Molecular dosimetry of DNA and hemoglobin adducts in mice and rats exposed to ethylene oxide.
Experiments involving ethylene oxide (ETO) have been used to support the concept of using adducts in hemoglobin as a surrogate for DNA adducts in target tissues. The relationship between repeated exposures to ETO and the formation of N-(2-hydroxyethyl)valine (HEtVal) in hemoglobin and 7-(2-hydroxyethyl)guanine (7-HEG) in DNA was investigated in male rats and mice exposed by inhalation to 0, 3, 10, 33, or 100 ppm ETO for 6 hr/day for 4 weeks, or exposed to 100 ppm (mice) or 300 ppm (rats) for 1, 3, 5, 10, or 20 days (5 days/week). HEtVal was determined by Edman degradation, and 7-HEG was quantitated by HPLC separation and fluorescence detection. HEtVal formation was linear between 3 and 33 ppm ETO and increased in slope above 33 ppm. The dose-response curves for 7-HEG in rat tissues were linear between 10 and 100 ppm ETO and increased in slope above 100 ppm. In contrast, only exposures to 100 ppm ETO resulted in significant accumulation of 7-HEG in mice. Hemoglobin adducts were lost at a greater rate than predicted by normal erythrocyte life span. The loss of 7-HEG from DNA was both species and tissue dependent, with the adduct half-lives ranging from 2.9 to 5.8 days in rat tissues (brain, kidney, liver, lung, spleen, testis) and 1.0 to 2.3 days in all mouse tissues except kidney (t1/2 = 6.9 days). The concentrations of HEtVal were similar in concurrently exposed rats and mice, whereas DNA from rats had at least 2-fold greater concentrations of 7-HEG than DNA from mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Walker
V E
VE
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709.
Fennell
T R
TR
Upton
P B
PB
MacNeela
J P
JP
Swenberg
J A
JA
D000818:Animals; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005027:Ethylene Oxide / Q000008:administration & dosage / Q000633:toxicity*; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006454:Hemoglobins / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000378:metabolism
D006454:Hemoglobins; C057442:2-hydroxyethylvaline; C035018:N(7)-hydroxyethylguanine; D006147:Guanine; D004247:DNA; D014633:Valine; D005027:Ethylene Oxide