Antiresistance Strategies - ACS Symposium Series (ACS Publications)

Feb 23, 1990 - 2 Ciba-Geigy Corporation, 410 Swing Road, Greensboro, NC 27419. Managing Resistance to Agrochemicals. Chapter 11, pp 170–183...
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Chapter 11

Antiresistance Strategies Design and Implementation in Practice 1

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F. J. Schwinn and H. V. Morton

1Ciba-Geigy Corporation, CH-4002, Basel, Switzerland Ciba-Geigy Corporation, 410 Swing Road, Greensboro, NC 27419

2

Recent experience with fungicide resistance underlines the need for the early development and implementation of effective, r e a l i s t i c , and enforceable anti-resistance strategies. These strategies should be developed by the agrochemical industry in collaboration with extramural partners. This partnership should also address the manifold problems that remain to be solved to protect the powerful and highly needed modern fungicides from becoming obsolete due to broad resistance development.

Resistance of pathogen populations to fungicides i s not only a concern but also a threat t o : - the e f f e c t i v e use and l i f e s p a n of modern fungicides; - the economic interests of the farmer; and - the image and r e l i a b i l i t y of chemical disease control. It i s of the utmost importance to investigate at an early stage i n the development of a new product i t s inherent v u l n e r a b i l i t y to fungal resistance. Once t h i s i s determined, strategies should be designed to prevent or at least delay the development of r e s i s t a n t strains i n the f i e l d . The terms "anti-resistance s t r a t e g i e s , " or "management of resistance" have come into usage f o r these endeavors. These strategies may r a i s e u n r e a l i s t i c expectations about the s o l i d i t y of the s c i e n t i f i c evidence on which they are b u i l t . In analyzing the short h i s t o r y of fungicide resistance, i t becomes evident that due to the fact that the phenomenon of resistance developed so unexpectedly and quickly, short-term solutions were urgently needed rather than having time to develop long-term strategic concepts. However, since the early 1980 s, such concepts are slowly emerging, with the corresponding endeavors c l e a r l y showing the need for more s c i e n t i f i c data. A b r i e f review of the s i t u a t i o n i n the major groups of fungicides prone to resistance i l l u s t r a t e s the d i f f i c u l t i e s . In the case of pyrimidines and benzimidazoles. the f i r s t groups of fungicides against which resistance occurred quickly a f t e r market introduction, to our knowledge the r i s k of resistance development was not evaluated, nor was the phenomenon expected to show up. In f

0097-6156/90AM21-0170$06.00/0 © 1990 American Chemical Society

In Managing Resistance to Agrochemicals; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

