Session 4
Environmental Control for Animal Housing



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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop Session 4 Environmental Control for Animal Housing

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop Environmental Controls (US Guidance) Bernard Blazewicz and Dan Frasier CURRENT US GUIDANCE Current guidance regarding environmental conditions for vivariums is primarily found in industry and government publications. The most widely accepted publication and the primary reference on animal care and use is the Guide for the Care and Use of Laboratory Animals (the Guide), published by the National Research Council (NRC 1996). Other pertinent references include the American Society of Heating, Refrigeration, and Air-Conditioning Engineers (ASHRAE 2003), the National Institutes of Health Design Policy and Guidelines (NIH 1999), the Biosafety in Microbiological and Biomedical Laboratories (CDC/NIH 1999), and the US Department of Agriculture ARS 242.1M (USDA 2002). The Guide places emphasis on performance standards, as opposed to engineering standards, for environmental control. Performance standards are viewed to be more flexible and more concerned with the outcomes than engineering criteria. To apply the Guide effectively, a team approach is recommended whereby facility users and designers can share expertise to meet desired outcomes. The Guide is not a how-to-build handbook on vivarium design; it provides broad recommendations for environmental conditions that have proven to work well. Individuals responsible for well-designed facilities begin with a thorough understanding of the scientific needs, and

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop then translate that information into a facility that meets the expectations of the users. The Guide allows for interpretation or modification in the event that acceptable alternative methods are available, or unusual circumstances arise when deviating from the Guide. For example, ventilation rates that exceed 10 to 15 air changes per hour (ac/h) would be allowable, given appropriate justification. When deviating from the Guide, thought should be given to other environmental factors that may be affected by the deviation. In the case of air change rates, it is possible that air movement, diffusion pattern influence on the animal’s microenvironment, and the relation of the type and location of supply-air diffusers and exhaust vents would warrant further consideration. ENVIRONMENTAL CRITERIA Environmental criteria topics that have been discussed include the following: temperature and humidity, ventilation rate, lighting, containment, and air quality. Each of these topics is briefly described below. Temperature and Humidity The most common source of data for temperature and humidity is ASHRAE; however, most data are outdated and date back to the 1950s or 1960s. Some researchers believe that the measurements concluded from past heat and moisture data are too low for today’s animals. Recent rodent data have provided evidence that rodents have higher metabolisms and heat generation (Riskowski and Mermazedeh 2000). Ventilation Rate Ventilation rates have historically followed the 10 to 15 ac/h (fresh air) recommendation from the Guide. This range has proven to be a good range although different approaches allow lower ventilation rates while maintaining a stable animal room environment (i.e., ventilated caging systems). Some applications, species, and rooms require more than 15 ac/h. It should be emphasized that 10 to 15 ac/h has historically proven successful in managing most animal thermal and respiration loads and equipment loads. However, the Guide is clear that calculations must be performed to determine the air change rates required to remove the thermal and moisture loads and provide any additional make-up air exhaust devices (i.e., fume hoods or biosafety cabinets).

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop Lighting Lighting normally consists of dual levels (day/night) and override for cleaning. Present methods of monitoring and controlling lighting are to use the building automation or environmental monitoring systems. Typical ranges applied are 30 foot-candles (f.c.) for day, 0 f.c. for night. Lighting levels for cleaning range from 70 to 100 f.c. for 1 hour. Containment Reduction of cross-contamination between holding rooms is normally accomplished through pressurization—supply/exhausting air to/from the room to direct air in or out of the room. Quarantine, isolation, biohazards, and nonhuman primates should be kept under negative pressure. Pathogen-free animals, surgery, and cleaning and equipment storage should be kept under positive pressure. The bubble diagram in Figure 1 is an illustration of different types of pressure schemes that can be found in a vivarium. FIGURE 1 Example of the different types of pressure schemes in an animal research laboratory vivarium.

