Report on the Informal Conference held during the Annual Meeting of Entomological Society of America in San Diego, CA, December 10, 2001
L. L. Larson, Conference Convener
Dow AgroSciences, Discovery Research
9330 Zionsville Road, Indianapolis, IN 46268-1053
Bifenazate–Registering a reduced risk pesticide
Paul T. McDonald of UniRoyal Chemical Company began the conference with a talk on the journey of a novel selective acaricide, bifenazate (Floramite, Acramite), to registration as a reduced risk pesticide. It may take 10 years and over $40 million to develop a new pesticidal tool. The road to registration can often be as tortuous as a mined road in Afghanistan. The reduced-risk process can make the road shorter and less tortuous.
Bifenazate, a novel selective acaricide discovered at the UniRoyal Laboratories in Connecticut, is being developed by Uniroyal for crop and non-crop uses. The reduced-risk process accelerates the registration of lower-risk products by comparing new products with all the existing alternatives in a jury process.
The categories considered include reduced risk for human health, non-targets, groundwater or surface water pollution, and environmental residual. The number of reduced risk pesticides have been growing since the program began in 1993. This was helped by the organophosphate alternative category added in 1998 following the passage of the Food Quality Protection Act (FQPA). Since 1994, 34 materials have been designated "Reduced Risk," including eight in 2001. EPA sees the program's purpose to broaden the adoption of integrated pest management (IPM) and to significantly reduce risk through replacing those that pose greater risk with alternative products.
In order to be considered, a significant market share must be projected for the material. The incentive for the reduced-risk paperwork is an accelerated review process. The average time to registration can be cut from 4 to 5 years to 1-1/2 to 2 years. The downside is the extensive effort required to produce the documentation package. Included in the package is the reduced-risk rationale, chemical composition, an FQPA registration application, tolerance petitions, and fees. The studies are required in triplicate. For bifenazate, with 52 food and 114 non-food uses, this amounted to 64 volumes of paperwork that weighed 800 lb.
After submission of the package, an EPA panel is held within 30 days. The registrant is allowed 10 minutes to summarize the submission and then answer the panel’s questions. The reduced-risk designation is conferred by a majority of six votes by the panel. The registrant is usually notified of the ruling the same day.
Bifenazate was considered a reduced-risk pesticide. Its mammalian toxicity is Category IV, and it is non-teratogenic, non-neurotoxic, non-mutagenic, non-cholinergic and non-oncogenic. It is not toxic to wildlife, slightly to moderately toxic to avian species, toxic to fish by flow-through. It is toxic to bees by contact, but non-toxic as a residual on foliage. It degrades rapidly in soil and water, and does not leach. It is safe to mammals, birds, aquatics, and non-targets. It has faster soil dissipation, lower use rates, and lower residues than the competition, and is efficacious and highly compatible with biological control agents. There is no cross-resistance to any known acaricides, and fewer applications are needed per year.
Bifenazate acts as a GABA agonist at the chloride ion channel. Resistance can be induced in the laboratory, but quickly reverts once the selection is stopped. Data has shown excellent efficacy on spider mites in roses, pome, stone, strawberries, cotton, and hops. The material also shows large margins of safety to beneficial insects and mites with very good crop safety.
Acramite is currently registered on nectarines, grapes, strawberries, early season cotton, and hops. Future crops will include pome and stone fruit and almonds. Endorsements that appear in the submission package include contract researchers, extension, pest control advisors, commodity groups, and members of the EPA/USDA Interregional Research Project #4 (IR-4).
Current reliance on one or two miticides will lead to a substantial market share for Acramite. At rates of 0.25 to 0.75 lb (AI)/acre, less active ingredient need to be applied over a season, and there is a 12-hour reentry period. Bifenazate has low toxicity, is safe to the environment, and compatible with insect pest management [DOES HE MEAN INTEGRATED PEST MANAGEMENT?].
