Mechanism of Non-genotoxic Occupational CarcinogensEPA Grant Number: R828083
Title: Mechanism of Non-genotoxic Occupational Carcinogens
Investigators: Pereira, Michael A.
Institution: Medical College of Ohio
EPA Project Officer: Hahn, Intaek
Project Period: April 20, 2000 through April 19, 2003
Project Amount: $834,714
RFA: Mechanistic-Based Cancer Risk Assessment Methods (1999) RFA Text | Recipients Lists
Research Category: Health Effects , Human Health , Human Health Risk Assessment , Health
Description:Understanding the mechanism of carcinogens present in the workplace and the environment has become increasingly important because of the use of mechanism-based approaches to extrapolate results from laboratory animals to humans. There is great uncertainty in interspecies extrapolation because the dose levels used in animal studies are usually much greater than doses resulting from human exposure. High dose levels are required in animal carcinogenesis studies because of the low sensitivity of the bioassay. The uncertainty in the extrapolation is especially great for non-genotoxic carcinogens. This is because non-genotoxic carcinogens are likely to have dose-response curve that are not linear and that include a threshold. Furthermore, they could induce cancer in animals by a mechanism that is not applicable to humans. Knowledge of the mechanism of these carcinogens allows the development of molecular and biological markers for their activity. One of these biomarkers is the hypomethylation of DNA and protooncogenes. Biomarkers could be used to determine whether the mechanism applies to humans and to better define the dose-response relationship extending it to exposures/dose levels not applicable to carcinogenesis bioassay. Lung and mouse liver non-genotoxic carcinogens will be investigated, since the lung is a major site of occupational-related cancer and mouse liver is a major target organ in carcinogenesis bioassays.
The hypothesis to be tested is that non-genotoxic carcinogens induce cancer by increasing cell proliferation and then decreasing the methylation of the newly synthesized DNA, i.e. 5-methylcytosine (5-MeC). Increased cell proliferation is required to form the hemimethylated DNA requiring methylation. Furthermore, it is hypothesized that the 5-MeC content of DNA is decreased by either reducing the availability of S-adenosyl-l-methionine (SAM) for DNA methylation or by blocking DNA methyltransferase. Specific Aim 1 will evaluate mouse liver and lung non-genotoxic carcinogens including arsenic, chloroprene, dichloroacetic acid, methylene chloride, and tetrachloroethylene for the ability to decrease the methylation of protooncogenes. Specific Aim 2 will determine the mechanism for the decreased methylation of protooncogenes. Specific Aim 3 will demonstrate that an agent that prevents or reverses the hypomethylation of DNA prevents the induction of tumors supporting the importance of DNA hypomethylation to carcinogenic activity.