Biotechnology Products Related to Agriculture - ACS Symposium

Mar 18, 1987 - Copyright © 1987 American Chemical Society ... for use in agriculture, forestry, mosquito control and homeowner situations (Table I)...
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Chapter

27

Biotechnology Products Related to Agriculture Overview

of

Regulatory

Decisions at the

U.S.

Environmental

Biotechnology in Agricultural Chemistry Downloaded from pubs.acs.org by UNIV OF CALIFORNIA SAN DIEGO on 01/26/17. For personal use only.

Protection Agency 1

F.Betz ,A. Rispin, and W. Schneider Office of Pesticide Programs, U.S. Environmental Protection Agency, 401 M Street, SW, Washington, DC 20460

New a g r i c u l t u r a l products are being developed using modern b i o technology. This paper discusses one group of such products, g e n e t i c a l l y engineered microbial p e s t i c i d e s , and the Environmental Protection Agency's (EPA) regulatory a c t i v i t i e s which a f f e c t these products. Microbial pesticides have been regulated under FIFRA since 1948. Since that date f i f t e e n naturally occurring microorganisms have been registered, including three v a r i e t i e s of B a c i l l u s thuringiensis, f o r use i n agriculture, forestry, mosquito control and homeowner situations (Table I ) . In formulating i t s regulatory program for genetically engineered microbial pesticides, the Agency i s drawing on t h i s past experience i n evaluating microbial pesticides. In the l a s t 18 months, the Agency has reviewed several "biotechnology products" under i t s interim p o l i c y on small scale f i e l d testing and experimental use permit (EUP) authority. Some products are now ready to be f i e l d tested and pose challenging s c i e n t i f i c and regulatory questions which are discussed i n t h i s paper.

1

EPA s REGULATORY RESPONSIBILITY EPA r e g u l a t e s p e s t i c i d e p r o d u c t s as r e q u i r e d by t h e F e d e r a l I n s e c t i c i d e , F u n g i c i d e , and R o d e n t i c i d e A c t (FIFRA). The Agency's p r i m a r y r e s p o n s i b i l i t y under FIFRA i s t o weigh t h e r i s k s o f p e s t i c i d e use ( t o humans, n o n t a r g e t s p e c i e s , and t h e environment) a g a i n s t the p o t e n t i a l b e n e f i t s . T h i s d e t e r m i n a t i o n i s made t h r o u g h premarket s c r e e n i n g and e v a l u a t i o n o f each p r o d u c t . EPA may t h e n r e g i s t e r t h o s e p r o d u c t s whose b e n e f i t s o u t w e i g h t h e i r r i s k s and whose use w i l l n o t pose u n r e a s o n a b l e a d v e r s e e f f e c t s on human h e a l t h o r t h e environment. Current address: Hazard Evaluation Division, TS-769C, U.S. Environmental Protection Agency, 1921 Jefferson Davis Highway, Arlington, VA 22202 This chapter not subject to U.S. copyright. Published 1987 American Chemical Society

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27.

BETZ ET AL.

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Overview of Regulatory Decisions

T a b l e I . EPA - r e g i s t e r e d m i c r o b i a l p e s t i c i d e s Year Registered

Microorganisms

Pest

Controlled

Bacteria Bacillus popillae lentimorbus B^. t h u r i n g i e n s i s

1948 1948 1961

15. _t. i s r a l i e n s i s EL _ t . a i z a w a i Agrobacterium radiobacter

1981 1981 1979

Japanese B e e t l e L a r v a e Japanese B e e t l e L a r v a e Moth L a r v a e ( i n c l u d e s garden uses) Mosquito L a r v a e Wax Moth L a r v a e Crown G a l l

Viruses H e l i o t h i s Nuclear Polyhedrosis Virus Tussock Moth NPV

(NPV)

Gypsy Moth NPV P i n e Sawfly NPV

1978 1983

C o t t o n Bollworm, Budworm Douglas F i r T u s s o c k Moth Larvae Gypsy Moth L a r v a e P i n e Sawfly L a r v a e

1981 1981 1982

Mites C i t r u s Strangler Vine Northern J o i n t Vetch

1980

Grasshoppers

1975 1976

Fungi H i r s i t e l l a thompsoni Phytophthora palmivora Colletotrichum gloeosporides

Protozoa Nosema l o c u s t a e

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Biotechnology in Agricultural Chemistry Downloaded from pubs.acs.org by UNIV OF CALIFORNIA SAN DIEGO on 01/26/17. For personal use only.

