Mutagenicity at the Hprt locus in T cells of female mice following inhalation exposures to low levels of 1,3-butadiene.
A study was conducted to test the hypothesis that repeated low level exposures to 1,3-butadiene (BD), approaching the OSHA occupational threshold for this chemical, produce a significant mutagenic response in mice. Female B6C3F1 mice (4-5 weeks of age) were exposed by inhalation for 2 weeks (6 h/day, 5 days/week) to 0 or 3 ppm BD, and then necropsied at 4 weeks after the cessation of exposures to measure the frequency of mutations (MF) at the Hprt locus using the T-lymphocyte clonal assay. At necropsy, T cells were isolated from spleen and cultured in the presence of mitogen, growth factors, and a selection agent. Cells were scored for growth on days 8-9 after plating to determine cloning efficiencies (CEs) and Hprt MFs. There was a marginal but significant reduction in the growth of splenic T cells from mice exposed to 3 ppm (n=27) compared with control mice (n=24) (P=0.004), suggesting the occurrence of BD-induced cytotoxicity at this low exposure concentration. In addition, the average Hprt MF in mice exposed to 3 ppm BD [1.54+/-0.82 (S.D.)x10(-6)] was significantly increased by 1.6-fold over the average control value of 0.96+/-0.51 (S.D.)x10(-6) (P=0.004). Comparisons of these data to earlier Hprt mutagenicity studies of mice exposed to high concentrations of BD (where significant mutagenic but not cytotoxic effects were observed) indicate that the ability to detect the cytotoxic and mutagenic responses of T cells to low levels of BD was enhanced by using a much larger sample size than usual for both the control and treatment groups. Additional analyses of the quantitative relationships between CE and MF demonstrated that CE had no significant effect upon MF values in sham-exposed control mice or mice exposed to low-level BD. Furthermore, the approaches for assessing the impact of CE and clonality on Hprt MFs in these control and BD-exposed mice were applied with the same rigor as in in vivo Hprt mutagenicity studies in human children. The overall study results support the conclusion that short-term low-level BD exposure is mutagenic in the mouse.
Meng
Q
Q
Wadsworth Center for Laboratories and Research, New York State Department of Health, P.O. Box 509, Empire State Plaza, Albany, NY 12201-0509, USA.
Henderson
R F
RF
Long
L
L
Blair
L
L
Walker
D M
DM
Upton
P B
PB
Swenberg
J A
JA
Walker
V E
VE
D000280:Administration, Inhalation; D000818:Animals; D002070:Butadienes / Q000008:administration & dosage / Q000633:toxicity*; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D005260:Female; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D008175:Lung Neoplasms / Q000139:chemically induced; D051379:Mice; D009152:Mutagenicity Tests; D009153:Mutagens / Q000008:administration & dosage / Q000633:toxicity*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology
D002070:Butadienes; D002273:Carcinogens; D009153:Mutagens; D007041:Hypoxanthine Phosphoribosyltransferase; C031763:1,3-butadiene