Document 3eqQEQXwb9MzbYk80YyQwLr8a

.\"v <;r * /- /J & r if f 't *~V* /<ff Cf;.'' Htri'Wf manufacturing chemists association 187? A CENTuHY OF .-ffiVlL. ' 2 U2 CONNECTICUT AVENUE. N. W. WASHINGTON. D C. 20009 (202) 483-6126 RECEIVED SEP 22 1972 A N. *HtfUR, JR. yc September 19, 972. / c- TO: SUBJECT: Occupetlonal Health Committee ----------- B OlP Toxicology and (Carcinogenesis of Plastics Gentlesien: I call to your attention the review article by Fritz Bischoff, "Organic Polymer Biocompatibility and Toxicology," appearing in the September issue of Clinical Chemistry (Vol. 16, No. 9, pages 869*894, 1972). In this publication. Dr. Bischoff discusses a wide range of safety and toxicity problems associated with the use of plastics, including those that have been of some concern to our Committee, such as vinyl chloride monomer and phthalate plasticizers. Sincerely, BT Kenneth D. Johnson Assistant Technical Director Occupational Health KDJtmkb Distribution "B" N cc : Vinyl Chloride Monomer Task Group Phthalate Esters Task Group ucc Q0G57Q Organfc Polymer Biocompatibility and Toxicology 02ZS Fritz Btodwlf Advene affects of organic polymers used for plasma aitandars, tissue adhesives, bone ce ments, contraceptive devices, prosthuscs, arti ficial organs, food packaging, cooking, and lab oratory ware are appraised. Parenteral polymer disintegration involves hydrolytic, redox, and degradation reactions. Accumulative toxiciiv of plasticizers, antioxidants, and mortomcts liber ated from plastic container wairants investiga tion. Main problems with heart-assist doviu's arc clotting and blood destruction: with plasma ex tenders. thesaurismetic reactions; with any lie bona glues, transitory hypotension; with aitificial kidneys, toss of metabolic essentials; with sdttnnc heart valves, uptake of lipids; with silicone chin implants, bone resorption; and with liquid silicone mammary amplification, lumpy bt<vt&b and mas titis. A polymer fume fever is linked with pytolysis fpolytotrafluoroothytone. Human solid-state cardnegonesis constitutes a calculated risk with nclymar implants. In rodents, all solid irolyumrs tested produced cancer; chemical carcinogenesis was inducad by a polyvinyl chloride copolymer, vinyl chloride, polycaprotoctam, liquid silicone, and soma brand* of poiytatrafluoroethylene. Additional Kayphraaas pr*ibtir i/mn*. <mij, ml ryou Hotting paiymerititliim t>ilirin- m wiw pHpmtr dogrodotiim carriNtw Mr**x < ri4met from txptrimenl* m awtnm/w xrlj-i hhwi iwtwwpiw md mriilt Arrow <i, ///< > u.'./- mgn mfHp biting proctilnr** > lif n minus At* eriww from tiltconf tUpOtt > Iiiiii,,i imlni fii . food Wlwwliw WS4! nj /mljfMtrt, III rill:,I lit (AwteUry pMpninglpijrruliihmr m, Ihyliii' l,mr- rykS rpM mrtijieiul kiiintij heart mfec* Itorin* lldt twenty billion |KKind> ,l synthetic pafyaeta were involved in AiMvicn consumer products Ike tea Waste BtiWam Cutlass II1-- pul P. O. ns, Mi IMwi, Calif. tMPU. lniinu\ (/). lly tjTI the ale* of low-density polyethylene alone lot ailed (t.4 billion (rounds (3). Synthrjtie polymer* are rapidly replneing time-i<*ted natural polymer* sneli as and cotton. The impact of sviilh.-ti, pelvn,er.4 in the. human environment, as itj food paek.-ig- inii. anil |trgic:d iniplantaiion. is unique mecau*c tier. h;i- heed m> np|M*r*nitv to apply the erfteria of long- slMidingj ex|srietie(> through the ages. In the history of man, the HiV.-t* of mail rials used fori new purpo-i - h;i' e l,,i n ifi'idinu* ;ii times, Powdered cjnnubarserved , \li ti'ively as a ei.-metie in atieietit Home Id), la-ad pin:.if.mg ({) a-e| the swix-tening of wilic with lead ronipitiilids prodm.-il wide^p-ead hxid poisoning during early Homan and Ht-nais>anee times (Ji. A false sen-e of s* enriiy may ari-i- from the implicatim that advert- rlini of new |`r liieis are prislieiahli- with tile so phI lifated Ion].,,! M-ienee. 'I lii inn evaluates the limitations as well a* t :i|,,.li, aiioie of s-ifetv testing for synthenr organic ln.lwie i iliai alleet the human seem-. It is hoped that pi >|" r ale-e.iiion of research funds fur the study of jBihuek- liiiM-oiupatibilitv will be stimulated. IVrhap* tis, mu- li mount i* s|M-nl on I he art ilieiitl heart ami no* em.ii-li mi testing tin* safety of polymers used in food piiekagling and rooking. An aging cardiac official hold ing resj-an-H puMe strings may give the artificial heart liigli priority even though it can only briefly prolong the life of a man with generalised vascular deteriora tion. T<> the young family, the ubiquitous long-term a- -oeiation with (silymer* ami the risk of iiisjdiou- ciimiilative toxicity are of more suhjjeetive interi-'i. In a M-iise then, the syntlieiie polymers may hnve elicited mon* ethical and moral problems than chemical ones. I Syntfjielic Organic Polymer Chemistry The pi.-.ent i view is limited to| maemmoli-eul. - er.-atisl in n*ei*ut times by the organic chemist and loo-s-ljv r.-li rn-d to as polymers or plastics. Polymer' ur- fornn d from small moWulcs by two types of chemie-tl p-.-ietiiiiis. In i|ie eondensation ppacess, the Wineromoll is pnHluo l lv tin* elimination of reaction pnslin is. AVilli aildi'ioii )wilynwrixation, which is achiev-d l,\*^tllie litieratiou of free radicals, no reaction products ail- eliniiii:ii.-d; the empirical formula of the monomer and Jthe (Kilymer derivi-d from it are tho aame. The lirotyins ami alaiehi-s an' macromoles formed b\ eon- CLINICAt CHEMISW. VOt.ri.tte.*. IW* *** ucc 000571 rteiuation reactions. The silicas exemplify inorganic .addition polymerization. The polymer chemist is not only confront ml with initiating the process of |><ilvtmii/aiin(i but also eontrolling it. Feroxid**, plmtosensitizcrs. ami redox catalyst* atr t**d to initiate a type of fm-radieal chain-reaction polymerization. Cationic or anionic polymerizatinn it induced by rom|MMiiui* with strongly cid or baric potentials. Slotalhr-org.inie eoni|tnunds are thought to bo ill this category. The fnx-r.idieal and anionic systems give imlvmer* of high moh enlar weight. Recently an organolii ilium catalyst was shown to orient stereoisomerism (>>). Other wihstamss r>tioed to atop or alow down the process of isdymcriration or to direct alternate paths of polymerization r Straight chain vs. aide chain. In describing a eointnereial polymer product it ut imtmrtiint to know whether it coot aim plasticizers, inhibitors, catalyst*, liller*. stubihiera, ontioxidants, curing agenta, and (or) nnreaetisl monomer (7,8). Condensation Polymerization Hie eondenaotion polymers of commerce include throe well-represented chemical categories. In tin* formation of the polyamides or polyesters, a diearhoxyitc acid derivative reacts with a diamine or with a dihydroxy compound, respectively. In the formation of the polycarbonates a carbonic arid derivative reacts with a dihydroxy compound. The dienrboxy chains linking with the two hydroxy gnai|M may lx; aromatic. I'olvhcxameihvlcnc adipamiih', one of the nylons, is an example of a jsilvamide eondciis.it ion |mlvmcr. Dacron ia a |K>lyctliylciic lcrc|>lithaln<c, e/j,, :m tiro* matic polyester. The chemistry of silicone formation is deaeribed in the section on itiliconcs. Addition Polymerization Ethylene and ita subatitntion products are the monomen involved in the vinyl addition imhmerizntioii* of commerce: ethylene, iMwpylcnc, vinyl rlikmdc, viaylidene chioride, vinylpyrrohdoim, vinyl benxene (styrene), vinyl cyanide, methyl met liaerylate, methyl -eyaaoacrylate ami its Itomoiog*. tclmfluoreethyleitc, ddorotriiluorocthyiene, etc. Hteatise vinyl alcohol does not exist, vinyl acetate io the starting material for tho preparation of ixdyvinyl alcohol. In these polymcrintinns, a freo-cadk-aJ catalyst usually breaks the double ethylene bond, beginning propagation. How ever, qNWtaneoue frre-radieal generation within the oniMUMr itaeif, aa at high temperatures or with mdiatin, initiates polymerisation. Poiynvrizatiou is ter minated when two ensuing chains, each with a fan houd, couple or rearrange. Instead of the breaking of a double bond, addition folymariaatiou mny lie initistisl by the breaking of a ring aa in tho amide linkage in 2-pyrrolidonc (to hm nylon 4) and in caprolactam (to form nylon tt), The bunking of the double bomIs between nitrogen and cariwu in the diianeyanates with addition of diols faram the polyurethanes, lids is another tv|s* of midi' da poiymoriaation, beesuae no react ion products araloat. Silicones f^ilirone* (0, I'i) comprise a vurie x <>f organa -i'll on I! compoimils that have in common Si-O-Si - II. --Si -(*-- linkages. They are *tnicturnllv rd:ifp. IJ the silicas and silicates, which alao have the --Si - !i )- Si linkage, but not to the ortho ester-of *ilirir ;lcii|. wliieh are monomers, The silicon atoms in a -ili, may have mu-, two, nr three oxv ten liukng<-. Tie*... wi|b two oxygen linkage* form eh ti in* or ring-. A ti rminal silicon atom in a -trnight Or side chain would have one o.\yg' n linkage. jlfvdride, hydroxyl, chloro, and other group- !ir, linked to the silicon tetrahedron to make tie -ilicin more reactive A fluid silicone it represented bv straight chain in which methyl groups are the organic radicals. Silicone gums have much longer chain-, com. prising thousand'' of silicon a I writ fvr silicone tip !-ci^le, A rubber i* formixl from a gum by ero--lii.km.' methyl carlsm* by a fn***radical vulcanization proc. -> Ismg-chain sifietmes are for tic ijiosi part forne d In condensation reactions that would not produce Injdieals. Ilecattsc silicon, like carbon, lias a valence of hair it i# tempting to consider the silicones with alkyl .r phenyl group* a* analogous to iinreaetive long-chin hydixs-urisins The cross-linkage of the methyl gron,.in the formation of a silicone : sibber dcmon-trai' t^ie molecule is vulnerable to chitnical attack, .Mot. oVcr, (be silicon oxygen ImmI is ionic a- well a- >< valent. It is therefore of great ilii|Hirtalien to i -tahii-1 by safety testing in cx|tcrimcntnl mimal* or In lid'observation whether there is any difference in i*i : hgie rrs|mnsc Imtween the long-i liain satur:i'' d 1 i1 C^rlmii-' and I he silii ones'. Silicic arid is reeogni7ed a* a Inormal bun: >' ' constituent that prnrtr.-'cs t)ie jlite-tina! w.dl a. I rapidly exerted in the urine <//>. llccently, i -'i p.Mn metabolic rob* have ls*m as*ignsl to silicic and i' ertebrate* (ft). Silicon is present in bone in conn n- Jrations exceeding that in adjaeynt tissue* during m live periosteal ami cndoehondnal calcification Possible analogous or hfockingeff"ects fo'r " sj|ie,.n. honk! bo kept in mind. Diaintagration of tho Foiymot in Vivo Physical disintegratioii at thi implant site am] i| ticarance of urinary tagged on n compounds aft' mplantntioti of tagged polyi T* demonstrate tin fKilymers an; not immune from tack by body doiVi,mechanism* (U). In general, a il.vmer has a great khwmvd toxicity over that of'its monomer Is i au of lessened solubility and traiUportubility by bmlv flitnls. Moreover, in a polymer [the vulnerable groui would ho less open to attack because of prolictc. ;bji' stivie ronfigurat ions. The | olymcr erigend>r- ;! fon-ign hrslv rrxtetiim ami Iwcoines surrmindisl bv tl fibrous en|swihi, which greatly rialuei1* exchange wol body fluids. *--^twnv, v*l ia. no. t, iwz ucc 000572 * ,Ch*mte4l Mechanisms fte iMrhsntMM of the chemical disintegration of polymers are speculative. Unkxgrs vulnerable in bydrolyus by way of hydrogen ions, hydroxyl wins, nr water would include thoseof the polyester* ;llM| (tolyuret Imins. h Polyhexsmcthylone odipamide and polyeaprolnetnm arc attacked hydrolytically, hut polyethylene terephthaiate to a much ktwee extent, |m*sibly lerunse it is hydrophobic. Types of pnlyuretliaiM-, Imw ever, fan be prepared that arc hydrolyzed to a lesser extent than polyethylene tercphtlmlate (/'). Tin; role of the hydro, lytic cusyuuio ia these hydrolysre is unknown. When dependent on hydrolysis breakdown, the hydrophilic nature of the polymer ia of great in|x>rtunce in deter mining its stability (76). Even though a twlymer may not be vulnerable to hydrolysis, a carbon to carbon linkage can be broken by a tissue free radical or attack by oxygen. Reduction-oxidation enzyme systems arc probably not involved, because they occur in the mito chondria. The breakdown of polyethylene, which would appear to consist of very stable linkages, nspitu s the presence of free radicate in tissue metabolism (7). An assent ially hydrocarbon structure like polyethylene is subject to oxidation when pressed into a lilm in the presence of air at the melting ixrint, fanning carltonyl. carboxyl, and alcohol grout** (**) Oxidation-reduction reactions sneh as alcohols ;oul aldehydes to rarboxylic acids, degradation react ions such as decarboxylation mmI cleavage of liouble bonds, and addilioii reactions to double txmds are tstssibl Thus the ester, carboxyl, ami amide gnni|>s of the |miI.' urethanes are vulnerable when other prois-rls-s ar,conducive to chemical reactimi. The faster deteriora tion of polyurethane fount emilrasted with rigid pJy* urethanes implanted in rats has bren noted flu); a oomicurod Silastic rubber eniinbhsl ami disintegrated under similar conditions (77). Tagged PMyntgrt When radioactive polystyrene, polyethylene, and polymethylmethacrylate films taw iinfdnuted sulteuUneovxly into rata, urinary redswettvitv. which was small, did not appear for 21, 2(1, and .71 weeks, respectively, and then continued until the ini|dants wore removed. Radioactive sty rene injtwtrd jnibrtifaneousiy into rats loot most of the rndiouctivity in :tr It by urinary excretion (76). This indicutd breakdown of the implanted polystyrene, because ann-arbsl tnnnomar would have beau released imnsxiintely after im plantation (Id). The eempound vulnerable to hydrol ysis, poiyiwctiiyfnmtliacryfnte. hod the longer latent period, and tbs vulnerability uf the rarbeto-<-nrbon liakaps lor the two other rootpoambi is indicated. Radioactive (<!}. and 1*11 Ipoiymcthylmcthnerylate implants ( X , X 12, 12 X 12, and In X 1.7 mm) were compared sulteulaixxwsly with iMmtagg<s| im plants in fsmais bwias mice. Radioactivity, which did not influence tumor incidence, was nnted in (Is* urim* for the filet tt weeks after implantathm, iislieating the prowmet ef trapped munoment (76). The in vivo degradation ef [l4Cjmctliyl-2-cyMNxierylate, tnggtd at the number three carbon, has btsai stutlied in rata. I,ess than! lOCe of t)..* radioactivity rem; iti'-il t the implant si|te after I .VI days Tin' t.-igg'd 'I* gradation prodiMs :ip|S'.ireil mostly in the urine aij*l feces, pirafinu of tagged carbon iliowd*. while ton mea.-itreij. was indicated by failure to airoimt for all the radio. activity (JW). Carcinogenic Mechanisms Related to tolymers Situs* sfilid.stale eareinogeicsis i* associated with |sd,voter implant', the latr-i research in this field uiil 1st envereil in some detail. The etiology of a polymerinduced cancer may relate to a ehetniea carcinogen, a solid-state sttrfaei. or a eomhination of x>th. Impor tant sfejsi in the determination of the so'id-state eareimtgenit: mechanism are outlined in Ta >lc 1 (/, 77, 67,22). Limitations of Safety Testing Disenchantment with the result- and proi**ltir nseil in safety testing (7. ,*/) i- relleetixl in the re|irts of tin- l-lissl I'rotectiou t'oimaittis of ill*' Nationa Academy] of Seiewes (J,M anil tlx- World Health Or- ganixatiojn (2.f). Tin- phenomenon f sf lid-stall- ear- einogemsfis at tlx- rodent suh'-utaneous test site was a major dhjert ion. Sluli*tinti aimly't*. S'aii-tieal analy is of e\|H'ri- iiiettlnl ilata was strongly intlni-mi-d in] this country and England by two artii-les in /'Aiy*ifttVu/ lt< > i< - (2.5, Ihtring tin- |htiisI 11*21* llttil the Vati-'* -*t*- n-eli.m f]or discontinuity was generally hot applied i" thi- elit-iVpiare four-fold table. The use <1 the himiniial distribution without correction for small numls-rs w.-i- widespread. With conventional e\|s-rinn[ntal numlnT- of 2*> lo at), tin- ii.i-idetiee of an i-X|s-rim)*ltal nb-erva- tioii woiihl have I i Is- iueri-asiil hy 1 or 2 to establish a ronfidirtice level of W.V j wh*-n the Yale's corris-tion is appliial. The erroia-ons assumption of signihe.-mre is miiigattsl when the control ineklenetl is 0. because only ha|f the frts|U(*ney curve should be used. There is, mttnstver. tin* tlts>n-tieal challenge that statistics are wttj nppliealtle when the control nteidetiee is t). With a s|sntamsms fihntsareoma incidence of \r,', or h*ss in th** eoloity, one local librosarvoma in an ex- }N*ri)ne>hal series of 20 may have significance (,;); |Ih* hteal area w|tn*sents a small fraetihn of the total artfl subject to spontaneous librosareonijt di-veloptnent. Siins- ifi has been rejs'atislly demons! rased that hiany rareinogenie resp-.nsett are se\- and strain-linked, the prnetieti of constituting ex|sTitnental( groups com prised of both sexes ami (or) multipi strains mtroduetsl factors that are not amenabli to statistical analysis. The injection vehicle. Natural Vegeta f oils sut-h as sesamej oil are commonly used as the iilv. vehicle for the test txim|Htuinl on sultculaneous inlis-tioti. Among tin* olijis-tions for banning tin* use of natural oily ve hieli-s(67)are: I tint normal variation from batch 11 batch, partie tilarly (or mimr i-onstitm-iits that an* often eliemii-ally reaeiiv^* both with the test eom|tound tnd cndugciiou' metaltoiites CLINICAL CHEMISTRY. VM. |l. No. 9.1972 *71 UCC 000573 Table 1. Historical Landmarks of Solid State Carcin genesis lapaHftaimnarMhtm*/ lavMtlfaMr* V*r CipMrtmtftt* ltd gr iHtMtltlUrt Production of local adenocarcinomas by flats tubes inserted in fufnea pig gall bladders. Production of local sarcomas by baitelite disks implanted sub cutaneously into rats. Mice faded to do so. Petrov and Krotkina Turner Production of local sarcomas through sub cutaneous or intra- peritoneal implanta 1933 tion of plat'num foils in rats. Nothdurft Recognition of choles terol-crystal smooth Bischoff and 1941 surface ca.'cinogenesis. and Bryson Production of local sarcomas in rats by cetkdaaa films wrapped around kidneys or Oppenheimar, implanted Oppanhaimar, subcutaneously. and Stout 1948 Production of local sarcomas by sub cutaneous implantstation of rigid tin foil in rats. Oppenheimer at al. Rocognition of foreign body carcinogenesis without the involve ment of a chemical carcinogen. Rocognition of the importance of the physical form of the implant in the etiology of foreign body tumors. Smooth surface carcinogenesis. Recognition that the carcinogenic process was involved in the formation of the fibrous capsule which was conditioned by the smoothness and size of the implant. Zollinger Alexander Nothdurft Correlation of local cancer production with physical state of 1952 foreign substanceliquid, semi-liquid, solid. Shubik et al. Introduction of `solid- state carcinogenesis' to replace `smooth 1954 surface carcinogenesis' because the smooth surfaces of liquids are not locally carcino Bischoff and genic. Bryson Production ot local sub cutaneous sarcomas by implanted n- dotriacontane disks Bryson and 1955 in rats. Bischoff Production of local sarcomas through encapsulation of MraperttoneaNy im planted gold leaves in rata. Hecht as cited by Nothdurft Before 1955 Production of local sub cutaneous sarcomas by implanted disks of chotesteryl or glycaryt palmitate in rats. Bischoff and Bryson To. 195$ 1960 1961 1962 1963 1966 1969 solubility factor* leading to solid de|xwits (solid* state carcinogenesis) toxic coanpouents producing smyloulosis in the boat MukUflt injections at the subcutaneous site. Multiple ePbcwtMeous injections of the test com|touud on a aiAty or biwoukly basis extending over many months ia*triers with norwial homeostatic control. Cancers as produced can lead tu false labeling of compounds aa carciaogmx. Tlw initial local re|>arntivc process te say MbcuUnrous injection is innocuous enough baeaaaa mature fibrous tissue results. Hepiated in* jocimo at the same site prevents the normal IteaUng process (40). The production of local fibrosarcomae la rata that meeived 74 wisely inp-ctsMis of rarimxy- rihyteeUukae, polyvinylpyrrolidone, and polyoxy* ethylma aorbitan monostearatc ("Tween 80") (87) would nut np|x-ar to have much significance. \Vh> n single sutxuluiicoux injection of a chemical lead.