Toxicity, maximum tolerated dose

Acute oral toxicity (maximum tolerated dose) Biodegradibility... 

For carckiogen pesticides (70,71), animal testkigs are subject to maximum tolerated doses (M I L)). M I D is the maximum amount of a substance that can be administered to an experimental animal without causkig extreme health consequences, such as death, to occur but while continuing to produce some measurable toxic effects. Current regulatory theory holds that carckiogen effects do not have a threshold and caimot be related to reference doses. 

Numerous experimental therapeutics have shown potency in vitro however, when they are tested in vivo, they often lack significant efficacy. This is often attributed to unfavorable pharmacokinetic properties and systemic toxicity, which limit the maximum tolerated dose. These limitations can be overcome by use of drug carriers. Two general types of carrier systems have been designed drug conjugation to macromolecular carriers, such as polymers and proteins and drug encapsulation in nanocarriers, such as liposomes, polymersomes and micelles. 

In practice it is obviously difficult to actually determine the toxic and effective dose in 50% of treated patients in the same population but the concept of a maximum tolerated dose compared with an effective dose is of great importance. 

Phase I - Involves 20 to 80 patients and investigates drug toxicity in healthy volunteers. Outcomes are the maximum tolerated dose and API concentration profile in the body. 

Doses selected for safety pharmacology studies are typically based on the criteria established in the ICH S7A guidance.25 Doses should exceed those projected for clinical efficacy and at the upper limit be bound by (1) adverse pharmacodynamic effects in the safety pharmacology study (2) moderately adverse effects in other non-clinical studies that follow a similar route and duration of dosing or (3) limit of solubility/toxicity. In the absence of adverse effects, the maximum administrable dose can be used. If nonreusable animals enter the study, then the maximum tolerated dose may be appropriate. Most importantly, the doses/concentrations should establish the dose/concentration-response relationship of the adverse effect. 

It is necessary to determine the toxicity of a drug. The maximum tolerable dose and area under the curve are established in rodents and nonrodents. There are two types of toxicity studies single dose and repeated dose. Single... 

Maximum tolerated dose (determined by 5-day toxicity tests in non-tumor-bearing mice). 

Animals, usually rodents, are exposed to a test substance by an appropriate route (usually oral or intraperitoneal injection, other routes may be appropriate) followed by administration of bromodeoxyuridine (BrdU). At least five female and five male animals per experimental and control group should be used. For an initial assessment, one dose of the test substance may be used, the dose being the maximum tolerated dose or that producing some indication of toxicity as evidenced by animal morbidity (including death) or target cell toxicity. For determination of dose-response, at least three dose levels should be used. A compound known to produce SCE in vivo should be employed as the positive control. A spindle inhibitor (e.g., colchicine) is administered prior to sacrifice. After sacrifice, tissue is obtained and metaphase preparations made, stained, and scored for SCE. 

In both mice and rats exposed 6 hours/day 5 days/week for 12 weeks, the no-effect dose was below 150 ppm and the maximum tolerated dose was below 600 ppm. At doses of up to 12 00 ppm there were few signs of overt toxicity, and at necropsy the only treatment related lesions occurred in the liver. Subchronic studies in monkeys showed no exposure-related adverse health effects or reproductive effects after exposure 6 hour/day, 5 days/week for 13 weeks to concentrations of up to 500ppm."... 

No effect dose level, lowest effect level and/or maximum tolerated dose level for maternal toxicity. 

Toxicity assessment. Ethanol (50%) extract of the seed, administered intraperito-neally to mice, produced a maximum tolerated dose of 1 g/kg . Hexane extract of the green leaf juice, administered in ration of rats, produced lethal dosejo greater than 10 g/kg . 

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