Dose-response relationships single

Acute Toxicity Studies. These studies should provide the following information the nature of any local or systemic adverse effects occurring as a consequence of a single exposure to the test material an indication of the exposure conditions producing the adverse effects, in particular, information on dose—response relationships, including minimum and no-effects exposure levels and data of use in the design of short-term repeated exposure studies. 

The critical effect of intermediate-duration exposure to -hexane in humans is neurotoxicity, specifically peripheral neuropathy. No inhalation MRL was derived for this duration because the reports of neurological effects in humans were predominantly case reports with inadequate documentation of exposure levels or comparison with unexposed groups. A large database on neurological effects in rats exists for this duration however, the design of these experiments precluded documentation of clear dose-response relationships within a single study. Because of the limited database for oral exposure to -hexane and the lack of toxicokinetic data for this route, no MRL was derived for oral exposure to -hexane. 

Decision Analysis. An alternative to making assumptions that select single estimates and suppress uncertainties is to use decision analysis methods, which make the uncertainties explicit in risk assessment and risk evaluation. Judgmental probabilities can be used to characterize uncertainties in the dose response relationship, the extent of human exposure, and the economic costs associated with control policies. Decision analysis provides a conceptual framework to separate the questions of information, what will happen as a consequence of control policy choice, from value judgments on how much conservatism is appropriate in decisions involving human health. 

Cernea S, Kidron M, Wohlgelernter J, and Raz I (2005) Dose-response relationship of an oral insulin spray in six patients with type 1 diabetes A single-center, randomized, single-blind, 5-way crossover study. Clin. Ther. 27 1562-1570. 

Single exposures to 12,000 mg/kg kerosene and 12,150 mg/kg Deobase by oral gavage induced unsteady gait and drowsiness in rats however, no neurological effects occurred from exposure to 8,000 mg/kg kerosene (Muralidhara et al. 1982). These data are limited since statistical analysis was not conducted and effects in the controls were not described. Also, a dose-response relationship cannot be identified from the Deobase data, since only one dose was tested. 

In the first step of the hazard assessment process, aU effects observed are evaluated in terms of the type and severity (adverse or non-adverse), the dose-response relationship, and NOAEL/LOAEL (or alternatively BMD) for every single effect in aU the available studies if data are sufficient, and the relevance for humans of the effects observed in experimental animals. In this last step of the hazard assessment, all this information is assessed as a whole in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). It is usual to derive a NOAEL on the basis of effects seen in repeated dose toxicity studies and in reproductive toxicity studies. However, for acute toxicity, irritation, and sensitization it is usually not possible to derive a NOAEL because of the design of the studies used to evaluate these effects. For each toxicological endpoint, these aspects are further addressed in Sections 4.4 through 4.10. 

For non-threshold mechanisms of genotoxic carcinogenicity, the dose-response relationship is considered to be linear. The observed dose-response curve in some cases represents a single ratedetermining step however, in many cases it may be more complex and represent a superposition of a number of dose-response curves for the various steps involved in the tumor formation (EC 2003). Because of the small number of doses tested experimentally, i.e., usually only two or three, almost all data sets fit equally well various mathematical functions, and it is generally not possible to determine valid dose-response curves on the basis of mathematical modeling. This issue is addressed in further detail in Chapter 6. 

The T25 is dehned as the chronic daily dose (in mg/kg body weight per day), which will give 25% of the animal s tumors at a specihc tissue site, after correction for spontaneous incidence, within the standard lifetime of that species. It is a value calculated from a single observed dose-response and based upon the assumphon of a linear dose-response relationship over the entire dose range. 

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. 

A typical feature of Phase [lb are dose response trials regarding a drug s safety, efficacy and side effects. No single study design can address all aspects of dose response relationships for a new drug, and so a number of different... 

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