Known Physical Carcinogens

Hard and Soft Materials

The category of hard and soft materials includes metals and metallic alloys, synthetic products, and other natural materials in the form of disks, squares, films, and foams. The studies performed in this field are nearly exclusively experimental, and the majority have been made on rats by intratissue implantations, mainly in the subcutaneous tissues, and more infrequently in other sites. The experiments of Minardi and colleagues, Oppenheimer and colleagues, and Nothdurft on squares and disks of metals and plastics are classic. ^{3– 7} For other references, see Hueper, ⁸ Maltoni and Sinibaldi, ⁹ and Maltoni and colleagues. ¹⁰

The most relevant available experimental data on the carcinogenicity of these materials are presented in Table 16.1. The observed tumors arise around implants and are sarcomas of different types: fibrosarcomas (Figure 16.1), rhabdomyosarcomas (Figure 16.2), and osteosarcomas.

Table 16.1

Hard and Soft Materials, of Different Shape and Dimension, Found to Be Carcinogenic When Implanted into Rodents.

Figure 16.1

Fibrosarcoma around an implant of a perforated vitallium disk, in a female Sprague-Dawley rat. Hematoxylin and eosin stain, original magnification × 200.

Figure 16.2

Rhabdomyosarcoma around an implant of an intact vitallium disk in a female Sprague-Dawley rat. Hematoxylin and eosin stain, original magnification × 200.

Studies on the sequence of changes taking place at the site of implants, for reconstructing the histogenesis of sarcomas have shown that the implanted material induces a fibrous reaction that remains apparently unchanged for several months, and may even undergo hyalinization. After several months, the cells in the more internal layer of the fibrous capsule, in direct contact with the implanted material, may start to proliferate (Figure 16.3) and then evolve into the formation of sarcomas. These changes and their sequence take place independently from the nature of the implanted material. ¹¹

Figure 16.3

Cellular proliferation in a fibrous capsule 15 months after implantation of an intact vitallium disk. The edge of the cavity containing the implant represents results of direct contact with the disk. Male Sprague-Dawley rat. Hematoxylin and eosin stain, (more...)

Various investigators have shown that intact films of certain polymers have more potent carcinogenic effects than perforated films of the same polymer of the same shape and are considerably more potent than powdered films. Other investigators, studying a different material, have been unable to confirm such a specific relationship between physical form and carcinogenesis. Testing vitallium in the form of intact disks, perforated disks of the same diameter and thickness, and fragments (in the amount equivalent to the weight of the intact disks), the fragmentation effect has been confirmed but not that of perforation; such disks proved to be as carcinogenic as intact disks (Table 16.2). ^{9, 10}

Table 16.2

Results of Long-term Carcinogenicity Bioassays of Vitallium, in Different Forms, Implanted into Subcutaneous Tissues of Sprague-Dawley Rats.

Surgical prostheses of metals, metallic alloys, and polymers are widely used. Only a few cases of human sarcomas around surgical implants of metals and plastics have been reported in the literature. ¹² More information on the potential carcinogenic risks of surgically implanted hard and soft materials could be provided by programed long-term follow-up of implanted patients.

Fibers

Natural and man-made mineral fibers have been investigated by epidemiologic and experimental studies for possible oncogenicity.

Asbestos

Among the fibrous materials, asbestos has attracted the most attention because of its industrial and commercial relevance (about 3,000 uses) and its diffusion in the occupational and general environment, and because of the early detection of its pathogenicity and carcinogenicity. Six fibrous silicates are currently characterized as asbestos: the fibrous serpentine mineral chrysotile (white asbestos) and the amphiboles actinolite, amosite, anthophyllite, crocidolite (blue asbestos), and tremolite. The most commercially important minerals of asbestos are chrysotile, amosite, and crocidolite. Chrysotile is produced in the largest amounts and is the most widely used and diffused into the environment. In the last several decades, asbestos has been mined at the rate of 3 to 8 million tons per year worldwide. Asbestos has mainly been used in insulating buildings, furnaces and pipes, in the paper industry, in maritime and railway carriers, and in the clutch and brake industry. Its wide use for insulation is the major cause of environmental and occupational exposure.

