Chemical carcinogenesis
Early evidence for the potential of chemicals to act as carcinogens was first observed in the late 18th century by two scientists named John Hill and Percivall Potts, a botanist and surgeon by profession, respectively.
First, Hill observed that the aristocratic elite in England who preferentially used ground powdered tobacco leaves as ‘snuff’, as opposed to the smoking of cigarettes by commoners, were more likely to develop symptoms of nasal cancer (Redmond, 1970). Shortly after, Potts reported an association between exposure to chimney soot and scrotal squamous cell carcinoma development in young boys who worked as chimney sweeps (Brown & Thornton, 1957). These two early clinical observations made by Hill and Potts supporting the potential for chemical carcinogenesis were later validated scientifically in the early 20th century through detailed studies by a Japanese pathologist named Katsusaburo Yamagiwa. In a series of in-vivo experiments, a highly reactive chemical species called benzo[a]pyrene, a polycyclic aromatic hydrocarbon found in coal tar, was topically painted onto the inner ear surface of rabbits chronically over a course of months, with the resultant development of squamous cell carcinoma (Yamagiwa & Ichikawa, 1977). Based on the experimental findings reported by Yamagiwa, a ‘cause and effect’ relationship was established between exposure to certain chemicals and the consequent development of cancer. These original seminal findings reported by Yamagiwa served as a foundation for establishing the National Toxicology Program under the US Department of Health and Human Services, which provides a current and cumulative list of 243 chemicals that have been identified as known carcinogens or reasonably anticipated to behave as carcinogens (National Toxicology Program, 2011). Building upon this infrastructure, the National Toxicology Program has launched Toxicology in the 21st Century (Tox21), an automated high throughput screen of potentially mutagenic compounds that are found in today’s industrialized world (Jeong et al., 2022).In addition to the list of known chemical carcinogens, many reactive chemical agents derived exogenously or endogenously through the cellular metabolism of dietary nutrients have the potential to participate in chemical carcinogenesis. Despite the multiple sources of chemical agents, mechanistically chemical carcinogens share a common mode of action: the creation of electrophilic substrates that have the capacity to react with nucleophilic sites in the purine and pyrimidine rings of nucleic acids. Specifically, chemically reactive carcinogens exert their effects by adding functional groups that form covalent bonds with DNA. The resultant chemically modified bases, called DNA adducts, can distort the organized helical structure of DNA, which in turn can promote errors in DNA replication and consequent gene mutations (Chambers, 1985; Hemminki et al., 1986; Rabes, 1986). Interestingly, the purposeful formation of DNA adducts is the basis for how some chemotherapeutic agents, such as alkylating agents, are used to fight cancer. Food and Drug Administration regulation of new alkylating agents includes the incidence of secondary malignancies, an unwanted side effect of persistent DNA adduct formation in normal tissues that can ultimately lead to cancer formation (Demoor-Goldschmidt & de Vathaire, 2019).
The ability of chemical carcinogens to act as electrophiles can be inherent (ultimate carcinogen) or require cellular metabolism with the consequent formation of reactive chemical species. Given that some xenobiotic chemicals require metabolic conversion prior to elimination, gene polymorphisms that influence activities of metabolic pathways, including the cytochrome P450 and other detoxification systems, have the potential to directly influence carcinogenic potency (Agundez, 2004, 2008; Bozina et al., 2009). Similarly, endogenous and normal cellular reactions, including oxidative respiration and lipid peroxidation, can produce gene mutations in cells through the generation of reactive oxygen species, which can react with DNA to produce oxidized nucleic acid bases such as 8-oxo-2’-deoxyguanosine (Cooke et al., 2003; Karihtala & Soini, 2007). The ability to form reactive oxygen species as a necessary by-product of cellular respiration suggests the risk of cancer formation is inextricably intertwined with the act of living.