Pesticides are biologically active chemicals used for the control of organisms that are considered pests including plants, insects, rodents, fungi, bacteria, and microbes. In some of the earliest human civilizations, elements (e.g., sulfur, arsenic, mercury, lead) and extracts from plants were used in crop production because of their ability to control pests (Kughur, 2012). Since the 1940s, with the chemical revolution that accompanied World War II, many pesticides were designed to target specific molecular pathways and cellular receptors in target species. Several categories of plant-derived pesticides, utilizing chemistry found naturally in botanicals, have now been developed (Kamrin, 1997). Pesticides have become vital to crop production and are an integral part of food production. About the herbicide glyphosate, for example, some environmental policy experts have written, “there is little doubt that [its] use massively boosts agricultural productivity, at least on the short term” (Dorlach and Gunasekara, 2023). The abrupt ban of the use of synthetic agrochemicals (including both pesticides and chemical fertilizers) in Sri Lanka in 2021 was disastrous for production of critical crops including rice and tea, contributing to an increase in measures of food insecurity (Drechsel et al., 2025). Although it was not possible to determine the impact of the ban on pesticides specifically (because chemical fertilizers were concurrently banned, and the country also experienced a severe drought during the growing season), a survey of farmers indicated that many reported an increased problem with both weeds and insects.

Yet, there are issues with some of the claims that have been made about the benefits of pesticides on crop production. In several regions of the world, crop yields have not improved in spite of the increased use of pesticides, and some yields may have even declined (Ray et al., 2012). Atrazine is a high production volume herbicide that has been described as essential for the production of corn (Mitchell, 2011). However, when atrazine use was restricted in several countries in the European Union, there was no effect on corn crop productivity in these locales (Ackerman, 2007). A 2014 analysis by agricultural economists concluded that elimination of the use of atrazine in the United States would lead to more than US$1.5B in additional revenues for corn growers, even if other pesticides were substituted for atrazine (Ackerman et al., 2014). Similarly, a regional ban of 14 agricultural pesticides that were considered highly hazardous in the Indian state of Kerala resulted in no evidence for reduced yield of eight crops in the year the ban was initiated (2011) or the following year (Sethi et al., 2022). These eight pesticides were selectively banned because they had contributed to thousands of poisonings that led to deaths. Sadly, suicide by pesticide poisoning disproportionately affects countries that utilize highly hazardous pesticides including Sri Lanka, Bangladesh, and other parts of India (Gunnell et al., 2007; Chowdhury et al., 2018; Bonvoisin et al., 2020).

When specific pesticides are phased out of use (due to regulation or loss of efficacy as resistant pests arise), typically one of two options is selected by agricultural producers. The first is the adoption of other pesticides; this has been observed in many global jurisdictions as herbicides like atrazine and glyphosate are used less frequently, and replacements such as dicamba and 2,4-D are used in their place (Wechsler et al., 2019). These replacements are especially concerning because of evidence that they may be even more toxic than the herbicides they are replacing. The second approach is to utilize integrated pest and pesticide management strategies (Peshin and Zhang, 2014), which can include a shift to less-toxic chemical pesticides, better use of transgenic crops, use of improved cultivation techniques, protection and enhancement of beneficial organisms, as well as non-chemical methods to control pests (Barzman et al., 2015).

Pesticides are not only used in the protection of crops, but also to control species that transmit deadly diseases that impact the health of human and wildlife populations such as West Nile virus, malaria, and Dengue fever, among others (Whitford, 2002). Thus, it has been argued that pesticides increase quality of life (Whitford et al., 2006) by reducing the impact of infectious diseases that, uncontrolled, would have morbidity and mortality rates potentially affecting more than a billion people (Hay et al., 2004).

