Pharmaceuticals and personal care products (PPCPs) constitute a heterogeneous group of emerging environmental contaminants (ECs). In the last years, an increasing number of studies has confirmed the presence of various PPCPs in different environmental compartments, and this raises concerns about the their potential effects to humans and wildlife. This is particularly true if the problem of the presence of mixtures in the environment is considered. In this framework, the present study aimed to contribute to the scientific knowledge about the potential environmental adverse effects of different classes of emerging contaminants. During the PhD, different issues were considered. In a first phase of the study, a prioritization method (RANKVET indicator) was developed and proposed for ranking the environmental risks of veterinary medicinal products (VMPs). As previously stated, the high number of substances that are likely to be found in an environmental compartment enlightens the need for screening tools useful to produce lists of priority substances. Particularly, RANKVET was developed on the basis of the specific requirements of the EU Directives and Regulations for placing VMPs on the market. In a further step, the toxic effects of pharmaceuticals (for veterinary and human use) and quaternary ammonium compounds (QACs) were assessed as single toxicants and as different combinations of binary and multicomponent mixtures by using Aliivibrio fischeri as test organism (Microtox® test system). In order to acquire knowledge about their mode of action (MoA), QSAR models, specifically developed for A. fischeri, were applied. Results showed a similar MoA for the two separate groups of toxicants: polar narcotic type behaviour for the majority of pharmaceuticals and a-specific reactive MoA for almost all the QACs. Assessed as single chemicals the toxic effects of pharmaceuticals were moderate, whereas a relevant bioluminescent inhibition was obtained for QACs. Single toxicity parameters were used in order to investigate the predictability of mixtures toxicity by using the two widely used eco-toxicological predictive models: Concentration Addition (CA) and Independent Action (IA). Results showed deviations from conceptual expectations in direction of synergistic and antagonistic effects for the majority of tested binary mixture of PhACs. The hypothesis of interactions among components were confirmed and quantified by the application of the Combination Index method. Synergistic interactions were observed at environmentally relevant concentrations in one case for QACs. From this study some main conclusions were drawn: (i) the knowledge of single toxicity parameters is not always sufficient for a good prediction of mixture effects, especially in the case of pharmaceutical active compounds; (ii) synergistic and antagonistic deviations seem to be confined to mixture of few compounds, (iii) deviations from additivity are mainly dependent of the specific tested combinations of chemicals and on the effect levels under consideration, whereas seem to be independent from the specific mode of action of toxicants towards the organism.

I prodotti farmaceutici e per la cura personale (PPCP) costituiscono un gruppo eterogeneo di contaminanti ambientali emergenti (CE). Negli ultimi anni, un numero crescente di studi ha confermato la loro presenza in differenti compartimenti ambientali, sollevando delle preoccupazioni circa i loro effetti per l’uomo e la fauna selvatica. Questo diventa particolarmente vero se si considera il problema della presenza delle miscele. In questo contesto il presente studio ha avuto lo scopo di contribuire alla conoscenza scientifica circa i potenziali effetti avversi per l’ambiente posti da differenti classi di CE. Durante il dottorato di ricerca sono state considerate diverse problematiche. In una prima fase dello studio è stato sviluppato e proposto un sistema di prioritizzazione attraverso un indicatore (RANKVET) per la classificazione del rischio ambientale di farmaci veterinari (veterinary medicinal products [VMP]). L’elevato numero di sostanze che potenzialmente può essere ritrovato in un compartimento ambientale mette in evidenza la necessità di strumenti di screening utili alla creazione di liste di priorità di sostanze chimiche potenzialmente dannose. Nello specifico, RANKVET è stato sviluppato sulla base delle specifiche informazioni richieste dalle Direttive e dai Regolamenti Europei per l’autorizzazione al commercio di VMP. In una fase successiva, gli effetti di diversi prodotti farmaceutici (ad uso umano e veterinario) e di composti quaternari di ammonio (QAC) sono stati valutati sia come singoli che come diverse combinazioni binarie e multicomponenti di miscele usando Aliivibrio fischeri come organismo test (Microtox® test system). Sono stati anche applicati i modelli QSAR (Quantitative Structure Activity Relationship) specificatamente sviluppati per A. fischeri allo scopo di indagare il modo di azione (MoA) dei CE selezionati sull’organismo test. Nello specifico, i risultati ottenuti hanno mostrato un simile MoA per i due differenti gruppi di contaminanti: narcotico polare per la maggior parte dei composti farmaceutici e un MoA reattivo aspecifico per la maggior parte dei QAC. Valutati come singoli composti chimici, i prodotti farmaceutici hanno mostrato una tossicità moderata, mentre i QAC hanno prodotto una rilevante inibizione di bioluminescenza in A. fischeri. Infine, sono stati utilizzati i principali parametri delle curve concentrazione-risposta dei singoli contaminanti allo scopo di studiare l’applicabilità di due modelli predittivi di tossicità di miscela ampiamente impiegati in eco-tossicologia: Concentration Addition (CA) e Independent Action (IA). Rispetto a quanto concettualmente atteso, i risultati ottenuti hanno mostrato delle deviazioni in direzione di effetti sinergici e antagonistici per la maggior parte delle miscele di farmaci testata. L’ipotesi della presenza di interazioni tossicologiche tra i componenti è stata confermata e quantificata mediante l’applicazione del metodo della Combination Index (CI). In un caso, per le miscele di QAC, sono state osservate interazioni sinergiche a concentrazioni rilevanti per l’ambiente. Da questi studi sono state elaborate alcune conclusioni principali: (i) la conoscenza dei singoli parametri delle curve concentrazione-risposta non sempre è sufficiente per una buona predizione degli effetti di tossicità di miscela soprattutto nel caso di miscele di prodotti farmaceutici; (ii) gli effetti sinergici e antagonistici sembrano essere confinati a miscele di pochi composti; (iii) le deviazioni dal concetto di additività sono principalmente dipendenti dalla specifica combinazione di sostanze chimiche testata e dal livello di effetto considerato, mentre sembrano essere indipendenti dallo specifico modo di azione dei contaminanti verso l’organismo test.

