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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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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 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]

Regulators and risk managers in general need to decide whether an allergenic food or ingredient is of such public health importance that it needs to be actively managed. There is therefore a need to scale the relative allergenicity of foods and ingredients according to the hazards they pose. Objective criteria increase transparency and trust in this decision-making process and its conclusions. This paper proposes a framework that allows categorisation and prioritisation of allergenic foods according to their public health importance. The challenge is to find a basis on which the allergenicity of foods can best be described and a method to combine the relevant measures of allergenicity into a scoring system that prioritises allergenic foods on the basis of their public health relevance. The framework is designed in accordance with the generic risk analysis principles used in food safety and can be used by regulators to decide whether or not a specific allergenic food or ingredient is of sufficient public health importance that it warrants regulation (i.e. mandatory labelling) when used in the production of food products. [ABSTRACT FROM AUTHOR]

The paper describes the importance of toxicology as a discipline, its past achievements, current scientific challenges, and future development. Toxicological expertise is instrumental in the reduction of human health risks arising from chemicals and drugs. Toxicological assessment is needed to evaluate evidence and arguments, whether or not there is a scientific base for concern. The immense success already achieved by toxicological work is exemplified by reduced pollution of air, soil, water, and safer working places. Predominantly predictive toxicological testing is derived from the findings to assess risks to humans and the environment. Assessment of the adversity of molecular effects (including epigenetic effects), the effects of mixtures, and integration of exposure and biokinetics into in vitro testing are emerging challenges for toxicology. Toxicology is a translational science with its base in fundamental science. Academic institutions play an essential part by providing scientific innovation and education of young scientists. [ABSTRACT FROM AUTHOR]

The preweaning piglet has been found to be a valuable research model for testing ingredients used in infant formula. As part of the safety assessment, the neonates' immune system is an important component that has to be evaluated. In this study three concurrent strategies were developed to assess immune system status. The methods included (1) immunophenotying to assess circulating innate immune cell populations, (2) monitoring of circulating cytokines, particularly in response to a positive control agent, and (3) monitoring of localized gastrointestinal tissue cytokines using immunohistochemistry (IHC), particularly in response to a positive control agent. All assays were validated using white papers and regulatory guidance within a GLP environment. To validate the assays precision, accuracy and sample stability were evaluated as needed using a fit for purpose approach. In addition animals were treated with proinflammtory substances to detect a positive versus negative signal. In conclusion, these three methods were confirmed to be robust assays to evaluate the immune system and GIT-specific immune responses of preweaning piglets. [ABSTRACT FROM AUTHOR]

Immune response is modulated by different substances that are present in the environment. Nevertheless, some of these may cause an immunotoxic effect. In this paper, the effect of organophosphorus pesticides (frequent substances spilled in aquatic ecosystems) on the immune system of fishes and in immunotoxicology is reviewed. Furthermore, some cellular and molecular mechanisms that might be involved in immunoregulation mechanisms of organophosphorus pesticides are discussed. [ABSTRACT FROM AUTHOR]

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]

The advent of the selective cholinergic toxin, 192 IgG-saporin, dramatically shaped subsequent research on the role of the basal forebrain in learning and memory. In particular, several articles (including the authors' 1995 Behavioral Neuroscience paper; M. G. Baxter, D. J. Bucci, L. K., Gorman, R. G. Wiley, & M. Gallagher, 1995) revealed that selective removal of basal forebrain cholinergic neurons had surprisingly little effect on spatial learning and memory. Here, as part of the series commemorating the 30th anniversary of Behavioral Neuroscience, we describe how our earlier findings prompted a reconsideration of the cholinergic contribution to cognitive function and also led to several new research directions, including renewed interest in basal forebrain GABA-ergic neurons and cholinergic contributions to neurocognitive development. The authors also describe how the successful use of 192 IgG-saporin led to the development and popularity of a wide range of selective new neurotoxic agents. Finally, they consider the utility of the permanent lesion approach in the wake of new transgenic and optogenetic methods. [ABSTRACT FROM AUTHOR]

