4
DEMOGRAPHY, COST, AND GENETIC MATERIAL

Chimpanzees have been important animals in many biomedical and behavioral research programs, as outlined in chapter 2. Because of restrictions against importation of these animals from the wild, research needs for chimpanzees have been met by captive breeding colonies since the Convention on International Trade of Endangered Species of Wild Fauna and Flora (CITES) became effective in 1975.

DEMOGRAPHY

Cost-effective management of the research chimpanzee population depends on an understanding of its demography. Whether the goal is to increase, decrease, or stabilize population size, demographic analysis of history and projection of future trends is critical for sound population management. Detailed demographic analysis requires that high-quality individual records be maintained. The five breeding facilities supported by the National Institutes of Health (NIH) and the facility at the Southwest Foundation for Biomedical Research (SFBR) have excellent records available to allow evaluation of demographic management issues.

Chimpanzee population demography resembles that of human populations and hence is quite different from that of other laboratory animal models. In addition to their long life span, chimpanzees have a relatively



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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use 4 DEMOGRAPHY, COST, AND GENETIC MATERIAL Chimpanzees have been important animals in many biomedical and behavioral research programs, as outlined in chapter 2. Because of restrictions against importation of these animals from the wild, research needs for chimpanzees have been met by captive breeding colonies since the Convention on International Trade of Endangered Species of Wild Fauna and Flora (CITES) became effective in 1975. DEMOGRAPHY Cost-effective management of the research chimpanzee population depends on an understanding of its demography. Whether the goal is to increase, decrease, or stabilize population size, demographic analysis of history and projection of future trends is critical for sound population management. Detailed demographic analysis requires that high-quality individual records be maintained. The five breeding facilities supported by the National Institutes of Health (NIH) and the facility at the Southwest Foundation for Biomedical Research (SFBR) have excellent records available to allow evaluation of demographic management issues. Chimpanzee population demography resembles that of human populations and hence is quite different from that of other laboratory animal models. In addition to their long life span, chimpanzees have a relatively

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use late onset of reproduction (7 yr for females is the youngest ever recorded in the NIH breeding program; 10-12 yr is more typical). Reproduction can be sustained by at least some individuals beyond the age of 40 yr. Chimpanzees almost always produce one offspring per pregnancy. These life-history characteristics mean that the growth potential of chimpanzee populations is much less than that of populations of all other species used in research, but growth in captivity can be achieved. The NIH breeding program averaged 10 live births per 100 animals during the peak years of 1987-1993. The birth rate was reduced later because of a potential surplus of chimpanzees for research. The age structure of a population is important for understanding population dynamics. The biomedical research chimpanzee population in the United States now has a generally stable age structure with captive-bred animals filling in the lower age classes as a result of the ban on importation of wild chimpanzees imposed by CITES in 1975. The NIH breeding-program population has a similar structure. Because of the success of the breeding program during a period when relatively few animals were being used, many younger animals are now in the population. Life expectancies of animals of various age classes can be calculated from the existing records. Life-table models can be used to forecast how rapidly a population will decline as a result of the background rate of mortality under existing captive-management conditions. The large number of animals available for research is ample for reasonable projections of research needs; hence, the recommendation of a 5-yr breeding moratorium. Thereafter, the ChiMP office can assess up-to-date research-need forecasts, the number of animals that have been moved to sanctuaries, and attrition due to natural mortality and then recommend needed changes to management. MODELS OF BREEDING COLONY SIZE If sanctuary options develop, the question of how many animals could be placed in sanctuaries might arise. Figures 4.1 and 4.2 provide

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use estimates of the size of the future breeding population for two possible scenarios of future research needs. Animals in excess of the needs of the breeding population in these models can be used in research or transferred to long-term care facilities. These animals are among the least likely chimpanzees to have been exposed to agents infectious to humans, so they might be considered for transfer to public sanctuaries. Figures 4.1 and 4.2 show projected future population sizes and trends for two of the long-term management options discussed in this report. Other options can be modeled, but these were selected as distinct examples of future management decisions by the proposed Chimpanzee Management Program (ChiMP) office discussed in chapter 5 that would depend on the perception of future research needs and goals. Figure 4.1 projects the future size of the breeding population on the basis of having to meet a national crisis every 10-yr, as discussed in chapter 2. This model begins in year 0 by removing 246 animals that are not needed for breeding from the 528 animals in the breeding program FIGURE 4.1 Ten-Year Crisis Breeding Colony Model

