The legacy of the F344 rat as a cancer bioassay model (a retrospective summary of three common F344 rat neoplasms)

Abstract

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.

Chemical-specific adjustment factors (inter-species toxicokinetics) to establish the ADI for steviol glycosides

“…Since the incidence of large granular lymphocytic type leukemia was found to be within the historical control range and given that noting that the presence of this neoplasm is now interpreted quite differently (Thomas et al, 2007) than at the time of the Toyoda et al (1997), there is no indication of a treatment-related effect. In addition, as recently discussed by Maronpot et al (2016), this neoplasm is a result of the species-strain specific biology of the F344 rat and is of little relevance to human risk assessment. As such it could be argued that in reality the top dose of 5% in the study was the true NOAEL, which equates to a dose level of 1,997 mg/kg bw/d in males and 2,387 mg/kg bw/d in females.…”

Proceedings of the 2017 National Toxicology Program Satellite Symposium

“…Spontaneous mesothelioma is a rare neoplasm in rats with an incidence of 0.2 – 5%, the highest frequencies of which are reported in the Fischer 344 (F344) rat strain. Rat mesotheliomas typically occur in aged male rats and originate from the tunica vaginalis with the potential to spread into the peritoneal cavity via transcoelomic extension or seeding; primary intrathoracic mesotheliomas are rare (Hall 1990, Boorman et al 1990, Percy and Barthold 2007, Maronpot et al 2009, Maronpot et al 2016, Creasy et al 2012). To date, 17 studies from the NTP have reported xenobiotic-induced mesotheliomas in F344 rats; the F344 rat is particularly sensitive to developing this tumor type and is the only rodent strain reported to develop mesothelioma following xenobiotic exposure by a route other than peritoneal injection (Maronpot et al 2009, Maronpot et al 2016).…”

“…Rat mesotheliomas typically occur in aged male rats and originate from the tunica vaginalis with the potential to spread into the peritoneal cavity via transcoelomic extension or seeding; primary intrathoracic mesotheliomas are rare (Hall 1990, Boorman et al 1990, Percy and Barthold 2007, Maronpot et al 2009, Maronpot et al 2016, Creasy et al 2012). To date, 17 studies from the NTP have reported xenobiotic-induced mesotheliomas in F344 rats; the F344 rat is particularly sensitive to developing this tumor type and is the only rodent strain reported to develop mesothelioma following xenobiotic exposure by a route other than peritoneal injection (Maronpot et al 2009, Maronpot et al 2016). Histologically, mesotheliomas may be difficult to distinguish from mesothelial hyperplasia as they can range from a single layer of hyperplastic mesothelial cells lining a thin fibrovascular stroma to papillary projections lined by multiple, irregular layers of cuboidal to polygonal cells that form a pavement or stratified pattern (Hall 1990, Boorman et al 1990, Percy and Barthold 2007, Maronpot et al 2009, Maronpot et al 2016, Creasy et al 2012).…”

“…To date, 17 studies from the NTP have reported xenobiotic-induced mesotheliomas in F344 rats; the F344 rat is particularly sensitive to developing this tumor type and is the only rodent strain reported to develop mesothelioma following xenobiotic exposure by a route other than peritoneal injection (Maronpot et al 2009, Maronpot et al 2016). Histologically, mesotheliomas may be difficult to distinguish from mesothelial hyperplasia as they can range from a single layer of hyperplastic mesothelial cells lining a thin fibrovascular stroma to papillary projections lined by multiple, irregular layers of cuboidal to polygonal cells that form a pavement or stratified pattern (Hall 1990, Boorman et al 1990, Percy and Barthold 2007, Maronpot et al 2009, Maronpot et al 2016, Creasy et al 2012). Rat mesotheliomas have a classification scheme similar to humans with sarcomatous, epitheliomatous or mixed types that stain positively with Wilm's tumor 1 (WT-1).…”

“…Rat mesotheliomas have a classification scheme similar to humans with sarcomatous, epitheliomatous or mixed types that stain positively with Wilm's tumor 1 (WT-1). Ultrastructural features of mesotheliomas include a distinct basal lamina, junctional complexes between mesothelial cells; microvilli; pinocytotic vesicles; abundant cytofilaments; and dilated rough endoplasmic reticulum (RER) (Hall 1990, Maronpot et al 2009, Maronpot et al 2016). …”