Animal Biotechnology: Science Based Concerns
National Research Council Aug02
5 Environmental Concerns
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The committee considered the greatest science-based concerns associated with animal biotechnology as those related to the environment, in large part due to the uncertainty inherent in identifying and environmental problems early on and the difficulty of remediation once a problem has been identified. The intent of this chapter is to develop a set of general guidelines to address concerns, based on first principles of risk analysis, that are general and their application and not limited to currently developed biotechnology. Where possible, examples from the scientific literature are used, while into others' hypothetical examples are used to illustrate a future concern. A committee explicitly recognizes that along with potential rests, there might be many benefits of biotechnology for alleviating human suffering and for addressing problems with growing food demands. The ultimate decision of when or where to use biotechnology will be evaluated not only in relation to these benefits, but also to those of alternate technologies. However, the charge to this committee was not to examine the benefits of biotechnology, or of the technical alternatives, but rather to "develop a consensus listing of risk issues in the food safety, animal safety, and environmental safety areas for various animal biotechnology product categories." Asked such, this chapter will seem to emphasize environmental concerns and risks posed by animal biotechnology however, the charge to the committee was also "to provide criteria for selection of those risk issues considered most important that need to be addressed or managed for the various product categories." By using definitions of risk and hazard established in previous NRC reports, the committee attempted to rank those concerns. In these
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two ways, the committee attempted to put those concerns and perspective and to provide a balanced viewpoint.
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 released. The discussion in this report focuses primarily on the latter category, of the committee has a high-level of concerns regarding the intentional release of GE organisms into the environment. This chapter focuses primarily on risks as a result of genetically engineered (GE) animals entering natural environments and transgene spread through vertical gene transmission (the sexual transfer of genetic information between genomes) followed by natural selection. The risk of horizontal gene transfer (the nonsexual transfer of genetic information between genomes, Kidwell, 1993) was discussed primarily in chapter 2.
This chapter, therefore, is organized into a discussion of: (1) general principles of risk analysis, (2) general aspects of the organism, transgene, or transgene function that can be used a priori to prioritize GE animals for level of confinement for concern, (3) risks posed by key classes of GE animals, and finally (4) the need for further research directed at improving our understanding of hazards and estimating risks posed by genetically engineered animals.
GENERAL PRINCIPLES OF RISK ANALYSIS
Consideration of environmental concerns posed by GE animals must be based on an understanding of key concepts underlying the science and practice of ecologic risk assessment. A seminal review of risk assessment methodology (NRC, 1983) states that "regulatory actions are based on two distinct elements, risk assessment, and risk management. Risk assessment is the use of the factual basis to define the health effects of exposure of individuals or populations to hazardous material and situations." Risk management is "the process of weighing policy alternatives and selecting the most appropriate regulatory action, integrating the results of risk assessment with engineering data and with social, economic, and political concerns to reach a decision." Clearly, risk management's beyond the scope of task of this committee, while elements of risk assessment are needed to prioritize concerns. [Italics] Understanding Risk; Informing Decisions in a Democratic Society [italics] (NRC, 1996) updated the prior study and provided to important definitions: [italics] Hazard [italics]: an act or phenomenon that has the potential to produce harm, and [italics] Risk [italics]: the likelihood of harm resulting from exposure to the hazard. While the 1983 NRC study details the steps in risk assessment as containing some or all of the following steps: (1) hazard identification, (2) dose-response assessment, (3) exposure assessment, and (4) risks characterization, the steps do not apply well to GE organisms in the
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environment because dose-response and exposure assessments are intended to apply to substances that can be quantified industry amounts and that cannot reproduce themselves. Adapting both studies (NRC, 1983; 1986) to the current problem, the committee used the definitions of risk and hazard to develop a set of working steps. Risk, as defined, is a probability that can be quantified and substituted into an equation, thereby providing a method to prioritize concerns. However, exacted probabilities of risk might be difficult or impossible to determine for all categories of possible harm. Indeed, all possible harm's might not be known or noble a priori, particularly with respect to secondary effects (see chapter 7 for discussion of unknown harms). On the other hand, based on current knowledge of population genetics, receiving ecologic communities, and experience with domesticated species, it is possible to classify GE organisms into categories of high to low probabilities of spread into the environment. Risk of possible harms (known and unknown) can then be inferred from the latter (i.e., risk of harm to a healthy natural population is low, but not zero, for reasons discussed below) if the transgene is purged from the population. This method to is used only to prioritize the likelihood of a GE organisms to destabilize a natural community; this approach does not address possible harms to humans, direct or indirect (direct risks to human health are examined in chapter 4). Because risk is a joint result of exposure and harm, it is the product of two probabilities: the probability of exposure, [italics] P (E), and the conditional probability of harm given exposure has occurred, [italics] P(H|E) [italics], that is, Risk, [italics]R=P(E) x P(H|E). In this context, the steps in risk analysis are: (1) to identify the potential harms regardless of likelihood, (2) to identify the potential hazards that might produce those harms, (3) to define what exposure means for a GE organisms and the likelihood of exposure, [italics]P(E), (4) to quantify the likelihood of harm given that exposure has occurred, [italics]P(H|E)[italics], and (5) to multiply the resulting probabilities to prioritize risk. Because all potential harms might not be known or cannot be known (see chapter 7), it will be necessary to update this procedure continually as knowledge of accumulates, using an adaptive management approach (NRC, 1996; Kapuscinski, 2001). The following sections are organized according to those steps.
