Document Qk10JODwBzqKmN1QBKppNLrK4

Review and Commentary on the Seminar on The Biology of Talc Used in Health P:roducts, held at the MRC Pneumocori.iosis. Unit in.Penarth, .. Wales, May 13 and 14, 1976 The seminar was held at the British Government's Medical Research Council Pneumoconiosis Unit in Llandough Hospital, Penarth, Wales, to review modern scientific data developed on cosmetic grade talc with experts in the field (see attached list of attendees), members of the MRC Pneumoconiosis Unit, . representatives e>f the British Toilet Preparation Federation, and the U.K. and Johnson & John.so.n personnel from.the U.S. A. .. Object of the Meeting The objectives of the meeting were: 1. To confirm with experts in the field. of pulmonary dust diseases that cosmetic grade talc as normally, used is not a hazard to health. 2. To identify what if any further studies 13hould be conducted with cosmetic grade talc to consolidate the available data on it. 3~ .To educate Eurl5pean participants at the meeting on the data: supporting the safety of cosmetic talc so that' theycan qmfirm the safety of talc with health authorities in Britain and other European countries. - . 4. To inform experts in pulmon_;ry dust diseases of recent talc studies so that they can act as, consultants or indust_ry when needed. Review of the Content of .the Meeting Although a complete transcript oi the meeting will be available from the taping of it, a review. of some pf the highlights of the meeting .is- subm1tted. The agenda most recent appropriate of the meeting (see attached) was designed to review the data on the biology of cosmet~c grade talc and allow:.for discussion of each paper presented. Protected Document--subject to Protective order JNJ 000026202 -2- I. The meeting was chaired by Dr. J. C. Gilson, MRC Pneumoconiosis Unit. who.is the Director of the Introduction to the Meeting Dr. Gilson expressed appreciation of the :opportunity for those present to review all available modern data on cosmetic grade talc. He indicated his concern for the.current.neurosis that-exists in the.world about health care matters and the uniortunate need to obtain extensive data o~ materials that have had wide usage. He indicated that the meeting was to re:view in depth the availabie s_cientific data ~n cosmetic talc and determine what further studies may be needed. Presentation # 1 Composition of U. K. and U. s.A. Commercial Cosmetic Talcs Dr. Pooley initially reviewed the gen.esis of talc, the nature of inclusion minerals and the contaminants that occur with talc. ;He submitted data on the composition of cosmetic taJcs. that he_ had a,nalyzed and indicated that they consisted of about 90% talc often associated with .quartz, chlorites and carbonates, .-and occasionally .amphobole minerals, but never with chrysotile. It was indicated that substitution of the magnesium within the talc lattice occurs bu.t the substitution would .be of limited biological importance as the surface o.f the.talc molecu.l_e was biologically inactive and the substituted mineral would be within.the lattice. He indicated that the fibers in talc that were important were those of small diameter and that a fiber .should be defined as ha,ving at least a 20: 1 ratio. The U.S .. definition of.cosmetic the U. K., and it was generally and acceptable to industry. grade agreed talc was discussed, tba"t the definitions as was that for were comparable Presentation #2 Talc Dust Concentrations Associated with Cosmetic Usage and Their Relation to Animal and Human Talc Studies Dr. F. R. Rolle, of Johnson &: Johnson, presented data on t1:ie dust concentrations used.in_ the reported animal and human talc studies and how they r.elated to the amount of tal~.to which babies are exposed .. The_ data showed that in those studies wh~re talc showed no effect .in animal or human studies the following safety.factors existed: . . 1. The hamsters in the Battelle'"inhalation study were exposed to 1,375 times the amount of talc to which a baby is exposed. per unit of time. Protected Document--subject to Protective Order JNJ 000026203 -3- z. Italian millers were exposed in each one year to -12, 000 times the amount of talc to which a baby is exposed in a one year period. 