Impact of agricultural chemicals on thyroid health in India

Pesticide Usage in Indian Agriculture

India is one of the world’s largest consumers of pesticides, with an estimated annual consumption of 58,000 metric tons.⁶ The regulatory framework governing pesticide use in India has evolved, but enforcement challenges and improper application practices remain widespread issues.¹ Organochlorines, organophosphates, carbamates, and pyrethroids represent the major classes of insecticides used in Indian agriculture, while various herbicides and fungicides are also commonly applied.⁶

The pattern of pesticide usage in India differs from that in many developed countries. While many organochlorine pesticides (OCPs) have been banned globally due to their persistence and toxicity, some continue to be detected in the Indian environment due to historical use, illegal application, or environmental persistence. Additionally, a lack of proper education on pesticide application among farmers often leads to overuse, improper mixing, and inadequate protective measures during application.¹

Mechanisms of Thyroid Disruption by Pesticides

Agricultural pesticides may interfere with thyroid function through multiple mechanisms^5,7-9:

1. Disruption of thyroid hormone synthesis: Several pesticides can inhibit key enzymes involved in thyroid hormone production, such as thyroid peroxidase (TPO), which catalyzes iodination and coupling of tyrosine residues to form thyroid hormones. For example, ethylenethiourea, a metabolite of ethylene bisdithiocarbamate fungicides, has been shown to inhibit TPO activity.^10,11

2. Alteration of thyroid hormone transport: Pesticides may compete with thyroid hormones for binding to transport proteins such as transthyretin and thyroid-binding globulin, potentially affecting hormone delivery to target tissues.¹² This competition can displace thyroid hormones from their carriers, leading to altered free hormone levels in circulation.

3. Interference with metabolism: Some pesticides can induce hepatic enzymes that accelerate thyroid hormone clearance, potentially leading to compensatory mechanisms that may eventually fail. Induction of UDP-glucuronosyltransferases and sulfotransferases can enhance T4 conjugation and biliary excretion.^12,13

4. Disruption of thyroid hormone receptor binding: Certain pesticides may interfere with thyroid hormone binding to nuclear receptors, affecting downstream signaling pathways. This can disrupt gene expression patterns regulated by thyroid hormones, even when circulating hormone levels appear normal.^12,14

5. Direct thyroid toxicity: Some pesticides may cause direct damage to thyroid follicular cells, affecting gland function. Chronic exposure to certain pesticides has been associated with histopathological changes in the thyroid gland in animal studies.¹⁵

6. Disruption of the hypothalamic-pituitary-thyroid (HPT) axis: Pesticides may interfere with the regulatory mechanisms controlling thyroid hormone production, including disruption of thyroid-stimulating hormone (TSH) production or action.^5,12

These mechanisms are not mutually exclusive, and a single pesticide may disrupt thyroid function through multiple pathways. Additionally, the combined effects of multiple pesticides, as is common in agricultural settings, may lead to more complex disruption patterns than would be predicted from single-compound studies. Figure 1 illustrates these six key mechanisms through which agricultural chemicals may disrupt thyroid function, with examples of specific compounds acting through each pathway.

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Figure 1:

Mechanisms of thyroid disruption by agricultural chemicals. TPO: Thyroid peroxidase, TR: Thyroid receptor, HPT: Hypothalamic-pituitary-thyroid, OCP: Organochlorine pesticide.

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OCPs

OCPs, despite restrictions, continue to be detected in the Indian environment and population due to their persistence and continued illegal use. Epidemiological studies have linked OCP exposure to thyroid dysfunction:

Goldner et al. reported a significant association between organochlorine pesticide exposure and hypothyroidism among female spouses of pesticide applicators, with an odds ratio (OR) of 1.2 (95% confidence interval [CI]: 1.0-1.6).¹⁶ A subsequent study by the same researchers found stronger associations among male pesticide applicators exposed to specific organochlorines, including chlordane (OR = 1.36, 95% CI: 1.12-1.66), heptachlor (OR = 1.3, 95% CI: 1.04-1.62), lindane (OR = 1.35, 95% CI: 1.1-1.66), and toxaphene (OR = 1.35, 95% CI: 1.07-1.7).¹⁷

Shrestha et al. reported age-dependent effects, with stronger associations between OCP exposure and hypothyroidism among older pesticide applicators (>62 years). Specifically, significant associations were observed for aldrin (hazard ratio [HR] = 1.28, 95% CI: 1.02-1.60), chlordane (HR = 1.21, 95% CI: 1.04-1.41), heptachlor (HR = 1.35, 95% CI: 1.07-1.70), and lindane (HR = 1.54, 95% CI: 1.23-1.94).¹⁸ This age-dependent effect suggests that longer cumulative exposure or age-related susceptibility may play important roles in pesticide-induced thyroid disruption.

