Conditioned flavor aversion induced by inhaled p-xylene in rats

Xylenes have the potential for widespread public exposure, yet their neurotoxic properties are poorly understood. The conditioned flavor aversion (CFA) paradigm provides a sensitive behavioral assay for the aversiveness of many drugs and toxic chemicals. Male Long-Evans rats were placed on a restricted water schedule (30 min/day) 1 week after arrival in the laboratory at 40 days of age. Ten days later, all rats received 0.1% saccharin in place of water, and then were exposed immediately either to filtered air or to 50, 100, 200, 400, 800 or 1,600 ppm p-xylene for 4 hr, or to air or 400 ppm p-xylene for 0.5, 1, 2, 4 or 8 hr. The restricted water schedule remained in effect for the next 72 hr, at which time the rats were given a choice between saccharin and water. Inhalation of all concentrations of p-xylene reduced relative saccharin intake, with maximal aversion at 800 and 1,600 ppm. The aversion produced by 400 ppm p-xylene was maximal at exposures of 2 or more hr, with shorter exposures producing intermediate effects. Total fluid intake was unaffected by p-xylene exposure with the exception of a slight (nonsignificant) decrease in consumption following 1,600 ppm. Exposure to saccharin 24 hr prior to p-xylene produce no aversion, indicating that the reduction in saccharin intake required close temporal pairing of saccharin and p-xylene. Thus inhaled p-xylene at a concentration of 1/2 its TLV (= 100 ppm) caused a significant, learned change in rats' normal consumption of saccharin-flavored water, without disrupting total fluid consumption.