Probiotics: immunomodulation and evaluation of safety and efficacy.

The intake of probiotics has been associated with beneficial effects on the immune system, such as improved disease resistance and diminished risk of allergies. This review gives an overview of the immunomodulatory effects of probiotics investigated with in vitro assays, experimental animal models, and clinical trials, and explores possible mechanisms underlying the immunomodulatory effects. Immunomodulation, however, is not always beneficial and might induce detrimental effects; therefore, a scheme is proposed for benefit-risk assessment of immunomodulation by probiotics. Within this scheme, expert judgment based on data derived from a panel of in vitro assays, animal models, and clinical trials should lead to conclusions on efficacy and safety aspects of probiotics

Mechanisms of Hexachlorobenzene-induced Adverse Immune Effects

Hexachlorobenzene (HCB) is an environmental pollutant that can induce adverse immune effects in humans and rats. Brown Norway rats (BN) appeared to be very susceptible to HCB-induced immune effects. Oral exposure causes inflammatory skin and lung lesions, enlarged spleen and lymph nodes (LN) and elevated humoral responses. Although the immunopathological effects induced by HCB are investigated comprehensively, the exact mechanisms involved are unknown. Experiments described in this thesis were performed to obtain more insight in the mechanisms underlying HCB-induced adverse immune effects, both on a cellular and molecular level. The immunomodulatory effects of the oxidative metabolites tetrachlorohydroquinone (TCHQ) and tetrachlorobenzoquinone (TCBQ) were assessed. Therefore, these metabolites were studied in the mouse reporter antigen popliteal lymph node assay (RA-PLNA) with TNP-Ficoll as a RA. In this assay an isotype switch to IgG1 indicates that the chemical injected is able to form neoantigens that can stimulate T cells. Both TCHQ and TCBQ induced an isotype switch to IgG1 and were thus capable of providing neoantigen-specific T cell help. Furthermore, this response was compound-specific as was shown in a secondary PLNA. In addition, gene expression profiles with DNA microarray analysis in BN rats were obtained. Transcriptome profiling was done in spleen, mesenteric lymph node (MLN), thymus, blood, liver and kidney. Data confirmed known effects of HCB such as stimulatory effects on the immune system and induction of enzymes involved in drug metabolism, porphyria and the reproductive system. New findings include the upregulation of genes encoding pro-inflammatory cytokines, antioxidants, acute phase proteins, mast cell markers, complement, chemokines, and cell adhesion molecules. In general, gene expression data provide evidence that HCB induces a systemic inflammatory response, accompanied by oxidative stress and an acute phase response. The role of T cells in HCB-induced immunotoxic effects was investigated further by using the Cyclosporin A (CsA). This immunosuppressive drug decreases peripheral T cell numbers and inhibit T cell activation. CsA treatment delayed the development of HCB-induced skin lesions and prevented the increase in spleen weight slightly. Furthermore, increase in ALN weight, lung eosinophilia and humoral responses were prevented completely by in HCB-exposed rats treated with CsA. Macrophage infiltration was independent of T cells and macrophages seem also important. Therefore, the relationship between macrophages and T cells was further investigated. Co-administration of clodronate-liposomes was used to eliminate macrophages in HCB-exposed rats. Results indicated that macrophages played an important role in HCB-induced skin lesions, in particular in the aggravation of skin lesions. Also, HCB-induced lung eosinophilia and elevation of anti-ssDNA IgM antibodies were less pronounced after depletion of macrophages. To obtain information on events that occur in the initiation phase a kinetic study was performed. This revealed that both skin and lung pathology were early inflammatory events. Furthermore, macrophage infiltrations in the spleen seemed to precede the increase in spleen weight. Remarkably, studies performed to further assess the functional role and specificity of T cells induced by HCB did not provide any evidence for the presence of T cells specific for TCBQ. Moreover, HCB-induced immune effects could not be adoptively transferred to naive recipients

Checklists for Applicants submitting dossiers on Cosmetic Ingredients to be evaluated by the SCCS

Checklists for Applicants submitting dossiers on Cosmetic Ingredients to be evaluated by the SCCSThe SCCS adopted these Checklists on 07 March 2017Checklists for Applicants submitting dossiers on Cosmetic Ingredients to be evaluated by the SCCSThe SCCS adopted these Checklists on 07 March 201