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use at the end of 1996. It then provides for a 5-yr breeding moratorium in years one to five with the number of the animals in both the breeding program and those ''not needed for breeding"1 declining because of normal mortality. Breeding begins in year six and continues for 10-yr, and 20 animals per year not needed for breeding move from the breeding program. In the first two years of a 10-yr breeding period, older adults are moved from the breeding program. Starting in the third year of a breeding period, a mixture of two-and three-year-old animals and adults is moved from the breeding program. The figure reflects a 5-yr breeding moratorium, a 10-yr breeding period, a 10-yr breeding moratorium, another 10-yr breeding period, another 10-yr breeding moratorium, and the beginning of a third 10-yr breeding period. When breeding is taking place in this model, animals older than 35 yr are moved to the "not needed for breeding" group. Figure 4.2 projects the future size of the breeding population on the basis of a research requirement for 10 new animals per year for a period of 50 yr. This model begins in year 0 by removing 360 animals not needed for breeding from the 528 animals in the breeding program at the end of 1996. There is a breeding moratorium in years one to five, and the number of animals in the breeding program and those no longer useful to the breeding program because of old age decline because of normal mortality. Beginning in year six, breeding takes place at a steady rate to replace animals in the breeding program that have died and 10 animals per year over 35 yr are moved from the breeding program into the "not needed for breeding" group. In the first 2 yr after the moratorium, older adults are moved from the breeding program into the "not needed for breeding" group. Starting in the third year after the moratorium, a mixture of 2- and 3-yr-old animals and older animals is moved into the "not needed for breeding" group. When breeding is taking place in this model, animals older than 35 yr are moved into the "not needed for breeding" group. From chapter 2, it might be concluded that 20 young "RSV 1   Both figures 4.1 and 4.2 model only the breeding program. In both cases, animals labeled "not needed for breeding" are available either for research or for transfer into long-term care or sanctuary facilities. Decisions on the use of these animals are to be made by the ChiMP office.

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use FIGURE 4.2 Stable-Production Breeding Colony Model naive" animals are needed per year. This model assumes that half that need can be met with existing animals. COSTS Cost is a major issue in evaluating the options for long-term maintenance of and future research with chimpanzees. Chimpanzees are among the most-expensive laboratory animal models. Their large size and complex social requirements demand housing and intensive care practices that are expensive, even if minimal. Chimpanzees are also long-lived animals; the average life span of males and females is about 25 and 34 yr, respectively, and maximums of 55 and 60 yr, respectively, have been reported (Dyke and others 1995, 1996). As a result, in the absence of

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use euthanasia or terminal research, the cost obligations for maintaining and breeding chimpanzees are not only high, but also of long duration. The high costs of maintaining and breeding chimpanzees are reflected in the "use fees" charged to researchers. Those fees are generally used to cover the continuing costs of chimpanzee facilities, although a portion (sometimes called an "endowment") is designated for the future care of the animals in some cases (for example, Eichberg and Speck 1988). The high cost of chimpanzees for research results in diminished use, which in turn increases costs to researchers who still use them because fewer use fees are available to cover the costs of breeding and maintenance. If the chimpanzee is to remain a viable animal model for research, mechanisms for increasing the cost effectiveness of chimpanzee breeding, maintenance, and research must be developed. The available information indicates that government funding now supports 900-1,000 chimpanzees. These animals are in several different categories, including those owned by the government (and maintained for diverse purposes, including the breeding program), non-owned animals supported in the breeding program, and diverse non-owned animals supported for various periods for research grants in science and medicine. Government has also made multimillion-dollar contributions to some facilities for long-term care of some animals, and in addition, researchers have paid use fees up to $55,000-66,000 per animal. The diversity of funding mechanisms, the different approaches used, and the absence of a central accounting summary made it impossible for the committee to determine actual expenditures by the various agencies. We recommend that the government assume ownership, or provide lifetime support, for this population of approximately 1,000 chimpanzees. The approximately 500 remaining chimpanzees in the total US research population are privately owned, not used in government research, or their owners might not be willing to transfer ownership to the government. The present direct cost of supporting these animals is $15-30 per day; the NIH National Chimpanzee Breeding and Research Program (NCBRP) animals are at the lower end of that range and animals in infectious-disease research are at the upper end. Using $20 for direct per diem costs and 1,000 for the number supported by government, we can estimate that