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop Air Quality Current guidelines provide no criteria to judge air quality. Past practices have included the use of high-efficiency particulate air (HEPA) filters. The Guide recommends HEPA filters for certain areas—surgery and post-operative holding rooms. Heating, ventilation, and air-conditioning (HVAC) systems normally use ASHRAE-rated filters, which are effective at keeping HVAC system components clean and extend the life of HEPA filters. TECHNOLOGICAL ADVANCES Recently, a greater focus has been placed on the room environment, which includes room allergen levels, the migration of airborne pathogens, temperature/humidity comfort levels, and biosafety containment. Animal facilities are now utilizing a more comprehensive and scientific approach to address these concerns. The analytical tool of choice to aid in the design of these rooms is computational fluid dynamics (CFD). CFD has been used successfully over the past 20 years for accurate modeling of air currents, temperature, and humidity levels. The method is further evolving to include fresh air dwell times, particulate movement, stagnation, and projected odor levels. Other parameters that may be studied include inlet diffuser type, animal heat loads, cage/rack placement, and exhaust air systems placement. CFD provides a visual representation of the effects of airflow in the holding room and a better understanding of the room dynamics. Together, these advances provide better scientific data for the development of future guidelines. Figure 2 is an illustration of a sample of CFD output that was used to determine odor migration in a canine holding room, modeling several different versions of supply/ exhaust placement, to determine which arrangement provided better containment of odor (AALAS 2003). GAPS IN CURRENT GUIDANCE AND CRITERIA Noise and Vibration Currently, there is no acoustical criterion for animal rooms contained in the Guide or from ASHRAE. The hearing ranges of animals are different from humans, and the ranges are different among species. Examples of ranges are shown in Figure 3. Limited published data are available on sound sources and mitigation techniques. Numerous internal studies have been performed, and techniques and strategies have been developed to mitigate noise, which

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop FIGURE 2 Computational fluid dynamics (CFD) analysis of a canine holding room. CFD was used to develop a three-dimensional model of a gas concentration in a room at the prescribed concentration level of 5 ppm. End view, NH3 isosurfaces measuring 5 ppm. FIGURE 3 Examples of differences among the hearing ranges of humans and various animal species. Modified from Warfield (1973) and Sales and Pye (1974).

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop can be helpful in developing criteria for future updates to current guidelines. Published vibration criteria for animal facilities are also very limited, but again, numerous internal studies have been performed that could help the industry establish such criteria. Performance Standard for Ventilated Cages Ventilated caging systems have evolved into many different airflow strategies based on the work of various manufacturers. Generally, manufacturers have worked closely with animal research professionals to develop caging systems that have well-founded concepts. It is recommended that the scientific community, along with industry professionals and manufacturers, develop a performance standard for ventilated cages to identify the knowledge base and the most important criteria. SUMMARY Established guidelines have proven to work well but have not been updated to reflect new trends in vivarium research that affect the environment. Technology has advanced our understanding of the macro- and micro-environment. Independent research and testing have produced new insights that have affected the vivarium environment. Additional guidance and work are required to close the gaps. Variances based on scientific data are recognized and allowed in the Guide. RECOMMENDATIONS Update ASHRAE guidance based on current research. Update the Guide to include criteria for noise and vibration. Develop a performance standard for ventilated cages. Provide guidance to industry in a new facility design guide that can incorporate technological advances and current practices. REFERENCES AALAS [American Association of Laboratory Animal Science]. 2003. Evaluating odor migration in a new kennel project using CFD analysis. Poster presentation at the October 2003 meeting of the American Association for Laboratory Animal Science held in Seattle, Washington. ASHRAE [American Society of Heating, Refrigerating and Air-Conditioning Engineers]. 2003. HVAC applications. In: ASHRAE Handbook. Atlanta, GA.

