Selection and combination of biomarkers to control and prevent the risk of occupational exposure to the mixture of lead, arsenic and manganese

Tese de doutoramento, Farmácia (Toxicologia), Universidade de Lisboa, Faculdade de Farmácia, 2014Lead (Pb), arsenic (As) and manganese (Mn) are metals with neurotoxic effects that are present in mines as metal mixtures, making miners potentially vulnerable to an increased risk of neurotoxicity. Biomarkers can be crucial tools to detect these disorders in their earlier stages enabling patients to avoid the disease progression. Several biomarkers for Pb, As and Mn have been investigated, yet only for single exposures despite the different metals can interact within the brain. The aim of this work was to identify biomarkers of neurotoxicity which may be used to control and prevent the risk of chronic low levels exposure to the mixture of Pb, As and Mn. After performing an in vivo assay with Wistar rats repeatedly exposed (for 8 days) to Pb, As, Mn or the 3-metal mixture, the co-exposure increased behavioral toxicity and augmented Pb’s deposition in brain more than upon single exposures, with blood Pb levels failing to reflect this alteration, thus, contributing to underestimate the risk associated with Pb-induced damages. Mechanistic insights concerning the consequences of in vivo Pb, As and Mn interactions revealed changes in neurotransmitters and heme precursors’ levels in the brain. Changes of these BMs in peripheral samples suggested their suitability to be used as BMs of exposure and/or neurotoxicity upon exposure to this mixture. A multibiomarker approach based on multiparameter analysis of independent markers was used; the results suggest that the combination of biomarkers is a better tool to predict the type of exposures and the magnitude of neurotoxic effects, better than when used alone. A preliminary human study in a mining population was performed to apply the results obtained in the in vivo model. According to the results, the miners might be exposed to excessive levels of Pb, As and Mn, and the integration of experimentally selected BMs, Pb and Mn blood levels and urinary Pb, As and delta-aminolevulinic acid levels, revealed to be a good tool to identify excessive exposed workers. Exploration of BMs’ integration methodologies seems certainly promising to assess “real-life” scenarios of exposure to chemical mixtures