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6 Pesticide Innovation and the Economic Effects of Implementing the Delaney Clause The economic effects in the agricultural sector of regulatory actions taken pursuant to the Delaney Clause will depend on a number of factors. These include the availability of effective currently registered alternative chemicals and the extent and success of chemical and nonchemical new product innovation in pest control. This chapter examines the innovation process and seeks to determine whether the Delaney Clause has had or will have an impact on it. This chapter also assesses the status of pest control innovation in major areas such as plant breeding, genetic engi- neering, and biological, cultural, and chemical pest control. As seen in Chapter 3, the committee's estimated current level of oncogenic risk is largely associated with old pesticides. Nearly all estimated herbicide and fungicide risk and more than half of the estimated insecticide risk are from pre-1978 products. If the Delaney Clause were applied to existing tolerances for currently registered, potentially oncogenic active ingredients, food tolerances for many economically valuable pesticides would be lost. The resulting void would create significant market opportunities for new non-oncogenic pesticides and other pest control technologies. The predictable losses in company income, however, might discourage overall investment in pesticide inno- vation research. Chapters 4 and 5 discuss four scenarios and tolerance reduction approaches that the EPA might follow in regulating oncogenic pesticides. Each scenario would require the revocation of many tolerances for fungicides. Herbicides and insecticides would be affected to a lesser 136

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PESTICIDE INNOVATION 137 extent. The two chapters focus on the short-term effects of the scenarios; this chapter examines the scenarios' long-term effects on pest control innovation. It is difficult to determine whether pest control R&D efforts are designed to eliminate oncogenic pesticide residues from the food supply. It is even harder to determine whether the Delaney Clause is causing the development of less-oncogenic or non-oncogenic pesticides. Experience from past changes in EPA policies provides some insight, but there have been few changes in federal regulation of cancer-causing agents. This lack of data prevents studies that attempt to correlate pesticide R&D invest- ments with different regulations on exposure to oncogens. Another important issue is the possible effects of rapid pesticide cancellations on R&D. In the past, single compounds have been canceled. There are no data on the effects of the few pesticide cancellations on total R&D activity. To gain information, the committee questioned industry research directors, reviewed available studies on the impacts of EPA pesticide regulations and FDA drug regulations, compiled information from various sources on past levels and rates of pesticide innovation, and analyzed other innovation indicators such as the number of new pesti- cides for certain crops field tested recently. THE INNOVATION PROCESS AND THE PESTICIDE INDUSTRY The pesticide innovation process involves finding and developing new compounds that are effective and safe, improving formulations of older compounds, expanding uses of older compounds to more crops and pests, and satisfying regulatory data requirements. The pesticide innovation cycle goes beyond industry's discovery of new compounds. It includes the government's approval or acceptance of product registrations, grower awareness and adoption of new products, and long-term product viability. The last two phases depend on a new pesticide's profitability, successful integration with other farming practices, availability for minor crop use, and susceptibility to pest resistance. The development of a new pesticide is a long and expensive process. The sequence of activities is shown in Figure 6-1. Usually 9 to 10 years will elapse from discovery to first registration. After registration, the market life for different pesticides varies greatly. Many pesticides widely used today, such as 2,4-D, parathion, and the ethylenebisdithiocarbamate (EBDC) fungicides, have been on the market for 35 years or more. But products may lose their market share and be removed from the market for many reasons. These include regulatory restrictions triggered by safety concerns; competition with more active, lower-cost pesticides or nonchemical pest controls; crop acreage adjustments; or pest resistance.

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~38 REGULATING PESTICIDES IN FOOD -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 YEARS -1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 (9 TARGET |~ SYNTHESIS 1---- (hi) BIOLOGICAL EVALUATION (PATENT APPLICATION) ~ ____ ~ RESEARCH FIELD USE O I I ~ _____ (a) FORMULATION I W PRODUCT DEVELOPMENT FIELD TESTS O (a) COMMERCIALIZATION DECISION I -- - - 08) PLANT AND ANIMAL METABOLISM STUDIES I ~ ENVIRONMENTAL CHEMISTRY BODIES I ma) RESIDUE STUDIES I . 1 (3 TOXICOLOGY STUDIES COMPOUND MANUFACTURE PROCESS CHEMISTRY ~ ---- (g) PESTICIDE TOLERANCE O PETITION APPLICATION am) EPA REVIEW I 1 _] @} EPA-ACCEP I ED LABEL I @) MARKETING--SALES I ENVIRONMENTAL EFFECTS I 1-- - ---- -- - - --- - OF PRODUCTION ma) ENGINEERING DESIGN I I em) MANUFACTURING PLANT CONSTRUCTION r I FIGURE 6-1 Pesticide development from production to commercialization. Source: Sharp, D. 1986. Metabolism of Pesticides An Industry View. Paper presented at the Sixth International Congress of Pesticide Chemists, Ottawa, Canada, August 10-15, 1986. Many of the organochlorine insecticides have been replaced for one or more of these reasons. Besides the variability of a product's market life, economic returns from a pesticide company's R&D investments can be greatly affected by the uncertainty in the process of actually finding new pesticides. For certain pesticides, particularly insecticides, it is increasingly difficult to find new, effective products through conventional screening of available chemicals. About 23,000 new compounds are now screened for each new pesticide discovered; 10 years ago the figure was 10,000.i It is not surprising that the pesticide industry devotes large sums of money to research. Multinational agrichemical companies spend from 9 to 15 percent of sales revenue on R&D.2 Most R&D in pesticide and pharmaceutical companies is internally financed and conducted. Other- wise, the company's proprietary information may be leaked. The

