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Review Article The Health Hazards of Plastics Robert E. Eckardt, M.D., Ph.D., and Richard Hindin A 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. lohn 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 BaIceland. 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. MeAcal R*ch Oivhkmi, Etw Hnmictt and Engwnng Company, linden. New lenev Reprint requnn to Director. Medical Reiearch Ovmon, Eho teieaich and Engmeenng Company. Box 45. linden. ML 07036 (Or Edtanft) 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 punty 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 m 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 194<7s. 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* 808 37 /s'# /?73 9Of- OLI 2317 moplastic resins, was patented in 1937 in Great Britain and was introduced in the U.5. in 1941. In 1946 polytetrafluoroethylene (PTFE), marketed as Teflon*, became available. It is unusually inert and resistant to all types of chemicals except molten alkali metals. The epoxy resins, derived from ethylene oxide, its homologs or derivatives, are among the newer plastics which have been developed. The prototype of this group was made by direct polymerization of ethylene oxide, which produced a straightchain, thermoplastic polymer. These resins have been used ex tensively as adhesives and in the production of protective coatings.2 The plastics which have been discussed are representative of different groups and are only a few of the many that have been and are being produced and used. From a toxicologist's viewpoint there are numerous health hazards in the manufac ture and use of these plastics. This paper will deal only with hazards associated with the finished product. The hazards of manufacturing processes will not be discussed. The health hazards of plastics can be divided into several broad areas. These include direct toxicity from oral ingestion, respirable particulate inhalation, and the toxicity of additives and unreacted chemicals; dermatological problems; aeroosteolysis; toxicity of thermal decomposition products; hazards from fillers in plastics; and toxicology in medical application. Carcinogenic potentials of plastics will be considered in the iasr section. Direct Toxic Effects It is generally accepted that plastics as a group have a moderately low order of acute toxicity as expressed by their oral LDso's, inhalation hazard, and skin irritation potentials. Certain specific exceptions to this generalization exist, and they will be discussed in this and in later sections of this paper. The purpose of this report is not to list all potential hazards for all of the existing plastics. Rather, groups of plastics will be discussed, along with the problems most frequently associated with them. Many plastics, including polyvinyl chloride, polyvinyl acetate, polyethylene, polystyrene, and methyl methacrylate, are more or less physiologically inert3 Acute oral LDso values are not readily available for them because they have to be ad* ministered in such large quantities that their sheer bulk effects overshadow their toxicity. This is not the case with the starting monomers which have varying degrees of toxicity associated with them. However, since this discussion will be confined to the finished plastic products, the toxicity of individual monomers will not be reviewed except where pertinent. A good review of the hazards of monomers and other reactants may be found in Patty,3 Malten and Zielhuis,4 and -McCollister.5 Many papers have been written on the potential hazards of epoxy resins. In contrast to most other plastics which may be conveniently produced long in advance of their actual use, epoxy resins must be prepared immediately before being used. Because of this, the hazards associated with manufactunng the resins cannot be easily separated from those associated with the finished plastic. Epoxy resins are prepared from two materials. One is the uncured resin which is a polyether with terminal reactive epoxy groups. The other is the cross-linking or curing agent. The uncured resins possess a low order of JOM/Vbl. IS. No. 10/0ctober 1973 toxicity.6 Borgstedt7 noted some central nervous system depression with doses of 1 to 15 gm/kg of the oligmeric (un cured) resin in mice. Cornish and 8lock8 reported data on three uncured resins with acute oral LDvTs ranging between 3 to 4 gm/kg. No other significant hazards have been reported with these resins. In contrast to the uncured resins, a variety of hazards have been reported with the various curing agents used. The most frequently used cross-linking agents are the amines. Aliphatic polyamines which are commonly used include ethylene diamine, diethylene triamine, and methylene tetramme. All are alkaline and are capable of causing extensive, corrosive tissue damage. The most commonly encountered problems arising from amines are skin rash, tenderness, and scaling. These will be discussed more fully in the next section. Another problem which commonly develops is bronchial asthma.' Because the curing reaction may be exothermic, fumes from the reactants often escape and can present a hazard. Also, the cross-linking agent is frequently added in excess in order to drive the reac tion to completion. This may result in unreacted amines being left in the product.7 Grinding, sanding, and polishing epoxy resins present other hazards, including the production of dust and fumes. Breysse10 has reviewed the health hazards from these procedures and has suggested various precautionary measures. Among these are adequate ventilation of working areas and proper personal protection, such as gloves, masks, and protective goggles for the eyes. In more recent work the chronic oral toxicity of a number of plastics has been studied. Vinyl chloride/vinyl acetate copolymers (molecular weight 25,000 to 30,000 by the Staudinger method) fed to rats in 1.5% and 12% of their diets produced no ill effects after two years." A chronic feeding study with polyvinyl-pyrrolidone (PVP) in dogs showed that in amounts up to 10% of their diet no ill effects were produced after two years, although PVP was tentatively identified in the lymph glands.11 A modified polyacrylamide resin was fed to rats at 500, 2,000, and 10,000 ppm in their diets for two years without any significant adverse effects, while a similar study with dogs fed 500, 2,000, and 10,000 ppm showed only