Octanol–Water Partition Coefficients of Aristolochic Acids and Implications to the Etiology of Balkan Endemic Nephropathy

The octanol–water partition coefficients (K_ow) of the aristolochic acids, AA I and AA II, were determined using the traditional shake-flask method as a function of pH and ionic strength. These compounds have been implicated in the etiology of Balkan endemic nephropathy, but evidence of a plausible exposure pathway remains elusive, and research is constrained by the absence of critical physical–chemical parameters on these compounds. Apparent K_ow values were determined across a range of pH and ionic strength conditions. The results show that the apparent K_ow decreased by approximately four orders of magnitude as pH increased from 2 to 9. The pH dependence was well described by a simple model that calculated the apparent K_ow based on the ionization fractions and intrinsic K_ow values for the neutral and ionized species. Higher ionic strength solutions resulted in higher K_ow values at high pH, but had no effect at low pH. These results suggest that transport of aristolochic acids will be highly dependent on pH and ionic strength, with significant aqueous-phase transport at neutral to slightly alkaline conditions, with the highest mobility occurring under low ionic strength conditions, and the possibility of significant partitioning to nonpolar phases, such as soil organic matter or plant material, at low pH. Much of the region where BEN is prevalent is a karst environment, and pH values are generally above 8, thus leaching and groundwater transport are favored, which can suggest possible exposure routes.