Abstract
Plant disease management has not significantly changed in the past 50 years, even as great strides have been made in the understanding of fungal biology and the etiology of plant disease. Issues of climate change, supply chain failures, war, political instability, and exotic invasives have created even more serious implications for world food and fiber security, and the stability of managed ecosystems, underscoring the urgency for reducing plant disease-related losses. Fungicides serve as the primary example of successful, widespread technology transfer, playing a central role in crop protection, reducing losses to both yield and postharvest spoilage. The crop protection industry has continued to improve upon previous fungicide chemistries, replacing active ingredients lost to resistance and newly understood environmental and human health risks, under an increasingly stricter regulatory environment. Despite decades of advances, plant disease management continues to be a constant challenge that will require an integrated approach, and fungicides will continue to be an essential part of this effort.
Despite considerable progress in understanding the biology and etiology of plant pathogens, plant disease management, which we define as the integrated deployment of disease-resistant varieties, avoidance, sanitation, and fungicides (including natural, synthetic, and biological), has not significantly changed in the past 50 years, relying primarily on fungicides. Like many other disciplines, plant pathology suffers from a protracted inability to apply discoveries in plant and fungal biochemistry, physiology, and genetics to the practical problem of protecting plants against pathogens and increasing crop yields. With 20 to 40% of the world’s potential crop production currently lost annually due to weeds, arthropod pests, and pathogens, the most successful interventions to mitigate these losses are pesticides, with fungicides continuing to play a primary role of managing plant diseases (FAOSTAT 2017; Oerke and Dehne 2004; Savary et al. 2019). Research in the field of plant pathology has expanded to address management of plant diseases through studying genetics, host plant−pathogen interactions, host plant resistance mechanisms, and pathogen−microbe interactions. However, none of this research (with the exception of breeding for resistant cultivars and genetically modified seed) has resulted in methods to manage disease as reliably as fungicides. Since the introduction of synthetic pesticides (including fungicides) over 80 years ago, growers have been able to increase crop production per unit area (Figs. 1 and 2; Oerke 2006). However, due to changing climatic conditions, crop losses are predicted to reach between 50 and 80%, doubling current losses and thus increasing the reliance of all pesticides, not just fungicides, for all plant production (FAO 2015; Phillips McDougall 2018). With the majority of the world’s cropland not producing up to its biological potential (Mueller et al. 2012; Sayer and Cassman 2013), issues of climate change, supply chain failures, war, and political instability have created serious implications for world food security (Harvey et al. 2018; van Meijl et al. 2022), underscoring the urgency for reducing disease-related losses with effective fungicides.
It is evident that fungicide use is rooted in the need to manage plant pathogens, thereby reducing losses to both yield and postharvest spoilage. In 2019, fungicide sales totaled approximately $16.4 billion, representing 27.3% share of the crop protection market (S&P Global 2022). This illustrates that fungicides are a significant part of the grower’s strategy for successful crop production, one that needs to be preserved for present and future food security. Sustainable fungicide use and stewardship of these chemistries requires integrated disease management (IDM) to combine multiple tactics in a comprehensive strategy that prevents overreliance on any one method, including fungicides. In this way, IDM strategies focus on the integration of fungicides with cultural practices (site, fertility, and irrigation), disease resistant germplasm (both GMO and non-GMO), and biological control agents to create economically and ecologically sustainable cropping systems. All of these integrated tactics are necessary to minimize both disease pressure and fungicide resistance risk, while maintaining effective and sustainable disease control.
Despite the widespread adoption of IDM practices (e.g., scouting, rotation, and disease forecasting tools), over 80% of the fruit and vegetable crops grown in the United States still receive fungicide applications every season (Atwood and Paisley-Jones 2017; Fernandez-Cornejo et al. 2014 and subsequent ERS Crop Bulletins, 2015−2022). Examples of crops and fungal pathogens, along with fungicide application schedules to manage them can be found in regional pest management guides (e.g., the Midwest Fruit Pest Management Guide [Beckerman et al. 2022] and previous guides, and the Midwest Vegetable Production Handbook [Phillips et al. 2023] and previous guides and many others), indicating fungal plant disease is a pernicious and pervasive problem of specialty crops. As a result, fungicide use in U.S. agriculture enhances farm income by approximately $13 billion annually with an estimated cost-benefit ratio of 1:3 for foliar disease management (Gianessi and Reigner 2006). For fluopyram-seed treatment of soybean alone, the net benefit was estimated to be (conservatively) at $407 million per year, with an overall benefit (net present value) of $5.8 billion over 15 years (Baetsen-Young et al. 2021); larger economic studies of fungicide seed treatment are currently lacking. Similarly, fungicides are critical to produce nonfood crops such as fiber and environmental horticulture crops (ornamentals) where aesthetics are a major factor in the consumers’ decision to purchase and maintain plant materials in residential and commercial landscapes. Examples of fungal diseases of ornamentals and pesticide management options can be found via the Pacific Northwest Plant Disease Management Handbook (Pscheidt and Ocamb 2022).
