Keywords

REACH, RTD, hepatotoxicity, nephrotoxicity, metabolism, kinetics


Objective

Halogenated alkenes are a family of chemicals that have been widely used in various industrial applications, like pesticides, solvents, and dry cleaning, and pose a significant hazard to human health. Occupational investigations and animal studies have indeed demonstrated that halogenated alkenes – especially trichloroethylene (TCE), perchloroethylene (PER), and hexachlorobutadiene (HCBD) – can cause various types of toxicity, including hepatotoxicity and nephrotoxicity. Mechanistic in vivo and in vitro animal studies have demonstrated that the renal toxicity of these chemicals is not caused by the parent compounds but is a result of several enzymatic reactions (GST, GGT, dipeptidase, and β-lyase) at hepatic and renal levels. The resulting reactive metabolites will lead to oxidative stress and mitochondrial dysfunction, which are considered key events in renal proximal tubule toxicity.
The case study aims to develop a quantitative model for halogenated alkene metabolism, distribution and target organ toxicity for halogenated alkenes, focusing on TCE.

 


Testing Strategy

An integrative workflow that includes in vitro hepatic studies for biotransformation of parent compounds, monitorisation of renal metabolism of hepatic conjugates and toxicity testing in hepatic, renal, and neuro in vitro systems has been developed. NAMs have been integrated into the testing approach. An in vitro model was developed utilizing human liver preparations, human recombinant enzymes, synthetic chemistry, and the human renal cell proximal tubule cell line RPTEC/TERT1. Metabolism stages and eventual mitochondrial toxicity have been evaluated in this system. LC-MS based analytical methods were applied to monitor the kinetics of parent compounds and tested metabolites which will also provide data for the support of an improved physiologically based pharmacokinetic (PBPK) model for human in vivo TCE, PER, and HCBD exposures.


Publications

Zgheib et al. 2018 [link]; Limonciel et al. 2018 [link]; van der Stel et al. 2020 [link]; Aschauer et al. 2015 [link]; Capinha et al. 2021 [link]


Contributors

VU, UL, UKN, BIOT, EwC, IRFMN, SIMCYP.