METODOLOGÍA, RESULTADOS Y DISCUSIÓN DE RESULTADOS

Toxicity

In humans, approximately 70% of inhaled styrene is absorbed [6]. Styrene is distributed throughout the body, with the highest concentration generally found in adipose tissue [1]. Metabolism of styrene occurs primarily in the liver via the styrene 7,8-oxide pathway. It is then excreted in the urine as mandelic and phenylglyoxylic acids [88]. After inhalation exposure, styrene can be metabolized in the lungs and nose,

resulting in toxicity and, less commonly, carcinogenicity [89]. Styrene metabolism is concentration-dependent, with metabolic saturation occurring at 140–280 ppm in humans [90].

The health effects of styrene have been studied primarily in experimental animal studies and occupational human studies. Occupational exposure to styrene has been associated, albeit inconsistently, with a variety of acute health effects. Irritation of the eyes, throat, and respiratory tract, and contact dermatitis [91] have been reported, but not replicated [1]. Respiratory conditions, including chronic bronchitis [92] and asthma [93, 94], and hematological changes [95] have been demonstrated in highly exposed styrene workers. Occupational styrene exposure is inconsistently associated with altered liver function and elevated serum bile concentrations [6, 96, 97]. In animal

studies, styrene exposure causes liver and lung toxicity in mice and nasal toxicity in rats and mice [71].

Based on limited evidence in humans and experimental animals for the carcinogenity of styrene, the International Agency for Research on Cancer (IARC)

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classifies it as possibly carcinogenic to humans (Group 2B) [6]. Data from both

laboratory and human occupational studies demonstrate that styrene exposure leads to formation of DNA adducts, DNA damage, and cytogenic effects [68, 70, 71, 98]. In styrene-exposed workers, levels of DNA adducts are up to five times higher than those in non-exposed controls [98].

Though styrene’s carcinogenic and genotoxic properties have been well

characterized [6], the Agency for Toxic Substances and Disease Registry (ATSDR) has identified the central nervous system as the primary target for styrene toxicity, with less marked effects in the peripheral nervous system [2, 99].

Neurotoxicity

Styrene monomer functions like many other VOCs, depressing the central nervous system and exhibiting anesthesia-like properties [6, 100]. Solvent-induced neurotoxicity, including that caused by styrene, produces symptoms of acute intoxication, commonly described as a feeling of drunkenness. Short-term acute intoxication is reversible, ceasing when styrene is cleared from the body. More concerning for overall health are the potential chronic, subtle but demonstrative, and irreversible effects that persist after styrene is cleared from the body [101]. It is not clear whether irreversible neurotoxic effects of styrene occur, and at what exposure levels.

Occupational studies demonstrate styrene-induced neurotoxicity, evident as central and peripheral nervous system effects, from both acute and chronic inhaled exposure among highly-exposed workers. Symptoms of neurotoxicity, including feeling “drunk” and tiredness [41], impaired vision [99, 102], vestibular dysfunction [12],

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headaches [103], delayed reaction time [104, 105], impaired attention and memory [9], hearing deficits [106], diminished nerve conduction velocity [9, 107-110], and abnormal EEG results [110, 111]. Dopaminergic [41, 112-114], functional [115, 116], and

psychiatric anomalies [103, 117] have also been associated with high occupational exposure (approximately 100 ppm) to styrene. Similar effects have been observed at lower occupational exposure levels, ranging from 10-30 ppm, in most [10, 99, 103-105, 114, 117-119], though not all [13, 120], studies. Increased mortality from diseases of the central nervous system, especially epilepsy, was associated with styrene exposure in a cohort study of reinforced-plastics industry workers [121].

Recent environmental studies evaluating effects of simultaneous exposure to multiple hazardous air pollutants have documented associations between environmental styrene and neurologic outcomes. When evaluating modeled ambient exposure

estimates for a variety of HAPs, styrene was associated with increased risk of autism spectrum disorder [122, 123] and amyotrophic lateral sclerosis [124]. A cross-sectional analysis of blood VOCs and neurobehavioral testing in NHANES III found a general lack of significant adverse effects, with the exception that a mixture of BTEX and styrene was modestly associated with slower reaction time [125]. These results suggest that styrene may impact neurologic function at environmental levels relevant to the general population, implicating low-level, chronic styrene exposure as a possible public health problem. The human health effects due to chronic styrene exposure at typical

environmental levels among the general population remain largely unknown – due in part to uncertainty regarding the magnitude of these levels and their underlying sources across populations [20]. Examining neurologic symptoms can reveal subclinical

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impairments in neurologic function that appear earlier in the progression of disease. While less severe, these symptoms may be more sensitive to lower exposure levels, more prevalent in the general population, and possibly persist after exposure recedes.

Mechanism

Studies in humans and experimental in vitro and in vivo animal models have attempted to determine the mode of action for styrene neurotoxicity, with a

dopaminergic mechanism gaining traction [71], but explanations remain speculative. Several studies suggest that styrene exposure alters dopamine metabolism, marked by decreased dopamine levels and increased dopamine receptors in rodents and humans [126-128]. The styrene metabolites phenylglyoxylic acid and mandelic acid were shown to deplete dopamine [129]. This mechanism is corroborated in blood samples of

styrene-exposed plastics workers for whom prolactin levels are elevated, as prolactin release from the anterior pituitary gland is chronically inhibited by dopamine [130]. The change in prolactin may signal diminished inhibition of prolactin release by dopamine, whether through lower dopamine levels or weakened inhibitory action [127]. A dose- dependent decrease in monoamine oxidase B was also observed in rats and workers exposed to styrene [41, 112].

Consistent with disturbance of the dopaminergic functions of the brain, styrene exposure potentiates a dose-dependent decrease in brain dopamine and an increase in homovanillic acid in male rats [128]. A decrease in dopamine and its metabolites in the corpus striatum, hypothalamus, and the lateral olfactory tract regions of the brain was observed in rats that were highly exposed to styrene [131]. Loss of motor function,

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lasting for approximately a month, accompanied these changes in dopamine. This physiological manifestation supports the hypothesis that dopamine mediates styrene exposure to impact neurologic function. Styrene also caused cell loss and dopamine depletion in retinas isolated from female rats [132], which supports the established association between occupational styrene exposure and impaired color vision [133].