Click for next page ( 2


The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 1
Guidance for the Description of Animal Research in Scientific Publications 1 Overview The publication of research articles involving animal studies is central to many disciplines in science and biomedicine. Effective descriptions in such publications enable researchers to interpret the data, evaluate and replicate findings, and move the science forward. To promote the inclusion of sufficient information in publications on animal studies,1 the National Research Council’s Institute for Laboratory Animal Research (ILAR) appointed a committee of experts in laboratory animal research and scientific publishing to provide guidance for journal editors, authors, and reviewers. Supported by private funding and other grants, the committee was charged as follows: [To] prepare a short report aimed at editors of journals that publish animal studies. The report will outline the information that should be included in scientific papers regarding the animal studies to ensure that the study can be replicated. The extent of the needed information will be determined by the committee, but will include for example, conditions of housing and husbandry, genetic nomenclature, microbial status, detailed experimental manipulations and handling and use of pharmaceuticals. Evidence-based rationale for the need to include this information will be presented. To complete its task, the committee conducted an extensive literature search about the impacts of various aspects of research animals and their environment. This report is the outcome of the committee’s work. The committee believes that journal editors have a role to play in promoting the proper use of animals in research through the publication of adequate descriptions. The committee urges journal editors to actively promote effective and ethical research2 by encouraging the provision of sufficient information to enable assessment and interpretation of research findings and advancement of knowledge based on reproducible results. This report provides journal editors, authors, and reviewers with guidance (and supporting references) for effective reporting of animal research in published articles based on adequate descriptions of • the research animal (section 3), with detailed information about the animals’ — age, sex, weight, and life stage (3.1), — source (3.2), — genetic nomenclature (3.3), — microbial/pathogen status (3.4), and — preparation and assignment (including control groups) (3.5); • the research animal environment (sections 4 and, for aquatic animals, 6), with detailed information about — the micro- and macroenvironment (4.4 and 6.1), 1 Including studies that use cells and tissues derived from animals for ex vivo and in vitro research. 2 The guiding principles for ethical animal research are the “three Rs”—reduction in the number of animals used, refinement of procedures to reduce animal stress and pain, and replacement of animals when possible (Russell and Burch 1959). 1

OCR for page 1
— diet (4.1 and 6.2), — water (4.2), and — housing (4.3 and 6.3); • basic animal methodology, including aspects of animal care and use that can affect research outcomes (section 5), with detailed information about — experimental effects (5.1), — administration of substances (5.2), — use of infectious agents (5.3), — sample acquisition (5.4), and — euthanasia (5.5). The ability to interpret, evaluate, and reproduce biomedical and other types of laboratory animal research and testing is a reasonable minimum standard for the assessment of effective reporting in research articles. Journal editors can substantially contribute to the achievement of this standard through the articulation of clear policies and criteria for their authors and reviewers. This report complements existing checklists and resources by providing guidance and scientific evidence for the specific types of information that should be included in research publications to promote the advancement of science involving animal studies. It also describes approaches to facilitate the provision of such information. 1.1 The Need for Guidance Analyses of published studies with research animals have demonstrated numerous deficiencies in the reporting of details in research methods for animal studies (Kilkenny 2009; Vesterinen et al. 2011). Despite multiple publications over the past 25 years calling attention to the critical factors and information necessary to enhance such reporting, most scientific journals provide relatively little specific guidance for authors and reviewers and there has been limited effort until quite recently (see next section) to address this systemic problem (Alfaro 2005; Ellery 1985; Öbrink and Rehbinder 2000; Smith et al. 1997). Most biomedical journal policies simply refer to regulatory requirements for animal use, without referring to critically important experimental design information. Lack of sufficient experimental procedural detail about animal studies in the research literature has both scientific and ethical implications: • It limits the ability to confirm and build on research findings. • It can lead to the unnecessary use of animals in studies that fail to reproduce the reported results. • It may mask problems in the quality of the design and conduct of animal studies (Dirnagl and Macleod 2009; Festing 2003; Festing and Altman 2002; Macleod et al. 2009; Rice et al. 2008). • It limits the ability to perform systematic reviews (Hooijmans et al. 2010; Peters et al. 2006; Ranstam 2010; Roberts et al. 2002). • The foregoing impacts may give rise to questions about experimental methods and the overall quality of the studies and thus erode support for the utility—and necessity—of laboratory animal research for informing human health treatments (Perel et al. 2007; Pound et al. 2004; van der Worp et al. 2010). The articulation of clear guidelines by journals for the reporting of animal-related studies will help to address many of these concerns. Useful journal policies will define requirements for accurate 2

OCR for page 1
descriptions of the research animal as an experimental test system, the critical elements of the research animal environment, and animal care and use practices that affect research results (Atlas 2003; Osborne et al. 2009). 1.2 Related Guidelines In recent years there have been growing, but incomplete, efforts to enhance the reporting of animal- related research: • The ARRIVE Guidelines (Animal Research: Reporting In Vivo Studies, www.nc3rs.org.uk/ARRIVE; Kilkenny 2010) from the UK National Centre for the 3Rs have been endorsed by a variety of journals and funding sources (Danos et al. 2010; Drummond et al. 2010; McGrath et al. 2010). A “Gold Standard Publication Checklist” (Hooijmans et al. 2010, 2011a,b) is also available for the reporting of animal studies. • Efforts to improve the reporting of biological and biomedical investigations resulted in the MIBBI project (Minimum Information for Biological and Biomedical Investigations, mibbi.org; Taylor et al. 2008). • The international EQUATOR Network (www.equator-network.org) was established to improve the reliability and value of medical research literature by promoting transparent and accurate reporting of research studies (Altman and Simera 2010; Simera et al. 2009, 2010). • Some journals (e.g., the British Journal of Cancer; Workman et al. 2010) and professional groups have adopted their own guidance, incorporating important aspects of animal care and use relevant to their fields of research (Auer et al. 2007; Ayala et al. 2010; Idris et al. 1996; Portaluppi et al. 2008; Touitou et al. 2006). In addition to these resources, guidance is available in occasional articles about animal-related information to include in reporting (e.g., genetic and environmental description of important factors that can result in study variability). Such guidance is the result of interest in harmonizing standard operating procedures and methods to facilitate the comparison of animal studies across laboratories (Ayala et al. 2010) and to allow the sharing of animal phenotyping data, particularly for genetically modified mice (Gates et al. 2011; Mandillo et al. 2008; McGuinness et al. 2009; Würbel 2002). Notwithstanding the examples cited above, there is no consensus or consistency among scientific publications about the basis for inclusion of adequate procedural detail in the reporting of animal research. The purpose of this report is to provide a firm basis for building such consistency. To the extent that a checklist approach is convenient, the committee cites as an example the ARRIVE Guidelines (Appendix A) and encourages journal editors and authors to use such a resource in conjunction with this report in determining the specific information to include in study reports for their publications. 1.3 Organization and Content of This Report This report is organized in general sections that align with the types of information to be considered for inclusion in the materials and methods section of a scientific manuscript, with discussion of particular aspects and variables that can influence outcomes: • the research animal (including source, genetics, microbial/pathogen status, preparation and study assignment, and monitoring during the study); • the research animal environment (including diet, water, housing, and micro- and macroenvironment); and • basic animal methodology (including administration of anesthetics, analgesics, and other substances; tissue and fluid sampling; and euthanasia). 3

OCR for page 1
These sections present criteria to consider and the rationales behind them, together with supporting references that provide scientific evidence of the potential impacts discussed. The committee acknowledges that this relatively concise guidance document cannot specifically address the array of animals and animal models used in biomedical research. Furthermore, because the vast majority are laboratory rodents,3 many of the references in this report pertain to these species, although they generally hold true for other animals used in research. In light of rapidly increasing research interest in zebrafish and other aquatic species, there is a separate section on aquatic systems. Finally, in light of space limitations especially in print publications, the report presents possible methods to facilitate the provision of appropriate procedural details and data. 2 Defining an Optimal Description of an Animal Study The definition of each journal’s policy will entail editors’ determination of the specific information to be included in descriptions of materials and methods, taking into account the field of endeavor, the intended audience of the publication, the type of study, the species and nature of the animal model, and the aims and objectives of the particular study being described. Complementing the criteria and checklists available, and in the absence of best practice standards, the following paragraphs present factors for journal editors to consider in determining their policy and for authors and reviewers to bear in mind in their approach to manuscript preparation and review. 2.1 How Much Detail Is Necessary? In descriptions of the materials and methods used in studies with animals, authors frequently simply state that the work was approved by the institutional animal care and use committee (IACUC) and/or conducted in an accredited facility4 without providing details of the conditions of the animal environment. IACUC approval and animal facility accreditation are general indications of program quality but in no way obviate the need for proper description of the test system and conditions of an experiment. As an example, multiple characteristics of a single environmental factor in an animal facility— lighting—affect behavioral and physiological processes and can thus influence a research endpoint (Bellhorn 1980; Dauchy et al. 2011). The description should therefore consider including type of lighting (natural vs. artificial), method of provision (fluorescent vs. LED), intensity, spectral qualities, duration, timing of light:dark cycles, control of method of onset, and methods used in reversal of circadian cycles. The amount of detail will depend on the type of study, the type of endpoint, and how light might affect the research—a study of phototoxic retinopathy in albino rodents or a breeding study in cats might require a very different description of lighting than the study of a surgical procedure in dogs. This report elucidates specific factors to consider when determining the details necessary for descriptions of research animal environment and husbandry, with selected references that provide information about species and types of models as well as factors known to induce variability in research outcomes. It is important to bear in mind that at the time of reporting the impacts of some factors may not be known; it is therefore better to err on the side of providing more rather than less detail. 3 In 2007 it was estimated that 60% of National Institutes of Health extramural funding supported research using animals, and that more than 80% of this research involved the use of mice (Valli et al. 2007). 4 Animal facilities are accredited internationally by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International and in accordance with European Union and national directives and legislation. 4

