Perhaps the first documented example of the induction of neoplasia by ionizing radiation was that of atypical epithelial hyperplasias and malignant epitheliomas observed on the hands of ra- diologists and scientists using x-ray devices and radium within a few years after their discovery near the turn of this century. In these cases, the human being was the experimental victim of radiation carcinogenesis. Fortunately, scientists rapidly became aware of the dangers of ionizing radiation and took precautions to prevent its effects in humans.
Radiant energy in our universe comes in a variety of general types, all related to the wave- length and frequency of the waves. A diagram of the electromagnetic spectrum is seen in Figure 3.26. With our present-day knowledge, there is no solid evidence that radiant energy of wave- lengths greater than 5 × 10–5 cm is carcinogenic. However, ultraviolet, Roentgen or x-rays, and gamma rays have carcinogenic effects. In addition, high-energy particles such as electrons, neu- trons, and alpha particles may also exhibit carcinogenic action. A major discussion of the phys-ics of ionizing radiation, radiant or particulate, is beyond the scope of this text, and the reader is referred to more extensive reviews such as those by Upton (1975) and others or to the report of the United Nations Scientific Committee on the Effects of Atomic Radiation (Sources and Ef- fects of Ionizing Radiation, 1977). Although in recent years substantial publicity has been given to the possible carcinogenic effect of electromagnetic field radiation of wavelengths greater than that of visible light, there has been little if any substantial evidence that such radiation is carcino- genic in experimental systems. However, some reports have suggested that low frequency elec- tromagnetic fields may serve to enhance the development of neoplasia by mechanisms that are discussed later in the text (Chapter 12) (Goodman and Shirley-Henderson, 1990).
Since ultraviolet and ionizing radiations are known to have specific mutagenic effects, it has long been assumed that the mechanism of carcinogenesis by such radiation is related to its effects on the genome (cf. Strauss, 1977). A variety of specific radiation-induced lesions in DNA are now known; a number of examples are seen in Figure 3.15. Ultraviolet radiation induces pyrimidine dimers in DNA of two different types (Haseltine, 1983). The cyclobutane type of
Figure 3.26 The electromagnetic spectrum showing the wavelength and frequency of the different classes of radiant energy. (Adapted from Glasser, 1944, with permission of the author and publisher.)
dimer is schematically noted in Figure 3.15, but there also occurs a 4,6 dimer which has signifi- cant mutagenic properties. Ultraviolet radiation also induces single-strand breaks in DNA and potentially protein-DNA crosslinks. Ionizing radiation, as indicated earlier (see above), has the greater propensity to produce DNA strand breaks, both single and double as well as protein- DNA crosslinks and hydroxylation of thymine, guanine, and other bases. In addition, ionizing radiation may cause a decrease in DNA methylation, possibly owing to the hydroxylation of 5-methylcytosine with subsequent repair (Kalinich et al., 1989).
The measurement of ionizing radiation has been of significant interest to physicists as well as physicians ever since the discovery of ionizing radiation and its biological effects. In Table 3.8 are listed many of the units of measurement employed for ionizing radiation. Within the last quarter century, terminology has altered from the original used in the earlier part of this century. Thus, the table indicates both the “old” and “new” units of measurement.
Some of the effects seen in Figure 3.15 may be termed the direct effects of radiation on DNA, such as DNA strand breaks and base elimination. However, there is substantial evidence that ionizing radiation has significant indirect effects that lead to base hydroxylation and other changes, not only of the genome, but also of other cellular structures (cf. Biaglow, 1981). Such indirect effects emanate largely from the formation of highly reactive species of other molecules in the biologic system. The predominant molecule in all biologic systems is water. High-energy irradiation of water leads to the formation of a variety of active molecules including the free radicals ⋅OH and ⋅H, as well as other molecules such as the perhydroxyl radical (HO2⋅) and singlet oxygen, ⋅O2 (Piette, 1991). Such free radicals may react with cellular molecules in ways analogous to those of the “ultimate” forms of chemical carcinogens. Unsaturated fatty acids are converted to free radicals and to lipid peroxides by reaction with these products of the radiolysis of water. Proteins and nucleic acids may also be oxidized and/or converted to free radical forms, which in turn are highly reactive. This may cause the cross-linking of DNA and protein, as indi- cated in Figure 3.15. In addition, the perhydroxyl radical may combine with itself to form hydro-
gen peroxide or may ionize to form the superoxide ion (O2⋅–). Tissues irradiated at higher oxygen tension show greater effects of ionizing radiation than those irradiated at lower oxygen tensions. Although the exact mechanism of this “oxygen effect” is not yet fully understood, it is quite likely that the formation of oxygen radicals is a critical factor.
Other factors more directly related to the nature of the ionizing radiation itself are also important in the genesis of cancer by radiation. It is clear that the likelihood of carcinogenesis depends on the rate of energy loss of charged particles, either as incident radiation or induced by the radiation. This rate of loss is termed the linear energy transfer (LET). Higher LET radiation
is usually more carcinogenic than radiation with a low LET (Wiley et al., 1973). One may also characterize the dose of radiation by its relative biological effectiveness (RBE). Thus, the same doses of neutrons and gamma rays expressed in terms of roentgens have different carcinogenic potencies, the neutrons being more effective and thus having a greater RBE. The importance of these considerations has been documented in a number of studies (cf. Broerse et al., 1989, 1991) in that both LET and RBE are very important for the formation of neoplasms in relation to the radiation dose. The efficiency with which various forms of ionizing radiation induce cellular damage is quite variable and depends, as noted above, on the average density of energy loss along the path of the particle in the biological environment. Some examples of this LET for various sources of radiation are given in Table 3.9 (Tannock and Hill, 1992). The energy loss of a photon or particle as it traverses the biological system is dependent on its velocity, its charge, and the electron density of the target. Thus, as a particle loses energy and slows in its rate, its effective LET increases. Furthermore, the larger the LET of the photon or particle of a given energy, the shorter the distance traveled by the particle in the tissue. As the particle or photon travels through the tissue and interacts with structures within the cell, the energy loss is a sum- mation of these interactive events along the particle track. Such events increase with increasing LET. Obviously, not all structures within the biological system will interact with a particle or photon track so that some will be altered or destroyed where interaction occurs, and others will not be affected in that no interaction with the particle or photon occurs. Such interactions be- come important in consideration of the carcinogenic effectiveness of ionizing radiation in rela- tion to both LET and dose rate, as noted below.
Experimental Radiation Carcinogenesis
Although humans were the first “experimental animals” in which radiation-induced cancer was demonstrated, there are now many examples of the experimental induction of cancer by radia- tion. The experimental induction of skin cancer in mice by Findlay (1928) and later by Rusch
and colleagues (1941) paved the way for a better understanding of the ultraviolet light–induced cancer in patients with xeroderma pigmentosum and in the human population in general (Chapter 12).