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ToxSci Advance Access originally published online on May 22, 2007
Toxicological Sciences 2007 99(1):3-19; 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 in Fischer 344 Rats as an Initial Step Toward Evaluating the Implication of the Endpoint to Human Cancer Risk Assessment

Johnson Thomas*,1, Joseph K. Haseman{dagger}, Jay I. Goodman{ddagger}, Jerrold M. Ward§, Thomas P. Loughran, Jr and Pamela J. Spencer*

* Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674 {dagger} JK Haseman Consulting, 1054 Tacketts Pond Drive, Raleigh, North Carolina, 27614 {ddagger} Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, 48824 § 10513 Wayridge Drive, Montgomery Village, Maryland, 20886 Penn State Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, 17033

1 To whom correspondence should be addressed at Veterinary Pathologist, The Dow Chemical Company, Midland, MI 48674. E-mail: jthomas4{at}dow.com.

Received February 9, 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 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 five 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.

Key Words: F344 rat; Large granular lymphocyte; Leukemia; LGLL and Human cancer risk assessment.


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