1.	Can we have a globally universal standard, in terms of panels of agents of which the rodents must be free to be accepted as the highest quality? In other words, could we truly have global harmonization of an infectious standard for each of the laboratory rodents? The answer is that between countries and regions, there would of course be substantial areas of overlap as there now is between the lists presented here as representing a US consensus and the published official FELASA lists. But equally true, there would probably always be discrepant agents of regional concern on the panels not regarded as significant elsewhere. As examples, the FELASA lists for rats and mice include Klossiella, Proteus, Leptospira, Escherichia coli, and Yersinia pseudotuberculosis—which you will note are not in the US panels presented here—whereas Pasteurella pneumotropica and Citrobacter rodentium are considered of importance in the United States but not by FELASA. Perhaps expert committees could be formed to critically examine whether discrepant agents need to retained or could be safely deleted from the regional panels.
2.	There is at present no means for ensuring a uniform standard for the potency, purity, or specificity of serologic test reagents, either of antigens or of positive control sera. Similarly, there is at present no means for ensuring availability of testing reagents for diagnostic labs. There should be, perhaps at the ICLAS level, some objective means of comparing and evaluating adequacy and availability of testing reagents to remove this potential variable to comparability of surveillance programs from laboratory to laboratory, and from country to country.
3.	The testing laboratories themselves, whether at the state, national, or private sector level, are not regulated and required to meet administered performance standards. Whether required for professional acceptability (dare I say accredited?) or by entirely voluntary participation, there should be some objective ongoing assessment of laboratory performance.
4.	Finally, I would like to give an opinion against patent protection for discoveries of new agents. An unfortunate trend has been the movement to cash in on diagnostic discoveries by patenting organisms as isolated from nature and subsequently characterized as pathogens. An example is Helicobacter hepaticus. We have seen that the patent on this agent has acted to restrict its availability for exploration and implementation of diagnostic tests to the detriment of improvements in rodent health surveillance. Presumably this was not the intention of the patent holders, but just as surely, that has been one of the net effects. The unintended effect of restricted availability should be noted and the impulse to patent such "discoveries" discouraged.

Baker, D.G. 1998. Natural pathogens of laboratory mice, rats and rabbits and their effects on research. Clin. Microbiol. Rev. 11:231–266.

ICLA [International Committee on Laboratory Animals]. 1971. Defining the Laboratory Animal. IV Symposium. National Academy of Sciences, Washington, DC.

Kraft, V., A. A. Deeny, H. M. Blanchet, R. Boot, A. K. Hansen, G. Milite, J. R. Needham, W. Nicklas, A. Terrot, C. Rehbinder, Y. Richard, and G. De Vroey. 1994. Recommendations for the health monitoring of mouse, rat, hamster, guinea pig and rabbit breeding colonies. Lab. Anim. 28:1–12.

Lussier, G. L., J. K. Davis, W. R. Shek, A. L. Smith, and G. Lussier. 1991. Detection methods for the identification of rodent viral and mycoplasmal infections. Lab. Anim. Sci. 41:199–225.

Rehbinder, C., P. Baneux, D. Forbes, H. Van Herck, W. Nicklas, Z. Rugnya, and G. Winkler. 1996. FELASA recommendations for the health monitoring of mouse, rat, hamster, gerbil, guinea pig and rabbit experimental units. Lab. Anim. 30:193–208.

Weisbroth, S. H. 1995. Pneumocystis carinii: Review of diagnostic issues in laboratory rodents. Lab. Anim. 24:36–40.

Weisbroth, S. H. 1996. Post-indigenous disease: Changing concepts of disease in laboratory rodents. Lab. Anim. 25:25–33.

J. Russell Lindsey

Professor, Department of Comparative Medicine

University of Alabama Schools of Medicine and Dentistry

Birmingham, Alabama

Following the pattern set by the previous Japanese speakers, Drs. Itoh and Mannen, Dr. Weisbroth has addressed the issue of ''testing methods,'' and I will speak on "current status" of pathogens in mice and rats. I am, of course, most familiar with the quality of animals in my own country, the United States. However, many of my comments will be applicable worldwide as biomedical research and its constituent parts, including the laboratory animals being used to generate much of the data and the journals that disseminate the results, are increasingly international activities.

Much progress has been made in eliminating pathogens from laboratory mouse and rat populations since the 1960s (Weisbroth 1996). This fact is borne out by several surveys conducted mainly in the early 1980s (NRC 1991, pp. 7–8) and one in 1988 (Casebolt and others 1988). During the period from the 1960s into the 1990s, there were also major efforts to (1) improve methods for detecting, eliminating, and preventing pathogen infections (Allen and Nomura 1986; Baker 1998; Bhatt and others 1986; NRC 1991); and (2) herald the seemingly endless detrimental effects that pathogens have on research results (Allen and Nomura 1986; Bhatt and others 1986; NRC 1991 [see partial listings on pp. 274–275]). More recently, many additional examples of pathogen effects have been published (Baker 1998). Although all of these past developments are noteworthy achievements that tend to engender a great sense of accomplishment among laboratory animal specialists, it seems to me far more important to take the

forward view and ask the question, "How well are these achievements serving contemporary research?" The answers to this question are rather disappointing for a number of reasons.

Dr. Jacoby and I recently surveyed the top 100 institutional recipients of National Institutes of Health (NIH) funds regarding their efforts to prevent pathogen infections in mouse and rat populations at their institutions. Responses were received from 72 of the 100 institutions, representing more than $5 billion in NIH support and use of 3 million mice and 1 million rats for the year of the survey (Jacoby and Lindsey 1997, 1998). The results were surprising. Only 70% of the mouse populations and 60% of the rat populations were considered specific pathogen free (SPF), meaning that many populations were, in reality, conventional. Furthermore, the survey was constructed so that each institution could define its use of the term SPF by checking presence or absence of each of 24 pathogens. The results showed enormous disparities among institutions in the definition of SPF. Agents such as ectoparasites, parvoviruses, mouse hepatitis virus, mouse rotavirus, Helicobacter sp., Theiler's encephalomyelitis virus, and cilia-associated respiratory bacillus, generally recognized as pathogens, were common in so-called SPF populations. There was also great variation in the frequency of testing for pathogens, the number of animals tested, and the test methods being used. These findings point to real problems with the terminology of pathogen status.

Unfortunately, the hard reality is that pathogen status is elusive because it is usually defined by words selected from a morass ("a marsh, swamp, or something that traps, confuses, or impedes") (Webster's Ninth New Collegiate Dictionary 1989) of terminology, including words such as germ free, defined flora, pathogen free, specific pathogen free, virus antibody free, barrier maintained, and conventional. The underlying problem is that these terms merely identify concepts. The results of the terminology morass are (1) there is no universal testing strategy or reporting terminology for clear and consistent definition of pathogen status in rodent populations, and (2) each institution (or investigator) selects its own list of pathogens, test procedures, animal sampling strategy, frequency of sampling, and reporting terminology. Definitions of the conceptual terms above should include the agents for which tests were actually done on the subpopulation(s) in question, test methods used, results of the tests, and frequency of the testing.

Based on the foregoing information, it appears that a number of key principles of rodent pathogen status are being compromised:

Terms such as "pathogen free" are actually concepts and must be defined each time they are used (Allen and Nomura 1986; Bhatt and others, 1986; NRC 1991).

Some of the reasons these principles are being compromised in the United States are as follows:

Since Dr. Jacoby and I published the results of the survey of institutions in the United States on their programs for protecting mouse and rat populations