questionable findings at the 1% level.11 Polyfluorotetraethylene (PTFE, marketed as Teflon*) was found to have no adverse ef fects on weanling rats at 25% levels in their diet for 90 days.14 Epoxy resins as 1% of a rat's diet for 26 weeks produced no abnormalities, but there was some weight loss. The low oral toxicity of many of these materials may be due to poor gastrointestinal absorption.7 Polyurethanes are another group of plastics whose toxicity is low but whose reactants have undesirable properties. Polyurethanes are basically the product of a reaction between a diisocyanate and a polyol. A catalyst, a blowing agent, and a catalyst accelerator are frequently used in the reaction. The most hazardous material used in the reaction is usually the diisacyanate. A commonly used one is toluene diisocyanate (TDI). This is a strong skin and respiratory irritant, and sen sitivity reactions with asthma-like symptoms along with severe respiratory embarrassment have been produced by it.1' This is primarily a hazard in the manufacture of the polyurethane or in in situ foaming applications of the finished product. However, residual TDI may be present in the foam product and can present a definite potential hazard. If p.p-diphenyimethane diisocyanate (MOI) is used as the isocyanate rather than TDI. sensitivity reactions can also develop16 809 OLI 2318 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 4jut. 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.1* 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 fn*-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 fx, 0 557/z , and 1 305p 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.21 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,22 Zapp,24 Wilson and McCor mick,2* Zieihuis,2* and Maiten 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,2* who also evaluated a number of specific compounds. Of the phthalate plasticizers tested, ten showed no toxic charactenstics, while seven others showed some toxicity. None of the five sebacates tested were toxic. Gtrate 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 nring 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 repotted to have caused a contact dermatitis in several cases. Three dermatological clinical syn dromes due to urea-formaldehyde resins have been noted.10 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.11 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.12 14 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.1* Another case of contact dermatitis was caused by Saran Wrap*, a copolymer of vinyiidine chloride and vinyl chloride. This, too, was confirmed by positive patch tests.1* 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.27 Epory resins are a prevalent source of dermatitis. As in the case of other dermatoses the reaction to the epoxy resins may Haaffli Hazards of Ffastics/Eckardt be con primar. type oi lead tr w i thou into tv. both i \ ft Boumt cold-c been i the ha freque more | were areas } follow \ ted w sent.4 finger paror di- or resint f mole curer mate and and arort trolli due mea SL cau1 core cast in I rest The be nur t siti- \ sea zot 1 ma nor to usi co 4 pr. N \A i n t* c. ( Vk J OLI 2319 be considered as being of two basic types: (1) a toxic or primary irritant due to direct epidermal damage: (2) an allergic type oMtypersensitivity reaction. Also, chronic irritation may lead to a chronic eczematous dermatitis which can persist without continuing exposure.* 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 cold-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.3 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 sent42 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 tandling various agents and con trolling these problems have been reviewed by many, in cluding Bourne4 and Calnan.3* 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 pnmarily 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.4 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 matenals, 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 91 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 lOM/Vol. IS. No. 10A)ctober 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.5* 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 40 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.1 The small metatarsal bones showed periosteal proliferation of cartilagelike 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 disuse and local microtrauma may be important.5 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.2*4 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.5 Other plastics may decompose directly when exposed to 811 OLZ 2320 to heat. For example, phenolic resins are relatively inert but are decomposed by heat to yield products including phenol and formaldehyde.64 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. Gaseous 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.6* 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 decQmposition.*> 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). However, 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, 13% ammonia and 1.3 to 1.4% HCN were released in the pyrolysis products.71 Hara and Matsumura71 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 ther mocutting and sealing of polyethylene tubes included for maldehyde and acrolein7* 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 fort in the chest described more as a feeling of retrosternal op pression 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.78 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 found 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 (CFs) and carbon dioxide. Other fluorocarbons were also found in lesser amounts. Scheel82 has confirmed COFi 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.81 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.88 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 88 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.* The hazards of polymer-fume fever are not limited only to the cases previously described. Since PTFE may decompose above 400F81 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 PJastia/Eckardt OLI 2321 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 Lim et al.