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Title: Toxicokinetics of acrylamide and glycidamide in Fischer 344 rats

Abstract

Acrylamide (AA) is a widely studied industrial chemical that is neurotoxic, mutagenic to somatic and germ cells, and carcinogenic in rodents. The recent discovery of AA at ppm levels in a wide variety of commonly consumed foods has energized research efforts worldwide to define toxic mechanisms, particularly toxicokinetics and bioavailability. This study compares the toxicokinetics of AA and its epoxide metabolite, glycidamide (GA), in serum and tissues of male and female F344 rats following acute exposure by intravenous, gavage, and dietary routes at 0.1 mg/kg AA or intravenous and gavage routes with an equimolar amount of GA. AA was rapidly absorbed after oral dosing, was widely distributed to tissues, was efficiently converted to GA, and produced increased levels of GA-DNA adducts in liver. GA was also rapidly absorbed, widely distributed to tissues, and produced increased liver DNA adduct levels. AA bioavailability after aqueous gavage was 60-98% and from the diet was 32-44%; however, first-pass metabolism or other kinetic change resulted in much higher internal exposures to GA (2- to 7-fold) when compared to the intravenous route. A similar effect on metabolism to GA following oral administration was previously observed under an identical exposure paradigm in mice. Furthermore, DNA adduct formationmore » in rat liver showed the same proportionality with the respective GA AUC value as did mice in the previous study. These findings suggest that as the AA content in food is reduced, species-differences in GA formation and subsequent DNA adduct formation may be minimized. These findings provide additional information needed to assess genotoxic risks from the low levels of AA that are pervasive in the food supply.« less

Authors:
 [1];  [2];  [2];  [2];  [2]
  1. National Center for Toxicological Research, Jefferson, AR 72079 (United States). E-mail: ddoerge@nctr.fda.gov
  2. National Center for Toxicological Research, Jefferson, AR 72079 (United States)
Publication Date:
OSTI Identifier:
20722021
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 208; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2005.03.003; PII: S0041-008X(05)00128-6; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACRYLAMIDE; ACUTE EXPOSURE; BIOLOGICAL AVAILABILITY; DIET; DNA; DNA ADDUCTS; EPOXIDES; FOOD; GERM CELLS; LIVER; METABOLISM; MICE; ORAL ADMINISTRATION; RATS

