Genetically modified organisms

The Term Genetically Modified Organism (GMO) is most frequently used to refer to an organism that has been changed genetically by recombinant DNA techniques. Historically, research with GMOs has been subject to special oversight that, to this day, differs, depending on the location of the research with the organism, whether inside (contained) or outside (so-called field research), type of organism (e.g., plant, animal, microorganism) or use (e.g., medical, agricultural, environmental), and country in which one works. The oversight mechanism for contained research is principally through guidelines developed by scientists and endorsed by the private and public sector. Outside research is currently overseen by a number of federal agencies. In some countries, such as the United States, there can be overlapping jurisdictions, differing interpretations of legal statutes, and different requirements or standards for compliance by scientists who do research with GMOs in the outside environment. Scientific issues deal with differences in perspective on the risks of introductions of GMOs into the environment, the types of data required prior to the introduction to conclude the experiment is of low risk, and the types of monitoring and mitigation practices, if necessary. Nonscientific issues are also considered and include those dealing with legal and social concerns. These differences in interpretation have resulted in few introductions into the environment of microorganisms. 

I. CONCERN OVER GENETICALLY MODIFIED ORGANISMS 

A. The concern over safety The new biology, dating to the 1970s and usually encompassing recombinant DNA techniques, enabled scientists to perform modifications of organisms with great precision and to combine DNA of organisms that can not, in current time, combine; yet these combinations are derived from components of naturally occurring organisms. The scientific community raised hypothetical questions about the safety of genetically engineered organisms, and the public questioned the potential adverse effects of organisms with the new combinations of genetic information on humans and the environment. It was argued that, as such, the organisms have not been subjected to evolutionary pressures, including dissemination and selection, and may pose a risk to humans or the environment. However, it was recognized that genetic modifications can arise by classical or molecular methods, ranging from selection of desirable combinations by farmers or bakers since antiquity to nucleotide insertion or deletion by molecular biologists. The new biology, often called biotechnology, has generated fear that the new organisms may be unpredictable in survival and dissemination and, particularly, that transfer of the gene for the modified trait to nontarget organisms might occur. However, gene transfer occurs whether or not humans intervene. Such gene transfers are expected to have minimal consequences unless selection is imposed. Increasing evidence supports the conclusion that microorganisms, particularly bacteria, usually maintain their fundamental characteristics and their essential identities and moderate the amount of change that can be absorbed by known and unknown mechanisms. Deleterious changes can occur, and will, whether or not microorganisms are manipulated. The preliminary testing under contained conditions that is requisite and standard practice in science should, however, identify most of such gross changes. Principles for assessing risk of GMOs as developed in scientific and public forums, are based on the premise that, if one begins with a beneficial organism and imparts a neutral or beneficial trait, the probability of harm from transfer of genetic information is minimal. Some scientists are more concerned about the widespread adoption of a beneficial organism in commerce, rather than about small-scale field research, because greater exposure is likely to increase the probability of risk. The concern over GMOs resides partly on a perceived increase in ability to survive or persist. Thus, some scientists and consumers argue that oversight of GMOs should be as stringent as that for toxic chemicals, physical disruptions such as water control projects, or exotic organism introductions. 

The strongest arguments for these concerns are voiced by persons who compare the risks of GMOs with that of introducing exotic organisms. The appropriateness of this analogy can be questioned because there is generally a familiarity with the organism being modified and the trait being introduced, and the fraction of the new genetic information is quite small (Table 44.1). In contrast, exotic organisms are unfamiliar and are entire genomes. There is also a perception by some that, should there be a problem with survival or dissemination of a microorganism, nothing can be done. Essentially, the assumption is that once the gene(s) is out, it cannot be recalled. However, orderly and inadvertent movement and dissemination of microorganisms occur repeatedly because of their presence on humans, plants, and animals that are moving throughout the world at increasing rates. There are also long-standing and environmental practices that are in use to decontaminate or mitigate unwanted effects of microorganisms. Such practices are known for microorganisms associated with plants and animals, as well as for free-living microorganisms. Immediate decontamination methods include, among others, burning, chemical control, and sanitation by various means. Short-term and long-term methods are abundant for plant- and animal-associated microorganisms, since a great deal of research on developing mitigation methods is conducted by scientists in the disciplines of plant pathology, veterinary medicine, and human medicine. Many of these deal with management practices and the use of genetic resistance and application of biological control organisms. Immunization of humans and animals is another type of long-term management practice to mitigate the effects of microorganisms. 