Just as basic economics drive fungicide use, economics drives the development of new fungicides. The primary players in the discovery, evaluation, development, production, and marketing of all crop protection products are large, private sector, multinational companies. As of this writing, four major multinational crop protection companies currently drive new product discovery in the United States and Europe (BASF, Bayer, Corteva, and Syngenta). Headquartered in Japan, ISK, Sumitomo, and Nichino engage in discovery of new active ingredients, which are then often formulated and marketed through channels of trade by market access partners. Beginning in the early 2000s, private-sector food and agricultural research and development (R&D) grew more rapidly than public-sector R&D. By 2014, the private sector spent approximately three times more than the public sector (Hellerstein et al. 2019). This investment comes with considerable cost. During the course of a product life cycle, new fungicides must accrue approximately $300 million in profit to simply defray research and development costs (Bryson and Brix 2019) (Fig. 3) meaning that economics and not biology prioritizes pathogen and crop targets for new fungicides (Oliver and Beckerman 2022). Consequently, the availability of new synthetic fungicides is based on their discovery and development by these crop protection companies that invest more than $3 billion annually in research and development of new products (Phillips McDougall 2016).
In the early history of fungicide discovery (circa 1950s), all crops and commodities, regardless of acreage, were considered for product development (Morton and Staub 2008). Today, the development pipeline targets pathogens infecting staple crops (e.g., soybeans, corn, potatoes, rice, and wheat) grown on large acreages throughout the world to offset the considerable investment required to bring a product to market. Specialty food and nonfood crops are considered later in the pipeline, but some of these crops may not provide a return on investment to the basic manufacturer before the active ingredient loses patent protection. For this reason, governmental agencies have sponsored programs to offset development costs for specialty crop markets (Box 1, Fungicide development for specialty crops). This further emphasizes that the crop protection industry’s role in enhancing food security is predicated on profit, not altruism, and that this interest is subject to the margins of profit and loss (Hewitt 2004). Although large multinational companies are the drivers of fungicide discovery (along with evaluation, development, production, and marketing), governmental regulators evaluate and approve all pesticides for use (Box 2, Hazard and risk). In the final step of the process, fungicides are marketed to growers who ultimately decide which fungicide is purchased, along with where, when, how, and how much to apply, as prescribed by the fungicide label.
Box 1
Fungicide development and registration for specialty crops
Specialty crops are defined in the United States as “fruits and vegetables, tree nuts, dried fruits and horticulture and nursery crops, including floriculture,” crops often grown on less than 300,000 acres (U.S. Government Publishing Office, United States Code 2018). As these crops are highly diversified, they lack the acreage and buying power alone to justify the considerable investment required to bring a fungicide to market. Crop protection companies initially focus discovery and development of new fungicides for pathogens affecting row crops such as wheat, corn, and soybeans and on potatoes. Pathogens of crops grown on smaller acreages are considered for registration later if efficacy and economic profits warrant. In this way, specialty crops are a supplementary market after success has been attained with the larger row crop commodities. Furthermore, since return on investment is low, the development and regulatory costs for amending registrations to include most specialty food crops may not be economically viable, despite the need to manage fungal diseases. Thus, fungicides may not be registered for specialty crops for several years after the initial registrations for row crops or, in some cases, they may not be registered at all.
To solve this conundrum for specialty crop growers in the United States, the U.S. Department of Agriculture (USDA) established the IR-4 Project (https://www.ir4project.org/). Started in 1963 with a focus initially on registrations for edible crops, the IR-4 Project succeeded in securing crop protection product registrations for fruit and vegetable producers. Growers of environmental horticulture crops expressed similar needs, and IR-4 expanded to environmental horticulture crops in 1977. In 1982, the Biopesticide Program began and now focuses on development of initial registration packages for new biofungicides including biochemical, microbial, and biotechnology tools. The IR-4 Project solicits potential projects from stakeholders (growers, extension educators, and researchers) and determines research priorities at workshops. Research priorities for food crops fall into food residue, product performance, and integrated solutions. For environmental horticulture, research projects focus on efficacy and crop safety. Projects within IR-4 span all types of tools that farmers or growers may use including biofungicides, fungicides, and other emerging technologies. To date, IR-4 has facilitated registration of 23,190 uses for food crops and 57,578 uses for environmental horticulture across all types of crop protection tools.
