**1. Introduction**

Lung cancer remains the deadliest form of cancer across the globe [1]. While smoking rates have decreased in many areas, it remains to be seen if the incidence and mortality of primary lung cancer will experience a similar shift, particularly in light of the observation that close to 25% of cases arise in individuals who have never smoked [2]. As one of the most environmentally-influenced malignancies, lung tumorigenesis can result from exposure to both physical and chemical carcinogens. Exposure to the mix of compounds present in particulate matter is another well-known factor affecting the development of lung cancer [3]. However, a number of single-agent compounds in the environment have been identified as key lung carcinogens, particularly arsenic, asbestos and radioactive radon (222Rn) gas [4]. These compounds are distributed at varying, potentially-dangerous concentrations in the environment, affecting hundreds of millions of people worldwide.

Exposure to each of arsenic, asbestos, and radon has been shown to induce widespread genetic and epigenetic alterations, which may account for their strong carcinogenicity, independent of smoking status [4]. Interestingly, the molecular aberrations associated with these compounds and the onset of lung cancer in never-smokers follows a mechanism distinct from that of tobacco smoke [5]. While strict guidelines regarding exposure to these compounds have been implemented in some regions, mounting evidence suggests that carcinogenic effects may result from chronic exposure to environmental levels that are well below those currently deemed "safe" [6, 7]. Additionally, individual differences may contribute to varying degrees of susceptibility to the carcinogenic effects of these compounds. For instance, women have been shown to have a higher incidence of lung cancer arising in never-smokers. This inequality can potentially be attributed to a historical bias towards women being more present in the home, resulting in increased exposure to high radon concentrations and polyaromatic hydrocarbons from various home combustion sources [8]. As these genetic and epigenetic aberrations might be indicative of specific molecular damage induced by these carcinogens, they may be able to be used to develop personalized approaches for risk assessment, monitoring and subsequent disease treatment. Thus, it is critical to uncover the extent of these events associated with exposure to environmental carcinogens.

Arsenic is a class I International Agency for Research on Cancer (IARC) carcinogen that threatens global health through its persistent accumulation in drinking water sources, leading to the onset of skin and lung cancers, among other diseases [9]. Asbestos fibers are naturally occurring silicate mineral fibers that have long been used in industry as building insulation, and are closely linked with not only the well-known outcome of mesothelioma, but also to 5–7% of all lung cancer cases [10]. Radon gas accounts for between 3 and 14% of all lung tumors in a given country and is the second most-common cause of lung cancer, behind smoking [11]. While the radioactive gas normally diffuses easily in open air, it can build up in indoor environments and is readily dissolved into water, which can lead to malignancies through radioactive decay and alpha particle emission [11]. Moreover, drinking water may be a particularly prevalent source of exposure to environmental carcinogens, as it is a primary route of exposure for both arsenic and radon, emphasizing the need for a focus on water contamination measurement and remediation. As arsenic, asbestos, and radon exert their carcinogenic effects through different exposure routes, they display similar, yet distinct mechanisms of genetic and epigenetic aberration, which may be useful in the identification and treatment of tumors caused by these agents.

In this chapter we highlight the molecular alterations induced by exposure to arsenic, asbestos, and radon in key lung cancer pathways, and finish with a discussion of the potential translational applications of environmentally-induced molecular damage.
