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The influence of temperature variation on the humoral immune response using the plaque-forming cell (PFC) assay in freshwater fish Channa punctatus (Bloch) was investigated. The fish was exposed to 1% concentration (v/v in water) of paper and pulp mill effluent under standard laboratory conditions in glass aquaria. Effect of effluent exposure on the organ weight and organ cellularity was also evaluated. In general, lower temperature in winter produced a subdued response in control as well as experimental group. At higher temperature of summer and rainy seasons, an elevated response was observed. It was revealed that though suppressive effect of effluent was evident during all the seasons, in summer, extent of suppression was greater as compared to winter. Paper and pulp mill effluent exposure resulted in a decrease in the splenic and pronephric (head kidney) cellularity, with more pronounced effect in the summer season. We also studied the effects of the length of exposure on various parameters. Fish were exposed for 15, 30, 60, and 90 days to effluent. Short-term exposure for 15 days induced an elevated PFC response, but change was not statistically significant. Conversely, the exposure for 30, 60, and 90 days significantly reduced (p < 0.05–0.001) the PFC response. Long-term exposure also caused significant reduction (p < 0.05–0.01) in the weights of lymphoid organs (spleen, head kidney, and total kidney). These results show a suppressive effect of chemical constituents of paper and pulp mill effluent on the immune functions. Furthermore, results demonstrated that though modulatory effect of the temperature on immune functions is recognized, it was not a major contributory factor to the elevated immunotoxicity of paper and pulp mill effluent in the seasons of high temperature. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies targeted against the immune checkpoint molecules CTLA-4 and PD-1 have recently obtained approval for the treatment of metastatic melanoma and advanced/refractory non small-cell lung cancers. Therefore, their use will not be limited anymore to selected hospitals involved in clinical trials. Indeed, they will be routinely prescribed in many cancer centers across the world. Besides their efficacy profile, these immune targeted agents also generate immune-related adverse events (irAEs). This new family of dysimmune toxicities remains largely unknown to the broad oncology community. Although severe irAEs remain rare (~10% of cases under monotherapy), they can become life-threatening if not anticipated and managed appropriately. Over the last 5 years, Gustave Roussy has accumulated a significant experience in the prescription of immune checkpoint blockade (ICB) antibodies and the management of their toxicities. Together with the collaboration of Gustave Roussy's network of organ specialists with expertise in irAEs, we propose here some practical guidelines for the oncologist to help in the clinical care of patients under ICB immunotherapy. [ABSTRACT FROM AUTHOR]

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]

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Perfluorinated compounds (PFCs) are a novel type of environmental pollutant with a specific structure. PFCs have become a global concern due to their environmental persistence and biotoxicity properties. In this paper, we review the hazardous effects, detection technologies, and treatment methods of PFCs. We present the current status of PFCs pollution in water, the atmosphere, soil, and organisms. Moreover, we show that PFCs have toxic effects, such as hepatotoxicity, neurotoxicity, immunotoxicity, endocrine disruption, and reproductive and developmental toxicity. Six sample pretreatment techniques and four assays for PFCs are listed in this paper. This review focuses on the analysis of the treatment methods for PFCs, such as physical adsorption, microbial degradation, photochemical oxidation, electrochemical oxidation, acoustic oxidation, Fenton oxidation, and so on. We systematically analyze the treatment effects, removal mechanisms, and future directions of various technologies to provide support and suggestions for PFCs pollution control technologies. [ABSTRACT FROM AUTHOR]

Background: Bisphenol (BP‐)A is a chemical used in Europe to produce polycarbonate plastics and epoxy resin or as colour developer in thermal paper. Due to its toxicity, BPA presence was restricted by European regulations. Therefore, substitute chemicals are replacing BPA. Objective: To assess the allergenic sensitizing potential of 27 substitutes to BPA used in the industry. Methods: The expression of two costimulatory molecules and six cytokines were analysed by flow cytometry in mouse bone marrow‐derived dendritic cells (BMDCs) exposed to the chemicals. Results: All substances except one induced overexpression of at least one receptor and were thus identified as having allergenic sensitizing potential. Based on the BMDC model, they were classified as extreme (1 out of 27), strong (20 out of 27) and moderate (5 out of 27) sensitizers. BPA was classified as a moderate sensitizer and BPF was the only substitute classified as a non‐sensitizer. The more potent substitutes induced more than 2‐fold secretion of CCL3, CCL4 and/or CCL5 by dendritic cells. Conclusion: Most of the BPA substitutes tested in this study have an allergenic sensitizing potential; 24 of them being more potent than BPA itself. Only BPE, BPF and 2,4‐BPS appeared to be weaker sensitizers than BPA. [ABSTRACT FROM AUTHOR]

The COVID‐19 pandemic is a highly dramatic concern for mankind. In Italy, the pandemic exerted its major impact throughout the period of February to June 2020. To date, the awkward amount of more than 134,000 deaths has been reported. Yet, post‐mortem autopsy was performed on a very modest number of patients who died from COVID‐19 infection, leading to a first confirmation of an immune‐thrombosis of the lungs as the major COVID‐19 pathogenesis, likewise for SARS. Since then (June–August 2020), no targeted early therapy considering this pathogenetic issue was approached. The patients treated with early anti‐inflammatory, anti‐platelet, anticoagulant and antibiotic therapy confirmed that COVID‐19 was an endothelial inflammation with immuno‐thrombosis. Patients not treated or scarcely treated with the most proper and appropriate therapy and in the earliest, increased the hospitalization rate in the intensive care units and also mortality, due to immune‐thrombosis from the pulmonary capillary district and alveoli. The disease causes widespread endothelial inflammation, which can induce damage to various organs and systems. Therapy must be targeted in this consideration, and in this review, we demonstrate how early anti‐inflammatory therapy may treat endothelia inflammation and immune‐thrombosis caused by COVID‐19, by using drugs we are going to recommend in this paper. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

The long-distance migration of polycyclic aromatic hydrocarbons (PAHs) promotes their release into the marine environment, posing a serious threat to marine life. Studies have shown that PAHs have significant immunotoxicity effects on bivalves, but the exact mechanism of immunotoxicity remains unclear. This paper aims to investigate the effects of exposure to 0.4, 2, and 10 μg/L of benzo(a)pyrene (B[a]P) on the immunity of Chlamys farreri under environmental conditions, as well as the potential molecular mechanism. Multiple biomarkers, including phagocytosis rate, metabolites, neurotoxicity, oxidative stress, DNA damage, and apoptosis, were adopted to assess these effects. After exposure to 0.4, 2, and 10 μg/L B[a]P, obvious concentration-dependent immunotoxicity was observed, indicated by a decrease in the hemocyte index (total hemocyte count, phagocytosis rate, antibacterial and bacteriolytic activity). Analysis of the detoxification metabolic system in C. farreri revealed that B[a]P produced B[a]P-7,8-diol-9,10-epoxide (BPDE) through metabolism, which led to an increase in the expression of protein tyrosine kinase (PTK). In addition, the increased content of neurotransmitters (including acetylcholine, γ -aminobutyric acid, enkephalin, norepinephrine, dopamine, and serotonin) and related receptors implied that B[a]P might affect immunity through neuroendocrine system. The changes in signal pathway factors involved in immune regulation indicated that B[a]P interfered with Ca2+ and cAMP signal transduction via the BPDE-PTK pathway or neuroendocrine pathway, resulting in immunosuppression. Additionally, B[a]P induced the increase in reactive oxygen species (ROS) content and DNA damage, as well as an upregulation of key genes in the mitochondrial pathway and death receptor pathway, leading to the increase of apoptosis rate. Taken together, this study comprehensively investigated the detoxification metabolic system, neuroendocrine system, and cell apoptosis to explore the toxic mechanism of bivalves under B[a]P stress. [ABSTRACT FROM AUTHOR]