B. Concerns over genetically modified domesticated organisms in agriculture and the environment Virtually all domesticated organisms used in the production of food and fiber have been genetically modified over long periods of time, including certain live domesticated microorganisms used in making bread, beer, wine, various types of cheese, yogurt, and other foods. Selected microorganisms that have been shown to be beneficial are also widely used in the environment. These uses include, among others, microorganisms that fix nitrogen and provide nutrients for trees (mycorrhizae), as well as those used in sewage treatment plants and oil drilling. Also, naturally occurring pathogenic microorganisms are used in the testing of domesticated plants to ascertain their disease resistance. In such critical tests with known deleterious organisms, there has been no documented case of untoward effects, such as a plant disease epidemic, arising from such standard field trials. It is widely accepted that the first step in risk assessment, whether in containment or in confined field trials, is identifying the risk by determining how much is known about the parental organism. It is also recognized that the risk can be minimized by the preferential selection of parental organisms that are generally recognized as safe because of their long history of use. In the oversight of food, such foods are categorized as GRAS, or generally recognized as safe. A similar category can be considered for microorganisms that would be introduced into the environment: GRACE, or those microorganisms that are generally recognized as compatible with the environment. Examination of the food safety issues associated with genetic modifications has led to the conclusion that potential health risks are not expected to be any different in kind than with traditional genetic modifications. All such evaluations rest on knowledge of the food, the genetic modification, the composition, and relevant toxicological data. Arecent international body concluded that rarely, if ever, would it be necessary to pursue all such evaluations exhaustively. There is reasonable agreement that a threshold should exist for regulation, or even of concern below which further evaluations on a genetically modified food product or its individual components need not be conducted. The International Food Biotechnology Council recommends flexible, voluntary procedures between food producers and processors and a regulatory agency. 

II. HISTORY OF GUIDELINES AND REGULATIONS 

The concern over the potential risks of GMOs led to the initiation of various mechanisms for the oversight of research conducted throughout the world. This oversight was in the form of guidelines, a set of principles and practices for scientists to follow, and regulation by laws applicable to certain processes or organisms used for certain purposes. The legal profession claims that this is the first case in which hypothetical or speculative risks have become the basis for regulation. Codified guidelines date back to the 1970s, when the previously described concerns were raised. This led the United States National Institutes of Health (NIH), under the Department of Health and Human Services, to develop guidelines for containment of research involving recombinant DNA molecules. The first guidelines were first published in 1976 and have been updated and republished numerous times, most recently in 2002 (66 FR 57970). A public-meeting body of peers and nonscientists was assembled as the NIH’s Recombinant DNA Advisory Committee (RAC) by the Office of Recombinant DNA Activities (ORDA) and was given the task to review all recombinant DNA experiments within the United States. Other countries soon followed suit. The RAC was to assess the risk of the experiment and recommend containment conditions under which they thought the risk would be minimized for the laboratory worker and the environment. The resulting guidelines, which are now available from the NIH Office of Biotechnology Activities (OBA) website (http://www.4.od.nih.gov/oba/), spelled out the recommended facilities and procedures for safety to individuals and to the environment. They included such specifics as the type of pipetting one should undertake, sterilization procedures, air filtration procedures, and decontamination and mitigation procedures. Within a short time, most of the microorganisms and experiments had been assigned a containment level, and the responsibility for overseeing such experiments was decentralized and delegated to local institutional biosafety committees (IBCs) and to other institutions in other countries. Many experiments to modify common laboratory strains of bacteria and yeast were judged to pose no risk and were exempted from the guidelines or any containment requirements. Research with other microorganisms, including viruses, required containment no greater than one would use for research with the microorganisms that did not involve genetic modification experiments. 

