INTRODUCTION

In Korea, 87.5% of women patients with lung cancer are non-smokers [1]. Exposure to cooking oil fumes (COFs) generated during frying is believed to be a major contributor to the increased incidence of lung cancer among non-smoking women [2]. The International Agency for Research on Cancer has classified COFs produced during high-temperature frying as probably carcinogenic to humans (Group 2A carcinogens) [3]. Pollutants released during cooking include more than 200 gases and various other compounds. These pollutants consist primarily of particulate matter (PM), both ultrafine (PM0.1, PM with diameter ≤0.1 µm) and fine (PM_2.5, PM with diameter ≤2.5 µm), as well as volatile organic compounds (VOCs), including polycyclic aromatic hydrocarbons (PAHs), aldehydes, and heterocyclic amines [3]. These compounds represent the major carcinogens in COFs.

COFs lack an established measurement method [4] and are not classified as hazardous agents subject to workplace environment monitoring in Korea. Instead, COF levels may be indirectly estimated by measuring components such as PAHs and PM in indoor air. Notably, molecular biomarkers associated with exposure to COF carcinogens can also be quantified.

In 2019, the Korea Occupational Safety and Health Agency conducted a workplace environmental assessment involving approximately 1300 food service workers across about 20 schools in Korea [5]. They found increased levels of COF components (PM2.5, VOCs) during cooking, highlighting issues with ventilation systems. Furthermore, inflammatory markers such as interleukin levels were elevated among the cooking staff. However, no evidence is yet available quantifying the extent of cooks’ exposure to COFs. We plan to secure such evidence indirectly by measuring biomarkers in the bodies of these workers.

Occupational Cooks in Korea With Lung Cancer [6]

In February 2021, a non-smoking school cafeteria worker (patient A) became the first in Korea to be recognized by the Korea Workers’ Compensation and Welfare Service as having an industrial accident in the form of lung cancer, following its determination that cooking fumes are causally related to occupational lung cancer [6]. The patient A worked as a cook at a middle school in Suwon, Gyeonggi Province, for 12 years, beginning in 2005. In 2017, while undergoing a health check for a transfer, this patient was diagnosed with stage 3 lung cancer and died in April of the following year. The middle school where patient A worked employed 4 cooks who rotated responsibilities for preparing rice (1 person), soup (1 person), and side dishes (2 people). A review of the menus from September 2016 to January 2017 showed that, out of 84 days of cooking, 68 days (81%) included fried, stir-fried, or grilled dishes. Of the 170 side dishes that required cooking, 85 were prepared by frying, stir-frying, or grilling, accounting for one-half of the cooked side dishes. According to the bereaved family, the cooks had requested repairs from the school since the summer of 2016 because the ventilation system in the cafeteria kitchen was not functioning properly. On May 16, 2017, patient B, a 52-year-old cook at the same school, collapsed in the cafeteria and was diagnosed with cerebral hemorrhage. The school initiated a hood and air conditioner replacement project on May 23, which was 7 days after patient B’s incident.

Target Carcinogen-associated Biomarkers

Benzo[a]pyrene diol epoxide DNA adducts

One measurable indicator of carcinogen exposure in COFs is benzo[a]pyrene, a 5-ring PAH classified as a group 1 carcinogen [7]. In the body, benzo[a]pyrene is metabolized by enzymes such as cytochrome and epoxide hydrolase into benzo[a]pyrene diol epoxide (BPDE). BPDE reacts with guanine in human DNA to form a covalent adduct, which contributes to cancer risk by increasing the probability of DNA repair failure and subsequent mutations. These adducts represent long-term overall exposure to PAHs in the human body and can be measured from peripheral blood mononuclear cells (PBMCs) using methods such as enzyme-linked immunosorbent assay (ELISA) and mass spectrometry [8].

PAH metabolites

PAHs are metabolized in the human body and excreted in urine as hydroxylated metabolites, which can be measured using mass spectrometry. These biomarkers represent short-term exposure to PAHs and can be influenced by acute exposures, such as food consumption. We measured 4 urinary PAH metabolites (1-hydroxypyrene, 2-naphthol, 1-hydroxyphenanthrene, and 2-hydroxyfluorene), which are commonly used as proxy markers for overall PAH exposure [9,10].

Methylation markers

Methylation of the cytosine base in DNA is associated with the body’s response to environmental factors [11]. Several methylation markers have been validated regarding their associations with carcinogens and lung cancer risk [12]. Among these markers, our primary targets are the F2RL3 CpG site (cg03636183) and the AHRR CpG site (cg05575921), which are also reportedly associated with occupational PAH exposure [13]. CpG site methylation can be measured using target pyrosequencing or methylation array platforms.

