Methylmercury-Biomarker Effect on Dose Reconstruction and Dose-Response. M. Bolger and C. Carrington, FDA/CFSAN, Washington, DC
In the risk assessment/analysis of an environmental contaminant like methylmercury the estimation of dose is largely dependent on the biomarker chosen. The uncertainty associated with the use of a biomarker arises from several areas. One is the proximity of the biomarker to the target tissue dose. Ingested dose is an obvious example of a biomarker that is generally viewed as being a very uncertain measure of systemic/target tissue dose. Another uncertainty is the relevancy of the time scale for the biomarker/dose with the adverse endpoint of concern. For example, a chronic biomarker of dose may be inaccurate when used in a dose-response assessment for a developmental endpoint with a narrow timeframe of susceptibility. The impact of these areas of uncertainty and the impact on the magnitude and slope of dose-response relationship will be explored using methylmercury as a case study. For many of the human methylmercury studies hair mercury (total or methylmercury) levels have been used as the biomarker of exposure. It is an appropriate metric for chronic exposure but may be a less precise measure of dose where effects on certain developmental endpoints may more dependent on exposures that are more intense and occur over a shorter period of time. Boot-strapping techniques can accommodate any prior description of the uncertainty in methylmercury dose or response. The utility of such an assessment is to quantitatively describe the biomarker effect on the dose-response relationship and resulting estimates of risk. This in turn can result in very different risk management conclusions about the effectiveness of different risk management techniques. In particular, setting limits for the level of mercury in fish is much more effective at managing risks when the relevant exposures are short term rather than long term.
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