Teratogen update: toluene

Extrapolating from animal data, at the level at which well-controlled occupational exposure to toluene vapor is encountered, in utero exposure does not pose a significant fetal risk. However, following chronic and excessive industrial accidents or intentional abuse, toluene exposure several orders of magnitude greater exists, and at these levels in utero exposures in both animals and humans have been shown to produce significant delays in fetal growth. At these greater exposure levels, both dose and gestational timing relationships can be demonstrated in animal models. Of note, in both animals and humans, postnatal persistence of growth deficiency has been observed. A pattern of teratogenicity similar to that of the fetal alcohol syndrome is prevalent in all human studies of excessive in utero exposure to toluene. In humans, the effects of in utero toluene exposure among intentional abusers is confounded by such variables as general health and exposure to other teratogens. Chronic toluene abuse produces a renal tubular acidosis with maternal hypokalemia and profoundly lowered serum pH. Further evaluation of greater numbers of infants with respect to maternal renal tubular acidosis will be needed to fully assess the contribution of chronic acidosis. The contribution of maternal acidosis to fetal teratogenicity remains speculative. Coabuse of additional agents, in particular alcohol, may increase the teratogenic risks. The overlap of features following in utero toluene abuse with those of fetal alcohol syndrome suggests a possible common pathway of craniofacial teratogenesis. Lastly, genetic variations that result in deficiency of ALDH2, an enzyme involved in toluene metabolism, may increase the risks of toluene teratogenicity in at-risk individuals at lower levels of exposure. Prospective studies of toluene-exposed pregnancies would provide more information on the fetal effects at these levels.