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r e t r o s p e c t , i t can be s a i d t h a t the b a s i c r i s k c o u l d have been p r e d i c t e d , based on i n v i t r o / i n v i v o model s t u d i e s . However, a t the t i m e o f t h e i r i n t r o d u c t i o n , t h e phenomenon o f f u n g i c i d e r e s i s t a n c e was o f no s i g n i f i c a n c e , and t h e t e c h n i c a l advantages o f f e r e d by the new p r o d u c t s were so i m p r e s s i v e t h a t r e s e a r c h f o c u s e d p r i m a r i l y on performance and use recommendations. W h i l e r e s i s t a n c e a g a i n s t p y r i m i d i n e s d e v e l o p e d q u i c k l y i n a l l t a r g e t pathogens, r e s i s t a n c e a g a i n s t b e n z i m i d a z o l e f u n g i c i d e s o c c u r r e d t o a w i d e l y v a r y i n g degree i n t h e d i f f e r e n t pathosysterns and d i d not appear i n o t h e r s Q). The h i s t o r y o f phenylamide r e s i s t a n c e (2) demonstrates t o what e x t e n t the r i s k p r e d i c t i o n depends on the e x p e r i m e n t a l methods a p p l i e d . Whereas the c l a s s i c a l s e l e c t i o n e x p e r i m e n t s d i d not i n d i ­ c a t e a r i s k ( 3 ) , the use o f c h e m i c a l mutagens showed t h e c o n t r a r y (4). I n p r a c t i c e , problems emerged u n e x p e c t e d l y q u i c k l y , but s i m i l a r t o the b e n z i m i d a z o l e s - a t d i f f e r e n t l e v e l s o f r e s i s t a n c e i n t h e v a r i o u s pathosystems and r e g i o n s ( 5 ) . However, phenylamides r e m a i n v a l u a b l e f u n g i c i d e s a g a i n s t many Oomvcete d i s e a s e s . I n the d i c a r b o x i m i d e s the s i t u a t i o n i s a g a i n d i f f e r e n t . I n v i t r o and i n v i v o e x p e r i m e n t s e a s i l y y i e l d r e s i s t a n t s t r a i n s ( 6 ) , but i n p r a c t i c e some p o p u l a t i o n s o f the major pathogen, B o t r v t i s c i n e r e a , showed extreme f l u c t u a t i o n s i n s e n s i t i v i t y from y e a r t o year. Only r e c e n t l y has f i e l d r e s i s t a n c e r e a c h e d c r i t i c a l l e v e l s i n some r e g i o n s o f i n t e n s i v e use ( 7 ) . To f u r t h e r c o m p l i c a t e the p i c t u r e , a b r i e f l o o k a t the ergos t e r o l b i o s y n t h e s i s i n h i b i t o r s , p a r t i c u l a r l y the d e m e t h y l a t i o n i n h i b i t o r s (DMI), shows t h e i r case i s a l s o d i f f e r e n t ( 8 ) . R e s i s ­ t a n c e i s o f a p o l y g e n i c n a t u r e and, i n g e n e r a l , i t does not d e v e l o p as q u i c k l y i n the f i e l d as i n the p r e v i o u s l y mentioned c a s e s , a l t h o u g h i n model s t u d i e s i n t h e l a b o r a t o r y i t was e a s i l y d e t e c t e d . F o r example, i n t h e f i e l d , powdery mildew o f s m a l l g r a i n c e r e a l s i s o n l y v e r y s l o w l y s h i f t i n g towards reduced s e n s i t i v i t y . However, s t r a t e g i c measures have a l r e a d y been i n t r o d u c e d by way o f m i x t u r e s i n order t o prevent f u r t h e r s h i f t i n g . I n c o n t r a s t , powdery mildew o f c u c u r b i t s has r e l a t i v e l y q u i c k l y become i n s e n s i t i v e t o the DMl's. Design of A n t i - r e s i s t a n c e S t r a t e g i e s As e x p l a i n e d above, i n the e a r l i e r c a s e s o f f u n g i c i d e r e s i s t a n c e , d e c i s i o n s on s t r a t e g i e s were made under time p r e s s u r e , because prob­ lems r e q u i r i n g immediate a c t i o n s emerged e a r l i e r t h a n a n t i c i p a t e d . S i n c e new t y p e s o f f u n g i c i d e s w i l l be d e v e l o p e d i n the f u t u r e , a more s t r u c t u r e d approach s h o u l d be used t o a l l o w a) e a r l i e r r i s k e v a l u a t i o n and b) the development o f s t r a t e g i e s on a more s o l i d e x p e r i m e n t a l b a s i s . Chemical companies and r e s e a r c h e r s can l e a r n some l e s s o n s from p r e v i o u s experience. R i s k E v a l u a t i o n . The main f a c t o r s i n f l u e n c i n g t h e r e s i s t a n c e r i s k a r e shown i n T a b l e I . C h a r a c t e r i s t i c s and r e l a t i v e importance o f t h e v a r i o u s d i f f e r e n t elements have been d e s c r i b e d by s e v e r a l a u t h o r s ( 9 , 10, 11, 12). Whereas management r i s k f a c t o r s can be i n f l u e n c e d , t h i s i s not t r u e f o r the p r o d u c t - and p a t h o g e n - i n h e r e n t f a c t o r s . However, t h o r o u g h and r e l i a b l e e v a l u a t i o n o f b o t h p r o d u c t and p a t h o g e n - r e l a t e d f a c t o r s i s needed t o e s t a b l i s h the t r u e b a s i s f o r the d e s i g n o f any r e a l i s t i c s t r a t e g y . Needless t o say, t h i s i s a d i f f i c u l t task.

In Managing Resistance to Agrochemicals; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

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MANAGING

Table I.

