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BackgroundKey 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.ObjectivesThe 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.MethodsA 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.DiscussionKCs 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.

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]

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

(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]