Assessing the satisfaction and burden within an academic animal care and use program.

Although animal research requires adherence to various regulations and standards, the manner in which compliance is maintained and the degree of additional constraints varies between institutions. Regulatory burden, particularly if institutionally imposed, has become a concern for institutions as increased regulatory expectations result in decreased resources available for research efforts. Faculty, research staff, and support staff engaged in animal research were surveyed to determine what institutional animal care and use committee (IACUC) processes were considered burdensome, the perceived value of some suggested modifications, and satisfaction with the IACUC administrative office and the animal resource unit. Although the results revealed overwhelming satisfaction with the IACUC administrative office and the animal resource unit, several IACUC processes were deemed burdensome, and therefore there would be value in modifying IACUC processes. When comparing the value of modifying IACUC processes, different groups within the animal care and use program (ACUP) tended to have different responses on many of the topics. This survey identified several perceived burdensome IACUC processes that would likely benefit individuals if modified. In today's environment of shrinking budgets for biomedical research, minimizing regulatory burden-particularly unnecessary, self-imposed burden-in the ACUP is particularly important to ensure that costs, time, and effort are appropriate to achieve animal welfare and quality of research endeavors.-Norton, J. N., Reynolds, R. P., Chan, C., Valdivia, R. H., Staats, H. F. Assessing the satisfaction and burden within an academic animal care and use program.

Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats.

D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague-Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 µg (the acute cohort) and 0, 0.05, 0.1, 0.35 µg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 µg (5/10 rats) and 0.35 µg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 µg, and the no-observed-adverse-effect-level was 0.05 µg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.

The cost of self-imposed regulatory burden in animal research.

U.S. federal regulations and standards governing the care and use of research animals enacted in the mid- to late 1980s, while having positive effects on the welfare and quality of the animals, have resulted in dramatic increases in overall research costs. In addition to the expenses of housing and caring for animals according to the standards, establishing the requisite internal compliance bureaucracies has markedly driven up costs, in both institutional monetary expenditures and lost research effort. However, many institutions are increasing these costs even further through additional self-imposed regulatory burden, typically characterized by overly complex compliance organizations and unnecessary policies and procedures. We discuss the sources of this self-imposed burden and recommend strategies for avoiding it while preserving an appropriate focus on animal well-being and research success.

Evaluation of Vibration as an Extrinsic Variable in In Vivo Research.

Vibration is inherent in research animal facilities due to the mechanical systems and practices required for animal care and use. Ample evidence indicates that vibration can change behavior and physiology in multiple species, potentially altering the results of research studies. Although one cannot eliminate environmental vibration, its control is important in research animal environments to decrease the possibility of introducing a research variable due to vibration effects. To assess the potential for a vibration source to alter experimental results and variability, one must understand the principles of vibration, its likely sources, and control methods. The literature regarding the effects of vibration, as it applies in a practical sense, can be challenging to interpret because the vibration frequencies tested to date have often not been within or near the most sensitive ranges of the species being tested. Some previous studies have used unrealistic vibration magnitudes and provided insufficient detail to duplicate or build upon conclusions. Standardization is essential for research examining the effects of vibration on animals to validate knowledge of this extrinsic variable in animal research and identify ways to mitigate the variable in research facilities.

Foreword and Introduction to This Issue on Contemporary Safety Topics in Animal Research.

Institutions with animal care and use programs are obligated to provide for the health and well-being of the animals, but are equally obligated to provide for safety of individuals associated with the program. The topics in this issue of the ILAR Journal, in association with those within the complimentary issue of the Journal of Applied Biosafety, provide a variety of contemporary occupational health and safety considerations in today's animal research programs. Each article addresses key or emerging occupational health and safety topics in institutional animal care and use programs, where the status of the topic, contemporary challenges, and future directions are provided.

Vibration in mice: A review of comparative effects and use in translational research.

Sound pressure waves surround individuals in everyday life and are perceived by animals and humans primarily through sound or vibration. When sound pressure waves traverse through a solid medium, vibration will result. Vibration has long been considered an unwanted variable in animal research and may confound scientific endeavors using animals. Understanding the characteristics of vibration is required to determine whether effects in animals are likely to be therapeutic or result in adverse biological effects. The eighth edition of the "Guide for the Care and Use of Laboratory Animals" highlights the importance of considering vibration and its effects on animals in the research setting, but knowledge of the level of vibration for eliciting these effects was unknown. The literature provides information regarding therapeutic use of vibration in humans, but the range of conditions to be of therapeutic benefit is varied and without clarity. Understanding the characteristics of vibration (eg, frequency and magnitude) necessary to cause various effects will ultimately assist in the evaluation of this environmental factor and its role on a number of potential therapeutic regimens for use in humans. This paper will review the principles of vibration, sources within a research setting, comparative physiological effects in various species, and the relative potential use of vibration in the mouse as a translational research model.

