Investigation of the pathological changes induced by stress in drug toxicity study

LIN Zhi; LI Wei; LI Shan-shan; L(U) Jian-jun; QU Zhe; HUO Gui-tao; ZHANG Di; YANG Yan-wei; GAI Wen-lin; WANG Xue; LI Bo

Abstract：Objective:To investigate the histopathological characteristics of multiple organs injury induced by stress in drug toxicity study by conducting a repeated toxicity study of epithelial growth factor receptor (EGFR) monoclonal antibody in cynomolgus monkeys.Methods:Cynomolgus monkeys were randomly divided into four groups including vehicle control,low-,middle-,and high-dose of anti-EGFR monoclonal antibody groups.All the animals were intravenously given vehicle or test drug every week continuously for 26 weeks followed by an 8-week recovery phase.The animals in the mid-and high-dose groups were sacrificed or performed into recovery phase after 22 weeks due to being moribund.Necropsy and histopathological examination were performed in all groups at the end of study.Also necropsies were conducted on 10 animals which died at an unscheduled interval.The expression of adrenocorticotropic hormone (ACTH) in the pituitaries of all animals was analyzed by immunohistoehemistry examination.Results:The most common phenomena observed in the test article-treated groups were diarrhea,loose stools,erythema,skin rash,depilation,desquamation,and ulceration.Obvious atrophy of immune organ occurred in the dead animals,including depletion of lymphocytes in thymus,spleen and lymph nodes.The weights of uteruses in the dead females were obviously decreased compared with the control females,and the histopatholgical change was uterus atrophy companied with fibrosis.In addition,diffuse hypertrophy of zona fasciculate of adrenal cortex occurred in the dead animals.The expressions of ACTH in the pituitaries of mid-and high-dose animals were higher than that in the control animals.Conclusion:The atrophy of immune organs induced by stress in drug toxicity study may be associated with hypertrophy of zona fasciculate of adrenal cortex.To differentiate whether the changes in histopathology are due indirectly to stress or directly to the test article,weight-of-evidence approach may be used to evaluate all the data in an integrated fashion.Also the expression of ACTH in pituitary may provide a good proof for examining the impact of stress in toxicity study.