Citation:

Lehmann, G. Consensus on the Key Characteristics of Immunotoxic Agents as a Basis for Hazard Identification - SRCoP Presentation 101023. Systematic Review Community of Practice Meeting, RTP, NC, October 10, 2023.

Impact/Purpose:

Systematic review methodology is a rigorous approach to answering a research question via review of existing evidence in a manner that maximizes transparency and minimizes bias in identifying, selecting, critically assessing and integrating relevant evidence. Systematic reviews reach conclusions based on a thorough assessment and synthesis of the body of evidence – the collection of studies with relevant data on the topic in question – rather than individual studies. The clear advantages of methodological rigor and transparency associated with these methods have resulted in systematic review approaches becoming the standard for literature-based reviews across many research fields including environmental health assessments conducted by the U.S. EPA. These advantages also apply to understanding and communicating in a hazard or risk assessment the potential for environmental exposures to modulate the immune system, and to increase the burden of disease. Thorough characterization of environmental hazards requires the integration of mechanistic data, such as that obtained from the key characteristics (KC) approach, with evidence on potential health effects associated with environmental exposures from studies in humans and experimental animals. The effective use of mechanistic data can add biological plausibility to the human and animal data, identify sensitive populations, and increase confidence in health effects conclusions. The KC approach provides a framework that will enable more effective and efficient use of mechanistic data through greater understanding of mechanisms and pathways relevant to immunotoxicity. For example, in a systematic review of literature relevant for understanding immunotoxic mechanisms, search terms based on the KCs can be used to support the literature searching and screening steps, and the KCs can also be used as an organizational framework to support evidence synthesis and interpretation.

Description:

Background: Key characteristics (KCs), properties of agents or exposures that confer potential hazard, have been developed for carcinogens and other toxicant classes. KCs have been used in the systematic assessment of hazards and to identify assay and data gaps that limit screening and risk assessment. Many of the mechanisms through which pharmaceuticals and occupational or environmental agents modulate immune function are well recognized. Thus KCs could be identified for immunoactive substances and applied to improve hazard assessment of immunodulatory agents. Objectives: The goal was to generate a consensus-based synthesis of scientific evidence describing the KCs of agents known to cause immunotoxicity and potential applications, such as assays to measure the KCs. Methods: A committee of 18 experts with diverse specialties identified 10 KCs of immunotoxic agents, namely, 1) covalently binds to proteins to form novel antigens, 2) affects antigen processing and presentation, 3) alters immune cell signaling, 4) alters immune cell proliferation, 5) modifies cellular differentiation, 6) alters immune cell-cell communication, 7) alters effector function of specific cell types, 8) alters immune cell trafficking, 9) alters cell death processes, and 10) breaks down immune tolerance. The group considered how these KCs could influence immune processes and contribute to hypersensitivity, inappropriate enhancement, immunosuppression, or autoimmunity. Discussion: KCs can be used to improve efforts to identify agents that cause immunotoxicity via one or more mechanisms, to develop better testing and biomarker approaches to evaluate immunotoxicity, and to enable a more comprehensive and mechanistic understanding of adverse effects of exposures on the immune system.

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