Because of its great production, numerous uses, and its practical indestructibility, asbestos may be considered ubiquitous. It is present in workplaces, the general environment, and the family environment, where it is brought by exposed workers on their clothes and in their hair. It is found in air, and traces of the mineral have been detected in water (including drinking water), in foods and drugs, and in a variety of consumer products. The following worker categories must be considered exposed: miners and millers of the mineral; manufacturers of asbestos products; laborers who repair, maintain, and clean structures and materials containing asbestos; workers handling waste made of or contaminated with asbestos; and workers and citizens living in an environment polluted by asbestos fibers.

The possible association between asbestos and cancer was suspected for the first time in 1935. In that year, Lynch and Smith described a lung carcinoma in a patient with asbestosis (fibrosis of the lung due to the inhalation of asbestos dust). ¹³ The carcinogenic effect of asbestos fibers of different types on various tissues and organs, both in humans and in experimental animals, is now definitively established by a large number of clinical, epidemiologic, and experimental studies. Several comprehensive reviews on asbestos carcinogenicity are available. ^{14– 17}

The major route of exposure in humans is inhalation. In animals (mainly rats, but also mice and hamsters), asbestos has been tested by inhalation, by intraperitoneal, intrapleural, and subcutaneous injection, and by ingestion. The tumors observed following exposure to asbestos fibers in humans and in experimental animals are listed in Table 16.3. Mesothelioma in its different sites (mainly pleura and peritoneum) is the tumor most specifically connected to asbestos, both in humans and in animals (Figs. 16.4 and 16.5). Mesotheliomas in humans have been found after occupational, environmental, and family exposure.

Table 16.3

Tumors Related to Asbestos Exposure in Humans and Experimental Animals.

Figure 16.4

Tubular epitheliomorphic mesothelioma of the pleura in an Italian railroad machinist. Hematoxylin and eosin stain, original magnification × 200.

Figure 16.5

Tubular epitheliomorphic mesothelioma of the peritoneum of a male Sprague-Dawley rat injected once with 25 mg of Canadian chrysotile in 1 mL H₂O. Hematoxylin and eosin stain, original magnification × 200.

The time of latency of asbestos-correlated tumors is long. In general, tumors start to appear 20 years after start of exposure. In people exposed to asbestos, lung carcinomas and mesotheliomas may be preceded by or associated with lung fibrosis and pleural plaques. These changes represent a marker of asbestos exposure, but a possible role in the natural history of these tumors has not been proved.

The number of occupational groups at risk of asbestos cancer has been growing, and the incidence of asbestos-correlated tumors in some occupational categories has also been increasing in recent years. A clear example of new risk groups, with an increasing frequency of asbestos-correlated tumors, is represented by the mortality due to mesothelioma among workers exposed to asbestos used in the railroads (Table 16.4, and Fig. 16.6), ^{18– 20} and among sugar refinery workers exposed to asbestos used in those factories as a heat insulator (Table 16.5). ^{21, 22} Considering the extent of the railroad network worldwide, there are reasons to anticipate that asbestos cancer among railroad workers may significantly increase.

Table 16.4

130 Cases of Mesothelioma in Italy due to Asbestos Used in Railroads: Distribution According to Category of Population Exposed and Site of Neoplasia.

Figure 16.6

Distribution, by death quinquennium, of 107 Italian cases of mesothelioma following exposure to asbestos used in railroads, showing a progressive increase in mortality.

Table 16.5

12 Cases of Mesothelioma in Italy due to Asbestos Used in Sugar Refinery Plants: Distribution According to Category of Population Exposed and Site of Neoplasia.

Also increasing are the reports of asbestos mesotheliomas due to family contact (see Tables 16.4, 16.5). Mesotheliomas due to environmental asbestos pollution may become a major problem. Three cases of mesothelioma have been reported to arise in housekeepers whose house and neighboring buildings had roofs of corrugated asbestos-cement, ²³ which have been shown to deteriorate under atmospheric corrosion, releasing asbestos fibers.

