Toxicity testing, single-dose

It is necessary to determine the toxicity of a drug. The maximum tolerable dose and area under curve are established in rodents and non-rodents. There are two types of toxicity studies single dose and repeated dose. Single dose acute toxicity testing is conducted for several purposes, including the determination of repeated doses, identification of organs subjected to toxicity, and provision of data for starting doses in human clinical trials. 

Similar results for rats were reported by Crowder et al. (1980). Oral administration of 1 mg/kg/day of methyl parathion (99.9% purity) in com oil on days 7-15 of gestation resulted in increased mortality in pups, relative to controls. Significant difference from controls in a maze transfer test was observed in pups from the treated group. However, use of a single-dose level precluded the assessment of dose-response, and several other behavioral end points were not affected. Furthermore, no information was presented regarding body weights or signs of toxicity in the treated dams. 

S4 Single Dose Acute Toxicity Testing for Pharmaceuticals Revised Guidance Availability Notice Aug 96... 

Metabolism and pharmacokinetic studies have greater relevance when conducted in both sexes of young adult animals of the same species and strain used for other toxicity tests with the test substance. The number of animals used in metabolism and pharmacokinetic studies would be sufficient to reliably estimate population variability. This usually means a separate (but parallel) set of groups of animals in rodent studies. A single set of intravenous and oral dosing results from adult animals, when combined with some in vitro kinetic results, may provide an adequate data set for the design and interpretation of short-term, subchronic and chronic toxicity studies. 

The initial strategy for Phase I is to conduct a single-dose safety study in normal volunteers. The first trial demands close 24-hour supervision in a clinical setting. Ethical considerations may, however, demand that only patients be used, for example, when evaluating an anticancer agent with predictable toxicity. A repeat dose tolerance and pharmacokinetic study in normal or patient volunteers is then conducted for chronically administered drugs. These studies will provide the necessary safety information to support efficacy testing. 

Part III This part is to ensure that safety tests have been carried out according to GLPThe data to be submitted are toxicity (single dose and repeated dose), reproduction function, embryo-fetal and perinatal toxicity, mutagenic potential, carcinogenic potential, pharmacodynamics, pharmacokinetics, and local tolerance. 

According to the definitions provided in the OECD test guidelines (TG 420 and 423), acute oral toxicity refers to those adverse effects that occur following oral administration of a single dose of a substance or multiple doses given within 24 h. 

Acute dermal toxicity is the adverse effects occurring within a short time of dermal application of a single dose of a test substance. The duration of exposure in the OECD TG 402 is 24 h, at the end of which residual test substance should be removed. 

SSDs are being routinely used for the display and interpretation of effects data (Parkhurst et al. 1996 Posthuma et al. 2002). An SSD for atrazine (shown in Figure 7.3) displays the typical S-shaped curve associated with many chemical dose-response relationships. Each point on the curve represents an LC50 for a particular species exposed to atrazine under standard toxicity test protocols. The SSD approach uses only a single statistically derived endpoint from each available toxicity test (e.g., the LC50 or EC50). In contrast, all data collected during any specific toxicity test can be used in a hierarchical model. The ability to use all available data to make inferential decisions is a marked improvement over the standard SSD effects distribution. 

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