Nematicides can be credited for having put the science of nematology firmly on the map. The enormous amount of crop damage and yield loss that plant-parasitic nematodes can cause was not known until the first trials with nematicides in the 1920s (Taylor, 2003). From the 1950s to the 1970s, the discipline of nematology was booming and research on nematode biology, physiology, and management was rapidly expanding. This optimism started changing in the 1960s and 1970s, when some of the less desirable side effects of nematicides started to emerge (Thrupp, 1991; Chitwood, 2003). This was primarily due to their high and broad-spectrum toxicity, and significant environmental impact (Chitwood, 2003). Unlike herbicides, insecticides, and fungicides, for which safer products have been available for decades, nematicides seem to have been stuck in the 1960s and 1970s, an age when regulatory requirements were in their infancy. Rachel Carson published ‘Silent Spring’ in 1962 (Carson, 1962), the first publication to raise awareness of the damage that pesticides can do to the environment, which eventually led to the establishment of the Environmental Protection Agency (EPA) in 1970 (Lewis, 1985). Almost all currently used nematicides predate the establishment of the EPA and would not pass the regulatory hurdles for new pesticides that are in place today. Traditionally, nematicides were broad-spectrum products, either fumigants (soil sterilants), or organophosphates or carbamates (neural toxins), and many of them have been banned in recent years. Several comprehensive reviews on nematicides have been written (Taylor, 2003, retroactively published in 2003; Wright, 1981; Hague and Gowen, 1987; Chitwood, 2003; Rich et al., 2004; Jones, 2017). A list of products that have been used as nematicides throughout history is given in Table 1.
Products that have been used as nematicides throughout history.
Common namea | First use (country) | Product type/chemistry | Mode-of-actionb | Signal wordsc |
---|---|---|---|---|
Carbon disulfide | 1869 (FR) | Fumigant | Multi-site | Danger** |
Chloropicrin | 1920/1936 | Fumigant | Multi-site | Danger |
Methyl bromide | 1932/1961 | Fumigant | Multi-site | Danger* |
Formaldehyde | 1930 | Fumigant | Multi-site | Danger** |
DD | 1943 | Fumigant | Multi-site | Danger** |
EDB | 1945 | Fumigant | Multi-site | Danger** |
DBCP | 1954 | Fumigant | Multi-site | Danger** |
1,3-D | 1954 | Fumigant | Multi-site | Danger |
Metam sodium | 1954 | MIT generator | Multi-site | Danger |
Fensulfothion | 1957 | Organophosphate | AChE | Danger** |
Ethoprop | 1963 (US) | Organophosphate | AChE | Danger |
Aldicarb | 1965 (US) | Carbamate | AChE | Danger* |
Dazomet | 1967 | MIT generator | Multi-site | Danger |
Carbofuran | 1969 | Carbamate | AChE | Danger* |
Fenamiphos | 1968 (DE) | Organophosphate | AChE | Danger* |
Oxamyl | 1972 (US) | Carbamate | AChE | Danger |
Terbufos | 1974 (US) | Organophosphate | AChE | Danger* |
Enzone | 1978 | Fumigant | Multi-site | Danger* |
Cadusafos | 1990? (US) | Organophosphate | AChE | Danger* |
Imicyafos | 2010 (JPN) | Organophosphate | AChE | Danger* |
Fosthiazate | 1992 (JPN) | Organophosphate | AChE | Danger* |
Ivermectin/Abamectin | 1981 (JPN) | Lactone | GluCl | Danger |
Spirotetramat | 2008 (US) | Tetramic acid | LBI | Caution |
DMDS | 2010 (US) | Fumigant | Multi-site | Danger* |
Methyl iodide | 2007 (US) | Fumigant | Multi-site | Danger** |
Allyl ITC | 2013 (US) | Fumigant | Multi-site | Danger |
Tioxazafen (seed) | 2017 (US) | Oxadiazole | Unknown | Caution* |
Fluensulfone | 2014 (US) | Thizaole | Unknown | Caution |
Fluopyram | 2010 (US), 2013 (HND) | Benzamide | SDHI | Caution |
Fluazaindolizine | 2020? | Carboxamide | Unknown | Caution |
The lack of nematicide research by industry from the 1960s to the last decade is in part due to the cryptic nature of nematodes, and the difficulty of recognizing and assessing impacts on crop yield, which often leads to an underestimation of the damage that they can cause. In addition, and probably the main reason for the research gap, is that the nematicide market is very small when compared with the herbicide, fungicide, and insecticide markets (Kang et al., 2016, Fig. 1). The entire history of nematicides in fact is one of accidental discoveries, as all of them were initially discovered not as nematicides, but rather as sterilants or fumigants (methyl bromide, 1,3-dichloropropene, metam), insecticides (oxamyl, ethoprop, and other organophosphates and carbamates), fungicides (fluopyram), or animal health drugs (abamectin).