In experimental systems, the various asbestos minerals (including the serpentine chrysotile) show a similar carcinogenic potency (Table 16.6). There is evidence that each of the major non-neoplastic and neoplastic diseases associated with asbestos in humans is produced by all of the different forms of the mineral, the amphiboles as well as the serpentine (chrysotile). ²⁴

Table 16.6

Results of Long-term Carcinogenicity Bioassays of Sprague-Dawley Rats Injected Into the Peritoneal Cavity with Various Asbestos Minerals.

The diffusion of asbestos minerals in the environment, the number of people exposed, and the high degree of carcinogenicity of these materials make asbestos carcinogenicity a major worldwide problem of public health.

Erionite

Erionite is a fibrous zeolite, whose fibers are similar in dimension to asbestos fibers. Zeolites are crystalline aluminosilicates, in which the primary structures are tetrahedra consisting of either silicon or aluminum atoms surrounded by four oxygen atoms. These tetrahedra combine, linked together by oxygen bridges and cations, to yield an ordered three-dimensional framework. Although there are more than 30 known natural zeolites, only four are fibrous (chabazite, clinoptilolite, erionite, and mordenite). Zeolite minerals are found as major constituents in numerous sedimentary vulcanic tuffs, especially where these were deposited and have been altered by saline lake water. Many hundreds of occurrences have been recorded of zeolite deposits in over 40 countries.

Natural zeolites have many commercial uses, most of which are based on the ability of these minerals to absorb molecules from air or liquids selectively. The exposure of humans can be occupational or environmental.

A vast excess of mortality due to pleural and peritoneal mesotheliomas, both in males and females, constituting 71 to 88% of the cancer deaths and 35–51% of all deaths, has been reported in remote Anatolian villages in the same area where erionite occurs. Lung cancer also appeared to be excessive. ²⁵ The high incidence of mesothelioma and lung cancer has been attributed to the presence of erionite in the soil, road dust, and building stones of the villages. ^{26, 27} Asbestos is not more common in erionite villages than in control villages where the excess of mesothelioma was not found.

It is significant that the registered increase of mesotheliomas in Sweden is partly due to cases of this neoplasm appearing in Turkish migrant workers, probably exposed to erionite at an early age in their own country of origin. ²⁸

A striking predilection to develop mesothelioma from erionite exposure was discovered in the disproportionate representation of certain human leukocyte antigens (HLA) among malignant pleural mesothelioma (MPM) patients compared to nonaffected village residents, and also compared to a referent healthy population (kidney donors). Among MPM patients, HLA-B41 antigen was present in 19.4% compared to 0.8% of villagers and 1.7% of donors (odds ratios [OR] 28.3 and 13.9, respectively). HLA B-58 was also significantly higher (OR 8.6 and 8.5), as was HLA DR-16. These data imply specific risk for certain genotypes and a potential screening tool for special avoidance of fibrous zeolites. ²⁹ Similar studies have not been reported for asbestos exposed populations.

The hypothesis that erionite is the causative agent of the Turkish mesotheliomas, and therefore that it is a human carcinogen, has been supported by experimental evidence. Following inhalation exposure and intraperitoneal and intrapleural injection, erionite causes the onset of peritoneal and pleural mesotheliomas in rats and mice. ^{12, 27, 30, 31} In rats, erionite has been shown to be the most powerful mesotheliomatogenic agent for pleura (Table 16.7).

Table 16.7

Comparative Mesotheliomatogenic Effects on Rat Pleura of Erionite and Asbestos (Crocidolite and Chrysotile) Following Injection in the Pleural Cavity.

The demonstration of the carcinogenic effect of erionite is also of particular relevance considering the large amount and diffusion of natural fibrous and nonfibrous zeolites, their widespread industrial uses, which are expected to increase, and the production of zeolites for several industrial applications (as detergents and as catalysts in the petrochemical and refining industries). A systematic and integrated project of long-term carcinogenicity bioassays of natural and manmade fibrous and nonfibrous zeolites was begun several years ago at the Bologna Institute of Oncology.

Other Natural and Manmade Mineral Fibers

Other fibers include (1) among the natural fibers, wollastonite (a fibrous silicate), attapulgite (a fibrous silicate), and the asbestiform fibers present in commercial talc and (2) among the manmade fibers, glasswool, rockwool, and slagwool (produced by blowing, centrifuging, and drawing molten rock or slag) and ceramic fibers.