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop CDC [Centers for Disease Control and Prevention]. 1999. Biosafety in Microbiological and Biomedical Laboratories. Atlanta, GA: CDC. NIH [National Institutes of Health]. 1999. NIH Design Policy and Guidelines. Bethesda, MD: NIH. NRC [National Research Council]. 1996. Guide for the Care and Use of Laboratory Animals. 7th ed. Washington, D.C.: National Academy Press. Riskowski, G.L., and F. Memarzadeh. 2000. Investigation of statis microisolators in wind tunnel tests and validation of CFD cage model. ASHRAE Trans 106:867-876. Ruys, T., ed. 1991. Handbook of Facilities Planning. Vol 2. Laboratory Animal Facilities. New York: Van Nostrand Reinhold. Sales, G., and D. Pye. 1974. Ultrasonic Communication by Animals. London: Chapman & Hall. UFAW [Universities Federation for Animal Welfare]. 1996. Noise in Dog Kennnelling: A Survey of Noise Levels and the Causes of Noise in Animal Shelters, Training Establishments, and Research Institutions. Herts, UK: UFAW. USDA [US Department of Agriculture]. 2002. ARS 242.1M. Washington, DC: Agricultural Research Service of USDA. Warfield, D. 1973. The study of hearing in animals. In: Gay, W., ed. Methods of Animal Experimentation. London: Academic Press. p. 43-143.

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop European Guidelines for Environmental Control in Laboratory Animal Facilities Harry J. M. Blom Like farm animals and pets, laboratory animals were originally derived from wild living ancestors. The early scientists started to house and breed those animal species, mainly mammals, which were easiest to maintain under artificial conditions in terms of economics and animal needs. Of course, other criteria also played an important role in the selection process. The species of choice needed to be accurate models for biomedical research, the results of which were to be extrapolated to humans. Further easy breeding, a short life cycle, and large numbers of offspring were preferred—arguments that resulted in the use of rodents for experimental purposes. However, when introduced in the laboratory, the animals had to go through a process of habituation to the artificial housing conditions that far from resembled the animal’s natural living environment. Animal enclosures in the modern animal facility are of a much better quality, and conditions are adequately controlled. Still, animals may be unable to adapt to these housing conditions and consequently may develop abnormal behavior, stress, affected physiology, and/or mental state. Therefore it is essential to define standards for housing conditions that meet the animals’ requirements. Preferably these standards should be based on scientific data. Prevailing expert views and daily practice are to be considered acceptable when scientific data are not available. The aim of international regulations for the care and use of laboratory animals is to enhance animal welfare, to set standards, to harmonize procedures, and to safeguard the quality of biomedical research. The Euro-

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop pean regulations for the protection of animals used for experimental and other scientific purposes are based on both scientific results and common sense. Directive 86/609/EEC provides mandatory guidelines for the 15 nations that are joined in the European Union. Convention ETS 123 has been set up by the 45 member states of the Council of Europe. The content of the Convention is mandatory in those member states that have signed and ratified this document. In both cases, the national authorities are obliged to transpose and implement the European regulations into national law. At this time, Appendix A to Convention ETS 123, providing guidelines for the housing and care of laboratory animals, as well as the European Directive are being revised. Other authors in these proceedings will elaborate on both revision processes. The focus of this presentation is on the new content of Appendix A. After a special workshop in Berlin, Germany, in 1995, a Multilateral Consultation in 1997, and seven consecutive 3-day Working Party meetings in the period 1999-2003 at the Council of Europe in Strasbourg, France, discussion has been finalized for the General Part of Appendix A and for the species-specific sections for rodents and rabbits, dogs, cats, ferrets, nonhuman primates, and amphibians. It is anticipated that discussion on the sections for farm animals, birds, reptiles, and fish can be closed during the next meeting in early June 2004. Late in 2004, a Multilateral Consultation should conclude the revision process. The documents that are still under debate are restricted. The information presented herein is therefore limited to the finalized sections. With respect to environmental conditions, the General Part contains provisions that are universally applicable to all laboratory animal species (Table 1). Where appropriate, the species-specific sections provide detailed guidelines, values, or ranges to meet the particular needs of the species concerned (Table 2). All provisions apply to inside enclosures. Where animals have access to outside enclosures, it is strongly recommended to prevent prolonged exposure to extreme climate conditions such as heat, frost, bright sunlight, or heavy rainfall. Although some species may tolerate such weather conditions relatively well, the animals should always have the ability to make a free choice to go inside or seek shelter. As mentioned, the new sections in the revised Appendix A are based on scientific results. Unfortunately the availability of such data is limited. Thus, where science could not support the discussions during the Working Party meetings, there was no other option than to rely on expert views and common sense—a procedure that is fully justifiable but that emphasizes at the same time the need for further research into the tuning of housing conditions in the laboratory with the needs of the animals living in this artificial environment. The main problem to be solved is to generate