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PESTICIDE INNOVATION 139 drawback with internal financing is that if products are unexpectedly canceled, funds available for R&D may shrink. REVIEW OF INDUSTRY R&D AND STUDIES TO DATE Although there have been no studies of how regulatory attempts to control carcinogens may affect pesticide innovation, there have been studies on how other EPA pesticide restrictions affect the total level and nature of R&D efforts. The committee examined four major studies in this area: (1) a 1981 study by the Council on Agricultural Science and Technology (CAST); (2) a 1981 report by the Office of Technology Assessment (OTA); (3) a 1982 Ph.D. thesis by U. Hatch; and (4) a 1984 study by H. G. Grawbowski and W. K. Viscusi. The four studies indicate how regulatory delay and uncertainty affect R&D activities. The CAST study found that from 1968 to 1978, direct costs of bringing a new pesticide to market increased; delays from discovery to first registration grew; and R&D expenditures shifted from synthesis, screening, and field testing to registration, environmental testing, and residue analysis.3 The OTA report emphasized that total pesticide R&D expenditures continued to rise following the 1972 amendments to the Federal Insecti- cide, Fungicide and Rodenticide Act (FIFRA). The increase in real R&D investments did not cause more new pesticide registrations, however.4 Hatch attempted to quantify the relationships among the following factors: delay from discovery to registration, FIFRA changes, and the number of new active ingredients registered per million dollars of R&D expenditures from 1967 to 1982. Total R&D expenditures and R&D expenditures allocated to new chemical discoveries were used for esti- mates. The estimated impact from a in percent longer delay in registration was a 7 to 9 percent decrease in products registered. The creation of the EPA in 1970 and the 1978 amendments to FIFRA seemed to have no effects on R&D productivity.5 Grawbowski and Viscusi showed that from 1971 to 1975, R&D allot- ments declined when compared to sales. These figures might have reflected rapidly rising pesticide sales rather than a reduction in invest- ments in response to the EPA's early activities. Grawbowski and Viscusi also showed that the effective patent life for commercial pesticides fell from 15 years during 1971 to 1976 to 12 years during 1977 to 1982. They suggested that the delay in commercialization might redect the longer time needed to develop new products or meet regulatory requirements for new technology compared with the regulation of variants of established

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140 REGULATING PESTICIDES IN FOOD products.6 A related study on the pharmaceutical industry by Graw- bowski and Vernon found that stricter regulations induced innovation only in techniques for complying with regulatory requirements, such as improved equipment for detecting drug residues.7 This indicates that the implementation of the Delaney Clause might not lead to development of non-oncogenic pest control methods. The committee also addressed the extent to which unexpected product cancellations might reduce R&D investments. The regulatory scenarios examined in Chapter 4 contemplate tolerance revocation for existing product uses. Increased uncertainty of pesticide profits would reduce pesticide investments. Cancellations of existing uses of some pesticides could increase R&D investments only if they provided new sales oppor- tunities for other pesticides and did not severely limit funds for internally financed reinvestment. Profit opportunities from cancellation of a competitor's products are affected by the availability of alternative pest controls and adjustments in crop patterns. Survey of R&D Directors The committee questioned the research directors of 20 pesticide compa- nies. These directors are involved in planning investment responses to changes in regulations by the EPA and other federal agencies. They want a regulatory environment that will give farmers and consumers confidence that pesticide products and food are safe. They also want to sell their products. Thus, their responses may reflect a wish to reduce regulatory impacts. A few summaries of results from the survey are described here. The complete survey and results are presented in Appendix E. Asked how many pesticides would be vulnerable to Delaney Clause restrictions during reregistration (assuming the EPA's current policies continue), the research directors responded that 24 percent of currently registered pesticides representing about 9 percent of total sales are in jeopardy. About half of the fungicides and 10 to 20 percent of the insecticides were cited as vulnerable. In addition to the loss of products, the research directors thought there would be a slight increase in testing costs (5 to 15 percent). More than half said that the EPA's implementation of the Delaney Clause had caused a one- to two-year delay in new product registrations. Companies often respond to a potential denial of registra- tions by attempting to change use patterns to reduce residues. They may not discontinue research or registration efforts for a potential new pesticide if initial testing indicates one with weak oncogenicity. The research directors viewed the Delaney Clause as an important regulation. They identified other problems such as groundwater contamination as more serious, however.