These assignments were generally consistent with the recommendations of the biomedical authorities, such as the Centers for Disease Control and Prevention in the United States. Experiments involving introduction of GMOs into the environment were first reviewed and approved by the RAC in the early 1980s. However, they were not conducted until 1986, after investigators received approval for their research from regulatory agencies. This action signaled the beginning of oversight for such experiments by centralized regulatory authorities, rather than through guidelines that describe principles and practices for confinement of the GMO to minimize risk. In the United States, regulatory oversight currently includes research conducted by any party and is under the jurisdiction of either the United States Department of Agriculture’s Animal and Plant Health Inspection Service (APHIS) or the Environmental Protection Agency (EPA). The former generally oversees plants and microorganisms that are or might be considered as plant pests, while the latter oversees research with so-called pesticidal organisms and microorganisms for other uses (industrial, manufacturing). Where there is research with microorganisms and plants, both agencies may be involved, as well as the Food and Drug Administration. More detailed descriptions of legal and jurisdictional issues can be found in publications included in the bibliography. At the present time, there is no decentralized body in any nation for oversight of field research that is comparable to the IBC for contained research (Table 44.2). The United States Department of Agriculture (USDA) published (Federal Register, Feb. 1, 1991) a draft of guidelines for conducting research under confinement in the open environment, prepared by an advisory committee of scientists. 

However, these guidelines were never implemented even though they provided generalized principles for assessing and managing the risks of microorganisms, as well as plant and animals that have been genetically modified, particularly by recombinant DNA. The principles laid out in these guidelines were sufficiently generic that they were to be applicable throughout the world. Later, in 1995, this USDA committee developed performance standards specifically for research with genetically modified fish and shellfish, since no statutory authority existed for oversight by a regulatory agency. These standards can be accessed through the Information Systems for Biotechnology website (http://www.isb.vt.edu) and give key points relevant for safety, are useful for researchers in designing containment systems and for IBCs in evaluating these designs. In many countries, the oversight of GMOs is essentially the same as for unmodified organisms, except for the contentious issue of planned introduction into the environment. In countries such as the United States and Canada, a sizable bureaucracy has built up to oversee both the research and product development. Even though the risks remain speculative, the fear of litigation and unknown hazards has served to minimize the actual number of introductions, particularly of microorganisms. Of the approximately 800 tests of plants, animals, and microorganisms introduced into the environment for research, approximately 10% have been microorganisms. Most of these microorganisms were modified to have marker genes that enabled them to be monitored in the environment. The first functional genes added to microorganisms and field-tested in the early 1990s were those encoding an insecticidal toxin from Bacillus thuringiensis added both to a pseudomonad and a coryneform bacterium. In the former case, the modified organism was killed before it was released. In the latter case, in field trials to test for insecticidal activity, plants inoculated with the GMO were successfully protected from the corn borer. But commercialization of this gene succeeded only when it was introduced into the genomes of corn (maize) and cotton.  

III. OVERSIGHT MECHANISMS 

A. Standards of practice All trained professionals learn and adhere to certain accepted procedures and practices with respect to safety and to the appropriate scientific methods for the profession. Most persons trained in microbiology and related disciplines using microorganisms are exposed to the same standards of practice that are used in training medically oriented professionals. These include safe preparation, use, and disposal of inocula and inoculated organisms, whether plants or animals, and appropriate decontamination/mitigation procedures, such as sterilization in contained facilities or incineration of animals or burial of plant material. Standards of practice for all scientists include procedures appropriate for conduct of experiments; the use of data, including statistical analysis techniques; publication ethics and standards; and sharing of biological materials after publication of results. Standards of practice in the open environment are particularly evident in agricultural and forestry research; the sites are evaluated, plots are designed to enable statistical analysis of results, criteria for evaluation of results are widely distributed and agreed upon through peer review, and results are disseminated through various publications. Practices to preclude significant risk to the environment and to mitigate possible untoward effects are routinely considered and used by researchers. B. Guidelines and directives Guidelines may be considered a statement of policy by a group having authority over that policy. Sometimes, such guidelines are also published as “points to consider.” These guidelines offer assistance to investigators and do not have legal authority, except if required by a funding or regulatory agency. Guidelines are generally considered far more flexible than are directives or regulations. Guidelines that have been adopted worldwide for contained research with GMOs are those originating from the U.S. NIH. 