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop Breakout Session: Environmental Control for Animal Housing—Impact on Metabolism and Immunology Leaders: Jann Hau and Randall J. Nelson Rapporteur: Stephen W. Barthold The introductory discussion focused on the impact of new guidelines on immune response and metabolism. Significant changes that may influence these responses include social grouping, environmental enrichment, and enclosure size. Questions: Is there consistent scientific evidence for an impact of social environment (or environmental enrichment) on the immune system and metabolism? If so, is the evidence species specific? Is there a need for additional research on the impact of social environment or environmental enrichment on immune system and metabolism? If yes, in which areas? Is it possible to produce guidelines (or “best practices”) for group sizes of different species (strains, sexes, age groups) that would be optimal (i.e., not cause added variation to immune system and metabolism parameters)? Does the answer to this question depend on the project or parameter studied? Will there be a need for single housing to control variation with respect to immune system and metabolism? To develop “best practices” how should the group categorize the species (e.g., rodents vs. primates; solitary vs. social)?

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop Is it necessary to code these “best practices,” or is a mixed model of voluntary AND regulatory practices most sensible? Is it necessary to distinguish clearly between “stock and use” situations (i.e., one type of housing for the “hotel” period and another type of housing for the “experiment” period)? Is it necessary to consider the case of breeding colonies? Drs. Hau and Nelson presented the following specific situations involving primates that illustrate these issues: Single-housed gorillas have elevated cortisol (Stoinsky and others 2002). Single housing of rhesus causes long-term immunosuppression (Lilly and others 1999). Single housing of African green monkeys induces immunosuppression (Suleman and others 1999). Pair housing of marmosets reduces cortisol response to novelty (Smith and others 1998). Social separation of cynomolgus monkeys exacerbates atherosclerosis (Watson and others 1998). Transfer from natal group to peer group of juvenile rhesus affects cortisol and T cell subsets (Gust and others 1992). Separation of juvenile rhesus from natal group induces immunosuppression (Gordon and others 1992). Formation of unrelated rhesus females into groups induces immunosuppression (Gust and others 1991). Social group stress induces endothelial dysfunction in cynomolgus monkeys (Strawn and others 1991). Examples of situations involving rats include the following: Isolation advances puberty; enrichment delays puberty (Swanson and van de Poll 1983). Single housing impairs testosterone synthesis and produces Leydig cell atrophy (Nyska and others 1998); increased exercise induces weight loss (Boakes and Dwyer 1997). Group-housed rats are less stressed than single-housed (Sharp and others 2002, 2003) but are more vulnerable to stress-induced ulcers (Pare and others 1985). Individually reared rats have a less than adequate response to aggression (Von Frijtag and others 2002). Single housing (accompanied by stress) does not reduce the immune response of the rat to an antigen (Baldwin and others 1995).