PRIORITIZING GE ANIMALS FOR LEVEL OF ENVIRONMENTAL CONCERNS
Identifying Potential Harms
And and ecologic context, harm is defined as gene pool, species, or community perturbation resulting in negative impacts to community stability.
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These include displacement or reduction in number of species that exist in a community or numbers within each species. This definition is all-encompassing and broad, but can be further refined once a particular GE organisms is identified and the environment into which it might escape or be released is known.
Identifying the Potential Hazards That Might Produce Those Harms
The hazard is the GE organisms itself because it is the agent that might cause negative impacts to community stability. These negative impacts might be either direct, for example, through direct competition for a limited food or resources, or indirect, by altering other biotic factors utilized or needed by the ecologic community (Scientists' Working Group on Biosafety, 1998).
Defining What Exposure Means for a GE Organisms and the Likelihood of Exposure: [italics]P(E) [italics]
Exposure is a threshold phenomenon because an initial escape or release of a GE organisms might not have a measurable effect on the community. Further, the organisms might not be able to establish itself in the community, and might be lost rapidly due to natural selection. Thus, provided the natural population is not already endangered, for a GE organism to prove a hazard, exposure must be more than just release or escape of the organism into a community. The GE organism must spread into the community. The committee therefore, defines exposure as the establishment of a GE organism in the community and and ecologic context, a better word for "exposure" would be "establishment" and in the following text, establishment will be substituted for exposure. For risk assessment, a critical factor is the likelihood the GE organism will become established in a community, which is [italics]P(E). This conclusion does not mean that risk cannot occur without establishment. As discussed later, if they transgene causes local species extinctions, either because the population size is critical, or produces a Trojan gene in fact, considerable harm might result. However, these are special cases that can be addressed as such.
The likelihood of establishment is dependent on three factors: fitness, ability to escape and disburse in diverse communities (Scientists' Working Group on Biosafety, 1998), who and qualities of the receiving community. Once a transgene is introduced into a community, whether by vertical or horizontal gene transfer, natural selection for fitness will determine the ultimate fate of the transgene if the population is large enough to withstand the initial perturbations (Muir and Howard, 2001]. Fitness is quantified relative to that of other individuals and the population and is simply the genetic contribution by an
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individual's descendents of future generations of a population (Ricklefs, 1990). Fitness in this context refers not to only to its survival component, but also its reproductive component, that is, to [italics] all [italics] of the organism's phenotype that affect spread of the transgene. Muir and Howard (2001; 2002a,b) reduced these aspects to 6 net fitness components: juvenile and adult viability, age at sexual maturity, female fecundity, male fertility, and mating success. The model is based on the assumption that natural selection acting through these components will determine the ultimate fate of the transgene. This last component, mating success, is often overlooked because it generally is not a factor in artificial breeding programs, but it is often the strongest factor driving natural selection (Hoekstra et al., 2001). For example, increased adult size and most species of fish is positively correlated with mating success (as, for example, in many salmonid species: Groot and Margolis, 1991; Jarvi, 1990; Jones, 1959; Schroder, 1982). With Japanese medaka [italics] Oryzias latipes [italics], males 25 percent above average in size realized a 400 percent increase in mating success (Howard et al., 1998. Such increases in mating success can result in spread of a transgene even if the transgene reduces survival rate (Muir and Howard, 1999).
From a population genetics perspective, if the fitness of a GE organism is greater than that of its wild relatives and that environment, then the GE organism eventually will replace its relative or become established in that community. If it is less, the engineered trade eventually will be removed from the receiving population. If the fitness of transgenic and non transgenic individuals is similar, the likely outcome is persistence of both transgenic and non transgenic genotypes (Muir and Howard, 2001; Hedrick, 2001). The effect of the genetic engineering on fitness can be determined either prospectively or retrospectively. Appendix A of the Scientists' Working Group on Biosafety (1998) provides a perspective assessment of factors that would affect and organism's ability to become established in the environment, while Muir and Howard (2001a,b; 2002) provide a retrospective method based on measurement of net fitness components.
From a perspective you, the key factor affecting fitness is transgene functionality within the GE organism. Functionality can be divided into four broad categories: those that increased adaptability of the GE organism to a wider range of environmental conditions, usually through new functionality; those that alter existing traits for improved performance within standard production agriculture; those that produce new or novel products; and those that produce animals or animal products for human medical benefit.
Increased Adaptability
A transgene might increased adaptation to a wider range of environmental conditions, for example, by increasing threes tolerance (Fletcher et al., 1992) or removing a limiting growth factor, perhaps allowing the organism to synthesize
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an amino acid that was previously limiting, or to digest previously indigestible carbon sources such as cellulose, or to obtain phosphorus from previously inaccessible sources, such as phytic acid (Golovan et al., 2001a,b). Finally, a transgene can be used to increased adaptability by increasing disease resistance, such as disabling retroviruses, producing coat proteins to activate the immune system against certain viruses or binding to receptor molecules by which viruses and yourselves, or producing antibiotics to protect against bacterial infections (Jia et al., 2000).
