Associations Between Urinary Metabolites of Polycyclic Aromatic Hydrocarbons and Liver Enzyme Levels Among Korean Firefighters
Article information
Abstract
Objectives:
Polycyclic aromatic hydrocarbons (PAHs), byproducts of incomplete combustion of organic compounds, have been linked to various adverse health outcomes; however, evidence associating PAHs with liver damage remains inconsistent. This study aimed to investigate the relationship between PAH exposure and liver enzyme levels among firefighters, who have an increased risk of PAH exposure.
Methods:
A total of 961 firefighters were included in the study. Urinary concentrations of 4 PAH metabolites (2-naphthol, 2-hydroxyfluorene, 1-hydroxyphenanthrene, and 1-hydroxypyrene) were measured and categorized into quartiles. Serum levels of liver enzymes, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were evaluated. Age, smoking status, alcohol consumption, body mass index (BMI), job position, and self-reported disease history were adjusted as covariates. Multivariable linear regression analyses were conducted to assess the association between PAH metabolites and serum AST and ALT levels. Logistic regression analyses evaluated associations between PAH metabolites and abnormal AST and ALT levels, defined as 40 IU/L or higher.
Results:
Participants in the highest quartile of urinary 2-naphthol had an increased risk of abnormal ALT levels compared to those in the lowest quartile (odds ratio, 2.00; 95% confidence interval, 1.09 to 3.65). No significant associations were observed for the other PAH metabolites. The association between urinary 2-naphthol and abnormal ALT levels did not differ significantly by smoking status, alcohol consumption, or BMI.
Conclusions:
Elevated urinary 2-naphthol levels were associated with abnormal liver enzyme levels among firefighters, suggesting that monitoring and managing PAH exposure may help protect liver health in this occupational group.
INTRODUCTION
Firefighting is considered one of the most hazardous occupations. Despite firefighters generally maintaining excellent physical fitness, they exhibit a higher risk of cardiovascular diseases and cancers compared to the general population [1-3]. This increased risk can be attributed to unique occupational risk factors inherent to firefighting. Firefighters commonly work irregular shifts and experience unpredictable emergency calls, contributing to inadequate physical activity and unhealthy dietary habits [3,4]. Additionally, they encounter various hazards, including noise, extreme temperatures, and numerous toxic substances at fire scenes [5-7]. Examples of toxic substances present at these scenes include ammonia, carbon monoxide, hydrogen cyanide, nitrogen dioxide, sulfur dioxide, and polycyclic aromatic hydrocarbons (PAHs) [7].
PAHs are a class of organic compounds composed of 2 or more fused aromatic rings produced through the incomplete combustion of organic materials [8]. Exposure to PAHs has been linked to numerous adverse health impacts, including cancer, respiratory disorders, and cardiovascular diseases [9-12]. PAHs are metabolized primarily in the liver, where they can induce oxidative stress and inflammatory responses, potentially leading to hepatocellular injury and consequently affecting systemic health negatively [13].
Only a limited number of studies have explored the relationship between PAHs and liver enzyme levels, which serve as indicators of liver injury [14-17]. A study of 288 petrochemical plant workers reported a positive association between urinary 2-naphthol and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels [15]. Additionally, a study involving 3194 adolescents from the National Health and Nutrition Examination Survey (NHANES) found positive associations between urinary PAH metabolites and ALT levels [16]. Conversely, a recent study involving 164 firefighters reported a positive association between urinary PAH metabolites and bilirubin levels but did not find a correlation with serum AST and ALT levels [17]. Given these inconsistent results and the limited evidence specifically concerning firefighters, a group highly exposed to PAHs occupationally, this study aimed to evaluate the associations between PAH exposure and abnormal liver enzyme levels among firefighters.