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop Single-housed rats are characterized by: Higher levels of cortisol and prolactin (Gambardella and others 1994); Increased substance P in the spinal cord (Brodin and others 1994); Reduction of hypertension in obese rats; and Reduced tumor growth (Steplewski and others 1987). Examples of situations involving laboratory rodents include the following: Single housing does not change glucocorticoid concentrations (Benton and Brain 1981; Misslin and others 1982) and does not affect reaction to a stressor (immunosuppression; Bartolomucci and others 2003). Single housing induces immunosuppression (Shanks and others 1994). Crowding males potentiates corticosterone response to acute stress (Laviola and others 2002). Single-housed rats and mice behave differently in behavioral tests (Karolewicz and Paul 2001; Palanza and others 2001). Minimal stress with four mice per cage compared with two or eight per cage (Peng and others 1989). Male aggression is greater in groups of eight than in groups of three to five. Decreasing floor space decreases aggression (Van Loo and others 2001). Social housing influences have included the following: Expression of heat shock proteins (Andrews and others 2000); Corticotropin-releasing factor and GABA receptors (Matsumoto and others 1997); Chemotherapeutic efficacy (Kerr and others 1997, 2001); Tumor growth (Kerr and others 2001; Rowse and others 1995; Weinberg and Emerman 1989); Streptozotocin-induced hyperglycemia (Mazelis and others 1987); and Hematopoiesis (Williams and others 1986). Experience from immunization has been documented. Group-housed males have: Higher cortisol levels and are immunosuppressed compared with single housed and family housed;

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop Primary response to an antigen is low but response to booster injection is normal (Abraham and others 1994); No reports on difference in titer (e.g., development in rabbits housed in different social groups). Examples of the effect of enrichment include the following: Barren-housed pigs have impaired long-term memory and blunted circadian cortisol rhythm (de Jong and others 2000). Environmental enrichment stimulates the hypothalamic-pituitary-adrenal axis and the immune system in mice (Marashi and others 2003). Numerous examples of the positive effect of enrichment on brain function are in the literature (e.g., reviews by Larsson and others 2002; Mattson and others 2001; Risedal and others 2002; Schrijver and others 2002). VARIANCE IN EXPERIMENTAL RESULTS The contribution of enrichment to variance in experimental results appears to depend on respective parameters. Dr. Nelson discussed the issue of density of animals in a room, using species variation as an example. He discussed data that indicated high-density populations result in high steroid concentrations and decreased immune function in mice (e.g., Csermely and others 1995; Tsukamoto and others 1994), but increased immune function in prairie voles (Nelson and others 1996). Thus, he concluded that intuition cannot be used in establishing guidelines, which reinforces the concept that guidelines must be science based and species sensitive. Dr. Nevalainen presented data regarding volatile compounds in bedding, and environmental enrichment with variable material. Some bedding materials contain chemicals known as pinenes, which are heat labile, but induce hepatic microsomal enzymes (Nevalainen and Vartainen 1996). He also emphasized the need to utilize consistent materials for enrichment that are inert to other environmental materials to which the animals are exposed. DISCUSSION AND POINTS RAISED BY PARTICIPANTS One participant raised the issue of diet as another environmental variable that is not well controlled. There is a trend to replace some ingredients with others, such as replacing fish protein with casein. It was also noted that there is a growing number of rodents with suppressed immune responses due to highly hygienic husbandry practices among commercial

