Document vVYvL448YGEok6JGnV11KvB66

REUNION DE GRENOBLE, SEANCE DU 2 MARS 1972 197 cas publies d'ichtyoses associees a des cancers du poumon (tel celui de Bran et Moulin presente a la Societe en 1965), du sein ou d'autres localisations sont beaucoup plus rares... Nous rapportons ici le cas d'une ichtyose acquise apparae au cours de revolution d'un cancer du sein. Mm' C... Marie-Louise, 75 ans, vient a la consultation du Service le 17 mai 1971 alors qu'elle est hospitalise depuis un mois dans le Service de Rhumatologie du C. H. U. de Grenoble pour des douleurs osseuses diffuses. Elle presente une ichtyose acquise typique avec peau seche, dcailleuse, mais desquamant peu. L'interrogatoire fait prdciser 4 la malade que cet dtat cutand remonte de fa$on nette 4 ses premieres douleurs costales, soit en novembre 1970 ; auparavant la peau etait nonnale. A l'examen, il n'existe pas d'hyperkdratose palmo-plantaire, pas de localisation particulidrc de I'ichtyose, pas d'dpilation. En novembre 1970, & la suite d'un effort minime, elle avait prdsentd une fracture au niveau des 6" et 7* cotes gauches. Malgre le traitement institud, la persistance des douleurs costales et la diffusion des douleurs osseuses ont fait hospitaliser la malade cinq mois plus tard. A l'entrde, V. S. & 100 a la premiere heure, anemic k 2 millions sans leucopdnie. La constatation d'une ostdose ddcaldfiante diffuse radiologiquement (cotes, sternum, vertdbres) fait rechercher un cancer ostdophile. L'examen dinique prdliminaire ayant dlimine une tumeur mammaire palpable, sont pratiquds : -- un examen scintigraphique et fonctionnel thyroidien qui s'avire normal ; -- une cytologic bronchique qui n'apporte aucun dldment diagnostique ; -- une urographie intraveineuse : nonnale ; -- le mydlogramme revient pauvre, mais avec sur une lame un amas d'dldments extrahdmatopoldtiques mdtastatiques d'un dpithdlioma, sans prdjuger de sa topographie ; -- une biopsie mddullaire est alors faite (crete iliaque) montrant un envahissement massif des espaces mddullaires par des cordons pauci-cellulaires d'un dpithdlioma d'origine glandulaire. Sur cette demiire donnde et malgrd l'absence de tumeur apprdciable diniquement, une mammographie systdmadque rdvele A droite une image dense et dtoilde avec un semis groupd de fines micro-calci fications. La malade est alors mise 4 la tdldrantgenthdrapie, au permastril et aux corticoldes. Cette thdrapeutique soulage notablement la malade dont les algies diminuent mais n'a aucun effet sur l'ichtyose, pas plus d'ailleurs que la vitaminothdrapie A, les bains au carbonate de soude et le glycdrold d'amidon. La malade a dtd revue il y a 10 jours avec un dtat cutand identique. 11 est 4 noter q'u'une biopsie cutande a dtd pratiqude en peau glabre objectivant une hyperkdratose orthokdratosique assez intense tapissant un corps muqueux moddrdment atrophique dont 1'dpaisseur de la couche granuleuse est nettement diminude, que la vitamine A n'a pas dtd dosde. Cette observai^n nous a para interessante par l'association peu frdquente represent^ ici d'une ichtyose acquise paraneoplasique et d'un cancer mammaire. V\ Acropathie polyvinylique professionnelle, P. Duoois, P. Amblard, B. de Bigni- court et J. Legrand. M. P... Roger, 34 ans, sans antdcddent pathologique notable, travaille depuis mars 1958 dans un atelier de polymdrisation du chlorine de vinyle. Nous l'avons vu pour la premiire fois en octobre 1960. 11 avait une scldrodennie ceddmateuse soignde depuis 2 ans 4 Lyon se manifestant par tumdfacdon et scldrodennie des mains, tumdfacdon des membres supdrieurs, des pieds et visage oeddmatid. Le malade avait repu cortancyl puis stigastdrol et sitostdrol sans grand succds, pais amdlioration par le mddrol. Le Pr Thiers nous confie le malade.--Au - premier examen, les doigts dtaient ceddmadds, mais GO Vi H O o 198 SOCIETE FRANCHISE DE DERMATOLOGIE ET DE SYPHILIGRAPHIE la peau se decolle fadlement. II se plaint de troubles vaso-moteurs de type Raynaud. Un traitement lipiodole est poursuivi pendant 6 mois, puis le malade est perdu de vue. En decembre 1970, a l'occasion d'une consultation pour prurit anal, on note seulement un hippocratisme digital avec scldrodactylie minime et des nodules sous-cutanes au niveau des poignets ; les troubles fonctionnels ont disparu depuis plusieurs annees. En aout 1971, quelques douleurs des doigts, qui n'aminent pas le malade a consulter, se produisent, mais ce n'est qu'h l'occasion d'un examen systematique en novembre que l'acro-ostdolyse est decouverte. L'dtat cutand n'est pas modifie, par contre, les cliches radiographiques montrent l'aspect caractdristique de l'affection : lyse des phalangettes avec debut a l'extremitd distale rdalisant des aspects en biseau ou en pointe. Maladie en rapport avec le travail de polymerisation du chlorure de vinyle. On apprend tardivement que la radiographic des mains a dtd pratiquee & Lyon en 1960 et qu'elle n'avait montrd aucune ldsion osseuse. Acrokeratose verruciforme, P. Amblard, B. de Bignicourt et J. Martel. D... Pierre, 53 ans, est venu consulter pour ldsions verruqueuses des doigts. On note dans les antecedents : une meningo-encdphalite en 1962, line comitialitd (absences, crises psycho-motrices) en 1963, un syndrome d'oblitdration artdrielle aigue du membre inferieur gauche ayant ndcessite une intervention sur le carrefour aortique en 1965. L'interrogatoire apprend que le malade est porteur de ces ldsions depuis de nombreuses anndes. Ses enfants sont indemnes de toute dennatose. Q est fils unique et a perdu ses parents depuis longtemps. L'examen met en Evidence sur les quatre membres des formations papuleuses et kdratosiques dvoquant une maladie de Darier. La biopsie d'un dldment montre une tres importante hyperkdratose orthoplasique avec hypergranulose et discrete acanthose. Dans le derme papillaire et moyen les artdrioles sont ici et 14 souligndes par quelques lymphocytes dpars. II n'y a pas d'anomalie du tissu dlastique. Les annexes sudoripares sont normales. Trois autres biopsies pratiqudes en diffdrents points du corps montreront des images tout h fait superposables. Aucune image de dyskdratose folliculaire n'a dtd retrouvde. Microscopie electronique (pr Agr. Stoebner) : les cellules du corps muqueux de Malpighi sont peu pigmentdes et leur cytoplasme condent frdquemment une grande vacuole h contenu sdro-protdique (exosdrose ?) qui peut faire hemie dans le noyau. Cette vacuolisation disparait dans la couche granuleuse oil le ddpot de la kdrato-hyaline parait mal se faire. Plusieurs strates de cel lules aplaties, aux contours anguleux rigides gdndralement encrofitds, sont ensuite. visibles et corres pondent aux ldsions d'hyperkdratose observdes histologiquement. Le cytoplasme de ces dldments condent un magma dense de fibrilles enchevetrdes dont Involution se fait vers une sorte d'homogdndisation vitreuse. De telles images correspoadent a ce qui a etd ddcrit dans l'acrokeratose verruciforme. Maladie de Waldenstrdm rdvelde par des manifestations cutanees, P. Dugois, P. Amblard, J.-P. Pinguet et J. Martel. J... Benoite, 70 ans, prdsente dans ses antdcddents une pdritonite h l'&ge de 22 ans et quelques malaises avec perte de connaissance qui l'ont fait sdjoumer h l'Hopital en 1966, et que i'on a attribuds it un dtat ndvrotique. E 62 5 .< s *U o B-SK :o -- _ v I j2</5? fe, S. = *" , ^ -uo.eflCfl'On"i 5-5-2 2j 52 '.i .-j S<!=oa: uii C " ZU SjjSq 2 4^0\ -J*= .-r _ <c > eggs REG OO C w - 2W <SS eo <3 Oe s ^3 5 co a;j . >' BF SI: 1 3 1 e 3 > * ^ Ou y o.o 2-a .-Ok C c2 =C ;5 m^ ^i w.^r -o .v-- t:; J ^M -- [2^<2gdg sy . ? p ~: -^sS-^sf s ^ fi* d3S^-S^-^- . 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Eckardt, M.D., Ph.D., and Richard Hindin NO net: THIS MATERIAL MAY Bt PROTECTED BY COPYRIGHT )AW (TITLE 17 U.S. CODE) GGU-1 r\ plastic has been defined as "a material that con tains as an essential ingredient an organic substance of large molecular weight, is solid in its finished state and, at some stage in its manufacture or in its processing into finished ar ticles, can be shaped by flow.... The terms plastic and resin are used in overlapping senses, but resin applies more specifically to the more or less chemically homogenous polymers used as starting materials in the production of molded articles, while plastic signifies the final solid product which may contain fillers, plasticizers, stabilizers, pigments, etc."1 Today plastics have assumed a very important place in our lives and are practically ubiquitous, being found in the home and in industry and as components of many everyday items we use. This review of the toxicology of plastics was un dertaken because of their importance and widespread use. The oldest synthetic plastic is celluloid. This is a cellulose nitrate, or pyroxyline type, whose discovery and development began with the early work of Braconnot in France in 1833 and Schoenbein in Germany in 1845. )ohn Hyatt, an American, however, is generally credited as being the first to work with cellulose nitrate as a plastic mass rather than in solution. His work was patented in 1869. In spite of its many uses, cellulose nitrate is readily decomposed by heat and is very unstable in sunlight. Its chief hazard, however, is its extreme flammability which led to the search for other products. The first and still important commercial synthetic resin was a phenol-formaldehyde condensation product, described and patented in 1909 in the U.S. by Bakeland. In contrast to cellulose nitrate, which was thermoplastic, the new resin, named Bakelite, was a thermosetting material. A modification of this type of material was the resorcinol-formaldehyde resin introduced in 1943 and used as a binding agent. Cellulose acetate was the next major product developed, beginning in 1927, although it had been known for many years prior to that. The advent of injection molding presses during this period greatly increased the use of this thermoplastic material. In addition to being highly resistant to impact it was much less flammable than the original cellulose nitrate product. Urea-formaldehyde resins were introduced commercially in 1929, and unlimited color possibilities became available with them. Light-weight and shock-resistant, they have been ex tensively used in the illuminating industry. Medical Research Division, Esso Research and Engineering Company, Linden, New Jersey. Reprint requests to Director, Medical Research Division, Esso Research and Engineering Company, Box 45, Linden, N.