OCR for page 1
2.2 A Values-Based Approach The following values-based approach is provided to assist editors, reviewers, and investigators in assessing descriptions of the research animal and its care and use. Ideally, the information will be detailed enough to: (1) enable the reader to effectively interpret and evaluate the work; (2) ensure that others can replicate the experiments described; and (3) clearly convey refinement and reduction measures both to ensure transparency about effects on animals and to prevent unnecessary animal use and/or harm in efforts to replicate studies. These three points are important and fall directly within the role and responsibilities of journals and editors in supporting reproducibility as a means to ensure both effective science and ethical animal use. The committee therefore strongly encourages journals to provide clear, customized guidance for their authors and reviewers about the information to be included in descriptions of the research animal, the research animal environment, and animal care and use methods. 3 The Research Animal 3.1 General The following information is appropriate to include in the research animal description: genus and species (with the proper Latin designation), sex, internationally accepted genetic nomenclature, age, weight, and source of the animals used. The provision of specific procedural detail for these basic variables is a starting point for enabling replication. Sex influences numerous biological outcomes (Holdcroft 2007). For studies with mixed sex groups (e.g., with difficult to produce genetically modified rodents), an explanation of the composition and numbers and of how subjects are assigned to the groups is useful. In addition, the physiologic (e.g., pregnant, castrated) and/or pathologic status of the animal is also appropriate to include (more on pathologic status below). Both age and body weight (with ranges) are critical parameters to provide for all animal studies. The use of terms such as “weanling,” “fry,” “fingerling,” “aged animal,” and “retired breeder” for research animal description in the materials section of manuscripts is not sufficient or clear for describing life stage or physiologic status. Age is a function not only of time but also of species, genetic, and environmental factors (including husbandry) (Deerberg 1991). Age alters many biological outcomes (Deerberg 1991; Huang et al. 2007) and affects lesions, disease course, physiologic state, and response to experimental variables. Many publications, especially those that involve rat and mouse models, indicate body weight instead of age, and some investigators believe that the approximate age of rodents can be determined from charts of body weight curves available from commercial suppliers. However, body weight is not identical to age; the correlation is highly dependent on the animal’s life stage, stock, and strain. In addition, numerous husbandry, nutritional, and environmental factors strongly influence body weight, often through incompletely understood interactions (Haseman et al. 1997, 2003; Keenan et al. 1999; Laroque et al. 1997). Because weight correlates with many biological outcomes (Gaines Das 2002) it is important to include it in the animal description together with age (Klimentidis et al. 2010). When life stage factors (e.g., age at weaning, parity status, breeding history) are relevant to a study, they should be described in detail. For studies with pregnant animals, appropriate details include whether the animals were procured from external breeding sources or bred internally. Breeding 5

OCR for page 1
conditions and gestational age at shipment before experimental use may also be important information to provide, as well as details about litters culled to common size groups. Experimental results can be strongly influenced by breeding and parity status, especially for endpoints and physiologic states that are dependent on endocrine factors (Walker et al. 2001). There are also potentially profound differences between aged animal cohorts and those that are “retired breeders” as husbandry conditions and other aspects of the animal environment often differ between these populations; differences may include the type of housing, method of housing with conspecifics, and type and composition of diet. Retired breeding stock are therefore not to be considered synonymous with nonbreeding aged animals. 3.2 Source Many study reports do not specify the source of the animals used and instead indicate only stock/strain and/or breeder. But differences in environmental and microbial conditions between commercial breeders and between production facilities within a commercial breeding operation can be substantial and may affect study outcomes depending on the types of study endpoints (Wahlsten et al. 2003, 2006), so information about source colonies or origin (i.e., location) is usually relevant for all animals used.5 Different colonies—even from the same commercial vendor—may have been raised under differing husbandry and environmental influences, resulting in differing incidences of lesions (Engelhardt et al. 1993). Rodent colonies also exhibit differences in gastrointestinal microflora, which are dependent on both genetic and environmental factors (Hufeldt et al. 2010); this particular parameter is believed to be important for certain endpoints such as effects of gut flora on xenobiotic metabolism (Levin and Dent 1982). In outbred large animal stocks such as nonhuman primates, studies have shown that the origin of the animals can affect the outcome of an experiment or the development of background or induced lesions (Burwitz et al. 2009; Menninger et al. 2002; Vidal et al. 2010). Editors and reviewers can help to reduce the risk of inconsistent research outcomes from these variables by ensuring that the animal source and origin are specified by the author and carefully considered in the experimental design so that animals are not assigned to study groups with bias. Additional relevant information in some studies concerns the provenance of the animals or animal models (e.g., surgical and/or genetic modifications). Were they produced or procured? If the latter, what were the transport and acclimation methods, the timing of animal treatment and manipulation? For studies that involve the use of surgically modified animals, what was the period of time between the surgical procedure and experimental use? How was the animal maintained during and after the surgery and throughout the experiment? Many institutions encourage the efficient use, sharing, and/or reuse of research animals as a way to reduce the overall numbers of animals used. When animals are used in more than one study, it is essential to specify the previous use, with an explanation of how the animals were chosen for reuse and assigned to the study in question. 3.3 Genetics The use of internationally accepted genetic nomenclature is critical, especially in light of the dramatic increase in the use of genetically modified mice during the past decade. Furthermore, biological data are increasingly shared, analyzed computationally, and archived (Sundberg and Schofield 2009, 2010). In 5 Such information may be particularly important when “random source” animals are used (e.g., from shelters, pounds, or other nonlicensed sources). The health and background of such animals (often simply called mongrels, for example, without any information about their source) may vary widely and yield research results that are inconsistent or difficult to interpret (NRC 2009). 6

OCR for page 1
addition to correct, complete genetic designations, the replicability of studies with genetically modified rodents can be supported with clear references to or descriptions of gene targeting strategies and of the breeding and gene expression methods, backcross generations, substrain designation, and specific genotype of embryonic stem cells. There are profound differences among laboratory rodent substrains and origins, and particularly among lines of mouse strains such as the 129 and C57BL/6, both of which are used commonly in the creation of genetically modified mouse models (Doetschman 2009; Linder 2001, 2006; Simpson 1997; Yoshiki and Moriwaki 2006). The 129 mouse has been genetically corrupted over the years and it is now recognized that there are at least 16 inbred 129 lines. It is therefore important to specifically identify 129 lines as well as 129-origin embryonic stem cells (Simpson 1997). The use of shortened stock and strain designations (e.g., Sprague-Dawley rat or C57BL mouse) instead of the fully defined genetic nomenclature is not appropriate in published animal descriptions. For example, “Crl:WI(Han) rat” indicates the origin and source of this outbred rat, compared to the term ‘Wistar Han rat,” which does not indicate the source of the rat or whether it is inbred or outbred. For gene nomenclature, allele designations should be superscripted and indicate the type of mutation and the laboratory of origin, according to international nomenclature recommendations Rules for mouse genetic nomenclature were first published in 1940 and subsequently revised by the International Committee for Standardized Genetic Nomenclature in Mice. Rules for rat genetic nomenclature were first published by the Committee on Rat Nomenclature in 1992. In 2003, the International Committee on Standardized Genetic Nomenclature for Mice and the Rat Genome and Nomenclature Committee unified the rules and guidelines for gene, allele, and mutation nomenclature in mouse and rats. Nomenclature guidelines are now reviewed and updated annually by the two international committees; current guidelines are available on the Mouse Genome Database (MGD) and Rat Genome Database (RGD) websites (www.informatics.jax.org/mgihome/nomen/index.shtml and http://rgd.mcw.edu/nomen/nomen.shtml, respectively). The current nomenclature policies take precedence over previously published versions. Journal policies that require authors to use current, complete genetic nomenclature for all experimental cohorts and control groups will help to minimize ambiguity and promote evaluation, interpretation, and replication. 3.4 Microbial/Pathogen Status A great advance in laboratory animal science has been the control of common infections that plagued commercial rodent colonies in the past. Challenges persist, however, with emerging pathogens and continued infections by some of the “classical” adventitious agents, many of which induce subclinical infections (Barthold 1998; Bohr et al. 2006). The microbial/pathogen status of a research animal or animal model can influence many types of biological effects and study responses (Baker 1998; Franklin 2006; NRC 1991) and thus affect the ability to replicate findings. One challenge for investigators in describing the microbial status of their animals is definition of the term specific pathogen-free (SPF) (Norin and Midtvedt 2010). There is no universal agreement about which agents are considered pathogens or which should be excluded for particular types of research or species. Use of the term SPF and the determination of pathogen exclusion status are particularly problematic with genetically modified laboratory rodents. These animals are susceptible to known or unanticipated immune function dysregulation, which can result in vulnerability to opportunistic pathogens (Franklin 2006). Professional judgment is necessary in this section of the animal description, but ambiguity can be reduced by accompanying the term SPF with a list of the pathogens excluded, reference to the pathogen 7

