Executive Summary

CONTEXT AND BACKGROUND

Research on genetic engineering has led to the development of a substantial variety of food and agricultural products as well as pharmaceutical and human health related products derived from several types of animals, including cows, sheep, goats, swine, fish, and insects. The federal regulatory system for genetically engineered animals and their products has been subject to increasing attention and discussion among research scientists and policymakers, as well as the public. In 2001, the Food and Drug Administration’s Center for Veterinary Medicine (CVM) recognized that it was an opportune time for external scientific discussion to identify the science-based risks and concerns associated with animal biotechnology prior to any regulatory review of the food and environmental safety of these products. CVM approached the National Research Council (NRC) and requested that the NRC’s Committee on Agricultural Biotechnology, Health, and the Environment convene an ad hoc committee of experts to identify these risks and to indicate their relative importance and potential impact.

Issues related to plant biotechnology have been addressed extensively in previous NAS reports (NRC 1989, 2000, 2002a), but a focus on animals was deemed necessary because animals have a number of unique attributes. The products of animal biotechnology, such as organs, tissues, and pharmaceuticals, can be used for direct human health needs and food. Animals present unique challenges in that they are mobile as adults and often need special care.



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Animal Biotechnology: Science-Based Concerns Executive Summary CONTEXT AND BACKGROUND Research on genetic engineering has led to the development of a substantial variety of food and agricultural products as well as pharmaceutical and human health related products derived from several types of animals, including cows, sheep, goats, swine, fish, and insects. The federal regulatory system for genetically engineered animals and their products has been subject to increasing attention and discussion among research scientists and policymakers, as well as the public. In 2001, the Food and Drug Administration’s Center for Veterinary Medicine (CVM) recognized that it was an opportune time for external scientific discussion to identify the science-based risks and concerns associated with animal biotechnology prior to any regulatory review of the food and environmental safety of these products. CVM approached the National Research Council (NRC) and requested that the NRC’s Committee on Agricultural Biotechnology, Health, and the Environment convene an ad hoc committee of experts to identify these risks and to indicate their relative importance and potential impact. Issues related to plant biotechnology have been addressed extensively in previous NAS reports (NRC 1989, 2000, 2002a), but a focus on animals was deemed necessary because animals have a number of unique attributes. The products of animal biotechnology, such as organs, tissues, and pharmaceuticals, can be used for direct human health needs and food. Animals present unique challenges in that they are mobile as adults and often need special care.

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Animal Biotechnology: Science-Based Concerns Furthermore, there is greater concern for the welfare of animals than of plants, in part because animals are considered sentient organisms. The Task of the Committee The specific task set before the committee was as follows: The committee will prepare a brief consensus report to identify risk issues concerning products of animal biotechnology. Goals of the report are to (1) develop a consensus listing of risk issues in the food safety, animal safety, and environmental safety areas for various animal biotechnology product categories. These categories include, but are not limited to, gene therapy, germline modifications, knockout technologies, and cloning, (2) provide criteria for selection of those risk issues considered most important that need to be addressed or managed for the various product categories, and (3) identify and justify risk issues that were considered but not identified as important for certain product categories. The Scope of the Report Although future policy decisions regarding the use of animal biotechnology will no doubt take into consideration its potential benefits as well as its potential risks, the committee was not asked to examine the potential benefits. The primary charge to which the committee responded was “…to identify risk issues concerning products of animal biotechnology…” (from NRC charge above). Not all risks identified have the same importance. Because it was difficult to set overall priorities comparing risks among these areas, the committee attempted to prioritize concerns within each main area examined: food safety, the environment, and the welfare of the animals. In its early deliberations the committee wrestled with the use of the terms “risk” and “concern”. Throughout the report the committee attempts to consistently use both terms. Descriptions of “risk” are often stated and used in terms of the likelihood of harm or loss from a hazard. “Likelihood”, in turn, suggests a probability, which requires that the event already has been shown to occur. The committee notes that a number of the biotechnology techniques, their applications, or products discussed in this report are still under development in research laboratories, and have not entered the environment or the food system. The term “concern”, used in the title and throughout the report, is defined in the dictionary as “an uneasy state of blended interest, uncertainty, and apprehension”. This definition more accurately characterizes many of the

