Susceptibility Genes and Dioxin Resistance in Fish Inhabiting a Superfund Site By Mark E. Hahn, Ph.D. , and

Should We Adjust our Current Cancer Potency Factors to Account for Likely Differences in Sensitivity Between Children and Adults? By Dale Hattis, Ph.D.

Wednesday, September 18, 2002

4:05-4:30 PM Social gathering, refreshments will be provided,
4:30 - 6:30 PM Program

Conference Room, CDM (Camp Dresser & McKee)
One Cambridge Place, 50 Hampshire Street, Cambridge, MA

Susceptibility Genes and Dioxin Resistance in Fish Inhabiting a Superfund Site

Mark E. Hahn, Ph.D. Associate Scientist,
Biology Department, Woods Hole Oceanographic Institute

Summary: Chlorinated dibenzo-p-dioxins, chlorinated dibenzofurans, chlorinated biphenyls (PCBs), and related chemicals are ubiquitous, persistent contaminants of terrestrial, aquatic, and marine environments. Exposure of animals to these dioxin-like compounds is associated with a variety of effects, including reproductive and developmental abnormalities. Among vertebrate animals, fish are extremely sensitive to these chemicals. The long-term impact of dioxin and PCB exposure on natural populations of fish is poorly understood. To better understand the effects of multi-generational exposure in fish, we are studying a population of Atlantic killifish (Fundulus heteroclitus) inhabiting the Acushnet River Estuary near New Bedford Harbor (MA), a federal Superfund site that is highly contaminated with PCBs and other chemicals. These studies have shown that adult fish from this site are 14-fold less sensitive to effects of dioxins than fish from a less-contaminated reference site, Scorton Creek (Sandwich, MA). The resistance is heritable, suggesting that it has a genetic basis. Dioxin toxicity in vertebrate animals occurs through activation of the aryl hydrocarbon receptor (AHR), a ligand-dependent transcription factor that belongs to the bHLH-PAS family of regulatory proteins. We have hypothesized that differences in the expression or function of the AHR or other components of the AHR signaling pathway might be responsible for the differences between sensitive and resistant killifish. In this talk, I will present some recent results of our investigation into the molecular mechanism of dioxin/PCB resistance in New Bedford killifish.

Biography: Mark Hahn received his Ph.D. in Environmental Toxicology from the University of Rochester School of Medicine in 1988. Since 1987, he has been in the Biology Department at the Woods Hole Oceanographic Institution (WHOI), where he is currently a tenured Associate Scientist. Dr. Hahn's major research interests include comparative toxicology, ligand-receptor interactions; mechanisms of adaptation and acquired resistance to chemical exposure; toxicology of dioxins and other persistent organic pollutants in fish, birds, and marine mammals; and molecular evolution. He is the author or co-author of over 70 peer-reviewed publications in these areas.

Dr. Hahn has served on the editorial boards of Toxicological Sciences, Environmental Toxicology and Chemistry, and Chemico-Biological Interactions. He currently is the Associate Editor of Aquatic Toxicology. Dr. Hahn also serves as the chairman of the Joint Committee on Biological Oceanography of the WHOI/MIT Joint Graduate Program in Oceanography and Oceanographic Engineering. He lives on Martha's Vineyard with his wife, Rachel Graber, and their 3-year-old son Sam.

Web site: http://www.whoi.edu/science/B/people/mhahn/hahnm.html

Representative publications:

Hahn, M.E., Karchner, S.I., Shapiro, M.A., and Perera, S.A. (1997) Molecular evolution of two vertebrate aryl hydrocarbon (dioxin) receptors (AHR1 and AHR2) and the PAS family. Proc. Natl. Acad. Sci. U.S.A. 94: 13743-13748.

Bello, S.M., Franks, D.G., Stegeman, J.J., and Hahn, M.E. (2001) Acquired resistance to aryl hydrocarbon receptor agonists in a population of Fundulus heteroclitus from a marine Superfund site: In vivo and in vitro studies on the induction of xenobiotic-metabolizing enzymes. Toxicol. Sci. 60: 77-91.

Hahn, M.E. (2002) Aryl hydrocarbon receptors: Diversity and Evolution. Chem.-Biol. Interact. 141: 131-160.

Hahn, M.E. (2002) Biomarkers and Bioassays for Detecting Dioxin-like Compounds in the Marine Environment. Sci. Total Environ. 289: 49-69.

Karchner, S.I., Franks, D.G., Powell, W.H., and Hahn, M.E. (2002) Regulatory interactions among three members of the vertebrate aryl hydrocarbon receptor family: AHR repressor, AHR1, and AHR2. J. Biol. Chem. 277: 6949-6959.

Kim, E.-Y. and Hahn, M.E. (2002) cDNA cloning and characterization of an aryl hydrocarbon receptor from the harbor seal (Phoca vitulina): A biomarker of dioxin susceptibility? Aquat. Toxicol. 58: 57-73.

Should We Adjust our Current Cancer Potency Factors to Account for Likely Differences in Sensitivity Between Children and Adults?

Dale Hattis, Ph.D.
Research Professor with the Center for Technology, Environment and Development (CENTED) of the George Perkins Marsh Institute at Clark University.

Summary: Currently most cancer potency/"slope factor" estimates are based on projections from bioassay data from experiments begun in the early adulthood of experimental animals, or from occupational epidemiology studies that similarly derive from adult exposures. The issue of whether and how these estimates should be adjusted for exposures during earlier life stages is currently being discussed extensively within EPA. This talk will have three parts:

1. the state of the technical/policy discussion of these issues;

2. the results of our previous work on human pharmacokinetic differences as a function of age; and,

3. our current efforts to build a database of differences between life stages in processes along the pathway to cancer based on data from both humans and animals.

Biography: Dale Hattis is Research Professor with the Center for Technology, Environment and Development (CENTED) of the George Perkins Marsh Institute at Clark University. For the past twenty-seven years he has been engaged in the development and application of methodology to assess the health, ecological, and economic impacts of regulatory actions. His work has focused on the development of methodology to incorporate interindividual variability data and quantitative mechanistic information into risk assessments for both cancer and non-cancer endpoints. Specific studies have included quantitative risk assessments for hearing disability in relation to noise exposure, renal effects of cadmium, reproductive effects of ethoxyethanol, neurological effects of methyl mercury and acrylamide, and chronic lung function impairment from coal dust, four pharmacokinetic-based risk assessments for carcinogens (for perchloroethylene, ethylene oxide, butadiene, and diesel (particulates), an analysis of uncertainties in pharmacokinetic modeling for perchloroethylene and an analysis of differences among species in processes related to carcinogenesis. He has recently been appointed as a member of the Environmental Health Committee of the EPA Science Advisory Board, and for several years he has served as a member of the Food Quality Protection Act Science Review Board. Currently he is also serving as a member of the National Research Council Committee on Estimating the Health-Risk-Reduction Benefits of proposed Air Pollution Regulations. He has been a councilor and is a Fellow of the Society for Risk Analysis, and serves on the editorial board of its journal, Risk Analysis. He holds a Ph.D. in Genetics from Stanford University and a B.A. in biochemistry from the University of California at Berkeley.