Similar government sponsored programs have arisen to serve growers throughout the world. Examples include Canada’s Pest Management Center (PMC; https://agriculture.canada.ca/en/agricultural-science-and-innovation/agriculture-and-agri-food-research-centres-and-collections/pest-management-centre) and Australia’s Australian Pesticides and Veterinary Medicines Authority (APVMA; https://apvma.gov.au/). Unlike IR-4, which is funded as a grant program through USDA’s National Institute of Food and Agriculture and is located within public academic institutions, PMC and APVMA are agencies within their country’s respective federal governments. IR-4, PMC, and APVMA work collaboratively along with other entities to support registrations for specialty crops worldwide. An example includes the Minor Use Foundation (https://minorusefoundation.org/), which develops new data, repackages existing data, conducts training and capacity building, and collects and communicates regional and global priorities for specialty crop growers internationally.
Box 2
Hazard and risk-based regulation
Ideally, government authorities (e.g., the United States Environmental Protection Agency [U.S. EPA], Canada’s Pest Management Regulatory Agency [PMRA], the European Union’s Plant Protection Organization [EPPO], and India’s National Plant Protection Organization [NPPO]) regulate pesticides utilizing risk assessment methodologies that balance the economic needs of their agricultural constituents within competing cultural and societal realities. These regulatory bodies take distinct approaches to understanding risk or hazard, resulting in differences in availability of certain pesticides throughout the world (U.S. Environmental Protection Agency 2022a, b). Pesticides are quite possibly the most regulated substances in the world. Today, a new active ingredient may be subjected to >150 studies (U.S. Environmental Protection Agency 2022a). For older active ingredients, re-registration decisions often result in updated data for additional review and consideration, often to evaluate specific concerns regarding environmental and health impacts.
The Food Quality Protection Act (FQPA) changed the regulatory environment drastically in 1996 by requiring the U.S. EPA to implement more refined risk assessments factoring a 10× safety factor unless sufficient health or exposure data are available to support a different level and including drinking water and residential exposure. This legislation also required U.S. EPA to consider aggregate exposure from multiple sources and develop cumulative risk assessments for active ingredients with a common mechanism of toxicity. Colloquially, the terms risk “cup” for a single active and risk “bucket” for multiple active ingredients is used. The FQPA also requires U.S. EPA to perform re-registration eligibility reviews for all active ingredients every 10 years. This legislation also established expedited timelines for active ingredients determined to be reduced risk comparably to other products in the marketplace for the commodities and uses requested.
The other major legislation impacting the U.S. regulatory landscape was the Pesticide Registration Improvement Act (PRIA) in 2004. This legislation added a new section to the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) creating a registration service fee system for pesticide registration applications, established set maximum residue levels for food and feed, and required the EPA to make a determination on the application within the established time periods. Fees covered 90 different categories of registration applications, but fee waivers were available for small businesses and for IR-4 petitions.
Consistent with the U.S. EPA, hazard is defined as the potential to cause harm; risk is defined as the likelihood of harm based on hazard exposure. Risk assessment involves the identification of either hazard or risk to humans (especially farmers), animals, plants, and the environment. Upon identification of the hazard, dose-response evaluations are measured against exposure and modeled to characterize the probability of harmful effects (risk). Dose refers to the amount of pesticide exposure; response describes the reaction to that exposure. Together, dose and response determine risk. Risk assessment is the scientific study that evaluates the relationship between chemical toxicity and human exposure (along with wildlife and ecosystem exposure) and quantifies the degree of hazard. Risk management evaluates the interacting scale of pesticide use to concerns about human health, the social and ecological impacts of pesticide use, and the technological and economic constraints of actions used to manage or mitigate the risk in question.
In 2009, the European Union (EU) began a distinct regulatory approach (1107/2009) that considers the ‘hazard potential’ of an active ingredient versus the risk (i.e., likelihood of harm based on hazard exposure). The goal of these more recent regulations is to provide extensive protection of human, animal, and environmental health in all member countries. As a result, substances are revoked from agricultural consideration based upon laboratory research that suggests the potential for hazard (i.e., toxicity, health risk or environmental persistence) as opposed to the actual risk a product may pose. This has resulted in the loss of multiple fungicides, including mancozeb in 2020 (Commission Implementing Regulation 2020/2087) and chlorothalonil, fenamidone, and propiconazole in 2021 (Commission Regulation (EU) 2021/155).
In contrast, the U.S. EPA primarily regulates pesticide use under congressionally enacted federal statutes. Chief amongst these is the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) that provides the basis for registration, sale, distribution, and use of pesticides in the United States. Inherent in this process is the recognition that regardless of the hazardous properties a substance may possess, the potential for harm is directly related to exposure, and potential benefits need to be weighed before ruling out any new product. Under this rationale, a substance of high toxicity can only cause harm if sufficient exposures occur and exposures cannot be mitigated to ensure protection of human health and the environment.
An outcome of these different approaches to regulation leads to different availability of tools for farmers, impacting productivity and profitability, in addition to market availability.