TO AGROCHEMICALS

Factors Influencing Resistance Risks After Staub and Sozzi (12)

Inherent Factors (Fungus Biology, Fungicide Chemistry) • Biochemical mode of action • Fitness and population dynam­ ics of resistant strains • Reproduction rate of target fungus and spore mobility Downloaded by LOUISIANA STATE UNIV on November 15, 2014 | http://pubs.acs.org Publication Date: February 23, 1990 | doi: 10.1021/bk-1990-0421.ch011

RESISTANCE

• Duration of high disease pressure (climate)

Management Factors Fungicide Usage • Duration of exposure (in genera­ tions) • Presence of other controlling factors (effective mixture partners, host resistance) • Size of target population, escape, overkill, (protective vs. curative use) • Proportion of crop area treated

Laboratory experiments on nutrient media, the use of mutagenic agents, the search for naturally occurring R-strains, studies on cross-resistance of R-strains to known fungicides, greenhouse test­ ing on pathogenicity, and fitness and survival of R-strains selected in vitro or from natural sources are a l l tests which may indicate the probability of resistant strains occurring and their potential behavior in competition to wild-type sensitive strains. However, a l l such studies suffer from the fact that they have to be done with relatively small populations and numbers of isolates, and thus l i t t l e genetic diversity. Further, they cannot include the impact of natural mixing with wild-type populations, or crop-related and weather-related factors. Therefore, the results of such studies need cautious interpretation. Only in cases where none of the above methods lead to the selection of a resistant strain can a clear conclusion be drawn, i . e . , that the risk for resistance development is very low. In a l l probability this will be a rare case; on the other hand the fact that resistance does develop in such studies does not justify the exclusion of such a candidate fungicide from further development. This we can learn from a l l the aforementioned commercially successful systemic fungicide groups. It has been stated repeatedly that field experiments are indis­ pensable in order to define the risk under realistic conditions covering crucial elements like size of treated population, continu­ ous mixes in the pathogen population by influx and efflux of spores, overwinter refugia, and impact of overkill, partial k i l l , and escapes on the population (11, 12). The problem here is with the risks derived from releasing resistant laboratory strains into the field, and/or the risk of selecting in such field experiments resis­ tant strains, the dissemination of which cannot be excluded. Industry is definitely reluctant to run such risks. Even i f this risk factor could be managed and field experiments carried out, they may not yield typical results because the size and dynamics of the treated population are atypically small. This means that despite favorable results of such studies, resistance may s t i l l

In Managing Resistance to Agrochemicals; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

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develop a f t e r broad commercial Introduction of a new fungicide. Such situations arose many years a f t e r commercial introduction i n the cases of Dodine for apple scab c o n t r o l , K i t a z i n P for r i c e b l a s t c o n t r o l , and benomyl for eyespot control i n cereals. However, negat i v e findings i n glasshouse and f i e l d experiments at least indicate that a build-up of resistance i s u n l i k e l y to happen quickly, so that there i s more time l e f t for development and implementation of a n t i resistance strategies. If early experiments show that a r i s k e x i s t s , the immediate development of anti-resistance strategies i s of the utmost importance. In conclusion, early r i s k evaluation i s an absolutely e s s e n t i a l feature or element i n the development of new products. The range and sequence of tests to be done at t h i s stage are subject to d i s cussion and various approaches can be chosen. A f i r s t attempt to e s t a b l i s h a structured r i s k evaluation scheme was made by G i s i and Staehle-Czech (13). This i s an i n t e r e s t i n g and valuable approach towards a more quantitative r i s k estimation. Design of Strategies. We have stressed the importance of e a r l y investigations of the inherent resistance r i s k factors because t h e i r r e s u l t s have a far-reaching impact on the strategy's design. As shown i n Table I, the managerial factors are of s i m i l a r importance. After evaluation of the r i s k factors, the design of strategies can be i n i t i a t e d . In t h i s phase the following key elements have to be considered (Table I I ) :

Table I I .

Key Elements of Anti-Resistance Strategies

1.

Technical elements • Early evaluation of inherent r i s k during product development • Establishment of s e n s i t i v i t y baselines for each pathosystem and development of monitoring methods • Design to be based on product-, crop-, and pathogen-specific parameters • Detection and monitoring programs under conditions of pract i c a l product use

2.

Managerial elements • Use recommendations (dosage, number of applications/season, duration of pathogen exposure, proportion of area treated) • Integration with other disease-suppressing methods • E n f o r c e a b i l i t y i n practice • Acceptance by companies, extension service, and users • Coordination with manufacturers of products with i d e n t i c a l resistance pattern • Early implementation before resistance becomes a problem

Among the key technical elements i s the establishment of s e n s i t i v i t y baselines, since they form the basis for a l l monitoring studies on s e n s i t i v i t y s h i f t s . In past cases of rapid development of resistance, the lack of such figures has caused problems.