|. 07036 (Dr. Eckardt). 808 Polyvinyl esters are another group of plastics which were known for many years prior to their commercial development in the U.S. in the late 1920's. The most important of these materials are polyvinyl acetate, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, and the polyvinyl acetals. Polyvinyl acetates are commonly used in adhesives and coatings for paper, textiles, and leather, whereas the polyvinyl chlorides are used in wire and cable coatings, packaging films, and flexible tubing. Polyvinyl butyrate has been used in laminated safety glass. Polystyrene, one of the oldest synthetic polymers, was prepared as early as 1839, by Simon. However, it was not until 1937 that a synthetic monomeric styrene of high purity could be produced commercially and a corresponding polymeric product made. Important properties of polystyrene include its low power factor and near zero water absorption which make it particularly well suited for radio-frequency insulation work. Newer processes use copolymerized styrene with butadiene to provide high-impact-strength materials. Cellulose acetate butyrate was first marketed in 1938, and ethyl cellulose, the first cellulose ether made in the U.S., was also developed during this period. Cellulose acetate butyrate has been used in photographic film, lacquers, and protective coating solutions, while ethyl cellulose has been used in adhesives, paper and fabric coatings, and wire insulation. Polyamides, of which the best known is nylon, were developed between 1929 and 1936 and came into use several years later as low-density, tough, high-tensile-strength plastics. Another group of plastics developed in 1939 was the melamine-formaldehyde resins. These have found widespread use in such areas as molded tableware products and ignition parts of aircraft engines. More recently they have been mixed with pulp products to provide wet strength for paper products. Polyesters, the alkyd resins, were developed in the early 1940's. Light-weight and rigid, they have been incorporated into many products including ducts for air-conditioning systems, luggage, and prefabricated housing panels. Silicones are a group of plastics which have also been recognized for many years, dating back to 1871. However, they were not commercially available until 1943. Because of their heat resistance they created a revolutionary advance in elec trical insulation. Silicone rubbers, too, have been developed. The silicone resins have been used in baked coatings for protection of radiators, heat exhaust pipes, and stacks, while silicone rubber has been used as a gasket material on search lights and aircraft. Polyethylene, the simplest member of a large group of ther- ' i~T-: vere nent hese Tiers itals. and 'inyl Ims, i in was jntil juld leric e its lake ork. e to and was rate live I in i. /ere era I tics, the ead tion xed cts. arly i ted ling een hey heir ec>ed. for Tile ch- ler- 1 moplastic resins, was patented in 1937 in Great Britain and toxicity.6 Borgstedt7 noted some central nervous system j was introduced in the U.S. in 1941. In 1946 polytetrafluoroeth- depression with doses of 1 to 15 gm/kg of the oligmeric (un ylene (PTFE), marketed as Teflon, became available. It is cured) resin in mice. Cornish and Block8 reported data on ! unusually inert and resistant to all types of chemicals except three uncured resins with acute oral LDsn's ranging between 3 i molten alkali metals. to 4 gm/kg. No other significant hazards have been reported 1 The epoxy resins, derived from ethylene oxide, its homologs with these resins. or derivatives, are among the newer plastics which have been In contrast to the uncured resins, a variety of hazards have developed. The prototype of this group was made by direct been reported with the various curing agents used. The most 1 polymerization of ethylene oxide, which produced a straight- frequently used cross-linking agents are the amines. Aliphatic j chain, thermoplastic polymer. These resins have been used ex- polyamines which are commonly used include ethylene i tensively as adhesives and in the production of protective diamine, diethylene triamine, and triethylene tetramine. All are coatings.2 alkaline and are capable of causing extensive, corrosive tissue j The plastics which have been discussed are representative of damage. The most commonly encountered problems arising different groups and are only a few of the many that have been from amines are skin rash, tenderness, and scaling. These will I and are being produced and used. From a toxicologist's be discussed more fully in the next section. Another problem viewpoint there are numerous health hazards in the manufac which commonly develops is bronchial asthma.9 Because the ture and use of these plastics. This paper will deal only with curing reaction may be exothermic, fumes from the reactants hazards associated with the finished product. The hazards of often escape and can present a hazard. Also, the cross-linking manufacturing processes will not be discussed. agent is frequently added in excess in order to drive the reac | The health hazards of plastics can be divided into several tion to completion. This may result in unreacted amines being broad areas. These include direct toxicity from oral ingestion, left in the product.7 Grinding, sanding, and polishing epoxy respirable particulate inhalation, and the toxicity of additives resins present other hazards, including the production of dust and unreacted chemicals; dermatological problems; acro- and fumes. Breysse'0 has reviewed the health hazards from osteolysis; toxicity of thermal decomposition products; hazards these procedures and has suggested various precautionary from fillers in plastics; and toxicology in medical application. measures. Among these are adequate ventilation of working Carcinogenic potentials of plastics will be considered in the areas and proper personal protection, such as gloves, masks, last section. and protective goggles for the eyes. In more recent work the chronic oral toxicity of a number of 1 Direct Toxic Effects plastics has been studied. Vinyl chloride/vinyl acetate copolymers (molecular weight 25,000 to 30,000 by the It is generally accepted that plastics as a group have a Staudinger method) fed to rats in 1.5% and 12% of their diets moderately low order of acute toxicity as expressed by their produced no ill effects after two years." A chronic feeding oral LDso's, inhalation hazard, and skin irritation potentials. study with polyvinyl-pyrrolidone (PVR) in dogs showed that in Certain specific exceptions to this generalization exist, and they amounts up to 10% of their diet no ill effects were produced ' will be discussed in this and in later sections of this paper. The after two years, although PVP was tentatively identified in the purpose of this report is not to list all potential hazards for all lymph glands.'2 A modified polyacrylamide resin was fed to of the existing plastics. Rather, groups of plastics will be rats at 500, 2,000, and 10,000 ppm in their diets for two years discussed, along with the problems most frequently associated without any significant adverse effects, while a similar study with them. with dogs fed 500, 2,000, and 10,000 ppm showed only Many plastics, including polyvinyl chloride, polyvinyl questionable findings at the 1% level.'3 Polyfluorotetraethylene j acetate, polyethylene, polystyrene, and methyl methacrylate, (PTFE, marketed as Teflon) was found to have no adverse ef | are more or less physiologically inert.3 Acute oral LDso values fects on weanling rats at 25% levels in their diet for 90 days.14 are not readily available for them because they have to be ad Epoxy resins as 1% of a rat's diet for 26 weeks produced no ministered in such large quantities that their sheer bulk effects abnormalities, but there was some weight loss. The low oral overshadow their toxicity. This is not the case with the starting toxicity of many of these materials may be due to poor monomers which have varying degrees of toxicity associated gastrointestinal absorption.7 I with them. Flowever, since this discussion will be confined to Polyurethanes are another group of plastics whose toxicity is I the finished plastic products, the toxicity of individual low but whose reactants have undesirable properties. ' monomers will not be reviewed except where pertinent. A Polyurethanes are basically the product of a reaction between , good review of the hazards