At the moment, over 350.000 chemicals are registered worldwide for production and use. Their application, however, may harm human health and the environment. To manage the safety of chemicals,... Show moreAt the moment, over 350.000 chemicals are registered worldwide for production and use. Their application, however, may harm human health and the environment. To manage the safety of chemicals, particular chemical legislations are in place, which make use of risk and hazard assessments. However, there are several challenges for current risk and hazard assessments, including i) a lack of (reliable) data, and ii) a relative slow and inefficient evaluation and regulation process. In this thesis, I investigate specifically whether more extensive and targeted use of chemical similarity within risk and hazard assessment has the potential to improve these aspects. Chemical similarity could be a valuable factor as similarities between two chemicals could be a sign of similar physicochemical and/or toxic properties. The separate sections within this thesis specifically focus on chemical similarity in relation to screening, data generation and evaluation of substances. The results of this thesis indicate that chemical similarity could be used to identify and evaluate hazardous properties of single and groups of chemicals. Accordingly, I promote more extensive use of chemical similarity within risk and hazard assessment as it has the ability to circumvent several issues related to a lack of data and evaluation efficiency. Show less
This read-across case study characterises thirteen, structurally similar carboxylic acids demonstrating the application of in vitro and in silico human-based new approach methods, to determine... Show moreThis read-across case study characterises thirteen, structurally similar carboxylic acids demonstrating the application of in vitro and in silico human-based new approach methods, to determine biological similarity. Based on data from in vivo animal studies, the read-across hypothesis is that all analogues are steatotic and so should be considered hazardous. Transcriptomic analysis to determine differentially expressed genes (DEGs) in hepatocytes served as first tier testing to confirm a common mode-of-action and identify differences in the potency of the analogues. An adverse outcome pathway (AOP) network for hepatic steatosis, informed the design of an in vitro testing battery, targeting AOP relevant MIEs and KEs, and Dempster-Shafer decision theory was used to systematically quantify uncertainty and to define the minimal testing scope. The case study shows that the read-across hypothesis is the critical core to designing a robust, NAM-based testing strategy. By summarising the current mechanistic understanding, an AOP enables the selection of NAMs covering MIEs, early KEs, and late KEs. Experimental coverage of the AOP in this way is vital since MIEs and early KEs alone are not confirmatory of progression to the AO. This strategy exemplifies the workflow previously published by the EUTOXRISK project driving a paradigm shift towards NAM-based NGRA. Show less
