Document vVgGoax9yOeX1J74Y1vxQmOQ9

* ' Observations on the Effects'of Powdered Pokmer in the Carcinogenic Process, ^ ................. T "" ~ ' ' Enid T. Oppenheimer, Margaret Willhite, I. Danishefsky, and Arthur Purdy Stout TTitm ** TrocncAi. Auustssc* or Gsoaos Tt* (TiutiiW* 0} Cane* RutmrcM, CoUtft tf Pkpmeimi and Svrftoni, Columiia Unimrwitf, Ift Yeti, N.Y.) SUMMARY - It has been shown that polymer powder*, in contrast to polymer and other films, are '--noncarcinogenic when imbedded subcutaneously. An important difference in response between fitTM and powders appears to be the fibrous pocket formed around the im- _ bedewed It is in the lining of this pocket that the tumors originate. No such pocket arises with powders. * - -It wss suggested that powder might perhaps induce tumors if presented directly to ' the cells of a pie-formed pocket. To test this hypothesis (1) polyethylene powder and (2) glass powder were asserted ' into pockets produced by imbedding glass Rb", both with and without the presence of thefilmr Results gave no evidence of any significant change in tumor incidence produced by the action of powder on the pocket cells. This was confirmed by histological observations, which showed a remarkable mmilar- ity in response to powder whether imbedded in ordinary connective tissue or introduced - into a pocket. A foreign-body reaction, with phagocytic giAnt cells, wss found con stantly with imbedded powder. It has been shown in this laboratory that sub connective tissue pocket whereas the letter does cutaneous imbedding of plastic films or metal not, it was suggested that this aaay be a critical foils in rodents can cause the appearance of sar factor in the process. This was strengthened by comas -and other malignant tumors (7-13). This the finding that removal of the pocket precludes carcinogenic response has been found with films tumor production (IS). having a wide range in chemical constitution and Although all films tested induced tumors, there has been confirmed by a number of investigators was a marked variation in actual tumor incidence (1, 3-6, 14). On the other hand, imbedding of the with films of different substances-This, in addition same plastics or metals in the form of powders to the fact that in some cases a slight degradation yielded only on* tumor out of 387 implants. These of the polymer molecule has been shown to occur facts established that the primary requisite,for after imbedding (8), suggested the possibility that tumor induction with them substances is that direct chemical action might piny some part, per they be in the* form of a film. Since a baric dif haps secondary, in the carcinogenic process. It ference between imbedding of film and powder was thought that, although powdered polymer is that the former becomes enclosed by a dense imbedded in normal connective tissue is not car * This investigation m supports'! by a usesicb grant. cinogenic if introduced into a pew-formed pocket, No. C-1M0 (C 4-8), tram tbs National Canesr Institute, it, or its breakdown product* might influence National Institutes of Health, United States Public Health tumor production by a reaction with cells of the Scrvic*. pocket wall. Received for publication September 3,1980. The present report describee experiments de- fa* R&sea^L. W ucc 041081 Oppenhedier ti aL--Effect* of Powdered Polymer in Carcinogeneei* 1SS vised to test this supposition. Pockets srese formed in rats by imbedding glass coverslips, which m themselves ue inorganic and chemically inert bat which induce tumors. Hie effect on tumor produc tion of introducing powders into these pre-formed pockets was then investigated. MATERIALS AND METHODS Glass coverslips, approximately 1.8 cm. in diam eter, were imbedded subcutaneously in the right and left abdominal walls of 90 TCistsrmts by pro cedures previously described (8). After 4 months, the animals were divided into three groups. In one group, in the right abdominal wall, polyethyl ene powder we* introduced into the pocket against the outer surface of the coverslip, and on the left ride glass powder was similarly inserted. In a second group, the coverslip# were removed from both sides, and polyethylene or glass powder was introduced into the empty pocket on the right or left ride, respectively. powder was introduced would be assumed to be due