# Low-Dose Benzene Exposure Monitoring of Oil Refinery Workers: Inhalation and Biomarkers
## 1 Introduction  
Benzene is one of the most studied and controlled substances in occupational exposure assessment and in safety handling procedures. Its wide usage as a solvent in the past has led to a variety of workers being exposed. Nowadays, workplace exposures to benzene are strictly regulated and are limited to petrochemical workers, mechanics, firefighters, and a few other jobs. To assess this exposure, in addition to personal air monitoring, biomonitoring may add information, such as sources and pathways of exposure. The toxic effects of benzene are related to its metabolism patterns (Figure 1) [1]. About 10% to 50% of benzene is eliminated from the body by exhaled air, while 0.1% is eliminated unmodified in urine. The remaining amount undergoes hepatic metabolism. Benzene oxidizes to benzene oxide, which mainly rearranges to phenol, which is excreted or metabolized to hydroquinone and 1,4-benzoquinone. The remaining benzene oxide hydrolyzes to catechol and 1,2-benzoquinone, rearranges in oxepine, or reacts with glutathione to form S-phenylmercapapturic acid (SPMA). Oxepin metabolism opens the aromatic ring, yielding reactive muconaldehydes and _t,t_-muconic acid (_t,t_-MA) [2]. The most commonly-used benzene biomarkers for estimating occupational exposure include urinary benzene (U-B) and its urinary metabolites, _t,t_-MA and SPMA. However, international regulatory institutions still do not concur on preferred biomarkers as the basis for Biological Limit Values (BLV). The American Conference of Government Industrial Hygienists (ACGIH) recommends both SPMA and _t,t_-MA end-shift urine sampling, with Biological Exposure Indices (BEIs) of a maximum of 25 and 500 \(\upmu\)g/g creatinine, respectively. Instead, the urinary benzene limit value in the EU is currently under revision. In 2018, a proposal from the Committee for Risk Assessment (RAC) suggested a BLV of 0.7 \(\upmu\)g/L for U-B and of 2 \(\upmu\)g/g creatinine for SPMA in end-shift urine, together with an inhalation occupational exposure limit (OEL) of 0.05 ppm. This suggestion was subsequently followed by an Advisory Committee on Safety and Health at work (ACSH) proposal of an ultimate limit value of 0.2 ppm to be reached four years after the directive's publication, with a transitional OEL of 0.5 ppm in the meantime. Even if a BLV was not specified in the proposal, since BLVs are not currently regulated by the Carcinogens and Mutagens Directive (CMD), ACSH suggested using the BLVs proposed by the RAC when developing guidelines for biomonitoring. BLV aims to watch over and understand occupational exposure in different scenarios. BLVs do not distinguish between hazardous and non-hazardous exposures; an individual's measurements might overcome the BLV without increasing the health risk due to biological variability. However, if specific markers in a worker's samples, sampled on different occasions, repeatedly exceed the BLV, or if most measurements of a group of employers at the same workplace surpass the BLV, the causes must be investigated, and corrective actions have to be taken. BLVs have been identified as those compounds that are most likely to be observed in biological samples collected from workers who are exposed by inhalation of at-risk chemicals. However, dermal route is gaining increasing attention; in 2000, the European Union identified 62 at-risk chemical substances and specified each one's OEL; of these, 25 compounds received a \"skin\" notation to pinpoint that skin exposure to these chemicals  
Figure 1: Excretion pathways of benzene. could lead to toxicologically significant intakes [3]. For such substances, monitoring ambient air concentrations may not be enough, and biological monitoring must be enacted and is necessary due to the different exposure pathways that may occur, such as the dermal route. However, valid and useful biomarkers must be identified and regulated. Concerning the canonical biomarkers of benzene exposure, several studies demonstrate a good correlation of _t,t_-MA and SPMA to airborne benzene concentration [4; 5].