Such adaptations also could allow the GE animals to invade or persist in ecosystems where they otherwise could not, such as salt or brackish water, while maintaining populations in communities where it normally occurs, such as freshwater lakes and streams. Such a combination could result in a sustained invasion of the new community by the species' original or introduced range until complete colonization results. Hence, a transgene that increases fitness or adaptation increases the probability of establishment and results and the highest level of concern for establishment.
Enhanced Existing Traits
Production traits and domesticated farm animals include, for example, growth rate, feed efficiency, a number, milk yield, litter size, fiber yield (e.g., wool). Many transgenic animals have been designed to express an enhanced growth rate (Hammer et al., 1985; Pursel et al., 1987; Devlin et al., 1994; 1995a; 1995b; Rahman and McLean, 1999). Experience with conventional selection for traits and domestic farm animals suggests that such modifications do not increase the fitness of animals in natural environments, for example, because of physiologic imbalances or growth demands in the excess of the food available in natural environments.
Transgenic animals designed to meet these objectives might be even less fit than those developed using selective breeding. Selective breeding is based on manipulation of polygenic inheritance, in which the resulting phenotype results from the cumulative effect of changes in allele frequencies of many genes with a distribution of effects from small to large (Lynch and Walsh, 1998) and which are selected upon over multiple generations. In contrast, transgenesis involves one or few genes with relatively large affects, introduced in a single founder generation. In the selective breeding process, the correlated traits needed to support enhanced growth and reproduction, such as skeletal and vascular systems, also are selected for indirectly; this is not always the case with Transgenics (Farrell et al., 1997; Muir and Howard, 2001; 2002b; see chapter six regarding animal well-being concerns). Because of these homeostatic imbalances, transgenic organisms expressing enhanced production traits might exhibit a greater reduction in fitness than selectively bred domesticated animals.
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Experience with GE animals developed today tends to support this prediction, for example, swine transgenic for growth hormone displayed a number of fitness problems (see chapter 4). Similarly, fish transgenic for growth hormone have a reduced juvenile viability (Dunham, 1994; 1996; Muir and Howard, 2001; Devlin et al., 2001). Thus, taking these arguments collectively, GE organisms developed for production traits would seem to have a low probability of establishment.
However, environmental concerns posed by animals expressing these types of transgenes not be dismissed as non-concerns. First, it is possible for GE organisms to overcome viability disadvantages if other fitness components are enhanced, such as mating success, fecundity, or age at sexual maturity (Muir and Howard, 2002b). Second, the introgression of genes decreasing fitness poses a near-term demographic risk to a small receiving population. That is, small populations might not remain liable on till the transgene is selected out, which poses a harm if a threatened or endangered or otherwise valued population is at issue. Finally, the magnitude of phenotypic change that is possible with transgenesis can exceed that of conventional breeding. At the heart of the issue is how species evolve. Domestication is widely believed to be the consequence of small increments in trade value, and the ecologic niche of the animal is not changed if the phenotype of a mutant individual is only slightly changed. Expression of transgenes, however, can pose mecca-mutations that instantaneously and subsequently change the phenotype of the transgenic organism. In terms of evolutionary theory, such a mecca-mutations could give rise to a switch from the currently-occupied adaptive peak to and other peak on the adaptive topography of Sewall Wright's (1969; 1982) shifting balance theory. If such a shift occurs, the GE organism might be able to establish itself in a community or to shift its niche within the current community. And illustrative example of a natural major mutation causing a shift and evolutionary trajectory was a major mutation for mimicry that occurred in the evolution of butterflies (Lande, 1983). The primary predator avoidance attributes and butterflies are to remain concealed (crypsis) or to closely resemble another species that is distasteful to birds (mimicry). Intermediate individuals that are neither effectively cryptic nor could mimics are likely to be eaten, thus selection acting by small steps cannot account for such evolutionary adaptations. Therefore, natural mutations followed by selection can and do result in new evolutionary lines. Similarly, a growth hormone transgene reducing up to 17.3-fold greater difference in weight by 14 months of age (Devlin et al., 2001) could act as a mega-mutation that, for example, could change in organism from being a prey of one species to being a predator upon it.
Transgenic organisms can be produced with changes in physiologic traits far beyond what is possible with naturally occurring mutations such as dwarfism or gigantism in mammals and poultry. These naturally occurring mutations are limited to approximate four times the size of a normal organism, while, for
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example, transgenic salmonids have alteration means reported of 4 to 11 times (e.g., Devlin et al., 1994; 2001). Naturally occurring mutations have been described as "hopeful monsters" because of their usual deleterious effect on the phenotype. With Transgenics, production of transgene constructs is not a random process, what is designed with the objective of increasing performance or functionality. Genetic variability results from natural mutation, but natural mutations primarily are the result of single base-pair or other minor changes rather than changes or additions of entire functional genes as is possible with transgene insertion.
Establishment of domesticated animals in the environment as a result of the adaptive peak shifts, either through conventional or transgenic technology, has not been documented, but presents a theoretical mechanism by which such organisms engineered for production traits might become established in communities. Hence, the concern for this mode of transgene establishment in natural populations is moderate to low based on currently available evidence. However, any such establishment of a transgene in the environment would pose a high level of concern.
