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Nonclinical Safety Evaluation of Drugs
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Thomas M. Monticello, Jeanine L. Bussiere
Immunotoxicity testing guidelines exist (ICH S8 2004) for small molecules where the toxicity is often unexpected or off-target and rodent species are typically used. A tiered approach is utilized for small molecules in that additional immunotoxicity testing is based on results of the standard toxicology studies. Indicators of possible immunotoxicity from a general toxicology study include hematologic changes, such as decreased neutrophil or lymphocyte counts; changes in weight or histopathology of immune organs such as the thymus, spleen, or lymph node; or evidence of increased infection (Haley et al. 2005). If the weight of evidence in general toxicity testing suggests an impact on the immune system, additional testing could be conducted such as the T-dependent antibody response (TDAR) or immunophenotyping of leukocyte populations. Despite the lack of specific guidance on immunotoxicity evaluation for biopharmaceuticals, similar approaches can be taken as for small molecules (Brennan et al. 2004). As the immune system is often the intended target of therapy for biopharmaceuticals, the immunomodulation observed may represent exaggerated pharmacology. It is important to distinguish between immunopharmacology, where the immune system is the target of the therapeutic effect, and immunotoxicity, where nontarget immune effects may be observed (e.g., immunosuppression), and to distinguish both of these from immunogenicity, which represents an immune response to the drug (Bussiere and Mounho 2008).
Determination
Published in David Woolley, Adam Woolley, Practical Toxicology, 2017
As with other organ systems, the function of the immune system may be enhanced or suppressed by xenobiotic chemicals. Unlike most other organ systems, the immune system is not a discrete organ but an interrelated set of tissues distributed throughout the body. It includes the thymus, bone marrow, Peyer’s patches, spleen, lymph nodes, and other lymphoid tissues. An effect on one part of this system may have contrary effects on other parts; consequently, interpretation of a small change in one area is made more complex by the difficulties of predicting the impact on other parts of the system. This complicates study of immune responses to xenobiotics with the added problem that, in general, animals are poor models for human immunotoxicity, particularly autoimmune reactions and hypersensitivity. With such a diffuse system, the best approach is to obtain a broad overview and then, if significant change is seen, to focus on the areas of interest in specific mechanistic studies. Accordingly, it is generally recommended that a tiered approach be adopted, the first tier being contained within the conventional toxicity tests. These examinations include differential leukocyte counts in peripheral blood, plasma protein fractions and the weights, and/or microscopic appearance of the lymphoid tissues. The distribution of lymphocyte subsets can also be examined by homogenization of tissues and flow cytometry. However, these investigations may not give a definitive answer as to whether there are changes that are truly indicative of a significant effect on immune function. The immune system is not static through the lifetime of an organism. The thymus involutes or atrophies with age, and this is quite normal; however, acceleration of involution relative to controls or expectation may well imply an immunotoxic effect. A further layer of complexity is added, when it is considered that such atrophy is also a response to stress, although this is usually accompanied by changes in the adrenal glands. The International Conference on Harmonisation (ICH) S8 guideline on immunotoxicity studies for human pharmaceuticals (Case Study 7.1) (ICH 2005) indicates that, in addition to findings in standard toxicity studies, additional prompts for immunotoxicity study may be the pharmacological action of the drug; the intended patient population; and factors such as similar structure to known immunotoxicants, drug disposition, and information from the clinic. Once change in the immune system has been identified, additional testing should be considered depending on the nature of the immunological changes observed, taking into account any concerns raised by the class of compound.
Preclinical Characterization of Engineered Nanoparticles Intended for Cancer Therapeutics
Published in Mansoor M. Amiji, Nanotechnology for Cancer Therapy, 2006
Anil K. Patri, Marina A. Dobrovolskaia, Stephan T. Stern, Scott E. McNeil
A growing body of evidence suggests that immunotoxicity provides a considerable contribution to onset and development of various disorders, including cancer and autoimmune diseases.137–139 Nevertheless, it was not until recently that this relatively new field of toxicology emerged as an important interface between the fields of novel drug design and pharmacology. Recognition of immunosuppressive properties of new pharmaceuticals during early drug development phase is very important to eliminate potentially dangerous substances from the drug pipelines. For example, treatment of patients diagnosed with Crohn’s disease and rheumatoid arthritis with infliximab and etanercept (both drugs represent neutralizing anti-TNF antibodies) resulted in increased incidence of tuberculosis and histoplasmosis.140–143 Although these data did not result in withdrawal of any of the products from the pharmaceutical market, they helped initiate the strategy of preparing patients for anti-TNF therapy by screening for, and treatment of, latent tuberculosis prior to administration of anti-TNF medications. Immunosuppression caused by pharmaceuticals can also lead to the development of lymphomas and acute leukemia.144–146 Undesirable immunostimulation caused by pharmacological intervention include immunogenicity, hypersensitivity, and increased risk of autoimmune response. The standard toxicology endpoints employed for safety assessment of new pharmaceuticals primarily rely on clinical chemistry and histopathological evaluation of immune organs and were developed several decades ago. Currently, there is an increasing demand for the development of new methods for immunotoxicity assessment because of drug candidates’ more complex structure as well as the application of new technologies in their manufacturing. The introduction of new molecular and immune cell biology methods into the immunotoxicology assessment framework is not a trivial and straightforward process. It requires not only scrupulous validation and standardization of the new techniques but also demonstration of the physiological relevance for the proposed battery of assays. These processes are expensive, time-consuming, and necessitate cooperation across the various pharmaceutical industry players. Unlike traditional drugs, multifunctional nanomaterials combine both chemistry-based and biotechnology-derived components, and therefore their characterization using standard methodologies requires adjustments and/or modification of classical experimental protocols. Below we will attempt to summarize data on critical aspects of immunotoxicological evaluation of nanomaterials and examine challenges in the application of standard methodologies for the assessments of nanoparticle safety to the immune system.