Repair and reconstruction of large bone defect were often difficult, and bone substitute materials, including autogenous bone, allogenic bone and artificial bone, were common treatment strategies. The key to elucidate the clinical effect of these bone repair materials was to study their osteogenic capacity and immunotoxicological compatibility. In this paper, the mechanical properties, micro-CT imaging analysis, digital image analysis and histological slice analysis of the three bone grafts were investigated and compared after different time points of implantation in rat femur defect model. Autogenous bone and biphasic calcium phosphate particular artificial bone containing 61.4% HA and 38.6% β-tricalcium phosphate with 61.64% porosity and 0.8617 ± 0.0068 g/cm3 density (d  ≤ 2 mm) had similar and strong bone repair ability, but autogenous bone implant materials caused greater secondary damage to experimental animals; allogenic bone exhibited poor bone defect repair ability. At the early stage of implantation, the immunological indexes such as Immunoglobulin G, Immunoglobulin M concentration and CD4 cells' population of allogenic bone significantly increased in compared with those of autologous bone and artificial bone. Although the repair process of artificial bone was relatively inefficient than autologous bone graft, the low immunotoxicological indexes and acceptable therapeutic effects endowed it as an excellent alternative material to solve the problems with insufficient source and secondary trauma of autogenous bone. [ABSTRACT FROM AUTHOR]

Increased expectations from a number of regulatory agencies, e.g., Environmental Protection Agency (EPA), Food and Drug Administration (FDA), European Medicines Agency (EMEA), and the Ministry of Health, Labour and Welfare (MHLW) of Japan, call for the evaluation of potential adverse effects on the immune system. As recently summarized in the ICH S8 guideline, the T-cell-dependent antibody response (TDAR) has been identified in a regulatory context as a main functional test of immunotoxicity. While the characterization of immunotoxic potential is pertinent to both the chemical and pharmaceutical industries, the use of immunotoxicology data for hazard identification and/or risk assessment in each case is different. Therefore, multiple approaches to immunotoxicity testing have evolved. The assays that evaluate TDAR function include both well-established tests, e.g., anti-sheep red blood cell plaque-forming cell (PFC) assay, and newer models, e.g., anti-keyhole limpet hemocyanin (KLH) antibody ELISA. These tests vary in the study design, antigen application and analytical methods. However, they all evaluate the same endpoint - a competent immune (e.g., antibody) response to an antigen. Numerous issues have been identified in the application of TDAR tests, including high animal to animal variability; differences in antigen source and potency; a lack of established "normal range" of the immune response and uncertainty about the degree of inhibition of the TDAR to be considered toxicologically important. As such, the need for a forum to discuss these issues was recognized by the immunotoxicology community, and was addressed at the 2006 Society of Toxicology (SOT) Workshop. A series of papers will summarize that forum with the ultimate objectives being to build a consensus among immunotoxicologists on the implications of these factors on using TDAR results in hazard identification and/or risk assessment, and to establish a criteria to classify compounds as immunotoxicants. [ABSTRACT FROM AUTHOR]

Plastic waste degrades slowly in aquatic environments, transforming into microplastics (MPs) and nanoplastics (NPs), which are subsequently ingested by fish and other aquatic organisms, causing both physical blockages and chemical toxicity. The fish immune system serves as a crucial defense against viruses and pollutants present in water. It is imperative to comprehend the detrimental effects of MPs on the fish immune system and conduct further research on immunological assessments. In this paper, the immune response and immunotoxicity of MPs and its combination with environmental pollutants on fish were reviewed. MPs not only inflict physical harm on the natural defense barriers like fish gills and vital immune organs such as the liver and intestinal tract but also penetrate cells, disrupting intracellular signaling pathways, altering the levels of immune cytokines and gene expression, perturbing immune homeostasis, and ultimately compromising specific immunity. Initially, fish exposed to MPs recruit a significant number of macrophages and T cells while activating lysosomes. Over time, this exposure leads to apoptosis of immune cells, a decline in lysosomal degradation capacity, lysosomal activity, and complement levels. MPs possess a small specific surface area and can efficiently bind with heavy metals, organic pollutants, and viruses, enhancing immune responses. Hence, there is a need for comprehensive studies on the shape, size, additives released from MPs, along with their immunotoxic effects and mechanisms in conjunction with other pollutants and viruses. These studies aim to solidify existing knowledge and delineate future research directions concerning the immunotoxicity of MPs on fish, which has implications for human health. [Display omitted] [ABSTRACT FROM AUTHOR]

The Extended-One-Generation Study [EOGRTS, OECD 443] is a study in which the toxic effects of test substances on reproduction (Cohort 1), neurodevelopment (Cohort 2), and development of the immune system (Cohort 3) in rats are evaluated. The latter two Cohorts are not always required according to the European Chemicals Agency (ECHA) based on data from previously performed toxicity studies. Although the Cohorts for developmental neurotoxicity (DNT) and developmental immunotoxicity (DIT) are often omitted, the F 1 -animals normally required for these Cohorts are still maintained for evaluation of sexual maturation since three F 1 -animals/sex/litter/group are required according to OECD Guidance Document (GD) No. 151. This review investigates whether two F 1 -animals/sex/litter/group would suffice for this endpoint by investigating the rationale provided by the GD and by comparing results of eighteen EOGRTSs in which three versus two F 1 -animals/sex/litter/group were evaluated. After a comprehensive literature research, we concluded that the rationale in the GD does not substantiate the decision to use three F 1 -animals/sex/litter/group. The scientific papers provided as rationale focused on male observations and the observations discussed do not match the observations for sexual maturation mentioned by the guidelines. The investigation using data from eighteen EOGRTSs showed that the toxicological conclusions, whether the test substance affected sexual maturation or not, matched when comparing data of two F 1 -animals/sex/litter/group to three F 1 -animals/sex/litter/group. To conclude, two F 1 -animals/sex/litter/group would suffice for the evaluation of sexual maturation, which negates the requirement for a so called "Cohort 1 C" (i.e. 160 animals (80 males and 80 females)) per EOGRTS, as well as the number of regulated procedures that need to be performed. • ECHA requires 3 pups/sex/litter for sexual maturation assessment in the EOGRTS. • This review investigates whether 2 pups/sex/litter would suffice for this endpoint. • A comparison was made for 2 versus 3 pups using data from 18 EOGRTSs. • It was concluded that 2 pups/sex/litter would suffice for a complete evaluation. • Thereby reducing treatment time and handling for 160 animals per study. [ABSTRACT FROM AUTHOR]