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PESTICIDE INNOVA TION ~ 4 ~ Historical Perspective of R&D A pesticide firm needs a dynamic R&D program if it is to remain competitive. As shown in Table 6-1, total deflated expenditures on R&D have risen steadily during the last 20 years. In 1985, about 64 percent of all expenditures on pesticide R&D in the United States were for discov- ering and developing new products, 23 percent for expanding uses of existing products, and 13 percent for defending older products.8 Industry experienced an increase of 14.4 percent for R&D expenditures in 1985 compared with 6 percent in 1983 (Table 6-11. This was in the face of a 9 percent drop in domestic pesticide sales between 1984 and 1985. Most pesticide R&D in the United States takes place at about 20 multinational corporations that manufacture active ingredients for pesti- cides. Hundreds of middle-sized and small companies develop, produce, TABLE 6-1 Pesticide Industry Total R&D Expenditures Annual Undeflated Deflateda Increase Year (millions of dollars) (millions of dollars) Deflated (%) 1967 $ 52.4 $ 65.9 1968 58.2 70.6 7.1 1969 64.1 73.8 4.5 1970 69.9 76.4 3.5 1971 87.7 91.4 19.6 1972 98.5 98.5 7.8 1973 110.7 104.7 6.3 1974 134.8 117.1 11.8 1975 160.5 127.6 9.0 1976 195.2 147.5 15.6 1977 250.1 178.5 21.0 1978 289.6 192.5 7.8 1979 332.3 203.3 5.6 1980 395.1 221.2 8.8 1981 449.9 230.1 4.0 1982 526.9 254.3 10.5 1983 580.2 269.5 6.0 1984 730.6 327.0 21.3 1985 868.9 374.2 14.4 Average 10.2 aThis column expresses deflation by the GNP deflator (1972 = 100). SOURCE: Hatch U., 1983, The Impact of Regulatory Delay on R&D Productivity and Costs in the Pesticide Industry, Ph.D. dissertation, University of Minnesota, St. Paul; National Agricultural Chemical Association, 1986, Industry Profile Survey: 1985, Wash- ington, D.C. Photocopy.

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142 REGULATING PESTICIDES IN FOOD and blend thousands of pesticide mixtures and retail products, but they conduct little research to develop new active ingredients. Smaller firms conduct more R&D in biological and genetically engineered pest control, however.9 Long- and short-term innovation prospects are important in assessing Delaney Clause implications. As discussed previously, the EPA schedule of pesticide reregistrations will require decisions in the next three to five years on many products that currently have large sales. This places an emphasis on pesticide development and marketing pesticides that have already entered field testing. Compounds being developed have the potential to lessen short-term effects of pesticide use cancellations. The next 9 to 10 years will probably be the shortest feasible time to bring new pesticide chemistry or biotechnology products to market. It will be even longer before the products are widely adopted by farmers. One indication of innovation's rate and trend is the number of pesti- cides registered for the first time each year. This information for the past 20 years is shown in Table 6-2. (Only about two-thirds of these pesticides have agricultural uses.) Overall, the introduction of products for agricul- tural use decreased, even though firms submitted 25 new pesticide compounds for registration in 1985, which was 10 more than in 1984. Some promising new herbicides were also registered for use in 1986. However, new products must compete with the performance of and farmers' loyalties to existing products. As a result there are considerable differences in the adoption and sales of new products compared with older ones. INSECTICIDES . In the last 40 years, the major three classes of pesticides insecti- cides, herbicides, and fungicides have evolved at different rates. The chemistry of insecticide products has developed through four genera- tions: (1) organochlorines, such as DDT, chlordane, aldrin, and dieldrin; (2) organophosphates, such as parathion; (3) carbamates, such as carbaryl and carbofuran; and (4) pyrethroids, including permethrin and cypermethrin. Changes in use patterns were influenced by acute and chronic toxicity, environmental effects, and insect resistance to widely used compounds. Regulatory actions based on chronic health and environmental effects have largely eliminated all uses of organochlorine insecticides on foods. Organophosphate and carbamate insecticides remain widely used; syn- thetic pyrethroids continue to gain market share. Pest resistance, how- ever, has become a limiting factor in the success of chemical insecticides. Synthetic pyrethroids were widely considered a breakthrough when