- t" local ncople*m, then the evidence for s chemical car cinogen is more conclusive. (See section on Plam.n Extenders and Wato-SolubU Polymers for complin tions arising with high tumor incidence in controls.) Theoretical Considerations Polymer free nulieals. Free-radical formation dure c polymerisation cun be measured by paramagnet,. resonance absorption spectroacopy (tS). At its n |tion a dimer lias one free radical per original moiu>tn< r For maerontole polymers ranging in molecular weight from thousuuds to millions, the ratio of free rude >.l to number of parent monomers becomes vanishing'', low. If the polymer produets used in everyday lit-- MTRV. Wat. 18, No. , 11/2 ucc 000574 - i-ooaiatcd vulHy of atable r-wcigbt imly- mera, there would he lM*l<* rationale fur pn-iulatieg rote tor free it fwdi nur taxicology. cvor, a wide variance in molecular weight is inherent in the overall aptvito conglomerate of a mimix n ini product, which may ctNilNiu enttap|ied iwilytmrs of ^ low molecular w eight and fri'e-mdic.il-forniingcatahsts. Polymer breakdown may incur through a fret-radical ajnrtrm involving oxygen (-W. The fate uf the free radical in the |Hilvmcr is best Hfurttwted by the reeently reviewed (//) elnlxirate atudiea ua the silicaa. In a thri'iMliiwnsiimul formula for aiiice, every oxygen atom alrnrca two silicon atom* and every silicon sliares four oxygens up to the bound ary. iilvro free radicals arc encountered. Most natural ailica crystals and precipitated silicas contain SiOff (siianol groups) on the surface (JO), indicating a re action with the original free radical, (las adsorption would be inevitable in the presence of free radieals. A precipitated silica with a thrco-diincnsioiml random core has three possible degrees of --OH Is Hiding at the surface: tlic silatioi group, hydrugen-liotidcd water at the siianol groups, and an outside layer of free or adsorbed water. In this model amt its extension to organic polymers, other jwlar substanees could pre sumably replace water. The itotential carcinogenic haxard of the isilytoer free radical is based on a tbcorixed transfer of unimircd electrons to molecules in tin tissues surrounding the polymer. Tlie free-radical clmiit reactions induced by radiation to produce cancer t-JI) as well as the formation of free radicals from carcinogens f.W) are nnalogoiis proreaaes. ft is unlikely that a free radical wonld survive the distance betwetni the imlyim-r and the target cell (S3), but it could exert its influence oil cellular materials (3.{) from the area outside t he cell w all. Considerable ex|efimental materia) with rodents (33) refutes the ladymer fret--radical theory of earner. Comjiarativc studies with true |alyrocr containing free radieals and macromolc condensation pnslucts (35) allowed no difference in carcinogenic effects, e.g., * a polyethyleito polymer ami eello|tlmiie, a jxilyctm* dentate. On implantation of (l4T|-taggrd |sdystyrcne, polyethylene, and polymethylmetliaerylnte polymer disks in rats, snudl amounts of tagged degnidalnui products were excreted in tin* urine (**- section on Dieinieyrotion of the Polymer in vim). The view that free-radical activity of tlie degradation product and not the original implanted (lolyiMr would initiate the earrinofenic prorew (/.{) was later withdrawn in favor ot solid-state rareinagciuwis (#). A more likely rob ot the free radical emergea when the tsilyimr is en gulfed by the phagocyte. With silica in tin- lung, tin; engulfing atacrophagc may die or release imtig-nie substances, which in turn prodin-e antilsslicn in the retkndocndothelial system (J7). l-or a similar defctise mechanism involving tin- plutgof-yte ms- the section on Poiymrrfumefever i* kumont (p MKt). The lyoomtmto in polymer rniriHoytorki*. A unitary theory of eareiisgemwix |sisttilates that damage to the lyansame memhrsne by poly tner hydrogen bonding, with rch-wsf id a DNAase, would induce chromosomal mutation tending to cancer; radiatirai, the chemical (sningnii, and vhiown all have been shown to affect the lysnommo (33). The tln-ory 'kss* not exfdain nor derive support from the phenomenon of olid-stnte carrinof-ruesis. Ill pOtn|ietlllg with the |lso<>|||e jtlU'lllhrutte for silicutc polymer*. poly-vim Ipyridinc I N-nxnl*. tj/yi is a us<ifill therapeutic tool hi tlie prevention and tr< ;tiim nt of silicatc-du-t pneumoconiosis With rI <- -ilieu-, in tislenls at the tMr.'iihor.'ieic site, the riiiinlmn n il sarcoma is the characteristic neoplastic nntnifi-tatioa (iO1. .^s iialicatid elsewhere in this review, water-' soluble pulwners tire td-o s-jsjsd in retieiiluni nil sarcoma prislucti.m, bin the evidence is not cotirhisive. ( arcintMHnir form in mliil-vUitr rarrinotjrncsis. Tinfocus of stircomntoiis proliferation line heeu a.-erib.-il to ecllji located outside the fibrous capsule that '-nvelojios the implant (JI), in the middle layers of tincapsule (.{2). and inside the capsule at the internal surfact- adjacent to the implant tJn. L'.-f;. Iti rabbit(.J.f) afal mice (.}-ib there was evidente that the curcitiogehic locus was net in the fibrous capsule Io;i n, cells residing on the illlplaiit. With M.:hcl|tuli'- it,. pliOits ol iinplastii i/i il \ ini 1 elderid--:e l late i ot" ' I di.-l,- ih mice of stiaitis mill teal w it In nit ti.I r*-tin o. marker, the pre-unpln-th- unit tir-t appear.<1 in *t. libroii- capsule during the process of formation . At latl-r stages t-lonal prog, ey could Is- found a- i!.. surlact- of the film and mii'ide the filinnl' cap-ul* . These exiierinwnt' sisaii to tccnm-ilc tin- uppatMitlv conflicting earls r observations in rat* und mice, p, rhajis tfveryinaly wtis right. However, species differ* in.and the use of unstable polymers leave undisclosed tl. fm us tif siliil-st!ite careinegeiii^is. v liii-h cannot establisbisl with certainty until highly unrea. tin- -u|.stanci's such as gold. tin. and dot rite-pet auc tile u-. .i I'olyvinyl chhiridc co|ily tin r i ill-'iiitc.l for -tteli .11: solid-Statc carcil.ogtiit-'is i-xi hisive of chemical t:e l.-l The vtilnerabili'y of the inrhoti-chloridc bend. !: breakdown of tin- |silvetliy|cttc nuch-us in vivo i?., tl**change iti surface characteristics when bathed in body finals, and the exchange of metabolites (or ingredient- (.J7) tire not eonducive to a study of bjisic mechtini-niAfter!its tmjmtni in the body, chemical lestitig of tb*. |Milvviiiyl cldorttl' cofmlymer was hjrking. Since tlw process ol iMilynierixatiou is nwersihle, the parciiagt-nic (Hiteutial of the monomer, polyvinyl ehlorafe. icniciai in evaluation of carcinogenic studies w- :i-th1 tl*. js-lynier. Hats ex|msed t a constiuit flow of :iir with fill nil <-t vinyl chloride per liter for nwinths laid a (si to "ft*, incithiice of cutaneous carcinoma in tlie area of the -ubmaxillary ami parotid ghimls. ami :i \xf > incidence lung csirciimmas ami lame osteochondromas. Such enneyrs did not apjs-ar in an iapud number of .* ('"ti* trols >x|Hi-csi to tin* same rate of ait mow (!S>- .\tu>.i g the ihireiichymai lesions ofro-rved in the vinyl ch|orid exposed rafs were tlegetientlion of fhe ci-ri-belleni. chronic lie|iatitis. interstitial pneumonia, and swelling of thekideny jniri-nchyma. TissueeultUP- of normal ami neoplastic iinaisi* ami rat tine in media containing OUJ to 0.1 mg of |sly vinyl -ulfatc js| ml dotii.iii-iraied inhibition of growth :is conipansl With control' (,'*) Tlicj imlynu-r with a vinyl group cannot be tliu- regnnhsl as inert Tin- difference in purcimigcnic effis-t UtwMii it and glass, which is an inorganic jstlymer imt affecting tissue culture ('>(/) atid having a mild local _______________ u,J IS Ma S 147? m ucc 000575 tawOe response ((/) was demnnstrail'd in comparative aludies (St); the latent |ri<l for glass a- mich longer. 18 to 80 month* for fi0% tumor development (K. 0. Brand, private communication). In a series <>t 43 iRM1, 25 developed tumors by the 12th moulli with vinyl chloride eeotide cn|ulymer implants < \6). (ilass eovmlips wwx* ow'd a* a control because their tumor* igcnie response was negligible during the nlisrrved tune period for thecotolyncr (SI). Cyst1 fwmmtio* arouiuf tmfdantnl /m/i/an it in rwricwls. In timin' scaffolding e\|ierime(its w'illi gin** tube* sheathed with nylon (J2) or with indented imttona of silicone rubber nr iwlyothyleiie (63), well, of rtM> fluid developed between tin: librous capsule and implant. Fluid waa ofaHcrxcd betwein implanted baki*Ktediricc and the local sarcomas (d.;). In experiments w ith dirt implants of dick-sterol needle*, chohsUerol plates, glyceryl paImitate, cholextcryl |ndnutate, and dotrineontane in rata (>/), the incidence of cyst formation to sarcoma yield was variable, with none for glyceryl palmitato (Table 8). C.vat fluid sometimes reached largo volumrn. Tltc internal cyst layer wan lined with *urcoma cells in some instance*. This was observid also with organic polymer* (4-1). Tlio premaligimnt cells could originate on the implant, be released into the cyst fluid, and ttieu invade the cyst ca|>sule. In ex|M>rini"nts with porous |K)lymethylmethacrylate implants (**) the hbroblast in the libnnis ca|isuie secim-d to originate' from mono-eytoid exudate cells in the cyst fluid. How ever, the aaline wash of fibrous t|*suh's seven monthx after iwlymer implantation recovered Im malignant cells (Xothdurft, as cpmtisl by Itryson and llixclmff, (01. Thr tolid-dalc ttrrinmjinir sc/e. The pretieophistie rodent fibrous capsules around siimolh surface solid iniplants is cdbpoor ami avascular, whereas the granulo matous reaction to fragmented implants is cell-rich, vaacul.tr, and noncarcitiogeiiic. Different tis-ne nqmnce* may arise at different ureas of the same im plant. The original nodule hi solid-state carcinogenesis doea not overlap a aharp cslgc or corner of an implant (M), in keeping with Hie eoncc|it (67) that ex tended irritation has an inflammatory mid nntiearcinogenie influence. Kvidencc (68) that mechanical stress would induce more of an inflammatory ansi at the diarper curves was obtained for rats by studying the fibrous capmiku surrounding Milieutamsats im|4anta of disks and spheres of rve polymer or nildsr for cell density at the surface adjacent to tbe implant. Forty minutes before sacrifice (aII|tbyinidiiie wa* in jected intrapcritooeallv and autorndiograpliic deter minations of the capsule were made. Cell density for the ghtmi waa random. For the disk Die highest, cell density occurred at the sharpest curve. 1 Cyst faaaiiw amaad impiatiis aim uhxii-. in himwn<. TIs* Mowing wsagda was Mussoitwnt iu thr lalsualory ( l)t. D. ft. Ilataa, Koala ftarisoa: A/Irr three yi-nis is > , the m*ap> wflwli |m tha IsiwC ,4 a wiiaian sbritiik aisl Is-rame hihai Mtctioood surfwm showed a pvri|ilMtl yrllnw-whiie "iidtlhi aiva 9 mm thick with a esotral sfssiay dolt-yethiw patiu. Oh tha omtsl mifsee id turn them was a ry*l, l:l min in diawWrr and 9 mm thick, MM with daw Hold, located Iwtwaea the pwipiuml ayah aad tha iagdant. m CUtMCAt ttMMMVftV, sk ML Mi. ft 1172 M Tahiti 2. Cyst Formation RcUtod to larcoma Yield toipUiit** <nfltrlal ki ftf Total Latal lacfll Mriomit faitircamifl wim ertti Glyceryl palmitatc Dotriacontane Hydrated cholesterol plates Cholesterol needles Hydrated cholesterol plates Cholesterol palmitate & 9 tf <f 9 Cowbinotivn / rhtmical and xolid-stn'e carriiwiiau The influence of gamma irradiation (100 megarads'. and coating with parallin mi the proiuctinn of local aaroopias bv subcutaneous implantation of |il\ca|>- rolactam disks in rate (69) indicated tlint a cle-mical rniction between the implant and surrounding ii--m-- was otie of the carritingenic facters. Hadiatiun nf the disk Was without demonstrable rITect: 14 H` vs. IT t| surcoinus for tin nmiirradiated serits. The paraffin surfaci- markedly decrea-isl the sarjoma ineideiir". 2,'41 Vs. 17/41 for intact disks, Hxt\t1- and intfnriiiriniHifni, on ini/ilanl rrtm/i'/ru< ms In Sw^ss mns* Is'aring -ulM'iiiaiusius ini plants nf gla-- m Tellmi. the injietiiin nf Tr\pan blue, which is a weak carcinogen and is taken op by the local fibrous capsule, and tfie addition of urelhan (1 g liter i to the drinking water did not influence the incidence of local sarcoma development. Implantation of radioaitive -urfaei - 11.1 lint enhance crcinogeiie-is as compansl with imn- radioaet ive surfaces (ni/j. Disks ix. nit*. In a study (HI) in w licli 11tb Wi-tar rats Isitli M'xes were implantisl with solid di-k- <>f |silyanii(|e. pol>ester. |silyelh> line, and |ml> propylene, or wiili nets of the polyester, the results conlirmeil earlier work (6d,H2) that the tumor i icidence depend' 00 tlie siirfaci' and size and is diminished wlun a foreign bmly giant-ci-ll reaction iw-rsi-ts (?). Knitie,! polytwtiT nets (2 X 2 cm) made from Td 40 polyeti-r yarn, whin placed sulicutaiieously cr over the liver intraiwritoneally in male ami female rats, elicited no local tumors during a 24-month |M'riod (03). htral eirryUilnii/ dittnikanrrx. Soli l-statc sarcomas are related to loonI eireuliitory disturbances that ile- velop in the fibrous eapsiile around (be implant ah' r the latent |NTiod. Im reasMl enpillary format e ' IliroiJilsisis, veiioii' ihstortioii ami eapinary di*t"it (//{) and eompri'ssion (/;.<) have bi en d senbeii Catinn ic and /i/yrr*. An attempt to 1 or- relate toxicologic including can inogi tiic act ivitv wiih pliysleui'heinieul pniiwrlies was made ly comparing tla- long-term tissue reaction in rats to ifnplants of a rat- ionic (lolyiner (polyvinylbenxyltrinri'thylammoniuini chloride, an aiiwmie |iolymcr (sodium polystyrene sulfonate), and a eomph'X ropfwdpii at 1si by both of tln-m (tat). Ueeatise ot the small liuirjbi r of rats, 1<> in achisi-ries, eiMH'lusions are limited: The cationic film waa sigutlicuiilly more tumongemc than the neutral lilm. The weakness of the study lies in the teriliiation of the lilma with formaldehyde. Sima the polymers are fi0% water, it is likely that, even after washing, some ucc 000576 fonwddchydo remained in the polymer after implnniation and would react with cell* adjnrent to the |*olvmor. The imiwrtance of thia early cellular reactivity Ims bow emphaaiaed (7). Also the eom|tarieoti of the films it aot atrictly o a phyaioehcniieui (ionic) basis, I*cotue the atyrene aulfonate croup (thrombo-rcsistant iu vivo) in one end the quaternary ammnnium base iu the othW would have toxicologic implication-, related to organic structure. The anionic and cationie films pfodneed artopic bone formation in the nonnialiguant fibrous capsules that engulfed them, whereas tlie neu tral film did not. Since the electric surface chance of polymers ia effectively nullified by the protein layer chaneteriatimlly formed on implants, its influence as a eareinegenie factor would be unlikely. Cationic |>olymers enhance virus plaques by accelerating the movoaaeot of the vimaea through the gels, which have be come positively charged (68). Human SoKd-Stata Carcinogenosis In addition to the human lung carcinomas tissncinliil with foreign bodies (6S) and the sarcomas associattsl with bullets or shrapnel (II), other human cancers re lating to soiid-ttate surfaces include: A sarooma arising locally 30 yean* after implanta tion of a relatively large metal lame plate (Mi) A chondrosarcoma occurring locally six years after hone-nailing (70) A giant cell tumor of the femur, probably malig nant, three years after implantation of a Moore pros thesis (7/) A meningioma surrounding a silver clip left in tlie area of the fronto-parietnl-parosagittwl lobe two years previously (75) A meningeal sarcomatous tumor (75) at. the site of a 1-cm wire that pieroed the skull of a male `JO years earlier A meningioma (74), with a latent period of 40 years, which arose at the site of a darning needle, in a 40-yeturotdmaie A foreign body-induced adenocarcinoma of the ciliary body (75) related to a nonmagnetic splinter from a detonator A tumor at the site of a bone splinter from the Tabula interna (75) A mammary eareinoma surrounding a needle en gulfed in a pus pocket (75). Thaw tumors arc relatui to inorganic solid surfaces. Local Uiaaon socribed to organic polymer implants follow a similar pattern. A human diondrosamuna intimately associated with tlie fibrous capsule sur* wooding polymethylmethacrylate spheres, which were implanted an a piombage 16 years previously, gave rise to tho dberieal picture of rodent solid-stale carrinoomob (7V). Became of the limited life I'xpectaney rf oat patients with occlusive vascular disturbances, thorn boa boon no blent period of 10 years to date amufi many patients subjected to isdvmer grafts. A fibrosarcoma of the thigh develops! locally in a young mgn Wi yearn after the repair of a laceration of the loft Mpcffieial fesaorsl artery with a pnartltesis conanting of wovea Teffort-Useron (77). A local enrsinoms sppeared bar years after a mammoplaaty with a Silastic implant Preceded by -implr ma-io-tomy f.,r ebrobir fibrocystic di-ea-i- (7S\ Tw O p.'lllvtlt- "ll'l histories Ilf fihroiystic di'"!l-e u Iim lad -llliple 1111tectoiPies and silicone implant uhsequentiy develop' <| bren-t cancer, bet not in immediate contact Willi the implants (76). Women with fibrocystic di-case hav< hiithe|r incidence of cancer of the breast than tiewithout (31). Since isolat'd case histories, interestim- athey are. rarely - ttle problems of carcinogenic dcmiililogy statistically, the role of the -ilicolie im plants as a carcinogenic factor remain; in doubt in tie two examples. In a survey relating to the rclalinb shortj-term enrrinogenic imtcntial of pla-tic foam im plants in the human female breast, no sub-tanlian i malignancy uccu.-red for lli.fiOU implants. One -nrc m howcVcr, reported three sureomas alter 1(M implant (SO). Effects of Polymers is ProsthosoS and in Artificial Organs llciplarcmcnt of funetinn. whether diichanical M i i.i phvsioclieiniral, is the most import.mj diim n-imi m il phvsiology of polymer compatibility. A pr*>*tl,i -itdeally suited to replace a normal ti4-ue should in a !> eoudi'inncd for not functioning in an abnormal -mrtion. If a living nteml>r:unm- surface [if :i lieart v:dve ivulnernhle to stenosis ur fu-ion alter bacterial itif!.ui.nation, the ensiling living membrane that fonued ,<n a heart valve prosthesis would he similarly vulm-Mbl-Sinct'stagnation of hliHsi in normal blood ve--el- r:,r. lead to clot ting -- bleed nigraii-c* fewer death- than ini ravaschlar elotting (It,)- - a polymer blood ves-c| ii pl.n. ment-would priHoiee the same clot ting under similar e"iidilions. (\>nver-el\, the gmnietrir h;|lHing eneounti i. <1 with kidney an 1 heart a--i-tanee ot replacement ihvieisf ismsi a dotting problem in itself--a noinhronilmsing surface at rest may induce rlhtting when active (83). (Sis* section on ('Mlini,.) A prasthei* may -atifiictprily replace one or more functions of an organ, inn it could hardly Is* expected to nwlnce all of them Thus nn artificial lung will serve for] adequate oxygen carbon dioxide rxchnngc. but lacks tlie regulator mectiatiisma involving hormones aril enxyme sy-t< un necessary to maintain all the functions of a living orgae The dilfiTenci's in piilsativevs. noupulsatile pre--uro to Insist action--problems with artifici tl heart- o'.fp - .ui reflectisl in peripheral pre--tire. lung, and kidney i'uiutioii. Here, density may preclude hydrodynamic II"" Shift flow is thought to replace camllary action in 11,. glomerular b<sl-' of the kidney uiid the alvisdi "f tinlungs (84). The liver may have ehi|ct*flow- action !< bence capillary flow alone is nn inadequate model f"r nMuswinghlmMl transport prohlems. | As polymers are prisluced which an* physically aid chemically more akin to the adjacent cellular isunp"nents that surround them after implantation, the proeins that become attnchisl to their surfaces will !