In Managing Resistance to Agrochemicals; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

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M o n i t o r i n g t e c h n i q u e s have been d e v e l o p e d f o r a b r o a d range o f pathogens ( 1 4 ) . They a r e u s e f u l t o o l s t o : check t h e occurrence o f r e s i s t a n t subpopulations i n the f i e l d b e f o r e t h e y cause damage t o t h e c r o p ; evaluate s u r v i v a l of r e s i s t a n t s t r a i n s ; t r a c k t h e p r o g r e s s o f r e s i s t a n c e w i t h t i m e ; and e v e n t u a l l y , c h e c k t h e v a l u e o f r e s i s t a n c e management strategies. F o r f u r t h e r d e t a i l s , s e e B r e n t ( 1 5 ) ; S o z z i and Staub ( 1 6 ) . However, i t i s n e c e s s a r y t o r e c o g n i z e t h e l i m i t a t i o n s o f t h e methods. The methods d e v e l o p e d s o f a r , w h i c h a r e m a i n l y b a s e d on s a m p l i n g and i n v i v o s e n s i t i v i t y s c r e e n i n g under l a b o r a t o r y c o n d i t i o n s , are not very s e n s i t i v e ; they w i l l only allow r e s i s t a n c e d e t e c t i o n when r e s i s t a n c e has a l r e a d y r e a c h e d a l e v e l o f more t h a n 1% i n t h e p o p u l a t i o n . Thus, i n t h e c a s e o f a v e r y dynamic pathogen, m o n i t o r i n g r e s u l t s may be t o o l a t e f o r t a k i n g a c t i o n s (.17). Here t h e development o f monoclonal a n t i b o d i e s o r DNA probes may l e a d t o much more s e n s i t i v e and f a s t e r methods o f d e t e c t i o n . I t a l s o has t o be s t r e s s e d t h a t m o n i t o r i n g i s o n l y an a u x i l i a r y element o f a s t r a t e g y ; i t does n o t by i t s e l f p r e v e n t p r o d u c t f a i l u r e s and c r o p l o s s e s , b u t i s o n l y an i n d i c a t o r o f s h i f t s w h i c h h e l p s t o judge t h e v a l i d i t y o f a c h o s e n s t r a t e g y . Last but not l e a s t , m o n i t o r i n g i s an i m p o r t a n t t o o l i n a n a l y z i n g p r o d u c t f a i l u r e s and r e s i s t a n c e rumors. I n t e g r a t i o n o f T e c h n i c a l Parameters and Management E l e m e n t s . I n c o n t r a s t t o t h e p r o d u c t - and p a t h o g e n - i n h e r e n t f a c t o r s w h i c h a r e beyond o u r c o n t r o l , t h e r e i s a range o f o p e r a t i o n a l f a c t o r s , as shown e a r l i e r i n T a b l e I . T h e i r r o l e and importance have been d e s c r i b e d ( 9 , 12, 10, 1 1 ) . T h e r e f o r e t h e y w i l l n o t be a d d r e s s e d here i n d e t a i l . I n s t e a d we w i l l e l a b o r a t e on t h e s p e c i f i c d i f f i c u l t i e s i n c o m b i n i n g t e c h n i c a l p a r a m e t e r s and management elements i n t o a s o l i d and r e a l i s t i c s t r a t e g y . Whereas t e c h n i c a l o r i n h e r e n t elements c a n be s t u d i e d by e x p e r i m e n t s w h i c h a l l o w , a t l e a s t t o some e x t e n t , r e a s o n a b l e extrapolations, i t i s d i f f i c u l t t o s c i e n t i f i c a l l y evaluate the r o l e and impact o f management f a c t o r s and a l s o t h e v a l u e o f p r o d u c t u s e strategies. S i n c e t h e p u b l i c a t i o n o f t h e f i r s t m a t h e m a t i c a l model s t u d i e s by K a b l e and J e f f e r y ( 1 8 ) , s e v e r a l computer-based models f o r r e s i s t a n c e management have been d e v e l o p e d ( 9 , 19, 20, 21, 22, 23. 24, 2 5 ) . These models v a r y i n t h e i r emphasis between t h e o r e t i c a l and a p p l i e d , and p a t h o g e n - and p r o d u c t - o r i e n t e d a s p e c t s , and v a r y from t h e g e n e r a l t o t h e s p e c i f i c . These a r e a l l u s e f u l , b u t t h e i r model c h a r a c t e r has t o be u n d e r l i n e d . The e x p e r i m e n t a l v a l i d a t i o n o f s u c h models has o n l y r e c e n t l y been a d d r e s s e d by s u c h r e s e a r c h e r s as Staub and S o z z i ( 1 2 ) ; S a n d e r s , e t a l . ( 2 6 ) ; L a l a n c e t t e , e t a l . ( 2 7 ) ; and Milgroom and F r y e ( 2 3 ) . To i l l u s t r a t e why l a r g e l y p r a g m a t i c approaches had t o be t a k e n t o d a t e t o d e v e l o p a t i m e l y s t r a t e g y , o n l y a few f a c t o r s w h i c h a r e s u b j e c t t o v a r i a t i o n a r e u s e d as a b a s i s f o r t h e s t r a t e g i e s , v i z : Reducing s e l e c t i o n pressure: No e x c e s s i v e u s e r a t e s L i m i t t h e number o f a p p l i c a t i o n s p e r growing c y c l e

