Toxic hyperplasia

Drugs have to be administered at very high doses (MTD). The paradox is that the safer the chemical, the higher the MTD, and the more likely that biochemical distortions will lead to cellular injury or cell death, abnormal compensatory cell replication, toxic hyperplasia, and toxicity-induced cancer, which is not... 

Leclere J, Bene MC, Aubert V, et al. Clinical consequences of activating germhne mutations of TSH receptor, the concept of toxic hyperplasia. HormRes 1997 47 158-162. 

Atterwill, C. K., C. Jones, and C. G. Brown. 1992. Thyroid gland II. Mechanisms of species dependent thyroid toxicity, hyperplasia and neoplasia induced by xenobiotics. In Endocrine toxicology, ed. C. K. Atterwill and J. D. Flack, pp. 137-182. Cambridge Cambridge University Press. 

As regards toxicity, pyrazole itself induced hyperplasia of the thyroid, hepatomegaly, atrophy of the testis, anemia and bone marrow depression in rats and mice (72E1198). The 4-methyl derivative is well tolerated and may be more useful than pyrazole for pharmacological and metabolic studies of inhibition of ethanol metabolism. It has been shown (79MI40404) that administration of pyrazole or ethanol to rats had only moderate effects on the liver, but combined treatment resulted in severe hepatotoxic effects with liver necrosis. The fact that pyrazole strongly intensified the toxic effects of ethanol is due to inhibition of the enzymes involved in alcohol oxidation (Section 4.04.4.1.1). 

Cyclosporine reduces production of cytokines involved in T-cell activation and has direct effects on B cells, macrophages, bone, and cartilage cells. Its onset appears to be 1 to 3 months. Important toxicities at doses of 1 to 10 mg/kg/day include hypertension, hyperglycemia, nephrotoxicity, tremor, GI intolerance, hirsutism, and gingival hyperplasia. Cyclosporine should be reserved for patients refractory to or intolerant of other DMARDs. It should be avoided in patients with current or past malignancy, uncontrolled hypertension, renal dysfunction, immunodeficiency, low white blood cell or platelet counts, or elevated Ever function tests. 

Mutations with similar outcomes have been identified in nonautoimmune autosomal dominant hyperthyroidism (toxic thyroid hyperplasia) (25,26,28,32,33). These variants are located in the third TM (Val509Ala), the seventh TM (Cys672Tyr), and the carboxyl tail (Asp727Glu) regions (34). These variants result in a form of congenital hyperthyroidism that is the germline counterpart of a hyperfunctioning thyroid adenoma, with similar functional characteristics (25,33). 

In rats, AAF had no demonstrable acute toxicity in quantities up to 50mg/kg subcutaneously and 1 g/% gastrically however, AAF was very toxic when administered in the diet." Incorporation of 0.031% AAF or higher for at least 95 days led to epithelial hyperplasia of the bladder, renal pelvis, liver, pancreas, and lung 19 of 39 rats developed malignant tumors, 16 of which were carcinomas." ... 

Exposure of rats to p-dichlorobenzene vapor concentrations up to 538 ppm for 2 generations resulted in Fq and Fi adult toxicity, including reduced body weights in both sexes and kidney effects (hyaline droplet neuropathy and renal tubular cell hyperplasia) in males, but... 

Continuous exposure of rats by inhalation to 0.0055 and 0.3mg/m for 100 days resulted in methemoglobinemia, lowered erythrocyte hemoglobin, leukopenia and reticulocytosis, and reduced muscle chronaxie. Doses up to 500mg/kg administered by gavage to rats and mice for 13 weeks caused cyanosis and decreased motor activity, as well as hemosiderosis in the spleen liver, kidney, and testes. Bone marrow hyperplasia was observed in rats, and mice had increased hematopoiesis in the liver. In general, all toxic effects could be attributed to chronic methemoglobinemia, erythrocyte destruction, and erythrophagocytosis. 

In chronic studies, DMMP was administered by gavage in corn oil for up to 2 years at doses of 500 or 1000 mg/kg/day to rats and at doses of 1000 or 2000mg/kg/day to mice. " Survival in dosed male rats was reduced, due in part to renal toxicity. Lesions of the kidney included increased severity of spontaneous age-related nephropathy including calcification, hyperplasia of the tubular and transitional epithelium, tubular cell adenocarcinomas, and transitional cell papillomas and carcinomas. Similar lesions were not seen in female rats or in mice of either sex, although reduced survival in male mice prevented adequate analysis. The... 

Several studies have reported hepatic effects in animals after exposure to HMX. Hepatocyte hyperplasia and cytoplasmic eosinophilia were noted in rats and mice orally exposed to 1280 and 300mg/kg/day, respectively, for 14 days. Clear evidence of hepato-toxicity was observed at a higher dose of 8504mg HMX/kg/day, which resulted in cen-trilobular degeneration in male rats exposed for 14 days. Collectively, the data from animal studies indicate that the liver is adversely affected by exposure to moderate to high doses of HMX. 

No exposure-related clinical signs or lesions of systemic toxicity and no oncogenic responses were observed in rats exposed by inhalation at concentrations of 0, 15, 45, or 135ppm 6 hours/day, 5 days/week, for 24 consecutive months." Dose-related changes occurred in the anterior portion of the olfactory epithelium and consisted of atrophy of the neurogenic epithelial cells followed by progressive hyperplasia of the reserve cells and ultimately loss of the upper epithelial cell layer. Opacity and neovascularization of the cornea were also observed in methyl acrylate-exposed animals. 

In 2-week and 13-week toxicity studies topical administration of MEKP (as a 45% solution in dimethyl phthalate) to both rats and mice resulted in a spectrum of necrotic, inflammatory, and regenerative skin lesions limited to the application site. Lesions considered secondary to the dermal lesions included increased hematopoiesis in the spleen in rats and mice and increased myeloid hyperplasia of the bone marrow in mice. 

In rats, exposure to 1000 ppm was lethal to two of six animals within 4 hours. Repeated 7-hour exposures at 3 00 ppm were rapidly fatal to 40% of female rats, and extensive mortality occurred in rats receiving prolonged exposure to 100 ppm. Toxicity also was marked in the rabbit, with prolonged and repeated exposures at 15-50 ppm producing mortality. Histopathologic changes in rats and rabbits included metaplasia and hyperplasia of the lungs. 

Leafy Spurge Root Extractives. Prior chemical examinations of leafy spurge have considered only aerial portions of the plant. Our recent chemical examination of root material relative to mammalian toxicity and/or allelopathy (29) resulted in the isolation and characterization of two new jatrophane diterpenes (esulone A (IX) and esulone B (X)) from the ether extract of the roots. Biological assay of esulone A showed it to be moderately phytotoxic (29% root length reduction (lettuce seeds) at 250 ppm), moderately toxic (LD50 78 23 mg/kg) and mildly Inflammatory (10 5 to 10 M, dermal) to mammals with no hyperplasia. 

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