Analysis of Genetic Polymorphism of Metabolic Pathways for Better Characterization of Variability in Human Populations.

Objective/Intended Use

The purpose of this project is to develop a series of nine manuscriptswould that describe the types of polymorphisms in the human population, the range of xenobiotic metabolizing enzyme activities, the population distribution of their polymorphic forms, and how they might affect in better characterizing human variability in response.

Abstract

Risk Assessments attempt to consider the influence of human variability on the range of risks possible from chemical exposure. A variety of host-specific factors such as age, gender, health and nutritional status and other special sensitivities can influence an individual's response to chemical exposure. These variability factors exist due to inter-individual genetic polymorphism in phramacokinetics or pharmacodynamics. Certain metabolic polymorphisms have been shown to govern human responses to drugs and environmental chemicals. Currently, cancer and non-cancer risk assessments of environmental chemicals do not address how genetic polymorphisms can modulate the magnitude of the risk in an individual or the degree of variability caused by polymorphisms across an exposed population. The project will attempt to analyze published information on genetic polymorphisms for certain metabolic pathways. It will focus on metabolic activation (Phase I) and detoxification (Phase II) reaction pathways because of having clear evidence of polymorphisms in the human population. It would include polymorphic pathways such as a cytochrome P-450, N-acetylation, paroxygenase, aldehyde dehydrogenase, etc. The underlying information will be developed from the published literature information which supports the concept of human allelic differences in polymorphic pathways. Emphasis will be placed on retrieving individual subject data to the extent possible so that inter-individual differences can be independently analyzed. The purpose of this effort is to evaluate the extent of the variance found across the studies for a given pathway. A frequency distribution analysis (e.g., normal, log-normal, biomodal, etc.) will be conducted to demonstrate the nature of the studied populations with respect to the polymorphism and to provide data on what percent of the population contains the allelic variant. The datasets will be described in a report that contains graphs, and tables of summary data and statistics, intergroup comparisons within a given polymorphism pathway, and comparison across pathways in terms of prevalence and degree of variability including a commentary on implications for risk assessment to improve uncertainty analysis. This effort is expected to better utilize information on inter-individual variability of chemical response, thus providing risk assessors a scientific basis for improved semi-quantitative risk estimates. Five manuscripts are in development for Journal publication and one was published in Tox Science in 2004.

Project Status

A cooperative research agreement awarded in early 2001 to the Department of Public Health, State of Connecticut. Preliminary literature search and review of key publications was completed in 2003. A final report and database was recieved in February,2003. Six manuscripts are being prepared for publication in a peer-reviewed journal.