As global annual agricultural use of pesticides increased from 1.81 million metric tons in 1990 to 3.69 million metric tons in 2022 (a 104% increase over 3 decades, see Figure 1), there are increasing concerns that pesticides are contributing to negative health outcomes in exposed individuals, including those that are exposed occupationally as well as the general public who consume agricultural products (Petit and Vuillerme, 2025). In this review, we discuss some of the earliest evidence that many pesticides are hormonally active, and thus are endocrine disrupting chemicals (EDCs), developmental toxicants, and reproductive toxicants. We examine several reasons why pesticides create global challenges, and examine pesticides using the framework of planetary boundaries, which evaluates how human activities impact earth systems and prevent the earth’s biophysical systems from being maintained sustainably.

In the early 1990s, a report from the US National Academy of Sciences documented the extent that pesticides were found in the diets of children (Council, 1993). Further concern was raised because of evidence that many pesticides had unintended effects on the endocrine systems of wildlife and humans (Colborn et al., 1993). The 1991 Wingspread Conference examined the consequences of pesticides, as well as other environmental chemicals and hormonally active pharmaceuticals. Researchers at this conference coined the term “endocrine disruptor” to describe chemicals that can bind to hormone receptors or alter some other aspect of hormone action to disturb the health of the individual (Colborn et al., 1993; Colborn and Clement, 1992). Even at that early date, there was clear evidence that hormonally active pesticides were disrupting development and reproduction of species including wildlife and humans.

This newfound scientific attention in the 1990s led the US Congress and several US regulatory agencies to acknowledge that many pesticides could induce harmful effects by mimicking or blocking the actions of sex hormones; several were also determined to be developmental and reproductive toxicants (Colborn et al., 1995; Krimsky, 2003). In 1996, the US Congress signed into law the Food Quality Protection Act (Congress, 1996) which required the US EPA to create a screening program to evaluate pesticides for several endocrine disrupting properties. In response to this law, the EPA assembled a scientific advisory committee (EDSTAC, 1998) which recommended the creation of a two-tiered endocrine disruptor screening program (EDSP) to identify chemicals that bind to the androgen, estrogen and thyroid hormone receptors (EPA, 2013). Unfortunately, as recently described (Maffini and Vandenberg, 2022), more than 1300 chemicals were identified as “high priority” for screening by the EPA because of their use in pesticides, but by 2022, fewer than 100 had been screened through the first tier of the EDSP, and none had been tested in Tier 2 (Oig, 2021).

In the European Union, early efforts undertaken to address the problem of EDCs were launched in 1999 with the “European Strategy on EDCs” (Kassotis et al., 2020). Although it was not specifically focused on pesticides, the strategy included significant funding for EDC research, and paved the road for EU laws on pesticides and biocides. However, it took until 2009 for the EU “Plant Protection Products Regulation 1107/2009” to be finalized, which specifically focused on regulating agricultural pesticides with endocrine disrupting properties. This regulation, together with the 2012 EU Biocides regulation, disallowed the authorization of substances identified as EDCs. Based on these laws, several pesticides have been banned from use in the EU. However, the EU Strategy has been criticized by public health advocates for being too slow, for having “blind spots” for some features of EDCs, and for not treating the problem of EDCs with sufficient gravity (van Vliet and Jensen, 2013).

Beyond the US and EU, the United Nations Environment Programme has acknowledged the global challenge of EDCs (Bergman et al., 2013) and the Organization for Economic Cooperation and Development (OECD) has led efforts to develop globally harmonized methods to test chemicals for some kinds of endocrine disrupting properties. However, these organizations also acknowledge that governments worldwide have very different approaches to the regulation of chemicals, including pesticides, which poses significant challenges to their testing and to regulatory oversight (Kassotis et al., 2020).

