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Appendix Historical Overview of Nucleic Acid Biotechnology: 1973 to 1989 The origins of current initiatives by federal agencies to regulate planned introductions of genetically manipulated organisms, pa~tic- ularly those derived from recombinant DNA techniques, lie In the concerns of scientists who recognized in the early 1970s that the ability to specifically alter the genetic code has far-reaching unplica- tions. Since then, the waxing and waning of interest by Congress, federal agencies, states, and local municipalities in regulation of mod- ern biotechnological methods and products has paralleled changing perceptions of risk (Korwek and de la Cruz, 1985~. Oversight mechanisms tailored to the methods and products of biotechnology began to emerge in 1974, when the National Academy of Sciences (NAS), responding to a letter from the attendees at the 1973 Gordon Conference on Nucleic Acids, convened a committee to evaluate the safety of research on recombinant DNA. The committee published its recommendations ~ Nature (Berg et al., 1974a) and Science (Berg et al., 1974b) caning for a voluntary moratorium on recombinant DNA experiments while questions of public safety were further evaluated. The letter also invited the National Institutes of Health (NIH) to establish a committee to oversee an evaluation of potential biological and ecological hazards and to devise guidelines for working with recombinant DNA. The debate over safety concerns was extended to include broader 133

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134 social issues at the February 1975 International Conference on Re- comb~n~t DNA Molecules (often called the Asilomar Conference), which was convened at the Asilomar Conference Center, California, by the Assembly of Life Sciences of the National Research Council. Participants at the Asilomar Conference also debated the ethical issues raised by recombm ant DNA research as wed as the legal li- abilities of the investigators and institutions in the event of injury arising from such research (Berg et al., 1975a; Berg et al., 1975b). Some participants argued that recombinant DNA research should proceed unrestricted by guiaelmes or special regulations, while oth- ers maintained that the potential dangers demanded restrictions or self-~rnposed guidelines. Ultimately, a statement of principles out- I~n~ng a proposed set of standards for recombinant DNA research was drafted, and researchers agreed to control their own research stringently until the safety of the new recombinant DNA technology could be ensured. FORMATION OF NIB GUIDELINES A second stage ~ the development of an oversight mechanism began when a committee of scientists appointed by NTH, known as the Recombinant DNA Advisory Committee (RAC), converted the statement of principles developed at the Asilomar Conference into research- and containment-oriented guidelines. The first guidelines for research involving recombinant DNA molecules were published in 1976 for use in overseeing NTH-funded research activities (NIH, 1976~. Their initial focus was on containment designed to ensure the safety of laboratory work and to prevent the accidental escape of recombinant DNA microorganisms. Risk categories for experiments were assigned; different types of exper~rnental work were to be conducted at different levels of physical and biological containment; and other experiments, including environmental introductions, were prohibited. As experience with contained applications of recombinant DNA accumulated, many of the risks feared to be associated with labora- tory recombinant DNA research were found to be greatly overesti- mated or simply nonexistent (Levin, 1984~. As a result, in 1978 the standards of containment required for a range of recombinant DNA experunents conducted ~ the laboratory were relaxed (NTH, 1978~. Subsequent revisions have included decentralization of responsibility for the administration of recombinant DNA experiments, sunplifica- tion of the administrative procedures for working with recombinant

