Systematic Review of Exposure to Polycyclic Aromatic Hydrocarbons and Obstructive Lung Disease

Background. There is fast-growing epidemiologic evidence of the effects of environmental chemicals on respiratory health. Polycyclic aromatic hydrocarbons (PAHs) have been linked with airway obstruction common in asthma and/or asthma exacerbation, and chronic bronchitis and emphysema. Objectives. A systematic review of the association between exposure to PAHs and obstructive lung diseases is not yet available. The present systematic review aims to evaluate the evidence available in epidemiological studies that have associated PAHs with obstructive lung diseases such as asthma, chronic bronchitis, emphysema. Methods. We performed a systematic literature search on PubMed, Google Scholar, and Scopus databases using relevant keywords and guided by predesigned eligibility criteria. Results. From the total of 30 articles reviewed, 16 articles examined the link between PAHs and lung function in both adults and children. Twelve articles investigated the association between PAHs and asthma, asthma biomarkers, and/or asthma symptoms in children. Two articles studied the relationship between PAHs and fractional exhaled nitric oxide (FeNO), a biomarker of airway inflammation and the relationship between PAHs and obstructive lung diseases and infections, respectively. One study assessed exposure to daily ambient PAHs and cough occurrence. Discussion. Twenty-seven studies found an association between PAHs and asthma and reduced lung function. In children it is reinforced by studies on prenatal and postnatal exposure, whereas in adults, reductions in lung function tests marked by low forced expiratory volume in 1 second, (FEV1), forced vital capacity (FVC), and forced expiratory flow (FEF25–75%) were the major health outcomes. Some studies recorded contrasting results: insignificant and/or no association between the two variables of interest. The studies reviewed had limitations ranging from small sample size, to the use of cross-sectional rather than longitudinal study design. Conclusions. The literature reviewed in the present study largely suggest positive correlations between PAHs and obstructive lung diseases marked mainly by asthma and reduced respiratory function. This review was registered with PROSPERO (Registration no: CRD42020212894) Competing Interests. The authors declare no competing financial interests.


Introduction
Polycyclic aromatic hydrocarbons (PAHs) are a common group of environmental pollutants that usually occur as complex mixtures of over 300 organic compounds composed of multiple aromatic rings. Polycyclic aromatic hydrocarbons are compounds of interest due to their widespread presence as well as their carcinogenic, mutagenic and toxicologic potential. 1 Globally, the negative impact of PAHs on health is a major public health concern. Apart from being linked to increasing risk of cancers, 2 impaired neurodevelopment, 3 genotoxicity, 4 cardiovascular disease, 5 metabolic syndromes, 6 and recently onset of diabetes mellitus, 7 PAH exposure may also lead to non-cancerous health effects, particularly respiratory diseases such asthma and chronic obstructive pulmonary disease (COPD). 8-10 The World Health Organization (WHO) estimate indicates that more than 80% of deaths associated with chronic obstructive pulmonary disease (COPD) occurred in low-and middle income countries (LMIC) in 2019, 11 although the burden of COPD attributable to PAHs remains unknown.
Human populations can encounter health risks from PAHs via a variety of exposure pathways, including inhalation of ambient air containing PAHs, e.g., tobacco smoke, contaminated air from incomplete burning of coal, consumption of charbroiled foods, and use of coal or wood stoves, fireplaces for cooking and residential heating, industrial processes, vehicle exhaust, fossil fuels, and dermal contacts with environmental media such as contaminated soil and water. 12-14 The use of biomass (solid fuel) for cooking, lighting, and heating residence generates PAHs. 15 Studies conducted by Pruneda-Alvarez et al. reported that women in developing countries using biomass as fuel in their home for cooking have greater exposure to PAHs than those who cook outside their homes or those who do not use biomass as fuel. 16 Exposure to PAHs in adults seems to be linked to respiratory function and symptoms demonstrated as spirometric lung function parameters such as reduced forced expiratory volume in 1 second, (FEV 1 ), which is the volume of air exhaled at the end of the first second of forced expiration; forced vital capacity (FVC), the volume of air that can be forcibly breathed out after taking the deepest breath possible and forced expiratory flow at 25 and 75% (FEF 25%-75% ) of the pulmonary volume. 17-19 A comprehensive review by Lag et al. supports the notion that air-borne and particulate-bound PAH exposure may contribute to the development and/or exacerbation of respiratory disease and dysfunction. 20 Jedrichowski et al. revealed a strong association between prenatal exposure to PAHs and particulate matter less than 2.5 micrometers in diameter (PM2.5) and asthma, wheezing, and cough in the first two years of life among children who were prenatally exposed. 21 Huang et al. observed that an increase in concentration of urinary PAH metabolites was significantly associated with elevated risk of adult asthma. 22 A cohort study by Zhou et al. reported negative associations between monohydroxy PAHs (OH-PAHs) and lung function. In this study, each unit increase in sum total of low molecular weight (LMW) and high molecular weight (HMW) -PAHs was associated with a decrease in FEV1 and FVC, respectively. 23 Adverse respiratory health outcomes in children such as bronchitis have also been linked to PAH exposure. 24-25 as well as decrements in lung function parameters. 26-29 Reductions in the ratio of FEV 1 /FVC among adults in work settings was found to be linked with increased PAH exposures. 30 Reviews exist on the association between PAHs in ambient air pollution and non-malignant respiratory diseases focusing on air pollution as the main source of exposure, but a comprehensive systematic review with a precise question about the link between obstructive lung diseases and PAHs exposure irrespective of the exposure route is non-existent. The purpose of this systematic review, therefore, was to evaluate the evidence available for an association between PAHs from all exposure routes (inhalation, ingestion, and dermal uptake) and obstructive lung diseases (asthma and COPD: chronic bronchitis and emphysema) as well as the strength of the association. The present study is expected to provide epidemiological evidence that could be useful in exploring the etiology of obstructive respiratory diseases.

