Technical guide to selecting critical effects and points of departure in PDE/HBEL assessments using clinical and non-clinical evidence.
The critical effect and its point of departure are central to a defensible HBEL. They determine which evidence anchors the health-based limit and therefore must be selected from the totality of the relevant data.
Critical effect
The critical effect should be sufficiently sensitive, relevant to the protected population and scientifically supported. It is not necessarily the most dramatic effect in the database.
Point of Departure
The PoD is the dose or exposure level associated with the selected critical effect. Depending on the evidence, it can be based on NOAEL, NOEL, LOAEL/LOEL or benchmark-dose information.
Clinical and non-clinical integration
Human pharmacology and adverse effects can be important, while non-clinical studies may reveal target-organ, reproductive/developmental or other effects not adequately characterized clinically.
Final selection
Different effects can generate different candidate limits; the final HBEL should be selected and justified scientifically rather than mechanically.
Frequently asked questions
Is the lowest dose always the correct PoD?
No. Relevance, study quality and uncertainty also matter.
Should clinical and non-clinical effects both be reviewed?
Yes, when adequate data are available.
Can BMDL be used as a PoD?
Yes, when supported by an appropriate benchmark-dose analysis.
Is the lowest therapeutic dose automatically the correct PoD?
No. Therapeutic dose reflects efficacy and should be interpreted within the full safety evidence.