Toxic effects of pesticides on cellular and humoral immunity: an overview
Published in Immunopharmacology and Immunotoxicology, 2022
Larissa Vivan Cestonaro, Sandra Manoela Dias Macedo, Yasmin Vendrusculo Piton, Solange Cristina Garcia, Marcelo Dutra Arbo
In this way, immunotoxicity assesses the adverse effects on the immune system's functioning as a result of exposure to chemical substances. Identifying immunotoxicants is difficult because chemicals can cause a wide variety of effects, being able to alter one or more immune functions, resulting in adverse effects to the body [3]. Furthermore, the immune responsiveness of exposure to these compounds depends on the levels (i.e. dose) and context (i.e. timing, route), which can result in suppressing or enhance of immunological response [4]. For this reason, immunotoxicity can be further subdivided into direct or indirect immunotoxicity. Direct immunotoxicity can occur by suppressing or activating the immune system, and immunosuppression is due to reduced immunocompetence. On the other hand, immunostimulation develops when the substance modulates the immune system and stimulates the function of one or more components [5]. In contrast, indirect immunotoxicity occurs during allergic reactions, caused by tissue damage after exposure [6,7]. Such relevance is justified by the fact that in recent years, numerous studies have been carried out to investigate the mechanisms of immunotoxicity, given the complexity of this system [4,8–10]. The immune system disorders are highlighted here because it is closely linked with multiple organs, including the nervous, endocrine, reproductive, cardiovascular, and respiratory systems, leading to transient or permanent changes [5,11,12].
Exposure to a mixture of 23 chemicals associated with unconventional oil and gas operations alters immune response to challenge in adult mice
Published in Journal of Immunotoxicology, 2021
Colleen T. O’Dell, Lisbeth A. Boule, Jacques Robert, Steve N. Georas, Sophia Eliseeva, B. Paige Lawrence
Overall, the study of immunotoxicity has largely focused on examining immune modulation by single chemical exposures. This is a valuable and important approach, particularly to understanding mechanisms of toxicity. For the mixture used in the current study, there is minimal, and in some cases no, extant data on possible immunomodulatory effects of many of the chemical constituents. However, there is some evidence that exposure to several components of this mixture, such as naphthalene and 2-ethyl-hexanol disturbs aspects of immune cell functions (Kawabata and White 1990; Yoshida et al. 2009; McGuire et al. 2021). Benzene and styrene are also known carcinogens and immunotoxicants in mammals (Veraldi et al. 2006; McHale et al. 2012). Other studies have shown that direct exposure to volatile organics, including ethylbenzene, styrene, and benzene, was associated with lymphopenia in an all-female study population (Baines et al. 2004). Similar to the current findings, another study found that inhalation exposure of male mice to formaldehyde, benzene, toluene, and xylene decreased the number of T-cells in peripheral immune organs (Wang et al. 2016).
Immunotoxicity studies of sulfolane following developmental exposure in Hsd:Sprague Dawley SD rats and adult exposure in B6C3F1/N mice
Published in Journal of Immunotoxicology, 2021
AtLee T. D. Watson, Victor J. Johnson, Michael I. Luster, Gary R. Burleson, Dawn M. Fallacara, Barney R. Sparrow, Mark F. Cesta, Michelle C. Cora, Keith R. Shockley, Matt D. Stout, Chad R. Blystone, Dori R. Germolec
Food and water consumption were monitored in F1 rats exposed to vehicle or sulfolane in drinking water. Water consumption data was used to calculate sulfolane intake. Daily clinical observations were recorded in all study animals. At necropsy, the liver, spleen, lungs, thymus, kidneys, adrenal glands, bone marrow (femur), gastrointestinal tract with Peyer’s patches (rats only), and mesenteric and popliteal lymph nodes (LN) were collected, fixed in 10% neutral buffered formalin, sectioned at 4–6 µm, and stained with hematoxylin and eosin for histopatho-logical evaluations in the rat study. The lymphoid organs were evaluated using enhanced histopathology (EH) guidelines (Elmore 2006a, 2006b, 2006c, 2006d, 2006e); non-lymphoid organs were evaluated by traditional histopathology. All evaluations were conducted in accordance with the NTP Immunotoxicity Study Pathology Specifications.