Developmental Toxicity of Prenatal Exposure to Toluene

Abstract

Organic solvents have become ubiquitous in our environment and are essential for industry. Many women of reproductive age are increasingly exposed to solvents such as toluene in occupational settings (ie, long-term, lowconcentration exposures) or through inhalant abuse (eg, episodic, binge exposures to high concentrations). The risk for teratogenic outcome is much less with low to moderate occupational solvent exposure compared with the greater potential for adverse pregnancy outcomes, developmental delays, and neurobehavioral problems in children born to women exposed to high concentrations of abused organic solvents such as toluene, 1,1,1-trichloroethane, xylenes, and nitrous oxide. Yet the teratogenic effects of abuse patterns of exposure to toluene and other inhalants remain understudied. We briefl y review how animal models can aid substantially in clarifying the developmental risk of exposure to solvents for adverse biobehavioral outcomes following abuse patterns of use and in the absence of associated health problems and co-drug abuse (eg, alcohol). Our studies also begin to establish the importance of dose (concentration) and critical perinatal periods of exposure to specifi c outcomes. The present results with our clinically relevant animal model of repeated, brief, high-concentration binge prenatal toluene exposure demonstrate the dose-dependent effect of toluene on prenatal development, early postnatal maturation, spontaneous exploration, and amphetamine-induced locomotor activity. The results imply that abuse patterns of toluene exposure may be more deleterious than typical occupational exposure on fetal development and suggest that animal models are effective in studying the mechanisms and risk factors of organic solvent teratogenicity.

Maternal and fetal blood and organ toluene levels in rats following acute and repeated binge inhalation exposure☆

“…The results also indicate that toluene concentrates in certain compartments, including maternal liver and brain, placenta, and fetal brain, at levels substantially higher than the apparent asymptotic level in maternal blood. These very high maternal solvent exposures typical of abuse can lead to perinatal death [3], morphological teratogenicity (e.g., [7]), prematurity and/or growth restriction, microcephaly, digital and/or facial dysmorphology, and the possibility of long-term detrimental outcomes [3,49,[59][60][61]. Using this same pattern of exposure in our preclinical model, we have shown that prenatal toluene exposure delays postnatal development, restricts growth, and increases likelihood of morphological and neurobehavioral teratogenic outcome [5,8].…”

“…In humans, exposure to high concentrations of toluene can have numerous deleterious effects including cerebellar damage [18,19,41,42], wide-ranging neuronal atrophy, and white matter abnormalities [35,41,46,48,51,63] as well as neurological syndromes such as ataxia, myopathy, peripheral neuropathy, convulsions, and encephalopathy [17,19,29,36,42]. Children who have been exposed to toluene in utero may also suffer from deficits in later development [7,32]. Toluene is lipid soluble, freely crosses the placenta [20,60], and clinical cases of toluene-related embryopathy and malformations are evident in women who have abused toluene during their pregnancies [3,21,27,28,49,59,60].…”

Reproductive Toxicology and Teratology of Abused Toluene

“…However, the patterns of incidental exposure under these occupational circumstances (i.e., relatively constant, low-level exposures) in typically wellregulated workplaces reduce that risk. In contrast, the repeated intentional inhalation of very high concentrations of toluene in binge patterns of exposure typical of solvent abuse-exposures that rapidly yield high peak blood toluene concentrations -may present a relatively greater risk [Bowen and Hannigan 2006]. However, that remains to be determined.…”

“…This current review elaborates a previous review of basic research on toluene abuse exposure during early development [Bowen and Hannigan 2006]. The prior brief review compared various animal models of prenatal toluene exposure, focusing primarily on behavioral outcomes, whereas the current, more extensive review emphasizes clinical studies, addresses a wider range of outcomes, and shows how our understanding of those outcomes is aided by the research in animal models of binge inhalation exposure.…”

Decreased sensitivity in adolescent vs. adult rats to the locomotor activating effects of toluene

“…While the effects of toluene have been investigated in younger animals, the majority of these studies have focused on gestational exposure followed by later assessment of toluene's effects in pre-weanling and older animals [see review [6]]. For example, results from our laboratory and others have shown that repeated, brief, high-concentration binge maternal toluene exposure adversely impacts prenatal development and early postnatal maturation of pups (PN22-PN63), as well as their spontaneous exploration and amphetamineinduced locomotor activity [6], [7], [22,27]. These results suggest that exposure to high concentrations of toluene during early development may be more deleterious than exposure during adulthood.…”