to the powder. Likewise, any significant in crease or decrease in the number of tumors, where the powder was added with the film *itu, would be directly attributable to the powder. Since polyethylene was previously shown to under go some degradation after imbedding (8), these experiments were devised to allow for comparison, between powders of this material and the! of ' glass. If the degradation products of the poly*' ethylene were carcinogenic, one would expect a higher tumor incidence with polymer powder than with powdered glass. The results obtained are shown in Table I. It is seen that glass coverslips by themselves yielded six tumors out of 84 imbedding*, or 25 per cent. As expected, mere removal of the coverslip at 4 months resulted in the complete absence of tumors. Insertion of glass powder into the empty pocket still gave no tumors, whereas polyethylene powder produced one only, more than 8 years after TABLE 1 Emets or Powncas ts Phe-towied Pocsxn Sn: Cowslip: PowdeR Imbeddio(K Tumor*: Percent***: Mesa latest period (days): 1 m ritn Febttk. *7 5 IS 57094 rib Glut *7 tt 547103 * Removed Pohetli. it 1 753 4 Removed Glut Tt 0 0 * Removed Xoo* 25 0 0 * S in sit*. Km 34 3' 35 5035S * In a third group, the glass coverslips were removed from the pockets on the right ride only, remaining in situ on the left, and no powder was introduced on either ride. Essentially, this procedure resulted in four ex perimental and two control categories. The experi mental groups included: 1. Polyethylene powder with coverslip in pocket 2. Glass powder with coverslip in pocket S. Polyethylene powder's! pocket, no coverslip 4. Glass powder in pocket, no coverslip The controls included: , 5. Coverslip removed from pocket--no powder 6. Coverslip in pocket--untonebed RESULTS AND DISCUSSION ... In these investigations the powders were intro duced between 4 and 5 months after imbedding of the original film because previous experiments; with polystyrene (IS), had shown that, if the films are removed within this period, no tumors occur. Thus, any sarcomas which might appear in the cases where the film was removed and the imbedding. The significance of a single tumor in this category is difficult to evaluate. Introduc tion of polyethylene or glass powder into the pock et without removal of the film gave 19 per cost . and 82 per cent of tumors, respectively.* Th.uk, ' these additions had no significant effect on the number of tumors as compared with the film alone, and certainly produced no increase. The time elapsing before the appearance of tumors (latent period) shows little difference whether powder was inserted or not, bat the longest latent period shown (752 days) was with the single tumor appearing when polyethylene powder wax placed in the pocket with no coverslip. These results lead to the conclusion that pow ders are ineffective in producing tamers even though a pocket hat already been formed, and they corroborate the previous proposition (2) that there is no direct chemical action involved in. carcinogenesis by plastics. If there were such an action, a higher incidence of tumors would be expected upon introduction of polyethylene pow d4er into the pocket because of the increased sur- t ucc 041082 Tt 1S4 Cancer Retearch / . Vol. S1, January 1961 - face available tor chemical reaction. The 'alight detailed histological study in a subsequent report. degradation of the polyethylene is probably not' Comparative studies of the chemistry of the tissue involved in the carcinogenic process but is merely. surrounding powders and film* me also ndrr a coincidental occurrence as far as tumor induction way in this laboratory. is concerned. The reason -for the difference in carcinogenic REFERENCES activity between powder and -film is still somewhat 1. Beane, E. A.. Jn.; UcLumm, R. 4 Emirs, J. B.; obscure, but one important factor may be that ad IxosAiuu, F. D. Production of Tumor* is Ram films, produce an enveloping pocket and powders by Implantation of Fun FoIyeUtyian*. Canear ^Tiairli > <f do not. Histological examination shows that a 16:300-801,1955. 3. Duomcr, L; OtMonun, E. T,; Wuuno, film becomes enclosed by a thick continuous wall. 1L: Btout, A. P.; and Fiudux, JlL U. Tfr lmniiil of collagen fibers packed closely together, with Change* during Caranogenaats by Plaatie Fibs*. Caaew a few flattened inactive fibroblasts between (Fig. Broaatrh. 