N7-glycidamide-guanine DNA adduct formation by orally ingested acrylamide in rats: a dose-response study encompassing human diet-related exposure levels.
Acrylamide (AA) is formed during the heating of food and is classified as a genotoxic carcinogen. The margin of exposure (MOE), representing the distance between the bench mark dose associated with 10% tumor incidence in rats and the estimated average human exposure, is considered to be of concern. After ingestion, AA is converted by P450 into the genotoxic epoxide glycidamide (GA). GA forms DNA adducts, primarily at N7 of guanine (N7-GA-Gua). We performed a dose-response study with AA in female Sprague-Dawley (SD) rats. AA was given orally in a single dosage of 0.1-10 000 μg/kg bw. The formation of urinary mercapturic acids and of N7-GA-Gua DNA adducts in liver, kidney, and lung was measured 16 h after application. A mean of 37.0 ± 11.5% of a given AA dose was found as mercapturic acids (MAs) in urine. MA excretion in urine of untreated controls indicated some background exposure from endogenous AA. N7-GA-Gua adduct formation was not detectable in any organ tested at 0.1 μg AA/kg bw. At a dose of 1 μg/kg bw, adducts were found in kidney (around 1 adduct/10(8) nucleotides) and lung (below 1 adduct/10(8) nucleotides) but not in liver. At 10, respectively, 100 μg/kg bw, adducts were found in all three organs, at levels close to those found at 1 μg AA/kg, covering a range of about 1-2 adducts/10(8) nucleotides. As compared to DNA adduct levels from electrophilic genotoxic agents of various origin found in human tissues, N7-GA-Gua adduct levels within the dose range of 0.1-100 μg AA/kg bw were at the low end of this human background. We propose to take the background level of DNA lesions in humans more into consideration when doing risk assessment of food-borne genotoxic carcinogens.
Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern , Erwin-Schroedinger-Strasse 52, 67663 Kaiserslautern, Germany.
Nico
N
Watzek
Nadine
N
Böhm
Julia
J
Feld
Denise
D
Scherbl
Franz
F
Berger
Karl Heinz
KH
Merz
Alfonso
A
Lampen
Thorsten
T
Reemtsma
Steven R
SR
Tannenbaum
Paul L
PL
Skipper
Matthias
M
Baum
Elke
E
Richling
Gerhard
G
Eisenbrand
D020106:Acrylamide / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine; D000818:Animals; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D018736:DNA Adducts / Q000378:metabolism*; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000378:metabolism* / Q000652:urine; D005260:Female; D006147:Guanine / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D002273:Carcinogens; D018736:DNA Adducts; D004852:Epoxy Compounds; D020106:Acrylamide; D006147:Guanine; C071834:glycidamide