NAM journal最新文献

Parkinson's disease (PD) prevalence has been steeply increasing over the last years. Environmental pollution, including certain pesticides, is considered a significant contributor to this rise. Certain genetic factors may pose an individual or subpopulation at increased risk to develop pesticide-induced PD. To support New Approach Methodologies (NAMs)-based hazard and risk assessment while considering known sources of interindividual variability, the aim of the current work was to identify biological factors related to increased susceptibility towards pesticide-induced PD onset and progression. To this end, a semi-systematic literature search was performed using Sysrev. We identified 61 relevant records. Potential gene-environment interactions were identified for several genes related to toxicokinetics, mitochondrial functioning, neurotransmission and proteostasis. These genes, except those related to toxicokinetics, have been described in Adverse Outcome Pathways (AOPs) leading to parkinsonian motor symptoms. Untargeted (epi)genetic analyses identified potential new targets. NAMs offer the opportunity to include human-relevant genetic interindividual variability in toxicological hazard and risk assessment. For example, an additional test condition with mutations of interest for each Key Event (KE) could be included in a test strategy. Whole-organism models combined with CrispR-CAS techniques are suitable to study the effects of specific mutations on PD risk. Induced pluripotent stem cells (iPSCs) are promising to study interindividual variability in disease susceptibility based on material from genetically diverse donors. Since additional experiments are resource-intensive, further research is required to establish the need and way to include genetic susceptibilities in a regulatory context.

•o-Phenylphenol (OPP) is safe when used as preservative up to a maximum concentration of 0.2 % in rinse-off cosmetic products.•o-Phenylphenol (OPP) is safe when used as preservative up to a maximum concentration of 0.15 % in leave-on cosmetic products.•Sodium o-Phenylphenate is safe when used as preservative up to a maximum concentration of 0.2 % in rinse-off cosmetic products.•Sodium o-Phenylphenate is safe when used as preservative up to a maximum concentration of 0.15 % in leave-on cosmetic products.•OPP and Sodium o-Phenylphenate, when used together, should not exceed the maximum concentration 0.15 % in leave-on cosmetic products.•OPP and Sodium o-Phenylphenate, when used together, should not exceed the maximum concentration 0.2 % in rinse-off cosmetic products.•Since this safety dossier related to dermally applied products only, the SCCS did not consider oral and inhalation routes.•This assessment did not cover the safety of O-Phenylphenol and Sodium o-Phenylphenate for the environment.

•BZP-4 is safe when used as UV filter up to a max. conc. of 5 % in sunscreen, all leave-on products (tot. dermal aggregate).•BZP-4 is safe when used as UV filter up to a max. conc. of 5 % in sunscreen, all rinse-off products (tot. dermal aggregate).•Same for lipstick, sunscreen propellant and pump spray (separately or in combination based on determ. aggregated exposure).•BZP-4 use as stabiliser when the product is exposed to light should remain within the conc. of. 5 %, incl. UV-filter use.•This assessment did not cover the safety of Benzophenone-4 for the environment.

The larval zebrafish (Danio rerio) locomotor response light/ dark (LMR L/D) assay may inform developmental neurotoxicity (DNT) hazard, but a lack of standardized data analysis techniques has limited cross-laboratory data comparisons and integration. The present work proposes a concentration-response modeling workflow for evaluating chemicals tested in the LMR L/D assay, comprising 13 endpoints measuring different types of behavioral response (habituation, average speed, startle response, and range of activity). Data were previously collected for 61 chemicals tested in the LMR L/D assay, including 47 chemicals with evidence of in vivo DNT and 14 putative negatives. Response values were normalized using a Box-Cox transformation to address challenges such as inter-fish variability and non-normally distributed data. We found that the commonly studied endpoints in the LMR L/D assay (four in this study) were the most active overall; however, we identified ten chemicals that were only active in the less commonly studied endpoints (nine in this study), suggesting the potential added value of these endpoints for detecting behavioral changes in developing zebrafish. Importantly, we found that bidirectional curve-fitting and biphasic concentration-response models were informative for modeling zebrafish behavior, particularly for effects occurring at lower concentrations. This standardized concentration-response modeling workflow for the LMR L/D assay successfully detected chemical-induced changes in zebrafish behavior and contributes to a global effort to increase data transferability, reproducibility, and integration across LMR L/D labs and other DNT assay technologies.

