毒理学基础个人总结Chater 7 General Toxicity Studies毒理学基础个人总结Chapter 7 General Toxicity Studies.docx

Chapter 7 General Toxicity Studies General Considerations Acute ≤24-h (single or repeated administrations) Subchronic ≥3-m in rats or 1-2y in dogs (up to 10% of life span, repeated administrations) Chronic 18-m in mice, 24-m in rats, or 7-10y in dogs and monkeys (entire/major life-span) Part 1 Acute Toxicity Studies ? Basic Conception ? One or more routes of administration, and one or more species of laboratory animals are used. ? Within 24 h of exposure duration ? 14 d for observation, to make sure all possible toxicity can be assessed. ? Toxic effects: Mortality, signs of intoxication, behavioral modifications, morbidity, etc. ? Objectives and Parameters of Studies 1. Objectives Quantitative estimation of acute toxicity (LD50); target organs and other clinical signs; reversibility; a basis of dosing for further studies. 2. Commonly Used ParametersMedian lethal dose (LD50), median lethal concentration (LC50, for inhalation), with 95% confidence limits, values affected by many factors related to the experimental conditions (p185). ? Experimental Design 1. Selection of Animal Species ? Mouse and rat most often used, suitable for both inhalation and oral toxicity test (preference is rat, but mouse is more economical). ? At least 5 d for acclimatizing the animals to the lab environment, at least 5 animals at each sex per dose level, females should be nulliparous and non-pregnant 2. Route of Administration ? The main routes for xenobiotics to enter the body: GI tract (ingestion), lungs (inhalation), and skin (dermal). ? By ingestion: in diet, in drinking water, by gastric gavage, or by gelatin capsules. ? By inhalation: using inhalation exposure chambers (static or dynamic) ? Dermal administration: ? By i.p., i.m., i.v., s.c., intradermal injection 3. Dosage and Experimental Groups ? Four or more doses are required for a classic LD50 determination. ? At lease 3 doses “effective” ? Low≥ 10 ? Middle≈ 50 ? High≤ 90 ? To improve the precision of LD50 (for a narrow