Grantee Research Project Results
PAH Metal Mixtures-Human in Vitro Mutagenicity Studies
EPA Grant Number: R827180Title: PAH Metal Mixtures-Human in Vitro Mutagenicity Studies
Investigators: Kaminsky, Laurence , Spink, David , Vakharia, Dilip , Gierthy, John , Singh, Navjot , Zhang, Qing-Yu , Walker, Vernon , Ding, Xinxin
Current Investigators: Kaminsky, Laurence
Institution: The State University of New York
EPA Project Officer: Aja, Hayley
Project Period: November 1, 1998 through October 31, 2001 (Extended to October 31, 2003)
Project Amount: $999,948
RFA: Chemical Mixtures in Environmental Health (1998) RFA Text | Recipients Lists
Research Category: Hazardous Waste/Remediation , Human Health , Safer Chemicals , Land and Waste Management
Description:
The long-term goal of this proposal is, through understandings of the mechanisms of interactions, the development of approaches to assess carcinogenic risks from exposure to environmental polycyclic aromatic hydrocarbon (PAH)/Metal mixtures. It focuses on the potential of the four most hazardous pollutant metals, individually and in mixtures, and mixtures of PAHs to affect the individual bioactivation of the five most hazardous PAHs, and thereby their carcinogenicity. All studies will be conducted in vitro using human cell cultures.Approach:
The specific aims investigate the effects of metals and PAHs on several aspects of PAH bioactivation: 1) to elucidate the effects and mechanisms of mixtures of the selected PAHs and metals on the induction by each of the PAHs of CYPIA2 and other involved enzymes: epoxide hydrolase, NADPH-P450 reductase, the aryl hydrocarbon (Ah) receptor and the Ah receptor nuclear translocating protein (Arnt) in primary cultures of human hepatocytes, and CYP1A1 and 1B1 in the MCF- 10A human mammary epithelial cell line; 2) to determine the influence of mixtures of the selected PAHs and metals on the susceptibility of the PAHs individually to be bioactivated by the CYP1 P450s, and thereby produce mutations; 3) to assess the potential of the selected metals individually and in mixtures to alter the induction by each of the selected PAHs of human glutathione S-transferases (GSTs) and to inhibit their catalytic activity; and 4) to exhaustively analyze an environmental PAH/metal mixture qualitatively and quantitatively for its PAH and metal constituents, and to determine its inductive capacity for CYP1A2, GSTA1-1, and GSTP1-1 in human hepatocyte cultures, and for CYP1A1 and 1B1 in MCF- 10A cells and to determine its mutagenic capacity in a lymphoblastoid cell system engineered to express the CYP1 forms and epoxide hydrolase enzyme. Results will provide the data for deriving mechanism-based risk assessments of PAH/metal mixtures.Publications and Presentations:
Publications have been submitted on this project: View all 25 publications for this projectJournal Articles:
Journal Articles have been submitted on this project: View all 8 journal articles for this projectSupplemental Keywords:
Health, RFA, Scientific Discipline, PHYSICAL ASPECTS, Waste, Health Risk Assessment, Physical Processes, Risk Assessments, chemical mixtures, Environmental Chemistry, Molecular Biology/Genetics, Biochemistry, environmental mutagens, mutagenic properties, mutatgenicity studies, PAH metal mixtures, epoxide hydrolase enzyme, bioactivation, cell cultures, carcinogenic, human exposure, cell culture, bioaccumulation, human in vitro mutagenicity studies, exposure, human health risk, PAH, characterizing chemical mixtures, cancer riskProgress and Final Reports:
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.