OCR for page 1
exclusion list from the commercial supplier, or reference to a guidance document such as that produced by the Federation of European Laboratory Animal Science Associations (FELASA; Nicklas et al. 2002). In addition, a description of the equipment and procedures used to maintain microbial biosecurity during the experiment can be helpful in reducing variability based on pathogen status. 3.5 Preparation and Assignment of the Research Animal to Study Adequate descriptions include the methods used to prepare animals for studies, including the periods and procedures for quarantine, acclimation, training, or surgery. The description of habituation methods (e.g., sham dosing, acclimation to restraint equipment) is important as animals’ habituation to experimental procedures and equipment can significantly affect study outcomes (Damon et al. 1986). Data to include in the descriptions of xenobiotic administrations used during study preparation or quarantine periods are the product name, manufacturer, dose, delivery route, method, and timing of administration. Certain commonly used prophylaxis procedures during quarantine (e.g., parasiticide treatment of rodents for pinworm or mite infestation, or of fish for external parasites) can affect both the animals and certain study endpoints (Altholtz et al. 2006; Gao et al. 2008; Johnston et al. 2006; Vento et al. 2008). Has the author explained how animals were assigned to the study and the methods and criteria used to minimize bias (e.g., through randomization, blinding, exclusion, inclusion, and/or removal) (Bebarta et al. 2003; Martin et al. 1986)? In some instances, especially with selected strains of mice, littermates are housed together and used to form experimental groups in an effort to minimize male aggression and fighting; it is appropriate to state the use of this approach. Information about control animals is relevant. How did the control groups relate to the experiment? Were the controls concurrent, historical, littermates? Were they matched for animal, husbandry, manipulation, or study parameters? 4 The Research Animal Environment (Study Conditions) The study conditions of the research animal environment can be difficult to succinctly describe but are critical to interpretation and evaluation (Reliene and Schiestl 2006). Numerous aspects of the animal facility environment can affect study outcomes, not all of which can be detailed in the materials and methods section (Clough 1982). Again, it is preferable to provide more rather than less specific information to enable other investigators to effectively assess and reproduce the research. At a minimum, the description in the materials and methods section specifies the type of diet, housing, bedding, water, and general environmental parameters (e.g., temperature, humidity, lighting) with ranges. Effective descriptions also include aspects of the animal facility environment that are known to affect the study type or endpoints. For example, in experiments with endocrine disrupters, leaching of estrogenic substances from plastic caging or water bottles, or phytoestrogen exposure in the diet, can affect study results, so it is appropriate to describe these factors in more detail than in other types of studies (Ashby et al. 2004; Everitt and Foster 2004; Hunt et al. 2003). Dosed-feed toxicity studies in rodents may be subject to experimental confounders from cross contamination by housing control cohorts and experimental groups in the same room, so a detailed description of caging, air flow, or handling procedures may be warranted. Similarly, fish used in toxicological studies may excrete metabolites into the water column that may affect cohorts in the same tank or fish in different tanks on the same filtration system. 8

OCR for page 1
4.1 Diet Diet is a potential source of variation in many types of studies, so a detailed description of food and feeding methods is important to include for every study (Haseman et al. 2003; Newberne and McConnell 1980; Newberne and Sotnikov 1996; Nold et al. 2001; Rao and Crockett 2003). Diets vary in type, form, nutrients, caloric content, levels of contaminants, and methods of preparation, and each of these characteristics can affect the animals and the study results (Barnard et al. 2009; Ford and Ward 1983). In addition to the frequency and method of feeding (e.g., ad libitum vs. portioned), effective reports include the type of diet, source, manufacturer, catalogue or batch number, dietary form, and any dietary supplements. Specialty diets, in particular, require detailed descriptions that may include handling and storage methods. Designations such as “standard laboratory chow,” “breeder chow,” “commercial dog food,” and “fish pellets” are never appropriate. When experimental substances are added, a description of the methods of feeding (e.g., pair feeding) and dose determination is relevant; the presentation of food consumption data may be warranted in these cases. Information about food handling and preparation procedures, such as autoclaving or irradiation, is also useful as these may adversely affect the food (e.g., its nutritional quality, palatability, or shelf life; Anderson et al. 1981; Ford 1977; Twaddle et al. 2004; Zimmerman and Wostmann 1963). For nutrition or metabolic experiments, an adequate description notes not only the specific feedstuffs (with nutrient and caloric content if customized diets are used and the reader cannot otherwise access such information) but also, when relevant, the extent and method of any dietary restriction because caloric intake affects many experimental parameters (Deerberg et al. 1990; Laroque et al. 1997; Masternak et al. 2005). Information about food contaminant levels, diet certification, or nutrient analysis is usually appropriate for nutrition or toxicology studies (Barnard et al. 2009; Newberne and Fox 1980; Newberne and Sotnikov 1996; Silverman and Adams 1983). For articles about endocrine- related research, readers will need detailed information about food handling procedures and the animals’ diet, especially in light of numerous reported differences between studies and between laboratories that study endocrine disruptor compounds (Brown and Setchell 2001; Heindel and vom Saal 2008; Muhlhauser et al. 2009; Naciff et al. 2004; Thigpen et al. 2003, 2004; Wang et al. 2005). 4.2 Water Specific information about drinking water source, delivery methods, and treatments (e.g., acidification, chlorination, sterilization) is important to provide; some treatments, in particular, are known to affect certain experimental parameters (Bjornsson et al. 2003; Hall et al. 1980; Hermann et al. 1982; Merne et al. 2001). In certain types of studies water delivery methods have been known to be an important component of husbandry as well (Gordon and Wyatt 2011). (Water environment for fish and other aquatic species is discussed separately in the section on Aquatic Systems.) 4.3 Housing Adequate descriptions of housing convey the physical, microbial, and social features of the animals’ proximate environment, including the following information: • the nature of the housing (controlled environment vs. outdoor), including temperature, humidity, lighting, with ranges; • type of caging (e.g., static vs. ventilated, filtered vs. unfiltered, style, composition, dimensions); 9

OCR for page 1
• bedding and nesting materials (composition, amount, analysis); • cage complexity (enrichment); • housing paradigm (group/multiple vs. single); • method of cage handling (frequency and methods, aseptic transfer, methods of sterilization); and • nondomiciliary specialized housing such as metabolism caging, isolators, or inhalation exposure housing. Taken together, these details will convey the animals’ microenvironment (including local microbial burden and air quality), which is influenced by numerous housing variables (Keller et al. 1989; Lipman 1999; Stark 2001). For example, the air quality in a rodent cage is affected by the type of cage (solid, filter-capped, ventilated), whether it contains direct contact bedding, the animals’ diet, and the number of animals (Keller et al. 1989; Krohn and Hansen 2002; Lipman et al. 1992; Macy et al. 2002; Memarzadeh et al. 2004; Rosenbaum et al. 2009). Caging type, size, and composition can affect behaviors and physiologic responses (Abramov et al. 2008; Freed et al. 2008; Gordon and Fogelson 1994; Kallnik et al. 2007; Mineur and Crusio 2009; Stark 2001; Steplewski et al. 1987; Tsai et al. 2003). Similarly, bedding type, manufacturer, source, treatment and storage before use, and quantity can be important because bedding is known to influence study outcomes through effects on the animals and/or their microenvironment, including through the presence of contaminants (Becker et al. 2010; Bohonowych et al. 2008; Buddaraju and Van Dyke 2003; Gordon 2004; Perkins and Lipman 1995; Potgieter and Wilke 1997; Potgieter et al. 1996; Rosenbaum et al. 2009; Sanford et al. 2002; Silverman and Adams 1983; Smith et al. 2004). Growing international interest in the welfare of research animals has led to support for the provision of environmental complexity and enrichment and, when possible, the housing of research animals in socially compatible groups. These elements of the housing environment have many effects both known and unknown (Bayne 2005; Gortz et al. 2008; Haemisch and Gartner 1994; Jankowsky et al. 2003; Lawson et al. 2000; Tsai et al. 2002; Whitaker et al. 2009). To account for possible effects that might introduce variability in the results, it is important to provide detailed descriptions (including source information) about all cage additions, including nesting and other materials used for enrichment, in the materials section. A description of the grouping of animals and details of their housing are relevant as a number of studies have reported dramatic differences in scientific outcomes based on single versus group housing (Andrews et al. 2000; Haseman et al. 1994, 2003; Nevalainen et al. 2007; Nyska et al. 1998). The handling of cages—for example, the frequency and method of cage changing—can affect study outcomes (Burn et al. 2006; Vesell et al. 1976). If microbial status is important in an experiment, description of cage sterilization methods and aseptic cage changing methods may be warranted. Because cage placement, both in rooms and on racks, has been associated with effects in long-term studies (e.g., for toxicity/oncogenicity or inhalation research), a description of methods to rotate cages on racks to minimize any environmental bias is useful (Herzberg and Lagakos 1992). 4.4 Macroenvironment The macroenvironment of the animal room—temperature, humidity, lighting, ventilation—influences the microenvironment and therefore is relevant information (Dauchy et al. 2011; Rosenbaum et al. 2010). For most studies the materials section includes specifics such as temperature range, relative humidity range, and aspects of lighting such as the timing of light:dark cycles and dimming to mimic circadian cycles. Ambient temperature affects many research endpoints (Jhaveri et al. 2007; Swoap et al. 10

