Dose-response relationships curves

Maximum air pollution concentrations —> Dose-response relationship/curve Median effective dose (ED J Dose-response relationship/curve Median lethal dose (LD g) Dose-response relationshipcurve Median lethal concentration (LCj ) Dose-response relationship/curve... 

Milhgrams/kilogram of body weight, a unit used in Dose-response relationship/ curve... 

No adverse effect level (NOAEL) —> Dose-response relationship/curve... 

A potential pitfall with stop-time experiments comes with temporal instability of responses. When a steady-state sustained response is observed with time, then a linear portion of the production of reporter can be found (see Figure 5.15b). However, if there is desensitization or any other process that makes the temporal responsiveness of the system change the area under the curve will not assume the linear character seen with sustained equilibrium reactions. For example, Figure 5.16 shows a case where the production of cyclic AMP with time is transient. Under these circumstances, the area under the curve does not assume linearity. Moreover, if the desensitization is linked to the strength of signal (i.e., becomes more prominent at higher stimulations) the dose-response relationship may be lost. Figure 5.16 shows a stop-time reaction dose-response curve to a temporally stable system and a temporally unstable system where the desensitization is linked to the... 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a specified magnitude of changes in a specified adverse response. For example, a BMDio would be the dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 10%. The BMD is determined by modeling the dose response curve in the region of the dose response relationship where biologically observable data are feasible. 

Dose-response assessment is the process of obtaining quantitative information about the probability of human illness following exposure to a hazard it is the translation of exposure into harm. Dose-response curves have been determined for some hazards. The curves show the relationship of dose exposure and the probabihty of a response. Since vahdated dose-response relationships are scarce, various other inputs are used to underpin the hazard characterization phase of risk assessment. 

Figure 2 Typical enzyme immunoassay calibration curve illustrating the inversely proportional dose-response relationship...

Interspecies 10—The 10-min LC50 value for the monkey was about 60% of the rat value and one-third the rabbit value. The mouse data were used to calculate the AEGL levels, because the data exhibited a good exposure-response relationship curve, and the endpoint of decreased hematocrit levels can be considered a sensitive indicator of arsine toxicity. In addition, arsine has an extremely steep dose-response relationship giving little margin between no effects and lethality. 

Nutrients enter into biological processes that are not characterized by a well-defined dose-response relationship. Therefore, in many cases, the dietary supplement itself is not expected to exhibit a characteristic dose-response curve. 

Dose-response relationships may be examined in individuals or in populations. The dose-response curves discussed above (e.g., figure 3.3)... 

As intake increases above the range of adequacy a region will be reached at which the adverse effects of excessive intake will begin to manifest themselves. Figure 9.1 depicts these interesting dose-response curves, and the curve at the right side of the figure represents a typical dose-response relationship for toxicity, in this case caused by excessive intakes of substances we cannot live without at lower doses. 

Other dose-response relationships may also be seen for certain compounds such as, e.g., essential metals, where symptoms of dehciency may occur if the intake is too low, whereas toxic symptoms may occur if the intake is too high. For such compounds, the dose-response curve is generally U-shaped as illustrated in Figure 4.2. It should be noted that the right part of the U-shaped curve representing the toxic effects in reality is the typical S-shape observed for toxic effects in general. 

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. 

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. 

In relation to the dose-response curve, KEMI (2003) stated that the slope always has to be considered. A moderate assessment factor (not further specified) may provide an adequate MOS if the dose-response relationship is relatively steep, but may not be sufficiently conservative if the dose-response curve is relatively shallow, see Figure 5.6. In relation to extrapolation from LOAEL to NOAEL, KEMI considered that analysis of several databases does support the statement that a... 

An additional assessment factor, of up to 10, has been apphed in some cases where the NOAEL has been derived for a critical effect, which is considered as a severe and irreversible effect, such as teratogenicity or non-genotoxic carcinogenicity, especially if associated with a shallow dose-response relationship. The principal rationale for an additional factor for nature of toxicity has been to provide a greater margin between the exposure of any particularly susceptible humans and the dose-response curve for such toxicity in experimental animals. 

---