of monomers and other reactants a diisocyanate and a polyol. A catalyst, a blowing agent, and a may be found in Patty,3 Malten and Zielhuis,4 and catalyst accelerator are frequently used in the reaction. The McCol lister.5 most hazardous material used in the reaction is usually the Many papers have been written on the potential hazards of diisocyanate. A commonly used one is toluene diisocyanate | epoxy resins. In contrast to most other plastics which may be (TDI). This is a strong skin and respiratory irritant, and sen j conveniently produced long in advance of their actual use, sitivity reactions with asthma-like symptoms along with severe epoxy resins must be prepared immediately before being used. respiratory embarrassment have been produced by it.15 This is I Because of this, the hazards associated with manufacturing the primarily a hazard in the manufacture of the polyurethane or in resins cannot be easily separated from those associated with in situ foaming applications of the finished product. However, i the finished plastic. Epoxy resins are prepared from two residual TDI may be present in the foam product and can materials. One is the uncured resin which is a polyether with present a definite potential hazard. If p,p-diphenylmethane terminal reactive epoxy groups. The other is the cross-linking diisocyanate (MDI) is used as the isocyanate rather than TDI, or curing agent. The uncured resins possess a low order of sensitivity reactions can also develop.16 JOM/Vol. 15, No. 10/0ctober 1973 809 24872003 Most plastics are not thought of as presenting an inhalation hazard in their finished states, with the exception of such materials as the polyurethanes just discussed. One material which does present a potential respiratory hazard is PVP when it is used in an aerosol form. However, several studies have shown that in actual use this has not caused any significant damage. Lowsma et al17 exposed rats to PVP aerosols for eight hours a day, five days a week, for a total of 30 exposures to average concentrations of 118 to 146 mg/cu m with particle sizes ranging between 0.5 to 4p. No inflammatory pulmonary response occurred, although there was some lymphoid hyper plasia and parenchymal hyperplasia. In another study using PVP-based hair lacquer sprays, no abnormal x-rays were seen in a large number of hairdressers to suggest the presence of thesaurosis.18 While another report did document the presence of thesaurosis in hairdressers, attempts to demonstrate the presence of PVP in the lungs were unsuccessful, as have been other attempts to reproduce this disease in experimental animals.19 20 Another potential hazard is that of pneumoconiosis from inhalation of plastic dusts. One case of pneumoconiosis caused by the inhalation of PVC dust has been reported.21 Other work on the respiratory deposition of polystyrene aerosols in man has also been reported. Aerosols of 0.188/4, 0.557/4 , and 1.305/4 were generated and inhaled by human subjects. The effects of such parameters as respiratory rate, tidal volume, and respiratory flow rates on deposition were discussed. Lower respiratory rates increased deposition, especially of the 1.305p particles, but tidal volume and flow rates did not affect deposition.22 Although the majority of the pure polymers used in making plastics have a low order of toxicity, the finished product may have a significantly higher degree of toxicity. This may be due to several factors. These include residual unreacted starting materials having their own individual toxic hazards; com pounds added to the plastics including additives, stabilizers, and plasticizers; and direct hazards encountered in working with the material. A good example of a plastic containing hazardous unreacted materials is seen with polyurethane foams which may contain TDI. The same is applicable to other plastics where unreac ted materials remain in the finished product. A second source of toxic hazards is from plasticizers, stabilizers, and other ad ditives, including hardeners in the plastic. Specific examples include the toxic tricresyl phosphate plasticizers and the less toxic phthalic acid derivatives. Stabilizers include lead salts, cadmium, and tin compounds.23 Again, it is not within the scope of this paper to discuss the toxicity of individual materials but rather to point out representative examples. A more detailed analysis of certain specific problems will be presented in the section on the toxicity of plastics in medicine. Several good reviews on hazards in manufacturing and using plastics are presented by Harris,23 Zapp,24 Wilson and McCor mick,25 Zielhuis,26 and Malten and Zielhuis.4 Further references are provided in the well-documented bibliography of Molzon.27 A good review on the toxicity of plasticizers, stabilizers, and various additives was published by Guess and Haberman,28 who also evaluated a number of specific compounds. Of the phthalate plasticizers tested, ten showed no toxic characteristics, while seven others showed some toxicity. None of the five sebacates tested were toxic. Citrate 810 esters were also relatively nontoxic. Of the stabilizers evaluated, all eleven organotin compounds showed some degree of toxicity. Barium, cadmium, and zinc compounds used as stabilizers were also studied. All of the compounds with cadmium or barium were toxic to some degree. However, the zinc compounds, and particularly those in combination with calcium or magnesium, were either nontoxic or far less toxic than the cadmium- or barium-containing compounds. Dermatitis Many of the dermatological problems caused by plastics oc cur in the curing or hardening process. This is especially true for several of the thermosetting resins, notably the phenolics, amines, epoxies, and polyesters where very little dermatitis is caused by the end product itself. Dermatitis associated with the manufacturing process is usually caused by the previously mentioned agents; monomers, low molecular weight polymers, condensate compounds, fillers, and additives such as cross-linking agents, catalysts, accelerators, plasticizers, and solvents.29 In this section several specific problems which have been encountered will be reviewed. Formaldehyde resins were reported to have caused a contact dermatitis in several cases. Three dermatological clinical syn dromes due to urea-formaldehyde resins have been noted.30 These are (1) the sudden development of an acute eczematous reaction, frequently with periorbital edema; (2) a reaction which starts as a typical eczema, affecting the interdigital areas and backs of the hands and forearms, which may appear after years of contact with the resin without any previous reaction; (3) a combination of both the primary and delayed hyper sensitivity reactions. Two common uses of formaldehyde resins are in facial tissue products where they are used to impart wet strength and in textile finishes. In one paper, facial tissues im pregnated with a urea-formaldehyde resin were found capable of inducing sensitization reactions in about 6% of the group studied.31 In textiles treated with formaldehyde resins to improve crease and shrink resistance a number of cases of contact der matitis have occurred. One report described patients with a contact dermatitis who had a positive patch test to a 1% phenol-formaldehyde resin without a concurrent sensitivity to formaldehyde. Furthermore, heating the resin for five minutes at 191 to 205C all but destroyed its reactivity.32 Similar results have been reported by others.33 34 A distinct problem with contact dermatitis has occurred in plastics containing tricresyl phosphates. One case report at tributed a woman's allergic reactions to PVC and cellulose acetate to the tricresyl and triphenyl phosphate plasticizers used in their formulations. This was confirmed by patch testing.35 Another case of contact dermatitis was caused by Saran Wrap, a copolymer of vinylidine chloride and vinyl chloride. This, too, was confirmed by positive patch tests.36 Nylon is another plastic which has caused dermatitis reac tions. Originally many of the nylon dermatoses reported were due to either the finishes on the nylon or the dyes used. However, there have been reports of dermatitis due to virgin nylon. In one study six cases with positive patch tests to virgin nylon (unspecified type) were described.37 Epoxy resins are a prevalent source of dermatitis. As in the case of other dermatoses the reaction to the epoxy resins may Health Hazards of Plastics/Eckardt izers omt jnds jnds ;ver, tion less ids. octrue ilics, is is with usly ight such and lave itact syn;d.30 tous :tion ireas after lionperisins wet imable oup rove derth a 1% y to lutes suits d in t atilose izers atch I by 'inyl ts.36 eacvere ised. irgin irgin 1 the may be considered as being of two basic types: (1) a toxic or primary irritant due to direct epidermal damage; (2) an allergic type of hypersensitivity reaction. Also, chronic irritation may lead to a chronic eczematous dermatitis which can persist without continuing exposure.38 Epoxy resins may be divided into two types on the basis of their curing process. There are both cold-cured and heat-cured resins and, according to Bourne et al, the dermatological hazard is greater with the cold-cured resins.39 The hazards from coId-setting resins have been reviewed by Grandjean in several factories.40 Clinically, the hands, forearms, and head and neck were the areas most frequently affected, with the eyelids