3. No cancer was reported in the MRC rat study, although some fibrosis was observed in the rats exposed to 4, 339 times the amount of talc to which a baby is exposed in a unit time. 4. No increase in cancers was noted in miners exposed to 120, 000 times the amount of talc to which a baby is exposed in one year. The importance of the safety factors was stressed as they give a real indicatic:m of the safety of expos.ure to cosmetic .talc and_ are fa.eta readily understood by both scientists and lay .people. Presentation #3 In vitro Effect of Talc on Cells Dr. A. C. Allison, of the MRC Clinical Research Center in Harrow, presented in vitro data on the effect of taic on blood macrophages which was i's~ed by measuring the release of enz"ymes. Dr. Allison was interested primarily in determining the fibrogenic property of quartz and is attempting to isolate the mediators of fibrogenesis produced by quartz. He was only interested in evaluating the cytotpxic and fibrogenic properties of talc and was not.;concerned wj.th evaluating its carcinogenic potentiai. Quartz was cited as having a highly active cytotoxic and fibrogenic action, and it was -ni. Allison's opinion that talc possessed fibrogenic and cytotoxic pr.ope:r;ties but of a much lower order than quartz; He indicated that the activi_ty of the talc was dose- dependent. He did not think that the"quartz content of up to 2% in the. Italian taic was .responsible for the "biologicai activity of talc and thought' that perhaps another component in the talc was ~esponsible for the data obtained. It was also pointed out that talc did not appear to influence the immune system or produce an immunological response~ In the discussion it was mentioned that a separate i.ri.dependent stildy .of the effect of talc on rat pulmonary mac:rophage~ _had. shown tli~t talc did not have a cytotoxic effect no:r_ impair their phagocytic actioz;i. Presentation #4 The Biological Activity of Talc - ~Revfew of Past Animal Studies Dr. G. H. Lor.d, of Johnson & Johnson, made an extensive review of past animal studies in which talc was utilized a~d pointed -~ut that .in:an Protected Document--subject to Protective order JNJ 000026204 -4- but the most recent studies no data were .availabie c_oncerning the_ dose or the type of taic that was used and as such the studies were of_l.ittle value. He reported on a study conducted by ~he F. D. A. in w}?,ich talc was found not to produce mutagenic or teratogenic activity in the studies conducted. He indicated that_all available data reviewed failed to show that talc was a carcinogen. Presentation #5 ..Chrop.ic Cosm~tic Talc ~nhalation Stud,y .C.o.l,').d.u.c:tein.d .Hams.te:rs Dr. A. P. Wehner, of Battelle Pacific Northwest Labs., reviewed the findings of an inhalation study conducted in hamsters in wJ::iich animals were exposed to Vermont talc in doses up to 1, 375 times the amount to which a baby is exposed on a unit time basis. He reported that no. abnormal findings were observed in_ any of the treated animals when they were co.mpared with the untreated control group.:. He also reported preliminary data concerning pulmonary clear.ance studies utilizing radioactive talc which were conducted in hamsters. to determine the fate of talc inhaled .by these animals. It was pointed out that haif the talc inhaled- by the animals wa_s eliminated from the lungs in 8 days and none found in the lungs 100 days after inhalation of the talc. Presenta_tion #6 --Review of Talc Toxicological Studies Conducted in Rats Dr. J. c. Wagner, of the MR C Unit, said that the_ objective of. the animal studies conducted at the Unit wa:s to deter_mine wheth~:i;._talc was a carcinogen. The design .of the inhalation studies was related to the talc exposure encountered-in ind~stry-and, accordingly, high doses of Italian talc were utilized. 'J;'he data showed that _alow order. of pulmonary fibrosis occurr_ed in the animals, although the dose used was 4,339 times, that - to which a baby is exposed in a unit time. Intrapleural injection of talc and oral ingestion produced no cancers .. The degree of fibrosis observed in the inhalation study ~as dose-related and cc>mparable to that obtained with asbestos. The data show:ed that talc did not p_roduce mesotheliomas and there was no evidence to sho.;._,that talc produc~d cancer when inhaled. Presentation #7 Review of Findings from a Prospective Study of Vermont Talc Mine Employees The objective of this study was to. assess the health and pulmonary function of talc mine employees on an ~ngoing basis tq see if there, were any changes noted in data recently obtained :when compared to data obtained Protected Document--subject to Protective order JNJ 000026205 -5- from the mine-rs on a previous occasion. The data presented in this pr_ospective study showed that pulmonary fu~ctiori anihealth data obtained from miners who do not smoke showed no abnormal changes over the periods that they have been studied. In miners who smoked, however, there was an incr_ease in pulmonary symptoms. The significance of the pulmonary symptorns was considered to be . related to smoking and the significance of the changes was not known. Presentation #8 Retrospective Study of the Cause of Death of Talc Miners ani;I Millers Dr. G. Piolatto, of the University of Tur.in, Italy, pr,esented data on a mortality study of miners and millers who _had worked in an Italian talc mine and compared the results