Although most commercially reared rodents, some rabbits, and relatively fewer dogs, cats, and primates can be obtained free of a list of certain infectious agents (ie, specific pathogen free), resident animal colonies must be monitored for naturally occurring disease as a measure of the effectiveness of the prevention and control program. Investigators should have easy access to information regarding the health status of their research animals and be alerted to changes and outbreaks immediately. In addition to monitoring for infectious disease, a quality assurance program should monitor for genetic integrity, especially for inbred mouse strains that are produced and maintained in the research facility, as well as for environmental factors (quality of feed, water, and bedding; efficacy of sanitation programs; air handling and quality; lighting; noise; etc) that can affect colony health.
Select Physiologic Data of Laboratory Animals a
Species | Gestation Period (days) | Litter Size | Age and Body Weight at Sexual Maturity | Usual Life Span (years) | Average Body Temperature (°C) | Heart Rate (bpm) | Water Consumption (per day)b |
|---|---|---|---|---|---|---|---|
Mice | 19–21 | 4–12 | 6 weeks (20–30 g) | 1–3 | 37 | 310–840 | 4–7 mL |
Rats | 21–23 | 6–14 | 1.5−3 months (0.2–0.3 kg) | 2–3 | 37.5 | 300–500 | 8–11 mL/100 g |
Guinea pigs | 59–72 | 1–4 | 2–4 months (0.4–0.6 kg) | 3–5 | 38 | 230–380 | 10 mL/100 g150 mL |
Hamsters, golden | 15–18 | 4–10 | 2–4 months (85–110 g) | 2–3 | 37 | 280–410 | 30 mL |
Gerbils | 25 | 2–9 | 3 months (60–100 g) | 2–5 | 38 | 250–600 | 4–7 mL/100 g |
Rabbits | 30−32 | 4–12 | 5–6 months (3–4 kg) | 5–7 | 39 | 200–300 | 300–700 mL |
Squirrel monkeys | 150 | 1 | 2.5–3.5 years (0.6–1.1 kg) | 16–20 | 39 | 300–380c | 70–110 mL |
Rhesus monkeys | 165–175 | 1–2 | 4–5 years (5–11 kg) | 15–30 | 39 | 120–180c | 80 mL/kg |
b Typical of an average adult; varies with body mass index, number of animals per cage, moisture in feed, temperature, etc. | |||||||
c Results obtained under anesthesia. | |||||||
Colony health monitoring consists of a defined program of regular physical and laboratory evaluations of animals within a unit, as well as a morbidity and mortality reporting system that enables timely identification of potential problems. Thorough investigations of illnesses, deaths, and unusual experimental outcomes in a colony are essential components of such a program. For selected physiologic data of some laboratory animals, See table Select Physiologic Data of Laboratory Animals a.
While certain general principles apply, a health monitoring program must be specifically developed for each species maintained in a facility. For example, generally, all primates are quarantined and isolated on arrival. Physical examinations, tuberculin testing (intradermal eyelid testing with mammalian old tuberculin as the antigen remains the standard), radiographs, and baseline hematologic and other clinical pathologic tests should be performed. Immune-based serologic assays are an alternative or adjunct to screening for tuberculosis because the animals will be in surveillance for Macacine herpesvirus type 1 (formerly Cercopithecine herpesvirus type 1, Herpervirus simiae, B virus), simian retroviruses, and other agents depending on the species of primate and desired pathogen status.
Primates should be released from quarantine only when both the health status and suitability for use are determined. Furthermore, primates should have regular health surveillance screens, each consisting of defined elements. Depending on the nature and value of the colony and research use, screenings may range from quarterly to semiannual or annual in frequency.
For colony-maintained rats and mice, programs for disease monitoring can consist of any or all of the following:
vendor surveillance
quarantine and isolation evaluation
ongoing clinical and postmortem evaluation during the course of studies
a combination of environmental sampling and live sentinel animal programs
evaluation at termination of the study
In addition, all transplantable tumors, cells, or other biologic products destined for animal passage should either be screened for murine and zoonotic pathogens or colony management practices used to appropriately isolate animals receiving these materials. Of particular concern to colony health is the occasional and justifiable need to obtain animals from less well-defined sources, such as an investigator’s colony at another institution or other inadequately characterized source. The presence of infectious agents either in transplantable tumors, other biological materials, or noncommercial animal sources can pose a substantial threat to resident colonies and personnel.
Colony monitoring of rodents is in transition, with slowly waning reliance on serology, bacteriologic, and parasitic evaluations and increasing emphasis on the evaluation of environmental, fecal, and fur samples using molecular biologic techniques such as PCR. Analysis and tracking of the microbiome, with its influence on phenotype, is a health profile option.
The proper use of filter-top caging technology impedes cage-to-cage transmission of infectious agents in rodent colonies, thus minimizing enzootic disease transmission and protecting naive animals from epizootics, but it presents challenges for health surveillance programs. Because most diseases of laboratory rodents do not cause clinical signs, and because there can be high and unpredictable turnover of research rodents, the standard for health monitoring was based on the premise that infectious agents were transmitted via soiled bedding to sentinels, which were tested for a variety of pathogens. This indirect exposure is suboptimal for the detection of many bacterial pathogens, agents transmitted by true aerosol, and fur mites. Agents that are shed intermittently, those with a self-limited, single window of shedding, those that require a high dose to be infective, and those that are unstable in the environment are difficult to detect by exposure to soiled bedding. The sentinels themselves may add confounding influences if their age or genetic background makes them relatively resistant to some infections. Prior to the widespread use of filter-top caging, dedicated sentinels in open cages were readily exposed to airborne fomite particles and true aerosols from infected animals in the colony. For small fish in aquatic systems, the sump is a useful source to obtain subjects for health monitoring.
The primary contemporary challenges to research rodent health—particularly for mice—are the noroviruses, parvoviruses, Helicobacter spp, pinworms, and fur mites that infect or infest colonies, perturbing biologic processes and introducing variation into research data. For the most part, these agents, along with mouse hepatitis virus, are thought to have gained entry to research colonies largely via the trading of live mice of unique genotypes between institutions. The situation is complicated by the inability of quarantine programs to reliably detect and exclude these agents. However, there is a body of substantial, compelling, anecdotal evidence that non-sterilized diets may be a source of introduction for some pathogens (eg, mouse parvovirus). Murine norovirus is the most widespread virus in domestic mouse colonies. The virus was described in 2003 but likely existed in research mice for decades. Mouse parvovirus was definitively discovered 10 years earlier.
New agents continue to be detected, such as a nephrotropic murine chapparvovirus (MuCPV) and murine astrovirus. These agents cause asymptomatic infection among immunocompetent mice but cause disease or remain of unknown effect for those with varying immune dysfunction.
The use of mice with increasingly extreme immunosuppression has been associated with resurging morbidity and mortality caused by Corynebacterium bovis. This bacterium and these nonenveloped viruses may persist for lengthy periods in even healthy mice and can contaminate and remain infectious in the environment for months, making them ideally suited to persevere in colonies kept in filter-top cage systems.
Rederivation by in vitro fertilization or more traditional caesarean section is an important tool in pathogen exclusion but also can contribute to narrowing of genetic and microbiome diversity, with potential reverberations across many biologic processes, behavior, and experimental repeatability.
