No-observed-adverse-effect level of hair pyrrole adducts in chronic n-hexane intoxication in rats

Abstract

n-Hexane has been reported to induce serious peripheral neuropathy in workers. Pyrrole adducts are the unique reaction products of n-hexane in organisms and have been demonstrated to be critical to n-hexane neuropathy. Our previous studies have demonstrated that pyrrole adducts could accumulate in hair and showed high correlation with neuropathy at the end of experiments in rat models. In the present study, we examined the time course of hair pyrrole adducts and behavioral changes in rats exposed to different dosages of n-hexane in both treatment (24 weeks) and recovery phases. Our results showed: 1. After treatment, 1.0, 2.0, and 4.0 g/kg dosage groups all lost weight, but the 0.5 g/kg dosage group showed no impairment; after recovery, all impaired rats regained weight. 2. After treatment, 1.0, 2.0, and 4.0 g/kg dosage groups all showed a rise in gait scores, decreased rotarod latency, and decreased motor nerve conduction velocity, whereas the 0.5 g/kg dosage group showed no impairment; after recovery, all impaired rats were completely rehabilitated. 3. After treatment, levels of pyrrole adducts in serum, urine, and hair of experimental groups increased; after recovery, serum and urine pyrrole adducts showed no difference from the control (P > 0.05), whereas hair pyrrole adducts were significantly different from the control (P < 0.01). 4. The half-lives of serum and urine pyrrole adducts were 47.8-78.0 h and 42.7-52.9 h, while the half-life of hair pyrrole adducts was 14-24 weeks. 5. During treatment and recovery, levels of serum, urine, and hair pyrrole adducts showed high correlation with gait scores (P < 0.01), and hair pyrrole adducts had the largest partial correlation coefficient. In conclusion, hair pyrrole adducts could serve as a stable and reliable biomarker for the prevention of n-hexane intoxication. Furthermore, the no-observed-adverse-effect level of hair pyrrole adducts in rats is 275.2 ± 61.5 nmol/g protein. Further studies are required for the definition of the biological exposure limit in humans.

Keywords: 2,5-Hexanedione; Intoxication; Neuropathy; No-observed-adverse-effect level; Pyrrole adduct; n-Hexane.