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Risk Assessment Strategies for Contaminants in Seafood (RASCS) is an EFSA Partnering Grant focusing on KEamong seven European Institutions. The project lasted from June 2021 to June 2023. The proposal was built to establish links among seven major research and regulatory institutions in the EU dealing with seafood safety: IPMA (Portugal), Istituto Superiore di Sanità (Italy), Ghent University (Belgium), BfR (Germany), ANSES (France), CREDA and IRTA (Spain). The purpose was to increase KEto foster harmonization and improve strategies for RA of contaminants in seafood products and the related risk communication to the population. RASCS included 6 work‐packages (WPs) focused on Hazard Identification, Dietary Exposure Assessment, RA: present and future strategies in a changing world and balance with nutritional benefits, Risk/Benefit Perception and Communication, Dissemination and outreach, and Management of the project. The project started during the COVID pandemic, and interaction during the first year was exclusively online. Although this circumstance partially limited interactions, the execution of the project was not significantly impacted. Exchange among partners was ensured through monthly meetings and additional exchanges by mail or web meetings, while during the second year also physical meetings were organised: the first meeting in Paris in June 2022, was followed by an additional interim meeting focused on specific webinars in Barcelona in November 2022. Four sessions of ToS were held in 2023 in Rome, Lisbon, Barcelona and Paris, and a final meeting in Parma at EFSA's premises in June 2023. The RASCS Partnering Grant has allowed to reach three main goals: i) Significantly improve the participant's knowledge within the subject of RA of contaminants in seafood, ii) Increase awareness on EFSA's goals and tools regarding RA, and iii) Strengthen links and network among multidisciplinary institutions and experts also for future consortia. [ABSTRACT FROM AUTHOR]

EFSA was requested by the European Commission to re‐evaluate the risks to public health related to the presence of plasticisers such as phthalates, structurally similar substances and replacement substances, as a consequence of migration from food contact materials (FCMs). In the first part of the two‐part mandate, EFSA was tasked with drawing up a protocol for assessing the hazards of plasticiser substances. The current hazard assessment protocol has been developed using the principles of, and following the recommendations provided in, the 'Draft framework for protocol development for EFSA's scientific assessments' (EFSA et al., 2020). The protocol describes how the two central questions on hazard identification and hazard characterisation will be addressed. It aims to describe as far as possible the strategy for retrieving, selecting and extracting the data, appraising the relevant evidence, and summarising, analysing and integrating that evidence in order to perform hazard assessments that will be used for the risk assessment of the prioritised substances. Outputs addressing the following three related tasks in the mandate will be published separately: (i) identifying and prioritising those substances used or potentially used as plasticisers in FCMs that may warrant further data collection and risk assessment; (ii) drawing up a protocol for the exposure assessment of the prioritised substances; and (iii) setting up calls for data and other information on the occurrence of the prioritised substances. [ABSTRACT FROM AUTHOR]

Human Risk Assessment (RA) of combined exposure to multiple chemicals follows the steps of RA namely problem formulation, exposure assessment, hazard assessment and risk characterisation. Over the last decade, scientific advisory bodies have published a range of harmonised guidance documents to provide practical approaches for risk assessors. These include the WHO, the US‐EPA, the Joint Research Centre (JRC) of the European Commission, the OECD and the recent EFSA MIXTOX guidance document dealing with harmonised methodologies for the human health, animal health and ecological RA areas. On May 21st 2021, the Scientific Committee of EFSA published a draft guidance document on scientific criteria to group chemicals in assessment groups using hazard‐driven criteria and prioritisation methods using exposure‐driven and risk‐based approaches. The latter guidance and future challenges were the topic of this international workshop which was held online in the afternoons of the 18th, 19th and 20st October 2021. First, a plenary session provided overviews of European and international activities in the field including WHO, OECD, US‐EPA, JRC and EFSA. With a total of 118 participants including national and international scientific advisory bodies, academics and researchers, NGOs, industry, risk assessors, risk managers, four discussions groups were created for three break‐out group sessions: 1) Hazard‐driven criteria for grouping multiple chemicals into assessment groups; 2) Exposure‐driven and risk‐based criteria for the prioritisation of multiple chemicals 3) Data gaps and future challenges for human health and environmental RA of combined exposure to multiple chemicals to identify priority topics of international relevance and a way forward to address these topics. A final discussion and wrap‐up session concluded the meeting. This event report provides a summary of the discussions together with conclusions and recommendations. [ABSTRACT FROM AUTHOR]

