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2016 ; 46
(8
): 641-75
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The legacy of the F344 rat as a cancer bioassay model (a retrospective summary of
three common F344 rat neoplasms)
#MMPMID27278595
Maronpot RR
; Nyska A
; Foreman JE
; Ramot Y
Crit Rev Toxicol
2016[Sep]; 46
(8
): 641-75
PMID27278595
show ga
The Fischer 344 (F344) rat was used by the National Toxicology Program (NTP) for
over 5 decades for toxicity and carcinogenicity studies. However, in 2006, the
NTP decided to switch to a different rat stock due largely to high background
control incidences of Leydig cell tumors (LCTs) and mononuclear cell leukemia
(MNCL), also known as large granular lymphocytic (LGL) leukemia. In the current
review, we aim (1) to provide a summary of NTP bioassays with
treatment-associated effects involving MNCL and LCTs in addition to male
F344-specific tunica vaginalis mesothelioma (TVM); (2) to describe important
pathobiological differences between these F344 rat tumor responses and similar
target tissue-tumor response in humans; and (3) to present the NTP reasons for
switching away from the F344 rat. We show that due to the highly variable
background incidence of F344 MNCL, more reliance on historical control data than
is usual for most tumor responses is warranted to evaluate potential effect of
any chemical treatment in this rat strain. The high spontaneous incidence of LCTs
in the testes of male F344 rats has made this tumor endpoint of little practical
use in identifying potential testicular carcinogenic responses. TVM responses in
F344 rats have a biological plausible relationship to LCTs unlike TVM in humans.
Given their high spontaneous background incidence and species-specific biology,
we contend that MNCL and LCT, along with TVM responses, in F344 rat
carcinogenicity studies are inappropriate tumor types for human health risk
assessment and lack relevance in predicting human carcinogenicity.