Data on the carcinogenicity of natural and manmade fibers is of great public interest because of the various industrial uses (the large majority as asbestos substitutes). At present, more than 5 million tons of manmade mineral fibers are produced annually in more than 100 factories located throughout the world. Glass fiber products comprise over 50% of the total.

Most of the carcinogenicity data come from experimental studies and only to a limited extent from epidemiologic investigations. The experimental bioassays on carcinogenicity have been performed on rodents, mostly rats, but also mice and hamsters, in which the materials were administered by inhalation and/or intrapleural and intraperitoneal injection/implantation. The data on the carcinogenicity of these fibers have been extensively reviewed. ^{2, 15, 27, 32, 33}

Results of the epidemiologic and experimental studies are shown in Table 16.8. Fibrous glass (glasswool) carcinogenicity deserves some comments. This material was and is the most widely used substitute for asbestos. Yet on the basis of the available information, both experimental and epidemiologic, glasswool should be reasonably anticipated to be carcinogenic for humans. The International Agency for Research on Cancer stated that “at least 13 studies demonstrate biologically plausible and statistically significant increases in the incidence of lung cancer and mesothelioma in rats and hamsters exposed to glasswool by various routes using standard scientific methods: intrapleural injection, intrapleural implantation, intraperitoneal injection, and intratracheal instillation.” ³⁴ Three epidemiologic studies on workers employed in fibrous glass manufacturing facilities, one in Canada (one factory), ³⁴ one in United States (17 factories), ^{35, 36} and one in Europe (13 factories), ³⁷ allow the conclusion that glasswool fibers play a role in causing the excess of lung cancer risk observed among those employees. ³⁸ Fibrous glass production and use should be regulated, and prompt measures of prevention should be undertaken.

Table 16.8

Results of Long-term Carcinogenicity Bioassays and Epidemiologic Investigations on Natural (Other Than Asbestos and Erionite) and Man-made Mineral Fibers.

Dacron vascular grafts, although highly oncogenic in rodents, have only rarely been associated with angiosarcomas and malignant fibrous histiocytomas in humans. Since thousands of such grafts have been inserted in the past four decades, it is unlikely that they exert equal oncogenicity across species. ³⁹ Given the serious problems for which the grafts have been used, the oncogenic risk is tolerable. Sarcoma should be entertained in the differential diagnosis of any mass or thromboembolic event associated with a vascular prosthesis.

Mechanisms of Carcinogenesis

It has been hypothesized that physical carcinogens produce cancer by some physical mechanisms rather than by chemical reaction. Such physical mechanisms have been regarded as a mere nonspecific irritative effect of hypothetical surface factors on cells, which could cause cellular proliferation, selection of spontaneously occurring transformed clones, and, finally, neoplasias. In favor of this view, there are several observations and considerations. The ratio between length and diameter of the fibers seems to be crucial in the carcinogenicity of asbestos and manmade mineral fibers. ^{14, 33} For example, the incidence of pleural mesothelioma in rats following a single intrapleural implantation ranged from 0/28 to 20/29, and correlated with fiber size rather than with physicochemical properties: the most carcinogenic fibers were those > 8 μm in length and < 1.5 μm in diameter. ^{44, 45} The form of implanted hard and soft materials, such as polymers and metallic alloys, also appeared to be crucial in some experiments: the carcinogenic effects of these materials is maximal when they are implanted in the form of intact disks, and they seem to decrease sometimes when the disks are perforated or when the material is fragmented. It has been hypothesized that the fibrous reaction observed around implanted disks, squares, and films would “immunologically protect” the transformed clones formed in the core of the capsule, in contact with the implants, therefore favoring the formation of tumors. The physical hypothesis comes from the assumption that the solid carcinogens are inert.