A cross-sectional study by Londoño et al. conducted among agricultural workers found significant associations between specific OCPs and subclinical hypothyroidism, including heptachlor (OR = 1.7, 95% CI: 1.0-3.2), endosulfan (OR = 6.2, 95% CI: 1.6-24.8), cis-chlordane (OR = 3.1, 95% CI: 1.0-9.4), and 4,4′-DDE (OR = 3.8, 95% CI: 1.6-9.2).¹⁹ The particularly strong association with endosulfan is noteworthy, as this pesticide was widely used in India until its recent phase-out.

Lerro et al. reported that higher exposure to aldrin was associated with subclinical hypothyroidism (ptrend < 0.01) among male pesticide applicators.²⁰

Dufour et al. reported that 4,4′-DDT exposure showed a borderline significant association with overt hypothyroidism (OR = 4.47, 95% CI: 0.96-20.8), suggesting that even legacy organochlorines that have been banned for decades may continue to pose thyroid health risks due to their environmental persistence.²¹

Organophosphate Pesticides (OPs)

OPs are among the most widely used insecticides in Indian agriculture. Evidence linking OPs to thyroid dysfunction includes:

Lacasaña et al. found inverse associations between urinary OP metabolite levels and total T4 and free T4 levels among floriculture workers, suggesting a potential impact on thyroid hormone levels. This study provides evidence for a dose-response relationship, as higher urinary OP metabolite concentrations were associated with greater reductions in thyroid hormone levels.²²

Shrestha et al. reported significant associations between several OPs and hypothyroidism, including coumaphos (HR = 1.44, 95% CI: 1.06-1.95), diazinon (HR = 1.27, 95% CI: 1.10-1.48), dichlorvos (HR = 1.42, 95% CI: 1.17-1.72), and malathion (HR = 1.23, 95% CI: 1.04-1.46).¹⁸ Notably, malathion is one of the most widely used organophosphates in Indian agriculture, suggesting potential public health implications.

Suhartono et al. found a significant association between OP exposure and subclinical hypothyroidism among school-aged children in agricultural areas, with a prevalence ratio of 2.4 (95% CI: 1.4-4.3).²³ This finding is particularly concerning, as it suggests that environmental exposures to OPs may affect vulnerable populations such as children.

Fortenberry et al. reported that urinary 3,5,6-trichloro-2-pyridinol, a metabolite of chlorpyrifos, was associated with decreased total T4 levels in the National Health and Nutrition Examination Survey (NHANES) population, particularly among women.²⁴ Chlorpyrifos has been widely used in Indian agriculture on various crops.

Piccoli et al. found that agricultural workers exposed to organophosphates had higher chances of hypothyroidism as compared to unexposed controls.²⁵

A recent study by Ranjith observed alterations in thyroid hormone levels mimicking thyrotoxicosis among patients with acute organophosphorus compound poisoning.²⁶

Other Pesticide Classes

Goldner et al. found a significant association between the carbamate insecticide carbofuran and hypothyroidism among male pesticide applicators (OR = 1.31, 95% CI: 1.08-1.59).¹⁷ Carbofuran has been widely used in rice cultivation in India, though its use has been restricted in recent years.

Wei et al. reported a strong association between exposure to 2,5-dichlorophenol (2,5-DCP), a metabolite of paradichlorobenzene, and overt hypothyroidism among US adolescents (OR = 12.86, 95% CI: 1.39-118.64).²⁷ While paradichlorobenzene is primarily used as a moth repellent and deodorant rather than an agricultural pesticide, this finding illustrates the potent thyroid-disrupting potential of certain halogenated compounds.

Evidence regarding pyrethroid insecticides, which are increasingly used as alternatives to organophosphates and organochlorines, is more limited. Du et al. demonstrated that several pyrethroid insecticides and their metabolites could interfere with thyroid hormone receptor signaling in vitro, suggesting a potential mechanism for thyroid disruption.¹⁴ However, epidemiological studies have generally not found significant associations between pyrethroid exposure and hypothyroidism.^16-18

Herbicide Usage in Indian Agriculture

Herbicide use in India has increased significantly in recent decades, with glyphosate, paraquat, 2,4-D, atrazine, and pendimethalin among the most commonly used products.¹ Labor shortages have further driven the adoption of herbicides as an alternative to manual weeding. The shift toward conservation agriculture and direct seeding in rice cultivation has also contributed to increased herbicide use.

