PAH Metal Mixtures-Human in Vitro Mutagenicity Studies

EPA Grant Number: R827180
Title: PAH Metal Mixtures-Human in Vitro Mutagenicity Studies
Investigators: Kaminsky, Laurence , Ding, Xinxin , Gierthy, John , Singh, Navjot , Spink, David , Vakharia, Dilip , Walker, Vernon , Zhang, Qing-Yu
Current Investigators: Kaminsky, Laurence
Institution: The State University of New York at Albany
EPA Project Officer: Mustra, David
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 , Health Effects , Land and Waste Management , Health , Safer Chemicals

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 project

Journal Articles:

Journal Articles have been submitted on this project: View all 8 journal articles for this project

Supplemental Keywords:

RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Waste, Environmental Chemistry, Health Risk Assessment, chemical mixtures, Risk Assessments, Biochemistry, Physical Processes, Molecular Biology/Genetics, mutagenic properties, exposure, environmental mutagens, PAH, mutatgenicity studies, PAH metal mixtures, characterizing chemical mixtures, bioactivation, human exposure, bioaccumulation, cancer risk, carcinogenic, cell culture, human health risk, environmental chemicals, epoxide hydrolase enzyme, human in vitro mutagenicity studies

Progress and Final Reports:

1999 Progress Report
2000 Progress Report
2001 Progress Report
2002 Progress Report
2003 Progress Report
Final Report