The e x t e n t o f EPA o v e r s i g h t depends o n the degree o f p e s t i c i d e u s e and e n v i r o n m e n t a l e x p o s u r e . That i s , u s e and exposure g e n e r a l l y c o r r e l a t e w i t h the s t a g e o f p r o d u c t development. For example, s m a l l s c a l e f i e l d t e s t i n g would be e x p e c t e d t o r e s u l t i n m i n i m a l exposure and r i s k and t h e r e f o r e w a r r a n t s l e s s EPA o v e r s i g h t . On the o t h e r hand, l a r g e s c a l e t e s t i n g and f u l l commercial use may r e s u l t i n more extensive exposure w i t h a g r e a t e r l i k e l i h o o d o f r i s k . Therefore, EPA g e n e r a l l y e x t e n d s more comprehensive o v e r s i g h t i n the l a t t e r situation. S m a l l - S c a l e F i e l d T e s t i n g . P e s t i c i d e d e v e l o p e r s g e n e r a l l y need t o conduct f i e l d s t u d i e s i n order t o gather product performance, use, and o t h e r t y p e s o f d a t a n e c e s s a r y t o s u p p o r t the r e g i s t r a t i o n o f t h e i r product. I n i t i a l l y , s u c h t e s t i n g may be conducted on a v e r y l i m i t e d b a s i s . The r e g u l a t i o n s g o v e r n i n g f i e l d s t u d i e s ^ g i v e t h e EPA a u t h o r i t y t o g r a n t a n e x p e r i m e n t a l use p e r m i t (EUP) t o c o n d u c t f i e l d t e s t s . The EUP r e g u l a t i o n s i n c l u d e a g e n e r a l l y a p p l i c a b l e p r e s u m p t i o n t h a t e x p e r i m e n t a l use p e r m i t s w i l l not be r e q u i r e d f o r s m a l l s c a l e t e s t s o f new p e s t i c i d e s ( i . e . , t e s t s conducted on 10 a c r e s o f l a n d o r l e s s and o n 1 a c r e o f w a t e r o r l e s s ) . However, due t o s p e c i a l c o n c e r n s such a s the a b i l i t y t o s u r v i v e and r e p l i c a t e , p o t e n t i a l f o r g e n e t i c t r a n s f e r and a b i l i t y t o s p r e a d i n d e p e n d e n t l y from the s i t e o f a p p l i c a t i o n , and t h e p o t e n t i a l l a c k o f n a t u r a l c o n t r o l mechanisms, the Agency c o n c l u d e d t h a t s u c h a p r e s u m p t i o n was inappropriate f o r biotechnology products ( i . e . , g e n e t i c a l l y engineered m i c r o b i a l p e s t i c i d e s ) a s w e l l a s n o n i n d i g e n o u s b u t n a t u r a l l y occurring microbial pesticides. As a r e s u l t , t h e Pgency i s s u e d a statement o f i n t e r i m p o l i c y addressing small s c a l e f i e l d t e s t i n g o f m i c r o b i a l p e s t i c i d e s i n O c t o b e r , 1984. The purpose o f t h i s p o l i c y i s t o p r o v i d e a mechanism f o r t h e Agency t o e v a l u a t e s m a l l s c a l e f i e l d t e s t p r o p o s a l s f o r t h e i r p o t e n t i a l f o r r i s k s t o human h e a l t h o r the environment and t o d e t e r m i n e whether, based on p o t e n t i a l r i s k s o f s m a l l s c a l e r e l e a s e , EUPs a r e r e q u i r e d b e f o r e i n i t i a t i o n o f t e s t i n g . A s s e t f o r t h i n the i n t e r i m p o l i c y , i n f o r m a t i o n i s r e q u e s t e d o n the m i c r o o r g a n i s m t o be t e s t e d ; i t s i d e n t i t y , g r o w t h , s u r v i v a l and c o m p e t i t i v e c h a r a c t e r i s t i c s ; h o s t r a n g e and p o t e n t i a l e f f e c t s o n n o n t a r g e t s p e c i e s ; how i t h a s been m a n i p u l a t e d ; i n f o r m a t i o n on the p a r e n t a l s t r a i n s ; and i n f o r m a t i o n o n t h e d e s i g n o f t h e proposed f i e l d s t u d y . The amount o f i n f o r m a t i o n and d a t a may v a r y deperîding upon the s p e c i f i c m i c r o o r g a n i s m under r e v i e w and t h e manner i n w h i c h i t i s t o be t e s t e d . Agency s c i e n t i s t s use t h i s i n f o r m a t i o n t o c o n s t r u c t a r i s k s c e n a r i o a p p r o p r i a t e t o the p a r t i c u l a r microorganism. I f the p r o posed f i e l d t e s t poses no f o r e s e e a b l e r i s k s and no a d d i t i o n a l d a t a a r e needed, t h e n no EUP i s needed b e f o r e t h e f i e l d t e s t . I f s i g n i f i c a n t r i s k g u e s t i o n s o r the tieed f o r a d d i t i o n a l d a t a o r m o n i t o r i n g i s 2

Ί

2

U.S. EPA, 1985. E x p e r i m e n t a l Use P e r m i t s ; T i t l e 40, Code o f F e d e r a l R e g u l a t i o n s , P a r t 172. US.EPA, 1984. M i c r o b i a l P e s t i c i d e s ; I n t e r i m P o l i c y o n S m a l l S c a l e F i e l d T e s t i n g , FR 49 ( 2 0 2 ) , 40659.

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Biotechnology in Agricultural Chemistry Downloaded from pubs.acs.org by UNIV OF CALIFORNIA SAN DIEGO on 01/26/17. For personal use only.

