Lab-scale (70 L) and industrial scale (70 m(3)) aerated fermenters are simulated using a commercial computational fluid dynamics code. The model combines an Euler-Euler approach for the two-phase flow, a population balance model for biological adaptation to concentration gradients, and a kinetic model for biological reactions. Scale-up at constant volumetric mass transfer coefficient is performed, leading to concentration gradients at the large scale. The results show that for a given concentration field and a given circulation time t(c), the population (physiological) state depends on the characteristic time of biological adaptation T-a. The population specific growth rate (T-a >> t(c)) is found independent of the spatial location and closely related to the volume average concentration. Oppositely, the population specific uptake rate (T-a approximate to t(c)) is spatially heterogeneous. The resulting local disequilibria between the uptake rate and the growth rate provide an explanation for the decreased performances of poorly macromixed industrial bioreactors. (c) 2013 American Institute of Chemical Engineers AIChE J, 60: 27-40, 2014