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135 DNA, ~d, to prevent duplicative review, exemption from RAC ~d NTH review for certain experiments submitted for review to a federal regulatory agency. Increased responsibility for oversight of recombi- nant DNA research also has been placed in the hands of local msti- tutional biosafety committees. The scope of the guidelines also has been expanded from a focus on research to a concern with large-sc~e operations, from in vitro work to possible applications of gene ther- apy to humans, and from laboratory containment to environmental introductions (V~denbergh, 1986; Korwek, 1988~. The guidelir es eventually became binding on aB institutions re- ceiving any federal funding, in addition to those receiving NIH grants, and their Sequence h" spread] beyond federally funded research ac- tiv~ties and beyond application of recombinant DNA techniques. In the period since their adoption, state and local governments, aca- dem~c institutions, the industrial community, and foreign countries have voluntarily applied the guidelines or modified versions of them. In addition, the RAC, which has been expanded to include persons in a variety of disciplines' has served as a mode! for the forma- tion of biotechnology advisory groups for federal regulatory agencies. The Environmental Protection Agency's Biotechnology Science Ad- visory Co~ruruttee (BSAC) and the U.S. Department of Agriculture's (USDA's) Biotechnology Research Advisory Committee (ABRAC) are examples of groups modeled after the RAC. These groups pro- vide advice on scientific and policy issues ~nvolv~g agency oversight of a broacI range of technologies, in addition to recombinant DNA. ENVIRONMENTAL RELEASES The modification of the guidelines to address the planned in- troduction into the environment of certain genetically manipulated orgamstns triggered another stage in the development of an oversight system and a new debate about hazards. Progress in research during the m~-1970s permitted the development of genetically manipulated m~croorganisrns designed to survive and function outside the labora- tory. As a result, the guidelines were amended in 1978 to continue the general prohibition on planned introductions, but to permit the NTH director, on the advice of the RAC, to grant exceptions (NIH, 1978~. Three requests between 1980 ~d 1983 to fielci-test plants and m~- croorgan~sms containing recombinant DNA forced the RAC to move from the ad hoc approach outlined In the 1978 guideline amendments

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136 to the creation of generally applicable release guidelines, but they also forced the development of federal regulatory initiatives. The first of these requests was made by Stanford University researchers in March 1980 to test maize (Zea mays} transformed by DNA cloned from Es- cherichia cold and the yeast Saccharomyces cerevisiae in an attempt to modify zein, a grain-storage protein. Cornell University next re- quested a field test for tomatoes and tobacco seedlings developed from pollen containing DNA from a hybrid plasmid vector carrying antibiotic resistance markers. Although both tests were approved by NIH and USDA (NIH, 1981; NIH, 1983), neither was carried out. The third request, in September 1982, came from researchers at the University of California at Berkeley and proved to be the most controversial. The RAC reviewed a proposal to field-test the plant bacteria Pseudomonas syringae subsp. syringae and Erwinia herb~cola with deletions of genetic information for the ice nucleation factor. The RAC requested that a revised version of the proposal to test these ~ice-m~nus" bacteria be prepared. It reviewed the re- vised proposal in October 1982 and approved it seven months after subTn~ssion of the initial request (NTH, 1983~. NTH approval of the ice-minus experiment then provoked a court challenge under the National Environmental Policy Act (NEPA) (U.S. Congress, 1982~. NEPA establishes procedures obligating many federal agencies to take environmental values into account for all major activities. It requires most federal agencies to conduct an environmental assessment and perhaps to prepare an environmen- tal unp act statement for each major action that may significantly Erect the environment. A federal district court enjoiner] the field test of Pseudomonas and Erw~nia isolates on the ground that the RAC review did not adequately consider the environmental Impacts of the release of these particular ic~minus ~rucroorganisms (Foun- dation on Economic Trends v. Heckler, 19843. The court enjoined NIH from approving future environmental release proposals on the ground that the RAC approval process required a programmatic en- vironmental unpact statement under NEPA. A federal appeals court subsequently reversed the district court's ruling requiring such an impact statement, but upheld the injunction against the ice-minus experiment pending NEPA review (Foundation on Economic Trends v. Heckler, 1985~. This case established a precedent for further NEPA challenges to other applications of modern methods of nucleic acid biotechnology (Foundation on Economic Trends v. Lyng, 19863.