Production of New or Novel Products
Milk, egg white, blood, urine, seminal plasma and silkworm cocoons from transgenic animals are candidates to produce recombinant proteins at an industrial scale (Houdebine, 2002) or milk (Wright to et al., 1991), or fibers such as spider silk and milk (Kaplan, 2002). Such alterations and physiology will result in additional energy demands without conferring any obvious fitness advantage. Such transgenic animals might have little chance of establishment in the environment (excepting silkworms), and hence raise the lowest levels of ecologic concern. However, other indirect aspects of expressing such products are still a concern, and will be discussed in a following section.
Production of Animals or Animal Products for Human Health and Medical Benefits
There are three categories of animals that fit this category: alteration of pets to reduce allergens, alteration of animals for xenotransplantation purposes (Tearle et al., 1996; Lai et al., 2002), and alteration of insects to control spread of disease (Braig and Yan, 2002; Spielman et al., 2002). the first two categories most likely will either not changed fitness or will result in a decline in fitness and, like the previous category, raise the lowest levels of concern with respect to the animal' s ability to establish itself in natural communities. The last
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category—alteration of mosquitoes not to carry parasites—has unknown effects on fitness of the mosquito. Some reports indicate that the parasite load reduces the fitness of mosquitoes carrying it (Braig and Yan, 2002; Spielman et al., 2002), suggesting that transgenes decreasing parasite load might increase fitness. In addition, driver mechanisms (meiotic drive and incompatibility systems) are being proposed as a way of establishing the GE mosquito in the community. Because establishment is the objective and is critical for biocontrol using these techniques, this category of genetic engineering raises the highest probability for establishment.
Ability to Escape, Disburse, and Become Feral
The other aspect of evaluating the probability of establishment of a GE animal in a community is the organism' s ability to escape, disburse, and become feral and diverse ecologic communities. This mainly as a function of the animal being transformed, though the receiving ecosystem also might be a factor (USDA, 1995).
The dispersal ability of GE animals is not known, but reasonably can be assessed from knowledge of similar domesticated species (Scientists' Working Group on Biosafety, 1998). Table 5-1 summarizes these characteristics for commonly farmed and laboratory species. Australia and New Zealand have dramatically affected communities, particularly by the rabbit, and others, while in the U.S. and Europe, pigs, cats mice and rats, and fish and shellfish have produced the greatest disruptions.
The more domesticated as species, the less likely it is to survive in natural environments. Highly domesticated species such as poultry or dairy cattle are not well adapted to natural conditions and might not be able to survive and reproduce any natural setting. However, if wild or feral populations exist locally, the escape transgenic organisms can breed with those and spread the transgene into populations that otherwise are well adapted to the local environment. If the GE animal is released into an area where a native wild or feral populations exists, makes might be readily available, and the transgene and spread by mating. Even in areas in which the GE species does not exist, it might breed with members of a closely related species which is reproductively compatible (e.g., transgenic rainbow trout [italics] Oncorhynchus mykiss [italics] with native cutthroat trout [italics] O. clarki [italics]; see reviews of hybridization, e.g., Dangel, 1973; Schultz, 1981; Campton, 1987).
In the North America agricultural system, certain agricultural animals are well confined. However, cattle and cheap Rohm open ranges in the West, feral pigs exist in Arkansas, for a, Florida, and California, and range chickens and turkeys exist in many states. Extensive damage has been reported for feral insects imported to improve agriculture production, such as Gypsy moth (Lepidoptera: Lymantriidae), a species imported for use as a silkworm (Gerardi and Grimm, 1979), and the Africanized honeybee ([italics] Apis mellifera scutellata [italics]), a species imported to improve foraging ability of the European honeybees (Caron, 2002).
TABLE 5-1. Factors Contributing to Level of Concern for Species Transformed
Factor Contributing to Concern number ability to likelihood community of become of escape disruptions level of animal citations1 feral2 captivity3 mobility4 reported5 concern6 insects6 1804 high high high many high fish7 186 high high high many mice/rats 53 high high high many 160 high high moderate many pig 155 high moderate low many goat 88 high moderate moderate some hourse 93 high moderate high few rabbit 8 high moderate moderate few mink 16 high high moderate none dog 11 moderate moderate moderate few chicken 11 low moderate moderate none cheap 27 low low low few cattle 16 low low low none low 1 number of scientific papers dealing with feral animals of the species. 2 based on number of feral populations reported. 3 based on the ability of organism to invade confinement measures by flying, digging, swimming, or jumping ability for any of the life stages. 4 relative dispersal distance by walking, running, flying, swimming, or hitchhiking in trucks, trains, boats, etc. 5 based on worldwide citations reporting community damage and extent of damage. 6 a ranking based on the four contributing factors. 7 did not include shellfish, some of which (such as zebra muscle Asiatic clam) have proven highly invasive. 18 limited to Gypsy moth and Africanized honeybee.
The committee concludes that animals that become feral easily, are highly mobile, and have caused extensive community damage, are the greatest concern. These include mice and rats, fish and shellfish, and insects. Animals that become feral easily, have moderate mobility, and have caused extensive damage to ecologic communities are next. These include cats, pigs, and goats. Animals that are less mobile, but have been known to become feral with moderate community impact, pose the next level of concern. These include dogs, courses, and rabbits. Finally, less mobile and highly domesticated animals that do not
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become feral easily, such as domestic chickens, cattle and sheep, present the least concern.
