Dose-response curves definition

Human embryonic kidney cells, 21 Human genome, 2 Hydrogen bonding, 10 Hypothesis testing definition of, 239 description of, 227, 233 dose-response curves for, 239-243 F-test, 242t... 

One of the most evident limitations in the NOAEL approach in the derivation of tolerable intakes is that it does not take into account the slope of the dose-response curve for the particular response of interest (Section 4.2.4). The NOAEL is by definition one of the doses tested, and apart from ensuring that the number and spacing of data points are adequate to provide a reasonable estimate of the NOAEL, all other data points are ignored. Although the NOAEL could be considered an estimate of the tme NAEL, the quality of the estimate cannot be assessed. For the dose-response relationship and precision in the NOAEL, consideration should therefore be given to the uncertainties in the NOAEL as the surrogate for the NAEL. 

The NOAEL is not very accurate with respect to the degree to which it corresponds with the (unknown) tme NAEL. One of the most evident limitations in the NOAEL setting is that it does not take into account the shape of the dose-response curve, including its slope, for the effect as the NOAEL by definition is one of the doses tested in the specific experimental study, and all other data points are ignored. In case a NOAEL cannot be set for the critical effect, a LOAEL is then set and extrapolated to a NOAEL this extrapolation can also be regarded as part of the dose-response analysis. 

The Margin of Exposure (MOE) in the context of the assessment of compounds that are both genotoxic and carcinogenic, as defined in EFSA (2005), is different from the OECD/IPCS definition given above The Margin of Exposure (MOE) is the ratio between a defined point on the dose-response curve (reference point) for the adverse effect of the compound in the animal carcinogenicity study and the estimated human intake of the compound. ... 

There are several problems associated with using the NOAEL approach to estimate RfDs and RfCs. The first obvious constraint is that the NOAEL must by definition be one of the experimental doses tested. Once this dose is identified, the rest of the dose-response curve is ignored. In some experimental designs where there is no identifiable NOAEL but LOAEL, the dose-response curve is again ignored, and the NOAEL is derived by application of uncertainty factors as described earlier. This NOAEL approach does not account for the variability in the estimate of the dose response, and furthermore experiments that test fewer animals result in larger NOAELs and thus larger RfDs and RfCs. 

Some aspects of degree of concern currently can be considered in a quantitative evaluation. For example, EPA considers human and animal data in the process of calculating the RfD, and these data are used as the critical effect when they indicate that developmental effects are the most sensitive endpoints. When a complete database is not available, a database UF is recommended to account for inadequate or missing data. The dose-response nature of the data is considered to an extent in the RfD process, especially when the BMD approach is used to model data and to estimate a low level of response however, there is no approach for including concerns about the slope of the dose-response curve. Because concerns about the slope of the dose-response curve are related to some extent to human exposure estimates, this issue must be considered in risk characterization. (If the MOE is small and the slope of the dose-response curve is very steep, there could be residual uncertainties that must be dealt with to account for the concern that even a small increase in exposure could result in a marked increase in response.) On the other hand, a very shallow slope could be a concern even with a large MOE, because definition of the true biological threshold will be more difficult and an additional factor might be needed to ensure that the RfD is below that threshold. 

High sensitivity is an intrinsically desirable property of any anal3d ical technique. The definition of sensitivity has, however, become a subject of considerable controversy particularly for immunoassays, being considered by different scientific groups as the slope in the middle of the dose-response curve [8,9], the midpoint ofthe dose-response curve (IC50) [10] or the minimal... 

Both models assume that the mixture under study is fully described in its chemical composition and that the dose-response curves of all compounds in the mixture are known. Both models are extensively covered in the literature both theoretically (Teuschler et al., 2002 Backhaus el al., 2003 Vighi et al., 2003) and when applied in case studies (Nirmalakhandan et al., 1997 Altenburger et al., 2000 Richardson et al., 2001 Backhaus et al., 2003). Using and interpreting either of the models, the reader has to be aware that both are mere simplifications of a very complex reality. A lot of cases can be found in the literature illustrating mixture effects not accounted for by the aforementioned models (Preston et al., 2000 Chu and Chow, 2002) and validity should be assessed case by case. A critical paper on how to deal with different mixture risk definitions has been written by Hertzberg and MacDonell (2002). 

It is important but difficult to give stringent definitions of various types of interactions or joint action. Because the dose-response curve seldom is linear, and because the relative response to one or more substances given either alone or together cannot exceed 1, we cannot define additive interaction as cases where p(a + b) = pa + pb. 

F. Efficacy Efficacy, often called maximal efficacy, is the maximal effect (E,.,.,) an agonist can produce if the dose is taken to very high levels. Efficacy is determined mainly by the nature of the receptor and its associated effector system. It can be measured with a graded dose-respon.se curve (Figure 2-1) but not with a quantal dose-response curve. By definition, partial agonists have lower maximal efficacy than full agonists (see below). 

Fig. 2 Dose-response curve of capsaicin cough challenge. In this study, C2 and C5 are identical, 31.25 pM (see the text for the definitions of C2 and C5)...

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