An Adverse Outcome Pathway for Sensitization of the Respiratory Tract by Low-Molecular-Weight Chemicals: Building Evidence to Support the Utility of In Vitro and In Silico Methods in a Regulatory Context

Sensitization of the respiratory tract is an important occupational health challenge, and understanding the mechanistic basis of this effect is necessary to support the development of toxicological tools to detect chemicals that may cause it. Here we use the adverse outcome pathway (AOP) framework to organize information that may better inform our understanding of sensitization of the respiratory tract, building on a previously published skin sensitization AOP, relying on literature evidence linked to low-molecular-weight organic chemicals and excluding other known respiratory sensitizers acting via different molecular initiating events. The established key events (KEs) are as follows: (1) covalent binding of chemicals to proteins, (2) activation of cellular danger signals (inflammatory cytokines and chemokines and cytoprotective gene pathways), (3) dendritic cell activation and migration, (4) activation, proliferation, and polarization of T cells, and (5) sensitization of the respiratory tract. These events mirror the skin sensitization AOP but with specific differences. For example, there is some evidence that respiratory sensitizers bind preferentially to lysine moieties, whereas skin sensitizers bind to both cysteine and lysine. Furthermore, exposure to respiratory sensitizers seems to result in cell behavior for KEs 2 and 3, as well as the effector T cell response, in general skewing toward cytokine secretions predominantly associated with T helper 2 (Th2) response. Knowledge gaps include the lack of understanding of which KE(s) drive the Th2 polarization. The construction of this AOP may provide insight into predictive tests that would in combination support the discrimination of respiratory-sensitizing from non- and skin-sensitizing chemicals, a clear regulatory need

World Health Organization estimates of the global and regional disease burden of four foodborne chemical toxins, 2010: a data synthesis

Background: Chemical exposures have been associated with a variety of health effects; however, little is known about the global disease burden from foodborne chemicals. Food can be a major pathway for the general population’s exposure to chemicals, and for some chemicals, it accounts for almost 100% of exposure. Methods and Findings: Groups of foodborne chemicals, both natural and anthropogenic, were evaluated for their ability to contribute to the burden of disease. The results of the analyses on four chemicals are presented here - cyanide in cassava, peanut allergen, aflatoxin, and dioxin. Systematic reviews of the literature were conducted to develop age- and sex-specific disease incidence and mortality estimates due to these chemicals. From these estimates, the numbers of cases, deaths and disability adjusted life years (DALYs) were calculated. For these four chemicals combined, the total number of illnesses, deaths, and DALYs in 2010 is estimated to be 339,000 (95% uncertainty interval [UI]: 186,000-1,239,000); 20,000 (95% UI: 8,000-52,000); and 1,012,000 (95% UI: 562,000-2,822,000), respectively. Both cyanide in cassava and aflatoxin are associated with diseases with high case-fatality ratios. Virtually all human exposure to these four chemicals is through the food supply. Conclusion: Chemicals in the food supply, as evidenced by the results for only four chemicals, can have a significant impact on the global burden of disease. The case-fatality rates for these four chemicals range from low (e.g., peanut allergen) to extremely high (aflatoxin and liver cancer). The effects associated with these four chemicals are neurologic (cyanide in cassava), cancer (aflatoxin), allergic response (peanut allergen), endocrine (dioxin), and reproductive (dioxin)

t4 Workshop Report: Integrated Testing Strategies (ITS) for Safety Assessment

Integrated testing strategies (ITS), as opposed to single definitive tests or fixed batteries of tests, are expected to efficiently combine different information sources in a quantifiable fashion to satisfy an information need, in this case for regulatory safety assessments. With increasing awareness of the limitations of each individual tool and the development of highly targeted tests and predictions, the need for combining pieces of evidence increases. The discussions that took place during this workshop, which brought together a group of experts coming from different related areas, illustrate the current state of the art of ITS, as well as promising developments and identifiable challenges. The case of skin sensitization was taken as an example to understand how possible ITS can be constructed, optimized and validated. This will require embracing and developing new concepts such as adverse outcome pathways (AOP), advanced statistical learning algorithms and machine learning, mechanistic validation and “Good ITS Practices”.JRC.I.5-Systems Toxicolog