The Likelihood of Harm Given That Exposure Has Occurred: [italics]P(H|E) [italics]
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, by releasing competing species from resource competition or praise species from predation (Kapuscinski and Hallerman, 1990); additionally, the survival of predatory species that depend on the eliminated species could be threatened. This concern is best exemplified by the classic experiment of Paine (1996) in the Rocky intertidal zone. By experimentally removing the top predator, a starfish—[italics] Piaster [italics] sp., the number of species in the plot was reduced from 15 to 8. Another example is the impact of pigs on plant species diversity reported by Hone (2002). Round rooting of feral pigs in Namadgi National Park, Australia, decreased the number of plant species, which declined to zero with intensive pig rooting. Thus, expansion of a species into new ecosystems can have a cascading impact on other species in the community with unpredictable harms (see chapter 7 for further discussion).
Transgenes that increase fitness or adaptability also could have negative ecologic impacts if they spread into pest populations. For example, phosphorus is the first limiting nutrient in many environments and critical for growth of all life forms securing this vital nutrient from the environment is critical for population growth. Phosphorus is contained within all seeds in the form of phytic acid. However, phytic acid is not digestible by non-ruminants (Golovan et al., 2001a). The addition of a phytase gene would allow GE non-ruminants such as pigs (Golovan et al., 2001b) or mice (Golovan et al., 2001a) to obtain needed phosphorus from seeds and grains, which would increase their ability to grow and produce more offspring, thereby resulting in a greater pest potential for feral pigs (Hone, 2002; Vtorov, 1993) and mice (King et al., 1996; Krebs et al., 1995).
Pleiotropic effects of transgenes that have antagonistic effects on different net fitness components can result in unexpected harms, ranging up to local extinction of the species into which the transgenes is introduced (Muir and Howard, 1999; Hedrick, 2000). For example, the transgenes might increase one component of fitness, such as juvenile or adult viability, but reduced another, such as fertility (Kempthorne and Pollak, 1970; Hedrick, 2000; Muir and Howard, 2002b). The effect of the transgenes in this category parallels the use of sterile mates to eradicate screwworms, except that in the case of sterile males they must be released continually to achieve control; a transgenes that increase is the viability component of fitness will spread on its own, while the reduced fertility brings about extinction, albeit over a longer time period. Similarly, if a
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transgene enhances mating success while reducing juvenile viability, less fit individuals obtain the majority of the matings, while the resulting transgenic offspring cannot survive as well as nontransgenic genotypes. The result is a gradual spiraling down of population size until eventually both while-type and transgenic genotypes become locally extinct (Muir and Howard, 1999; Hendrick, 2000). This is an example of harm as result of a transgene bedspreads into the receiving community but fails to become established because the population becomes extinct. Results of Devlin et al. (2001) suggest that transgenic fish might have this potential. They showed that growth hormone (GH)-transgenic rainbow trout were both larger at sexual maturity and lower and viability than while-type sibs. Although the mating success of transgenic males relative to while-type males is presently unknown in rainbow trout, large body size is known to enhance male mating success in many salmonid species (Groot and Margolis, 1991; Jarvi, 1959; Schroder, 1982).
The conclusion that natural selection will determine the ultimate fate of a transgene assumes that population size is of the native and/or competing populations are large enough to be able to rebound from a temporary inflow of possibly maladapted genes or competitors, thereby allowing time for natural selection to operate. Escape of domesticated animals, whether or not transgenic, into wild or feral populations also might adversely affect while-type populations by introducing alleles or allele combinations that are poorly adapted to natural environments (Lynch and O'Hely, 2001).
Released animals also could introduce diseases or compete with native species for limited resources, causing population declines. If introduced males are sterile, but still made with while females, reproductive efforts of those females are wasted, also contributing to population decline. In these regards, harms from escaped transgenic organisms race many of the same concerns as newly introduced species (Regal, 1986; Tiedje et al., 1989.
Finally, use of genetically engineered animals can harm the environment, indirectly by changing demand for feed, number of animals use, or amount of resulting waste, and by the effects of wastes containing novel gene products on microbial and insect ecologies. Most biopharmed animals will be highly valuable and most likely will be carefully confined, but there is some likelihood that the gene products themselves would pose environmental harms. Should the milk from transgenic livestock be spilled, most novel proteins would be degraded rapidly along with other milk proteins. However, not all novel proteins will be degraded quickly, such as spider silk—a proteins that could be expressed in milk (Kaplan, 2002). The possibility that novel proteins are present
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in significant amounts in the meat, stools, urine, or other secretions of the animal would need to be evaluated. Risk assessment of these products can follow traditional methods.
Long-term and transit Tory environmental harms are dependent on the stability and resilience of the receiving community. The community is deemed stable if and only if ecologic structure and function variables returned to the initial equilibrium following perturbation from it—local stability, if such a return applies for small perturbations—global stability, if such a return applies from all possible perturbations (Pimm, 1984). The quantitative stability of many systems has been investigated by Jefferies (1974), and mathematical methods to quantify stability were summarized by Ricklefs (1990).
These definitions potentially 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 result in the least harm with the greatest harm occurring to unstable (fragile) communities. The committee recognizes that characterization of community stability and resilience might not prove straightforward. Ricklefs (1990) states that ecologists disagree on exactly how to parameterize these models and that "we are far from resulting some of these questions, and the ultimate resolution, if it is possible, will likely come from the reconciling accommodation of viewpoints that, at present, focus separately on dynamical control, energetics, and add at stations of individual species."