Thyroid-Disrupting Potential of Herbicides

While herbicides have received less attention than insecticides in thyroid disruption research, several commonly used herbicides in India have shown thyroid-disrupting potential:

Atrazine: Freeman et al. reported no significant association between atrazine exposure and thyroid cancer in the Agricultural Health Study cohort.²⁸ However, laboratory studies suggest that atrazine may affect thyroid hormone homeostasis by altering HPT axis regulation.²⁹ Specifically, atrazine has been shown to affect the expression of thyroid hormone-responsive genes in rats, suggesting potential disruption of thyroid signaling pathways.³⁰

Glyphosate: Laboratory studies suggest that glyphosate-based formulations may disrupt thyroid hormone-dependent gene transcription, potentially through non-genomic signaling pathways rather than direct interaction with thyroid hormone receptors.³¹

2,4-D (2,4-dichlorophenoxyacetic acid): Limited evidence suggests potential thyroid effects, but epidemiological data specifically examining thyroid outcomes are sparse.³² A recent study by Xu et al. showed a positive correlation between 2,4-D exposure and FT3 (p = 0.041), meaning higher levels of this herbicide metabolite were associated with higher levels of FT3.³³

Pendimethalin: This herbicide is widely used in India, particularly in rice and wheat cultivation. Lerro et al. reported that higher exposure to the herbicide pendimethalin was associated with subclinical hypothyroidism (ptrend = 0.02) and anti-TPO positivity (ptrend = 0.01) among male pesticide applicators.²⁰

The scarcity of data on herbicides and thyroid function represents a significant research gap, particularly given the increasing use of herbicides in Indian agriculture.

Fertilizer Usage Patterns in India

India is the world’s second-largest consumer of fertilizers, with nitrogen, phosphate, and potassium fertilizers being the most widely used.^34,35 Urea accounts for approximately 60% of all fertilizer consumed in the country.³⁴ Fertilizer subsidies have contributed to increased usage, often beyond agronomic recommendations, leading to potential environmental contamination.

Potential Impacts on Thyroid Function

Iodine Status and Vulnerability to Thyroid Disruptors

India has historically faced challenges with iodine deficiency, though the national iodized salt program has improved iodine nutrition.⁴⁰ However, certain regions still report inadequate iodine intake. Iodine deficiency may exacerbate the thyroid-disrupting effects of agricultural chemicals by making the thyroid more vulnerable to disruption.⁷

The potential interaction between iodine status and agricultural chemical exposure represents a critical consideration in the Indian context. In regions with marginal iodine status, even relatively modest thyroid-disrupting effects of pesticides or fertilizer-derived nitrates may have significant clinical implications. Conversely, adequate iodine nutrition may provide some resilience against the thyroid-disrupting effects of agricultural chemicals, although this protective effect is likely limited.

Occupational vs. Environmental Exposure

In the Indian agricultural context, both occupational and environmental exposures are relevant. Farmworkers face direct exposure during pesticide application, often without adequate protective equipment. Meanwhile, the general population may be exposed through contaminated food, water, and air. Women and children in agricultural communities may face particular risks.⁴¹

Occupational exposure among agricultural workers in India is often characterized by:

• Limited use of personal protective equipment

• Improper mixing and application practices

• Use of backpack sprayers that increase dermal exposure

• Reentry into treated fields before recommended intervals

• Storage of pesticides in residential areas

Environmental exposure pathways for the broader population include:

• Dietary exposure through pesticide residues in food

• Contamination of drinking water sources

• Aerial drift during application

• Residential proximity to agricultural areas

• Use of empty pesticide containers for household purposes

These multiple exposure pathways complicate risk assessment and management, requiring comprehensive approaches that address both occupational and environmental exposures.

Multiple Chemical Exposures

Indian agricultural practices often involve the application of multiple pesticides, herbicides, and fertilizers, potentially leading to complex mixture effects. Dufour et al. found that mixtures of persistent organic pollutants, including pesticides, were associated with thyroid pathologies, suggesting that studying single compounds may underestimate risks.²¹

The cocktail effect of multiple agrochemicals represents a significant challenge for risk assessment and management. Most toxicological studies focus on single compounds, while real-world exposures involve complex mixtures that may interact additively, synergistically, or antagonistically. Recent approaches utilizing mixture-based risk assessment methodologies may provide more realistic estimates of health risks associated with agricultural chemical exposures.