In Managing Resistance to Agrochemicals; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

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T i m i n g o f a p p l i c a t i o n s t o be aimed a t a c r i t i c a l p a r t o f pathogenesis/epidemiology Mode o f a p p l i c a t i o n s h o u l d n o t f a v o r extended exposure ( e . g . , s o i l a p p l i c a t i o n v s . f o l i a r pathogen) These s t r a t e g i e s t r a n s l a t e b a s i c a l l y i n t o two main t a c t i c s : (1) The e x c l u s i v e use o f m i x t u r e s o f t h e p r o d u c t a t r i s k w i t h a s t r o n g , c h e m i c a l l y u n r e l a t e d companion p r o d u c t , and (2) The a l t e r n a t i n g use o f s t r a i g h t p r o d u c t s t h a t a r e a t r i s k and o t h e r s o f d i f f e r e n t mode o f a c t i o n . There a r e p r o s and cons f o r t h e two t a c t i c s , as shown i n Table I I I . In general the mixture s t r a t e g y looks s u p e r i o r , p a r t i c u l a r l y f o r products with high inherent r i s k . However, t h e judgment a l s o v a r i e s w i t h t h e i n h e r e n t c h a r a c t e r i s t i c s o f t h e p r o d u c t a t r i s k , t h e t y p e o f pathogen, growing p a t t e r n o f t h e c r o p , climatic conditions, etc.

Table I I I .

Comparative

M e r i t s o f t h e Two B a s i c A n t i - R e s i s t a n c e Use S t r a t e g i e s Mixtures vs. A l t e r n a t i o n s

Merit



Reduction of s e l e c t i o n pressure

=



Reduction o f crop l o s s r i s k i n case of r e s i s t a n c e

>



Potential for synergistic

>



User c o m p l i a n c e



Competitor



Overall disease control

effects

with strategy

compliance

with strategy

» » >

Adapted from Staub and S o z z i ( 1 2 ) .

T h i s c a n be i l l u s t r a t e d by t h e phenylamide use s t r a t e g y . I t s p l i t s i n t o two s e p a r a t e s t r a t e g i e s f o r f o l i a r and s o i l / s e e d - b o r n e pathogens as showin i n T a b l e IV. S i n c e i n t r o d u c t i o n i n 1981 t h e s e s t r a t e g i e s have c l e a r l y h e l p e d t o slow down development o f r e s i s t a n c e when t h e y were i n t r o d u c e d p r i o r t o i t s o c c u r r e n c e , and t h u s have m a i n t a i n e d t h e h i g h l e v e l o f p r o d u c t performance and c o n f i d e n c e o f t h e u s e r i n t h e p r o d u c t s ' u s e f u l n e s s . Whereas t h e m i x t u r e s t r a t e g y o f FRAC (5) recommended f u l l r a t e s o f phenylamides i n mixt u r e s , Sanders, e t a l . (26) o b t a i n e d b e t t e r r e s u l t s i n terms o f resistance-delaying efficacy at half rates.

In Managing Resistance to Agrochemicals; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

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Table IV.

AGROCHEMICALS

Elements of Phenylamlde Anti-Resistance Strategy After Urech and Staub (5)

A.

