Metabolome-wide association study of the relationship between chlorpyrifos exposure and first trimester serum metabolite levels in pregnant Thai farmworkers.

INTRODUCTION: Organophosphate (OP) insecticides, including chlorpyrifos, have been linked with numerous harmful health effects on maternal and child health. Limited data are available on the biological mechanisms and endogenous pathways underlying the toxicity of chlorpyrifos exposures on pregnancy and birth outcomes. In this study, we measured a urinary chlorpyrifos metabolite and used high-resolution metabolomics (HRM) to identify biological perturbations associated with chlorpyrifos exposure among pregnant women in Thailand, who are disparately exposed to high levels of OP insecticides. METHODS: This study included 50 participants from the Study of Asian Women and their Offspring's Development and Environmental Exposures (SAWASDEE). We used liquid chromatography-high resolution mass spectrometry to conduct metabolic profiling on first trimester serum samples collected from participants to evaluate metabolic perturbations in relation to chlorpyrifos exposures. We measured 3,5,6-trichloro-2-pyridinol (TCPy), a specific metabolite of chlorpyrifos and chlorpyrifos-methyl, in first trimester urine samples to assess the levels of exposures. Following an untargeted metabolome-wide association study workflow, we used generalized linear models, pathway enrichment analyses, and chemical annotation to identify significant metabolites and pathways associated with urinary TCPy levels. RESULTS: In the 50 SAWASDEE participants, the median urinary TCPy level was 4.36 µg TCPy/g creatinine. In total, 691 unique metabolic features were found significantly associated with TCPy levels (p < 0.05) after controlling for confounding factors. Pathway analysis of metabolic features associated with TCPy indicated perturbations in 24 metabolic pathways, most closely linked to the production of reactive oxygen species and cellular damage. These pathways include tryptophan metabolism, fatty acid oxidation and peroxisome metabolism, cytochromes P450 metabolism, glutathione metabolism, and vitamin B3 metabolism. We confirmed the chemical identities of 25 metabolites associated with TCPy levels, including glutathione, cystine, arachidic acid, itaconate, and nicotinamide adenine dinucleotide. DISCUSSION: The metabolic perturbations associated with TCPy levels were related to oxidative stress, cellular damage and repair, and systemic inflammation, which could ultimately contribute to health outcomes, including neurodevelopmental deficits in the child. These findings support the future development of sensitive biomarkers to investigate the metabolic underpinnings related to pesticide exposure during pregnancy and to understand its link to adverse outcomes in children.

Health Risk Assessment of Heavy Metals in Indoor Household Dust in Urban and Rural Areas of Chiang Mai and Lamphun Provinces, Thailand.

Indoor exposure to heavy metals poses human health risks worldwide, but study reports from Thailand are still limited, particularly in rural and urban areas. We measured the heavy metals in a hundred indoor household dust samples collected from urban and rural areas in Chiang Mai and Lamphun provinces and found a significantly higher concentration of As in rural areas and Cd in urban areas with industrial activities. The source identification of the heavy metals showed significant enrichment from traffic emissions, paint, smoking, and mixed sources with natural soil. From health risk assessment models, children were more vulnerable to noncarcinogenic risks (HI = 1.45), primarily via ingestion (HQ = 1.39). Lifetime cancer risks (LCRs) due to heavy metal exposure were found in adults (LCR = 5.31 × 10-4) and children (LCR = 9.05 × 10-4). The cancer risks from As were higher in rural areas via ingestion, while Cr and Ni were higher in urban areas via inhalation and ingestion, respectively. This study estimated that approximately 5 out of 10,000 adults and 9 out of 10,000 children among the population may develop cancer in their lifetime from exposure to indoor heavy metals in this region.

Urinary Levels of Sirtuin-1, π-Glutathione S-Transferase, and Mitochondrial DNA in Maize Farmer Occupationally Exposed to Herbicide.