e s t a b l i s h e d , t h e n t h e Agency may d e t e r m i n e t h a t an EUP i s needed b e f o r e t h e f i e l d t e s t i s i n i t i a t e d and t h e a p p l i c a b l e EUP r e q u i r e ments must be f u l f i l l e d . L a r g e S c a l e F i e l d T e s t i n g and R e g i s t r a t i o n . An EUP must be o b t a i n e d b e f o r e l a r g e s c a l e f i e l d t e s t i n g o f any p e s t i c i d e , i n c l u d i n g m i c r o b i a l p r o d u c t s . Data and i n f o r m a t i o n r e q u i r e m e n t s f o r an EUP a r e a s u b s e t o f t h o s e t h a t a p p l y t o p r o d u c t s f o r r e g i s t r a t i o n and a r e s e t f o r t h i n a r e g u l a t i o n t i t l e d Data Requirements f o r P e s t i c i d e R e g i s t r a t i o n (40 CFR 158)3. P e r m i s s i o n t o conduct f i e l d t e s t i n g i s g r a n t e d u n d e r an EUP f o r a s p e c i f i c t i m e p e r i o d ( e . g . , one y e a r ) on a t e s t p l o t s u i t a b l e f o r t h e purpose o f t h e t e s t b u t l i m i t e d i n acrage. T h e r e f o r e , t h e e x p o s u r e and p o t e n t i a l r i s k s a s s o c i a t e d w i t h s u c h t e s t s may be c o r r e s p o n d i n g l y l i m i t e d . A l l p e s t i c i d e s must be r e g i s t e r e d b e f o r e t h e y may be u s e d on a f u l l c o m m e r c i a l s c a l e . EPA e x t e n d s the most comprehensive o v e r s i g h t a t t h i s s t a g e o f development due t o t h e h i g h p o t e n t i a l f o r human o r e n v i r o n m e n t a l e x p o s u r e t h a t may r e s u l t from p r o d u c t s r e g i s t e r e d f o r a v a r i e t y o f u s e s on e x t e n s i v e acreage. A c c o r d i n g l y , the f u l l data r e q u i r e m e n t s and p r o c e d u r e s as s p e c i f i e d i n 40 CFR 158 and 1 6 2 a r e a p p l i c a b l e . G u i d e l i n e s f o r d e v e l o p i n g t h e n e c e s s a r y d a t a f o r an EUP o r r e g i s t r a t i o n a r e p r o v i d e d i n S u b d i v i s i o n M o f the P e s t i c i d e Assessment G u i d e l i n e s . Mechanisms a r e a v a i l a b l e t o i n c r e a s e o r d e c r e a s e the d a t a r e g u i r e m e n t s as a p p r o p r i a t e t o t h e s p e c i f i c situation. f

4

5

CURRENT STATUS 1

A t p r e s e n t , E P A s I n t e r i m P o l i c y on S m a l l S c a l e F i e l d T e s t i n g a p p l i e s t o a l l g e n e t i c a l l y eiîgineered o r m a n i p u l a t e d m i c r o b i a l p e s t i c i d e s . T h i s i n c l u d e s p r o d u c t s d e r i v e d by recombinant DNA (rDNA), recombinant RNA (rRNA), c e l l f u s i o n , t r a n s f o r m a t i o n , and c o n j u g a t i o n as w e l l as p r o d u c t s d e r i v e d by d i r e c t e d and u n d i r e c t e d m u t a g e n e s i s t e c h n i q u e s . The Agency s o l i c i t e d p u b l i c comment on i t s I n t e r i m P o l i c y when i t was p u b l i s h e d and a g a i n when t h e Agency p u b l i s h e d i t s P r o p o s e d P o l i c y on t h e R e g u l a t i o n o f C e r t a i n M i c r o b i a l P r o d u c t s i n December, 1984 as p a r t o f a government-wide p o l i c y s t a t e m e n t on t h e r e g u l a t i o n o f b i o t e c h n o l o g y . We have c a r e f u l l y c o n s i d e r e d t h e numerous comments r e c e i v e d from i n d u s t r y , t r a d e a s s o c i a t i o n s , p u b l i c i n t e r e s t groups and academics and a r e now i n t h e p r o c e s s o f r e v i s i n g t h e I n t e r i m P o l i c y i n r e s p o n s e t o t h e s e comments and t h e e x p e r i e n c e we have gained over the p a s t year i n e v a l u a t i n g s e v e r a l s m a l l s c a l e t e s t i n g 6

"3 4

5

6

U.S. EPA, 1985. Data Requirements f o r P e s t i c i d e R e g i s t r a t i o n ; T i t l e 40, Code o f F e d e r a l R e g u l a t i o n s , P a r t 158. U.S EPA, 1985. R e g u l a t i o n s f o r t h e Enforcement o f t h e F e d e r a l I n s e c t i c i d e , F u n g i c i d e , and R o d e n t i c i d e A c t ; T i t l e 40, Code o f F e d e r a l R e g u l a t i o n s , P a r t 162. U.S. EPA, 1983. P e s t i c i d e Assessment G u i d e l i n e s , S u b d i v i s i o n M - B i o r a t i o n a l P e s t i c i d e s , National Technical Information Service, S p r i n g f i e l d , VA, # PB83-153965. O f f i c e o f S c i e n c e and Technology P o l i c y , 1984. Proposal f o r a C o o r d i n a t e d Framework f o r R e g u l a t i o n o f B i o t e c h n o l o g y ; N o t i c e FR 4 9 ( 2 5 2 ) , 50882.

