title: Urinary excretion of acrylamide and metabolites in Fischer 344 rats and B6C3F(1) mice administered a single dose of acrylamide.
abstract: Acrylamide (AA) is a widely studied industrial chemical that is neurotoxic, mutagenic to somatic and germ cells, and carcinogenic in mice and rats. AA is also formed during cooking in many commonly consumed starchy foods. Our previous toxicokinetic investigations of AA and its genotoxic metabolite, glycidamide (GA), in rodents showed that AA is highly bioavailable from oral routes of administration, is widely distributed to tissues, and that the dietary route, in particular, favors metabolism to GA. Formation and accumulation of mutagenic GA-DNA adducts in many tissues support the hypothesis that AA is carcinogenic in rodent bioassays through metabolism to GA. The current investigation describes the quantification of 24 h urinary metabolites, including free AA and GA and their mercapturic acid conjugates (AAMA and GAMA, respectively), using LC/MS/MS in F344 rats and B6C3F(1) mice following a dose of 0.1 mg/kg bw given by intravenous, gavage, and dietary routes of administration. Similar groups of rodents were used previously for serum/tissue toxicokinetic and adduct determinations (DNA and hemoglobin). The goal was to investigate relationships between urinary and circulating biomarkers of exposure, toxicokinetic parameters for AA and GA, and tissue GA-DNA adducts in rodents from single doses of AA. Significant linear correlations were observed between urinary levels of AA with AAMA and GA with GAMA in the current data sets for rats and mice. Concentrations of AA and AAMA correlated significantly with average AUC values determined previously for AA in groups of rats and mice similarly dosed with AA. Urinary GA and GAMA concentrations showed significant correlations with average AUC values for GA and liver GA-DNA adducts determined previously in rats and mice similarly dosed with AA. Despite statistical significance, considerable inter-animal variability was observed in all urinary measurements, which limited the degree of correlation with either average toxicokinetic or biomarker data collected from different groups of animals. These results suggest that urinary measurements of AA and its metabolites may be useful for prediction of internal exposures to AA and GA.
authors.affiliation: National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079, USA. daniel.doerge@fda.hhs.gov
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Doerge
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Twaddle
authors.forename: Melanie I
authors.initials: MI
authors.lastname: Boettcher
authors.forename: L Patrice
authors.initials: LP
authors.lastname: McDaniel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Angerer
mesh_terms: D000111:Acetylcysteine / Q000652:urine; D020106:Acrylamide / Q000493:pharmacokinetics* / Q000652:urine*; D000818:Animals; D019540:Area Under Curve; D015415:Biomarkers; D001711:Biotransformation; D002853:Chromatography, Liquid; D004032:Diet; D005260:Female; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011916:Rats, Inbred F344; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D015415:Biomarkers; D007202:Indicators and Reagents; D020106:Acrylamide; D000111:Acetylcysteine