With a growing interest in the concept of a circular economy, the use of lignocellulosic residues, such as lignins and humins, as potential renewable feedstock for biorefining processes looks increasingly promising. Many challenges remain for the sustainable use of humins, starting from the need to provide reference data reflecting actual usable feedstocks of such materials. This paper offers the first study, from this perspective, of the potential environmental fate of those materials and components, all related to furanics, a family of compounds the toxicity of which is still a matter of debate. Conventional ecotoxicity and biodegradability tests required by European regulation on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) for the primary evaluation of environmental hazards were conducted in combination with fish immunomarker tests to study possible long‐term effects on aquatic ecosystems. These first results are promising as humins did not give rise to any immediate ecotoxicological concerns, and hence their use could be considered in environment‐friendly applications. © 2018 Society of Chemical Industry and John Wiley & Sons, Ltd [ABSTRACT FROM AUTHOR]

The immunotoxic potential of drug candidates is assessed through the examination of results from a variety of studies and endpoints. While the functional assessment of CD8+ cytotoxic T-lymphocytes (CTL) is well-characterized in the clinic, the lack of a robust macaque CTL functional assay has been an important hurdle in evaluating and accurately quantifying cell-mediated CD8+ T-cell effector responses in the nonclinical setting. This paper describes the development of an assay to measure CTL activity in peripheral blood mononuclear cells (PBMC) isolated from Cynomolgus macaques. A human EGFR/CD3 Bispecific T-cell Engager (BiTE®) was used to mount a robust CD8+ T-cell response in the presence of target-expressing cells. Upon target engagement, degranulation of CD107a and production of interferon (IFN)-γ both reliably indicated a robust functional response in CD8+ T-cells. The BiTE®-mediated stimulation method proved to be favorable when compared to other methods of stimulation in the absence of target cells. These studies demonstrated acceptable longitudinal variability of the functional assay and sensitivity to dexamethasone-mediated immunosuppression. Taken together, the results indicated an assay leveraging CD3-bispecific antibodies and target-expressing cells can provide a robust approach to the in vitro or ex vivo assessment of CTL function in Cynomolgus macaques. Because the impairment of CTL activity by immunomodulators is recognized to be an important contributor to decreased antiviral defense and increased carcinogenicity risk, we believe that this novel assay to be a valuable addition to the immunotoxicology assessment of therapeutic drug candidates. [ABSTRACT FROM AUTHOR]

Polychlorinated biphenyls (PCBs), and similar environmental contaminants, have been linked to virus outbreaks and increased viral induced mortality since the 1970s. Yet the mechanisms behind this increased susceptibility remain elusive. It has recently been illustrated that the innate immune viral detection system is tightly regulated by small non‐coding RNAs, including microRNAs (miRNAs). For virus infections miRNA‐155 expression is an important host response against infection, and deregulation of this miRNA is closely associated with adverse outcomes. Thus, we designed a targeted in vitro study using primary chicken fibroblasts, first exposed to a mixture of PCBs (Arochlor‐1250) before being stimulated with a synthetic RNA virus (poly I:C), to determine if PCBs have the potential to deregulate miRNA‐155. In this paper, we provide the first data for the deregulation of miRNA‐155 when a host is exposed to a mixture of PCBs before a virus infection. Thus, we provide important evidence that PCBs can be involved in the deregulation of important miRNA pathways involved in the immune system; thereby demonstrating novel insights into the mechanism of PCB toxicity on the immune system. [ABSTRACT FROM AUTHOR]

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are persistent organic pollutants in the environment and have serious health risks, including endocrine disrupting properties, immunotoxicity and developmental effects etc. The photochemical degradation has been proven to be a low-cost, efficient and sustainable technology for the removal of PFOX (X = A or S) in water. At present, most of the investigations have been conducted in ultrapure water and at concentrations much higher comparing to those detected in the real wastewaters. Furthermore, there are few studies about the toxicity of treated water. In this paper, the state of knowledge on the photocatalytic degradation of PFOX, including photo-oxidative and photo-reductive degradation, is reviewed comprehensively. Compared with photo-oxidation, photo-reduction appears to be more suitable for the PFOX removal since it is more favorable for the defluorination of PFOX and further complete mineralization. The effects of key parameters on the photocatalytic degradation and defluorination process of PFOX are commendably accessed, such as light wavelength, photocatalyst concentration, initial PFOX concentration, pH, reaction atmosphere, temperature, and coexisting organic or inorganic matters. The mechanisms of PFOX photodegradation process are also elucidated in detail. This paper will help to deeply understand PFOX decomposition process and put forward better perspectives in the future for researchers who work in this field. [ABSTRACT FROM AUTHOR]

2,2′,4,4′-Tetrabrominated biphenyl ether (BDE-47) is a polybrominated diphenyl ether (PBDE) homologue that is ubiquitous in biological samples and highly toxic to humans and other organisms. Prior research has confirmed that BDE-47 can induce oxidative damage in RAW264.7 cells, resulting in apoptosis and impaired immune function. The current study mainly focused on how Isoliquiritigenin (ISL) and Licochalcone B (LCB) might protect against BDE-47's immunotoxic effects on RAW264.7 cells. The results show that ISL and LCB could increase phagocytosis, increase the production of MHC-II, and decrease the production of inflammatory factors (TNF-α, IL-6, and IL-1β) and co-stimulatory factors (CD40, CD80, and CD86), alleviating the immune function impairment caused by BDE-47. Secondly, both ISL and LCB could reduce the expressions of the proteins Bax and Caspase-3, promote the expression of the protein Bcl-2, and reduce the apoptotic rate, alleviating the apoptosis initiated by BDE-47. Additionally, ISL and LCB could increase the levels of antioxidant substances (SOD, CAT, and GSH) and decrease the production of reactive oxygen species (ROS), thereby counteracting the oxidative stress induced by BDE-47. Ultimately, ISL and LCB suppress the NF-κB pathway by down-regulating IKBKB and up-regulating IκB-Alpha in addition to activating the Nrf2 pathway and promoting the production of HO-1 and NQO1. To summarize, BDE-47 causes oxidative damage that can be mitigated by ISL and LCB through the activation of the Nrf2 pathway and inhibition of the NF-κB pathway, which in turn prevents immune function impairment and apoptosis. These findings enrich the current understanding of the toxicological molecular mechanism of BDE-47 and the detoxification mechanism of licorice. [ABSTRACT FROM AUTHOR]