and face usually showing more involvement than the forearms and hands. The genitalia were also frequently involved from finger contact.38 41 The areas affected showed an erythema which was usually followed by swelling and erythroedema, and were often dot ted with vesicles and blebs. Severe itching was usually ab sent.42 A case of allergic rhinitis has been reported,43 and fingernail bed involvement may lead to the development of paronychia.39 Most of the problems listed occurred from the di- or triamine curing agents used. The lower molecular weight resins also may have some irritating properties, but the higher molecular weight uncured resins and all of the completely cured resins generally may be handled without any der matological effects.44 With regard to the amines, the primary and secondary amines are more irritating than tertiary amines, and the aliphatic groups are more irritating than the aromatics.45 Methods of handling various agents and con trolling these problems have been reviewed by many, in cluding Bourne4* and Calnan.38 Controls include such measures as clothing, gloves, washing, and ventilation. Spandex, a polyurethane elastomer, has been an important cause of contact dermatitis from clothing. First reported, ac cording to Porter,47 by D. Munro-Ashman in 1965, numerous cases have been noted since then. Spandex is used extensively in brassieres and girdles, and the contact dermatitis which resulted has been primarily localized to the skin in these areas. The reaction appears initially as an acute erythema, which may be followed by scaling and sometimes by pigmentation.48 In a number of cases it was noted that patients also exhibited sen sitivity to rubber and other elastic threads. This in turn led to a search for an agent common to both materials. Mercaptobenzothiazole (MBT), a rubber accelerator, was identified in both materials, and patients who were allergic to Spandex were noted to have positive MBT patch tests. By changing clothing to brands of Spandex not containing MBT the dermatitis was usually prevented.49 50 53 However, Carr has reported cases of contact dermatitis in nine women due to Lycra, a Spandex product not previously associated with contact dermatitis.52 None of the patients had a positive patch test to MBT. Acro-osteolysis Acro-osteolysis is a new and unique occupational disease associated with manufacturing polyvinyl chloride (PVC). It has not been seen with any other plastics. After an early, tentative case report in 1963, a large number of cases were reported.53 Marin et al described five cases of acro-osteolysis in French workers in 196754 and shortly afterwards Wilson et al reported 31 cases of acro-osteolysis.53 The disease in both reports in volved only the hands. These and other authors have described JOM/Vol. 15, No. 10/0ctober 1973 a syndrome characterized by the initial development of Raynaud-like phenomena (intermittent pallor of the ex tremities, especially of the fingers and toes, brought on by cold or emotion). This was later followed by distal phalangeal oste olysis.53"56 Clinically, the onset of the disease is usually first signaled by complaints consistent with a Raynaud-like phenomenon, which is often the only finding. In addition, nonspecific com plaints of tingling, aching, stiffness, or numbness of the fingers may appear with increasing time. Radiographic findings frequently take a year or more to develop and may be associated with fingertip tenderness. The initial radiographic abnormality is usually a marginal defect of one or more of the tufts of the distal phalanges. With the passage of time the defect develops into a fracture line through the distal phalangeal tuft. The fracture line may then progressively widen as the tuft becomes more separated from the remaining shaft. This has progressed in some cases to the point where the bony tuft disappears, leaving only the shaft of the distal phalanx.57 Several features are common among these reports. The only workers affected were those involved in hand-cleaning the PVC polymerization autoclaves. No other factory workers mentioned in these or any other reports suffered risks of this disease.58 Other production facilities which cleaned the reac tors chemically or by jet water streams, rather than having them scraped manually, did not report the development of this disease. In most reports the osteolysis was confined only to the terminal phalanges of the hand. However, some authors found evidence of osteolytic changes in the sacroiliac joints59 and portions of the patella.57 Osteolytic changes have also been reported in the phalanges of the feet.59 60 No specific etiological agent for acro-osteolysis has been identified. To evaluate the role of vinyl chloride monomer, Viola exposed rats to levels of 30,000 ppm vinyl chloride for 4 hours per day, 5 days a week, for 12 months.61 The small metatarsal bones showed periosteal proliferation of cartilage like material, while bone and connective tissue changes similar to those in acro-osteolysis were observed. While such results are interesting, they do not establish vinyl chloride as being the causative agent in acro-osteolysis. Other speculation on ten tative etiologies include a combination of physical insult and an unidentified chemical toxicity. It has also been pointed out that a predisposition of the workers to circulatory disease and local microtrauma may be important.56 In a recent review Dinman, Cook, Dodson et al restudied the problem, confirming that only workers who hand-cleaned the reactors were at risk. Again no causative, agents could be identified.62'64 Thermal Decomposition Hazards from the thermal decomposition of plastics are variable and depend on the particular plastic involved. In general, hazards include flammability, the evolution of both combustible and noncombustible gases, and smoke and par ticulate formation. Nitrocellulose, one of the oldest known plastics, is extremely flammable, and x-ray film made from it was responsible for a fire in a Cleveland clinic in 1929 which killed 125 persons. Combustion products of the nitrocellulose included carbon monoxide, nitrogen dioxide, and nitrogen tetraoxide.65 Other plastics may decompose directly when exposed to 811 m 24872005 iiiVMMi I'HUTiiita eat. For example, phenolic resins are relatively inert but are decomposed by heat to yield products including phenol and formaldehyde.66 Melamine-formaldehyde and urea-formalde hyde begin to decompose after 30 minutes at temperatures above 350F with the release of formaldehyde vapors.67 Stankevich and Ivanova studied amino plastics and found that the decomposition products which formed were directly related to temperature.68 At 130 to 200C aldehydes and hydrogen cyanide (HCN) were formed, while at 250 to 270C carbon monoxide (CO) was also formed. The amount of the com pounds formed increased with higher temperatures. The decomposition products of polyvinyl chloride (PVC) were also found to be a function of temperature. Caseous hydrogen chloride was released from PVC when the tem perature reached about 450F. The rate of release depended upon the temperature and density of the material. Above 650F carbonaceous degradation occurs.69 Hydrogen, methane, ethylene, ethane, benzene, and toluene have also been report ed as PVC decomposition products at temperatures between 350 to 850C. Furthermore, the same decomposition products were found in both air and helium atmospheres, indicating the importance of temperature rather than oxygen during thermal decomposition.70 Cornish and Abar71 studied the toxicity of pyrolysis products of vinyl plastics in rats. Subjecting rats to decomposition products of 1 to 2 grams of PVC at tem peratures up to 550C for up to two hours resulted in death for about 50% of the animals. Death was attributed primarily to CO (maximum concentrations were in excess of 3,000 ppm). jwever, when death from CO was prevented by adding oxygen to their air stream, pulmonary edema and interstitial hemorrhage developed.71 Thermal decomposition studies were also done on Acrilan (an acrylonitrile), Orion (an acrylic product), and related fibers. One author reports that while heating these polymers to 200 to 320C either in air or nitrogen, 2.3% ammonia and 1.3 to 1.4% HCN were released in the pyrolysis products.72 Hara and Matsumura73 found that below 400C no HCN was formed from melamine, polyamides, or polyurethane. However, HCN began forming from urea resins and cyanoacrylates above 325C and 375C, respectively. A summary of the thermal decomposition products from these and various other plastics is listed in a table presented in a Michigan Occupational Health Bulletin.74 Polyethylene, too, has been studied during thermal decom position. Pyrolysis products which formed during the thermocutting and sealing of polyethylene tubes included for maldehyde and acrolein.75 Polytetrafluoroethylene (PTFE, Teflon) presents an unusual and unique thermal decomposition hazard which has been called Polymer-Fume Fever. D. K. Harris,76 one of the first to call attention to this problem, reviewed several of the early case histories of workers exposed to PTFE decomposition fumes. The presenting clinical symptoms were discussed and, as noted by Harris, there was always a latent interval between exposure to the fumes of PTFE pyrolysis and the development of symptoms. The first symptom noted was a sense of discom<~'1 in the chest described more as a feeling of retrosternal op- sion