovembar meeting with Dr Vagner. Rosa and Ralph have been given copies of your letter. i I AP00007615 Report of a Meeting Between Representatives of the CIA and the MRC Pneumoconiosis Unit, held At Llandough Hospital on 9.11.76. to discuss . recent findings on BP Paste Polymers,, and suggestions for action by the CIA Those present wares Dr; P. Elsies Dr* ? Smith Dr* J. C. Wagner and a number of Dr* Wagner's team from the MRC * and Dr* C* II. B. Binna (BP) Dr. G. Piggott (ICI) /xvr Dr. M. Sharrafct (BP) Mr. C, H. Thompson (BP) ;/ $ Dr, D. M. J. Williams (BP) H* The meeting had been suggested because Dp; Wagner's recent findings had added a further dimension to the vinyl chLrfride/PVC problem. Dr. Wegner began his studies on the effects or PVC particles injected-into the right pleural cavity (the space between/che chest wall end the lungs) of rats some time ago. The first experiment was discontinued .because of infection In the animals and the nr^aaot^xperiment was started in August 1975. He has Injected 20 mg of CP B130/&polymer into the pleural cavity of 24 male and 24 female Wistar rats originating from the ICI laboratories at AlderIcy Park. The particle sire of the polymer ranges from 0.07 to 1.56 microns with a mean of 0.508 microns (determined by EM). Surfactant on the surface of the .particles is moderately stable, being removed by alcohol .but not by water washing. To date, five of Dr. Wagner's rats have died or have been killed. . The findings on four are to be described in a letter which the MRC hope yill be published in "Nature" within the next month or so. Briefly, the changes described by Dr. Vagner in the five rats were: 1* Killed because of breast cancer (e conanon finding in these rets) but the liver showed the presence of "enlarged hyperplastic. Kupffer cells" end the spleen "hyperplastic histiocytes". a 2. Died with kidney dlease (again e common abnormality) but the liver contained "clumps of atypical histiocytes, with some bizarre nuclei"* Abnormal cells of uncertain origin were present in the spleen* 3* Died. The liver cells were largely "replaced by tumour consisting of retieulum-like cells with occasional foci of grossly atypieal histiocytic cells". The spleen wee similar to that in animal 2 r but the cells in the red pulp "were clearly mdllgnant, giving the appearance of a tumour arising in situ". 4. "Malignant histiocytic tumour nodules In the right pleural cavity, lung, spleen and bone marrow and occasional foci of grossly atypieal ' histiocytes In the sinusoids of the liver". 5. Rat examined only reconcly* Smears showed a "monocytic leukaemle type of picture". All rate have email granulomata In the eheat e&vlty. AP00007616 L -2- Dr* Piggott described ICI's findings with a similar type of polymer* Polymer wich a surfactant: coating could kill macrophages (cells which cake up particles in the body) when cultures of die cells were in contact with them. Silica and asbestos also kill macrophages while many "nuisance" dusts do not. However* when Che polymer was washed free of surfaccanc it was no longer harmful to the cells. In rats receiving the ICZ polymer via the trachea* only minimal fibrosis was seen; these rats were not kepTlong enough to demonstrate that B by this routs a Wagner-typo reaction did not oepur. * Dr. Wagner is concerned that inhaled particles of PVC dust might be taken up by the tissues* transported to the liver and produce a reaction in man similar to that which he has found in rats. One of his interests is in the mechanism by which the polymer particlos move around the body. He has, as yet, no direct evidence that PVC particles move from the chest cavity but* by analogy yith the behaviour of silica particles* he feels it reasonable to assume that they do. He considers It possible that the particles migrate through the "bare area" of the liver* (the part of the liver immediately In contact with the diaphragm) to the blood vessels of / the liver where they are taken up by specialised cells (most likely the i Kupffer or similar calls) which then* presumably on becoming malignanti \ pass to other parts of the body. Dr. Wagner would like to repeat hie study using paste polymer and alcohol-washed polymer. He would be willing to