Inhalation exposure or body burden? Better way of estimating risk – An application of PBPK model

• Inhalation exposure to benzene was determined for groups with varying exposure.
• Body burden of benzene in human subject has been estimated from urinary t,t-MA.
• Physiologically based pharmacokinetic (PBPK) model was used as a tool.
• Body burden of benzene has a non-linear relationship with its level of exposure.
• Body burden is a key parameter of carcinogenic risk assessment.

We aim to establish a new way for estimating the risk from internal dose or body burden due to exposure of benzene in human subject utilizing physiologically based pharmacokinetic (PBPK) model. We also intend to verify its applicability on human subjects exposed to different levels of benzene. We estimated personal inhalation exposure of benzene for two occupational groups namely petrol pump workers and car drivers with respect to a control group, only environmentally exposed.Benzene in personal air was pre-concentrated on charcoal followed by chemical desorption and analysis by gas chromatography equipped with flame ionization detector (GC-FID). We selected urinary trans,trans-muconic acid (t,t-MA) as biomarker of benzene exposure and measured its concentration using solid phase extraction followed by high performance liquid chromatography (HPLC).Our estimated inhalation exposure of benzene was 137.5, 97.9 and 38.7 μg/m3 for petrol pump workers, car drivers and environmentally exposed control groups respectively which resulted in urinary t,t-MA levels of 145.4 ± 55.3, 112.6 ± 63.5 and 60.0 ± 34.9 μg g−1 of creatinine, for the groups in the same order.We deduced a derivation for estimation of body burden from urinary metabolite concentration using PBPK model. Estimation of the internal dose or body burden of benzene in human subject has been made for the first time by the measurement of t,t-MA as a urinary metabolite using physiologically based pharmacokinetic (PBPK) model as a tool. The weight adjusted total body burden of benzene was estimated to be 17.6, 11.1 and 5.0 μg kg−1 of body weight for petrol pump workers, drivers and the environmentally exposed control group, respectively using this method. We computed the carcinogenic risk using both the estimated internal benzene body burden and external exposure values using conventional method. Our study result shows that internal dose or body burden is not proportional to level of exposure rather have a non-linear relationship. At a higher exposure level such as for occupational exposure of petrol pump workers and drivers, the conventionally estimated risk is higher than risk estimated from internal body burden. Likewise, for environmental exposure the conventional risk estimation predict lower level than estimated in our study. This emphasizes the importance of body burden and to consider it as a key parameter while estimating health risk at varying level of exposure.

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