125 Uncertainty in Estimating Exposure Using a Toxicokinetic Model The Example of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin ALBERTO SALVAN, a,b KARL THOMASETH, b PAOLA BORTOT, c AND NICOLA SARTORI c b Institute of Systems Science and Biomedical Engineering (LADSEB-CNR), National Research Council, Corso Stati Uniti 4, 35127 Padova, Italy c Department of Statistics, University of Padova, via San Fracesco 33, 35121 Padova, Italy ABSTRACT: This paper deals with sources of uncertainty in the use of a mini- mal physiological toxicokinetic model to obtain dose estimates for a dose- response analysis of cancer in an occupational cohort. Toxicokinetic models make it possible to construct exposure parameters that are more closely relat- ed to the individual dose than traditional measures of exposures to toxic agents. However, the process introduces a wide array of sources of uncertainty. Selecting a model structure to describe the kinetics of a toxic agent implies nec- essarily making simplifications and assumptions that influence the range of ap- plicability of the model. Once a model has been selected, the value of certain model parameters (constants) must be assigned, for example, from anthropo- metric data. The question then arises of how sensitive the model predictions are to variations in the values of these constants. Other model parameters, typ- ically those describing the kinetics of the agent, are next estimated from actual data. There may be limitations in the data concerning, for example, sparseness (too few observations per subject) or missing values. The methods used for pa- rameter estimation carry their own set of assumptions that need to be appro- priate to the situation at hand. In summary, the dioxin example is used to characterize the sources of uncertainty at different levels, such as model struc- ture, methods and data used for parameter estimation, estimation of occupa- tional exposure, and imputation of missing values in exposure indices derived from the kinetic model. INTRODUCTION This papers deals with sources of uncertainty in the use of a kinetic model for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for dose-response analyses in an occu- pational cohort. Attention is restricted to a minimal physiological toxicokinetic (MPTK) model. The scope of the model is the construction of individual exposure indices in the presence of arbitrarily complex temporal patterns of TCDD intake. Minimal models can be contrasted with statistical models on one hand and with physiological models on the other. a Address for correspondence: Alberto Salvan, Ph.D., LADSEB-CNR, Corso Stati Uniti 4, 35127 Padova, Italy. +39-049-829-5771 (voice); +39-049-829-5763 (fax). e-mail: salvan@ladseb.pd.cnr.it