Establishing an occupational exposure limit for glyphosate in China

Introduction

Glyphosate (N-phosphonomethylglycine, CAS number: 1071-83-6, chemical formula C₃H₈NO₅P) is a colorless, odorless, crystalline solid substance that primarily exists in the form of acid and salt, with glyphosate isopropylamine salt being the most common form. It was originally screened and synthesized by the Monsanto Chemical Company in the 1960s (1) and has since become a widely used herbicide in agriculture for the control of annual and perennial plants (2-4) by inhibiting aromatic amino acid synthesis in plants (5). The extensive use of glyphosate has resulted in its widespread environmental dispersion. Occupational exposure is particularly prevalent in the production and application of glyphosate, especially within manufacturing enterprises due to the complex production processes. Over the past few decades, there have been several case reports of glyphosate poisoning. Xu et al. reviewed the clinical data of 60 patients with glyphosate poisoning. The patients ingested 20–120 mL of glyphosate at a concentration of 11%, and the mortality rate from poisoning was zero. Among the poisoned patients, 20 cases showed liver function damage (6). Thirteen glyphosate poisoning cases were observed during the treatment to describe the clinical feature and determinate the utility of the glyphosate concentration in blood and urine (7). Liu et al. reported 5 cases of acute glyphosate poisoning in children, 4 cases exhibited mild symptoms, with only slight gastrointestinal symptoms. Only a patient developed acute progressive kidney failure, severe liver dysfunction and respiratory failure (8). Poisoning cases highlighting the potential risks associated with its use. Common symptoms such as oropharyngeal ulceration, nausea, and vomiting were identified in the research (9), revealing potential toxic effects of glyphosate including teratogenic, tumorigenic and hepatorenal effects (10,11). The International Agency for Research on Cancer (IARC) classified glyphosate as a probable human carcinogen in 2015 (12), based on studies of occupational exposure in the United States (13), Sweden (14) and Canada, and the key characteristics of carcinogens for glyphosate were discussed (15). This classification has drawn significant attention to the potential health consequences of glyphosate (16-20). Numerous researchers have focused on the method to determine workers’ personal exposure levels to glyphosate for risk assessments (21,22). However, there has been a lack of research on the establishment of occupational exposure limits (OELs) for glyphosate. The Japanese Society for Occupational Health (JSOH) is one of the few entities to propose an OEL-mean (OEL-M) of 1.5 mg/m³ based on animal experiments (23). Prior to this research, the occupational health standards in China did not specify OEL for glyphosate. The national food safety standard in China stipulates that the glyphosate residue in fruits should not exceed 0.1 mg/kg, while the limit for sugarcane is set at 2.0 mg/kg. Additionally, the permissible level of glyphosate in drinking water is 0.7 mg/L. This study, following the guidelines outlines in GBZ/T 210.1-2008 (24), revealed a significant dose-response relationship among workers exposed to glyphosate. Subsequently, the OEL was determined using the US Environment Protection Agency (EPA) method (25) based on the no observed adverse effect level (NOAEL) and benchmark dose (BMD) calculation tools. In addition to analyzing population data, the suggested OEL was compared with those of other pesticides. Our subjective is to address the lack of OELs for glyphosate in China and provide guidance for occupational risk assessment. Establishing OELs can also encourage enterprises to create a safer working environment, ultimately safeguarding the health of workers.

Methods

Subjects

We conducted occupational health investigations on five representative glyphosate enterprises in developed eastern China, denoted as A–E, based on their production process and capacity. Our study involved 968 workers, with 526 in the exposed group and 442 in the control group, to investigate the dose-response relationship. The exposed group consisted of workers who had direct contact with glyphosate, and the workshops where the exposed group was located did not produce other pesticides. The control group included individuals from other positions in the selected enterprises who were not exposed to glyphosate. All workers included in the study had no previous history of significant liver or kidney diseases, and they were not been exposed to other pesticides or only had minimal and occasional exposure when using mosquito repellent spray containing pyrethroid pesticides.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The Ethics Committee of Jiangsu Provincial Center for Disease Control and Prevention approved our study (2014005), and all participants provided informed consent. Additionally, we collected occupational health monitoring records and information on the workers to ensure the accuracy of our findings.