Prebiotics are known as the ‘food’ for beneficial gut microbiota that are capable of promoting host health. Their effects depend on the product of gut fermentation or metabolites. This paper discusses the role of prebiotics on cytotoxicity, genotoxicity, and cell integrity. Metabolites produced from the fermentation of prebiotics can be used to understand gut diseases such as colorectal cancer. Fecal water fromin vivoorin vitrostudies can be used to understand the relationship between prebiotics and gut diseases because of its close contact with colon epithelium. Besides, fecal water has compounds that are capable of modifying colonocytes. [ABSTRACT FROM AUTHOR]

Flow cytometry is a unique technology useful in the examination of effects of immunotoxic agents on target cells of the immune system. The purpose of this workshop was to provide an overview of the use of flow cytometry in new and established models of immunotoxicity, with emphasis on the potential applications, assay validation, and potential pitfalls. This overview begins with a discussion of methods useful in the assessment of Ca2+ -dependent mechanisms of lymphoid cell activation in surface marker-defined human B cells, T cells, and monocytes. A discussion of the use of flow cytometry in analysis of apoptosis is also presented in this paper. The second paper presents data on the development and use of flow cytometry as an alternative to a Cr51 release assay for an assessment of cytotoxic T cell activation. The use of surface markers for characterizing and distinguishing the effects of chemical irritants from sensitizers is next presented, followed by an overview of the use of fluorescent probes to assess cell thiol status and overall oxidant-induced injury to lymphoid cells. Finally, an interlaboratory study designed to compare and evaluate the use of flow cytometry procedures in rat splenic cell subtyping is presented. Overall, these studies demonstrate the utility of flow cytometry assays in immunotoxicologic research, but further efforts are needed in the validation of many of these assays for routine use in immunotoxicologic testing. [ABSTRACT FROM AUTHOR]

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).

Plant protection products (PPPs) and the active substance(s) contained within them are rigorously and comprehensively tested prior to registration to ensure that human health is not impacted by their use. In recent years, there has been a widespread drive to have more relevant testing strategies (e.g., ILSI/HESI-ACSA and new EU Directives), which also take account of animal welfare, including the 3R (replacement, refinement, and reduction) principles. The toxicity potential of one such new active substance, sulfoxaflor, a sulfoximine insecticide (CAS #946578-00-3), was evaluated utilizing innovative testing strategies comprising: (1) an integrated testing scheme to optimize information obtained from as few animals as possible (i.e., 3R principles) through modifications of standard protocols, such as enhanced palatability study design, to include molecular endpoints, additional neurotoxicity and immunotoxicity parameters in a subchronic toxicity study, and combining multiple test guidelines into one study protocol; (2) generation of toxicokinetic data across dose levels, sexes, study durations, species, strains and life stages, without using satellite animals, which was a first for PPP development, and (3) addition of prospective mode of action (MoA) endpoints within repeat dose toxicity studies as well as proactive inclusion of specific MoA studies as an integral part of the development program. These novel approaches to generate key data early in the safety evaluation program facilitated informed decision-making on the need for additional studies and contributed to a more relevant human health risk assessment. This supplement also contains papers which describe in more detail the approach taken to establish the MoA and human relevance framework related to toxicities elicited by sulfoxaflor in the mammalian toxicology studies: [ABSTRACT FROM AUTHOR]

Deleterious health effects induced by inorganic vanadium compounds are linked with carcinogenic, immunotoxic and neurotoxic insults. The goal of this review is to provide a summary of mammalian cell culture studies (from the 1990s to most recent) looking into the mode of the above-mentioned adverse actions of vanadium. Regarding the carcinogenicity potential, the key cell-based studies have evidenced the ability of vanadium to induce genotoxic lesions, cell morphological transformation and anti-apoptotic effects in a certain type of cells. Two contradictory effects of vanadium on the immune functions of cells have been observed in cell culture studies. The first effect involves reduction of cell immune responses such as vanadium-dependent inhibition of cytokine-inducible functions, which may underlie the mechanism of vanadium-induced immunosuppression. The second one involves stimulation of immune activity, for example, a vanadium-mediated increase in cytokine production, which may contribute to vanadium-related inflammation. So far, an in vitro evaluation of vanadium neurotoxicity has only been reported in few articles. These papers indicate probable cytotoxic mechanisms resulting from exposure of neurons and glial cells to vanadium. In summary, this literature review collects in vitro reports on adverse vanadium effects and thus provides vanadium researchers with a single, concise source of data. [ABSTRACT FROM AUTHOR]

Although the adverse health effects of nanoparticles/materials have been proposed and are being clarified, their facilitating effects on preexisting pathological conditions have not been fully examined. In this paper, we provide insights into the immunotoxicity of nanoparticles/materials as an aggravating factor in hypersusceptible subjects, especially those with immune-related respiratory disorders using our in vivo experimental model. We first exhibit the effects of nanoparticles/materials on lung inflammation induced by bacterial endotoxin (lipopolysaccharide: LPS) in vivo as a disease model in innate immunity, and demonstrated that nanoparticles instilled through both an intratracheal tube and an inhalation system can exacerbate the lung inflammation. Secondly, we introduce the effects of nanoparticles/materials on allergic asthma in vivo as a disease model in adaptive immunity, and showed that repetitive pulmonary exposure to nanoparticles has aggravating effects on allergic airway inflammation, including adjuvant effects on Th2-milieu. Taken together, nanoparticle exposure may synergistically facilitate pathological inflammatory conditions in the lung via both innate and adaptive immunological abnormalities. [ABSTRACT FROM AUTHOR]

Suitable assays and test strategies are needed to analyze potential genotoxic and immunotoxic health effects caused by nanoparticle exposure. The development and validation of such methods is challenging because nanoparticles may show unexpected behavior, like aggregation or interference with optical measurements, when routine in vitro assays are performed. In our interdisciplinary study, the effects of inorganic gold (4.5 nm) and iron oxide (7.3 nm) nanoparticles with a narrow size distribution were tested on human cells using different assay systems. The results show that cytotoxicity as well as immunotoxicity and genotoxicity induced by these two inorganic nanoparticles was low or absent when using a panel of cell-based tests in different laboratories. However, several technical issues had to be tackled that were specific for working with nanoparticles. The methods used, their suitability for nanotoxicity testing, and the technical problems encountered are carefully described and discussed in this paper. [ABSTRACT FROM AUTHOR]