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137 CONGRESSIONAL INITLATIV1DS The development of genetically modified microorganisms de- signed to function outside the laboratory has also prompted several congressional hearings into the environmental hazards of planned introductions and the adequacy of regulatory oversight mechanisms. No specific legislation has been enacted. In June 1983, Congress- men Douglas WaIgren (chairman of the Subcomrn~ttee on Science, Research and Technology) and Albert Gore (chairman of the Sum committee on Investigations and Oversight) conducted a hearing on the environmental implications posed by commercial applications of recombinant DNA technology (U.S. Congress, 1983~. This hearing followed the United States Supreme Court's decision in Diamond v. Chakrabarty (U.S. Congress, 1980; Wade, 1980), which upheld the patentability of life forms and provided a stimulus to the commer- cial development of genetically manipulated microorganisms for both laboratory and noniaboratory use. The report of the hearing concluded that predicting the envi- ronmenta] effects from the introduction of genetically manipulated organisms is difficult, but that any highly negative consequence had a low probability of occurring (U.S. Senate, 1984~. The report also questioned the ability of federal agencies to regulate planned mtro- auctions in light of the unquantifiable nature of the risks, and it concluded that more information on the environmental fate of these introduced organisms was needed to ascertain whether such releases posed a risk to the ecosystem. Similarly, ~ September 1984, the Subcommittee on Toxic Sum stances and Environmental Oversight of the Senate Committee on Environmental and Public Works held a hearing on "the potential environmental consequences of genetic engineering (U.S. Senate, 1984~. Representatives from the Environmental Protection Agency (EPA), NIH, and USDA testified that existing statutes, regulations, and guidelines would benefit from clarification, but were adequate to address release issues without congressional intervention. Before the Senate hearing, an interagency working group was formed under the White House Cabinet Council on Natural Resources and the Envi- ronment to review biotechnology regulation and to begin the process of coordinating the biotechnology activities of the federal agencies. DEVELOPMENT OF REGULATORY OVERSIGHT In December 1984, the working group proposed a regulatory

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138 strategy including a matrix of laws applicable to biotechnology it also included individual policy statements from USDA, EPA, and the Food and Drug Administration (FDA) outlining their regulatory roles (OSTP, 1984~. The working group also proposed the formation of a scientific biotechnology science board to coordinate regulatory activities of the different agencies ~d to provide advice on scientific issues related to biotechnology. In response to criticism that the Biotechnology Science Board would further complicate an already complex regulatory system, the board was replaced in October 1985 when the Biotechnology Sci- ence Coordinating Committee (BSCC) was created to develop a cornrnon scientific approach within the coordinated federal regula- tory framework for biotechnology (OSTP, 1985~. In addition, the responsibilities for biotechnology coordination within the Reagan administration were shifted to the Domestic Policy Council Working Group on Biotechnology within the Office of Science and Technology Policy (OSTP, 1985~. in June 1986, OSTP published the Coordinated Framework for Regulation of Biotechnology, which identifies the agencies responsible for approving biotechnology products and their respective Jurisdic- tions for regulating planned introductions (OSTP, 1986~. Overall, the coordinated framework reiterates the earlier view that the current laws are adequate to oversee current biotechnology clevelopments. Since the possibility of regulatory overlap exists, particularly among EPA, FDA, and USDA, the document identifies which regulatory bodies have been designated ~ lead agencies for particular biotech- nology products or their uses. Although the current oversight framework Is still evolving, the regulatory agencies continue to rely on existing laws for oversight of biotechnology activities. Under existing statutes and the Ig86 Coordinated Framework, products of biotechnology and research and commercial applications may be regulated differently and by different agencies. Variables that may tugger regulatory oversight include the extent of the genetic manipulation and the intended use of the product, for example, whether a product is to be used as a pesticide, food, or drug. ~ other respects oversight depends on whether a plant or animal pathogen may be involved. Some laws prevent duplication of federal and state review while others do not, thus leading to the possibility of oversight of biotechnology by more than one federal or state agency. This diversity In the bases for regulation and in the oversight mechanisms is (lerived from the

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139 variety of federal and state laws that have been enacted to protect human health and the environment. The current oversight framework is based on the authority in various laws to require permits or other types of agency review be- fore introduction. It may be briefly characterized by (1) attempts by federal and state agencies to coordinate their regulatory activities (with various degrees of success), to prevent overlapping regulation; (2) reliance on outside committees, such as BSAC and ABRAC, for review of scientific and other issues; (3) ongoing efforts to modify and refine existing regulatory mechanisms; (4) a case-by-case approach, especially in reviewing proposed field tests; and (5) a shifting em- phasis from scrutiny of only the processes utilized (for example, recombinant DNA techniques) to scrutiny of the characteristics of the derived products. Recurrent difficulties In the oversight of planned Introductions have involved a variety of considerations, including whether adequate scientific bases exist for the federal agencies to differentiate releases of greater and lesser concern, whether data requirements are am propriate, and whether emerging regulatory approaches (which tend to be product- rather than process-based) will extend the reach of oversight to areas not traclitionaDy subject to federal review. With the shift of focus from process to product, a new problem has arisen: Regulatory oversight might be triggered not only for new nucleic acid technologies, but also for those that have not been manipulated at all or that have been developed through classics techniques, such as mutagenesis. As a result, the product-based approach engenders the possibility that planned introductions of products of older technologies may also become subject to special oversight, ~ many cases for the first time, perhaps even despite a long history of safe use. With respect to risk-assessment issues, a fundamental concern is whether the Ignited current understanding of microbial ecology (McGarity and Bayer, 1983; Strauss et al., 1986) enables the envi- ronmental fate of released organisms to be predicted. The oversight of planned introductions by NIH and the federal regulatory agencies can generally be described as science-based, and the more than 50 re- leases that have been, perrn~tted thus far have been allowed because of their perceived "Iow-r~sk~ status, ~ light of the characteristics of the genetically manipulated organism and the small scale of the field-test environment into which it Is introduced.