Study Questions

The study questions include the following: (1) Do human exposure levels differ based on occupational cooking exposure status? (2) What measures can reduce occupational exposure during cooking? (3) What strategies can improve the exposure environment of occupational cooking?

Hypotheses and Objectives

(1) Environmental exposure in the cooking environment impacts the levels of carcinogen-associated biomarkers in the human body. (2) Carcinogen-associated biomarkers differ depending on the exhaust and ventilation systems in school cafeterias. (3) Due to differences between home cooking and occupational cooking environments, individuals exposed to occupational environments have higher levels of carcinogen-associated biomarkers than those exposed only to home cooking. (4) Workers involved in both occupational and domestic cooking will exhibit higher levels of carcinogen-associated biomarkers than those engaged in only one of these practices. (5) Differences in carcinogen-associated biomarker levels are observed between groups with low and high levels of environmental pollutants, potentially due to interactions between pollutants—including PM—and the cooking environment, which may serve as a carrier for PAH exposure. (6) Dietary and food substances can inhibit or regulate the uptake of PAHs in the human body. (7) Indirect education provided during the study explanation and consent process in the primary survey may act as a natural intervention, leading to differences in the levels of carcinogen-associated biomarkers in the body.

We intend to conduct this study to investigate the hypotheses mentioned above.

METHODS

Study Design

The primary objective of this study is to assess the level of exposure to carcinogen-associated biomarkers (BPDE-DNA adducts, PAH metabolites, and methylation markers) among individuals working in kitchen environments (Objective 1). To achieve this, we are conducting a cross-sectional field study targeting chefs and kitchen staff. Based on the data collected, the study aims to evaluate the extent to which exposure to the kitchen environment influences PAH levels in the body (Objectives 2-6).

Secondarily, to determine whether PAH exposure markers exhibit different time-based variations between the exposure and control groups, the study will include a follow-up measurement with the same participants after a 4-month interval. When contacting participants for follow-up recruitment, we reach out to the schools that participated in the first study. We can also recruit new participants at each school, as some new individuals may have joined the school during the months separating the first and second studies. In other words, the second round of cross-sectional data collection incorporates both newly recruited participants and previously involved participants. This unique study design enables a post-hoc analysis to determine whether prior participation in the study influences the level of carcinogen-associated biomarkers compared with those who did not participate in the initial survey. In this context, participation in the initial survey serves as a natural intervention, and since newly recruited participants lack prior baseline data, the study adheres to a cross-sectional post-test only quasi-experimental design (Objective 7) [14].

Sample Size Calculation

The required sample size for this study is determined based on the primary objective of comparing BPDE-DNA adduct levels between COF-exposed and unexposed (control) groups in a cross-sectional design. Because no studies measuring BPDE-DNA adducts in cooks are yet available, we referred to previous research conducted among a coke oven emission cohort in China [15]. In that study, the mean leukocyte BPDE-DNA adduct levels were reported as 1.59 adducts/10⁸ nucleotides (standard deviation [SD], 1.33 adducts/10⁸ nucleotides) in the group exposed to high carcinogenic PAHs, including benzo[a]pyrene, and 1.00 adducts/10⁸ nucleotides (SD, 1.10 adducts/10⁸ nucleotides) in the control group, defined as having low carcinogenic PAH exposure. Using these estimates, with a power of 80%, a significance level of 0.05, and a 1:5 ratio between control and exposure groups, the minimum required sample size was calculated as 33 participants for the control group and 165 participants for the exposure group. Based on prior pilot study results, we selected a 1:5 ratio to ensure sufficient statistical power. Assuming a 10% dropout rate for the follow-up survey, the final target sample size was adjusted to at least 37 participants in the control group and 182 participants in the exposure group.

Target Population

The study targets workers exposed to COFs, primarily chefs and kitchen staff, working in school kitchens in Seoul, Korea. According to the 2023 Ministry of Education school meal facility database, the source population consists of 1276 chefs and 5897 kitchen staff members, totaling 7173 individuals in Seoul. Given the lack of a centralized registry or access mechanism for this occupational group, the study focuses on the 1101 schools that operate their own kitchens out of the 1346 schools providing meal services in Seoul.

