Dose-effect curve slope

This expression makes it possible to use dose effect curves to give both target number (m), related to the shoulder on sigmoid curves, and target size (v), related to the final exponential slope. 

The dose-effect curves for two hypothetical drugs, A and B—the terms slope, efficacy, and potency are illustrated on the cun/es... 

Three concepts derived from a dose-effect curve offer valuable information about a drug s action slope of the curve, drug efficacy, and drug potency. 

Daunomycin and related derivatives were found to affect cell proliferation and MSV (M) foci production differently. In both tests, the activity of daunomycin and adriamycin was found to be a linear function of the dose. However, as the dose-effect curve of foci inhibition has a steeper slope than that of cell proliferation, the two lines cross over. Hence higher doses give greater inhibition of foci formation than of cell proliferation. Almost total inhibition of foci formation could be achieved by treatment with daunomycin or adriamycin at about 0.025 jug/ml. 

True or false The slope of the cumulative dose-effect curve provides a general indication of the biological variability of the test population. Explain. 

What is the public health significance of the slope of a dose-effect curve Describe two factors that could affect the slope. 

The steeper the slope in a dose-effect curve, the more members of an at-risk population are affected by each increase in exposure. A sleep dose-effect curve indicates that a chemical has the potential to become a public health problem more quickly than a chemical with a shallow dose-effect curve. The slope is mainly a function of the toxic chanical itself. In addition, the strain of animals used in the toxicity test can affect the slope. 

To.xicity values for carcinogenic effects can be e.xprcsscd in several ways. The slope factor is usually, but not always, the upper 95th percent confidence limit of the slope of the dose-response curve and is e.xprcsscd as (mg/kg-day). If the extrapolation model selected is the linearized multistage model, this value is also known as the ql. That is ... 

If the exposure level (E) exceeds tliis tlireshold (i.e., E/RfD exceeds unity), tliere may be concern for potential noncancer effects. As a rule, tlie greater tlie value of E/RfD above unity, tlie greater tlie level of concern. However, one should not interpret ratios of E/RfD as statistical probabilities a ratio of 0.001 does not mean tliat tliere is a one in one tliousand cliance of the effect occurring. Furtlier, it is important to empliasize tliat tlie level of concern does not increase linearly as tlie RfD is approached or exceeded because RfDs do not have equal accuracy or precision and are not based on tlie same severity of toxic effects. Thus, tlie slopes of the dose-response curv e in excess of the RfD can range widely depending on tlie substance. 

The Furchgott method can be effectively utilized by fitting the dose-response curves themselves to the operational model with fitted values of x (before and after alkylation) and a constant KA value. When fitting experimental data, the slopes of the dose-response curves may not be unity. This is a relevant factor in the operational model since the stimulus-transduction function of cells is an integral part of the modeling of responses. Under these circumstances, the data is fit to (see Section 3.13.3 and Equation 3.49)... 

A side effect, dystonia of the neck muscles, often appeared after the higher doses of 302034 or fluphenazine, usually about 12-16 hours following administration. (This was quickly relieved by 50 mg of Lm benadryl.) Slopes of the dose-response curves were... 

As shown in Table 2-2, 300 mg/kg/day is the cancer effect level (CEL) for renal tubular cell adenomas in male rats and 600 mg/kg/day is the CEL for hepatocellular carcinomas and hepatoblastomas in mice (NTP 1987). A qj (the upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure) of 6x10 per mg/kg/day has been calculated from the data on renal tumors in rats (Battelle and Crump 1986). The qi for the mouse liver tumor data is 2.4x10 per mg/kg/day (HEAST 1992). These values are currently under review by the EPA (HEAST 1990) and have not been included in the IRIS (1998) database. 

ECETOC (1995) recommended a factor of 2 to be used in case the extent of the relevant effect is of minor importance, and the slope of the dose-response curve reasonably justifies the assumption that a halving of the LOAEL would be likely to arrive at the no-effect dose. A factor of 3 was recommended as a default value, which would be used in the majority of cases. Extent and severity of the effect at the LOAEL and/or a very flat dose-response curve may justify the use of a higher factor. 

ECETOC (2003) recommended that if an appropriate NOAEL is available, then no extrapolation and hence, no assessment factor is necessary. Where it is considered more appropriate to use the LOAEL, a default assessment factor of 3 was recommended however, the factor may need to be adjusted depending on the effects observed at the LOAEL and the slope of the dose-response curve. The BMD could be an alternative approach for defining or confirming a NOAEL depending on the data quality and dose spacing. 

TNO has stated that when a reliable dose-response curve for the relevant adverse effect has been established, the slope of this curve should be taken into account (Hakkert et al. 1996). The steeper the dose-response curve, the smaller the assessment factor. The assessment factor depends on expert judgment, the default value is 1. 

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 range of doses and plasma concentrations that exhibited pharmacodynamic effects in animals, the nature of the effects, and the slope of the dose-response curve... 

TCDD TEQ/g sediment, the 30X diluted extract gave a DR CALUX response of 34.9 6.1 pg 2,3,7,8-TCDD TEQ/g sediment. In general, an effect of dilution on the total DR CALUX TEQ content in sediment samples is observed. Although the exact nature for this observation is not known, it is hypothesized that this is due to the presence of various compounds in sediment extracts showing variable affinity toward the Ah receptor. Dose-response curves in the DR CALUX bioassay of individual compounds have been studied and showed obvious differences (Hosoe et al, 2002) both in maximum response and slope of the curve fit. 

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