>< tlmse that rent the tuljneeul cell surfaces: but heenu-c the |H>lymer is not identical to tin- living cell (Ihtc will lx* a kind of denaturatioi: at the plasma membram-. which could v ry well evoke an ai toimnrune reaction ending in a rejection phenomenon. An example of I Intype of rejection involved nonpolymer subcutaneous CLINICAL CMEMISTHV, not. 11. No. , 1972 ns UCC 000577 implantation. In (critifof .'tit fi mak1 1'ivaii- rat--, implant* tf. IK-mm dism* ter ehoh-.t.-rc.l hydrate di*ks oomp*r>d will* dotriacontane disk- ,,f tin- s.-inu -ire produced ft ,r.'{% and 10'.;, incidence of rejn-i ion, re spectively, The natural IhsIv omitin-nt ittli*nhn*-<l in tn abnormal physical -fate di-played |<-- hiornmpatibilitytlmn the inert livdmcarhoti {II). With highly inert snwsith-.-iirfnee solids made from noble metals, tin, dotnaroiitatu, etc., the initial in* flamHistory rowf-iiue Jift* r tin- implantation give;* way tn the forotfttion of a fibrous ca|isule, which nets as :t liemtMM-tit harrier to mi-tafnlir exchange and tnav istaist with itn enelowsl lorrign Issly lor the liletinn of the recifftent. At how; tutim, this limy h iui to malignant h^L-neration face Human Stdul-Slatr. <Jarrm<>u< < *!" I. A Isme pnwthMM tliftt ilevebqis a layer of fibrous ti.--uc introduce an vmiitiil complication. By using prois-r porous material**--a diacotit-inmaiH solid-state surface-- bone formation instead of the hynlininsl collagen tajs sole in enomiragid both within and without. the pros thesis, and the prosthesis reninins more biocompatible () An iduftl prosthesis would Is- one that takes over the function of the replaced tissue, at him lut'-stlie formation of the repiact-d tissue, and is itself ultimately re-nr'a-d. This wiaild solve the proltlents of the two estrones-the autoimmune nttction and tlte librous mp-nle. Ideal suture materials an; well known; these ultimately disappear from tin; site of application after they served I hi; |Hir|MiMC of arresting hhssling or wistnd elosttre (90). The Artificial Kidney The ceiluiosic iitemliraiies used foe repetitive hetnoilinlysis in patients with chromr kidney failuie operate by imssage of solutes throiinli micro-lmles. Ite.-l known of these is celkiplmin*, reconstituted from the natural iwnduct cellulose. It can serve as a reference for -yuthetic organic |stlymer dialysing membrane* of thc future. Permeability of ceiluiosic membranes is cor related with the imilecuhir volumn of the substance crossing tite barrier, However, of two sultstnnces having the same molecular volume, it may not la- desirable for both to diffuse tlinstgh I lie Imrrier (97). When the siaes >. T molecuh-s ap|irtuieli the sine of tlui membiune pore, tlieti surface forces come into |tlay, so that, even with the ecilukmtc memlimnes, transfer may be inHucimmI by factors other than |mrr sise (ftti). Transfers across the cdkgihaiift memliraiM! can la* influenced by the ninnpniiitiiin of tin* dialysate. Htslinm, calcium, magMM<im, chloride, ami acetal* imis an* added to the (Jiatyaing Wttid tn iwevrnt their km*. Plmejilmtc ions an; omitted boeause their removal is a major problem (HO). The filma originally used in the artificial kidney are isnabi rsnmr and fragile, nisi tlte equipment associated with them ban a large voiuw. Smaller equipment 1ms bro* designed by aubst it tiling coils and hollow fils-rs, width mcreanc wanbrsne area and lend strength of To duplicate mars easeliy tin* normal kidney, it would be dwdmbhs to develop membrane* that would sfpftiwte molecules cm Uh- bads of ciu'niieal pni|s;rties as well aa aiae (#7). A waishleraMe annamt iif nwareh has hesm mrtwxl out it* <leveio|i partition membranes fur hemodialysi- l.iiear Imm >|silym> rl which have the di-irapb- hvdrnp'iilir prop, r*:.-., ,|,, .(lt|,r.rn, nieeh;inie;il sirencth und< r 'hi- r-mdilions of dial\-i. Itandom ropolyni.-r* cave i<n l,,ti,r prnmi-e HI- copnlijni'-rs and ''rie---litik,| pulvne-r. ran hav. hydroplnln- and hvdrophobie I'Cnp.-rie-. i,-> >, l ha\ a. * Is > n |ablt- to a-*'-- the e\tent In which p.r'Ua nu mhjrane- have been u-<-d fur human liemodiah -i- In h'ldili'iu " the dialyzing sv-ieni. 'aif artitici,! kiilney require- heparmiyalion, width nui-t In- a<h. qietl' lv coiitrolleil (/>/1 A practical device for ci.n. tii'eliiiig tlie |ial,eiit's arteriii-venou- :vstem with tic- artificial kiilnev i- the extractirjioreal cimnt. An arti-r\ and vein an- con-a cti-l by phi>tic implant- with a >lium tills-, which is reniovahle. Thii problem of thrombosis as-oeiateil with tlic artificial kidney i- well appreciated; the washing out of constituent- es-eminl to normal met iholi-ni by cn- tiinnd use <*f the urtilicial kidney is more difficult to asM---1 but probably i- the limiting factor in the effec tive d-e nf the artificial kidney. There is little infor mation regarding the release, if any, of breakdown material or entrapped material from the dialyzing system. A* tin- synthetic organic ]s*lv nrsTs replace the celluhisic niembran<s> in tie- artilicial kidney, the p><-- -ilslitv of cotraimsl toxic -ule-tance- reipiiri-s further evaluation. Heart Valves Thy natural heart valve in its uriioii engi-udi-reentral flow in toiitra-t to the lateral flow with eert.un t\|s-sof pro-thetie valve- -ueh :i- the raged hall, enind di-k, pr tilting disk attaeln-d to ois- -ide. Attempt- have lsi-11 made to u-e |hiI\liter eup valvi4 in-tead of aortavalve homograph-, wliieli have been useful (fl-. -'Af. bill diflictilt to pr*icure or replace. Kni ti-d Teflon cu-p valvei* tenil to promote a fibnui- reaction, with calrificatiun. and to fracture (H-t). Siln-tic-impregnateil cusp valvi- are in the same category (94). Both typemay prisluce hensily-is. With the cxtensively-u.-i-d hall valve, complications include (85] thrombuctnboli. obstruct ion, infection, detnehment of valve, and anemia five section on SiUnmt for tipiil absoi-ption by silicon heart valves). Assessmeat of cloth-covered Staijr-Kdward- pro-- thiw<| in 100 paMents indicatisi that t he hemodynamic function became unsatisfactory in many of the-.patients. Cerebral endsili, hemolytic imemia, and cloth and strut- wear (fki) have occurred Thromboemboli fornuition ami dt general ion of the silicone bull u.-<-d initially prompted its discontinuation in favor of a hollow stellite ball. Altluaigh tin- clot h covering is n.u idi-ntifiisl in these experiments, carli >r references {!;< indicate that knitted Dacron fabric, Dacron strut-, and Teflon oriiices were used. In patiimts with Starrl-'.dwarils valves, deterioration and fragment at ion of Tefliiit has occurn-d. Some of the cardiac, cen-brul, and other artifacts obw-rvxl for patients 4iith thcac valvemayW Teflon emboli (07). Artificial Hearts end Heart-Assist Devices An excellent review on artificial iiearts and heart- m GLMNCtt. OHCHttniV, VM. M. Nft. I, 1WI ucc 000578 Aiwitft device* (98) will not bo elaborated An artificial heart is do*ietud to replace completely tin- circulatory function of a natural hoart. A heart-assist device partially rciicve* n tinturaI bean of its pumping activity, usually on a temporary basis. Tin* heart-assist device with in-parallel rontux-tions between the atrium and descending aorta, wit It in-series rotim-etions be tween the ascending anti ih-scinding aorta, ami with in parallel connection* between the left ventrirle and d*- Mcnding aorta have not gainisl wide elininil arce|i-. taacc or are still in the experimental stagi-s. Intra-nortic balloon* are readily install**! by threading the ball anil catheter by way of tin* femoral artery to the aorta (99). Such inner! ion* have been made with promising results in about 200 patient*. Among the isilymers used for a*>i*t device* are Dacron, Dnmm velour, epoxy resin, polycarbonate, polyurethane, polyurethane copolymers, and Silastic. Excefit for an artificial heart that kept a man alive <14 h, it has not yi-t found practical clinical use (82). Among the |H>lymer* unxI for making exjieri- mcntal artificial hearts are Dacron, Dacron velour, polyurethane, and polyvinylchloride. Clotting and Cellular Destruction Clotting, a basic problem in prosthetic replacement of blood Vc*ncIs, hemodialysis systems, and heart-lung devices, is stimulated hv siagtmtion or turbulence of blot*l flow, junction* of different materials, or Itv any foreign bo<ly. l)e|ieoding ihi physical and chemical properties, each |*ilymer prosthesis creates -tHei;il problems. For the vascular system, the ultimate aim is a prosthesis that is negatively charged and semie,induc tive, acmipcrmeable, and onitpiely callable of alisorhing. releasing, ami exchanging Urns with |io*ittvc (barges (100) . Among the polymer* having relatively less chitpramoting properties are polyurethane ami Du Font's ``Delon" acetal resin (82). Coagulation time is not decreased by a writable surface as formerly believed (101) , nor is seta potential (108). The negative charge (-3 to --13 mV) of the blond vowel linings repels the platelet*, which are similarly charged. IIoptore of platelet* attaciicd to n damaged blood vessel or polyitw-r initiates tlie clotting mechanism. Htpnrin. Recaunr liepnrin is a welbktmwti antieoagutaiit, it* incorptmtiou into and release from |miyro*cs used an artificial organ* lias bnu extensively investi gated both with ionic and covalent bonding systems. Moat polymer* such a* silicone, Ducron, Teflon, poly propylene, polystyrene, polyurethane, jsilycnrbonate, and the epoxide* do not bind heparin, which has a nega tive chalice. To promote binding, positively charged surfnes are prepared by a eolluidal gra|hitc mating that bn* absorbed benxalkimbtm chloride (Zephimn chloride) (IOS), by absorbing tridodfcyhncthylummomum chloride (TOMAC) (/<M), or by incorporation of Tsumnopropyttrictlioxy silane (82). A covalent iMparhi band to a polyirnT is Achieved by meium of the Isocyanate radical (109). None of the ile viem.that make use of ionic bonding have the neenwary rffcctivc iwnmnenee; the covalent binding give* even las* oatiriaetory remits. Ho that the |**>l of lieimrin may be inaeaand, the whole fabric is not bomb'd to, but instead huf*ngnatad witli heparin (82), Imt the gain in elective time span is not suflicient for p.riniiient deviees O.ie of the problem* with heparin I. p... ehapgc in ph>'ie.d pr*t|iert j,~. of some polymers to winch it is added in high ronrentrntion*. Heparin dm- n..t apiH^tr to funrii'm as an anticoaguliint on the polymer surface, but nut*t lie releasisl into (he bnthing fluid- Ifbtuogeiious solutions containini: a rat ion ie ttrethime heparin eontplex are used lo.pfe|*ire thrntnbnr*t.i*f;*nf films on (w>)lore)bane tubing. The n. w family of cationic ]s,lvurelhani"- nr* sytitln-iznl frutn rntipiiereial poly ethers. The tliromboresistance viaevahtaltxl bv s*atitiiitg electron niiemseopy for plati let iiilhj'sioii rates, 'I'here was little (pj.-int it alive differenre hetikeen uncoalisl eotntnereial polyurethane and tmliealjgrade silicone tubing; the thrmpborcsistance of tie coat ing wasdemonstrated (IOC). The liriii'i fill mtmbranr. Tlie fibrous cap-ule that dev|i*lo|is nriiue.il implantetl foreign bodies does nut in duce the clotting mechanism, because it is made up "f endogenous tx'lls, A velour coating (107) has been u-. d to i|ndtiet` a proliferation of living rhlls on polymer iniplaiits usual in vascular systems. The original micro chip* are replaced hv fibrous repair tissue. Instead of a velbur, use of a mat of Dacron fibers and seeding w ith embryo fibroblast* of the same *p*ics arcelerate- tie cel) growth in vivo (I'kt*. The process may b*' begun in vifpi (109). The drawback to living cell membrane, i. thii lack of eontrol over their growth. Too thick a lav* of cell, result- in uudrrM<>iiri*h*l and dead cell, will ensuing .loughs anti |h,I. ntial emlioli. Itu|v*l.ii tulfrii tit flow ha- been din-ini-hed In a very tide wi>"po|\ptopyleu* idler- anchored to -iiicnii* r il l : <: polvurethane `Si). (Hlur loib'.si'/uhoit mrrhnnismlt, AlthoiiL.ii I p riuir.ed tunl o'her surface* designed to have int.itiii ehargi-s are thrninh*ire-i*lant, a group of materials thaf tlnjes not fall iiitti either of these categories has 'iirfac. chkirticteristics that achieve the same purpo-e ninPyrolytic carbon. graphite-polyuretlmne-polyvinyl *>r mHallographie tnlhiw surfaces, segmented surfaces (a* with pdyuretliaw-polyether or pjdyurct ham-si )n\: 111 ctjltnlymcr), and also albuminattjd polystyrene. fhmrinattxl siliciHie rtthher, or acrylic hydrogel fall into this category. Since virtually all foreign stibsiano' bathed in bftmd absorb proteins fill), the particular protein layer formed wi'h the**' hrosthesi- or devin nfipttrenfly iohilHtschu formationjAn intrinsic conme. i pix|HTty of the surfaces of the**- materials that prevent. rhitting or induces nd*nrntion of Ihromboresistant jir tein is yet to be ascertained. Xojtionic detergent- at. 1 wetting agents such a* polyoxyajkylene derivative* jwtuiylene glycol are incorporated in polymer* -uch polyurethanes and cpnxidea to cijeate a layer of wat* r on the embeddtxi |tolymer; a barrier is erected again-' platelets and red cell*. An nlbamin layer serve* tiesum** iMirposo. Silicon*- rubbeti polystyrene, p"!' urethane, Teflon, and many other polymers can * treated to have albumin layer* (W). "Pyrwlite" carbm.jn> highly thromlsirise'tant when properly pn-paf! tin alverse |>roperty f*tr intraya*cular prostin-.e. itheir rigliy. Techniqtws have b*x'n dcvelo|*xl to *! |Nvit adherent carbon ctsitings on flexibh' jmlynwr 'uh Strates such as polyurethane (/itt. An exjeTtincntal nrlilicial left ventfielc made of a ucc 000579 CLINICAL CMIMI*THy. Vol. II, No. 1. 1972 77 VI contractile alloy, which simulate* the heart muscle, would iltduor clotting noli** routed with no ethylene vinyl acetate polymer. Tin* cunt met ile net inn over come* the blood stasis problem inherent in hydraulic designs (J/3). ked etU and white ctU domain-. Ly>i* of ml cell* shaken in (law with rather inert sitlMnncro was descrilwd in 1884 (Hi). This phenomenon has Iwsti noted with im planted polymer heart valves (tli) anil is not sub* clinical in all cares. Hetnolv t ic anemia has riovelnpeil in patimta with prosthetic heart valves ami also from dis ruption af silicone rubber, Dacron, anil Teflon aw tic Icaflcta (HO). I*eukoeytes are also injured by |>olymer mtcrfaeial contact*, bit the clinical significance is not aa dear aa that for rod cells (117). Hhim tiMwi mi Watnr-SnluWn Polymers Polyvinylpyrrolidone The polyvinylpyrrolidones (rvr), which for practicsd purpocr* range in molecular weight from 10,000 to M>,000 form colloidal ai|uenu solutions and hence be long to the group of water-soluble iwlymer*. A rvr waa used aa a plaama extender in World War 11 in more than 500,000 caeca, ami rather cxhimivelv over the period 1830 to 1900. rvr polymers have also Is-en de signed to delay the resorption of iienicillin. procaine, and insulin and to hasten the clearance of certain dye* from tlic reticuloendothelial system (118). eve plasma extenders oom|trising a whle ranee of mohvular weights (20,000 to SO,000) entail consideration of the fractinn uncleared by the kidney (I 111) and the retentioii by the lyaoeomca of the rotieuks-ndotheliul wystem. lndue*ioti of latent hepatic Ittions in humans who recivnl a rvr solution (100) raises questions nf toxicology us do the results of experiments on rodents that, have al legedly produced cancer (121). (For a disctission of all types of plasma extenders see Jiupenmtnry of the Untied Steiee ofAmerica, 2tii h txl., J. 11. Lij>|incott Co., Philadelphia Ta., 1955, p|> 1*11-1815.) Thmamiamatk reactions. When administered parentarally to mice, rats, and rabbits, rvr was stored in many organs and tissues regardless of the polymer's molecular weight (101). Ktornge was most iwmotmeed in rabbits, least in mice. Fatty tissue at the site of im plantation, meninges, adjacent glial ceils, lungs, ettduthalial cells in the blood vessels, myocardium, Kujdler cells, mediastinal and abdominal lymph node*, spleen, renal glomeruli, and endometrium were observed to take up rvr. The retention involved parenchymal as well aa phagocytic cell*. Ifvtierplaatic reactions were obmrved. Proliferation of cells waa noted in efwndymal, aharaid, and meningeal cells, and multifocal adenomattama in tha pulmonary alveoli. OWyvinjff MwwIOl The polyvinyl aloohob aro generally water soluble or water-alcohol soluble ami liml use in tlm plastics induetry Ut surface coating* of goods intimate to the human environment and as mixture* to pnslure >|nstomem. In the body, the storage distribution of i*dyvinyl aleahol, which had also been studs*! in dugs, was very limilarts that of rvr (100). Ri* Wnter-rohihlc polyvinyl ale0 polymer-, ranging;in molecular weight from to SPt.tttXt, wi re giyen Mibeutaneou-K in rats. All prUluced anemia and infiltrated <l,e h\popliv.-i* and kidney. The-e common re*|oiisr.* a* wi II a* chemical attraction for Congo tied may he u-crihod to chemical propertie*. The two polymer* that cau-id hypertension, vascular h- siou.*, and renal pathology had a lower solpbiJitv in cold wtiter. There was no correlation lif putholnginl efTerts With molecular weight, but those with vin\| acetate residue* hud the higher eold-water solubility (U.i). Testing for Carcinogenic Hazards A rajthcr ambitious program of safrty testing for water-soluble marromolectdes was conducted at the National Cancer Institute (/-?/) and included watersoluble rvr imlynvrs and a |*dyvinyl alcohol prepara tion with an average molecular weight nf J J0.000. The conclusions drawn ore not very convincing because of inadequate control. Although more than 1000 rat* re ceived j|H*lymer* by variou* routes, there were only .'(X) normal ctmtrol*. The s|0 mire also used ns controls had nvcivijd wool fat, gelatin, tricaprylin. dr test chemical* ami approached the nuiidsT* that received polymer-. Tumor tncidettee j* given on the basis of beginning numbers, not effective numts-r*. which would be tho** that survived long enough to develop (tumor*. Tin- *e\ of the [animals is tint given; control pathology indicate* that shine were feinale*. The r\|M`rimewi* were tint per formed concurrently. One of the candidate* that wumneluded to show a carcinogenic re*ponc wa* i rvr with a molectihtr weight of `.'(I,(XXI. It pkiducd ii'gativ tumorigentc result* in mict and rabbjt (three expert* mental serie*). If the contro! rat colony is assumed valid for pi^rjHi*es of stati*tical analysis, chi-square wit It Yale's correction would indicate a carcinogenic resfMinsp in mily one of the three series, This assumption i* not) valkl boeatisc the control coliny was not ob served concurrently. Because the cojttrol rat tumors were predominantly reticulum coll sarcomas with a rather high incidence, the observation of these same type* of tumors in tin* series dosed with polymers i* not Com|*'lling evidence for a carcinogenic effect.'Of -l<><) rats tlhat received rvp, 11.5% developed reticulum cell sarcomas; the control incidence was 3.3%. The chal lenge) to the use of tumor incidence in |he normal colony instead of concurrent controls is illustrated in Table ;t fur lymphoiti tumors freticulum ceil sarcomas and lymphomas). Although the females ware followed longer than the mules, ihe iucidetircof these (tumors is lower in females than in male* for each of the five series tdter 11)00. Whether to pool the data for the two anatomic sites and whether to pool the two types of tumors. a* waa done in the Tabic, would be controversial. Contraceptive and Eractilo I Polyethylene Polymers Tin1 safety testing for polyethylene intrauterine ermtlwreptive devices is more extensile than for mo-l |Kdymeru*ew. Skbcutaneoiu and intrauterine implant*. On sub- e* cuwcm. CMMMentv, Ml Ma. h ten ucc 000580 UCC,S801 TftMft l. Icid#ne* of Soontaoooj** Rotieulud Coll Sarcoma* and lymphomas inlvan*Ratsow a Six-Year Period (F. Riachoff and Q. Bryson) TtnMI Toy * to tsoio*otoia* Monitor OtMMt (MmIMo mtor lotturumtoorr*M, flte lo*truOmtoo'rH*,ofsta*l 1956 15 30 27 11 7 9 22 47 35 6 11 MS7 d* 22 41 29 24 ` 3 9 24 38 28 4 14 MM <r 18 36 36 17 11 9 19 35 27 11 0 19M <# 23 40 26 39 9 24 77 59 31 8 0 WO d* 19 41 30 33 9 22 36 26 15 0 0 1971 d1 20 79 71 16 9 23 76 57 10 1 2 eutoneouo implantation in rats, a bilateral comparison of 10-mm diameter polyethylene disks made of a mesh of hard consistency with soft pliable films of the Mime material ahowed no Mgiiificuiit difference in sarcoma yield during 18 to 24 months; 4/411 vs. I/.si (/.