The NIH RAC guidelines have been considered de facto regulations, as commercial concerns have also adopted them as standards of good manufacturing practice. Since NIH is not a regulatory agency, it can require compliance only for its grantees. Directives, particularly those issued by governments, are orders or instructions. Directives are currently an overarching method of oversight implemented by multinational groups, such as the European Union (EU). Countries are being urged to implement the directives within the next few years that would ideally harmonize oversight within the EU. However, individual countries would still have the prerogative of overseeing the details of such directives or even making them more stringent. Groups such as the United Nations, the World Health Organization (WHO), the Organization for Economic Cooperation and Development (OECD), and others also make informed statements for governments to consider as they develop their own oversight policies and mechanisms. C. Regulations Regulations are laws or rules to control or govern procedures or acts. In the case of GMOs, some countries have implemented new laws for oversight of field tests, especially in Europe. In other countries, no laws are currently applicable. In the United States, legal interpretations of current statutes have resulted in extensive oversight of research involving field trials. The laws have legal penalties for noncompliance, whether in the public or private sector. This type of oversight in the United States has resulted in an elaborate permitting, evaluation, interagency coordination and reporting system that may be viewed as time-consuming, cumbersome, and costly to some and inadequate to others. In addition to federal and national laws, other governmental entities, such as states or cities, have enacted their own regulations, compounding the difficulty of conducting field research. Confidential business information is protected in all cases, including oversight by guidelines or by competent authorities, unless such information relates to safety issues. 

IV. COMPLIANCE AND APPROVALS FOR RESEARCH IN THE UNITED STATES 

A. Contained research under the NIH guidelines The current version of the “Guidelines for Research Involving Recombinant DNA Molecules” is available from the NIH Office of Biotechnology Activities (http://www4.od.nih.gov/oba/). Since 1978, compliance with these guidelines has been mandatory for all research utilizing recombinant DNA techniques at an institution receiving federal research funding. The guidelines are promulgated only for NIH-funded research, but all other Federal agencies funding research also require compliance with these guidelines. An investigator working with or constructing a GMO must first determine whether or not the research is exempt from or subject to the guidelines. If the research is exempt, no further action is needed but it is recommended that the containment conditions in Biosafety Level 1 (see following) be followed during the course of the research. If the particular research is not exempt from the guidelines, the Biosafety Level recommended for the research will be specified therein, and certification of compliance is the responsibility of the local IBC before or at the time the research is begun (notification). Only experiments with human gene therapy, and the occasional new organism or special request for change in recommended containment level, now require review by the RAC and approval of the NIH. Appendix A of the guidelines lists organisms exempt from oversight because they naturally exchange genetic information with each other. Only bacteria are currently listed. Sublist A is the largest and includes all species in the genera Escherichia, Shigella, Salmonella, Enterobacter, Citrobacter, Erwinia, and certain species in the genera Pseudomonas, Serratia, and Yersinia. Sublist B includes eight species of Bacillus, Sublists C and D each list three species of Streptomyces. Sublists E and F include certain species of Streptococcus. If the research is not exempt, the investigator determines the recommended containment, depending on the type of experimentation and the risk level of the organism and vector system being used. The IBC certifies compliance for this level, in accordance with Section III of the guidelines. Risk levels for many microorganisms can be found in Appendix B, “Classification of Human Etiologic Agents on the Basis of Hazard” and are summarized in Table 44.3. Included are those biological agents known to infect humans, as well as selected animal agents that may pose theoretical risks if inoculated into humans. The listing in Appendix B reflects the current state of knowledge and serves as a resource document for commonly encountered agents, but is not intended to be all inclusive. The classification is based on agent risk assessment information compiled by the Centers for Disease Control and Prevention; further guidance on agents not listed in Appendix B may be obtained from the CDC. The list is to be reviewed annually by a special committee of the American Society for Microbiology, and its recommendations for changes are to be presented to the Recombinant DNAAdvisory Committee for consideration as amendments to the NIH Guidelines. Organisms that are not agents of human disease are not included in the listing in the guidelines. 

