Computational journey to unveil organophosphorothioate pesticides' metabolism: A focus on chlorpyrifos and CYP2C19 mutational landscape.

Organophosphorothioates (OPT) are pesticides impacting human, animal and environmental health. They enter the environment worldwide, primarily due to their application as insecticides. OPTs are mainly neurotoxic upon bioactivation and inhibition of brain and serum acetylcholinesterase (AChE).

Cross-mapping of terms used in chemical risk assessment with those used in systematic review: research protocol.

The focus on implementation of systematic review (SR) principles in chemical risk assessments (CRAs) is growing as it has the potential to advance the rigour and transparency of the CRAs. However, the SR and CRA communities use their own specific terminologies. Understanding the meaning of core SR and CRA terms and where they overlap is critical for application of SR methods and principles in CRAs.

Promotion of environmental public health and environmental justice in communities affected by large and long lasting industrial contamination: methods applied and lessons learned from the case study of Porto Torres (Italy).

Introduction: Communities affected by large scale and long lasting industrial contamination are often keen to understand whether their health has been impaired by such contamination. This requires answers that integrate environmental public health and environmental justice perspectives. At these sites, exposure scenarios from environmental contamination over time by multiple chemicals, often involving different environmental matrices, are complex and challenging to reconstruct.

Protocol for designing INVITES-IN, a tool for assessing the internal validity of studies.

This protocol describes the design and development of a tool for evaluation of the internal validity of studies, which is needed to include the data as evidence in systematic reviews and chemical risk assessments. The tool will be designed specifically to be applied to cell culture studies, including, but not restricted to, studies meeting the new approach methodology (NAM) definition. The tool is called INVITES-IN (IN VITro Experimental Studies INternal validity).

Metabolites in the regulatory risk assessment of pesticides in the EU.

A large majority of chemicals is converted into metabolites through xenobiotic-metabolising enzymes. Metabolites may present a spectrum of characteristics varying from similar to vastly different compared with the parent compound in terms of both toxicokinetics and toxicodynamics. In the pesticide arena, the role of metabolism and metabolites is increasingly recognised as a significant factor particularly for the design and interpretation of mammalian toxicological studies and in the toxicity assessment of pesticide/metabolite-associated issues for hazard characterization and risk assessment purposes, including the role of metabolites as parts in various residues in ecotoxicological adversities.

Co-Occurrence of Taste and Odor Compounds and Cyanotoxins in Cyanobacterial Blooms: Emerging Risks to Human Health?

Cyanobacteria commonly form large blooms in waterbodies; they can produce cyanotoxins, with toxic effects on humans and animals, and volatile compounds, causing bad tastes and odors (T&O) at naturally occurring low concentrations. Notwithstanding the large amount of literature on either cyanotoxins or T&O, no review has focused on them at the same time. The present review critically evaluates the recent literature on cyanotoxins and T&O compounds (geosmin, 2-methylisoborneol, β-ionone and β-cyclocitral) to identify research gaps on harmful exposure of humans and animals to both metabolite classes.

Prediction of prenatal chlorpyrifos exposure leading to developmental neurotoxicity in humans based on toxicity data by quantitative extrapolation.

: Epidemiological studies in children suggested that in utero exposure to chlorpyrifos (CPF), an organophosphate insecticide, may cause developmental neurotoxicity (DNT). We applied quantitative - extrapolation (QIVIVE) based on concentration and non-choline esterase-dependent effects data combined with Benchmark dose (BMD) modelling to predict oral maternal CPF exposure during pregnancy leading to fetal brain effect concentration. By comparing the results with data from epidemiological studies, we evaluated the contribution of the endpoints to the mode of action (MoA) for CPF-induced DNT.

Congeners-Specific Intestinal Absorption Of Microcystins In An 3D Human Intestinal Epithelium: The Role Of Influx/Efflux Transporters.

Microcystins constitute a group of over 200 variants and are increasingly considered as emerging toxins in food and feed safety, particularly with regards to sea-food and fish consumption. Toxicity of MCs is congener-specific, being characterised by different acute potencies, likely related to the differential activity of metabolic enzymes and transporters proteins involved in their cellular uptake. However, the active transport of MCs across intestinal membranes has not been fully elucidated.

- Extrapolation by Physiologically Based Kinetic Modeling: Experience With Three Case Studies and Lessons Learned.