Abstract: Oxidative stress and DNA damage are the most studied mechanisms by which ochratoxin A (OTA) induces its toxic effects, which include nephrotoxicity, hepatotoxicity, immunotoxicity and genotoxicity. Zinc, which is an essential trace element, is considered a potential antioxidant. The aim of this paper was to investigate whether zinc supplement could inhibit OTA-induced oxidative damage and DNA damage in HepG2 cells and the mechanism of inhibition. The results indicated that that exposure of OTA decreased the intracellular zinc concentration; zinc supplement significantly reduced the OTA-induced production of reactive oxygen species (ROS) and decrease in superoxide dismutase (SOD) activity but did not affect the OTA-induced decrease in the mitochondrial membrane potential (Δψm). Meanwhile, the addition of the zinc chelator N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) strongly aggravated the OTA-induced oxidative damage. This study also demonstrated that zinc helped to maintain the integrity of DNA through the reduction of OTA-induced DNA strand breaks, 8-hydroxy-2′-deoxyguanosine (8-OHdG) formation and DNA hypomethylation. OTA increased the mRNA expression of metallothionein1-A (MT1A), metallothionein2-A (MT2A) and Cu/Zn superoxide dismutase (SOD1). Zinc supplement further enhanced the mRNA expression of MT1A and MT2A, but it had no effect on the mRNA expression of SOD1 and catalase (CAT). Zinc was for the first time proven to reduce the cytotoxicity of OTA through inhibiting the oxidative damage and DNA damage, and regulating the expression of zinc-associated genes. Thus, the addition of zinc can potentially be used to reduce the OTA toxicity of contaminated feeds. [Copyright &y& Elsevier]

Abstract: The US Air Force wrote the specification for the first official hydrocarbon-based jet fuel, JP-4, in 1951. This paper will briefly review the toxicity of the current fuel, JP-8, as compared to JP-4. JP-8 has been found to have low acute toxicity with the adverse effects being slight dermal irritation and weak dermal sensitization in animals. JP-4 also has low acute toxicity with slight dermal irritation as the adverse effect. Respiratory tract sensory irritation was greater in JP-8 than in JP-4. Recent data suggest exposure to jet fuel may contribute to hearing loss. Subchronic studies for 90 days with JP-8 and JP-4 showed little toxicity with the primary effect being male rat specific hydrocarbon nephropathy. A 1-year study was conducted for JP-4. The only tumors seen were associated with the male rat specific hydrocarbon nephropathy. A number of immunosuppressive effects have been seen after exposure to JP-8. Limited neurobehavioral effects have been associated with JP-8. JP-8 is not a developmental toxicant and has little reproductive toxicity. JP-4 has not been tested for immune, neurobehavioral or reproductive endpoints. JP-8 and JP-4 were negative in mutagenicity tests but JP-4 showed an increase in unscheduled DNA synthesis. Currently, JP-8 is being used as the standard for comparison of future fuels, including alternative fuels. Emerging issues of concern with jet fuels include naphthalene content, immunotoxicity and inhalation exposure characterization and modeling of complex mixtures such as jet fuels. [Copyright &y& Elsevier]

Abstract: Introduction: Immunosuppressive drugs are associated with an increased risk of infections and in some cases neoplasia, particularly non-melanoma skin cancers. This paper describes the development of a model to test the effects of immunosuppressive drugs on local invasion and metastases of a squamous cell carcinoma in syngeneic, immunocompetent mice. Methods: SCC VII cells were labeled with 655 quantum dots (QDs), injected intramuscularly into C3H HEN mice and traffic and progressive growth in the draining popliteal lymph node were evaluated. Results: SCC VII cells express RAE-1, an NKG2D ligand, and were sensitive to natural killer (NK) cells in vitro. QDs were stable in SCC VII cells and showed no evidence of toxicity to the cells. In vivo, confocal microscopy showed that QD-labeled SCC VII cells could migrate to the draining node and microfluorimetry showed progressive traffic of QDs to the node. There was no evidence of systemic toxicity of QDs. Primary immunosuppression in SCID and SCID-beige mice and treatment of normal mice with immunosuppressive agents (anti-asialoGM1 and cyclophosphamide) can enhance traffic of QDs and/or metastases to the draining lymph node. In contrast, cyclosporine had no effect on traffic or metastases. Conclusion: This model of local invasion and metastases may be useful in immunotoxicology for identifying and characterizing the hazard posed by selective immunosuppressive drugs. [Copyright &y& Elsevier]

