In contrast-enhanced digital breast tomosynthesis (CE-DBT) there are several challenges in attempting to relate the reconstructed iodine signal to the true concentration in the patient. One such challenge arises from a change in iodine concentration during image acquisition. Here, we study this phenomenon experimentally. Fifteen projection images of a phantom with simulated spherical lesions ranging from 4 to 9.5 mm in diameter were acquired over a 40° angular extent, representing a clinical exam of about 15 s in duration. Iodine concentrations were varied to simulate changes of 0.1 mg/mL between successive projections. Signal enhancement due to the presence of iodine is characterized by the signal-difference between lesion and background from the central slice through the lesion. In a variety simulated lesion enhancement profiles, signal difference accurately represented the mean of the iodine concentration during image acquisition, but a dependence on lesion size was observed. Quantitative CE-DBT may require calibration for lesion size.