The number of anti-inflammatory and immunomodulatory drugs being developed in the pharmaceutical industry has increased considerably in the past decade. This increase in research and development has been paralleled by questions from both regulatory agencies and industry on how best to assess decreased host resistance to infections or adverse immunostimulation caused by immunomodulatory agents such as anti-cytokine antibodies (e.g., the tumor necrosis factor-α inhibitors), anti-adhesion molecule antibodies (e.g., anti-α-4 integrin inhibitors) and immunostimulatory molecules (e.g., anti-CD28 antibodies). Although several methods have been developed for nonclinical assessment of immunotoxicity, highly publicized adverse events have brought to light significant gaps in the application of nonclinical immunotoxicity testing in assessing potential risk in humans. Confounding this problem is inconsistent application of immunotoxicology methods for risk assessment within the scientific community, limited understanding of appropriate immunotoxicity testing strategy for immunomodulators and inconsistent testing requests by regulatory agencies. To address these concerns, The Immunotoxicology Technical Committee (ITC) of the International Life Science Institute (ILSI) Health and Environmental Sciences Institute (HESI) organized a workshop on Immunomodulators and Clinical Immunotoxicology in May 2007. The Workshop was convened to identify key gaps in nonclinical and clinical immunotoxicity testing of anti-inflammatory and immunomodulatory agents and to begin to develop consistent approaches for immunotoxicity testing and risk assessment. This paper summarizes the outcome of the HESI ITC Immunomodulators and Clinical Immunotoxicology Workshop. Topics not discussed at the Workshop were outside the scope of this report. Although more work is needed to develop consistent approaches for immunotoxicity assessment of immunomodulators, this Workshop provided the foundation for future discussion. [ABSTRACT FROM AUTHOR]

Cyanobacteria (blue-green algae) have been present on Earth for over 2 billion years, and can produce a variety of bioactive molecules, such as cyanotoxins. Microcystins (MCs), the most frequently detected cyanotoxins, pose a threat to the aquatic environment and to human health. The classic toxic mechanism of MCs is the inhibition of the protein phosphatases 1 and 2A (PP1 and PP2A). Immunity is known as one of the most important physiological functions in the neuroendocrine-immune network to prevent infections and maintain internal homoeostasis in fish. The present review aimed to summarize existing papers, elaborate on the MC-induced immunotoxicity in fish, and put forward some suggestions for future research. The immunomodulatory effects of MCs in fish depend on the exposure concentrations, doses, time, and routes of exposure. Previous field and laboratory studies provided strong evidence of the associations between MC-induced immunotoxicity and fish death. In our review, we summarized that the immunotoxicity of MCs is primarily characterized by the inhibition of PP1 and PP2A, oxidative stress, immune cell damage, and inflammation, as well as apoptosis. The advances in fish immunoreaction upon encountering MCs will benefit the monitoring and prediction of fish health, helping to achieve an ecotoxicological goal and to ensure the sustainability of species. Future studies concerning MC-induced immunotoxicity should focus on adaptive immunity, the hormesis phenomenon and the synergistic effects of aquatic microbial pathogens. [ABSTRACT FROM AUTHOR]

It has long been known that the developing immune system is more sensitive and susceptible than the adult immune system to some drugs and environmental contaminants. However, notable advances have been made in the database of studies supporting developmental immunotoxicity (DIT) over the past 5 years. There is considerable evidence that responses of the immune system can be quantitatively or qualitatively different from normal adult responses when xenobiotic exposure occurs during critical periods of immune system development. Qualitative differences of DIT relative to adult exposures include examples of more persistent effects, a latency of effects, and immune dysfunction that is fundamentally different than effects observed when adults are exposed. A symposium was presented at the Society of Toxicology annual meeting to provide an update on advances in the maturing field of developmental immunotoxicology and to facilitate discussion on the range of DIT and later life effects following developmental exposure. In particular, presentations focused on implications of neuroendocrine cross-talk for DIT, the association between developmental air pollutant exposure and asthma, and recent evidence that developmental exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin may increase the risk of autoimmune responses. Several important concepts relative to DIT assessment were illustrated, i.e., (1) Screening for immunosuppression alone is not sufficient to identify all potential immunotoxic effects; (2) DIT cannot be reliably predicted from studies that only utilize adult exposures; (3) Functional testing protocols are preferred in the assessment of DIT; (4) Gender-related differences should be routinely assessed; (5) Latency (i.e., later-life adverse outcomes resulting from developmental exposures) is an important consideration that cannot be detected in adult exposure studies; and, (6) There is increasing support for DIT testing protocols with continuous exposure throughout development until the immune assay is performed. [ABSTRACT FROM AUTHOR]

This paper presents the results of long-term monitoring of insecticide resistance in populations of agricultural pests in Russia. Over the last 45 years, resistance developments were recorded for 36 arthropod pest species in 11 agricultural crops and pastures in relation to nearly all commonly used plant protection products. Development of group, cross and multiple resistance has been revealed in populations of many economically important pests. Toxicological and phenotypical (for Colorado potato beetle) methods have been devised to monitor the development of pesticide resistance. Based on experience over the last century, systems aimed at preventing the development of pest resistance to insecticides and acaricides are elaborated. These systems are based on resistance monitoring and using plant protection measures which minimize the toxic pressure on agroecosystems. [ABSTRACT FROM AUTHOR]

Several papers published over the last year represent significant progress in closing the gap between rodent immunotoxicity data and human risk and indicate that, at least for the developing immune system, the concern raised by rodent data is justified. The studies reviewed here show that suppression of immune responses in rodents is predictive of suppression of immune responses in humans and that there is a relationship between immune suppression following developmental exposure to the toxicants and enhanced risk of infectious or neoplastic disease in humans. The three cases highlighted here are remarkable in that they all deal with real-world environmental exposures that represent different media—air (cigarette smoke), water (arsenic), and food (polychlorinated biphenyls [PCBs])—and constitute very real risks. Moreover, the arsenic and PCB studies actually demonstrate a quantitative relationship between human exposure and immune suppression. There is evidence that in utero exposure to cigarette smoke and arsenic but not PCBs is associated with increased risk of allergic disease as well. There is clearly potential for designing studies that could address both issues. [ABSTRACT FROM PUBLISHER]

There is growing evidence that heavy metals in general, and mercurial compounds in particular, are immunotoxic. The purpose of this study was to explore the mechanism of MeHg in inducing cell death of mouse peritoneal neutrophils. In this paper we demonstrate that MeHg induces apoptosis and necrosis depending on MeHg concentration. In vitro exposure of mouse peritoneal neutrophils to MeHg resulted in a time- and concentration-dependent cell death. MeHg (15 μM) induced neutrophil necrosis in 13 min. The type of cell death was attributed to necrosis based on cells permeable to the fluorescent dye, propidium iodide and DNA appeared as a smear. With fura-2 microfluorimetric technique, we found that the entry of external Ca2+ into the cytosol played a crucial role in inducing cell necrosis by 15 μM MeHg. However, at lower concentrations, MeHg (10 μM)-induced apoptosis is confirmed by the observation of morphological features characterised by apoptotic bodies and fragmented DNA ladder. MeHg (10 μM) caused an immediate fall in pHi as revealed by the pH-sensitive fluorescent probe 2′7′-bis (carboxyethyl)-5(6)-carboxyfluorescein. We have found that MeHg induced cellular acidification prior to DNA fragmentation so as the other two apoptosis-inducing agents (ZnCl2 and EGTA). Furthermore, acid-activated endonuclease was increased by MeHg in neutrophils, which we considered to play a possible role in chromatin digestion leading to apoptosis. Taken together, these findings indicate that MeHg induces necrosis at higher concentrations by a rapid increase of [Ca2+]i and apoptosis at lower concentrations by acid activation of endonuclease. [ABSTRACT FROM AUTHOR]