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use the direct cost for chimpanzee support now being paid from multiple government budgets is $7,300,000 per year. Available figures indicate that the NCBRP supports more than half of the 1,000 animals (573) with about half the estimated total, or $3,608,8842 for FY 1996. PROJECTED BREEDING COLONY COSTS The "crisis" model presented in figure 4.1 assumes a national crisis affecting the nation's public health will recur every 10-yr. Another aspect of this model is depicted in figure 4.3 as consisting of breeders (lower, light-colored bars) and those not needed for breeding (upper, dark-colored bars). The cost associated with this model are determined by the size of those two subgroups that begin in year 0 with a breeding colony of 282 animals, at an annual direct cost of $2,058,600, and 246 animals not needed for breeding, at an annual direct cost of $1,795,800. It remains more expensive than the stable-production model until year 35, after which it declines to only 39 animals by year 50 because of natural mortality, at an annual direct cost $284,700. Figure 4.2 presented a model in which a low but stable birth rate is needed for many years. Another aspect of this model is depicted in figure in 4.4 as consisting of breeders (lower, light-colored bars) and those not needed for breeding (upper, dark-colored bars). The costs associated with this model are determined by the size of those two subgroups that begin in year 0 with a breeding colony of 168 animals at an annual direct cost $1,226,400. At year 50, this model projects 148 animals remaining in the breeding colony at an annual direct cost of $1,080,400. Chimpanzees not needed for breeding might remain the responsibility of the government as "available for research," or they might be transferred to lower-cost long-term care or no-cost sanctuary facilities. Tables 4.1 and 4.2 enable determination of the cost to the government for the two models presented in figures 4.3 and 4.4. The annual cost for each model is based on the number of government-supported animals. For example, figure 4.3 shows that at year 16, 546 animals (251 breeders and 2    Data provided by the NIH, National Center for Research Resources, Comparative Medicine Program and include research and equipment costs associated with the NCBRP awards.

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use FIGURE 4.3 Crisis Model: Annual Number of Chimpanzees in Breeding and Not Needed for Breeding. 295 not needed for breeding) must be supported. If those not needed for breeding are removed from government support, the cost obligation is limited to the 251 breeders. Tables 4.1 and 4.2 provide the annual direct costs, at $20 per day, for breeders and those not needed for breeding that are represented in figures 4.3 and 4.4, respectively. For example, table 4.1 shows that at year 16, the annual support for the 251 breeders in the crisis model is $1,832,300. If the government also supports the 295 animals not needed for breeding, the total government obligation is increased by $2,153,500, for a total of $3,985,800. REDUCING COSTS THROUGH SIMPLIFYING FUNDING AND ENHANCING COORDINATION We recommend elsewhere that the government accept ownership, or

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use FIGURE 4.4 Stable Production Model: Annual Number of Chimpanzees in Breeding and Not Needed for Breeding. provide a mechanism for lifetime support, of animals not owned, but now being supported by the government. We believe that a large component of the general public and the scientific community feel that society, acting through government, has responsibility for these animals. We point out that this does not increase current government animal-support annual costs—the animals are already being financially supported by the government. In fact, simplification of the support mechanisms would likely save some costs and make animals available to a wider segment of the research community for important research. Simplification and centralization would also allow better coordination of population management in response to perceived national needs. At present, decision-making and accountability for overall population management are too fragmented and complex to function properly. We recommend elsewhere, on the basis of our perception of current