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]

Abstract: A protocol to evaluate the potential developmental and reproductive effects of test chemicals has been developed by the Life Stages Task Force of the International Life Sciences Institute (ILSI)/Health and Environmental Sciences Institute (HESI) Agricultural Chemical Safety Assessment (ACSA) Technical Committee. Since the original publication, several international groups have provided public comment on conducting the test. The extended one-generation reproductive toxicity test is now under consideration as a potential test guideline. The protocol uses a flexible approach that is markedly different from the current multigenerational guidelines. It encourages the use of toxicokinetics when setting the doses, evaluates more than one rat per sex per litter in the F1 offspring and does not necessarily require mating of the F1 to produce an F2 (F1 mating may be triggered by the presence of effects in the P0 and developing F1 rats). A number of additional reproductive endpoints, and the neurotoxicity and immunotoxicity cohorts are included. The ACSA protocol was developed with the goal of assuring that the methods are scientifically appropriate and the toxicological endpoints and exposure durations are relevant for risk assessment. Compared to existing testing strategies, the proposed approach uses substantially fewer animals, provides additional information on the neonate, juvenile and pubertal animal, and includes an estimation of human exposure potential for making decisions about the extent of testing required. In this paper, the evolution of the protocol since the 2006 publication is discussed. These changes reflect the collective input of a U.S. expert panel of government and industrial scientist convened in 2007 and discussions of an OECD expert group held in Paris, France (October, 2008). [Copyright &y& Elsevier]

Abstract: Consumers are exposed to organotin compounds (OTCs) via contaminated fish and seafood due to the accumulation of these compounds in marine organisms. Certain OTCs are immunotoxic and may also have endocrine disrupting properties resulting in adverse effects on the reproductive tract in mollusks and mammals. Since effects of in utero exposure to endocrine disrupting chemicals on the reproductive system are dependent on the critical window of exposure during its development, we conducted a comprehensive study with the aim to identify the most sensitive window of exposure to TPTCl and to investigate the effects of pre- and postnatal treatment on sexual development in rats. Male and female offspring rats were exposed to 2 or 6mg TPTCl/kg b.w. and day either in utero and during lactation (gestation day 6 until weaning on PND 21) or from gestation day 6 until termination. As previously reported, offspring in the 6mg TPTCl dose group exhibited high perinatal mortality and therefore no further evaluation was carried out at this dose level (Grote, K., Hobler, C, Andrade, A.J.M., Wichert Grande, S., Gericke, C., Talsness, C.E., Appel, K.E., Chahoud, I., 2007. Effects of in utero and lactational exposure to triphenyltin chloride on pregnancy outcome and postnatal development in rat offspring. Toxicology 238, 177–185). In the present paper, results on postnatal development obtained from surviving offspring of dams exposed to 2mg TPTCl/kg b.w. are reported. Male offspring were sacrificed on PND 64 or 65 and female offspring at first estrus after PND 58. A clear sex difference in response to treatment was observed. Male postnatal development was severely affected with decreases in body weight gain, reproductive organ weights and testosterone concentration as well as a significant delay in the age at preputial separation. In contrast, females exhibited a precocious completion of vaginal opening while all other endpoints were unaffected. Most of these effects were already present in animals that were only exposed until weaning indicating that these effects may be irreversible and continued treatment until termination had contributed less than expected to the severity of the observed effects. The results of the present study suggest that the sensitive window for the evaluated endpoints seems to be the period of prenatal development and that male offspring rats were more susceptible to treatment. [Copyright &y& Elsevier]

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]