Literature data collection

We conducted a comprehensive literature review to elucidate the toxicological properties of glyphosate and to identify existing OELs for this substance. In addition to clinical symptoms, our focus extended to the identification of target organs and relevant key effect markers, which played significant roles in our subsequent statistical analysis.

On-site occupational health survey

To gain a comprehensive understanding of the working conditions, we conducted on-site field investigations in the selected enterprises, which included an examination of their production processes, production layouts, workforce demographics, post-settings, work shifts, frequency of exposure, as well as the utilization of occupational and personal protective equipment.

Detection of glyphosate exposure levels in the workplace air

Area sampling

We selected several representative locations for short-term air sampling, following the guidelines outlined in the Sampling Practices for Monitoring Harmful Substances in Workplace Air in China (GBZ/T 159-2004) (26). This sampling was based on the results of on-site occupational health surveys. To collect glyphosate in the workplace air, we used air samplers and ultra-fine glass fiber filter paper. At a flow rate of 2.0 L/min, we collected 2 to 3 samples, with each sampling duration lasting 15 minutes.

Personal sampling

Additionally, we selected 2–3 workers from each designated post to perform personal sampling in order to determine the time-weighted average concentration (C_TWA) of glyphosate. This was achieved at a flow rate of 1.0 L/min, using ultra-fine glass fiber filter paper as air collectors, with a sampling duration of 8 hours.

Laboratory testing

After ultrasonic elution with deionized water, the samples were analyzed using ion chromatography with a conductivity detector (27) in the laboratory.

Occupational medical examination

Occupational medical examinations are a crucial tool in effectively preventing the occurrence and progression of occupational diseases. In our study, workers from the enterprises under investigation provided informed consent, completed a questionnaire detailing work-related information and living habits, with a focus on smoking and daily alcohol consumption. They then underwent an occupational health examination, which included general assessments of the ear, nose, throat (ENT), internal medicine, and surgery, as well as blood and urine routine tests, B-ultrasound of the liver and kidneys, electrocardiogram, high-kilovolt X-ray, pulmonary function tests, and other relevant assessments.

Exploration of dose-response relationship

The dose-response relationship serves as the foundation for all hazard assessment testing, and dose-response model extrapolations are based on this relationship (28). In this study, we estimated the dose-response relationship between glyphosate exposure and key effect parameters by analyzing the results of physical examinations and glyphosate levels in the workplace air.

Data derivation and statistics

OEL deduced from the BMD method using BMDS software

The BMD method, introduced in 1984, was developed to address the limitations of the EPA method, which relied heavily on experimental data. BMD represents a statistically lower confidence limit to a dose that produces a predetermined increase in response, calculated using a mathematical dose-response model. This approach appropriately considers sample size and the shape of the dose-response curve (29). In our study, we utilized the BMDS software to calculate BMD and lower confidence limits of the benchmark dose (BMDLs) (30) based on a specific dose-response relationship.

OEL derived from the EPA method based on NOAEL

According to EPA research, the OEL can be calculated using Eq. [1] (25):

OEL=(NOAEL×BW)/(SF×BR)[1]

where BW is the body weight of adults, SF is the safety factor, and BR is the respiratory volume of adults in 8 hours.

Statistics

We used SPSS 22.0 software for statistical analysis. Balance tests were initially conducted between the exposed group and the control group. T-tests were used to analyze differences in key effect markers, while the Chi-square test was applied for the analysis of categorical data. A significance level of P<0.05 was considered significant for both approaches.

Results

Results of literature data collection

Clinical manifestation

The clinical manifestations of glyphosate poisoning include initial symptoms such as nausea, vomiting, dizziness, weakness, abdominal pain, sore throat, and decreased blood pressure following oral administration. In severe cases, patients may exhibit cyanosis of the mouth and lips, breathing difficulties, wheezing, and rales in both lungs (31-33). Some patients may also experience hypokalemia (or hyperkalemia), pulmonary edema, abnormal chest X-ray results, and metabolic acidosis (34). Additionally, other symptoms such as arrhythmia, renal injury, and hepatotoxicity could occur (35).