Dogs play an important role in toxicology because of their importance as a large animal, pre-clinical model for evaluating potential toxicity in human drug development including the effects of investigational drugs on the immune system. The purpose of this paper is to review the development of the canine immune system during the fetal, neonatal and postnatal periods and to compare it with that of the human immune system. Unlike rodents, the development of the canine immune system shares many similarities to that of the human. In both dogs and humans, the immune system, including the mucosal immune system, is fully developed before birth although the maturity of the immune response may continue into the postnatal period. [ABSTRACT FROM AUTHOR]

The goals of this paper will be to present a critical review of the state of the science of pesticides and autoimmunity, and to discuss research that addresses the potential links between environmental chemicals and autoimmune disease. To date, the science of immunotoxicology has primarily focused on immunosuppression and hypersensitivity/allergy, and test methods are available to address these outcomes. So much progress has been made to address immunosuppression and contact sensitization that there are regulatory guidelines in the U.S. included in the registration of pesticides. In contrast, there are no validated approaches to assess autoimmunity. The overall objective of this paper will be to use pesticides as an important class of environmental chemicals to critically evaluate the state of the science for addressing chemical-induced autoimmunity. Specific examples of studies with pesticides will be discussed in the context of the following types of approaches: animal studies using standard immunotoxicological parameters; animal studies using specialized models of autoimmunity; human studies after environmental or occupational exposure; and human studies after accidental poisoning. [Copyright &y& Elsevier]

Since the early 2000s, studies of the evolution of venom within animals have rapidly expanded, offering new revelations on the origins and development of venom within various species. The venomous mammals represent excellent opportunities to study venom evolution due to the varying functional usages, the unusual distribution of venom across unrelated mammals and the diverse variety of delivery systems. A group of mammals that excellently represents a combination of these traits are the slow (Nycticebus spp.) and pygmy lorises (Xanthonycticebus spp.) of south-east Asia, which possess the only confirmed two-step venom system. These taxa also present one of the most intriguing mixes of toxic symptoms (cytotoxicity and immunotoxicity) and functional usages (intraspecific competition and ectoparasitic defence) seen in extant animals. We still lack many pieces of the puzzle in understanding how this venom system works, why it evolved what is involved in the venom system and what triggers the toxic components to work. Here, we review available data building upon a decade of research on this topic, focusing especially on why and how this venom system may have evolved. We discuss that research now suggests that venom in slow lorises has a sophisticated set of multiple uses in both intraspecific competition and the potential to disrupt the immune system of targets; we suggest that an exudate diet reveals several toxic plants consumed by slow and pygmy lorises that could be sequestered into their venom and which may help heal venomous bite wounds; we provide the most up-to-date visual model of the brachial gland exudate secretion protein (BGEsp); and we discuss research on a complement component 1r (C1R) protein in saliva that may solve the mystery of what activates the toxicity of slow and pygmy loris venom. We conclude that the slow and pygmy lorises possess amongst the most complex venom system in extant animals, and while we have still a lot more to understand about their venom system, we are close to a breakthrough, particularly with current technological advances. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) is a known endocrine disruptor found in many consumer products that humans come into contact with on a daily basis. Due to increasing concerns about the safety of BPA and the introduction of new legislation restricting its use, industry has responded by adopting new, less studied BPA analogues that have similar polymer-forming properties. Some BPA analogues have already been shown to exhibit effects similar to BPA, for example, contributing to endocrine disruption through agonistic or antagonistic behaviour at various nuclear receptors such as estrogen (ER), androgen (AR), glucocorticoid (GR), aryl hydrocarbon (AhR), and pregnane X receptor (PXR). Since the European Food Safety Authority (EFSA) issued a draft re-evaluation of BPA and drastically reduced the temporary tolerable daily intake (t-TDI) of BPA from 4 mg/kg body weight/day to 0.2 ng/kg body weight/day due to increasing concern about the toxic properties of BPA, including its potential to disrupt immune system processes, we conducted a comprehensive review of the immunomodulatory activity of environmentally abundant BPA analogues. The results of the review suggest that BPA analogues may affect both the innate and acquired immune systems and can contribute to various immune-mediated conditions such as hypersensitivity reactions, allergies, and disruption of the human microbiome. [ABSTRACT FROM AUTHOR]

It is assumed that mycotoxins have been present in feed and food since the beginning of eukaryotic fungi's life on Earth. With the recognition of the symptoms of the first intoxications, the so-called mycotoxicosis, there was a desire to find strategies in the fight against secondary metabolites of different types of fungi. The mycotoxins that most commonly contaminate feed are aflatoxin B1 (AFB1), deoxynivalenol (DON), zearalenone (ZEN) and fumonisin B1 (FB1). These mycotoxins can primarily cause hepatotoxicity, immunotoxicity, neurotoxicity and nephrotoxicity, and consequently cause adverse effects on animal health and performance. Today, in the 21st century, the need to find a multidisciplinary and integrated plan in the fight against mycotoxins has grown with the realization that mycotoxins cause large-scale damage in livestock. Physical, chemical, biological and nutritional strategies have been developed to combat mycotoxins in the feed industry. Meanwhile, the use of each of these strategies achieves benefits, but also has drawbacks, including being expensive or impractical to apply on a large scale. [ABSTRACT FROM AUTHOR]