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140 Although the data requirements of the federal regulatory agen- cies are not identical, they share several common features. Where DNA has been moved from one organism to another, each agency usually requires information about the parent or source organism and its characteristics, the identity and function of the genetic material transferred, and the mechanism by which the DNA was transferred. The agencies also require information on the organism that is the subject of the genetic work, including data on the characteristics expressed before and after manipulation, such as the likelihood of competitive success ~ the environment and of subsequent genetic transfer to other organisms. The agencies usually also require data on the characteristics of the planned introduction, such as the environment into which the genetically manipulated organism will be released, the size of the release area, and the number of organisms to be introduced. Release requirements often include containment principles that will limit the proliferation of the introduced organism, such as the limiting characteristics of the organism itself and other biological and physical mechanisms that help prevent dissemination beyond the test site. Fin ally, the agencies have attempted to retain the flexibility to require additional data where needed. EVALUATION OF OVERSIGHT CAPABILITIES Several recent reports have discussed the regulatory regune, em pecially r~sk-assessment capabilities and the adequacy of oversight mechanisms. In September 1987, an NAS white paper (NAS, 1987) concluded that there is no evidence that the introduction into the environment of organisms modified by recombinant DNA present unique hazards, but rather that the risks are the same that as in- curred in the introduction into the environment of unmodified organ- is~. Consistent with the oversight approaches sometimes utilized by the regulatory agencies and others, the white paper concluded that dectsion-mak~ng on the environmental use of genetically manipulated organisms should be based on the organisms' relevant properties and not on the process by which the organisms were produced. It also rec- ommended that the scientific community provide guidance to assist investigators and regulators in evaluating the planned introduction of modified organisms from an ecological perspective (Tiedje et al., 1989~. A May 1988 report by the Office of Technology Assessment

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141 (OTA) illustrated a range of options for congressional action ~ ma- jor areas of public policy, including the criteria for review of planned introductions for potential risk, the adrn~nistrative mechanisms for applying such review criteria, and the research base supporting planned introductions (OTA, 1988~. The OTA report concluded that although reasons exist to continue to be cautious about envi- ronmenta] introductions, there ~ no cause for alarm. The report also noted that some questions can be answered only with practical experience, that is, with realistic small-scale field tests, which are not likely to result In environmental problems. It also called for the establishment of broad categories that can be used to sort proposed introductions for low, medium, or high levels of review. At the behest of the Subcommittee on Oversight and T~vestiga- tions of the House Committee on Energy and Commerce, the Gen- eral Accounting Office (GAO) issued a report in June 1988 reviewing the federal risk management of genetically engineered organisms in- tended for agricultural and health use in the environment (GAO, 1988~. The report evaluated the scope of regulatory policies appli- cable to smaD-scale releases, reviewed the adrn~nistrative procedures for ~rnplementing policies, and identified technical methods available to control and monitor risks posed by field testing. It states that the probability of ecological disruption from introductions ~ low, but the magnitude of the impact may be extremely severe. The report also notes that USDA, EPA, and FDA have made efforts to coordinate their policies and review procedures, but they have lim- ited experience with genetically manipulated organisms used in the environment and are uncertain about the effects of the organisms. Recommendations include the elimination of certain classes of in- troductions that are currently exempt from federal agency review because of the incompleteness of the scientific underpinning needed to justify these exemptions.

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