Molt accelerating compounds
Gary Thompson of Dow AgroSciences gave a report on the global management of the insecticide technology of molt accelerating compounds (MACs) in a rapidly changing environment. Thompson reviewed the merger with Rohm and Haas that brought MAC technology to Dow AgroSciences. On March 1, Dow announced its intentions to purchase Rohm and Haas. A 90-day period of silence followed, during which the final details were cleared with governments around the world.
The drivers for this consolidation were declining to flat markets and the promise of spreading costs across more products. A broadened portfolio also leads to better control and better industry-wide stewardship. Larger companies mean larger and better information and communication networks.
MACs were discovered by Rohm and Haas in 1983. Tebufenozide was discovered in 1986, methoxyfenozide in 1990, and halofenozide in 1991. These products exhibit ovicidal activity and are very selective to lepidoptera.
Confirm was the first reduced-risk insecticide and the first insect growth regulator with molt accelerating properties. These materials are ecdysone agonists that causing premature lethal molt, as well as ingestion toxicants with little contact activity. Pests stop feeding when the materials are consumed. The metabolic breakdown of these materials is very slow, and at very low concentrations, they inhibit cuticle synthesis.
Methoxyfenozide is broader in spectrum than tebufenozide in controlling European corn borer and Southwestern corn borer. These materials are safe to workers, handlers, applicators, and consumers. They are also safe to bees, fish, birds, and natural enemies. They received the 1998 Presidential Green Chemistry Award.
Significant selection pressure will result in resistance development. However, the frequency of resistant individuals declines when the selection pressure is reduced. Proactive resistance management programs have been instituted against those pests that are especially at risk, such as the codling moth, obliquebanded leafroller, tea tortrix, and beet armyworm. Particularly targeted are environments that are conducive to resistance development, such as greenhouses, tropical, and irrigated deserts. Baseline data are collected before the material is launched, then populations are tracked every 2 to 3 years for sensitivity.
Interestingly, there has been little correlation between Confirm and Intrepid tolerance in the populations tested so far, indicating something other than a site-of-action insensitivity mechanism operating in the field. There was also no correlation between the sensitivity to organophosphates and MACs.
There have been reports of field activity problems on codling moth in Southern France. These strains were tolerant 2- to 11-fold , a level that falls within the normal baseline susceptibility. Here in the United States, there has also been resistance to benzoylphenylureas, that were not target-site related. In Thailand, due to the cultural practices of growing cabbage in a tropical climate on raised overhead-irrigated beds to cool them, they have produced an insecticide graveyard. Tebufenozide was sold for two years against the beet armyworm under these conditions, then was pulled from the market due to lack of efficacy. Beet armyworm strains were found to be 30X tolerant in diet incorporation and 164X tolerant in leaf dip tests. Methoxyfenozide showed 47X and 102X tolerance in the two tests.
When resistant individuals were crossed to a susceptible USDA strain, the progeny came down to 10X tolerance, showing an inheritance pattern of incomplete dominance. Studies showed that these strains were susceptible to indoxycarb, emmamectin benzoate, and chlorofenapyr. The resistance in the Thai strain is reversed by piperonyl butoxide, and so is probably mediated by mixed-function oxidase, although there is also some increased excretion in this strain.
The strategy is to preserve MACs as long as we can. The label prohibits the treatment of more than 2 to 3 successive generations. We require IPM programs and avoid low rates. Local business units own the resistance management programs and limit market share. Rotation with other materials is encouraged, as well as limited application windows and reduced market supply. MACs are excellent insect resistance management tools.
Tomato pest management with Avaunt
A presentation co-authored by John Andaloro, Daniel Sherrod and Wayne Steele from DuPont Crop Protection was presented on Avaunt for tomato pest management. Indoxacarb is the active ingredient, representing a new mode of action from the chemical class, oxadiazine. Avaunt is effective against all worm species on tomato and suppresses leafminer. It is available globally as a 30% WDG and a 15% SC. Field-use rates for all crops range from 25 to125 grams AI/ha.