Managing Research Animal Specimens and Laboratory Safety.

The procedures necessary to perform testing in a veterinary diagnostic laboratory have inherent associated risks to personnel in regard to exposure to infectious agents. In research institutions animals can be experimentally infected, acquire naturally occurring infections and can also be exposed to other hazards such as toxic chemicals or radiologic entities. A critical component of the use of animals in a research environment is the collaboration between the responsible researcher and the veterinary diagnostic laboratory with the institutional health and safety professionals to ensure that the proper engineering controls, personal protective equipment, laboratory procedures and training are in place for personnel working with the animals or their specimens. Unlike the typical researcher, the veterinary diagnostic laboratory generally has to be equipped to safely process and work with a wide range of potential hazards where the communication of pertinent information from the researcher to the diagnostic laboratory regarding the identity of the potential hazard is paramount. Diagnostic laboratory design, safety equipment, personal protective equipment, laboratory procedures, occupational health program and personnel training must be sufficient to address hazards based on a risk assessment performed in conjunction with safety professionals. This article will summarize safety considerations with the various areas of concern in the operation of a diagnostic laboratory for research animal specimens.

Vibration-induced Behavioral Responses and Response Threshold in Female C57BL/6 Mice.

Despite documented adverse effects, limits for rodent exposure to vibration in the laboratory animal facility have not been established. This study used female C57BL/6 mice to determine the frequencies of vibration at which mice were most sensitive to behavioral changes, the highest magnitude of vibration that would not cause behavioral changes, the behavioral changes that occur in response to vibration, and the extent to which mice habituate to vibration. Mice were exposed to frequencies of vibration between 20 and 190 Hz at accelerations of 0.05 to 1.0 m/s2. Behavioral responses were videorecorded and subsequently scored. Mice showed the most behavioral responses at 1.0 m/s2. At intermediate accelerations of 0.5 and 0.75 m/s2, behavioral responses were most prevalent at frequencies of 70 to 100 Hz. In contrast, at an acceleration of 0.05 m/s2, mice did not show any discernible behavioral response. Behavioral responses induced by the initiation of vibration were transient, generally lasting only 2 to 10 s. Behaviors in awake mice included abrupt freezing of motion, hunched posture, and surveying the cage environment. In mice that were asleep, responses consisted of lifting the head suddenly with or without prior shifting of body position. When exposed to multiple periods of vibration over a short time, responses seemed to decrease. In summary, mice were particularly sensitive to vibration between 70 to 100 Hz, did not respond to the slowest acceleration (0.05 m/s2), and exhibited transient responses at the initiation of vibration.

Vibrating Frequency Thresholds in Mice and Rats: Implications for the Effects of Vibrations on Animal Health.

Vibrations in research facilities can cause complex animal behavioral and physiological responses that can affect animal health and research outcomes. The goal of this study was to determine the range of frequency values, where animals are unable to attenuate vibrations, and therefore may be most susceptible to their effects. Anesthetized and euthanized adult rats and mice were exposed to vibration frequencies over a wide range (0-600 Hz) and at a constant magnitude of 0.3 m/s(2). Euthanized animals were additionally exposed to vibrations at an acceleration of 1 m/s(2). The data showed that at most frequencies rodents were able to attenuate vibration magnitudes, with values for the back-mounted accelerometer being substantially less than that of the table. At frequencies of 41-60 Hz mice did not attenuate vibration magnitude, but instead the magnitude of the table and animal were equal or amplified. Rats experienced the same pattern of non-attenuation between 31 and 50 Hz. Once euthanized, the mice vibrated at a slightly more elevated frequency (up to 100 Hz). Based on these results, it may be prudent that in laboratory settings, vibrations in the ranges reported here should be accounted for as possible contributors to animal stress and/or biomechanical changes.

Characteristics of Vibration that Alter Cardiovascular Parameters in Mice.