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p r o p o s a l s . A r e v i s e d p o l i c y o n s m a l l s c a l e f i e l d t e s t i n g s h o u l d be a v a i l a b l e i n 1986. I n t h e meantime we w i l l e x p e d i t e r e v i e w s f o r p r o d u c t s l i k e l y t o pose n e g l i b l e r i s k . As o f t h i s w r i t i n g ( W i n t e r , 1985), EPA has r e c e i v e d and e v a l u a t e d s e v e r a l p r o p o s a l s t o conduct s m a l l s c a l e f i e l d t e s t i n g w i t h g e n e t i c a l l y a l t e r e d microorganisms. I n t h r e e c a s e s , EPA determined t h a t a n EUP would be r e q u i r e d and i n a n o t h e r c a s e , d e t e r m i n e d t h a t t h e p r o d u c t was n o t s u b j e c t t o t h e I n t e r i m P o l i c y . Two EUP a p p l i c a t i o n s a r e c u r r e n t l y under review. The Agency has e v a l u a t e d and approved EUP a p p l i c a t i o n s f r o m t h e Advanced G e n e t i c S c i e n c e s Company (AGS). AGS h a s o b t a i n e d EPA p e r m i s s i o n t o conduct s m a l l s c a l e f i e l d t e s t i n g t o e v a l u a t e t h e f r o s t p r o t e c t i o n p o t e n t i a l o f two s t r a i n s o f g e n e t i c a l l y a l t e r e d b a c t e r i a . The Agency r e v i e w e d a v e r y s i m i l a r p r o p o s a l from t h e U n i v e r s i t y o f C a l i f o r n i a (Drs. Lindow and Panopoulos) and determined t h a t t h e y t o o would need t o o b t a i n an EUP p r i o r t o c o n d u c t i n g f i e l d t e s t s . T h e i r EUP a p p l i c a t i o n has been r e c e i v e d and i s c u r r e n t l y u n d e r r e v i e w . I n the t h i r d c a s e , EPA e v a l u a t e d a p r o p o s a l f r o m t h e Monsanto Company t o conduct a f i e l d t e s t t o e v a l u a t e the i n s e c t i c i d a l p r o p e r t i e s o f a s o i l borne b a c t e r i u m g e n e t i c a l l y a l t e r e d t o c o n t a i n t h e i n s e c t t o x i n p r o d u c i n g gene from B a c i l l u s t h u r i n g i e n s i s . Here a g a i n the Agency determined t h a t an EUP would be r e q u i r e d . I n r e s p o n s e , Monsanto s u b m i t t e d an EUP a p p l i c a t i o n c o n t a i n i n g , among o t h e r t h i n g s , d a t a t o e n a b l e t h e Agency t o e v a l u a t e e n v i r o n m e n t a l f a t e and e f f e c t s o n nont a r g e t organisms o f the g e n e t i c a l l y a l t e r e d m i c r o b i a l p e s t i c i d e . These d a t a a r e now under review. Further d e t a i l s concerning these and o t h e r r e l a t e d p r o p o s a l s a r e p r o v i d e d i n T a b l e I I . The Agency i s e s t a b l i s h i n g s i g n i f i c a n t s c i e n t i f i c and p o l i c y makirig p r e c e d e n t s i n i t s r e v i e w s and d e c i s i o n s f o r t h e s e f i r s t applications t o f i e l d test genetically altered microbial pesticides. T h e r e f o r e , a s d e s c r i b e d i n t h e f o l l o w i n g s e c t i o n , EPA has i n s t i t u t e d a mechanism t o o b t a i n o u t s i d e p e e r r e v i e w o f i t s s c i e n t i f i c a s s e s s ments from o t h e r F e d e r a l A g e n c i e s a s w e l l a s a p a n e l o f independent s c i e n t i s t s . The b a l a n c e o f t h i s paper c o n c e n t r a t e s o n EPA s r e g u l a t o r y program f o r s m a l l s c a l e a p p l i c a t i o n s o f g e n e t i c a l l y a l t e r e d m i c r o b i a l p e s t i c i d e s , a l t h o u g h we e x p e c t t h a t l a r g e r s c a l e t e s t s and f u l l r e g i s t r a t i o n w i l l r e q u i r e a s i m i l a r review process. 1

REVIEW PROCESS FOR SMALL-SCALE FIELD TEST PROPOSALS EPA has u p t o 90 days t o r e v i e w each n o t i f i c a t i o n o f i n t e n t t o c o n d u c t s m a l l - s c a l e f i e l d t e s t i n g and t o determine whether an EUP i s r e q u i r e d . The Agency encourages p r o s p e c t i v e a p p l i c a n t s t o meet w i t h EPA p r i o r t o s u b m i s s i o n o f t h e i r n o t i f i c a t i o n t o d i s c u s s t h e i r f i e l d t e s t and d e t e r m i n e what s p e c i f i c d a t a and i n f o r m a t i o n would be necessary t o e v a l u a t e the product. E P A s r e v i e w p r o c e s s w i l l i n c l u d e some o r a l l of t h e elements d e s c r i b e d i n t h e f o l l o w i n g paragraphs and d e p i c t e d i n F i g u r e 1. As the Agency b u i l d s a b a s e l i n e o f r i s k assessment d a t a and g a i n s more e x p e r i e n c e i n e v a l u a t i n g t h e s e p r o d u c t s , c e r t a i n s t e p s may no l o n g e r be n e c e s s a r y . I n c e r t a i n c a s e s , a n a b b r e v i a t e d r e v i e w p r o c e s s may be a p p r o p r i a t e (e.g., review o f a p r o p o s a l t h a t i s s i m i l a r t o an a l r e a d y r e v i e w e d c a s e ) . Such a d e t e r m i n a t i o n w i l l be made o n a case-by-case basis. 1

rDNA d e l e t i o n product INA~ Bacteria for frost protection Pseudomonas syringae and P. fluorescens

rDNA d e l e t i o n product · INA~ Bacteria for frost protection - Pseudomonas · syringae and P^ fluorescens

rDNA d e l e t i o n product INA"" Bacteria for f r o s t protection Pseudomonas syringae

(2) AGS - EUP

(3) U. C a l i f o r n i a Notification

Type of Product

(1) AGS - N o t i f i c a t i o n

Applicant & Type of Submission

December 84 - N o t i f i c a t i o n · received February 85 - SAP provided comments • March 85 - l e t t e r to Lindow requesting additional data and an EUP June 85 - OPP met with NIH and Cabinet Council (Cohrssen) to discuss the two Agencies' reviews and conclusions concerning INA" bacteria

Continued on next page

+

Potential adverse e f f e c t s on plants, insects, weather patterns Competitiveness of INA~ products and potential to displace INA bacteria

· AGS submitted documentation of t h e i r findings, as requested · Additional data submitted on competitiveness, plant pathogenicity and c o l o n i z a t i o n , i d e n t i f i c a t i o n , and detection Assertions of low r i s k substantiated by data

