Effect of methyl substitution of benzene on the percutaneous absorption and skin irritation in hairless rats

The permeation rate and skin retention of benzene and methylbenzenes were assessed in vitro using hairless rat skin. The effects of unocclusive dermal exposures of these chemicals (15 μl every 2 h for 8 h a day for 4 days) on the transepidermal water loss (TEWL), erythema and skin histopathology were measured in CD hairless rats. The expression of IL-1α and TNF-α in the skin and blood were measured at the end of dermal exposures. The flux of benzene was about 1.5-, 2.5- and 80-fold higher than toluene, xylene and tetramethyl benzene isomers (TMB), respectively, and the values were inversely correlated with molecular weight ( r 2 = 0.7455) and log octanol–water partition coefficient ( r 2 = 0.7831). The retention of chemicals in stratum corneum (SC) was in the order of TMB > xylene > toluene ≈ benzene. The TEWL and erythema data demonstrated that the irritation was in the following order: TMB > xylene > benzene. The histo-pathological examination showed that xylene and TMB induced granulocyte infiltration, swelling of the epidermis, and extensive disruption and damage of stratum corneum. Likewise, the expression of IL-1α in the blood and TNF-α in the skin after dermal exposures was higher for TMB followed by xylene and benzene compared to control. In conclusion, the aromatic hydrocarbon chemicals induced cumulative irritation upon low-level repeat exposures for a 4-day period and the irritation increased with the number of methyl groups of benzene. The affinity of the chemical to SC and their gradual accumulation in the skin in the present study is the reason for the differences in the skin irritation profiles of different aromatic chemicals. Our ultimate goal is to develop a biologically based model that connects skin retention of chemical to the skin irritation response. The findings of the present study will be helpful in understanding the role of these chemicals in the jet fuel and various petroleum based fuels in inducing skin irritation response.