High-dose exposure to synthetic chemicals, hormones, or homeostatic substances in experimental animals or humans can induce artefactual pathology

Abstract

The maximum tolerated dose (MTD) provides the highest probability of a positive result in a toxicology bioassay. The assumption underlying the MTD in animal bioassays is that adverse effects at very high doses are qualitatively the same as those occurring at low doses. In contrast with the MTD, the optimal top dose in a toxicology animal study is the highest dose that does not produce a pathological end point that presents no risk at lower doses, for example, the dose below which cytotoxicity induces tumors in the absence of genotoxicity or other carcinogenic mechanisms. Normal concentrations or biological activity levels of many substances necessary for normal physiological function induce pathology when found at high levels. For example, the demonstration that ingestion of abnormally high levels of certain dietary fats can cause or exacerbate atherosclerosis in relevant animal models like rhesus macaques does not demonstrate that normal levels of these fats should be considered as toxic. Excessive estrogenic stimulation is associated with breast, ovarian, and endometrial cancers. This does not imply that normal age-appropriate levels of estrogen are toxic. Normal wound healing is associated with transforming growth factors beta 1 and 2. Excessive stimulation of fibroblasts by these growth factors results in hypertrophic scarring and keloid formation. An understanding of the mode of action of a test substance can facilitate the selection of dose levels much higher than those expected to be experienced by humans, but not beyond a dose level at which pathology is an experimental artefact of the high-dose level.

Categorizing the characteristics of human carcinogens: a need for specificity

“…Given the high doses routinely applied in toxicology studies (Buckley and Dorato 2009;Smith and Perfetti 2020), tens of thousands of chemicals and pharmaceuticals currently in commerce would be expected to display a positive finding in one or more of the TKCs (IARC 2017). This is especially true in light of the fact that many in vivo studies employ a non-physiological route of administration (e.g., intraperitoneal).…”

Histological Changes in Rat Testicles Induced by Different Concentration of Cadmium Chloride

“…Oxidative stress is the most common mechanism causes damage in the testicular tissue due to overproduction of reactive oxygen species and free radicals lead to a state of oxidative stress and resultant damages of lipids, protein, and DNA (Patra et al, 2011).Additionally, International Agency of Research on Cancer has stated cadmium have carcinogenic effects on most of organs such as liver and testis (Tomatis, 1976;Smith and Perfetti, 2020).…”