Mechanisms of Adult and Developmental Immunotoxicity (#757)
R. R. Dietert1
1 Cornell University, Microbiology and Immunology, Ithaca, New York, United States of America
Detection of immunotoxicity has the greatest impact when it can help to reduce the most significant human health risks. As a result, a reverse engineering approach working backwards from human disease to immune alterations and dysfunction can guide priorities as to when and how immunotoxicity testing would be most effective. The most prevalent global causes of death are chronic, noncommunicable diseases and conditions (NCDs) with the major immune dysfunctional categories being allergic, autoimmune, and immune-inflammatory driven diseases. These diseases are currently epidemic, are largely driven by immune dysfunction and unresolving inflammation, have a high level of comorbidity, have been emerging at earlier ages in the recent decades, and have biomarkers for even adult-onset diseases that can be detected in children (e.g. biomarkers of atherosclerosis and eventual “foam cell” [aberrant macrophage] formation). Additionally, most of the immune dysfunction driven diseases involve immune cell populations in the periphery such as in mucosal tissues. This presentation will discuss the issues of how best to capture age-related immunotoxicity that drives most human pathology and disease. Mechanistic categories of immunotoxicity will be described using examples from among environmental chemicals, drugs, and food additives. Finally, the utility of using a systems biology approach to include the broadest network of human disease-relevant mechanisms of immunotoxicity will be discussed.
Keywords: age-related immunotoxicity, human disease, systems biology approach
Adversity of changes in immune parameters and findings in developmental immunotoxicity studies. (#775)
1 National Institute for Public Health and Environment (RIVM), Center for Health Protection (GZB), Bilthoven, Netherlands
In the last decades, there is increasing prevalence of immune-based diseases in children such as allergy, inflammatory and autoimmune diseases. The role of chemical exposures in the development of these immune-based diseases is currently unclear. It is thought that the developmental immune system is more susceptible to toxicant exposure than the mature immune system. Developmental immunotoxicity (DIT) testing is nowadays not or minimally included in regulatory toxicology requirements.
Retrospective analysis of animal data from available DIT studies showed that the immune system is very sensitive to the disruption of toxicants. Most reviewed toxicants show more sensitivity to the functional immune parameters, like antigen specific parameters, then for the structural immune parameters. These conclusions were based on data from different study designs (e.g. route, window and duration of toxicant exposure). This stimulates the importance of including functional parameters in the current DIT protocols. However, the only currently available OECD test guideline that contains perinatal exposure and prescribes testing structural as well as functional immune parameters is the OECD TG 443 EOGRTS. In line with current requirements for reproductive toxicity studies, this study is only carried out in specific cases, covering only a small minority of compounds.
The analysis performed, showing the relative prominence of adverse effects on the developing immune system, warrants reconsideration of whether this study should be mandatory for more compounds. Collecting this important piece of information for a far larger subset of compounds on the market will get more insight into the sensitivity of compounds to DIT. This would provide a higher level of protection, especially for the relatively sensitive group of the unborn and the developing child.
Keywords: Developmental immunotoxicity, EOGRTS
Skin sensitisation and developmental immunotoxicity – is there any mechanistic association? (#122)
K. Malkiewicz1, I. A. Mohammed1, A. Arabi1
1 Swedish Chemicals Agency, Sundbyberg, Sweden
The aim of this presentation is to stimulate research focused on regulatory questions. Understanding of mechanistic associations between skin sensitisation and developmental immunotoxicity (DIT) is relevant for testing industrial chemicals under the Regulation (EC) No 1907/2006 (REACH).
Testing for DIT can be performed as part of the Extended One-Generation Reproductive Toxicity Study (EOGRTS) (OECD 443). According to REACH (Annex IX and X, Section 8.7.3, Column 2) testing for DIT may be required “in case of particular concern” defined as e.g. “abnormalities”, “adverse effects” or “specific mechanisms/modes of action (…) with association to DIT”. According to the ECHA guidance (R7a, 2017) data that can trigger DIT test in EOGRTS concerns e.g. changes in haematology, weight or histopathology of immune organs, in immune function, and hormonal mechanisms/MoA with association to the immune system and as a supportive factor (respiratory) sensitisation.
Uncertainty remains if skin sensitisation should trigger DIT investigation in EOGRTS. It is established that skin sensitisers act via pathways involving reactive oxygen species, gene regulators nuclear factor (Nrf2) (OECD 442D, OECD 168) and aryl hydrocarbon receptor (Ahr). There is evidence that these pathways play also a role in other immunological reactions including immunosuppression. However, a comprehensive review on the association between mechanisms of skin sensitisation and DIT is not available. Based on analysis of 56 substances causing skin sensitisation “no obvious link to effects on the core set of immune system endpoints” has been reported (Dewhurst 2015).
Immunosuppressive potential of Nrf2 activators has been reported including decreased lymph node weight (Kitsukawa 2014), inhibition of human T-cell activation and cytokine production in vitro (Zagorski 2013, Macoch 2015, Turley 2015), altered Th1/Th2 differentiation of murine cells in vitro (Rockwell 2012, Zagorski 2018). The Nrf2 pathway is shown to protect the foetus against oxidative stress (Sarah 2015) but the role of Nrf2 in the developing immune system is not elucidated. In addition, activation of the Ahr pathway is implicated in both cellular response to skin sensitisers (Kohle 2007, Johansson 2011, Roggen 2014) and modulation of the immune system (Hogaboam 2007).
Better understanding of mechanistic association between skin sensitisation and DIT could improve testing strategies and ultimately identification of developmental immunotoxicants.
Keywords: REACH, EOGRTS, DIT, sensitisation, Nrf-2
Regulatory aspects under REACH relating to the developmental immunotoxicity (DIT) cohort in the extended one-generation reproductive toxicity study (EOGRTS) (#214)
I. Bichlmaier1, L. Rossi1, P. Sakha1, O. Leppäranta1, H. Huuskonen1
1 European Chemicals Agency, Helsinki, Finland
The DIT cohort in the EOGRTS provides information on the immunotoxic potency of substances after exposure during sensitive life stages. The EOGRTS, which is the information requirement in the REACH Regulation for higher tonnage substances, only requires investigations on DIT if a particular concern on it is identified. Inclusion of the DIT cohort is justified by information showing that exposure to a substance or its structural analogues causes adverse (D)IT effects or exerts specific mechanisms which are associated with such adverse effects. The regulatory consideration whether a particular concern on DIT exists, is based on evaluating and weighing all the data from different sources for quality (relevance, reliability, and adequacy), consistency, statistical significance and biological relevance of information. Especially, identifying a particular concern on the basis of mechanistic information may prove challenging, for example when asking if a substance displaying sex hormone-related activity such as (anti)oestrogenicity or (anti)androgenicity might induce adverse effects on the developing immune system. So far, the most frequent findings representing a particular concern have been relevant changes in blood parameters or immune organs in adult animals. DIT is not covered by any other study within REACH requirements, but might be useful for further hazard and risk assessment. Currently there is not much experience on the interpretation of DIT results, in particular for regulatory risk management measures such as hazard classification and labelling.
Keywords: REACH, developmental immunotoxicity, regulatory risk management, extended one-generation reproductive toxicity study, EOGRTS