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~44 REGULATING PESTICIDES IN FOOD introduced in the 1970s. But the emergence of resistance of some pests to pyrethroids in some areas is worrisome. In particular, pockets of resis- tance to pyrethroids by the tobacco budworm have been shown in cotton-producting areas of Texas. Since the pyrethroids, no new major chemical class of insecticide has been commercialized. Several new classes of insecticide show promise for a wide range of agricultural and public health uses, but there are no new classes of proven materials for control of the budworm and the bollworm. HERBICIDES The invention of new herbicides has flourished during the past 40 years with the development and wide acceptance of many different chemical classes. These include phenoxy herbicides, such as 2,4-D; triazines, such as atrazine and cyanazine; benzoic acids, such as dicamba; acetanilides, such as alachlor and metolachlor; ureas, such as linuron; and the nonselective, broad-spectrum glyphosate. In the past few years, the number of newly registered herbicides introduced into the market sub- stantially surpassed the number of new agents in all other major catego- ries of pesticides combined. Several new herbicides were registered in 1986. These compounds represent the first marketable results of resew herbicide chemistry. The two most important classes of new herbicides are the imidazolinones and the sulfonylureas. Tests show that these herbicides are non-oncogenic. They are generally applied at rates lower than the herbicides in wide use today. The principal factor behind the success in chemical herbicide innova- tion is the size of the herbicide market. Agricultural herbicide sales in the United States are about $2.7 billion. This is about two and one-half times the size of the domestic insecticide market and about 10 times greater than the fungicide market. As discussed previously, some of the widely used herbicides are suspected or confirmed animal oncogens. Oncogenic herbicides account for about 60 percent of current expenditures for chemical weed control (see Chapter 31. Possible regulatory actions restricting the use of these herbicides could create opportunities for new herbicides or other weed control methods. FUNGICIDES The unique case of fungicides has been discussed at length in Chapters 3-5. Fungicides registered in the 1940s and 1950s currently dominate the market because they are relatively inexpensive, effective against a broad

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PESTICIDE INNOVATION 145 range of pathogens, less prone to pest resistance problems, and exhibit low acute toxicity. In addition, they are often important in integrated disease management programs. These factors give existing products a formidable competitive edge over new fungicidal compounds. Yet, it is in dealing with fungicides that a strict application of the Delaney Clause may most significantly affect current product use. Ninety percent of all fungicide acre treatments are with potential animal oncogens. Furthermore, chronic toxicity to humans is likely to remain a problem because it is difficult to develop fungicides that are not toxic to genetic material. As a result, the fungicides, and growers who rely heavily on them, are particularly vulnerable to actions to restrict dietary exposure to potential oncogenic compounds. To aggravate this problem, the science involved in producing new fungicides is extremely complex, and developments in recent years have been minor.~ For example, in the past 15 years, only four new fungicides have been introduced that account for more than 5 percent of sales in any food crop. This is not because fungicide research and development expenditures have lagged. These investments are nearly twice as high relative to sales as are investments for herbicides and insecticides. Because total fungicide sales are rela- tively small, however, total fungicide research is modest. Also, because individual fungicide markets are small, there is less economic incentive for innovation and product expansion. Further, the development of products for minor crops is not often profitable for pesticide companies. (The influence of market size on pesticide registration is discussed at greater length later in this chapter.) Some new product work in Europe has been directed toward combinations of old and new fungicides. FUTURE PROSPECTS IN CHEMICAL PEST CONTROL It is difficult to obtain an accurate count of the pesticides for which new registrations are being sought that will become available for commercial use. Using the number of tolerance petitions for this purpose can be misleading because the percentage of petitions for new active ingredient tolerances not granted is unknown. Because of these uncertainties, the committee obtained information from specialists in crop protection and published reports of field tests to learn which unregistered pesticides are now being field tested. The inquiry concentrated on the production of selected crops that might be affected by the cancellation of currently marketed pesticides. Some of the pesticides being reviewed are already registered for use on other crops; others have no current registration. The results help clarify which compounds are being developed and provide some indication of chemical substitution possibilities in the next five years.

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|46 REGULATING PESTICIDES IN FOOD TABLE 6-3 Evaluation of Experimental and Unregistered Citrus Insecticides Comparison to Best Commercially Available Standard Target Pest Number of Compounds Better Similar Poorer Thrips Compounds near registration 4 Compounds under evaluation 6 Red mite California red scale 10 4 0 1 3 0 0 6 3a 0 0 4 NOTE: A total of 19 insecticides were tested by insecticide and acar~cide tests. aEvaluations for only 3 of the 10 materials were adequate to provide a comparison to commercial standards. The remaining 7 need additional testing. SOURCE: York, Alan C., ed. 1985. Insecticide and Acaracide Tests. Vol. 10. College Park, Md.: Entomological Society of America. Citrus and Cotton Insecticides The committee's findings for the citrus insecticides are presented in Table 6-3. Except for three products to control red mites and one to control thrips, the compounds being tested were judged less effective than currently available insecticides and acaricides. Thirteen unregistered cotton insecticides were evaluated and reported in Insecticide and Acaricide Tests. Some were tested on more than one pest. Eight new materials were tested on bollworms, eight on boll weevils, two on cotton heahoppers, one on cotton aphids, and six on spider mites. Variability in results precluded a valid comparison with the best commercially available insecticides. Cotton pest control research is inspired more by potential pest resis- tance than by the Delaney Clause. Currently available non-oncogenic cotton insecticides and integrated pest management programs appear adequate to sustain the U.S. cotton industry. Corn and Soybean Herbicides Several products representing new chemistry (most notably the imidazolinone and sulfonylurea compounds) have been commercially introduced in the past several years. Manufacturers now are more sophisticated in designing new molecules with herbicidal activity. Be- cause one or more functional groups of chemicals are known to affect