OCR for page 1
2004; Zhao et al. 2010), and relative humidity can directly affect animals and interact with other environmental parameters such as temperature to influence study outcomes (Ashida and Denda 2003; Diercks et al. 2010; Drickamer 1990; McJilton et al. 1976). Other aspects of the physical environment, such as sound, ventilation, and vibration, can affect the outcome of certain types of studies (NRC 2010, 45-47). Discussion of the degree to which the animal environment was controlled and to what extent there was variance from the reported values will assist readers in interpreting and reproducing the results. 5 Basic Animal Methodology 5.1 Description of the Research Animal during the Study A description (in the results and/or discussion) of any significant effects of the study on the animal subjects, including clinical effects or the removal or loss of animals, will be of interest to readers. Criteria for removal from the study are relevant, accompanied by a description of any clinical assessment or scoring systems (Ray et al. 2010; Toth 2000). This portion of the report is also the place for authors to note animals that died or were euthanized during the study and to discuss the cause of death and its implications for the study. (Euthanasia is further discussed in the section on Basic Animal Methodology.) 5.2 Administration of Anesthetics, Analgesics, and Other Substances It is important to identify all substances administered to research animals, including those not part of the experiment (e.g., treatments for clinical conditions that arise during the study), with generic description, trade name, catalogue or batch number if relevant, and vendor name and address, together with a description of the preparation and handling of the substances, including any modifications to concentration. Similar details are appropriate for vehicles and excipients. Adequate reporting also includes information about the relationship of dose administration to feeding or fasting (Adams et al. 2009) and about methods to minimize bias such as timing (and order) of dose administration, food or water removal, or blinding. All preanesthetic agents, anesthetics, and analgesic drugs have the potential to induce numerous and varied effects on studies and consideration and discussion of these effects is warranted (Adams et al. 2008; Avsaroglu et al. 2007; Flecknell 1993; Hampshire et al. 2001; Heavner 2003; Katz et al. 2002; Murphy et al. 2001; Nakai et al. 2005; Suliburk et al. 2005). If drugs are dosed to effect, the discussion will include strategies for dose determination as well as monitoring methods. It is appropriate to describe the frequency, route, buffering (e.g., for fish anesthetic), and method of substance administration. The choice of enteral administration method, for example, can affect animals and study results (Atcha et al. 2010; Brown et al. 2000; Craig and Elliott 1999; Nickerson et al. 1994), so specific information about the method used (e.g., oral via syringe, dosed water, or dosed feed; gavage tube into the stomach; or intragastric injection) is appropriate in reports of studies involving enteral administration. The same is true for the administration of substances via vascular and other parenteral routes. Clear descriptions of the treatment of control animals will indicate whether they were treated identically to dosed animals (e.g., subject to sham handling and vehicle treatment, identical diet in a dosed-feed study, inhalation exposure apparatus). 11

OCR for page 1
fracture research: Seeking consensus in optimising both animal welfare and scientific validity for appropriate biomedical use. BMC Musculoskel Disord 8:72. Avsaroglu H, van der Sar AS, van Lith HA, van Zutphen LFM, Hellebrekers LJ. 2007. Differences in response to anaesthetics and analgesics between inbred rat strains. Lab Anim 41:337-344. Ayala JE, Samuel VT, Morton GJ, Obici S, Croniger CM, Shulman G, Wasserman DH, McGuinness OP. 2010. Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice. Dis Model Mech 3:525-534. Baker DG. 1998. Natural pathogens of laboratory mice, rats, and rabbits and their effects on research. Clin Microbiol Rev 11:231-266. Barcellos LJG, Kreutz LC, Quevedo RM, da Rosa JGS, Centenaro GKL, Pottker E. 2009. Influence of color background and shelter availability on jundia (Rhamdia quelen) stress response. Aquaculture 288:51-56. Barnard DE, Lewis SM, Teter BB, Thigpen JE. 2009. Open- and closed-formula laboratory animal diets and their importance to research. JAALAS 48:709-713. Barthold SW. 1998. Opportunistic infections in research rodents: The challenges are great and the hour is late. ILAR J 39:316-321. Bayarri MJ, Madrid JA, Sanchez-Vazquez FJ. 2002. Influence of light intensity, spectrum and orientation on sea bass plasma and ocular melatonin. J Pineal Res 32:34-40. Bayne K. 2005. Potential for unintended consequences of environmental enrichment for laboratory animals and research results. ILAR J 46:129-139. Bebarta V, Luyten D, Heard K. 2003. Emergency medicine animal research: Does use of randomization and blinding affect the results? Acad Emerg Med 10:684-687. Becker CE, Mathur CF, Rehnberg BG. 2010. The effects of chronic exposure to common bedding materials on the metabolic rate and overall health of male CD-1 mice. J Appl Anim Welf Sci 13:46-55. Bellhorn RW. 1980. Lighting in the animal environment. Lab Anim Sci 30:440-450. Berger-Sweeney J, Berger UV, Sharma M, Paul CA. 1994. Effects of carbon dioxide-induced anesthesia on cholinergic parameters in rat brain. Lab Anim Sci 44:369-371. Bertani S, Carboni L, Criado A, Michielin F, Mangiarini L, Vicentini E. 2010. Circadian profile of peripheral hormone levels in Sprague-Dawley rats and in common marmosets (Callithrix jacchus). In Vivo 24:827-836. Bertolucci C, Pinotti M, Colognesi I, Foà A, Bernardi F, Portaluppi F. 2005. Circadian rhythms in mouse blood coagulation. J Biol Rhythms 20:219-224. Bjornsson MJ, Velschow S, Stoltze K, Havemose-Poulsen A, Schou S, Holmstrup P. 2003. The influence of diet consistence, drinking water and bedding on periodontal disease in Sprague-Dawley rats. J Periodontal Res 38:543-550. Bohonowych JE, Zhao B, Timme-Laragy A, Jung D, Di Giulio RT, Denison MS. 2008. Newspapers and newspaper ink contain agonists for the Ah receptor. Toxicol Sci 102:278-290. Bohr UR, Selgrad M, Ochmann C, Backert S, König W, Fenske A, Wex T, Malfertheiner P. 2006. Prevalence and spread of enterohepatic Helicobacter species in mice reared in a specific-pathogen- free animal facility. J Clin Microbiol 44:738-742. Brown AP, Dinger N, Levine BS. 2000. Stress produced by gavage administration in the rat. Contemp Top Lab Anim Sci 39:17-21. Brown NM, Setchell KD. 2001. Animal models impacted by phytoestrogens in commercial chow: Implications for pathways influenced by hormones. Lab Invest 81:735-747. Buddaraju AK, Van Dyke RW. 2003. Effect of animal bedding on rat liver endosome acidification. Comp Med 53:616-621. 16

OCR for page 1
Burn CC, Peters A, Day MJ, Mason GJ. 2006. Long-term effects of cage-cleaning frequency and bedding type on laboratory rat health, welfare, and handleability: A cross-laboratory study. Lab Anim 40:353- 370. Burrows RE. 1964. Effects of accumulated excretory products on hatchery-reared salmonids. US Fish and Wildlife Service Research Report 66. Burwitz BJ, Pendley CJ, Greene JM, Detmer AM, Lhost JJ, Karl JA, Piaskowski SM, Rudersdorf RA, Wallace LT, Bimber BN, Loffredo JT, Cox DG, Bardet W, Hildebrand W, Wiseman RW, O’Connor SL, O’Connor DH. 2009. Mauritian cynomolgus macaques share two exceptionally common major histocompatibility complex class I alleles that restrict simian immunodeficiency virus-specific CD8+ T cells. J Virol 83:6011-6019. Butler MM, Griffey SM, Clubb FJ Jr, Gerrity LW, Campbell WB. 1990. The effect of euthanasia technique on vascular arachidonic acid metabolism and vascular and intestinal smooth muscle contractility. Lab Anim Sci 40:277-283. Clough G. 1982. Environmental effects on animals used in biomedical research. Biol Rev Camb Philos Soc 57:487-523. Correa CF, Cerqueira VR. 2007. Effects of stocking density and size distribution on growth, survival and cannibalism in juvenile fat snook (Centropomus parallelus Poey). Aquacult Res 38:1627-1634. Craig MA, Elliott JF. 1999. Mice fed radiolabeled protein by gavage show sporadic passage of large quantities of intact material into the blood, an artifact not associated with voluntary feeding. Contemp Top Lab Anim Sci 38:18-23. Damon EG, Eidson AF, Hobbs CH, Hahn FF. 1986. Effect of acclimation to caging on nephrotoxic response of rats to uranium. Lab Anim Sci 36:24-27. Danos O, Davies K, Lehn P, Mulligan R. 2010. The ARRIVE guidelines, a welcome improvement to standards for reporting animal research. J Gene Med 12:559-560. Dauchy RT, Dupepe LM, Ooms TG, Dauchy EM, Hill CR, Mao L, Belancio VP, Slakey LM, Hill SM, Blask DE. 2011. Eliminating animal facility light-at-night contamination and its effect on circadian regulation of rodent physiology, tumor growth, and metabolism: A challenge in the relocation of a cancer research laboratory. JAALAS 50:326-336. Deerberg F. 1991. Age-associated versus husbandry-related pathology of aging rats. Neurobiol Aging 12:659-662. Deerberg F, Rapp KG, Kaspareit-Rittinghausen J, Lörcher K. 1990. The effect of food restriction by time- scheduled feeding on the development of body-weight, lifespan and incidence of spontaneous tumours and diseases in male Han:SPRD rats. Z Versuchstierkd 33:9-17. deSouza MS, Smith AL, Beck DS, Kim LHJ, Hansen GM, Barthold SW. 1993. Variant responses of mice to Borrelia burgdorferi depending on the site of intradermal inoculation. Infect Immun 61:4493-4497. Diercks AK, Schwab A, Rittgen W, Kruspel A, Heuss E, Schenkel J. 2010. Environmental influences on the production of pre-implantation embryos. Theriogenology 73:1238-1243. Di Marco P, Priori A, Finoia MG, Massari A, Mandich A, Marino G. 2008. Physiological responses of European sea bass Dicentrarchus labrax to different stocking densities and acute stress challenge. Aquaculture 275:319-328. Dirnagl U, Macleod MR. 2009. Stroke research at a road block: The streets from adversity should be paved with meta-analysis and good laboratory practice. Br J Pharmacol 157:1154-1156. Doetschman T. 2009. Influence of genetic background on genetically engineered mouse phenotypes. Methods Mol Biol 530:423-433. d’Orbcastel ER, Ruyet JPL, Le Bayon N, Blancheton JP. 2009. Comparative growth and welfare in rainbow trout reared in recirculating and flow through rearing systems. Aquacult Eng 40:79-86. Downing G, Litvak MK. 2001. The effect of light intensity and spectrum on the incidence of first feeding by larval haddock. J Fish Biol 59:1566-1578. 17