with data obtained froni the Italian male population as a control group. The control data obtained from national data were used in additio~ to the original control data optained from the mortality findings in a population living in a rural city. The reason f?r using the second population was to confirm the initial observations reported by Dr. Rubino.' Results of the. analysis of data comparing .the mortaliti of the mine employees with the ~talian population showed.that the data were essentially the same as those obtained where the control group was a rural population. The researchers were commended for. their workin obtaining comparative data from the Italian population which confirmed their initial findings. Presentation #9 Retrospective Study of Patients Treated i:nt~apleurally with Talc Mr. G. Berry, of the MR C Pneumoconio_sis Unit, described the design of a study that was being conducted by the MR C Un.it to determine whether talc int:todu,ced in the pleural cavity produced cancer. The study. consisted of identifying patients from a bospitaJ near'. Cardiff and two hospitals in London who had been _treated for collapsed lungs with the :introduction of talc into the pleura. >Records of 62 patient~ treated in a local hospital were located showing that 2 to 5 grams of iodized talc was administered intrapleurally during the period from 1950 to 1960. _In addition, records of 148 patients were located in_ two London b_ospitals. At this _time no data were available concerning the outcome of the .210 patients but follow-up data were being sought~;. Some concern was expressed about the study in relation.to the nature of the underlying disease in the patients a~d. the type of talcs us~d/ Presentation #1.0 i i. Epidemiological Studies of Industrial Work~i-s Exposed to Cosmetic Talc ; The Boots Company in England are conducting two epidemiological studies on e. m. ployees who had be..eri expbs e. a . to. talc.,; one is a morbid:i. ty. .... ..,,,_:. Protected Document--subject to Protective order ,'.. ' . JNJ 000026206  -6- i I. study and the other a mortality study. The ~orbidity study is bein-g conducted by Dr. M. L. Newhouse, an epidemiologist who has worked extensively in the asbestos field. In this study all current workers are being evalllated for pulmonary function and syr::i,ptoms of ill health in relation to ihe amount of talc dust to which they_ have been exposed. Some 22 men and 20 women subjects exposed to talc have been studied and the -data obtained compared with 40 men and 40 women who were not exposed to talc dust. The talc dust concentrations to which the workers were exposed ran,ged from l to 3. 5 mppcf but no data were available on the duration of the exposure. '.!'he data obtained -10 date reveal no difference in data obtained from .the treated and control. subjects, although Dr. Newhouse. indicated-that there was a trend in the reduction in pulmonary function in those exposed to the higher doses of talc dust.: The m.ort~lity study is being conducted by Dr . W. K. S. Moore, of The Boots Company. In this study the records of 3, 000- ex-employees have been located and an attempt is being made to find the government. records on these subjects that would give information concerning the cause of death ofthose who died. The incitjence of the cause of death will be compared with that recorded for the U. I<.. population~ At this time only 47 death ce],"tificates have been located, and these data were considered insufficient for analysis. Discussion . A period of discussion took place at the end ~f .the formal papers, with Professor Gareth Green being chairman of. the. discussion session. - The objective of the discussion period was_to summarize the data proviqed and determine what further studies would seem indicated. The initial discussion centered around the composition and definition of cosmetic talcs. The biological role played by individual minerals in cosmetic talc dusts was discussed and it was_ s_u_ggested that further . studies might be considered which would identify the biological activity of each mineral., It was pointed out, however,- that talcs had fixed com.positions and that evaluation of the total __product in cells, animals and man should in fact give confirmation of the. safety o{ the talcs and study of individual components would !)e_of limited value _or interest. It was mentioned that Italian grade.tak rep~es.ented a grade of talc with which other cosmetic grade talcs _could be compared. ., : Protected Document--subject to Protective order JNJ 000026207 -7- The animal studies were discussed and it w~s pointed out that the Battelle study was designed to assess cosmetic grade talc exposure encountered by the public and the doses used failed to reach an effect dose, while the MRC study was concerned with industrial exposure