Against f o l i a r pathogens • Prepacked mixtures with fungicides of d i f f e r e n t mode of action at high rate • Application i n t e r v a l s no longer than 14 days i n case of residual mixture partner • Only two to four consecutive sprays, preferably early i n the season • Preventive but no curative use of mixtures • No s o i l use against airborne diseases • Integrated approaches

B.

Against seed and soil-borne pathogens • Against systemic pathogens use straight product i n view of lack of suitable systemic mixture partners • On perennial crops alternate with unrelated fungicide • For seed-dressing against non-systemic pathogens use mixtures with conventional fungicides

Looking at the established anti-resistance strategies for the other major groups of systemic fungicides, most of them are also based on the use of prepack mixtures (Table V). However, they each take i n t o account the differences i n inherent r i s k levels of the various product groups. In the case of the phenylamides, with a proven high r i s k p o t e n t i a l , the strategies need to be much more stringent and enforceable than i n the case of the DMl's, where resistance has a multigenic base and apparently i s developing slowly.

Table V.

Class

Anti-Resistance Strategies for Major Groups of Systemic Fungicides

Mixtures

Alternat.

Limited Use

Benzimidazoles

XX

Single treatment post-harvest

Dicarboximides

XX

2 (-3) (for straight product)

DMI Fungicides

XX

For single product

Other(s)

Alternation singly or i n blocks Example: Bananas

In Managing Resistance to Agrochemicals; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

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Last but not least, we should l i k e to address the importance of another element i n the design of anti-resistance strategies, i . e . , integration with other disease-controlling factors under the concept of Integrated Crop Production. Here careful consideration of crop management and - again - product use factors i s c r u c i a l . Details are shown i n Table VI (28). Much stronger e f f o r t s than i n the past need to be made towards t h i s goal.

Table VI.

Elements of Anti-Resistance Strategies U t i l i z i n g Integrated Crop Production Practices

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Crop Management



Resistant c u l t i v a r s

->

Lower disease levels



Sites with low disease occurrence

->

Reduce s e l e c t i o n pressure



Lower N f e r t i l i z a t i o n

->

Lower disease levels



Sound sanitation

->

Less

inoculum

Fungicide Use



Based on forecasting

->

Reduce s e l e c t i o n pressure



Protective use

->

Hit small pathogen populations



Mixtures

->

Reduce r i s k of resistance selection



Alternating use

->

Reduce r i s k of resistance selection

Implementation of Anti-Resistance Strategies The successful implementation of anti-resistance strategies and t a c t i c s requires: - acceptance by in-house marketing and salesmen; - acceptance by extension service, regulatory a u t h o r i t i e s , and users; - coordination with manufacturers of products with i d e n t i c a l resistance pattern; and - continuous open communication among a l l parties involved. As a f i r s t step, company researchers have to reach agreement with t h e i r product management and sales colleagues on the p r i n c i p l e s and elements of the strategies to be chosen for a given product at r i s k . It i s e a s i l y conceivable that i n cases l i k e metalaxyl, due to

In Managing Resistance to Agrochemicals; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

