Extrapolation guidance

It is clear, that the various modes of LSV at the dme require an integrated and coherent regulation of sweep time, current sampling and drop knocking, preferably by an electronic device and on with computer guidance. A disadvantage of LSV. at the dme, in contrast to normal DC polarography, is that for mixtures of components the latter yields a simple evaluation by curve extrapolation on the basis of additivity [see Fig. 3.34(a)], whereas the former suffers from an uncertain evaluation [see Fig. 3.34(b)],... 

It should be noted that, for establishment of a 1-h Emergency Exposure Guidance Level (EEGL) for another halocarbon, the NRC (NRC 1996 Bakshi et al. 1998) recommended application of a single interspecies UF of 10 to the cardiac sensitization test with the dog. Because blood concentrations of several halocarbons rapidly reached equilibrium, the NRC also extrapolated this 10-min test to the longer time period of 1 h. Controlled human data were not available for many of the materials considered by the NRC, whereas human data are available for HCFC-141b. 

The object of this publication is to provide practical guidance on assessing the useful service life of plastics. It covers test procedures and extrapolation techniques together with the inherent limitations and problems. There is a wealth of information which can be applied to help maximise the effectiveness of a durability testing programme which the guide aims to direct the user towards. 

The approach of deriving a tolerable intake by dividing the N/LOAEL, or alternatively a BMD for the critical effect(s) by an assessment factor has been described and discussed extensively in the scientihc literature. It is beyond the scope of this book to review all these references. This chapter presents an overview of pubhshed extrapolation methods for the derivation of a tolerable intake based on the assessment factor approach, i.e., limited to address effects with threshold characteristics, and is not meant to be exhaustive. The main focus is on the rationale for and the use of the assessment factors. Pertinent guidance documents and reviews for the issues addressed in this chapter include WHO/IPCS (1994, 1996, 1999), US-EPA (2002, 2004), IGHRC (2003), ECETOC (2003), KEMI (2003), Kalberlah and Schneider (1998), Vermeire et al. (1999), and Nielsen et al. (2005). 

Such uncertainty about the future is a major reason why agencies such as NICE determine a future point in time when their guidance will be reviewed and specify the additional research they would like to see duringthe intervening period. From a methodological standpoint, analysts should not present just one set of cost-effectiveness estimates using a single method of extrapolation. Rather, a series of scenarios should be presented based on different extrapolation techniques. This will provide an indication of how robust the cost-effectiveness results are to the extrapolation approach. 

Fig. 3. kcs vs. -AGCS relations in MCH (A), Tol (O), THF(D) and simulations (solid lines) with Ulstrup - Jortner equation (eq.(l)). The dashed lines are extrapolations just for eye guidance. 

The FDA guidance document recognizes the difficulty of extrapolating the results obtained with recombinant enzymes to the situation in liver microsomes. Experiments with recombinant CYP enzymes provide valuable information on which CYP enzymes can and which ones cannot convert a drug candidate to a particular metabolite, and this information alone is particularly valuable in guiding the design or interpretation of correlation analysis, chemical inhibition, and antibody inhibition experiments. 

An array of extrapolation types for matrix and media extrapolations has been given, with specihc approaches being dependent on compound, medium and matrix, and species and ecosystem properties. Guidance to provide a systematic orientation in the array of methods is useful when considering their practical use in a regulatory context. Using a tiered approach (see Chapter 1), the tiers for media and matrix extrapolation listed in Table 2.11 are recommended. 

The Community-Level Aquatic Systems Studies Interpretation Studies (CLASSIC) guidance document, which deals with the interpretation of results of microcosm and mesocosm tests in the risk assessment procedure of pesticides, recommends that regulatory model ecosystem experiments be conducted in spring to midsummer (Giddings et al. 2002). On the basis of the limited number of model ecosystem experiments described above, it seems that threshold concentrations for effects observed in early-season studies are reasonably predictive for threshold concentrations later in the season. Above these threshold concentrations, however, the intensity and duration of the responses (direct and indirect effects) may vary during different periods of the year. Consequently, the extrapolation of NOECcommunity values from one season to another seems to be possible with lower uncertainty than hazard estimates of higher concentrations in which both direct and indirect effects are involved. 

Guidance on the Application of Extrapolation Methods in Ecological Exposure and Effects Characterization of Chemicals... 

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