Rodent chronic bioassay

A chronic bioassay (one year) in a non-rodent mammalian species (usually the dog). 

Two-year rat chronic bioassay in rodents was performed Increased incidence of adrenal medullary hyperplasia and pheochromocytoma observed... 

Results of the database surveys proposed that rats were more sensitive then mice and that tumorigeni-city detected in mice only was never the sole reason for regulatory action. Furthermore, findings in rats only were twice as frequent as in mice only all known human carcinogens were positive in rats. Therefore, it was proposed that normally one long-term study in one rodent species would suffice. The species should be the most appropriate and on practical convenience, the rat would be preferred. From the European point of view, one chronic bioassay in the rat would be sufficient. However from the US perspective, an additional short-term study was requested. The shortterm models are further explained later in this article. 

Finally, a third approach has been proposed with five stages that focus on the chemical structure, DNA-reactivity, epigenetic effects, limited bioassays, and finally, the application of accelerated bioassays. These accelerated bio assays require 40 weeks and apply to the use of sensitive markers for induction of neoplasia in comparison to positive control compounds for important organs in human carcinogenesis. It enables data acquisition of the entire carcinogenesis process directed toward developing mechanistic information. This system would have the potential to replace the chronic bioassay in rodents in some circumstances and could serve a analternative to a chronic bioassay in a second species. ... 

Genetically modified mice have been useful to show the relationships between the key events in the PPARa MOA. PPARa-null mice provided critical evidence establishing the rodent MOA for PPARa activator-induced hepatocarcinogenesis. Evidence that a particular compound induces key events in wild-type mice but not in mice lacking PPARa would be considered strong support for a PPARa MOA for that particular compound. To date, three chronic bioassays have been conducted in these mice (Hays et al. 2005 Ito et al. 2007 Peters et al. 1997). A greater body of data exists in which precursor events for cancer have been assessed in wild-type and PPARa-nuU mice after acute or subacute exposures. 

Brusick D. 1983. Evaluation of chronic rodent bioassays and Ames assay tests as accurate models for predicting human carcinogens. In Milman HA, ed. Application of biological markers for carcinogen testing, 153-163. 

Chronic administration of peroxisome proliferators to rodents results in sustained oxidative stress due to overproduction of peroxisomal hydrogen peroxide. The induction of peroxisomal fatty acid P-oxidation by cinnamyl anthranilate in vivo under bioassay conditions (Lake et al, 1997) supports this h othesis. Other data on the induction of oxidative stress are not available for cinnamyl anthranilate. 

Neonatal tolerance induction in rodents Option of dosing animals very early in life to produce animals tolerant to subsequent chronic administration of human proteins (potential to conduct rodent bioassay) Use of clinical product No data on positive controls Limited if any data on biopharmaceuticals... 

Flammang TJ, Von Tungeln LS, Kadlubar FF, Fu PP. Neonatal mouse assay for tumorigenicity alternative to the chronic rodent bioassay. Regul Toxicol Pharmcol 1997 26 230 10. 

Ideally, the doses selected for rodent bioassays for non-genotoxic pharmaceuticals should provide an exposure to the agent, and adequate margin of safety, no significant chronic physiological dysfunction and compatible with good survival. 

COC (2002) Committee on Carcinogenicity of Chemicals in Food, Consumer Products and the Environment (COC). COC statement on ILSI/HESI research programme on alternative cancer models. COC/02/S3, April 2002 Flammang TJ, Von Tungeln LS, Kadlubar FF, Fu PP (1997) Neonatal mouse assay for tumorigenicity. Alternative to the Chronic rodent bioassay. Reg Toxicol Pharmacol 26 230-240... 

Results of chronic MTBE exposure studies are the most widely available of all studies on the ether-like fuel oxygenates (MTBE, ETBE, TAME, DIPE). Evidence from animal bioassays demonstrates that long-term, high-level exposures to MTBE by either ingestion or inhalation cause cancer in rodents. Inhalation exposure to MTBE produced an increased incidence of renal and testicular tumors in male rats and liver tumors in mice. Oral administration of MTBE produced an increased incidence of lymphomas and leukemias in female rats and testicular tumors in male rats. Chronic exposure to ethanol also produces cancers (e.g., esophageal) in laboratory animals. 

Rodent bioassays have shown that chronic APFO (most widely used salt of PFOA) exposure is associated with a variety of tumor types. The mechanisms of APFO tumorigenesis are not clearly understood. The US Environmental Protection Agency (EPA) is currently evaluating the scientific evidence and has not reached any conclusions on the potential significance to humans of the rodent cancer data. 

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