Studies of the mechanisms of neurotoxicity and toxicokinetics of acrylamide

To investigate the mechanisms of acrylamide neurotoxicity, cytoskeletal protein phosphorylation in rat brains and the toxicokinetics of a single oral dose of acrylamide in adult White Leghorn hens were studied.; Male Sprague-Dawley rats were intraperitoneally administered daily doses of acrylamide or glycidamide equivalent to 50 mg/kg acrylamide. Rats developed hindlimb and forelimb ataxia after 10 days of acrylamide or 18 days of glycidamide. Acrylamide increased phosphorylation of brain calcium/calmodulin-dependent kinase II 374%, endogenous brain microtubule-associated protein 2 (MAP-2) 117%, and exogenous MAP-2 207%. Glycidamide increased phosphorylation of the kinase 550%, endogenous MAP-2 332%, and exogenous MAP-2 74%. In control rats, myelin basic protein (MBP) displayed negligible phosphorylation. Acrylamide and glycidamide treated rats displayed moderate MBP phosphorylation.; The toxicokinetics of a single oral dose of (2,3-{dollar}sp{lcub}14{rcub}{dollar}C) acrylamide (50 mg/kg, 18-25 {dollar}mu{dollar}Ci/kg, purity {dollar}>{dollar} 98.5%) was studied in adult White Leghorn hens. Elimination of radiolabel and parent acrylamide from all tissues was biphasic with most terminal half-lives longer than 10 days. Blood (0.42%), plasma (0.36%), liver (0.22%) and muscle (0.20%) contained the greatest percentage of administered dose, with less than 0.02% in brain. Within 12 hr, 70% of the administered dose was excreted, 89% within 24 hr, and more than 99% within 48 hr. Within 5 days, eggs accumulated 0.52% of the administered dose.; A physiologically based pharmacokinetic (PBPK) model was developed from this data. Absorption was modeled by a first-order rate constant (0.061 hr{dollar}sp{lcub}-1{rcub}{dollar}). Absorption from gut was estimated as 5.1% of administered dose. Metabolism and elimination were modeled by a first-order rate constant (16 hr{dollar}sp{lcub}-1{rcub}{dollar}). Nonlinear plasma elimination was modeled by a plasma binding site for acrylamide with a first order rate constant (0.0056 hr{dollar}sp{lcub}-1{rcub}{dollar}). In eggs, distribution was modeled as a saturable process with a maximum transport rate (0.56 {dollar}mu{dollar}g/hr) and a saturation constant (0.82 ng/mL).; These studies suggest that acrylamide produces neurotoxicity by mechanisms similar to OPIDN, that acrylamide metabolites accumulate in tissues, and that a PBPK model can be used to describe the toxicokinetics of acrylamide.