Teratogen Update: Toluene

Toluene (methylbenzene) is an aromatic hydrocarbon widely used as an organic solvent in both industrial settings and common household products such as gasoline, glue and paint. (U.S. Public Health Service, ’89; Verschueren, ’77). Inhalation of air-borne toluene as a vapor is the most common route of human exposure. Approximately 80% of an initial inhaled dose is absorbed with decreasing absorption following continued exposure (Low et al., ’88). A small amount of toluene is expired unchanged while most is metabolized by the liver (American College of Toxicology, ’87; Low et al., ’88). While other routes of exposure, such as ingestion following hazardous waste contamination, are possible, their relative contribution to the total load of toluene exposure is minimal (American College of Toxicology, ’87; U.S. Environmental ProtectionAgency, ’88). Air-borne exposure to toluene vapor represents a significant concern to both industrial workers and consumers. Workers in the production andmanufacturing of various industrial chemicals including benzene, toluene diisocyanate, phenol, benzyl, benzoic acid, toluene sulfates, nitrotoluenes, saccharin, and styrene face risks from chronic low-level exposure as well as industrial accidents. Current standards for a permissible exposure limit (PEL) for toluene have been established by U.S. Occupational Safety and Health Administration (OSHA) at 100 ppm (375 mg/mm3), calculated as a time weighted average over an 8-hour day (Donald et al., ’91). Inadvertent, low-level consumer exposure occurs daily through household use of gasoline, glues, rubber cement, stain removers, paint thinners, fabric dyes, inks, and cigarette smoke (U.S. Public Health Service, ’89). Intentional toluene vapor exposure, known as ‘‘sniffing’’ or ‘‘huffing,’’ remains a popular form of substance abuse. A sense of euphoria is generally achieved with exposures of at least 500 ppm, five times the OSHA Permissable Exposure Level (PEL). At 600–800 ppm, confusion, auditory and visual hallucinations, inhibition, and incoordination occur (Brozosky and Winkler, ’65). In chronic abusers, levels of toluene exposure often reach 5,000 ppm, 50 times the OHSAPEL (Ron, ’86). As a drug of abuse, inhalation of toluene through the sniffing of gasoline, glue, and spray paints has been reported since the 1950s. The popularity of toluene abuse has been governed by its relative ease of accessibility, low cost, and misperceived lack of addictive qualities. In chronic abusers, both irreversible neurologic toxicity and reversible renal damage have been noted. Deaths have been attributed to long-standing CNS and/or renal damage as well as to acute suffocation during inhalation. In the late 1980s, toluene abuse was a problem primarily among teenagers and young adults with 20% of recent high school students from various socioeconomic backgrounds acknowledging vapor abuse at least once (National Survey, ’91). Data from the early 1980s documented occasional use in 10% and regular abuse in 4% of adolescents surveyed (Lowenstein, ’85). Regarding potential teratogenicity, as a lipid soluble compound, toluene readily crosses the placenta and has been recovered from various fetal tissues, amniotic fluid, and human neonates following documented in utero exposure (Goodwin, ’88). In animals, approximately 10% of an inhaled dose rapidly crosses the placenta with organ distribution being gestational age dependent. Persistence of toluene in the fetal animal compartment can be documented for at least 24 hours. In mice, a greater accumulation in the liver with advancing gestational age has been reported (Ghantous and Danielsson, ’86). In utero toluene exposure thus poses theoretical risks for both organ specific teratogenicity and overall fetotoxicity. To fully assess the impact of toluene exposure on the fetus, animal exposure studies (Donald et al., ’91), available human studies, and a discussion of the confounders are considered in this review. The teratogenic effects of in utero toluene exposure may be influenced by maternal metabolic acidosis secondary to toluene-induced renal damage, the biologic variation in the metabolism of toluene, and the impact of concomitant drugs of abuse, particularly alcohol.