Demethylation pathways in caffeine metabolism as indicators of variability in 1,1,1-trichloroethane oxidation in man

Twenty volunteers were exposed to 191 +/- 7 p.p.m. 1,1,1-trichloroethane or 50 +/- 2 p.p.m. perchloroethylene vapour for 6 hr. They were then evaluated for their rate of caffeine metabolism, mephenytoin hydroxylation and debrisoquine hydroxylation. Seven subjects were identified as 'fast acetylators' of caffeine and one person as a slow metabolizer of debrisoquine. The "slow acetylators" exposed to perchloroethylene excreted an average of 3.83 +/- 0.35 mg trichloroacetic acid within 24 hr (N = 13, +/- S.E.) and the 'fast acetylators' 3.58 +/- 0.48 mg (N = 7, +/- S.E.). The excretion of trichloroethanol by the same persons after 1,1,1-trichloroethane exposure was 14.1 +/- 1.12 mg and 16.7 +/- 1.48 mg, respectively. The excretion of trichloroacetic acid in the latter exposure varied significantly between the seven 'fast' and 13 'slow acetylators' (0.43 +/- 0.08 mg versus 1.03 +/- 0.19 mg; +/- S.E.; P = 0.037). A multiple linear regression analysis confirmed this association when other factors, such as body weight, creatinine clearance, smoking habit and alcohol consumption, were taken into account. One volunteer proved to be a poor hydroxylator of debrisoquine and excreted half the amount of trichloroacetic acid in the perchloroethylene exposure and half the amount of trichloroethanol in the 1,1,1-trichloroethane exposure compared to the others. A reduction in the solvent metabolism could thus be predicted by the debrisoquine test. On the other hand, the caffeine test predicted faster oxidation of trichloroethanol which could be of toxicological and pharmacological importance e.g. in the clinical use of chloral.