rather than pain. A dry cough may or may not develop. Systemic symptoms appeared after a few hours with a gradual, increase in temperature and pulse rate, followed in most cases by an episode of chills and sweating. The tem 812 perature did not exceed 104F. Muscle and joint pains have also been reported,77 as well as headaches, nausea, weakness, and shortness of breath.78 Recovery takes place fairly rapidly and is usually complete within two days.76 The toxicity of the products of pyrolysis have been studied, as well as the con ditions under which they form. In one study using rats the 3hour LCso was 31.5 gm/hr for pyrolysis at 375C, whereas it was 23.5 gm/hr at 400C.79 In another study the principal toxic com ponent was found to be a particulate. This may have had other toxicants absorbed on it.80 In one report on the identification of the products of pyrolysis, Coleman et al81 fpund that carbonyl fluoride (COF2) was the principal toxic agent which formed when PTFE was pyrolyzed in air at temperatures between 500 to 650C. Above 650C the major products were carbon tetrafluoride (CF-t) and carbon dioxide. Other fluorocarbons were also found in lesser amounts. Scheel82 has confirmed COF2 as the principal toxic component of pyrolysis at 550C. In other reports, however, the major degradation product at 200 to 400C was the monomer, while above 500C perfluoroisobutylene, a highly toxic compound, was formed.83 Analytical methods for identifying the volatile products of pyrolysis are discussed by Boettner and Weiss.84 Although these facts are known about the thermal decomposition of PTFE, the specific agent responsible for polymer-fume fever and the mechanism involved is unknown. Numerous cases of polymer-fume fever have been reported in several different environments. One report described several cases where all of the men who developed symptoms had handled Teflon*-contaminated material, and all were moderate or heavy smokers. When smoking on the job was forbidden the symptoms ceased.85 Other cases of polymerfume fever which resulted from smoking cigarettes con taminated with PTFE dust have also been noted.86 Welti and Hip87 have reported that cigarette smoking apparently wors ened the effects of PTFE fume exposure. Another source of ex posure is through aerosols containing PTFE. Here also con tamination of cigarettes was responsible for cases of polymerfume fever.88 89 One rather unique set of symptoms resembling polymer-fume fever occurred in 39 of 40 persons aboard a C54 aircraft in flight. Fumes arising from Teflon-impregnated asbestos tape wrapping on the exhaust manifold of an auxiliary power plant were determined as being responsible for the symptoms.90 The hazards of polymer-fume fever are not limited only to the cases previously described. Since PTFE may decompose above 400F,83 environments in which Teflon is exposed to these temperatures will predispose to this problem. This is especially important in industrial processes in which PTFE may be subjected to grinding and burnishing. To prevent the hazard of polymer-fume fever several general preventive measures should be taken. These include: (1) prohibiting workers from smoking in PTFE-contaminated environments; (2) careful per sonal hygiene in workers exposed to PTFE products, especially dust, before smoking; (3) elimination of PTFE from en vironments where thermal decomposition may occur except where essential; (4) ventilation control in environments where PTFE thermal decomposition may occur. Fillers Many plastics are compounded with fillers in them to im- Health Hazards of Plastics/Eckardt provi wide reinfi and 1 by L reinfi bumi prodi six si tratra stanc with polye polye fiberf polye force The f havin whid CaCC prepa withe dust: 'll! U occur the si CaCC*^ plasti filler inhal; tion, the s excef phagi by S< The studii. were CaSC for te tides) How< 10/x group samp Otf ture c reinfo ed, a respo dusts. fC An< Here, 00 proce carcir dling O for as Plasti Plas J0M/V prove their properties and give them additional strength. One widely used filler is fiberglass. Health hazards from fiberglassreinforced plastics are associated with both their manufacture and use. A good review of manufacturing hazards is presented by Li'm et at.91 One of the chief hazards in using fiberglassreinforced plastics arises when the material is sawed, ground, burnished, or otherwise handled in such a way that dust is produced. In one study on the pathogenicity of these plastics six substances were evaluated by several routes, including in tratracheal, intravenous, and subcutaneous injection. Sub stances studied were: (1) fiberglass-reinforced polyester plastic with a calcium sulfate (CaS04) filler; (2) fiberglass-reinforced polyester plastic with a calcium carbonate (CaCQj) filler; (3) polyester plastic with a CaCOi filler without the fiberglass; (4) fiberglass (pulverized and ball-milled) without the plastic; (5) polyester plastic without either filler or fiberglass rein forcement; and (6) flake glass (pulverized and ball-milled). The fiberglass-reinforced plastics (1 and 2) were described as having the same physical properties as in another report92 in which the particle size was less than lOp. The plastic with the CaCOi filler but without the fiberglass reinforcement was prepared in a similar fashion. The particle size of the fiberglass without the plastic or filler varied from 20(i to 70p. The plastic dust alone (5) was 3ju or less in size, while the flake glass was Ip to 5p in size. The data show a moderately high mortality occurred in all groups following intratracheal administration of the samples. Pneumoconiotic lesions were more severe with CaCC>3 than with CaSO< containing fiberglass-reinforced plastics. This was also observed for plastics containing CaCC>3 filler but without fiberglass reinforcement. Intratracheal inhalation of fiberglass alone produced only a minimal reac tion, but vesicular emphysema was seen in all groups. None of the substances administered subcutaneously caused fibrosis except the fiberglass. Finally, lesions were resolved through phagocytosis of the retained particles.93 In another study done by Schepers," similar results were obtained. The effects of fiberglass-reinforced plastics have also been studied with regard to their effects on tuberculosis.95 Animals were exposed to fiberglass-reinforced plastic dusts with a CaSOx filler at levels of 399 (range 18-775) x 106 particles/ft3 for ten months or with a CaCOt filler 338 (52-792) x 106 par ticles/ft3 for 24 months. (Particle size was not specified. However, in a similar report92 the particle size was less than lOp .) The tuberculosis infection was intensified in both groups but was more severe in the animals exposed to the sample containing CaCOr. Other work was reported on dust generated in the manufac ture of molded automobile body parts made from a fiberglassreinforced polyester plastic. Again, similar results were report ed, and limited pulmonary reactions were produced. The responses obtained were classified as those seen with "inert" dusts.92 Another material which may be used as a filler is asbestos. Here, the hazard of generating dust from sawing or grinding processes is quite significant because of the known pulmonary carcinogenic hazard from asbestos. Precautions taken in han dling the various forms of asbestos should probably be used for asbestos-containing plastics. Plastics in Medicine Plastics have found widespread use in medicine because of JOM/Vol. 15, No. 10/0ctober 1973 their strength, inertness, light weight, moldability, and their many available forms. Harris96 has reviewed their uses in many areas, including syringes, prostheses, and transfusion ap paratus. Potential hazards from the medical use of plastics arise from: (1) effects of the plastic on the body; and (2) effects of the body in altering the properties of the plastic.97 Toxic effects of plastics on the body may be either indirect or direct. A good example of indirect toxicity from plastics is shown by their interaction with drugs. Several potential problems exist, as outlined by Autian.98 These include permeation, leaching, sorption (both adsorption and absorption), chemical reactivity, and alteration in the physical properties of the plastics. Permeation may be a minor or a very serious problem, depending upon the drug involved. For example, if the drug is very sensitive to oxidation the entrance of air (oxygen) into the product through its plastic container may accelerate degradation of the drug. If the gas is carbon dioxide, chemical reaction may lower the pH of the solution and may result in a precipitate forming. Conversely, permeation of the drug out through the plastic container may result in decreased activity.99 Leaching is always a potential hazard, and a few examples will be briefly discussed later. Sorption may decrease the activity of a drug. Problems with permeability and sorption make nylon unsuited for storing antibiotics, while polyethylene tubing has been found to absorb small concentrations of steroids and a number of alkaloids according to a review by Autian.100 Chemical reactivity between a drug and its plastic container is a potential problem. Drugs including adrenalin, apresoline, aqua mephyton, aramine, streptomycin, and terramycin have been found to discolor plastics, although the discoloration was generally due to degradation products rather than the drug it self.101 Direct toxic effects arise with both