Another limitation of this approach is that one cannot necessarily limited spread of a GE organism to a particular community. Thus, based on the precautionary principle, one must assume that the GE animal will become established in all possible communities for which it can gain access. If any one of these communities is fragile, the concern would be high for this ecosystem. For this reason, the precautionary principle suggest that risk always should be assessed and managed for the most vulnerable ecosystem into which the escaped or released GE animal is likely to gain access following a given application.
Prioritizing Risk
Prioritizing concerns always will be on a case-by-case basis because of the uniqueness of each GE construct, transgenic founder individual from which a line is derived, and receiving ecosystem (USDA, 1995). However, based on the principles of risk, the committee will attempt to prioritize those concerns. Three variables are needed: (1) effect of the transgene on the fitness of the animal in the environment of transgenic animal escape or release, (2) the species transformed, and (3) the stability and resiliency of receiving community. Concern for harm from establishment in a community always should be
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considered high. Ranking the overall concerns then can be based on the product of three variables cited above. Because the overall concern is a product of three sub-variables (and not the some), if one of the concerns is negligible for any one of the categories, the overall concern would be low (at not negligible). A transgene that increases fitness of a highly mobile species that becomes feral easily raises the greatest level of concern, (e.g., a transgene conferring salt tolerance on catfish or the phytase gene in mice). A transgene that does not increases fitness and a low mobility species that does not become feral easily raises the least concern (e.g., a gene for spider silk in cows; Kaplan, 2002).
The committee stresses that these are a priori listings of concerns. When an actual transgenic organisms produced, for any GE animal that has the potential to become feral, those concerns can be assessed more directly by use of the net fitness approach, as suggested by Muir and Howard (2002a,b).
RISK POSED BY KEY CLASSES OF GE ANIMALS
Examination of the Current State of Understanding, Regulatory Issues, and Key Findings Related to Hazard Assessment
Against the background of the discussion of principles of hazards, associated risks, and the potential harms posed by genetically engineered animals: terrestrial vertebrates (laboratory and domesticated animals), fresh trail in vertebrates (insects, mites, other Arthur Potts), and aquatic animals (fish and shellfish).
Terrestrial Vertebrates
The dangers of some terrestrial animals escaping in establishing themselves in the environment are considerable. Escaped cats, rabbits, mice, rats, pigs, dogs, Fox, pigs, and goats have become feral and resulted in environmental disruptions in Australia, New Zealand, parts of Europe, and the Western and southern United States. Any these animals transgenic for functions that allow greater or wider adaptation to environmental conditions can pose significant ecologic harm. Such functions include, for example, increased nutrient utilization, or new anabolic pathways allowing nutrient synthesis ability, viral or bacterial resistance in any species, and heat or cold tolerance. Few GE terrestrial vertebrates have been produced that fit this category; the best examples to date are the phytase mouse and take (Golovan et al., 2001a,b).
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Further studies will be needed to examine environmental implications of these and other GE terrestrial animals should they be produced.
Terrestrial Invertebrates
One of the primary alternatives to the use of insecticides for control of insects is the use of agriculturally unofficial insects, such as predators and parasitiods. Unfortunately, such beneficial insects often are destroyed as a result of insecticides applications, yet if one waits for the beneficial insects to multiply in order to control the pest, unacceptable levels of damage to the crops already would have occurred. To address this problem, insects used for biocontrol could be genetically engineered for resistance to insecticides, thereby allowing simultaneous use of both biologic control mechanisms (Braig and Yan, 2002).
Another means of biocontrol is the release of sterile males. Unfortunately, such programs are expensive, might require the release of sterile females where the insects cannot be sexed before release, and techniques used to induce sterility, such as it ready H. and, often render the insect noncompetitive as a potential mate. A possible solution to these problems is to genetically engineer the insect to allow either genetic sexing, for example through a female lethal gene, or through of direct production of sterile males. I only, GE insects can be developed to produce visual markers, such as green florescent protein (GFP), to determine the effectiveness of sterile release programs (Braig and Yan, 2002).
Another application of transgenesis this to control transmission of diseases by such vector organisms as mosquitoes. With GE technology it might be possible to disrupt and insect's ability to carry and transmit diseases, such as [italics] Plasmodeum [italics], the malaria parasite (Braig and Yan, 2002; Spielman et al., 2002; Ito et al., 2002). And environmental concern is presented because the parasite has a negative effect on fitness of the mosquito (Braig and Yan, 2002; Spielman et al., 2002). Elimination of the parasite could result in release of mosquitoes from a form of biocontrol, with a possible associated increase in mosquito populations. An increase in mosquitoes also could lead to increased spread of other mosquito-borne diseases to both animals and humans.
The development of molecular methods for genetic engineering of terrestrial arthropods (reviewed by Atkinson et al., 2001; handler, 2001) has not been matched by advances in understanding how to deploy GE arthropods in practical pest management, or of how to evaluate potential harms associated with their release into the environment (Spielman, 1994; Hoy, 1995; 2000; Ashburner et al., 1998). Key issues pertaining to environmental risk (Hoy, 2000) include the possibility that transgenic insects released into the environment with pose unknown ecologic impacts, and that gene constructs inserted into insects could be transferred horizontally through known or unknown mechanisms to other species, thereby creating new pests.
