Review Article: Chlorothalonil and Cancer: A Comprehensive Overview

Abstract

Chlorothalonil, a broad-spectrum fungicide, has been extensively used in agriculture for over five decades. It plays a vital role in preventing fungal diseases in various crops, contributing significantly to increased agricultural productivity. However, concerns about the safety of chlorothalonil have arisen, particularly regarding its potential to cause cancer. The International Agency for Research on Cancer (IARC) classified chlorothalonil as a possible human carcinogen (Group 2B), which has led to intensified scrutiny of its long-term effects on human health. This review aims to critically evaluate the existing body of evidence on chlorothalonil’s potential carcinogenicity, examining toxicological data, mechanisms of action, and epidemiological studies, while also discussing regulatory actions and future research directions.

Introduction

Chlorothalonil (2,4,5,6-tetrachloroisophthalonitrile) is a chlorinated organic compound that has been used globally as a fungicide since the 1960s [1]. Its primary application is in agriculture, where it is utilized to prevent fungal infections in crops such as potatoes, tomatoes, peanuts, and various cereals. Chlorothalonil is also used in turf management and horticulture to maintain the health of ornamental plants and golf courses [2]. Due to its widespread usage, chlorothalonil residues are commonly detected in agricultural runoff, surface water, and sometimes in drinking water sources [3].

While chlorothalonil’s economic importance is undeniable, the compound has been subject to increasing regulatory scrutiny due to its potential health impacts. The IARC’s classification of chlorothalonil as a possible human carcinogen (Group 2B) has raised concerns about its potential role in increasing cancer risk, particularly among agricultural workers and communities exposed to high levels of the chemical [4].

The objective of this review is to summarize and analyze current research on chlorothalonil’s carcinogenic potential, with a focus on toxicological findings, epidemiological data, and insights into its mechanisms of action. We will also consider the implications of these findings for public health policy and regulatory frameworks.

Chemical Properties and Usage of Chlorothalonil

Chlorothalonil is a polychlorinated compound that functions as a broad-spectrum, non-systemic fungicide [5]. It is typically applied to crops as a protective agent before the onset of fungal infections. Its mode of action involves the inhibition of several enzymatic processes crucial to fungal growth, including the disruption of cellular respiration [1]. By affecting multiple biochemical targets, chlorothalonil is effective against a wide variety of fungal species, making it a popular choice in agriculture [6] (Figure 1).

Figure 1. How Chlorothalonil Affects Fungal Infection.

In addition to its agricultural applications, chlorothalonil is used in paint, wood treatments, and as a preservative in various industrial products [7]. Its non-systemic nature means that chlorothalonil remains on the surface of plants and does not translocate to other parts, leading to concerns about its persistence in the environment and accumulation in food chains [8].

Mechanisms of Toxicity and Carcinogenicity

Chlorothalonil’s fungicidal action relies on its ability to generate reactive oxygen species (ROS) and disrupt cellular respiration in fungal organisms [9]. However, these same mechanisms are believed to contribute to its toxic effects in mammals, including humans. Chlorothalonil has been shown to induce oxidative stress, causing damage to cellular components such as DNA, proteins, and lipids [10]. The accumulation of ROS can lead to mutations, which may initiate carcinogenesis (Figure 2).

Figure 2. Mechanisms of Toxicity and Carcinogenicity.

DNA Damage and Mutagenicity

Several studies have demonstrated that chlorothalonil can cause genotoxicity, including DNA strand breaks and chromosomal aberrations, in mammalian cells. The mutagenic potential of chlorothalonil has been observed in in vitro and in vivo assays, which raises concerns about its potential to initiate cancer at sites of exposure, particularly the kidneys and gastrointestinal tract [11, 12].

Kidney Toxicity and Nephrocarcinogenicity

Animal studies have provided substantial evidence that chlorothalonil is nephrotoxic at high doses [13]. In rodent models, chronic exposure to chlorothalonil has been associated with the development of renal tubular adenomas and carcinomas [14]. These findings suggest that chlorothalonil may pose a specific risk to the kidneys, particularly under conditions of prolonged or high-dose exposure. The exact mechanism of chlorothalonil-induced kidney carcinogenesis is not fully understood but is thought to involve oxidative damage to renal tubular cells, which leads to abnormal cell proliferation and tumor formation [15].

Forestomach Tumorigenesis

In addition to its nephrotoxic effects, chlorothalonil has been found to induce tumors in the forestomach of rodents [16]. This is thought to occur due to direct contact irritation, leading to hyperplasia and subsequent tumor development. While humans do not have a forestomach, these findings are still concerning because they indicate the potential for chlorothalonil to cause gastrointestinal cancers through prolonged exposure.

Epidemiological Studies

Epidemiological studies examining the relationship between chlorothalonil exposure and cancer in humans have yielded mixed results. The primary population of concern includes agricultural workers, pesticide applicators, and individuals living in proximity to treated agricultural fields, who are at the greatest risk of chronic exposure to chlorothalonil [17].