Methods
First, a search was performed on existing systematic reviews available in suitable electronic databases to ensure similar study had not yet been previously published to avoid duplication. A review protocol was then developed for our review question and the protocol was registered with PROSPERO (International prospective register of systematic reviews, 2020, CRD42020212894). 31

Study criteria and search strategy
The present study searched electronic databases of PubMed, Google Scholar, and Scopus in between August and September 2020. An advanced search builder was used to search in PubMed and Scopus. We considered studies with cohort, crosssectional, case-control, and panel study designs, and articles written in the English language with no restrictions on publication date, and studies reporting both prenatal and post-natal exposure to PAHs, studies Review that examined exposure in children and adults with no age restrictions investigating the association between PAHs and obstructive lung diseases such as asthma and COPD. Studies were excluded if they were reviews, abstracts, editorials, commentaries, measured other pollutants aside from PAHs, or were published in languages other than English. The search strategy was modified when searching different databases. The following keywords were used to retrieve relevant articles: "polycyclic aromatic hydrocarbons" OR "PAHs" OR "anthracene" OR "pyrene" OR "hydroxypyrene" OR "1-OHP" OR "benzo(a)pyrene" OR "BaP" OR "phenanthrene" OR "hydroxyphenanthrene" OR "fluorene" OR "hydroxyfluorene" OR "naphthalene" OR "hydroxynaphthalene" AND "obstructive lung disease" OR "asthma" OR "wheezing" OR "bronchitis" OR "emphysema" OR "COPD. " In addition, the references of the retrieved articles were checked for additional studies. A reference manager (Endnote, version X9.2, Clarivate analytics, Philadelphia, USA) was used to manage the retrieved literature and to check for duplicates.