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 (CaSOr) filler; (2) fiberglass-reinforced polyester plastic with a calcium carbonate (CaCOt) 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 bail-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 CaCOt 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 20ju to 70p. The plastic dust alone (5) was 3 ft or less in size, while the flake glass was 1ft to 5ft 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 CaCOi than with CaSOs containing fiberglass-reinforced plastics. This was also observed for plastics containing CaCOi 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.92 In another study done by Schepers,94 similar results were obtained. The effects of fiberglass-reinforced plastics have also been studied with regard to their effects on tuberculosis.99 Animals were exposed to fiberglass-reinforced plastic dusts with a CaSOr filler at levels of 399 (range 18-775) x 10* particles/ft1 for ten months or with a CaCOi filler 338 (52-792) x 10* partides/ft1 for 24 months. (Partide size was not specified. However, in a similar report*1 the partide size was less than IOji .) The tuberculosis infection was intensified in both groups but was more severe in the animals wposed to the sample containing CaCOi Other work was repotted on dust generated in the manufac ture of molded automobile body parts made from a fiberglassreinforced polyester plastic Again, similar results were repott 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. IS. No. 10A)dober 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.9* 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 dtug 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.1*0 Chemical reactivity between a drug and its plastic container is a potential problem. Drugs including adrenalin, apresoline, aqua mepbyton, 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 jhort- 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 indude 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.1 Strips of plastic from 48 different devices, mast 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. Crossly 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 al1 studied 50 pieces of currently used plastic tubings, most of wfech 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 OLI 2322 or opaque zone seen grossly around the implant with microscopic evidence of necrosis, eosinophilia, inflammation, giant cells, and fibroendothelial proliferation. Although the toxic components still could not be identified, it appeared that safer additives were being used in the newer tubing, based on the lower incidence of toxic reactions. Tissue reactivity to nylon, Orion (a polymerized acrylonitrile). Dacron (a polyester made from polyethylene terephthalate), Teflon* (PTFE), and Marlex* (trade name for a family of olefin polymers) was studied by implantation into the peritoneal cavity of dogs for seven days. Nylon and Orion both produced numerous adhesions. Dacron produced filmy adhesions, while the .Teflon* caused only a few filmy adhesions. However, it should be noted that the Marlex* was used in the form of tiny pellets, while the other plastics were used in the form of the undyed shredded yarn, the pellets being unavailable.104 Processing of a plastic may also introduce toxic substances into the polymer. This is particularly important where ethylene cnide is used for sterilization of thermolabile plastics. After a brief review of toxic and dermatological problems encountered with ethylene oxide, O'Leary and Guess105 studied the relation ship between the content of the plasticizer di-2-ethylhexylphthalate in a plastic and ethylene oxide sorption. Sorption was found to increase directly as a function of di-2-ethylhexylphthalate content. Data were also presented on ethylene oxide solubility in dimethyl, dipentyl, and dinonyl phthalate. The toxic effects of ethylene oxide on human erythrocytes was studied, and cell culture studies were done on ethylene oxide sterilized polymers. It was also noted that ethylene oxide can function as a solvent for acrylic plastics such as Lucite and Plexiglas. Another hazard associated with ethylene oxide sterilization is the formation of ethylene chlorohydrin. As an alternative method to gamma-irradiation for the sterilization of heat sen sitive materials, ethylene oxide exposure has been valuable. For example, with PVC tubing ethylene oxide sterilization does not cause the discoloration and decomposition effects seen with irradiation. However, Cunliffe and Wesley10* consistently found the toxic substance ethylene chlorohydrin (con centration not reported) in physiological saline or an ticoagulated blood after these fluids had been exposed to PVC tubing previously sterilized with ethylene oxide. Relatively greater amounts of ethylene chlorohydrin were present if the plastic was preirradiated experimentally before being exposed to ethylene oxide. Washing PVC which had only been irradiated revealed small amounts of chloride. Furthermore, if the plastic sterilized with ethylene oxide alone (without prior irradiation) was then not exposed to a fluid containing chloride ions, no ethylene chlorohydrin formed. On this basis, the authors recommended that PVC tubing sterilized by irradiation should be discarded after use. Plastics sterilized with ethylene oxide should be stored for at least a week before being used because of the hazard of residual ethylene oxide on the plastic. Analytical methods for the determination of ethylene oxide and ethylene chlorohydrin m plastics and rubber surgical equipment were discussed by Brown.w Silicones are a group of plastics which have received much attention for their use in cosmetic and prosthetic devices. One area in which silicones have been used is breast mass augmen 814 tation. A number of cases have been reported in which silicone has been injected into the breast with adverse effects. In three such cases reported by Winter et al10B foreign body granulomata resulted. In the first case a giant cell infiltrate oc curred after 18 months. The preparation used was a liquid silicone whose purity was unknown. In the other cases a silicone fluid containing 1% animal and vegetable fats was in jected into the breast or mandible. Again, it could not be deter mined if the reactions were due to the silicone or impurities. In another case report repeated injections of silicone fluid were followed by granulomatous mastitis in two cases. Potential problems include: (1) a local sclerosing granulomatous reac tion with permanent scarring; (2) histiocytosis secondary to carriage of silicones from