Occupational Exposure and Cancer Risk

Several cohort studies have investigated the potential link between chlorothalonil and cancer in pesticide applicators [18]. The Agricultural Health Study (AHS), a large cohort study of licensed pesticide applicators in the United States, examined associations between chlorothalonil exposure and cancer incidence [19]. Although the results suggested a slight increase in the risk of kidney cancer, this association was not statistically significant, and no strong links were found for other cancer types.

Other case-control studies have examined cancer incidence among agricultural workers exposed to chlorothalonil [17]. Additional studies have reported increased risks of stomach and lung cancers, though these findings are inconsistent and often confounded by exposure to other carcinogens.

General Population Exposure

Studies examining cancer risks in the general population due to environmental exposure to chlorothalonil are limited. Chlorothalonil residues have been detected in drinking water, especially in regions where it is extensively used for crop protection [20]. However, the levels detected are generally low, and there is no conclusive evidence that these low-dose exposures are associated with increased cancer risk. Further research is needed to assess the long- term health impacts of low-level environmental exposure to chlorothalonil.

Toxicological Data from Animal Studies

Rodent Studies

Rodent models provide important insights into the carcinogenic potential of chlorothalonil [6]. Chronic exposure studies have consistently demonstrated that chlorothalonil induces tumors in both the kidneys and forestomach of rats and mice. At high doses, chlorothalonil has been associated with a dose-dependent increase in the incidence of renal tubular adenomas, carcinomas, and forestomach squamous cell carcinomas.

Relevance to Humans

While the results of animal studies are concerning, it is important to consider the differences in exposure levels between laboratory animals and humans. The doses of chlorothalonil administered to rodents in these studies are typically much higher than those experienced by humans, even in occupational settings. Moreover, the relevance of forestomach tumors in rodents to human cancer risk is debated, given the anatomical differences between species. Nonetheless, the consistent findings of tumor formation in multiple organ systems highlight the need for caution and further research into the potential carcinogenic effects of chlorothalonil in humans.

Regulatory Perspectives

Regulatory agencies around the world have reviewed the available data on chlorothalonil and established guidelines to minimize human exposure. In the United States, the Environmental Protection Agency (EPA) has classified chlorothalonil as a “likely” human carcinogen based on animal data. The EPA has set Maximum Contaminant Levels (MCLs) for chlorothalonil in drinking water and established safety limits for its use in agricultural practices.

In the European Union, the European Food Safety Authority (EFSA) has taken a more precautionary approach. In 2019, the EU withdrew approval for the use of chlorothalonil, citing concerns about its potential carcinogenicity and the risk it poses to groundwater. The ban reflects growing concerns about the long-term environmental and health impacts of chlorothalonil use.

International Differences

The discrepancy between regulatory actions in different regions highlights the uncertainty surrounding chlorothalonil’s safety. While some countries continue to permit its use with restrictions, others have adopted more stringent measures to protect public health. This divergence underscores the need for a global consensus on chlorothalonil’s risks and the establishment of uniform safety standards.

Discussion

The evidence regarding the carcinogenic potential of chlorothalonil is complex and somewhat conflicting. Toxicological studies in animals provide strong evidence of carcinogenicity, particularly in the kidneys and forestomach. However, human epidemiological studies have produced less conclusive results, with some suggesting an increased risk of specific cancers, while others show no significant associations.

The variation in epidemiological findings may be due to differences in study design, exposure assessment, and the confounding effects of other pesticides. Moreover, the relevance of animal data to human cancer risk remains a topic of debate, particularly given the high doses used in animal studies compared to typical human exposures. Nonetheless, the consistent findings of chlorothalonil- induced tumors in animal models should not be dismissed, and further research is needed to clarify the mechanisms by which chlorothalonil induces cancer in humans, particularly in light of the differences between rodent models and human biology.

The potential for chlorothalonil to act synergistically with other pesticides or environmental contaminants also warrants further investigation. Additionally, the impact of chlorothalonil exposure on vulnerable populations, such as children, pregnant women, and immunocompromised individuals, is largely unexplored.

In conclusion, chlorothalonil continues to be a widely used fungicide with significant economic importance. However, its potential to cause cancer, particularly in the kidneys and gastrointestinal tract, raises important public health concerns. While toxicological studies in animals indicate a clear carcinogenic risk, human epidemiological data are less definitive. Nonetheless, the consistent findings of chlorothalonil-induced tumors in animal models underscore the need for caution.

Regulatory agencies should continue to monitor and assess chlorothalonil exposure levels, particularly in occupational settings where the risk of exposure is highest. Precautionary measures, including tighter restrictions on its use and continued research into its health effects, are essential to protect public health.

Given the evolving nature of the evidence, it is imperative that future research address the gaps in our understanding of chlorothalonil’s long-term health effects. Only through rigorous scientific investigation can we fully assess the risks and ensure that appropriate safety standards are in place.