OCR for page 1
Drickamer LC. 1990. Environmental factors and age of puberty in female house mice. Dev Psychobiol 23:63-73. Drummond GB, Paterson DJ, McGrath JC. 2010. ARRIVE: New guidelines for reporting animal research. J Physiol 588:2517. Ellery AW, chair. 1985. Guidelines for specification of animals and husbandry methods when reporting the results of animal experiments. Working Committee for the Biological Characterization of Laboratory Animals/GV-SOLAS. Lab Anim 19:106-108. Engelhardt JA, Gries CL, Long GG. 1993. Incidence of spontaneous neoplastic and nonneoplastic lesions in Charles River CD-1 mice varies with breeding origin. Toxicol Pathol 21:538-541. Everitt JI, Foster PM. 2004. Laboratory animal science issues in the design and conduct of studies with endocrine-active compounds. ILAR J 45:417-424. Fenske M, Maack G, Schaefers C, Segner H. 2005. An environmentally relevant concentration of estrogen induces arrest of male gonad development in zebrafish, Danio rerio. Environ Toxicol Chem 24:1088-1098. Fernandez I, Peña A, Del Teso N, Pérez V, Rodríguez-Cuesta J. 2010. Clinical biochemistry parameters in C57BL/6J mice after blood collection from the submandibular vein and retroorbital plexus. JAALAS 49:202-206. Festing MF. 2003. We should be designing better experiments. Vet Anaesth Analg 30:59-61. Festing MF, Altman DG. 2002. Guidelines for the design and statistical analysis of experiments using laboratory animals. ILAR J 43:244-258. Fiedler H, Cooper K, Bergek S, Hjelt M, Rappe C, Bonner M, Howell F, Willett K, Safe S. 1998. PCDD, PCDF, and PCB in farm-raised catfish from Southeast United States: Concentrations, sources, and CYP1A induction. Chemosphere 37:1645-1656. Flecknell PA. 1993. Anaesthesia of animals for biomedical research. Br J Anaesth 71:885-894. Ford DJ. 1977. Effect of autoclaving and physical structure of diets on their utilization by mice. Lab Anim 11:235-239. Ford DJ, Ward RJ. 1983. The effect on mice of practical diets containing different protein and energy levels. Lab Anim 17:336-339. Franklin CL. 2006. Microbial considerations in genetically engineered mouse research. ILAR J 47:141-155. Freed C, Martinez V, Sarter M, DeVries C, Bergdall V. 2008. Operant task performance and corticosterone concentrations in rats housed directly on bedding and on wire. JAALAS 47:18-22. Gachon F, Firsov D. 2011. The role of circadian timing system on drug metabolism and detoxification. Expert Opin Drug Metab Toxicol 7:147-158. Gaines Das RE. 2002. Role of ancillary variables in the design, analysis, and interpretation of animal experiments. ILAR J 43:214-222. Gao P, Dang CV, Watson J. 2008. Unexpected antitumorigenic effect of fenbendazole when combined with supplementary vitamins. JAALAS 47:7-40. Gates H, Mallon AM, Brown SD. 2011. High-throughput mouse phenotyping. Methods 53:394-404. Gordon CJ. 2004. Effect of cage bedding on temperature regulation and metabolism of group-housed female mice. Comp Med 54:63-68. Gordon CJ, Fogelson L. 1994. Metabolic and thermoregulatory responses of the rat maintained in acrylic or wire-screen cages: Implications for pharmacological studies. Physiol Behav 56:73-79. Gordon A, Wyatt J. 2011. The water delivery system affects the rate of weight gain in C57BL/6J mice during the first week after weaning. JAALAS 50:37-40. Gortz N, Lewejohann L, Tomm M, Ambrée O, Keyvani K, Paulus W, Sachser N. 2008. Effects of environmental enrichment on exploration, anxiety, and memory in female TgCRND8 Alzheimer mice. Behav Brain Res 191:43-48. 18

OCR for page 1
Haemisch A, Gartner K. 1994. The cage design affects intermale aggression in small groups of male laboratory mice: Strain specific consequences on social organization, and endocrine activations in two inbred strains (DBA/2J and CBA/J). J Exp Anim Sci 36:101-116. Hall JE, White WJ, Lang CM. 1980. Acidification of drinking water: Its effects on selected biologic phenomena in male mice. Lab Anim Sci 30 (Pt 1):643-651. Hampshire VA, Davis JA, McNickle CA, Williams L, Eskildson H. 2001. Retrospective comparison of rat recovery weights using inhalation and injectable anaesthetics, nutritional and fluid supplementation for right unilateral neurosurgical lesioning. Lab Anim 35:223-229. Haseman JK, Bourbina J, Eustis SL. 1994. Effect of individual housing and other experimental design factors on tumor incidence in B6C3F1 mice. Fundam Appl Toxicol 23:44-52. Haseman JK, Young E, Eustis SL, Hailey JR. 1997. Body weight-tumor incidence correlations in long-term rodent carcinogenicity studies. Toxicol Pathol 25:256-263. Haseman JK, Ney E, Nyska A, Rao GN. 2003. Effect of diet and animal care/housing protocols on body weight, survival, tumor incidences, and nephropathy severity of F344 rats in chronic studies. Toxicol Pathol 31:674-681. Hauser R, Jankowski Z, Gos T, Krzyzanowski M. 2001. Haemorrhages in head tissues during the asphyxiation process. Forensic Sci Int 124:235-236. Haywood GP. 1983. Ammonia toxicity in teleost fishes: A review. Can Tech Rep Fish Aquatic Sci 1177:1- 35. Head AB, Malison JA. 2000. Effects of lighting spectrum and disturbance level on the growth and stress responses of yellow perch Perca flavescens. J World Aquacult Soc 31:73-80. Heavner JE. 2003. Toxicity of anaesthetics. Best Pract Res Clin Anaesthesiol 17:1-3. Hecht T, Uys W. 1997. Effect of density on the feeding and aggressive behaviour in juvenile African catfish, Clarias gariepinus. S Afr J Sci 93:537-541. Heindel JJ, vom Saal FS. 2008. Batch-to-batch variability in estrogenic activity in commercial animal diets: Importance and approaches for laboratory animal research. Environ Health Perspect 116:389- 393. Hermann LM, White WJ, Lang CM. 1982. Prolonged exposure to acid, chlorine, or tetracycline in the drinking water: Effects on delayed-type hypersensitivity, hemagglutination titers, and reticuloendothelial clearance rates in mice. Lab Anim Sci 32:603-608. Herzberg AM, Lagakos SW. 1992. Cage allocation designs for rodent carcinogenicity experiments. Environ Health Perspect 97:277-280. Holdcroft A. 2007. Integrating the dimensions of sex and gender into basic life sciences research: Methodologic and ethical issues. Gend Med 4 (Suppl B):S64-S74. Hooijmans CR, Leenaars M, Ritskes-Hoitinga M. 2010. A gold standard publication checklist to improve the quality of animal studies, to fully integrate the Three Rs, and to make systematic reviews more feasible. Altern Lab Anim 38:167-182. Hooijmans CR, de Vries R, Leenaars M, Curfs J, Ritskes-Hoitinga M. 2011a. Improving planning, design, reporting and scientific quality of animal experiments by using the Gold Standard Publication Checklist, in addition to the ARRIVE guidelines. Br J Pharmacol 162:1259-1260. Hooijmans C, de Vries R, Leenaars M, Ritskes-Hoitinga M. 2011b. The Gold Standard Publication Checklist (GSPC) for improved design, reporting and scientific quality of animal studies GSPC Versus ARRIVE guidelines. Lab Anim 45:61. Hossain MAR, Beveridge MCM, Haylor GS. 1998. The effects of density, light and shelter on the growth and survival of African catfish (Clarias gariepinus) fingerlings. Aquaculture 160:251-258. Huang K, Rabold R, Schofield B, Mitzner W, Tankersley CG. 2007. Age-dependent changes of airway and lung parenchyma in C57BL/6J mice. J Appl Physiol 102:200-206. 19

