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DOSE RECONSTRUCTION FROM URINARY BIOMARKERS USING PHARMACOKINETIC MODELS
Citation:
Okino, M S. AND J J. Quackenboss. DOSE RECONSTRUCTION FROM URINARY BIOMARKERS USING PHARMACOKINETIC MODELS. Presented at American Institute of Chemical Engineers, Dallas, TX, October 31-November 5, 1999.
Description:
The use of biomarkers for human health risk assessment is attractive because they are an indicator of the dose that actually entered the body by all mechanisms. This is an important consideration given the need to include aggregate exposures from diet and other pathways for pesticides. Quantitative relationships between biomarker and environmental concentrations are often unclear, because what is seen in a urine sample depends on the route and time-profile of the exposure.
Urine samples have the advantage of being one of the simplest and least invasive biomarkers to collect for human monitoring, and a wide range of compounds can be detected. The ease of collection is important to consider for human studies to ensure satisfactory response and compliance rates. We have been focusing on the concentrations of a chemical of interest, the parent compound, or its metabolites in urine. The parent compound may be
absorbed into the body through a combination of routes: dermal, oral, and respiratory. Absorption, transport, and metabolism are not instantaneous, so there will be a delay before the parent compound or its metabolites are excreted into the urine. A spot urine measurement represents the time-integrated average of the urinary excretion rate over the time period since last urination.
Pharmacokinetic (PK) models describe the dynamics of the chemical in the body. By inverting the appropriate mathematical expressions, the absorbed dose can be calculated from the concentration of the parent compound or a metabolite in a spot urine sample. The use of PK models enables the researcher to obtain a dose estimate while employing less burdensome collection schemes.
The goal of this paper is to review the assumptions used in interpreting urinary biomarkers and highlight the role of PK models in reconstructing dose from spot urine measurements. We will use both simple and physiologically based PK models for some non-persistent pesticides to demonstrate the methods. The appropriate analytical solutions can be obtained directly for simple PK models (1-2 compartments), while model reduction may be necessary for larger physiologically based models. We will demonstrate the effect of scenario and model uncertainties on the dose estimates, and how the uncertainty analysis may be used to guide the design of a study. For an occupational assessment, we will compare the uncertainty associated with collecting spot samples versus total urine collection. We will also discuss the role of biomarker measurements in comprehensive survey studies.
The U.S. Environmental Protection Agency (EPA), through its Office of Research and Development (ORD), funded this research and approved this abstract as a basis for an oral presentation. The actual presentation has not been peer reviewed by EPA.