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

Our plain-English summary of The legacy of the F344 rat as a cancer bioassay model (a retrospective summary of three common F344 rat neoplasms), by R.R. Maronpot, A. Nyska, J.E. Foreman, et al (Critical Reviews in Toxicology, 2016).

The study

• Authors: R.R. Maronpot, A. Nyska, J.E. Foreman, Y. Ramot
• Journal: Critical Reviews in Toxicology
• Published: 2016;46(8):641-75
• Type of article: Review
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This review used published National Toxicology Program (NTP) reports on cancer tests in Fischer 344 (F344) rats. The authors focused on three tumors: mononuclear cell leukemia (MNCL) and Leydig cell tumors of the testis (LCTs), both frequent in untreated F344 rats, and tunica vaginalis mesothelioma (TVM), a mesothelioma of the testis lining that is rare in untreated males. The tested chemicals included furan, acrylamide and glycidol. The authors counted 40 NTP studies with a possible chemical-related rise in MNCL. NTP rated nine as clear evidence of carcinogenicity for MNCL in one or both sexes. The authors found the data consistent with that rating for furan and tetrafluoroethylene, and debatable for the other seven. Seven studies showed a Leydig cell tumor response. Seventeen showed a treatment-related rise in TVM in males. No mesothelioma response was seen in female rats, even in a study where abdominal injections inflamed the abdominal lining in both sexes. From human reports, the authors noted that asbestos exposure is reported in only 30–40% of human TVM cases. The authors concluded these three rat tumors lack relevance for predicting human cancer. They said the review was not comprehensive.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review: a retrospective summary and evaluation of published NTP technical reports and database records, plus a literature review comparing the rat tumors with human tumors
• Who was studied: Male and female F344 rats in NTP cancer bioassays from 1978 to 2006, when NTP stopped using this rat
• Exposure: Various chemicals tested by NTP, given in feed or drinking water, by gavage, by inhalation, on the skin or by injection (for example furan, tetrafluoroethylene, acrylamide, glycidol, o-nitrotoluene). Asbestos was not one of the tested exposures. The article mentions it only when discussing human TVM and earlier studies.
• Main results:
  • The authors described MNCL and Leydig cell tumors as having a high background incidence in F344 rats, and TVM as occurring rarely.
  • TVMs are rarely seen in untreated (control) male F344 rats, which made increases relatively easy to detect.
  • Of the 40 studies with a possible chemical-related increase in MNCL, NTP ultimately concluded that two chemicals were not carcinogenic. Of the remaining 38, nine had MNCL as the only tumor response in one or both sexes.
  • NTP rated nine studies as clear evidence of carcinogenicity for MNCL in one or both sexes. The authors found the data consistent with that rating for furan and tetrafluoroethylene. For the other seven, they called the clear-evidence rating for MNCL debatable and the supporting data less compelling. This assessment concerned MNCL only, not the studies' findings at other sites.
  • Twenty-six chemicals were associated with a decrease in MNCL in one or both sexes. Most of these also showed splenic toxicity.
  • Seven NTP studies showed an increased Leydig cell tumor response. One (isoprene) was judged clear evidence and six equivocal evidence. Five of the seven were inhalation studies.
  • The NTP historical control rate of Leydig cell tumors in F344 rats ranged from 54% to as high as 98%.
  • Seventeen NTP studies showed a treatment-related increase in TVM in male F344 rats. Fourteen of these were judged clear evidence or positive.
  • No mesothelioma response was ever seen in female rats. This included the cytembena study, in which the chemical was injected into the abdominal cavity and caused peritoneal inflammation in both sexes.
  • From their review of published human reports (not new data), the authors noted that asbestos exposure is reported in only 30–40% of human TVM cases.
• The authors' conclusion: The authors concluded that MNCL, Leydig cell tumor and TVM responses in F344 rat cancer studies lack relevance for predicting cancer in humans. They also said that analyses of F344 rat MNCL warrant more reliance on historical control data than is usual.
• Limitations the authors state:
  • The authors stated that the review was not intended to cover all existing literature on these three tumors.
  • The authors based their judgment of human relevance on tissue site-concordance between rats and humans, but acknowledged that such concordance is not universal.
  • For six early studies, which were done before NTP's levels of evidence and often lacked historical control data, the authors said they could not draw firm conclusions about MNCL.

Topics

Medical terms in this study, explained in our Lexicon: Neoplasm, Testicular Mesothelioma, Carcinogenic.

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