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use TABLE 4.1 Crisis Model: Annual Costs for Breeding and Not Needed for Breeding   $20.00 per day 365 days per year Year Breeding Colony Not Needed for Breeding Breeding Colony Not Needed for Breeding Require Support 0 282 246 $2,058,600 $1,795,800 528 1 271 237 $1,978,300 $1,730,100 508 2 261 228 $1,905,300 $1,664,400 489 3 251 219 $1,832,300 $1,598,700 470 4 241 211 $1,759,300 $1,540,300 452 5 232 203 $1,693,600 $1,481,900 435 6 237 215 $1,730,100 $1,569,500 452 7 242 227 $1,766,600 $1,657,100 469 8 247 238 $1,803,100 $1,737,400 485 9 252 249 $1,839,600 $1,817,700 501 10 257 260 $1,876,100 $1,898,000 517 11 261 270 $1,905,300 $1,971,000 531 12 264 280 $1,927,200 $2,044,000 544 13 265 289 $1,934,500 $2,109,700 554 14 264 298 $1,927,200 $2,175,400 562 15 261 307 $1,905,300 $2,241,100 568 16 251 295 $1,832,300 $2,153,500 546 17 241 284 $1,759,300 $2,073,200 525 18 232 273 $1,693,600 $1,992,900 505 19 223 263 $1,627,900 $1,919,900 486 20 215 253 $1,569,500 $1,846,900 468 21 207 243 $1,511,100 $1,773,900 450 22 199 234 $1,452,700 $1,708,200 433 23 191 225 $1,394,300 $1,642,500 416 24 184 216 $1,343,200 $1,576,800 400 25 177 208 $1,292,100 $1,518,400 385 26 178 220 $1,299,400 $1,606,000 398 27 179 232 $1,306,700 $1,693,600 411 28 181 243 $1,321,300 $1,773,900 424 29 181 254 $1,321,300 $1,854,200 435 30 179 264 $1,306,700 $1,927,200 443 31 176 274 $1,284,800 $2,000,200 450 32 171 284 $1,248,300 $2,073,200 455 33 165 293 $1,204,500 $2,138,900 458 34 157 302 $1,146,100 $2,204,600 459 35 148 310 $1,080,400 $2,263,000 458 36 143 298 $1,043,900 $2,175,400 441 37 137 287 $1,000,100 $2,095,100 424 38 132 276 $963,600 $2,014,800 408 39 127 266 $927,100 $1,941,800 393 40 122 256 $890,600 $1,868,800 378 41 118 246 $861,400 $1,795,800 364 42 113 237 $824,900 $1,730,100 350 43 109 228 $795,700 $1,664,400 337 44 105 219 $766,500 $1,598,700 324 45 101 211 $737,300 $1,540,300 312 46 91 223 $664,300 $1,627,900 314 47 81 235 $591,300 $1,715,500 316 48 68 246 $496,400 $1,795,800 314 49 55 257 $401,500 $1,876,100 312 50 39 267 $284,700 $1,949,100 306

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use TABLE 4.2 Stable Production Model: Annual Costs for Breeding and Not Needed for Breeding   $20.00 per day 365 days per year Year Breeding Colony Not Needed for Breeding Breeding Colony Not Needed for Breeding Require Support 0 168 360 $1,226,400 $2,628,000 528 1 162 346 $1,182,600 $2,525,800 508 2 156 333 $1,138,800 $2,430,900 489 3 150 320 $1,095,000 $2,336,000 470 4 144 308 $1,051,200 $2,248,400 452 5 139 296 $1,014,700 $2,160,800 435 6 140 295 $1,022,000 $2,153,500 435 7 140 294 $1,022,000 $2,146,200 434 8 141 293 $1,029,300 $2,138,900 434 9 144 292 $1,051,200 $2,131,600 436 10 147 291 $1,073,100 $2,124,300 438 11 151 290 $1,102,300 $2,117,000 441 12 155 289 $1,131,500 $2,109,700 444 13 158 288 $1,153,400 $2,102,400 446 14 160 287 $1,168,000 $2,095,100 447 15 162 286 $1,182,600 $2,087,800 448 16 162 285 $1,182,600 $2,080,500 447 17 161 284 $1,175,300 $2,073,200 445 18 159 283 $1,160,700 $2,065,900 442 19 157 282 $1,146,100 $2,058,600 439 20 155 281 $1,131,500 $2,051,300 436 21 154 280 $1,124,200 $2,044,000 434 22 152 279 $1,109,600 $2,036,700 431 23 152 278 $1,109,600 $2,029,400 430 24 151 278 $1,102,300 $2,029,400 429 25 152 278 $1,109,600 $2,029,400 430 26 152 278 $1,109,600 $2,029,400 430 27 153 278 $1,116,900 $2,029,400 431 28 153 278 $1,116,900 $2,029,400 431 29 154 278 $1,124,200 $2,029,400 432 30 155 278 $1,131,500 $2,029,400 433 31 155 278 $1,131,500 $2,029,400 433 32 155 278 $1,131,500 $2,029,400 433 33 154 278 $1,124,200 $2,029,400 432 34 153 278 $1,116,900 $2,029,400 431 35 151 278 $1,102,300 $2,029,400 429 36 150 278 $1,095,000 $2,029,400 428 37 148 278 $1,080,400 $2,029,400 426 38 147 278 $1,073,100 $2,029,400 425 39 147 278 $1,073,100 $2,029,400 425 40 147 278 $1,073,100 $2,029,400 425 41 147 278 $1,073,100 $2,029,400 425 42 148 278 $1,080,400 $2,029,400 426 43 149 278 $1,087,700 $2,029,400 427 44 150 278 $1,095,000 $2,029,400 428 45 151 278 $1,102,300 $2,029,400 429 46 151 278 $1,102,300 $2,029,400 429 47 150 278 $1,095,000 $2,029,400 428 48 149 278 $1,087,700 $2,029,400 427 49 149 278 $1,087,700 $2,029,400 427 50 148 278 $1,080,400 $2,029,400 426