Since the earliest policy and regulatory responses to the question of agrochemicals with endocrine disrupting properties, an increasing understanding of the endocrine system and the principles of endocrinology has allowed for more advanced knowledge of the mechanisms by which pesticides with endocrine disrupting properties affect the health of individuals and populations (Zoeller et al., 2012; Vandenberg et al., 2013; Gore et al., 2015; Schug et al., 2013). There has been debate amongst scientists and regulators around the world about the best ways to define (and thus identify) EDCs (Zoeller et al., 2014). However, the development of ‘key characteristics’ of carcinogens, EDCs, and male and female reproductive toxicants have provided a useful framework by which chemicals can be evaluated and the evidence for their toxicity clearly assembled (La Merrill et al., 2020; Luderer et al., 2019; Arzuaga et al., 2019). Such approaches have started to be used for the evaluation of pesticides including dichlorodiphenyltrichloroethane (DDT), endosulfan, atrazine, and glyphosate (Calaf et al., 2020; Vandenberg et al., 2020; Muñoz et al., 2021; Rana et al., 2023).

DDT is perhaps one of the most well-studied pesticides, and its effects have been felt globally. This insecticide targets voltage-gated sodium channel proteins found in the membranes of nerves and neurons, and binding of DDT to these proteins disrupts the normal transmission of nerve impulses, leading to seizures or paralysis, followed by death (Davies et al., 2007). In addition to this mechanism of action, DDT has been shown to be a non-genotoxic carcinogen, an activator of the constitutive androstane receptor, an inhibitor of gap junctions, and an inducer of oxidative stress (Harada et al., 2016). DDT and its metabolites are known EDCs, possessing both estrogen receptor agonist and antagonist activities (Vandenberg et al., 2020). Furthermore, dozens of epidemiology and wildlife studies have shown associations between DDT exposures adverse health outcomes including cancer, altered immune system functions, disruptions to reproductive health including alterations to the sperm epigenome which could impact future generations, and altered neurological development in humans (World Health Organization, 2003; Marlatt et al., 2022; Lismer et al., 2024).

Systematic reviews have provided evidence that several pesticides are developmental and reproductive toxicants. For example, occupational exposure to pesticides (defined broadly) has been shown to be associated with measures of male reproductive toxicity, including adverse effects on measures of sperm motility and DNA integrity (Knapke et al., 2022). Pregnant women exposed to pesticides (defined broadly) were also shown to be at increased risk for spontaneous abortion (Albadrani et al., 2024). Systematic reviews that examine specific pesticides have also provided evidence that these chemicals alter reproductive outcomes in exposed animals and/or human populations. For example, the fungicide mancozeb has been shown to alter fertility outcomes in multiple species of laboratory animal (Runkle et al., 2017); the fungicide vinclozolin alters sperm motility, sperm count, and epididymal weight in exposed rodents (Feijó et al., 2021); and the insecticides malathion and diazinon are male reproductive toxicants that damage the Leydig cells in the testis, decreasing the production of androgens and reducing sperm quality in rodents (Delorenzi Schons and Leite, 2023). Furthermore, meta-analyses have revealed an increased risk of breast cancer in women associated with exposures to the insecticide hexachlorocyclohexane (Liu et al., 2023). Evidence for other forms of toxicity (e.g., neurotoxicity) has also been assembled for pesticides like paraquat and chlorpyrifos (Vaccari et al., 2019; Coleman et al., 2025).

