Comparison of PBTK model and biomarker based estimates of the internal dosimetry of acrylamide

Abstract

Estimates of internal dosimetry for acrylamide (AA, 2-propenamide; CASRN: 79-06-1) and its active metabolite glycidamide (GA) were compared using either biomarkers of internal exposure (hemoglobin adduct levels in rats and humans) or a PBTK model (Sweeney et al., 2010). The resulting impact on the human equivalent dose (HED, oral exposures), the human equivalent concentration (HEC, inhalation), and final reference values was also evaluated. Both approaches yielded similar AA HEDs and HECs for the most sensitive noncancer effect of neurotoxicity, identical oral reference doses (RfD) of 2×10(-3) mg AA/kg bw/d, and nearly identical inhalation reference concentrations (RfC=0.006 mg/m(3) and 0.007 mg/m(3), biomarker and PBTK results, respectively). HED and HEC values for carcinogenic potential were very similar, resulting in identical inhalation unit risks of 0.1/(mg AA/m(3)), and nearly identical oral cancer slope factors (0.4 and 0.5/mg AA/kg bw/d), biomarker and PBTK results, respectively. The concordance in estimated HEDs, HECs, and reference values from these two diverse methods increases confidence in those values. Advantages and specific application of each approach are discussed. (Note: Reference values derived with the PBPK model were part of this research, and do not replace values currently posted on IRIS: http://www.epa.gov/iris/toxreviews/0286tr.pdf.).

Keywords: AA; AA ToxReview; AAVal; AUC; Acrylamide; BMD; BMDL; BMR; Biomarkers of exposure; CF; Dosimetry; EPA; EPA’s Toxicological Review of Acrylamide; GA; GAVal; Glycidamide; HEC; HED; Hb; Hemoglobin adducts; IRIS; IUR; Integrated Risk Information System; OSF; PBTK; PBTK model; POD; RfC; RfD; U.S. Environmental Protection Agency; UF(A); acrylamide; acrylamide-hemoglobin-terminal-valine adduct, N-(2-carbamoylethyl)valine; area under the concentration time curve; benchmark dose; benchmark response; conversion factor (used to convert an internal dose to an external dose, or vice-versa); glycidamide; glycidamide-hemoglobin-terminal-valine adduct, N-(2-carbamoyl-2-hydroxyethyl)valine; hemoglobin; human equivalent concentration (inhalation route of exposure); human equivalent dose (oral route of exposure); inhalation unit risk; lower confidence limit on the benchmark dose; oral slope factor; physiologically-based toxicokinetic model; point of departure; reference concentration (inhalation route of exposure); reference dose (oral route of exposure); uncertainty factor used to account for uncertainty in the animal-to-human extrapolation.