Modern Fungicides
Early fungicide production (∼1950s) consisted of synthetic organic compounds (organic meaning they included carbon atoms) that possessed multisite modes of action (FRAC M). These FRAC M fungicides are valuable tools for both disease control and resistance management. They tend to be broad-spectrum and do not penetrate plant surfaces. Multisite compounds disrupt multiple metabolic processes in fungal cells. Therefore, the likelihood of resistance to multisite compounds is remote. Furthermore, when applied in a tank mix or as part of a combination fungicide product, multisite fungicides limit fungicide resistance risk by reducing exposure to the single-site partner fungicides (Amiri et al. 2019; Beckerman et al. 2015; Elderfield et al. 2018). However, these fungicides are not without risks, and research into their discovery and development declined from the 1960s (Fig. 4) (Oliver and Beckerman 2022).
Fungicide development since 1970 consists of human-designed chemicals that are iteratively less toxic to nontarget organisms and thus more ecologically safe than their predecessors (Table 1). They have single-site modes of action, may provide activity for a short period after the fungus has entered the host tissue, and are often applied at lower rates than previous fungicides (Table 1). These new fungicide introductions demonstrate the power of analog chemistry. New introductions also allow crop protection companies to examine competitors’ patents to identify “orphans” (i.e., commercially undeveloped active ingredients with perceived limited potential for profitability), which can be further modified and developed as new active ingredients (Fig. 4) (Russell 2005).
It was expected that as registrants gained expertise in understanding fungicide mode of action on target pathogens, along with an improved understanding of basic fungal biology (fungal physiology, genomics, and host−pathogen interactions), that improvements in the discovery and development process would follow. To date, there have been only few and limited inroads into understanding how fungicides impact fungi to a degree that scientists could biorationally design new fungicides to disrupt essential biochemical function and provide disease control while protecting plant, human, and environmental health. However, this lack of a biorational approach has not stymied the production of new analogs, as evidenced by the recent surge in the succinate dehydrogenase inhibitor (SDHI, FRAC 7) class of fungicides, the fastest growing FRAC group, now consisting of 17 compounds (Fig. 4).
The chemistries introduced in the 1970s provided growers with fungicides that could be used at lower rates and also move systemically within the plant and provide curative control of pathogens already there (Table 1). Convincing growers to adopt these improved products took little effort—their superior efficacy was obvious and provided growers an opportunity for remedial treatment of infected plants. In addition to clear benefits (expanding choice, improved application timing, flexibility, and intrinsically broader spectrum disease control compared with older fungicides), these fungicides provided growers a better return on investment. As a result, reliance on older chemistries declined and newer chemistries, particularly the sterol biosynthesis inhibitors (SBI, FRAC 3) were adopted rapidly (Beckerman et al. 2015). Unfortunately, the development of fungicide resistance was not well understood at the time, so SBI fungicides were used repeatedly despite having single-site modes of action. Growers, companies, and most scientists failed to recognize the risk of fungi evolving fungicide resistance, despite the fact that resistance had been reported in the early 1960s to organomercury seed treatments (Noble et al. 1966), dodine (Szkolnik and Gilpatrick 1969), and benomyl (Schroeder and Provvidenti 1969). Fortuitously, the supply of new fungicides with different modes of action quickly met grower needs almost as quickly as older products failed (Beckerman et al. 2015, references therein) so the loss of any one chemistry or class of chemistry did not register immediate concern (Box 3, Fungicide discovery and displacement). The rise of fungicide resistance has since taken a serious toll on the cost of crop production. The total economic cost of resistance against all pesticides in the United States was calculated at $1.5 billion in 2005; Today that cost would be approximately $2.3 billion (CPI inflation calculator), not counting for the additional pesticide use necessary to control the loss of highly target-specific compounds due to resistance. With over 219 fungicides active ingredients (FRAC, 2016), resistance has been identified in ∼75% of the mode of action groups (FRAC, 2020); this number is only expected to increase as resistance evolves to the active ingredients of newer fungicides.
Box 3
Fungicide discovery and displacement
Historically, the supply of new fungicides met grower needs almost as quickly as older products failed. Early losses for Botrytis control by benomyl (FRAC 1) in berry and vegetable crops were resolved by the introduction of dicarboximides (FRAC 2). However, resistance to this class rapidly evolved as well. It was not until the 1990s that phenylpyrrole (FRAC 12) and anilinopyrimidine (FRAC 9) chemistries were released for Botrytis management; resistance was reported a few years later.
Early loss of benomyl and dodine for apple production were answered with sterol biosynthesis inhibitors, with increasing intrinsic activity against apple scab with each subsequent fungicide introduction, masking the seriousness of the fungicide resistance issues. This phenomenon of newer products replacing older less intrinsically active ones has occurred with SDHI (FRAC 7) fungicides as well, with a particular focus on Botrytis management. Early management by flutalonil was replaced by boscalid, which was later replaced by fluxopyroxad and penthiopyrad; benzovindiflupyr was replaced by pydiflumetofen.
