Report of the Interagency Biotechnology Working Group - ACS

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Report of the Interagency Biotechnology Working

Group

Description of the Toxic Substances C o n t r o l A c t

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David L. Dull,/Matthew Hale, Anne K. Hollander, Jane Rissler, and Carl Mazza Office of Toxic Substances, U.S. Environmental Protection Agency, 401 M Street, SW, Washington, DC 20460

A biotechnology working group of the Cabinet Council on Natural Resources and the Environment recently proposed a coordinated federal approach to the regulation of new commercial products of biotechnology. This paper summarizes the recent a c t i v i t i e s of the working group and describes i n more d e t a i l the proposed approach of the Environemtnal Protection Agency (EPA) p a r t i c u l a r l y under the Toxic Substances Control Act (TSCA). Under TSCA, EPA w i l l have r e s p o n s i b i l i t y for reviewing new genetically engineered microorganisms i n a range of environmental and a g r i c u l t u r a l applications, including p o l l u t i o n control and nitrogen f i x a t i o n . (Foods, pesticides, and drugs are excluded from coverage under TSCA, although EPA w i l l review genetically engineered p e s t i cides under the Federal Insecticide, Fungicide and Rodenticide Act.) This paper discusses EPA s review authority under TSCA, the nature and scope of the TSCA biotechnology program, and the review procedures and assessment principles EPA i s now developing. 1

S i n c e the 1970's, the 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 Recombinant DNA A d v i s o r y Committee (NIH RAC) has p r o v i d e d o v e r s i g h t f o r b i o t e c h n o l o g y r e s e a r c h , e s p e c i a l l y recombinant DNA r e s e a r c h . However, i t i s now c l e a r t h a t the v a r i o u s r e g u l a t o r y a g e n c i e s c o n c e r n e d w i t h p u b l i c h e a l t h and the environment must d e f i n e t h e i r r o l e s i n the r e g u l a t i o n o f the commercial uses o f t h i s r a p i d l y growing t e c h nology. Toward t h i s end, l a s t y e a r the U.S. C a b i n e t C o u n c i l on N a t u r a l Resources and Environment formed a b i o t e c h n o l o g y working group. T h i s group i s c h a i r e d by the Deputy D i r e c t o r o f the O f f i c e o f S c i e n c e and T e c h n o l o g y P o l i c y and i n c l u d e s r e p r e s e n t a t i v e s from the U.S. Department o f A g r i c u l t u r e (USDA), the Department o f H e a l t h and Human S e r v i c e s (HHS), the E n v i r o n m e n t a l P r o t e c t i o n Agency (EPA),

This chapter not subject to U.S. copyright. Published 1987 American Chemical Society

LeBaron et al.; Biotechnology in Agricultural Chemistry ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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BIOTECHNOLOGY IN AGRICULTURAL CHEMISTRY

and several other agencies. The main accomplishment of this group to date has been the preparation and publication on December 31, 1984 of a FEDERAL REGISTER Notice on biotechnology, which presented (1) the proposed p o l i c i e s of the USDA, the Food and Drug Administration (FDA), and EPA toward the products of biotechnology, (2) a regulatory matrix of Federal authorities over biotechnology, and (3) a proposal for a coordinated Federal s c i e n t i f i c advisory mechanism for biotechnology. This notice represents a major i n i t i a l success i n interagency cooperation that can provide industry with coordinated regulatory information. Our presentation today addresses the potential role of EPA s Toxic Substances Control Act (TSCA) within the framework of Federal oversight of biotechnology, as defined by the Cabinet Council working group. Despite the benefits that can be derived from this technology, concerns have been raised about the possible r i s k s involved. These concerns include the p o s s i b i l i t y that biotechnology products such as genetically engineered microorganisms may have increased virulence, a broadened host range, and/or the a b i l i t y to r e p l i c a t e and spread beyond the application s i t e . The novel genetic t r a i t s induced i n these organisms may be transferred to others and microorganisms can be d i f f i c u l t to i d e n t i f y and monitor after their release into the environment. There are several regulatory issues that are of immediate concern when considering the application of TSCA to biotechnology. I have included i n today's presentation three of these issues: f i r s t , the d i s t i n c t i o n between a "new" and a "naturally occurring" chemical substances for the purpose of the a p p l i c a b i l i t y of the premanufacture n o t i f i c a t i o n (PMN) requirement of TSCA; second, the scope of the research and development exemption from the PMN requirements, and i t s implication for open f i e l d testing of microorganisms; and third the type and amount of information that EPA might need for risk/benefit analyses of new microorganisms. I will also b r i e f l y mention some technical areas i n which further research would greatly f a c i l i t a t e the processes of risk/benefit assessment. 1