*{). Hie low ureoma yield was predictable, because the siae of the diske approached threshold site as evaluated by others (St). In oompariug subcutaneous implants of u polyethylene segment (ii'20 mg) with shredded pol.v* ethylene packed in gelatin ea|>sules, there was m> signif icant difference in local sarcoma prpduclioii; 7/20 vs. 5/20 in CB stock rats. The mean time of tumor induc tion was eight weeks earlier for the segment. No tumors appeared in surgical controls or nits implanted with empty gelatin ca|>sule- (US). The packing would achieve the effect of a emitinuous surface to some digree and tlie sarcoma yiekls in both groupa would be prodictable oo this basis. Comparison of response to polyethylene |M>!yner loops, spirals, and sheets on subcutaneous implantation in rats indicated a correlation of tumor incidence with degree of continuous surface (Ud). Under tin* same conditionc, stainkaenttis-l rings with a noncoutinuous mrface produced no tumors. In eum|mritig similar intrauterine eontraeeptive device material* (127), local sarcomas were produced with both the imlyethylcne polymer and stamless steel. From a chemical stand point, theetainlrss cteel dmw not npjiear to have nn mivantage over the polymer. Hina1 more rrh-vnnt results (1ST) to the problem of intrauterine devices would ocertse from intrauterine implantation, portions of stainkae steel and polyethylene ititrnuteriiie devices were eufgkilly mtroduotsi into each uterine Imrn in tee pwpi of MO juvenile female Wistar nits. During a Vwo-year period six r*ndennoid carcinomas arose in with etainle** Steel Slid five with polyethylm; no oudi earrinomss develofMxi in 400 control rats. Endometritis and endometrial squamous hyperplasia, .which were concomitant with ihe development of etmkiwiuid cordnomas in the rats, do not nptsur to peniiat in woman with intrauterine devices. If they were prelude to eaiUNMgencsin in the rat, firediction* for Immjnti* u-ing devices tire not forthcoming on thi- ba-i- Squamous mdiipl isin occur- from silk suture* and au tologous or hoiiiiilugiiu- -kin graft* at the uterine sib ,,f the fat; this ch;.rrieri-tir r< -|x>n-e rtither than a -<.lul- state surface efT.cl mav be more rloL-ly related in ibe prisluetion of il-e epidermoid ramiuijuus. h)lroprriliHttt>l im/ilnnt*. Uthuilgji uterine p< rfor.i- tions by ois'ii-eodetl polyeilivlene intrauterine ,|,vi<,- aie (rare, a study of tlie filodal iMtijliou of -ueb Innp* introduced intruperihuioullv in rabbit- was mad*' in ordil-r to evaluate ilie problem a In n it ocnir- m l,n- maifs (72.V). In snliie in-latire- the -lerilinsl device w Intmluced din-nly into the peritomjal cavity, in otb< r- viu;the emloui' lrial ravin or via the vagina, cervix, nndj emhunetri.il cavity. The typical response was ,-,d- Itesjon formation; this was not dependent on barter,al contamination. Seventy percent the devices mi grated to another area of the pcritjmcul cavity before hccbmmg nnchuretl by adhesion formation. Since tle re is a greater tendency for adhesion formation in mi- than in rabbits, the results with the devices are cou- sklensl of signiiiennt importance in predicting tln ir fatf if they herniated into the human peritoneum. In earlier work (17). six local sarcomas developeil in female Uothcsda black rats implautra intraperitonenlly with polyethylene |si|ymiT films. These sarcomas aro-e 10 to 24 months after implantation. On covering ex perimentally itHiuoii uIc.ts (1 X 1 cm) in the rat parietal peritoneum with polyeilivlene polymer sheeting, di'iiomental adhesion* and marked hbro- blastic activity, but no frank neoplasms. were nb- setfvixl (IJ9). Because rats were killed only 3. 6.0. or 12 months after implantation, few sarcoma* would cx|Kttcd. I rmiIt iwfUnntg. Polyethylene hi* been used for tin surgical treatment of human impotence. By implant a- tion of polyethylene rods into the penis, an organ akin to; that of the o- jienis of the dog has la-on achieved in 700 |iatieiits over a seven-year period. The pructice, r< - ported from the T'nitiil Arab Kepiblic (ISO), does not upfs-ar to have a wide following in the United Stab- Silicone and acrylic prosthcscs have also been tried for CLINICAL CHEMlSTXV, |vol. 1, No, 11972 171 UCC 000581 rcc,58i llii* Tin- nHiniaii' fai- f t|,i%i- implant- untild I|- -ivii- -|>r,i,- `- ili""i.< i-:n,',(.',||v i-1 line rm* nr ! rrri-i. 1 |Wf IliH-T***. || ni'ili-lr^li'l :* -".iliiiliitivitnu- rr:if i'll, urn ii I 1* . f* rim yI |i`/lvni'i. I illt im i ,n niii.'-ini ri-|H>ii-- 11.--1--) "I III- due- vli fi fnlln.in| n,r I'A" M r-, 11i#* r .i- nf - TtMtfO AtfMtfvM yi :r;! tli`- f'tll'i .-up | - rii .j fur ilu- n i i. n* .1 civ> i flMlTT-p-pHrirr--./- nnlf il rai* vi-lupml nn tumor- iA PoiycyaiKMcrytate liii(li Jin iili-m-i- * f il.ri'Uilm-i- |i vi-Inja-J in hnih art* ri. nii'l v,,in- nf 'Iil'- wli`n n-hui1. !-J-i*;'!innarr> l:it>- mu- Tin- alkyl-`J-eyannaer. l.-.i*- rnniiniii<-r* have In <-n -lil'lled -XtMi-iV- t i i . -u- iiilii- ivi - ll-H) be:;iu*e iinim-y mniiicl* 'I til'- luin' n nf iIt** v-- -Is './!,I >. Hui-rylal*- (t-nlui' i I-J-I \ :iim;.rrvla *> -tii.Ii*-I III-/) a- a |mti-illial "--iiiihir aill.i-ii-i- in tin- ii.ni-ii-- il.i-y i**" rapidly mu-n <1 to ti- formitix slrmtx bond local ti--lit- irritation IIN)| Mi-cm-is lia- liei-li mi I V<-| .-a- illect ail It -nine U-U i-.ira fit IJ Hi-iall'i- nf till- nb-iTVIti <J.-|||.-ii;..'ie i!fi-t- In lln- nii'Mli- nnl iiiih r i-ar- anil lln- f nl ii. lifliii-Vi- fiiuctinli.il ill.inn In-Iui-iU tli|* n--irl*- I' v t:t7). Tin- briukdotiii anti resorption nf *<n i-rnl- ur-tsol a \xi\ymir us'd :i- ii ii.--hi- splint hi liimnrrbntn- I '.iii lil.li il tlml llii- i \ ann.if-rt lull- itei- in-itl.' r Imr if-i-fnl a*III" -ill- fnr lln- lailn-- nf 11,, nii.l-li' .r iniitr'n-t I......... ii.jM-iinii i \|"-niin ip- mil. r i.| - ilHi-rii-ni i- more ib-irubli- than one that i- fM-rumm-nt, i-nbiiK l-J-cyiii in-ri lair . -llii --iv*- j r-..l.ii-- 1 . i-: if till- f-orplinn prnci-- i* hoi toxic (Sii). *icallv, iiniini'iil Kt:iuul`>ii.;.tnii- k rat it i- win i. ii-.-.l i i In-. llii* bri-akdnuu produel- of tin* evann;"ri litii- anformaldehyde, uliicli unuld lx- haclerio-tiitie, and til* kylci.inii.iei-t.iti.. Tin- U-- iif |/iil\n'nliii,'iffv!ali,` ill pi-rfi ruli'il :tr--i ln.trk-i-||v iH-rintir .rin-a n! Illlll.lt. (l-l1!). Ill 11 -til'll nitll kliit i`\tr,ini-.il ;r ini|-r(|i'-, tlii* ri'|il:ii-iiii.-ni nf -iiluri IV it It pli.-lu- :.'l- medicine de|M-hdN on xIm-Hiit iln-ir breakdm-. n i- slow cunuph to miuithixn local and .-y.-ti-mic toxicity. blond In -iyi- fiippiir.-ntly i-nlmiit-'J-riii: lln:ii-r\killluiiml in fa- in.|ir,-iiii*"il iMrnii-i- nf ili.'iili'ipliil'- |ml.viin-ri(4M lIt'- cyanoacrilali- monoin'-rs more rapidly etri i|irtli and inai-i-umi" hi ini-n-uri-d i pl;ll-l-|l1i'l.t I : I Ilian water. That ||m- |mlymeiiitatinii in vin eh mica! < `nnlitiunii- -utiiri- uiiri'nva--iil:ir : iiii'tiiliiii-.'- ml lNilili( through t*ro4-in aiiiHm Kr<i<i|ii i*i indical# d lCIUIM-tlien-Ulltihlt polymer lia-hot extlaetnl by |ml> im-r tMI ninnnliliini` iit n;. Imi v.itc enmp: rii| with ir.'l-i i ml ! anaatuiun-i? by ti-itic i-nlmi l-'J-ryatinarri. i>*- nolveiit*. Timiii- !iittniivi"* should have spreading "liar* adliifriv*- ami thri-r -tav -tifiir*--* in -tinli*- iii'li I nderi-licu tlml ilepi-nil hii siirluce, ini*-ilin iiil i en-ions, I lin-nf I In-`if nl llii' in Imi emiip fail*-il ii-rumpar.'l ! I nii<l mint rale surface mii-ibv U-tH). l-nhutvl and re llV- fif **< Ilf lll-yaiin.-ii-n lain (irmip Tin- latti r lT"'|)' Imtyl eyannaerylale |mknn iixe rapidly and an- h -- -linut-il ili'p'ii'ratinii ..I t* - intima llnl ll'-pn-il i* lnail- limn tin- methyl ili-nvitiivi-1 l-ilt), Im* 11n-v nri* imi i-ali-itiiii in tin- vi--i-l-, ala! a mnri- pmlni.ui'il aii'l mi i broken ikiMii rapidly in vivo il ',>>>. J.-obiitvI-'J-naiin- inri-iun-linily rn.-u'tinn II {.Vi. Tl.i' injjtry tn th*- art* n i1 I acrylate formed a imlvmerixinu adhe-ive with whole miilia by llii' i-nli.it11 di-rivativ l.a- I'lplal I" ll lilmal nr Idood fractions. Tin- rungululinli ptnpcities nf w il Ii lln- mt-UivI di-rivat i\i-11-I ;i. blond were nnl alTi-cliil liy rximeurc In (In- fnimid ladyiuer, a |>riili-iii poll uter complex, nr l lie iimnnitHT. .Monomer sprayed on Irann-cted ring kidm-ts formed an Polyurethanes adlnwivc layer, which progressively disintegrated with hh-ediug anil cuncctilration nf Inikiwyiin (/{/). 0,A,A-Triflmieimi|ini|iyl-cyummcrylnle iipttenrs In I'nlyuri tltiiiifs and |mlyiiri-tlianr p.rrp, nl,y..n..t.i.T..-....l...ai. lnN*ii iiiii lly nIiuIunI a- imnMtluri- a*Hii -ivi-s (/ |mimi I In* di-siruble proper! iiw nf 1mlIi lln- methyl iumI higher homologs without lluir undesirable i|tmfiti-*, I'ulytin-thtini- ii as alerf) -lutliiil as a tn inc (dm* (I Stifi ly kuliii'i. Alt IkiukIi tin* partir liar pnlyur. i)i .ii' ami i now under invi-Nliitnliiai (Ml). Although met by I- sulijiTtiat in >:.fi-iy teslinit fnr caicinoft'-nic lia*... H-eyaiwucryliile monmncr has lain liwd iis a I issue glm* in-ri- mil tin- |Hilvnr-lliatt-N di-icm-1 for u-- a- tilu'-. since UNO, im n||illent inn (Mil) aa ailI iin lltal nf the higher botmdog* ill clinical surgi-ry liaa tint lai n wait- a| in-ail. IVmm Ttneium. ('nlltitti'ii fnrttialimi |irmilil l>,V fjhaililwt iavaainw matiinlly iNwura in nimnil lii-ulinK ami nfaln In liamiii- aln-nKtli. In ruin, a iaini|uiriiliyiatoniy (lift) nf llin-i- ryaiNNicrylali- imminiM-n iliipi-m<rf kn in|iliUrtiNl jmlyvinyl alnilinl ^miiiki-n Nlinaitl Uiai tfm miliyl tii-rtviilivi- inliiliili-il iIIK',ii forma* tinN, wln-maa tin; hi-ayl anil itiyl ik-rivalivi-N ilM mil. tlu-y an n-pnri'd In-ri- a- ri-pri-i-ntit ii a rlnsi-lv n-l-it* -1 clit-- of nrcauii' (-niutmimil-. In rat*, a ciunpar,.' study (r,l) nf |Milyuii-tliatu- -Imi-In. f. ant. and pmtil< r- ! fnaiit sulTi-rN frnm ..... Ii iiiiati- laintri l. lb*ri*. tin- -In * t and foam tmi- dilTi-ri-nl in iliai lit" former in-r.- ai'~ inatic, tin- lalli-r alipliati*-. Mnrinii-r, tl.v fnam i"-. tiiincil castnr ml, diiiti-t liy litmitt)* nli ate. dimrtlii Ip-lirilixjoitt*t and Iri-d-clilnrix-thyl plur|)iiati-. Ib-uli.- at tin- xiibcututn-ouN Mite wort- cNNontiillv m-icativi-. Tt." fnam ln-n intrniliirMl inlro|H-ritn n-allv pnalui-i-d ; All Ikrrat |inaluM<4 mnri- ixli'mn lluiil- Tin- ili-cyl anil Imayl HHnmmi-rN diri mil ilmlilil* ikin-InfMim itranulnUnn Ummii an did tin- im-lliyl di rivalivi*. Tin- Inrail Inxicily nf mrtbyl-S*tjratNMM!rylttii| ladyim-r ia lln- huiim; aa llial nf Umi mnnomif. Tln-n* ia a mirndaiinn laiwi-i-n tin- rati- af h-MiiyiiiiNi and di-Kna- nf Incai inflaminalinn (nr Hitcyamniitylaliw. MHliyl*2-cyaniMirr>lHli- ia lln- muit hiBnificant tuinitn-r nf udi-nncurcinimaa ari-ime frnn. tin- c-ctd mucu a; |xnvdi-rl foam did not. Tin- n -ult obviously do iil pmvi- tlml |K>lyurcthane is a cln .itiral cnrrinm-i-tt In't-auiM- tin- array of adc itivc-s b*-clnuils tl>' issue. In femaleC'('-`7\V min*, intra ,'ayinal appliratim. of |iolytin*lliitiie nr buliidiem- earbotvlate latex spongeovif ii 10- IMt-iuimlli t-riil imluetd premnlimi .m liMlnlmut. rluiltKet* it* the cervieal uleriiie an I itilraviigiiiul pi A aludy nf amuad Imlyl eyanimcrylali- tiaaun ad- 11ndium (ISO). Une liiindnNl four Su iss albino mice t Im' OUMOdi CMOMTNY, *f. It, No. >, 11/7 .. -- ___ ________ ucc 000582 pirvived am year afar implantation of a polyctherurothn ^ooge brorotb the mammnry gland* developed local eanom. The sponge* become distorted and krankfn tod elicited * foreign-body reaction (161). On* year would be too abort for the evaluation of cxrnagonic potential. Clear palymm of methylmethacrylate are readily forward, aad koown in thr industry a* "latrite," 'Tkxi- etc. Polymm and eoftolymora |>repared from the monomer are used in dentistry. The monomer is 11n* active ingredient Mi Dementx serving to implant boll and cup proctheaea in orthopedic*. Us* of Acrylic Polymors in Humans "Seif-curing reaina" have b*n**i uard in spine (US), Sip (183), and elbow-joint surgery (/d^), and for con taining intracranial aneurysms (185). A typical autopolymeriting bone eement is formed by mixing :i liunid ontaining methylmethacrylate monomer, ascorbic add as a stabiliser, ami dimethyhp-tohiidinc ns a cat alyst with a powder containing polymethylmethac rylate and bensoyl peroxide ns an activator. Thu monomer, methylmethacrylate, which may tienctrate rubber gloves such as arc used by surgeons and art technicians, can produce a dermatitis (>*>) In patch testa bansoyl peroxide and mcthylmetliacrylate were positive. Because the polymerisation process used to produce acrylic cement is exothermic, local temperaturns, which can reach IOOC in ortlmjsilir prosthetic fixation, may Cun*e > t*-roH (157). Absorption of the monomer into the: blood stream causes a fall in blood pressure and possible lung lesion*. These itTects are minimised by improved surgical technique* (158,158), In a study of 30 patients undergoing surgical replace ment of arthritic hip joints in which a cold-curing methylmethacrylate cement was used at both tlie ace tabulum and femur, a fall in systemic arterial pressure occ srred in every patient, though not always with both procedures. In one ca*e the fall in blood pressur.: was critical. The study waa prompted by a death after the sement was used for replacement of a fractured femoral head. It cites ineidouts of cardiac arrest and cirdiovaaeular collapse undt^eomparaWeeimimstances (100), fins communications concerned with hone cement and cardiac anast or plumonary embolism do not give the chemical composition of the cement (Hit-188); the re^oacIMlit) for this failure rests with the editor* of tho journal that published those pn|*T*. In a study of fl,N> hip repiaooment* (182) only four ruses of cardiae nut were reported; the Mlworption of the monomer, which baa a very strong odor, can be minimised by nut cementing too roriy, thus giving the monomer time to polymerise. IV sonerntration of th* momtowr in th smgery atmosphere, aa manifested by it* <sior, would obviotjriy bo of oome coneern to surgical personnel working with the ermmt because of its cytotoxicity. Eoriier npati indicated that the implanted pnlymcriscd eroicnta gamed no serious adverse long-term reac tions (18$, HfT), am wsa there pronounced decompnsition (Igl). In tbs rabbit or monkey, satf-ouring aaothyh mctharrvkitc produced no more ndveroj t Muc ro-ictinu than "Vitallium" (H>9). In a study olj 23 human pa tients who had bone-cement junction? and were f..|lowvd for it* long x- seven years, new lyjforntdd ari a- of fibroe.irtihigu at isolated points indicated transitu--ion of l.md from cement to bone. .Mrchunical pre*-ure on fibrous tissue stinmlated development of ari :ts of o--itiCation. The pres< uce of a giant-evil foreign-body r< act tinn isfnot regard d ;i* a rejection phenomenon berau-e the success of the procedure was dcmnnstrat'xi over inn hum a period. Fa* was -torod within if) am of the la ment, indicating absence of chemical irritation. (Iran- uloinatous or ensouling arras were not observed (15-) Considerable heat is generated when metliylmot h:ic- rylutc is molded directly on the fhor in orbital fracture repair (170) and the exact molding is difficult. Plates of this polymer, in various share's and sige*. arc therefore prefabricated and then surgically implanted, with ex cellent results (171). A comparison of 9-inm di-ks of noiymcthucrylutn with disks of bOhj polyinethacrylatP and 'JO* j anor ganic bone was made in (lie skulls of Norway rats and showed that bmie developed only with tin* latter PolyuiethaCrylatc became surrninuhjd by .fibrous con nective tissue. Neither the polymethacrylate m.r tin btmo are completely identified as to rhemical fompo-ition| (172). Rats whose skin Wa painted three tune' weekly for four month* wit h met hvlnielhncrx lat e or sub cutaneously embedded with pellets Containing bcnz'-yl periwidedevelop'd no raticcrs (/.{). j IhmQtopvicni* in ilmna'trtl bone, A jirosthesi* do, - n>. take over hematopoietic functions in bone rephicinut.' With a partial replacement, influence on In-ma'"poiesis anti the carrinogetiie potenti d of the -olid--ta'e surfaces of the pro*tlie-is or of dtjud bone are to be Considered. (See section on solid--tte ctirrinogenesis ' Local environmental ami traumatic influences ,,n hematopoiesis have been studied (IJ7S) in rats by -tibeutjnncousiy implanting living sternum* and femur- .te tained from littermates of a highly inbred strain, Re ject ion ns sloughs was TJ.-VJ (5 out of dfl) ov. r a .'(> month implant period. Ten percent of the impl.ii.-- ti. coitus necrotic hut were not rejected over a lb-io 1 perssl, Fourteen implants were viable with artiv hemalo|*>iesiii during a -'JO month period. \- je n- is of necrosis were observe*l in nine with perio-toa! aanimation and fibrosis in some. Chronic o-teomv- eliti* occurred in four femurs. In sternum implauts. t" bowed hypercellular bone marrow, and one lymph cytic hyperplasia in the marrow. LAn implant<*l femur gave rise to a benign exuberant nbrohistiocytic r< ac tion. The absence of malignant degeneration associated wjith the living implants indicates adequate metabolic exchange or % noninhibited inflammatory reaction, cpiiditiom not pci>vailing in the jmvironment of im-rt nonlivingsolid-state implant*, j Safety Testing Polymethyimethacrylatc SubeulMCiius, intrui#riUmrol, rod inlramutcufw in. plant*. A study of |*lymethacfylate* and their c>jsdyinefs that might linil a use in dentistry, >urgir\. and opthalmotogy compared hard and oft resins. n> o^ral or alkaline hvdrocolloid*, and solid or perforat'd plate* at the snbcutmi"oiia or intraperitc?*'"1 site m ^ qoo Og ->o CLINICAL CHCMiatgr. Vol. II. N*. , W2 111 rote rod rabbits. Only the sola! plates produced tocnl Mftomaa. Negative results for the other forms indicate the absence of aehemiCid carcinogen (174). The effects of intramuscular implants of stainlcssetcel and polymethylmethacrylate disks of three -izes (IK, 12 and 4 mm in diameter) in four- to six-month-old Hartley guinea pigs and thrcc-month-ohl Cluster Beatty rats were compared (176). One liondred thirtythree guinea pigs deveh|><-d no local sarcomas during a Hmonth period; aft<-r prolonged implantation the' fibrous capsules around tin* implants in this sjM-cies thinned, with reduction of ceiluiarity apparently cor related with defeneration of the inner niarfin. Con firming the work of others, sarcoma yield for the rat was correlated with implant sisc: The 4-tntu diameter disks |irodueed no eaneem. Local tumor yield for js>lymethylmethacrylatc wiut 34/153 for tlic large, 17/142 for tbu medium siae disks, and 5/42 and 2/37, resin-ctivdy, for stainless steel. Since solid-state-induced sub cutaneous sarcomas in rats do not usually melast-isisc initially [they do after transplantation (/)], it is of in teract that metasCases were found in the lungs or me senteric glands of 13 rats with sarcomas arising nt the intragluteul implant site. Lack of local surrnmu pro duction in the guinea pig might relate to suhthroshold sc, a prolonged latent period, or a *|*!cies difference in response to a carcinogenic effect. Plasma ctU tumor inifurtion. 1'olymWhylmeI )acry late plastic disks, commercial mineral oils, 7--liesyloctadecunc, squalene, and prist am; were implanted intraperitoneall) into bai.u/c. mice. All prodma-d tibroor oicogranulomatous reactions with obstruction of lymphatic drainuge, bical ami systemic plasma eelI hyperplasia Mid |>lusmneytomas urising in the |x-ritoneal granulomas. Tumor yields rungixl from 23 to 70% (176). Hie carcinogenic process apparent ly dejiemled on stimulated plasma ocll clonal derivatives t rop|sxl within granuloma, because material that migrated to the bone marrow, lymph nodes, spleen, and liver pruilueed no neoplasms. This polymer is well known for its urn* in the la)>eratory, both as a fining and ns tubes, \ asculur ?