This phenomenon was not limited to fungicides for the control of true fungi, but novel chromistacides as well. Widespread and successful use of mefenoxam (which replaced metalaxyl) for control of Phytophthora and downy mildew species was followed by the introductions of mandipropamid, dimethomorph, cyazofamid, and fluopicolide in the late 1980s through early 2000s, and by oxathiopipralin a decade later. Fungicide resistance to all these products except dimethomorph and mandipropamid (both FRAC 40) has been detected in P. capsici (Kousik and Keinath 2008; Siegenthaler and Hansen 2021). Interestingly, resistance to dimethomorph and mandipropamid has not yet been reported in Phytophthora species to date (Siegenthaler and Hansen 2021). Resistance to these products have been documented in vitro and observed in vivo for multiple downy mildew pathogens (Gisi and Sierotzki 2015; Kenaith et al. 2019; Massi et al. 2021; Mboup et al. 2022). Unfortunately, fungicides with single site mode of actions that pose lower resistance risks are only recognized in retrospect, after years of use (Russell 2006), and it remains to be seen if the durability of dimethomorph and mandipropamid will persist.
Neither growers nor fungicide manufacturers were entirely oblivious to these resistance issues, with different tactics and strategies employed to manage the problem. Tank-mixes were used, rotations of different chemistries were applied [often with older multisite mode of action fungicides (FRAC M)], and some products were withdrawn from the marketplace on the mistaken assumption that resistant strains would die-off from the populations because of any fitness penalties that fungicide resistance costs these isolates (Hawkins and Fraaije 2018 and references therein; Chapman et al. 2011; Moyano et al. 2004; Walker et al. 2013). None of these strategies or tactics resulted in widespread success. By the end of the 1970s, growers, scientists, and industry recognized that fungicide resistance requires both global and integrated management. Thus began the Fungicide Resistance Action Committee (FRAC) to develop better tactics and coordinate resistance management strategies across industry partners and growers. This committee is still active today.
The SBI/DMI fungicide (FRAC 3) expansion continues to this day (mefentrifluconazole was introduced in 2019 [Tesh et al. 2019]), offering improved intrinsic activity with reduced plant growth regulator effects. New FRAC 3 compounds continue to be developed, each offering an advantage, usually greater intrinsic activity, over its predecessors, although occasionally greater mobility, broader spectrum activity, or persistence is promoted to growers. Examples of this include the promotion of fenbuconazole and difenoconazole to manage Venturia inaequalis with resistance to earlier generation FRAC 3 chemistries (Chapman et al. 2011; Villani et al. 2015). Worldwide, the FRAC 3 class of fungicides continues to be one of the most widely deployed classes of fungicides due to the combination of efficacy, the greater intrinsic activity later fungicides possessed that compensated for fungicide resistance, and the “stepwise” process of resistance evolution that is distinct compared with QoI (FRAC 11) or methyl benzimidazole carbamates (MBC, FRAC 1) resistance (Koller and Scheinpflug 1987).
Post-Modern Fungicides
In the last 50 years, the discovery and development of crop protection tools has gone through rapid change, including the development and widespread adoption of herbicide-resistant crops which has contributed to a correspondingly rapid increase in overall yields across all crops, from slightly less than 4 t/ha in 1960 to more than 6 t/ha today—an increase of around 50% (FAOSTAT 2017). One recurring theme is the release of newer, more intrinsically effective products (Table 1) associated with the evolution of resistance to these products, creating challenges to growers and companies trying to steward their chemistries.
FRAC faced its greatest challenge with the release of the QoI/strobilurin (FRAC 11) chemistries, a novel and significant class of fungicides based on naturally occurring compounds with activity against true fungi and Chromista. Now composed of 21 different active ingredients (Fig. 4) with a wide range of activity, mobility, and translaminar activity. All penetrate plant surfaces, but three (azoxy-, fluoxa-, and picoxy-strobin) are xylem mobile. QoI fungicides share the same single site mode of action (binding at the Qo site on cytochrome b), but not all are strobilurins (e.g., famoxadone, fenamidone, and metyltetraprole) (Bartlett et al. 2002; FRAC 2022). Within a few years of release, resistance was documented in multiple pathosystems (Bartlett et al. 2002). With the release of newer QoI chemistries, at least one early study noted that metyltetraprole is effective against some QoI resistant isolates of Zymoseptoria for the time being (Matsuzaki et al. 2020), once again demonstrating that later analogs often provide greater intrinsic activity than earlier fungicide discoveries within the same class.