short- and long-term direct (primarily subcutaneous) tissue contact. Short-term ex posure is often a potential source for leaching of materials. Long-term contact has been associated with carcinogenesis, which will be discussed in the last section. Other direct con tact hazards include an allergic response to the plastic and problems resulting from processing procedures. One allergic response was seen in persons wearing acrylic dentures. The source of the reaction was later determined as being unreacted monomer remaining in the dentures.99 Short-term direct tissue toxicity from various plastics was studied by Lawrence et al.102 Strips of plastic from 48 different devices, most of which were from vinyl tubing, were im planted through the beveled point of a 15G needle in tramuscularly into rabbits and through surgical implantation into rats and mice. Twenty-five of the 48 materials caused a toxic reaction when examined at seven days. Grossly the toxic reaction consisted of encapsulation with a whitish zone around the implant, while histologically multinucleated giant cells as well as polymorphonuclear leukocytes were seen. Analysis by gas chromatography showed that the toxic materials were probably additives in the plastic rather than plasticizers. In a follow-up study several years later Lawrence et al103 studied 50 pieces of currently used plastic tubings, most of which again were vinyl compounds. This time, specimens were studied for seven days in both rabbits and in tissue cultures. Approximately 32% of the tubings studied caused a tissue reaction. Criteria of tissue toxicity again were a whitish 813 or opaque zone seen grossly around the implant with tation. A number of cases have been reported in which microscopic evidence of necrosis, eosinophilia, inflammation, silicone has been injected into the breast with adverse effects. giant cells, and fibroendothelial proliferation. Although the In three such cases reported by Winter et al'08 foreign body toxic components still could not be identified, it appeared that granulomata resulted. In the first case a giant cell infiltrate oc safer additives were being used in the newer tubing, based on curred after 18 months. The preparation used was a liquid the lower incidence of toxic reactions. silicone whose purity was unknown. In the other cases a Tissue reactivity to nylon, Orion (a polymerized silicone fluid containing 1% animal and vegetable fats was in acrylonitrile). Dacron (a polyester made from polyethylene jected into the breast or mandible. Again, it could not be deter terephthalate). Teflon (PTFE), and Marlex (trade name for a mined if the reactions were due to the silicone or impurities. In family of olefin polymers) was studied by implantation into another case report repeated injections of silicone fluid were the peritoneal cavity of dogs for seven days. Nylon and Orion followed by granulomatous mastitis in two cases. Potential both produced numerous adhesions. Dacron produced filmy problems include: (1) a local sclerosing granulomatous reac adhesions, while the Teflon* caused only a few filmy tion with permanent scarring; (2) histiocytosis secondary to adhesions. However, it should be noted that the Marlex* was carriage of silicones from their site of inoculation to regional used in the form of tiny pellets, while the other plastics were lymphatic nodes; and (3) possible carcinogenic activity.109 In a used in the form of the undyed shredded yarn, the pellets British Industrial Biological Research Association (BIBRA) being unavailable.'04 Bulletin editorial entitled "The Price of Inflation""0 the Processing of a plastic may also introduce toxic substances question of toxicity of silicone fluids for cosmetic injection was into the polymer. This is particularly important where ethylene discussed. It was noted that, although tumors have been I oxide is used for sterilization of thermolabile plastics. After a found, a causal relationship has not been proven and that the brief review of toxic and dermatological problems encountered reactions may be due to contaminants. In discussing the safety i with ethylene oxide, O'Leary and Guess105 studied the relation of silicone for breast augmentation, Snyderman"' advises ship between the content of the plasticizer di-2-ethylhexyl- against using injectable silicone because of its known ability to I phthalate in a plastic and ethylene oxide sorption. Sorption was found to increase directly as a function of di-2-ethylhexyl- migrate to regional lymph nodes. Instead, a silicone bag filled with liquid silicone, which could be removed later if phthalate content. necessary, was recommended ` to increase breast size. A I Data were also presented on ethylene oxide solubility in bibliography on the use of silicones in bandages, blood dimethyl, dipentyl, and dinonyl phthalate. The toxic effects of vessels, prostheses, and organs has been prepared by the ethylene oxide on human erythrocytes was studied, and cell National Library of Medicine."2 culture studies were done on ethylene oxide sterilized Plastics Fiave also been used extensively in blood storage polymers. It was also noted that ethylene oxide can function as bags and in transfusion equipment. Extraction and leaching of I I a solvent for acrylic plastics such as Lucite and Plexiglas. toxic substances from the plastic is always a potential hazard. Another hazard associated with ethylene oxide sterilization is Marcel and Noel"3 reported that blood stored in plastic trans the formation of ethylene chlorohydrin. As an alternative fusion bags for 4, 8, 15, and 21 days extracted 4, 7, 11.5, and method to gamma-irradiation for the sterilization of heat sen 11.5 mg% of dihexyl phthalate, respectively, laeger and sitive materials, ethylene oxide exposure has been valuable. Rubin"4 found that blood stored in bags at 4C for 21 days ex For example, with PVC tubing ethylene oxide sterilization does tracted 5 to 7 mg% of the plasticizer di-2-ethylhexylphthalate not cause the discoloration and decomposition effects seen (DEHP). Also, patients who received these blood transfusions with irradiation. However, Cunliffe and Wesley'06 consistently had DEHP levels of 0.025 mg/gm (dry weight) in their spleens found the toxic substance ethylene chlorohydrin (con and 0.270 mg/gm (dry weight) in the abdominal wall fat. As centration not reported) in physiological saline or an the authors state, the phthalate ester plasticizers are generally- ticoagulated blood after these fluids had been exposed to PVC considered to be of a low order of toxicity. However, this is tubing previously sterilized with ethylene oxide. Relatively based primarily on the absence of overt toxic symptoms. greater amounts of ethylene chlorohydrin were present if the Therefore, although such tissue levels are not presently known plastic was preirradiated experimentally before being exposed to be associated with toxic manifestations, further work on to ethylene oxide. Washing PVC which had only been "subtle toxicities" may reveal hazards not presently irradiated revealed small amounts of chloride. Furthermore, if recognized. the plastic sterilized with ethylene oxide alone (without prior Tissue perfusion with plastic tubing has also been used for irradiation) was then not exposed to a fluid containing assessing plastics toxicity. Several effects have been noted. In chloride ions, no ethylene chlorohydrin formed. On this basis, one report the normal pulmonary response of increased the authors recommended that PVC tubing sterilized by pulmonary vasculature resistance in response to hypoxia was irradiation should be discarded after use. Plastics sterilized partially abolished when PVC tubing was used to perfuse with ethylene oxide should be stored for at least a week before isolated cats' lungs. Two types of surgical grade plastic tubing being used because of the hazard of residual ethylene oxide on were used, both containing the same plasticizer, acetyl-tri-n- the plastic. butyl citrate in epoxy soya-bean oil. However, different Analytical methods for the determination of ethylene oxide stabilizers were used, and the tubing containing the cadmium- and ethylene chlorohydrin in plastics and rubber surgical zinc stabilizer appeared less toxic than the plastic with the oc equipment were discussed by Brown.'07 tyl-tin stabilizer."5 Silicones are a group of plastics which have received much Atkins et al"6 evaluated several types of perfusion apparatus attention for their use in cosmetic and prosthetic devices. One using Eagle's minimal essential medium (MEM) as the per area in which silicones have been used is breast mass augmen fusate, with bone marrow cultures in agar-gel to test for 814 Health Hazards of Plastics/Eckardt cyt pie noi pei wi> arr im PV oq ha w< re| fol m. At th sa th cF d<. ar bl ht at h. h dx ii c u s ( t F t i I, I I JO CO <1 JO o o GO [ i which e eff gn l , trate oca liquid cases a was in>e deter- I cytotoxins. Toxic effects were present with polypropylene, studies. In the data they presented, the plasticizer dimethyl . plexiglass, and stainless steel apparatus. Specific toxins were sebacate killed four of the cell cultures but did not affect the I not identified. Meyler et al1,7used five brands of PVC tubing to growth of chick embryo cells. Butyl octyl phthalate was found | perfuse isolated rats' hearts. Three brands of tubing interfered to be innocuous in tissue cultures but did produce egg embryo 1 with' cardiac function