To recruit at least 182 COF-exposed participants, approximately 2.5% of the targeted schools (i.e., 34 schools) must be included. The local distribution of the schools is not considered in this estimate. Since the exact number of kitchen staff per school is not readily available, recruitment prioritizes schools with the highest meal service capacity. Contact with potential participants continues until the required sample size is reached. Concurrently, to recruit the unexposed control group, we also gather volunteers from non-kitchen job categories (such as nutritionists, food transport and distribution staff, and administrative personnel) from each school until the minimum required sample size for the control group (n=37) is met. Recruitment for the exposure and control groups is conducted through each school meal service coordinator. Participants eligible for the exposure group are adults who either are directly employed in school kitchens or work within the school meal service environment, the control group contains those not directly engaged in cooking while working at the school.

Exposure From Home Cooking

The unexposed (control) group includes individuals exposed only to the home cooking environment (the home cooking-only exposure group). Meanwhile, the COF-exposed group includes individuals who are additionally exposed to home cooking (both-exposure group). According to our pilot study results, the frequency of exposure to the home cooking environment is approximately 80% in both groups (30 individuals from the control group and 146 from the exposure group), based on the definition of home cooking as at least 30 minutes per day.

Participant Recruitment Strategy

Multiple approaches are used to contact participants. Announcements are posted on schools’ internal networks, and school cafeterias and administrative offices are directly contacted by phone to introduce the study. Research information sheets are distributed to kitchen staff to ensure they are well informed about the research. Participant recruitment is conducted on a school-by-school basis. To facilitate participation, including follow-up measurements, we ensure the study flow is comfortable for participants by visiting schools in person to conduct surveys and collect samples.

Measurements

Table 1 details the specific measurement items used to assess the exposure of school kitchen workers to carcinogens in their working environments, focusing on PAH and benzo[a]pyrene.

Basic demographic and lifestyle information

Basic demographic information is collected, including general medical and family histories. In addition, cigarette smoking (including history of secondhand smoke), alcohol consumption, and physical activity are assessed.

Kitchen work environment

The conditions of the kitchen environment are crucial for tracking the history of carcinogen exposure among kitchen workers. Data are collected on the respondent’s current job role and the duration of work in the kitchen (in days, weeks, and over the lifetime) to estimate cumulative exposure. COFs usually originate from the combustion of oil, particularly during frying. Accordingly, information on the most frequently used cooking methods, the frequency of different cooking styles, and the types of food prepared each week were gathered. Furthermore, data regarding ventilation systems, such as exhaust hoods, and personal protection systems (e.g., various types of masks) were gathered, as these are essential for protecting workers from COFs. The workers’ subjective perceptions of health changes related to kitchen work are also documented to help assess the work environment.

Home cooking habits

Because home cooking is a more pervasive and long-term exposure than that encountered in the workplace, we also collect information on cooking habits at home. This includes the time spent cooking and the primary cooking methods used. The frequency of stir-frying, frying, and grilling is recorded to assess exposure to cooking methods that may produce harmful substances.

Food and beverage consumption

Food is another source of PAH exposure in daily life, particularly arising from manufacturing processes. Participants are asked about the frequency with which they consume charred foods, fried or grilled dishes, and flame-grilled items. Because phytochemicals in green vegetables may reduce PAH toxicity through chemoprevention, consumption of these foods is also investigated [16].

Biosampling, measurement of PAH substrates, and biobanking

Routine blood and urine tests are conducted, including complete blood count (CBC), liver function tests, and assessments of metabolic traits. Researchers visit the schools where participants work to collect biosamples. Participants are required to fast for 8 hours prior to sample collection. Venipuncture is performed to collect 10 mL of whole blood and 5 mL of blood, for a total of 15 mL, and an additional 15 mL of urine is collected. CBC parameters and differential counts (neutrophils, lymphocytes, monocytes, eosinophils, and basophils) are assessed using flow cytometry. Hemoglobin A1c levels are determined using the turbidimetric inhibition immunoassay method. Creatinine levels are measured with the modified Jaffe method, while aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase are quantified using International Federation of Clinical Chemistry approaches. Glucose levels are analyzed via colorimetry, and triglycerides as well as high-density lipoprotein, low-density lipoprotein, and total cholesterol levels are measured using enzymatic methods. PBMCs are isolated from whole blood using a density gradient, and genomic DNA (gDNA) is extracted from the PBMCs with commercial purification kits. BPDE-DNA adduct levels are measured using a BPDE-DNA adduct ELISA kit (Cell Biolabs Inc., San Diego, CA, USA). Methylation markers—including the F2RL3 CpG site (cg03636183) and the AHRR CpG site (cg05575921)—in the extracted gDNA are measured using the Illumina 850k EPIC Methylation Array (Illumina, San Diego, CA, USA). Four urinary PAH metabolites (1-hydroxypyrene, 2-naphthol, 1-hydroxyphenanthrene, and 2-hydroxyfluorene) are quantified using gas chromatography-mass spectrometry (GC-MS; Agilent, Santa Clara, CA, USA). Urinary creatinine levels are measured using the modified Jaffe method, while sodium and potassium levels are analyzed using the ion-selective electrode method. Finally, serum, plasma, urine, gDNA, and PBMCs are banked in a deep freezer (-70°C) for future research.