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use research needs, that a smaller breeding and reserve population be maintained. The government-supported experiment-naive young animals and old animals released from the breeding population (to reduce its size and potentially lower the cost to the government) can be used for research, or moved to long-term care or sanctuary settings. The scientific community should be better informed about the availability of these animals for important research and about the elimination of use fees. Reduced costs to investigators through elimination of use fees should result in greater use and understanding of the chimpanzee as an animal model. Payment of use fees generally inhibits the use of chimpanzees in research. Some investigators have appealed to the present committee to recommend elimination of such fees. Use of animals that belong to a government-owned or lifetime-supported resource would accomplish that goal. With the recommended 5-yr breeding moratorium in place, natural mortality will reduce the population size. Survival rates of chimpanzees in biomedical research facilities are better than those in the wild (Dyke and others 1995), so this will take time. An initial estimate is an annual reduction of 3%. Over five years, we would project a reduction in size of about 15%, caused by natural mortality. Applied to our estimate of $7.3 million in current support, that would reduce the annual support costs for the government-owned population by one million in constant dollars. Dyke and others (1996) have calculated lifetime costs for various segments of the captive-chimpanzee population. The cost of supporting a single chimpanzee, at the per diem rates needed in existing facilities and aggregated over its long expected life span, is estimated at $125,000-300,000. Such large figures argue for careful population management and multiple use whenever possible. We believe that these lifetime cost calculations are an important warning about financial encumbrances in the future. We also recognize that most of society's budget decisions are made on an annual or limited-year grant basis, and that is the level at which the value and costs of research chimpanzees will be continually assessed. SANCTUARY CONSTRUCTION In order to evaluate the options for long-term care of chimpanzees no longer needed for research or breeding, the committee prepared

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use "what if" financial models of sanctuaries. The models were used to evaluate the potential cost savings that would result from the lowering of per diem costs in a purpose-built "sanctuary." The models included capital construction costs for the sanctuary, a fixed annual cost of operating and maintaining the facility, and marginal costs related to the number of chimpanzees housed. As might be expected, the models showed that the larger the number of animals moved to a sanctuary and the lower the annual marginal costs of adding one chimpanzee to the facility, the more the construction cost could be justified. For some plausible ranges of values, the models indicated net savings could be achieved from sanctuary construction. The committee believes that funds for long-term care of chimpanzees, especially the phase when they are no longer needed for research or breeding, should not come from biomedical research budgets, and it urges that creative approaches to develop and support sanctuaries be sought. Societal obligations to chimpanzees no longer needed for research or breeding require cooperative support from federal agencies, Congress, commercial companies, and nongovernment organizations. GENETIC MANAGEMENT Conservation-oriented genetic management traditionally has been used to manage captive nonhuman primate colonies. That approach emphasizes preservation of genetic variability and avoidance of inbreeding as the primary goals of genetic management, with a general objective of preserving the evolutionary potential of the population (Soulé 1986, 1987). However, genetic management in the research environment does not operate with the aim of preserving a species in perpetuity for possible reintroduction into the wild. Rather, research-oriented genetic management must balance the goals of preserving the long-term viability of the population with those of specific research needs (Williams-Blangero 1993). The pedigree is the primary source of information for genetic management. With good record-keeping and single-male breeding groups, available pedigree information is generally sufficient for most genetic management procedures. The colony pedigree can be constructed from basic record information on dam and sire for all individuals.