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150 REGULATING PESTICIDES IN FOOD 70 ~ 60 on a: I_ Ad LL X C, As of: cr 50 40 30 20 10 o 1~ RISK i R&D EXPENDITURES INSECTICIDES . I ~ FUNGICIDES HERBICIDES FIGURE 6-2 Estimated dietary oncogenic risk and R&D expenditures by pesticide type. Increasing costs for required test data to support tolerances for registration or reregistration; Shortening the commercial lives of pesticides through tolerance revocations or product cancellations; Increasing the borrowing costs when tests and other procedures prolong the time from discovery to marketing; and Increasing net return variability and thereby discouraging investment because of uncertainty about EPA implementation strategies. INNOVATION PROSPECTS IN PEST CONTROL Plant Breeding Although plant breeding for resistance to pests began in the late nineteenth century, the development of crop varieties resistant to insect pests was not pursued energetically until recently. This lack of interest was primarily because resistance was difficult to achieve, and other low-cost, effective controls were often available. Nevertheless, plant breeders have developed more than 150 cultivars with insect resistance. The rewards of successful insect resistance research can be great. For example, federal, state, and private agencies spent about $9.3 million on developing resistance in wheat to the Hessian fly and wheat stem sawfly;

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PESTICIDE INNOVATION ~5 ~ in alfalfa to the spotted alfalfa aphid; and in corn to the European corn borer. Savings to farmers from resistant varieties are estimated at several hundred million dollars annually, not including savings from eliminating pest control chemicals. Additional examples of insect-resistant crop cultivars include the resistance of rice to the brown planthopper, alfalfa to the pea aphid, and sorghum to the green bug. Breeding for resistance to plant diseases has been pursued vigorously and to much greater advantage than for resistance to insects. This is in spite of the fact that some cultivars can resist only a few diseases, which enhances the possibility of an epidemic, such as the southern corn leaf blight in 1970. Resistant cultivars of cereal crops have been the mainstay of disease protection for many years. Success in crop breeding includes disease resistance of corn to southern corn leaf blight and other blights, wheat to stem rust, cucurbits to powdery mildew, cotton to Fusarium wilt, alfalfa to bacterial wilt, pears to fire blight, tobacco to bacterial wilt, and sugarcane to mosaic disease. Resistant cultivars have also been the major means of controlling parasitic nematodes, especially some species of root-knot, cyst-causing, and stem nematodes. Some plants naturally produce chemicals that protect them against weeds and other pests. Cultivars are being developed that have traits for producing metabolites that are toxic to specific weeds, fungi, insects, or even grazing animals. For example, chemicals from the wild Bolivian potato have been correlated with its resistance to insect pests that attack potatoes cultivated in the United States. Scientists are working to breed these traits into U.S. potato varieties. But, resistant cultivars do not necessarily stay resistant. Depending on crop management and biological factors, mutant organisms frequently develop. Therefore, different types of resistance must be incorporated into cultivars. Breeding for resistance requires no more time than the development of a new pesticide, and the expenditures of time and resources have been well worth it in many cases. Genetic Engineering Specific genetic characteristics can be manipulated in microbes and plants to achieve crop protection. (For an in-depth discussion, see Agricultural Biotechnology: Strategies for National Competitiveness. ]2) Genetic engineering could increase the potential for effective insect control via modification of bacteria, viruses, and fungi. For example, bacteria and viruses infecting insects could be genetically engineered to produce toxins that only kill specific insects. A possible candidate is the baculovirus, which infects only specific pests and is harmless to

