Using exposure prediction tools to link exposure and dosimetry for risk-based decisions: A case study with phthalates

Abstract

A few different exposure prediction tools were evaluated for use in the new in vitro-based safety assessment paradigm using di-2-ethylhexyl phthalate (DEHP) and dibutyl phthalate (DnBP) as case compounds. Daily intake of each phthalate was estimated using both high-throughput (HT) prediction models such as the HT Stochastic Human Exposure and Dose Simulation model (SHEDS-HT) and the ExpoCast heuristic model and non-HT approaches based on chemical specific exposure estimations in the environment in conjunction with human exposure factors. Reverse dosimetry was performed using a published physiologically based pharmacokinetic (PBPK) model for phthalates and their metabolites to provide a comparison point. Daily intakes of DEHP and DnBP were estimated based on the urinary concentrations of their respective monoesters, mono-2-ethylhexyl phthalate (MEHP) and monobutyl phthalate (MnBP), reported in NHANES (2011e2012). The PBPK-reverse dosimetry estimated daily in-takes at the 50th and 95th percentiles were 0.68 and 9.58 μg/kg/d and 0.089 and 0.68 μg/kg/d for DEHP and DnBP, respectively. For DEHP, the estimated median from PBPK-reverse dosimetry was about 3.6-fold higher than the ExpoCast estimate (0.68 and 0.18 mg/kg/d, respectively). For DnBP, the estimated median was similar to that predicted by ExpoCast (0.089 and 0.094 mg/kg/d, respectively). The SHEDS-HT prediction of DnBP intake from consumer product pathways alone was higher at 0.67 mg/kg/d. The PBPK-reverse dosimetry-estimated median intake of DEHP and DnBP was comparable to values previously reported for US populations. These comparisons provide insights into establishing criteria for selecting appropriate exposure prediction tools for use in an integrated modeling platform to link exposure to health effects.

Physiology-based toxicokinetic modelling in the frame of the European Human Biomonitoring Initiative

“…With regard to phthalates, a PBTK model has been developed by Moreau et al (2017) for di-2ethylhexyl phthalate (DEHP) and dibutyl phthalate (DnBP) as case compounds. This modelling effort aimed at providing exposure estimates starting from the NHANES biomonitoring data and compared these estimates with high-throughput HT Stochastic Human Exposure and Dose Simulation model (SHEDS-HT) and the ExpoCast heuristic model and non-HT approaches based on chemical specific exposure estimations in the environment in conjunction with human exposure factors.…”

“…Later, a PBTK model was established as an exposure prediction tool for DEHP and DnBP in humans (Moreau et al, 2017), based on the model of Gentry et al (2011), including the four interconnected sub-models for the diester, the hydrolytic monoester, the oxidative metabolites and the glucorinide conjugate. Diester distributed in the gut wall was passed to the liver via the portal blood, while their monoester metabolites MEHP and MBP were readily absorbed in the gut.…”

Assessing Human Exposure to Chemicals in Materials, Products and Articles: The International Risk Management Landscape for Phthalates

“…With the exception of the IMAP assessment, the various exposure assessments all include exposure estimates derived from both biomonitoring data and scenario-based exposure estimates. These approaches complement each other and can give a relatively complete picture of the exposure situation if the results are combined effectively and with an understanding of the strengths and weaknesses of each approach. , With studies such as the National Health and Nutrition Examination Survey (NHANES), the Canadian Health Measures Survey (CHMS), and the European DEMOCOPHES project providing more information, the trend is to put more emphasis on biomonitoring results. In comparison, scenario-based exposure assessments rely mostly on a similar (though expanding) body of literature and equations, often citing each other in the process.…”

Assessing Human Exposure to SVOCs in Materials, Products, and Articles: A Modular Mechanistic Framework

“…This is especially true for semivolatile organic compounds (SVOCs) due to their multimedia behavior. Unlike volatile organic compounds (VOCs) or most metals, SVOCs partition among multiple indoor compartments, including people, according to their physicochemical properties. ,− As the number of source/chemical combinations increases steadily, traditional assessment approaches are challenged to keep pace given that key emission and exposure parameters have only been measured for very few combinations that do not necessarily span the full range of exposure conditions. ,, Potential approaches to facilitate the transition from hazard-driven, single-chemical assessments toward rapid, risk-based, high-throughput (HT) prioritization are already being developed and include procedures to estimate exposure, toxicity, and toxicokinetics. ,− For example, HT screening methods allow testing of large numbers of samples with highly automated instruments in combination with advanced data processing software. ,,, Substantial efforts have been made in generating HT hazard information and HT toxicokinetics, but essential information to predict human exposure to chemicals released from indoor sources is frequently missing. , To fully realize the potential of new chemical risk assessment approaches, reliable chemical exposure models need to be coupled with quickly accessible toxicity data. ,− …”