(2017). STUDIES OF MIXTURE EFFECTS OF EMERGING CONTAMINANTS IN THE ENVIRONMENT. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2017).

STUDIES OF MIXTURE EFFECTS OF EMERGING CONTAMINANTS IN THE ENVIRONMENT

DI NICA, VALERIA
2017

Abstract

Pharmaceuticals and personal care products (PPCPs) constitute a heterogeneous group of emerging environmental contaminants (ECs). In the last years, an increasing number of studies has confirmed the presence of various PPCPs in different environmental compartments, and this raises concerns about the their potential effects to humans and wildlife. This is particularly true if the problem of the presence of mixtures in the environment is considered. In this framework, the present study aimed to contribute to the scientific knowledge about the potential environmental adverse effects of different classes of emerging contaminants. During the PhD, different issues were considered. In a first phase of the study, a prioritization method (RANKVET indicator) was developed and proposed for ranking the environmental risks of veterinary medicinal products (VMPs). As previously stated, the high number of substances that are likely to be found in an environmental compartment enlightens the need for screening tools useful to produce lists of priority substances. Particularly, RANKVET was developed on the basis of the specific requirements of the EU Directives and Regulations for placing VMPs on the market. In a further step, the toxic effects of pharmaceuticals (for veterinary and human use) and quaternary ammonium compounds (QACs) were assessed as single toxicants and as different combinations of binary and multicomponent mixtures by using Aliivibrio fischeri as test organism (Microtox® test system). In order to acquire knowledge about their mode of action (MoA), QSAR models, specifically developed for A. fischeri, were applied. Results showed a similar MoA for the two separate groups of toxicants: polar narcotic type behaviour for the majority of pharmaceuticals and a-specific reactive MoA for almost all the QACs. Assessed as single chemicals the toxic effects of pharmaceuticals were moderate, whereas a relevant bioluminescent inhibition was obtained for QACs. Single toxicity parameters were used in order to investigate the predictability of mixtures toxicity by using the two widely used eco-toxicological predictive models: Concentration Addition (CA) and Independent Action (IA). Results showed deviations from conceptual expectations in direction of synergistic and antagonistic effects for the majority of tested binary mixture of PhACs. The hypothesis of interactions among components were confirmed and quantified by the application of the Combination Index method. Synergistic interactions were observed at environmentally relevant concentrations in one case for QACs. From this study some main conclusions were drawn: (i) the knowledge of single toxicity parameters is not always sufficient for a good prediction of mixture effects, especially in the case of pharmaceutical active compounds; (ii) synergistic and antagonistic deviations seem to be confined to mixture of few compounds, (iii) deviations from additivity are mainly dependent of the specific tested combinations of chemicals and on the effect levels under consideration, whereas seem to be independent from the specific mode of action of toxicants towards the organism.
FINIZIO, ANTONIO
VILLA, SARA
Prioritization,; Mixture,; Concentration; Addition,; Synergism
Prioritization,; Mixture,; Concentration; Addition,; Synergism
BIO/07 - ECOLOGIA
English
29-giu-2017
SCIENZE - 80R
29
2015/2016
open
(2017). STUDIES OF MIXTURE EFFECTS OF EMERGING CONTAMINANTS IN THE ENVIRONMENT. (Tesi di dottorato, Università degli Studi di Milano-Bicocca, 2017).
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/170817
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