Toxicity prediction and effect characterization of 90 pharmaceuticals and illicit drugs measured in plasma of fish from a major European river (Sava, Croatia)

Malev, Olga; Lovrić, Mario; Stipaničev, Draženka; Repec, Siniša; Martinović-Weigelt, Dalma; Zanella, Davor; Ivanković, Tomislav; Đuretec, Valnea Sindičić; Barišić, Josip; Li, Mei; Klobučar, Göran

doi:10.1016/j.envpol.2020.115162

Cited by 34 publications

(18 citation statements)

References 57 publications

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“…The ZF embryo assays consist of up to 1092 compounds (by ID) tested on diverse developmental malformations. Such data sets are valuable for creating models on broad chemical spaces and low concentrations, which are key for evaluating the risk due to many novel compounds present in mixture at nanoto-micro-concentration ranges in fish [14] and in river surface water and sediment [15], with often unknown MoA and synergistic actions.…”

Section: Introductionmentioning

confidence: 99%

Predictive Capability of QSAR Models Based on the CompTox Zebrafish Embryo Assays: An Imbalanced Classification Problem

et al. 2021

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The CompTox Chemistry Dashboard (ToxCast) contains one of the largest public databases on Zebrafish (Danio rerio) developmental toxicity. The data consists of 19 toxicological endpoints on unique 1018 compounds measured in relatively low concentration ranges. The endpoints are related to developmental effects occurring in dechorionated zebrafish embryos for 120 hours post fertilization and monitored via gross malformations and mortality. We report the predictive capability of 209 quantitative structure–activity relationship (QSAR) models developed by machine learning methods using penalization techniques and diverse model quality metrics to cope with the imbalanced endpoints. All these QSAR models were generated to test how the imbalanced classification (toxic or non-toxic) endpoints could be predicted regardless which of three algorithms is used: logistic regression, multi-layer perceptron, or random forests. Additionally, QSAR toxicity models are developed starting from sets of classical molecular descriptors, structural fingerprints and their combinations. Only 8 out of 209 models passed the 0.20 Matthew’s correlation coefficient value defined a priori as a threshold for acceptable model quality on the test sets. The best models were obtained for endpoints mortality (MORT), ActivityScore and JAW (deformation). The low predictability of the QSAR model developed from the zebrafish embryotoxicity data in the database is mainly due to a higher sensitivity of 19 measurements of endpoints carried out on dechorionated embryos at low concentrations.

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Section: Introductionmentioning

confidence: 99%

Predictive Capability of QSAR Models Based on the CompTox Zebrafish Embryo Assays: An Imbalanced Classification Problem

et al. 2021

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“…Based on ECOSAR methodology, the acute-to-chronic toxicity ratio used in this case would be a factor of 10, which would bring the predicted environmental concentration (PEC) to chronic toxicity end point ratio to 2.35 × 10 –6 . Additionally, plasma levels of a wide array of compounds were measured in freshwater fish, and results emphasized the importance of also considering other factors such as synergistic and additive effects of different pharmaceuticals, including dexamethasone, 59 which have not been taken into account in this study.…”

Section: Resultsmentioning

confidence: 99%

COVID-19 Treatment Agents: Do They Pose an Environmental Risk?

Desgens-Martin

Keller

2021

ACS EST Water

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The end of 2019 was marked by reports of a previously unknown virus causing coronavirus disease 19 (COVID-19). With over 800 new daily hospitalizations at the peak in Los Angeles (LA) County, the potential for high use of COVID-19 treatment agents, remdesivir and dexamethasone, warranted a screening assessment of their fate and toxicity risk for aquatic organisms. We predicted environmental concentrations (PECs) using the ChemFate model and hospitalizations data and compared them to predicted ecotoxicity concentrations generated using Ecological Structure Activity Relationships (ECOSAR) to assess risk to potentially exposed organisms. The lowest predicted toxicity thresholds were between 2 and 11 orders of magnitude greater than the highest PECs for freshwater and saltwater. We conclude that had all eligible patients in LA County been given the recommended treatment regimen, exposure of aquatic organisms in regional water bodies to remdesivir, dexamethasone, and their evaluated metabolites would not be likely to be affected based on ECOSAR predictions. Conservative, protective assumptions were used for this screening analysis, considering limited toxicity information. Modeling tools thus serve to predict environmental concentrations and estimate ecotoxicity risks of novel treatment agents and can provide useful preliminary data to assess and manage ecological health risks.

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“…In addition to those “classic” illicit drugs, new psychoactive substances are constantly appearing [ 34 ]. Concentrations of many of these illicit neuroactive substances in the aquatic environment can be in the same range as the concentrations of neuroactive pharmaceuticals taken for medical reasons [ 35 , 36 , 37 ]. This is readily understood when it is realised that the UK’s National Crime Agency reported that British people consumed 117 tonnes (nearly 120,000 kg) of cocaine in 2019 alone.…”

Section: Discussionmentioning

confidence: 99%

Environmental Occurrence and Predicted Pharmacological Risk to Freshwater Fish of over 200 Neuroactive Pharmaceuticals in Widespread Use

Sumpter

Margiotta-Casaluci

2022

Toxics

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There is a growing concern that neuroactive chemicals released into the environment can perturb wildlife behaviour. Among these chemicals, pharmaceuticals such as antidepressants and anxiolytics have been receiving increasing attention, as they are specifically prescribed to modify behavioural responses. Many laboratory studies have demonstrated that some of these compounds can affect various aspects of the behaviour of a range of aquatic organisms; however, these investigations are focused on a very small set of neuroactive pharmaceuticals, and they often consider one compound at a time. In this study, to better understand the environmental and toxicological dimension of the problem, we considered all pharmaceuticals explicitly intended to modulate the central nervous system (CNS), and we hypothesised that these compounds have higher probability of perturbing animal behaviour. Based on this hypothesis, we used the classification of pharmaceuticals provided by the British National Formulary (based on their clinical applications) and identified 210 different CNS-acting pharmaceuticals prescribed in the UK to treat a variety of CNS-related conditions, including mental health and sleep disorders, dementia, epilepsy, nausea, and pain. The analysis of existing databases revealed that 84 of these compounds were already detected in surface waters worldwide. Using a biological read-across approach based on the extrapolation of clinical data, we predicted that the concentration of 32 of these neuroactive pharmaceuticals in surface waters in England may be high enough to elicit pharmacological effects in wild fish. The ecotoxicological effects of the vast majority of these compounds are currently uncharacterised. Overall, these results highlight the importance of addressing this environmental challenge from a mixture toxicology and systems perspective. The knowledge platform developed in the present study can guide future region-specific prioritisation efforts, inform the design of mixture studies, and foster interdisciplinary efforts aimed at identifying novel approaches to predict and interpret the ecological implications of chemical-induced behaviour disruption.

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Toxicity prediction and effect characterization of 90 pharmaceuticals and illicit drugs measured in plasma of fish from a major European river (Sava, Croatia)

Cited by 34 publications

References 57 publications

Predictive Capability of QSAR Models Based on the CompTox Zebrafish Embryo Assays: An Imbalanced Classification Problem

Predictive Capability of QSAR Models Based on the CompTox Zebrafish Embryo Assays: An Imbalanced Classification Problem

COVID-19 Treatment Agents: Do They Pose an Environmental Risk?

Environmental Occurrence and Predicted Pharmacological Risk to Freshwater Fish of over 200 Neuroactive Pharmaceuticals in Widespread Use

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