their site of inoculation to regional lymphatic nodes; and (3) possible carcinogenic activity.10* In a British Industrial Biological Research Association (BIBRA) Bulletin editorial entitled "The Price of Inflation"110 the question of toxicity of silicone fluids for cosmetic injection was discussed. It was noted that, although tumors have been found, a causal relationship has not been proven and that the reactions may be due to contaminants. In discussing the safety of silicone for breast augmentation, Snyderman111 advises against using injectable silicone because of its known ability to migrate to regional lymph nodes. Instead, a silicone bag filled with liquid silicone, which could be removed later if necessary, was recommended to increase breast size. A bibliography on the use of silicones in bandages, blood vessels, prostheses, and organs has been prepared by the National Library of Medicine.112 Plastics have also been used extensively in blood storage bags and in transfusion equipment Extraction and leaching of toxic substances from the plastic is always a potential hazard. Marcel and Noel113 reported that blood stored in plastic trans fusion bags for 4, 8, 15, and 21 days extracted 4, 7, 11.5, and 11.5 mg% of dihexyl phthalate, respectively, jaeger and Rubin114 found that blood stored in bags at 4C for 21 days ex tracted 5 to 7 mg% of the plasticizer di-2-ethylhexylphthalate (DEHP). Also, patients who received these blood transfusions had DEHP levels of 0.025 mg/gm (dry weight) in their spleens and 0.270 mg/gm (dry weight) in the abdominal wall fat. As the authors state, the phthalate ester plasticizers are generally considered to be of a low order of toxicity. However, this is based primarily on the absence of overt toxic symptoms. Therefore, although such tissue levels are not presently known to be associated with toxic manifestations, further work on "subtle toxicides" may reveal hazards not presently recognized. Tissue perfusion with plastic tubing has also been used for assessing plastics toxicity. Several effects have been noted. In one report the normal pulmonary response of increased pulmonary vasculature resistance in response to hypoxia was partially abolished when PVC tubing was used to perfuse isolated cats' lungs. Two types of surgical grade plastic tubing were used, both containing the same plasticizer, acetyl-tri-nbutyl citrate in epoxy soya-bean oil. However, different stabilizers were used, and the tubing containing the cadmiumzinc stabilizer appeared less toxic than the plastic with the oc tyl-tin stabilizer.*15 Atkins et al11* evaluated several types of perfusion apparatus using Eagle's minimal essential medium (MEM) as the per fusate, with bone marrow cultures in agar-gel to test for Healtt Hazards of Plastacs/Eckardt OLI 2323 cytotoxins. Toxic effects were present with polypropylene, plexiglass, and stainless steel apparatus. Specific toxins were not identified. Meyler et al117 used five brands of PVC tubing to perfuse isolated rats' hearts. Three brands of tubing interfered with cardiac function causing negative inotropic effects, arrhythmias, and cardiac arrest Two brands used caused no immediate deleterious effects. The cardiotoxic effects of the PVC were believed to be a result of the stabilizers used. The organotin stabilizer was very toxic, but the barium-cadmium had no observable toxic effect. Specific compounds, however, were not identified. One unique hazard from extracorporeal circulation was reported by Lindberg et al.118 Here, ten human patients died following open-heart surgery during which perfusion was maintained with the DeWall extracorporeal pump-oxygenator. At autopsy, clear refractile emboli were seen in capillaries of the brain, heart, and kidney. These were later identified as the same silicone antifoam material which had been used to treat the surface of the oxygenator column and helical debubbfing chamber. Identical lesions were produced in the kidneys of dogs perfused on the DeWall pump-oxygenator. An unusual problem in the use of plastics occurs when they are used as aortic valve replacements. As Little119 notes, arterial blood is a very efficient oxidizing agent and is also a good hydrolyzing agent. Therefore, any plastic which relies on an antioxidant for stability, like polypropylene, is unsuitable for a heart valve. Leaching may be associated with both short- and long-term hazards. Short-term hazards may occur with prolonged en dotracheal intubation for respiratory assistance. The PVC used in endotracheal tubes contains stabilizers which can leach out of the plastic and cause severe irritation after several days of use. Ethylene chlorohydrin may form if the plastic has been sterilized with ethylene oxide, as discussed previously.110 Guess and Stetson111 have reported an increasing incidence of glottic inflammatory reactions after the use of endotracheal tubes. The toxic substance causing the reactions was identified as an organotin stabilizer. On the basis of these reports, organotin and octyl-tin stabilizers appear to be not only tonic but extractable from plastic tubing. It would therefore appear advisable not to use them as stabilizers in plastics which are to be used for medical application. Long-term leaching hazards occur when lead-stabilized PVC is used for food packaging and for water pipes. The problem of leaching out PVC stabilizers by water was evaluated for a com pound stabilized with 3.77% basic lead phosphite and lubricated with 0.94% basic lead stearate - as ppm of lead were extracted after 18 months at ambient temperature; no lead was extracted with hard water. On this basis, the plastic was judged as being safe for use in pipes containing flawing water.111 Toxicity standards for plastics have been advocated. In ad dition to gross parameters for evaluating toxicity by acute and chronic oral feeding studies. Brewer111 has outlined a series of extraction testing procedures and implantation standards for plastics used in medicine. Guess et al114 have described other methods for evaluating more subtle forms of toxicity. These in dude growth in tissue culture, electron and phase microscopy of tissue that has been in contact with the plastic, hemolytic ef fects, effects on antibody production, and embryonated egg JOM/Vol. IS, No. 10/October 1973 studies. In the data they presented, the plasticizer dimethyl sebacate killed four of the cell cultures but did not affect the growth of