>atclcs and tubea an noted In the Mention on Jf|rrti <*/ Polymen at Prwfinn and m ArtiJieM Organt. The pol> tetrafluorocthyiene (mm) polymers of eommeren arc linear fluorocarbon compounds. Because the carbon-fluorine bond is one of the strongest chemical linkages, Dm-sc polynun are rdntivdy inert, with high tlierni:il stubifity and oxtiunuiy low solubility. The useful temperatmu range to -75* to +2 j0oC (177). At 325*C there to wflroing. and at 400*C a lircakiiown to the monomar anenra. Toxieologic investigntiona are conrrmcd with the polymer itself wlien used at nsmi and body timpseature and with the dceompoMtion product* at derated temperatures. Decomposition products rosutoing from heat proeeming in tin production of jsilymer aettotoa may bo entrained in material utiliaod at mom temperature. Pyrolyiii prmlurh. The chemical eom|sisilion d * particulate fraction (tiuorinated acids and olefins) produaad by m pyrolysis is influrnctsl by the humkiitycf teeter (in). By eomparing filtered and unfiltered * i otwneM. cMomtTirr. v*. u. no..w niistrC:ims of ptff. pvroly-is product?, it was il'inonstruted that particulate matter was associated with tintoxic jnuiiifestutions in test animals (iv$). The purtieulate material r.my have toxic components ad-nrbij <m it. I'erfluornisnb'ityleiie is the principal toxic ag. nt formed :)C above tin- lowest temp* rature that produe,-* toxic pnshiets. The temperatuie at which toxic pyrolysis produei- develop depi-nds on the mnh-ctil.ir weight of the wn: polymers of higher molecular weight nsptire a higher temperature, There i- agn-.n.ent that the rate of pyrolysis of ptfb is not -ub- iitial below 4"0 (' (ISO). Carbonyl fliioride (fl-inpl.... gone) is the principal toxic component :it 5*jOsC. Tissue Reaction to Polytetrafluoroethylene Safely ieih'uy. Tliere was no significant difference in local tumor incidence in comparing plain with perfo rated mi (Teflon) disks on subcutam ous implanl at ion into rats (14) or plum with fragmented di-ks in mien (181). Chemical factors were more important than the continuous surface in eliciting the carcino genic response. The te-t conditions wen- comparable 1m those used for polyvinyl chloride polymer, Dacron, and pylon (/-{). The Tefloo experiments in which tin* sarcoma incidence rungixl from 13 tj 24^}- indicated a chemical carciriogenie response, possibly through release of flimrid*- its an enzyme poi-xm, the pn-enre t f entraimxi monomer, or pyrolysi- prodjict* if the polymer had (*x-n subject ixl to heat treatment </). In cmitra-t. neither subcutamsiu.- implant* of Tenon ine-l) -urmr.d out flow patehes nor -linxl- of the same material l/,*-,'! proditcixl cancer* in rat-. Tor this particular material a chemical carcinogen was not imlicutixi. The ant-in.|s netruble mesh, after implantation, became rover,-d witht moderately vusculurizixl, thin, nyulinizcd puteln-of connective tissue. The shredded | material was ingulfcd in flattened mounds of granulomatous tis-ue. Tim results on sufety testing for Teflon in three lab oratories and two strains of rodents ore thus in con flict. and may relate to possible product difference. Parenteral in man. Intracnrdal injection of |iolytef (Teflon) for functional improvement of pathologic conditions of tlic liuman larynx mny be followed by progressive fibrosis with cither a redding or persistent foreign-body miction. Recommendid particle size of the Teflon for injection purposes is ketween 50 and 100 microns, because migration throw h the lymphatics undblood vessel* was observed with pastes containing smaller particles (183). Toxic Reactions to Pyrolysis Products Ten! animate. The monomer, tetmflunroethylenc. and pyrolysis products of its polymer were subjcctixl to toxicohigic examination in rats rod robbits US.1,). The lethal monomer concentration, in sir is 2.5 to 4 vol %. Tlic toxicity of dcpolymerisktion rod pyroly.-iproducts arc ascribed to difluorophdsgene, perfluoroi-obutylmic, and other highly toxie eobipounds. As te-ted in doipi and rodents the pyrolysii products of mr arefmoderately toxic, os evaluated by the Hine and Jaeohero toxicity wale. The pathological changes ucc 000584 JCC.584 Mocifttrd with particulate material observed in lung* after exposure demohxtniUxl tut irritative etTeet tm.re than imn day* efter inhalation. After tlx* acute hmnfThage and edema, im-vi'rxiblo ti^ie damage dsmtnmteated by foeal cmidiysem* and interstitial flhfoeia ensue*. Fatty degeneration of the liver was atao nhwrrnl in throe experiments. The tnxie <*ffectM of eorboeyl fluoride an* ascrilmi to its hydrolysis product, hydrofluoric acid (ISO, IMS). OUaradmWne*. Toxicological studies with the pponlyria product* of polychlorotriflooris-thylcne at UT and 400*C indicate*! that tlie lethal effect may bo dur to inhalation of particulate products of hydmlyrii. A chemical pneumononitis waa demonstrated ia rate (140). fdpur fvm fmm in humatt. At the sintering temperature of UO'C, woelwrs involved in tlx* molding of nn dtvalopod a temporary influciixa-like illness. Throe symptom* have not been rcfwoducixl in expmiiantal animals {178). When cigarettes eontiuninated with fluorocarbon polymers, including fluoro* omhon telomer aerosol, an; smoked they can produce u polymer fume fever. Pyrolysis product* an- apparently the responsible agents (187). Fevers (188) classified as secondary result front dehydration, hypernatremia, and infection. So-called toxic fevers an* classified as matabolie, induced either by thyroid extrael. dinitnvphonol, and pentaehloroplKiiol, or l*y leuko-vtie pyrogens ouch as endotoxins sine oxide, or polymer daoompoation products of rms. A worker who was exposed to mv-aonied metal filaments and smoked on the job developed the latter kitul of fever. Polymer fume fever is rare among liaise manufacturing the polymer, more common among Ohm* exiswd to *ujhtbented products or contaminated cigarettes. Domestic High Temperature Use TuAoii has been used f0 |jm. <xM,kin|[ nicnsih pans, dutch ovens, chicken fryers, >kilh-ts. gml mvillin tins, and cookie sheet'. In pan f tying or griii (189)\ the temperature ranges from 130* to 2 In roasting and baking the maxitrum tempera of the oven may exceed this range sliahtly but the it-elf is below this maximum. Tef on-lined uti ami dome'tic heat applianre* such .is Hat iron- ; |siteiltial hazard if temperatures are accidently ren at which the polymer decomposes. Usm and Abuses f Silicon* Solubility The solubililii's of a number of ersmetic material', alcohols, and solvents in silicone fluids ("Medical Fluitj 300") having viscosities of `JO, 3.T0, and 1000 centistokes (cast), tcstixl in ratios of 10 to 1, 1 to 1, and I to 10, are available (11)0). Data for lipids and a number of normal body constituents are given in Tablk.* 4 (1 stoke 1 cm*/* * 10"4 jn\ s). Endogenous Lipid Uptake Uptake of lipid' anti other endogijnnu* material' hv injectixl liquid silicone in hnmans has not been reisirled. Sneh studies were made in conjunction with safety testing for rarritwigeiiie hazards in rats and mint (HU). A modified Zak proeifdure sub'tituimg --propanol for glacial aeetie acidlwas adapted f -r cltutysterol ami lathosterol detenniijatioM. Ultraviolit -isidroscopy and the Zinnnerinatiii reaction served for detection of A4-U-ketn#tcroids. The content' "f Table 4. IdsMIHy of Natural Products in Dew Corning 310 (350 cSt) Silicon* Fluid r4v- *c SstsSWHy. "*/"* spectrophotometry 454 nm* Bowmen A Wed color 38 38 25 0.24 1.2 0.7 peknttel* 48 1.5 42 1.0 38 0.5 Cstredtot* 38 0.01 38 <0.02 OHro ofl spectrophotometry 280 nm4 38 0.011 visuel turbidity* 38 >10 spectrophotometry 231 nm* 38 1.1 vteual color* 25 <0.002 100 <0.002 spectrophotometry 232 r>m** 38 38 0.15 0.25 visual observehon of precipitate*** visual obsotwflen of 56 6 53 2.4 38 <0.04 Hint). t (tea UCC 000585 CUNtCAL CMEUtSTItV, pal. U. No. . 1972 MI large rvgts were removed for chemical analysis. Multilocular cyst* mul silicone granulomas were no* analysed because the silicone subjeeted u> analyses liml tn be frio of formed element*. Tin* silicone cyst contents was diluted with spectra grade 2.2,l-trimcthyl|*,ntunc nnd wanned fr ultraviolet absorbancy against a control containing the oriicuml silimm- in the s-ime dilution. The Ittlioofte samples front six rat cysts taken 12 to 21 months after injection into the uianitnary tract ilmwod 0.7 to 2.0 mu of cholesterol |mt milliliter of silianne. The cholesterol values. 0.2 to 0.7 mg/ml of silicone, for eigtht mice II to 17 months after dosage into tlic mammary tract are lower than are those for rate. The values actually exceed the solubility of chutes* (oral in the silicone in some instances, This reflects either the uptake of some caters of cholesterol, or the enhancement of aolubility in the injected silicone by the uptake of other lipids, four rat and two mice nlioone cysts demonstrated no A4-3-ketostcroid* by ultraviolet spectroscopy. Two showed concent rat ions of 0.G and 1.6 mg/ml, calculated as progesterone. This was confirmed in one by the Zimmermann re* action, which also indicated 0.1 mg of a 17-kctostcmid. There was no measurable latltosteml in either the mice or rat silicotic from cysts. Since latliosterol in the color test gives about 0.0 the color at its |>eak (3M6 nm) that cholesterol does at its |Mtik (.*>30 tun), the minimum amount of detectable latliosterol would be 10% ol the cholesterol value. The uptake by siliomie of a siilistance with the ultra* violet absorbance characteristics of a A*-H-l.etostcroid and the Ziinmerm.-uiii test charaeteristics of progesterone is of diuical inten-sl. In female humans, fat depots take up a higher |rrcentage of ingested progesterone than of estradiol (106, 10',). Tin* cor relation of endometrial carcinoma with obesity may be related to the uptake of |>rogestcrac by tin.* fat, thus prolonging the minis effect; estrogen-accreting tumors enhance the incidimco of this type of cancer (10$). The affinity of liquid silicone for progesterone [at 38*C, progertoroae is more than .10 tinws as soluble in liquid silicone m is estradiol or estrone ($1)1 must be considered in evaluating its carcinogenic potential M indicated in the studies with mice. Liquid Silicon* as an Oxygen Carrier The solubility of oxygen (30 vd %) at 37*0 in Dow Coming 300 alienne with 1 eSt viscosity is 12.5 times that in isotonic saline (10$), and of thu same order ss that in perduorobutyitetrahydrofiiran. The solubility thus exceeds that of the volume of exygsn taken up by whole blood (20 vol %). At 2f*C a rilieoM laid with 20 cSt viscosity dissolves 0.3 thuse as much oxygen as water (100). Hamsters immsmsd in certain pnriuorinated organic liquids or dheonca sntwmted with oxygen are able to survive variable psrtods of time ranging from 10 min to 24 h. Pulmonary shangsa such as leukocytic inlilt rnlimi of focal atelectatic areas, alveolitis, bronchitis and alveolar and twrivaaeular edema ami hemorriiage were more extensive end lethal with the silicones. The silicone with a viaaodty of 10 <t showed jihngoeytiacd amterial in foam nil formation; Urn siliootM* with 1 :iiii| ."i cSt vi*eo-ity prnduerd fih. Hike preeiptt it. i* the alveoli \I07). The 10 cSt n| iwa* to 1 <. r tolerated than I In- 1,0, 1.,"*, j,iul * 0 cSt -lllcii-- Mire.1 eat. ;'{ dug* have a,'mi survive 1 after hri'.at lung oxygenated fhioroearlsin liquid* (/.'>> I, The *atur I perOdorfS'arlsii's have no hydrocarbon linkage*. Tissue Reaction to Liquid Silicone in Rodents Following inter-cupular injection of liipiid into a mown, macrophages formed a local tumor and demnfe-frated engulfed silicone, described a* a -illCnnoina (100). This pli>*nomeuon w.-c- confirmed wit I, the stime specie* at the same injection site, Cl-.ir Vacudlc* wen- seen ill the cytoplasm of the macrophages. laical subcutaneous injection in a Inllnaii produci-d a local reaction, in tlie discharg- il fluid, white mils showed vucuolt-s dtnilar to th which develop'd in siliconc-injccti-d mice It W i' possible to pmduec the name effect by shaking human blood with liquid silicone (200). Local atrophv of fat ctflls W'itli phagocyti's containing dear vueuoh-s observed following -ulMMitamsnis injertion of liipuil silicone into laboratory animal*. Aft r Isith MilM'ipaneoiM and intr.ipcritoncal injection of silictlllt* nil'l mice, tlieir ailreiial*. lymph node- liver, kidney-, spleen, pancreas, and ovarie* showed focal inlilt rat e-i of macrophage* with large clear ectoplasmic, are;,. (201), Fourteen week* after intrnpcrttimc.nl inject ion of silicone into adult mice, .ilicoiie granuloma* appear- -I it the cnrtiromcdullarv junction tf ihe adr-unl(enerali/a-d fo.i of fat atrophy were al-o nb*.r\'--I, the lihagoeytix-d silicone wa* tran-pnrt.-d to regional lymph node* tml di-tritmtisl through the retienl-rmlofhelial sy-li-tn (20!). I'liagocytosi- of *ilicotie al-> occuiis ill balsam*; red cell* of rats dosed with siliconalso show Vacuolir.nl ion (20.1). A granulomaton- re action was observed after injectionJof liquid silicon-into flic peritoneal cavity of rats (20u). The phagocy tosis jof li<|uid silicone by rolls of the reticuloendothe lial system him its counterpart in the role of the rnacrophages in silicosis ami asbestosis (//). The analogoupatliologic defense mechanism* may relate to structural chemical similarities between the silicones and tiesilicate*. Effect on Experimentally Induced Adhesions Medical-grade silicone fluids of 321), 3oO, nnd I0O0 [tSt. Viscosity, applied infraperitonea Ily to the bow-1. lid hot prevent but augmented iintestinal adhe-i'-n Formation induced in rats by sturdpanper abra-inn. LJranukwnatous reartimis to riiic wen* nbserviil tcven weeks to four month* after silkicotie application (205). In rabbits, silicone fluid (3fl0 qSt) appeared to augment postoperative pelvic adIhhesiomi s us evaluated two to four woi ks after silicone admin,i stratum ($06). In rats, i-ither locnlly applied hydrocortisone or dliconc (20 cSt) diminished the uuitnber of standardixed experimentally induced peril one I adhesions (207). The period of observation, only tl rce weeks, *eem too short to evaluate ultimate effort in view of the loonr-term results of t he same silicon* in nts (205). m cumcM. CHCMtsm, vm it, im. A in UCC 000586 of Drugs from Silicone Depots Gradual, continuous liberation of small amounts of osrtein borwwoc* (wmulsting endogenous releai*) markedly inenaaos their physiologic effectiveness a* compared with a sudden release of the same total amount, flooding the target cclIa (nos, SOU) The s*th- HUneoua injection of regular insulin illustrates the auddi raioaae whereas the injection of m* iti-iluble insulin aneh sa histone insulin shows the slow release. The sagamntation effect may be achieve*! by divided finest* 11 many injections over a period of time. Thus, three hjeetiooa of mtradiol-178 per day for three daya produced a 72% augmentation of uterine weight hi tha immature rat as compared with one injection perday ofthe same total amount of catrudiol (0.15 mc). Except for the organic polymera, no attempt will be made to review the extensive literature on the various hormone and drug preparations designed to delay rcoorption and minimise the number of injections. It should he noted that all hormones do not demon strate the augmentation effect (4/0). Because of their aolubility in silicone rubber, many drugs, hormones, and oilier compounds may be diffused at rather uniform rates through silicone rubber carrier depots, whether implanted panutcrdly or inserted into the blood stream. The less p,dar compounds difiuse more rapidly (*//), in keeping with increased solubility of nonpolar compounds in ihpiid silicone (see page 883). Gaseous anesthetics swell the silicone ruhler, which returns to its original siie idler the gas lets been relesaed. A silicone rubber capsule containing iwnvd-rid triiodothyronine and isoproterenol implanted in the myocardium of dop with heart block produced a pace maker effect for a week. The effect was reinstated by transplanting the rubber capsule to another area after removing it from the fibrous capsule that had been forming (///). This experiment demonstrates the diffusion through silicone rubber. It also illustrates an inherent liability to its practicability: the lessening of diffusion by the ensuing foreign-body reaction. In contrast, riUeona capsule* containing mekwgtstrol ecotatc, implanted intramuscularly into sheep, abolished ovulation over a two-year period <tlS). Among the compounds sliown to produce pharmacologi cal activity after diffusing through a silicone rubber barrier that baa been implanted pnrcntcruily or in serted into the bloodstream are amines such us w.- apinaphrina, b-phenylainitinc, Histamine, atropine, and pipersrina; steroids such as estradiol, progesterone, testpaterae, and cortisol; and gaseous anesthetic* Stub as ether, nitrous oxide, and pydopropnnc (211). It has aat hesn prsctiesl to extend the action of a rin0e injection of a depot insulin beyond the period of a day banana* of the uncertainty of resorption into s variable vascular had. Depots designed to release a fixed amount of hormone over days, weeks, months, or yean eoostitutr a considerable hasanl if conditions develop in whiah all of the depot is released at one time. With the wtieows ndfcco, the problems of dirintcgrnr tion, optaha of lipids, foraiga body reaction, and local vascular Amps will have to be met if parenteral hwplantetiona art to he effectively used in humans. Under study am s plastic device that glaucoma patients may insert under the eyelid to release im pregnated pilocarpine f,>r a uniform release during 21 hours, and a polymeric inlrnutcrihc capsule that released a reservoir of enclosed progesterone during u year. The released progt-terune in completely metab olized by the uterus, so the menstrual cycle is not off* cleil. The polymers comprising there devices were not identified (4/-i). ( j '' Silicone Carcinogenesis A ^olid-state silicone surface wil produce local sarcoma* when implanti'd in rodent*, as do all *-*diil- state surfaces (->3, 14). The questito whether (lie effect is aolely related to the solid state or reinforced or inhabited by local chemical effects is be#t evaluated b.v studies with liquid silicone. A summation of the extensive safety testing for silicone rubber and gum (//, Hi, 17) in rodents is of special interest because the surfaces involved are not rigid.! With a rubber that liad a tendency to crumble at the subcutaneous site, two cpicardial mesotheliomas in addition to local sarcomas, 10/30, wore found in rat*. A similar tunor type, a (H'ricardial mesothelioma, wins induced in a mousy bv intrutiioracically injected diatntnsccous earth (/). The induction of mesovheiiotnas remote from j the lest site is possible an example of chemical earcitiogcncMti, whereas the local mesothelioma a-- Snciaifd with dintomaceous earth injection would relate to physicid carcinogenesis. AM of interest is the correlation of high local tumor yield with a low in- flamijnatory response a* elicited by silicone rubber. tn., the potential carcinogenic roll of inhibit,*! ii flamtnatory activity (315, 57). .Most experiment- with liqui^i silicone were not carried ou: long enough to evaluate carcinogenic potential (11). Long-term effects, including the carcinogenic, of injected Dow Corning 3(10 dimethyl polysiloxane nte.|- ical fluid of 3o0 c^t viscosity were studied in both Long-Cvum* rats and Marsh mice (31, 192). Each experimental group was comprised of 36 to 70 animal* of one sex with nn equal number of ittermate controls receiving the some volume of isotonic saline at the same site. The injections were male at 2-3 months of age ami tb experiments were terminated 17 to 21 month* uft*r dosage, depending on the survival rate assuring an effective number. Effective ntimh.r-. those developing tumors plus those) surviving, rat.;.- d from 22 to H4. T,hr intraptriUmml TuU. Thi* rdute was t*-t* ,i .0 tnuljc and female rats and miee. Female rat- r, c< -iv 1.0 ml of liquid silicone, the malm 2.0 ml. ITm.de mieje receive*10.4 ml. the males 1.0 ml. On the bosir- of effective numbers. 8/34 of the silicone-dosed fcm.de ratg developed reticulum cell sarcomas in the lung <>r peritoneal cavity, and one tntr^pcritoncal adeii't- earcinoma during 17 months. 27 controls, one reticulum cell sarcoma and one xed type aro.