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Groundwater flow and radionuclide transport at the Milrow underground nuclear test site on Amchitka Island are modeled using two-dimensional numerical simulations. A multi-parameter uncertainty analysis is adapted and used to address the effects of uncertainties associated with the definition of the modeled processes and the values of the parameters governing these processes. In particular, we focus on the effects on radioactive transport of uncertainties associated with conduction and convection of heat relative to the uncertainties associated with other flow and transport parameters. These include recharge, hydraulic conductivity, fracture porosity, dispersivity and strength of matrix diffusion. The flow model is conceptualized to address the problem of density-driven flow under conditions of variable salinity and geothermal gradient. The conceptual transport model simulates the advection–dispersion process, the diffusion process from the high-velocity fractures into the porous matrix blocks, and radioactive decay.For this case study, the uncertainty of the recharge-conductivity ratio contributes the most to the output uncertainty (standard deviation of mass flux across the seafloor). The location of the freshwater–saltwater transition zone changes dramatically as this ratio changes with the thickness of the freshwater lens and the location of the seepage face changing as well. In the context of radionuclide transport from the nuclear test cavity that is located in the area where the transition zone is uncertain, travel times of radionuclide mass from the cavity to the seepage face along the seafloor are significantly impacted. The variation in transition zone location changes the velocity magnitude at the cavity location by a large factor (probably an order of magnitude). When this effect is combined with porosity and matrix diffusion uncertainty, the uncertainty of transport results becomes large. Although thermal parameters have an effect on the solution of the flow problem and also on travel times of radionuclides, the effect is relatively small compared to other flow and transport parameters.