July 85 - EUP a p p l i c a t i o n s received August 85 - Announce receipt in FR Sept. 85 - Received public comments (E. L. Rogers) Sept/Oct. 85 - Received SAP & inter-Agency review comments November 85 - announced approval November 85 - Agency sued by Foundation on Economic Trends

+

• Potential adverse effect on plants, insects, weather patterns * Competitiveness of INA" products and potential to displace INA bacteria

Major Issues

November 84 - N o t i f i c a t i o n received January 85 - SAP Subpanel Meeting February 85 - l e t t e r to AGS requesting a d d i t i o n a l informat i o n and an EUP

Chronology of Events

Table I I . Summary of microbial p e s t i c i d e n o t i f i c a t i o n s and experimental use permits

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Relative l e v e l of r i s k posed by products of undirected muta­ genesis compared to other g e n e t i c a l l y altered products The extent of data and i n f o r ­ mation needed (and i s p r a c t i c a l to obtain) on these products for n o t i f i c a t i o n Toxin gene i n s e r t i o n mechanism may cause environmental problem P o s s i b i l i t y of adverse e f f e c t s on non-target species

January 85 - N o t i f i c a t i o n received A p r i l 85 - 90-day clock suspended; OPP requested a d d i t i o n a l information May 85 - USDA withdrew notification

January 85 received March 85 meeting A p r i l 85 requesting mation and

October 85 - EUP a p p l i c a t i o n received Currently undergoing in-house review W i l l be reviewed by the SAP subpanel and other agencies

Undirected mutagenesis product Two species of fungi to be used to control pest fungi Trichoderma v i r i d e and T. harzianum

rDNA a d d i t i o n product B.T. toxin gene inserted into P. fluorescens for insect control

rDNA a d d i t i o n product B.T. toxin gene inserted into P. fluorescens f o r insect control

(6) USDA Notification

(7) Monsanto Notification

(8) Monsanto - EUP

L e t t e r to Monsanto additional infor­ an EUP

SAP subpanel

Agency reviewing data generated by company to address major s c i e n t i f i c issues i d e n t i f i e d in the n o t i f i c a t i o n Determination of Confidential Business Information status of the submission

A p p l i c a b i l i t y of Interim Policy - Mycogen provided data to substantiate n o n - v i a b i l i t y of their product

A p r i l 85 - N o t i f i c a t i o n received June 85 - Mycogen informed that Interim Policy does not apply to their " k i l l e d " product.

rDNA a d d i t i o n product B.T. toxin gene inserted into Pseudomonas for insect c o n t r o l ; CELLS KILLED

(5) Mycogen Notification

- Notification

Agency reviewing data generated by applicant to address major s c i e n t i f i c issues i d e n t i f i e d in n o t i f i c a t i o n

Major Issues

December 85 - applications received Currently undergoing in-house review

Chronology of Events

rDNA d e l e t i o n product INA - Bacteria for frost protection - Pseudomonas syringae (2 strains)

Type of Product

(4) U. C a l i f o r n i a EUP

Table II - Continued Applicant & Type of Submission

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BETZ ET AL.

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O f f i c e of Pesticide Program Review • Environmental fate • Ecological e f f e c t s • Human health Product analysis

Preliminary

scientific

position

Intra-Agency Review O f f i c e s • Toxic Substances • Research and Development • Policy Planning and Evaluation • General Counsel

Inter-Agency Review • USDA • NIH • FDA

Science Advisory Panel Microbiologist Microbial ecologist S o i l microbiologist Meteorologist Plant pathologist Community ecologist

Public comment

Final scientific

Figure

1.

position

EPA assessment p r o c e s s .