-e, For the male rats that were 1 for 18 roomM. tint significant trend for the fema 1 was not ob-erved: 7/34 lung or intrnperitoneal retieilum cell sarcoma- forthe silicon** scries, K/M for the aaline controls ami 4/35 for undos*si controls, lfowtmr, the silicone -ri- devclopod oue fibrosarcoma of tlie lung. In female mice 22 were living 18 months aft tr dosing; 23 saline* dosed controls survived the same p< riod. One malignant UCC 000587 CLINICAL CH6MI8TNV, Vol. II, No. 9.1972 M 'Urtiocytie prolifer*! ion, one d-genoratiim, two instanc*1* <>f ext rumi-diillary hematnpuiesi.* of thi* Jiver, ami niic local lilirosarcoma dcvelnped iii tin* silicone scries; itl^o an infill ration nf lymph nodi- and a local nccro*i" with focal calcification. Tin1 controls did not allow these types of patliologifal changes. Twenty of till' mule min* that received silicon)' infra* peritonctilly wore livinic I'd montlis later. For Ihesiliemie cries, 4/22 lyinpltoiii tumors va, J/'2y for s;dme-do*ed control* ia not significant. Not only was tln*r** a li|>- franwlomatnus reaction, Imt also leukocyte infiltration, calcification, ami necrosis wen ohservixi at tlie intn- peritoneai silicone dose site, T\vi`nfy*one mire si,owed one or all of tlica* reactions. TV tubculaneuu* titr, This site wn- studied in male mice that received 0.4 ml of li|Uil silicone Tin- nuimmury-ghind site was studied in both female rats mid mice, the former receiving a 1.0-ml injection, the latter 0.2-ml injections each in two nianiinary arcs. For the rata the effective numliers for dosed ami controls, 21 months after dosing, were til and *7, re-pectively. There was no indication of a carrinoin-nic effect' one silicone dosed and one control developed breast adeno carcinoma*. A local follirular aileuonia, akin to a similar dinicid entity of women with libroev*tie disease of the breast was probably due to blocking of tin* ilucts by rilioune, a deposit of which was niciNil in a fibrous wall in the center of the adenoma. l-ocal silicone cysts showed a granulomatous reaction. The effixstive num ber of female mice that received iii|uid silicone in jections ill the mammary tracts was -lit. In contrast to tin* rats, one fibrosarcoma, one spindle cell sarcoma, one pleomorphic sarcoma, one maliitaaof (ihrohi*tiocytic ncoplusm, iuic adenocarriimmu ami <iih' hainarlom.atoils epidiTtnai cystic inclushm di`Velo|Nsl at the local liquid silicone sife. No corresismiling local f moors developed in tlic controls (effixdive ntmdter. .11). The adenocarcinoma cannot be ascrilsxl to tin* silicone because its appearance is charactered ie for tin- colony where mothers are rebrol. Tliis carcinoma. Isiwever, was riddled with silioniie ih'imsits. At the subcutaneous rite in the male mice one each fibrosarcoma, neurofi broma, diffuse lymphoma, ulcerating benign hyper plasia of the skin, and lieterntnpie bone formation develo|ied at the liquid silicone dine site. These uuuiifestetions were absent in tiie coulnda. The seven local cancers of mesenchymal origin that developed at the liquid rilicnne injection site in the mioc cannot hr attrihnteil to rhance because none developed in Uie eiuitniis. A s)ms*m!s difference is infrtH because such tumors did not occur in the nil. However, in the female rat injectixl at the intra- poitoMal rite, liquid silicone induced an ineteasi' in hH| ami peritonea! lymphoid tumors. A similar trend wan aloe ohaerved for tin* male mice. It is conclmkxi that liquid rilioooc has a low-grade carcinogenic poten tial la rodeats, the specificity depending upon the site. Qualitatively the response ia akin to that of the silicates WhM9 Is Upri Hiticow tn Note the mmotb<4inma* for crumbled silicone nthher. in rifieuris, the phagocyte that engulfs the silica imrticle ht the lung dies; the engulfing process is repented with ririuing ntusrive fibrosis and ultimate earring iwea. At the subcutaneous rite in tuinito, asbewtos produce1* the local sarcnmn* of michenchvmal origin The rupturing of silicone cysts with format imi m" le ones may be i.nalogniis to the tra llalie effect i.f r> peated local injiX'tinns, which lead* to carcinogen- in rodents. Human Considerations FikmI. ('irrum*tuntial clinical evidence, sugge.t- tj, food* maV tal tip met hylpolysilox mi* when e-->k-d in ifropriotarv hraml* of cooking oils containing t!i- I vjH1 of *ilici,ho. Tie* <`ffeetiveness uf unticoan-ilahm, dross like warfarin nr phenimlione .as iiiea*uri d l>\ a ihrdmhntc-t wa- markedly reilueeii :it period- 111r11,l' which such food* were inge-ted by pa' i-mt* i, m/i/o/.i hfi xilirnnr four! nl/ir*. The eriind obstruction oi Silastic (silicone) heart-valve hall* oh*ervisl in a number of patients is ascribed to the increase in vohirne of the halls as a result of lipid ah- sorjltion (2/7). Solubility studies ia which the balls were ix|tiilihr:ded in a simple lipid solution similar to human plasma showed a 1..VJJ maximum Volume incijeas)* oceurr*al in weeks. Larger Volume m- creuses were ob-erved in halls after chrome implanta tion in human*. Analysis for five patients with variant ami obstructive Siia*tie occluders showed total - \- t Diet able lipids ranging from ti.2 to |ti.lrf. In anal\*-- of balls wbicb slioweil a volume imrease greater than leVfj, tbi> lipul distribution was (0ti.*r7 chole.i. r-! i-stiys, fo-20'V triglycerides, .Vf ftce fatty acid, and W/,, clmlesleiid. Atrophy ami fracture of the sihe.-n bail lias also Ims<ii r'|M>rtid ill pati-uts more than Jl months after aortic valve replaeaudit (2/,s'). lie effects of curing, aihhlion of a silicoi dioxide tiller, and the use of )>ther |wilymer are Ii Is* ct>n*iderid in evaluatingtliebmcompatibility of In art valve*. .t/a/umapMs/y. Augmentation mimmaplasty in 1. t- maJis bits ilepemled on the implantation of a pro-tln -i- or the injection of a (hiid that has or develop* tie- consistency of body fat. The prosthesis may be a rubficry polymer or a prclilled or inflatable bag tilled with liquid silicone. A silicone fluid that gels by suin' catalytic process, a preformed gel, or a pure li<|tiid silicone have Iicon injected. This technique i- now outlawed in the Tinted State*. Complications that inav arise with tin1 silicone gel iiuludc extravasation of blood, lumny mNliilar breasts, nrigration of the gel, silicone mast it is {2Ui). Ileenus); Ihpiiil silicone has a tendency to migrate front ait injerlhut >(**, mhlitives 1 rere intr'slueed << fuxsluce tnorr of n local inflainmatory reaction, an effect believed tn enhance anchoring. The oxnci chem ical nature of tin; ailditives has only been inferred-- vegetable oils, or posibl.v mineral oils (220). because liquid silicone takes up endogenois lipids, it "mild be {difficult to establish categorically whether the origi nal injected silicone carried a li|dd additive unl--s its history was on record. A wealth of clinical material demonstrates the serknis complications that may ripe when liquid silieime is injeetetl locally into human fetnak-s for mammary uinphficatim (220-222). The load timue resctioii would be influenced by tl<e general reaction to a foreign sulistanee, tie chemical activity of tho silicone, and the ndativc solu bility of ................ QUMeai CHOMsniv. vsl m. no* A tt/z ucc 000588 It*** tissue and fluid metabolites in the silicone. Bilateral groituloinatnus mastitis di'vrlojied after repented injeetiotM of liquid silicone into two women (Iff). th> histiocytic reaction to silicone droplets Wits tmilsr to that of a parafliimma. Axillary lymph nodes were affected. Loss of both breasts preceded by a delayed allergic reaction ensued iifter augmentation with iaquMt itienne (220). A bilateral inflammatory reaction to a polyethylene bhulder implanted for mammary augmentation was noted (222). OUur utu of tiliamr. Silieone frames are tt-txl for reconstruction of the external ear; numerous adverse reactions with induration and scrims drainage iiave been reported (223), Liquid silicone as an urtilicial lubricant for oatenarthrotic joints of biinmns Was not superior to aline, lliern was no difference in reduction of stiffness m measured with a knee arthmgraph. In experinw nts with rabbits, induced cartilaginous defects did not heat faster alien silicone was injected into the joint, and obstruction to lymphatic outflow was indicated by use of a tagged protein for the objective measure (.V!). Emboli of silicone were found in the capillaries of the heart, brain, and kidney in 10 humans who died after open-heart surgery involving tierfusiou ispiipment that used a sibwine atilifnaming agent (223). Bone rcaorption wim observed in II of patients who had plastic implants in Ik chin. Of t hose slwiwing resorption, silieone rubber was used in seven (22u), Silicone rubber tubing its a shunt has Imxxi used successfully in hydrocephalus for draining cranial fluid to another part of the body. Two hundred thou sand Americans have lieen so treated (M2), The ti--ue reaction to two silicone whiter sliunfx with the forma tion of a hyaline collugenixtsl ca|tsule, a typical foreignbody reaction, is illustrated (f). Food Packaging and PMymnr Oitkwara In addition to the packaging of raw* or uncocked foodstuffs, polymers are also used in their storage, protection from bacterial contamination, in keeping them warm, and to enclose them while they are Wing cooked. Although subject to Kcdcrnl lhttg Act n|iproval, there is conqmratively little safety toting of these polymers nqxtrtisl in tlie scientific literature. Polymem invoived with one or iimro of I la* abovedescribed purposes include polyvinyl chloride, poly styrene, polystyrene fortilied with rubber, nybm. and polymtcr. Permeability to gases, such os water vapor, and thivmsl stability have to be oonsidensi in designing their appKcation. The parenteral sites of the animal body me surprisingly hostile to the stability of various polymers, as described elsewhere in this review. Morn information w tmeemary on the effects of the |trotcins, fata, and carbohydrates and the other constituents of hsidsluffs in profMgpsf contact with |*l.vmers at various temperature* ami oxidative condilituts. 1`he amounts of uunactcd monomer and other ingnxiictitx mnd to induce polymerixation or iiroduec the dcsirtxl product, as well as the ihssompositiiMi products of the latter arc also important. Routine safety tiwting by the Knnd and Drug Ad* iamlratinn for phUisIsle iwter phwtietseni has not r-v< rilij**! ill effort-, but the y,f*Uv of fnnd-pnek.icinu materials containing them will have ti hr reevaluated iti light nf the uptake nf piiihalate rjsters in hunian organs (227) (See sect inn on fjk ('k of Polymrrx in Chnirtfl (%mislfj.) A '1'ft-itivr tissue culture test for hiocobipatihility of pla-tir- extracts the plastic with plasma, l'eritoneal mnernplcigrs from the rat uiu] calf kjduey, as well a- cliicfc ixnhryn fibrnb/u-t-. are' usis| in the cell cultures to uhieh the plasma extract iU(l<le,| (222). 1`iiljfrlhiilrne, A scheme for the iklfiitiliration of antioxidants in polyethylene* for plL-tic foist con* taiuers uses four solvent systixtis tii simulate food types; water, dilute () nil/lCHI ml) acetic acid, ethanol* water (10:1)11 by voj), and ethvl ether. Antioxidant- from several products tested migrated to one or more of the solvent system- (22!}). Aqueous and oily (\tractsidf fonirnercial polvethvlenes such as are found in thij home and in tin* food imlu-try were fed to mice for fopr weeks. The -kin of the mice was then painted with jd.t-beiizpyrene, No co-earcinogcnic effect wn* ob-ervtxl in the malignant transformation of the in* dtieed papillomas (220). Canadian chrysotile Ian a-he-to-) absorbed oil from polyethylene bag- whim stored in them. A constituent ,.f til**ofl Was eonVi-rt<s| to (lipli'Xmquuidlic. The relation ship between tW weak carcinogenic activity of organic material extracted from the asbestos and the oxidation products of the |Hilyethyler.e was not resolved i.Wt Mtluiugh food was not -tend in tlje-e |tolv, 'In hag'jthe (lemon-1rated exi-h.-nige froiij the poly. tlo ! : is relevant to the problem of f<sl pack igmg. I'iif)l\l>liinf. \ study mi the e\|K>-ure of limn Volunteers to stymie I 212) give- koine liua-Ur* hitman tolerance. Since intake wax by way of Me- respiratory tract, the tc-t only qualitatively a-e-e* Hfccfs nf intake by way of the gn-tniintctinnl trad a jsir-sible route involving styrene polymers a- food Containers. Human subjects were exposed to to So gl/l of ethyl benzene or 22 d I of styrene for x li in a gas chamber. N'o exbalisl st y rene and only traces of et by I Ivxtunc were detected in expired air when the va|ior- inhalation pha-v of the experiment was ended; during viqsir inhalation about two-thin|s rjf the vapor- wi re retaimsl. Urinary excretion of the hydrocarbons " a* negligible. The main excretory product for both liydro- earboiis was maudelir acid with some phenylglyoxylic acid, also some nwthy IphenylcarbinoJ for ethyl Irenzeiie. Under the c\|ierimc>il:il conditiops tin* metalsilu- degrndatiim of these hydrocarboiw apparently doe- not pnduec harmful end products and only slightly toxic intermixiiate products. When the exposure to hitninns itcwdol the amount ued in the tests, com- plainls of fatigue, sleepiness, headache, ami mild irri^ttiiHi of the eyes tuid respiratory tracts were oh- scrvtd. Derm dologic lesions in wwkers exposed to styittme used for tlw production of rttsins may be caued by ot her silled niees. j Six* six:!ion on f 'sex awl Abuses /Nilmnir for is'ssihe effect of ailiconc in cooking oils. | Thh Um of Folymort in Clinfcnl Chnmistry PlaMie AutoAnal:rr nip$, Sei m calcium is ud- CLINICAL CHEMISTRY, ' fat. II, No. f, 1WI W ucc 000589 .s6r|xxIon piantic AutoAmdyxcr cups for scrum storage when the pH of the serum rises altovc X.O. More calcium . wiw adsorbed by polystyrene cu|ik limn by |*olyptopylenc cups. Ton permit of Hie calcium winy be lest Wider wwtimum ari^on^um emiditionx. If scrum is stored at 4*C with minimal pit change, this sampling error in avoided (AM). Polfimrr ayringf. Uptake and diffusion of oxygen occurs with polytiM'f* suoli us imlyprnpvlt'iif, |mlvXtyrcoc and 8.A.X. copolymer. In oxygen tension determination, glass syringes are preferable for blood collection and storage. For true values to he obtained, Mood MMMt be injected into I In-elect rode within seconds after it is collected in tin- plastic syringes. lueses from glass syringes occur at a considerably slower rate Pktlitinle ttkr plattiemrx. Of the Sol) million | sitied* of phthalatc esters currently produced in the United States, plnstic manufacture consumes the bulk. IMas* ticiscrx like some |ditludate >sters may leach or even volatilise from plastics. A number of diesters of plil Italic acid art* used as plasticisers in the mniuilartiiie of plastic transfusion packs. Ih-(2-et hylhexy I) phthalatc plasticiser was rreovived from plasma (II. 1 mg 100 ml) stored 21 days in a polyvinyl chloride pack (313, $90). The LDm intraperitoneal dose in mice, greater than 75 g per kilo, vastly exceeds the amount :i litinmn would receive in a transfusion. WIicIImt the aiiionnt of a lipid-aolublc plasticiser has any adverse elfect when received in a transfusion is not known. Blood from laboratory and aurgical tubing for hemodndytis and heart-lung-bypass systems extracted phthulalo ester plastieiscra (3.17). Plasticizers were also found in the tissues of patients that Inal received transfusions. The rat liver was aide to de-cslcrify Imtylphlhalylbutvl alveolate to glycol.vl phi liulalc: di-(2-et liyllnwyl)phthalate remained intact tinder similar cx|criinontul conditions, but accumulated intraeelhilarly (3.(7). Phthalatc ester residues have Ix-en found in waters and marine animal life in industrial localities, also in hatchery lish. Toxicity studies indicate that a very low concentration of di-(2-ct hyihcxyl)-pht lialat e inhibit s the growth and reproductarti of tlu; water Hist si mind. Absorptions in guppies and deaths of xebraiish wire prtaluccd by food containing phthnkitc esters (J.W). I)i-(2-cthy(hexyl)-phthalatc, a|tfiarctilly as an optically active isomer of the commercial |imduct , has bust identified in the mitocltottdria of the heart-ninsele edls of cows, dngt rabbits, amt rats. Kims- the liver of rat* can synthesise plitItalic acid and certain bacteria can cstcrify it, it is not established to what degree the phthalatc cater comm from tin? external environmitit ($39). The toxieoiogy brought to light hy th; above studies suggests, nevcrtla-h-ss, a nvevaluntsui of tin; environmental impas* of plilhalatecstcrs. Una review refutes the myth that tint silicone* are biologically inert when introduced |mrcnterally into mammals. The local tissue reaction is analogous to that of other pulymrra with sitniiar physical and clammal pixgiertMa. The cstructioM and rehxtse of emiogwarn lipids by mfiannes involve abnormal shifts in tad awicentraeion gradiniU. The migration of in jected liipiid liticoce and it- uptake by the reticule- endotlleh.d sv-ti in app"ar rather in-idiini'. (Yrtait.l\ I lie siljfoiie- do Hot ipialifv a- safe f,H,, additive- III,, human race dm*- not ;dwa\- profit f,\ last exp* r.i-n,. III a past era. the deh.ii'le f llouing In' injecti >11 ,.f paralliii for r"-mii,ir elli-el *h"tild have been a warning that lilpud silicone. will* it- -inular phy deal and r>e tm. etil proper! ie-, would follow a similar pal tern. Pandering of Madison Avenue to the "little boy" mentality ..f so majiy American male* must be b'ld account.il>|>. for the whoji-sale tragedy resulting from silicone m.nn- maty :jmplifirati"ii In other culture- the hypertrophied female breast is recognized :t" a disease. At the cla-tc:d Japanese Kabtiki theater it- serves as comedy relief. In Ireland "brea-ts are for babies." a* d in Argentina. North American females selectively bnxl for large breaslialuess tnay he referred to as ri W*. The de-ill- of the American female to eater to hi infantile friend or husband l-i| t>> the silicone (jraze. While tin aflermalli death' by emboli, necrosis lumpy br.-a-t-, and bfeasf ainputaiion- after silicone injection' ill hnjiefully sober the exuberance for ind ulging thi- form of sexual variance, tin genet ie outcome of preoccupa tion wjitli the female brea-l may iiorp'tuate a rare ,,f top-laiavv rather lian intelligent women. The etbet of surgically implanti-d siliemie and other brea-t pro-- tlu-esj-- falling ill love with a hag of silicone--i' in 11,. same Category ns silicone injections when related to mental health. Plastic surgery with the organic poly mers has reached thednhioiis -t ate of an where humans t:an 1st- outfitted with a dog-like |N*nis and pig-like breasts. 