METHODS
Study Participants
The data for this study were obtained from the Firefighter Research on Enhancement of Safety & Health (FRESH) cohort study [18]. The FRESH study was designed as a prospective cohort study to investigate health risk factors among firefighters. A total of 1022 firefighters were recruited from 3 university hospitals (Severance Hospital in Seoul, Wonju Severance Christian Hospital in Wonju, and Gyeongsang National University Hospital in Jinju) between 2016 and 2017. Baseline assessments were initially conducted, followed by 2-year follow-up assessments between 2018 and 2019.
The present study utilized data from the baseline assessment. Among the original 1022 participants, 61 were excluded: 44 female participants and 17 participants with missing or invalid data for exposures and covariates. Thus, the final analysis included 961 participants.
Exposure Assessment
Urine samples were analyzed to determine concentrations of 4 PAH metabolites: 2-naphthol, 2-hydroxyfluorene (2-OHF), 1-hydroxyphenanthrene (1-OHPHE), and 1-hydroxypyrene (1-OHP). All laboratory analyses were conducted by Green Cross Laboratories Co., Ltd. (Yongin, Korea), utilizing gas chromatography–mass spectrometry (GC-MS).
Gas chromatography separation of urinary PAH metabolites was performed using a Clarus 680 (PerkinElmer, Waltham, MA, USA) instrument equipped with a splitless injector and a B-5MS Ultra Inert 122–5532 UI capillary column (30 m×0.25 mm×0.25 μm; Agilent Technologies, Santa Clara, CA, USA). PAH concentrations were normalized to urinary creatinine (μg/gCr) [19] and then divided into quartiles.
Outcome Variable
The outcome variables were serum AST and ALT levels, which are sensitive indicators of liver cell injury [20]. Serum AST and ALT were analyzed both as continuous variables and binary variables, with abnormal defined as serum levels of 40 IU/L or greater, consistent with previous research [15].
Covariates
The covariates included in analyses were age (continuous variable), smoking status (non-smoker, past smoker, and current smoker), alcohol consumption (no drinking; low-risk drinking: ≤40 g/day; moderate to high-risk drinking: >40 g/day) [21], body mass index (BMI), job position (school educators and retirees, fire-control workers, paramedics and rescue workers, and office administrators), and self-reported history of diseases (hypertension, dyslipidemia, and diabetes mellitus).
Statistical Analysis
Descriptive analyses were performed to examine the distribution of general characteristics within the study population. Differences in serum AST and ALT levels according to quartiles of urinary PAH metabolites were examined using the Kruskal-Wallis test (continuous dependent variable) and the chi-square test (binary dependent variable). Multivariable linear regression (for continuous dependent variables) and logistic regression (for binary dependent variables) analyses were conducted to evaluate associations between urinary PAH metabolites and liver enzyme levels after adjusting for the stated covariates.
Post-hoc analyses were conducted to evaluate potential effect modification by BMI (<25 vs. ≥25 kg/m²), smoking status, alcohol consumption status, and job position using stratified analyses. Furthermore, statistical interaction was assessed by comparing regression coefficients across BMI strata using the Altman and Bland test of interaction [22]. A 2-sided p-value of <0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).
Ethics Statement
All procedures were performed in accordance with the relevant guidelines and regulations of the Declaration of Helsinki. The study’s protocols received approval from the Institutional Review Boards of Severance Hospital, Yonsei University Health System in Seoul, Korea (4-2016-0187), Wonju Severance Christian Hospital in Wonju, Korea (CR316014–002), and Gyeongsang National University Hospital in Jinju, Korea (GNUH 2016-04-015-006). Informed consent was obtained from all participants.
RESULTS
Table 1 summarizes the general characteristics of the study population. Among the 961 participants, the mean age was 42.0 years. Past smokers accounted for 530 participants (55.2%), and 793 participants (82.5%) reported low-risk alcohol consumption. The distribution of job positions was as follows: fire-control workers represented the largest group, with 433 participants (45.1%), while office administrators accounted for 173 participants (18.0%), paramedics and rescue workers comprised 186 participants (19.4%), and school educators and retirees comprised 169 participants (17.6%). The median urinary concentrations of PAH metabolites were 1.76 μg/gCr for 2-naphthol, 0.13 μg/gCr for 2-OHF, 0.12 μg/gCr for 1-OHPHE, and 0.13 μg/gCr for 1-OHP. The median serum AST and ALT levels were 24 IU/L and 23 IU/L, respectively (Table 1).