We hypothesized that short-term exposure of mice to vibration within a frequency range thought to be near the resonant frequency range of mouse tissue and at an acceleration of 0 to 1 m/s(2) would alter heart rate (HR) and mean arterial pressure (MAP). We used radiotelemetry to evaluate the cardiovascular response to vibration in C57BL/6 and CD1 male mice exposed to vertical vibration of various frequencies and accelerations. MAP was consistently increased above baseline values at an acceleration near 1 m/s(2) and a frequency of 90 Hz in both strains, and HR was increased also in C57BL/6 mice. In addition, MAP increased at 80 Hz in individual mice of both strains. When both strains were analyzed together, mean MAP and HR were increased at 90 Hz at 1 m/s(2), and HR was increased at 80 Hz at 1 m/s(2). No consistent change in MAP or HR occurred when mice were exposed to frequencies below 80 Hz or above 90 Hz. The increase in MAP and HR occurred only when the mice had conscious awareness of the vibration, given that these changes did not occur when anesthetized mice were exposed to vibration. Tested vibration acceleration levels lower than 0.75 m/s(2) did not increase MAP or HR at 80 or 90 Hz, suggesting that a relatively high level of vibration is necessary to increase these parameters. These data are important to establish the harmful frequencies and accelerations of environmental vibration that should be minimized or avoided in mouse facilities.

Ocular melanoma in a Long Evans rat.

During a long-term study, a rat exposed to half-amplitude band pass fluorescent blue light (434 to 475 nm) and receiving a calcium channel blocker developed an ocular mass. By visual examination, a presumptive diagnosis of ocular melanoma was made. Subsequent surgical removal of the eye, followed by histopathology, confirmed the lesion as a highly pigmented epitheliod melanoma.

Comparative vibration levels perceived among species in a laboratory animal facility.

The current study was performed to determine the vibration levels that were generated in cages on a ventilated rack by common construction equipment in frequency ranges likely to be perceived by humans, rats, and mice. Vibration generated by the ventilated rack blower caused small but significant increases in some of the abdominal, thoracic, and head resonance frequency ranges (RFR) and sensitivity frequency ranges (SFR) in which each species is most likely to be affected by and perceive vibration, respectively. Vibration caused by various items of construction equipment at 3 ft from the cage were evaluated relative to the RFR and SFR of humans, rats, and mice in 3 anatomic locations. In addition, the vibration levels in the RFR and SFR that resulted from the use of a large jackhammer and were measured at various locations and distances in the facility and evaluated in terms of humans, rats, and mice in 3 anatomic locations. Taken together, the data indicate that a given vibration source generates vibration in frequency ranges that are more likely to affect rats and mice as compared with humans.

Noise in a laboratory animal facility from the human and mouse perspectives.

The current study was performed to understand the level of sound produced by ventilated racks, animal transfer stations, and construction equipment that mice in ventilated cages hear relative to what humans would hear in the same environment. Although the ventilated rack and animal transfer station both produced sound pressure levels above the ambient level within the human hearing range, the sound pressure levels within the mouse hearing range did not increase above ambient noise from either noise source. When various types of construction equipment were used 3 ft from the ventilated rack, the sound pressure level within the mouse hearing range was increased but to a lesser degree for each implement than were the sound pressure levels within the human hearing range. At more distant locations within the animal facility, sound pressure levels from the large jackhammer within the mouse hearing range decreased much more rapidly than did those in the human hearing range, indicating that less of the sound is perceived by mice than by humans. The relatively high proportion of low-frequency sound produced by the shot blaster, used without the metal shot that it normally uses to clean concrete, increased the sound pressure level above the ambient level for humans but did not increase sound pressure levels above ambient noise for mice at locations greater than 3 ft from inside of the cage, where sound was measured. This study demonstrates that sound clearly audible to humans in the animal facility may be perceived to a lesser degree or not at all by mice, because of the frequency content of the sound.

A sample postapproval monitoring program in academia.

The primary goal of an animal care and use program (ACUP) should be to ensure animal well-being while fostering progressive science. Both the Animal Welfare Act (and associated regulations) and the Public Health Service (PHS) Policy require the institutional animal care and use committee (IACUC) to provide oversight of the animal program through continuing reviews to ensure that procedures are performed as approved by the committee. But for many committees the semiannual assessment does not provide an opportunity to observe research procedures being performed. Furthermore, IACUC members are typically volunteers with other full-time commitments and may not be able to dedicate sufficient time to observe protocol performance. Postapproval monitoring (PAM) is a tool that the IACUC can use to ensure that the institution fulfills its regulatory obligation for animal program oversight. When performed by attentive and observant individuals, PAM can extend the IACUC's oversight, management, training, and communication resources, regardless of program size or complexity. No defined PAM process fits all institutions or all situations; rather, the monitoring must match the program under review. Nonetheless, certain concepts, concerns, and conditions affect all PAM processes; they are described in this article. Regardless of the style or depth of PAM chosen for a given program, one thing is sure: failure of the IACUC to engage all available and effective oversight methods to ensure humane, compassionate, efficient, and progressive animal care and use is a disservice to the institution, to the research community and to the animals used for biomedical research, testing, or teaching.