'Ihy overview of silicone toxicology chang'd whin silicic acid wa' recognized a- an e.intial body cmist it (lent. Bi'cau-e of the close structural relal ion-hip to silicic jaeiil, the silicones could cniiciivulily act a- block ing agent- in siltc'c acid metabolic nroci'sses. as the sulfa drug' block /i-aininobenzoic acid (03). Tin* carcitiogeiiieity nf liipiid silicone in micrJ us ilescribed in this review, may stem from such ii blocking phe nomenon: tbi' nteialstlic pr.eesses de|M'ndent ujsiii silicic acid and the cancers derived {through silicone both involve eel Is of incsenehymul origin. It iii rat her utiiipie that in cancer ti'sling for |v>lvmers IImti' is no disagreement Is-twish rijsuit* of varimi* workers; the objis'tive measure, the production "f a cancer, is not contioversial. The long latent period for solid-state carcinogenesis in the rodiiit (33) and the rarity of canc<*rs ussoeiaii-d with foreign bodies in liuniatiH suggest that the life span of most personafter implantation of solid polymers mv mid be its* short for th|*m to develop this type of cancel. In humans, the intrathoracic site is more sieccptihle tv* evidenced by the high earcinog- nic |mtetitial of the avascular fibrosis associated with silicosis and usbestoai*. Such formatimis. analogous to the rodent subcutaneous histological foreign-body reactions, are likewise characterized by a long hit ent period ftir canecr, 20 to 30 v ars (/1). Medicoh-gal complications probably deter .he rt'porting of some human case histories involvirg solid-state or chemical carcinogenesis related to implants. The li-t of cases in this review includi's snnte that weri- overInnkfd by etiriier reviewers. Much potential clinical tiiaierial is nevet followed through, fit her pist-surgi cally or postmortem. CUmctL nauanr m u ucc 000590 Report* on the clinicftl applications of tin- polvtner* re often mcamnglece because they did not identify the exact chemical composition of the jmlvnier ti-ssi. It m frequently difficult tn evaluate the extent of clinical aiqdication of polymerH ;s in exemplified by tbe cyanoacrylate* studied for use as surgical glues (/. $40). One surefire means of raising money for ranter naoanh is to proffer the rure nr test for eanoei- ju*t round the corner. Apparently thi* funding -*rmgy also nodes for srtificisl heart research. With Nome notable exception)*, tin; |Milymers that have become s part of the human same do not produce manifest stions of acute toxicity. Degradation for any one polymer it* slow enough that body zb-fense ineclmnwm are able to eupr with it. However, the sum lotui of such breakdowns of all the polymers to which a human is exposed eould conceivably overtax the defense mechanisms. It is too early in this age of the itolyiucr* to assess whether such an insidious process will be forthcoming. With polymer dishware. unforeseen rnmpiieations may occur with uses to which they may be inadvertently subjected and for wliicii they were not designed: microwave heating of materials not designed for high temperatures acidic foods or beverages stores! in nnn-acid-resistant materials alcoholic beverages placed in alcohol-extract able polymers dishwashing in strong detergents :md high temjM-raturcs of material designed for "throwaway" attet one use Volatile plasticiser* from ixdyvinvl ehI* aide np* hoistery used in cars have been held accountable for the fogging of car window s as shown by gas chromato graphic analysis of windshield deposits (,,'.}/), Ilie plasticisers act as binders for airborne materials. The effect* on humans wlw inhale tliese plastieiser* is a matter of eoncem. (unwnary linkages vulnerable to hydrolysis contribute to polymer breakdown in vivo ami ilipml mi tin* hy drophilic nature of the fsilymer. Free radicals in tissue metabolism may induce rapture of a rarbon-lo-carbon linkage, as in the polyethylene*. Oxidation reduction resetions involving alcohol and aldehyde*, d*-gradation reactions such as decarboxylation, ami cleavage of double bonds arc possible. Tagged polymer* demon strated breakdown after impbaitixtion in rodents. All acgaitic polymem tested as soiids with smooth aaf>M of critical sise produced soMd-state eariiHtgannaa at the rodent subcutaneous site. At th subeutawaoua site, humans an: not as susceptible ns r>slents to this type of cancer; human serous membrane* arc. Free radicals in polymers ih* not tqipenr to ennaf itnte a raroinagraic threat. A polyvinyl chloride acetate copolymer, vinyl chloride, |sdyca|iroliictani, some brands'of Ttfin, and liquid ntlicmiu act*si as chemical careinogms in rodents. The factor limiting effective continuixl us*; of the artificial kidney probably is the worthing out of contitoante caaciitial to norjnal nmtabidism. Crucial problems with hesrf-a--i-t devices ,m,| urtifteiat leartinvolve chitting mid deMnntinn ,.f .linlsr elementof lluf blood. Polymer pro-tlie-e* phy-icallv and chem ically! akin to adjacent cellular con pouent* ri-k ;*n mi'oitntiuinereai a inn ending tn a rejection phenomenon I'olyvinylpyrr .lidom pla-ma oxtinder- te-teil m roileiits produce ! the-aurismotic rear I ion*, V* hutnmi* rireiying a fracti m. liver h-sinn* occurred, Tie- -ti-ngi- of polyvinyl lileehols in the b*sly w;i< similar to *hat nf the |ilyvinvlpyrrolidones; some iiroduced anemia and Vascular lesions in rat-. In ruder its, safety t.-i n,j. for human cancer is inronohi-ive. .Safety testing for |m|yethylenc intrauterine con- trnwjptive device- demonstrated the u-ual solid-oate carcinogenic effect at the subcutaneous and nitra|*Titoue;d sites. The intrauterine ri-*|Hin-e -enilo- ni'*tr)itis, squamous metaplasia. ami carcinoma--ap pears to be characteristic of foreign bodies in the rut at t ifis site. ln| contrast to self-curing tnethylnjethacrx late re-in- u*e*| as bone cements, rapidly |*ilymeririiig nlki cyanoacrylates and prv|*ilymer jsjlyurethane- li.iw not found exten-ive rlinical application ;t- ti--i|e adhesiVes. Toxicological problem- relating to nntlolmetfiacrylate at the time of application need forth-r resolution both for patients and surgical staff. tn--e suerji*--fully in-tall<sl. the long-term ri-sult* are prom ising. Nt chemical carcinogenic effect was noted f-.r tie- monomer in -afety test ing. iVilyleiralluoniethylene ii-ed at h gh temperature < its tnutamiliat'oli of cigarette- rail irodnee a p--lvn. I fonie fever in human* inhaling the nymlv.-i- |>r- 1-n-*Safety testing of |*ilyietr:illuor<>etliv|eue pr-t.l'ie. .| Variable rcsjinn-e. indicating a cln mical carrin-ig'en- effect for some prodnei -. *l|Tw uptake of endogenous lipids has limited t lie iro - fulness of silicones a- heart valve*. Similar uptake to liquid silicone ih'jsit- correlated with a local carein<genic rcsptxisc in mice. A wealth of clinical niat-ru! deiiwmstrates the serious complies ions possible from local liquid Nilicone iuji-ction* for nammary amplifica tion in women. Horn* resorption h followed -ilicutnlants in the human chin. Liquid silicone i- phago- Sicd by cells of the reticulis'iidoi helial sv*trm. wig-term -ulverse effect- from jsihiner food wra|i- aml dishware are yet unknown. The t**xieit> **f phthulate ester pla-tirixers in some packaging mate rials iHs-fls re-evaluation. Tlieaiitiokidantseniit.'iined in soine polvfthvlnnn fissl emitainer* are ext rail.-I,I. umler certain eomiitiim*. Since ftyrenc is tnxie to hutnans at critical ctmc**nt rat ions, the long-term eliect- ofiusing polystyrene dishware should be appraised. Polystyrene and tmlvpropyline AutoAnalyzer cup- useil for scrum toragi' nmy adsoib calcium at a pH above X,lM*In.-*Kyringi`* are preferable to some |*ilyiin r syringes for colli-ctioti and storage of blissi for oxygen lejnsion determination. Phthalate esters in polyvinyl chloride trate lusion pack* have tieen recoverisi fron storeil plasma. UCC 000591 The niither gratefully sHmowkslfwi the intwe*t nd silv-,-- *.l (imrgr W K. Csmill, I). It. Ihcksu. sad 1C M Ksilina. ami ihe serreiarial n--i-liice ijf Hwnttta Hi-rheff snil MiMmd Wault-ir. The -luilv was aaiipurwd ia ptt by tlie Max ( CLINICAL CHEMISTRY. VOl. t*. No. *. 1972 Ml TMor'imann FmindalJnii I.f NtvaiU and ll,, I'ailt,,,, Fi.timlntinti, In:-, Itaranaa id III* Ifncili ( tin* r*vi*w, * *ii!iili in partial MWnt id H* |mlil|ilnm pt..vid*,| l.y lit* Halil* llnrliala (Vllac* IIh^nIkI Inalifiil*, 1. Bryann, (i., nwl IMwhntf, I , Tin- limitalkiii* nf nitty tinting. /`mr Ksp. Tumor Hr*. II, KNt flfttitt). 2. ItaliBtry/l.ii-u.i' * "<t" < i.tn.11-: liaatii-* inti li..,k Iniatil. likrm. toy. Ali w* 4V, III 11 >1*1-. li, M)711. t. King, IS. It., Mtvaiirv' It*, "rirtilihr hnlnry amI if* riflr in pkpni-nl i4t*mi>lrv ami rltrinM'lirniiMiiy. Ana. A.K. denrf. Sri. 4B,Mil(l9T.7). 4. Viiriiviu* I'nllin, M., la Arrliiiatsura, 1*1 itmIiiiv ll.d. In Mailm'" A Cnmprilnitttri Irtnhr* nn Innr\i*tnu unit Thinritunt I'hrmiSry 7, f,,Hi*mam<, linrii A INrw Vink. N.V., IIKJ7, p aim $, Millnr, J, W., A (imipndM'iruvi' Trtali nn lM.n*iitiir atnl Tbmii-liral IVmitlry 7, limpiiMi*, liimi A I'11., Ni'' Vink, R.Y., MHI7, p fim. ti> Mnrtrm, M,, l*r>4ilrni* at ill i-*i d in lailyim* n inm-. f'lum. toy. A'nw At, 4.'. ISafit. 27, 11171). 7. f#vinp, H, NMurray nl liiima|ii*nl mnli-1 i*l * ami *iMr nln aunt |imlit*ma. Auu. AM'. Amd. Mri. 14*, :i I HHIX). 2. IUI|m, II. I,, Itantai |nlywm. Ann. A.I'. Arud. Sri. 146, Itn (IWM). 2. Mrakt, R. N., and latm, K. M., Hiliniw*. Itrinlmld I'nlil. (*>rfi., Now Yntk, N.V., IW.MI. I2l FiaiHtam, H., Hllfamntn. IdiikiaMtitttral liltrary Inr., Nmr Vnrfc, N.V., 11*11. 11. Ilrywm, II., and IWIndT, I'.. KilirdtHiHlwnl nnt|ilamnH. /'raff. top. Tumur Km. 6,77 IIWI7). 12. < 'mrlinli*, I". M., Hilitt.n an twnfial idnmnil fin I la- rltirk. Fnf. 1`rmr. 21, 7MM 1972). 12. I`iHi4i\ H. M.,Ktliinn: A |a*al4i'(at'lnr inlatnnmlia'iralMMi. Srirmt 147,2711(111711). 14. (Ippaniwinir*. II. H., OpppnlK'inH'r, I,', 'I'., I luni l.f. ky, I,, Mtatl, A. I'., ami KirMi, I', It., Knrlltrr almlin ,4 |*4vht* an rarrinngpid* aRiitU In animal*, I'nnnr tot. If, 1'U (IlkV.i. II, l,yman, I). J,, Hinnmlii'al ,adytum. Ana. AM'. 2nd. Sri. 144, XI (IWM). M. Ilntfar, If. (!,, C*nm imlm-luiu liy |t>4ytir*tlinn and |*dy* alinat* plantlm, J. Alai. 4 Vrarrr InA. 22, IIMI (ltH44), IT. Ill*w, W. C., (farrimarni* atndkm nn aralrt4n*t4ul4a pnlymm. /'alkaf. MlntM. 24, 77 (IHHI). II HaidaboMv. I., and WiUbilr, H,, Tin mrtalailiam id atynmr tulbarat. J. Hiul. Vhmi11,3H IAVI). 14. Tinnalkt. la, Htil**tl*m**t* twr4map*a'n Ity '*4' ami Ml hlnUwl (udyuwlbylmrtarrylain Mm*. Tumuti Si, ISA (Halil). 24. 1`aawvai, J. la. Wmalwatd, M. <*., ISihmhi, li. J., Wrmian, 11. K-, Mrnnili*. II., Kutkami, II. K., ami lamiuml, V., Tbn dvnhliMi nl ryamwtTvInlr ti mua ndbraiva. 1. Smprtp M, 4*24 (1444). It, Mak4, T,, Cnwatti inr idnia nI i4*nid*. Adrnu. Lipid ton. T, l (MM). 12. KhM, T* and Mrviain, li., (Viknrw-lt tlmatah tatlid MMaiawhaw. IV^r. top. I'nrnar IT,*. S,M!I|HM4). 12. mh IlMnal id Ihn Atinl FAU Willi Ki|w< C'nntmillt* im T'aad AdditHnn: Ktralualinn ,d (It* ra,iiman*<n hatnril* id Itanl addMivm. ITmM b*M (Ayna., Tirk. top. Srt. 224 (IIMI I. M. I Man, II, la, A|ddlra4iiai nI alaliatiral mrtlkida in pfcy>*4. nty. I%pm4. ton. 4,27* (ItKMI. fl. Hnra, 4. II., IM naaa id kidipral amy. Ilyad. Mr. M, IM (MW). IM (inaa, I*., and Hull r*, I*. Mvkntlaiaai mrnm>n aa an Mdn nl tariam^ada (mianry. lad Catmrt. Tnrtrwl. 4, 247 <)*). *T. lady, U M., and Ntdmn, A. A., Kdinanmian* indiliad by M QlllHOAi OHE22MIHV, VM. M. M*. li 1272 iMi^ip|d* iihT`iii'iiiTviiM injMr*ior iif lar^itvTnrthyVrll'.'. fntn^iLn. wifiMii#r1avtV*lhC>l,ra'\r"f.u.t.liMAAltltti.. l7A^*'../..I1/'WTItjr_,n_Mt.l|<*1|*6t,y.;iliya.i(y|r'|t'h,7k1li'ii* vir)>.' 22. Frmnkrl, ft. K., Hir-linti, J. M,. and 1Wallin*. C , D*t*.' til p..Kiiii-rirti'.n fadiml" Itv paramagn*m* fnainatirr J. An., f ^m. Mur. 74, M!M 1 24. Mark. II. I, and Mirr>4tian, R. B, i:ff**t id inv**n |ih\-ii*l ami 'f'initial J*n>p*rtim id l*ilyin*r*. A nan. li. /*W I him. I, :*. (l'i'4ti. V. Sti-ipiin. I., anti An.*, ||. fj.f Boy id watrr in -ilica ai l J I'hiin. ( him. 17, 2Hl 11'tVI). II. fit rImalt. A Malitnant tumnrti and hi*h pnlvnirr. .iSvm'yniiiri IiII*4, 7nn";i '' I'tVti. Ij 32.i If. F.t Itwlf* *f ihf tripitirH i, Coilti"! f'htnt 54* l ivi t in1 <rtn m>k!* *! 33.1 OpIM'iilM'iiM'f. H. S., Oppi'iiltrimrr,I..v.....T...., stiMi*. \ r J>ilhi'fii ftkyt f., ainl f'iirit'Jt, F, f{,, Mlii;nftti( tmHimvr-* ,vnj f.'i:1 fvciljym*m St11 nn lift* 34. Sytii|'^unmi tlrStrnHii*iind Fmvlint; nf the* Nfrniliraf.*- NiMil SurfufM tif (VlU, /Vr, /f.`iith*m. Sot., i. J 43, IT l> t Vftil 33* biuikrry, ll,, nmJ Si*hni:ih1, 1)., Wirk'im vnn l'u|vntliylhi*FiilH,ii nn Hfttifit. 7.. Xntutfowk. 9ft, .V2*i 11 ' 39, (^v|M'tiltniiM*r, |l. S., 0]>prnhvimc*r, K. T, Stunt. A I'. IKinUlti'f kv. I.. d*wl Willlnti*, M,t Studio nf ihf *if l.y litiu-. Alfa f'nt# Int, Contta (`Qwrtn 15, Mi (1*1.71). ' 37^ 'Vidiwti, Kh mn| IVnii*, R.t An imniiirtnlHfiiil jtppwft'h t.. MiltrvTwiw. PnK*. l'iK*umi*'MiiimiM (4unf.j Jiihftmi<M>nrff, tV>'t l.inld*, tlmwn A (V* lln^nit, Mhh, 11)0(1 |>p BV4U7. )ft| Allium, A., |.\*dMiin^ in rrlxlit'ti lj cniMfr mdurtiuti m.*l tnuliHHit. AW. J. 1'anrtr J* 4m( i I'HWl, Jvj SrMi|4n('lFf, II.-U,, ninl HrmUiniiJ A., Nf*w |w.lytn**r Int* lilijiiiMi'4 in Inlt 31m/. nr 7, I ( 4f)* WrtCniT, (*, J., Ttii* iiit)u*`iiiiti of Imttjiur'* 1>,V ftec* ititr-tfilt'uml itpHiilnhon** if vtuiini** !\|n** uf n*)*i*wlit* dn**l. I*truitni /').NHif hit. Clttof. t fllftiri, dVI 1 ItNili), 41* I|iMffH*rl W. llxiH'rinmtitii) pn*dn(li*>n of emu^r liv tn> c nf j itiifdiifiirij ffr.Ivtirftiiiitff* p*.'<*. Amir. J. Chi1. /VW }4. 42. Xvillnlurfl, H.f mtd Muhr, 11.-3.* Harknmar:f :; ::i* imt KhihIh fin4*. 45, I9.1D. 43, J. M*, < I#. V.j llnikhliu* N. T,, m.-i Iv*iHivn, l>. J.. I'nmitnrntitrp almiy nf alinruaitmi' intlnml >> 7.r.'*lltn*lliyll>*ii|a|Biillirnp atnl puiyirtrr flints in tin- -tili- Ptilamama nmitmiaa liaatn* id fat*. J. Ajaf. Vanrrr Inn. 22, 1V (HM2). I 44, (dam, J,, l>n* Kiahrilnnc dar pnnaft I'olymathyImp!li nkrt. Inlp. ZrdatM. A Up, IWM. I'tnhal. AuntJ 42, 'til (Hl-V't 45, Hratnl. K. ti.. Mitnan, I,. If., ami lUtiml, I., ( timmt**ttfi (mm (Btlvinrr `lltttlnnl.: Nrtr aspaal* fmtn Hifttnnmmal at.'l lrktM|il.mlntiiin kltnlimt tint in* iMamaliitiiani'y. J. Xnl. f'n<'< ' In*. M.fdUOWi*). [ 46. Ilraial, K. (i, Htmmt. L. C., and Brand I., Ftim*n l*.iy Itmtnriainirsbi: Ttniin* and ktaalion Of pmion|iiat>lir tfvrni- J. .Vaf. Caaarf 7/nf. 47, W! (l*)7l). 4l7i.. liinntkk*t1.. IIII.. X.. aammii Vmaiin', J. tt., Anl advama affaat of p-lt- rinvlfliliirnla liiltin* ti'ml rimilation. /.o* M, III (I2QH). 42. Yinla. r. I*. Uiffitlli, A., and <*a|mtc .... Oneoamir raptin>* id rat akin. Imp, aial UtmTM In vinyl ` kirido. Cnunr tot. 31. 212(1971). 4*. Itnvmiakii, Yn. A.. Kilart id pidyvmi aulfato nn arowih am! milnlir arlivilv id ra|ilniti of nnrmal r nmfiliV'iir mim-a ami ral imatira. Fid Tmr (Tnmd. SnppI.); T7M0924). 20. Wnmt, I)., 11ana*all. P., and Bi nff, F., filaaa riotIt na a *4*1 anti1 (* tiwna aidtini-. J. Xnl. (* InS. 10,27 (194!*). SI. Ilrand, K. ti.. Bnnan. L. an IranalitraiatHin ami mainratnni in (kilmiar tnamrifaumia. /Tor. Aar. J Brand. I , Malianaiti lividin* <*U durin* Biol. Uid. 124, 27.1 (1947). ucc 000592 CC,592 U. M?, If., PHneamM, P, and TUrath, M., fmlnriii.n ,,f UajMnlantable fihronareoma* liy merhaliiral titrate,. Onrulyin (BaaW) 14,44 (IBM). HMwft, H-. Saih,*mrrHigiing |ni Hullhi dnnh intplan*rn Ffvmdk<>rp*r. Reprint H, C. V. Hnehhtigrr * Hnhnr (imbll. li--nkrim IMI, P9 M&-H. 14, Tamar, F. Ci Bartmmnn at Mini iif mfhciiMMiHi*lv iinfittoiitcd Malil*Mi*in rat*. J. Nat. Cnnnrlno.2,Nl (Mill). II Mm*, J., implantation nf pnron* pnlvim'lhvt mttbarryiatm and I In' relation III llwir mmiertivi; to-nr i-n|.-tdn It pMiMtulitinit limnit', IWw Hie/. (Prague) S, Sllli (1929 |. , M. Mmhdwft, H.t Tumnrrrr.rncung dttrcfa Krennihm|tei miidanIM. 444. ZAftrf. AM. Wmt. Hi rim, HI. Uni. 1, Ml (1900). If. Myamon, L. S., The nil* of intiantniatnm in tltc mechttni-tn of iWtMflgMrtr. ea-furrmnemtc awl rettain ant i-earriw.genic 4wU MW. <W. (URSIt) T, 44 (I'MI). M. nantwiviH, V., Klirher, K,, ami Wieiteeke, II., Antnrvlin- MMm UMwwirhuncni wnhreni) iler eiperinientclleii Caremogenea* dwell Ffemdktwprf im|4uit*tion. Z. Knbefarark. 74,17* (IWON). M. Pu-tngamva. (J. A., Tuiiiiir.imlurinl effect nf pnly'Mpri lactam dt*m after gamma-irradiation lir mating with pnraltin. Yap. Onto/ If, 74 (1449). 44. Twaatia, I,., and Shidalt, I*., IiiNhhihi nf nrcthnne mi mil*, mtananu* earcimypnmiaby `Tdhitt" iin|ilanlii. Hulun (London) MB, MM) (IMS). 41. Kavacki, K., lari4mre id tumor* after implantat'.on nf pbalk Malarial*, Fatal. Fa., Hapftf. 1, 293 (1900). 4t. Inchoff, f., Carritmgcnanin through ehnlmtend ami ilrrivatiaaa. Frogr. Zip. Fantar Km. J, 412 (1903). 44. Kill H,, Kaweeki, K., and Saewraak, K., Studie* on mrrinnm4i aa4 the tmefulnw* id pntvcnier yarn in aUnpianty. 4ir4. Immmml. Thet. Htp. 12, 730 (IMM). 44. Krylova. N. V., and Kogan, A. Kb., Itbaid e"i4.` in n'niiin.t induced by piantim. Kelta. A And. Mid. A'tti HSSH 24, :M (1909). 45. Mnhr, II.J., Tumnrenlwirkhtn* nml Fremdkorprr im Tien vervueh. Dml. CrmtMlbiiw. 1`tlM. 22,22 ( Mi. r*rt*r, B. I,., Mm*. K. J. and I'cto, II., Tnnntr induction l,v plaxtir film*: Al'ciii|,t In mm-lalc raniwaniir activity arilli certain phyainnwhciniiid pngiertie* of Iht im|ilnnl. J. Hat. Canon In*. 44,1277(1071). 47. Dnbbaratain, J., Barlinrr Symposium niter Ktagcr. tier Carabiar-- 414. Oral. A had. H im. Berlin, HI. Uni. 2, OH (1940). 41 Watt*, C., aad Mtiaiek, J. U, Mrcbanwm Ilf cnhiincrinmt of viruapiaqua*by ralinnirpolymer*. J. Virol, t, 247 (IOC*). 41 MeDougall, A., Malianant laMut ai *M* id bnu* |4*lii. J. Bane Jami Hurt- MB, 7W (1114), 71 RimiMlar, V., Haiknm* nail KaiubniMllung. UemtUmhr. UnfuNHrM. 42, 121 (MftB). 71. Cm R4mAi id Man*. (Wm. Un^Hal, Cm 34.I41V (iianl atM pmbabiy nanfdaatis IttMur nf fmmr in raama of a 4lnura praaUaada. Nm faff. J. Uni. 271,444 (1944). 72. (tabalM, A., and Una**, B , Dnrrh Kiem,lk<inH- imlniicrla ManiniauM KalMabnac. HrHr. Niararkir. It, i7 (19BH). 71 Btfakardt, O., Trauma--framdUiniar--Ilimwii*niN. Ktaaba. Mat. ITaMtaacAr. 71,200(142*). N. HAaaidt, H., mat ImihH, Ci--II.. Mm*iamim*nliaekwi tun ruaiMTini ZmtraM. NmrarUr. 24,44 (Inal). 71 IMabaiaaMa, V., and M**, It., A m** nf adennrawtaiinm at * lady. KNa. fbaaa 24. *1 (14MM. 71 nampaaa, 2, ft., and KMia, H. I)., Primary miraahaMal dhandraMvaama. Mapaat at a mn* arming in rmijnwiinn *Hh mlragtamat brnMa M pbanhw Count 22, KM (ItlWi). 77. Ilwinmaa, i. B., Kanbimaa, M., K4Wy. K. J., and llnnw, W. A.,TibaaMM at lb* IbiWk awirialrd with a pnartbntie aaaaaiMgiafl. Maw W- J. Urt. 244,ill (IWTl). 71 K., Rmlaa, J. and Knrlb, M. J., Carrinmaa M 14a hraaat bdtnadag magd* amMarlomy and Mamnnddanly. Indiala 41414 (M44). 74. Biia*r, T). O., Jr, ami nwllailer. C B , Rrta*t rtnri-r ,f.rr ..|ifl> tic 'iiln'ti'Am-nn. tn,,.ii i `'iinii-. anr renmintriicfi.n, u,,h Silnutii |irir>lhHn. I;..,n, lr Sury 44, Ml (|Mi!|. 0. 11nrri". If. I.. Snrvrv ..( |,r*arl intytlitti a frnm Ihr |*nnl ,.f vitt (>f (.',1 nmi*'iiei*. I'lu.i N'famtr. Surf. 21, Ml (1001;. 41. l|nr*l*iii, A. II., ami I'l.inki-I. V. II., Til* viarn*lactii` pr.,|>- nf hiIim* Imunfiitl iii:,it.ri;,|. An*. AM*. Artiil. Sn 146. JMO'IOS). 42. sjamh'M. H. J , Arlifmnl nrgaaa. ('km. taf. Sra* 49, (12 (Apr. `I. 11*711 41. Sunviiar, I. It, Vian'T*. f{. K., Itntiol, ,*. B-, U'TM|. j . ItciaiT. K., nml Mri. S A., I*r*tln*tir ln**rt vl,i. nplmiim-nt, da*. .V )". Ar,,il, Sri. 144, 3*9 (190S I 44, .Nnliiii, H. S., Trennf, II. M,, and piiiig. Y. f*., Mnrphi.mi.lric hania nf th* sh**l.fli.* ntiiir-pt nf lb* pnlim nary alv*niar rnii'ricirmlalinn in the cm. / 'ire. Hu. 24, .197 (102)0). 4$. Nm* prunth*-*".: U*> of m*lal pnvdn*. ('Ann. Eng. Hurt 49,14 (Nov. I.*., 1971). 6, Wmwiwani. S. ('., I'liyKink^irai and bairhcmiml rvnlumion nf ini|>lmilrtJ (mlymar*. Ana. V.i'. Anid. Sn. 146, 3i`, (HMinl 47. 1 viiinn. II. J , Thnirfin al nml practiral ilc'itn of nn'nil>rmii` mntiTmls. Meprint- nf pnin-n mi "Sviiilictjr and Nmuritl Mein- liranr* in Mmin io*," I'm ifii' ( onfvmic* on Ch*mi'ii> *ml .*p*rtroMiipy, Annheim, C'nlif., (M. .TO-Nijv. I, MCI (1907). 41 t.yinnn, I). J,, New >vnthHir m*mtiraWi fir *mrmvr|inrral lirinndi.'U\>in. Ann. V.l" Annl.Sri 144, 113 (196*). 4. (^crilmer, H. II., The arulinal kidney and the treatment ..( chrome uremia, ".eitrinl* id pttj*n. on "Syuthrtii- nml Na'nr it Mentliranm in VtnlH'ine," l':i. the Cmif'reniT nil <"ln.iin- r\ andMpretnwcopy, Annlu'ini, CoJif.. Ort. ,`WI-Vov. I, MAI M'*<7 90. ttnlhiw filler iim* in water treatment eapand*. /'A>. Aim .Yr4* 44,29 (Jim* 7,1971). 41. Kitnmn-rmrver, K., Rinmaterinl*--imveiopmenl nml n|o tdii'iitinnn. /.'Aim. Tirkitul, 1,719 0971). 92. Ilnimtt-lbivi' , II. <!., leiw. J. II. Cole. I). S . :iim| K< IK , ll. T, llnlimarafi vmIvc if|3:iiftm*tit foi mirtie vnlvc itr.i*.v** I konit 20, 49.2 (l'Ni-'i). 42. Ilavien, II., Ij'.md, M. II., Ilnliertn, C. I., and Ho--. It. N . tlnnmgrnfl TepiweniHil <`f nortn- valve: 1 `'oJl.ia-lip .1 mii-- m 12 pat ictit'. lemnt *, 930 v I'.Hm). 44. IWe-are, V"., Hath. C.,atid Iltifnnel,C., llemolytn anemia it merhnnieal mgin a'ilh anrtie.valve [m>the*i. ,V,ie Any.'. J. Uni. 272, 1042 119021. 45. | llein, II, I,., fllanev, I). L.., O'BriHi, S., Kpelein, S K . nil-1 Mottow, A. It, flinienl nml bemmiynami p enieni' of fi ri * nnfrred Mlarr>Ki|wanl* prtvllietic valve>. J. Tkorar. t'a`hai Sura 24, 94 (1970). 94. Ilrntmwabl, N. S., ami Mimvnr, A. IK. Tiiie ii.tt -w t, ! tin- rignl heart valv*. J. Tketnr. Canhar. I'urg. S4, nC t t'.Hi' 47i Nile*, N. It., Teflon emUJinni feint Starr-KilatiriU valv,J. Tkamt. Cartier. Surf. 24,794 (1970). 4gi Kamhi*, II. J,, Artifieial organ*. Part 2. CAtm. Eng. .Vm 49, 01 (April 12, 1971). 