Inter-individual variability of benzene metabolism to trans-trans-muconic acid and its implications in the biological monitoring of occupational exposure

Unmodified benzene (UBz) and trans,trans-muconic acid (t,t-MA) were measured in urine samples collected at the end of the first half-shift in 80 bus drivers from a large city in Northern Italy. Mean UBz was 1155 ng/l (S.D. = 494), range 85-1980 ng/l; these values roughly correspond to 10-1000 micrograms/m3 of benzene in air. Mean t,t-MA was 297 micrograms/g creatinine; the range was large (20-1295 micrograms/g creatinine), and the distribution of values was bimodal. At further analysis of t,t-MA data, two subgroups of 59 and 18 subjects were identified (3 outliers were excluded): mean values of the index were 108 (S.D. = 65) and 916 (S.D. = 264) micrograms/g creatinine respectively, and the values within each subgroup were normally distributed. The mean ratio between t,t-MA and UBz in the subgroups were 0.15 and 0.85, respectively; the difference was significant. The first subgroup was defined as 'poor t,t-MA metabolizers', the other as 'efficient t,t-MA metabolizers'. No inter-subgroup differences were observed regarding the main characteristics (age, dietary and smoking habits, etc.). As the parent compound of t,t-MA, trans,trans-muconaldehyde is myelotoxic, and its production has been implicated in benzene-induced leukemia. 'efficient' t,t-MA metabolizers may be at higher risk of developing benzene toxicity. If confirmed in further studies, the inter-individual variability rate of metabolizing benzene to t,t-MA may introduce some limitations in the application of this metabolite as an exposure index of low benzene exposure. Nevertheless, the t,t-MA/UBz ratio may be an important index of susceptibility to benzene toxicity.