Linear systems dynamics in toxicokinetic studies.

Abstract

Linear systems dynamics are introduced to study kinetics particularly in experimental exposure to toxic agents and to extrapolate the experimental results to the field of occupational exposure. The relationship between the agent input (e.g. dose, external exposure) and the concentration-time curve [C(t)] in biological media plays a central part. When this relationship has been established the C(t) can be predicted or the dose as function of time can be estimated retrospectively on an individual basis. Linear systems dynamics offer a kinetic model-independent approach which means that no assumptions are required about compartments, bloodflows, partition coefficients, etc. The systems dynamics appear to be a powerful tool to predict the time courses of an agent or toxic metabolites in, for example, blood or a target organ on the basis of a short-term experimental exposure. The power of systems dynamics becomes obvious especially in the case of non-constant rates of inputs (dose) into systemic blood at, for example, dermal exposure. Also the systems approach appears to be suitable to determine the metabolic rate of entrance into the system blood as function of the parent agent or a second agent. The paper emphasizes the value of human exposure experiments under controlled conditions in order to verify the outcomes of physiologically based simulation models and to provide experimental data for these models.