Relationships between biomarkers of exposure and toxicokinetics in Fischer 344 rats and B6C3F1 mice administered single doses of acrylamide and glycidamide and multiple doses of acrylamide.
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 describes 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(8) nucleotides. This approach may prove useful in extrapolating human cancer risks from findings in rodent bioassays.
Tareke
Eden
E
National Center for Toxicological Research, Jefferson, AR 72079, USA.
Twaddle
Nathan C
NC
McDaniel
L Patrice
LP
Churchwell
Mona I
MI
Young
John F
JF
Doerge
Daniel R
DR
D020106:Acrylamide / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002853:Chromatography, Liquid; D018736:DNA Adducts / Q000378:metabolism; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D009153:Mutagens / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D015203:Reproducibility of Results; D018570:Risk Assessment; D021241:Spectrometry, Mass, Electrospray Ionization; D013997:Time Factors
D015415:Biomarkers; D018736:DNA Adducts; D004852:Epoxy Compounds; D006454:Hemoglobins; D009153:Mutagens; D020106:Acrylamide; C071834:glycidamide