Toxicological data

The European Food Safety Authority (EFSA) established a new threshold for long-term toxicity at 350 mg/kg bw/d based on hepatic dysfunction (18). The acceptable daily intake (ADI) was calculated to be 0.5 mg/kg bw/d. In comparison, the reference dose (RfD) in the USA was set at 2 mg/kg bw/d (36). Based on these findings, the NOAEL for developmental toxicity was determined to be 175 mg/kg bw/d from rabbit teratogenicity studies, and the NOAEL for systemic toxicity was identified as 362 mg/kg bw/d (37).

Identifications of target organs and key effect indicators

After entering the human body, most poisons or drugs are metabolized by the liver and excreted by the kidneys, which can make them more toxic to these organs. In Jayasumana’s research (38), farmers exposed to glyphosate showed a significant increase in kidney damage. Mesnage concluded that the end-effect organs of glyphosate and other herbicides were the liver and kidneys (39), coincident with the conclusions in other researches (40). Therefore, the liver and kidneys were identified as the target organs of glyphosate. Furthermore, glyphosate is an organophosphorus pesticide, and one of the diagnostic criteria of organophosphorus concentration poisoning is the decrease in ChE activity (41). Hence, ChE was used as a key effect marker, along with liver and renal function. In addition to analyzing the overall distribution of these indicators, abnormality rates were also considered.

Results of on-site survey

Production process

There are various synthetic routes for the industrial production of glyphosate, with the most competitive processes being the Iminodiacetic Acid Method (IDA) (42) and the Glycine Method (43), both of which are included in the manufacturers under investigation. In the IDA method, the first step involves synthesizing IDA, followed by the synthesis of N-(phosphonomethyl) iminodiacetic acid (PMIDA), and glyphosate is then produced through oxidation. The Glycine Method involves four steps: depolymerization, addition, condensation, and hydrolysis, using glycine, paraformaldehyde, and dimethyl phosphite as the main raw materials, triethylamine as the catalyst, and methanol as the solvent. While the processes of the two methods differ, the key steps generally include synthesis, centrifugation, and packaging, with some enterprises also involving suction filtration, oxidation, and hydrolysis. Following the investigation, it was found that in selected enterprises, the main positions exposed to glyphosate included centrifugation (oxidation), filtration, drying, and packaging. Consequently, workers in these positions were considered as the exposure groups, while workers in other positions such as synthesis and hydrolysis were chosen as the control groups.

Current status of occupational health

Table S1 presents the results of the on-site survey, detailing the total number of subjects, production layouts, frequency of exposure, and the use of occupational protective devices and personal protective equipment.

Results of glyphosate concentration tests in the workplace air

Area sampling

The sampled sites included positions such as centrifuge, suction filtration tank, dryer, packaging machine, feed and packaging of water carrier, finished products warehouse, and pellet mills. A total of 152 samples were collected, with 112 samples showing a concentration lower than 1 mg/m³, accounting for 73.68% of the total samples, and 14 samples showing a concentration greater than 5 mg/m³, accounting for 9.21% of the total samples. The highest concentration of glyphosate in the workplace air was 20.68 mg/m³, and the lowest was below the detection limit. The average concentration was 1.21 mg/m³. The test results are presented in Table 1.

Personal sampling

A total of 89 samples were collected through personal sampling, as detailed in Table 2. The C_TWA ranged from 0.03 to 48.91 mg/m³. Out of these samples, 56 samples showed a concentration lower than 1 mg/m³, accounting for 62.92% of the total, while 13 samples exhibited a concentration higher than 5 mg/m³, making up 14.61% of the total samples. Overall, the C_TWA for most positions was found to be less than 1 mg/m³.