causing negative inotropic effects, changes. Rosenbluth et al125 also found tissue culture methods I arrhythmias, and cardiac arrest. Two brands used caused no to be good indicators of toxicity when a cell monolayer ; immediate deleterious effects. The cardiotoxic effects of the technique was used. A good bibliography on these techniques [ PVC were believed to be a result of the stabilizers used. The and methods has been compiled by Molzan.126 rities. In id were 'oteniial js reacdary to I organotin stabilizer was very toxic, but the barium-cadmium ! had no observable toxic effect. Specific compounds, however, 1 were not identified. Plastics and Carcinogenicity One unique hazard from extracorporeal circulation was An association between plastic films implanted into animals reported by lindberg et al.118 Here, ten human patients died and subsequent tumor formation was recognized in the early egional 109 In a 8IBRA) following open-heart surgery during which perfusion was 1940's. Turner,127 in 1941, implanted Bakelite discs 18 mm in maintained with the DeWall extracorporeal pump-oxygenator. diameter, 1-1/2 mm thick, subcutaneously into rats. After a ( At autopsy, clear retractile emboli were seen in capillaries of period of 18 months or more, four of nine rats developed no the j the brain, heart, and kidney. These were later identified as the fibrosarcomas. However, for reasons which were unclear, no on was been ' same silicone antifoam material which had been used to treat tumors formed when pieces of Bakelite 10 mm square, 1-1/2 the surface of the oxygenator column and helical debubbling mm thick, were implanted in mice. Several years later Op- hat the chamber. Identical lesions were produced in the kidneys of penheimer et al128 implanted 2 to 3 cm square pieces of cel safety idvises ility to ; filled iter if ze. A dogs perfused on the DeWall pump-oxygenator. lophane subcutaneously into one group of rats and wrapped An unusual problem in the use of plastics occurs when they the kidneys of another group with cellophane. After 11 are used as aortic valve replacements. As Little119 notes, arterial months, 35.7% of the survivors from the first group developed blood is a very efficient oxidizing agent and is also a good tumors, and 34.8% of the surviving rats whose kidneys were hydrolyzing agent. Therefore, any plastic which relies on an wrapped in cellophane developed tumors. These tumors could j antioxidant for stability, like polypropylene, is unsuitable for a be successfully transplanted into other rats. Out of the 23 blood 1 heart valve. primary tumors there were 17 fibrosarcomas, 2 tiposarcomas, 1 y the Leaching may be associated with both short- and long-term rhabdomyosarcoma, 1 undifferentiated sarcoma, 1 osteogenic I hazards. Short-term hazards may occur with prolonged en sarcoma, and 1 plasmocytoma. orage dotracheal intubation for respiratory assistance. The PVC used Further work revealed that this tumorigenesis phenomenon ng in endotracheal tubes contains stabilizers which can leach out was not specific for only a few plastics but occurred with izard. of the plastic and cause severe irritation after several days of many materials. In a later report Oppenheimer et al129 were trans- , use. Ethylene chlorohydrin may form if the plastic has been able to produce malignant tumors in rats and/or mice using . and and ' sterilized with ethylene oxide, as discussed previously.120 cellophane (which had previously been processed in various | Guess and Stetson121 have reported an increasing incidence of ways), polyethylene film, a pure polyethylene film, PVC film, s ex- glottic inflammatory reactions after the use of endotracheal Silastic (a silicone product). Teflon, Dacron, polystyrene, and alate tubes. The toxic substance causing the reactions was identified nylon film. Oppenheimer et al130 also demonstrated the car sions as an organotin stabilizer. cinogenic potential of metals in rodents. Silver, tin, tantalum eens On the basis of these reports, organotin and octyl-tin vitallium, and stainless steel foils in the form of circles or t. As stabilizers appear to be not only toxic but extractable from squares 1.5 cm wide (thickness not specified) were implanted rally plastic tubing. It would therefore appear advisable not to use into male rats. All of the foils except the tin foil induced iis is them as stabilizers in plastics which are to be used for medical tumors. These were identified as fibrosarcomas except for one >ms. 1 application. osteogenic sarcoma induced by vitallium. In contrast to the jwn Long-term leaching hazards occur when lead-stabilized PVC other metals studied, the tin foil was friable and was found in on i is used for food packaging and for water pipes. The problem of every case to have broken down into a fragmentary mass. This ntly | leaching out PVC stabilizers by water was evaluated for a com- change in physical form may have been responsible for lack of I pound stabilized with 3.77% basic lead phosphite and tumor formation. In other work, Oppenheimer et al131 demon for | lubricated with 0.94% basic lead stearate - 0.5 ppm of lead strated that glass coverslips alone produced tumors in 25% of In i were extracted after 18 months at ambient temperature; no the rats studied, whereas glass powder alone did not produce sed 1 lead was extracted with hard water. On this basis, the plastic tumors even when placed into tissue pockets previously for vas was judged as being safe for use in pipes containing flowing med with coverslips. Polyethylene powder also induced no jse water.122 tumors except in one questionable case. ing j Toxicity standards for plastics have been advocated. In ad- Tumor formation has also been produced by other materials. -n- . dition to gross parameters for evaluating toxicity by acute and Thick polyvinyl alcohol ("Ivalon") sponges produced sar ?nt | chronic oral feeding studies, 8rewer123 has outlined a series of comas in 14 of 20 animals.132 Polyurethane in sheet, foam, and m- I extraction testing procedures and implantation standards for powdered forms was capable of inducing tumors both by sub >c- plastics used in medicine. Guess et al124 have described other cutaneous and intraperitoneal administration.133 Stinson134 ! methods for evaluating more subtle forms of toxicity. These in reported that polymethylmethacrylate (Acrylic) and stainless us clude growth in tissue culture, electron and phase microscopy steel discs implanted into guinea pigs produced metaplastic of tissue that has been in contact with the plastic, hemolytic ef bone changes, while malignancies were produced in rats. or fects, effects on antibody production, and embryonated egg The mechanism responsible for polymer tumorigenesis is un dt | JOM/Vol. 15, No. 10/0ctober 1973 815 clear. Numerous observations have been made, and several neories have been proposed to explain it. One theory suggests .hat carcinogenesis is due to the physical properties of the im planted film and that it is a nonspecific phenomenon not dependent primarily on chemical interaction between the im plant and the tissue. Another suggests that a chemical reaction does indeed occur between the implanted polymer and ad jacent tissue which leads to tumor formation.135 Data are available which support both theories, and no one explanation of tumorigenesis is currently accepted. Physical properties are known to be important in tumor for mation. As discussed earlier, a film of polyethylene or glass coverslips will produce tumors, but the polyethylene and glass in the powdered form won't. The porosity of the polymer is significant. Brues et al136 reported that tumor production with 0.1 id pore size filters was comparable with nonporous materials. Pore sizes of Ip and larger almost completely prevented tumors, while in the intermediate range (0.1 to 0.45 p) there was an inverse relationship between pore size and tumor incidence. Coldhaber137 136 reported similar ob servations. After 18 months Millipore filters of 50 mp and 100 mp were found to cause 60% and 52.9% tumors in mice. When the pore size was increased to 450 mp, only 5% developed tumors.1,7 These results are consistent with the con cept of physical carcinogenesis on the basis that films interfere with normal diffusion rates of specific metabolites to or from surrounding cells. Introduction of pores into the film decreases this interference and permits more normal patterns of diffusion. The influence of a smooth film surface in carcinogenesis has ' ->en studied by Bates and Klein.139 Using polyethylene discs mm in diameter and 0.015 inches thick, a significantly higher incidence of sarcomas formed in mice that had received discs having a smooth surface than with discs that had a roughened surface. The theory that polymer tumorigenesis is due to a chemical interaction between the implant and the host has received much attention, and many authors have investigated the biochemical and cellular changes which take place as malignancies occur. Oppenheimer et al140 have reviewed several possibilities for the mechanism of carcinogenesis. The question of a low molecular weight impurity acting as the car cinogenic agent was considered. However, since numerous tumors were induced with pure plastics, the primary car cinogen appears to be the macromolecule itself rather than an additive or an impurity. Furthermore, no relationship existed between the number of sarcomas produced and the degree of purity of the