19:1334-88, ISSO. 1). while the tissue reaction to powders shows a much looser, more open, and less regular ar 3. Didcoit, H. tad Smrln, D. Canearogen* TVirknag' von Kentoff Fobs. Ztsehr, Naturforaeh., TliUML 1S63. v : rangement of fibers around the individual powder 4. Lasers, D. M.; Boueos, L B.; sad Wmnun, J. p. " masses, fibroblasts with large rounded nuclei whi$h Espaiimautal Production of Sarcoma* by Methyl Uatb- '* remain continuously active, as well as many phag- , ocytic multinudear giant cells (Fig. 2). This active foreign-body reaction continues apparently in- definitely. -. V When the powder was inserted into a pro-formed pocket with the film still in' situ, the powder appeared to stimulate the adjacent inactive pocket wall to a foreign-body reaction very similar to that found in ordinary loose connective tiisue (Fig. S). Removal of the film from its surrounding -aciyUt* Implants. Proc. Soc. Expor. Biol. It Mad,, 87: 830-83, IBM. 5. Norasamrr, H. Dio axparimastaD* Eratugnag von Su- komon boi Rattan and Mtam durch Implantation vno - Bundtcbaiban sat Gold. 83bw, Flatia odor EtftsSrin. ' - NatumiiaanscbafUn. 43:75-78,1955. 8. " tJbar die SeriramanalQeaag dunk FrandkOrpar- . implantation** boi Battoa in Abhlngigkait von dor Fen* dor Tiaplautat*. Ait, p. 108. - 7. Orrcyacptrm. B. S.; Oraatnrxuca. E. T-; Bjutammtr, I.; sad Stoot. A. F. Carenogaaic Effaet of Uatak ia Bodanta. Canear Basaaich. 16:499-41,1858. pocket has been found to result in the slow re 8. Owcnunaa, B. 8.; Owemnin, E.X-; Dinsunat gression and ultimate disappearance of the pocket wall. When powder was introduced into a pocket upon removal of the film, this regression was Li Stoct, A. P.; and Emm, F. R. Further State . of Polymer* a* Carcinogenic Agent* ia Animala. Research, 16:333-40,1SS5. 8. Oprcntenies, B. S.; Omanteoirn, E. T.; and Starr, -dl accompanied by the usual tissue reaction to pow der, and after poany months the surrounding tissue A- P- Sarcomas Ioducad in Rats by Implanting Cellophane. Proc. Soc. Exper. Biol, ft Med-, 87:83-84,1948. resembled that in which powder alone had been imbedded. The reaction of powder with pocket cells, whether with a film or without, appears 10. ------- - Sarcoma* Induced in Rodent* by Imbaddiog Vari* oua Plaatie Pilau. Ibti., 79:388-89,1953. 11. Oikbmo, B. S-; OncnoMti, E. T.; Stove, A. ?4 and DAXiattcraKT, I. Malignant Tumora Raoulting from very similar to that with ordinary connective Imbadding Plaatie* in Rodents. Scienca, 118:305-8,1953. " tissue. No histological evidence of carcinogenic 13. Orrrx*eaten, B. S.: Onaramtt*, E. T.; Srocr. A. P-; action by the powder was observed in this investi gation. Owing to the difficulty of cutting microscopic sections of tissues containing insoluble powders of glass and polyethylene, we have been unable Daxiomcruxx, I.; and Wmunre, iL Studies of tba Mack-anism of Cardnogeiweis by PUitica. AcU Internal. Unto contra cancrum, 15:859-83, 1958. 18. Omnunin, B. S. Orrexwruiea, E. T-; Stout. A. P-: Wuuarx, At; and Damismdskt. I. Tha latent Period ia Camnogenuie by Flastka in Bata and Its Relation in this experiment to follow every stage of the reactions to powder imbedding*. Experiments are in progress, however, with a polymer which can be dissolved out, and we hope to present a more to tha Pmarcomatoin Staga. Canear, 11:304-18,1958. 14. Zoucnot, H. U. Experiment*!)* Eratugung taaEgaac Niennkapaattomoranbaidar RattrdurdiDrucknu (Fla*tie-Kap*aln). Schwab. Ztsehr. Allgam. Bath. Bakt- 16: 868-T1,1953. Flo. 1.--Inactive, fbrom thkk-w*fl*d poekat formed around glass covarslip: 31 month* *ftar subcutaneous imbadding. H. It E. X310. Fra. 3.--Tissue (urrouoding polyethylene powder, showing foreign-body reaction with markad fibroblastic activity and many phagocytic giant crib; 40 days after subcutaneous im bedding. H. k. E. X400. 041084 , * - Pin. 3.--Result of inserting priyrthylrne powder In pre formed pocket showing similar intense fibroblastic activity in the wall, with numerous giant crib; 7 months after insertion of powder. H. L E. X43. Flo. Regrettingpocket wall 1* months after insertion of priy*thyiene powder and removal of (lass covcrdip. Wall b markedly reduced in thickening, but fibroblastic activity with pant crib b still present around the powder. H. k E. XUO. ucc 041085