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use If multimale breeding groups are used, paternity testing might be required to resolve pedigrees. Genetic-marker analyses have resolved most paternity questions in the NCBRP population. However, even in captive colonies that use single-male breeding schemes, mistakes in pedigree assignments can occur. The need for routine pedigree verification with genetic-marker analysis has been emphasized in many genetic management schemes. The expense of fully verified pedigrees might be warranted for a long-term, large-scale chimpanzee breeding program designed to sustain research demands for multiple generations. However, if the ChiMP office does not expect a long future for chimpanzee experimentation or a substantial increase in genetic research with these animals, genetic management programs involving extensive genetic-marker analysis might not be justified. Pedigree information alone will allow evaluation of founder contributions, inbreeding coefficients, and kinship coefficients between potential mating pairs or potential sample animals (Williams-Blangero and Dyke 1992). This basic level of genetic information generated from colony records permits avoidance of inbreeding, maximization of effective population size through equalization of founder contributions, and selection of unrelated experimental animals. ''Pooling" and sharing of colony records so that multicolony pedigrees are available to each colony manager (as done through the International Species Information System, ISIS) will allow managers to consider genetic diversity and minimize inbreeding in their colony with reference to the pedigree of the total research chimpanzee population. The finite size of the US research chimpanzee population indicates that inbreeding is inevitable if chimpanzee breeding is to be continued in perpetuity. That implies that genetic-management techniques should be used to avoid inbreeding and maintain genetic variability. Although high levels of inbreeding have been shown to have important consequences for colony viability (Crawford and O'Rourke 1978; Noble and others 1990; Ralls and Ballou 1982), the potential negative effects of long-term inbreeding at low levels in nonhuman primates remain to be seen. Many unrelated potential mating pairs are present in the research chimpanzee population, so inbreeding can be easily avoided for many years through selection of unrelated breeding pairs. Genetic studies have shown that there is substantial genetic variability in the US research chimpanzee population (Williams-Blangero and

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use others 1993, 1994). Thus, although genetic management techniques are needed to maintain variability, intensive strategies for increasing genetic diversity (such as high rates of intercolony transfer and introduction of new animals from other nonresearch captive populations) might not be warranted. Effective population size is the proportion of the number of breeders to the total population and is predictive of the extent of genetic variability that can be maintained in a population (Lande and Barrow-clough 1987). Captive nonhuman primate populations often have relatively low effective population sizes (for example, breeders represent 13.8% of the total population in the SFBR chimpanzee colony) [Williams-Blangero and others 1992], because of the inequitable distribution of offspring among founders, thus reflecting heavy reliance on proven breeders to produce animals. Increasing founder representation is a simple mechanism for maintaining variability and increasing effective population size (for example, Lacy 1989). The effective population size of a colony can be evaluated through computer simulation analyses of pedigree information (for example, Waples 1989). Maintenance of heterozygosity is a common component of genetic management programs and can be evaluated through computer simulation analyses of pedigree data or directly from genetic-marker data. The emphasis on heterozygosity in conservation genetics is based on Fisher's fundamental theorem of natural selection, which predicts that the evolutionary potential for adaptation is a function of genetic variance (Allendorf and Leary 1986). The applicability of heterozygosity measures for assessing the status of captive groups is limited because heterozygosity is relatively unaffected by changes in breeding structure when the initial effective population size is greater than 20. The rate of allelic loss is more sensitive than heterozygosity to changes in breeding structure; allelic loss is halved by doubling of the effective population size (Kimura and Ohta 1969). Allelic diversity can be used in both genetic management and some experimental protocols. Selection of unrelated mates and equalization of founder contributions can be used in colonies to maintain genetic diversity. With due concern to avoid transmission of disease, exchange of animals between colonies can also be useful for long-term avoidance of inbreeding and maintenance of genetic diversity. Such temporary or permanent transfer

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use of animals between colonies for genetic-management purposes requires diligent recordkeeping within a colony and among colonies, as is currently provided for the multi-institutional NCBRP by ISIS. FUTURE BREEDING Current genetic management decisions must be considered in the light of long-term demographic consequences. Animals bred to meet current or projected research demands entail a substantial financial liability because of their long life span. The costs associated with the future maintenance of chimpanzee colonies should be important considerations for current genetic and demographic management (Dyke and others 1996). As previously discussed, appropriate numbers and proportions of breeders among research animals can be evaluated with computer simulation techniques. The underlying assumptions for the demographic projections in these simulation analyses will be based on the guidelines generated by the ChiMP office. Key points to be considered include the expected number of naive research animals required per year, the expected number of previously used research animals that can be reused per year, and the appropriate age and sex structures of the experimental animal population. For example, will experimental protocols require primarily young animals, adolescent animals, or adult animals? Will males and females be equally useful? Will experimental groups require age-or sex-matched animals? Research protocols generally assume that individual animals can be treated as independent cases. That assumption does not hold if an experimental sample contains related animals, which necessarily share a genetic background. If potentially confounding genetic relationships exist among animals, they should be well defined so that they can be explicitly considered in statistical analyses of resulting experimental data. Ignoring the nonindependence of related sample animals can lead to increased type I errors, in that sample sizes will be overestimated. Adding the restriction that sample animals be unrelated to existing protocol requirements regarding animal histories (such as experimental, reproductive, and caging backgrounds) and characteristics (such as age,