Results and analysis of occupational health examination

Test results of liver function

Three liver function parameters, alanine aminotransferase (ALT), total protein (TP) and albumin/globulin (A/G) were tested in both the exposure and control groups. With the results presented in Table 3, a t-test was conducted to assess the difference. The findings revealed significant variances in ALT and TP values between the control groups and exposure groups, although the mean values for both parameters were within the normal range. While there was no significant difference in A/G, the mean values also fell within normal limits. The overall abnormality rates of liver function in the exposure and control groups were 14.4% and 5.0%, respectively, with a statistically difference between the two groups (χ²=23.679, P<0.001). These results suggest that excessive exposure to glyphosate may lead to abnormal increases in ALT and TP levels.

Test results of renal function

Renal function was assessed using blood urea nitrogen (BUN), creatinine (Cr), and uric acid (UA) as indicators, as presented in Table 4. The statistical analysis revealed a significant difference in UA levels between the two groups, with the exposure group showing significantly higher values than the control group. However, no significant differences were found in Cr and UA. The mean values of renal function indicators in both groups were within the normal range. The abnormality rates of renal function were 16.2% and 6.1% for the exposure and control groups, respectively, and the difference was statistically significant (χ²=23.715, P<0.001). These findings suggest that excessive exposure to glyphosate may increase the risk of kidney disease, which is consistent with previous research (36).

Test results of ChE activity

ChE activity serves as a sensitive indicator of organophosphorus pesticide poisoning, as demonstrated in Table 5. The test results revealed a noticeable disparity between the two groups, with the exposure group displaying significantly lower ChE activity compared to the control group. However, the mean values for both groups remained within normal limits, and the disparity in abnormality rates was statistically significant. In other words, exposure to glyphosate led to a reduction in ChE.

Determination of dose-response relationship

Based on the analysis of physical examinations and glyphosate levels in the workplace air, workers with different degrees of occupational exposure were categorized into various groups (low-dose group: ~1 mg/m³, medium-dose group: ~10 mg/m³, high-dose group: >10 mg/m³). A clear dose-response relationship was observed in relation to the change in key effect indicators across different exposure levels. Figures 1-3 present the dose-effect relationships based on liver function, renal function, and ChE activity as effect markers regardless of units of parameters. As shown in Figures 4-6, there were intuitive change trends in indicators of ChE, TP and UA with the change of glyphosate concentrations.

Figure 1 Dose-effect analysis of liver function. ALT, alanine aminotransferase; TP, total protein; A/G, albumin/globulin.

Figure 2 Dose-effect analysis of renal function. BUN, blood urea nitrogen; Cr, creatinine; UA, uric acid.

Figure 3 Dose-effect analysis of ChE activity. ChE, cholinesterase.

Figure 4 Dose-effect relationships based on ChE. ChE, cholinesterase.

Figure 5 Dose-effect relationships based on TP. TP, total protein.

Figure 6 Dose-effect relationships based on UA. UA, uric acid.

Deduction of OELs

Calculation using the BMD method

The BMDS software Version 2.6 was utilized to compute the BMD and BMDL, with a baseline of 10% and a 95% confidence interval selected based on the model with the best goodness of fit. The results are presented in Table 6, and the equations demonstrated good fit when P>0.05. Using TP as the effect index, the OEL was determined to be 10.75 mg/m³ (P=0.96).

Calculation using the EPA method

In Eq. [1], BW was set at 70 kg, SF at 500, and BR at 10 m³ (24). The minimum NOAEL of glyphosate is 175 mg/kg/d, based on developmental toxicity. Consequently, the resulting OEL is calculated to be 2.45 mg/m³. However, as pregnant women were not included in the survey, this value cannot be effectively analyzed in relation to the actual on-site conditions. In other words, even if the concentration of glyphosate is lower than 2.45 mg/m³, it cannot be conclusively determined whether there is no risk of developmental anomalies.

Based on the NOAEL for systemic toxicity established by the EPA and the World Health Organization in 1994, which was 362 mg/kgbw/d, the calculated OEL was determined to be 5.73 mg/m³, assuming that the main parameters were the same as those used for developmental toxicity. Table 7 presents the abnormality rates of key effect indicators at varying glyphosate concentrations. When the concentration of glyphosate in the workplace air was below 5 mg/m³, there was no significant difference in the abnormality rates of liver and renal function between the exposure and control groups (P>0.05). However, at a concentration of 6 mg/m³, the difference in abnormality rates of renal function compared to the control groups was found to be statistically significant (P<0.05).