OCR for page 1
Hufeldt MR, Nielsen DS, Vogensen FK, Midtvedt T, Hansen AK. 2010. Variation in the gut microbiota of laboratory mice is related to both genetic and environmental factors. Comp Med 60:336-347. Hunt PA, Koehler KE, Susiarjo M, Hodges CA, Ilagan A, Voigt RC, Thomas S, Thomas BF, Hassold TJ. 2003. Bisphenol A exposure causes meiotic aneuploidy in the female mouse. Curr Biol 13:546-553. Idris AH, Becker LB, Ornato JP, Hedges JR, Bircher NG, Chandra NC, Cummins RO, Dick W, Ebmeyer U, Halperin HR, Hazinski MF, Kerber RE, Kern KB, Safar P, Steen PA, Swindle MM, Tsitlik JE, von Planta I, von Planta M, Wears RL, Weil MH. 1996. Utstein-style guidelines for uniform reporting of laboratory CPR research. A statement for healthcare professionals from a task force of the American Heart Association, the American College of Emergency Physicians, the American College of Cardiology, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, the Institute of Critical Care Medicine, the Safar Center for Resuscitation Research, and the Society for Academic Emergency Medicine. Circulation 94:2324-2336. Jankowsky JL, Xu G, Fromholt D, Gonzales V, Borchelt DR. 2003. Environmental enrichment exacerbates amyloid plaque formation in a transgenic mouse model of Alzheimer disease. J Neuropathol Exp Neurol 62:1220-1227. Jhaveri KA, Trammell RA, Toth LA. 2007. Effect of environmental temperature on sleep, locomotor activity, core body temperature and immune responses of C57BL/6J mice. Brain Behav Immun 21:975-987. Johnston NA, Bieszczak JR, Verhulst S, Disney KE, Montgomery KE, Toth LA. 2006. Fenbendazole treatment and litter size in rats. JAALAS 45:35-39. Kallnik M, Bieszczak JR, Verhulst S, Disney KE, Montgomery KE, Toth LA. 2007. Impact of IVC housing on emotionality and fear learning in male C3HeB/FeJ and C57BL/6J mice. Mamm Genome 18:173-186. Karakatsouli N, Papoutsoglou SE, Panopoulos G, Papoutsoglou ES, Chadio S, Kalogiannis D. 2008. Effects of light spectrum on growth and stress response of rainbow trout Oncorhynchus mykiss reared under recirculating system conditions. Aquacult Eng 38:36-42. Katz Y, Lustig S, Ben-Shlomo I, Kobiler D, Ben-Nathan D. 2002. Inhalation anesthetic-induced neuroinvasion by an attenuated strain of West Nile virus in mice. J Med Virol 66:576-580. Keenan KP, Ballam GC, Soper KA, Laroque P, Coleman JB, Dixit R. 1999. Diet, caloric restriction, and the rodent bioassay. Toxicol Sci 52:24-34. Keller LS, White WJ, Snider MT, Lang CM. 1989. An evaluation of intra-cage ventilation in three animal caging systems. Lab Anim Sci 39:237-242. Kilkenny C. 2009. Survey of the quality of experimental design, statistical analysis and reporting of research using animals. PLoS One 4:e7824. Kilkenny C. 2010. Reporting in vivo experiments: The ARRIVE guidelines. Exp Physiol 95:842-844. Klimentidis YC, Beasley TM, Lin H-Y, Murati G, Glass GE, Guyton M, Newton W, Jorgensen M, Heymsfield SB, Kemnitz J, Fairbanks L, Allison DB. 2010. Canaries in the coal mine: A cross-species analysis of the plurality of obesity epidemics. Proc R Soc B publ online 24 Nov 2010; doi: 10.1098/rspb.2010.1890. Krohn TC, Hansen AK. 2002. Carbon dioxide concentrations in unventilated IVC cages. Lab Anim 36:209- 212. Kroupova H, Machova J, Piackova V, Blahova J, Dobsikova R, Novotny L, Svobodova Z. 2008. Effects of subchronic nitrite exposure on rainbow trout (Oncorhynchus mykiss). Ecotoxicol Env Saf 71:813-820. Kurien BT, Everds NE, Scofield RH. 2004. Experimental animal urine collection: A review. Lab Anim 38:333-361. Laakso ML, Porkka-Heiskanen T, Stenberg D, Johansson G, Männistö PT. 1990. Lighting conditions affect serum and pituitary TSH in male rats. Am J Physiol 259:E162-E169. Lambert Y, Dutil JD. 2001. Food intake and growth of adult Atlantic cod (Gadus morhua L.) reared under different conditions of stocking density, feeding frequency and size-grading. Aquaculture 192:233- 247. 20

OCR for page 1
Länge R, Hutchinson TH, Croudace CP, Siegmund F, Schweinfurth H, Hampe P, Panter GH, Sumpter JP. 2001. Effects of the synthetic estrogen 17α-ethinylestradiol on the life-cycle of the fathead minnow (Pimephales promelas). Environ Toxicol Chem 20:1216-1227. Laroque P, Keenan KP, Soper KA, Dorian C, Gerin G, Hoe CM, Duprat P. 1997. Effect of early body weight and moderate dietary restriction on the survival of the Sprague-Dawley rat. Exp Toxicol Pathol 49:459-465. Lawson DM, Churchill M, Churchill PC. 2000. The effects of housing enrichment on cardiovascular parameters in spontaneously hypertensive rats. Contemp Top Lab Anim Sci 39:9-13. Levin AA, Dent JG. 1982. Comparison of the metabolism of nitrobenzene by hepatic microsomes and cecal microflora from Fischer-344 rats in vitro and the relative importance of each in vivo. Drug Metab Dispos 10:450-454. Lewis WM, Morris DP. 1986. Toxicity of nitrite to fish: A review. Trans Am Fish Soc 115:183-195. Linder CC. 2001. The influence of genetic background on spontaneous and genetically engineered mouse models of complex diseases. Lab Anim (N Y) 30:34-39. Linder CC. 2006. Genetic variables that influence phenotype. ILAR J 47:132-140. Lipman NS. 1999. Isolator rodent caging systems (state of the art): A critical view. Contemp Top Lab Anim Sci 38:9-17. Lipman NS, Corning BF, Coiro MA Sr. 1992. The effects of intracage ventilation on microenvironmental conditions in filter-top cages. Lab Anim 26:206-210. Macleod MR, Fisher M, O’Collins V, Sena ES, Dirnagl U, Bath PM, Buchan A, van der Worp HB, Traystman RJ, Minematsu K, Donnan GA, Howells DW. 2009. Good laboratory practice: Preventing introduction of bias at the bench. Int J Stroke 4:3-5. MacLusky NJ. 2009. Euthanasia in endocrinology: The choices get more complex. Endocrinology 150:2505-2506. Macy JD, Cameron GA, Ellis SL, Hill EA, Compton SR. 2002. Assessment of static isolator cages with automatic watering when used with conventional husbandry techniques as a factor in the transmission of mouse hepatitis virus. Contemp Top Lab Anim Sci 41:30-35. Mahl A, Heining P, Ulrich P, Jakubowski J, Bobadilla M, Zeller W, Bergmann R, Singer T, Meister L. 2000. Comparison of clinical pathology parameters with two different blood sampling techniques in rats: Retrobulbar plexus versus sublingual vein. Lab Anim 34:351-361. Mandillo S, Tucci V, Hölter SM, Meziane H, Al Banchaabouchi M, Kallnik M, Lad HV, Nolan PM, Ouagazzal A-M, Coghill EL, Gale K, Golini E, Jacquot S, Krezel W, Parker A, Riet F, Schneider I, Marazziti D, Auwerx J, Brown SDM, Chambon P, Rosenthal N, Tocchini-Valentini G, Wurst W. 2008. Reliability, robustness, and reproducibility in mouse behavioral phenotyping: A cross-laboratory study. Physiol Genomics 34:243-255. Martin RA, Daly A, DiFonzo CJ, de la Iglesia FA. 1986. Randomization of animals by computer program for toxicity studies. J Environ Pathol Toxicol Oncol 6:143-152. Masternak MM, Al-Regaiey KA, Bonkowski MS, Panici JA, Bartke A. 2005. Effect of every other day feeding diet on gene expression in normal and in long-lived Ames dwarf mice. Exp Gerontol 40:491- 497. McGrath JC, Drummond GB, McLachlan EM, Kilkenny C, Wainwright CL. 2010. Guidelines for reporting experiments involving animals: The ARRIVE guidelines. Br J Pharmacol 160:1573-1576. McGuinness OP, Ayala JE, Laughlin MR, Wasserman DH. 2009. NIH experiment in centralized mouse phenotyping: The Vanderbilt experience and recommendations for evaluating glucose homeostasis in the mouse. Am J Physiol Endocrinol Metab 297:E849-E855. McJilton CE, Frank R, Charlson RJ. 1976. Influence of relative humidity on functional effects of an inhaled SO2-aerosol mixture. Am Rev Respir Dis 113:163-169. 21