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Animal Biotechnology: Science-Based Concerns questions and issues surrounding animal biotechnology and its products that engaged the committee and resulted in this report. Criteria for Selecting Concerns The primary criterion for selection of concerns that emerged from committee discussions in each of these areas is based on the judgment of the immediacy and potential severity of the risk based on scientific information. The committee also categorized risks by examining a) differences between products of conventional breeding and those produced by biotechnology that might affect food safety; b) adverse effects of biotechnology on the environment in comparison to conventional techniques; c) adverse effects of biotechnology on the health and welfare of animals in comparison to conventional techniques; d) unintended genetic effects resulting from biotechnology techniques; and e) the existence of regulatory authority and the technology platform for detection and regulation of potentially hazardous biotechnology procedures. As in any analysis of risks resulting from new technologies, it almost is impossible to state that there is “no concern” associated with an aspect of that technology. The issues identified in this report were listed as science-based concerns because the committee identified one or more outcomes that reasonably can be expected to carry some risk—even if small. Some concerns were discussed for which the committee could find no scientific basis. These were identified in the text. While the sponsor of this study is a U.S. regulatory agency, all of the concerns discussed in this report are not restricted to the U.S. and are relevant wherever this technology might be considered or applied. Finally, the committee notes that this report is “a snapshot in time”; many of the concerns and risks that are discussed are typical of any new technology, and the initial methodologies that are developed are rapidly replaced with less risky and more sophisticated techniques. It is likely that a similar rate of evolution will occur with the applications of animal biotechnology as evidenced by advances in plant biotechnology. Nonetheless, the committee often was challenged by the paucity of data that might have provided stronger insights of the relative risks for the techniques and applications that were discussed; the committee notes this point where relevant throughout the report. INTRODUCTION Rapid advances in biology made since the structure of DNA was clarified provide techniques that have enhanced food production and improved human health. Advances are expected to continue and are likely to have an even greater impact in the future. However, the benefits of advanced technology rarely come

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Animal Biotechnology: Science-Based Concerns without attendant hazards. The focus of this report is to identify the science-based concerns related to modern, genetically-based animal biotechnology. Biotechnology is that set of techniques by which living creatures are altered for the benefit of humans and other animals. Animal biotechnology has a long history, beginning as far back as 8,000 years ago with the domestication and artificial selection of animals. Rapid changes in animal production had been made in previous decades through procedures such as artificial selection, vaccination to enhance health, and artificial insemination to enhance reproduction. However, modern, genetically-based, biotechnology only began in the 1960s, following the discovery of the genetic code. In this report the committee moves beyond the scientific advances to examine new genetically-based technologies. New procedures involving direct gene insertion and manipulation allow for much more rapid selection of desirable traits than older procedures. These new procedures will be described (Chapter 2) and discussed with reference to possible concerns related to the production of medical products (Chapter 3), food safety (Chapter 4), environmental issues (Chapter 5), and animal welfare (Chapter 6). The committee recognizes that the practice of biotechnology does not occur in the absence of the social, policy, and regulatory environments. Therefore, the committee concludes its report by briefly addressing these topics (Chapter 7). During the committee’s deliberations, five overarching concerns emerged. The first was whether anything theoretically could go wrong with any of the technologies. For example, is it theoretically possible that a DNA sequence from a vector used for gene transfer could escape and unintentionally become integrated into the DNA of another organism and thereby create a hazard? The second was whether the food and other products of animal biotechnology, whether genetically engineered, or from clones, are substantially different from those derived by more traditional, extant technologies. A third major concern was whether the technologies result in novel environmental hazards. The fourth concern was whether the technologies raise animal health and welfare issues. Finally, there was concern as to whether ethical and policy aspects of this emerging technology have been adequately addressed. Are the statutory tools of the various government departments and agencies involved sufficiently defined? Are the technologic expertise and capacity within agencies sufficient to cope with the new technologies should they be deemed to pose a hazard? Among the topics considered by the committee, the effects on the environment were considered to have the greatest potential for long-term impact. The taxonomic groups that present the greatest environmental concerns are aquatic organisms and insects, because their mobility poses serious containment problems, and because unlike domestic farm birds and mammals, they easily can become feral and compete with indigenous populations.