Controlled laboratory experiments with model organisms have generated evidence that animals are affected by low dose exposures to pesticides and other environmental chemicals, even when such chemicals are administered to animals below the doses that are used to generate toxicological no-observed-adverse-effect-levels (NOAEL) (Bergman et al., 2013; Zoeller et al., 2012; Gore et al., 2015; Vandenberg et al., 2020; Vandenberg, 2014; Hill et al., 2018; Vandenberg, 2019; Diamanti-Kandarakis et al., 2009; Kortenkamp et al., 2011). More specifically, many of the highest volume pesticides have been shown to have an endocrine mode of action, and many also affect development and/or the reproductive health of animals exposed in controlled laboratory settings (see Table 1). Although risk assessments are required for all pesticides (at least in the United States and EU), hundreds of studies have demonstrated associations between pesticide exposures and adverse health effects in human populations, even when such exposures are low (Gore et al., 2015; Stillerman et al., 2008; Crain et al., 2008; Skakkebaek et al., 2016; Kahn and Trasande, 2018; Wan et al., 2021; Mendes et al., 2021; Rocha et al., 2021; Kahn et al., 2021; Fernández-Martínez et al., 2020; Ribeiro et al., 2020; Fu et al., 2020; Bliatka et al., 2020; Nelson et al., 2020; Rivollier et al., 2019; Wen et al., 2019; Ghassabian et al., 2022). Many environmental epidemiology studies (almost exclusively focused on non-occupationally exposed individuals) have shown associations between exposures to pesticides and adverse health outcomes, including effects on neurobehaviors in children (Thistle et al., 2022), metabolic syndrome (Lamat et al., 2022), risk of cancers (Rossides et al., 2022), and other serious health effects. These outcomes in exposed human populations suggest that the approaches used to evaluate chemical hazards are insufficient to identify “safe” levels of exposure for the general population (Vandenberg, 2019; Vandenberg, 2021).

The production of pesticides has been on an upward trajectory for several decades, leading to increasing rates of release into the environment. In this section, we describe how this increasing production of pesticides contributes to exposures (and effects) in non-target species (including humans), especially because pesticides do not stay where they are used.

Public health scientists have demonstrated that there are inequities in health outcomes in human populations, making it critical to understand, consider, and address how social determinants of health contribute to such disparities (Baltruks et al., 2022). More recent analyses have examined how global factors are linked to specific health risks, and many of these risks are influenced by other social determinants of health including race and ethnicity, sex and gender, occupation, socioeconomic status and income (Kemarau et al., 2024).

Organochlorine pesticides (OCPs) are a class of pesticides that are highly persistent in the environment and have been linked to altered hormone action, neurotoxicity, cancer, and liver and kidney damage (Jayaraj et al., 2016). As a result, OCPs were banned from use in the United States and most other high-income nations in the 1970s and 1980s. Beta hexachlorocyclohexane (β-HCH) is the most chemically and physically stable isomer of the insecticide lindane, making it highly resistant to degradation in the environment (Rubini et al., 2020). β-HCH has a half-life in humans of about 7 years and can bioaccumulate in lipids, so exposures can last long beyond the direct use and production of this chemical. Despite being banned for use in the United States in the 1980s, β-HCH was still found at detectable levels in the general population 30 years later, although concentrations continue to decline with time (Figure 3A). A study based on NHANES data found an average serum concentration of 3.29 ng/g lipid β-HCH detected in people in the U.S. in the 2015–2016 cycle (Li et al., 2022). β-HCH is an example of a pesticide with disproportionate exposures across general human populations; in the US, levels of β-HCH were consistently twice as high in Mexican Americans compared to non-Hispanic white and non-Hispanic Black populations (Figure 3B). For all ethnicities other than Mexican American, non-Hispanic white, and non-Hispanic Black (i.e., the “other” category includes Indigenous, Asian, and non-Mexican Hispanic populations), exposure was three times as high as white Americans. The disproportionate exposures in marginalized racial groups may contribute to other health disparities.

Sex also appears to be an important factor influencing exposures (Figure 3C). A study in Italy of a population surrounding a chemical dumping site with high levels of β-HCH contamination found consistently higher serum concentration in females compared to males, even when adjusting for confounding factors such as age (Narduzzi et al., 2020). Whether women are exposed at greater rates or metabolism and excretion rates are slower in females, a disproportionate impact on women is cause for concern, especially because β-HCH, like other OCPs, can cross the placental barrier and be passed to offspring through breastmilk. Higher pesticide exposures in pregnant women could have detrimental impacts on these women directly, as well as on fetal development.