TSCA The Toxic Substances Control Act (TSCA) was enacted i n 1976 to provide EPA with authority to address risks posed by a broad range of "chemical substances." Under TSCA, EPA can assess and control exposure to these substances through a l l phases of their commercial l i f e cycle, including research and development, commercial product i o n , use, and disposal. TSCA coverage extends to chemical substances and mixtures used in a wide range of i n d u s t r i a l , commercial and consumer applications. As defined i n section 3(2) of the Act a "chemical substance" i s "any organic or inorganic substance of a p a r t i c u l a r molecular i d e n t i t y , including...any combination of such substances occurring i n whole or in part as a result of a chemical reaction or occurring i n nature..." When examining the products of biotechnology, such as recombinant DNA and RNA, for example, i t can be seen that they are organic chemical substances of p a r t i c u l a r molecular i d e n t i t i e s and


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therefore TSCA "chemical substances." By extension, a l i f e form i s composed of "chemical substances" as defined i n TSCA. A d d i t i o n a l l y , l i f e forms are themselves "chemical substances" under TSCA because they are combinations of organic substances of p a r t i c u l a r molecular i d e n t i t i e s that occur i n nature or that occur i n whole or i n part as a result of chemical reactions. As noted, TSCA coverage extends to chemical substances and mixtures used i n a broad range of i n d u s t r i a l , commercial and consumer applications. Some examples of the types of microbial products that would be subject to TSCA are microorganisms used to produce pesticides and other commercial chemicals, to convert biomass to energy, for pollutant degradation and enhanced o i l recovery, i n metal extraction and concentration, and i n certain non-food agriculture applications, such as nitrogen f i x a t i o n . Certain substances are s p e c i f i c a l l y excluded from TSCA, namely, pesticides, tobacco and tobacco products, nuclear materials, foods, food additives, drugs and cosmetics. Even though TSCA does not cover pesticides (they are covered by EPA under the Federal I n s e c t i cide, Fungicide, and Rodenticide Act-FIFRA) i t does cover the microorganisms that produce pesticides and the intermediates used to prepare pesticides. However, the intermediates used to prepare other substances such as foods, food additives, drugs and cosmetics have not been regulated under TSCA. In addition, while EPA has asserted that microorganisms are covered under TSCA, the December policy statement did not propose that genetically engineered l i v i n g plants and animals either as whole organisms or as i n v i t r o cultures be made subject to TSCA requirements. Regulatory Issues Premanufacture N o t i f i c a t i o n

Requirements

For biotechnology, the most important provision of TSCA i s the section 5(a) requirement that companies n o t i f y EPA at least 90 days before beginning to manufacture or import a "new chemical substance" for commercial purposes. This reporting requirement i s known as premanufacture n o t i f i c a t i o n or PMN. Any substance that i s not l i s t e d by name on EPA s Chemical Substances Inventory or that i s not "naturally occurring" i s defined as "new" and therefore subject to PMN requirements. Because genetically engineered microorganisms and nucleic acids are neither "naturally occurring" nor l i s t e d i n the TSCA Inventory, they are subject to PMN requirements under TSCA. However, what i s "new" or "naturally occurring" i s not always clear cut and needs additional d e f i n i t i o n when applied to this new technology. In establishing the o r i g i n a l Chemical Substances Inventory and the PMN regulations EPA adopted the p o l i c y that human intervention at a r e l a t i v e l y simple l e v e l does not remove a substance from the category of naturally occurring. Under these regulations, the act of i s o l a t i n g a substance from nature by manual, mechanical or gravit a t i o n a l means, or by d i s s o l u t i o n i n water, f l o t a t i o n , or heating s o l e l y to remove water, does not a l t e r i t s status as "naturally occurring" and make i t subject to PMN requirements. On the other hand, chemical substances that are chemically extracted from a 1