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Animal Biotechnology: Science-Based Concerns Applications of Biotechnology Techniques The art and science of producing genetically engineered animals have advanced very rapidly in the past few years. Production of genetically engineered animals for research purposes and commercial applications has been ongoing for approximately 20 years and is increasing in frequency and scale. Much of the early work on mammalian biotechnology is based on studies of the laboratory mouse and a few other common laboratory animals. Genetically engineered mice have become models of choice in many biomedical applications. Where appropriate, studies on laboratory animals such as the mouse are presented but are not the focus of this report. The focus is on concerns related to animal products used in agriculture and medicine. It now is possible to generate animals with useful novel properties for dairy, meat, or fiber production, for environmental control of waste production, and for production of useful products for biomedical purposes or other human consumption. Animals also can be produced that are nearly identical copies of animals chosen for useful traits, such as milk or meat production, high fertility, and the like. A number of methods presently employed can modify the germline of various animal species for these purposes. These technologies include: introduction of new genes by transfection, retrovirus vectors, or transposons; removal or modification of genes by direct germline manipulation; and propagation by nuclear transfer of nearly identical copies of an animal. A brief description of these technologies is provided in Chapter 2, including an indication of how aspects of the procedures might result in risks. The specific concerns for risks associated with these technologies are described in subsequent chapters in which the application of the technology is described. Several methods presently are employed for genetic engineering of various animal species. Most of these were developed originally in mouse and Drosophila models, and more recently have been extended to other domesticated animals. Modification of the germline of mammals can be achieved through: (1) direct manipulation of the fertilized egg, followed by its implantation into the uterus, (2) manipulation of the sperm used to generate the zygote, (3) manipulation of early embryonic tissue in place, (4) the use of embryonic stem (ES) cell lines which, after manipulation and selection ex vivo, then can be introduced into early embryos, some of whose germline will develop from the ES cells; and (5) manipulation of cultured somatic cells, whose nuclei then can be transferred into enucleated oocytes and thereby provide the genetic information required to produce a whole animal. The last two methods have the advantage of allowing cells containing the modification of interest to be selected prior to undertaking the expensive and lengthy process of generating animals, and greatly decreasing the number of animals used. The technology for modifying the germline of domestic animals is advancing at a very rapid pace. Indeed, some major advances were reported

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Animal Biotechnology: Science-Based Concerns during the brief period in which this report was prepared. Although many of the details of the techniques described will no doubt soon become outdated and replaced by new ones not yet considered, some general issues will remain. In particular, there will (probably) always be concerns regarding the use of unnecessary genes in constructs used for generation of engineered animals, the use of vectors with the potential to be mobilized or to otherwise contribute sequences to other organisms, and the effects of the technology on the welfare of the engineered animals themselves. Engineering of Animals for Human Health Purposes Genetic engineering has the potential to produce domestic animals that can be used for biomedical purposes (see Chapter 3). Such uses can be divided into three major categories: live cells, tissues, and organs for xenotransplantation; biopharmaceuticals for animal or human use; and raw materials for processing into other useful end products. The committee identified several areas of concern associated with these uses. The development of xenotransplantation as a part of clinical practice promises great benefits in terms of making it possible to dramatically increase supplies of replacement tissues and organs where severe shortages exist today. Recipients of xenotransplanted cells, tissues, or organs, however, will be exposed to considerable risk, including the risk of novel infectious disease. Such risk is not qualitatively different from the development of other new medical procedures and might be acceptable to the recipient because of the benefits of receiving a transplanted organ. The principal concern is that the uniquely close relationship created between xenotransplanted tissue and the host will allow novel opportunities for transmission of infectious disease (e.g., one derived from porcine endogenous retroviruses, or PERVs), and possibly creation of new disease agents in the process. PERVs are of special concern since the transplant might provide the opportunity for the virus to evolve into a pathogen with the potential for transmission to others. There is a theoretical potential for microorganisms to acquire—by recombination or transduction—genes from the vector constructs used in gene transfer. However, there is yet no uncontested example of acquisition of any gene, including drug resistance markers, by bacterial flora living in a transgenic animal. Of greater concern is the theoretical possibility of the generation of potentially pathogenic viruses by recombination between sequences of a viral vector containing a transgene and related, but nonpathogenic, viruses present in the same animal, since analogous events have been observed in the laboratory. Although animals engineered to produce useful products will not be intended for consumption by humans or other animals, there are grounds for concern that adequate controls be in place to ensure restriction on the use of

