Duration of intake above the ADI/TDI in relation to toxicodynamics and toxicokinetics.

The duration of intake necessary for the production of a toxic response depends on the mechanism of toxicity and the accumulation of the chemical to reach a toxic body load. There is a paucity of data on the cellular processes and changes associated with non-cancer effects detected in subchronic and chronic studies, and which are usually the basis for calculation of health-based exposure limits, such as the ADI. Data on the time course for the critical mechanistic process are normally unknown at the cellular level. Consequently, the duration of an excess intake in humans must be compared with the time course for the generation of the overall toxic effects in animals, which will include both toxicodynamic and toxicokinetic components. The extent of accumulation of a chemical during chronic intake is directly proportional to the half-life. The duration of intake at dosages above the ADI, necessary to produce body loads greater than those resulting from intake at the ADI, depends on the magnitude of the excess intake, the elimination half-life of the chemical, and the initial intake and body load. The effect on the body load of a short period of intake above the ADI is inversely proportional to the half-life of the chemical.