Indoxacarb is registered in over 40 countries for over 15 crops under the trade names Ammate, Avatar, Rumo, Steward, and Avaunt. In the United States, Avaunt is currently registered for lettuce, cruciferous crops apple, pears, peppers, and tomato. Avaunt has reduced risk to mammals and exhibits excellent environmental safety. It inhibits the flow of sodium ions and exhibits potent insecticidal activity against major crop pests. It is bioactivated by insects to the active metabolite. Lepidopterous larvae are especially effective at the conversion that takes place, especially in the fat bodies.
Registered as a reduced-risk pesticide with EPA, Avaunt is low in mammalian toxicity (1687-1867 mg/kg oral and > 5000 mg/kg dermally) and is non-teratogenic, non-mutagenic, and non-oncogenic. Its preharvest interval is 1 to 3 days for most vegetables. It is safe to most beneficials, since it is most effective when ingested. It does, however, have effects on certain predatory beetles and fire ants due to cleaning and preening behavior. Adult predatory beetles are more susceptible than larvae, generally affected only in the first 3 days following highest use treatments. The material shows excellent environmental safety and is non-volatile with a 16-to-27-day half-life in soil. Indoxacarb has minimal effects on earthworms, avian species, and aquatics.
This is new chemistry that is critical for resistance management. It is a sodium channel blocker causing paralysis and death of the insect. DuPont is conducting baseline susceptibility work around the world for multiple lepidopteran species. On tomatoes, Avaunt is effective against tomato fruitworm, loopers, fall armyworm, tomato pinworm, Southern armyworm, and hornworm. It exhibits modest translaminar activity that is enhanced by oil-based adjuvants. However, it does not move into the vascular system of the plant, so it is more effective on leafhoppers and plant bugs than on aphids.
Avaunt has shown more activity against lepidopterous leafminers, such as pinworms and tentiform leafminers, than dipterous leafminers. Against the Brazilian tomato pinworm, Avaunt at 16 grams of product/100 liters + Assist (mineral oil) gave excellent control. It takes 2 to 3 days for most treated insects to die; however Avaunt prevents crop feeding quickly.
Highly potent to lepidopterous larvae, Avaunt is active against larvae of all sizes, but since ingestion is the major mode of action, application at egg laying through hatch is recommended. Good spray coverage is also essential.
Avaunt exhibits a strong feeding-cessation effect. In the laboratory, tomato fruitworm larvae will not feed on foliage treated with 1 ppm indoxacarb. Avaunt also controls adults when sprayed directly or if they come into contact with a wet surface. The addition of an oil, such as a methylated seed oil, aids in control.
Avaunt is effective and stable under a variety of environmental conditions. It is also stable from pH 5-10, so there is no need for buffering. Avaunt has a positive temperature correlation, low water solubility, and is rainfast 2 hours after application. This is the first year of commercialization in the United States on vegetables and tree fruits. Avaunt has an excellent fit in the tomato peat management system, with minimal impact on the environment and has a high degree of efficacy against important tomato pests, while conserving beneficial insects.
Regulating resistance management
Gary Thompson of Dow AgroSciences gave a second talk, this one on regulating resistance management, "Do We Have the Knowledge and Resources?" Thompson postulated that history has and will continue to show that, in general, regulations are not cost effective in delaying resistance. On the other hand, regulators have done a great job with little to guide them in facilitating the debate on regulation of resistance management. There are many good cost-effective regulations, such as patent and variety protection and safety regulations, that are needed by the crop protection industry. However, resistance management does not lend itself to regulations.
Before transgenics, the focus was to have a new alternative available by the time resistance developed. There were few dramatic examples of resistance management regulations. The exceptions were the government tender programs that succeeded in increasing resistance problems. In 1991, the European Union proposed a resistance risk evaluation and mitigation program that was finally in place in 2000.