Demographic and clinical characteristics of the study population
None of the differences in serum AST and ALT levels across quartiles of urinary PAH metabolites reached statistical significance. However, a statistically significant difference was observed in the proportion of abnormal ALT levels among urinary 1-OHPHE quartiles (p-value=0.018); no other significant differences were observed (Table 2).
Participants in the highest quartile (Q4) of urinary 2-naphthol showed a significantly higher risk of abnormal ALT levels compared to those in the lowest quartile (Q1) (odds ratio [OR], 2.00; 95% confidence interval [CI], 1.09 to 3.65). None of the other metabolites showed statistically significant associations with abnormal liver enzyme levels (Table 3).
In the stratified analyses, none of the differences in associations by BMI, smoking status, alcohol consumption, or job position were statistically significant (Figure 1 and Table 4). Notably, among participants with a BMI of 25 kg/m2 or higher, those in the highest quartile (Q4) had an increased risk compared to those in the lowest quartile (Q1) (OR, 2.08; 95% CI, 1.00 to 4.33). In contrast, no significant association was observed among those with a BMI below 25 kg/m2.
Association between urinary 2-naphthol and proportion of abnormal alanine aminotransferase (ALT) levels, stratified by body mass index (BMI) status. The models were assessed using multivariable logistic regression, adjusted for age, smoking status, alcohol consumption status, job position, history of diseases. Abnormal ALT levels were defined as 40 IU/L or higher. p-values for comparing adjusted odds ratios across different strata of BMI using the Altman and Bland test of interaction. OR, odds ratio; CI, confidence interval; Q, quartile. *p<0.05.
DISCUSSION
This study investigated the relationship between PAH exposure and liver enzyme abnormalities among nearly 1000 firefighters, a population highly susceptible to PAH exposure. We identified a positive association between urinary 2-naphthol and abnormal ALT levels among firefighters. This association was consistent across various subgroups, with no significant effect modification observed by BMI, smoking status, alcohol consumption, or job position.
Previous studies have also reported associations between PAH exposure and liver enzyme levels. A cross-sectional study of 288 petrochemical plant workers found a positive relationship between urinary 2-naphthol and serum AST and ALT levels, consistent with our findings [15]. Similarly, a cross-sectional analysis of 3194 adolescents from NHANES revealed that mixed PAH exposure (evaluated through a weighted quantile sum model including 1-naphthol, 2-naphthol, 2-OHF, 3-OHF, 1-OHP, and 1-OHPHE) was associated with elevated ALT levels specifically among female adolescents [16]. Among individual PAH metabolites, only urinary 2-OHF was significantly associated with increased ALT levels. Variations between these findings and our results could stem from differences in the age, gender, ethnicity, or occupational backgrounds of the participants. Another study of 164 firefighters identified a positive association between mixed PAH exposure (assessed via a weighted quantile sum model including 1-naphthol, 2-naphthol, 2-OHF, 3-OHF, 1-OHP, and 2,3-OHPHE) and bilirubin levels, but no association was observed with serum AST and ALT levels [17]. These discrepancies may reflect differences in the age distribution (mean age: 26.4 years) of participants or may be due to the relatively small sample size. Further research on PAH exposure and liver enzyme abnormalities among firefighters is needed to clarify these inconsistencies.
Although job position did not significantly modify the observed effects, the likelihood of abnormal liver enzyme levels associated with PAH exposure tended to be higher among office administrators than among fire-control and rescue workers, who are typically presumed to experience greater exposure to PAHs. In our study, urinary 2-naphthol levels were notably low among fire-control workers (median: 1.62 μg/gCr), comparable to or even lower than those observed in the general Korean population [23]. The absence of elevated urinary PAH metabolites among firefighters likely indicates an underestimation of acute occupational exposures, attributable to the short half-lives of PAHs [24] and the time interval between firefighting activities and sample collection. Nonetheless, these findings provide valuable insights into the chronic or background occupational PAH exposure levels in firefighters [25].