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Animal Biotechnology: Science-Based Concerns carcasses from such animals. Entry of surplus animals into the food chain poses a concern because of the possibility of people in the general population being exposed to the transgene and its expressed products. Food Safety Concerns The committee attempted to identify potential human health and food safety concerns for meat or animal products derived from animal biotechnology (see Chapter 4). The species considered include ruminants, such as beef and dairy cattle, sheep, and goats; poultry and eggs; swine; rabbits; and a wide array of finfishes and shellfishes. Specifically, the committee considered non-genetically engineered animals that are propagated by nuclear transfer or other cloning techniques, genetically engineered animals developed primarily for meat or animal products such as milk and eggs, and genetically engineered animals developed to produce pharmaceuticals and other medical or non-medical products. The nature of concern for all foods or food products is that they should be free of agents—chemical or biologic—which affect the safety of the food for the human or animal consumer. The committee notes that the primary food safety concern in the U.S. currently is microbial pathogens primarily originating from animal fecal contamination. The principles for assessing the safety of food from genetically engineered animals are qualitatively the same as for non-engineered animals, but animals genetically engineered for non-food products (e.g., pharmaceuticals) might present additional concerns relating to the nature of the products which they express. Female animals might be genetically engineered to produce non-food products in their milk or eggs. The males produced through this process or the unused females might enter the food supply. The safety of food products that are derived from animals engineered for non-food purposes might present a concern. Since expression of the transgene only has limited predictability, there is a concern that the product of the transgene might enter the animal’s general circulation. A small percentage of proteins present in food can exert effects beyond nutrition, including allergenicity, bioactivity, and toxicity. The genetic engineering of animals intended for use as food will involve the expression of new proteins in animals—hence the safety, including the potential allergenicity of the newly introduced proteins, might be a concern. Allergenicity only can be reasonably assessed when the protein is known to trigger an immune response in sensitive subjects. The committee notes that the range of immune responses (allergic reactions) triggered by these novel proteins are likely to be consistent with those triggered from known allergens. The possibility that particular novel gene products might trigger allergenicity or hypersensitivity responses in some consumers will vary with the gene product at issue, and because of the

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Animal Biotechnology: Science-Based Concerns potentially highly significant impacts in these individuals, poses a moderate level of food safety concern. A lower level of food safety concern exists for transgenically-derived bioactive molecules used to enhance a trait such as growth or disease resistance that could retain their bioactivity after consumption. The likelihood that a bioactive product poses harm will depend on the gene product, the food product, and the consumers involved. However, the committee concluded that this poses a low to moderate level of food safety concern. Products that might induce toxicity are of least concern because they likely would be identified by current food safety assessment procedures. Expression of transgenes also might result in changed nutritional attributes or improvements in the safety of food products. For example, products might include eggs that are lower in cholesterol, or meat with enhanced vitamin content or with fat content modified in quality or quantity. If these changed products were labeled in order to appeal to targeted consumers and identifiable to those who might have medical or other reasons to avoid such foods, they would be of low concern. The committee also considered potential risks associated with cloning technologies. The cloning technologies of embryo splitting and nuclear transfer using embryonic cells were introduced into dairy cattle in the 1980s, and although they have not become widely used, over 1,400 cows were registered by the Holstein association. These cloned animals were produced to obtain more offspring from genetically valuable cows and they successfully produced calves and were milked commercially. Although there are as yet no substantial analytical studies of meat and milk composition that compare the products of the donor and the cloned animals, the milk and meat of such clones have entered the food supply, and few concerns have been raised about using these types of cloned animals for food. Based on current scientific understanding, products of embryo splitting (EMS) and blastomere nuclear transfer (BNT) clones were regarded as posing a low level of food safety concern. Nevertheless, the committee believes that an evaluation of the composition of food products derived from cloned animals would be prudent to minimize any remaining food safety concerns. The products of offspring of cloned animals were regarded as posing no food safety concern because they are the result of natural matings. While it is not likely that there are changes in gene expression directly related to embryo splitting or nuclear transfer that would raise nutritional or food safety concerns, the cloning of animals from somatic cells is a more recent and rapidly changing technology. This makes it difficult to draw conclusions regarding the safety of milk, meat, or other products from individuals that are themselves somatic cell cloned individuals. The key scientific issue is whether and to what degree the genomic reprogramming that occurs when a differentiated nucleus is placed into an enucleated egg and forced to drive development results in gene expression that raises food safety concerns. There currently are no data to indicate whether abnormalities in patterns of gene

