Prof. Noel Aquilina from the Department of Chemistry at the University of Malta and Prof. Roy M. Harrison, the Queen Elizabeth II Birmingham Centenary Professor of Environmental Health, from the School of Geography, Earth and Environmental Sciences, at the University of Birmingham, UK have published an important paper in the influential journal Environment International entitled “Evaluation of the cancer risk from PAHs by inhalation: are current methods fit for purpose?”
Why lung cancer? Why Polycyclic Aromatic Hydrocarbons (PAHs)? What are the problems with the lung cancer risk estimation methodology? What does the extremely limited new data show? What can be improved and how? The scope of this paper was intended to address these pertinent questions.
Why lung cancer is still very important to consider? Normally about 90% of lung cancer cases are related to tobacco smoking and 1–2% are accounted for by outdoor air pollution and secondhand smoke. According to the International Agency for Research on Cancer (IARC) of the World Health Organisation (WHO), globally in 2020, 11.4% (2.2 million) of the new cancers (19.3 million) were lung cancers, being at a similar incidence and occurence of breast cancer. For the same year, for both sexes at all ages, the number of deaths due to lung cancer topped the list at 18% (1.8 million) out of almost 10 million deaths. A look at the 2021 European Commission State of Health in the EU, Country Health Profile for Malta shows that since 2000, although the life expectancy in Malta increased in the last decade (is two years higher than the EU average) and deaths from cardiovascular disease and cancer have declined substantially, according to the IARC, in Malta in 2020, lung cancer ranks third of all new cancers (10.3%), and also ranked first for the number of deaths (20.1%).
Beyond tobacco smoking, which are the main drivers of lung cancer? It is well known that fine particulate matter (PM2.5) is a culprit not to be underestimated. Closely linked to the composition of PM2.5 and their sources are PAHs, but what are these? These are a class of compounds which are emitted in any combustion process being it natural or from man-made activities. Their presence in the atmosphere is ubiquitous and they are always found as a highly complex mixture containing both compounds of known carcinogenic activity and others which do not exhibit carcinogenicity in their pure form. Studying the exposure to PAHs in particulate matter is a challenging issue.
Why and how are they of an environmental concern? Why are they monitored and regulated? When the United States Environmental Protection Agency (U.S. EPA) was set up in 1970, in the 1976 consent decree, a list of “65 toxic pollutants” was presented for regulation. There were several shortcomings, including that the list contained only a sub-group representative of large groups of PAHs, sampling, extraction and analytical methodologies were still rudimentary and more importantly few Quality Assurance/Quality Control requirements were in place when compared to today’s standards.
Three PAHs were in the original list, seven more were selected because an analytical standard was then available, another three were chosen because they were suspected carcinogens in water and an additional three were included because they were easily found in tars or dyes. These 16 legacy PAHs (16-EPA) were considered as the best group representative of PAHs at the time, and were enshrined in US law soon after, and thus recommended by the U.S. EPA for monitoring and reporting. The European Commission followed suit in the Air Quality Directive 2004/107/EC of 2004, where originally the sole compound to be monitored was benzo(a)pyrene (B[a]P) as a marker compound of the PAHs to which a limit value is applicable. An amendment to this directive was included in the Commission Directive (EU) 2015/1480 to monitor a sub-group of the 16-EPA. These were a group of seven PAHs predominantly found in the particle-phase and are carcinogenic to a different degree.
Thousands of studies have sought to measure the 16-EPA only, following the U.S. EPA recommendations. In the last four decades, collection and extraction methods have been improved and advanced analytical instruments have been developed. These advancements led to the discovery of a whole class of polycyclic aromatic compounds, namely more PAHs and other derivatives. Simultaneously more toxicity studies were carried out, indicating that some PAHs beyond the 16-EPA, in addition to B[a]P were highly carcinogenic and/or genotoxic, mutagenic and eco-toxic. Some studies have demonstrated that considering only the 16-EPA group is liable to underestimate carcinogenicity, and to give a false outcome to source attribution of carcinogenic activity.
Why are PAHs of primary concern in relation to lung cancer? Historically, the choice of B[a]P as a marker was based on occupational exposure studies of workers occurring predominantly through inhalation and by dermal contact. The exposure to airborne PAHs by the inhalation pathway and the corresponding health impact of most concern, lung cancer, has been historically addressed at an occupational level, in coke oven workers, workers in aluminium reduction plants and other industries. Key studies carried out in the 1970s in the abovementioned work environments indicated that B[a]P stands out to be the most representative individual PAH. This led to B[a]P being used for the derivation of unit risk.
This paper explored the issues involved with the use of the unit risk for B[a]P as a marker of PAHs exposure in ambient air, and methods which seek to sum the risks associated with other compounds in a mixture, and sought to clarify what is known with confidence regarding the associated cancer risk by the inhalation route.
Both the WHO and the U.S. EPA have estimated unit risk factors for lung cancer from exposure to PAHs. The former was estimated using data from occupational exposure to coke-oven emissions, whilst the latter used an animal inhalation study. The two obtained values differ because of the assumptions and approach taken. Over the years several approaches have been proposed to estimate the cancer risk associated with the exposure to PAHs mixtures.
A very common error which appears throughout the literature is to estimate cancer risk by multiplication of a B[a]Pequivalent concentration by the WHO Unit Risk. This can significantly overestimate risk as the correct procedure is to use the concentration of B[a]P alone as a surrogate for the entire mixture, as adopted by WHO when deriving the Unit Risk.
It is still debatable if potency factors derived from carcinogenicity tests are valid and secondly the B[a]Pequivalent approach depends upon the expectation that all carcinogens in the PAH mixture have been accounted for, which definitely is not the case. The use of the 16-EPA does not represent the carcinogenic activity shown by a range of environmental exposures as has been shown for diesel exhausts, cigarette smoke or wood smoke to mention a few. The presence of other carcinogenic or co-carcinogenic compounds in particulate matter could be confounding factors as they may potentially add to or modify the carcinogenic activity of the complex PAH mixture.
The new data used in this paper, to evaluate the relative carcinogenic potency was derived from a handful of studies which monitored PAHs beyond the 16-EPA. A sensitivity analysis of the carcinogenic potency of the reported mixtures was studied as a range of toxicity values are available for different PAHs. Calculations showed that in different environments, assuming an additive effect of extra PAHs, the carcinogenicity of the mixture could increase by 2-12% over that of the 16-EPA, although it could be much higher given the nature of a more carcinogenic mixture whose composition is largely unknown. This new information empasizes the fact that the use of B[a]P as an index compound of the PAH mixture, or of the 16-EPA to derive the risk attributable to PAH exposure is open to high uncertainty. This paper also outlined research gaps in understanding better the chemical composition of the PAH mixture and new approach methodologies for risk assessment applicable to complex mixtures.