Somatic Cell Nuclear Transfer (SCNT) is a technology early in its development. Cloning has been accomplished in relatively few species, with most of our current information stemming from studies in cattle, swine, goats, and mice. This Risk Assessment has addressed the hazards and potential risks that may be experienced by domestic livestock (i.e., cattle, swine, sheep, and goats) involved in the cloning process (Animal Health Risks) and whether edible products from animal clones or their progeny pose food consumption risks beyond those of their conventional counterparts (Food Consumption Risks).
The Risk Assessment employed a weight of evidence approach for drawing conclusions regarding risks to animal health and for consumption of food products from clones and their progeny. This approach consisted of four steps:
Evaluation of the empirical evidence (i.e., data on molecular mechanisms, physiological measurements, veterinary records, and observations of general health and behavior) for the species being considered;
Consideration of biological assumptions predicated on our growing understanding of the molecular mechanisms involved in mammalian development;
Evaluation of the coherence of the observations with predictions based on biological mechanisms; and
Evaluation of the consistency of observations across all of the species considered, including the mouse model system.
The Risk Assessment also assumes that animal clones, their progeny, and all food products derived from either clones or progeny must meet the same federal, state, and local laws and regulations as conventional food animals or their edible products.
Because no exogenous genes have been introduced into animals derived via SCNT, the underlying assumption has been that adverse outcomes observed in animal clones arise from epigenetic modifications due to incomplete reprogramming of the donor cell nucleus. Methodological and technological components (e.g., selection of donor cell, cell cycle stage, in vitro factors associated with the SCNT process) may also affect outcomes as they do for other ARTs. Further, because food products from clones are subject to the same controls as corresponding food products from sexually-derived animals, we have stipulated that animals that would fail FSIS inspection, including clones and their progeny, will not enter the human food supply. Therefore, any hazards in clones leading to food consumption risks would be subtle.
To assess the health of animal clones for both the animal health and food consumption risk portions of this risk assessment, we have developed the Critical Biological Systems Approach (CBSA), which divides the life cycle of clones into five distinct Developmental Nodes. Available data for each species has been sorted into these Developmental Nodes to evaluate the data systematically and to determine whether there are common developmental difficulties among the livestock clones or whether animals “recover” from initial infirmities related to cloning.
The results of the CBSA indicate that significant adverse health outcomes have been reported for animal clones and their surrogate dams. These tend to result in dystocia and high gestational mortality. Post-natal mortality in clones tends to be concentrated in the perinatal period, and is higher in clones than in animals produced using other assisted reproductive technologies (ARTs), although as the technology matures, the rate of live births or deliveries appears to be increasing.
To date, no adverse outcomes have been noted in clones that have not been observed in animals derived via other ARTs or natural mating. The incidence of these adverse outcomes appears to be higher in clones than in other forms of ARTs. Common adverse developmental outcomes that have been observed in cattle and sheep fall under the heading of Large Offspring Syndrome (LOS). Newborn animals with LOS tend to be heavy for their breed and species, may show edema or other abnormalities of the lungs and other parts of the body, and exhibit cardiovascular and respiratory problems. Other species (goats and swine) tend to develop without significant abnormalities. Mice, which may provide useful information as model systems, can exhibit different anomalies from those observed in domestic livestock species including obesity and decreased lifespan.
Animal clones that survive the critical perinatal period appear to develop normally. Even animals with physiological perturbations, including less severe manifestations of LOS, seem to resolve them, usually within a period of weeks. Umbilical abnormalities that have been noted can be treated successfully with surgery. To date, all of the physiological instabilities that were observed resolve by the time the animals reach adolescence. Clones that reach reproductive age appear to be normal in all of the measures that have thus far been investigated, and appear to give rise to healthy, apparently normal progeny.
Studies that have evaluated epigenetic reprogramming in live, healthy clones indicate that although there is some variability between clones and their sexually-derived counterparts, these clones have undergone sufficient epigenetic reprogramming to carry out coordinated functions necessary for survival and normal functioning. Molecular analyses reveal relatively small methylation differences, and either the animals are tolerant of such differences, or the epigenetic differences are below the threshold that poses observable adverse health outcomes.
In order to evaluate potential food consumption risks associated with healthy-appearing clones, we have developed a two-pronged approach. The first part of the approach is based on the hypothesis that a healthy animal is likely to be safe to eat, and relies on the CBSA. The second component, or the Compositional Analysis Approach, assumes that if there are no material differences between the composition of milk and meat from animal clones (and their progeny) and their non-clone counterparts, then edible products derived from clone meat or milk would be as safe to eat as corresponding products from non-clones. This assessment assumes that animal clones and their progeny would be subject to all of the existing federal and state requirements for milk and meat, and that food products from animals that would fail FSIS inspection do not enter the human food supply.