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Animal Biotechnology: Science-Based Concerns expression persist in adult clones and are associated with food safety risks; nor are there substantial analytical data comparing the composition of meat and milk products of somatic cell clones, their offspring, and conventionally bred individuals. Somatic cell cloned cattle reportedly are physiologically, immunologically, and behaviorally normal, and exhibit puberty at the expected age, with high rates of conception upon artificial insemination. The committee felt that it is difficult to identify concerns without additional supporting data using available analytic tests regarding food product composition. In summary, there is no current evidence that food products derived from adult somatic cell clones or their progeny present a food safety concern. Environmental Concerns The committee considered environmental issues to be the greatest science-based concerns associated with animal biotechnology (see Chapter 5), in large part due to the uncertainty inherent in identifying environmental problems early on and the difficulty of remediation once a problem has been identified. Any analyses of GE organisms and their potential impact on the environment needs to distinguish between organisms engineered for deliberate release and those that are engineered with the intention for confinement, but escape or inadvertently are released. The discussion in this report focuses primarily on the latter category, but the committee has a high level of concern regarding the intentional release of GE organisms into the environment. The concerns that follow primarily focus on risks resulting from GE animals entering natural environments. The release or escape of GE animals could result in a transgene spreading through reproduction with wild type individuals of the same species. The risk of horizontal gene transfer (i.e., the nonsexual transfer of genetic information between genomes by the vector) is of considerably lower probability but of high risk should it occur in some ecosystems. The likelihood of a transgenic animal becoming established in the environment is dependent on two factors: a) its ability to escape and disperse in diverse communities, and b) its fitness in that environment. Once a transgene is introduced into a population, natural selection for fitness will determine the ultimate fate of the transgene if the population is large enough to withstand the initial perturbations. Fitness in this context refers not only to the GE organism’s survival, but also to its reproductive ability, including juvenile and adult viability, age at sexual maturity, female fecundity, male fertility, and mating success (i.e., to all aspects of the organism’s phenotype that affect spread of the transgene). The GE organism eventually might replace its relative or become established in that community if it is more fit than its wild relatives in that environment. If it is less fit, the engineered trait eventually will be removed from the receiving population. If the fitness of transgenic and nontransgenic

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Animal Biotechnology: Science-Based Concerns individuals is similar, the likely outcome is persistence of both transgenic and nontransgenic genotypes. Transgenic organisms can be produced with changes in physiologic traits far beyond what is possible with naturally occurring mutations. For example, natural dwarfism or gigantism in mammals and poultry has effects which are limited approximately to four times the size of that of normal animals, while mean alteration in size-at-age of four to eleven times has been reported in GE salmonids. Such introduced GE animals might upset the predator–prey balance in an otherwise stable environment. The ability of certain GE organisms to escape, disperse, and to become feral in diverse communities is of high concern. Animals that become feral easily, are highly mobile, and have a history of causing extensive community damage are of greatest concern. They include insects, shellfish, fish, and mice and rats. Mice and rats—while known to become feral easily—are not likely to escape since these transgenically altered rodents are maintained under close confinement in laboratory colonies. Animals that become feral easily, have moderate mobility, and have caused extensive damage to ecological communities raise the next most serious concerns; these include cats, pigs, and goats. Animals that are less mobile, but have been known to become feral with minimal community impact, pose the next level of concern; these include dogs, horses, and rabbits. Less mobile and highly domesticated animals that do not become feral easily, such as domestic chickens, cattle, and sheep, present the least concern, along with transgenic animals produced for human medical benefits such as xenotransplantation, which have little chance of becoming established in the environment. Colonization by GE animals might result in local displacement of a conspecific population, which could have a disruptive effect on other species in a community. For example, the survival of predatory species that depend on a prey species eliminated by a GE organism that had become feral could be threatened. The impacts of transitory and long-term environmental harms are dependent on the stability and resilience of the receiving community. A community is deemed stable if ecologic structure and function return to the initial equilibrium following perturbation from it. These definitions allow a prioritization of potential harms from GE animals based in part on the receiving community’s stability and resilience. Those that are most stable will sustain the least harm with the greatest harm occurring to unstable communities. It might be impossible to limit which communities a GE organism will gain access to; thus, if any of these communities are fragile, the concern that the GE organism will cause environmental harm will be high. Prioritizing environmental concerns always will be on a case-by-case basis because of the uniqueness of each GE construct, founder, and receiving ecosystem. However, based on the principles of risk, the committee attempted to prioritize those concerns. Three variables were considered: (1) effect of the transgene on fitness of the animal in the environment after the escape or release

