QSAR models for the prediction of dietary biomagnification factor in fish

Xenobiotics released in the environment can be taken up by aquatic and terrestrial organisms and can accumulate at higher concentrations through the trophic chain. Bioaccumulation is therefore one of the PBT properties that authorities require to assess for the evaluation of the risks that chemicals may pose to humans and the environment. The use of an integrated testing strategy (ITS) and the use of multiple sources of information are strongly encouraged by authorities in order to maximize the information available and reduce testing costs. Moreover, considering the increasing demand for development and the application of new approaches and alternatives to animal testing, the development of in silico cost-effective tools such as QSAR models becomes increasingly important. In this study, a large and curated literature database of fish laboratory-based values of dietary biomagnification factor (BMF) was used to create externally validated QSARs. The quality categories (high, medium, low) available in the database were used to extract reliable data to train and validate the models, and to further address the uncertainty in low-quality data. This procedure was useful for highlighting problematic compounds for which additional experimental effort would be required, such as siloxanes, highly brominated and chlorinated compounds. Two models were suggested as final outputs in this study, one based on good-quality data and the other developed on a larger dataset of consistent Log BMFL values, which included lower-quality data. The models had similar predictive ability; however, the second model had a larger applicability domain. These QSARs were based on simple MLR equations that could easily be applied for the predictions of dietary BMFL in fish, and support bioaccumulation assessment procedures at the regulatory level. To ease the application and dissemination of these QSARs, they were included with technical documentation (as QMRF Reports) in the QSAR-ME Profiler software for QSAR predictions available online

Progetto "Acque pulite"

Abstract not availableLe aree montane, soprattutto in territori ricchi di acqua come quello del Verbano Cusio Ossola e del bacino del Lago Maggiore, sono da sempre oggetto di utilizzo per la produzione di energia elettrica da fonti rinnovabili, principalmente attraverso impianti idroelettrici. Il giusto equilibrio tra il mantenimento della qualit? ecologica degli ecosistemi torrentizi e la produzione di energia elettrica da fonti rinnovabili non ? di facile attuazione, soprattutto in assenza di studi e sperimentazioni dedicate. Lo sfruttamento delle acque a scopo idroelettrico pu? determinare l\u27alterazione e, a volte, la perdita di habitat, causando una riduzione della biodiversit?, con effetti negativi maggiori sui taxa pi? sensibili (ad esempio macroinvertebrati e fauna ittica), causando contestualmente, il degrado della qualit? ecologica di parte o addirittura dell\u27intero corso d\u27acqua a seconda delle tipologie di prelievo/i a cui ? stato sottoposto. Diventa quindi importante, nel contesto locale, ma anche nazionale e internazionale, dove le energie rinnovabili sono un punto focale per la futura produzione di energia, trovare il giusto equilibrio tra la qualit? ecologica degli ecosistemi, e la richiesta di energia pulita e di sviluppo economico. E\u27 proprio in questo contesto che nasce l\u27idea del Progetto "Acque Pulite", che grazie alla disponibilit? e al finanziamento di IDROENERGY S.r.l. ha visto la realizzazione di uno studio pilota sul Torrente San Giovanni. Il Torrente San Giovanni ? uno dei principali immissari del Lago Maggiore e per tale motivo risulta importante conoscere la sua qualit? ecologica e gli effetti su di essa delle diverse attivit? umane che insistono all\u27interno del suo bacino. In particolare, con il Progetto "Acque Pulite" si sono voluti verificare gli effetti della presenza di un\u27opera di presa e di una traversa, costruite per scopo idroelettrico, sulla qualit? idro-morfologica, chimica e biologica dei tratti di torrente a monte e a valle di tali opere

QSAR Models for the Prediction of Dietary Biomagnification Factor in Fish

Xenobiotics released in the environment can be taken up by aquatic and terrestrial organisms and can accumulate at higher concentrations through the trophic chain. Bioaccumulation is therefore one of the PBT properties that authorities require to assess for the evaluation of the risks that chemicals may pose to humans and the environment. The use of an integrated testing strategy (ITS) and the use of multiple sources of information are strongly encouraged by authorities in order to maximize the information available and reduce testing costs. Moreover, considering the increasing demand for development and the application of new approaches and alternatives to animal testing, the development of in silico cost-effective tools such as QSAR models becomes increasingly important. In this study, a large and curated literature database of fish laboratory-based values of dietary biomagnification factor (BMF) was used to create externally validated QSARs. The quality categories (high, medium, low) available in the database were used to extract reliable data to train and validate the models, and to further address the uncertainty in low-quality data. This procedure was useful for highlighting problematic compounds for which additional experimental effort would be required, such as siloxanes, highly brominated and chlorinated compounds. Two models were suggested as final outputs in this study, one based on good-quality data and the other developed on a larger dataset of consistent Log BMFL values, which included lower-quality data. The models had similar predictive ability; however, the second model had a larger applicability domain. These QSARs were based on simple MLR equations that could easily be applied for the predictions of dietary BMFL in fish, and support bioaccumulation assessment procedures at the regulatory level. To ease the application and dissemination of these QSARs, they were included with technical documentation (as QMRF Reports) in the QSAR-ME Profiler software for QSAR predictions available online

In Vitro Biotransformation Prediction-Suite (IVBP-Suite)

Software for the prediction of the hepatic biotransformation in vitro of organic substances in mammalsSoftware per la predizione della biotrasformazone epatica in vitro di sostanze organiche in mammifer