After transgenics arrived in 1995, there was early recognition that constant expression could rapidly lead to resistance. This led to a focus to preserve Bt, and when Event 176 was conditionally registered on 8 Aug 1995, it contained a resistance reporting system and required a final resistant management plan by 1998. This plan was adopted by the EPA Scientific Advisory Panel in September 1998, reviewed by the working group of industry and outside stakeholders in April 1999, and implemented in October 2001. This plan calls for a 20% corn refuge in the corn belt and a 50% refuge corn in the cotton belt. In cotton, the original conditional registration called for a 4% untreated or a 20% treated refuge. In July 2000, further requirements were imposed, and in September 2001, the extended conditional registrations required registrants to study the north-south movement of Heliothis. In potatoes, there was a voluntary refuge in 1995 with the first registration; then in 1998, it was made mandatory. In 2000, a 20% refuge was required.
The main concern is adopting rigid programs that require a change in law to modify policing of compliance by industry and require basic research on pest biology as a condition of registration. The NAFTA Uniform Labeling Initiative is an example of beneficial regulation. This involves enhanced labeling with recognition of the mode of action for resistance management. The effort has been on consensus and multinational systems.
Voluntary plans are being implemented through 2001, and it may become mandatory after that. The European guidelines for resistance management involve laboratory and field studies. Where there is a risk of resistance, they focus on sensitivity and management strategies. The guidelines are now being developed and appear to involve different regulations in each country. The discussion currently involves how residues and efficacy impact the risk of resistance and at what stage resistance claims become reportable, in what form, and to whom. They are looking for options to resolve conflicts and whether baseline susceptibility is necessary for every pest. It has been difficult to test resistance management strategies, due to the long timeframe and biological and abiotic factors.
Resources are also short in these declining to flat markets. Consolidation in the industry only makes economic sense if the resources per product are reduced, leading to limited budgets. Research and development resources are down while regulatory costs are up. Only those product offerings that make sound financial sense are being considered. Resistance management regulations are adding significant recurring costs that could lead to fewer offerings and more resistance due to a lack of alternatives. At the same time, the government is downsizing, leading to reduced funding for USDA education efforts. For EPA, this is an intensive area, and they have cited a lack of resources for not being more responsive.
Farmers are calling for a simple and cost-effective resistance-management plan. It is a documented fact that no material with less than a 30% market share has ever developed significant resistance. We need to lower the hurdle rates and have the IR-4 protect products for high-risk pests. Labeling for resistance management could be improved. Enforcement responsibility should not be placed on the industry being regulated. Basic research on pest biology is still needed, but it should not be placed on industry as a requirement. All stakeholders have an interest in reducing the development of resistance. With limited resources, we need to explore our options and only use regulations for resistance management in limited situations.
The IR-4 Project
Keith Dorschner with IR-4 Project at Rutgers gave a talk on the "IR-4 Odyssey, Where We Have Been and Where We are Going." IR-4, a minor-crops partnership between USDA and land grant universities, is the only publicly funded program that conducts research and submits petitions for pesticide registration. In 1997, minor crops accounted for $39.7 billion, or 40%, of the total $98.1 billion in raw agricultural commodities. To date, IR-4 has submitted 5,500 food-use petitions and 8,000 ornamental-use petitions. In addition, over 200 biopesticide clearances have been obtained. Currently, the IR-4 budget, used to fight for the benefit of society, is $13.5 million per year.
In the late 1950s, a survey of the states was undertaken, and a wish list of 548 desired clearances surfaced. By 1962, it was apparent that minor-crops registration was a major problem, so IR-4 was born on 1 July 1963. The congressional bill was entitled "Evaluation of current data and needed research to determine tolerance levels for minor crops." The headquarters was established at Rutgers University that already had similar programs, and at the time, most of the agricultural chemical companies were headquartered in New Jersey. The focus of the organization was "the clearance of chemicals in the public service,"resulting in safe and effective pest control chemicals for the nation's food supply. The structure of the organization includes a technical committee, advisors, state liaison representatives, a national project leader, and one assistant director.