dosage and the dosage used did not show a no-effect dose. The desirability for a rat study in showing a no-effect dose following chronic inhalation was suggested. A re-reyiew of the dosages used both ~nimal and human studies _was made which showed the very large multiples in dosage required to produce pathology in animals or man in relation to the talc exposure encountered by a baby. Dr . Green concluded by saying that the data presented was no evidence to show that cosmetic use of .cosmetic a hazard to health and there was no disagreement with from the group. showed that there grade talc was this statement Dr, Gilson concluded the meeting by saying that cosmetic talc as used cosmetically was safe and, apart from a possible study to obtain a dose response in rats and possible biological study of contaminants in talc, there was ;no need for further stud~es to be conducted with cosmetic grade talc. He pointed out that it was. important to disseminate the data presented at the meeting to others in: the scientific community. interested in them and recommended .that the proceediqgs of the meeting be published in a scientific Journal. He requested that reference, samples of the Italian and Vermont talcs b:e made available to the MRC. Gom1nentary on the Meeting The following points can be made about the meeting: 1. The datapresented on cosmetic talc represent virtually all the data required for a new drug application on an ethical . pharmaceutic.al product .. 2. The data were presented to a group of experts in the field of dust diseases for review and discussio~. Dr. :J, C, Gilson,. who is Director of the MR C Pneumoconiosis Unit, and his colleagues represent the official government' specialists ; concerned with advis:j..ng the British. Government on health matter-s .relating to dust environments .. Protected Document--subject to Protective order JNJ 000026208 3. Dr. Gilson was satisfied that the data presented talc to be safe as normally used. show~d-cosmetic 4. Dr. Gilson did not see any reason tp do further studies, although Dr. Wagner expressed an interest in conducting a rat inhalation study to obtain a dose response, and Dr. Allison suggested that biological cell studies might be conducted with contaminants of talc. S. Dr. -Gils0n is .a,n,x,fous to have ,thedata provided published in the medical literature and will cooperate in developing a suitable manuscript for publication. The manuscript will not pre-empt any data presented at the meeting that have already been submitted for publi<;ation. 6. Representative.s of the British Toilet Preparation.Federation were well satisfied with the meeting and its outcome. 7. Dr. F. Roe, consultant to the TPF and tobacco industry; indicated his desire to write a position paper on talc for the TPF which.could be published. Suggested Future Action on Talc As the result of the Card.if meeting, the following action is recommended: 1. Type the procee~ings from the tapes of the meeting.. The typing of the proceedings will be done by J&J U. K. 2. Send a copy of the typed. original proceedings of the meeting to Dr. Gilson for his review-and further <;:omment as to how he considers the discussion sections of.the tapes should be. edited prior to release of the ~dited proceedings to those who attended the meeting._ . 3. Discuss with Dr.. Gilson the format of the manuscript to be submitted for publication in a medical journal and how the format is to be achieved. 4. Provide Dr. Roe with the proceedings of the meeting as well as Dr. Lo'rd's manuscript and manuscripts developed by Dr. Hildick-Smith~ tc:ipermit.him to develop a position paper on talc_- Dr Roe'.s manuscript prior to .release for the TPF. will be re\riewed ~ by .J&J ::.,::., Protected Akt&ZUt ELGA. Document--Subject .., to Protective order JNJ 000026209 ,. -9- 5. Develop a manuscript on the safety factor data presented by Dr. Rolle and have the manuscript published in a medical journal. 6. No more studies on talc should be conducted at this time, \ as the meeting failed to identify the need for any further. essential studies on talc. 7. Assembleavailable data on talc in a form which could be used by the OTC. Panel if and when n~eded. 8. Consider which consultants znight be available and could be used if needed for any open hearings that may occur in the OTC Panel review of talc. 9. Develop a nomenclature to clearly identify cosmetic grade talc from industrial grade talc fo-r use in the market and in all publications. 1O. Insure that if there are any cosmetic grade talcs on the market containing deteciable amounts of asbestos that they are withdrawn-from the market as soon as possible. 11. Consider provision of the edited proceedings meeting to the FDA and OTC Panel. of the Cardi Attachments May 25, 1976. Protected oocument--subject to Protective order JNJ 000026210