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Abstract

Human exposure to environmental stressors is widespread. Highly dynamic, these chemical, physical and social factors, collectively termed as the exposome, interact with internal factors such as genetics, sex, gut microbiome and general health status, and dictate susceptibility and risk for an onset of diseases.
Human exposure to the chemicals is addressed through human biomonitoring which follows the biomarkers of exposure in various biological specimens and determines the distribution and the levels of these chemicals of concern within studied population. This is typically achieved by targeting preselected chemicals of concern, however by doing so, the exposure assessment is limited only to this narrow number of chemicals. Due to an ever-increasing number of potentially concerning chemicals, a new and more comprehensive approach to complement the traditional ones is required. In this respect, the non-targeted screening aims at identifying all known, suspected and unknown exposures, however the appropriate methodology is yet unavailable.
Within the scope of the dissertation, a novel non-targeted workflow was developed. It included development of the sample preparation procedure, chemical analysis and data processing protocol. The workflow was validated and applied to a cohort of Slovenian children, in which 74 urinary biomarkers of exposure were tentatively identified. Some of the identified biomarkers of exposure were known endocrine disrupting chemicals, so to cross-confirm the results of the non-targeted and suspect screening, a targeted analysis of bisphenols, parabens and triclosan was conducted. The analysis quantified the levels and showed that Slovenian children were widely exposed to these chemicals, however their levels were low and comparable to those determined elsewhere. The analysis also provided insight into determinants of exposure and susceptibility to adverse health effects. Targeted identification of these biomarkers of exposure confirmed and validated the results obtained by non-targeted screening.
We tested the applicability of the non-targeted data processing protocol also on a different setting: biodegradation of cytostatic drug imatinib. We identified 8 transformation products, out of which 6 are new to science and we detected one of them in real wastewater samples. As the results show, non-targeted exposomic analysis can be conducted quickly with data processing currently being the main limiting factor. Nonetheless, it can be efficiently applied to routine analysis and human biomonitoring schemes and other fields of research. The capabilities of such global scale analysis were demonstrated through analysis of the exposure of children, which along with the traditional targeted approach showed that the children were exposed to a large number of chemicals, some of which are restricted from use in the European Union. As the toxicity of chemical mixtures can be enhanced due to their synergistic action, the exposure is concerning and can contribute to the development of chronic diseases later in life. With the development of non-targeted screening in human biomonitoring, the capabilities of the approach will be extended in the future and the coverage of chemicals will be even further increased. This will lead to efficient and fast detection of newly emerging chemicals and with this, to reducing the health risks associated with the exposures as they appear.