The initial funding was $25,000 per year for salaries of the Director and Assistant Director, and there was no money for research. This necessitated using data from other protocols and programs especially within USDA. Early on, IR-4 developed interfaces with growers, regional USDA offices, and the USDA Pesticide Regulatory Division, and later, EPA's Office of Pesticide Programs.
During the 1970s, IR-4 grew and matured. In 1971, IR-4 was the first to propose crop groupings to solve the minor-crops registration problem. In 1975, IR-4 began regional analytical laboratories and regional field coordinators at land grant universities, allowing IR-4 to acquire the funds and personnel to conduct research, a pattern that remains today.
In 1976, USDA’s Agricultural Research Service began their own minor-use program, bringing even more resources to IR-4. Also in 1976, IR-4 succeeded in obtaining an exemption from tolerance for all crops for Bt. In 1977, IR-4 began a national program for clearance of pesticides for minor or specialty non-crop uses.
The 1980s was the decade of funding challenges. With the Federal Insecticide, Fungicide, and Rodenticide Act amendments in 1988 (FIFRA 88) came Good Laboratory Practices requirements that added greatly to the cost of conducting research. IR-4, lumped with other federal programs deemed unessential, was cut several times only to be reinstated by Congress. FIFRA 88 required the re-registration of older pesticides, and 1,000 important minor uses were in danger of cancellation. Two-thirds of the IR-4 operating budget was devoted to defending already-registered uses. Also, the prescribed procedures of Good Laboratory Practices made the routine suddenly unacceptable. Many cooperators retired rather than face this new world. Also, the concept of the field research center was born, and research costs increased 40%. In 1982, IR-4 began the Biopesticides Program to include early stage and minor uses in animals.
The 1990s saw focus and planning take center stage. The Commodity Liaison Committee was started. This group, a voice in Congress for the program, includes food processors, progressive farmers, and ranchers. The Biopesticides Program was expanded to include a competitive grants program with 115 projects and 200 clearances. Workshops were started, and the Quality Assurance Department grew to 10 people. IR-4 has had 30 EPA inspections with no negative citations. It is now separate from the animal drugs program.
The emphasis has now shifted to reduced-risk pesticides in partnership with industry. Minor crops are now addressed up front with new chemistries. IR-4 now cooperates with Mexico and Europe. A special relationship has developed with the California Department of Pesticide Regulation with 20 petitions successfully submitted last year. IR-4 has quarterly technology working group meetings with EPA. Right now super crop groupings are being discussed to cover crops in between. Electronic petitions are working well, as is the reduced-risk category. IR-4 also has a Quarterly Newsletter. For more information on the project, see http://pestdata.ncsu.edu/ir-4/.
XDE-225–A new pyrethroid product
Mark Hertlein of Dow AgroSciences gave a talk on the first year field performance of XDE-225 (gamma-cyhalothrin, GCH), a new fully resolved pyrethroid product from Pytech Chemicals GmbH. GCH is being developed as a joint venture between DowAgrosciences and Cheminova. The joint-venture company is know as Pytech Chemicals GmbH.
GCH is the ultimate, resolved, single active isomer of lambda-cyhalothrin (LCH). As such, it joins a small, elite group of latest-generation, fully-resolved pyrethroid products. Worldwide launches will occur during in 2002 through 2006. Given that LCH contains two isomers, one active and the other basically inactive, the single-isomer GCH is expected to demonstrate equivalent field performance at half the label rate of LCH; this is referred to as the "2:1 activity assumption." Given the unique chemical relationship between GCH and LCH, the first-year, field testing program always involved a direct comparison between these two products, with LCH tested at its 1X field rate and GCH at 0.5X the lambda rate. Field tests during 2000 examined the overall performance, knockdown, and residual efficacy of GCH vs. LCH. A total of 155 global field trials were run during 2000, directed against the key primary and secondary pest species commonly targeted by pyrethroids. Frequency analyses were used to summarize the global field trial dataset.
