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Bolon B.,Amgen Inc. | Bolon B.,GEMpath Inc. | Stolina M.,Amgen Inc. | King C.,Amgen Inc. | And 6 more authors.
Journal of Biomedicine and Biotechnology | Year: 2011

Rodent models of immune-mediated arthritis (RMIA) are the conventional approach to evaluating mechanisms of inflammatory joint disease and the comparative efficacy of antiarthritic agents. Rat adjuvant-induced (AIA), collagen-induced (CIA), and streptococcal cell wall-induced (SCW) arthritides are preferred models of the joint pathology that occurs in human rheumatoid arthritis (RA). Lesions of AIA are most severe and consistent; structural and immunological changes of CIA best resemble RA. Lesion extent and severity in RMIA depends on experimental methodology (inciting agent, adjuvant, etc.) and individual physiologic parameters (age, genetics, hormonal status, etc.). The effectiveness of antiarthritic molecules varies with the agent, therapeutic regimen, and choice of RMIA. All RMIA are driven by overactivity of proinflammatory pathways, but the dominant molecules differ among the models. Hence, as with the human clinical experience, the efficacy of various antiarthritic molecules differs among RMIA, especially when the agent is a specific cytokine inhibitor. © 2011 Brad Bolon et al.

Dr. Peter S. Spencer, a pioneering neurotoxicologist of international renown, delivered the keynote address at the 2010 Joint Scientific Symposium of the Society of Toxicologic Pathology (STP) and the International Federation of Societies of Toxicologic Pathologists (IFSTP). He has made many landmark discoveries during his four-decade career. Dr. Spencer's address communicated several fundamental principles of past and present toxicologic neuropathology research, and he also predicted future trends in the field. First, classic approaches to toxicologic neuropathology emphasized morphologic techniques such as light microscopic and ultrastructural assessment. However, neuropathology methods alone rarely reveal the mechanism(s) and etiology of neurotoxic conditions, so neurotoxicity problems are now being investigated using a multidisciplinary approach in which neuropathologic assessment is but one component of the analysis. The two primary trends for future toxicologic neuropathology investigations, in both animals and humans, will be an increased use of noninvasive neural imaging and greater preference for in situ molecular ("omic") methods, which provide functional information in a structural context. These trends will significantly enhance the ability of scientists to translate animal data to human situations, thereby improving our understanding of disease mechanisms and facilitating efforts to design new therapies for neural diseases.

Neuropathology analyses as end points during nonclinical efficacy and toxicity studies are challenging and require trained personnel and particular equipment to achieve optimal results. Accordingly, many regulatory agencies have produced explicit guidelines for designing and performing neuropathology assessments for nonclinical studies. This compilation of international regulatory guidance for toxicologic neuropathology end points represents a set of criteria recommended for general toxicity studies and specialized neurotoxicity studies that should facilitate the efforts of individuals who plan, perform, analyze, and report neuropathology evaluations in nonclinical toxicity studies.

Bolon B.,GEMpath Inc.
Toxicologic pathology | Year: 2011

Investigations in toxicologic neuropathology are complex undertakings because of the intricate spatial and temporal diversity in the anatomic, functional, and molecular organization of the central and peripheral nervous systems. This compilation of toxicologic neuropathology resources has been designed to consolidate a broad range of useful neurobiology, neuropathology, and neurotoxicology resources in a single reference. This collection will increase familiarity with the basic knowledge, skills, and tools required for the proficient practice of toxicologic neuropathology and should help to improve the analysis and interpretation of pathology data sets from neural tissues in toxicology studies.

Kerlin R.,Pfizer | Bolon B.,GEMpath Inc. | Burkhardt J.,AbbVie Research and Development | Francke S.,College Park | And 3 more authors.
Toxicologic Pathology | Year: 2016

Recommendations (best practices) are provided by the Society of Toxicologic Pathology's Adversity Working Group for making consistent interpretations of test article-related effects as "adverse" and assigning a "no observed adverse effect level" (NOAEL) in nonclinical toxicity studies. Adverse is a term indicating "harm" to the test animal, while nonadverse indicates lack of harm. Adverse findings in the study reports should be defined in relation to effects on the test species used and within the context of the given study. Test article-related effects should be described on their own merits, and decisions to consider them as adverse or nonadverse should be justified. Related effects may be discussed together; in particular, markers of toxicity that are not in and of themselves adverse ideally should be discussed in conjunction with the causal toxicity to determine adversity. Adverse findings should be identified in subreports (clinical data, pathology data, etc.) if sufficient information is available, and/or in the final study report as individual or grouped findings, but study NOAELs should be established at the level of the overall study report. Interpretations such as "not biologically relevant" or "not toxicologically important" should be avoided unless defined and supported by scientific rationale. Decisions defining adverse findings and the NOAEL in final study reports should combine the expertise of all contributing scientific disciplines. Where possible, use of NOAELs in data tables should be linked to explanatory text that places them in context. Ideally, in nonclinical summary documents, NOAELs from multiple studies are considered together in defining the most important adverse responses in the most sensitive species. These responses are then considered along with an understanding of their likely mechanisms, as well as other information such as variability in species sensitivity, comparative pathology, reversibility and progression, kinetics, and metabolism of the test substance to help assess human risk. © The Author(s) 2015.

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