chick embryo cells. Butyl octyl phthalate was found to be innocuous in tissue cultures but did produce egg embryo changes. Rosenbluth et alia also found tissue culture methods to be good indicators of toxicity when a cell monolayer technique was used. A good bibliography on these techniques and methods has been compiled by Molzan.116 Plastics and Carcinogenicity An isociation between plastic films implanted into animals and subsequent tumor formation was recognized in the early 1940's. Turner,117 in 1941, implanted Bakelite discs 18 mm in diameter, 1-1/2 mm thick, subcutaneously into rats. After a period of 18 months or more, four of nine rats developed fibrosarcomas. However, for reasons which were unclear, no tumors formed when pieces of Bakelite 10 mm square, 1-1/2 mm thick, were implanted in mice. Several years later Oppenheimer et al128 implanted 2 to 3 cm square pieces of cel lophane subcutaneously into one group of rats and wrapped the kidneys of another group with cellophane. After 11 months, 35.7% of the survivors from the first group developed tumors, and 34.8% of the surviving rats whose kidneys were wrapped in cellophane developed tumors. These tumors could be successfully transplanted into other rats. Out of the 23 primary tumors there were 17 fibrosarcomas, 2 liposarcomas. 1 rhabdomyosarcoma, 1 undifferentiated sarcoma, 1 osteogenic sarcoma, and 1 plasmocytoma. Further work revealed that this tumorigenesis phenomenon was not specific for only a few plastics but occurred with many materials. In a later report Oppenheimer et al119 were able to produce malignant tumors in rats and/or mice using cellophane (which had previously been processed in various ways), polyethylene film, a pure polyethylene film, PVC film, Silastic (a silicone product). Teflon*, Dacron, polystyrene, and nylon film. Oppenheimer et al1M also demonstrated the car cinogenic potential of metals in rodents. Silver, tin, tantalum vitallium, and stainless steel foils in the form of circles or squares 1.5 cm wide (thickness not specified) were implanted into male rats. All of the foils except the tin foil induced tumors. These were identified as fibrosarcomas except for one osteogenic sarcoma induced by vitallium. In contrast to the other metals studied, the tin foil was friable and was found in every case to have broken down into a fragmentary mass. This change in physical form may have been responsible for lack of tumor formation. In other work, Oppenheimer et al111 demon strated that glass coverslips alone produced tumors in 25% of the rats studied, whereas glass powder alone did not produce tumors even when placed into tissue pockets previously for med with coverslips. Polyethylene powder also induced no tumors except in one questionable case. Tumor formation has also been produced by other materials. Thick polyvinyl alcohol ("Ivalon") sponges produced sar comas in 14 of 20 animals.111 Polyurethane in sheet, foam, and powdered forms was capable of inducing tumors both by sub cutaneous and intraperitoneal administration.111 Stinson114 reported that polymethylmethacrylate (Acrylic) and stainless steel discs implanted into guinea pigs produced metaplastic bone changes, while malignancies were produced in rats. The mechanism responsible for polymer tumorigenesis is un- 815 OLI 2324 dear. Numerous observations have been made, and several theories have been proposed to explain it. One theory suggests that carcinogenesis is due to the physical properties of the im planted film and that it is a nonspecific phenomenon not dependent pnmarily 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 fi pore size filters was comparable with nonporous materials. Pore sizes of 1 t and larger almost completely prevented tumors, while in the intermediate range (0.1 to 0.4S u) there was an inverse relationship between pore size and tumor incidence. Goldhaber137 reported similar ob servations. After 18 months Millipore filters of 50 mp and 100 m(i were found to cause 60% and 52.9% tumors in mice. When the pore size was increased to 450 mp, only 5% developed tumors.137 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 been studied by Bates and Klein.1W Using polyethylene discs 20 mm in diameter and 0.015 inches thick, a significantly higher incidence of sarcomas formed in micfe 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. Oppenhetmer 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 macromoiecule 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 ngidily of the film. However, results of Oppenhetmer's work using radioactiveiy tagged molecules, as reported in this paper, show that polymers were in fact degraded and metabolized after implantation in the rat. Although the amount of breakdown was minute and no metabolites 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.141 143 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.'* 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 OLX 2325 18 months after implantation. A foreign body reaction to the implant had occurred with histological inflammatory changes similar to those seen in the rats, but there was no evidence of malignant changes. The possibility was raised, however, that malignant transformation may not have occurred only because the human implants had been in position for too short a time.147 The carcinogenic potential of intrauterine contraceptive devices (lUD's), many of which are now made from plastic, has received much attention. Southam and Babcock146 im planted various plastic and steel lUD's, as well as sheets of plastic from which the lUD's were made, subcutaneously into rats. All of the plastic lUD's and some of the plastic sheets con tained barium sulfate. None of the rats with stainless steel spiral ring implants developed tumors for periods up to 26 months. All of the plastics studied, including the three types of plastic lUD's currently used, induced fibromas or fibrosar comas when implanted subcutaneously into rats. However, as the authors state, this does not indicate an oncogenic potential in humans where the lUD's are placed into the uterine cavity rather than imbedded in connective tissue. Ober,w studied endometrial changes in 208 women using polyethylene lUD's. After a mean period of 2S.1 months, 200 adequate endometrial biopsies were obtained. In 107 biopsies from symptomatic patients (bleeding, pelvic pain, and vaginal discharge), 25.2% showed significant lesions, including diffuse inflammatory changes and atypical glandular hyperplasia with quasi-neoplastic architecture. Minor lesions, including a lym phocytosis, minute foci of granulation tissue, focal disap pearance of glands, and endometrial morphology asyn chronous by seven days or more from the stated day of the cycle, were seen in 45.8% of the symptomatic patients. In 93 biopsies from asymptomatic patients, 9.7% showed significant lesions, and 50.5% showed minor changes. Conclusion Plastics serve many useful and vital functions in a wide number of areas. They are associated with both general and specific hazards in their manufacture and use. A knowledge of these hazards as outlined in this paper is important for control and elimination of these problems in the safe handling of plastics. References 1. Rose A and Rose E, editors: The Condensed Chemical Dictionary, ed 6. New York, Reinhold Publishing Corp. 1961. 