OCR for page 1
Memarzadeh F, Harrison PC, Riskowski GL, Henze T. 2004. Comparison of environment and mice in static and mechanically ventilated isolator cages with different air velocities and ventilation designs. Contemp Top Lab Anim Sci 43:14-20. Menninger K, Wieczorek G, Riesen S, Kunkler A, Audet M, Blancher A, Schuurman HJ, Quesniaux V, Bigaud M. 2002. The origin of cynomolgus monkey affects the outcome of kidney allografts under Neoral immunosuppression. Transplant Proc 34:2887-2888. Merne ME, Syrjanen KJ, Syrjanen SM. 2001. Systemic and local effects of long-term exposure to alkaline drinking water in rats. Int J Exp Pathol 82:213-219. Mineur YS, Crusio WE. 2009. Behavioral effects of ventilated micro-environment housing in three inbred mouse strains. Physiol Behav 97:334-340. Muhlhauser A, Susiarjo M, Rubio C, Griswold J, Gorence G, Hassold T, Hunt PA. 2009. Bisphenol A effects on the growing mouse oocyte are influenced by diet. Biol Reprod 80:1066-1071. Murphy SJ, Smith P, Shaivitz AB, Rossberg MI, Hurn PD. 2001. The effect of brief halothane anesthesia during daily gavage on complications and body weight in rats. Contemp Top Lab Anim Sci 40:9-12. Naciff JM, Overmann GJ, Torontali SM, Carr GJ, Tiesman JP, Daston GP. 2004. Impact of the phytoestrogen content of laboratory animal feed on the gene expression profile of the reproductive system in the immature female rat. Environ Health Perspect 112:1519-1526. Nakai JS, Elwin J, Chu I, Marro L. 2005. Effect of anaesthetics/terminal procedures on neurotransmitters from non-dosed and aroclor 1254-dosed rats. J Appl Toxicol 25:224-233. Neptun DA, Smith CN, Irons RD. 1985. Effect of sampling site and collection method on variations in baseline clinical pathology parameters in Fischer-344 rats. 1. Clinical chemistry. Fundam Appl Toxicol 5 (Pt 1):1180-1185. Nevalainen TO, Nevalainen JI, Guhad FA, Lang CM. 2007. Pair housing of rabbits reduces variances in growth rates and serum alkaline phosphatase levels. Lab Anim 41:432-440. Newberne PM, Fox JG. 1980. Nutritional adequacy and quality control of rodent diets. Lab Anim Sci 30 (Pt 2):352-365. Newberne PM, McConnell RG. 1980. Dietary nutrients and contaminants in laboratory animal experimentation. J Environ Pathol Toxicol 4:105-122. Newberne PM, Sotnikov AV. 1996. Diet: The neglected variable in chemical safety evaluations. Toxicol Pathol 24:746-756. Nickerson DF, Weaver ML, Tse FL. 1994. The effect of oral dose volume on the absorption of a highly and a poorly water-soluble drug in the rat. Biopharm Drug Dispos 15:419-429. Nicklas W, Baneux P, Boot R, Decelle T, Deeny AA, Fumanelli M, Illgen-Wilcke B; FELASA (Federation of European Laboratory Animal Science Associations) Working Group on Health Monitoring of Rodent and Rabbit Colonies. 2002. Recommendations for the health monitoring of rodent and rabbit colonies in breeding and experimental units. Lab Anim 36:20-42. Nold JB, Keenan KP, Nyska A, Cartwright ME. 2001. Society of Toxicologic Pathology position paper: Diet as a variable in rodent toxicology and carcinogenicity studies. Toxicol Pathol 29:585-586. Norin E, Midtvedt T. 2010. Intestinal microflora functions in laboratory mice claimed to harbor a "normal" intestinal microflora: Is the SPF concept running out of date? Anaerobe 16:311-313. NRC [National Research Council]. 1991. Infectious Diseases of Mice and Rats. Washington: National Academy Press. NRC. 2009. Scientific and Humane Issues in the Use of Random Source Dogs and Cats in Research. Washington: National Academies Press. NRC. 2010. Guide for the Care and Use of Laboratory Animals, 8th ed. Washington: National Academies Press. 22

OCR for page 1
Nyska A, Leininger JR, Maronpot RR, Haseman JK, Hailey JR. 1998. Effect of individual versus group caging on the incidence of pituitary and Leydig cell tumors in F344 rats: Proposed mechanism. Med Hypotheses 50:525-529. Öbrink KJ, Rehbinder C. 2000. Animal definition: A necessity for the validity of animal experiments? Lab Anim 34:121-130. Örn S, Holbech H, Madsen TH, Norrgren L, Petersen GI. 2003. Gonad development and vitellogenin production in zebrafish (Danio rerio) exposed to ethinylestradiol and methyltestosterone. Aquat Toxicol 65:397-411. Osborne NJ, Payne D, Newman ML. 2009. Journal editorial policies, animal welfare, and the 3Rs. Am J Bioeth 9:55-59. Papoutsoglou SE, Mylonakis G, Miliou H, Karakatsouli NP, Chadio S. 2000. The effect of background color on growth performances and physiological responses of scaled carp (Cyprinus carpio L.) reared in a closed circulated system. Aquacult Eng 22:309-318. Paull GC, Filby AL, Giddins HG, Coe TS, Hamilton PB, Tyler CR. 2010. Dominance hierarchies in zebrafish (Danio rerio) and their relationship with reproductive success. Zebrafish 7:109-117. Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, Macleod M, Mignini LE, Jayaram P, Khan KS. 2007. Comparison of treatment effects between animal experiments and clinical trials: Systematic review. BMJ 334:197. Perkins SE, Lipman NS. 1995. Characterization and quantification of microenvironmental contaminants in isolator cages with a variety of contact beddings. Contemp Top Lab Anim Sci 34:93-98. Peters JL, Sutton AJ, Jones DR, Rushton L, Abrams KR. 2006. A systematic review of systematic reviews and meta-analyses of animal experiments with guidelines for reporting. J Environ Sci Health B 41:1245-1258. Pinotti M, Bertolucci C, Portaluppi F, Colognesi I, Frigato E, Foà A, Bernardi F. 2005. Daily and circadian rhythms of tissue factor pathway inhibitor and factor VII activity. Arterioscler Thromb Vasc Biol 25:646-649. Portaluppi F, Touitou Y, Smolensky MH. 2008. Ethical and methodological standards for laboratory and medical biological rhythm research. Chronobiol Int 25:999-1016. Potgieter FJ, Wilke PI. 1997. Effect of different bedding materials on the reproductive performance of mice. J S Afr Vet Assoc 68:8-15. Potgieter FJ, Wilke PI, van Jaarsveld H, Alberts DW. 1996. The in vivo effect of different bedding materials on the antioxidant levels of rat heart, lung and liver tissue. J S Afr Vet Assoc 67:27-30. Pound P, Ebrahim S, Sandercock P, Bracken MB, Roberts I; Reviewing Animal Trials Systematically (RATS) Group. 2004. Where is the evidence that animal research benefits humans? BMJ 328:514-517. Pullium JK, Dillehay DL, Webb S. 1999. High mortality in zebrafish (Danio rerio). Contemp Top Lab Anim Sci 38:80-83. Randall DJ, Tsui TKN. 2002. Ammonia toxicity in fish. Mar Pollut Bull 45:17-23. Ranstam J. 2010. Reporting laboratory experiments. Osteoarth Cartil 18:3-4. Rao GN, Crockett PW. 2003. Effect of diet and housing on growth, body weight, survival and tumor incidences of B6C3F1 mice in chronic studies. Toxicol Pathol 31:1-8. Rappe C, Bergek S, Fiedler H, Cooper KR. 1998. PCDD and PCDF contamination in catfish feed from Arkansas, USA. Chemosphere 36:2705-2720. Ray MA, Johnston NA, Verhulst S, Trammell RA, Toth LA. 2010. Identification of markers for imminent death in mice used in longevity and aging research. JAALAS 49:282-288. Reed B, Varon J, Chait BT, Kreek MJ. 2009. Carbon dioxide-induced anesthesia results in a rapid increase in plasma levels of vasopressin. Endocrinology 150:2934-2939. Reliene R, Schiestl RH. 2006. Differences in animal housing facilities and diet may affect study outcomes: A plea for inclusion of such information in publications. DNA Repair (Amst) 5:651-653. 23

OCR for page 1
Rice AS, Cimino-Brown D, Eisenach JC, Kontinen VK, Lacroix-Fralish ML, Machin I; Preclinical Pain Consortium, Mogil JS, Stöhr T. 2008. Animal models and the prediction of efficacy in clinical trials of analgesic drugs: A critical appraisal and call for uniform reporting standards. Pain 139:243-247. Roberts I, Kwan I, Evans P, Haig S. 2002. Does animal experimentation inform human healthcare? Observations from a systematic review of international animal experiments on fluid resuscitation. BMJ 324:474-476. Rogers IT, Holder DJ, McPherson HE, Acker WR, Brown EG, Washington MV, Motzel SL, Klein HJ. 1999. Influence of blood collection sites on plasma glucose and insulin concentration in conscious C57BL/6 mice. Contemp Top Lab Anim Sci 38:25-28. Rosenbaum MD, Vandewoude S, Johnson TE. 2009. Effects of cage-change frequency and bedding volume on mice and their microenvironment. JAALAS 48:763-773. Rosenbaum MD, VandeWoude S, Volckens J, Johnson T. 2010. Disparities in ammonia, temperature, humidity, and airborne particulate matter between the micro- and macroenvironments of mice in individually ventilated caging. JAALAS 49:177-183. Rotllant J, Tort L, Montero D, Pavlidis M, Martinez SE, Wendelaar B, Balm PHM. 2003. Background colour influence on the stress response in cultured red porgy Pagrus pagrus. Aquaculture 223:129-139. Russell WMS, Burch RL. 1959. The Principles of Humane Experimental Technique. London: Methuen & Co. Sanford AN, Clark SE, Talham G, Sidelsky MG, Coffin SE. 2002. Influence of bedding type on mucosal immune responses. Comp Med 52:429-432. Saxby A, Adams L, Snellgrove D, Wilson RW, Sloman KA. 2010. The effect of group size on the behaviour and welfare of four fish species commonly kept in home aquaria. Appl Anim Behav Sci 125:195-205. Silverman J, Adams JD. 1983. N-nitrosamines in laboratory animal feed and bedding. Lab Anim Sci 33:161-164. Simera I, Moher D, Hoey J, Schulz KF, Altman DG. 2009. The EQUATOR Network and reporting guidelines: Helping to achieve high standards in reporting health research studies. Maturitas 63:4-6. Simera I, Moher D, Hirst A, Hoey J, Schulz KF, Altman DG. 2010. Transparent and accurate reporting increases reliability, utility, and impact of your research: Reporting guidelines and the EQUATOR Network. BMC Med 8:24. Simpson EM. 1997. Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice. Nat Gen 16:19-27. Smith CN, Neptun DA, Irons RD. 1986. Effect of sampling site and collection method on variations in baseline clinical pathology parameters in Fischer-344 rats. II. Clinical hematology. Fundam Appl Toxicol:658-663. Smith E, Stockwell JD, Schweitzer I, Langley SH, Smith AL. 2004. Evaluation of cage micro-environment of mice housed on various types of bedding materials. Contemp Top Lab Anim Sci 43:12-17. Smith JA, Birke L, Sadler D. 1997. Reporting animal use in scientific papers. Lab Anim 31:312-317. Stark DM. 2001. Wire-bottom versus solid-bottom rodent caging issues important to scientists and laboratory animal science specialists. Contemp Top Lab Anim Sci 40:11-14. Steplewski Z, Goldman PR, Vogel WH. 1987. Effect of housing stress on the formation and development of tumors in rats. Cancer Lett 34:257-261. Strand A, Alanara A, Staffan F, Magnhagen C. 2007. Effects of tank colour and light intensity on feed intake, growth rate and energy expenditure of juvenile Eurasian perch, Perca fluviatilis L. Aquaculture 272:312-318. Suliburk JW, Gonzalez EA, Kennison SD, Helmer KS, Mercer DW. 2005. Differential effects of anesthetics on endotoxin-induced liver injury. J Trauma 58:711-716. Sundberg JP, Schofield PN. 2009. A mouse by any other name... J Invest Dermatol 129:1599-1601. 24