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If a genetically engineered arthropods is to be released within a practical pest management program, any potential ecologic risks associated with its release into the environment must be assessed, although guidelines for conducting such an assessment do not yet exist (Hoy, 1992a; 1992b; 1995). Anticipation of ecologic risks will depend upon predictions of the impact of changed abundance or dynamics of the engineered species upon resources or species with which the organism interacts in the environment, including predators, prey, competitors and hosts.
Further, the methods by which horizontal gene transfer (chapter 2) could occur should be investigated so that it can be determined whether and how to assess this particular Hazard (Hoy, 2000). Should horizontal transfer of a transgene be demonstrated, it poses significant effects for the evolution of a species (Droge et al., 1998). Horizontal gene transfer with pose no harm if the gene that is moved were lost, inactivated, or benign. However, if horizontal gene transfer confers increased fitness, perhaps by establishing the dominant, selectable antibiotic or pesticide resistant trade used in the production of the transgenic arthropod, then harm would be realized. Risk posed is not dependent solely on the frequency of transfer. Even rarer advance might pose ecologic impacts if transferred gene increases the fitness of the recipient (Droge et al., 1998).
Considerable progress has been made in development of methods for genetic engineering of the mosquito germline and in identification of parasite-inhibiting molecules (Beernsten et al., 2000; Blair et al., 2000). Despite the technical progress, there remain important scientific questions that must be addressed prior to a program releasing GE mosquitoes (Braig and Yan, 2002; Spielman et al., 2002). Can parasite-inhibiting gene constructs indeed spread and become fixed and wild mosquito populations? In order to do so, a drive mechanism will have to be developed that would cause a disproportionate frequency of offspring of the released mosquitoes to carry the introduced constructs (Braig and Yan 2002; Spielman et al., 2002). Such drive-in mechanisms might include competitive displacement, meiotic drive (Sandler and Novitski, 1957), biased gene conversion, and others (Braig and Yan, 2002). The fate of parasite-inhibiting gene's would be determined not only by a that mechanism used to drive the fixation of the genes, but also by the magnitude of any loss of fitness in the host, and also by a range of ecologic and antibiotic environmental factors. Possible human effects posed by genetic engineering of disease vector insects are discussed in chapter 3.
In the context of environmental concerns posed by GE arthropods, it is clear that purposeful release of transgenic arthropods will depend upon prior risk assessment and risk management. Hoy (1997) calls for effective contaminants of transgenic arthropods in laboratory and thorough. You by scientists and regulatory agencies prior to any field release. However, there are no U.S. or
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international guidelines for contaminants of transgenic arthropods. Additionally there are no proven techniques for retrieving transgenic insects after environmental release should they perform an unexpected ways. A number of scientific uncertainties regarding environmental harms and associated risks will have to be result before release of GE arthropods can be purposefully undertaken.
Fish and Shellfish
Considerable research effort has been devoted to development of GE fish and shellfish stocks, as they pose considerable benefits to producers (chapter 1). Production of some GE fish or shellfish could result in environmental benefits. For example expression of growth hormone transgenes has been shown to increased feed conversion efficiency (Coke et al., 2000; Fletcher et al., 2000), decreasing the amount of feed needed to bring fish to market size, while reducing wastes per unit of mass-produced. Production of fish expressing a phytase transgene might allow use of less fish meal in feeds while decreasing phosphorus in affluent from aquaculture operations. However, transgenic fish and shellfish might pose environmental hazards (Kapuscinski and Hallerman, 1990; 1991; Hallerman and Kapuscinski, 1992a,b; 1993 Muir and Howard, 1999; 2001; 2002a,b). Below, the committee briefly reviews a series of empirical studies to examine potential ecologic risks posed by escaped or released transgenic fish and shellfish. As indicated in table 1, there are a number of important factors that contribute to risk. The risk factors for establishment in a community were high for all categories because: (1) cultured fish and shellfish stocks are not far removed from the wild type, (2) aquaculture production systems frequently are located in ecosystems containing wild or feral populations of conspecifics, (3) aquatic organisms exhibit great dispersal ability, and (4) aquacultured organisms often are marketed live.
Transgenic Atlantic salmon pose a near-term regulatory issue, and a brief review of hazards posed provides a useful illustration of the environmental hazards posed by GE aquatic species more generally. Cultivated salmon escaped from fish farms in large numbers (Carr et al., 1997; Youngson et al., 1997; Fisk and Lund, 1999; Volpe et al., 2000), posing ecologic and genetic risks to native salmon stocks (Hindar et al., 1991; Hanson et al., 1991). Several studies that have focused on Atlantic salmon [italics] Salmo salar [italics] expressing a growth hormone (GH) gene constructs suggest that transgenesis might affect fitness, but do not provide net fitness estimations needed for parameterizing fitness models predicting outcomes should such fish enter natural systems. GH transgenic salmon consume food and oxygen at more rapid rates than controlled salmon (Stevens et al., 1998); although gill surface area was 1.24 times that in control
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salmon, it did not compensate for they 1.6-time elevation and oxygen uptake, and the metabolic coast of swimming was 1.4 times that for control salmon (Stevens and Sutterlin, 1999). Growth-enhanced transgenic fish were significantly more willing to risk exposure to a predator in order to gain access to food (sees Abrahams and Sutterlin, 1999, but reduced their exposure to predators when risk was heightened further, suggesting that they might not be significantly more susceptible to predation. Transgenic salmon lost their juvenile parr markings sooner than non Transgenics, suggesting early readiness for adaptation to see water. Thus, findings to date are fragmentary, and it is difficult to assess the likely ecologic or genetic outcomes should transgenic Atlantic salmon escaped captivity and invade while populations.