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop breeders. Dr. Hardy cited an instance in which BALB/cByJ mice have a 4- to 10-fold decrease in total immunoglobulin (Ig)G, decreased mass to organized lymphoid tissue, and resulting shifts in immune reactivity. In highly sensitive studies, there is an increased trend of using gnotobiotic mice that are significantly affected by this phenomenon of immune system hypoplasia. For this reason, it was felt that it is important to determine the standards for rodent microflora. Users have a high sensitivity to issues relating to “microbial drift” in breeder colonies, which in turn have a large impact on breeders. Some strains of mice, including many transgenic mice, are more sensitive than others to these effects. Other effects of this immune hypoplasia syndrome include plasmacytogenesis in BALB mice primed with pristane, in which the mice have decreased yield and primarily IgM, rather than IgG. Susceptibility to other infections such as Giardia is also seen. Biological endpoints have changed drastically and are generally more sensitive. Thus, the impact of environmental variables becomes more obvious and poses challenges for high-throughput analyses. How long do animals need to acclimate before being placed in test environments? Most people use a range of 24 hours to 5 days, but there have been no new data for more than 20 years. The animals may never acclimatize, such as when they are singly housed after having been maintained in a group. Many participants indicated that guidelines and regulations are not the answer. The Materials and Methods sections in scientific publications must provide documentation of the study design, including such variables. Unfortunately, journals encourage less, rather than more, detail, which reduces the reproducibility of science and increases unnecessary use of animals to obtain reproducible results in other laboratories. The underlying principle is that “variance varies with various variables,” and guidelines or regulations with straight and narrow standards or limits interfere with this concept. When discussing the possibility of developing guidelines for optimal group sizes, participants indicated that consideration needs to be given to factors such as species, sex, and strain, which make such rigid guidelines impossible. The answer depends on the project, and science must guide science, not rigid regulations. The current Guide (NRC 1996) dictates the number of mice per unit area of cage, and these guidelines, which are not based on science, are still often used as rigid standards. Considerable discussion revolved around the fact that the Guide is a guide, and that it is being misused by regulators. More details in any new iterations of the Guide will likely create more rules, without real benefit to animals or science. Dr. White’s presentation accurately depicted the reality. The Guide has only three musts in the entire book. IACUCs and regulatory agencies need better education regarding the purpose and limitations of the Guide.

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop The Canadians seem to be doing the best, with a highly flexible and adaptive system of guidelines and oversight. Finally, discussion of enriched versus nonenriched environments continued. Moving animals from unenriched production environments to different enriched environments for holding, then nonenriched environments for experimentation, creates enormous variation in response. Thus, it was felt that consideration must be given to the impact of new guidelines that may be well intentioned but not based on science and their impact on science. REFERENCES Abraham, L., O’Brien, D., Poulsen, O.M., Hau, J. 1994. The effect of social environment on the production of specific immunoglobulins against an immunogen (human IgG) in mice. In: Bunyan, J., ed. Welfare and Science. London: Royal Society of Medicine Press. p. 165-170. Andrews, H.N., Kerr, L.R., Strange, K.S., Emerman, J.T., Weinberg, J. 2000. Effect of social housing condition on heat shock protein (HSP) expression in the Shionogi mouse mammary carcinoma (SC115). Breast Cancer Res Treat 59:199-209. Baldwin, D.R., Wilcox, Z.C., Baylosis, R.C. 1995. Impact of differential housing on humoral immunity following exposure to an acute stressor in rats. Physiol Behav 57:649-653. Bartolomucci, A., Sacerdote, P., Panerai, A.E., Peterzani, T., Palanza, P., Parmigiani S. 2003. Chronic psychosocial stress-induced down-regulation of immunity depends upon individual factors. J Neuroimmunol 141:58-64. Benton, D., and Brain, P.F. 1981. Behavioral and adrenocortical reactivity in female mice following individual or group housing. Dev Psychobiol 14:101-107. Boakes, R.A., and Dwyer, D.M. 1997. Weight loss in rats produced by running: effects of prior experience and individual housing. Q J Exp Psychol [B] 50:129-148. Brodin, E., Rosen, A., Schott, E., Brodin, K. 1994. Effects of sequential removal of rats from a group cage, and of individual housing of rats, on substance P, cholecystokinin and somatostatin levels in the periaqueductal grey and limbic regions. Neuropeptides 26:253-260. Csermely, P., Penzes, I., Toth, S. 1995. Chronic overcrowding decreases cytoplasmic free calcium levels in T lymphocytes of aged CBA/CA mice. Experientia 51:976-979. de Jong, I.C., Prelle, I.T., van de Burgwal, J.A., Lambooij, E., Korte, S.M., Blokhuis, H.J., Koolhaas, J.M. 2000. Effects of environmental enrichment on behavioral responses to novelty, learning, and memory, and the circadian rhythm in cortisol in growing pigs. Physiol Behav 68:571-578. Gambardella, P., Greco, A.M., Sticchi, R., Bellotti, R., Di Renzo, G. 1994. Individual housing modulates daily rhythms of hypothalamic catecholaminergic system and circulating hormones in adult male rats. Chronobiologia Int 11:213-221. Gordon, T.P., Gust, D.A., Wilson, M.E., Ahmed-Ansari, A., Brodie, A.R., McClure, H.M. 1992. Social separation and reunion affects immune system in juvenile rhesus monkeys. Physiol Behav 51:467-472. Gust, D.A., Gordon, T.P., Wilson, M.E., Brodie, A.R., Ahmed-Ansari, A., McClure, H.M. 1992. Removal from natal social group to peer housing affects cortisol levels and absolute numbers of T cell subsets in juvenile rhesus monkeys. Brain Behav Immun 6:189-199.

