Toxicity high-dose

Adverse effects in patients include nausea, vomiting, diarrhea, damage to intestinal mucosa, depressed bone marrow, and hepatic toxicity (high dose). LD50 in rats (intraperitoneal), 30 mg/kg.2... 

Methane is a natural gas present in coal mines, marsh gas, and sludge degradations. Although at low concentrations it causes no toxicity, high doses lead to asphyxiation in animals and humans. 

Acute tubular necrosis has followed the administration of cephaloridine in doses greater than 4 g/day this agent is no longer available in the U.S. Other cephalosporins, when used by themselves in recommended doses, rarely produce significant renal toxicity. High doses of cephalothin... 

Hepatic toxicity High doses of tetracyclines, especially in pregnant patients or in patients with preexisting hepatic disease, may impair liver function and lead to hepatic necrosis. 

Classification Polyhydric alcohol Formula CH20H(CH0H)nCH20H Properties Solid (m.w. > 1000), llq. (m.w. < 600) Toxicology Low toxicity high doses can cause kidney damage... 

The vitamin is safe to at least 10 x RDA. However, high doses can produce side effects including flushing, hives and GI discomfort and even liver toxicity. High doses of nicotinamide are generally better tolerated than high doses of nicotinic acid. 

Hydraziae is toxic and readily absorbed by oral, dermal, or inhalation routes of exposure. Contact with hydraziae irritates the skin, eyes, and respiratory tract. Liquid splashed iato the eyes may cause permanent damage to the cornea. At high doses it can cause convulsions, but even low doses may result ia ceatral aervous system depressioa. Death from acute exposure results from coavulsioas, respiratory arrest, and cardiovascular coUapse. Repeated exposure may affect the lungs, Hver, and kidneys. Of the hydraziae derivatives studied, 1,1-dimethylhydrazine (UDMH) appears to be the least hepatotoxic monomethyl-hydrazine (MMH) seems to be more toxic to the kidneys. Evidence is limited as to the effect of hydraziae oa reproductioa and/or development however, animal studies demonstrate that only doses that produce toxicity ia pregaant rats result ia embryotoxicity (164). 

Lead is toxic to the kidney, cardiovascular system, developiag red blood cells, and the nervous system. The toxicity of lead to the kidney is manifested by chronic nephropathy and appears to result from long-term, relatively high dose exposure to lead. It appears that the toxicity of lead to the kidney results from effects on the cells lining the proximal tubules. Lead inhibits the metaboHc activation of vitamin D in these cells, and induces the formation of dense lead—protein complexes, causing a progressive destmction of the proximal tubules (13). Lead has been impHcated in causing hypertension as a result of a direct action on vascular smooth muscle as well as the toxic effects on the kidneys (12,13). 

Health and Safety Factors. Terephthahc acid has a low order of toxicity. Inhalation by rats for 6 h/d, 5 d/wk for 4 wk produced no fatahties at a dust exposure level of 25 mg/m. The mean acute oral toxicity for rats is over 18 g/kg (86), and for mice over 6 g/kg (87). When terephthahc acid was fed as 3% of the diet to rats, urinary calcuh formed in 90 d, some of which led to cancer. High doses of terephthahc acid lead to formation of calcium terephthalate at levels exceeding its solubihty in urine. This insoluble material leads to the calcuh and provides a threshold below which cancer is not observed (88). Normal precautions used in handling industrial chemicals should be observed with terephthahc acid. If ventilation is inadequate, a toxic-dust respirator should be used to avoid prolonged exposure. 

In 1969, a chronic toxicity study on a cyclamate saccharin (10 1) blend indicated bladder cancer problems in rats. Cyclamate was soon banned by the FDA, but saccharin remained an approved sweetener. In 1977, the FDA proposed a ban on saccharin because of the discovery of bladder tumors in some male rats fed with high doses of saccharin. Because no other nonnutritive sweetener was available at that time, the proposed ban faced strong opposition. 

Along with increasing evidence of health benefits from consumption of vitamins at levels much higher than RE) A recommendations comes concern over potential toxicity. This topic has been reviewed (19). Like all chemical substances, a toxic level does exist for each vitarnin. Traditionally it has been assumed that all water-soluble vitamins are safe at any level of intake and all fat-soluble vitamins are toxic, especially at intakes more than 10 times the recommended allowances. These assumptions are now known to be incorrect. Very high doses of some water-soluble vitamins, especially niacin and vitamin B, are associated with adverse effects. In contrast, evidence indicates that some fat-soluble micronutrients, especially vitamin E, are safe at doses many times higher than recommended levels of intake. Chronic intakes above the RDA for vitamins A and D especially are to be avoided, however. 

Toxicity. Vitamin D toxicity was known as eady as the year 1429 (217). Accidental toxicity has been reported in monkeys, dogs, horses, pigs, chinchillas, and humans, and particulady in catde when extremely high doses of vitamin D have been used to treat milk fever. 

Several chemical compounds may cause inflammation or constriction of the blood vessel wall (vasoconstriction). Ergot alkaloids at high doses cause constriction and thickening of the vessel wall. Allylamine may also induce constriction of coronary arteries, thickening of their smooth muscle walls, and a disease state that corresponds to coronary heart disease. The culprit is a toxic reactive metabolite of allylamine, acrolein, that binds covalently to nucleophilic groups of proteins and nucleic acids in the cardiac myocytes. 

Compounds that Cause Kidney Damage Several drugs and some anesthetic compounds such as methoxyflurane cause kidney damage when present at high doses. Kidney-toxic compounds found in occupational environments include mycotoxins, halogenated hydrocarbons, several metals, and solvents (see Table 5.16). 

The therapeutic range of theophylline blood levels is 10 to 20 p,g/mL. Levels greater than 20 pig/mL may cause toxicity. In some patients, toxicity may occur with levels between 15 and 20 pg/mL. Toxicity is more likely to occur in patients requiring high doses or during prolonged dierapy. 

LEUCOVORIN. When leucovorin is administered after a large dose of methotrexate, the timing of tiie administration is outlined by tiie primary health care provider. It is essential that the leucovorin be given at tiie exact time ordered because tiie purpose of folinic acid rescue is to allow a high dose of a toxic drug to remain in tiie body for only a limited time... 

The drug should be administered at three levels by the route proposed for humans. The high dose level should be set so as to have relevance in humans. For drugs that display significant toxic effects, this may be related to the maximally tolerated dose in the toxicity tests, for example, the dose causing less than 10% deviation in body weight versus controls. If there is little evidence of toxicity it may be more appropriate to base the dose level on a multiple (usually 25-fold) of the maximum therapeutic dosage recommended in humans. 

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