Country-specific usage of pesticides is also a critically important social determinant of pesticide exposure. Brazil has one of the highest levels of pesticide use, accounting for 800,650 metric tons in the year 2022, accounting for almost a quarter of all pesticides applied across the globe (Faostat Analytical Brief, 2022). Approximately one-third of all pesticides used in Brazil have been banned from use in the EU, and the maximum residue limits allowable for others can be 400-times higher in Brazil compared to the EU. These striking disparities in pesticide use between the global north and the global south may exacerbate other environmental vulnerabilities that have been observed in countries like Brazil (Perobelli, 2025).

Occupation is perhaps the most critical social determinant of pesticide exposure. Agricultural workers bear the brunt of pesticide exposure as these individuals apply the chemicals and directly handle crops where pesticides have been used. Mexican immigrants make up 69% of the population that is tasked with directly handling pesticides in the US (Mehta et al., 2000). Exposures to farmworkers occur through the oral, dermal and inhalation routes, and are documented in pesticide applicators as well as crop pickers (EPA). Migrant farmworkers have some of the worst documented health outcomes in the US, and although these outcomes are not due solely to occupational chemical exposures, the contribution of pesticide exposures cannot be discounted (McCauley et al., 2001).

The disproportionate exposure of farm workers to pesticides also carries over to their families. The “occupational take-home pathway” of pesticide exposure means that households of farmworkers have greater concentrations of pesticides in house dust compared to non-farmworker houses (Bennett et al., 2019). Pesticides can linger on clothing and other personal belongings that travel to work with the workers, and since these individuals often live close to where they work, pesticides can enter their homes via air (McCauley et al., 2001). The implications of increased exposure to pesticides for children in the house cannot be understated, and the inequities in exposure based on job status, occupation, and other socioeconomic factors influencing the family adds another layer of injustice to the global health threat of pesticides.

Despite their negative impact on the environment and human health, the use of OCPs is increasing worldwide as low-income countries continue to use OCP insecticides such as DDT and β-HCH. Although the use of DDT for agricultural uses was banned or heavily restricted in most high-income countries starting in the 1970s and 1980s, in 2006 the World Health Organization advocated for the spraying of DDT in some low- and mid-income countries for the control of malaria-carrying mosquito populations (Organization, 2006). Furthermore, studies of agrarian countries like Ethiopia reveal that DDT is not only used as vector control for malaria, it also continues to be used for agricultural purposes (Negatu et al., 2021; Debela et al., 2023), contributing to high DDT exposures of wildlife (Yohannes et al., 2013), measurable residues in staple crops (Mekonen et al., 2014) and dairy (Deti et al., 2014), and in human biomonitoring samples, including in breast milk (Gebremichael et al., 2013).

These findings emphasize an issue of inequity surrounding global regulation and continued use of pesticides. While regulation of pesticides is critical for reducing exposure and the burden of harm on human health, banning or restricting the use of a pesticide in high-income jurisdictions is not a comprehensive solution to exposure if usage continues in other parts of the world.

The concept of planetary boundaries was introduced more than a decade ago as a framework to understand and evaluate how human actions impact various earth systems, and whether such actions prevent the earth’s biophysical systems from being maintained sustainably (Rockström et al., 2009). As a part of this framework, scientists from across disciplines worked to establish “safe operating spaces” for humans and their activities’ impact on the ecological systems of the earth. This initial work arose from a shared understanding that human activities were having significant, and sometimes irreversible effects, on key aspects of environmental health.

Thus, planetary boundaries (sometimes referred to as Earth System Indicators) became a concept for addressing global challenges from the perspective of sustainability. Nine boundaries were proposed (Steffen et al., 2015) (Figure 4):

• climate change (including carbon dioxide in the atmosphere as well as measures of global temperature),

Although this framework continues to be updated from its original conception, and new information contributes to the understanding of the threshold for each planetary boundary, the concept has become adopted across numerous fields that focus on sustainability (Kemarau et al., 2024). Global discussions on planetary boundaries recognize that human activities that push beyond the threshold for one or more of these boundaries could lead to instability of the planet’s health, and ultimately put the survival of both ecosystems and human societies at risk.

