Metabolism and Hemoglobin Adduct Formation 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 objectives of this study were to evaluate the metabolism of AM in humans following oral administration, to compare hemoglobin adduct formation on oral and dermal administration, and to measure hormone levels. The health of the people exposed under controlled conditions was continually monitored. Prior to conducting exposures in humans, a low-dose study was conducted in rats administered 3 mg/kg (1,2,3-13C3) AM by gavage. The study protocol was reviewed and approved by Institute Review Boards both at RTI, which performed the sample analysis, and the clinical research center conducting the study. (1,2,3-13C3) 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 (3 mg/kg oral dose) were analyzed for AM metabolites using 13C NMR spectroscopy. Approximately 86% of the urinary metabolites were derived from GSH conjugation and excreted as N-acetyl-S-(3-amino-3-oxopropyl)cysteine and its S-oxide. Glycidamide, glyceramide, and low levels of N-acetyl-S-(3-amino-2-hydroxy-3-oxopropyl)cysteine were detected in urine. On oral administration, a linear dose response was observed for N-(2-carbamoylethyl)valine (AAVal) and N-(2-carbamoyl-2-hydroxyethyl)valine (GAVal) in hemoglobin. Dermal administration resulted in lower levels of AAVal and GAVal. This study indicated that humans metabolize AM via glycidamide to a lesser extent than rodents, and dermal uptake was approximately 6.6% of that observed with oral uptake.

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.…”

“…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. A small amount of unchanged glycidamide was also determined in human urine [11]. Acrylamide and its metabolites accumulate in blood by combining with hemoglobin.…”

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

“…Toxicokinetics of acrylamide were investigated mainly in rodents, whereas recently, some data on acrylamide disposition in healthy volunteers after acrylamide administration in a test-meal (8,9), in drinking water (10,11), or dermally (12) have been published. As shown in rats and mice (6,10,13) and in humans (8)(9)(10), acrylamide is readily absorbed and widely distributed to tissues, crosses the human placenta, and is transferred into the breast milk (8,14).…”

“…As shown in rats and mice (6,10,13) and in humans (8)(9)(10), acrylamide is readily absorbed and widely distributed to tissues, crosses the human placenta, and is transferred into the breast milk (8,14). Acrylamide is in part biotransformed to the epoxide glycidamide.…”

“…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.…”