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 bladder cancer associated with environmental levels of arsenic exposure and the development of biomarkers of arsenic exposure and susceptibility in a US population. Building on their population-based studies, Dr. Karagas and her research team have completed interviews with approximately 1,140 New Hampshire residents with basal cell carcinoma, 880 with squamous cell carcinoma, 850 with bladder cancer and 1,190 individuals 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. Overall, the researcher’s findings indicate that toenail measurement of arsenic is not subject to external contamination and serves as an integrated, long-term measure of arsenic exposure. Results from the researcher’s skin cancer study raise the possibility of an excess risk at toenail concentrations that correspond to relatively low drinking water intake, and their initial findings on bladder cancer also indicate this possibility. In addition to a biomarker approach, the researchers are estimating cumulative lifetime drinking water exposure to arsenic. This involves the collection and testing of drinking water arsenic concentrations from the private wells of participants previous households, along with estimation of arsenic levels from municipal supplies used in the past. These data will allow the researchers to estimate risk during specific time periods (e.g., latencies) and to compare multiple approaches to exposure assessment. They continue to explore molecular, genetic and proteomic markers that will help to clarify the mechanisms of arsenic's carcinogenic effects and to identify those who may be at greatest risk of arsenic-induced malignancies. The study findings support use of biomarkers to characterize early biologic response as well as clinical endpoints. The project investigators observed a striking inverse relationship between mRNA levels of specific genes involved in DNA repair mechanisms. Importantly, toenail arsenic concentrations correlated better with decreased DNA repair gene expression than drinking water concentrations even after accounting for water intake. As a follow-up, the researchers expanded the sample size, and will perform both proteomic and DNA repair capacity assessments. They have completed the analysis of GSTM1, GSTT1, MTHFR and numerous DNA repair gene polymorphisms in the first study phase; these data indicate potential gender differences in effects and modification of risk associated with arsenic exposure and genetic variation. Further, the researchers have performed detailed standardized pathology review on over 700 bladder cancers to date. In collaboration with Dr. Karl Kelsey at the Harvard Superfund Program they are exploring the molecular and genetic changes that may be involved in the carcinogenic process at low level arsenic exposure.