Abstract: The toxic effects of Aroclor 1254 (0.05, 0.5, 5 and 50μgl−1) on scallop (Chlamys farreri) immune system in vivo were studied. The results showed that Aroclor 1254 had significant toxic effect on the parameters tested in this paper (P <0.05). The total number of haemocytes, the proportion of granulocytes, phagocytosis in all groups as well as the lysosomal membrane stability (LMS) in 5, 50μgl−1 and bacteriolytic activity 0.5, 5, 50μgl−1 treatments decreased significantly, while the proportion of hyalinocytes and the production of O2 - in all treatments remarkably increased during the sampling time and tended to be stable gradually after 6–15d. The bacteriolytic activity in 0.05μgl−1 treatments, LMS in 0.05, 0.5μgl−1 groups and the DNA damage (comet ratios and arbitrary values) in all treatments increased at the beginning of exposure and reached their peaks on day 1, day 1, day 6 and day 3, following that they all decreased gradually and became stable after 9–15d. When the indices reached stability, except for DNA damage was higher than controls, the others were all significantly lower than those of controls (P <0.05). Thus, Aroclor 1254 has evident toxic effects on scallop immune system, which supports the view that a relationship exists between pollution and immunomodulation in aquatic organisms. Also it supports the speculation that the PCBs pollution is one of the important reasons of the mass mortality of the C. farreri. [Copyright &y& Elsevier]

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]

Abstract: Transgenic plants offer a promising system for large-scale production of therapeutic proteins such as monoclonal antibodies (mAbs). This paper describes a membrane-based process suitable for purification of a humanized mAb expressed in tobacco. Most monoclonal antibody purification schemes rely on the use of Protein A as the affinity ligand for antibody capture. The main objective of our work was to develop non-Protein A-based purification methods to avoid some of the problems and limitations associated with this ligand, e.g. cost, immunotoxicity, and antibody aggregation during elution. Ion exchange membrane chromatography (IEMC) was used for primary capture and preliminary purification of the mAb from tobacco juice. Hydrophobic interaction membrane chromatography (HIMC) was then used for high-resolution purification, followed by ultrafiltration for polishing, desalting and buffer exchange. Using this scheme, both high mAb purity (single peak in size exclusion chromatogram, i.e., ca. 100% purity) and high recovery (77% of mAb spiked into the tobacco extract) were achieved. Membrane chromatography is generally considered unsuitable for resolving bound proteins by gradient elution and is therefore commonly used in the bind and elute mode with a single-step change of mobile phase. We show that the gradient elution process in the HIMC step can be optimized to increase the resolution and thereby obtain product of high purity. [Copyright &y& Elsevier]

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]

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]

Abstract: Besides pathology endpoints, additional immune function endpoints have been included in the Note for Guidance on Repeated Dose Toxicity by the European Union (July 2001), which concern the analysis of antibody responses to a T-cell-dependent antigen. Guidance papers of other regulatory authorities are published as well. The main issue is the need for functional immunotoxicity testing to detect unintended immunosuppression. The International Conference on Harmonization (ICH) has surveyed studies from the files of the pharmaceutical industry to find the proportion of compounds that can be detected by additional immunotoxicity testing. Preliminary analysis shows that 10–15% of the compounds in the survey only react positively to the additional tests. More data are requested from the pharmaceutical industry. The Expert Working Group of the ICH has decided to choose a cause-for-concern approach to immmunotoxicity rather than a routine-screening approach. The causes for concern are to be defined during ICH negotiations. [Copyright &y& Elsevier]

Abstract: In this paper we undertake a combined analysis of several studies in which marmoset monkeys received immunotoxic lesions of the cortical cholinergic projections from the basal nucleus of Meynert (NBM) bilaterally and/or in combination with immunotoxic lesions of other parts of the cholinergic system or ablations of the target inferotemporal neocortical area. Analysis of the mean learning scores across all visual discriminations learning tasks for each lesion combination revealed highly significant impairments where the NBM was lesioned bilaterally or where an NBM lesion in one hemisphere was crossed with an inferotemporal cortical ablation in the other hemisphere. This demonstrates that the cholinergic projection from the NBM to the major target area of neocortex involved in visual discrimination learning, i.e. the inferotemporal cortex, makes an important contribution to the perceptuo-mnemonic processes necessary for this type of learning. A new study demonstrates a significant effect of a subtotal bilateral cholinergic lesion confined to the NBM on a concurrent object-reward association task using black objects which is perceptually and mnemonically demanding. These results do not preclude the possibility that cholinergic projections from the NBM to other parts of the neocortex make a contribution to other cortical functions which are not mnemonic. It is well established that lesions of the cholinergic projection from the diagonal band of Broca disrupts the mnemonic functions of the hippocampus. The results described here suggest that degeneration of the cholinergic projections in Alzheimer''s disease and other dementias will contribute to the loss of those mnemonic functions which are dependent on the neocortex. [Copyright &y& Elsevier]

