β-
Chloroprene (2-chloro-1,3-butadiene), a monomer used in the production of
neoprene elastomers, is of regulatory interest due to the production of multiorgan
tumors in mouse and rat
cancer bioassays. A significant increase in female mouse lung
tumors was observed at the lowest exposure concentration of 12.8 ppm, whereas a small, but not statistically significant increase was observed in female rats only at the highest exposure concentration of 80 ppm. The metabolism of
chloroprene results in the generation of reactive
epoxides, and the rate of overall
chloroprene metabolism is highly species dependent. To identify potential key events in the mode of action of
chloroprene lung
tumorigenesis, dose-response and time-course gene expression microarray measurements were made in the lungs of female mice and female rats. The gene expression changes were analyzed using both a traditional ANOVA approach followed by pathway enrichment analysis and a pathway-based benchmark dose (BMD) analysis approach. Pathways related to
glutathione biosynthesis and metabolism were the primary pathways consistent with cross-species differences in
tumor incidence. Transcriptional BMD values for the pathway were more similar to differences in
tumor response than were estimated target tissue dose surrogates based on the total amount of
chloroprene metabolized per unit mass of lung tissue per day. The closer correspondence of the transcriptional changes with the
tumor response is likely due to their reflection of the overall balance between metabolic activation and detoxication reactions, whereas the current tissue dose surrogate reflects only oxidative metabolism.