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Perfluorinated substances (PFAS) are a class of synthetic chemicals widely used in industry, to which people and ecosystems are exposed. Epidemiological studies have shown that PFAS can cause immunosuppression, increased risk of infections and decreased response to vaccination, with the underlying mechanism(s) of action still remaining elusive. The aim of this project was to fill some of the data gaps identified in the 2020 EFSA Opinion, using new approach methodologies (NAMs). In particular, we aimed to get information on the mode of action for the immunosuppression effects observed in epidemiological studies (i.e., reduction in the vaccination efficacy and possible increase in the susceptibility to infectious disease), and to address the immunotoxicity of PFAS other than PFOS and PFOA (PFNA and PFHxS), including the assessment of a possible common mode of action and to provide insight into the relative potencies of the tested PFAS. To reach these goals, an integrated testing strategy (ITS) consisting of in vitro and in silico methods was developed. The effects of PFAS were investigated using target immune human cell‐based in vitro models, suitable to assess the relevant immunotoxic parameters observed in epidemiological studies (i.e. decreased antibody production). Results obtained fully support the evidence from human epidemiological studies. Furthermore, mathematical fate and distribution models were used to identify nominal concentration of PFAS in the in vitro cell system and physiologically based kinetic (PBK) models were used to perform quantitative in vitro to in vivo extrapolation. The 'Universal Immune System Simulator' was used to complete the ITS and investigate the reduced response to vaccination also on vulnerable populations. The use of these selected NAMs may provide a tool to support, by providing mechanistic information, regulatory risk assessment and to study the immunotoxic potential of other PFAS. The participation of immunotoxicologists, molecular biologists, risk assessors, and computational experts within the Consortium, together with EFSA's engagement, ensured the successful performance of this project and delivery of a NAMs‐based strategy that allows generating mechanistic information on PFAS immunotoxicity and support risk assessment. [ABSTRACT FROM AUTHOR]

Background: Key characteristics (KCs), properties of agents or exposures that confer potential hazard, have been developed for carcinogens and other toxicant classes. KCs have been used in the systematic assessment of hazards and to identify assay and data gaps that limit screening and risk assessment. Many of the mechanisms through which pharmaceuticals and occupational or environmental agents modulate immune function are well recognized. Thus KCs could be identified for immunoactive substances and applied to improve hazard assessment of immunodulatory agents. Objectives: The goal was to generate a consensus-based synthesis of scientific evidence describing the KCs of agents known to cause immunotoxicity and potential applications, such as assays to measure the KCs. Methods: A committee of 18 experts with diverse specialties identified 10 KCs of immunotoxic agents, namely, 1) covalently binds to proteins to form novel antigens, 2) affects antigen processing and presentation, 3) alters immune cell signaling, 4) alters immune cell proliferation, 5) modifies cellular differentiation, 6) alters immune cell-cell communication, 7) alters effector function of specific cell types, 8) alters immune cell trafficking, 9) alters cell death processes, and 10) breaks down immune tolerance. The group considered how these KCs could influence immune processes and contribute to hypersensitivity, inappropriate enhancement, immunosuppression, or autoimmunity. Discussion: KCs can be used to improve efforts to identify agents that cause immunotoxicity via one or more mechanisms, to develop better testing and biomarker approaches to evaluate immunotoxicity, and to enable a more comprehensive and mechanistic understanding of adverse effects of exposures on the immune system. https://doi.org/10.1289/EHP10800, Introduction The concept of agents or exposures having properties that confer potential hazards called key characteristics (KCs), was developed during review of the diverse agents identified as established (Group 1) [...]

As a complex system governing and interconnecting numerous functions within the human body, the immune system is unsurprisingly susceptible to the impact of toxic chemicals. Toxicants can influence the immune system through a multitude of mechanisms, resulting in immunosuppression, hypersensitivity, increased risk of autoimmune diseases and cancer development. At present, the regulatory assessment of the immunotoxicity of chemicals relies heavily on rodent models and a limited number of Organisation for Economic Co-operation and Development (OECD) test guidelines, which only capture a fraction of potential toxic properties. Due to this limitation, various authorities, including the World Health Organization and the European Food Safety Authority have highlighted the need for the development of novel approaches without the use of animals for immunotoxicity testing of chemicals. In this paper, we present a concise overview of ongoing efforts dedicated to developing and standardizing methodologies for a comprehensive characterization of the immunotoxic effects of chemicals, which are performed under the EU-funded Partnership for the Assessment of Risk from Chemicals (PARC). [ABSTRACT FROM AUTHOR]

(1) Background: The insecticide cypermethrin (Cypm) and the herbicide glyphosate (Glyp) are among the most widely used pesticides. While the two pesticides have been considered to have low toxicity in mammals, some indication of potential immunotoxicity has emerged. The aim of this work was to investigate in vitro the effects of Cypm and Glyp on bacteria lipopolysaccharide (LPS)-induced immune cell activation and of Cypm on 2-mercaptobenzothiazole (MBT)-induced maturation of dendritic cells (DCs). (2) Methods: The release of the inflammatory cytokines TNF-α and IL-8, the expression of the surface markers CD54 and CD86 in human primary peripheral blood mononuclear cells (PBMC), and THP-1 cells were investigated together with CD83, HLA-DR, IL-6, and IL-18 in DCs. (3) Results: While no significant modulation on LPS-induced immune cell activation was observed following Glyp exposure, with only a trend toward an increase at the highest concentration tested, Cypm reduced the responses to LPS and to MBT, supporting a direct immunosuppressive effect. Overall, the present study contributes to our understanding of pesticide-induced immunotoxicity, and the results obtained support evidence showing the immunosuppressive effects of Cypm. [ABSTRACT FROM AUTHOR]