No data are available on the natural variation of BPDE-DNA adducts in populations exposed or not exposed to COFs. Since BPDE-DNA adducts indicate long-term exposure to benzo[a] pyrene [15,17], an additional biosampling measurement is performed approximately 4 months after the baseline survey —the maximum interval allowable within 1 school semester, chosen to minimize follow-up loss. This repeated measurement is conducted using the same methods as the baseline survey (Table 1).

Occupational environment measurement

To assess working conditions in each school kitchen, measurements of carbon monoxide (CO), carbon dioxide (CO₂), PM₁₀, PM_2.5, PAHs, formaldehyde, total VOCs, nitrogen dioxide (NO₂), temperature, hood function, and a smoke test are performed near pots during cooking. PM samples (PM₁₀ and PM_2.5) are collected using polytetrafluoroethylene (PTFE) filters over a 6-hour sampling period and weighed with an electronic microbalance. NO₂ is collected using triethanolamine-impregnated molecular sieve and quantified using ion chromatography. Formaldehyde is sampled with a silica gel cartridge coated with 2,4-dinitrophenylhydrazine (300/150 mg) and quantified via liquid chromatography. Total VOCs are analyzed using a thermal desorption GC-MS system. PAHs are collected with a sampling device operating at a flow rate of 2 L/min connected to an adsorption tube (washed XAD-2 resin, 100 mg/50 mg) equipped with a front-facing PTFE filter (37 mm, tared, 2 µm PTFE). The collected adsorbates are extracted with a desorption solvent following thermal desorption, and GC-MS is used for qualitative and quantitative analyses. CO₂ is measured using a non-dispersive infrared sensor that detects CO₂ concentration by quantifying the absorption of specific infrared wavelengths. CO concentrations are measured using an electrochemical sensor-based gas concentration meter (Tenmars Electronics Co., Ltd., Taipei, Taiwan). Continuous automatic measurements of CO₂ and CO concentrations are performed over 6 hours. For high-temperature measurements, a QUESTemp heat stress monitor (QT-34 model; TSI Incorporated, Shoreview, MN, USA) is used to record ambient air temperature on an hourly basis.

Review of ventilation and exhaust systems

We record whether the kitchen is located underground; the numbers of exhaust hoods, air conditioners, and external windows; and the structure of each cooking room. The data collection and biosampling methods used in this study resemble those employed in previous cohort studies [18]. However, because cooking habits and PAH exposure are key factors in this study, the focus is on occupational and environmental factors and their associated markers.

Statistical Analysis

In this cross-sectional study, the primary analysis compares the mean levels of BPDE-DNA adducts, PAH metabolites, and DNA methylation at CpG sites (cg03636183 and cg05575921) as continuous variables between the exposure and control groups. Statistical associations are evaluated using unpaired t-tests or multivariable linear regression analyses, adjusting for confounding factors such as age, gender, smoking status, body mass index, dietary factors, and home cooking exposure time. Additionally, participants are matched based on age for the analyses. Since most participants are women and non-smokers, the sample is further restricted to women non-smokers to minimize potential confounding effects. Considering that long-term exposure in the cooking area may affect carcinogen-associated biomarkers, cumulative working years in the school kitchen is also included as an independent variable in the linear regression model of biomarker levels among cooks.

Ethics Statement

The study protocol for this study was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. H-2204-179-1322).

CURRENT STUDY PROGRESS AND PILOT STUDY RESULTS

Of the 1101 targeted schools, we have contacted a total of 342, each serving approximately 800 meal recipients or more. Currently, a total of 28 schools (8% of those contacted) have been recruited. Among potential participants in these 28 schools, over 90% have consented to participate. In total, 252 participants completed the first survey, including 204 in the COF exposure group (22 more than the target number) and 48 in the control group (11 more than the target number). In the second survey, 213 people from 22 schools participated, including 189 from the initial group and 24 new participants (Table 2). We have conducted biosampling and administered questionnaires for all participants, and occupational environmental assessments are complete. We are currently processing the measurements for each item and performing statistical analyses on the results. During an initial pilot study involving approximately 52 participants, we conducted preliminary assessments, including an analysis of 1-hydroxypyrene levels (Supplementary Material 1).

