Styrene is an organic compound commonly utilized as a solvent and cross-linking agent in the manufacture of plastic products. As such, the chemical can be found in disposable containers, insulation materials, automobile parts, and even some artificial flavoring products. In the US, industrial production of styrene has increased steadily in recent decades, more than doubling between 1977 and 2010.
Concomitant with this rise in production, there was a surge in observational human studies investigating the neurotoxic properties of styrene—particularly among styrene workers, who are exposed to concentrations >1000 times higher than those typically found in the environment (<5 parts per billion (ppb) in outdoor air and <12 ppb in indoor air). A large portion of these studies examined the effects on vision—a sensitive early marker of neurotoxicity—using the D-15d panel. The D-15d is an arrangement test used to calculate an individual’s Color Confusion Index (CCI), the main measure of solvent-induced dyschromatopsia. In sum, the relevant studies seemed to suggest that prolonged occupational exposure to styrene results in acquired dyschromatopsia, or color vision loss.
Before 2017, there were only two systematic reviews/meta-analyses on the topic of styrene-induced dyschromatopsia. Notably, they excluded studies from the past decade and presented conflicting results. One review team (first author Vernon Benignus) affirmed the suspected exposure-outcome relationship, while the other (first author Galina Paramei) was somewhat irresolute, citing significant statistical heterogeneity between studies.
To provide clarity on this putative relationship, we systematically reviewed all published studies of occupational styrene-induced dyschromatopsia. Three electronic literature databases were queried for relevant literature: PubMed, EMBASE, and Web of Science. We included only those studies that reported a direct measurement of styrene exposure (either biological or airborne), denied significant co-exposure to chemicals other than styrene, and were available in the English language. No restrictions were imposed with respect to study design for full coverage of the literature. From eligible studies, we performed a comprehensive data extraction of both quantitative and qualitative/descriptive variables.
Our systematic review synthesized fifteen studies (1949 total participants), published between 1991 and 2015: eight cross-sectional studies, six cohort studies, and one case report. Only four studies specified a minimum duration of employment (i.e., exposure) for inclusion, but styrene-exposed workers—often employed in the reinforced plastics industry—demonstrated long tenures of employment nonetheless; across studies, the lowest mean or median tenure was 4.5 years. Of the thirteen studies that measured airborne styrene exposure, eleven reported mean or median values of 25 parts per million (ppm) or lower. It is worth noting that many regulatory agencies advise an exposure threshold around or above this level. In fact, current Occupational and Safety Health Administration (OSHA) guidelines indicate a threshold limit value time-weighted average (TLV-TWA) of 100 ppm over 8 hours—appreciably higher than any mean measurement in our review.
With only one exception, studies administered the D-15d panel for measurement of dyschromatopsia. All but one study presented findings supporting the hypothesis of occupational styrene-induced dyschromatopsia, and all but two—one of these being a two-subject case report—described statistically significant findings, most often in the form of a higher mean CCI in the exposed group.
From a subset of identified studies—specifically, those that compared CCI measures between exposed and non-exposed workers—we also estimated, via meta-analysis, the styrene-induced effect. Assuming cross-study heterogeneity, we employed a random effects model and calculated the standardized mean difference (Hedges’ g). We also conducted assessments of between-study heterogeneity (using the I2 statistic, Cochran’s Q, and DerSimonian-Laird estimator for τ2) and publication bias (using funnel plot assessment and the nonparametric trim-and-fill method). In contrast to previous review groups, we addressed the mean-variance relationship by performing a variance-stabilizing, natural log-scale transformation of the mean CCI.
Among the fifteen studies in our review, eight qualified for meta-analysis. Our quantitative synthesis demonstrated significantly greater dyschromatopsia among exposed workers relative to their non-exposed counterparts, with a Hedges’ g of 0.56 (interpreted as a medium-size effect). We found low-to-moderate heterogeneity between studies, along with evidence of mild publication bias (possible under-publication of smaller studies with negative results) from funnel plot and trim-and-fill analyses.
In conclusion, both qualitative and quantitative syntheses of the evidence supported the putative relationship between prolonged occupational styrene exposure and color vision loss. There remain several open questions, however. All cases of dyschromatopsia in our review were described as “subclinical,” suggesting subtle manifestations of color vision loss. Even so, the functional significance of acquired dyschromatopsia—let alone styrene-induced dyschromatopsia—remains unclear and understudied. (In contrast, the clinical impact of congenital dyschromatopsia, with regard to instrumental activities of daily living (IADLs), is well characterized.) It is worth noting that acquired dyschromatopsia is uniquely mutable. We cannot rule out—without further longitudinal study—the possibility of developing clinically significant dyschromatopsia as a result of long-term (or elevated) styrene exposure.
Considering that many agency-prescribed w0rkplace limits exceed the exposure levels in our review, experimental study of current work practices (e.g., use of personal protective equipment) and conditions (e.g., ventilation systems) in the reinforced plastics industry is warranted. In fact, further investigation is needed more generally. With 15 available studies (from just eight independent research groups), our interpretation of the evidence is inherently limited by a small study pool. Slight statistical and methodological between-study heterogeneity only compound this issue, as do common methodological shortcomings across studies (such as the lack of blinding in ten out of fifteen studies). Despite these limitations, we believe that this joint review and meta-analysis—highlighting the current state of research—represents an important step forward in our understanding of styrene-induced dyschromatopsia.
This review/meta-analysis, Occupational styrene exposure and acquired dyschromatopsia: A systematic review and meta-analysis, was recently published in the American Journal of Industrial Medicine.