Incidence and severity in relation to magnitude of intake above the ADI or TDI: use of critical effect data.

Noncancer effects are considered to show thresholds, such that no effect would be produced when the intake is below the threshold. Application of a 100-fold uncertainty factor to the no-observed-adverse-effect level (NOAEL) for the critical effect in animal studies provides an estimate of an intake for sensitive humans (the acceptable daily intake or ADI) without significant adverse health effects. The risks of intakes by humans above the ADI theoretically move the most sensitive subjects from negligible risk to possible risk. An increase in intake above the ADI would move the population distribution of internal dose toward the dose-response curve for sensitive subjects. The proportion of a population affected depends on the magnitude of the excess intake, the relationship of the NOAEL and the biological threshold in animals, and the coefficient of variation for the kinetic parameters (e.g., clearance and bioavailability) which determine the internal dose in humans. The severity of any effect in sensitive and high-intake individuals depends on the magnitude of the excess intake, the nature of the critical effect, and the slope of the dose-response relationship.