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n a t u r a l s u b s t a n c e a r e n o t n a t u r a l l y o c c u r r i n g and must be r e p o r t e d under PMN r e q u i r e m e n t s i f they a r e not a l r e a d y l i s t e d on t h e TSCA inventory. The Agency proposed i n t h e December 31, 1984 FEDERAL REGISTER n o t i c e t h a t s i m i l a r l o g i c c o u l d be f o l l o w e d t o determine whether a m i c r o o r g a n i s m i s new. N a t u r a l l y o c c u r r i n g m i c r o o r g a n i s m s would be those t h a t e x i s t as a r e s u l t o f n a t u r a l events o r p r o c e s s e s o r have been d e v e l o p e d as a r e s u l t o f l i m i t e d m a n i p u l a t i o n o f n a t u r a l processes. F o r example, t h e normal e v e n t s o f r e p r o d u c t i o n o r e v o l u t i o n would n o t c r e a t e "new c h e m i c a l s u b s t a n c e s . " The Agency t h e n proposed t h a t t h e t e c h n i q u e s o f R-NDA, R-RNA and c e l l f u s i o n , which a l l o w t h e c o m b i n a t i o n o f g e n e t i c m a t e r i a l from organisms t h a t do n o t exchange g e n e t i c m a t e r i a l i n n a t u r e , produce organisms t h a t c o u l d be c o n s i d e r e d "new" and s u b j e c t t o PMN r e q u i r e m e n t s . Comments r e c e i v e d by EPA i n response t o t h e December F e d e r a l R e g i s t e r N o t i c e were h i g h l y c r i t i c a l o f t h i s " p r o c e s s - b a s e d " approach, c l a i m i n g t h a t i t would p e n a l i z e some t e c h n o l o g i e s and was u n r e l a t e d t o any r i s k s t h a t might be p r e s e n t e d by t h e p r o d u c t s o f t h e s e t e c h n o l o g i e s . EPA i s working toward r e s o l u t i o n o f t h i s d i f f i c u l t i s s u e . Basic options f o r a f i n a l p o l i c y statement t h a t a r e b e i n g e v a l u a t e d i n c l u d e : 1. 2. 3.

a t t e m p t i n g t o e s t a b l i s h a l i s t o f organisms t h a t exchange DNA in nature, d e v e l o p i n g a taxonomic approach t o what i s new, and c o n t i n u i n g w i t h t h e c r i t i c i z e d p r o c e s s - b a s e d approach t o what i s new.

Small-Scale F i e l d

Testing

New c h e m i c a l s u b s t a n c e s produced o n l y i n s m a l l q u a n t i t i e s s o l e l y f o r r e s e a r c h and development a r e exempt from PMN r e q u i r e m e n t s . This exemption g e n e r a l l y e x c l u d e s s m a l l s c a l e f i e l d t e s t i n g o f a g r i c u l t u r e c h e m i c a l s from PMN r e q u i r e m e n t s . Field testing of traditional c h e m i c a l s has a low r i s k because t h e a r e a o f a p p l i c a t i o n i s geog r a p h i c a l l y c i r c u m s c r i b e d and t h e s m a l l q u a n t i t y used f o r t e s t i n g i s not l i k e l y t o s p r e a d away from t h i s s i t e . Many p e o p l e have e x p r e s s e d c o n c e r n t h a t s i g n i f i c a n t r i s k s c o u l d o c c u r i f r e s e a r c h and development open f i e l d - t e s t i n g o f new m i c r o organisms was performed w i t h o u t p r i o r Agency r e v i e w . Unlike t r a d i t i o n a l chemicals, l i v i n g , reproducing microorganisms can i n c r e a s e i n number and be d i s s e m i n a t e d from t h e a p p l i c a t i o n s i t e a f t e r r e l e a s e i n t o t h e environment. EPA r e v i e w a t a l a t e r , commercial s t a g e , f o r t h e s e types o f p r o d u c t s may be t o o l a t e t o p r e v e n t widespread exposure. Such e a r l y r e v i e w a t t h e r e s e a r c h and development s t a g e now t a k e s p l a c e under RAC s g u i d e l i n e s and i n E P A s p e s t i c i d e program. T h e r e f o r e , EPA i s c o n s i d e r i n g whether t o i n i t i a t e a p o l i c y o f r e v i e w i n g TSCA m i c r o b i a l p r o d u c t s p r i o r t o f i e l d t e s t i n g . 1

I n f o r m a t i o n Requirements

1

i n PMN

Submissions

A t p r e s e n t , t h e r e i s an absence o f g e n e r a l l y a c c e p t e d p r i n c i p l e s o f r i s k assessment f o r m i c r o b i a l p r o d u c t s , e s p e c i a l l y when t h e i r use i n v o l v e s d i r e c t r e l e a s e i n t o t h e environment. F o r t h i s r e a s o n , and


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because there i s the potential to produce a wide variety of microorganisms for very different applications, EPA believes that for the present much of the information required under TSCA for the evaluation of these products should be decided on a case-by-case basis. In a l l cases, certain minimal up-front information would be required to i d e n t i f y the microorganism unambiguously, both to support r i s k assessment and to l i s t the organism on the Inventory. This would include: 1. 2. 3.

the source of the introduced nucleic acids the processes by which the nucleic acids were manipulated including hosts, vectors, etc. i d e n t i f i c a t i o n of the protein or special function produced.