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152 REGULATING PESTICIDES IN FOOD beneficial insects, vertebrates, and plants. However, development prob- lems exist with baculoviruses, including the need to expand the range of particular viruses to encompass more than one pest species, the need to improve their environmental stability, and the facilitation of their large- scale commercial production. Fungi also might be engineered as safe, effective insect and weed control agents. Many fungi produce specific toxins that act against insects or plants. Their "toxin" genes could be enhanced and transferred to new fungal hosts to create biological control agents that would attack only specific insects or weeds. Plants themselves can be targets of genetic engineering. A crop can be genetically altered to express a specific, limited portion of a plant virus's genetic information, which would give the crop resistance to infection by that virus. Scientists have already achieved plant resistance to the tobacco mosaic virus, which causes large commercial losses of tomatoes and bell peppers as well as tobacco. In a related strategy, the gene responsible for a plant's natural resis- tance to certain pathogens can often be transferred to a susceptible cultivar which might differ only by that single "resistance" gene. Alternatively, the pathogen or its toxin can be used in the laboratory to select resistant cultivars from cell cultures. Intensive investigation on this front has led to isolation of some disease-resistant plants. Research on herbicide-resistant crops is in progress. Resistant cultivars can be selected from cell cultures, a strategy that has been used to select imidazolinone-resistant corn. "Resistance" genes from other plants or even bacteria can be genetically engineered; glyphosate- resistant plants have been created by this technique. And, the two techniques are being combined to create crops resistant to sulfonylurea herbicides. Fruit and vegetable seed markets, because they are small, will not stimulate rapid development of biotechnology products. Developments in pest control for minor crops from genetic engineering and conventional plant breeding are not likely to come soon enough to replace the many potential pesticide use cancellations in the next three to five years. Private genetic engineering firms will probably produce animal drugs and herbicide-resistant cultivars of major crops rather than alternative pest controls for those canceled by the Delaney Clause. Legal and regulatory issues have significantly curtailed development and testing of genetically engineered biological control agents. Until these issues are resolved, the benefits that these agents could provide will not be available to farmers in this country.

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PES TI CIDE INNO VA TI ON 1 5 3 Biological Control Biological control is the regulation of pest populations by natural enemies. In this report, biological pest control involves the intentional release or introduction of any biological organism, such as viruses, predators, pathogens, and parasites. In the United States, biological control currently plays a limited but significant role in agriculture. In certain crops in some regions, biological control strategies are critical to continued production of important cash commodities. In many cases biological control methods have been integrated with selective use of chemical pesticides. For example, the release and establishment of predatory mites biologically controls spider mites on almonds in some areas of California. The predatory mites were selected in the laboratory for resistance to insecticides commonly used in almond production. This program has reduced the need to apply acaricide sprays and is less costly than total reliance on chemical pest control. Compared with synthetic chemical pesticides, however, biological controls are applied against relatively few economically important agri- , , _' . em. . . . ~ . . . , , . . . ~ ~ cultural nests. The potential tor biological pest control has been s~gn~- cant for specific pests, as evidenced by valuable programs for certain crops. The development of biological control agents and systems is limited by the following factors: The implementation and maintenance of effective management prac- tices. Biological control is complex compared with chemical spray treatments, schedules, and practices. The specificity of biological control organisms. Although some organisms may control a few pest species, usually a unique biological control is needed for each pest. The mobility of certain control organisms. This factor may lead to free benefits for some farmers from pest control paid for by other growers. ~3 Biological systems to manage insect pests have been established in several crops, most notably citrus, nuts, and apples. In addition, biolog- ical insect control agents are used as components of integrated pest control in cotton, citrus, rice, nuts, soybeans, fruits, vegetables, and deciduous fruit crops. Several biological compounds are now registered or being considered for registration to control various insect pests. The use of Bacillus thuringiensis to control lepidopteran larvae is widespread. A few bacterial compounds are near final registration; among them are Trichoderma for

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~54 REGULATING PESTICIDES IN FOOD the control of Armillaria root rot and Agrobacterium radiobacter for the control of crown gall. Control can also be achieved by using insect pheromones, normones, or their analogs to attract and trap pests, induce fruitless mating, or arrest development of insect larvae. Juvenile hormones are currently registered and sold to control flies, mosquitoes, Heas, and cockroaches. When applied as a spray, they arrest insect development at an immature stage, preventing reproduction as well as destructive adult-stage activities. Although the genetically engineered Pseudomonas syringae protects crops from frost, not disease, it is a potentially significant biological control. Once field tests are permitted, tests with other genetically engineered organisms are expected to follow. Nuclear polyhedrios viruses (NPVs) are being considered for control of a range of pests including the cotton bollworm, tussock moth, gypsy moth, alfalfa looper, and European pine sawfly. A granulosis virus has been identified that controls the coaling moth. Several insecticidal fungi are in use in various countries. It is necessary to remember, though, that some chemical fungicides kill insecticidal fungi unless applications are timed to avoid this. Historically, biological control of weeds has been successful only for uncultivated areas. Recently, however, the control of several weeds in cultivated crops by fungal pathogens has been moderately successful. Unfortunately, the elimination of a weed species results in its replacement by another weed that may be more or less damaging than the first. Research on the biological control of plant diseases is increasing so rapidly that the American Phytopathological Society will soon start publishing a journal devoted to that topic. Cultural Pest Control Cultural pest control involves manipulation of the crop or soil to make it less favorable for pests. Various cultural practices have been used since agriculture's beginnings, and will continue to be used. The incorporation of cultural practices into integrated pest management programs can be expected to increase because of cost savings. These practices include tillage, selection of a planting date to avoid a specific pest, crop rotation, stripcropping, interplanting, and destruction of crop remains to reduce habitats for overwintering pests. Increased emphasis is being placed on the management of economically important pests on crops including citrus, cotton, tomatoes, and alfalfa. Although integrated pest manage- ment programs can be highly effective, they frequently can be profitably applied only in limited regions. Nonetheless, in the future, more oppor-

