You are here:
INTERPRETATION OF THE CANCER RESPONSE TO POTENTIAL RENTAL CARCINOGENS IN THE TSC2 KNOCKOUT (EKER) RAT IS DEPENDENT ON LENGTH OF TREATMENT.
Citation:
McDorman, K AND D C. Wolf. INTERPRETATION OF THE CANCER RESPONSE TO POTENTIAL RENTAL CARCINOGENS IN THE TSC2 KNOCKOUT (EKER) RAT IS DEPENDENT ON LENGTH OF TREATMENT. Presented at Alternative Methods for Carcinogenicity Testing, ICSI Meeting, Leesburg, Virginia, 11/1-3, 2000.
Description:
INTERPRETATION OF THE CANCER RESPONSE TO POTENTIAL RENAL CARCINOGENS IN THE TSC2 KNOCKOUT (EKER) RAT IS DEPENDENT ON LENGTH OF TREATMENT.
Genetically increasing the function of oncogenes or knocking out the function of a tumor supressor gene has dramatically increased the ability to screen xenobiotics for potential carcinogenicity .While manipulating the genetics of a rodent can dramatically decrease tumor latency, it can also create difficulties in interpretation. Although being able to treat rodents for 6 months instead of 2 years can shorten the time to identify a carcinogen, these data will not provide sufficient information for mechanistic understanding of tumor development in many cases. Not including a sufficient number of time points in an abbreviated cancer study in genetically susceptible animals can result in erroneous conclusions on the potential carcinogenic activity of a compound. The tissue response at one time point may be the opposite of that from an earlier or later time point such that a minimum of 2 time points are necessary for accurate interpretation and classification of a xenobiotic as a complete carcinogen or as a tumor promoter.
Hereditary renal cell carcinoma in the rat, originally reported by Reidar Eker in 1954, is an example of a dominantly inherited cancer in an experimental animal. Eker rats develop hereditary renal cell carcinoma secondary to a germline mutation in the tuberous sclerosis complex 2 (Tsc2) gene and are highly susceptible to the effects of nephrotoxicants and renal carcinogens. The mutation is an insertion of 6.3 kbp of DNA of unknown origin into the 3'- portion of the Tsc2 gene that leads to a new 3 '-terminus and elimination of the distal portion of the Tsc2 gene. The utility of this model in studying potential renal carcinogens is due to an ordered progression of proliferative lesions that can be identified and counted microscopically. Renal epithelial lesions begin as atypical tubules that may progress to atypical hyperplasias, adenomas, and often carcinomas. Studies using the Eker rat model illustrate the importance of chronic exposure and more than one time point for appropriate interpretation of the tissue response.
Male Eker rats were treated with 500 ppm of sodium barbital (BB), a nephrotoxicant and tumor promoter, in the feed. This dose of BB increased proximal tubule cell proliferation with minimal nephrotoxicity. Animals were euthanized at 6 and 12 months of age (4.5 or 10.5 months of treatment). While this exposure regimen did significantly increase the number of renal tumors present at 6 months of age (4.5 months of treatment) there was no increase in the number of renal tumors at 12 months of age (10.5 months of treatment) when compared to control animals. There was also no statistically significant difference in the number of renal tumors present in rats given 500 ppm BB and necropsied at 6 months of age compared to control or treated rats necropsied at 12 months of age. The BB treatment only caused the spontaneous preneoplastic lesions to grow to a size morphologically consistent with a diagnosis of tumor sooner compared to untreated control. If only the 6 month data were considered then BB could be classified as a renal carcinogen and if only the 12 month data were considered then BB would be thought to have no effect. This study showed that BB promoted hereditary renal tumors but did not increase the multiplicity of the tumors within a rat. This interpretation was made possible by collecting data from more than one time point.
In a series of studies, male Eker rats were treated with low or high concentrations of four individual disinfection by-products (DBPs) in drinking water. Potassium bromate (KBrO3), a DNA-damaging agent through oxidation, 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)- furanone (MX), a direct acting mutagen, chloroform (CHCl3), a cytotoxicant, or bromodichloromethane (BDCM), a cytotoxicant with weak mutagenic activity, were administered in drinking water at non-carcinogenic concentrations of 0.02,0.005, 0.4, and 0.07 g/L, respectively and carcinogenic concentrations of 0.4, 0.07, 1.8 and 0.7 g/L, respectively. Animals were euthanized at 6 or 12 months of age (4.5 or 10.5 months of treatment). At 6 months of age, all high concentration exposure groups showed a statistically significant increase in total renal lesions compared to controls but, the compound with the greatest effect was CHCI3. At 12 months of age, increased numbers of adenomas and carcinomas were observed in animals exposed to high concentrations of KBrO3 and MX. The compound with the greatest effect at 12 months of age was MX. Exposure to high concentration CHCl3 resulted in no increases in renal tumors compared to control, consistent with its tumor promoting activity. If one only had the 6 month data the interpretation of which of these 4 chemicals is the most potent renal carcinogen would be different than the interpretation at 12 months.
The results of these studies have implications for other genetically susceptible or transgenic rodent models and their use in carcinogenicity testing. More than one time point, in the above studies, influenced the interpretation of the tissue effects of the compounds. This points out the necessity of designing studies appropriately when examining poorly characterized xenobiotics in genetically enhanced rodent models, because the final interpretation of the potential hazard of a xenobiotic may be as much a function of the design of the study as the properties of the compound.
This abstract does not reflect U. S. EPA policy.