Physiologically based kinetic (PBK) modeling has been increasingly used since the beginning of the 21st century to support dose selection to be used in preclinical and clinical safety studies in the pharmaceutical sector. For chemical safety assessment, the use of PBK has also found interest, however, to a smaller extent, although an internationally agreed document was published already in 2010 (IPCS/WHO), but at that time, PBK modeling was based mostly on data as the example in the IPCS/WHO document indicates. Recently, the OECD has published a guidance document which set standards on how to characterize, validate, and report PBK models for regulatory purposes.

Scientific Opinion of the Scientific Panel on Plant Protection Products and their Residues (PPR Panel) on testing and interpretation of comparative metabolism studies.

EFSA asked the Panel on Plant Protection Products and their residues to deliver a Scientific Opinion on testing and interpretation of comparative metabolism studies for both new active substances and existing ones. The main aim of comparative metabolism studies of pesticide active substances is to evaluate whether all significant metabolites formed in the human test system, as a surrogate of the situation, are also present at comparable level in animal species tested in toxicological studies and, therefore, if their potential toxicity has been appropriately covered by animal studies. The studies may also help to decide which animal model, with regard to a particular compound, is the most relevant for humans.

Guidance Document on Scientific criteria for grouping chemicals into assessment groups for human risk assessment of combined exposure to multiple chemicals.

This guidance document provides harmonised and flexible methodologies to apply scientific criteria and prioritisation methods for grouping chemicals into assessment groups for human risk assessment of combined exposure to multiple chemicals. In the context of EFSA's risk assessments, the problem formulation step defines the chemicals to be assessed in the terms of reference usually through regulatory criteria often set by risk managers based on legislative requirements. Scientific criteria such as hazard-driven criteria can be used to group these chemicals into assessment groups.

Remediation Strategies to Control Toxic Cyanobacterial Blooms: Effects of Macrophyte Aqueous Extracts on (Growth, Toxin Production and Oxidative Stress Response) and on Bacterial Ectoenzymatic Activities.

Increasing toxic cyanobacterial blooms in freshwater demand environmentally friendly solutions to control their growth and toxicity, especially in arid countries, where most drinking water is produced from surface reservoirs. We tested the effects of macrophyte allelochemicals on and on the fundamental role of bacteria in nutrient recycling. The effects of aqueous extract, the most bioactive of four Moroccan macrophyte extracts, were tested in batch systems on growth, toxin production and oxidative stress response and on the ectoenzymatic activity associated with the bacterial community.

The EU chemicals strategy for sustainability: in support of the BfR position.

The EU chemicals strategy for sustainability (CSS) asserts that both human health and the environment are presently threatened and that further regulation is necessary. In a recent Guest Editorial, members of the German competent authority for risk assessment, the BfR, raised concerns about the scientific justification for this strategy. The complexity and interdependence of the networks of regulation of chemical substances have ensured that public health and wellbeing in the EU have continuously improved.

OpenCYP: An open source database exploring human variability in activities and frequencies of polymophisms for major cytochrome P-450 isoforms across world populations.

The open source database "OpenCYP database" has been developed based on the results of extensive literature searches from the peer-reviewed literature. OpenCYP provides data on human variability on baseline of activities and polymophism frequencies for selected cytochrome P-450 isoforms (CYP1A2, CYP2A6, CYP2D6, CYP3A4/3A5 and CYP3A7) in healthy adult populations from world populations. CYP enzymatic activities were generally expressed as the metabolic ratio (MR) between an unchanged probe drug and its metabolite(s) in urine or plasma measured in healthy adults.

Prediction of the dose range for adverse neurological effects of amiodarone in patients from an in vitro toxicity test by in vitro-in vivo extrapolation.

Amiodarone is an antiarrhythmic agent inducing adverse effects on the nervous system, among others. We applied physiologically based pharmacokinetic (PBPK) modeling combined with benchmark dose modeling to predict, based on published in vitro data, the in vivo dose of amiodarone which may lead to adverse neurological effects in patients. We performed in vitro-in vivo extrapolation (IVIVE) from concentrations measured in the cell lysate of a rat brain 3D cell model using a validated human PBPK model.

Is Chronic Exposure to Raw Water a Possible Risk Factor for Amyotrophic Lateral Sclerosis? A Pilot Case-Control Study.

Background: The etiopathogenesis of amyotrophic lateral sclerosis (ALS) is still largely unknown.

Methods: We performed a case-control study (33 cases and 35 controls) in Umbria, Italy. We investigated associations between common lifestyle, clinical factors, as well as environmental exposures potentially implicated with ALS onset.