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop Karolewicz, B., and Paul, I.A. 2001. Group housing of mice increases immobility and anti-depressant sensitivity in the forced swim and tail suspension tests. Eur J Pharmacol 415:197-201. Kerr, L.R., Grimm, M.S., Silva, W.A., Weinberg, J., Emerman, J.T. 1997. Effects of social housing condition on the response of the Shionogi mouse mammary carcinoma (SC115) to chemotherapy. Cancer Res 57:1124-1128. Kerr, L.R., Hundal, R., Silva, W.A., Emerman, J.T., Weinberg, J. 2001. Effects of social housing condition on chemotherapeutic efficacy in a Shionogi carcinoma (SC115) mouse tumor model: influences of temporal factors, tumor size, and tumor growth rate. Psychosomat Med 63:973-984. Larsson, F., Winblad, B., Mohammed, A.H. 2002. Psychological stress and environmental adaptation in enriched vs. impoverished housed rats. Pharmacol Biochem Behav 73:193-207. Laviola, G., Adriani, W., Morley-Fletcher, S., Terranova, M.L. 2002. Peculiar response of adolescent mice to acute and chronic stress and to amphetamine: evidence of sex differences. Behav Brain Res 130:117-125. Lilly, A.A., Mehlman P.T., Higley, J.D. 1999. Trait-like immunological and hematological measures in female rhesus across varied environmental conditions. Am J Primatol 56:73-87. Marashi, V., Barnekow, A., Ossendorf, E., Sachser, N. 2003. Effects of different forms of environmental enrichment on behavioral, endocrinological, and immunological parameters in male mice. Horm Behav 43:281-292. Matsumoto, K., Ojima, K., Watanabe, H. 1997. Central corticotropin-releasing factor and benzodiazepine receptor systems are involved in the social isolation stress-induced decrease in ethanol sleep in mice. Brain Res 753:318-321. Mattson, M.P., Duan, W., Lee, J., Guo, Z. 2001. Suppression of brain aging and neurodegenerative disorders by dietary restriction and environmental enrichment: molecular mechanisms. Mech Ageing Dev 122:757-778. Mazelis, A.G., Albert, D., Crisa, C., Fiore, H., Parasaram, D., Franklin, B., Ginsberg-Fellner, F., McEvoy, R.C. 1987. Relationship of stressful housing conditions to the onset of diabetes mellitus induced by multiple, sub-diabetogenic doses of streptozotocin in mice. Diabetes Res 6:195-200. Misslin, R., Herzog, F., Koch, B., Ropartz, P. 1982. Effects of isolation, handling and novelty on the pituitary—adrenal response in the mouse. Psychoneuroendocrinology 7:217-221. Nelson, R.J., Fine, J.M., Moffatt, C.A., Demas, G.E. 1996. Photoperiod and population density interact to affect reproductive, adrenal, and immune function in male prairie voles (Microtus ochrogaster). Am J Physiol 270:R571-R577. Nevalainen, T., and Vartainen, T. 1996. Volatile organics compounds in commonly used beddings before and after autoclaving. Scand J Lab Anim Sci 23:101-104. NRC [National Research Council]. 1996. Guide for the Care and Use of Laboratory Animals. 7th ed. Washington, DC: National Academy Press. Palanza, P., Parmigiani, S., vom Saal, F.S. 2001. Effects of prenatal exposure to low doses of diethylstilbestrol, o,p’DDT, and methoxychlor on postnatal growth and neurobehavioral development in male and female mice. Horm Behav 40:252-265. Pare, W.P., Vincent, G.P., Natelson, B.H. 1985. Daily feeding schedule and housing on incidence of activity-stress ulcer. Physiol Behav 34:423-429. Peng, X., Lang, C.M., Drozdowicz, C.K., Ohlsson-Wilhelm, B.M. 1989. Effect of cage population density on plasma corticosterone and peripheral lymphocyte populations of laboratory mice. Lab Anim 23:302-306.

