Methyl bromide (MB) is a fumigant used worldwide for controlling pests in soils and agricultural products, including grains, fruits, and wood, owing to its efficacy against pests and its permeability to commodities (1–3). Although MB should be phased out due to it has been identified as an ozone-depleting substance under the Montreal Protocol, MB currently is still a world-wild recognized effective fumigant and heavily used for quarantine pre-shipment treatment and a critical use exemption for soil fumigations (4).

MB is also highly toxic to humans. It is mostly absorbed into the body by inhalation, which leads to peripheral neurological disturbances (5), central neurological effects (6–9), or swallowing disorders (10). Recent studies on asymptotic workers exposed to MB have reported negative effects on the central and autonomic nervous systems (11, 12). Moreover, acute coronary syndrome occurred in a patient exposed to MB from an old fire extinguisher, leading to cardiogenic shock (13). Therefore, concerns of work safety and health issues are still a challenge to those who conduct MB fumigation and inspect MB-fumigated shipping container and cargoes (14).

Bromide ion (Br⁻) concentrations have been utilized as biomarkers in workers exposed to MB, with Br⁻ detected in both blood and urine samples (15–17). Nevertheless, individuals with high MB concentrations can remain asymptomatic (16, 18). One possible explanation is the variation in symptom development among individuals (18). Therefore, we utilized Electroencephalogram and heart rate variability as sensitive markers of nervous function, confirming damage to the central and autonomic nervous systems in exposed individuals (11, 12). However, the impact of MB fumigation on cardiovascular health, including arterial function, remains unexplored. Biomarkers that can effectively assess vascular health have not yet been identified in workers exposed to MB.

Vascular load and aging are typically evaluated using the second derivative of the photoplethysmogram (SDPTG), which can be a valuable parameter in determining the vascular effects of conditions such as hypertension, atherosclerosis, and aging (19–21). The pulse wave in the photoplethysmogram (PTG) method measures changes in the amount of light absorbed by hemoglobin and generally reflects a change in blood volume (22–25). Pulse wave changes provide more information on blood pressure than simple systolic-diastolic blood pressure measurements (20) and have, therefore, been used to evaluate the elasticity of arterial vessels. However, detailed shape information such as the inflection points in the PTG is difficult to grasp visually. The SDPTG, developed by utilizing second derivative waves of the PTG to enhance recognition accuracy, has since been widely adopted as an objective and dependable measurement technique (20, 26–28). The SDPTG-derived indices exhibit a linear correlation with age and, thus, serve as a valuable tool for evaluating the decline in vascular function (20, 29, 30). We developed in a previous study (31) a linear regression model to analyze various SDPTG indices (b/a, c/a, d/a, e/a, and the SDPTG aging index [SDPTG-AI] based on the age of Korean participants) and used identical instruments and protocols in the current study. The findings of our previous study indicate that these SDPTG indices could be useful and sensitive tools for assessing arterial deterioration.

This study aimed to evaluate the potential impact of occupational exposure to MB on the health of workers. SDPTG levels were measured both before and after fumigation, and traditional biomarker analysis of Br⁻ in urine was conducted to assess whether workers had been exposed to MB and to quantify the extent of exposure.

SDPTG has been employed to quantitatively evaluate vascular health in relation to diseases such as hypertension, atherosclerosis, and aging in many studies (21, 37, 39–41). Specifically, a clear regression model of various SDPTG indices has been recently presented with age in healthy Korean adults, and thus reference ranges have been supplied depending on the age groups (31): SDPTG indices exhibited an age-related increase in b/a and SDPTG-AI while showing a decrease in c/a, d/a, and e/a. In the present study, SDPTG indices were used to measure the effects of MB on humans. The mean values of the SDPTG indices in the fumigator group after MB work were significantly different from those before work: b/a, c/a, and SDPTG-AI decreased after work, whereas d/a and e/a significantly increased (Table 2 Figure 2). Except for c/a, values for SDPTG in the fumigator group after work changed in reverse with aging even if the mean concentration of urinary Br⁻ in the fumigator increased after work. The SDPTG indices of the inspectors in the control group did not change significantly (Table 2 Figure 2).

Only the parameter c/a did not follow the same pattern as that of the other indices. It should be excluded due to the nonsignificant correlation between SDPTG indices and Br⁻. All SDPTG indices except c/a showed correlations with urinary Br⁻ levels, in all individuals before and after work (Table 3; Figure 3).

Pulse waves, the raw data of SDPTG, reflect the pressure in the ascending aorta. This pressure can be divided into two components (20). The initial systolic component is attributed to the left ventricular ejection, whereas the subsequent component is amplified by peripheral reflection waves (20, 42). Among the SDPTG indices, the b/a ratio reflects the early systolic component, which is lower when the vascular wall has a low vascular load. The d/a ratio reflects the second component and is higher when the peripheral arterial wall has a low vascular load (20). The c/a ratio, calculated using the c wave, which is a connected wave between the b and d waves, is higher in the young arterial wall or with a low vascular load (28). The e/a ratio reflects the initial rise in the diastolic wave, which is higher in young and flexible arterial walls or under low vascular loads (20). The SDPTG-AI, calculated as b/a-c/a-d/a-e/a, indicates that the functional aging level of the artery is lower in young and flexible artery walls or under low vascular loads (31). A low vascular load can be caused by high flexibility or poor left ventricular ejection. Considering that an old man exposed to MB had a cardiogenic shock with a left ventricular ejection fraction of 30% (13), it can be presumed that MB exposure lowered the b/a and SDPTG-AI of fumigators while raising their d/a and e/a values due to decreased left ventricular ejection. Therefore, we can infer that the inverse alteration in SDPTG values within the fumigator group as they age, despite an increase in the mean concentration of urinary Br- after work, may be attributed to a reduction in left ventricular ejection due to MB exposure.