Citation Formats

Doerge, Daniel R., Young, John F., McDaniel, L. Patrice, Twaddle, Nathan C., and Churchwell, Mona I. Toxicokinetics of acrylamide and glycidamide in Fischer 344 rats. United States: N. p., 2005. Web. doi:10.1016/j.taap.2005.03.003.
Doerge, Daniel R., Young, John F., McDaniel, L. Patrice, Twaddle, Nathan C., & Churchwell, Mona I. Toxicokinetics of acrylamide and glycidamide in Fischer 344 rats. United States. doi:10.1016/j.taap.2005.03.003.
Doerge, Daniel R., Young, John F., McDaniel, L. Patrice, Twaddle, Nathan C., and Churchwell, Mona I. Tue . "Toxicokinetics of acrylamide and glycidamide in Fischer 344 rats". United States. doi:10.1016/j.taap.2005.03.003.
@article{osti_20722021,
title = {Toxicokinetics of acrylamide and glycidamide in Fischer 344 rats},
author = {Doerge, Daniel R. and Young, John F. and McDaniel, L. Patrice and Twaddle, Nathan C. and Churchwell, Mona I.},
abstractNote = {Acrylamide (AA) is a widely studied industrial chemical that is neurotoxic, mutagenic to somatic and germ cells, and carcinogenic in rodents. The recent discovery of AA at ppm levels in a wide variety of commonly consumed foods has energized research efforts worldwide to define toxic mechanisms, particularly toxicokinetics and bioavailability. This study compares the toxicokinetics of AA and its epoxide metabolite, glycidamide (GA), in serum and tissues of male and female F344 rats following acute exposure by intravenous, gavage, and dietary routes at 0.1 mg/kg AA or intravenous and gavage routes with an equimolar amount of GA. AA was rapidly absorbed after oral dosing, was widely distributed to tissues, was efficiently converted to GA, and produced increased levels of GA-DNA adducts in liver. GA was also rapidly absorbed, widely distributed to tissues, and produced increased liver DNA adduct levels. AA bioavailability after aqueous gavage was 60-98% and from the diet was 32-44%; however, first-pass metabolism or other kinetic change resulted in much higher internal exposures to GA (2- to 7-fold) when compared to the intravenous route. A similar effect on metabolism to GA following oral administration was previously observed under an identical exposure paradigm in mice. Furthermore, DNA adduct formation in rat liver showed the same proportionality with the respective GA AUC value as did mice in the previous study. These findings suggest that as the AA content in food is reduced, species-differences in GA formation and subsequent DNA adduct formation may be minimized. These findings provide additional information needed to assess genotoxic risks from the low levels of AA that are pervasive in the food supply.},
doi = {10.1016/j.taap.2005.03.003},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 208,
place = {United States},
year = {Tue Nov 01 00:00:00 EST 2005},
month = {Tue Nov 01 00:00:00 EST 2005}
}
  • Acrylamide (AA) is a widely studied industrial chemical that is neurotoxic, mutagenic to somatic and germ cells and carcinogenic in rodents. AA is also formed in many commonly consumed starchy foods during cooking. Our previous toxicokinetic investigations of AA and its important 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. Measurements of DNA adducts in many tissues supported the hypothesis that AA is carcinogenic in rodent bioassays through metabolism to GA. The current investigation describesmore » the development and validation of methodology for measuring hemoglobin (Hb) adducts with AA and GA in the same rodents previously used for toxicokinetic and DNA adduct measurements. The goal was to investigate possible relationships between these circulating biomarkers of exposure and serum toxicokinetic parameters for AA and GA and tissue GA-DNA adducts in rodents from both single and repeated dosing with AA. Significant correlations were observed between GA-Hb and liver GA-DNA adducts for either single or multiple dosing regimens with AA. Using available GA-Hb adduct data, empirical and allometric relationships permitted estimation of liver DNA adducts in humans in the range of 0.06-0.3 adducts/10{sup 8} nucleotides. This approach may prove useful in extrapolating human cancer risks from findings in rodent bioassays.« less
  • Cited by 9
  • Acrylamide (AA) is an important industrial chemical that is neurotoxic in rodents and humans and carcinogenic in rodents. The observation of cancer in endocrine-responsive tissues in Fischer 344 rats has prompted hypotheses of hormonal dysregulation, as opposed to DNA damage, as the mechanism for tumor induction by AA. The current investigation examines possible evidence for disruption of the hypothalamic-pituitary-thyroid axis from 14 days of repeated exposure of male Fischer 344 rats to doses of AA that range from one that is carcinogenic after lifetime exposure (2.5 mg/kg/d), an intermediate dose (10 mg/kg/d), and a high dose (50 mg/kg/d) that ismore » neurotoxic for this exposure time. The endpoints selected include: serum levels of thyroid and pituitary hormones; target