Integrating biokinetics and in vitro studies to evaluate developmental neurotoxicity induced by chlorpyrifos in human iPSC-derived neural stem cells undergoing differentiation towards neuronal and glial cells.

For some complex toxicological endpoints, chemical safety assessment has conventionally relied on animal testing. Apart from the ethical issues, also scientific considerations have been raised concerning the traditional approach, highlighting the importance for considering real life exposure scenario. Implementation of flexible testing strategies, integrating multiple sources of information, including in vitro reliable test methods and in vitro biokinetics, would enhance the relevance of the obtained results.

Minimization of spreading of SARS-CoV-2 via household waste produced by subjects affected by COVID-19 or in quarantine.

Currently available evidence supports that the predominant route of human-to-human transmission of the SARS-CoV-2 is through respiratory droplets. Indirect hands contact with surfaces contaminated by infectious droplets subsequently touching the mouth, nose or eyes seems to be another route of an indirect contact transmission. Persistence of the virus on different surfaces and other materials has been reported in recent studies: SARS-CoV-2 was more stable on plastic and stainless steel than on copper and cardboard.

Phosmet bioactivation by isoform-specific cytochrome P450s in human hepatic and gut samples and metabolic interaction with chlorpyrifos.

Data on the bioactivation of Phosmet (Pho), a phthalimide-derived organophosphate pesticide (OPT), to the neurotoxic metabolite Phosmet-oxon (PhOx) in human are not available. The characterization of the reaction in single human recombinant CYPs evidenced that the ranking of the intrinsic clearances was: 2C18>2C19>2B6>2C9>1A1>1A2>2D6>3A4>2A6. Considering the average human hepatic content, CYP2C19 contributed for the great majority (60%) at relevant exposure concentrations, while CYP2C9 (33%) and CYP3A4 (31%) were relevant at high substrate concentration.

In vitro detoxication of microcystins in human samples: variability among variants with different hydrophilicity and structure.

Cyanotoxins, among which >200 variants of Microcystins (MC), constitute an emerging issue in food safety. Microcystins (MC) toxicity is congener-specific; however, the in vitro inhibition of PP1/PP2A (the key molecular event of MC toxicity) by single MC variants is comparable and MC toxicokinetics seems to be the critical point. Here, the variability in GSH conjugation catalysed by human recombinant enzymes and human hepatic cytosol has been compared between hydrophilic (MC-LR and MC-RR) and hydrophobic (MC-LW, MC-YR and MC-LF) variants, according to measured logPow.

Serum concentrations of perfluorinated alkyl substances in farmers living in areas affected by water contamination in the Veneto Region (Northern Italy).

Human exposure to per- and polyfluorinated alkyl substances (PFASs) is a major public health concern because in the last decades several cases of overexposure of people to PFASs, in particular through contaminated water, occurred worldwide. In 2013-2017 a PFAS drinking water contamination was discovered and investigated in northern Italy (Veneto region) and high PFAS serum levels were detected in exposed people. 629 subjects were enrolled: 257 residing in municipalities in the areas under impact, 250 residing in municipalities in areas at presumed background exposure and 122 farmers living in contaminated rural areas producing and consuming own livestock and vegetables and frequently using well water.

Health and Climate Change: science calls for global action.

Climate changes affect social and environmental health determinants such as clean air, ecosystems health, safe drinking water and safe sufficient food. Globally, people at greatest risk of adverse health effects associated with climate change include children, the elderly and other vulnerable groups. Temperature-related death and illness, extreme events, polluted or stressed ecosystems represent relevant issues raising concern for both health and economic consequences.

Advice to the European Commission as Regards Type and Criteria for Comprehensive Studies to Be Requested From Manufacturers: The Opinion of the Scientific Committee on Health, Environmental, and Emerging Risks (SCHEER).

Unlabelled: The European Commission has established a priority list of 15 additives contained in cigarettes and roll-your-own tobacco subject to enhanced reporting obligations. The European Union (EU) Tobacco Products Directive (TPD) prescribes that Member States shall require manufacturers and importers of tobacco products to carry out comprehensive studies on these additives to assess their contribution to any of the properties listed in Article 6 of the TPD: toxicity or addictiveness, characterizing flavor, inhalation facilitation, nicotine uptake, and carcinogenic, mutagenic, or toxic for reproduction. The Scientific Committee on Health, Environmental, and Emerging Risks (SCHEER) has provided guidance on the type and criteria for comprehensive studies, and on the most suitable methodologies to test these 15 tobacco additives as well as additives on future updated lists.