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PESTICIDE INNOVATION 155 "unities to combine genetic, chemical, biological, and cultural control strategies will emerge, changing the control of pests. SPECIAL CHALLENGES TO INNOVATION The Minor-Use Issue Factors that determine the minor-use status of a particular crop or crop and pest combination include gross sales from the crop's potential pesticide market (generally a function of total crop acreage); relative value of the crop per unit area; susceptibility of the crop to pest damage throughout the season; and availability of nonpesticide controls. Production of most minor crops typically requires several pesticides. However, there is little incentive for pesticide manufacturers to pursue registration of their products for uncommon pests and crops grown on limited acreage except as a step in establishing a share in a larger market. The volume of pesticides used is often so low that a manufacturer's costs to obtain and maintain registration are not compensated by revenues from pesticide sales. This fact has important consequences, because all vege- table, fruit, and ornamental crops are in the minor use category. Vegeta- bles and fruits currently constitute about 20 percent of consumer diets, and the percentage is increasing. Minor-use tolerances for many pesticides are not supported by studies meeting current data requirements for oncogenicity, environmental ef- fects, and residue chemistry. For some minor-use pesticides not regis- tered for a major crop, particularly those no longer protected by patents, the cost of meeting the EPA's data requirements may make it uneconomi- cal for manufacturers to pursue reregistration. Nearly all important minor-use pesticides are also registered for some major uses, however, and are less likely to encounter this problem. In these cases, registration for minor crop uses often is obtained as a label expansion after the product generates revenue from its major crop uses. LIABILITY The threat of liability suits is a cost that must be considered in entering any market. Liability for crop failures or crop injury resulting from product use is another impediment to pesticide registration for minor crop uses. The problem can be especially serious for many vegetable, fruit, and ornamental crops. These crops tend to have relatively high values per acre, have low pesticide sales potential relative to possible liabilities, and are expected to meet high-quality standards. Even when these consider- ations do not impede registration, if the acceptable daily intake for a

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156 REGULATING PESTICIDES IN FOOD pesticide is used fully by other tolerances involving larger markets, the minor-use tolerance generally will not be sought because it would necessitate restriction of use in a larger market. The minor-use problem is a product of the 1972 amendments to FIFRA, which among other things made it unlawful to use any registered pesticide in a manner inconsistent with its label. These amendments banned the application of registered pesticides for uses not specified on the label, which meant that each crop and pest combination had to appear on the label. In addition to the costs of obtaining specific registrations for each crop and pest combination, the registrant was liable for phytotoxicity and other product-related failures. Later amendments to FIFRA in 1978 and the EPA's announcement of new policies in 1986 have helped to ease the minor-use problem. The agency has announced a new definition of "use inconsistent with label- ing," which permits application of a pesticide to control an unnamed target pest as long as the pesticide is registered for use on the crop. The EPA's new policies allow the agency to adjust its data demands and registration fees for minor-use registrations in light of the anticipated extent of use, degree of human and environmental exposure, toxicity of the compound, volume of use, geographic distribution of potential use, and cost of data requirements for registration. INTERREG~oNA~ PRo~EcT 4 Another important factor in dealing with the minor-use issue is the U.S. Department of Agriculture's Cooperative State Research Service Inter- Regional Project 4 (IR-41. JR-4 provides a mechanism for state agricul- tural research and extension workers to identify specific pesticides that will meet particular needs on minor crops. These workers will be able to cooperate with others in research and extension to develop the efficacy and residue data necessary to obtain tolerances and secure registrations for minor uses. In all cases, the company developing or marketing the pesticide or a third party must agree to serve as the registrant before the JR-4 will develop data needed to support a minor crop use registration. Although its financial resources are limited, JR-4 efforts at the federal and state levels can relieve companies of some of the financial burden of obtaining minor-use tolerances. The JR-4 has helped to obtain tolerances and registrations for pesticide uses on many minor crops, which other- wise would not have been pursued by the pesticide companies. Although policy changes are addressing the problem of obtaining new pesticide registrations for minor crops, the problem of liability remains. Also remaining is the lack of incentive for manufacturers to develop pesticide products that have potential uses on a small number of minor