tissue expression of genes involved in hormone synthesis, release, and receptors; neurotransmitters in the CNS that affect hormone homeostasis; and histopathological evaluation of target tissues. These studies showed virtually no evidence for systematic alteration of the hypothalamic-pituitary-thyroid axis and do not support hormone dysregulation as a plausible mechanism for AA-induced thyroid cancer in the Fischer 344 rat. Specifically, there were no significant changes in: 1) mRNA levels in hypothalamus or pituitary for TRH, TSH, thyroid hormone receptor {alpha} and {beta}, as well 10 other hormones or releasing factors; 2) mRNA levels in thyroid for thyroglobulin, thyroid peroxidase, sodium iodide symporter, or type I deiodinases; 3) serum TSH or T3 levels (T4 was decreased at high dose only); 4) dopaminergic tone in the hypothalamus and pituitary or importantly 5) increased cell proliferation (Mki67 mRNA and Ki-67 protein levels were not increased) in thyroid or pituitary. These negative findings are consistent with a genotoxic mechanism of AA carcinogenicity based on metabolism to glycidamide and DNA adduct formation. Clarification of this mechanistic dichotomy may be useful in human cancer risk assessments for AA.« less
  • The rodent carcinogen acrylamide (AA) is formed during preparation of starch-containing foods. AA is partly metabolized to the genotoxic epoxide glycidamide (GA). After metabolic processing, the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA), rac-N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA) and rac-N-acetyl-S-(1-carbamoyl-moyl-2-hydroxyethyl)-L-cysteine (iso-GAMA) are excreted with urine. In humans, AAMA can be sulfoxidized to AAMA-sulfoxide. The aim of this study was to assess potential species-differences in AA-toxicokinetics in rats and humans after single oral administration of doses similar to the daily human dietary exposure. Male Fischer 344 rats (n = 5/dose group) were administered 20 and 100 {mu}g/kg b.w. {sup 13}C{sub 3}-AA in deionized water via oral gavage.more » Human subjects (n = 3/gender) were orally administered 0.5 and 20 {mu}g/kg b.w. {sup 13}C{sub 3}-AA with drinking water. Urine samples were collected in intervals for 96 and 94 h, respectively. Urinary concentrations of {sup 13}C{sub 3}-AAMA, {sup 13}C{sub 3}-GAMA and {sup 13}C{sub 3}-AAMA-sulfoxide were monitored by liquid chromatography-tandem mass spectrometry. The recovered urinary metabolites accounted for 66.3% and 70.5% of the 20 and 100 {mu}g/kg b.w. doses in rats and for 71.3% and 70.0% of the 0.5 and 20 {mu}g/kg b.w. doses in humans. In rats, {sup 13}C{sub 3}-AAMA accounted for 33.6% and 38.8% of dose and 32.7% and 31.7% of dose was recovered as {sup 13}C{sub 3}-GAMA; {sup 13}C{sub 3}-AAMA-sulfoxide was not detected in rat urine. In humans, {sup 13}C{sub 3}-AAMA, {sup 13}C{sub 3}-GAMA and {sup 13}C{sub 3}-AAMA-sulfoxide accounted for 51.7% and 49.2%, 6.3% and 6.4% and 13.2% and 14.5% of the applied dose, respectively. The obtained results suggest that the extent of AA bioactivation to GA in humans is lower than in rodents.« less
  • We examined the metabolism and disposition of aniline, which induces spleen hemangiosarcomas in rats but no tumors in mice, in normal and predosed Fischer 344 rats, and C57BL/6 X C3H F1 mice administered low (50 and 100 mg/kg, respectively) or high (250 and 500 mg/kg, respectively) doses. Of 11 tissues examined, the highest levels of binding of (/sup 14/C)aniline to DNA were in the kidney, large intestine, and spleen of high-dose rats that had received prior dosing; these tissues had covalent binding indices of 14.2, 4.3, and 3.7 mumol/mol nucleotides/dose, respectively. Protein and RNA were the major macromolecular targets formore » binding of radioactivity from (/sup 14/C)aniline. Relative to controls, most tissues from predosed mice (low dose and high dose) showed less binding to protein and RNA; but for most tissues from predosed rats administered 50-mg/kg doses of (/sup 14/C)aniline, there was more extensive binding. Also relative to controls, binding of radioactivity in the spleen of predosed rats given (/sup 14/C)aniline (50 mg/kg) was 148% greater for protein and 302% greater for RNA. For rats administered 250 mg of (/sup 14/C)aniline per kg, however, there were no outstanding differences in binding to RNA and protein between normal and predosed animals. The profiles of urinary metabolites produced by rats and mice were not appreciably different in animals predosed with aniline. For rats, however, the profiles were different for the low and high doses, suggesting that the main metabolic pathway was saturated at the higher dose. p-Acetamidophenyl sulfate represented over 70% of the total radioactivity recovered from the urine of rats dosed with 50 mg of aniline per kg but only 30% in the urine of those dosed with 250 mg/kg. The urine of the high-dose rats contained greater percentages of p-aminophenyl sulfate, p-acetamidophenyl glucuronide, and unconjugated metabolites.« less