chapter  2
34 Pages

Dose–Response Assessment: Significance in Risk Assessment

Dose-response assessment includes two processes. The first process is an assessment of all data that are available or can be gathered through experiments to document the dose-response relationship(s). Frequently this range of data points may not include sufficient information to identify a critical region where the adverse effect starts to occur (i.e., the dose that is low enough not to cause the effect or reference dose shown in Fig. 2.1) in the human population. The second process consists of extrapolation to estimate the risk of potential adverse effect beyond the lower range of available data to make inferences about the critical region where the dose level begins to cause the adverse effect in the human population. The extrapolation may involve a high-to low-dose extrapolation and/or animal-to-human extrapolation. The initial step of dose-response assessment is to evaluate the scientific information for a better biological understanding of how each type of toxicity or response (adverse effect) occurs (i.e., a sequence of key events and processes, starting with interaction of an agent with a cell, proceeding through operational and anatomical changes, and resulting in the effect) also known as mode of action. Depending on the chemical’s mode of action, different approaches (nonlinear or linear dose-response assessment) are used to estimate the potential risk posed by a chemical substance. For example, many regulatory organizations assume that noncarcinogenic and nonmutagenic effects have a threshold, a dose level below which an empirically observable response is unlikely because homeostatic

compensation and adaptive mechanisms in the exposed tissue protect against or effectively repair toxic effects. In contrast, chemicals that cause cancer by a mutagenic or unknown mode of action are assumed not to have a threshold. On the basis of this mode of action, the risk assessor determines the nature of the extrapolation used in the second process discussed in the preceding text, either through nonlinear or through linear dose-response assessment.