Exposure of embryos to mixtures of environmental chemicals can result in congenital malformations. Mixture experiments can provide an indication of the joint effects of substances, but it is practically infeasible to test all possible combinations. The development of mechanistic approaches and integrated models able to predict the effects of mixtures from the concentrations of their individual components, are crucial to assess mixtures associated risks. Azole fungicides can induce craniofacial defects, both after in utero and in vitro exposure. Results obtained in vitro have shown a significant enhancement of teratogenic effects after co-exposure to azoles in comparison to the single exposures. In this project, we evaluated the hypothesis that those molecules concur to imbalance the retinoic acid pathway in specific responsive embryonic tissues. We developed a quantitative adverse outcome pathway for craniofacial malformations, able to simulate the formation of the physiological retinoic acid gradient in the rat embryo hindbrain and its perturbation after exposure to cyproconazole, flusilazole, triadimefon and to their binary mixtures. The underlying system biology model was calibrated using in vitro data and is reasonably predictive of mixtures' effects for those azoles, thereby confirming the plausibility of the hypothesized pathogenic pathway. This quantitative AOP could have mechanistic or predictive applications in pesticides risk assessment. Highlights
The RHAPS (Redox-Activity And Health-Effects Of Atmospheric Primary And Secondary Aerosol) project was launched in 2019 with the major objective of identifying specific properties of the fine atmospheric aerosol from combustion sources that are responsible for toxicological effects and can be used as new metrics for health-related outdoor pollution studies. In this paper, we present the overall methodology of RHAPS and introduce the phenomenology and the first data observed. A comprehensive physico-chemical aerosol characterization has been achieved by means of high-time resolution measurements (e.g., number size distributions, refractory chemical components, elemental composition) and low-time resolution analyses (e.g., oxidative potential, toxicological assays, chemical composition). Preliminary results indicate that, at the real atmospheric conditions observed (i.e., daily PM1 from less than 4 to more than 50 μg m−3), high/low mass concentrations of PM1, as well as black carbon (BC) and water soluble Oxidative Potential (WSOP,) do not necessarily translate into high/low toxicity. Notably, these findings were observed during a variety of atmospheric conditions and aerosol properties and with different toxicological assessments. Findings suggest a higher complexity in the relations observed between atmospheric aerosol and toxicological endpoints that go beyond the currently used PM1 metrics. Finally, we provide an outlook to companion papers where data will be analyzed in more detail, with the focus on source apportionment of PM1 and the role of source emissions on aerosol toxicity, the OP as a predictive variable for PM1 toxicity, and the related role of SOA possessing redox-active capacity, exposure-response relationships for PM1, and air quality models to forecast PM1 toxicity.
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