Meeting Summary: Nonrodent Species in Toxicologic Pathology

Abstract

Nonrodent species are widely used in safety testing of chemicals and pharmaceuticals to meet worldwide regulatory requirements. As such, evaluation of nonrodent species may comprise a large percentage of the toxicologic pathologist’s work effort. This year, the STP Annual Symposium focused on the species other than rodents that may be encountered in the day-to-day activities of the pathologist, namely primates, dogs, minipigs, and fish. The Symposium provided a venue for comparison among these models, where these species differ from rodent models, the cross-species relevance of nonrodents models, and the relative importance of observations made in these species relative to risk assessment. Spontaneous tissue alterations and intercurrent diseases that may confound the interpretation of toxicology studies were addressed. A major theme of each of the speakers was how unique features of a particular species or model system may interfere with interpretation or be misinterpreted as potential compound related alterations. A broad spectrum of expertise provided numerous stimulating, and sometimes challenging and provocative, presentations. Our keynote speaker, Dr. Bernard Schwetz, Senior Advisor for Science in the US FDA, spoke on what the future for toxicologic pathology can and should hold. He made it clear that toxicologic pathologists must be intimately engaged in the transition to implement new technologies. This is necessary to assure that the outcome reflects the knowledge and discipline that are the hallmarks of informed regulatory decisions and links molecular data to the interpretation in the broader context of the whole animal. We must all reflect on his comments that the future role of the toxicologic pathologist will, in part, be determined by how well and how rapidly we adapt as the field moves from “:::icities” to “::: omics.” He did note, though, that we must not lose sight of what we do today, as these activities remain highly valuable for appropriate conclusions to be drawn from toxicologic studies. The first session provided a general overview of fundamental issues related to the use of the dog in toxicologic pathology and began with a discussion of common spontaneous lesions and aging changes in the beagle. The session then moved through presentations on specific aspects on the use of the dog, including interpretation of clinical pathology data, intravascular infusion models, evaluation of effects on QT interval, pharmacokinetics and drug metabolism, diagnosis of vascular injury and myeolodysplasia, and a vivid technicolor presentation on evaluating CNS toxicity. This was followed by an introductory discussion on the minipig as an alternative model to the dog in drug and chemical safety assessment. Fish, especially the zebrafish model, have been proposed as an attractive alternative to mammalian systems for drug discovery and testing safety of chemicals. The second session presented a general overview of fish as model systems in toxicologic pathology. Discussions focused on the utilization of the various models for risk identification and assessment. After a presentation on GLP issues and special procedures, the rainbow trout, zebrafish, and medaka models were described and relevant examples on the utility of these models were presented. The third session was devoted to practical examples of the use of primates in toxicologic pathology and began with a review of common diseases in primates. It was emphasized that all species are not alike and that biological differences among the species must be considered when interpreting potential pathological alterations. The session then proceeded with presentations on simian retroviruses, interpretation of clinical pathology data, intravascular infusion models, studies on immune modulators and antisense compounds, and the use of cynomolgus monkeys in teratology evaluations. The marmoset was presented for its important utility in the development of biotechnology products, but with the caveat of its unique set of challenges for husbandry. The session ended with a panel discussion on the appropriate use of primates in toxicology studies. The last session was devoted to regulatory perspectives in relation to nonrodent models. Broader issues on animal use were addressed in 2 presentations and a panel discussion. Our organization may have an unrealized social role beyond our role of assuring safety of medicines and agrichemicals. Indeed, we have the opportunity to influence international regulations on acceptable study designs and endpoints. The panel discussion, which included members from industry, academia, and regulatory agencies, addressed other study design issues and the regulatory perception of data derived from toxicology studies using nonrodent species. In particular, does the age of animals confound the pathology evaluation and is there a need to evaluate the reproductive tract in young nonrodents? Finally, this year brought record attendance to the symposium to hear presentations on a new variety of topics. I want to thank my session chairs, Suzanne Botts, Dennis Hoover, Mac Law, and Stu Levin, for their efforts in coordinating the various speakers and for bringing my vision for this symposium to fruition.