This external scientific report summarises the results from thearticle 36 grant GA/EFSA/SCER/2015/01″Modelling human variability in toxicokinetic and toxicodynamic processes using Bayesian meta‐analysis, physiologically‐based (PB) modelling and in vitro systems". Extensive literature searches, data collection and modelling of human variability in toxicokinetics (TK) (phase I, Phase II enzymes and transporters) and toxicodynamics (TD) are summarised and further elaborated in supplementary material and EFSA knowledge junction, open source databases(MS Excel) and peer reviewed publications (objective 1 and 2). In addition,in vitro TK and TD information from laboratory studies and literature searches are summarised for a range of case studies relevant to EFSA including pesticides (i.e. triflumuron, chlorpyrifos, phosmet), natural toxins (e.g. microcystin variants, mycotoxins), food additives and polyphenols (i.e. resveratrol, tyrosol), food additives as well as drugs (i.e.amiodarone). These include isoform‐specific metabolism and kinetic parameters for single chemicals and inhibition constants for multiple chemicals (TK) and identification of molecular targets (TD). Finally, generic quantitative in vitro in vivo extrapolation (QIVIVE) models, PB‐kinetic (PBK) and PBK‐dynamic (PBKD) models were developed in the R freeware, calibrated and validated usingcase studies for single and multiple chemicals. Supplementary material and model codes are available on EFSA knowledge junction. The results are in line with EFSA priorities for the implementation of the use of new approach methodologies (NAMs) for human risk assessment (RA) of chemicals and the need to develop open source TK TD databases data and PB‐K and PB‐KD models have been identified as key steps of this process. Future perspectives are discussedincluding the integration of pathway‐related variability and generic human QIVIVE and PB‐K models and PB‐K‐D models into TKplate, a Toxicokinetic Modelling Platform under development in EFSA. [ABSTRACT FROM AUTHOR]

The article presents a study which investigates the effect of lindane (LIN), an organochlorinated compound, on steroid hormone metabolism mediated by cytochrome P450 (CYP) in male mice after in utero exposure. It states that the study measured the liver microsomes of the male mice with the use of tritiated-water formation assay and also applied statistical analysis for its data. It concludes that lindane can induce and affect the hormone regulation processes of the male mice.

Exposure to methylphenidate (MPH) during adolescence is the elective therapy for attention deficit/hyperactivity disorder (ADHD) children, but raises major concerns for public health, due to possibly persistent neurobehavioral changes. Rats (30- to 44-days old) were administered MPH (2 mg/kg, i.p once daily) or saline (SAL). At the end of the treatment we collected plasma, testicular, liver, and brain (striatum) samples. The testes and liver were used to evaluate conventional reproductive and metabolic endpoints. Testes of MPH-exposed rats weighed more and contained an increased quantity of sperm, whereas testicular levels of testosterone (TST) were markedly decreased. The MPH treatment exerted an inductive effect on enzymatic activity of TST hydroxylases, resulting in increased hepatic TST catabolism. These findings suggest that subchronic MPH exposure in adolescent rats could have a trophic action on testis growth and a negative impact on TST metabolism. We have analyzed striatal gene expression profiles as a consequence of MPH exposure during adolescence, using microarray technology. More than 700 genes were upregulated in the striatum of MPH-treated rats (foldchange >1.5). A first group of genes were apparently involved in migration of immature neural/glial cells and/or growth of novel axons. These genes include matrix proteases (ADAM-1, MMP14), their inhibitors (TIMP-2, TIMP-3), the hyaluronan-mediated motility receptor (RHAMM), and growth factors (transforming growth factor-β3 [TGF-β3] and fibroblast growth factor 14 [FGF14]). A second group of genes were suggestive of active axonal myelination. These genes mediate survival of immature cells after contact with newly produced axonal matrix (laminin B1, collagens, integrin alpha 6) and stabilization of myelinating glia-axon contacts (RAB13, contactins 3 and 4). A third group indicated the appearance and/or upregulation of mature processes. The latter included genes for: K+ channels (TASK-1, TASK-5), intercellular junctions (connexin30), neurotransmitter receptors (adrenergic alpha 1B, kainate 2, serotonin 7, GABA-A), as well as major proteins responsible for their transport and/or anchoring (Homer 1, MAGUK MPP3, Shank2). All these genes were possibly involved in synaptic plasticity, namely the formation, maturation, and stabilization of new neural connections within the striatum. MPH treatment seems to potentiate synaptic plasticity, which is an age-dependent developmental phenomenon that adolescent rats are very likely to show, compared to adults. Our observations suggest that adolescent MPH exposure causes only transient changes in reproductive and hormonal parameters, and a more enduring enhancement of neurobehavioral plasticity. [ABSTRACT FROM AUTHOR]

The organophosphorothioate (OPT) pesticide malathion (MAL) in mammals is readily hydrolyzed by mammalian carboxylesterases (CE). The reaction competes with the CYP-catalyzed formation of malaoxon (MOX), the toxic metabolite. Alterations or individual variations in CE activity may result in increased MOX formation, enhancing MAL toxicity. We have characterized the human hepatic CE activity in a panel of 18 human liver microsomes as well as the inhibitory effect of IsoMAL, a major impurity of MAL commercial formulations, parathion (PAR), chlorpyrifos (CPF), and chlorpyrifos-oxon (CPFO). CE activity showed a low level of variation among individuals (4-fold). The reaction consists of two different phases, differing in their affinity for MAL ( Km1 = 0.25-0.69 μM; Km2 = 10.3-26.8 μM). The relatively low Km1 values confirmed that human CE efficiently detoxify MAL. IsoMAL was shown to be a potent noncompetitive inhibitor of MAL detoxification ( Ki = 0.6 μM), with a higher inhibitory potency than CPF and PAR ( Ki = 7.5 μM and 50 μM, respectively). These two latter compounds very likely act as mixed inhibitors. CPFO showed the highest inhibitory potency toward CE-mediated detoxification, being characterized by a Ki = 22 nM. The present results provide useful information for a better understanding of possible interactions between different OPTs and for assessing the potential cumulative risk for exposure to OPT mixtures. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:406-414, 2005; Published online in Wiley InterScience (). DOI 10.1002/jbt.20106 [ABSTRACT FROM AUTHOR]