The 2-D disc and 3-D RWV cultures showed quite a big discrepancy in a diversity of biological responses. The reasons are still poorly understood. We hypothesize that such discrepancy could arise from the genotypic variance and the microenvironment interventions involving the physical, chemical, and biological parameters. Theoretical elucidation showed 3D-cultures exhibit larger total surface area (>78.54ï‚´10-6 cm2), larger effective surface area available for mass transport (>52.36ï‚´10-6 cm2 per cell), and larger contact surface area for anchorage (>26.18ï‚´10-6 cm2). The 3-D and not the 2-D culture always faces a rotating force 3.107ï‚´10-9 N/cell and a weaker gravitational force, ï‚£ 6.77ï‚´10-7N/cell. As contrast, the 2-D cultured cells uniquely encounter a static hydraulic pressure 37.51 N/cm2. Kinetic analysis indicated 2-D culture mostly is accompanied with diffusion control over the substrate, contrasting with the kinetic control of 3-D cultures. For note, in principle severe cytotoxicity or mutagenicity only can occur at higher level toxicant under a kinetic control regime.