PROBLEM 5-2(C)

Two kinds of extrapolation:

I. Lifetime Average Daily Dose (LADD) to dose over a specified period of time.

Naïve but common approach:

Convert by simple proportion -

Equivalent Average Daily Dose (ADD) over period of exposure is

ADD = LADD/(fraction of lifetime exposed)

Generalization:

Area Under Curve (AUC): Net exposure is area under the concentration curve.

Other Possible Dose Metrics (measures of dose):

Absorbed rather than exposed dose
Body burden: amount of substance in the body

Includes all sources, including exogenous and accumulation

Peak exposure

Ideal Dose Metric:

Reflects mode of action
Target tissue dose: form of chemical (e.g., parent compound, metabolite, peak concentrations, net exposures as area under the concentration curves) that is believed to be most closely associated with the toxic effects.

II. Extrapolating between oral animal intake and inhaled human intake.

Terminology varies!

From EPA draft guidelines:

Applied dose: Amount of an agent presented to an absorption barrier (e.g., skin, lung membranes, digestive tract membranes) and available for absorption

Internal dose: Amount crossing the absorption barrier

Delivered dose: The amount available for interaction with the organ, tissue, or cell of concern.

OUR ASSUMPTIONS:

1. The same applied dose gives the same delivered dose, whether stomach or lungs.

2. Absorption rates are the same for test animals and humans.