PDE / ADE Methodology: How a Health-Based Exposure Limit Is Derived

2. Identify the critical effect

A critical effect is selected from the available evidence and the point of departure is justified. The assessment should explain why the selected effect and endpoint are appropriate for the health-based limit.

3. Apply adjustment factors

Adjustment factors address relevant sources of uncertainty, such as interspecies extrapolation, human variability, study duration and severity of the effect. The choice of factors should be justified.

4. Consider clinical data and route

Good-quality human clinical information can be highly relevant. Route-to-route extrapolation may also require consideration where the exposure route changes bioavailability materially.

5. Document the final limit

The final PDE should be transparently linked to the critical effect, point of departure, adjustment factors and intended application, with references to the underlying evidence.

6. Further reading

For optional scientific background on PDE derivation, see Challenges in setting permitted daily exposure limits for pharmaceuticals: A review by Ahuja and Krishnappa (2022), or view its PubMed record. This is a scientific review, not a regulatory guideline.

For official EMA and ICH references, see the HBEL, PDE, OEL and impurity references page.