“…Subchronic and chronic rat toxicity studies have identified the kidney as a primary target organ (Charles et al , 1996a, b; Gorzinski et al , 1987), consistent with the observation that 2,4-D is accumulated in renal proximal tubules through the action of a saturable, metabolically active renal organic anion transporter, OAT1 (Berndt and Koschier, 1973; Hasegawa et al , 2003; Hook et al , 1974). The OAT1 transporter plays a critical role in the dose-dependent systemic renal clearance of 2,4-D in rats and is saturated at oral gavage and dietary doses of approximately 50mg/kg, resulting in distinct nonlinear toxicokinetic (TK) behavior (Gorzinski et al , 1987; Saghir et al , 2006; Timchalk, 2004; van Ravenzwaay et al , 2003). Importantly, OAT1 is the primary transporter responsible for renal clearance of 2,4-D in humans (Nozaki et al , 2007), and thus, 2,4-D would be expected to exhibit analogous dose-dependent nonlinear TK in humans.…”