DILI (Drug Induced Liver Injury) is one of leading cause of failure in drug development due to adverse reaction outcomes and health hazards. Besides, understanding DILI is challenging due to lack of relevant in vitro models] that recapitulate human in vivo physiological responses. Current in vitro models employing primary human Kupffer cells (PHKCs) or alternative cells such as THP-1 derived macrophages are either complex or do not recapitulate physiological drug-induced cytokine responses. We leveraged on human iPSC derived Kupffer cells (iKCs) that functionally resemble PHKCs to establish a human in vitro inflammatory liver model (HIVIL) that is complex enough to be physiological and simple enough to be robust. HIVIL, comprising of iKCs co-cultured with iPSCs derived hepatocytes can recapitulate physiological levels of DILI associated inflammatory response of known DILI drugs in vitro. Out of 18 drug candidates tested, the cytokine responses of 16 drugs correlated (88.9 %) well with the reported serum cytokine profiles of DILI patients implying a closer-to-physiological relevant immune responses and cytochrome P450 expression . Moreover, HIVIL model was able to mechanistically distinguish the TNF⍺ mediated hepatotoxic effect of Trovafloxacin over Levofloxacin. RNA-Seq analysis provided further insight into the interactions between the cytokines and drug-induced liver injury. In contrast, HIVIL using THP-1 derived macrophages instead of iKCs did not recapitulate the cytokine responses upon treatment with paradigm compounds, demonstrating the importance of KCs-produced cytokines on hepatocyte xenobiotic metabolism. In summary, our study demonstrates for the first time, the use of iKCs and iHeps as a simple, robust and physiologically relevant in vitro drug testing model for DILI candidates.

Traditional regulatory frameworks for assessing the environmental safety of chemicals have historically focused on evaluating in vivo data from standard ecologically representative species. This approach relies heavily on apical effect studies performed on whole organisms. However, there is now a strong regulatory and ethical push towards adopting non-animal approaches that incorporate novel methodologies and enhance the mechanistic understanding of toxicological responses across various species. Despite this progress, their implementation in environmental risk assessment remains limited. We propose a conceptual framework for conducting safety assessments that leverages mechanistic data, extending beyond traditional types, to inform environmental safety decisions. This approach aims to support the application of new approach methodologies in environmental risk assessment, without the need for generating additional animal data. We then evaluate the approach with three case studies based on different modes of action, including 17R-Ethinyl Estradiol, Chlorpyrifos, and Tebufenozide. The overall strategy involves the collection and integration of available relevant effect data across human health and the environment to demonstrate the suitability of mechanistic-based information to support and strengthen current practices. The results demonstrate that integrating historical in vivo data, in vitro functional assays, and in silico computational tools enhances confidence in safety decision-making through identification of the most sensitive species where evolutionary conservation of biological targets and toxicological outcomes are in agreement. This approach offers a valuable weight-of-evidence method to understand potential toxicity effects better and points to practical future applications.

Obesity is a global health concern linked to various diseases. Recently, chemicals known as "obesogens" have been identified as significant contributors to obesity, highlighting the need for reliable methods to screen chemicals for their obesity-promoting potential. This study aimed to develop a standardized adipogenesis assay using primary human bone marrow-derived multipotent mesenchymal stromal stem cells (hBM-MSCs) to evaluate the adipogenic potential of chemicals. Lipid accumulation in hBM-MSCs was measured after chemical exposure. Assay conditions including cell confluency, fluorescent staining of neutral lipids and fluorometric detection were optimized and standardized. Using the established method, we evaluated the effects of six selected chemicals on the adipogenic responses of hBM-MSCs from different donors, including an in-house generated immortalized hBM-MSC cell line. Not all donor-derived hBM-MSCs were shown to be suitable for the assay, but we observed comparable results among suitable hBM-MSCs and between primary hBM-MSCs and their immortalized derivative cell line. Comparisons with the well-established 3T3-L1 preadipocyte model revealed a strong correlation with the hBM-MSCs assay. We observed that experimental details such as cell density, fluorescent measurement and cell donors can greatly affect outcomes; this stresses the importance of a well described standard operating procedure (SOP). Our developed test method, including a detailed SOP, paves the way for a validated test methodology that is urgently needed and currently lacking for the identification of obesogenic endocrine disruptors.