The Pacific salmon include a number of aquaculturally important species that have been the subject of a large number of transgenesis experiments and a small number of risk assessment experiments. The studies collectively show results similar to those obtained with Atlantic salmon, but also show that the outcomes of introgression of the transgene might differ among receiving populations. Coho salmon ([italics] Onchorhynchus kisutch [italics]) expressing a growth hormone constructs exhibited extraordinary growth (Devlin et al., 1994), underwent parr-smolt transformation approximately six months before nontransgenic siblings, and some males matured at just two years of age (Devlin et al., 1995b). However, swimming performance of Transgenics was poor (Farrell et al., 1997), perhaps because of the developmental delay or from disruption of locomotor muscles or associated support systems, such as the respiratory, circulatory, or nervous systems. Some growth-enhanced fish exhibited abnormalities of opercular (gill cover close currencies morphology that might disrupt respiration and contribute to poor swimming performance. In competitive feeding trials, Devlin et al. (1999) show that GH transgenesis increases the ability to compete for food, suggesting that transgenic fish might compete successfully with native fish and the wild. Devlin et al. (2001) noted that the greatest response to expression of the transgene was in Coho hybrids of a wild and domesticated strain; hence, the effects of and introduced growth hormone gene might differ among stocks.
In a steady posing implications for introgression of transgenes into while populations, Devlin et al. (2001) examined the fitness of the effects of expression of a GH construct in both wild and selectively bred commercial rainbow trout ([italics] O. mykiss [italics]) strains. Transgenic wild-strain rainbow trout retained the slender body morphology of the wild-type strain, but their final size at maturity was much greater than that of their nontransgenic ancestors. Both domestic and wild-strain trout exhibited reduced viability; and the domestic strain, all transgenic individuals died before sexual maturation. The trade-off of size (and likely matings assess) and decreased viability parallels the case modeled by Muir and Howard (1999), and suggest that the viability of a receiving populations might be compromised. Devlin et al. (2001) noted that the greatest response to
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expression of the transgene was in hybrids of a wild and domesticated strain; hence, the effects of and introduced growth hormone gene might differ among stocks. The importance of genetic background on expression of growth hormone was demonstrated also by Siewerdt et al. (2000a, b) and Parks et al. (2000a, b). Well indicative that risk issues must be regarded with seriousness, the growing collection of and peer goal risk assessment studies of transgenic salmonids does not yet provide a body of data useful for parameterizing a model useful for predicting the likelihood that transgenes would become permanently introgression to wild or feral salmon populations.
However, many of the same physiological and behavioral differences seen in GE salmon can be induced by using growth hormone implants (Johnsson et al., 1999). As such, and planted fish can model the effects of the transgene and allow the fish to be safely tested in native habitats—experiment that would be hazardous with GE fish. Working with brown trout [italics] Salmo trutta [italics], Johnsson et al., 1999). show that survival of GH-implanted trout did not differ from that of controls under field conditions with natural predation levels. They concluded that GH-manipulated fish might compete successfully with wild fish despite behavioral differences observed in the laboratory for characteristics such as predatory avoidance, foraging ability, and over-winter survival (Johnsson et al., 2000). These results emphasize the need to measure all components of fitness under conditions similar to those found in nature—a task that might not be possible for some species.
Possible environmental hazard pathways posed by escaped of transgenic crustaceans and mollusks into natural ecosystems have not yet been thoroughly considered. Research has not yet assessed ecologic risk posed by production of these organisms. Many freshwater crustaceans, such as crayfishes, are capable of overland dispersal; further, they are produced in extensive systems, where confinement is difficult. Many Marine crustaceans have planktonic larvae, thus complicating confinement. Confinement of mollusks can prove difficult at the larval stage (USDA, 1995). Further, because the larval stage is drift in the water column he for settlement and metamorphosis to the sessile juvenile form, they have great dispersal capability.
The committee's review of ecologic principles and empirical data suggests a considerable risk of ecologic hazards becoming realized should transgenic fish or shellfish enter natural ecosystems. In particular, greater and peer goal knowledge is needed to predict the outcomes should transgenes become introgression into natural populations of aquatic organisms.
NEED FOR MORE INFORMATION CONCERNING RISK ASSESSMENT AND RISK MANAGEMENT
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Many critical unknowns complicate risk assessment and risk management for genetically engineered animals. Greater knowledge in these areas would support and informed judgment of whether and how to go forward with approval for marketing particular genetically engineered animals. For example, results of well-designed, interdisciplinary studies could prove useful for parameterizing net fitness-based models predicting whether transgenic genotypes would persist in natural populations. Should GE animals be approved, post commercialization monitoring would provide a check on the utility of predictive models, suggest improved means of risk management, and support adaptive management of GE animals (Kapuscinski et al., 1999; Kapuscinski, 2001). More information supporting risk assessment AND risk management also would support regulatory decision-making and would promote public confidence in the environmental safety of genetically engineered animals.
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End of Chapter 5
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