Discussion

This study marks the first establishment of the OEL for glyphosate in China and possibly worldwide. Glyphosate exposure is pervasive in daily life due to its presence in various ecosystems, including water, air, and soil, particularly in workplaces involved in glyphosate production. Prior to this study, hygienic standards had not clearly defined OELs for glyphosate. The national hygienic standards of China, OELs for hazardous agents in the workplace, part 1: chemical hazardous agents (GBZ 2.1-2019) (44), include OELs encompassing permissible concentration-time weighted average (PC-TWA), permissible concentration-short term exposure limit (PC-STEL), and maximum allowable concentration (MAC). During field investigations, exposure to high concentrations of glyphosate for short periods did not cause acute effects on workers, such as irritation, asphyxia, or inhibition of the central nervous system. Based on this premise, the OEL for glyphosate in this study refers to PC-TWA.

First, extensive literature reviews were conducted to gather toxicology information on glyphosate. In chronic toxicity studies involving rats, liver abnormalities were observed when the dose reached the lowest observed adverse effect level (LOAEL). Additionally, clinical data on glyphosate poisoning indicated that liver and kidney function abnormalities were the most prominent indicators. As a result, liver function and renal function were chosen as key markers for the research. Subsequently, ample population data and on-site detection data from typical glyphosate manufacturing enterprises were obtained through occupational health testing and occupational medical examinations, providing a foundation for analyzing the dose-response relationship.

The recommended OEL was thoroughly validated and assessed from various perspectives. Through calculations, the OEL was determined to be 2.45, 5.73, and 10.75 mg/m³. The value of 2.45 mg/m³ was derived from the NOAEL data of developmental toxicity. However, this value was not adopted in our research due to the lack of effective research data, as pregnant women were not included in the study population, and they are generally not employed in glyphosate production roles. In our analysis, the concentration of 5 mg/m³ emerged as a threshold, as significant differences in the abnormality rates of key effect markers related to renal function between the exposed and control groups were observed when the glyphosate concentration exceeded 5 mg/m³. As the concentration increased, the abnormality rate of the effect marker also increased accordingly. Therefore, it was recommended that the PC-TWA for glyphosate be set at 5 mg/m³.

Based on the results of the BMD method, the calculated OEL was 10.75 mg/m³ when using TP as the effect index, which was approximately twice the limit derived from the NOAEL. The higher BMD value may be attributed to the complexity of the study population and the dose component level. It’s important to note that the dose group classification was based on the highest exposure concentration observed in the study. For instance, the dose group of ~5 mg/m³ referred to the group exposed to glyphosate with a concentration ranging from 3 to 5 mg/m³ in this study, potentially leading to an overestimation of the OEL. When using RfD as the starting point for calculation, the allowable daily intake for adults weighing 70 kg was determined to be 140 mg, leading to a permissible concentration of 14 mg/m³ based on an assumed respiration rate of 10 m³ over an 8-hour period. However, when considering a respiration rate of 25 m³ over 24 hours, the calculated OEL was 5.6 mg/m³, which closely aligns with the proposed OEL.

Drawing an analogy from the perspective of typical organophosphorus pesticides with low toxicity, both the OELs and the median lethal dose (LD₅₀) were used as reference parameters to evaluate the recommended OEL for glyphosate. As shown in Table S2, the LD₅₀ of glyphosate is approximately 2.8 times and 8.9 times that of malathion and trichlorfon, respectively. Based on this, the OEL of glyphosate is estimated to be 5.6 and 4.5 mg/m³, respectively. Similarly, considering that the NOAEL of glyphosate is about 3.6 and 10.2 times that of malathion and acephate, the inferred OEL for glyphosate should be around 7.2 and 3.6 mg/m³, respectively. The suggested OEL in this study was 5 mg/m³, which aligns closely with the above results. Furthermore, it’s worth noting that the OEL was more stringent than that calculated from the LD₅₀ and NOAEL of malathion, the LD₅₀ of which was similar to that of glyphosate.