film. The lack of carcinogenicity of the monomers styrene, methylmethacrylate, and hexamethylene diamine would indicate that unreacted monomer is not likely to be the active agent for at least these particular polymers. Because plastics were believed to be essentially insoluble in aqueous systems and chemically rather inert, any interaction between them and surrounding tissue was thought to be unlikely. It was also noted that there was no correlation between car cinogenicity and the stiffness or rigidity of the film. However, results of Oppenheimer's work using radioactively tagged molecules, as reported in this paper, show that polymers were in fact degraded and metabolized after implantation in the rat. ough the amount of breakdown was minute and no . .abolites were identified, the possibility of chemical car cinogenesis was raised. This could be mediated either through 816 degradation products or the intermediate production of free radicals. These products in turn could interact with the nucleic acids, or the nucleic acids could be altered by the newly formed reactive centers in the polymer itself. Several interesting observations have been made by Brand et al.141 In contrast to the rapid and sudden malignant trans formation which may occur with a virus, they suggest that polymer tumorigenesis may be regarded as an evolutionary process. Here a chain of premalignant cell generations forms in which there is a gradual selection for more autonomous clones. This is supported by several findings. It is known that after a polymer is implanted in an animal a capsule develops around it. If the film and the capsule are removed within a cer tain period no tumors develop. Also, if the film alone is removed and the capsule is left in the animal, no tumors develop if this is done before a certain irreversible stage. These observations, and the point at which tumor formation can no longer be prevented by removing the film or film and capsule, are explained by the work reported in this141 and other papers by Brand et al.142 143 They found that two to eight months before the tumor appears premalignant cells have formed. These cells appear to be firmly attached to the film and are not found in the surrounding capsule tissue. Tumorigenic cells then detach from the plastic film and invade the capsule tissue only a few weeks before macroscopic growth of the tumor oc curs. Buoen et al144 reported similar results. They found that premalignant cells could be transferred along with pieces of film five to six months after initial implantation and up to nine months before the tumor appeared grossly. In addition, cells attached to the film did not undergo normal mitosis, suggesting that malignant transformation and maturation occurred in non dividing cells. They, too, reported that capsular tissue remained free of premalignant cells until one month before the gross ap pearance of the tumor. Johnson et al145 studied 49 tumors induced in mice by sub cutaneous implantation of plastic films. Histologically, four classes of tumor were present. These were well-differentiated fibrosarcomas, spindle-cell sarcomas, anaplastic round-cell sarcomas without giant cells, and anaplastic sarcomas with giant cells. Biochemical studies on the capsular tissue have been carried out, and enzyme assays were performed on lactic, malate, and glucose-6-phosphate dehydrogenase activities. These three en zymes had their highest activity one month after polymer im plantation and then dropped to lower levels. Nucleic acid con centrations remained constant or decreased slightly. The soluble collagen was highest in the early stages and then decreased significantly, while the insoluble collagen increased with time until a maximum was reached. It then remained constant or decreased slightly.146 The implications of polymer tumorigenesis are significant from a medical standpoint because the potential carcinogenic hazard from many prostheses is unknown. Plastic sponges have been studied in rats and in human breast implants. Rats which received thin (20 x 20 x 2 mm) implants of "Ivalon" (polyvinyl sponge) developed tumors in 20 months, while those receiving thick implants (20 x 20 x 5 mm) developed tumors after 14 months. Tumors developing from the thick im plants were invaded by spindle-cell sarcomas arising from out side the implant. The human breast implants were studied 4 to Health Hazards of Plastics/Eckardt 18 mo implan similar malign malign the hu time.14' The device* has r& plantec plastic rats. Al tained spiral i months plastic comas the autl in hum rather t Ober polyeth adequa from s> dischar; inflamn quasi-n phocytc pearanc^** chronoi cycle, v biopsie: lesions, Concli Plasti numbei specific these h and eli plastics Refere 1. Ros ed 6. N. Z Err terscienc Church Publishir 3. Patl Vol. 2, e 2377. kk 4. Mai CO in the Pr 258 pp. N 5. Met macof 6 6. Hin 17:129-1 O 7. Bor: 32:426-4! 8. Cor JOM/Vol. I I ] 18 months after implantation. A foreign body reaction to the resins and amine curing agents, AMA Arch Ind Health 20:390-398, implant had occurred with histological inflammatory changes 1959. ( similar to those seen in the rats, but there was no evidence of 9. Demehl CU: Hazards to health associated with the use of epoxy resins, / Occup Med 5:17-21, 1963. > malignant changes. The possibility was raised, however, that 10. Breysse PA: Plastics in automobile body repair shops, Ind Med I malignant transformation may not have occurred only because Surg 30:141-144, 1961. the human implants had been in position for too short a 11. Smyth HF Jr and Weil CS: Chronic oral toxicity to rats of a vinyl time.147 chloride-vinyl acetate copolymer, Toxicol Appl Pharmacol 9:501-504, 1966. I The carcinogenic potential of intrauterine contraceptive 12. Polyvinyl pyrrolidine (PVP) toxicology, Food Cosmetics Toxicol devices (lUD's), many of which are now made from plastic, 1:212-213, 1963. ( has received much attention. Southam and Babcock148 im- 13. Christofano EE et al: The toxicology of modified polyacrylamide | planted various plastic and steel lUD's, as well as sheets of resin. Paper, Eighth Annual Meeting, Society of Toxicology, Williams burg, Va, March 10-12, 1969; Abstr. Toxicol Appl Pharmacol 14:616, plastic from which the lUD's were made, subcutaneously into May 1969. ( rats. All of the plastic lUD's and some of the plastic sheets con- 14. Polytetrafluoroethylene toxicology. Food Cosmetics Toxicol 1:90- j tained barium sulfate. None of the rats with stainless steel 91, 1963. *r spiral ring implants developed tumors for periods up to 26 15. Dernehl CU: Health hazards associated with polyurethane foams, | months. All of the plastics studied, including the three types of I Occup Med 8:59-62, 1966. 16. Konzen RB et al: Human response to low concentrations of p,p' plastic lUD's currently used, induced fibromas or fibrosar- diphenylmethane diisocyanate (MDI), Amer Ind Hyg Assoc I 27:121- | comas when implanted subcutaneously into rats. However, as 127, 1966. the authors state, this does not indicate an oncogenic potential 17. Lowsma HB et al: Effects of respired polyvinylpyrrolidone in humans where the lUD's are placed into the uterine cavity aerosols in rats, Toxicol Appl Pharmacol 9:571-582, 1966. | rather than imbedded in connective tissue. 18. McLaughlin AIG and Bidstrup PL: The effects of hair lacquer sprays on the lungs, Food Cosmetics Toxicol 1:171-188, 1963. Ober149 studied endometrial changes in 208 women using 19. Bergmann M et al: Thesaurosis due to inhalation of hair spray. polyethylene lUD's. After a mean period of 25.1 months, 200 New England I Med 266:750-755, 1962. adequate endometrial biopsies were obtained. In 107 biopsies 20. Kinkel H) and Eder H: Toxicological inhalation studies on the ab from symptomatic patients (bleeding, pelvic pain, and vaginal sorption and excretion of resinous basic components of hair spray, Internat Arch Cewerbepath Cewerbehyg 22{No. 1):10, 1966; Abstr. Bull I discharge), 25.2% showed significant lesions, including diffuse Hyg 41:1080, 1966. | inflammatory changes and atypical glandular hyperplasia with 21. Szende B et al: Pneumoconiosis caused by the inhalation of poly quasi-neoplastic architecture. Minor lesions, including a lym- vinylchloride dust, Med Lavoro 61:433-436, 1970. | phocytosis, minute foci of granulation tissue, focal disap 22. Momotani H: The respiratory deposition of polystyrene in aerosols in man, lapan I Hyg 21:417, 1967; APCA Abstr 13: No. 9463, pearance of glands, and endometrial morphology asyn 1968. chronous by seven days or more from the stated day of the 23. Harris DK: Some hazards in the manufacture and use of plastics, | cycle, were seen in 45.8% of the symptomatic patients. In 93 Brit I Ind Med 16:221-229, 1959. biopsies from asymptomatic patients, 9.7% showed significant 24. Zapp |A |r: Toxic and health effects of plastics and resins. Arch I lesions, and 50.5% showed minor changes. Environ Health 4:335-346, 1962. I 25. Wilson RH and McCormick WE: Plastics. The toxicology of syn thetic resins, AMA Arch Ind Health 21:536-548, 1960. 26. 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I JOM/Vol. 15, No. 10/0ctober 1973 819 24872013 flj > 3 a "CO5D o oc a. co IO rt S O CO >N o XJ CoO < o >< o z C3 c o i5|slftllilgl5 i>..i>.3`i; i Sis*?*'! SS cocci'11 2m 2^' id 8.1'*" ,;3.r-|r > > 'S 2J< wC2j<uCaLt OO oOffl W P * >>" i,* p>: - * -it:-5 =='"- = g u cr c'O <<mW >,^ ^X JP2 1* ? >< Uiso Oo 0" 4 N> Sc3J o H F \dept\all\pfeblank.wp