The key characteristics of cardiotoxicity for the pervasive pollutant phenanthrene
E. M. England, J.W. Morris, Cyrill Bussy, Jules C. Hancox, Holly A. Shiels
Abstract
The key characteristic (KCs) framework has been used previously to assess the carcinogenicity and cardiotoxicity of various chemical and pharmacological agents. Here, the 12 KCs of cardiotoxicity are used to evaluate the previously reported cardiotoxicity of phenanthrene (Phe), a tricyclic polycyclic aromatic hydrocarbon (PAH), and major component of fossil fuel-derived air pollution. Phe is a semi-volatile pollutant existing in both the gas phase and particle phase through adsorption onto or into particulate matter (PM). Phe can translocate across the airways and gastrointestinal tract into the systemic circulation, enabling body-wide effects. Our evaluation based on a comprehensive literature review, indicates Phe exhibits 11 of the 12 KCs for cardiotoxicity. These include adverse effects on cardiac electromechanical performance, the vasculature and endothelium, immunomodulation and oxidative stress, and neuronal and endocrine control. Pharmaceutical agents that have similarly damaging effects on the cardiovascular system are heavily regulated and monitored via guidance for narrow therapeutic index drugs. Yet globally there is no air quality regulation specific for PAHs like Phe. Environmental monitoring of Phe is not the international standard with benzo[a]pyrene being frequently used as a proxy despite the two PAH species exhibiting significant differences in sources, concentration variations and toxic effects. The evidence summarised in this evaluation highlights the need to move away from proxied PAH measurements and develop a monitoring network capable of measuring Phe concentration. It also stresses the need to raise awareness amongst the medical community of the potential cardiovascular impact of PAH exposure. This will allow the production of mitigation strategies and possibly the development of new policies for the protection of the societal groups most vulnerable to cardiovascular disease. Approximately 4.2 million premature human deaths worldwide are attributed to air pollution. Phenanthrene is a dominant polyaromatic hydrocarbons in air pollution, present in the gas phase and adsorbed to particular matter. There is strong epidemiological evidence linking phenanthrene to cardiovascular disease, and it has recently been shown to block human ion-channels associated with repolarisation, and cause arrythmias in mice. Here we used the 12 Key Characteristics framework to show phenanthrene and/or its derivatives induced 11 of the 12 Key Characteristics of cardiovascular toxicity including impaired contractility, excitability, and endothelial dysfunction, altered vascular homeostasis, and induction of oxidative stress and inflammation.