High frequency of codon 61 K-ras A -> T transversions in lung and Harderian gland neoplasms of B6C3F1 mice exposed to chloroprene (2-chloro-1,3-butadiene) for 2 years, and comparisons with the structurally related chemicals isoprene and 1,3-butadiene

Chloroprene is the 2-chloro analog of 1,3-butadiene, a potent carcinogen in laboratory animals. Following 2 years of inhalation exposure to 12.8, 32 o r 80 p.p.m. chloroprene, increased incidences of lung and Harderian gland ( HG) neoplasms were observed in B6C3F1 mice at all exposure concentrations. The present study was designed to characterize genetic alterations in the K - and H-ras protooncogenes in chloroprene-induced lung and HG neoplasms, K- ras mutations were detected in 80% of chloroprene-induced lung neoplasms (3 7/46) compared with only 30% in spontaneous lung neoplasms (25/82), Both K- and H-ras codon 61 A-->T transversions were identified in 100% of HG neopl asms (27/27) compared with a frequency of 56% (15/27) in spontaneous HG neo plasms. The predominant mutation in chloroprene-induced lung and HG neoplas ms was an A-->T transversion at K-ras codon 61, This mutation has not been detected in spontaneous lung tumors of B6C3F1 mice and was identified in on ly 7% of spontaneous HG neoplasms. In lung neoplasms, greater percentages ( 80 and 71%) of A-->T transversions were observed at the lower exposures (12 .8 and 32 p.p.m.), respectively, compared with 18% at the high exposure. In HG neoplasms, the percentage of A-->T transversions was the same at all ex posure concentrations. The chloroprene-induced ras mutation spectra was sim ilar to that seen with isoprene, where the predominant base change was an A -->T transversion at K-ras codon 61, This differed from 1,3-butadiene, wher e K-ras codon 13 G-->C transitions and H-ras codon 61 A-->G transitions wer e the predominant mutations. The major finding of K-ras A-->T transversions in lung and Harderian gland neoplasms suggests that this mutation may be i mportant for tumor induction by this class of carcinogens.