Public Health Burden

The high prevalence of thyroid disorders in India, particularly hypothyroidism, suggests a significant public health burden. If agricultural chemicals contribute to this burden, addressing agrochemical exposure could represent an important preventive approach.

Several large-scale epidemiological studies, including the Agricultural Health Study in the United States, have consistently reported associations between pesticide exposure and hypothyroidism.^16–18 A recent meta-analysis by Sirikul and Sapbamrer confirmed an increased risk of hypothyroidism associated with pesticide exposure, with a pooled relative risk of 1.76 (95% CI: 1.56-2.00).⁴²

While direct evidence from Indian populations is limited, the consistency of findings across different agricultural populations suggests potential relevance to the Indian context. Given the widespread use of agrochemicals in India and the high prevalence of thyroid disorders, even modest contributions of agricultural chemicals to thyroid dysfunction could translate to substantial public health impacts at the population level.

Vulnerable Populations

Certain populations may be particularly vulnerable to the thyroid-disrupting effects of agricultural chemicals:

1. Pregnant women and developing fetuses: Thyroid hormones are critical for fetal neurodevelopment, making pregnancy a particularly vulnerable period for thyroid disruption.⁴³ Maternal thyroid dysfunction during pregnancy, even if subclinical, can have lasting impacts on child neurodevelopment. Given the importance of the agricultural sector for female employment in rural India, occupational exposure among pregnant women represents a specific concern.

2. Children: Developing endocrine systems may be more susceptible to disruption, and children in agricultural communities may face higher exposures. Studies like that of Suhartono et al., demonstrating associations between OP exposure and subclinical hypothyroidism in children, highlight this vulnerability.²³ Additionally, the neurodevelopmental impacts of thyroid disruption may be more pronounced in children, even at subclinical levels of dysfunction.

3. Agricultural workers: Direct occupational exposure without adequate protection places agricultural workers at particular risk. The studies by Goldner et al.^16,17 and Shrestha et al.¹⁸ consistently demonstrated increased risks of hypothyroidism among pesticide applicators, with specific associations for several pesticides commonly used in India.

4. Residents of intensive agricultural regions: Environmental exposure through contaminated water, air, and food may affect larger populations in agricultural regions. The increasing intensification of agriculture in certain regions of India, coupled with high population density, creates scenarios where large populations may be environmentally exposed to agricultural chemicals.

5. Individuals with pre-existing thyroid conditions or genetic susceptibilities: Those with underlying thyroid dysfunction or genetic polymorphisms affecting thyroid hormone metabolism may be susceptible to the effects of thyroid-disrupting chemicals.

The complex relationship between agricultural chemical exposure and thyroid health in India involves multiple pathways and modifying factors, as illustrated in Figure 2. This conceptual framework depicts how various agricultural chemicals (pesticides, herbicides, fertilizers, and mixtures) lead to both occupational and environmental exposures, which are then modified by factors such as iodine status, genetic susceptibility, and nutritional status before manifesting as subclinical effects or clinical outcomes. Understanding this pathway is crucial for identifying appropriate intervention points and vulnerable populations for targeted public health measures.

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Figure 2:

Conceptual framework of agricultural chemical exposure pathways and thyroid health outcomes.

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India-Specific Research Needs

Most epidemiological studies linking pesticides to thyroid outcomes have been conducted in Western populations. India-specific research is needed to account for:

1. Unique exposure patterns: Different application practices, chemical formulations, and regulatory frameworks characterize Indian agriculture. For example, certain pesticides banned in Western countries may still be in use in India, while application practices often differ substantially from those in more mechanized agricultural systems.

2. Genetic factors: Potential population-specific susceptibilities to thyroid disruption, including genetic polymorphisms affecting pesticide metabolism or thyroid hormone homeostasis, may influence individual vulnerability to agricultural chemical exposures.

3. Nutritional interactions: Interactions between iodine status, other micronutrients, and thyroid disruptors in the Indian diet may modify the impacts of agricultural chemical exposures. For example, selenium status, which affects thyroid hormone metabolism, varies considerably across India and may interact with the effects of thyroid-disrupting chemicals.

4. Environmental conditions: Climate and environmental factors that may affect chemical degradation and exposure patterns differ substantially from those in temperate regions, where most studies have been conducted. Higher temperatures, intense rainfall patterns, and unique soil characteristics in India may influence the environmental fate of agricultural chemicals and thus exposure patterns.

