1998 Progress Report: Mechanism of Carcinogenesis of Thia-PAHs

EPA Grant Number: R826192
Title: Mechanism of Carcinogenesis of Thia-PAHs
Investigators: Kumar, Subodh
Current Investigators: Kumar, Subodh , Sikka, Harish C.
Institution: The State University of New York at Buffalo
EPA Project Officer: Hahn, Intaek
Project Period: November 3, 1997 through November 2, 2000
Project Period Covered by this Report: November 3, 1997 through November 2, 1998
Project Amount: $500,827
RFA: Exploratory Research - Human Health (1997) RFA Text |  Recipients Lists
Research Category: Health Effects , Human Health , Health

Objective:

Exposure to a wide variety of complex chemical mixtures such as in automobile exhaust, soot, coal tar and pitch, mineral oils, shale oil, coal-gasification residues and cigarette smoke has been considered to be associated with increased incidence of cancer in human population. These complex mixtures contain a number of polycyclic aromatic hydrocarbons (PAHs), and their heterocyclic analogues (especially, aza-PAHs and thia-PAHs) many of which are carcinogens. In order to fully understand the risk that various carcinogenic chemicals in a complex mixture may present to human health, it is important that these chemicals be studied for their mechanism of carcinogenic action. Most of the mechanistic studies conducted in the past involve predominantly PAHs, and to some extent aza-PAHs. In contrast, thia-PAHs have been studied very little in spite of the observations that these thia-PAHs are present up to 50% of the total hydrocarbons in some of the crude oils and emissions from coal-fired residential furnaces. In addition, thia-PAHs are also known to be more persistent, bioaccumulated and carcinogenic compared to their homocyclic analogues (PAHs). Thus, despite the potential biohazard associated with thia-PAHs, there is extremely limited information available on the mechanism by which they induce their carcinogenic effects. The objective of the proposed research is to investigate whether thia-PAHs are activated by the mechanism similar to that of PAHs, or follow a different metabolic activation pathway(s) due to the presence of sulfur heteroatom. The purpose of the proposed research is to identify the metabolic activation pathway(s) of benzo[b]phenanthro[2,3-d]thiophene (BPT), a model thia-PAH, known to be more carcinogenic than its PAH isoster dibenz[a,h]anthracene.

In order to accomplish the project objectives, we propose: (i) to study the metabolism of BPT by mouse liver microsomes from induced or uninduced mice and identify the metabolites formed; (ii) to assess the mutagenicity of BPT and its metabolites; (iii) to characterize the DNA adducts produced in mouse skin treated with BPT.

The projected schedule for the first year of the project was: (i) to synthesize BPT and its sulfoxide, sulfone, 5,6-oxide, 5,6-dihydrodiol, 5-hydroxy-, 6-hydroxy-, and 7,13-quinone derivatives as reference standards; (ii) to synthesize benzo[b]naphtho[2,1-d]thiophene, phenanthro[1,2-b]thiophene and their sulfoxide and sulfones as UV markers; and (iii) to synthesize and study the metabolism of [G-3H]BPT

Progress Summary:

In order to achieve our objective, the initial phase of the project was devoted to the synthesis of BPT, its various derivatives, and tritium labeled BPT. These compounds are required for studying the metabolism of BPT, and for quantifying and identifying the metabolites formed. We have completed the synthesis of BPT in a gram quantity, and the synthesis of pure tritium labeled BPT is near completion. In addition, we have either accomplished or made a significant progress toward the synthesis of BPT sulfoxide, BPT sulfone, BPT-trans-5,6-dihydrodiol, BPT-cis-5,6-dihydrodiol, BPT-5,6-oxide, 5-hydroxyBPT, 6-hydroxyBPT, 3-hydroxyBPT, and BPT-trans-3,4-dihydrodiol which are the potential primary metabolites of BPT. While studying the synthesis of BPT-trans-3,4-dihydrodiol which is predicted to be involved in the metabolic activation of BPT, we have developed a new general method which can be applicable to the synthesis of phenolic and dihydrodiol metabolites of several carcinogenic thia-PAHs. We have also completed the synthesis of several UV markers that include benzo[b]naphtho[2,1-d]thiophene and its sulfoxide and sulfone.

Future Activities:

Future activities include: (1) the continuation of the synthesis of BPT derivatives, and (2) the studies on the metabolism of BPT, and quantitation and identification of the major metabolites formed by incubation of BPT with mouse liver microsomes.

Journal Articles:

No journal articles submitted with this report: View all 8 publications for this project

Supplemental Keywords:

RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, Air, Waste, air toxics, Genetics, Environmental Chemistry, Health Risk Assessment, chemical mixtures, Risk Assessments, Biochemistry, Physical Processes, complex mixtures, cumulative risk, furnace emissions, mutagenic properties, heterocyclic analogues, sulfur heteroatom, exposure and effects, automobile exhaust, mineral oils, exposure, cigarette smaoke, PAH, DNA adducts, metabolic activation, human exposure, cigarette smoke, cancer risk, carcinogenic

Progress and Final Reports:

Original Abstract
  • 1999 Progress Report
  • Final Report