A Role for Heavy Metal Toxicity and Air Pollution in Respiratory Tract Cancers

Abstract

Cigarette smoke and air pollution have been associated with lung cancer and naso pharyngeal and laryngeal cancer, respectively. Significant concentrations of select heavy metals including lead and cadmium have been isolated in popular cigarette brands, and these heavy metals can be inhaled via smoking. Lead is able to mimic the activity of calcium in the human body, thereby leading to toxic effects in a variety of target organs. Lead perturbs and alters the release of intracellular calcium stores from organelles like the endoplasmic reticulum (ER) and mitochondria. A rise in mitochondrial calcium stimulates the generation of reactive oxygen species (ROS) and free fatty acids which can further promote calcium release and, ultimately, result in cell death. In the case of cadmium, the renal proximal tubule of the kidney accumulates freely filtered and metallothionein-bound metal, which is degraded in endosomes and lysosomes. This results in the release of free cadmium into the cytosol where it can generate reactive oxygen species and activate cell death pathways. In developing countries, indoor air pollution due to the domestic use of unprocessed biomass fuels such as wood, dung, and coal is another cause of respiratory tract cancers in humans. In some developed countries such as Australia and Canada, the alarming increase in forest fire frequency due to climate change and the associated smoke released into the environment is also likely to pose a future human health risk. Polycyclic organic particles in biomass and forest fire smoke can include carcinogens such as benzo[a]pyrene, which is also found in cigarette smoke. Benzo[a]pyrene can induce apoptosis in mammalian cells by initiating mitochondrial dysfunction, activating the intrinsic caspase pathway (caspase-3 and caspase-9), and via p53 activation. The constitutive activation of apoptotic pathways has been linked to carcinogenesis in a number of cancer models.