Data screening and extraction
To select relevant articles, two members of the review team first reviewed the articles independently based on title and abstract. Having examined the titles, name of author, year of publication, journal name and issue number, duplicates were removed. We carefully screened articles again by titles and abstract, and finally by full texts available. Articles that were relevant to our objective were selected for inclusion while the others were excluded. Data from all the included studies were extracted with the help of a form predesigned by the reviewers (Supplemental Material 1) The data can be found in the summary of epidemiological studies included (Supplemental Material 2). Data includes: first author and publication year, study design, study participants and age at exposure, country of study or setting, exposure assessment, exposure metrics/study period outcome indicators, and key findings. The eligibility criteria mentioned earlier guided the entire screening process. Disagreements on article screening and data extraction were resolved by consulting with the third reviewer. Two reviewers disagreed on the inclusion of articles whose titles showed joint effects of PAHs and other pollutants. This was resolved by the third review who felt that those studies should be excluded on the grounds that the presence of other pollutants might have confounding effects on reported outcomes.

Risk of bias assessment
Assessment of the quality of individual studies was done using the approach outlined by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. The STROBE statement is a 22-item checklist used to effectively report observational studies. These items assessed the following sections of the articles: Title and abstract (item 1), Introduction (items 2 and 3), Methods (items 4-12), Results (items 13-17), Discussion (item18-21), and other information (item 22 on funding). 32 Using the 22-item checklist, two reviewers independently appraised the methodological quality of the included studies. For a study, each item was assigned "0, " "1" or a maximum score of "2, " depending on how they meet the requirements of each item. By assigning one score to each item, papers could get a total minimum score of 22 and a maximum score of 44. These ratings are provided in a Articles that scored 22 points and above were included in our review.

Results
Study selection was done using an adapted PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) 33 diagram and shown in Figure 1. Studies included in our review are summarized in Supplemental Material 2, and the characteristics of included studies are summarized in Table 1.

Discussion
Polycyclic aromatic hydrocarbons are widely distributed in the environment

Figure 1 -A Study Selection Flowchart
Review Epton et al. recorded no significant difference in FEV1 between asthmatics and non-asthmatics although the ratio of FEV1/FVC was significantly lower in the asthmatic participants who were exposed to PAHs. 51 Han et al. reported that although an increase in total PAHs was associated with reduced FEV1 in children with pre-existing asthma, there was no significant association between urinary PAHs and lung function among non-asthmatic children. 37 The studies in this review have a number of strengths. A significant proportion of the studies (twenty-two studies) 17-19,21,22,27,29,30,34-37,39,41,42-47 Urinary assessment for PAHs is the most reoccurring means of exposure assessment in the studies reviewed. This is most likely due to its noninvasiveness and ease of collection which is convenient especially for studies involving a large number of participants. However, some studies 18,30,35 opined that the use of single spot urine samples for exposure assessment has its limitations as it only reflects recent exposures but cannot indicate a past long-term level of PAH exposures. Repeated urine metabolite measurement and the use of 24hour urine to measure past, chronic exposures were stated as preferable options to adequately describe this association. 18,30 Theoretically, 24hour void may be more reliable than spot urine, but it is not convenient to collect from study subjects and non-compliance can introduce bias in the sampling process. The use of first morning void as an alternative can be explained on the basis that it is often associated with 24-h void. 54-55 Large epidemiological studies involving a large number of participants, may encounter difficulties trying to collect first-morning voids, hence, spot urine has been used as a more practical, less cumbersome method. Although PAHs are varied in nature, this review has observed that both the LMW-PAHs: naphthalene, fluorene, phenanthrene and HMW PAHs: those with 4 or more fused rings such as pyrene were associated with obstructive lung diseases.
Finally, we observed that majority of the studies were conducted in higher income countries, mainly China and the United States. It is therefore recommended that more studies be carried out in sub-Saharan African and other LMIC where there are often weak environmental pollution controls and more than 60% of heating and cooking fuel is derived from solid fuel such as coal and firewood. 15

Conclusions
Overall, the findings of the present review provide substantial evidence of the association between PAH exposure and obstructive lung diseases such as asthma, bronchitis, and emphysema, which is marked by reduced respiratory function. We therefore recommend that efforts be put in place to check future exposures, both prenatal/post and adult exposures, through policy making and other public health actions. Further research should focus on LMIC using longitudinal studies with long-term follow-up. This study can provide useful data in the evaluation of respiratory disease as patient exposures prior to disease onset is crucial to a fuller understanding of disease development.