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ToxSci Advance Access published online on May 22, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm098
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A Review of Large Granular Lymphocytic Leukemia (LGLL) in Fischer 344 rats as an Initial Step Toward Evaluating the Implication of the Endpoint to Human Cancer Risk Assessment

J Thomas, JK Haseman, JI Goodman, JM Ward, TP Loughran, Jr and PJ Spencer

Fischer 344 Rat LGLL Expert Panel Review Midland MI 48674

Received February 9, 2007; revision received April 16, 2007; accepted April 24, 2007


  Abstract

Large granular lymphocyte leukemia (LGLL) is a common fatal disease in aging F344 rats. The current understanding of rat LGLL and a search for mechanistic data/correlations to human leukemia were examined with the goal of improving evaluation of the LGLL endpoint in cancer bioassays as it relates to human cancer risk assessments. The exact cell of origin of the F344 rat LGLL is not fully resolved, although Natural Killer (NK) cell characteristics were demonstrated in most, if not all cases. Similarities between rat LGLL and a rare human NK-LGLL exist, invalidating claims of no human counterpart, although the underlying etiopathogenesis may be different. There is insufficient data to establish a mode of action (MOA) of chemical induced rat LGLL. Evaluation of the National Toxicology Program database revealed only 34 substances (out of over 500 studied) that were possibly associated with increased incidences of LGLL. Of these, only 5 produced definitive LGLL effects in both sexes; the remaining 29 produced single sex responses and/or only ‘equivocal’ associations with LGLL. Trends of increasing background/variability in LGLL incidence and its modulation by extraneous factors (e.g. corn oil gavage) are key confounders in interpretation. Given that LGLL is a common tumor in control F344 rats, interpretations of bioassays can be improved by increasing the statistical stringency (e.g. p<0.01 over traditional p<0.05), as an indicator of possible carcinogenic effects, but that alone would be insufficient evidence for declaring treatment-related increases. Thus it was concluded that the evaluation of possible chemically-related increases in rat LGLL utilize a ‘weight of evidence’ approach.


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