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Oice a n o t i f i c a t i o n i s r e c e i v e d , s c i e n t i s t s i n the O f f i c e o f P e s t i c i d e Programs (OPP) r e v i e w each p r o p o s a l and a s s e s s t h e p o t e n t i a l r i s k s a s s o c i a t e d w i t h t h e p r o p o s e d e x p e r i m e n t . OPP reviewers are trained i n the relevant d i s c i p l i n e s , including microb i o l o g y , m i c r o b i a l e c o l o g y , and m o l e c u l a r b i o l o g y . A s noted above, a r i s k s c e n a r i o i s c o n s t r u c t e d f o r each proposed t e s t u s i n g t h e d a t a and i n f o r m a t i o n s u b m i t t e d b y t h e a p p l i c a n t . OPP d e v e l o p s a w r i t t e n s c i e n t i f i c p o s i t i o n f o r each p r o p o s a l w h i c h i d e n t i f i e s p o t e n t i a l problems o r s i g n i f i c a n t unanswered q u e s t i o n s and s e t s f o r t h a s t a t e ment o f t h e o v e r a l l l i k e l i h o o d o f s i g n i f i c a n t r i s k from t h e proposed field test. OPP o b t a i n s comments on i t s assessment from a workgroup w i t h i n EPA and from s e v e r a l o t h e r f e d e r a l a g e n c i e s (USDA, N a t i o n a l I n s t i t u t e s o f H e a l t h , Food and Drug A d m i n i s t r a t i o n , arid N a t i o n a l Science Foundation). T h e i r comments a r e i n c o r p o r a t e d i n t o t h e s c i e n t i f i c p o s i t i o n , as a p p r o p r i a t e . OPP c o n t a c t s t h e a p p r o p r i a t e s t a t e p e s t i c i d e r e g u l a t o r y a u t h o r i t i e s t o e n s u r e t h a t t h e y a r e aware o f t h e p r o p o s a l and t o d i s c u s s E P A s assessment. These c o n t a c t s e n s u r e t h a t t h e a c t i o n s o f EPA and t h e s t a t e a g e n c i e s a r e a s c o n s i s t e n t a s p o s s i b l e . OPP a l s o n o t i f i e s the A n i m a l and P l a n t H e a l t h I n s p e c t i o n S e r v i c e (APHIS) o f t h e USDA s o t h a t t h e y c a n d e t e r m i n e whether any a s p e c t o f t h e p r o p o s e d e x p e r i m e n t f a l l s w i t h i n APHIS j u r i s d i c t i o n and, i f s o , t o a v o i d d u p l i c a t i v e o r c o n f l i c t i n g assessments. I f t h e n o t i f i c a t i o n r a i s e s complex o r c o n t r o v e r s i a l s c i e n t i f i c q u e s t i o n s , OPP p r o v i d e s t h e n o t i f i c a t i o n package and i t s s c i e n t i f i c p o s i t i o n t o a g r o u p o f independent s c i e n t i s t s c o n s t i t u t e d a s a s u b p a n e l o f O P P s S c i e n t i f i c A d v i s o r y P a n e l (SAP). S e p a r a t e s u b p a n e l s may be formed t o r e v i e w each p r o p o s a l s i n c e each m i c r o o r g a n i s m and i t s proposed u s e may d i f f e r and r a i s e g u e s t i o n s t h a t r e q u i r e t h e a n a l y s i s o f i n d i v i d u a l s w i t h d i f f e r e n t e x p e r t i s e . The purpose o f t h e SAP s u b p a n e l i s t o o b t a i n a n independent p e e r r e v i e w o f t h e OPP s c i e n t i f i c p o s i t i o n , t o address s p e c i f i c s c i e n t i f i c questions r a i s e d by OPP, and t o i d e n t i f y any a d d i t i o n a l p o i n t s , q u e s t i o n s o r problems. A t t h e c o n c l u s i o n o f t h e r e v i e w , t h e Agency t h e n d e c i d e s whether an EUP i s r e q u i r e d . The d e c i s i o n document s e t s f o r t h O P P s conclusions with respect t o p o t e n t i a l r i s k s associated with the p r o p o s a l , i d e n t i f i e s any r e m a i n i n g q u e s t i o n s o r a d d i t i o n a l d a t a t h a t may be needed t o complete t h e r i s k assessment, and, i f an EUP i s r e q u i r e d , may recommend r e s t r i c t i o n s , l i m i t a t i o n s , o r m o d i f i c a t i o n s o f t h e p r o p o s a l t o a d d r e s s a r e a s o f c o n c e r n . I f an EUP i s n o t r e q u i r e d , t h e a p p l i c a n t may proceed w i t h t h e proposed f i e l d t e s t . I f a n EUP i s r e q u i r e d , t h e a p p l i c a n t must a p p l y f o r a p e r m i t , p r o v i d i n g t h e n e c e s s a r y d a t a and i n f o r m a t i o n r e q u i r e d t o s u p p o r t t h e a p p l i c a t i o n . The Agency may d e c i d e t o r e q u i r e an EUP t o e n s u r e t h a t t h e e x p e r i m e n t i s conducted w i t h c e r t a i n d e f i n e d l i m i t s , o r i n order t o o b t a i n the necessary data t o assess the proposal, o r t o e n s u r e t h a t c e r t a i n k i n d s o f d a t a w i l l be d e v e l o p e d d u r i n g t h e t e s t and r e p o r t e d t o t h e Agency. 1

1

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RISK FACTORS EPA has i d e n t i f i e d s e v e r a l f a c t o r s t h a t may c o n t r i b u t e t o r i s k s from t h e e n v i r o n m e n t a l a p p l i c a t i o n o f g e n e t i c a l l y a l t e r e d m i c r o b i a l p e s t i c i d e s . EPA has c o n s i d e r e d t h e s e f a c t o r s i n d e v e l o p i n g i t s

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Biotechnology in Agricultural Chemistry Downloaded from pubs.acs.org by UNIV OF CALIFORNIA SAN DIEGO on 01/26/17. For personal use only.