The potential for chemicals to adversely affect human immunologic health has traditionally been evaluated in rodents, under laboratory conditions. These laboratory studies have generated valuable hazard identification and immunotoxicologic mechanism data; however, genetically diverse populations exposed in the wild may better reflect both human exposure conditions and may provide insight into potential immunotoxic effects in humans. In addition, comparative studies of species occupying reference and impacted sites provide important information on the effects of environmental pollution on the immunologic health of wildlife populations. In this symposium overview, Peter Hodson describes physiological changes in fish collected above or below the outflows of paper mills discharging effluent from the bleaching process (BKME). Effects attributable to BKME were identified, as were physiological changes attributable to other environmental factors. In this context, he discussed the problems of identifying true cause and effect relationships in field studies. Mohamed Faisal described changes in immune function of fish collected from areas with high levels of polyaromatic hydrocarbon contamination. His studies identified a contaminant-related decreases in the ability of anterior kidney leukocytes to bind to and kill tumor cell line targets, as well as changes in lymphocyte proliferation in response to mitogens. Altered proliferative responses of fish from the contaminated site were partially reversed by maintaining fish in water from the reference site. Peter Ross described studies in which harbor seals were fed herring obtained from relatively clean (Atlantic Ocean) and contaminated (Baltic Sea) waters. Decreased natural killer cell activity and lymphoproliferative responses to T and B cell mitogens, as well as depressed antibody and delayed hypersensitivity responses to injected antigens, were identified in seals fed contaminated herring. In laboratory studies, it was determined that rats fed freeze-dried Baltic Sea herring had higher virus titers after challenge with rat cytomegalovirus (RCMV) than rats fed Atlantic Ocean herring; perinatal exposure of rats to oil extracted from Baltic herring also reduced the response to challenge with RCMV. Keith Grassman reported an association between exposure to polyhalogenated aryl hydrocarbons and decreased T cell immunity in the offspring of fish-eating birds (herring gulls and Capsian terns) at highly contaminated sites in the Great Lakes. The greatest suppression of skin test responses to phytohemagglutinin injection (an indicator of T cell immunity) was consistently found at sites with the highest contaminant concentrations. Judith Zelikoff addressed the applicability of immunotoxicity studies developed in laboratory-reared fish for detecting altered immune function in wild populations. She presented data from studies done in her laboratory with environmentally relevant concentrations of metals as examples. Although the necessity of proceeding with caution when extrapolating across species was emphasized, she concluded that published data, and results presented by the other Symposium participants, demonstrate that assays similar to those developed for use in laboratory rodents may be useful for detecting immune system defects in wildlife species directly exposed to toxicants present in the environment. [ABSTRACT FROM AUTHOR]

Dust, both industrial and household, contains particulates that can reach the most distal aspects of the lung. Silica and nickel compounds are two such particulates and have known profiles of poor health outcomes. While silica is well-characterized, nickel compounds still need to be fully understood for their potential to cause long-term immune responses in the lungs. To assess these hazards and decrease animal numbers used in testing, investigations that lead to verifiable in vitro methods are needed. To understand the implications of these two compounds reaching the distal aspect of the lungs, the alveoli, an architecturally relevant alveolar model consisting of epithelial cells, macrophages, and dendritic cells in a maintained submerged system, was utilized for high throughput testing. Exposures include crystalline silica (SiO2) and nickel oxide (NiO). The endpoints measured included mitochondrial reactive oxygen species and cytostructural changes assessed via confocal laser scanning microscopy; cell morphology evaluated via scanning electron microscopy; biochemical reactions assessed via protein arrays; transcriptome assessed via gene arrays, and cell surface activation markers evaluated via flow cytometry. The results showed that, compared to untreated cultures, NiO increased markers for dendritic cell activation, trafficking, and antigen presentation; oxidative stress and cytoskeletal changes, and gene and cytokine expression of neutrophil and other leukocyte chemoattractants. The chemokines and cytokines CCL3, CCL7, CXCL5, IL-6, and IL-8 were identified as potential biomarkers of respiratory sensitization. [ABSTRACT FROM AUTHOR]

In November of 2021, the European Food Safety Authority (EFSA) released a draft scientific opinion on bisphenol A (BPA) exposure and health outcomes released to the public. EFSA concluded that the most sensitive outcome category to BPA exposure is the immune system. In this scientific opinion, EFSA utilized a weight of evidence approach to conclude that it is likely that BPA exposure promotes the development of TH17 cell-mediated atopic respiratory disease (eg, wheezing, rhinitis and asthma). Here, we present a dissenting analysis to that put forward in the draft EFSA scientific opinion and raise concerns about the studies and EFSA's interpretation of data that were used to arrive at their conclusion. [ABSTRACT FROM AUTHOR]

Background: Exposure to perfluorinated alkylate substances (PFAS) is associated with harmful effects on human health, including developmental immunotoxicity. This outcome was chosen as the critical effect by the European Food Safety Authority (EFSA), which calculated a new joint reference dose for four PFAS using a Benchmark Dose (BMD) analysis of a study of 1-year old children. However, the U.S. Environmental Protection Agency (EPA) recently proposed much lower exposure limits. Methods: We explored the BMD methodology for summary and individual data and compared the results with and without grouping for two data sets available. We compared the performance of different dose-response models including a hockey-stick model and a piecewise linear model. We considered different ways of testing the assumption of equal weight-based toxicity of the four PFAS and evaluated more flexible models with exposure indices allowing for differences in toxicity. Results: Results relying on full and decile-based data were in good accordance. However, BMD results for the larger study were lower than observed by EFSA for the smaller study. EFSA derived a lower confidence limit for the BMD of 17.5 ng/mL for the sum of serum-PFAS concentration, while similar calculations in the larger cohort yielded values of about 1.5 ng/mL. As the assumption of equal weight-based toxicity of the four PFAS seems questionable, we confirmed dose-dependencies that allowed potency differences between PFAS. We also found that models linear in the parameters for the BMD analysis showed superior coverage probabilities. In particular, we found the piecewise linear model to be useful for Benchmark analysis. Conclusions: Both data sets considered could be analyzed on a decile basis without important bias or loss of power. The larger study showed substantially lower BMD results, both for individual PFAS and for joint exposures. Overall, EFSA's proposed tolerable exposure limit appears too high, while the EPA proposal is in better accordance with the results. [ABSTRACT FROM AUTHOR]

Micro- and nanoplastics (MNPs) are emerging pollutants with scarcely investigated effects on human innate immunity. If they follow a similar course of action as other, more thoroughly investigated particulates, MNPs may penetrate epithelial barriers, potentially triggering a cascade of signaling events leading to cell damage and inflammation. Inflammasomes are intracellular multiprotein complexes and stimulus-induced sensors critical for mounting inflammatory responses upon recognition of pathogen- or damage-associated molecular patterns. Among these, the NLRP3 inflammasome is the most studied in terms of activation via particulates. However, studies delineating the ability of MNPs to affect NLRP3 inflammasome activation are still rare. In this review, we address the issue of MNPs source and fate, highlight the main concepts of inflammasome activation via particulates, and explore recent advances in using inflammasome activation for assessment of MNP immunotoxicity. We also discuss the impact of co-exposure and MNP complex chemistry in potential inflammasome activation. Development of robust biological sensors is crucial in order to maximize global efforts to effectively address and mitigate risks that MNPs pose for human health. [ABSTRACT FROM AUTHOR]

