Chemically-Induced Immunopathology and Immune Functional Changes

Vos, J.G.; Kuper, C. Frieke

doi:10.1293/tox.17.137

Cited by 3 publications

(2 citation statements)

References 48 publications

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“…These changes, however, were recognized to have occurred to similar degrees in the dietary restriction groups (R15 and R18). Changes in the lymphoid organs due to immunotoxicants appear as a decrease in the blood cell count 21,22 . Mature granulocytes are not significantly affected; however, cytotoxic fungal metabolites have been shown to cause a decrease in the immature myelocyte count 23 .…”

Section: Discussionmentioning

confidence: 99%

“…Decreases in the count of total granulocytic series in bone marrow and telangiectasis were more pronounced in the FU15 and FU18 groups than in the dietary restriction groups. A standard histopathological evaluation is necessary for evaluation of the organs of the immune system 21 . However, the above changes were considered to be related to the effects of the drug decreasing the blood cell count 7 and causing blood vessel disorder 29 in addition to being associated with poor nutrition.…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of Myelotoxicity in Dietary Restricted Rats

et al. 2009

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The purpose of this study was to clarify the effect of decreased food consumption on evaluation of myelotoxicity in routine general toxicity studies. Male rats were divided into the following 7 groups: 12, 15, and 18 mg/kg 5-fluorouracil (5-FU) treatment groups (FU12, FU15 and FU18); dietary restriction groups (R12, R15 and R18 receiving the same amount of food as the rats in the FU12, FU15 and FU18 groups, respectively); and a nontreated control group (NT). We compared the changes in body weight, hematology and the results of cytological analyses of bone marrow and histopathology among the groups after administration and recovery periods of 14 and 7 days, respectively. At the end of the administration period, the FU15 and FU18 groups showed decreases in many hematologic and bone marrow parameters that were all similar to those in the corresponding dietary restriction groups (R15 and R18). A granulocyte abnormality (polyploidy: frequency of 1% or less) was also observed in all 5-FU treated groups. At the end of the recovery period, increases in the reticulocyte and platelet counts and extramedullary hematopoiesis of the spleen were observed in the 5-FU treated groups. These results indicate that the results of general toxicity studies in rats should be evaluated in consideration of dietary restriction effects when food consumption is decreased at about 30-40% or more. Careful morphological observation of hemocytes would be helpful in distinguishing the effect of a drug from that of dietary restriction in relation to hematological and bone marrow parameters. Performance of a recovery test to determine the reactive response of hematopoiesis is also recommended.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evaluation of Myelotoxicity in Dietary Restricted Rats

et al. 2009

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Successful Drug Development Despite Adverse Preclinical Findings Part 1: Processes to Address Issues and Most Important Findings

Ettlin¹,

Kuroda

Plassmann³

et al. 2010

J Toxicol Pathol

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Unexpected adverse preclinical findings (APFs) are not infrequently encountered during drug development. Such APFs can be functional disturbances such as QT prolongation, morphological toxicity or carcinogenicity. The latter is of particular concern in conjunction with equivocal genotoxicity results. The toxicologic pathologist plays an important role in recognizing these effects, in helping to characterize them, to evaluate their risk for man, and in proposing measures to mitigate the risk particularly in early clinical trials. A careful scientific evaluation is crucial while termination of the development of a potentially useful drug must be avoided. This first part of the review discusses processes to address unexpected APFs and provides an overview over typical APFs in particular classes of drugs. If the mode of action (MoA) by which a drug candidate produces an APF is known, this supports evaluation of its relevance for humans. Tailor-made mechanistic studies, when needed, must be planned carefully to test one or several hypotheses regarding the potential MoA and to provide further data for risk evaluation. Safety considerations are based on exposure at no-observed-adverse-effect levels (NOAEL) of the most sensitive and relevant animal species and guide dose escalation in clinical trials. The availability of early markers of toxicity for monitoring of humans adds further safety to clinical studies. Risk evaluation is concluded by a weight of evidence analysis (WoE) with an array of parameters including drug use, medical need and alternatives on the market. In the second part of this review relevant examples of APFs will be discussed in more detail.

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Ultrastructure of rat cerebral cortex cells in normal and experimental dioxin poisoning

et al. 2022

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Purpose the study of the ultrastructure of the cerebral cortex of rats in normal and experimental poisoning with dioxin. Materials and methods. We studied the ultrastructure of the cells of the pyramidal layer of the cerebral cortex of rats of the control and experimental groups that were chronic poisoned with small doses of dioxin (2,3,7,8-tetrachlorodibenzo-para-dioxin or TCDD). Morphometric analysis was carried out to determine the length of synaptic clefts, the number of synapses per unit area, the thickness of the myelin layer of the processes and the number of wrappers of myelin sheaths. Results. The pathology of neurons has been observed both at the optical and ultrastructural levels. It is characterized by a decrease in nuclei, cell death, thinning of myelin sheaths and demyelination. The dose of poisoning correlates with the degree of destruction of neurons: with an increase in the dose of dioxin, changes become more significant. The number of synaptic contacts decreases but there is a significant increase in their average length. Conclusions. The processes of demyelination, impaired cellular respiration and destruction of synaptic contacts indicate the ability of dioxin to indirectly cause accelerated aging of neurons and their death (apoptosis).

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Chemically-Induced Immunopathology and Immune Functional Changes

Cited by 3 publications

References 48 publications

Evaluation of Myelotoxicity in Dietary Restricted Rats

Evaluation of Myelotoxicity in Dietary Restricted Rats

Successful Drug Development Despite Adverse Preclinical Findings Part 1: Processes to Address Issues and Most Important Findings

Ultrastructure of rat cerebral cortex cells in normal and experimental dioxin poisoning

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