Predicting the Bioconcentration Factor in Fish from Molecular Structures

The bioconcentration factor (BCF) is one of the metrics used to evaluate the potential of a substance to bioaccumulate into aquatic organisms. In this work, linear and non-linear regression QSARs were developed for the prediction of log BCF using different computational approaches, and starting from a large and structurally heterogeneous dataset. The new MLR-OLS and ANN regression models have good fitting with R2 values of 0.62 and 0.70, respectively, and comparable external predictivity with R2ext 0.64 and 0.65 (RMSEext of 0.78 and 0.76), respectively. Furthermore, linear and non-linear classification models were developed using the regulatory threshold BCF >2000. A class balanced subset was used to develop classification models which were applied to chemicals not used to create the QSARs. These classification models are characterized by external and internal accuracy up to 84% and 90%, respectively, and sensitivity and specificity up to 90% and 80%, respectively. QSARs presented in this work are validated according to regulatory requirements and their quality is in line with other tools available for the same endpoint and dataset, with the advantage of low complexity and easy application through the software QSAR-ME Profiler. These QSARs can be used as alternatives for, or in combination with, existing models to support bioaccumulation assessment procedures

QSARINS-Chem ECO.44

QSARINS-Chem ECO.44: prediction of in vitro intrinsic hepatic in mammal

ECO44 \u2013 A TOXICOKINETIC MAMMALIAN MODELLING FRAMEWORK FOR BIOACCUMULATION ASSESSMENT (2018- 2020)

Historically, the globally accepted model for bioaccumulation (B) determination has been fish. The basis of B screening and assessment has been driven by the octanol-water partition coefficient (KOW) and data and assessment endpoints for aquatic species (e.g., bioconcentration factors; BCFs); however, nearly two decades of evidence has highlighted the need to examine B in air-breathing organisms specifically. Emerging regulatory guidance, e.g., REACH Chapter R11: PBT / vPvB Assessment, includes B screening threshold criteria for air-breathing organisms linked to KOW and the octanol-air partition coefficient (KOA): \u201dAn efficiently absorbed, non-biotransformed neutral organic substance with a log KOA 65 5 in combination with a log KOW 65 2 has the potential to biomagnify in terrestrial food chains and air-breathing marine wildlife as well as in humans, while the substances with log KOW < 2 are being quickly eliminated by the urinary excretion, and therefore do not biomagnify even though their KOA is high.\u201d In addition to KOW and KOA, it is acknowledged that considerations of dietary absorption efficiency and biotransformation rates are also necessary for B assessment. While certain tools for simulating B in mammals and other air-breathing organisms exist, it is desirable to further develop and refine tools and data streams more explicitly. General Objective The general objective of this project is to build a toxicokinetic (TK) modelling framework for mammals and develop and integrate various data streams for mammalian B assessment. This research will expand the development, evaluation, and application of the CEFIC-LRI funded Bioaccumulation Assessment Tool (BAT) and other B, TK, and risk assessment models for mammals. A particular focus of this project is to address data gaps and uncertainty in biotransformation half-lives. To satisfy these general objectives, this project will: 1) Assimilate critically evaluated data from various sources of in vitro and in vivo TK data (rodents and humans), as well as field B data in mammals (TMF and BMF). Quantitative Structure-Activity Relationship (QSAR) model predictions will be included to compare and analyze various data streams. 2) Develop and test one-compartment TK (1-CoTK) and generic physiologically-based TK (G-PBTK) models for mammalian species. The models will be parameterized for laboratory test mammals (rats, mice), and evaluated along with in vitro-in vivo extrapolation (IVIVE) models to integrate TK data with collected in vivo and in vitro laboratory data. 3) Develop and test various QSAR models for predicting biotransformation half-lives and other endpoints relevant for TK and B model applications 4) Refine the BAT for mammalian species and evaluate model predictions for mammals with field and laboratory data. 5) Synthesize the state of the science and available data streams to develop an integrated testing strategy (ITS) for additional priority chemicals. This will inform future testing needs to address current measurement gaps and QSAR model uncertainties

New BODIPYs for photodynamic therapy (PDT): Synthesis and activity on human cancer cell lines

A new class of compounds based on the 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene core, known as BODIPYs, has attracted significant attention as photosensitizers suitable for application in photodynamic therapy (PDT), which is a minimally invasive procedure to treat cancer. In PDT the combination of a photosensitizer (PS), light, and oxygen leads to a series of photochemical reactions generating reactive oxygen species (ROS) exerting cytotoxic action on tumor cells. Here we present the synthesis and the study of the in vitro photodynamic effects of two BODIPYs which differ in the structure of the substituent placed on the meso (or 8) position of the dipyrrolylmethenic nucleus. The two compounds were tested on three human cancer cell lines of different origin and degree of malignancy. Our results indicate that the BODIPYs are very effective in reducing the growth/viability of HCT116, SKOV3 and MCF7 cells when irradiated with a green LED source, whereas they are practically devoid of activity in the dark. Phototoxicity occurs mainly through apoptotic cell death, however necrotic cell death also seems to play a role. Furthermore, singlet oxygen generation and induction of the increase of reactive oxygen species also appear to be involved in the photodynamic effect of the BODIPYs. Finally, it is worth noting that the two BODIPYs are also able to exert anti-migratory activity

QSAR prediction of in vitro biotransformation in human and rodents

10sinonenoneBertato Linda; Casartelli Ilaria; Mazzucotelli Matilda; Chirico Nicola; Sangion Alessandro; Foster Karen; Arnot Jon; armitage James; Embry Michelle; Papa EsterBertato, Linda; Casartelli, Ilaria; Mazzucotelli, Matilda; Chirico, Nicola; Sangion, Alessandro; Foster, Karen; Arnot, Jon; Armitage, James; Embry, Michelle; Papa, Este