2. Encyclopedia of Chemfcaf Technology. New York. The Interscience Encyclopedia, Inc. 10*.800-B14. 1951 Also, Simoods HR and Church |M: A Concise Guide so flashes, cd 2- New York, Remhoid Publishing Corp, 1963. 3. Patty FA. editor: Industrial Hygiene and Toxicology: Toxicology, Vot. 2, ed 2 (Rev). New York, Interscience Publishers, 1963, pp. 8312377 4. Malten KE and Zielhuis RL: Induseial Toxicology and Dermaaology m die Production and Processing of flasecs. New York, Elsevier, 1964, 258 pp. 5 McCoilister DD et al: Toxicology of acrylamide, Toxicol Appl Phar macol 6 172-181, 1964. 6. Hine CH et al: The toxicology at epoxy resins, Arch Ind Health 17:129-144, 1958. 7. Borgstedt HH: The toxic hazards of epoxy resins, Ind Med Surg 32:426-429, 1963. 8. Cornish HH and Block WD: The toxicology ot uncured epoxy JOM/Vof. 15, No. 10/0ctotwr 1973 resins and amine curing agents, AMA Arch Ind Health 20:390-398, 1959. 9. Demehl CLJ Hazards to health associated with the use ot epoxy resins, / Occup Med 5:17-21, 1963. 10. Breysse PA: Plastics m automobile body repair shops, Ind Med Surg 301 41-144, 1961. 11. Smyth HF |r and Weil CS. Chronic oral toxicity to rats of a vinyl chloride-vinyl acetate copolymer, Toiticol Appl Pharmacol 9:501-504, 1966 12. Polyvinyl pyrrolidine (PVP) toxicology, food Cosmetics Toxicol 1:212-213, 1963. 13. Christofano EE et al: The toxicology of modified polyacrylamide resin, Paper, Eighth Annual Meeting, Society of Toxicology, Williams burg, Va, March 10-12, 1969; Abstr. Toxicol Appl Pharmacol 14:616, May 1969. 14. Polytetrafluoroethylene toxicology, food Cosmetics Toxicol 1:90- 91, 1963. 15. Demehl CU: Health hazards associated with polyurethane foams, I Occup Med 8:59-62, 1966. 16. Konzen RB et al: Human response to low concentrations of p.p- diphenylmethane diisocyanate (MDI), Amer Ind Hyg Assoc I 27:121127, 1966. 17. Lowsma HB et al: Effects of respired polyvinylpyrrolidone aerosols in rats, Toxicol Appl Pharmacol 9:571-582, 1966. 18. McLaughlin AIG and Bidstrup PL: The effects of hair lacquer sprays on the lungs, food Cosmetics Toxicol 1:171-188, 1963. 19. Bergmann M et al: Thesaurosis due to inhalation of hair spray, New England I Med 266:750-755, 1962. 20. Kinkel H| and Eder H: Toxicological inhalation studies on the ab sorption and excretion of resinous basic components of hair spray. Inremat Arch Cewerbepath Gewerbehyg 22(No. 1):10, 1966; Abstr. Bull Hyg 41:1080, 1966. 21. Szende B et al: Pneumoconiosis caused by the inhalation of poly vinylchloride dust, Med Lavoro 61:433-436, 1970. 22. Momotani H: The respiratory deposition of polystyrene in aerosols in man, lapan I Hyg 21:417, T967; APCA Abstr 13: No. 9463, 1968. 23. Harris DK: Some hazards in the manufacture and use of plastics, Brit I Ind Med 16:221-229, 1959. 24. Zapp IA (r: Toxic and health effects of plastics and resins. Arch Environ Health 4:335-346, 1962. 25. Wilson RH and McCormick WE: Plastics. The toxicology of syn thetic resins, AMA Arch Ind Health 21:536-548, 1960. 26. Zielhuis RL: Systemic toxicity from exposure to epoxy resins, hardeners, and styrene, / Occup Med 3:25-29, 1961. 27. Moizon AE: Plaslec Note 5: Health Hazards and Toxicity oil Plastics: A Cross-Indexed Bibliography, Dover, New lersey. Plastics Tech Evaluation Center, Picatinny Arsenal, 1962, 20 pp. 28. Guess WL and Haberman 5: Toxicity profiles of vinyl and poiyolefinic plastics and their additives, I Biomed Mat Res 2:313-335, 1968. 29. Key MM: Occupational dermatitis from plastics, I Med Assoc ot Georgia 57:421-24, 1968. 30. Harris DK: Health problems in the manufacture and use ot pushes. Brit / Ind Mid 10.255-268, 1953. 31. tack SM and Palitz LL: Sensitization to facial tissues with ureaformaldehyde resin (wet-strength), IAMA 160:1226, 1956. 32. Gaul LE: Absence of formaldehyde sensitivity in phenol-formal dehyde resin dermatitis. I Invest Derm 40:405, 1967; Abstr. Bull Hyg 42:1079, 1967. 33. Betrens L et al: Free formaldehyde in textiles in relation to for malin contact sensitivity, Bnt I Derm 76:110. 1964: Abstr. food Cosmetics Toxicol 2.622, 1964. 34. Malten KE: Textile-finish contact hypersensitivity. Arch Derm 09:215, 1964: Abstr. food Cosmetics Toxicol 2:622. 1964. 35. tagum |S: Contact dermatitis from plastics containing tn-aryt phosphates. Brit / Derm 70:626. 1966; Abstr. food Cosmetics Toxicol 5:830, 1967. 36. Osbourn RA; Contact dermatitis caused by saran wrap. JAMA 1001159. 1964. 37. Moms GE: Nylon dermatitis. New England / Med 263:30, 1960. 38. Calnan CD: Dermatitis (tom epoxy resin systems, Trans Assoc Ind Med Officers 13:38-41, 1963 39. Bourne L8. Milner FIM and Albetman KB: Health problems of epoxy resins and amine-cunng agents, Bnt / Ind Med 16 81-97, 1959 817 OLI 2326 40. Grandiean 6 The danger of dermatoses due to cold-setting ethoxyline resins (epoxide resins). Brit I Ind Med 141-4, 1957 41. Stevenson Cl Epoxy resin dermatitis. The current position, Ann Occup Hyg 8.127-130, 1965 42. Gaul LE. Prevalence of epoxy resin dermatitis, Arch Derm 96.227230, 1967. 43. Morns GE: Allergic rhinitis acquired during the processing of epoxy resins. Annals of Allergy 17 74-75, 1959. 44. Birmingham Q|- Clinical observations on the cutaneous effects associated with curing epoxy resins, AMA Arch Ind Health 19:365-367, 1959. 45. Broughton WE: Epoxy resins in industry. The hazards and their control, Ann Occup Hyg 8 1 31-142, 1965. 46. Bourne LB: Epoxide resins. Epoxide resins and amine catalysts. Chem & Ind No. 19:578-579. 1957. 