Succinate dehydrogenase inhibitor (SDHI) fungicides show a similar pattern of development (Sierotzki and Scalliet 2013) and displacement (Box 3), as new analogs were identified and developed, replacing earlier chemistries. To date, 24 SDHI fungicides belonging to 12 distinct chemical subgroups have been identified (Fig. 4) (FRAC 2022). The first SDHI fungicide, carboxin (registered in 1966), along with flutolanil controlled mainly basidiomycete fungi, chiefly smuts and Rhizoctonia (Oliver and Beckerman 2022). Second-generation SDHI fungicides expanded control to ascomycete fungi and include boscalid (a portmanteau of the fungi Botrytis, Sclerotinia, and Alternaria) and isofetamid. Third-generation SDHI fungicides (penthiopyrad, fluxopyroxad, fluopyram, benzovindiflupyr, and pydiflumetofen) further expanded the range of pathogen control to additional foliar fungi including the powdery mildews and rust fungi, along with Cercospora, Septoria, and Venturia spp. (Oliver and Beckerman 2022). Like QoI fungicides, fungicide resistance risks limit the application of these products to four or fewer application per season.
Consequently, the strategies and tactics to manage crops, protect against food insecurity, and steward new chemistries all require better integration. It is important to note that even with the integration of transgenic crops (e.g., glyphosate-resistant corn and soybean), pesticide use is still necessary and, in some cases, has increased (Benbrook 2016). It has become increasingly apparent over the last decades that the reproductive capabilities of microbes (including fungi) and their higher probability to generate viable mutants in their respective populations will continue to provide opportunity for selection pressure facilitating emergence of strains resistant to genetically modified hosts, biological control agents, and pesticides in highest use at a given moment.
As microbes have evolved, so has product development. There have been significant reductions in product application rates per unit area—growers therefore can apply a lower dose of a crop protection product to achieve the same efficacy (Table 1). For example, prior to the development of synthetic fungicides, growers would apply 8.5 to 22.5+ kg per hectare when using copper and sulfur compounds. By the 1950s, the average application rates were 1.2 to 2.4 kg of active ingredient used per hectare for fungicides. By the 2000s, the average use rates were reduced 0.1 kg/ha. Today, farmers use approximately 95% less active ingredient than used in the 1950s. It was hypothesized that this intrinsically higher biological activity and efficacy could be associated with a higher probability of increased overall hazard (Russell 2006; Table 3). In reality, for most fungicides in agricultural markets, application rates represent a compromise that allows the active ingredient to be used in its most effective way without posing undue health risks to the users, consumers, or the environment, while recognizing that hazard needs to be taken into context with dose and exposure, all while determining whether the risk can be mitigated with application patterns or timings (Bryson 2022; Jeschke 2016; Leadbetter 2015; Leadbeater et al. 2000; Russell 2006).
Sustainable plant production is a multifaceted, contingent, and conflicting process (Rittel and Webber 1973). Today, the worldwide adoption of IDM principles has shifted the argument to one between agricultural intensification (increased reliance on chemistry for greater efficiency on decreasing land) versus extensification (more holistic but less efficient production on increasing land mass) (Foley et al. 2011; Rudel et al. 2009). Modern and post-modern fungicides have provided an increase of efficacy and systemicity, with reduced rates and fewer risks; however, all of these improvements come with tradeoffs. With systemicity comes issues of persistence, which are managed by extended pre-harvest intervals (when warranted). Most modern and post-modern fungicides provide a broad host range against a diversity of fungi, but with a single site mode of action. Most post-modern fungicides have a soil half-life that is lower than their protectant counterparts (Table 2). Taken together, post-modern fungicides reduce the reliance on older FRAC M fungicides, but do not eliminate their continued need, particularly in the highly managed pathosystems frequently found in fruit, vegetable, and ornamental plant production. No human-designed fungicide released in the last 30+ years has been able replace FRAC M utility.
Biological Fungicides and Multisite Redux
The development of broad-spectrum fungicides with multiple modes of action for the twin needs of disease and fungicide resistance management seems unlikely at this juncture. For a diversity of reasons, modern regulatory protocols do not favor broad-spectrum fungicides with nonspecific modes of action (Table 3) (Box 4, Copper and the intensification versus extensification debate). Despite the need of these products for fungicide resistance management, the development and subsequent regulatory passage of a fungicide with (i) a wide target range coupled with (ii) a nonspecific mode of action, and (iii) nontarget toxicity for an improved safety and use profile, is highly unlikely. Without a potential replacement for captan, copper, chlorothalonil, or mancozeb to reduce the reliance on these products, their use will continue and even increase (Figs. 5 and 6), particularly in light of the fact they provide these benefits at a low cost.
Box 4
Copper and the intensification versus extensification debate
Although many people view organic farming as the antithesis of conventional farming in terms of pesticide use, organic growers still use pesticides, although they are limited to a list of pesticides approved for organic production. The particular chemicals vary somewhat with the government or organization certifying organic production. The backbone of organic fungicides includes natural products (e.g., sulfur and copper fungicides), along with pesticidal soaps and oils (e.g., some horticultural oils, neem oil, etc.). In the United States, there is an official National List of Allowed and Prohibited Substances for growers that wish to be certified as organic by U.S. Department of Agriculture (USDA-Agricultural Marketing Service 2022).
