Biotechnology in Agricultural Chemistry - ACS Publications - American

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


27.

BETZ ET AL.

317

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

318

BIOTECHNOLOGY IN AGRICULTURAL CHEMISTRY


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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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.


320


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


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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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 .


324


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

27.

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325


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 .

326


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


27.

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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

Biotechnology in Agricultural Chemistry - ACS Publications - American

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