Those microbial agents associated with plant and animal diseases are subject to the regulations of APHIS. Permits from USDA are currently required for transporting any plant pathogenic agent between laboratories and specific containment conditions are specified on a case-by-case basis, often with on-site inspection by USDA personnel. In Appendix C, exemptions are explained and listed. Exempt research includes using, as the host organisms for cloning DNA, E. coli K-12, Saccharomyces cerevisiae and S. uvarum, asporogenic Bacillus subtilis and B. licheniformis, and also certain extra-chromosomal elements of gram positive organisms propagated and maintained in them. Using DNA from organisms that are Risk Group 3, Risk Group 4, or otherwise restricted is not exempt. Cloning potent vertebrate toxin genes is also not exempt, except under conditions explained in Appendix F. Appendix E lists certified cloning vectors, including plasmid, bacteriophage, and others, for each of the above host systems and for Neurospora crassa, Streptomyces, and Pseudomonas putida. The rationale for the safety of these host–vector  systems, and the process for certification of new systems for a particular degree of biological containment based on the survival of the host and the potential for transfer of the vector to another organism, is explained in Appendix I—Biological Containment. Detailed descriptions of physical facilities and practices to be followed by researchers to assure containment of organisms and safety to workers and the environment in standard laboratory research are given in Appendix G. Four Biosafety Levels, BL-1 through BL-4, represent increasing stringency and control of the environment. Their use generally corresponds to research with organisms in the Risk Group 1–4 classification of etiologic agents (Table 44.3), whether or not recombinant DNA technology is being used. 

Appendix K specifies physical containment facilities and practices for large-scale uses of recombinant DNA molecules, and Appendices P and Q specify physical and biological containment facilities and practices for experiments involving plants and animals in greenhouses and animal pens, respectively. In practice, APHIS assists the investigators and the IBCs in certifying containment in these facilities. Other appendices deal with shipment, committees, and human gene therapy. B. Research outside of containment Any research with GMOs that is to be conducted in facilities that are not specified in the NIH guidelines is considered a planned introduction into the environment. Under current policies, such research, regardless of the funding source of the researcher, is subject to regulations of either the USDA or EPA. Neither agency has a codifications similar to that of NIH for contained research. Instead, each introduction is treated as a distinct case and application must be made by the investigator to the appropriate federal agency for permission to conduct the research. This includes all research with genetically modified microorganisms, plants, animals, and vaccines. The current status of each agency and of approval processes can be obtained most readily by viewing their home pages. Each of the agencies has recently published policy statements or has issued Final Rules describing how regulations they enforce are applicable to research with GMOs. For example, EPA’s Final Rule under the Toxic Substances Control Act, published in the April 11, 1997, Federal Register (62 FR 17910-17958), is accessible at the Office of Pollution Prevention and Toxics site at http://www.epa.gov/opptintr/biotech/. 