47. Porter PS, Contact dermatitis due to spandex. Arch Derm 95 666, 1967 48. Allenby CF et al. Contact dermatitis from spandex yam, 8nt Med I 1:674, 1966 49. Fisher AA Allergenic elements in spandex garments, /AMA 201:894, 1967. 50. loseph HL and Maibach HI: Contact dermatitis from spandex brassieres, IAMA 201:880-882, 1967 51. Porter PS and Sommer RG. Contact dermatitis due to spandex, Arch Derm 95:43-44, 1967. 52. Carr RD: Spandex dermatitis. Arch Derm 96:642-645, 1967. 53. Wilson RH et al: Occupational acroosteoiysis: Report of 31 cases, IAMA 201:577-581, 1967. 54 Marin A et al: Occupational acro-osteolysis. Revue de Rhumatisme 34 340-351. 1967; Abstr. Occup Safety Health Abstr 6.373, 1968. 55. Benoit IP* Occupationally-Induced Acro-osteolysis, Lyon, France, Impnmene Bose Freres, 1967, pp 88; Abstr. Occup Safety Health Abstr 6:738, 1968 56. Kovac A et al: Acropathy of the extremities associated with vinyl chloride polymenzation--a new occupational disease, Ufecntcki Vjesnik 91:5-17, 1969; Abstr. Occup Safety Health Abstr 7:427, 1969. 57. Dinman BO et al: Occupational acroosteoiysis--a clinical in vestigation of polyvinyl chloride synthesis workers, Proceedings, XVI Int'l Congress on Occup Health, Tokyo, lapan. Sept. 22-27, 1969, pp. 293 2% 58. McCord CP. A new occupational disease is bom, / Occup Med 12:234, 1970, 59. Hams DK and Adams WGF: Acro-osteolysis occurring in men engaged in the polymenzation of vinyl chlonde. Brit Med 13:712-714, 1967. 60. Cordier |M et al: Acro-osteolysis and associated skin lesions in two workmen employed to dean autoclaves. Cahiers de Medicine du Travail 4.1-39. 1966. 61. Viola. PL1 Pathology of vinyl chloride, Med lavoro 61.174-180, 1970. 62. Dinman BO et al. Occupational acroosteoiysis I. An epidemiological study. Arch Environ Health 21:61-73, 1971. 63. Cook WA et al: Occupational acroosteoiysis. II. An industrial hygiene study, Arch Environ Health 22:74-82, 1971. 64. Dodson VN et al: Occupational acroosteoiysis. III. A clinical study, Arch Environ Heaftri 22:83-91, 1971. 65. The hazard of tome gases from combustion of roentgen-ray Aims, IAMA 92.1764. 1929. 66. Effects of plastic dust Brit Med 1 1:42. 1963. 67 Cleary WM Thermoplastic resins decomposition. Mich Occup Health 14 5-6. Spnng 1969 68 Stankevich W and Ivanova ZV: Toxicity and hygienic stan dardization of substances formed from the thermal destruction of polymers. SB, From Toksikol i Klmika Prof Zabofevarm Kfxm Etiof 1962. p 141-144. Abstr Chem Abstr 6111230, 1964. 69. Hazardous product produced by electneal insulation. NB5 Technical News Bulletin 54 54. March 1970. 70 Tsuchiya Y and Sumi K Thermal decomposition products of polyvinyl chloride, / Appl Chem 17 364. 1967; Abstr food Cosmetics Toxicol 7 391. 1969 71 Cornish HH and Abar EL Toxicity of pyrolysis products ot vinyl pfasites. Arch Inviron Health 19:15*21, 1969 72. Lohs Kh The thermal decomposition of polyacrytonitnie fibers 818 into prussic acid as potential source of poisoning, Zentr Arbeitsmed Arbeitsschutz 14,287, 1964, Abstr. Chem Abslr 62:12355e, 1965. 73. Hara N and Matsumura Y- Production of hydrogen cyanide by heating of bindeis, Ind Health 2:208, 1964. 74. A summary of decomposition products, Mich Occup Health 7:3, Spring 1962. 75. Hovding C: Occupational dermatitis from pyrolysis products of polythene, Acta Dermatovenereologka No. 49:147,1969; Abstr. Occup Safety Health Abstr 8:726, 1970. 76. Hams DK: Polymer-fume fever, Lancet 2:1008, 1951. 77. Gualtier M et at: Polymer fever--physiopathological and diagnostic problems, Archives des Maladies Professtonnelles 31:237-' 241, 1971; Abstr. Occup Safety Health Abstr 9:52, 1971, 78. Robbins )| and Ware RL: Pulmonary edema from teflon fumes. Report of a case. New England / Med 271.360-361, 1964. 79. Bimbaum HA et al. The toxicology of the pyrolysis products of polychlorotrifluoroethylene. Amer Ind Hyg Assoc I 29.61-65, 1968, 80. Want! RS and Kwon BK: The inhalation toxicity of pyrolysis products of polytetrafluoroethylene heated below 500C, Amer Ind Hyg Assoc I 29:19-26, 1968. 81. Coleman WE et al: The identification of toxic compounds in the pyrolysis products of polytetrafluoroethylene (PTFE), Amer Ind Hyg Assoc / 29:33-40, 1968. 82. Scheel LD et al: The toxicity of polytetrafluoroethylene pyrolysis products--including carbonyl fluoride and a reaction product, silicon tetrafluoride, Amer Ind Hyg Assoc I 29:41-48, 1968. 83. Polytetrafluoroethylene toxicology. Food Cosmetics Toxicol 1:9091, 1963. 84. Boettner EA and Weiss B: An analytical system for identifying the volatile pyrolysis products of plastics, Amer Ind Hyg Assoc I 28:535540, 1967. 85. Barnes R and (ones AT: Polymer-fume fever, Med / Aust 2:60-61, 1967; Abstr. /AMA 201(No. 8)192, 1967. 86. Lewis CE and Ketby GR: An epidemic of polymer-fume fever, IAMA 191:375-378, 1965. 87. Welti DW and Hipp M|: Polymer-fume fever. Possible relation ship to smoking, I Occup Med 10:667-671, 1968. 88. Bruton DM: Polymer-fume fever, Brit Med I 1:757, 1967. 89. "Polymer-fume fever" in Connecticut, Nat Clearinghouse lor Poison Control Centers Bulletin, Oct. 1961, p. 1-4. 90. Nuttall IB et al: Inflight toxic reactions resulting from fluorocarbon resin pyrolysis. Aerospace Med 35:676-683, 1964. 91. Lim I et al: Fiber glass reinforced plastics. Associated oc cupational health problems. Arch Environ Health 20:540-544. 1970. 92. Schepers CWH et al: The biological action of fibeiglas-pfastic dust (an experimental inhalation study of the dust generated in the manufacture of automobile body parts from a commercial product with a calcium carbonate filler), AMA Arch Ind Health 18:34-57, 1958. 93. Schepers CWH: The pathogenicity of glass-reinforced plastics, Arch Environ Health 2:620-634, 1961. 94. Schepen GWH: Pulmonary histologic reactions to inhaled flbeiglas-plaslic dust. Amer I Pathol 35.1169-1187, 1959; Abstr. APCA Absb 7: No. 3947, 1961. 95. Schepers GWH: Influence of fibeiglas-plastic dust on tuber culosis; an experimental inhalation study of two variables of dust. Histopathologic observations, Amer Rev Tuberc Pulmonary Dis 78:512523, 1958; Abstr. APCA AbsW S: No. 2639, 1959. 96. Hams DK; Medical and surgical applications of plastics, Chem A Ind 8.236-242. 1968. 97. Autian I: Toxicological aspects of implants, / Biomed Mat Res 1:433-449. 1967. 96. Autian I: Toxicity, untoward reactions, and related considerations in the medical use oil plastics, / Phatm Set 53:1289-1301, 1964. 99. Bishop WR and Autian |: Modem Plastics Encyclopedia 1970-71. Toxicology d Plastics in Medicine 47. No. 10A:8. Oct. 1970. 