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop Breakout Session: Environmental Control/ Engineering Issues Leaders: Bernard Blazewicz and Dan Frazier Rapporteur: Janet Gonder Participants began by listing a series of issues for possible discussion. Topics included biosafety and biosecurity; ventilation rates and effectiveness of ventilation; ventilated caging systems; relative humidity control; sources of humidification; monitoring; need for filtration; and sources of contaminants. Several of these issues were discussed. Discussion of the engineering issues related to biohazard research centered around biosafety level (BSL) 3 and BSL4 housing for agricultural animals and nonhuman primates. The impetus for this discussion is the new funding for facility construction for national and regional containment laboratories and other research programs. Current design and construction references include the Centers for Disease Control and Prevention (CDC/NIH) Biosafety in Microbiological and Biomedical Laboratories (BMBL), National Institutes of Health (NIH) Guidelines and Policies, and the US Department of Agriculture (USDA) document ARS 242.1M. Of the many design considerations for this type of facility, it has become apparent that interpretation of the requirements is changing as experience is gained with these facilities. Participants identified a need for tracking these changes and experiences. It was noted that some of this information is available through the American Biological Safety Association (ABSA). The need for consideration of system redundancy was discussed, along with the need for more information to enable institutions to perform adequate risk assessments to maintain safety. It was also pointed

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The Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop out that there is a critical need for knowledgeable engineering staff in these facilities to monitor and maintain the systems. Ventilation rates of 10 to 15 air changes per hour (ac/h) have been cited in the Guide for the Care and Use of Laboratory Animals (Guide) as a reasonable general guidance. However, it was agreed that in some circumstances less than 10 ac/h may be adequate, whereas in other cases, more than 15 ac/h are needed to address the cooling load. The general endorsement from the breakout group is that the design of facilities should begin with calculations of the cooling load posed by the intended use of a room, and that the efficiency of ventilation depends not only on the rate but also on the room airflow distribution and the microenvironment of the primary cage, among other factors. One particular gap identified by participants was how to determine cooling load in a room with ventilated caging systems, that is, how much of the load is removed from the room by the exhaust and how much heat is transferred to the room from the cage. Data are needed in this area. This topic led to a discussion of ventilated caging systems. Approximately 12 systems are commercially available worldwide, and all are different in one or more respects. How can these systems be differentiated or evaluated for use under different use situations? Participants discussed a need for guidance on selection of ventilated caging systems based on criteria such as airflow balance to individual cages; airflow distribution within cages; ammonia levels; filtration expectations (e.g., control of particulates); temperature and humidity; containment (negative vs. positive pressure); noise; vibration; exhaust choices; and ergonomics. The group felt in general that standardized test methods for these and other parameters are needed.

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