The recent focus on nematicides is in large part a response to the overall increasing regulatory pressure on hazardous products (Class 1 pesticides, which until recently all nematicides belonged to), and more specifically the fact that some of the most effective and popular nematicides, including methyl bromide, fenamiphos, and aldicarb have become severely restricted (Ristaino and Thomas, 1997; Cone, 2010; EPA, 2010). These factors, combined with a growing awareness of the importance of managing nematodes in agriculture, and the expectation of more crop damage attributed to nematodes in the future due to agricultural intensification, soil degradation, and warmer climate, have triggered a new sense of urgency and opportunity within the agricultural industry.
A. L. Taylor wrote several publications on nematicides staring in the 1940s (Taylor and McBeth, 1940, 1941a, 1941b; Taylor, 1943, 1949). This was the time when first the fumigants and later the organophosphate and carbamate nematicides were introduced, and many fumigants were openly sold to the public in glass jugs (Nemagon, a.i. 1,2-dibromo-3-chloropropane; DBCP) or cans (Dowfume, a.i. methyl bromide). In one of his last papers from 1977 (retroactively published in 2003), Taylor (2003) ends with the following sentence: ‘During the course of an investigation started in 1977, the Environmental Protection Agency of the United States Government cited health hazards (‘groundwater contamination and male sterility’ note from author)… in manufacture, handling and application of DBCP… This event will certainly have a considerable influence on the future history of nematicides. Perhaps it is the beginning of a new era.’ DBCP, one of the most effective and widely used nematicides in history, was banned two years later (Babich et al., 1981). However, DBCP was effectively replaced by methyl bromide, and it was not until methyl bromide was phased out 30 years later (being a major ozone-depleting substance) (Ristaino and Thomas, 1997), that Taylor’s new nematicide era finally began to emerge. In response to the phasing out of methyl bromide, many companies realized the new opportunity at hand, and initiated new nematicide discovery programs.
Ideas for new nematicides can come from a variety of sources, such as chemical libraries, scientific literature, natural products, and patents. Pharmaceutical and crop protection companies may have libraries of several million compounds, and often have exchange agreements. Cross-industry patent searches, especially of newly released patents, are another common source for starting points. Historically, the ‘spray and pray’ approach, meaning a large number of unknown or novel compounds are evaluated in some type of high-throughput screening against a certain target pest, and visually evaluated for efficacy, has been the most commonly used approach (Drews et al., 2012; Slomczynska et al., 2015). If a new molecule shows activity, extensive chemical research is then used to identify and modify its structure to improve its performance. While this approach is still common, random screening of compounds has given way to more targeted efforts, such as combinatorial chemistry (Lindell et al., 2009) and structure-based design (Baker and Umetsu, 2001). The idea is that compounds fit some a priori hypothesis (Lamberth et al., 2013) or are pre-filtered for agrochemical-like properties (Jeschke, 2016). The rapid advances in the ‘omics’ fields have created more opportunities for target-based discovery and the synthesis of specific molecules that bind to specific proteins; however, this approach has not yet lived up to the high expectations.
