Measurement of plasma or urinary metabolites and Hprt mutant frequencies following inhalation exposure of mice and rats to 3-butene-1,2-diol.
Studies were performed to determine if the detoxification pathway of 1,3-butadiene (BD) through 3-butene-1,2-diol (BD-diol) is a major contributor to mutagenicity in BD-exposed mice and rats. First, female and male mice and rats (4-5 weeks old) were exposed by nose-only for 6h to 0, 62.5, 200, 625, or 1250 ppm BD or to 0, 6, 18, 24, or 36 ppm BD-diol primarily to establish BD and BD-diol exposure concentrations that yielded similar plasma levels of BD-diol, and then animals were exposed in inhalation chambers for 4 weeks to BD-diol to determine the mutagenic potency estimates for the same exposure levels and to compare these estimates to those reported for BD-exposed female mice and rats where comparable blood levels of BD-diol were achieved. Measurements of plasma levels of BD-diol (via GC/MS methodology) showed that (i) BD-diol accumulated in a sub-linear fashion during single 6-h exposures to >200 ppm BD; (ii) BD-diol accumulated in a linear fashion during single or repeated exposures to 6-18 ppm BD and then in a sub-linear fashion with increasing levels of BD-diol exposure; and (iii) exposures of mice and rats to 18 ppm BD-diol were equivalent to those produced by 200 ppm BD exposures (with exposures to 36 ppm BD-diol yielding plasma levels approximately 25% of those produced by 625 ppm BD exposures). Measurements of Hprt mutant frequencies (via the T cell cloning assay) showed that repeated exposures to 18 and 36 ppm BD-diol were significantly mutagenic in mice and rats. The resulting data indicated that BD-diol derived metabolites (especially, 1,2-dihydroxy-3,4-epoxybutane) have a narrow range of mutagenic effects confined to high-level BD (>or=200 ppm) exposures, and are responsible for nearly all of the mutagenic response in the rat and for a substantial portion of the mutagenic response in the mouse following high-level BD exposures.
Walker
Dale M
DM
Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA.
McDonald
Jacob D
JD
Meng
Quanxin
Q
Kracko
Dean A
DA
Bauer
Michael J
MJ
Seilkop
Steven K
SK
Walker
Elizabeth L
EL
Henderson
Rogene F
RF
Walker
Vernon E
VE
D000818:Animals; D002070:Butadienes / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000097:blood* / Q000652:urine*; D005260:Female; D006018:Glycols / Q000097:blood* / Q000633:toxicity* / Q000652:urine*; D006454:Hemoglobins / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D019570:Inhalation Exposure; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D015203:Reproducibility of Results; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D013997:Time Factors
D002070:Butadienes; D004852:Epoxy Compounds; D006018:Glycols; D006454:Hemoglobins; C080053:3,4-epoxybutane-1,2-diol; D007041:Hypoxanthine Phosphoribosyltransferase; C031763:1,3-butadiene; C034598:3-butene-1,2-diol