Inhaled particles and lung cancer. Part A: Mechanisms.
Both occupational and environmental exposure to particles is associated with an increased risk of lung cancer. Particles are thought to impact on genotoxicity as well as on cell proliferation via their ability to generate oxidants such as reactive oxygen species (ROS) and reactive nitrogen species (RNS). For mechanistic purposes, one should discriminate between a) the oxidant-generating properties of particles themselves (i.e., acellular), which are mostly determined by the physicochemical characteristics of the particle surface, and b) the ability of particles to stimulate cellular oxidant generation. Cellular ROS/RNS can be generated by various mechanisms, including particle-related mitochondrial activation or NAD(P)H-oxidase enzymes. In addition, since particles can induce an inflammatory response, a further subdivision needs to be made between primary (i.e., particle-driven) and secondary (i.e., inflammation-driven) formation of oxidants. Particles may also affect genotoxicity by their ability to carry surface-adsorbed carcinogenic components into the lung. Each of these pathways can impact on genotoxicity and proliferation, as well as on feedback mechanisms involving DNA repair or apoptosis. Although abundant evidence suggests that ROS/RNS mediate particle-induced genotoxicity and mutagenesis, little information is available towards the subsequent steps leading to neoplastic changes. Additionally, since most of the proposed molecular mechanisms underlying particle-related carcinogenesis have been derived from in vitro studies, there is a need for future studies that evaluate the implication of these mechanisms for in vivo lung cancer development. In this respect, transgenic and gene knockout animal models may provide a useful tool. Such studies should also include further assessment of the relative contributions of primary (inflammation-independent) and secondary (inflammation-driven) pathways.
Knaapen
Ad M
AM
Department of Health Risk Analysis and Toxicology, University of Maastricht, The Netherlands.
Borm
Paul J A
PJ
Albrecht
Catrin
C
Schins
Roel P F
RP
D000393:Air Pollutants / Q000633:toxicity*; D000395:Air Pollutants, Occupational / Q000633:toxicity; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004781:Environmental Exposure / Q000009:adverse effects; D006801:Humans; D008168:Lung / Q000187:drug effects; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors
D000393:Air Pollutants; D000395:Air Pollutants, Occupational; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species