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178

MANAGING RESISTANCE TO AGROCHEMICALS

I t s o u t s t a n d i n g p e r f o r m a n c e , s t r a t e g y elements l i k e l i m i t e d number o f a p p l i c a t i o n s o r e x c l u s i v e use o f p r e p a c k m i x t u r e s a g a i n s t f o l i a r pathogens were n o t e a s i l y a c c e p t e d , p a r t i c u l a r l y when r e s i s t a n c e had not appeared i n a g i v e n crop or r e g i o n . I t must be s t r e s s e d t h a t i t i s of c r u c i a l importance t h a t a uniform, c o n s i s t e n t s t r a t e g y i s a p p l i e d i n m u l t i n a t i o n a l companies. E a r l y communication w i t h t h e e x t e n s i o n s e r v i c e i s n e c e s s a r y i n o r d e r t o a c h i e v e t h e i r s u p p o r t f o r t h e c h o s e n s t r a t e g y . The e x t e n s i o n s e r v i c e c a n h e l p i n t h e e a r l y development o f use i n s t r u c t i o n s f o r t h e farmer and i n e d u c a t i o n towards u n d e r s t a n d i n g t h e t h r e a t o f r e s i s t a n c e and t h e need f o r t h e s t r a t e g i c measures. E a r l y c o o r d i n a t i o n w i t h c o m p e t i t o r s i s a n o t h e r i m p o r t a n t element. Implementation and s u r v e i l l a n c e o f a n t i - r e s i s t a n c e s t r a t e g i e s r e q u i r e c o n s t a n t and i n t e n s i v e communication w i t h i n a c o m p l i c a t e d network, as shown i n T a b l e V I I and as e x p l a i n e d i n d e t a i l by U r e c h ( 2 9 ) . The d i f f i c u l t i e s i n c o o r d i n a t i n g s t r a t e g i e s among s e v e r a l competing companies s h o u l d n o t be o v e r l o o k e d . Even though i n d u s t r y s t a r t e d e a r l y on t o e s t a b l i s h c o o r d i n a t i o n groups under the g u i d a n c e o f t h e F u n g i c i d e R e s i s t a n c e A c t i o n Committee (FRAC) o f GIFAP ( 3 0 ) , i t was o f t e n d i f f i c u l t t o reach consensus, not o n l y a t the t a b l e but a l s o a t the sales front. I t a l s o needs t o be mentioned t h a t consensus between academic r e s e a r c h / e x t e n s i o n s e r v i c e p e r s o n n e l and commercial comp a n i e s i s n o t always e a s i l y r e a c h e d . In c e r t a i n s i t u a t i o n s , the views o f t h e two p a r t i e s may c l e a r l y d i f f e r , e s p e c i a l l y i f r e s e a r c h e r s base t h e i r c o n c l u s i o n s on t h e o r e t i c a l o r model s t u d i e s w i t h no c l e a r p r o o f under c o n d i t i o n s o f a g r i c u l t u r a l r e a l i t y , and i f i n d u s t r y r e s e a r c h e r s have t o r e s p e c t m a r k e t i n g c o n s i d e r a t i o n s . As i n d i c a t e d above, i n d u s t r y i s n o t t h e o n l y p a r t n e r i n t h e r e s i s t a n c e management p u z z l e . Extension consultants, regulatory a g e n c i e s , and p e s t i c i d e u s e r s a r e a l s o l a r g e l y i n v o l v e d i n d e s i g n i n g and i m p l e m e n t i n g s t r a t e g i e s , as d e s c r i b e d by U r e c h ( 2 9 ) , Johnson ( 3 1 ) , Hawkins ( 3 2 ) , and F r i s b i e , e t a l . (33)The r o l e s o f t h e v a r i o u s groups i n v o l v e d a r e shown i n T a b l e V I I I . I n d u s t r y sees an important r o l e o f r e g u l a t o r y agencies i n a s s u r i n g the a v a i l a b i l i t y o f c o n v e n t i o n a l m u l t i s i t e - i n h i b i t i n g f u n g i c i d e s as companions, and i n s u p p o r t i n g t h e m i x t u r e s t r a t e g y by a p p r o v i n g adequate m i x t u r e s f o r use i n t h e i r c o u n t r y (34, 3 5 ) . The r o l e o f e x t e n s i o n / c o n s u l t a n t s f o c u s e s on t h e e d u c a t i o n and and g u i d a n c e o f f a r m e r s so t h a t t h e y a r e m o t i v a t e d and s u p p o r t i v e i n f o l l o w i n g a n t i - r e s i s t a n c e strategies. Conclusions In c o n c l u s i o n , t h e i n d u s t r y f a c e s problems i n c o n n e c t i o n w i t h a n t i r e s i s t a n c e s t r a t e g i e s as o u t l i n e d i n T a b l e IX. Beyond i n d u s t r y ' s problems i n d e s i g n i n g and implementing r e a l i s t i c a n t i - r e s i s t a n c e s t r a t e g i e s , there are c l e a r research d e f i c i e n c i e s i n t h i s f i e l d , as i n d i c a t e d e a r l i e r . They a r e summar i z e d i n T a b l e X. We s h o u l d l i k e t o s t r e s s t h e need f o r b a s i c r e s e a r c h on t h e s e t o p i c s , t h e r e s u l t s o f w h i c h w i l l be o f g r e a t h e l p f o r coping w i t h f u t u r e f u n g i c i d e r e s i s t a n c e problems. I n a more l o n g - t e r m p e r s p e c t i v e , s t r a t e g i e s f o r l o w e r i n g t h e r i s k s o f r e s i s t a n c e and e n l a r g i n g t h e spectrum o f t o o l s t o cope w i t h

In Managing Resistance to Agrochemicals; Green, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

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