Biologically-based models

Biological Antioxidant Models. Tea extracts, tea polyphenol fractions, and purified catechins have all been shown to be effective antioxidants in biologically-based model systems. A balance between oxidants and antioxidants is critical for maintenance of homeostasis. Imbalances between free radicals and antioxidants may be caused by an increased production of free radicals or decreased effectiveness of the antioxidants within the reaction system. These imbalances can be caused by the radicals overwhelming the antioxidants within the system, or by an excess of antioxidants leading to a prooxidant functionaHty (105—118). When antioxidant defense systems are consistently overwhelmed by oxidative reactions, significant damage can... 

Dose-response assessment today is generally performed in two steps (1) assessment of observed data to derive a dose descriptor as a point of departure and (2) extrapolation to lower dose levels for the mmor type under consideration. The extrapolation is based on extension of a biologically based model (see Section 6.2.1) if supported by substantial data. Otherwise, default approaches that are consistent with current understanding of mode of action of the agent can be applied, including approaches that assume linearity or nonlinearity of the dose-response relationship, or both. The default approach is to extend a straight line to the human exposure doses. 

In the absence of sufficient data to develop a robust, biologically based model for quantitative risk assessment, a single curve-fitting model for each type of data set is preferred. It is noted that many different curve-fitting models have been developed, and those that fit the observed data reasonably well may lead to several-fold differences in estimated risk at the lower end of the observed range. Therefore, the US-EPA uses a standard curve-fitting procedure for tumor incidence data. 

The first step of the dose-response assessment is the evaluation of the data within the range of observation. If there are sufficient quantitative data and adequate understanding of the carcinogenic process, a biologically based model may be developed to relate dose and response data. Otherwise, as a default procedure, a standard model can be used to curve-fit the data. For each mmor response, a POD from the observed data is estimated to mark the beginning of extrapolation to lower doses. The POD is an estimated dose (expressed in human-equivalent terms) near the lower end of the observed range, without significant extrapolation to lower doses. 

Fig. 3.9. Biologically-based model of the cancer induction process used to estimate the dose-response relationship of chemicals causing stochastic effects (Andersen etal., 1987).

Toxicodynamic Studies of Chemical Mixtures Using Physiologically or Biologically Based Modeling... 

Within the held of ecotoxicology, promising approaches for explaining and predicting effects as a function of exposure time, using biologically based models, such... 

If sufficient data are available to support the use of a biologically based dose-response model, it may represent the most appropriate method for using the observed data to extrapolate to exposure below the observed dose range. If data are not available for a biologically based model, which is the case for the majority of chemicals studied, a point of departure (POD) approach is recommended. The POD represents a dose within the range of observed data associated with a 10% extra tumor... 

Medinsky MA, Kimbell JS, Morris JB, et al. 1993. Advances in biologically based models for respiratory tract uptake of inhaled volatiles. Fundam Appl Toxicol 20 265-272. 

Risk assessment frequently involves estimating safe exposure concentrations for exposure durations that were not tested experimentally. Generally applicable biologically based models have to be applied. Before developing such a model, extensive data are needed to build its form as well as to estimate how well it conforms to the observed data to support confidence in results. 

Crump, K., Subrmaniam, R., and Chen, C. (2007). Uncertainty inherent in biologically-based models. In Resources for the Future, October 22-23, 2007, Washington, D.C. 

The likelihood can be used to estimate not only the secular terns (birth cohort and period effects), but also the parameters of the biologically based model. In addition, if the data can be broken further by carcinogen(s) exposure (dose and duration) by age and period, one can also estimate in principle dose-response parameters. 

Moolgavkar, S. H., Krewski, D., and Schwarz, M. (1999). Mechanisms of carcinogenesis and biologically based models for estimation and prediction of risk. lARC Sci Puhl 131, 179-237. 

Conolly, R. B. (2002). The use of biologically based modeling in risk assessment. Toxicology 181-182, 275-279. 

Skin compartments can be a simple, well-stirred compartment with diffusion or a more complex compartment, including some of the utfique structural complexity of the skin. An important principle in biologically based modeling is to use the... 

Table 6.3 Examples of Biologically Based Models That Illustrate the Scope of Their Utility...

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