Comparative estimation of the neurotoxic risks of n-hexane and n- heptane in rats and humans based on the formation of the metabolites 2,5- hexanedione and 2,5-heptanedione

Abstract

In rats and humans, inhalation kinetics of n-hexane (HEX) and n-heptane (HEP) were compared with urinary excretion of 2,5-hexanedione (HDO) and 2,5- heptanedione (HPDO), respectively. Furthermore, the reactivities of HDO and HPDO with Nα-acetyl-L-lysine towards the formation of pyrrolyc adducts was studied. By means of the data gained, the potency of HEP for inducing peripheral neuropathy is compared with the well known one of HEX. In rats, kinetic analysis revealed two different metabolic processes for HEX and HEP, one process characterized by high affinity and low capacity (maximal rate of metabolism Vmax1: HEX 84, HEP 112 μmol/h/kg) and one by low affinity and high capacity (Vmax2: HEX 456 μmol/h/kg). For HEP, Vmax2 cannot be given, since the deviation from linearity of the curve representing the rate of metabolism versus the exposure concentration was too small within the concentration range studied of up to 10000 ppm. Urinary excretion of HDO resulting from exposure to HEX correlated with the first process, whereas the corresponding excretion of HPDO as a metabolite of HEP correlated with the second process. In humans, rates of metabolism of HEX and HEP increased linearly with the exposure concentrations up to the tested values of 300 ppm (HEX) and 500 ppm (HEP), the pulmonary retention at steady state being 23% (HEX) and 35% (HEP) at rest. Of totally metabolized HEX during and after HEX exposure to 300 ppm, about 0.5% was excreted as HDO in urine. Of totally metabolized HEP during and after HEP exposure up to 500 ppm, only about 0.01% was excreted as HPDO in urine. Background excretion of HPDO was found in urine of rats and of both γ-diketones in urine of humans; the sources are still unknown. In rats, urinary excretion of HPDO resulting from exposure to 500 ppm HEP was about 7 times less and in humans about 4 times less than that of HDO resulting from exposure to 50 ppm HEX over the same time span. In vitro, the rate of pyrrole formation from the reaction of HPDO with Nα- acetyl-L-lysine was about half that obtained with HDO. This indicates a lower neurotoxic potency of HPDO. From our findings it becomes intelligible that HEP was not neurotoxic in rats in contrast to HEX. Furthermore, for humans we also conclude the neurotoxic potency of HEP to be significantly lower than that of HEX.