In the end, the best place to find biological activity is still in other biologically active compounds, such as existing pesticides, pharmaceuticals, and natural products. With the demand for biological products in agriculture growing steadily, many companies now have microbial and natural product libraries. One reason for the suitability of natural products in agriculture, or at least as lead candidates for further discovery, is their biologically relevant chemical diversity. Natural products have evolved with and against their biological targets, which is often manifested in high affinity interactions. Throughout history, nature has been a prolific source of drugs (Dias et al., 2012), as well as of some highly effective pesticides. There are many examples of pesticides that are natural products or derivatives thereof, such as avermectins (insecticide/nematicide), spinosyns (insecticide), pyrethrins (insecticide), strobilurins (fungicide), and triketones (herbicide) (Cantrell et al., 2012). Between 1979 and 2010, natural products accounted for almost 70% of all new active ingredient registrations (Cantrell et al., 2012). Biological nematicides will likely become more important in the future. They will not be covered in this review but merit another full review of their own.
Sometimes new active compounds are discovered accidentally, such as with penicillin (Fleming, 1929), but in most cases, they are the result of a targeted discovery effort, using one or more specific assays. A nematicide discovery program is only as good as the biological assay that is in place to detect its activity, and the ‘best’ screening method is always a compromise between speed and accuracy. This will primarily depend on the target and the throughput. Different systems and nematode models can be used, including in vitro or whole plant assays. Nematicidal activity can be measured by visual observations of the body shape or movement of nematodes. However, such observations are not always the most reliable, as nematodes may respond very differently depending on the mode-of-action of the tested compound. Another concern is the timing of the evaluation or observation. If the observation is done too soon, slower-acting compounds may be missed, if done too late, nematodes may be able to recover. Ultimately, the time it takes for mass screening of large numbers of compounds is critical, and a balance needs to be found between accuracy and efficiency. While it is impossible to exclude errors, they need to be minimized. It is especially critical to minimize type II errors or false negatives (no activity is found where there is activity), as this may lead to missing out on potentially promising compounds.
The bacterial-feeding nematode
Once the initial nematicidal activity has been found, the focus is to improve this activity. At the same time, other activities need to be done, such as studies on toxicology and environmental impact, mode-of-action, soil behavior, formulations, patent situation, cost of manufacturing, and use rates and potential uses. The early discovery research is always confidential, and it is typically not until a few years before registration, that the research is made public. Figure 2 outlines a nematicide discovery process in industry, starting from idea generation, to the discovery process, and up to the commercial development phase. The entire process is highly integrated and requires a wide range of experts working together. It is estimated that only one in 140,000 active ingredients discovered today will pass the rigorous testing requirements to become a registered pest management product (Sparks, 2013).
Majority of research done on new nematicides is focused on their risk assessment on the environment and human health, that include potential impacts on wildlife, fish, plants, and other non-target organisms. Safety to non-target organisms is becoming increasingly important, and safety studies include organisms such as collembola, soil and predatory mites, honeybees, spiders, and water fleas. For soil-applied nematicides, the product’s impact on the soil environment is an important source of concern, and many regulatory requirements are put in place to address this. Pesticide registration nowadays is a very complex, highly regulated, and involved process from start to finish.
The cost of bringing a new chemical active ingredient to market is increasing every year, and is now estimated to be more than US$250 million, about 10-fold what it was in the 1960s (Sparks, 2013). Similarly, the average time from product discovery to market launch has increased and is now >10 years. This trend will probably continue, making it increasingly harder for smaller firms to bring new products to the market, as they simply cannot afford to invest the time and money, much less deal with the substantial amount of regulatory documentation.
The new nematicides that will be discussed are listed in Table 2. These new nematicides are very different from previous products, in large part due to the regulatory requirements on human and environmental safety. Soil behavior – such as leaching potential, soil persistence, effects on beneficial soil organisms, degradation and metabolism pathways – is now a critical component of the registration and development process (Table 3). Ideally, a nematicide will only affect plant-parasitic nematodes, work consistently, does not leave residue in the soil or plants, is easy and safe to apply, and is inexpensive. Combining all these traits is a challenge, but the pay-off could be quite substantial. The new generation of nematicides certainly have a much better profile in terms of operator safety and selectivity, and with more companies stepping up their efforts, more nematicides will continue to become available in coming years. An overview of the most significant new chemical nematicides to emerge in the last decade is provided (Table 2).
