How are uncertainty factors applied when deriving a Reference Dose (RfD) or TDI?

• A. They are applied to the PK of the chemical after marketing approval.
• B. They are used to determine maximum tolerated dose.
• C. They remove all interspecies differences.
• D. They are applied to the POD to account for interspecies differences and human variability.

Answer: (D)

Uncertainty factors are used to convert the point of departure into a safe daily exposure by accounting for differences between animals and humans and for variability within the human population. You start with a point of departure, typically a NOAEL or LOAEL (or a benchmark dose) from toxicology data, and then divide that value by a series of uncertainty factors. The most common default is a total factor of 100 (10 for animal-to-human differences and 10 for human variability). If the data are less complete or you’re using a LOAEL instead of a NOAEL, additional factors are added. The result is the Reference Dose or TDI, an estimate of a daily exposure not expected to cause harm over a lifetime.

This approach specifically uses the point of departure and adjusts it for interspecies differences and human variability, rather than adjusting pharmacokinetics after the fact, determining maximum tolerated dose, or claiming that all differences are removed.