Data conversion, dose-response

Conversion of experimental dose/response data into a form suitable for extrapolation of human risk using least squares or, more usually, maximum likelihood curve fits. 

Figure 19.8. Dose-response plot showing functional differences between partial and full agonist. These data illustrate that two compounds of similar potency may differ in functional efficacy. In this case, the full agonist causes the same degree of stimulation as does the endogenous ligand. Conversely, the partial agonist, although of similar potency, is only partially efficacious. These data are modified from actual published studies from the authors laboratory (Brewster et al. J. Med. Chem. 330 1756-1764, 1990).

Since a risk assessment for a particular chemical is related to the exposure scenario, toxicity data generated in in vitro systems need to be translated to a dose or a dosage regime for an intact organism. This process, referred to as QIVTVE , includes an interpretation of the chemical s biokinetic behavior. This enables the conversion of an in vitro-derived concentration-effect relationship to a dose-response relationship in vivo. The processes involved in this reverse dosimetry are described in Chap. 24. The development of physiologically based biokinetic (PBBK) models [19] is crucial in this process [13, 20]. 

The committee conclndes that, given these considerations, the results from the Boston Naming Test in the Faroe Islands study should be used. For that end point, dose-response data based on Hg concentrations in cord blood should be modeled. For that data set, the K-power model (K > 1) is the model of choice. This analysis estimates a BMD of 85 ppb and a BMDL of 58 ppb. Using a conversion factor of 5 ppb of blood per ppm of hair, that point of departure approximately corresponds to a BMD based on a hair Hg concentration of 17 ppm and a BMDL of 12 ppm. Those values are veiy close to the values estimated directly from the analysis based on hair Hg concentrations. 

Recent data indicate that PTX-2 is much less toxic orally than by intraperitoneal injection. Although early studies suggested that PTX-2 was orally toxic, these data are questionable because of the absence of a dose response-relationship. In a later study, no deaths or other changes were recorded with PTX-2 at a dose of 5000 [tg/kg. The low oral toxicity of PTX-2 may reflect poor absorption from the gastrointestinal tract or conversion to a less toxic material, such as PTX-2 seco acid, in the gut [26]. 

Fig. 1. (A) Chemical structures of CI-976 and DuP-128. (B) The effect of CI-976 (50 /jlM) and DuP-128 (5 //M) on Golgi membrane-associated LPAT activity. LPAT activity is represented as the percentage of the control (Golgi membranes alone for 1 h at 37°). (C) Dose response of CT976 inhibition of LPAT activity. The conversion of LPC to PC was monitored by incubating isolated rat liver Golgi membranes, arachidonyl-CoA, inhibitors, and [ " C]LPC for 1 h at 37°. Each data point represents the mean plus 1 S.D. of quadruplicate samples. Figure was taken from Drecktrah et al. (2003) and reprinted here with permission from Molecular Biology of the Cell.

An adequate treatment of health risk characterizations for Pb in humans requires that all three input components be evaluated. Reliable dose—toxic response data also require reliable exposure characterizations to complete the risk assessment. Conversely, well-characterized exposures would further require well-established dose—response relationships for the particular toxic contaminant. Absence of hazard assessment data prevents the evaluation of toxic responses in any dose—response relationships regardless of the quality of the dose or exposure characterizations. 

In order to extrapolate laboratory animal results to humans, an interspecies dose conversion must be performed. Animals such as rodents have different physical dimensions, rates of intake (ingestion or inhalation), and lifespans from humans, and therefore are expected to respond differently to a specified dose level of any chemical. Estimation of equivalent human doses is usually performed by scaling laboratory doses according to observable species differences. Unfortunately, detailed quantitative data on the comparative pharmacokinetics of animals and humans are nonexistent, so that scaling methods remain approximate. In carcinogenic risk extrapolation, it is commonly assumed that the rate of response for mammals is proportional to internal surface area... 

While comparisons of individual treated groups with the control group are important, a more powerful test of a possible effect of treatment will be to carry out a test for a dose-related trend. This is because most true effects of treatment tend to result in a response which increases (or decreases) with increasing dose, and because trend tests take into account all the data in a single analysis. In interpreting the results of trend tests, it should be noted that a significant trend does not necessarily imply an increased risk at lower doses. Nor, conversely, does a lack of increase at lower doses necessarily indicate evidence of a threshold (i.e., a dose below which no increase occurs). 

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