Genetic toxicity carcinogenicity

By the time Phase III testing is completed, some additional preclinical safety tests must also generally be in hand. These include the three separate reproductive and developmental toxicity studies (Segments I and III in the rat, and Segment II in the rat and rabbit) and carcinogenicity studies in both rats and mice (unless the period of therapeutic usage is intended to be very short). Some assessment of genetic toxicity will also be expected. 

As a Screen. An agent that is positive in one or more genetic toxicity tests may be more likely than one that is negative to be carcinogenic and, therefore, may not warrant further development. 

Tennant, R.W., Margolin, B.H., Shelby, M.D., Zeiger, E., Haseman, J.K., Spalding, J., Caspary, W., Resnick, M., Stasiewicz, S., Anderson, B. and Minor, R. (1987). Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. Science 236 933-941. 

Tennant RW, Margolin BH, Shelby MD, et al. 1987. Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. Science 236 933-941. 

Then, in the mid 1970s, Professor Bruce Ames of the University of California at Berkeley came along. We discussed in Chapter 5 Professor Ames role in the development of tests for genetic toxicity, tests that tell us something about mechanisms of carcinogenicity. 

Tennant, Raymond W., Barry H. Margolin, Michael D. Shelby, Errol Zeiger, Joseph K. Haseman, Judson Spalding, WiUiam Caspary, Michael Resnick, Stanley Stasiewicz, Beth Anderson, and Robert Minor. 1987. Prediction of Chemical Carcinogenicity in Rodents from in Vitro Genetic Toxicity Assays. Science 236 (May 22) 933-41. 

Sram, R.J., Tomatis, L., Clemmesen, J. Bridges, B.A. (1981) An evaluation of the genetic toxicity of epichlorohydrin. A report of an expert group of the International Commission for Protection against Environmental Mutagens and Carcinogens. Mutat. Res., 87, 299-319... 

The NIEHS has sponsored a carcinogenicity study with 4-nitrophenol to be conducted FY 1990 by Litton Bionetics, Inc. (NTP 1990). In addition, NIEHS sponsored a mutagenesis/genetic toxicity study with 4-nitrophenol to be completed FY 1990 the performing organization was not specified (NTP 1990). An acute/chronic toxicity study on 4-nitrophenol sponsored by the FDA was to be completed FY 1990 (NTP 1990). 4-Nitrophenol has been selected for a... 

Peptide Class Safety Pharmacology VChronic Toxicity Carcinogenicity Testing Genetic Toxicity Method of Manufacture Approval Date... 

LD50 is a measure of acute toxicity. Over time, many other test requirements have been added to establish safety as shown in the safety decision tree developed by the Food Safety Council (1982). In this system an organized sequence of tests is prescribed (see Figure 12-1). Other tests in this system involve genetic toxicity, metabolism, pharmacokinetics (the pathways of chemicals in the system and their possible accumulation in organs), subchronic toxicity, teratogenicity (birth defects), and chronic toxicity. To all this are added tests for carcinogenicity and... 

This theoretical example of a QSAR assessment is presented to exhibit FDA s current approach to using S AR as a tool in the safety evaluation of substances proposed for use as food contact materials. If anthrafurin (1,6-dihydroxy anthraquinone CASRN 117-12-4 Fig. 7.3) were expected to be an impurity in a food contact material, an immediate initial concern would be raised due to reports in the literature of positive results in the bacterial reverse mutation assay and other in vitro genetic toxicity tests. A literature search did not identify relevant carcinogenicity data for anthrafurin. 

Ashby J, Kier L, Wilson AG, Green T, Lefevre PA,Tinwell El, Willis GA, Eieydens WE, and Clapp MJ. Evaluation of the potential carcinogenicity and genetic toxicity to humans of the herbicide acetochlor. Eium Exp Toxicol 15 702-735,1996. 

FDA. Office of Pharmaceutical Science, Genetic Toxicity, Reproductive and Development Toxicity, and Carcinogenicity Database 2006. Retrieved from http // www.fda.gov/Cder/Offices/OPS IO/. Accessed March 18, 2009. 

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