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Animal Biotechnology: Science-Based Concerns of a GE animal, (2) the species transformed, and (3) stability and resiliency of receiving community. Inserting a transgene that increases fitness of a highly mobile species that becomes feral easily raises the greatest level of concern (e.g., a gene that increases salt tolerance in catfish). A transgene that increases fitness of a moderately mobile species that can become feral (e.g., the phytase gene in the pig) raises the next level of concern. Inserting a transgene that does not increase fitness in a low mobility species, which does not become feral easily (e.g. a gene for a protein of industrial value in cows), raises the least concern. One case of immediate concern is the release of transgenic fish and shellfish. Production of some GE fish and shellfish might result in environmental benefits when compared to conventional aquacultural practices. For example, production of fish expressing a phytase transgene might allow use of less fishmeal in feeds while decreasing phosphorus in waste products from aquaculture operations. However, transgenic fish and shellfish might pose environmental hazards. Cultivated salmon have escaped into the wild from fish farms and these salmon already pose ecologic and genetic risks to native salmon stocks. In studies of transgenic salmon under laboratory conditions, some of these transgenic lines grew four to six times faster than nontransgenic salmon, with a 20 percent increase in feed conversion efficiency. In order to support their rapid growth, GH transgenic salmon consumed food at a more rapid rate than control salmon. In addition, their oxygen uptake is about 60 percent more than that of controls during routine activity and during sustained swimming. These findings suggest that the GE Atlantic salmon might show increased fitness, but gaps still exist in our understanding of the key net fitness parameters to allow an assessment of the impact of their entry into wild populations. Possible environmental hazard pathways posed by escape or stocking of transgenic shellfish into natural ecosystems have not yet been thoroughly considered. Information is not yet available to assess ecologic risk posed by production of these organisms, but it is clear that confinement of these aquatic organisms will be difficult and they are likely to escape. Animal Health and Welfare Concerns The effects of genetic manipulation on animal health and welfare are of significant public concern. Animal welfare has proven difficult to assess because it is so multifaceted and involves professional and ethical judgments. The committee considered the following facets of animal welfare in discussing transgenic and cloning technologies: their potential to cause pain, distress (both physical and psychologic), behavioral abnormality, physiologic abnormality, and/or health problems; and, conversely, their potential to alleviate or to reduce

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Animal Biotechnology: Science-Based Concerns these problems. Both the effects of the technologies themselves and their likely ramifications are addressed. The applications of biotechnology can have adverse effects on the welfare of animals. For example, ruminants produced by in vitro culture or nuclear cell transfer methods—whether or not they carry a transgene—tend to have higher birth weights and longer gestation lengths than calves or lambs produced by artificial insemination. Large offspring syndrome (LOS) is much more frequent in cattle produced by in vitro techniques. Because of LOS, difficult calvings can be a problem and might require special husbandry or veterinary procedures such as caesarian sections. Additional health and welfare problems requiring special attention include respiratory distress, lack of suckling reflex, and a variety of pathologic conditions. Some of the techniques in use are extremely inefficient in the production of transgenic animals. Efficiencies of production range from 0 to 4 percent in pigs, cattle, sheep, and goats, with about 80 to 90 percent of the mortality occurring during early development. Of the transgenic animals that survive, many do not express the inserted gene properly, often resulting in anatomical, physiologic, or behavioral abnormalities. The variability and subtly of response makes assessment difficult. Unexpected phenotypic effects—especially on behavioral traits of genetically altered animals—might occur. Work with knockout and cloned mice has demonstrated, in some instances, elevated levels of aggression and impairment of learning and motor tasks, suggesting additional studies of cloned livestock are warranted. Although there generally are fewer potential animal welfare concerns associated with the production of transgenic farm animals for biomedical purposes than for agricultural purposes, some concerns remain. A common method to produce pharmaceuticals in animal tissues or fluids is to produce transgenic cattle or goats that express the protein of interest in mammary tissue. The recombinant protein then is secreted in milk when the female lactates. Those proteins either might be expressed in non-mammary tissues, or might “leak” out of the mammary gland into the circulation. If the protein is biologically active in the species in which it is produced, it could cause pathologies and other severe systemic effects. An important animal welfare concern related to xenotransplantation is the management and housing of pigs intended for use as organ source animals. The pigs are maintained in sterile, often isolated environments to minimize transmission of disease to human recipients, but this environment might lead to abnormal behavioral development.