41 Kanlmvit/, V, Tjdnneland, S. Freed, P., rhillip-. 9 Biltlner, N., ami Sherman, J., Initial Minteal e*penne *!* intraanHi* ladbun pumping in rardiarinhoek. J. Ann. M..I Am. 242, 113 0909). 141 Sawyer, P. N., Btirmwen. C., Ognnijtk. J., Smith, A, <>. ami Wewdnmdd, 8. A., Innie arehiteetuee of the eaw-ular wall interfar*. Trane., Amrr. Hat. Artif. /a/era Oraaa* 14,310 (19641. 141. Iliw, J.. C.reenfieUI, I,. J., Bowman, 11. I,., and Mnrtow. A, <1., nm chcmieal *tmetnre and eurfaca pmpertie* id avnthetir polymer* and their iriMimmip to thrombo-e It. fy*a/Ar/ie Vain,-i far Cnnhat Surprry; A. Me/ethm*. 121 f^mriea CHamms Sintnalieid, III- 1901 ,pp 212-23:1. It,mm. F. K., llimeh. V. O., Wnd,. I,. A-, aad Wright, IS. *are eneeta on hh*ni-ehilling emnpWn ent* ** determined Kv ^tepilftliah, J, Oit. ftn 4 24,2I022U0). 142. Oott, V. I... Whiffn., J li., and Dutmu, R. C.. Heparin hnading un enHonial gra|ihite *nrfmy. intata 142, 1797 (196.1 CUNtCAl CHCMIBTRV VOL U. No. 7.1777 Ml ucc 000593 CC,593 Mt Falb, R. n.. Geode. O. A., awl Iirinincir, II I, ili^onaw to tbe human ldy. gutter Hum. Trrkiitl. J*, 1 >H (I'MMt). M. Lmutt, R- I-, FnHi, It. I)., and Cirmlc, A., BhxnlMTIllHa plagliw. 4m. NT. Arad. Jri. 144, It (19/i.s). Mk Kendmiim, A., Yen, M. I*. H., Ingram, M,, Newton, J V., <r,, Ha, C. L., Frodiar, W. and Itarfcoor. It. II.. Platelet dapoxitian on tNpafiudmnded and he|tarin4rrr Mirfit S. COTf. Polymer Group, Auier. Cheat. Ami, Nov. 17-1*1,1*171,|i 4. Ml. Nall, C. W., liotta, l>., tlhithuii, i., aul IM-Hakcy, M. I'.. Vdbur fahriot applied to medicine. J. Htomul. Mnur. Hit. I, 17V (HOT). Nt Bamtoed, W. F., Huxaiu, M. George, J. It., .uni Curt!'*, G. W., Fatal MiniMaxtx an a sulMralnm for |*-ru,t, M-mlit hchxl dmkyMantOli pftixthetir Mtrfarc*. Surgir'/40, 2*4 (1969). HO. Brauaweld. N. S., and IMnar, It. K, A rritiral unalyi*w af the ataiua uf ptwtbatic valves and humograiili*. I'rogr. Curdio*. Dm. II, 113 (IMS). IIS. Gatt, V. L., and Futuna, A., Aiitithmml>gt'iiii* Mirfarv, damifioatmn aad in vivo evaluation. Fid. Pmr. io, IU7U (1071). III. Fallt, K. D., and Gmde, A., Covalent bunding of pnitctiH toaoiidaurfaam. Fid. fw.M, 1688(1971). 113. SHtotn, F. J., and Ximwilrn, l>. IV, Flexible iiirlmn mated polytaaia for bionindieal application. Nyuiposinni n Polymeric MMtttohl in Artificial Organ*, Pandena, Calif., Nov. Mi IU71, t . IIS. Ifaadin, It., Nitond, alloy with mimnl fatigue stow guality, uaed in Work on artMMal heart. Htomul. Ann 3, 4 (MW). 114. Mdtwr, 8. J., and WetHi, W. 11.. The behaviour of the red Maud mrpunctot whan ahakau with indifferent xukwtancru. J. Fftynel. (Loudon) 1,335 (MM). US. Andaman, M. N., (ialieieti, K., and Sin, J. A., Chrome hamnlyian in paliunl* with Iwit-valve proMthe-ieH. J. Tkorat. CWm. Any. M. (Mil (1063). . 114. Batmdain, K. F., Certain expect* of 14*l iutetfaiial phaMMMaa--red Uaod rvttx. Fed. Fmr. 30, Uin (l7f lit. Kuaamw, B., Lamm, |(., and Nieholx, J., IVrfu -ton- and mifaea induced injury in leukocyte*. Ftd. /`me. 30,1.Ilf* 11971). lit. UJ. DiapunaaMty. J. B. Lippincott Co., Phil-idi'lphia, Pa., 10SS, p M14. Hi Artvood Htaith, M. J,, ISdyvinyl|tyrroliilone Mduliom* uaad ia piaxau eapandaw potaalial caranogrox? IMat 1, 13M (1*71). MB Gal. E. A., AHaawiar, W. A.. Krhiff, lo, Hamilton, It. I,., BeaunaUiti, H., Qiuad, J., Jr., and FMnma, It. <S., Ifni Nntw loMawiag iawavanuaa adadnMnlhm uf polyvinyl pytndidnna (m) Aour.J. Clia. PMAaf. U, HOT (1033). III. Huepar, W. C., CMagNu xtudiex on watrr.'olublr and igailuhli taacwiaudaaalm. Arch. I'oHml. 67, SMO (1030). US. Oetlai, H., Oaaundhejtxgffahrdiuig dutch Xunxlxtiifft* 4nA. Etp. MM. MimM. 232,77 f HUN). 133. Hal, C. K* aad Hal, U., INilyvinyl alenlnd: KrViiiuuxMp af phytanoahtmical penpatlirx to hypertension ami other pntho> phydiMIl mender. /** fmrd. 12,731 (UNCI). IM. Mm*, Jx Vianitirr, T.t aad Neatuan, Z., < xonjuualivc MOT at aavaama lermatlinn by implanted pukrthylrae Mm aad mnOTtoahitoraW. Bnt.J. Flu*. Aery, it, 33S( HNH). UR Gartm, K. L., and Hoe, F, i. C+ Indartion of xaimata* in aaM^^^jwl^aa^ftagmantad^ C. M., aad BabnaOT, V, 1,, Indnethm oI xuhia mta by ftm4k bmpa aad xpitala. 4*av, J. IMdOtW). P, A, aad Michart, It. hi.. Induction in rat* at i by piantic and utainlem atari daviem. Amer. J. fNrtil. (Jpartwf. 40.MN7 (HOT). It., and ladger, W. J., htHtard laynua to faudua. OfabL Oyuaf. 31,70S (I00H). i. B., aad Wtdutof, II. V., Tie affeata of hmg- term implant at i-.n of |v>1vetbvtene In he peritonea' ravitv d<*. Am. 119, IT.* (!*<!. 1301. Heheri, Cl- I! . Surgical treatment of impotence 7'..i' hiroimtr. Surf, if, 92 (I !Miti! III. Itellevigtie, W , Rolferth, C. C., Jr.. Jonex, X.. and Mat-utiHit.i, 1',, Cvaiewerylate monomer* a* at allaxivr. Ank. >',j 102, 49:t (1971). 132. A.'iliv, ('.. V.. Wext, II. I*, and Jabnlte. K, J , Jr., M-. eartlial re*|*in-e i>. tl,e application of tixeue adhc-ivr*. Cnmpari- ou of ructlul-.*-' *....... and butybevanoaerviate .4>.n A'lirg. 165, 42'* , I'*** >. 132. fioetc. It. II.. Wi'il*erg. D.t and limpetiMein. It., Va>t neiVoxix rnuoxl in* Hpi'lirntton of methvl 2-ryanoacrvtatc .4 ** Suit. I6J, 242 (Haiti). 134. Jniidixon. J. II.. II. Moody, It. A., )`uu --cruv. It K., I.c h T., and Wang, M C. II.. The nxxue re-pot ix*e to a plaetir adhe-ive nxejil in niinliinution with iiiuin xurgiial l cchniqor in recuh-iru ttiol'nll otf xnumulli arntcrie*. aSuurryy<iry nMo, ,3i7,y9 t(1iu9u0)). US. Lehin.ni, It. A., Ilnye*. f,. J.. and lienonard, F., Toxii it y alkyl J-eyanoaiTylale*. I. Penplieral nerve. ,Arrh. Surj. VJ, 141 m(KKuH;i)i. 136. Wfpu.tx'rg. It., ami (Ineti, H. II., Xerrini* of arterial ua!l foljowing aptdim! ion of ineiLv! ^-cvanoacrvlate. Surg. (ir, IIV, DUX (I9ti4). j 137. Wixalward, S. C.. Herrmann, J. B,, Cameron, J. 1... Bran'!*--, ti.j Pulacki, K. J., n'nl laxuinrd, F., Ilixtoioxicity of i;. i' .. acryl.ite terniemlliexive in tlie m>. dan. .'iirg. 142, 113119*1", US. Leonard, F., The \>alkylalphaey inoaerylate tibt4ivp>. ,4*a. .V, Y. Ami. Sri. 146,1*93 (ItUiai, 136. M.aottsxnmnio, T,, Ilanlaxav, It. M , lleixterknmp. f, A . III, Patti, K. C., and lemnrd, F., Hither homologmi* ty-u,.> arjvlate tiwue nlhr-ivc in Mirgery of internal nrg.ui' ,t' AVry. 44, NOT (l!Ni7). 140. Pmu, K. tihidieux, ti., ltrninh', ti., Kulkarni. I: K iiihI laxniitnl, I ., Theitegriidalioii of n-ln til alpha rvati.,u r>!.i'> liifur ndliC'ivr. II. Surg. r:i 63,4N| IliNis . 141. r.ollnli, S , Sehe* liter. I>. (',, anti V till. A. W,, Ilflll' --t--. hlamd rimgnlatioii. and i-*.l*i>tvl cyanoi rylate tl--llC inlh.-'iv* .Sitrg. f/yniref. (Adi/. 130,3 < ItiTtti. III. Herrmann, J. It., ami W*nlwarti, S. C., The clli * t rvanoaiTviate tixxiH' aillic-ivi' u|kin granulation tiwue fmiita in Ivahm *ponge impiautx in the rat. Suigiry 59,330 (I'.niti 143. Malxuineto, T., and llcixterkamp C. A.. HI, L<uig.irri' xHiiumdv of acroiol eyanoaerylata tUxue allx-ive apray: (Vhi Mfilieity and otter nntowanl effertx. Amir. Surf. 35, KTi ( I'.ni'i' 144. Hehretr, W, L.. and MatMimoto, Cvanoaen-late ti-' ic adhesive: Thrvmlaigetiieeffect. Amrr. Sijiry.34,4U(l970i 145. Kerr, A. and Pnivlli, G. I). L., Buerylata (i'*,h>it*i cytinoaervlate) ax an o"icu!ar adhrxivg. jerk. Utolaryuf'l 64. 129(1971). 146. Ferry, A. )*., and Itarnert, A. If., [iranttlnmatnu' keratit Moulting fpnm ti*e uf rvaixenlate _x_il_ie'ive for .l<-ure ( perforated corneal ulcer. Amir. J. Oykikilmnl. 71, .W1 iu7| 147. Ihinlap* K. A.. I Mi1111, M., and lit vximondo. IL, Oh-erv., time* on the n*e of placitr adheaivm in nttxfle xurger> with t new laugntial appiirationx. Tiwm. Amlrr. Opkllmlmol. So7. 283 (I9601. 1*0. Smillter, H. O., f^vit'ky, 8., and Kahertg W. C,, Bucrjlat*' liUe adiiexiva for fnirruvarruiar aMwtomnxw. Arrk. Surf 103, 496(1971). 140. Ifalpem, B. D., Poiytnm in medicine. Ana. .V.)'. Acad Sti. 14*. 103 MtlfiN). llO. Vnl'finm, N. I., I'rvmalignant idea of llte eervii-.' uterine and vaginal epithrlinm nf niiW Muvd bv inlravagn.'il ailminintiatinw of plant ie xponge. Win/. Kktp. Hitt. Mid 34, *I 151. IMmaif, ('. R., Slulxnlnird, W. T., and Conwav. II. * *' tdrvalhmn 00 xul*cuioei*oJy im ' ited polvethertireihai.c wunae in mire. ,*tnry. <7gmcaf. (IbM. 11^.434(1003). 152. Charttley. J., Artylie Cement Orthopaedic Surgery R. * 8. livinptuua, Kdinbutffh, 1070. r, Vaf. Id, Ma. 1.1*77 UCC OOOS94 f 111. kntffet, 0*. VkfMpmd afrylir inlay* in tin* Irririmenl id MiriaaJ urf lumbar HWftdjliuii* Mid itUier mwiilHHK. /atari ( A. 1*7 (MM). HI Tim, R., a*A Rwtttawn, l>. it., Tntal irjdvmieiii arthn- iaaly (d tha Ear. Ray. *- M* ft* HwimuiM iitMiii: Two ww. . MI9VU). IK. MWi J.. Awjle investiHnit id intracranial aiwiiryMn*. HL Nw> J. R. and Madhnwi, V. A., C-mriai* ih-miatiiis tr*,m aaMtfMian af fuhlwr riuvy. by artyMe imummer. Hrit, Alii. J. ITmI <W71K MV. WaNm, P. 8., u4 Bimrmrinrk, M., Fixation pnqiertir' of aMyriarmaml *<. JTaay itry. 1,27 (1971). MR Gald. . L, VnfWbMmt ntnwrvatiunx an riled by R': Hit, P. R, awd NfBaartnek, M . fiiaiinn pregartimid any lie cement. Rm.Refg.4tnc.2iw. 1,27(1971). MR drum, T., UnpnMiahed ulmviilmu an cited l>v Walker. P. R, Mid Rtancaatoek, M., Tin'inn (irupartx-o id acrylic cement. Rm. Jfatp. Sprt. duff. I, 27 (1971). MR TImmim, T. A.. Sutherland, 1. and Walcrhmi-e, T. 11., Cbid faring acrylic buaa cemcul. Amuethni* 26, `JIM (l'J7l). Ml. Powatl, J. N., Mrliralli, I*. J , ladriri, S. K., and Hit*. 1*., CMdiar aiM aanuciated with Imim cement. Brit. Mnl. J. IRM(M70), Ml. Pmet, P. M., Cardiac airanl Mid buna iwiient. tint. Mnt. J. ill, AM (1670). MR Buunb, D. M., Cardiac and and Iwoe cement. Uni. Mtd. J. Id, AM (1670;. MR MVf) A. H. C., and Qcnx.nl, J. A., Pulmonary emboinan and baaa mment BrU. Mti. J. i, &22 (1V7). MR Michriiaakia, E,, Murgan, It. II., and Curtin, IV J , Orariatory anwi and Inna mama. Hr*. Alni. J. ill, M (1671). MR NfMidUMi, E., Janeeti, K., and Kmgh-I'nuUixi, W., !.' paiaantil taiarimtiwi id the Imk icactimi in Mrylic {dwtim, AemOrthp. Attend. 12, Ml (lUTt-'l). MV. Humay, C. A., Tnllue, II. 8., Amlrtann, 8., ami Fen anti. N. I)., Phyaioiogical naqueiac (nun ini|dnn(alii>n nf raimlo-ure acrylic compound*. Urtlm|iaedir ItwcuKh Kwirtjr llwliif, New York, N.Y., January 17, IIWU. MR Lante--rhiager, K., Proper!ic*ida pnlymethyl Mrthmtylali band wapMlr. Gordon Hcawdi Cmdcranee on KnHitnltfiabi, Naw Hiapdiw, June 24,1970. MR VUtaa, L. L., Hall, K. II., ami Knmdiic.M, l>. I>. 8., t .fieri--eta! etadim regarding the pniUr we id <wlf-ewrtng acrvlic in arttupaadir aurgary. J. User Jemt Aery. 16, Mil < li*r7). ITR Brawaiag, C. V., AHupbed Malariain in oHiital repair. 4mm. d. Opft/MmW. 61, fSft (1967). IT1. Millar, tt. K.t and Tenwd. It. H., <Mial fracture rcfiair With Mathyjmmharryifl implant*. 4anr. J. tlyMAnland. 6R 717 (NM). in. NadoM, Pam, M., and 8UMr, ti,, Kipcrinnwilal (hading of naw hana fcaamthm alter rat akidl impianlK id pidy- MatAacrydat* and aMpae haa /1M. kuvntt. Jwy. 44, let (MM). ITR Nryaaa, O., and Murhud, P., Laying miHiRatate uurfare iMhan in Evmm rata. Vm. Jmt. Am. Cannr krt. 11, I <Mtf*Mn>. IN. NmwM M., Tha martinn id the nrgnnbm ( aityin- inndanta and Ahr ntdiapah tdfrrt in tllifhdy. Arta Unm. IM.. Afad. R Ttff (MM). HR Mtaaan, N. R, Ha thm reartinn hniuerd in tala and gaiaawgip Mr ydyWMthyWlharryiate (artylir) and MaiidwH atari. (Ml. J. *M>. I'adM., 21 (IW). MR AadwnMI, P. N., PlaaMa eri tamnr inductinn in liAIJI/c mm. Fm. Awmr. Am.Cmnrkn. II,3(M70). ITT. Mank Indn, wit nd. Marck mA (i... Inc., Itahway, NJ., MdRpMO. ITR V ilwnn, V. K.. Nekeri, I,. IK, and (hm.ki, C. H., The gailltlM (Malting Man giilyletrrihHWnrthylMW |rm) |>>ttdyi in*. Amm.hi. Km- Am. J. M. ft* (MM). I7'i. f!:t\ i-iti. .1 \V , ,li . TIi.. xii'tiv -1 > |. nl i t-fi-miii* <' rlii'in" il i > a^iit hi t, ( I'H.Jl W. . 160. Srlii'i`1. 1.- I*.. I..'iiii*. Vt t . |,,H| i'l.lenian, W. ),. 4. In\in1\ nf |mlvli*li.i!liiiifclhvli*fi^ |*y r,tKpi. |irn*lni'*. nul'Mnie larlmnyl iliimiilv c:nl n rein tux, pf.ntiu), ilxnn IrtriUtii..ii. itn^r. /m/. tl;iij. .b' /. 26, II i IMt), III. I tmiHli^, f.., Snililt a in ii|ilHitt. t.f *11** him| TrHttii m mtrr. t'ti\"rnm IV, WI7 (***>. riirrtiftf<*iii'|a |(|| t'&it*' Ini 1 *i,y i Ini. IliV'dHi, imI lit*- litifT. t\f IVmI Irm^ in IS |Nt(\tiMi imfiUtiu l{t'|inil- iitt 1*01vnuf <`licmi'-try. p|t i.'t I A. > ri4vi#*r <iiii|i, AM^ntAii S.ir4\ <f-i W'tt. Ititf. Mrrlmtf. VtiiiliiMin. ( aid.,Oti. :tt*-Ntiv 1. 1`.h,7 113, Mtiii*', J. W.. .\rn**M, K.. C. H, IiiUif .ir.l il |m1vtW (Ti-llun) iiijr^iiou. (Knhirtinjol. 91, AOH ' t**7n Ilk XlirtiMMik'i, A. l,, Ttt\ii*tiy of i^ltftfluurethx lri* 7>. ).* HtHf/nul. SaHtt.-thg, ,\h*t !n*l. 44, Kt4 |( 19$, Srlttvl, h. 11., MrMi!l:in, |,,, anil V ('. Him hi-mir^t ihniurt'i wilktttYir ttt|H'lvtflr:iMu.-i.rtMlit lei.c tiyjt*i)>t*ii pitdlwki Jinr. Jn*f. ttmf. A*!* / 29, I!* t IlinilKittm, II. A * Stitt***!, 1*. |1.4 anjl ('*ilt*m:th, \V 11 . Ttn* *C tin* jivn*K>i' }irltit-t** u>( }to',\h|i-i*-'i!l t.i: .. HltvIi'iM*. A w t. lhtl. Hit*:. }, If, 1*1 jllHiM, |Hf7* lUiiiuii, D Me, IVlvinrr f..nn` fvvfr, firit. J. 1, 77.7 UiftT). Iff. <;nttliH-r, M , '|*hitfttiAli. M.. (t*rvfi'.. I*, mtl l,t|Hr*l V.; vii* tin |mlyiirf-n-. 1'mtiU`tiM*' ||)|Y^|4*pnl lit l> >t*N || ;iili|ig)i"l|i|IHii. .trd. Mill, I'rei Mul 7 rur, Nimr, .W, 31, Zfl (197(1). 1M. Art 111:111, N. It., Ilrniiil and nxiil1 nil fata. A-It an I. / ; H\*. 7, 2*.'i(l9tl9>. 160. Ihtw t'nrtiknc Mdlirnl Mnlnidi l>aia liulletin. It-i>>'. Mnv, Itntl. M- Sl:iill)lli U. I>., :iit.l Ui-iImiIT, F,, StJiiltilitv ii`tn tiu'i.i' i*. tt( clttl<Marnl ItlJvlIHrt'ltily III ttrgaitlt1 aJvt'Mb, ft.IN. ('ll! v 1C. ^ O'.Hili). 162. Iti-idxilf. V.. Si:.iit(i-t. I!. 11.. and liry...... I! . l.ipid ii>*-ikibv liquid >duxi|l0 iiihI Iim iiI tunmr linin' Inm, t /'r, 11, S|l (1972). |4j. T*niiilili*y, ti. II., Siliiinwr. S,, and l^vio, M.. l-i*! iiii-iii.d ramvr, idn-ilv, and r.imgenii' rvcwiun in xi iinn Amir. J. Willi, iiiieimt, 12. 121 M9BI >. idf. Ibtvi-, M, 1... and Muir, K. J- I liirnuuii-" in linin.m n IHiHliiilimi. Part II. Ynrilier inve.tigatiin id .trruid ntrialmli-iu ill human prcgnani v. Amir. J. fltad. (i(mfnl, 76,9.19 11'1".' ItL PHi-tmih, It. K,, Meanimnrnt id the nduliiliiy id ga-i- in ill. Fill. Free. 26, 171* 197u,. 16a. Singr'd. J- " and 8HH, It. J., lV'*|v*rti(** nf periln-una'i-d liquab. Ful. Cm. . 26, IIVW . IIITtl*. 167. Pall*. M. \1 , S/nni'i. I'., Vale- It., and Lnne. t> M , Survival and hMiipnlhnhasir rhange- in lung- >d Initn'i*'' fiilluwiiigayiilhetir Inpihl lin-alhing. Fnl. Frer. 26, 174" I9*n 1UR lant'i-uciein. K., I.ininln, I, C. H., Mndetl. J- H-. ........ . \V. (1.. Hiul I.aver. M. 1).. Pre-ervaliulnW evi l-l raiuncbtnit- >>' vnilitaliiiH with In;uni llunriHartaui. Fill. Frer. 2*. ITT.'i ` Pb" (66. llra-IInr, N.. ami Neuman, t... Silinumma--atn'itifi Ulaix-IHII, rreikur-e tn dinx*lhyl|oly41ii.vau. t'lul. W.rna-:r Awl. 16, 2W(IWei). 200. Amlrrwa, J. M., C'dlulnr hrtiafinr to injn-il Hniil: A |in.4inuinry n*)rfi. CtciC. Hieariarr. Surg. M. >1 < i'Hl*i *, 201. llera, T. 11., Hnllanlynr, l. li Jr.. Seulman. 1 . and llawthurtie. tl. A., Vbmal raepmielr tn wbratMie-ux an l llilra|ieritiinml injertinna id eilinme n mire. FM. K-ronnr .Vary. 16,4tl2 (I1M7). 262. Hm-IIur, N., Ilia-, T. ittd Ballantynr, IK I.. J< <*iim|eirtiuniad ilea ailinHwa liqiiiikTM (dllidlhylpoly'il-iaani- eilHxme liquid IVI ernii-inke viacueriy) injertt** rnct I animal Ami. Chir. FIM. 12, 242 (1911?). lg|. Heat, T. IK. Briiantyne, IK L., Jr.. nd llawthnrnr, G. A CLINICAL CHOtlllTW. V"*. 1R ** R M72 acc,595 ucc 000595 _ Vi 'iMrtmr iuid rwaarrb. Phaf. Ktremmr. Kurt 44, 4ft ( 1117(1) * ' 144. I fcaly, ft L, and F*ry. (V F., ISfiUMMi rmumA b> i . Lad! <lrr*. Auf*., B7(IWM) Mi. Fwy. C. F., TVihw. ('., ami llnaty, Mithamp fluid in tl* *im af KWM adhraiuna. in*. Mur*. M, XU (IMT). taary. J. V. tWrr, A. F., and Fddmau. M. A. K., z. i ii tha pMeaaliaa af prime arihadnaa Amr. Hurt M, , H. Ontono*, I.. V., and I'm, A <1., Kiliww i hi ha pmnidhn at adMnhaw. Nnl. hrf. a. w (lari). I, F.t and JmRMr4, I,. If., INvhlwl diauap ul r./. Pl|anf lit, 14* (IMT). I. F* Mi PHbau, H. M., Mummy id rtitmiri hurP*m aaAmmm laaryt arilata nMia a Mm dn. Aawr. /. PiyMf. IM, 444 (MHT). Mi HhM F, IaSmaaa af hliH immInm imi i prilf t - " j - -- || * " awn. ML FaMmab, J,, AAi MaA, V. II., IMiMiib uf anrBlIutti,* and fvWvf* ftaaa. N.Y. Ami. Am. M, IIK7 (HIM), lit. Frihiaaa, 4., And luina* l>. M., Jr., TV tuw id riNaMm rubber m a terrier for pmlnnanl drag thrtapy. J. Muff. An. 4, IM0M4). IU. Drink, F. I., Ml Cank, ,, fan ar uf ulrmiibi thrimgh . MmhiIai w, Wt (KAMI). ML ZaFaaeai, A., Man Mimy ayrtww may ntwl drug Iharqty. OhM. inf. faN 4A, W (Kept. L l7l). IIS. rinfMI, I. A., Carritaigtnir. agent* jirnuut in almuBpln-n. mi inddenae ti primary lung Unnuuru in mira. Hra. J, Erp. PmU. 10,133 (IMS). ML Talbot, J. M., and Mrarir, N. W., tiffari uf mIIihhTM iw ita Maon*inn id tatin^aliiii drug*. lumrrl I, 1202 (l?l). MT. Mtllanry, M. M.. Undid, K. A., T'imik. W. V., Hibf, <1. K., Jr., aM Hjna, I*. M., (Mind idwlmrlnni id iwwihrlir hasri vahw Am In Bpid idiniqiliun ly Hdwdii-. J. Tluar. CaMma. fur*. M, 4IS (l7). ML Roberta, W. C, and Murmur, A. <1., Fatal dnruoratuui id tba adiaaM nddiw bai id Ur HiwnMaAdi |m*thaiic aurtk mlm. Amtr. /. CmAkt. M, 014 (ItMN). ML jaa did, K., Tba 4**mliaatimai of aMgaimtaihni maim --piarty by dimaa Martin*. Jbd. J. Ptmt. Hurt- 21, Ml (IMS). SSL OMdi*. C. , Lam af tnrih Wanita hum iuk-tiiu id rti--a (MM adflhiea). Ptmt. KamaM. Aap.44. 447 (ISM). Ml. Da CTdiaty, T., Frmcni dab af najpnantatinn am airtdarty. Cmm. Met M. MK (1474V SSL ir--a. W. M. C, Hiienna --aUUa hi "HA--i" WAtUrtaM ami 'him- "I her yar.rtiu' id fnn>i(n.hidv niaatiti* lirit M. .1, J hi, ISMOBH). T 1U. < intin. and Haiiaf, K. F., lrifiruvad inluiin 4irr..[iil Mlirom raniti.irtirtiuu tltaj nininl car. J*f,, Mirtmutr. Surf 44, .1*2 (IBtiO >. ML Wriai". ' llarhH'k. I). I., Dun^Hi. I) . drtlar, IV C . Kfpfms M., KyaluatiiNi <>f uilinma a* an artificial luliriiant u, r.lnmrthnitii juiat*. Hril. .1hi, J. I, 370 llttTI). 225. Uniting. I>.. Ijif*- . Stuaatmi. J , ami Malm, J II ,Si|i,,,,,,. mntyihaAtinn diiMint rlimml and hrurt Miri;rv m^kiyiiiA a Inlliiili-niyai-iitlur. Amrr. J. "alhtl J4, I'JI' I'm,| ' i!n24._ Hi4am.ii. M . Hmih< rmryiina mulw piactir ''hilt tni|il:,,,i. Atrrk, (Aaiarfaaai. 45, :< (I`l72). 217. tiantipiMfs; l uuiul in haart nK>. Ckrm. n/. .Yru< 44, 7 (Nuja.lt, 1071). 72L ('iinning, It. M . ami Firth. J., ToniiHjtv uf pn|\|ir<.pil> ,,p ,,, tkiMta culture. Feui Ctemil. Tftitfl. 7, 461 114. ttiikiiliiahifci. It,, liinitificatiuii id lintimidaiiK iiu>,l pdyrthylnH.. II. Iilnitiliraliun in planlir nan anil iiivr.iiaaim,, id thair inigraliuu. Hart. f`a*nv. /.akl. Jfia. 20, fltil (IW.i i. 2JL Braun, l>. I).. Pimiltle nrarrimiMit tffrru id nirm. id tligh-HirnMty jaUyrlhv Ii^m* Hniruni fur h,iu-rtH,l,i :,i,,| (.., wr in thr IibbI iiHknarv. Vp. f'daa. 27,7a (Itttini. Ml. ('uwMnimi, II. T., and <lildw, (i. W., runtainiiiatinc urcsi:i' malarial in antwBtiai. Nrif. J. Citnrrr M, 3."i411060). Mli. It irdiidc), 7... ami Bnnlilrjiiirii, K., Hint ranf,irtnitinn ,,f i-lliyl lu'iutrtir, nivimr, mill i|dl*mrthvlitvrrnr in imin An.r. 1*1. 11^. A. J. II, Will I l"7<ti. 215. Hull, It. A., ami Wlnti'linul. T. P. AiLnrption id *rr tm aljiuni l*v lUl'tli' nanit'li' rii|u. J. rim. /' l/hol 23. .12)1 ' t'1"" 214. Sriit1,1*. V., 1lurii.il, J. X., ami Mnnli"">ii. W. W . d kimi ft,.in IttiHHl unit Buirf ,,ani|ili4 .ti.rr>l in |.l:i.ii. .U 'l dJ>. ytiliA'. Hril. M. .1 J. hi, .M2 11071 j. 2JS. fiiuJiB. It. M , BII Kurliim., X. J., (`imtiiminntiiin >>f t>|... utnint in filn.tii |r,rk.- /.`I'n. 11. 1227 (10 in 2m. Mnm-I, Y. I... anil Niu-I, S. Hitamiiinti..n utuiiiilinidartH'|imk>. f.mu.1 i, 1."i< 107(11 llT. Jaeger. It, J . ami lliiliiii, It. J., I'lBBlirimr. fmm I' V (' hmril H, 77H (107(1). 2M. Xlavar, F. L, Pla'iiiiMT'. 1'krm. Etl- A*ivi 40, (Xnv, 1. ltl). Uf. Naxir, II. J., Alrarry, A. P., Marl, I. A.. Brriita. M.. ami Hair, P. P., ImlittiiHi, nh-ntiAralinn andl if.uiilc litraliutii.il nf di-XatbylhByl phihatair in burin# (war. arnada mitnrhniulria. NMAradrtrr 1A, 42W (1071). ML 1Barnard, F., Cam|mmida uMid aa leal iua. Cheni Eng Kfm SL 21 (Fell. 14, 1073). Ml. Intrmatiiuiel oinrriiiratm: Ptantirirara ariiiilua.. Cfcim. Km- /fmm 44,17 (Iter. 13,1STI). WLUNLlMtt >UCC,596 ucc 000596