5. Agricultural practices: The smaller average farm size, greater reliance on manual labor, and different crop patterns in Indian agriculture create exposure scenarios that may differ substantially from those in more mechanized agricultural systems.

Methodological Considerations for Future Research

Future research should address several methodological challenges:

1. Improved exposure assessment: Biomonitoring for relevant metabolites rather than relying solely on self-reported exposure would strengthen the evidence base.⁴⁴ This is particularly important in the Indian context, where recall bias may be significant and where literacy levels among agricultural workers may affect the reliability of self-reported exposure data.

2. Longitudinal designs: To establish temporality between exposure and thyroid outcomes, longitudinal studies following exposed populations over time are needed. Most existing studies are cross-sectional or retrospective, limiting causal inference.

3. Mixture effects: Evaluating combined effects of multiple agricultural chemicals rather than single-compound analyses would better reflect real-world exposure scenarios. Advanced statistical approaches, such as weighted quantile sum regression or Bayesian kernel machine regression, may help characterize the health effects of complex mixtures.

4. Mechanistic studies: Incorporating mechanistic biomarkers to elucidate pathways of disruption would strengthen evidence for causal relationships. This might include measures of TPO inhibition, thyroid hormone receptor activation, or markers of HPT axis regulation.

5. Integration of -omics approaches: Genomics, proteomics, and metabolomics approaches may help identify biomarkers of effect and susceptibility, improving risk assessment and potentially identifying vulnerable subpopulations.

6. Community-based participatory research: Engaging agricultural communities in research design and implementation may improve study relevance, participant recruitment and retention, and translation of findings into practice.

Regulatory Approaches

1. Stricter regulation: Reassessment of approved agrochemicals based on thyroid-disrupting potential should be considered. This might include incorporating endocrine-disrupting potential into risk assessment frameworks for pesticide registration.

2. Enhanced surveillance: Biomonitoring programs to track population exposure to agricultural chemicals would provide valuable data for risk assessment and management. India’s existing biomonitoring capabilities could be expanded to include markers of pesticide exposure and thyroid function.

3. Regional policies: Targeted interventions in high-exposure regions, particularly those with known thyroid disorders or iodine deficiency, may be warranted based on local risk profiles.

4. International harmonization: Alignment with international standards for pesticide regulation, while accounting for India-specific agricultural needs and exposure scenarios, may help reduce risks while maintaining agricultural productivity.

Agricultural Practice Modifications

1. Integrated Pest Management (IPM): Promoting IPM approaches to reduce chemical inputs while maintaining productivity offers a promising strategy for reducing exposure risks. IPM has been successfully implemented in various Indian agricultural systems, but requires continued support for wider adoption. As illustrated in Figure 3, IPM represents a holistic approach that prioritizes prevention and monitoring, with chemical interventions used only as a last resort.

2. Training programs: Educating farmers on safe handling practices and appropriate application methods can significantly reduce occupational exposure. Training should be culturally appropriate, accessible to farmers with limited literacy, and include practical demonstrations.

3. Protective equipment: Ensuring accessibility and use of personal protective equipment is essential for reducing occupational exposure. Protective equipment should be affordable, comfortable in hot climates, and culturally acceptable to maximize adoption.

4. Buffer zones: Establishing buffer zones around water bodies, residential areas, and schools can reduce environmental and bystander exposure to agricultural chemicals.

5. Precision agriculture: Where feasible, promoting precision application technologies can reduce overall chemical use and exposure potential. While advanced technologies may not be accessible to all farmers, simpler forms of targeted application can still reduce unnecessary chemical use.

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Figure 3:

Integrated Pest Management (IPM) framework and implementation in the Indian agricultural context.

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Clinical Considerations

1. Awareness among healthcare providers: Recognizing occupational and environmental exposures as potential risk factors for thyroid disorders is important for clinical practice, particularly in agricultural regions.

2. Targeted screening: Consideration of thyroid function testing in highly exposed populations, especially those with additional risk factors for thyroid disorders, may facilitate early detection and management.

3. Integration of occupational and environmental health into medical education: Strengthening training on environmental health topics, including agricultural chemical exposure, in medical curricula, would improve healthcare providers’ capacity to recognize and address environmental factors contributing to thyroid disorders.

4. Clinical guidelines: Development of guidelines for evaluating and managing potential thyroid effects of agricultural chemical exposure would support consistent and evidence-based clinical practice.