Kinetics of Elimination of Urinary Metabolites of Acrylamide in Humans

Abstract

Acrylamide (AM), used in the manufacture of polyacrylamide and grouting agents, is produced during the cooking of foods. Workplace exposure to AM can occur through the dermal and inhalation routes. The objective of this study was to define the kinetics of elimination of AM and its metabolites following oral and dermal administration. This is the second part of a study in which metabolites and hemoglobin adducts of AM were determined in people (Fennell et al., 2005, Toxicol. Sci. 85, 447-459). (1,2,3-(13)C(3))AM was administered in an aqueous solution orally (single dose of 0.5, 1.0, or 3.0 mg/kg) or dermally (three daily doses of 3.0 mg/kg) to sterile male volunteers. Urine samples were collected at 0-2, 2-4, 4-8, 8-16, and 16-24 h following administration orally, or at 0-2, 2-4, 4-8, 8-16, and 16-24 h following each of three daily dermal doses. (13)C(3)-AM and its metabolites in urine, (13)C(3)-glycidamide, (13)C(3)-N-acetyl-S-(3-amino-3-oxopropyl)cysteine and its S-oxide, and (13)C(3)-N-acetyl-S-(3-amino-2-hydroxy-3-oxopropyl)cysteine, were quantitated using liquid chromatography-tandem mass spectrometry. The recovered urinary metabolites accounted for 45.6, 49.9, and 39.9% of a 0.5, 1.0, and 3.0 mg/kg oral dose (0-24 h), respectively, and for 4.5% of the dose after 3 mg/kg was administered daily for 3 days dermally (0-4 days). These results indicate that after oral administration AM is rapidly absorbed and eliminated. The half-life estimated for elimination of AM in urine was 3.1-3.5 h. After dermal administration, AM uptake is slow. This study indicated that skin provides a barrier that slows the absorption of AM, and results in limited systemic availability following dermal exposure to AM.

In vivo Role of Cytochrome P450 2E1 and Glutathione-S-Transferase Activity for Acrylamide Toxicokinetics in Humans

“…With respect to the metabolic pattern of acrylamide and total dose recovery in the reference period, the toxicokinetic parameters were in accordance to the data from other human studies with acrylamide dosing (9)(10)(11)(12). For the disulfiram period, almost complete inhibition of CYP2E1 by the drug is expected.…”

“…Acrylamide and glycidamide are conjugated to glutathione, which is the main pathway of acrylamide metabolism in both rodents and humans (10)(11)(12)(22)(23)(24). As products of this conjugation, the following mercapturic acid metabolites have been observed: N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA); N-acetyl-S-(2-carbamoylethyl)-cysteine-S -oxide; N -(R,S )-acetyl-S -(2-hydroxy-2-carbamoylethyl)-cysteine (GAMA); and Nacetyl-S -(1-carbamoyl-2-hydroxyethyl)-cysteine.…”

Scientific Opinion on acrylamide in food

“…This modelling used all the male F344 rat data sets, including partition coefficients, blood and tissues, Hb adducts and urinary metabolites, previously fit by Young et al (2007) and Walker et al (2007). The human model was fit using the Hb adduct and urinary metabolite data from Fennell et al ( , 2006 (Sweeney et al, 2010) or Hb adduct measurements in rats and humans (Doerge et al, 2005a,b,c;Tareke et al, 2006). The human equivalent doses and reference values (i.e.…”

Evaluation of Some Renal Function Parameters in Rats Treated with Acrylamide

“…Epoxidation of equal amounts of acrylamide to glycidamide is 2-4 times less in humans when compared to rodents [11][12][13]. Toxicokinetic studies in humans indicated that 60% of absorbed acrylamide is mostly eliminated in urine (86%) as GSH and just 4.4% of this incoming acrylamide was unchanged.…”