100. Autian k Drug packaging in plashes. Drug A Cosmet Ind 102:5462. 154-158, April 1968. 101. Guess Wl et al: Drugs which discolored plastics. Amer / Hosp Phatm 22.181. 1965. 102. Lawrence WH ei al Toxicity of plastics used in medical prac tice. I. Investigation of tissue response in animals by certain unit packaged polyvinyl chloride administration devices, f Pharm Set 52 958-963. 1963 103 Lawrence WH et al Re-evaluation of plastic tubings currently Health Hazards of Ptajtics/Eckardt OLI 2327 used in medical and paramedical applications, / Biomed Mat Res 3.291-303. 1969. 104, Usher FC and Wallace SA: Tissue reaction to plastics. A com parison of nylon, orlon. dacron, teflon, and marlex, AMA Arch Surg 76:997-999, 1958. 105 O'Leary RK and Guess WL. The toxicogenic potential of medical plastics sterilized with ethylene oxide vapors, / Biomed Mat Res 2:297- 311, 1968. 106. Cunliffe AC and Wesley F: Hazards from plastics sterilized by ethylene oxide, Brit Med / 2:575-576, 1967, 107 Brown D|: Determination of ethylene oxide and ethylene chlorhydrin in plastic and rubber surgical equipment stenlized with ethylene oxide, I Assoc Off Analyt Chem 53 263, 1970. 108. Winer LH et al: Tissue reactions to injected silicone liquids. Arch Derm 90-588-593, 1964. 109. Symmers WStC Silicone mastitis in "topless" waitresses and some other varieties of foreign-body mastitis, Bnt Med I 3:19-22, 1968. 110. The price of inflation, BIBRA Bull 7:266, 1968. 111. Snyderman RK: Is injectable silicone safe for breast augmen tation? /AMA 215,303-304, 1971. 112. Toxicology of Silicone Plastics. Mid-1963 - June 1965. New Bibliographic Series No. S.B. 13-65. Washington, O.C, Bibliographic Services Div., Nat'l Library of Med., 1965, 4 p. 113. Marcel YL and Noel 5P: Contamination of blood stored in plastic packs, Lancet 1:35-36, 1970. 114. Jaeger Ri and Rubin RJ: Plasticizers from plastic devices: Ex traction. metabolism, and accumulation by biological systems, Science 170:460-461, 1970. 115. Duke HN and Vane IR- An adverse effect of polyvinylchloride tubing used in extracorporeal circulation. Lancet 2:21-23, 1968. 116. Atkins RC et al: Cytotoxins released from plastic perfusion ap paratus, Lancet 2:1014-1015, 1968. 117. -Meyler FL et al: The influence of polyvinyl Chloride (PVQ tubing on the isolated perfused rat's heart Circulation Res 8:44-46, 1960. 118. Lindbeig DAB et al: Silicone embolization during clinical and experimental heart suigery employing a bubble oxygenator, Amer / Pathol 39:129-144, 1961. 119. Little K: Stricter rules needed for medical plastics. New Scientist p. 118-119, 1969. 120. Hazards of prolonged intubation and tracheotomy equipment JAMA 204:624-625, 1968. 121. Guess WL and Stetson IB: Tissue reactions to organotinstabilized polyvinyl chiande (PVC) catheters, /AMA 204:580-584,1968. 122. Chancellor SF: Toxicity of plastics, Nature 185:841, 1960. 123. Brewer |H; Toxicity sandards for plastics. Bull Parenteral Assoc 19:22-28, 1965. 124. Guess WL et al: Characterization of subtle toxicity of certain plastic components used in manufacture of the polyvinyls, Amer I Hosp Pharm 24:495-501. 1967. 125. Rosenbluth SA et al: Tissue culture method for screening toxicity of plastic materials to be used in medical practice, / Pharm Sci 54:156159. 1965. 126. Moizon AE: Plastec Note 4: Pfaides in the Medical Industry: A Cross-Induced Bibliography. Dover, New lersey. Plastics Tech. Evaluation Center, Picatinny Arsenal. 1962, 46 pp. 127. Turner FC Sarcomas at sites of subcutaneously implanted bakelite disks in rats, / Nat Cancer Inst 2.81, 1941. 128. Oopenhetmer BS et al: Sarcomas induced in rats by implanting cellophane, Proc 5oc Bxptl Biol Med 67:33*34, 1948. 129. Oppenhetmer BS et al: Malignant tumors resulting from em bedding plastics in rodents. Science 118:305-306, 1953. 130. Oppenheimer BS et al: Carcinogenic effect of metals in rodents, Cancer Res 16:439-441, 1956. 131. Oppenheimer ET et al: Observations on the effects of powdered polymer in the carcinogenic process, Cancer Res 21:132-134, 1961. 132. Polyvinyl sponge implants and malignancy, Lancet 2:653, 1962. 133. Hueper WO Experimental production of cancer by means of implanted polyurethane plastic. Amer I Clin Pathol 34 328-333, 1960. 134. Stinson NE: The tissue reaction induced in rats and guinea-pigs by polymethylmethacrylate (acrylic) and stainless steel, Bntl Fxp Pathol 45:21, 1964; Abstr. Food Cosmetics Toxicol 2:503-504, 1964. 135. Perilous plastics? Food Cosmetics Toxicol 3:512-515, 1%5. 136. 8rues AM et al; Influence of porosity on sarcoma production by subcutaneous implants, Abstr. Proc Amer Assoc Cancer Res 10. No. 38, 1969. 137. Goldhaber P: Further observations concerning the car cinogenicity of millipore filters, Abstr, Proc Am Assoc Cancer Res 4: No. %, 1962. 138. Goldhaber P: The influence of pore size on carcinogenicity of subcutaneously implanted millipore filters, Abstr. Proe Am Assoc Can cer Res 3: No. 100, 1961. 139. Bates RR and Klein M: Importance of a smooth surface in car cinogenesis by plastic film, J Nat Cancer Inst 37:145-152. 1966, 140. Oppenheimer BS et al: further studies of polymers as car cinogenic agents in animals. Cancer Res 15:333-340, 1955. 141. Brand KG et al: Malignant transformation and maturation in nondividing cells during polymer tumorigenesis, Proc Soc (xpd Biol Med 124:675-678, 1967. 142. Brand KG et al: Premalignant ceils in tumorigenesis induced by plastic film, Nature 213:810, 1967, 143. Brand KG et al: Carcinogenesis from polymer implants: New aspects from chromosomal and transplantation studies during premalignancy, / Nat Cancer Inst 39:663-679, 1967. 144. Buoen LC et al: Studies on polymer tumorigenesis, Abstr. Fed Proc 26:626, 1967. 145. (ohnson KH et al: Polymer tumorigenesis: Clonal determination of histopathoiogkal characteristics during early preneoplasia: rela tionships to karyotype, mouse strain, and sex, I Nat Cancer inst 44:785- 793, 1970. 146. Danishefsky I et al: Biochemical changes in the connective tissue pocket surrounding subcutaneously imbedded films. Cancer Res 27:633-837, 1967. 147. Possible carcinogenicity of plastic sponges, Brit Med 12:1595- 15%, 1962. 148. Southern CM and Babcock VI: Induction of subcutaneous tumors in rats by plastic loops and spirals, Amer I Obit Gynecol 96:134-139, 1966. 149. Ober WO; Endometrial morphology and polyethylene in trauterine devices, Obstet Gynecol 32:782-793, 1968, mm. IS, No. 10/0ctotar 19/3 819 OLI 2328