There are, however, other facts that oppose the physical hypothesis as the unique carcinogenic mechanism of physical carcinogens and support a possible contribution of chemical mechanisms. Many plastic polymers (the most specific example of inert material) embedded in tissues undergo progressive deterioration at varying rates, indicating some chemical interaction between the xenobiotic material and biologic substrates. The leaching of microquantities of soluble material out of the physical carcinogens into the body may be sufficient to transform cells that are in intimate contact. The perforation effect has not been confirmed by other investigators nor by us in the course of vitallium disk carcinogenesis. The discrepancy between these experimental results may be explained by different experimental conditions in various laboratories (e.g., the duration of experiments), particularly when one is analyzing experiments performed many years ago, when standards of good laboratory procedures may not have been uniform. The fragmentation effect may be explained by the fact that fragments or powders, after insertion, usually tend to form a compact spherical mass in the tissues, with less surface of interaction with the biologic substrate than the surface area of a disk. Therefore, the chemical mechanism cannot be discarded. Recent data have shown that asbestos (crocidolite and chrysotile) is mutagenic per se (T Hei, C Waldren, personal communication). Moreover, it has been demonstrated that chrysotile fibers have the ability to introduce plasmid DNA into cells, and that this DNA is able to function in both replication and gene expression. The introduction of exogenous DNA into eukaryotic cells could cause mutations in several ways and thus contribute to asbestos-induced carcinogenesis. ⁴⁶

The mechanisms of action of physical carcinogens are not only scientific puzzles; they also have specific practical implications: a chemical mechanism would imply a possible mutagenic effect and therefore a nonthreshold dose. It is therefore a topic that deserves further research.

Electromagnetic Fields

Electromagnetic fields have been the subject of much controversy. Recent extensive studies of electric utility workers show a minimal increase in relative risk of brain tumors (1.12) and of leukemia (1.09) per 10 microTesla years of exposure, although both risks had 95% confidence intervals (CI) that spanned 1.0. ⁴⁷

A meta-analysis of all available studies of childhood leukemia, none of which was individually significant, showed a slight but consistent elevation of OR for association of leukemia with residential magnetic field exposure. ⁴⁸

A study of electromagnetic field exposure during pregnancy and postnatally on the incidence of acute lymphoblastic leukemia up to the age of 14 was carried out retrospectively by interview with 640 mothers and 640 mothers of matched control children. The OR for use of an electric blanket or mattress pad during pregnancy was 1.59 and during childhood was 2.75, both with CI above 1.0. Risks rose with increasing hours of television watching, but, paradoxically, there was no relationship to usual distance from the screen. Similar inconsistencies existed in other multiple comparisons. In a companion study, measured 60-Hz magnetic fields and wire category coding showed no effect.

Indeed, those living in the highest wire-code category homes had an OR of 0.88 compared to the lowest category. The authors from the Division of Cancer Epidemiology and Genetics of the National Cancer Institute caution that these contrary residential data must be considered before ascribing causality to the observed effects of household exposures to electromagnetic fields. ^{49, 50}

Using a different approach, childhood cancer patients were compared to controls for measured magnetic field exposures from ground currents, which are often found in homes with uninterrupted metallic plumbing paths to other houses. The OR for high magnetic exposure was 3.0 (CI 1.3–68) in children who had lived in the same houses throughout the study period, suggesting a positive effect. ⁵¹

The most recent and largest study lends no support to the proposition, however. In the United Kingdom, 3838 cases of childhood cancer of all kinds were compared with 7629 randomly selected age and sex matched controls. Interviews were conducted in all, and electromagnetic field measurements made at home and often at school for 2226 matched pairs. For lymphoblastic leukemia, all leukemia, CNS tumors and all tumors, there was no evidence of greater mean exposure to electromagnetic fields. ⁵²

The avalanche of conflicting data means that this controversial topic will continue to command attention, and clearly the question of causality needs to be solved.

Conclusions

Physical carcinogenesis may be considered an important public health, economic, and social problem because of the wide use of particulate nonfibrous and fibrous industrial materials in the general and domestic environment and workplace, and the frequent and increasing use of xenobiotic implants in plastic, orthopedic, vascular, dental, and other types of surgery.

The dramatic carcinogenic effect of asbestos, the available data about other environmental, industrial, and mineral fibers, the expected introduction of new types of fibrous and nonfibrous materials in the environment, and the expanding use of alloplastic surgery all call for more systematic and critical studies of physical carcinogenesis. When such studies are positive, the consequent measures of control will mainly be preventive. Similarly, and perhaps more acutely, a resolution of the controversy about electromagnetic fields and oncogenesis awaits the critical definitive study.

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