Individual dose response

Fig. 6.4 X -X are individual dose-response curves Y is the average dose-response curve for the population.

The pharmacokinetics of stimulants are characterized by rapid absorption, low plasma protein binding, and quick extracellular metabolism (Patrick et al., 1987). Although some investigators claim that the dose-response relationship is affected by the child s weight, others have shown that individual dose-response stimulant effects are independent of the child s weight (Rapport et al., 1989). 

Proper mapping of individual dose-response or concentration-response curves is useful in situations where the drug product has plasma levels that are either higher or lower than those of the reference product... 

It is well known that there is a major problem in the health care system in the United States related to providing new drugs that are effective and relatively safe in a wide diversity of patients with undifferentiated diseases whose individual dose-response relationship varies based on genetic, disease, environmental, and life-style factors. While many may argue over... 

In the RPF method (eqn (1)), the user must identify the constraints of the application of a set of RPFs. For example, the health effect, dose range of component doses, route(s) of exposure, and dura-tion(s) of exposure for which the RPFs can be applied must be specified (e.g., a set of RPFs may be constrained to oral exposures and not be used for exposures to the same mixture through the inhalation route). To apply the method, an RPF is estimated for each mixture component the RPF estimates the toxicity of the component relative to that of the IC. RPFs commonly are estimated from a ratio of equally toxic doses of the individual dose-response functions for the component and the IC. For example, the quotient of the effective dose at which ten percent of a test population exhibits an effect (EDio) of the IC and the component could serve as a value for the component s RPF obviously, the RPF for the IC equals 1. The index chemical equivalent dose of an individual component is the product of the component dose and the RPF of the component. These equivalent doses are summed across all components. The risk posed by the mixture is estimated by comparing the summed index chemical equivalent doses of the mixture to the dose-response function of the IC ... 

In addition to the effect of biological variabihty in group response for a given exposure dose, the magnitude of the dose for any given individual also determines the severity of the toxic injury. In general, the considerations for dose—response relationship with respect to both the proportion of a population responding and the severity of the response are similar for local and systemic effects. However, if metabohc activation is a factor in toxicity, then a saturation level may be reached. 

There are some basic differences between toxic and allergic reactions. The most important differences are (1) an allergic reaction always requires a prior exposure to the compound, and this reaction only occurs in sensitized individuals and (2) a dose-response relationship is characteristic to a toxic reaction, whereas such a relationship is much less clear for an allergic reaction. Even minute doses can elicit an allergic reaction in a sensitized individual (see Fig. 5.42). ... 

Using dose-response information from homogeneous animal populations or healthy human populations to predict the effects likely to be observed in the general population consisting of individuals with a wide range of sensitivities... 

Variability arises from true heterogeneity in characteristics such as dose-response differences within a population, or differences in contaminant levels in tlie enviromiient The values of some variables used in an assessment change witli time and space, or across tlie population whose exposure is being estimated. Assessments should address tlie resulting variability in doses received by members of the target population. Individual exposure, dose, and risk can vary widely in a large population. The central tendency and high end individual risk descriptors are intended to capture tlie variability in exposure, lifestyles, and other factors tliat lead to a distribution of risk across a population. 

FIGURE 11.14 Data set consisting of a control dose-response curve and curves obtained in the presence of three concentrations of antagonist. Panel a curves fit to individual logistic functions (Equation 11.29) each to its own maximum, K value, and slope. Panel b curves fit to the average maximum of the individual curves (common maximum) and average slope of the curves (common n) with only K fit individually. The F value for the comparison of the two models is 2.4, df = 12,18. This value is not significant at the 95% level. Therefore, there is no statistical support for the hypothesis that the more complex model of individual maxima and slopes is required to fit the data. In this case, a set of curves with common maximum and slope can be used to fit these data. 

FIGURE 11.15 Aikake s information criteria (AIC) calculations. Lower panel shows three dose-response curves that can alternately be fit to a three-parameter logistic such that each curve is fit to its own particular value of maximum and slope (individual fits), with common maxima but individual slopes (common maxima), or with common maxima and slope. The IAC values (Equation 11.30) for the fits are shown in the table above the figure. It can be seen that the lowest value corresponds to the fit with common maxima and slope. Therefore, this fit is preferred. 

Toxic equivalency factors (TEFs) are estimated relative to 2,3,7,8-TCDD, which is assigned a value of 1. They are measures of the toxicity of individual compounds relative to that of 2,3,7,8-TCDD. A variety of toxic indices, measured in vivo or in vitro, have been used to estimate TEFs, including reproductive effects (e.g., embryo toxicity in birds), immunotoxicity, and effects on organ weights. The degree of induction of P450 lAl is another measure from which estimations of TEF values have been made. The usual approach is to compare a dose-response curve for a test compound with that of the reference compound, 2,3,7,8-TCDD, and thereby establish the concentrations (or doses) that are required to elicit a standard response. The ratio of concentration of 2,3,7,8-TCDD to concentration of test chemical when both compounds produce the same degree of response is the TEF. Once determined, a TEF can be used to convert a concentration of a dioxin-like chemical found in an environmental sample to a toxic equivalent (TEQ). 

Responses to individual doses are given in those cases in which an LD50 could not be calculated. The LD50 for oral administration to rabbits was calculated using the method of Litchfield and Wilcoxon 9) the remaining values were calculated using the Weil modification of the method of Thompson 15). 

NOAEL (no-observed-adverse-effect level) is defined as the highest dose at which no adverse effects are observed in the most susceptible animal species. The NOAEL is used as a basis for setting human safety standards for acceptable daily intakes (ADIs), taking into account uncertainty factors for extrapolation from animals to humans and inter-individual variabilities of humans. The adequacy of any margin of safety or margin of exposure must consider the nature and quality of the available hazard identification and dose-response data and the reliability and relevance of the exposure estimations. In some cases, no adverse endpoint can be identified such as for many naturally occurring compounds that are widespread in foods. In that case, an ADI Not Specified is assigned. ... 

Plant physiologists and other biological scientists also have their important role to play in allelopathy. They must devise suitable bioassays to detect the suspected allelopathic compounds, follow the biological activity of the individual and associated chemicals, develop activity profiles for identified chemicals, and determine the conditions (dose/response) for chemicals to arrive at the threshold levels. They must also determine which chemicals contribute... 

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