Effects of inhaled combined Benzene, Toluene, Ethylbenzene, and Xylenes (BTEX): Toward an environmental exposure model
Introduction
Volatile Organic Compounds (VOCs) are ubiquitous and practically indispensable in numerous household, commercial, and industrial products with substantial economic importance (Bergman, 1979; Joshi and Adhikari, 2019). VOCs are also common byproducts of fossil fuel combustion (NCEH, 2018). The alkylbenzenes Benzene, Toluene, Ethylbenzene, and Xylene(s) (BTEX; Table 1) in particular are four solvent VOCs used heavily in industry and in the home as chemical intermediates, solvents, fuel additives, and cleaners. BTEX are typically present together at low levels in the air in urban areas, although local concentrations vary considerably depending on geography, season, weather, and proximity to industry, refining and traffic (Huang et al., 2017; McKenzie et al., 2012; Miller et al., 2012; Miri et al., 2016). Given their utility, prevalence and economic importance, BTEX will likely remain persistent environmental contaminants in air for the foreseeable future (Bolden et al., 2015).
Studies of environmental exposure capitalize on demographics and/or epidemiology, as well as geospatial modeling, to assess the impact of air pollution and/or specific pollutants. These studies are important for informing our understanding of the general impact of pollutants, but they are limited in determining the specific impact of individual or mixed BTEX separate from other environmental and population factors (e.g., water pollution, demographics, socioeconomic status, nutrition, etc.; Bolden et al., 2015; Dehghani et al., 2018). Animal models and experimental designs that control or eliminate confounding factors and that systematically manipulate exposures to mimic environmental patterns would aid in understanding the neurobehavioral impact of combined BTEX. Current models mimicking inhalation exposures typical of solvent abuse or occupational settings have demonstrated negative health outcomes following exposure to the individual BTEX components and their binary mixtures, but the whole mixture is under-studied in the laboratory.
BTEX exposures in any community pose a clear risk to public health (Montero-Montoya et al., 2018; Webb et al., 2018). While there is experimental evidence of the deleterious health and neurobehavioral consequences of exposures to the individual components of BTEX, these effects are typically assessed using higher concentrations and exposure patterns that differ from environmental exposure. With much less known about the specific combined effects of BTEX, there is a clear need to examine the effects (and risks) of acute and chronic combined BTEX exposures at typical ambient environmental levels (Billionnet et al., 2012). Here we review relevant research on environmental BTEX exposures in animal models, drawing on findings from models of inhalant abuse and occupational exposures, and focusing on neurobehavioral outcomes. Environmental, occupational and abuse exposures of volatilized BTEX components share the inhalation route of exposure, but differ in the concentrations, durations, and patterns of exposure (Table 2). Even though inhalation of combined BTEX components by people is common with environmental or occupational exposures, there are currently limited animal models of these exposures. The results of research using abuse and occupational models of inhaled VOC exposure will be used to inform an animal model of combined environmental exposure to BTEX.
Section snippets
Environmental burden
VOCs, particularly BTEX, are significant components of air pollution which is the fifth leading risk factor for premature mortality in the world (HEI, 2019). Ninety percent of people worldwide live in areas that exceed the World Health Organization (WHO) standards for air quality, and half of those individuals live in areas not meeting the least stringent standards (HEI, 2019). Environmental BTEX contribute significantly to poor air quality and pose a public health hazard (Bolden et al., 2015;
Chemistry and metabolism
All BTEX components are structural variants of benzene with similar molecular weights and varying in the number and position of attached methyl groups; ethylbenzene has one ethyl group (see Table 1). BTEX, like all VOCs, have high vapor pressures and so distribute (dissipate) readily through air at ambient temperatures. Several excellent reviews detail the absorption, distribution, metabolism and clearance of each individual BTEX component (ATSDR, 2004, 2007a, 2007b, 2010, 2017). BTEX are
Health effects
This section describes health effects in general, based on clinical and epidemiological studies and includes different types of VOC exposure. Section 6, below, on neurobehavioral effects focuses on different models of VOC exposure, mostly in animals.
Abuse models
Most basic research studies of the neurobehavioral effects of BTEX have focused on the individual components. Nearly all of those studies dealt with high levels of toluene, modeling abuse or “glue-sniffing”/“huffing” for its intoxicating effects (Balster et al., 2009; Bowen et al., 2006; Bowen and Cruz, 2014; Cruz et al., 2014; Cruz and Balster, 2013). Inhalant abuse is modeled by episodic exposures to very high concentrations (e.g., toluene 1000 ppm to 30,000 ppm) for relatively brief
Neurobehavioral effects
Studies of VOCs like the components of BTEX have assessed wide-ranging behaviors including activity, motor function, indices of impulsivity and anxiety, learning and memory, and responses to reward. Prior studies largely dealt with single components, usually toluene, and almost exclusively using abuse models of exposure. The relatively few papers reporting these outcomes, and others, in animals using designs that approximate environmental exposures are summarized in Table 3; none use combined
Other behavioral and medical outcomes
The research reviewed above focuses on outcomes associated with exposures to individual components of BTEX although the impact of combined BTEX exposure is largely unknown. The behaviors affected in rodents tend to be relatively simple. However, there are also associations of BTEX exposure with complex developmental neurobehavioral and cognitive disorders, such as attention deficit hyperactivity disorder (ADHD) in epidemiological studies of human populations (e.g., Dellefratte et al., 2019;
Conclusions: demands of an environmental model of BTEX exposure
Sustained environmental exposures to VOCs pose a constant risk to public health. The potential public health risks of environmental levels of combined BTEX exposure, in particular, appear well appreciated (Bolden et al., 2015; Dehghani et al., 2018), although not always well characterized. Our goal here is to describe what is necessary for a useful animal model of environmental exposures to combined VOCs, in particular BTEX. Animal research investigating environmental patterns of exposure to
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgments
This work was supported in part by a grant from the National Institute for Environmental Health Sciences (P30 ES020957), the Betty J. Neitzel Psychology Faculty Research Grant, from the Department of Psychology, Wayne State University.
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