Characteristics of new synthetic nematicides as compared to older products (fumigant and carbamate nematicides).
Chemical name | Chemical structure | Water solubility | Soil 1/2 life | Mode-of-action | Signal words |
---|---|---|---|---|---|
Fumigant (1,3-D) |
|
Gas | Short < 14 d | unknown | Danger |
Carbamate (oxamyl) |
|
240,000 ppm | Short 7 d | AChEa | Danger |
Fluensulfone |
|
545 ppm | Short 7-17 d | Beta oxidation inhibitor | Caution |
Fluopyram |
|
10 ppm | Long > 200 d | SDHIb | Caution |
Fluazaindolizine |
|
2000 ppm | Medium 30 d | unknown | TBD |
Spirotetramat |
|
30 ppm | Short (< 1 d) | ACCc inhibitor | Warning |
Tioxazafen |
|
1.24 PPM | Long (48-303 d) | Disrupts ribosomal activity | Caution |
Characteristics of the ideal nematicide.
Grower perspective | Regulator perspective | |
---|---|---|
Intrinsic activity | Broad-spectrum, controls all parasitic nematodes | Selectivity (safe to non-target/beneficial organisms) |
Soil behavior | Good soil movement and long soil residual activity | No leaching and low soil persistence |
Plant behavior | Systemic activity, low phytotoxicity | No crop residues, no negative impact on produce quality |
Application | Flexibility, low rates | Safe to handlers, low human toxicity |
Fluensulfone, fluopyram, and fluazindolizine are new nematicides that all have a trifluoro (3-F) group in their molecular structures and are hereby referred to as 3-F nematicides. These nematicides have a much safer toxicity profile than the older nematicides (fumigants, organophosphates, carbamates) (Table 2). However, they are quite different in terms of their chemical and physical properties, and their modes-of-action.
Several
Fluopyram is a very fast-acting and potent nematicide, with
Fluazaindolizine has irreversible effects on
Similar to fluensulfone, there can be some variation in how populations of the same plant-parasitic nematode species respond to fluazaindolizine. Five populations of
Application rates for the new nematicides are similar or somewhat lower than rates of old organophosphate or carbamate nematicides (1-2 kg ai/ha), and much lower compared to fumigant application rates of 200 to 300 kg ai/ha. Rates of application for the new nematicides range from 1 to 2 kg ai/ha for fluensulfone and fluazaindolizine, and less than 0.5 to 0.7 kg ai/ha for fluopyram and spirotetramat.
While initially marketed as an insecticide, spirotetramat began to receive attention as a nematicide in 2009 (McKenry et al., 2009) (Table 4). Since this initial report, there have been several greenhouse and field studies evaluating the nematicide against a range of plant-parasitic nematodes; in all cases spirotetramat was applied foliarly. Optimal efficacy occurred when spirotetramat application coincided with early stages of nematode root infection (Vang et al., 2016). Single (0.017 kg/ha) and dual applications (0.017 and 0.26 kg/ha) of spirotetramat to peach in a greenhouse study reduced
Summary of the literature evaluating new reduced-risk agricultural nematicides.
