Dose-effect curve variations

Several overall conclusions can be drawn based on the statistical evaluation of the data submitted by the participants of the DR CALUX intra-and interlaboratory validation study. First, differences in expertise between the laboratories are apparent based on the results for the calibration curves (both for the curves as provided by the coordinator and for the curves that were prepared by the participants) and on the differences in individual measurement variability. Second, the average results, over all participants, are very close to the true concentration, expressed in DR CALUX 2,3,7,8-TCDD TEQs for the analytical samples. Furthermore, the interlaboratory variation for the different sample types can be regarded as estimates for the method variability. The analytical method variability is estimated to be 10.5% for analytical samples and 22.0% for sediment extracts. Finally, responses appear dependent on the dilution of the final solution to be measured. This is hypothesized to be due to differences in dose-effect curves for different dioxin responsive element-active substances. For 2,3,7,8-TCDD, this effect is not observed. Overall, based on bioassay characteristics presented here and harmonized quality criteria published elsewhere (Behnisch et al., 2001a), the DR CALUX bioassay is regarded as an accurate and reliable tool for intensive monitoring of coastal sediments. 

Pharmacologists use the dose-effect curve as a standard way to represent graphically the size of an effect in relation to the dose of a drug taken. The prototype dose-effect curve has an S shape, but variations depend on the effects studied. 

In animal experiments exposures can be carefully controlled, and dose-response curves can be formally estimated. Extrapolating such information to the human situation is often done for regulatory purposes. There are several models for estimating a lifetime cancer risk in humans based on extrapolation from animal data. These models, however, are premised on empirically unverified assumptions that limit their usefulness for quantitative purposes. While quantitative cancer risk assessment is widely used, it is by no means universally accepted. Using different models, one can arrive at estimates of potential cancer incidence in humans that vary by several orders of magnitude for a given level of exposure. Such variations make it rather difficult to place confidence intervals around benefits estimations for regulatory purposes. Furthermore, low dose risk estimation methods have not been developed for chronic health effects other than cancer. The... 

Fig. 2.6 Effect of variation in absorption rate on plasma drug concentration. The graph shows simulated plasma concentration-time curves for theophyUine after oral administration, illustrating a 20% difference in Cpmax values resulting from variation in the absorption rate constant. Absorption rate constants top curve 2.2 per h (Cpmax 20 pg/mL) middle curve 1.0 per h (Cptnax 18 M-g/mL) bottom curve 0.7 per h. Note that tmax also changes. The established therapeutic concentration of theophyUin is 10-20 pg/mL. The most rapidly absorbed formulation produces the highest concentration and greatest chance of side effects. Also, the duration for which the plasma concentration is within the therapeutic range also varies. Pharmacokinetic parameters dose, 400 mg bioavaUabiUty, 0.8 volume of distribution, 29 L half-Ufe, 5.5 h.

With a rise in dose of the substance entered, effect grows up irrespective of route of its entry into the organism. The higher dose of an anti-cholinesterase substance, the higher degree of both acetyl cholinesterase (AChE) inhibition in neural tissue and intoxication evidence. At high levels of exposure, any dose-effect dependence can be described by an exponential curve. The dynamics of efficient doses of lower level shows different variations, which however always come to either S-like or exponential curves [5, 8, 13],... 

The assays to be discussed in the following sections are based on bovine TSH (standards), and most studies of the biochemical effects of TSH have involved the use of b-TSH. International standards are available for both b-TSH and h-TSH assays, and these may be obtained from the British Medical Research Council. The response to a particular TSH varies with the type of assay (Bl). Therefore, when TSH is assayed, dose response curves must be based on a reference standard. Species variation is valuable in identifying differences between TSH and other TSH-like material. LATS, for example, does not stimulate thyroid function in the chick (L3). 

This lAC approach offers satisfactory sensitivity (LOD for FA 6.8 ng), comparable with those reported previously, with a wide dynamic range, four orders of magnitude (dose response curves obtained from lAC columns are exhibited in Figure 23.11). With its acceptably sensitive LOD, reusability, portability of the assay procedure, high accuracy and precision [coefficient of variation (CV) < 10%], cost-effectiveness and high assay speed (analysis times <30 min), this optimized liposome-based lAC assay should allow the... 

With increasing dose, the RBE decreases, reaching an asymptotic value close to one for very high doses. Figure 15 shows the dose dependence of RBE for the example shown in Fig. 14. It should be pointed out here that although RBE varies with dose, this does not imply actually a variation of the effectiveness of the charged particle radiation with dose. Instead, it merely reflects the Increase of the effectiveness of the reference radiation with dose, as expressed in the nonlinearity of the dose response curve in this case. 

Studies of variations in temperature and pVi on mutation induction are sometimes difficult, because the shape of dose-response curves can vary considerably (see Schwaier )), At any rate, if effects of j H, temperature, or other factors on the genetic activity of a certain agent are to be investigated, this cannot be done using just one standard dose rather, an entire dose-response curve has to be established in order to arrive at reasonable conclusions. Westergaard has used the optimal dose, the dose which gives the highest mutation frequency, as a basis of comparison. 

Daneshmend [104] measured the serum concentration of miconazole in 11 healthy adult females for 72 h following a single 1200 mg vaginal pessary. The mean peak serum miconazole concentration was 10.4 pg/L and the mean elimination half-life was 56.8 h. The mean area under the serum concentration-time curve was 967 pg/L/h. The calculated mean systemic bioavailability of the vaginal pessary was 1.4%. There was large intersubject variation in serum miconazole pharmacokinetics. This formulation may provide effective single dose treatment for vaginal candidiasis. 

The dose-response relationship for each biopharmaceutical can be analyzed, and the variation between subjects in the study population can be derived. A representative curve, presented as drug concentration versus effect intensity, is shown in Figure 5.8. It indicates that variation exists in intensity at a given drug concentration and in drug concentration at a given level of intensity. The steepness or slope of the... 

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