Three sources of variability in tumor incidence were investigated. To assess the impact of random variability, we evaluated the operating characteristics of several statistical procedures for comparing tumor incidences. We found that those techniques that use pre-determined levels of significance (e.g., p<0.01) for all comparisons may produce unacceptably high false positive rates. We concluded that a procedure derived by Westfall and Soper, if used properly, seems to provide a reasonable balance between controlling the overall false positive rate and maintaining power for detecting carcinogenic effects. To investigate the impact of body weight differences on tumor incidence, we evaluated data from the NTP Dietary Restriction Study. Our investigation suggests that a dietary restriction strategy that focuses on achieving similar body weights in dosed and control groups may produce false positive outcomes if substantially more food restriction is required for control groups than for dosed animals. We also found that equal food restriction to dosed and control animals may produce false negative outcomes if the resulting body weights are substantially different in dosed and control groups. Alternative methods of reducing body weight are being studied, including dietary modifiation and requiring lighter animals from the breeder. Finally, we evaluated the impact Helicobacter hepaticus infection on the incidence of liver neoplasms. Control B6C3F1 male mice from nine NTP studies infected with Helicobacter hepaticus showed increased (p<0.05) liver tumor incidences compared with controls from 26 uninfected bioassays. The increased incidences of hepatocellular neoplasms were seen primarily in those males exhibiting H. hepaticus associated hepatitis. We concluded that interpretation of carcinogenic effects in the liver of B6C3F1 mice may be confounded if there is H. hepaticus associated hepatitis.

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Kissling, Grace E; Haseman, Joseph K; Zeiger, Errol (2015) Proper interpretation of chronic toxicity studies and their statistics: A critique of ""Which level of evidence does the US National Toxicology Program provide? Statistical considerations using the Technical Report 578 on Ginkgo biloba as an example"". Toxicol Lett 237:161-4
Ferguson, Sherry A; Law, Charles Delbert; Kissling, Grace E (2014) Developmental treatment with ethinyl estradiol, but not bisphenol A, causes alterations in sexually dimorphic behaviors in male and female Sprague Dawley rats. Toxicol Sci 140:374-92
Thigpen, Julius E; Setchell, Kenneth D R; Padilla-Banks, Elizabeth et al. (2007) Variations in phytoestrogen content between different mill dates of the same diet produces significant differences in the time of vaginal opening in CD-1 mice and F344 rats but not in CD Sprague-Dawley rats. Environ Health Perspect 115:1717-26
Kissling, Grace E; Dertinger, Stephen D; Hayashi, Makoto et al. (2007) Sensitivity of the erythrocyte micronucleus assay: dependence on number of cells scored and inter-animal variability. Mutat Res 634:235-40
Ghanayem, B I; Witt, K L; El-Hadri, L et al. (2005) Comparison of germ cell mutagenicity in male CYP2E1-null and wild-type mice treated with acrylamide: evidence supporting a glycidamide-mediated effect. Biol Reprod 72:157-63
Nwosu, Veronica C; Kissling, Grace E; Trempus, Carol S et al. (2004) Exposure of Tg.AC transgenic mice to benzene suppresses hematopoietic progenitor cells and alters gene expression in critical signaling pathways. Toxicol Appl Pharmacol 196:37-46
Kanno, Jun; Onyon, Lesley; Peddada, Shyamal et al. (2003) The OECD program to validate the rat uterotrophic bioassay. Phase 2: dose-response studies. Environ Health Perspect 111:1530-49
Kanno, Jun; Onyon, Lesley; Peddada, Shyamal et al. (2003) The OECD program to validate the rat uterotrophic bioassay. Phase 2: coded single-dose studies. Environ Health Perspect 111:1550-8
Ozaki, Keisuke; Haseman, Joseph K; Hailey, James R et al. (2002) Association of adrenal pheochromocytoma and lung pathology in inhalation studies with particulate compounds in the male F344 rat--the National Toxicology Program experience. Toxicol Pathol 30:263-70
Eastin, W C; Mennear, J H; Tennant, R W et al. (2001) Tg.AC genetically altered mouse: assay working group overview of available data. Toxicol Pathol 29 Suppl:60-80

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