Experimental venue | |||||
---|---|---|---|---|---|
Nematicide | Nematode | Laboratory | Greenhouse | Field | Reference |
Spirotetramat |
|
Nursery plant | Chalanska et al. (2017) | ||
|
Wheat | Smiley et al. (2011, 2012) | |||
|
Lima bean | Lima bean | Jones et al. (2017) | ||
|
X | Peach | Shirley et al. (2019) | ||
|
Nursery plant | Nursery plant | Baidoo et al. (2017) | ||
|
Multiple perennials | McKenry et al. (2009) | |||
|
X | Peach | Shirley et al. (2019) | ||
|
Multiple perennials | McKenry et al. (2009) | |||
|
Wheat | Smiley et al. (2012) | |||
|
Raspberry | Zasada et al. (2010) | |||
|
Multiple perennials | McKenry et al. (2011) | |||
|
X | Waisen (2015) | |||
|
Multiple perennials | McKenry et al. (2009) | |||
|
Multiple perennials | McKenry et al. (2009) | |||
|
Multiple perennials | McKenry et al. (2009) | |||
Fluopyram |
|
Strawberry | Watson and Desaeger (2019) | ||
|
X | Soybean | Heiken (2017) | ||
|
Strawberry | Watson and Desaeger (2019) | |||
|
X | Tomato | Wram and Zasada (2019) | ||
|
X | Tomato | Faske and Hurd (2015) | ||
|
X | Tomato | Heiken (2017) | ||
|
Lima bean | Lima bean | Jones et al. (2017) | ||
|
Cucumber | Hajihassani et al. (2019) | |||
|
Carrot | Becker et al. (2019) | |||
|
Tomato | Silva et al. (2019) | |||
|
Tomato | Desaeger and Watson (2019) | |||
|
Strawberry | Watson and Desaeger (2019) | |||
|
x | Tomato | Faske and Hurd (2016) | ||
Fluensulfone |
|
Strawberry | Watson and Desaeger (2019) | ||
|
Potato | Grabau et al. (2019) | |||
|
Potato | Norshie et al. (2016) | |||
|
Pepper | Oka (2019) | |||
|
Strawberry | Watson and Desaeger (2019) | |||
|
x | Tomato | Wram and Zasada (2019) | ||
|
Carrot | Becker et al. (2019) | |||
|
Tomato | Silva et al. (2019) | |||
|
Lima bean | Lima bean | Jones et al. (2017) | ||
|
Cucumber | Hajihassani et al. (2019) | |||
|
Sweet Potato | Ploeg et al. (2019) | |||
|
Cucumber | Morris et al. (2016) | |||
|
Tomato | Desaeger and Watson (2019) | |||
|
Potato | Grabau et al. (2019) | |||
|
Lettuce | Oka (2019) | |||
|
Strawberry | Watson and Desaeger (2019) | |||
|
Chickpea | Oka (2019) | |||
|
Potato | Grabau et al. (2019) | |||
|
Fig | Oka (2019) | |||
Fluazaindolizine |
|
Strawberry | Watson and Desaeger (2019) | ||
|
Strawberry | Watson and Desaeger (2019) | |||
|
x | Tomato | Wram and Zasada (2019) | ||
|
Tomato | Silva et al. (2019) | |||
|
Carrot | Becker et al. (2019) | |||
|
X | Thoden and Wiles (2019) | |||
|
Cucumber | Hajihassani et al. (2019) | |||
|
Tomato | Desaeger and Watson (2019) | |||
|
Strawberry | Watson and Desaeger (2019) |
The 3-F nematicides (fluensulfone, fluopyram, fluazaindolizine) have been evaluated on a variety of crops for their ability to suppress a diversity of plant-parasitic nematodes (Table 4). However, most have focused on their efficacy against
As stated above, it appears that fluopyram may be a poor ovicide. Fluopyram applied at the labeled rate (249 g a.i./ha) to the soil surface of tomato plants two days post inoculation with
Both fluopyram and fluensulfone were effective nematicides against
The impact of initial nematode density on efficacy of the 3-F compounds has also been explored (Hajihassani et al., 2019). In this microplot study, initial population densities of
Becker et al. (2019) found contradictory results when examining the effects of these compounds on carrot production over multiple years. Fluensulfone and fluopyram were unable to consistently lower final population densities of
Desaeger and Watson (2019) also found that the use of these compounds could help prevent rapid re-infestation of roots. When field grown tomatoes were treated with drip applied non-fumigant nematicides, fluensulfone had the most consistent suppression of
When evaluating these compounds for control of nematodes outside of
In a greenhouse study, Oka (2019) also evaluated the effects of fluensulfone exposure pre- and post-plant on
Several studies have evaluated the effects of fluensulfone on plant-parasitic nematodes infecting tuber crops like potato and sweet potato (Table 4). A full rate of fluensulfone in liquid and granular form resulted in comparable suppression of
As indicated, the bulk of efficacy data of 3-F nematicides is on
