Physical carcinogenesis
Broadly, physical carcinogens comprise a diverse set of agents including electromagnetic radiation of differing energetic levels (ultraviolet and ionizing radiation), temperatures, mechanical trauma, and solid materials.
Mechanistically, physical carcinogens have the capacity to damage cellular DNA either directly, as is the case with electromagnetic radiation, or through chronic trauma and non-specific irritation with consequent oxidative injury (Nelson, 1965; Spadari et al., 1987). Although a vast body of scientific studies has characterized the mutagenic effects of various physical factors, clinical observations derived from human beings exposed to radiation or asbestos serve as foundational evidence for carcinogenesis induction through non-chemical mechanisms. While there is strong evidence linking cancer formation with physical carcinogens, the latency period for cancer formation can often be protracted, even in the range of several decades for humans.With respect to radiation-induced carcinogenesis, differences in energy levels influence the type of DNA alteration. For ultraviolet radiation, a photochemical reaction occurs between intrastrand thymine or cytosine bases in DNA, resulting in molecular lesions termed pyrimidine dimers, which commonly include the formation of cyclobutane pyrimidine dimers and 6,4 photoproducts (Epstein, 1970; Granstein & Sober, 1982). The formation of pyrimidine dimers results in a conformational ‘kink’ in the three-dimensional helical structure of DNA, which requires repair to avert genetic alterations. At least two cellular mechanisms exist for the repair of pyrimidine dimers, including spontaneous photoactivation and repair by nucleotide excision repair mechanisms (Sinha & Hader, 2002). In human beings that have defective nucleotide excision repair, a genetic disease condition called xeroderma pigmentosum, exposure to normal sunlight increases the incidence of skin cancer formation by 1,000-fold (Takebe et al., 1989).
Higher energy electromagnetic radiation, such as ionizing radiation, directly causes damage to nucleotide bases, as well as inducing single- and double-strand breaks in the DNA structure (Ward, 1988). Additionally, ionizing radiation can interact with water molecules within a cell and result in the production of free radicals, which can also damage DNA. The generation of free radicals from ionizing radiation interaction with water is responsible for most (67%) DNA damage induced by radiation therapy. Collectively, the mutagenic and carcinogenic effects of ionizing radiation are principally a consequence of unrepaired or mis-repaired double-strand breaks in DNA, which predispose to global genomic instability and chromosomal aberrations (Hoeijmakers, 2001a, 2001b).Another well-studied physical carcinogen is asbestos exposure. Asbestos is a naturally occurring silicate mineral that exists as a fibrous crystalline with physical properties, including thermal resistance, which historically made asbestos suitable for the fabrication of building materials. The carcinogenic potential of chronic asbestos inhalation in humans, for the development of mesothelioma and bronchogenic carcinoma, has been recognized for over 50 years (Borow et al., 1973). The potential mechanisms for asbestos’s carcinogenic properties have been scientifically proposed and include three non-mutually exclusive theories: (1) oxidative stress theory, (2) chromosome tangling theory, and (3) adsorption theory (Barrett et al., 1989; Toyokuni, 2009). The oxidative stress theory has gained the broadest scientific support, as the role of chronic irritation as a risk factor for carcinogenesis is well characterized (Ohshima & Bartsch, 1994). The oxidative stress theory postulates that free radicals are produced in the immediate microenvironment by asbestos fibers serving as substrates for the Fenton reaction or through the liberation of free radicals (oxidative burst) by tissue resident macrophages that engulf asbestos fibers. As such, asbestos acts as a physical carcinogen through the chronic production of reactive oxygen species and consequent mutagenic changes to the DNA of resident cells. These changes to DNA with the consequent manifestation of malignancy (mesothelioma) occur over long stretches of time, and the average latency period from asbestos exposure and cancer formation is several decades (Frost, 2013).