Notably, the recommended OEL was concluded in March 2015. From April to June 2015, the research team sent out letters soliciting opinions to pesticide manufacturers, local centers for disease control and prevention, occupational disease prevention and treatment institutes, universities, and completed the opinion solicitation work. Afterward, it underwent numerous rigorous reviews by experts in multiple conferences. In 2019, the proposed OEL was approved by the Technical Review Committee of the National Occupational Health Standards Committee in China, and was added into OELs for hazardous agents in the workplace Part 1: Chemical hazardous agents (GBZ 2.1-2019), which was published in August 2019 with positive feedback received since the implementation in 2020. In addition, TWA of glyphosate stipulated by ACGIH is also 5 mg/m³, issued later than in China. Main EU countries have not yet issued OELs for glyphosate.

As a result, the C_TWA of several positions in the investigated enterprises significantly exceeded the recommended OEL, particularly in roles such as packaging, where workers are required to operate around packaging machines for extended periods. However, with the advancement of mechanization and automation, some glyphosate manufacturers have transitioned from manual packaging to automatic packaging processes. This shift has the potential to substantially reduce the occupational exposure to glyphosate, thereby mitigating the health risks associated with prolonged exposure in these roles.

From the perspective of prevention, it is necessary to strengthen the engineering ventilation at worksites and guide workers to take proper individual protective measures to avoid the inhalation of glyphosate in aerosol form. Last but not least, health examination items focused on liver, kidney toxicity and cholinesterase (ChE) inhibition should be established to improve occupational health monitoring for glyphosate.

In terms of LD₅₀, glyphosate is generally classified as a low-toxicity chemical. Its target organ toxicity is not very specific, unlike certain heavy metals that produce significant effects on the nervous system, blood, or bones. The commercial glyphosate-based herbicides are mixtures of glyphosate and other components, such as surfactant and auxiliary, which may cause effects on the health of those exposed. More attention should be paid on the components of auxiliary to distinguish toxic effects caused by glyphosate and other chemical substances.

Conclusions

This study aimed to establish the OEL for glyphosate by leveraging a clear dose-response relationship and precise limit calculation methods. The research involved comprehensive literature data collection, on-site occupational investigations, and occupational health examinations. As a result, the PC-TWA of glyphosate was determined to be 5 mg/m³. Furthermore, there is a commitment to closely monitor the impact of current technological transformations on glyphosate concentration in workplace air. This ongoing analysis will serve as the foundation for potential modifications and enhancements to the OEL. Ultimately, the proposed OEL is intended to drive the optimization of the working environment and safeguard the health of workers.

Acknowledgments

The authors are indebted to the funders of Jiangsu commission of health and Chinese Center for Disease Control and Prevention. We would also like to thank CDCs of Nantong, Zhenjiang and Yangzhou for their help in the field work. Last but not the least, we have been very appreciative for the support and cooperation from enterprises A–E and front-line workers participated in this study.

Footnote

Data Sharing Statement: Available at https://jphe.amegroups.com/article/view/10.21037/jphe-24-75/dss

Peer Review File: Available at https://jphe.amegroups.com/article/view/10.21037/jphe-24-75/prf

Funding: This work was funded by Jiangsu Province’s Outstanding Medical Academic Leader program (CXTDA2017029), National Occupational Health Standards (20140701), and Occupational Health Research Project of Jiangsu Province (JSZJ20231209).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jphe.amegroups.com/article/view/10.21037/jphe-24-75/coif). B.Z. serves as the Editor-in-Chief of Journal of Public Health and Emergency from January 2022 to December 2026. All authors reported this work was funded by Jiangsu Province’s Outstanding Medical Academic Leader program (CXTDA2017029), National Occupational Health Standards (20140701), and Occupational Health Research Project of Jiangsu Province (JSZJ20231209). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The studies involving human participants were reviewed and approved by the Ethics Committee of Jiangsu Provincial Center for Disease Control and Prevention (2014005). The participants provided their written informed consent to participate in this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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