Toenails as a Biomarker of Arsenic Exposure: Refinements in Characterization, Validation, and Application

EPA Grant Number: F5D30797
Title: Toenails as a Biomarker of Arsenic Exposure: Refinements in Characterization, Validation, and Application
Investigators: Slotnick, Melissa
Institution: University of Michigan
EPA Project Officer: Hahn, Intaek
Project Period: September 1, 2005 through December 31, 2007
Project Amount: $72,766
RFA: STAR Graduate Fellowships (2005) RFA Text |  Recipients Lists
Research Category: Academic Fellowships


The objective of this research is to refine knowledge surrounding the use of toenails as a biomarker of exposure to arsenic in drinking water, with application to a population-based case-control study. This objective will be accomplished through four different avenues:

  1. investigating the sensitivity of the biomarker in reflecting refinements in the arsenic exposure assessment,
  2. examining potential modifying factors in the exposure-biomarker association,
  3. determining the response of the biomarker to temporal variability in exposures, and
  4. evaluating the facility of the biomarker to assess the exposure-disease relationship in a case-control study.


A population-based case-control study of arsenic in drinking water and bladder cancer has been initiated in an eleven-county study area of Michigan with historically high groundwater arsenic concentrations. A goal of 700 bladder cancer cases and 700 controls will answer detailed questions on medical history, smoking, diet, dietary supplement use, fluid consumption patterns, and occupational and residential mobility. Water samples will be collected at the current residence, and toenail clippings will be provided as a biomarker of exposure. Drinking water and toenail samples will be analyzed for arsenic using an inductively coupled plasma mass spectrometer. Historic data will be used to estimate arsenic concentrations at places where samples are not collected.

Several different exposure metrics will be developed to determine the ability of the biomarker to capture changes in exposure estimates. First, the simple association between arsenic concentration in drinking water and arsenic concentration in toenail samples will be investigated. Subsequently, additional exposure metrics will be developed to determine the influence of refinements in the exposure calculation on the exposure-biomarker association. For example, arsenic exposure per day at home (ug/L * L/day), and arsenic exposure per day at home and work ([ug/Lhome*L/dayhome] + [ug/Lwork*L/daywork]). Additional models will build on these estimates by including or adjusting for other variables to determine the sensitivity of this biomarker in its ability to reflect changes in exposure calculations.

Evidence of metabolic interactions between arsenic and selenium reiterates the need to consider the possibility of these elements as modifiers of the exposure-biomarker association. Exposure to these elements will be assessed via dietary supplement use and toenail concentrations. By calculating differential correlations, this study will contribute knowledge surrounding the ability of these variables to modify the exposure-biomarker association, thus furthering the process of biomarker validation.

Thirdly, this study will address the response of the biomarker to temporal variability in arsenic exposure. Additional samples will be collected from approximately 20% of the households to evaluate temporal changes in tap water and toenail clipping arsenic concentrations. Multiple drinking water and toenail samples will be integrated with fluid consumption patterns to evaluate temporal variability in concentrations and intake estimates, and to assist in determining what integrated time-period of exposure the biomarker most reflects.

The investigations proposed herein will address issues regarding sensitivity and temporal stability of toenails as a biomarker of arsenic exposure; however, the possibility of the influence of the disease on the biomarker must also be considered if this biomarker is applied to case-control studies. To date, no known studies address these concerns. Therefore, my proposed research will evaluate modification of the exposure-biomarker association by bladder cancer status. Such findings will have great implications for use of this biomarker in future epidemiological investigations.

Expected Results:

The prospect of application of this biomarker to large-scale epidemiological studies is exciting; however, it is critical to characterize and validate the biomarker before widespread use. The knowledge gained from my research will refine issues concerning sensitivity of the biomarker to exposure metrics, the ability of the biomarker to reflect temporal variations in exposure, and influence of disease status on the exposure-biomarker association. In particular, these findings will support exposure assessment efforts in epidemiological investigations addressing the risks associated with low-level arsenic exposure, which in turn have broad-scale implications for risk assessment and protection of public health.

Supplemental Keywords:

Arsenic, Environmental Epidemiology, Exposure Assessment, Biomarkers, Public Health,, RFA, Scientific Discipline, PHYSICAL ASPECTS, INTERNATIONAL COOPERATION, Water, POLLUTANTS/TOXICS, Environmental Chemistry, Health Risk Assessment, Arsenic, Epidemiology, Physical Processes, Water Pollutants, drinking water, exposure, toenails, chronic health effects, exposure-biomarker association, arsenic exposure, biological effects, biomarker data

Progress and Final Reports:

  • 2006
  • 2007
  • Final