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Extended histopathology in immunotoxicity testing: Interlaboratory validation studies

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Author: Germolec, D.R. · Nyska, A. · Kashon, M. · Kuper, C.F. · Portier, C. · Kommineni, C. · Johnson, K.A. · Luster, M.I.
Institution: TNO Voeding
Source:Toxicological Sciences, 1, 78, 107-115
Identifier: 237658
doi: doi:10.1093/toxsci/kfh049
Keywords: Biology · Physiological Sciences · Histopathology · Immunology · Immunopathology · Lymph node · Pathology · Risk assessment · Spleen · Thymus · chemical agent · analysis of variance · animal cell · animal tissue · article · cellular distribution · concentration response · controlled study · disease severity · error · experience · factorial analysis · female · germinal center · health program · histopathology · immunopathology · immunotoxicity · intermethod comparison · laboratory test · lymph node · lymphatic system disease · lymphoid tissue · medical education · medical expert · mouse · nonhuman · observer variation · organogenesis · pathologist · quantitative analysis · reproducibility · screening test · sensitivity analysis · spleen cell · thymus · tissue injury · tissue structure · toxicity testing · validation process · Allergy and Immunology · Animals · Computational Biology · Data Interpretation, Statistical · Dose-Response Relationship, Drug · Histology · Immune System · Laboratories · Models, Statistical · Reproducibility of Results · Terminology · Toxicology


There has been considerable interest in the use of expanded histopathology as a primary screen for immunotoxicity assessment. To determine the utility of a semiquantitative histopathology approach for examining specific structural and architectural changes in lymphoid tissues, a validation effort was initiated. This study addresses the interlaboratory reproducibility of extended histopathology, using tissues from studies of ten test chemicals and both negative and positive controls from the National Toxicology Program's immunotoxicology testing program. We examined the consistency between experienced toxicologic pathologists, who had varied expertise in immunohistopathology in identifying lesions in immune tissues, and in the sensitivity of the individual and combined histopathological endpoints to detect chemical effects and dose response. Factor analysis was used to estimate the association of each pathologist with a so-called "common factor" and analysis-of-variance methods were used to evaluate biases. Agreement between pathologists was highest in the thymus, in particular, when evaluating cortical cellularity of the thymus; good in spleen follicular cellularity and in spleen and lymph node-germinal center development; and poorest in spleen red-pulp changes. In addition, the ability to identify histopathological change in lymphoid tissues was dependent upon the experience/training that the individual pathologist possessed in examining lymphoid tissue and the apparent severity of the specific lesion. © Society of Toxicology 2004; all rights reserved.