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ToxSci Advance Access published online on December 22, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh049
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received September 22, 2003; accepted November 28, 2003
© 2003 Society of Toxicology

Immunotoxicology

Extended Histopathology in Immunotoxicity Testing: Interlaboratory Validation Studies

D. R. Germolec 1*, A. Nyska 2, M. Kashon 3, C. F. Kuper 4, C. Portier 5, C. Kommineni 6, K. A. Johnson 7, and M. I. Luster 8

1 Laboratory of Molecular Toxicology/National Toxicology Program, National Institute of Environmental Health Sciences, RTP, NC
2 Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, RTP, NC
3 Biostatistics Branch, National Institute for Occupational Safety and Health, Morgantown, WV
4 TNO Nutrition and Food Research, Zeist, The Netherlands
5 Laboratory of Computational Biology and Risk Assessment, National Institute of Environmental Health Sciences, RTP, NC
6 Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, WV
7 Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, MI
8 Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health, Morgantown, WV

* To whom correspondence should be addressed. E-mail: germolec{at}niehs.nih.gov.


  Abstract

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, 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 with varied expertise in immunohistopathology and in identifying lesions in immune tissues and 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 thymus cortical cellularity, 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 possesses in examining lymphoid tissue and the apparent severity of the specific lesion.


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