Epidemiologic studies have suggested an association between agrochemical exposure and risk of renal injury. Farmers face great risks to developing adverse effects. The most appropriate biomarker related to renal injury needs to be developed to encounter earlier detection. We aim to study the association between early renal biomarker and occupational herbicide exposure in maize farmers, Thailand. Sixty-four farmers were recruited and interviewed concerning demographic data, herbicide usage, and protective behavior. Two spot urines before (pre-work task) and after (post-work task) herbicide spraying were collected. To estimate the intensity of exposure, the cumulative herbicide exposure intensity index (cumulative EII) was also calculated from activities on the farm, type of personal protective equipment (PPE) use, as well as duration and frequency of exposure. Four candidate renal biomarkers including π-GST, sirtuin-1, mitochondrial DNA (mtDNA) were measured. Most subjects were male and mostly sprayed three herbicides including glyphosate-based herbicides (GBH), paraquat, and 2,4-dichlorophenoxyacetic acid (2,4-D). A type of activity in farm was mixing and spraying herbicide. Our finding demonstrated no statistical significance of all biomarker levels between pre- and post-work task urine. To compare between single and cocktail use of herbicide, there was no statistical difference in all biomarker levels between pre- and post-work task urine. However, the urinary mtDNA seems to be increased in post-work task urine. Moreover, the cumulative EII was strongly associated with change in mtDNA content in both ND-1 and COX-3 gene. The possibility of urinary mtDNA as a valuable biomarker was promising as a noninvasive benchmark for early detection of the risk of developing renal injury from herbicide exposure.

Urinary glyphosate kinetics after occupational exposure.

Glyphosate-surfactant herbicides are the most used and imported herbicide in Thailand. Urinary biomonitoring is a very important tool for evaluating glyphosate exposures and its adverse health effects. However, the data for glyphosate toxicokinetics, especially in Asian populations, is relatively limited. The majority of farmers in Thailand have long term experience with glyphosate use, but they generally follow poor safety practices, including insufficient or incorrect use of personal protective equipment during pesticide handling activities. Therefore, this study aimed to determine the toxicokinetics of glyphosate and its metabolite in urine among maize farmers from the northern region of Thailand. The effects of personal protective equipment usage, as well as farmer behavior during work, on urinary glyphosate levels were also studied. Full-voided spot urine samples were collected over the exposure assessment period (0-72 h). Urinary glyphosate levels were determined by liquid chromatography tandem mass spectrometry. The maximum concentration in urine (uCmax), the time of peak glyphosate levels in urine (uTmax), and the urinary elimination half-life (ut1/2) were analyzed using the PKSolver program. The median of uCmax were 27.9, 29.2 and 17.1 µg/g creatinine in a one-time spray group, a two-time spray group Day 1 and a two-time spray group Day 2, respectively. The uTmax was 11.0 h in both study groups. The median of elimination ut1/2 in the one-time and the two-time spray group were 7.0 and 18.1 h, respectively. Although these estimated urinary elimination half-lives may have been impacted by the variation in exposure doses among the participants, it provides the first urinary toxicokinetic data of glyphosate among the Asian population. The toxicokinetic information could be used to increase knowledge and awareness amongst farmers, particularly to minimize the risk of exposure to glyphosate and reduce possible adverse health effects from using pesticide.

Effect of Occupational Exposure to Herbicides on Oxidative Stress in Sprayers.

BACKGROUND: Herbicides such as glyphosate, paraquat, and 2,4-dichlorophenoxyacetic acid have been reported to cause adverse side effects through production of reactive oxygen species. However, there were no data representing the adverse effects of a mixture herbicide usage in farmers, especially the changes in oxidative marker and antioxidant defense. This study aimed to determine the urinary malondialdehyde (MDA) and glutathione (GSH) level in farmers using mixed herbicides. METHODS: Ninety-three farmers were recruited, and two spot urine samples (before and after work) were collected. The urinary MDA level was evaluated by thiobarbituric acid reactive substance assay, and the urinary GSH level was determined using the enzymatic recycling method. RESULTS: Sixty-two percent of the participants were men, and 59% of the participants worked in a farm for 20-40 years. The common combinations of herbicide usage were glyphosate with 2,4-dichlorophenoxyacetic acid (36.5%). There was no significant difference between pre- and post-work urinary MDA and GSH levels among the 3 groups of herbicides. However, the urinary MDA levels in farmers using the combination of glyphosate and paraquat were significantly higher than those found in farmers using glyphosate alone. The associated factors with changes in MDA levels found that the exposure intensity index (B = 0.154), the cumulative exposure intensity index (B = 0.023), and wearing gloves while working (B = -2.347) were found to be significantly associated with MDA level. CONCLUSION: The results suggest that the combined use of glyphosate and paraquat caused a significant increase in urinary MDA levels. Moreover, intensity of exposure to herbicide and wearing gloves were associated with the level of MDA.