While the biological mechanisms underlying the hepatotoxic effects of PAH exposure remain incompletely understood, several potential mechanisms have been proposed. PAHs are known to induce oxidative stress via reactive oxygen species production, resulting in mitochondrial dysfunction and lipid peroxidation in hepatocytes [13,26]. Additionally, animal studies have demonstrated that PAH exposure can alter liver lipid profiles, potentially leading to hepatocyte membrane damage, inflammation, and non-alcoholic fatty liver disease [27,28]. Notably, naphthalene, the parent compound of 2-naphthol, exhibits unique hepatotoxic properties due to metabolic activation to 1,2-naphthoquinone [29]. This redox-active quinone depletes glutathione, promotes reactive oxygen species overproduction through mitochondrial redox cycling, and directly damages hepatocyte membranes through covalent binding [29,30]. In contrast, other PAH metabolites analyzed in this study typically undergo detoxification via glucuronidation or sulfation without generating persistent oxidative intermediates [31]. The distinct hepatotoxic mechanism of naphthalene, along with relatively lower variability in levels of other PAH metabolites in our study population, may explain why only 2-naphthol showed significant associations with elevated liver enzymes in this study. Moreover, the observed association specifically with ALT, a more liver-specific marker than AST, further supports the biological plausibility of naphthalene-induced hepatocellular injury in this context [32].
This study has several limitations. First, we used cross-sectional data, with urinary PAH metabolite data available only at baseline. Thus, a temporal relationship between PAH exposure and liver enzyme abnormalities cannot be definitively established. Second, despite adjusting for age, BMI, smoking status, and other relevant factors, residual confounding may still exist. Although stratified analyses by BMI, smoking status, alcohol consumption, and job position showed no significant effect modification, unmeasured confounders such as physical activity or exposure to other pollutants (e.g., per- and polyfluoroalkyl substances, volatile organic compounds) could influence our findings. Third, correction for multiple testing was not applied, aligning with the exploratory nature of the study. Lastly, this study included only man firefighters, limiting our understanding of potential effects in women, who might exhibit different toxicological responses to PAH exposure compared with men [33]. Furthermore, our findings may not be generalizable to the broader population or other occupational groups due to the unique exposure patterns among firefighters and potential healthy-worker effects inherent in occupational cohorts.
In conclusion, our study found associations between urinary 2-naphthol levels and abnormal ALT levels among firefighters. Although these results should be interpreted cautiously considering study limitations, they indicate that monitoring and managing PAH exposure may play an important role in protecting the liver health of firefighters.
Notes
Conflict of Interest
The authors have no conflicts of interest associated with the material presented in this paper.
Funding
This work was supported by the Fire Fighting Safety & 119 Rescue Technology Research and Development Program funded by the National Fire Agency ("MPSS-Firesafety-2015-80") and Smart HealthCare Program (www.kipot.or.kr) funded by the Korean National Police Agency (KNPA, Korea) [Project Name: Precision & Personalized Medicine for Predicting Cardiovascular Disease Risk in Police Officers (4Ps study) / Project Number: 220222M02].
Acknowledgements
None.
Author Contributions
Conceptualization: Lee J. Data curation: Bae MJ, Kim MJ, Oh SS, Park KS, Lee CJ, Park S, Lee SK, Koh SB, Kim C. Formal analysis: Lee J. Funding acquisition: Park KS, Koh SB, Kim C. Methodology: Lee J, Park KS, Park S, Koh SB, Kim HC, Kim C, Cho J. Project administration: Park KS, Koh SB, Kim C. Visualization: Lee J. Writing – original draft: Lee J. Writing – review & editing: Bae MJ, Kim MJ, Oh SS, Park KS, Lee CJ, Park S, Lee SK, Koh SB, Kim HC, Kim C, Cho J.