Physiologically Based Pharmacokinetic/Pharmacodynamic Model for Acrylamide and Its Metabolites in Mice, Rats, and Humans

Abstract

A physiologically based pharmacokinetic model was developed for acrylamide (AA) and three of its metabolites: glycidamide (GA) and the glutathione conjugates of acrylamide (AA-GS) and glycidamide (GA-GS). Liver GA-DNA adducts and hemoglobin (Hb) adducts with AA and GA were included as pharmacodynamic components of the model. Serum AA and GA concentrations combined with urinary elimination levels for all four components from male and female mice and rats were simulated from iv and oral administration of 0.1 mg/kg AA or 0.12 mg/kg GA. Adduct formation and decay rates were determined from a 6 week exposure to approximately 1 mg/kg AA in the drinking water and subsequent 6 week nonexposure period. Human urinary excretion data and Hb adduct data were utilized to extrapolate to a human model. The steady-state human liver GA-DNA adduct level from exposure to background levels of AA in the diet was predicted to be between 0.06 and 0.26 adducts per 10(8) nucleotides.

Scientific Opinion on acrylamide in food

“…When compared to the experimentally measured serum AUC value for AA and GA in rats treated by gavage with 0.1 mg AA/kg b.w. (Table 17), the predicted AUCs (Table 18) from Young et al (2007) were similar, but the predictions from Walker et al (2007) are consistently 2-to 3-fold higher than the measured values. Sweeney et al (2010) did not report AUCs for rats.…”

“…First-order kinetics were used in all cases because of the very high K m values for oxidation of AA to GA (4-14 mmol/L) reported from rodent and human hepatic microsomes (Tareke et al, 2006). The PBPK/PD model of Young et al (2007) fit all of the data available for low and high doses of AA and GA in rodents and dietary doses of AA in humans. GA data were fit first because it was the simplest simulation, then the GA parameters were held constant to optimally fit the AA dosing data.…”

“…Although no human modelling was attempted, the reported rat model was considered by the authors as 'a first step in providing a tool to assist in developing (human) exposure limits'. Young et al (2007) used a general-purpose PBPK model to simulate a more extensive number of data sets. The PBPK model contained sub-models for AA, GA, and their GSH conjugates.…”

“…reported in . and B6C3F 1 mice (Doerge et al, 2005b The Young et al (2007) model produced statistically significant differences in the metabolic parameters when comparing sex, dose and route of administration in rats. The values of metabolic parameters for the mouse were within the same range as the rat values.…”

“…Although the format of model output data reported by Sweeney et al (2010) was not directly equivalent to those reported by Young et al (2007) and Walker et al (2007), some comparisons of the three models' output for rat and human internal dosimetry for AA and GA are possible. When compared to the experimentally measured serum AUC value for AA and GA in rats treated by gavage with 0.1 mg AA/kg b.w.…”