Michael Cunningham, Ph.D., D.A.B.T.

Host Susceptibility Group


Michael L. Cunningham, Ph.D., D.A.B.T. Chemist/Toxicologist: Tel (919) 541-3799
cunning1@niehs.nih.gov
Curriculum Vitae (148KB); P.O. Box 12233
Mail Drop K2-08
Research Triangle Park, North Carolina 27709
Delivery Instructions

Michael Cunningham, Ph.D., D.A.B.T., is certified in general toxicology by the American Board of Toxicology and studies the mechanisms of toxicity and carcinogenicity of chemicals for the National Toxicology Program (NTP). He was president of the North Carolina Society of Toxicology (NCSOT) in 1996 and is a member of the Society of Toxicology (SOT), the American Association for Cancer Research (AACR) and the Environmental Mutagen Society (EMS), affiliated with both the national and North Carolina chapters (GEMS Board of Directors 1992-1995; president 2001). Cunningham recently helped organize the latest SOT Current Concepts in Toxicology workshop "Use of Genomic Data in Risk Assessment: State of the Art 2001" as a member of the SOT Risk Assessment Task Force. He also serves as an Associate Editor for Toxicological Sciences.

Strain Differences in Absorption, Distribution, Metabolism and Elimination (ADME) of Chemicals

Species vary widely in rates and routes of ADME of chemicals. This, in large part, explains the differences in effects of exposures to chemicals between rodent species and between rodent species and humans. As part of a series of studies to investigate the genetic diversity of mouse strains to the toxicity of chemicals to which humans are exposed and identify and/or create better models for extrapolation of rodent-to-human toxicity data, an investigation into strain differences in ADME properties was initiated. Clearly, significant differences in ADME properties could go far in explaining strain differences in toxicity following chemical exposure. The present study has begun to address potential strain differences in ADME properties in the NTP strains recently chosen as strains representative of those with genetic variability comparable to that found in human populations.

The following mouse strains were selected for initial ADME evaluation: 129S1/SvImJ, A/J, AKR/J, BALB/cByJ, BTBR T+ tf/J, C3H/HeJ, CAST/EiJ, DBA/2J, FVB/NJ, KK/HlJ, MOLF/EiJ, NOD/LtJ, NZW/LacJ, PWD/PhJ, WSB/EiJ, as well as the standard B6 strain. Benzene was chosen for the initial environmental agent for ADME studies due to its widespread human exposure, well understood ADME properties in commonly used mouse strains, and proven human adverse effects following chronic exposure (leukemia). Male and female mice of each strain will be exposed to a single oral gavage dose of unlabeled and 14C-labeled benzene (10 mmole/kg; 2 uCi per mouse). Groups of 5 mice will be dosed and sacrificed at 5, 10, 15, 30, and 60 minutes. Total radioactivity in blood will be measured, and the data analyzed by WinNonLin to calculate maximum blood concentration (Cmax), time to maximum blood concentration (Tmax) and the elimination rate constant beta. These data will be evaluated to determine the strains with the lowest and highest blood radioactivity (a measure of absorption and distribution) beta (a measure of elimination). Several strains will then be selected to analyze in depth the metabolic profile of benzene in blood and urine (metabolism). These data will allow an analysis of ADME differences in 16 strains of mice that vary in genetic diversity similar to the genetic diversity observed in human populations.

These data will also direct functional phenotyping of various constitutive ADME pathways such as cytochrome P450 isozymes, epoxide hydratases, UDPGT glucuronyltransferases, glutathione transferases, etc. Variations in these pathways may significantly impact bioactivation and detoxification of xenobiotics, resulting in higher or lower concentrations of reactive intermediates causing the observed variations in response to chemical exposure.

Cunningham received a B.A. in biochemistry and molecular biology and a B.A. in pharmacology from the University of California at Santa Barbara, and a Ph.D. in pharmacology and toxicology from the University of Arizona in Tucson. He served as a postdoctoral fellow at Sandoz Research Institute and Argonne National Laboratory before coming to the National Institutes of Health (NIH) at the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park in 1987. He is presently a Chemist/Toxicologist in the NTP and was co-leader of the Toxicology/Pathology Working Group in the National Center for Toxicogenomics. He is Project Officer on an ADME contract and study scientist on numerous chemicals.