Extrapolation of dose-response carcinogen data from animals to establish """"""""safe"""""""" levels for human exposures (1 in a million) is challenging as it requires modeling of dose-response over at least 4 orders of magnitude. In many cases, the conservative approach is assumed linearity. The largest tumor study in a rodent model used 24,192 mice to detect 1 cancer in 100. The trout tumor model has proven valuable in identification of carcinogens and their mechanism of action. Trout are very sensitive to the hepatocarcinogenicity of aflatoxin B1 (AFB1), the only IARC human carcinogen where exposure is through the food supply. Hepatocellular carcinoma (HCC) is responsible for over 600,000 deaths a year worldwide and accounts for 10-15% of all deaths in certain regions. HCC is the most rapidly increasing solid tumor in the U.S. For AFB1, the target organ, metabolism, DNA adduction and gene targets are similar in trout and human and, in this example, the trout model is superior to mouse. The trout model can utilize large numbers of animals to evaluate cancer across a wide range of doses. This approach is possible due to a number of advantages of this model including low spontaneous tumor incidence and low per diem costs. We have recently completed the largest cancer study in any animal model, utilizing 42,000 trout to assess carcinogenicity of dibenzo[a,l]pyrene (DBP) at ultra-low doses. The target was an order of magnitude lower than the mouse ED01 study, to one cancer in 1000. Our data established a dose of DBP that resulted in 1 cancer in 5,000 trout and the dose-response was non-linear. We now propose to utilize this ultra-low dose model to test the hypothesis that the non-linearity of cancer incidence at ultra-low dose also applies to AFB1. Tumor incidence data will be coupled with measurements of molecular dosimetry, cell proliferation, apoptosis and gene expression utilizing a custom microarray in order to test the second hypothesis, that in contrast to tumor incidence, these biomarkers of carcinogenicity exhibit linearity across the entire tumor dose-response range.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES013534-02
Application #
7085542
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Shreffler, Carol K
Project Start
2005-07-01
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$501,768
Indirect Cost
Name
Oregon State University
Department
Type
Organized Research Units
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
Benninghoff, Abby D; Orner, Gayle A; Buchner, Clarissa H et al. (2012) Promotion of hepatocarcinogenesis by perfluoroalkyl acids in rainbow trout. Toxicol Sci 125:69-78
Williams, David E (2012) The rainbow trout liver cancer model: response to environmental chemicals and studies on promotion and chemoprevention. Comp Biochem Physiol C Toxicol Pharmacol 155:121-7
Benninghoff, Abby D; Bisson, William H; Koch, Daniel C et al. (2011) Estrogen-like activity of perfluoroalkyl acids in vivo and interaction with human and rainbow trout estrogen receptors in vitro. Toxicol Sci 120:42-58
Salinas, K; Hemmer, M J; Serrano, J et al. (2010) Identification of estrogen-responsive vitelline envelope protein fragments from rainbow trout (Oncorhynchus mykiss) plasma using mass spectrometry. Mol Reprod Dev 77:963-70
Bailey, George S; Reddy, Ashok P; Pereira, Clifford B et al. (2009) Nonlinear cancer response at ultralow dose: a 40800-animal ED(001) tumor and biomarker study. Chem Res Toxicol 22:1264-76
Williams, David E; Orner, Gayle; Willard, Kristin D et al. (2009) Rainbow trout (Oncorhynchus mykiss) and ultra-low dose cancer studies. Comp Biochem Physiol C Toxicol Pharmacol 149:175-81
Benninghoff, Abby D; Williams, David E (2008) Identification of a transcriptional fingerprint of estrogen exposure in rainbow trout liver. Toxicol Sci 101:65-80
Tilton, Susan C; Orner, Gayle A; Benninghoff, Abby D et al. (2008) Genomic profiling reveals an alternate mechanism for hepatic tumor promotion by perfluorooctanoic acid in rainbow trout. Environ Health Perspect 116:1047-55
Tilton, Susan C; Hendricks, Jerry D; Orner, Gayle A et al. (2007) Gene expression analysis during tumor enhancement by the dietary phytochemical, 3,3'-diindolylmethane, in rainbow trout. Carcinogenesis 28:1589-98