Superfund Research Program
Epidemiology, Biomarkers and Exposure Assessment of Metals
Project Leader: Margaret R. Karagas
Grant Number: P42ES007373
Funding Period: 1995-2021
Final Progress Reports
This project focuses on characterizing the risk of cancer associated with environmental levels of arsenic exposure and the development of biomarkers of arsenic exposure and susceptibility in a U.S. population. Building on population-based studies, Dr. Margaret Karagas and her laboratory have completed interviews with over 6,000 New Hampshire residents selected from the general population. Arsenic exposure is measured both in toenail clipping samples and from tap water samples. Biologic samples include blood (or buccal cells), urine and tumor tissue on which to evaluate molecular, genetic and proteomic markers. Further, the lab performed a detailed standardized pathology review and archived samples of the original tumor tissue for molecular genetic analyses. Specifically, they are investigating factors that may influence arsenic-induced cancers focusing on three putative pathways: DNA repair, oxidative signaling and methylation/metabolism. Laboratory analyses using high through-put (i.e., SNP array methods) are completed, and additional SNPS, (i.e., haplotype tagging SNPs) of genes of particular interest are currently underway. In collaboration with the Biomarkers Core, they are designing computational programs to develop complex models from these extensive genetic and epidemiologic data. These include novel approaches to assess multifactor gene-gene and gene-environment interactions.
Numerous publications emerged from the study this year. These include a report on gene-gene interactions for bladder cancer identified with both conventional and alternative approaches (including the one developed by Dr. Moore) appearing in Human Heredity. Findings of an interaction between a polymorphism in the DNA repair gene XPD and arsenic exposure in skin cancer risk was published in Environmental Health Perspectives. Dr. Karagas’ lab also collected and analyzed urine samples for arsenic metabolism in two laboratories using ultra-trace detection methods and recently developed approaches for stabilizing arsenic species. The inter-laboratory comparison between the Dartmouth Trace Element Core Laboratory and that of the Arizona Superfund Program revealed the importance of separating arsenobetaine from inorganic arsenic, MMA, and DMA to achieve a high degree of concordance. Scientists are currently evaluating whether statistical adjustment for dietary intake of fish and seafood improves the concordance rates in the absence of arsenobetaine determination. Additionally, they conducted an intra-laboratory comparison of instrumental neutron activation and ICP-MS analysis of toenail arsenic and submitted a manuscript for publication. In collaboration with Trophic Transfer of Toxic Metals in Aquatic Food Webs we are performing a comprehensive analysis of the contribution of diet (e.g., specific foods) on body burden of arsenic both in the presence and absence of arsenic in individuals’ drinking water. Dr. Karagas’ lab continues to collaborate with Dr. Karl Kelsey (now at Brown University) on the molecular and genetic changes that may be involved in the carcinogenic process at low-level arsenic exposure. This year, they received a new NIH R01 (CA121147) to expand this work. Presentations were made at conferences sponsored by NIEHS, national organizations and universities nationally and internationally. Moreover, presentations were made to obstetrics practices and hospitals in the State to enlist cooperation in the proposed reproductive outcomes study, for which a pilot study was initiated this year.