NTP Workshop: Animal Models for the NTP Rodent Cancer Bioassay: Stocks and Strains—Should We Switch?

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Toxicologic Pathology (Impact Factor: 1.92). 02/2006; 34(6):802-5. DOI: 10.1080/01926230600935938
Source: PubMed

ABSTRACT The National Toxicology Program (NTP) hosted a workshop, "Animal Models for the NTP Rodent Cancer Bioassay: Strains and Stocks--Should We Switch?" on June 16-17, 2005, at the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina. The workshop's objectives were to determine (1) whether the currently used models, the F344/N rat and B6C3F1/N mouse, continue to be appropriate to identify substances that may pose a carcinogenic hazard for humans and (2) whether the NTP should consider conducting cancer bioassays using multiple strains of rats and/or mice to better capture the range of genetic variability. Workshop participants advised the NTP to discontinue using the current F344/N strain due to the recent issues with fertility, seizure activity, and chylothorax and provided several options on how the program should approach identifying and selecting a new rat model. Participants believed that the B6C3F1/N mouse is still appropriate for use by the NTP, but suggested the NTP take steps to better understand and address increases in background rates of liver tumors in this strain. Finally, the participants supported the NTP exploring the use of the multiple strain approach, although they raised many questions concerning data interpretation and feasibility. This article also outlines the NTP's next steps in pursuing the workshop recommendations.

Download full-text


Available from: Kristina Thayer, Jul 05, 2014
  • Source
    • "Sprague-Dawley (SD) rats are a common choice for regulatory toxicology studies, but recently the Wistar Han (WH) strain has been increasingly used. The growing popularity of the Wistar strain can be attributed to their reduced size, which requires less test material, as well as a higher survival rates (longer lifespan) and lower incidence of background tumors relative to the more traditionally used Sprague-Dawley strain, which make them more desirable for use in carcinogenicity studies [1]. In addition to these differences, there have also been anecdotal reports based on reproductive performance data that the male WH rat attains sexual maturity about 2 weeks later than the Sprague-Dawley strain. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Given the increasing use of Wistar Han (WH) rats in regulatory toxicology studies, these studies were performed to characterize the onset of sexual maturation in maturing WH rats as compared to Sprague-Dawley (SD) rats. Beginning on postnatal day (PND) 38 through PND 91 groups (n=8) of untreated WH rats were evaluated for maturation of the male reproductive system. Testicular spermatid head counts increased beginning on PND 42 until PND 70. Sperm were detected in the caput, corpus, and cauda epididymis on PND 45, 49, and 49, respectively, and counts increased through PND 91. Sperm motility was at adult levels by PND 63. The morphology of the testis/epididymis of all animals at day 70 or older was consistent with qualitative sexual maturity. Based on these endpoints, WH rats were determined to be sexually mature at PND 70, and many of these endpoints evaluated in SD rats exhibited nearly identical trends.
    Reproductive Toxicology 02/2013; 38. DOI:10.1016/j.reprotox.2013.02.003 · 2.77 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: For over 35 years, many synthetic and natural chemicals have been tested by government agencies, private companies and research institutes for carcinogenic activity in rats and mice in classical 2 year studies as part of a toxicity profile ultimately used for human toxicity and carcinogenicity risk assessment. With an increasing number of pharmaceutical and agricultural chemicals shown to be carcinogenic in these bioassays, research into the mechanisms of toxicity and carcinogenesis has intensified. The relevance of the induced tumors in rodents has been questioned after much research. Research has provided evidence to some scientists that doses used in the bioassays may represent situations where toxicity pathways do not develop in humans exposed to levels of these chemicals, toxicity itself may create situations where tumors develop only under those situations, species specific responses may exist, and tumors induced may not be relevant to human risk. Regulatory agencies have considered these and other factors when preparing regulatory decisions on regulation of these chemicals. Thus, the USA FDA often has approved drugs despite their carcinogenicity in rodents and the USA EPA has explored many situations where considerations of the mechanisms of carcinogenesis in rodents and humans play a role in their regulatory decisions. Unfortunately, much of the decisions are based on unproven and hypothetical mechanisms of carcinogenesis in rodents and humans. Despite this situation, the impact of these decisions on future considerations and decisions for regulation of chemicals suggests that the US regulatory agencies consider that the occurrence of increased incidences of tumors in standard 2 year rodent carcinogenesis bioassay is often not relevant to human carcinogenesis risk assessment.
    Journal of Toxicologic Pathology 03/2007; 20(1):13-19. DOI:10.1293/tox.20.13 · 0.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The National Toxicology Program (NTP) is currently reviewing its research portfolio as part of its efforts to implement the NTP Roadmap to achieve the NTP Vision for the 21st century. This review includes a recent workshop, "Hormonally Induced Reproductive Tumors-Relevance of Rodent Bioassays," held 22-24 May 2006, that was organized to determine the adequacy and relevance to human disease outcome of rodent models currently used in the 2-year bioassay for four types of hormonally induced reproductive tumors (ovary, mammary gland, prostate, and testis). In brief, none of the workshop's breakout groups felt the currently used models are sufficient. For some types of tumors such as prostate, no adequate animal models exist, and for others such as ovary, the predominant tumors in humans are of different cellular origins than those induced by chemicals in rodents. This inadequacy of current models also applies to the testis, although our more complete understanding of the responses of Leydig cells to hormonal changes in rats may prove predictive for effects in humans other than cancer. All breakout groups recommended that the NTP consider modifying its testing protocols (i.e., age at exposure, additional end points, etc.) and/or using alternative models (i.e., genetically engineered models, in vitro systems, etc.) to improve sensitivity. In this article we briefly review the workshop's outcome and outline some next steps forward in pursuing the workshop's recommendations. Breakout group reports and additional information on the workshop, including participants, presentations, public comments and background materials, are posted on the NTP website.
    Environmental Health Perspectives 10/2007; 115(9):1351-6. DOI:10.1289/ehp.10135 · 7.98 Impact Factor
Show more