In this study, MB was found to negatively affect the cardiovascular health of fumigators. This result is consistent with the effects of MB on health observed in previous studies. Negative MB effects on the central nervous system and autonomic nervous system of asymptotic workers exposed to MB were recently reported (11, 12). In addition, the environment in the same workplace as that in the present study was exposed to almost 1,000 ppm MB in the proximities of fumigation containers during injection and degassing processes, which is much higher than the permissible exposure limit of 1 ppm for MB (43). It can be inferred that the elevated MB concentration has resulted in increased Br⁻ concentration in the urine of workers, thereby exerting a detrimental impact on their cardiovascular health.

The effects of MB on SDPTG indices and Br⁻ levels before and after work have been compared between the two groups while controlling for pre-work SDPTG and Br⁻ concentrations. The parameters d/a, e/a, and Br⁻ concentrations showed significant trend differences between the two groups. Considering that b/a and c/a, which reflect the early systolic component, did not show any differences between the two groups, it can be presumed that MB affects peripheral artery compliance more than aortic distensibility.

Despite all fumigators reporting the use of gas masks, as indicated in Table 1, their health still was adversely effected. Several factors may have contributed to MB exposure. Korean phytosanitary treatment regulations mandate that fumigators wear gas masks during fumigation tasks (33). While quarantine inspectors supervise the fumigation process on-site, their oversight is primarily focused on the moments when MB is applied or just before the gas is released. Fumigators engaged in other tasks may not wear masks due to inconveniences like impaired visibility or breathing difficulties. An earlier study also identified another sources of MB exposure (16). The gas mask can develop leaks at contact points with the face. Additionally, the use of inadequate respirator canisters during fumigation work heightens the risk of exposure. Two kinds of canisters can be affixed to the gas mask: MB and organic vapor (OV). The OV canister has a shorter time before breakthrough compared to the MB canister, and any absorbed MB within the OV canister can be emitted during breathing. In Korea, all fumigators employ OV canisters, which may elevate the likelihood of fumigation workers encountering greater MB concentrations.

Due to strict workplace access control, the selection of participants and locations for this study was challenging. Nonetheless, this study enhances our understanding of the health consequences of MB exposure on fumigators, who do not display any symptoms. However, this study has also some limitations, one of which is the relatively small sample size of 44 fumigators and 20 inspectors because only 76 fumigators and 36 inspectors were registered in the Busan Port area with the APQA. Additionally, our data do not explain the disparity of the c/a ratio of fumigators compared to the aligned trends of other indices. Furthermore, we remain uncertain whether the alteration in SDPTG observed in workers is a result of secondary changes stemming from the neurotoxicity of MB or its direct cardiovascular toxicity. Future studies should thoroughly examine the impact of MB on the arterial system, as well as its long-term effects on the health of fumigators. Despite these limitations, this study found evidence of the negative effects on the health of workers exposed to MB, including elevated urinary Br⁻ levels and altered SDPTG indices after work. The findings of this study have practical implications for enhancing fumigation procedures, mitigating hazards, and safeguarding the well-being of the employees. Additionally, they establish the groundwork for restricting the usage of MB and advocating the use of alternative approaches.

We evaluated 44 fumigators (study group) and 20 inspectors (control group) by measuring their SDPTG indices and urinary Br⁻ concentrations before and after fumigation. These indices serve as indicators of vascular load and aging. The post-work SDPTG indices (b/a, c/a, d/a, e/a, and SDPTG-AI) and Br⁻ levels of the fumigators demonstrated significant changes compared to their pre-work values, indicating a negative impact of MB on cardiovascular health. However, the SDPTG indices and Br⁻ levels of the inspectors did not exhibit such differences. We also observed in all individuals’ significant correlations between Br⁻ levels and all SDPTG indices except c/a. These findings suggest that in the fumigator group, Br⁻ levels and SDPTG indices varied after work involving MB, causing detrimental effects on their health despite the absence of symptoms.

The data analyzed in this study is subject to the following licenses/restrictions: All the data supporting the findings of this study are available from the corresponding authors upon reasonable request. Requests to access these datasets should be directed to pmg@korea.kr.

The studies involving humans were approved by Institutional Review Board of Dong-A University (IRB number: 2-1040709-AB-N-01-201806-BR-004-04). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

JC conceived and designed the study. M-GP wrote the first draft of the manuscript. JC and M-GP reviewed the manuscript. WC contributed to data acquisition. All authors contributed to the article and approved the submitted version.

This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. NRF-2022R1F1A1074196). This research was also supported by “Research Base Construction Fund Support Program” funded by Jeonbuk National University in 2023.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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