Introduce fine (eosmecic grade) tale as a control since this produces fibrosis (the granulomata in the chest) but not cancer (in man). He would also Like some polymer to investigate the feasibility of producing dust clouds suitable for a long-term vet Inhalation experiment. Ha suggested that industry might consider approaching Harwell to carry out studies on the migration of PVC costed radioactive iodine particles into the body; this he felt would answer quickly whether or not PVC particles could enter the body tissues following inhalation; the same material could, of course* be used to trace particles from the chest and so would be useful to Dr. Wagner In investigating his theory of particle migration* s The CIA's concern will be not so much with the theory of mechanisms of particle transport as with the relevsnce of the findings to man. Three aspects are of interat: a) do PVC particles of the size found In paste polymers enter the tissues in significant quantities when inhaled (and therefore ingested)? b) does the surfactant coating play any role? . e) if particles do enter the tissues will similar response to that in rats occur in man?. Zn relation to a) and b) it would seem reasonable for the CZA to provide the samples requested by Dr. Wagner, that is 1) ^ paste polymer as previously tested % 2) alcohol-washed pasts polymer - preferably giving e negative macrophage response Continued... AP00007617 S^* dUL&toa_ TRPSaAl/CHEMICAL INDUSTRIES LIMITED -1J11/A O&r-JLU*PnLAShTICS DIVISION TO: SPI VINYL SUBCOMMITTEE FROM: W R SORENSON/W D DAVIS paper for emas meeting, 5 may 1978 at regina house JUNE 28, 1978 PVC DUST RECEIVED RESEARCH & DEVELOPMENT JUL 5 1978 Summory Note on Meeting with MRC Pneumoconiosis Research Unit \ht M SMITH 31 January 1978 --------- " * Introduction Under CIA auspices, a meeting was held on 31 January 1978 with H$E. EMAS, DHSS, TUC, BIBRA and CXA representatives present to disco?f the MRC work on PVC dust. The following points arose. (a) Dr Wagner of the MSC in August 1975 gave 48 rats a singje 5 r,-i.ro pleural injection of 20 ragm of PVC emulsioh polymer in scline. Between 12 ond 18 months, 9 animals died end of these 5 he*-' liver tumours. Pathologists agree 3 tumours were malignant, arising from Kupffer cells. One tumour occurred at the injection site. Nothing further was found until rats 33-45 died and showed iwer ond spleen fibroses and Kupffer cell damage. *3 animals stil.l .survive. (b) In January 1977, Dr Wagner exposed 48 rats to inhale an atmosphere containing 12 mg/n> PVC emulsion polymer dust for 7 hrs doy/5 days week for 5 months. In June 1977, 6 exposed rats were sacrificed and evidence found of dust deposition in macrophages in the alveoli, lung tissue, liver ond spleen. In January 1976, a further 6 rats were sacrificed and found to have interstitial fibrosis and multiple gronulomata in lungs, aggregates of dust around splenic vessels and occasional particles in Kupffer cells in the liver. (c) In post mortem examinations of human cases in the Llandough Hospital, Dr Wagner found PVC particles in lungs ond liver of a man who died from Kupffer cell sarcoma, PVC in the liver of a man who died from o liver tumour, PVC particles in Liver ond spleen (and interstitial fibrosis) in o man who died from bleeding oesophagal varices and PVC particles in lungs ond spleen of a South Wales factory employee who died of bronchitis and emphysema. (d) Dr Pigott of ICI's CTL described in vitro end in vivo experiments with PVC powders. In vitro, emulsion polymers were cytotoxic when some specific surfactants were left on the particles' surface. Introperitoneal and intratracheal injection of emulsion polymers into animals showed no response after 6 months. Dr Pigott concluded the PVC powders he had tested in this way were unlikely to produce fibrosis in man. (e) Dr Elmes ond Dr Wagner thought it was too early for Dr Pigott to draw such a conclusion. Moreover there was scattered clinical evidence in the literoture to support the possibility that PVC dust may be fibrogenic but Dr Elmes agreed an epidemiological survey would be required to prove this. All agreed that such a survey could not be warranted on the basis of the present evidence. AP00007618