Comparing LCH at 1X label rate with GCH at 0.5X, the overall performance was: In 79% of trials, there were no statistically significant differences (t-tests at each observation point; P = 0.05) detected between the performance of GCH and LCH; in 8% of trials, GCH was superior to LCH; and in 14% of trials, GCH was inferior to LCH (n = 155). The results of knockdown were: In 88% of trials, there were no statistically significant differences between GCH and LCH at the first observation time point; in 4% of trials, GCH was superior to LCH; and in 9% of trials, GCH was inferior to LCH (n = 129). Numerical trends also showed a slight but consistent advantage for LCH in terms of knockdown. The results of residual efficacy were: In 92% of trials, there were no statistically significant differences between GCH and LCH at the last observation time point; in 5% of trials, GCH was superior to LCH; and in 3% of trials, GCH was inferior to LCH (n = 135). Numerical trends also showed a slight but consistent advantage for GCH in terms of longer residual efficacy than LCH. Slight formulation differences between the GCH capsule suspension (CS) and that of LCH may help to explain these numerical trends. In summary, first-year field trials fully support the 2:1 activity ratio between GCH and LCH in terms of overall control, knockdown, and residual efficacy.
Where do we go from here?
Larry Larson from Dow AgroSciences gave the concluding remarks, entitled "Where Do We Go from Here?" Biotechnology is expected to evolve over the coming decade from its crop protection beginnings to include animal nutrition, nutraceuticals, and various output products that replace non-renewable feed stocks for industrial uses. Biotech input products have been rapidly adopted primarily in the Americas in soybeans, corn, cotton, and canola.
In the cotton market, where input traits were first marketed, there has been a dramatic decrease in acres treated for bollworm and budworm control as a direct result of the technology. At the same time, treatment for other pests has remained reasonably constant. Transgenics have decreased the total size of the cotton market by about 25-million-acre treatments, or about a quarter of the market. New products, including naturalytes, have eroded the market share of the older products, but due to a diversity of pests, a diversity of products for cotton will be necessary far into the 21st century. The corn insect control market has grown dramatically with the launch of transgenics for corn borer control. Currently over 10 million acres of corn is planted with the various Bt-corn products. This number go as high as 40 million acres in 2005 when the rootworm products now in development mature in the market. The vegetable market will remain rather stable with only a few transgenics entering the market by 2005. Biologicals and naturalytes will grow at the expense of older products.
The impact of transgenics on the crop protection industry has already been large. Currently $1.4 billion of cotton insecticide sales has been shifted to resistant varieties. In 2000, 32% of all cotton planted was Bollguard cotton, a $200 MM [WHAT'S MM?] of revenue shifted to seeds. In corn, $75 MM in new revenue has been generated from previous non-users of corn insecticides. The effects of these new products will be even more dramatic in the future. Up to a 64% reduction in corn insecticide treatments is projected once we have rootworm resistant varieties, 30% in cotton, 22% in vegetable crops treated acres. Overall, this could result in up to a 36% reduction in sprayable insecticides from 1995 to 2005.
The impact of biotechnology on row crop pest control will also be dramatic. Thanks to changes in public perception and customer attitudes favoring higher activity and greater application and environmental safety, the industry has responded with more highly active and selective pest management tools. These have already made a large reduction in the pounds of conventional insecticide applied to crops in the United States, and this trend promises to continue. The materials in the pipeline have never been more impressive and carry the promise for even better pest management systems. However, in general, the new materials are narrower in spectrum, leaving gaps that will take more management than current ones, and for the foreseeable future, must be filled by older materials. Although there are many new exciting materials coming from the industry, resistance management demands rotation strategies with a mix of old and new modes of action. We cannot afford to lose any tools in this battle. We will continue to discover new materials with varied modes of action and environmental compatibility that will allow for more opportunities for robust resistance management schemes. Sprayable products will always be necessary to lower pest outbreaks, and through the use of pest management, we can preserve these new tools for many years to come. Thanks to new innovations from a variety of companies, and better recognition of the value of resistance management, the future for pest management tools has indeed never been brighter.