As a new alternative to perfluorooctane sulfonic acid (PFOS), 6:2 fluorotelomer sulfonic acid (6:2 FTSA) has been widely produced and used in recent years, and its concentration and frequency of detection in the aquatic environment and aquatic organisms are increasing. However, studies of its toxicity in aquatic biological systems are alarmingly scarce, and the relevant toxicological information needs to be improved. In this study, we investigated AB wild-type zebrafish (Danio rerio) embryos subjected to acute 6:2 FTSA exposure for immunotoxicity using immunoassays and transcriptomics. Immune indexes showed significant decreases in SOD and LZM activities, but no significant change in NO content. Other indexes (TNOS, iNOS, ACP, AKP activities, and MDA, IL-1β, TNF-α, NF-κB, TLR4 content) all showed significant increases. These results indicated that 6:2 FTSA induced oxidative stress and inflammatory responses in zebrafish embryos and exhibited immunotoxicity. Consistently, transcriptomics showed that genes involved in the MAPK, TLR and NOD-like receptor signaling pathways (hsp70, hsp701, stat1b, irf3, cxcl8b, map3k8, il1b, tnfa and nfkb) were significantly upregulated after 6:2 FTSA exposure, suggesting that 6:2 FTSA might induce immunotoxicity in zebrafish embryos through the TLR/NOD-MAPK pathway. The results of this study indicate that the safety of 6:2 FTSA should be examined further. [ABSTRACT FROM AUTHOR]

Immunotoxicity, defined as adverse effects of xenobiotics on the immune system, is gaining increasing attention in the approval process of industrial chemicals and drugs. In-vivo and ex-vivo experiments have been the gold standard in immunotoxicity assessment so far, so the development of in-vitro and in-silico alternatives is an important issue. In this paper we describe a widely applicable, easy-to use computational approach which can serve as an initial immunotoxicity screen of new chemical entities. Molecular fingerprints describing chemical structure were used as parameters in a machine-learning approach based on the Naïve-Bayes learning algorithm. The model was trained using blood-cell growth inhibition data from the NCI database and validated externally with several in-house and literature-derived data sets tested in cytotoxicity assays on different types on immune cells. Both cross-validations and external validations resulted in areas under the receiver operator curves (ROC/AUC) of 75% or higher. The classification of the validation data sets occurred with excellent specificities and fair to excellent selectivities, depending on the data set. This means that the probability of actual immunotoxicity is very high for compounds classified as immunotoxic, while the fraction of false negative predictions might vary. Thus, in a multistep immunotoxicity screening scheme, the classification as immunotoxic can be accepted without additional confirmation, while compounds classified as not immunotoxic will have to be subjected to further investigation. [ABSTRACT FROM AUTHOR]

Zinc oxide (ZnO) nanoparticles (NPs) have potential applications in cosmetics, food packaging and biomedicine but concerns regarding their safety need to be addressed. In the present study, the immunotoxic potential of ZnO NPs was evaluated in different ages of BALB/c mice after sub-acute exposure. The cytokine release, immunophenotyping, distribution of ZnO NPs and ultrastructural changes were assessed. A significant (p < 0.05) change in the CD4- and CD8-cells, levels of IL-6, IFN-γ and TNF-α and reactive oxygen species were observed in aged mice. In juvenile mice, increase in reactive oxygen species and IL-6 and TNF-α levels was observed with no significant changes in adult mice. A significant (p < 0.05) increase in the expression levels of mitogen activated protein kinase (MAPK) cascade proteins such as phospho-ERK1/2, phospho-JNK and phospho-p38 were also induced in aged mice. Collectively, our results indicate that the aged mice are more susceptible to ZnO NP induced immunotoxicity. [ABSTRACT FROM AUTHOR]

Ochratoxin A (OTA), a toxin produced by Aspergillus ochraceus and Penicillium verrucosum, is one of the most abundant food-contaminating mycotoxins worldwide. OTA mainly exerts nephrotoxicity, immunotoxicity, mutagenicity, carcinogenicity, teratogenicity, and neurotoxicity. This paper describes a simple and sensitive aptamer/single-walled carbon nanohorn (SWCNH)-based assay for OTA detection. SWCNHs can protect DNA from DNase I cleavage. However, aptamers can be detached from the surface of SWCNHs through specific target binding, exposing them to enzymatic cleavage and releases the target for a new cycle. Cycling of targets leads to significant signal amplification and low limit of detection (LOD), resulting in a nearly 20-fold reduction in LOD for OTA assay compared with non-target recycling under the same experimental parameters. This technique responded specifically to OTA without interference from other analogues (Ochratoxin B, Ochratoxin C, warfarin, and N -acetyl- l -phenylalanine). Moreover, the application of this technique in real sample has been verified using red wine samples spiked with a series of OTA concentrations. This aptasensor offers a great practical importance in food safety and can be widely extended for detection of other toxins by replacing the sequence of the recognition aptamer. [ABSTRACT FROM AUTHOR]

This paper evaluates the coexistence risks of triphenyltin (TPT) and norfloxacin (NOR) to aquatic organisms in the aquatic environment. Carp (Cyprinus carpio) was used as the test organism, the control and exposure groups (1 μg/L TPT), 1 mg/L (NOR), 1 μg/LTPT+1 mg/LNOR (TPT_NOR)) were set up according to the environmental concentration in the severely polluted area for 42 days. The single/combined toxic effects of TPT and NOR on aquatic organisms were evaluated by analyzing carp brain transcriptome sequencing, gut microbiota structure, and detection of biochemical indicators and RT-qPCR. Our results show that TPT and NOR induce lipid metabolism disorder in carp brain tissue, affecting the metabolism of cytochrome P450 to exogenous substances, and NOR also induces immunosuppression in carp. Long-term exposure to TPT combined with NOR amplifies the monotoxicity of TPT or NOR on lipid metabolism and immunosuppression in carp, induces immune dysfunction in brain tissue and changes in gut microbiota structure. However, TPT_NOR has no obvious neurotoxicity on the brain, but it can inhibit the level of intestinal MDA. This highlights that co-exposure of TPT and NOR amplifies metabolic disorders and immunosuppressive functions in carp. [Display omitted] • TPT induces disorder of lipid metabolism in carp. • NOR induces lipid accumulation in carp and leads to immune dysfunction. • TPT combined with NOR amplifies the immunotoxicity and metabolic toxicity to carp. [ABSTRACT FROM AUTHOR]

In the current paper, a new strategy for risk assessment of nanomaterials is described, which builds upon previous project outcomes and is developed within the FP7 NANoREG project. NANoREG has the aim to develop, for the long term, new testing strategies adapted to a high number of nanomaterials where many factors can affect their environmental and health impact. In the proposed risk assessment strategy, approaches for (Quantitative) Structure Activity Relationships ((Q)SARs), grouping and read-across are integrated and expanded to guide the user how to prioritise those nanomaterial applications that may lead to high risks for human health. Furthermore, those aspects of exposure, kinetics and hazard assessment that are most likely to be influenced by the nanospecific properties of the material under assessment are identified. These aspects are summarised in six elements, which play a key role in the strategy: exposure potential, dissolution, nanomaterial transformation, accumulation, genotoxicity and immunotoxicity. With the current approach it is possible to identify those situations where the use of nanospecific grouping, read-across and (Q)SAR tools is likely to become feasible in the future, and to point towards the generation of the type of data that is needed for scientific justification, which may lead to regulatory acceptance of nanospecific applications of these tools. [ABSTRACT FROM AUTHOR]