Also required upon submission of a PMN would be information on intended use, the amounts manufactured, amounts released, and disposal methods. However, the amount and type of data required for the r i s k assessment of a microorganism would vary according to the r i s k potential of the organism. This approach i s e a s i l y accommodated by the s p e c i f i c provisions of TSCA. L i t t l e up-front information i s generally required for a PMN; no s p e c i f i c battery of testing i s mandated. Rather, i n an appropriate case EPA has the authority under section 5(e) of TSCA to require by administrative order s p e c i f i c data needed to complete i t s r i s k assessment and to prevent commercial manufacture u n t i l this data i s provided. For example, the Agency would expect more d e f i n i t i v e information for genetically engineered organisms that are intended to be released into the open environment, and/or are able to survive and reproduce i n the environment. These organisms would have a greater potential for widespread exposure than those used i n a closed system or those that could not survive. Organisms that are derived from or are themselves toxic, pathogenic or e c o l o g i c a l l y disruptive could also be considered a higher r i s k and therefore, require more detailed information for r i s k assessments than organisms that do not have such properties. In the case of organisms that are released into the environment, information on application techniques and descriptions of the target environments may be necessary to determine the organisms a b i l i t y to survive, reproduce, be transported, or exchange genetic material with other organisms. Factors that l i m i t or enhance the mobility or s u r v i v a b i l i t y of organisms or their genetic material may also be s i g n i f i c a n t considerations i n r i s k evaluations. If the organism i s used to produce commercial substances, companies may be asked to submit data on the purity of the f i n a l product and the presence of any residual organisms or contaminants i n the product. As the Agency gains experience i n the review of genetically engineered microorganisms and their products and i s able to develop appropriate r i s k assessment methods, i t may be possible to establish more s p e c i f i c guidelines on the levels of test data and other i n f o r mation that might be submitted and how these data might be used i n the evaluation of the products of biotechnology. 1


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EPA has a strong t r a d i t i o n i n the PMN program of establishing a working relationship with PMN submitters to identify data needs prior to submission, and thus encourages manufacturers to consult with the Agency prior to submitting a PMN on a new microorganism. Such prenotice consultations could prove to be an extremely valuable way to expedite the review process. During such meetings, manufacturers would have the opportunity to describe the s p e c i f i c s of their s i t u a t i o n and EPA would be able to provide guidance on the appropriate levels of information needed. This approach minimizes the use of EPA s administrative order authority and avoids needless delays i n commercial production. 1

Research Needed In addition to the policy issues that I have mentioned today there are numerous research areas that need further development to allow for more informed regulatory review. Significant work i n these areas i s being funded from our laboratories at Gulf Breeze, F l o r i d a and C o r v a l l i s , Oregon. Of p a r t i c u l a r interest to EPA are refinement of microcosm procedures to assess s u r v i v a b i l i t y and growth of test microorganisms, development of methods to assess the s t a b i l i t y of novel genetic t r a i t s , and development of genetic markers i n engineered organisms to permit i d e n t i f i c a t i o n and monitoring. The Agency i s also interested i n development of general methods for the assessment of potential adverse e f f e c t s , and methods to assess transport p o s s i b i l i t i e s . EPA i s devoting substantial resources toward finding solutions to these problems. In 1986, 4.2 m i l l i o n dollars w i l l be allocated to fund extramural and intramural biotechnology research programs. Conclusion Currently, we are evaluating the public comments that we received on the December 31 FEDERAL REGISTER notice. We are using these and information compiled from panels of s c i e n t i f i c and technical experts as a basis for the formulation of a revised statement of policy on biotechnology. I've hinted today at some of the directions being considered for the key issues of what i s "new" and therefore what products are subject to premanufacture n o t i f i c a t i o n . The potential benefits of biotechnology for the U.S. economy are enormous. A wide array of new commercial products, such as drugs, pesticides and other a g r i c u l t u r a l products, p o l l u t i o n control products, and foods, are expected to be introduced into the marketplace i n the near future. New biotechnological techniques, such as recombinant-DNA have been safely used i n the laboratory under the oversight of the NIH/RAC. We believe, however, that the risks of these techniques become increasingly uncertain as we move from the r e l a t i v e l y well contained setting of laboratory s c i e n t i f i c research into situations i n which the products of biotechnology w i l l have f u l l contact with society and the environment. In view of the current uncertainty, EPA, other Federal agencies, and many i n the s c i e n t i f i c , i n d u s t r i a l and public communities believe that some regulatory oversight i s appropriate. However, a major question i s how much oversight i s appropriate. We


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must be sensitive to the fact that i l l - c o n s i d e r e d , duplicative or excessive regulation of the new products of this technology could have a disastrous effect on innovation and could drive research and commercial development overseas. Therefore, i t i s important to develop a balanced and f l e x i b l e approach that allows new products to move into the marketplace expeditiously while adequately protecting public health and the environment. RECEIVED November 18, 1986


Report of the Interagency Biotechnology Working Group - ACS

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