Study Area

This study is part of the etiome research field. The term “etiome” combines the word “etiology” with the suffix “-ome.” Etiology is the study of the causes of a phenomenon, while “-ome’ signifies a comprehensive compendium. Etiome research identifies and clusters the genetic and environmental factors that cause human diseases. The ultimate goal of etiome research is to identify risk factors for disease and use that information to prevent disease progression, cure patients, or prevent adverse outcomes [19]. The present study qualifies as an etiome study because it investigates human exposure to occupational cooking environments, assesses air quality through environmental measurements, and evaluates molecular biomarkers associated with carcinogen exposure in the human body.

Mechanistic Studies of Lung Carcinogenesis in Occupational Cooking Environments

Data on the carcinogenic effect of PAHs on human lung cancer development are limited, although the mechanism of PAH-induced lung carcinogenesis is well established in murine models [20]. In vitro human lung organoids facilitate the study of the effects of PAHs on human lung carcinogenesis [21]. Adult human stem cell-derived airway organoids closely resemble the cellular environment of the human airway, making them valuable models for studying respiratory carcinogenesis [22]. As these organoids are derived from normal human lung epithelial cells, they provide more accurate insights into how human lung tissues respond to exogenous substances than animal models.

STRENGTHS AND WEAKNESSES

Workers in occupational cooking environments are at risk of lung cancer from airborne carcinogens due to the nature of their work [23]. However, it is challenging to directly determine the association between cooking environments and lung cancer risk because the number of exposed workers is small and a long latency period separates exposure and disease occurrence [24]. In this study, we aim to verify the utility of biomarkers as pre-disease surrogates for lung cancer by examining the relationship between the biological dose of carcinogens in the human body and external exogenic occupational exposures. We will investigate changes in human exposure markers based on exposure levels in occupational cooking environments and propose measures to reduce exposure during cooking. To achieve these objectives, we plan to apply etiome research [19], including a baseline questionnaire addressing occupational and home cooking environments, dietary and food intake factors that may inhibit or regulate PAH uptake, air quality measurements in occupational settings, assessments of the proper functioning of exhaust and ventilation systems in cooking facilities, assays of molecular and genomic biomarkers, and verification of lung carcinogenesis through organoid experiments. Our results can support a rationale for implementing appropriate interventions aimed at those exposed to COFs, who are at high risk of lung cancer, for disease prevention. Moreover, this cross-sectional study can be expanded into a cohort or interventional study to definitively establish the cancer risks associated with COFs and evaluate potential interventions. In addition, to estimate the disease burden associated with COFs, we are calculating the overall population attributable fraction of lung cancer caused by exposure in both occupational and household settings [25].

School food service cooks in Korea, supported by their labor union, have been able to identify health problems related to environmental exposure and effectively pursue industrial accident compensation. However, most high-risk workers with greater occupational exposure to carcinogens work in commercial restaurants, such as Chinese restaurants and other establishments that prepare fried foods like chicken. In these settings, where the sole proprietor is responsible for occupational accidents and diseases and typically employs only a few workers, employees have no union, and research recruitment is limited. Consequently, no epidemiological investigations have been conducted on environmental exposure and its health effects, estimation of carcinogens in the human body, or air measurements in these occupational settings. Additional research should be performed among these high-risk groups exposed to occupational cooking environments.

DATA ACCESSIBILITY

The clinical data, test results, and biobank specimens are scheduled to be transferred to the Korea National Cancer Center, and regulations governing data availability will likely be announced later.

Supplemental Materials

Notes

Conflict of Interest

The authors have no conflicts of interest associated with the material presented in this paper.

Funding

This study is supported by the National R&D Program for Cancer Control through the National Cancer Center (NCC), funded by the Ministry of Health & Welfare, Republic of Korea (HA21C0140). This research was also supported by a grant from the MD-PhD/Medical Scientist Training Program through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea.

Acknowledgements

None.

Author Contributions

Conceptualization: Moon S, Park SK. Data curation: Moon S, Sung S. Formal analysis: Moon S. Funding acquisition: Park SK. Methodology: Moon S, Park SK. Project administration: Moon S. Visualization: Moon S. Writing – original draft: Moon S, Park SK. Writing – review & editing: Moon S, Park SK, Sung S.

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Figure & Data

References

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