The common indoor air pollutant α-pinene is metabolised to a genotoxic metabolite α-pinene oxide

1. alpha-Pinene caused a concentration-responsive increase in bladder hyperplasia and decrease in sperm counts in rodents following inhalation exposure. Additionally, it formed a prospective reactive metabolite, alpha-pinene oxide. 2. To provide human relevant context for data generated in animal models and explore potential mechanism, we undertook studies to investigate the metabolism of alpha-pinene to alpha-pinene oxide and mutagenicity of alpha-pinene and alpha-pinene oxide. 3. alpha-Pinene oxide was formed in rat and human microsomes and hepatocytes with some species differences. Based on area under the concentration versus time curves, the formation of alpha-pinene oxide was up to 4-fold higher in rats than in humans. 4. While rat microsomes cleared alpha-pinene oxide faster than human microsomes, the clearance of alpha-pinene oxide in hepatocytes was similar between species. 5. alpha-Pinene was not mutagenic with or without induced rat liver S9 in Salmonella typhimurium or Escherichia coli when tested up to 10000 mu g/plate while alpha-pinene oxide was mutagenic at >= 25 mu g/plate. 6. alpha-Pinene was metabolised to alpha-pinene oxide under the conditions of the bacterial mutation assay although the concentration was approximately 3-fold lower than the lowest alpha-pinene oxide concentration that was positive in the assay, potentially explaining the lack of mutagenicity observed with alpha-pinene.

Automated summary

alpha-Pinene exposure through inhalation caused an increase in bladder hyperplasia and a decrease in sperm counts in rodents. It also formed a reactive metabolite called alpha-pinene oxide. By investigating the metabolism of alpha-pinene to alpha-pinene oxide and the mutagenicity of both substances, it was found that alpha-pinene oxide was formed in both rat and human cells with some species differences. Although the rat microsomes cleared alpha-pinene oxide faster than human microsomes, the clearance of alpha-pinene oxide in hepatocytes was similar between species. While alpha-pinene was not mutagenic, alpha-pinene oxide showed mutagenicity.