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]

As any new drug in development, gene transfer products have to be tested for their potential toxicity in preclinical studies. Strategies for preclinical safety evaluation of gene transfer compounds are similar to those undertaken for biotechnology-derived pharmaceuticals with the added complexity of having to test additional components, such as the vector and genetic material. Some recommendations have been issued by regulatory agencies to provide assistance in the toxicological assessment of gene transfer products before administration to humans. However, the design of such studies is complicated and has to be approached case-by-case. Crucial aspects for safety evaluation are: (1) the choice of animal models with respect to the pharmacological activity of the gene transfer product, the susceptibility to infection in the case of viral vectors, and to the immunogenicity of all entities; (2) biodistribution of the vector after administration, avoiding germinal transmission. Immunological and immunotoxicity endpoints should also be assessed. This paper reviews some of the properties of gene transfer vectors with emphasis on their potential effects on the immune system, and also highlights some of the problems likely to be encountered during the preclinical safety evaluation. [Copyright &y& Elsevier]

Cyhalofop-butyl is a kind of aromatic phenoxypropionic acid herbicide widely used in agriculture. However, studies on its immunotoxicity to aquatic organisms have not been reported. In this study paper, morphological, immunological, cytological, biochemical and molecular biology methods were used to study the effects of cyhalofop-butyl on the developmental toxicity and immunotoxicity in zebrafish. After cyhalofop-butyl exposed, the results showed that the zebrafish embryos had shorter length, yolk sac edema, significantly reduced number of immune cells, inflammatory response and immunocytes apoptosis. In addition, we found that the expression of immune-related genes and pro-apoptotic genes were up-regulated, and the JAK-STAT signaling pathway mediated the immunotoxicity induced by cyhalofop-butyl. Therefore, our results indicate that cyhalofop-butyl has developmental toxicity and immunotoxicity to zebrafish, and this study offer new contents for the effects of cyhalofop-butyl exposure on aquatic organisms. Image 1 • Cyhalofop-butyl induces developmental toxicity and immunotoxicity to zebrafish. • Cyhalofop-butyl induces oxidative stress and apoptosis of immune cells in zebrafish. • Jak-STAT signaling pathway is involved in cyhalofop-butyl-induced immunotoxicity in zebrafish. [ABSTRACT FROM AUTHOR]

The mammalian immune system is a highly complex, interactive network of cells that facilitates innate and adaptive immune responses. The neonatal immune system may be more susceptible to chemical perturbations than that of the adult. The effects of immunotoxicants during development may not be fully detected in toxicity studies performed on adult animals. Studies characterizing the ontogeny of the immune system in developing animals have shown that there are different critical windows of susceptibility to immunotoxicants. Developmental differences are evident among species compared to humans. Functional immune assays, such as the T-cell antibody dependent response assay, in rat models have been validated for use in the assessment of immunotoxicity with other assays. Recently, published studies have explored the feasibility of using additional techniques, such as in vitro studies using human whole blood cells or cell lines, mostly lacking either sensitivity or proper validation for regulatory purposes. However, some techniques may be developed further to enable translation of animal toxicity findings to human risk assessment of potential immunotoxicants. This paper summarizes the information on the developing immune system in humans versus rats and how the currently available assays might be used to contribute to the safety assessment of food contact substances. [ABSTRACT FROM AUTHOR]

Presents an abstract of the paper `The Immunotoxicity of a Municipal Gas Plant Residues: Evaluation of Synergistic Interactions Between the 2-Ring, 3-Ring, and 4-Ring Polycyclic Aromatic Hydrocarbon Constituents,' presented at the 1993 meeting of the Gulf Coast chapter of the Society of Toxicology, by N. Harper, M. Steinberg, and S. Safe.