Importantly, longitudinal evaluations of the nine planetary boundaries suggest that these continue to be transgressed, and that the situation has become more dire with time. Table 2 summarizes the evolution of the framework and the assessment of the thresholds for each boundary in 2009, 2015, and most recently in 2023 (from (Kemarau et al., 2024)). The continued assessment of planetary boundaries revealed emerging evidence that several boundaries have been crossed.

There is strong evidence that pesticides are impacting ecosystems, and can contribute towards pushing several planetary boundaries past their established thresholds of safe operations. Significant work has examined the impact of pesticides (on their own, or in concert with other agrochemicals) on biogeochemical cycles. First, phosphorus extraction is essential for the production of numerous pesticides (Yuan et al., 2018) and concerns have been raised that the planet’s reserves are insufficient to support continued and growing needs. Furthermore, phosphorus reserves are not distributed evenly around the planet, leading to disruptive extraction practices in localized places (especially in the Sahara region), and the processing of phosphate rock can release radioactive materials and heavy metals into the environment (De Boer et al., 2019). Also relevant to biogeochemical cycles is the impact of pesticides on the nitrogen cycle including microbial composition and activities of microbes (e.g., respiration, enzymatic activity, and ultimately nitrogen fixation). There is increasing evidence that several herbicides are toxic to nitrifying and nitrogen-fixing bacteria, and their presence can compromise this aspect of soil fertility (Brochado et al., 2023).

Pesticide use also has demonstrated impacts on biosphere integrity, including loss of biodiversity. As described previously, many pesticides are known or suspected EDCs (Demeneix, 2020) and reproductive and developmental toxicants, and have been shown to be associated with declines in the populations of wildlife in many different ecosystems (Gore et al., 2015; Crain et al., 2008; Guillette, 2006). Numerous studies have focused on whether pesticides, and especially neonicotinoid pesticides, might be contributing to the deaths of non-target species including pollinator insects (Brittain et al., 2010), freshwater invertebrates (Beketov et al., 2013), and other species that are critical to the health and function of ecosystems.

Certainly, there is also evidence that pesticide use can impact the availability of freshwater, considering the extensive evidence that these chemicals contaminate drinking water supplies (Syafrudin et al., 2021). Pesticides can enter drinking water through both agricultural run-off and production processes. In the US, evaluations conducted between 1992 and 2001 by the Department of the Interior and the US Geological Survey revealed that pesticides were detected in more than 90% of all streams, and in more than 25% of all aquifers (Gilliom et al., 2006). Similar contaminations have been observed in drinking water sources such as the Tengi river in Malaysia, where concentrations of the insecticide imidacloprid were reported as high as 60 ppb, and the fungicide tebuconazole were as high as 510 ppb (Elfikrie et al., 2020); the Shinano River in Japan where detectable levels of 22 herbicides, 15 insecticides, and 11 fungicides were reported, with the highest levels exceeding 8,000 ppb for the fungicide isoprothiolane (Tanabe et al., 2001); and the Dongjiang River in China, where the presence of pesticides commonly used in the surrounding agricultural region was reported, with concentrations of this same fungicide found above 250 ppb (Zhang et al., 2020). These studies highlight that the contamination of drinking water sources is a global concern.

Of course, the greatest challenge posed by pesticide use is the “novel entities” boundary, which focuses specifically on the introduction of synthetic chemicals and materials into the environment. Although pesticides are only estimated to account for ∼2% of all synthetic chemicals made globally (Alavanja, 2009), because these chemicals are designed to be biologically active, their disproportionate effects raise significant concern for the health of people and the environment. The release of pesticides and other synthetic chemicals into the environment is one of the fastest growing challenges to planetary boundaries, with a greater rate of change than other agents challenging sustainability including release of carbon dioxide into the atmosphere (Shattuck, 2021). Unfortunately, even organizations dedicated to studying global agents of change have given little attention to the challenges posed by synthetic chemicals to planetary health, sustainability, and the resilience of the planet to human activity (Bernhardt et al., 2017).