, 2005). Given this limitation, measurements of conjugated or total BPA may be useful surrogates of free BPA. Specifically, Akt inhibitor if there is small variation in the ratio of free to conjugated BPA within and between individuals (with respect to the variation in exposure levels), then conjugated or total BPA may be an accurate and precise surrogate of free BPA, and of BPA exposure in general. This example underscores the importance of understanding relationships between exposure and biomarkers, different types of biomarkers

(parent vs. metabolites in their respective matrices), and biomarkers and biological targets, while ensuring that the appropriate research question is addressed. It further highlights the possibility of trade-offs when selecting an individual biomarker of exposure (for BPA, biological relevance could be optimized at the expense of ability to detect the chemical). A Tier 1 biomarker of exposure in a specified matrix is an accurate and precise surrogate of target dose (for hypothesis-driven studies with a known target) or of external exposure (for studies without a known target). For a Tier 2 biomarker, evidence exists for a relationship between the biomarker in a specified matrix and external exposure, this website internal dose, or target dose. A Tier 3 biomarker in a specified matrix is a poor surrogate (low accuracy and precision) for exposure/dose. It can be challenging in epidemiological

studies to perform meaningful comparisons of short-lived biomarker measurements and long-term health IKBKE outcomes. Particularly in cross-sectional studies, a key assumption is that current biomarker levels reflect past exposures during time windows that were relevant for disease onset. Biomarkers of effect offer a means to evaluate exposure–response relationships

in target populations, during critical time windows, prior to disease onset. Findings are interpreted based on the strength of association between biomarkers of exposure and effect, and between biomarkers of effect and the adverse health outcome. The progression from an exposure event to an adverse health effect can be defined using adverse outcome pathways (AOPs) (Ankley et al., 2010). The AOP for a particular health outcome begins with a molecular initiating event at a target within the body. Effects at the molecular target, initiated by exposure events, progress to effects at the cellular, tissue, and organ levels, and ultimately to the whole organism. “Key events” are intermediate steps along the AOP that can be experimentally monitored to evaluate progression along the AOP. Measurements of these key events in accessible biological media from living intact organisms are called bioindicators. Bioindicators are considered ideal biomarkers of effect because they reflect a biological function linked to a specific adverse outcome; they “provide a high degree of confidence in predicting the potential for adverse effects in an individual or population” (www.epa.gov/pesticides/science/biomarker.