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CHEMICAL MUTAGENESIS AND CARCINOGENESIS: INCORPORATION OF MECHANISTIC DATA INTO RISK ASSESSMENT
Citation:
Preston, R J. CHEMICAL MUTAGENESIS AND CARCINOGENESIS: INCORPORATION OF MECHANISTIC DATA INTO RISK ASSESSMENT. Presented at 3Oth Annual Meeting of the European Environmental Mutagen Society (EEMS), Budapest, Hungary, 8/22-26/2000.
Description:
CHEMICAL MUTAGENESIS AND CARCINOGENESIS: INCORPORATION OF MECHANISTIC DATA INTO RISK ASSESSMENT
The current understanding of cancer as a genetic disease, requiring a specific set of genomic alterations for a normal cell to form a metastatic tumor, has provided the opportunity for mechanistic data to be considered in the cancer risk assessment process. For some tumors, the specific steps and accompanying genetic alterations have been provisionally identified. However, the rate-Iimiting step(s) for tumor development remain to be elucidated. Such information is essential for establishing the shape of a tumor dose- response curve at exposure levels below that at which tumor incidence can be reliably assessed. The ultimate drivers of chemical carcinogenesis are DNA replication and cell division, but the substrates for these processes to give rise to errors are, for example, DNA damage, altered transcription, and cell cycle dysregulation. The protectors against carcinogenesis are, for example, DNA repair, cell cycle checkpoints and apoptosis. The probability of tumor development is, in part, a consequence of where the balance lies between drivers and protectors. Recent information has provided a high degree of understanding of how these fundamental cellular processes function. This information can be incorporated into cancer risk assessment for considerations of high to low dose extrapolation, interspecies extrapolation, chronic vs. acute exposures, susceptible subpopulations, and sensitive subgroups (e.g. children). The end product will be a reduction in the uncertainty for the cancer risk assessments derived from the various approaches employed.
This abstract does not necessarily reflect U.S. EPA policy