p o l i c i e s c o n c e r n i n g t h e s e p r o d u c t s and i n s p e c i f i c f i e l d t e s t i n g p r o p o s a l s . I t s h o u l d be emphasized t h a t t h e Agency b e l i e v e s t h e s e a r e i m p o r t a n t t o c o n s i d e r i n t h e r i s k assessment, b u t t h a t they do n o t n e c e s s a r i l y c o n s t i t u t e a r i s k i n any s p e c i f i c s i t u a t i o n . P e s t i c i d a l Nature. The p r o d u c t s d i s c u s s e d i n t h i s p a p e r a r e p e s t i c i d e s a i d by t h e i r n a t u r e a r e d e s i g n e d o r i n t e r d e d t o have some b i o l o g i c a l a c t i v i t y t o " c o n t r o l " o t h e r p o p u l a t i o n s o f organisms ( i . e . , p e s t s ) . For example, m i c r o b i a l p e s t i c i d e s may c o n t r o l p e s t s by i n f e c t i v e / p a t h o g e n i c a c t i o n , p r o d u c t i o n o f a t o x i n , by a f f e c t i n g a p e s t ' s g r o w t h o r r e p r o d u c t i o n , o r by p h y s i c a l l y d i s p l a c i n g a p e s t organism from i t s normal e c o l o g i c a l n i c h e . As w i t h c h e m i c a l s , t h e c o n c e r n i s t h a t n o n t a r g e t organisms may be a d v e r s e l y a f f e c t e d as well. E n v i r o n m e n t a l A p p l i c a t i o n . Many p e s t i c i d e s a r e a p p l i e d o u t d o o r s t o major f o o d c r o p s , f o r e s t s , and r a n g e l a n d . These a p p l i c a t i o n s may encompass v a s t acreage u s i n g a e r i a l o r ground b r o a d c a s t s p r a y s . T h i s i s i n marked c o n t r a s t t o o t h e r u s e s o f g e n e t i c a l l y a l t e r e d m i c r o organisms i n f e r m e n t o r s , l a b o r a t o r y o r o t h e r p h y s i c a l l y c o n f i n e d s i t u a t i o n s . T h e r e f o r e , t h e r e maybe s i g n i f i c a n t p o t e n t i a l f o r human a i d environmental exposure t o g e n e t i c a l l y a l t e r e d m i c r o b i a l p e s t i c i d e s when u s e d on a f u l l commercial b a s i s . Competitiveness. U n l i k e chemical p e s t i c i d e s , m i c r o b i a l p e s t i c i d e s a r e l i v i n g e n t i t i e s w h i c h may s u r v i v e , r e p l i c a t e and compete w i t h o t h e r s p e c i e s f o r space a i d f o o d s o u r c e s . These f a c t o r s , a l o n e , do n o t c o n s t i t u t e a h a z a r d , b u t do r e q u i r e an e v a l u a t i o n f o r w h i c h t h e r e i s no c o u n t e r p a r t f o r c h e m i c a l p e s t i c i d e s . Such an a n a l y s i s must c o n s i d e r whether c h a r a c t e r i s t i c s have been e n g i n e e r e d i n t o a m i c r o organism w h i c h may p e r m i t i t t o e s t a b l i s h i t s e l f i n new e n v i r o n m e n t a l n i c h e s . I f s o , t h e n i t s p o t e n t i a l t o e x e r t a d v e r s e e f f e c t s on n o n t a r g e t s p e c i e s must be c o n s i d e r e d . E c o l o g i c a l E f f e c t s . C l a s s i c a l chemical t o x i c i t y t e s t i n g , alone, i s i n a p p r o p r i a t e f o r most m i c r o b i a l p e s t i c i d e s . T o x i n p r o d u c t i o n i s one a s p e c t t o be c o n s i d e r e d . However, i n f e c t i v i t y and p a t h o g e n i c i t y must a l s o be e v a l u a t e d as p o t e n t i a l e i d p o i n t s . Host range i s a l s o a r e l e v a n t q u e s t i o n f o r m i c r o b i a l p e s t i c i d e s t h a t may have p a t h o g e n i c o r t o x i c e f f e c t s on t h e i r t a r g e t h o s t s . F o r example, i f an o r g a n i s m i s e n g i n e e r e d t o produce a new t o x i n , then we must e v a l u a t e whether o r iKDt t h e h o s t range w i l l be extended beyotd t h e p e s t s p e c i e s . Moveable G e n e t i c Elements. I t i s known t h a t g e n e t i c m a t e r i a l can be t r a n s f e r r e d among organisms i n n a t u r e . However, t h e s i g n i f i c a n c e o f t h i s phenomenon and t h e e x t e n t t o w h i c h i t may o c c u r i n t h e e n v i r o n ment i s n o t u i d e r s t o o d . D e p e i d i n g on how an o r g a n i s m i s e n g i n e e r e d , g e n e t i c m a t e r i a l may be s u b j e c t t o movement t o o t h e r s p e c i e s and t h i s may be o f c o n c e r n i f the t r a n s f e r r e d g e n e t i c m a t e r i a l e n a b l e s r e c i p i e n t organisms t o e l i c i t adverse e f f e c t s .

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Human H e a l t h . The l i k e l i h o o d o f r i s k s t o human h e a l t h i s v e r y l o w f o r g e n e t i c a l l y a l t e r e d m i c r o b i a l p e s t i c i d e s used i n s m a l l s c a l e f i e l d s t u d i e s . T h i s assumes t h a t t h e p a r e n t m i c r o o r g a n i s m s i s n o t a mammalian pathogen and t h a t we have a good u n d e r s t a n d i n g o f t h e p a r e n t a l s t r a i n s and how t h e y have been m a n i p u l a t e d . L a r g e r s c a l e a p p l i c a t i o n s may i n v o l v e more human exposure ( e . g . t o a p p l i c a t o r s ) and would w a r r a n t more e x t e n s i v e e x a m i n a t i o n , p a r t i c u l a r l y w i t h respect t o potential f o r allergenic effects. I n any e v e n t , t h e Agency b e l i e v e s t h a t f u l l h a r i d l i r i g p r e c a u t i o n s and p r o t e c t i v e c l o t h i n g s h o u l d be u s e d a s a p r u d e n t and p r a c t i c a l measure even i n s m a l l s c a l e f i e l d t e s t s . F i n a l l y , t h e u s e o f a n t i b i o t i c r e s i s t a n c e markers i s n o t o f g r e a t c o n c e r n p r o v i d e d t h e m a r k e r s used a r e n o t f o r c l i n i c a l l y important a n t i b i o t i c s . I f used w i s e l y , the b e n e f i t s o f u s i n g a n t i b i o t i c r e s i s t a n c e m a r k e r s f o r d e t e c t i n g and i s o l a t i n g t h e m i c r o o r g a n i s m i n t h e environment would appear t o outweigh t h e p o t e n t i a l risks. Thus f a r , OPP s r e v i e w s o f s m a l l - s c a l e f i e l d t e s t i n g p r o p o s a l s f o r g e n e t i c a l l y a l t e r e d m i c r o b i a l p e s t i c i d e s have addressed s e v e r a l of t h e s e r i s k f a c t o r s . F o r example, OPP h a s i d e n t i f i e d p o t e n t i a l r i s k s associated with the transfer o f inserted genetic material t o other organisms, t h e competitiveness o f the engineered organism compared w i t h t h e p a r e n t a l organisms i n t h e environment, and t h e a b i l i t y o f t h e e r q i n e e r e d o r g a n i s m t o become e s t a b l i s h e d i n a new e c o l o g i c a l n i c h e and t h e r e b y pose a p o t e n t i a l a d v e r s e e n v i r o n m e n t a l impact. OPP has a d d r e s s e d t h e s e and s i m i l a r q u e s t i o n s o n a case-by-case b a s i s i n i t s r i s k assessments. To answer t h e s e q u e s t i o n s , EPA has n o r m a t i v e d a t a r e q u i r e m e n t s and t e s t methods d e v e l o p e d f o r n a t u r a l l y o c c u r r i n g microorganisms. Use o f t h e s e t e s t s ( o r t i e r e d s e r i e s o f t e s t s ) e n a b l e t h e Agency t o t o e s t a b l i s h whether t h e e f f e c t o f c o n c e r n i s l i k e l y t o m a t e r i a l i z e under f i e l d c o n d i t i o n s . I n some c a s e s , a p p l i c a n t s have addressed q u e s t i o n s b y r e v i s i n g t h e c o n d i t i o n s o f t h e proposed t e s t o r b y m o d i f y i n g t h e t e s t m i c r o o r g a n i s m t o minimize p o t e n t i a l r i s k .