An 80-page document entitled “Points to Consider in the Preparation of TSCA Biotechnology Submission for Microorganisms” is available from EPA. In this regulation, research and development activities are subject to TSCA if funded, in whole or in part, by a commercial entity; or if the researcher intends to obtain an immediate or eventual commercial advantage from the research. Microorganisms that are covered are those “new micoorganisms” that are intergeneric and have been formed by the deliberate combination of genetic material originally isolated from organisms of different taxonomic genera. Intergeneric microorganisms also include those containing a mobile genetic element (including plasmids, transposons, viruses) first identified in a microorganism in a genus different from the recipient microorganism. Reporting to or obtaining approval from EPA is required prior to manufacturing such organisms in containment or releasing them experimentally. However, an exemption is provided for researchers conducting smallscale field tests with the nitrogen-fixing bacteria Bradyrhizobium japonicum and Rhizobium meliloti, providing certain conditions are met. Researchers complying with the NIH Guidelines may also be granted an exemption from EPA for contained research. V. APPROPRIATENESS OF GUIDELINES AND REGULATIONS FOR RESEARCH A. Contained research The conditions described in the NIH guidelines have served as a codification of practices for conducting research with both unmodified and modified organisms within a traditional laboratory setting and for large-scale fermentations with many microorganisms to produce many products of biotechnology. There is no indication that exempting certain organisms from containment requirements, or conducting most other experiments at the lowest containment conditions, has caused any problem to individual workers or the environment. The guidelines have served both national and world interests well for over 20 years. Although mandatory only for federally funded research, private companies have embraced them and established their own IBCs. Conditions for conducting research with other organisms that require other conditions for optimum growth, such as plants, animals, and microorganisms associated with them, have also been described in the guidelines. The practices are based on those developed as standards of practice in research, and there is no evidence of adverse effects upon the environment when these practices have been followed.  Rapid advances in plant and animal biotechnology, however, have practically made the guidelines for contained research with certain genetically modified plants and animals absolete. For example, engineered soybean and corn grow extensively in farmers’ fields, yet when grown in a greenhouse for research purposes, such plants become subject to the NIH guidelines and treated as a potential threat to the environment. 

The Guidelines need to be updated and exemptions made for those plants and animals, as well as microorganisms, judged by regulatory agencies to be of no risk for commercial uses in the environment. B. Research involving planned introduction into the environment The United States raised questions about the safety of planned introductions and examined such introductions in multiple ways. In 1987, the National Academy of Sciences made major conclusions regarding risk, one of which stated that there is no evidence that unique hazards exist, either from the use of recombinant DNA techniques or from the movement of genes between unrelated organisms. Further, the risks of the introduction of GMOs carrying recombinant DNA are the same in kind as those associated with the introduction of unmodified organisms and organisms modified by other methods. The final conclusion was that assessment of risks of introducing GMOs carrying recombinant DNA into the environment should be based on the phenotype of the organism and the environment into which it is introduced, not on the method by which it was produced— product, not process. In going further with the assessment of risk, another study by the National Academy of Sciences in 1989 posed three fundamental questions to assess risk. 

(1) Are we familiar with the properties of the organism and the environment into which it may be introduced? (2) Can we confine or control the organism effectively? and (3) What are the probable effects on the environment should the introduced organisms or genetic traits persist longer than intended or spread to nontarget environments? Similar questions for focusing on risk were elaborated by the Ecological Society of America in greater detail. Questions still remain on how to scale regulatory oversight on the basis of risk. The principles espoused in the preceding types of publications have played a major role in the risk assessment policies developed by international bodies such as the European Union, the OECD, and others. Various bodies have provided for the responsible oversight of recombinant DNA research and field trials in countries in which formal oversight mechanisms are lacking. C. In principle: needs and options The objectives of a sound oversight policy are to develop a sensible, scientifically based policy that is consistent with a reasonable and accepted degree of safety (rarely absolute or “ensured” safety). Regulatory agencies also recognize procedures that do not pose an unreasonable risk to humans or the environment, i.e., one cannot be absolutely certain that no deleterious effects can occur. Oversight ideally should balance risks with expected benefits. Many issues that deal with GMOs, particularly introduction into the environment, are subject to change and remain unresolved. These include the following: 1. The scope of oversight: what organisms or parts of organisms (genetic elements and sequences) should be subject to oversight? 2. By whom and at what level (e.g., professional organization, standards of practice, institutional biosafety committees, local regulatory bodies, federal agencies, or some combination) should oversight be conducted? Should all experiments be examined at a federal or national level or can some be decided upon at a local level? Decentralization of authority to make decisions on field releases has not yet occurred, although APHIS has expedited approvals for many plants. 3. Can consistent definitions be developed? Definitions differ among agencies and countries and can lead to problems in legal interpretations. The meaning of the phrase “release or planned introduction into the environment” and even “pathogen” or “pesticide” are yet to be agreed upon. For example, the EPA has proposed a new class of plant-pesticides based on use of microbial components engineered into plants with the intent of making disease- or insect-resistant plants. This also affects whether different considerations apply to plant pathogens that are applied as beneficial biological control agents. 4. To what degree should the manner of open and peer review be part of policy making? 5. What appeal procedures, if any, should there be for scientists and others disagreeing with the oversight bodies? 