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PESTICIDE INNOVATION ~57 crops and limited potential uses on any major crops. In addition, the forthcoming reregistration of currently registered pesticides will probably create serious new problems for some existing minor-use registrations. The EPA has identified a substantial number of pesticides with minor-use tolerances as animal oncogens. Some tolerances and registrations for these pesticides will probably be lost during reregistration. The impact will be greatest on fungicides, which are essential for commercial fruit and vegetable production in humid production areas, and for which there are virtually no registered alternatives. Moreover, there are few potential replacements under investigation or development. The impact on minor- use insecticides and herbicides is likely to be less severe. So far the Delaney Clause has had little impact on the registration and reregistration of minor-use pesticides. This is because the EPA has not yet applied the clause to tolerances established before contemporary oncogenicity data requirements were established. Only a small percent- age of all minor crops with processed food forms are currently included in the residue chemistry guidelines (Subsection O of the Pesticide Assess- ment Guidelines; see Table 3-11) listing crops for which the EPA requires processing studies or in the National Food Processors Association's list of proposed additions to Subsection O (see Table 3-131. If the number of minor crops listed in Subsection O is expanded, the effects of the Delaney Clause will become proportionately larger. The Pesticide Resistance Problem Pesticide resistance is an increasingly serious problem. In 1984, 447 species of insects and mites, 100 species of plant pathogens, 55 species of weeds, 2 species of nematodes, and 5 species of rodents were known to be resistant in some location to one or more pesticides used for their control.~4 Combining pesticides having different modes of action, reduc- ing application frequencies, and rotating pesticide types are important tactics of pesticide resistance management requiring the availability of several effective pesticides. To the extent that pesticide cancellations limit the number and spectrum of available pesticides, the crop produc- er's ability to manage pesticide resistance will be hampered. The problem of managing pesticide resistance is likely to be acute in the case of fungicides, because many of the protectants in use for many years without causing resistance are under regulatory review at the EPA. Loss of these fungicides would lead to greater reliance on newer systemic, site-specific, eradicant fungicides, such as metalaxyl and benomyl. The long-term viability of relying on such fungicides is suspect, because plant pathogens commonly develop resistance to these types of fungicides. If the older oncogenic protectant fungicides are lost as a result of regulatory

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158 REGULATING PESTICIDES IN FOOD actions, innovation in integrated disease management will become not only valuable but necessary. To slow the selection of resistant pathogens, the use of site-specific fungicides must be precisely managed. A major feature of resistance management in crop diseases is the mixing of eradicant site-specific fungicides with older, protectant fungicides. Such mixtures combined with fungicide rotation help prevent resistance. Pesticide companies and land-grant universities are developing disease resistance management schemes to prolong the effectiveness of fungicides such as triadimenol, metalaxyl, and benomyl, because resistance has developed in high-use areas. Disease-resistant crop varieties are also being introduced to reduce fungicide use and resistance. Tolerance reductions that encourage more judicious use of protectant fungicides would enhance disease manage- ment innovation and reduce the oncogenic risk associated with residues of these fungicides. NOTES 1. National Agricultural Chemicals Association. 1986. Industry Profile Survey. Washing- ton, D.C., p. 9. 2. Ibid. 3. Council on Agricultural Science and Technology. 1981. Impact of Government Regu- lation on the Development of Chemical Pesticides for Agriculture and Forestry. Report - No. 87. Ames, Iowa: Council on Agricultural Science and Technology. 4. Office of Technology Assessment. 1981. Technological Innovation and Health, Safety, and Environmental Regulation. Washington, D.C.: Office of Technology Assessment. 5. Hatch, U. 1983. The Impact of Regulatory Delay on R&D Productivity and Costs in the Pesticide Industry. Ph.D. dissertation. University of Minnesota, St. Paul. 6. Grawbowski, H. G., and W. K. Viscusi. 1984. EPA Regulation and Pesticide Innova- tion: An Exploratory Analysis. Washington, D.C. 7. Grawbowski, H. G., and J. M. Vernon. 1983. The Regulation of Pharmaceuticals: Balancing the Benefits and Risks. Washington, D.C.: American Enterprise Institute. 8. National Agricultural Chemicals Association, p. 13. 9. U.S. Environmental Protection Agency. 1980. Guidelines for Contents of Economic Impact Analysis. Washington, D.C.: U.S. Environmental Protection Agency. 10. Brent, K. J. 1985. One hundred years of fungicide use. In Fungicides for Crop Protection: 100 Years of Progress. BCPC Monograph No. 31. Bordeaux, France. 11. York, A. C., ed. Insecticide and Acaricide Tests. 1984. Vol. 9. College Park, Md.: Entomological Society of America. 12. National Research Council. 1987. Agricultural Biotechnology: Strategies for National Competitiveness. Washington, D.C.: National Academy Press. 13. Reichelderfer, K. H., G. A. Carlson, and G. A. Norton. 1984. Economic Guidelines for Crop Pest Control. Food and Agriculture Organization Plant Production and Protection Paper No. 58. Rome: Food and Agriculture Organization. 14. National Research Council. 1986. Pesticide Resistance: Strategies and Tactics for Management. Washington, D.C.: National Academy Press.

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APPENDIXES

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