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Animal Biotechnology: Science-Based Concerns Policy and Institutional Concerns While policy issues might be considered beyond the scope of this study, the committee took account of their existence in identifying science-based concerns about animal biotechnology. The policy framework ultimately determines the scientific questions that the regulatory process must address, and the manner in which it must address them. Although the committee’s charge is limited to addressing science-based concerns, the committee notes that (1) socially, politically, and ethically determined factors influence both the nature of scientific research and the interpretation of data, (2) how one addresses scientific uncertainty or the importance of various concerns that result from introduction of a proposed technology is influenced by political and ethical considerations, and (3) technologies often have impacts on social, political, economic, religious, and spiritual conditions or values which, in turn, might impact health and the environment. New technologies, such as biotechnology, often are characterized by a variety of uncertainties resulting in unexpected outcomes. Uncertainties can be placed in three categories—statistical, model, and fundamental. These categories of uncertainty generally correspond to technical, methodologic, and epistemologic considerations respectively, which also can be described as inexactness, unreliability, and insufficient knowledge. Regardless of the category, uncertainty also relates to the difficulty of placing potential impacts into the policy context within which proposed biotechnologies will be addressed. Biotechnologic techniques can both impact upon, or be impacted by social, political, and ethical factors. Concern exists that certain biotechnologies can favor a particular kind of agricultural system that might induce unexpected and unwelcome changes for certain segments of the agricultural community such as small-scale farmers, or for animals or the environment. Alternatively, those changes might result in increased efficiency in food production for a growing population, improvements in animal welfare, or better protection of the environment. The socioeconomic impacts of animal biotechnologies might be manifest at the level of the individual, family, community, or corporation. For example, religious or cultural groups might have dietary norms or rules that might be violated by genetic engineering of animals used for food. Regulatory decisions and enforcement are difficult in the absence of an ethical framework underlying regulatory decisions related to animal biotechnologies or a regulatory framework for addressing unique problems and characteristics associated with animal biotechnologies. Ethical considerations range broadly, generally are normative, and cannot be resolved scientifically. Some people, irrespective of the application of the technology, consider genetic engineering of animals fundamentally unethical. Others, however, hold that the ethical significance of animal biotechnologies must derive from the risks and

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Animal Biotechnology: Science-Based Concerns benefits to people, the animals, and/or the environment. Yet another view focuses on the right of humans to know what they are eating or how their food or pharmaceuticals are being produced, and therefore labeling becomes an issue to be addressed. The current regulatory framework might not be adequate to address unique problems and characteristics associated with animal biotechnology. The responsibilities of federal agencies for regulating animal biotechnology are unclear. How each agency will deal with scientific uncertainty remains to be seen. The committee notes a particular concern about the lack of any established regulatory framework for the oversight of scientific research and the commercial application of biotechnology to arthropods. In addition to the potential lack of clarity about regulatory responsibilities and data collection requirements, the committee also notes a concern about the legal and technical capacity of the agencies to address potential hazards, particularly in the environmental area. The committee considers it appropriate to identify some of the potential social implications of animal biotechnology. The committee is concerned that the regulatory agencies are not clear with regard to the scope and limitation of their mandates to address such matters that do not directly affect health and the environment. Specifically, there is a need for clarity about whether the regulatory agencies consider it within their charge to consider only the direct health and environmental impacts of biotechnology, or also the social or economic impacts of a technology that, in turn, might have an adverse health or environmental impact.