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UNANSWERED QUESTIONS 1

During t h e course o f EPA s review o f f i e l d t e s t i n g p r o p o s a l s , s i g n i f i c a n t q u e s t i o n s o f s c i e n c e p o l i c y have been i d e n t i f i e d . F o l l o w i n g a r e some examples: Review o f " S i m i l a r " M i c r o o r g a n i s m s . To what e x t e n t c a n d a t a d e v e l o p e d on one s t r a i n o f a s p e c i e s be used t o a s s e s s a c l o s e l y r e l a t e d s t r a i n ( e . g . , one t h a t has been s u b j e c t e d t o f u r t h e r "minor" g e n e t i c a l t e r a t i o n ) ? How d i f f e r e n t must two s t r a i n s be t o w a r r a n t a complete d a t a s e t o n each s t r a i n ? To t h e e x t e n t p o s s i b l e , EPA would w i s h t o a v o i d d u p l i c a t i n g complete d a t a s e t s on s i m i l a r s t r a i n s o r minor g e n e t i c m o d i f i c a t i o n s . T e s t P r o t o c o l s . What a r e t h e most a p p r o p r i a t e t e s t s p e c i e s f o r a s s e s s i n g r i s k t o n o n t a r g e t organisms. How adeguate a r e t e s t s on s u r r o g a t e mammalian s p e c i e s f o r a s s e s s i n g human h e a l t h e f f e c t s ? Can

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microcosm o r m u l t i p l e s p e c i e s t e s t i t i q be u s e d t o p r o v i d e a b e t t e r p r e d i c t i v e measure o f a d v e r s e e f f e c t s o f m i c r o o r g a n i s m s and how u s e f u l a r e t h e r e s u l t s o b t a i n e d f r o m g r o w t h chambers o r c o n t a i n e d greenhouses i n p r e d i c t i n g f a t e o r e f f e c t s u n d e r a c t u a l f i e l d conditions? F u r t h e r l a b o r a t o r y and greenhouse t e s t methods development i s needed t o a s s e s s t h e p o t e n t i a l a d v e r s e e f f e c t s o f g e n e t i c a l l y a l t e r e d m i c r o b i a l p e s t i c i d e s . A l t h o u g h some t e s t methods a r e a v a i l a b l e and a n a l y s i s o f f i e l d t e s t i n g p r o p o s a l s c a n p r o c e e d o n a case-by-case b a s i s , t h e r e i s a need f o r f u r t h e r r e s e a r c h i n t e s t method development. F i e l d T e s t i n g i n Remote S i t e s . How e f f e c t i v e i s f i e l d t e s t i n g i n remote s i t e s a s an approach t o c o n t a i n m e n t ? F a r t h e r a n a l y s i s i s needed t o d e t e r m i n e whether t h i s i s a p r a c t i c a l ( o r v a l i d ) a p p r o a c h , p a r t i c u l a r l y when b a l a n c e d a g a i n s t t h e need t o f u l f i l l t h e applicant's o b j e c t i v e f o r conducting t h e t e s t - which i s u s u a l l y t o o b t a i n d a t a on whether t h e p r o d u c t w i l l work under f i e l d c o n d i t i o n s . E n v i r o n m e n t a l M o n i t o r i n g . How u s e f u l a r e f i e l d m o n i t o r i n g d a t a f o r assessing p o t e n t i a l adverse e f f e c t s o f g e n e t i c a l l y a l t e r e d m i c r o o r g a n i s m s a p p l i e d i n t h e environment? A b a s i c dilemma a r i s e s i n i n t e r p r e t i n g t h e r e s u l t s o f any e f f o r t t o m o n i t o r m i c r o b i a l p o p u l a t i o n s i n t h e environment. Due t o t h e i n h e r e n t l i m i t s o f d e t e c t i o n f o r any m i c r o o r g a n i s m , i t s a p p a r e n t absence does n o t mean t h a t i t i s n o t s t i l l p r e s e n t i n low, b u t u n d e t e c t a b l e numbers. Under p r o p e r e n v i r o n m e n t a l c o n d i t i o n s , t h e m i c r o o r g a n i s m may r e a c h h i g h numbers and be e c o l o g i c a l l y s i g n i f i c a n t . RECEIVED December 15,1986