The toxicity of particulate matter (PM) is strictly associated with its physical-chemical characteristics, such as size or chemical composition. While these properties depend on the origin of the particles, the study of the toxicological profile of PM from single sources has rarely been highlighted. Hence, the focus of this research was to investigate the biological effects of PM from five relevant sources of atmospheric PM: diesel exhaust particles, coke dust, pellet ashes, incinerator ashes, and brake dust. Cytotoxicity, genotoxicity, oxidative, and inflammatory response were assessed in a bronchial cell line (BEAS-2B). BEAS-2B cells were exposed to different concentrations (25, 50, 100, and 150 μg/mL medium) of particles suspended in water. The exposure lasted 24 h for all the assays performed, except for reactive oxygen species, which were evaluated after 30 min, 1 h, and 4 h of treatment. The results showed a different action of the five types of PM. All the tested samples showed a genotoxic action on BEAS-2B, even in the absence of oxidative stress induction. Pellet ashes seemed to be the only ones able to induce oxidative stress by boosting the formation of reactive oxygen species, while brake dust resulted in the most cytotoxic. In conclusion, the study elucidated the differential response of bronchial cells to PM samples generated by different sources. The comparison could be a starting point for a regulatory intervention since it highlighted the toxic potential of each type of PM tested. [ABSTRACT FROM AUTHOR]

In 2015, EFSA established a temporary tolerable daily intake (t‐TDI) for BPA of 4 μg/kg body weight (bw) per day. In 2016, the European Commission mandated EFSA to re‐evaluate the risks to public health from the presence of BPA in foodstuffs and to establish a tolerable daily intake (TDI). For this re‐evaluation, a pre‐established protocol was used that had undergone public consultation. The CEP Panel concluded that it is Unlikely to Very Unlikely that BPA presents a genotoxic hazard through a direct mechanism. Taking into consideration the evidence from animal data and support from human observational studies, the immune system was identified as most sensitive to BPA exposure. An effect on Th17 cells in mice was identified as the critical effect; these cells are pivotal in cellular immune mechanisms and involved in the development of inflammatory conditions, including autoimmunity and lung inflammation. A reference point (RP) of 8.2 ng/kg bw per day, expressed as human equivalent dose, was identified for the critical effect. Uncertainty analysis assessed a probability of 57–73% that the lowest estimated Benchmark Dose (BMD) for other health effects was below the RP based on Th17 cells. In view of this, the CEP Panel judged that an additional uncertainty factor (UF) of 2 was needed for establishing the TDI. Applying an overall UF of 50 to the RP, a TDI of 0.2 ng BPA/kg bw per day was established. Comparison of this TDI with the dietary exposure estimates from the 2015 EFSA opinion showed that both the mean and the 95th percentile dietary exposures in all age groups exceeded the TDI by two to three orders of magnitude. Even considering the uncertainty in the exposure assessment, the exceedance being so large, the CEP Panel concluded that there is a health concern from dietary BPA exposure. This publication is linked to the following EFSA Journal article: http://onlinelibrary.wiley.com/doi/10.2903/j.efsa.2023.p210401/full [ABSTRACT FROM AUTHOR]

This report is the outcome of an EFSA procurement (NP/EFSA/PREV/2020/01) which aims at contributing to the development of adverse outcome pathways (AOPs) to be integrated in a network addressing uterine adenocarcinoma in mammals. The outcome is intended to support the identification of substances with endocrine disruptor mode of action. For this specific purpose, an evidence‐based approach methodology was adopted. Available evidence was systematically mapped from the literature to identify Molecular Initiating Events (MIEs) and Key Events (KEs) linked to adverse outcome (AO) "uterine endometrioid adenocarcinoma" independently from prototypical stressors, by means of: 1. a priori defined search strategies initially addressing the AO and biologically plausible MIEs, 2. application of machine learning technique (Topic modelling) that automatically analyzes text data to identify biologically plausible KERs, 3. systematic literature review and critical appraisal of prioritized evidence, taking into account human, in vivo and in vitro studies. Estradiol and tamoxifen, two recognized human risk factors for endometrioid adenocarcinoma, were used as tool chemical compounds to empirically support the response and temporal concordance of the identified key event relationships (KERs). All evidence has been then integrated by means of the AOP conceptual network. An evidence‐based AOP starting from activation of uterine estrogen receptor‐alfa leading to endometrial adenocarcinoma via epigenetic modulation was postulated. This publication is linked to the following EFSA Journal article: http://onlinelibrary.wiley.com/doi/10.2903/j.efsa.2023.7744/full [ABSTRACT FROM AUTHOR]