Rainbow trout (Oncorhynchus mykiss) and ultra-low dose cancer studies.
Cancer risk assessment utilizing rodents requires extrapolation across five orders of magnitude to estimate the Virtually Safe Dose (VSD). Regulatory agencies rely upon the Linear Extrapolated Dose (LED) except when sufficient information on mechanism of action justifies alternative models. Rainbow trout (Oncorhynchus mykiss) has been utilized at Oregon State University as a model for human cancer for forty years. Low cost and high capacity, made possible by our unique facility, along with low spontaneous background and high sensitivity, allow design and conduct of statistically challenging studies not possible in rodents. Utilization of custom microarrays demonstrates similarities in gene expression in trout and human hepatocellular carcinoma (HCC). We have completed one study employing over 42,000 trout with dibenzo[a,l]pyrene (DBP) and determined the dose resulting in 1 additional cancer in 5000 animals, a 50-fold enhancement over the mouse ED(01) study. Liver tumor incidence at low dose deviated significantly from linearity (concave down), whereas, DBP-DNA adductions deviated slightly (convex up). A second study is underway with aflatoxin B(1) (AFB(1)). Results to date indicate AFB(1) at low dose, in contrast to DBP, elicits a linear dose-response function on the log-log scale which falls below the LED with a slope slightly greater than 1.0. Such studies demonstrate the statistical power of the trout cancer model and strengthen the case for incorporation of these data-sets into risk assessment for these environmental human carcinogens.
Williams
David E
DE
Department of Environmental and Molecular Toxicology, Oregon State University, USA. david.williams@oregonstate.edu
Orner
Gayle
G
Willard
Kristin D
KD
Tilton
Susan
S
Hendricks
Jerry D
JD
Pereira
Clifford
C
Benninghoff
Abby D
AD
Bailey
George S
GS
D000348:Aflatoxins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001580:Benzopyrenes / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics*; D015394:Molecular Structure; D017686:Oncorhynchus mykiss / Q000235:genetics*; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D018570:Risk Assessment
D000348:Aflatoxins; D001580:Benzopyrenes; D002273:Carcinogens; D011084:Polycyclic Aromatic Hydrocarbons; C021146:dibenzo(a,i)pyrene