Somewhat ironically, copper plays a critical role in both organic and conventional agriculture, providing low economic costs with efficacy against a wide spectrum of pathogens, particularly bacteria, while providing persistent disease control, depending upon formulation. However, even organically approved products like copper are not without reconsideration. Copper has demonstrable risk to soil microbes, invertebrates, aquatic organisms and is broadly biocidal, potentially harming populations of beneficial microbes and invertebrates. In nonagricultural soils, copper concentrations range from 3 to 100 mg/kg; their inorganic nature makes decomposition an impossibility (Table 2). However, in vineyards and orchards, extensive copper use is associated with soil copper levels in excess of 500 mg/kg (Andrivon et al. 2018). Like all older, multi-site synthetic fungicides, copper is under increasing scrutiny and is subject to prohibition for organic growers in Denmark and the Netherlands. Copper does provide an interesting case study regarding the complex interplay of benefits and trade-offs that result when balancing perception, environmental protection, and food production.
Biofungicides and other natural products have been promoted as essential tools for IDM, fungicide resistance management, and more sustainable alternative to FRAC M fungicides. Biologically based fungicides (FRAC BM) often have multiple modes of action: They may be toxic to target pathogens or may stimulate the host plant’s natural defense mechanisms against infection. The early partnership between large multinational companies and niche biopesticide companies has evolved to the point where large multinationals have started their own biological R&D programs that focus on improving efficacy, persistence, and the spectrum of biological fungicides. This R&D requires significant scientific and commercial investments. Similar to analog chemistry, the development of biologicals relies upon a few microbes (Bacillus subtilis, Bacillus amyloliquefaciens, Trichoderma harzianum, etc.). Although biological fungicides are advocated to serve in this capacity, their higher cost, reduced efficacy and inconsistent efficacy has resulted in growers still relying on the older FRAC M chemistries, even as new rotations (using biological fungicides, surfactants, etc.) are developed to reduce the reliance on these products (Abbott and Beckerman 2018; Ayer et al. 2021; Cordova et al. 2019; Jacometti et al. 2010). As a result, they are primarily marketed as a supplement for fungal disease management, ability to reduce fungicide resistance and reduce fungicide residues, while lessening the reliance on FRAC M chemistries.
Meta-analyses of the many efficacy studies to date indicate moderate and inconsistent effectiveness for most biological control products (Ojiambo and Scherm 2006 and references therein). This lack of efficacy limits their use as partners in disease suppression, as they lack the reliability and consistency that older FRAC M fungicides provide in both disease and resistance management. Finally, there is no reason to believe that plant pathogens, particularly fungal plant pathogens, with their diversity of responses to evolve against other antagonisms both biological and chemical would be unable to evolve from this as well. The well-documented, inconsistent efficacy of various biological control agents (BCAs) under field conditions likely results from the genetic diversity within the pathogen population to BCA antagonism, even though efficacy was very good in controlled conditions (Bardin et al. 2015 and references therein; Ojiambo and Scherm 2006 and references therein; Duffy et al. 2003). This should come as no surprise: Under laboratory and field conditions, microbes regularly evolve resistance to multiple fungicides, antibiotics, and multigenic (‘stacked’) resistance genes of many cultivated plants (Chapman et al. 2011; McDonald and Linde 2002; Rupp et al. 2017).
When measured appropriately, pesticide use patterns and crop loss data quantify the impact that each intervention provides, thereby serving both as baseline and informing policy decisions. However, for the newest fungicides, due to the short time they have been in use, insufficient data exist to serve this purpose (Fig. 4). In reviewing these tradeoffs in fungal disease management, it is clear that the release of new products has coincided with significant reductions in the application rates (product per hectare) compared with the rates of older chemistries (Table 1). The impact of this reduction in rate is often misconstrued when data are analyzed with an eye only to product per hectare (Fig. 6). Furthermore, use rate for these products is often constrained by label restrictions to manage fungicide resistance issues (one to four applications per seasons versus 10 or more for older FRAC M products at a higher rate and without resistance risks). Even as science is guiding some policy changes, opportunities for improvement in evaluation, tracking cost-benefit differentials, better incorporation of IDM, development of improved biologicals, and mitigating the risk of hazard would aid growers in continuing to manage fungal disease in their crops without posing undue regulatory risks to the user, the consumer, or the environment (Bryson 2022; Russell 2006).
While fungicides remain key tools within IDM, the adoption of fungicides with reduced impact on nontarget organisms has been variable among commercial producers of food and nonfood specialty crops. Contrast the lessening of fungicide use within California among environmental horticulture crop growers with the increase among tree nut growers (Figs. 7 and 8). For environmental horticulture, there is a reduction in the use of FRAC M1 mode of action, while for tree nut growers all FRAC M multisite mode of action fungicides increased, probably due to the ability of copper compounds (FRAC M1) to manage bacterial diseases such as walnut bacterial blight (Xanthomonas arboricola pv. juglandis) in addition to fungal diseases.
