Biological response models

The first step in the application of the concept was to determine the critical load values for the different regions of eastern Canada. This was done using historical measurements of lake acidity in concert with the Integrated Assessment Model (IAM) which links atmospheric transport and deposition models with water chemistry and empirical biological response models. Details of the method are given in Jeffries and Lam (1993). 

Sinkkonen A (2001) Density-dependent chemical interference - an extension of the biological response model. J Chem Ecol 27 1513-1523... 

Shau, H., Isacescu, V., