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Ch21 Physical Carcinogens 21 Physical Carcinogens Morando Soffritti, MD Franco Minardi, MD Cesare Maltoni, MD† †Deceased Broadly, physical carcinogens includes a wide films, and foams. The studies performed in this Table 21-1 Hard and Soft Materials, of Different range of agents: electromagnetic radiations of dif- field are nearly exclusively experimental, and Shape and Dimension, Found to Be Carcinogenic ferent kinds, corpuscular (alpha and beta) radia- the majority have been made on rats by intratis- When Implanted in Rodents tions, low and high temperatures, mechanical sue implantations, mainly in the subcutaneous traumas, and solid and gel materials. More restric- tissues, and more infrequently in other sites. The Metals Gold tively, however, the term is ordinarily used to experiments of Oppenheimer and colleagues and Platinum define solid and gel materials, water-insoluble or of Nothdurft on squares and disks of metals and Silver 3–6 slightly soluble, that are capable of producing can- plastics are classic. For other references see Steel cer. Both physical carcinogens and solid carcino- Hueper,7 Maltoni and Sinibaldi,8 and Maltoni Tantalum gens have been widely used in an oversimplified and colleagues.9 Nickel manner to identify agents that produce cancer Table 21-1 presents the most relevant available Metallic alloys mainly, if not exclusively, through their physical experimental data on the carcinogenicity of these Vitallium (chromium, cobalt, molybdenum) properties and physical effects, rather than materials. The observed tumors arise around Water-insoluble polymers through their chemical properties and actions, as implants and are sarcomas of different types: Hydrocarbon polymers (synthetic) opposed to chemical carcinogens. Physical car- fibrosarcomas (Figure 21-1), rhabdomyosarco- Polyethylene (Polythene) cinogens include hard and soft materials, fibrous mas (Figure 21-2), and osteosarcomas. Polymethylmethacrylate (Lucite) particles, nonfibrous particles, and gel materials. Studies on the sequence of changes taking Polyvinylbenzol (Polystyrol) The first scientific demonstration of the car- place at the site of implants, for reconstructing Cross-linked polyvinyl alcohol (Ivalon) Polyester condensate of terephthalate and cinogenic capacity of physical agents was made the histogenesis of sarcomas, have shown that ethylene glycol (Dacron) by Turner, who found that Bakelite disks, the implanted material induces a fibrous reaction Phenol-formaldehyde condensate (Bakelite) implanted in rats, provoked local fibrosarco- that remains apparently unchanged for several 1 Halogenated-hydrocarbon polymers (synthetic) mas. Anecdotal cases of tumors that arose months, and may even undergo hyalinization. Polyvinyl chloride (PVC, Igelit, Vestolit, Vinnol) around foreign bodies (including bullets in After several months the cells in the more inter- Polyvinylidene chloride (Saran) wartime) were reported earlier. nal layer of the fibrous capsule, in direct contact Polyfluor(chlor)-olefine (Teflon) The identification of physical carcinogens is with the implanted material, may start to prolif- Polymethylmethacrylate chloride (Pliofilm) based on epidemiologic and/or experimental data. erate (Figure 21-3) and then evolve to the forma- Copolymer of vinyl chloride and acrylonitrile The extrapolation of experimental results to tion of sarcomas. These changes and their (Vinyon N, Dynel) humans is improved by the use of experimental sequence take place independently from the Aminized hydrocarbon polymers (polyamides) models as closely equivalent to human situations nature of the implanted material.10 (synthetic) as possible. Experimental intratissue inserts of Various investigators have shown that intact Polyhexamethylene diamine adipanide (nylon) metallic alloys or plastics may well reproduce the films of certain polymers have more potent car- Poly-e-caprolactam, polyurethane (Perlon) situations in which allogenic prostheses are cinogenic effects than perforated films of the Hydrocarbon polymers (semisynthetic and natural) implanted surgically in the human body; con- same polymer and of the same shape, and are Processed latex gum (rubber) Processed polyglucose (cellulose) (cellophane) versely, the inhalation of particulate materials may considerably more potent than powdered films. Processed cellulose (linen, parchment paper) correctly reproduce the exposure of laborers work- Other investigators, studying a different mate- ing in a dusty occupational environment. In the rial, have been unable to confirm such a specific Natural organic materials (silk, keratin, ivory) Silicon polymers (synthetic) preamble of the Reports on Carcinogens of the US relationship between physical form and carcino- Processed polydimethylsiloxanes (silicone National Toxicology Program (NTP), it is stated genesis. Testing vitallium in the form of intact rubber) (Silastic) that (1) known carcinogens are “those substances disks, perforated disks of the same diameter and for which there is sufficient evidence of carcino- thickness, and fragments (in the amount equiva- Mixture of different siloxanes (silicone gel for genicity from studies in humans to indicate a lent to the weight of the intact disks), the frag- prostheses) causal relationship between the agent and human mentation effect has been confirmed, but not that cancer,” and (2) substances reasonably anticipated of perforation: such disks proved to be as car- to be carcinogens to humans are “those substances cinogenic as intact disks (Table 21-2).9 FIBERS Natural and synthetic mineral fibers for which there is limited evidence of carcino- Surgical prostheses of metals, metallic have been investigated by epidemiologic and/or genicity in humans and/or sufficient evidence of alloys, and polymers are widely used. Only a few experimental studies for possible oncogenicity. carcinogenicity in experimental animals.”2 cases of human sarcomas around surgical Asbestos Among the fibrous materials, implants of metals and plastics have been asbestos has attracted the most attention because KNOWN PHYSICAL CARCINOGENS reported in the literature.11 More information on of its industrial and commercial relevance (about HARD AND SOFT MATERIALS The category of the potential carcinogenic risks of surgically 3,000 uses), and its diffusion in the occupational hard and soft materials includes metals and implanted hard and soft materials could be pro- and general environment, and because of the metallic alloys, synthetic products, and other nat- vided by programmed long-term follow-up of early detection of its pathogenicity and carcino- ural materials, in the form of disks, squares, implanted patients. genicity. Six fibrous silicates are currently char- 314 SECTION 3 / Cancer Etiology materials containing asbestos; workers handling waste made of, or contaminated with asbestos; and workers and citizens operating/living in an environment polluted by asbestos fibers. The possible association between asbestos and cancer was suspected for the first time in 1935, when Lynch and Smith described a lung carcinoma in a patient with asbestosis (fibrosis of the lung caused by the inhalation of asbestos dust).12 The carcinogenic effect of asbestos fibers of different types on various tissues and organs, both in humans and in experimental ani- mals, is now definitively established by a large Figure 21-1 Fibrosarcoma around an implant of a perfo- number of clinical, epidemiologic, and experi- Figure 21-3 Cellular proliferation in a fibrous capsule 15 rated vitallium disk, in a female Sprague-Dawley rat. mental studies. Several comprehensive reviews months after implantation of an intact vitallium disk. The Hematoxylin and eosin stain; original magnification ×200. on asbestos carcinogenicity are available.13–16 edge of the cavity containing the implant represents results The major route of exposure in humans is of direct contact with the disk. Male Sprague-Dawley rat. × inhalation. In animals (mainly rats, but also Hematoxylin and eosin stain; original magnification 200. acterized as asbestos: the fibrous serpentine mice and hamsters) asbestos has been tested by mineral chrysotile (white asbestos), and the inhalation, by intraperitoneal, intrapleural, and amphiboles actinolite, amosite, anthophyllite, subcutaneous injection, and by ingestion. Table The absence of a sequential relationship crocidolite (blue asbestos) and tremolite. The 21-3 lists the tumors observed following expo- between asbestosis and lung cancer obliges us to most commercially important minerals of sure to asbestos fibers in humans and in experi- include smokers with a limited exposure to these asbestos are chrysotile, amosite, and crocidolite. mental animals. Mesothelioma in its different mineral fibers in our examination of the role of Chrysotile is produced in the largest amounts sites (mainly pleura and peritoneum) is the asbestos in the onset of this tumor.19 and is the most widely used and diffused into the tumor most specifically connected to asbestos, Outstanding epidemiologic studies show that environment. In the last several decades asbestos both in humans and in animals (Figures 21-4 tobacco smoke enormously increases the car- has been mined at the rate of 3 to 8 million tons and 21-5). Mesotheliomas in humans have been cinogenic effect of asbestos on the lung, as indi- per year worldwide. Asbestos is mainly used in found after occupational, environmental, and cated by Table 21-4. On the basis of available insulating buildings, furnaces and pipes, in the family exposure. knowledge, tobacco smoke
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