6. Decision-making: Who should decide whether approval of field-testing is needed? Is it the public, the scientists, or the courts? What role is there for common sense? Should the decision be based on risk alone or include other factors, such as socioeconomic considerations? 7. Should there be a “sunset” clause on termination of oversight of research with some organisms or certain types of experiments? There has been general agreement that a centralized database for field trials would be desirable in order to compare information, including negative results that are not always published. The USDA through its Information Systems for Biotechnology program (http://www.isb.vt.edu) and the OECD (http:// www.olis.oecd.org/biotrack.nsf/?opendatabase) through its Biotrack monitoring database have compiled a great deal of this information. Whether or not these activities serve the purpose of the scientific and commercial community and allay the concerns of the public remains to be seen. Thousands of tests worldwide have been conducted up to the present time and no unpredictable effects have been detected. However, it can be argued that such effects may occur in later years, and, hence, monitoring will be necessary to assess any problems that might arise. Another question that remains unanswered is how long monitoring should occur, compared with naturally occurring organisms. Given the different views of different countries and applicable laws, global agreements on oversight likely will not be forthcoming. However, there is reasonable general agreement on standards of practice through the scientific and professional societies of the world for conducting research. There are also areas of reasonable agreement in principle, acknowledging that the process by which a genetic modification is made is not as significant as the effects of that modification, i.e., the phenotype. The same degree of oversight is not applied to unmodified organisms and organisms modified by traditional approaches. Hence, the process of modification is still the “trigger” for oversight. Asecond area of agreement is that familiarity or knowledge of the organism and its modification are likely to be good predictors of the characteristics of the modified organism. A third is that knowledge of the ability to confine an organism or mitigate its effect, if need be, offers a reasonable indicator of expected risk and of the potential for its management. VI. CONCLUSIONS Differing perspectives remain on the safety to humans and the environment of genetically modified organisms, particularly those that have been modified by recombinant DNA techniques. The concerns are particularly high with respect to the use of microorganisms in the environment. 

Discussions are likely to continue for several more years. It is too early to predict whether or not such tests will go forward with reasonable ease, given the stringency of the requirements to conduct the tests. The scientific concerns may not warrant the expenditure of time, effort, and money to conduct field research, since risks unique to GMOs have not yet been identified. The same question could be asked about the oversight of contained research. Several potential oversight mechanisms would be commensurate with risk assessment and risk management and have been demonstrated as effective for laboratory research. These could include (1) categ orical exclusions, (2) only notification requirements, (3) review and approval by a local organization (e.g., institutional biosafety committees), (4) review and approval by a federal agency with an advisory group consisting of members familiar with the relevant research area, or (5) review and approval by an international agency, in cooperation with a member country. A reasonable policy of oversight will encourage research with GMOs, especially those modified by recombinant DNA techniques. Competing perspectives may occur in different countries, and within a country, and may not be reconciled. There is no perfect oversight mechanism for any human activity, including environmental releases for research, development, or commercial purposes. There is also the recognition that various viewpoints or perspectives cannot always be accommodated or reconciled. Thus, persons of reason and broad vision will be needed to resolve some of the contentious issues dealing with planned introduction of GMOs into the environment.