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BackgroundKey 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.ObjectivesThe 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.MethodsA 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.DiscussionKCs 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. https://doi.org/10.1289/EHP10800.

One of the principal challenges facing a toxicologic pathologist is to determine and differentiate a true adverse effect from a nonadverse or an adaptive response. Recent publications from the Society of Toxicologic Pathology (STP) and the European STP provide guidance for determining and communicating adversity in nonclinical toxicology studies. In order to provide a forum to inform and engage in a discussion on this important topic, a continuing education (CE) course was held during the 2016 STP Annual meeting in San Diego, CA. The lectures at this course provided guidance on determining and communicating adversity using case studies involving both clinical pathology and anatomic pathology. In addition, one talk also focused on data quality, study design, and interpretation of artifacts that could hinder the determination of adversity. The CE course ended with a talk on understanding adversity in preclinical studies and engaging the regulatory agencies in the decision-making process. This manuscript is designed to provide brief summaries of all the talks in this well-received CE course. [ABSTRACT FROM AUTHOR]

Many chemicals and drugs can induce a neuroendocrine stress response that can be immunosuppressive. Mathematical models have been developed that allow prediction of the immunological impact of such stress responses in mice on the basis of exposure to the important stress-related mediator corticosterone. The area under the corticosterone concentration vs. time curve (AUC) has been used as an indicator of cumulative corticosterone exposure in these modeling studies. In the present study, an immunotoxicant known to induce a stress response, 3,4-dichloropropionanilide (propanil), was evaluated to determine if corticosterone AUC values are related to suppression of immunological parameters in mice treated with this chemical. Linear relationships between corticosterone AUC values and suppression of the following parameters were noted in B6C3F1 female mice: thymus cellularity and thymus subpopulation percentages, splenic subpopulation percentages, natural killer cell activity, MHC class II protein expression, and IgG1 and IgG2a antibody responses to antigen. Linear models derived in previous studies using mice treated with exogenous corticosterone or with restraint stress effectively predicted the immunological effects of 3,4-dichloropropionanilide on the basis of corticosterone AUC values. The models derived using immobilization stress were more effective (r2 for observed vs. predicted = 0.90) than the models derived using mice treated with exogenous corticosterone (r2 for observed vs. predicted = 0.65). This was expected, because most stressors induce a variety of immunomodulatory mediators, not just corticosterone. These findings have implications for risk assessment in immunotoxicology. [ABSTRACT FROM PUBLISHER]

HIV-specific therapeutics have advanced during the two decades of HIV drug development from 1 class to now 6 approved classes of anti-HIV drugs. These six approved classes of drugs include Nucleoside Reverse Transcriptase Inhibitors, Non- Nucleoside Reverse Transcriptase Inhibitors, an Integrase Strand Transfer Inhibitor, Protease Inhibitors, a CCR5 Co-receptor Antagonist, and a Fusion Inibitor. These different classes of medications have varying toxicities, which may be either drug specific toxicities or potentially class effects. FDA has developed Guidances to assist Sponsors in the drug development process. For nonclinical risk assessment, Guidances for anti-HIV therapeutics are similar to other therapeutics. However, drugs for life threatening indications such as HIV infection has historically been allowed to progress more quickly through the regulatory pathway. This usually allowed for quicker access to life-saving medications. As drug development advances to treat this chronic disease, drug development issues have changed as the treatment of HIV has changed. Some of the recent issues that appear to be confounding Sponsors are: timing for carcinogenicity testing, relating juvenile toxicity studies to a pediatric indication, and when/if combination studies are necessary. It is often helpful for Sponsors to work with the Division to get feedback, when necessary, for the particular drug development issue. This presentation will address the available guidance documents that define a scientifically sound pathway for the development of anti-HIV therapeutics. [ABSTRACT FROM AUTHOR]