Because each clone arises from an independent event, identification and characterization of potential subtle hazards is best accomplished by the evaluation of individual animals, at as fine a level of resolution as possible. Characterization of the overall functionality of clones, however, is likely best considered by evaluating the animal as a whole, in particular assessing the degree to which highly complex functions have been integrated, for example by demonstrating successful reproduction.
Progeny of animal clones are not anticipated to pose special animal health or food consumption concerns, as they are the product of sexual reproduction. The production of gametes by clones is expected to reset even those residual epigenetic reprogramming errors that could persist in healthy, reproducing clones. A large, well-controlled study on the health of swine clone progeny indicates that they are healthy and indistinguishable from other sexually-derived swine comparators. Because the value of clones lies in their genes, they are most likely to be used as breeding stock, and their food use would be incidental. Almost all of the production animals (i.e., sources of meat and milk) from the overall SCNT process are therefore likely to be sexually-reproduced progeny of clones.
Most of the data on which the preceding conclusions are drawn have been generated from cattle, in particular, from a set of data including both health and physiological measurements on clones generated by Cyagra. Data on reproductive function in bovine clones indicates that healthy clones surviving to reproductive age have normal reproductive function and produce normal offspring. Although the database for swine clones is smaller than for cattle clones, physiological and health outcomes were consistent with normal functionality among the clones. Almost no data on the health of sheep clones were available for review. The dataset on goat clones contains information on reproductive function in males, and preliminary physiological measurements on males and females that are consistent with those evaluated for cattle and swine indicating that the clones function normally.
Analysis of the composition of meat from bovine and swine clones and milk from bovine clones consistently indicates that there are no biologically relevant differences between the composition of food from clones, their close comparators, or food commonly consumed from these species on a daily basis. An extensive dataset on the progeny of swine clones indicates that the composition of meat from those animals does not differ from that of comparator animals.
The food consumption portion of the risk assessment postulates that because the only hazards that may be present in clones would arise from epigenetic dysregulation, and because only healthy animals meeting the same standards that conventional food animals or their edible products meet would be permitted for use as food, the only hazards that could be present in these animals would be subtle. Allergenicity and mutagenicity studies confirm that there are no food safety hazards.
Although the data indicate that the clones meeting the criterion described above would not likely pose a food consumption risk, some residual uncertainty is associated with this judgment. The source(s) of the uncertainty may be sorted into three categories:
Uncertainties associated with empirical observations. Uncertainties are lowest for those individual clones whose health has been thoroughly evaluated and, by inference, clones produced subsequently using the same methodology. The uncertainties associated with the evaluation of empirical observations can be a function of the size, consistency, and quality of the data being evaluated. For example, the degree of confidence that can be placed in judgments arising from a well-conducted, consistent, and extensive dataset is much higher than from a small, poorly designed, and highly variable dataset. Further, because datasets tend to arise from an individual laboratory or producer, the uncertainties associated with that producer and method are lower than for other laboratories or producers for which less information is available.
Uncertainty stemming from biological sources can be minimized by the evaluation of the clones themselves. The most important factor in this evaluation is the healthy survival and functionality of individual clones, indicating that either the animal has minimal epigenetic dysregulation, or that any initial epigenetic dysregulation has been resolved. Uncertainty would be the lowest for individual clones demonstrating successful reproduction.
Uncertainties stemming from technological or methodological grounds encompass the degree to which judgments regarding clones arising from technologies in use when this risk assessment was conducted can be applied to modifications of the technology. These may only be resolved by the evaluation of the outcomes of those technological changes (i.e., the actual clones).
Thus, our overall conclusions are:
For Animal Health: SCNT results in an increased frequency of health risks to animals involved in the cloning process, but these do not differ qualitatively from those observed in other ARTs or natural breeding. The frequency of live normal births appears to be low, although the situation appears to be improving as the technology matures. Cattle and sheep exhibit a set of clinical signs collectively referred to as LOS that do not appear to be present in swine or goats. Surrogate dams are at risk of complications from birth if the fetus suffers from LOS, or from accumulation of fluid in the cavities of the placenta (hydrops). Clones exhibiting LOS may require additional supportive care at birth, but can recover and mature into normal, healthy animals. Most clones that survive the perinatal period are normal and healthy as determined by physiological measurements, behavior, and veterinary examinations. Progeny of animal clones also have been reported as normal and healthy.
For Food Consumption Risks: Extensive evaluation of the available data has not identified any food consumption risks or subtle hazards in healthy clones of cattle, swine, or goats. Thus, edible products from healthy clones that meet existing requirements for meat and milk in commerce pose no increased food consumption risk(s) relative to comparable products from sexually-derived animals. The uncertainties associated with this judgment are a function of the empirical observations and underlying biological processes contributing to the production of clones. There is less uncertainty about the health of clones as they age and have more time to exhibit the full range of functionality expected of breeding stock. Edible products derived from the progeny of clones pose no additional food consumption risk(s) relative to corresponding products from other animals based on underlying biological assumptions, evidence from model systems, and consistent empirical observations.
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