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use sex, weight, and health status) might substantially reduce the pool of available experimental animals in a colony. Under the perview of the ChiMP office, breeding-colony production programs should be designed to ensure availability of adequate samples for experimental protocols. CRYOPRESERVATION OF GAMETES OR EMBRYOS Cryopreservation of chimpanzee gametes or embryos has been suggested as a mechanism for preserving chimpanzee variability in the absence of numerous breeding colonies (Ballou 1992). However, this approach will not be inexpensive for adult female chimpanzees still would be needed in the future to serve as recipients of frozen embryos or frozen sperm. Frozen storage of human and nonhuman primate sperm and embryos is possible (Balmaceda and others 1986; Dresser 1996; Durrant 1990; Lambert and others 1991; Pope and others 1984, 1986ab; Rall 1993; Sankai and others 1992, 1994; Summers and others 1987; Tollner and others 1990), but almost no research has been done specifically with chimpanzee gametes or embryos, except for the freezing of chimpanzee sperm (Gould and Styperek 1989). Cryopreservation of oocytes has been accomplished in numerous species from mouse to humans and most recently in macaques (Younis and others 1996). Attempts to store oocytes with cryopreservation have resulted in live births in mice (Harp and others 1994; Schroeder and others 1990), cattle (Fuku and others 1992), and humans (Chen 1986; Van Uem and others 1987), but efficiency has been low. Problems associated with the process include damage to the subcortical microfilaments and to microtubules that control chromatin assembly and spindle formation (Parkes and Ruffing 1989), which has caused aneuploid and polyploid chromatin abnormalities in the resulting embryos or fetuses (Al-Hasani and others 1986; Kola and others 1988). To avoid those problems, Gosden and others proposed removing slices of ovarian tissue containing follicles with oocytes of early stages, freezing them, and returning them to the ovary by transplantation. The

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use ovarian tissue transplantation procedure has resulted in mature oocytes that were fertilized and resulted in offspring in mice (Carroll and others 1990; Gosden 1992) and sheep (Gosden and others 1994). In primates, follicular development has been restored after cryopreservation and transplantation of ovarian tissue (Candy and others 1993); however, the fertilizability, embryo production, and normalcy of embryos or offspring are as yet untested. RECOMMENDATIONS The government should anticipate initial annual expenditures of approximately $7.3 million to support approximately 1,000 chimpanzees. The ChiMP office should determine when breeding is to be reinitiated on the basis of projected research demand and the vitality of the population. The ChiMP office should determine the number of births needed to meet research needs for chimpanzees and the size and demography of the breeding population to sustain that population. Genetic management should be an important component of the overall management of the research chimpanzee population. Inbreeding should be avoided whenever possible. When unrelated mates are unavailable, pairs should be formed from the least-related potential mating pairs. Managers should try to equalize founder contributions in order to maintain diversity. High-quality recordkeeping is essential for genetic management. Pedigree records should be maintained for all animals (both living and dead) that have ever resided in a colony. The records for a given animal should include identification number, the sire's identification number, the dam's identification number, birthdate, sex, acquisition date, disposition date, and a disposition code that reflects whether the animal left the colony because of death, loan, sale, or other reasons. Guidelines for items to be included in standardized laboratory animal records at individual colonies are provided by Dyke (1993) and the Guide for the Care and Use of Laboratory Animals (NRC 1996). In addition to

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Chimpanzees in Research: Strategies for their Ethical Care, Management, and Use recordkeeping at local facilities, a centralized source of records should be maintained for the entire US research chimpanzee population, as is currently done by ISIS. Given the state of the art, cryopreservation does not yet allow for a drastic reduction in or elimination of breeding colonies of chimpanzees.