The continuing challenge for the agrochemical industry is to develop new fungicides to improve upon previously developed chemistries, while replacing AIs lost to resistance and newly understood environmental and human health risks. This work dovetails that of applied plant pathology researchers, whose challenge is to devise grower-relevant tools that improve upon current technologies and management skills, while improving the bottom line (Abbott and Beckerman 2018; Ayer et al. 2021; Beckerman and Abbott 2019; Holb and Schnabel 2005; Reuveni et al. 2022). Success in this arena requires meeting growers at their level economically and educationally, and multiple challenges exist in achieving these modest goals. The failures of science (particularly the extension of science) have fostered a growing distrust of the integrated cast of players that contributed to the very success of production agriculture (government regulators, agricultural scientists, extension specialists, technology, and of the growers themselves) at a time when more of the population is dependent on these people. The reality is that ∼1% of the U.S. population produces plants for food, fiber, aesthetics, and ecosystem services (Center for Sustainable Systems, University of Michigan 2021; Roser 2019; U.S. Department of Agriculture-Economic Research Service 2020a). This production benefits the growers themselves and the remaining 99% of the population, while generating a surplus to export (∼24% of horticultural crop production, valued at $34.8B (U.S. Department of Agriculture-Economic Research Service 2020b); the export share of U.S. agricultural production averaged 20% from 2011 to 2013 (U.S. Department of Agriculture-Economic Research Service 2020b). Despite the overwhelming success of U.S. agriculture, and fungicides as a contributor to that success, disease management will be closely scrutinized against the environmental impacts of crop production, even as pesticides become more target-specific with less risk of environmental damage.
The very successes of IDM to provide a robust and safe food supply has resulted in a decline in our ability to perceive and address the food security challenges we face. Increases in crop production have reduced the number of growers needed to maintain current levels of productivity (Sumner et al. 2014 and references therein), while their average age increased to 57.5 years (U.S. Department of Agriculture-National Agriculture Statistical Service 2017). Furthermore, increases in productivity have resulted in increasing the technical assistance required to successfully manage these crops (Sumner et al. 2014 and references therein). Unfortunately, as with many technological improvements, the technical advances required to maintain these improvements do not provide a means to address new needs or respond to the very challenges and consequences these changes elicited. In fact, at the same time, the erosion of extension and the lack of partners to independently evaluate products and technology result in the loss of the ‘diffusion of innovation’, contributing to the continued reliance on older fungicides (captan, mancozeb, etc.). The degree to which a new fungicide or tactic is adopted depends upon the degree of perceived improvement, offset by the risk that inaction costs. Fewer extension specialists have resulted in gaps for evaluating new products, developing programs to improve growers’ fungicide rotations, and result in fewer scientists assessing the degree to which any technologies, including new fungicides, are adopted (Everts et al. 2012; Wang 2014). Fungicide efficacy and disease control assessment is an immense task given the pathosystems, available fungicides, available technologies (smart sprayers, forecasting systems, resistant cultivars, etc.), the diffusion of technological innovation, and the typically poor documentation of their impact (Gent et al. 2013).
Conclusion
Fungicides have and will continue to play a central role in crop protection, reducing yield loss, enhancing quality, and preserving food security worldwide. Prior to human entry into the Industrial Age (mid-19th century), a majority of the world’s population worked on farms. Today, within the developed countries a minority of people work on farms and in grower operations; for example, less than 1% of the U.S. workforce has jobs in agriculture (U.S. Department of Agriculture-Economic Research Service 2020a). Issues of starvation have been supplanted by issues of obesity, and concerns about famine have shifted to fear of cancer in first world countries. It is both easy and convenient to ignore or forget that global food security is a fragile, complex process that exists in a dynamic equilibrium involving plants, pests, pathogens, and people. It is also a process that can fail without continued vigilance. The ability of all microbes (including fungi) to evolve outpaces human efforts at plant breeding, fungicide development, and our ability to manage their evolution. FAO projections predict the addition of another 2.5 billion people to urban populations by 2050 (FAOSTAT 2017). To feed this growing population, agricultural productivity must be maintained and even increased, requiring innovation in all areas of pest management, including fungicides. Disease management will continue to be a constant challenge to food security that will require not only an integrated approach, but new tactics and strategies to fulfill the promises of IPM and protect the very food security humans depend upon. Fungicides will continue to be an essential part of this effort. We end this review where we started it. Despite considerable progress in the understanding of the biology and etiology of plant pathogens, management of fungal pathogens has not changed significantly in the past 50 years. And even if it does, it will still rely on fungicides.
Acknowledgments
We thank Rick Latin, emeritus professor, Purdue University, for editing and comments and Keith Branly, SummitAgro, U.S.A., for assistance.
Funding: Support was provided by the U.S. Department of Agriculture−National Institute of Food and Agriculture (grants 2021-170004781 and 2021-34383-348482).
The author(s) declare no conflict of interest.