OCR for page 1
Sundberg JP, Schofield PN. 2010. Mouse genetic nomenclature: Standardization of strain, gene, and protein symbols [Commentary]. Vet Pathol 47:1100-1104. Swoap SJ, Overton JM, Garber G. 2004. Effect of ambient temperature on cardiovascular parameters in rats and mice: A comparative approach. Am J Physiol Regul Integr Comp Physiol 287:R391-R396. Taylor CF, Field D, Sansone SA, Aerts J, Apweiler R, Ashburner M, Ball CA, Binz PA, Bogue M, Booth T, Brazma A, Brinkman RR, Clark AM, Deutsch EW, Fiehn O, Fostel J, Ghazal P, Gibson F, Gray T, Grimes G, Hancock JM, Hardy NW, Hermjakob H, Julian RK Jr, Kane M, Kettner C, Kinsinger C, Kolker E, Kuiper M, Le Novère N, Leebens-Mack J, Lewis SE, Lord P, Mallon AM, Marthandan N, Masuya H, McNally R, Mehrle A, Morrison N, Orchard S, Quackenbush J, Reecy JM, Robertson DG, Rocca-Serra P, Rodriguez H, Rosenfelder H, Santoyo-Lopez J, Scheuermann RH, Schober D, Smith B, Snape J, Stoeckert CJ Jr, Tipton K, Sterk P, Untergasser A, Vandesompele J, Wiemann S. 2008. Promoting coherent minimum reporting guidelines for biological and biomedical investigations: The MIBBI project. Nat Biotechnol 26:889-896. Thigpen JE, Haseman JK, Saunders HE, Setchell KD, Grant MG, Forsythe DB. 2003. Dietary phytoestrogens accelerate the time of vaginal opening in immature CD-1 mice. Comp Med 53:607- 615. Thigpen JE, Setchell KD, Saunders HE, Haseman JK, Grant MG, Forsythe DB. 2004. Selecting the appropriate rodent diet for endocrine disruptor research and testing studies. ILAR J 45:401-416. Tomasso JR. 1994. Toxicity of nitrogenous wastes to aquaculture animals. Rev Fish Sci 2:291-314 Toth LA. 2000. Defining the moribund condition as an experimental endpoint for animal research. ILAR J 41:72-79. Touitou Y, Smolensky MH, Portaluppi F. 2006. Ethics, standards, and procedures of animal and human chronobiology research. Chronobiol Int 23:1083-1096. Traslavina RP, King EJ, Loar AS, Riedel ER, Garvey MS, Ricart-Arbona R, Wolf FR, Couto SS. 2010. Euthanasia by CO inhalation affects potassium levels in mice. JAALAS 49:316-322. Tsai PP, Pachowsky U, Stelzer HD, Hackbarth H. 2002. Impact of environmental enrichment in mice. 1: Effect of housing conditions on body weight, organ weights and haematology in different strains. Lab Anim 36:411-419. Tsai PP, Oppermann D, Stelzer HD, Mähler M, Hackbarth H. 2003. The effects of different rack systems on the breeding performance of DBA/2 mice. Lab Anim 37:44-53. Twaddle NC, Churchwell MI, McDaniel LP, Doerge DR. 2004. Autoclave sterilization produces acrylamide in rodent diets: Implications for toxicity testing. J Agric Food Chem 52:4344-4349. Valli T, Barthold SW, Ward JE, Brayton C, Nikitin A, Borowsky AD, Bronson RT, Cardiff RD, Sundberg J, Ince T. 2007. Over 60% of NIH extramural funding involves animal-related research. Vet Pathol 44:962-963, author reply 963-964. van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, O’Collins V, Macleod MR. 2010. Can animal models of disease reliably inform human studies? PLoS Med 7:e1000245. van de Nieuwegiessen PG, Olwo J, Khong S, Verreth JAJ, Schrama JW. 2009. Effects of age and stocking density on the welfare of African catfish, Clarias gariepinus Burchell. Aquaculture 288:69-75. Vento PJ, Swartz ME, Martin LBE, Daniels D. 2008. Food intake in laboratory rats provided standard and fenbendazole-supplemented diets. JAALAS 47:46-50. Vesell ES, Lang CM, White WJ, Passananti GT, Hill RN, Clemens TL, Liu DK, Johnson WD. 1976. Environmental and genetic factors affecting the response of laboratory animals to drugs. Fed Proc 35:1125-1132. Vesterinen HV, Egan K, Deister A, Schlattmann P, Macleod MR, Dirnagl U. 2011. Systematic survey of the design, statistical analysis, and reporting of studies published in the 2008 volume of the Journal of Cerebral Blood Flow and Metabolism. J Cereb Blood Flow Metab 31:1064-1072. 25

OCR for page 1
Vidal JD, Drobatz LS, Holliday DF, Geiger LE, Thomas HC. 2010. Spontaneous findings in the heart of Mauritian-origin cynomolgus macaques (Macaca fascicularis). Toxicol Pathol 38:297-302. Wahlsten D, Metten P, Phillips TJ, Boehm SL 2nd, Burkhart-Kasch S, Dorow J, Doerksen S, Downing C, Fogarty J, Rodd-Henricks K, Hen R, McKinnon CS, Merrill CM, Nolte C, Schalomon M, Schlumbohm JP, Sibert JR, Wenger CD, Dudek BC, Crabbe JC. 2003. Different data from different labs: Lessons from studies of gene-environment interaction. J Neurobiol 54:283-311. Wahlsten D, Bachmanov A, Finn DA, Crabbe JC. 2006. Stability of inbred mouse strain differences in behavior and brain size between laboratories and across decades. Proc Natl Acad Sci U S A 103:16364-16369. Walker CL, Cesen-Cummings K, Houle C, Baird D, Barrett JC, Davis B. 2001. Protective effect of pregnancy for development of uterine leiomyoma. Carcinogenesis 22:2049-2052. Wang H, Tranguch S, Xie H, Hanley G, Das SK, Dey SK. 2005. Variation in commercial rodent diets induces disparate molecular and physiological changes in the mouse uterus. Proc Natl Acad Sci U S A 102:9960-9965. Whitaker J, Moy SS, Godfrey V, Nielsen J, Bellinger D, Bradfield J. 2009. Effects of cage size and enrichment on reproductive performance and behavior in C57BL/6Tac mice. Lab Anim (N Y) 38:24- 34. Workman P, Aboagye EO, Balkwill F, Balmain A, Bruder G, Chaplin DJ, Double JA, Everitt J, Farningham DA, Glennie MJ, Kelland LR, Robinson V, Stratford IJ, Tozer GM, Watson S, Wedge SR, Eccles SA; Committee of the National Cancer Research Institute. 2010. Guidelines for the welfare and use of animals in cancer research. Br J Cancer 102:1555-1577. Würbel H. 2002. Behavioral phenotyping enhanced: Beyond (environmental) standardization. Genes Brain Behav 1:3-8. Yan N, Zhou L, Zhu Z, Chen X. 2009. Determination of melamine in dairy products, fish feed, and fish by capillary zone electrophoresis with diode array detection. J Agric Food Chem 57:807-811. Yoshiki A, Moriwaki K. 2006. Mouse phenome research: Implications of genetic background. ILAR J 47:94-102. Zhao ZJ, Chi QS, Cao J, Han YD. 2010. The energy budget, thermogenic capacity and behavior in Swiss mice exposed to a consecutive decrease in temperatures. J Exp Biol 213:3988-3997. Zimmerman DR, Wostmann BS. 1963. Vitamin stability in diets sterilized for germfree animals. J Nutr 79:318-322. 26