Differences in nematicide efficacy across trials may be due to the physical properties of the new products, especially their solubility in water and half-life in soil (Table 3). Water solubility is important in that it will determine how well the molecule moves through the soil profile. Higher water solubility will give better soil coverage and distribution of the active but will also increase the risk of leaching. Soil half-life determines how long the molecule stays active in the soil. Longer soil half-life will give longer soil residual activity and more extended nematode control, but also increases the risk of soil accumulation. Fluensulfone and fluazaindolizine are relatively similar in terms of solubility and soil half-life, but fluopyram is quite different, having low water solubility, and a much longer soil half-life (Table 3). Overall, all the 3-F nematicides have much lower water solubility, but longer soil half-lives than oxamyl. A lack of uniform soil distribution, combined with the typically patchy field distribution of nematodes, could explain some of the variability observed in the above field trials. Also, the lack of standardization in terms of sampling procedure, sampling time, and extraction method is another source of variability. Like in any other discipline, a keen understanding of the pest, i.e. nematode biology and plant-nematode interactions, is critical to understand, interpret, and validate the inherent variability of nematode field trial data. It should come as no surprise that a background specific to applied nematology is now a discipline in high demand, but also in short supply. Fortunately, both industry and universities have started to notice this gap in expertise, and many have started hiring applied nematologists again.
The practice of soil fumigation is facing increasing societal and regulatory pressure, but nevertheless remains the primary nematode management tool in the production of many high-value crops. Soil fumigation is convenient, as it gives growers weed, soil disease, and nematode control all at once. Also, fumigants are often the only nematicides available to growers, with many crops not having a single registered nematicide available until recently. The recent entry of safer and more selective nematicide alternatives is welcome news for growers, but questions remain about their efficacy and adoptability. Their selectivity, both among plant-parasitic and non-parasitic nematodes, needs to be studied further, as well as how these new products can best be integrated into existing nematode management programs.
Nematode resistance was never a major concern for nematicides in the past, probably due to the broad-spectrum nature, and relatively limited use of most of the old products. With the new nematicides being more selective, and potentially used more frequently, resistance may be more likely to occur. For instance, SDHI compounds like fluopyram, having long soil persistence and similar mode-of-action towards fungi and nematodes, are likely to put significant selection pressure on target nematodes. It is also well-known that many of the older organophosphate and carbamate nematicides can lose efficacy over time due to accelerated degradation in the soil caused by microbial adaptation (Smelt et al., 1987; Johnson, 1998). Certainly, this is something that should be monitored for all the new 3-F nematicides as well. Recently, a new IRAC (Insecticide Resistance Action Committee) Nematode Working Group was established to investigate the resistance risk of new nematicides and to develop a mode-of-action classification scheme similar to insecticides and acaricides (IRAC, 2019).
The future impact of the new nematicides will depend on (i) how effective they prove to be under field conditions – they have to show they can reduce nematode damage consistently, and improve crop vigor and yield, (ii) the future regulatory status of fumigants – if regulatory pressure continues to increase, growers are more likely to turn towards non-fumigant options, and (iii) cost of the new nematicides – with many growers facing increasingly shrinking margins, the price tag will be more important than ever. If the new nematicides are to replace fumigants, they will have to be integrated with a weed and soil disease management program, and such a strategy will have to provide comparable control at a similar cost than a fumigant program. There is probably no standard recipe for such a non-fumigant soil management program, as no fields are the same, and nematicides may work differently depending on soil and nematode type, and agronomic practice. Soil management programs will have to be more prescription-based and tailored towards the specific issues and needs of individual fields. Certainly, there are other advantages of moving away from fumigants and other more toxic nematicides, in terms of safety, public perception, and overall soil health. In the long-term, improved soil health and more resilient soils may be one of the greatest benefits of moving away from soil fumigants and adopting more selective and safer nematicides.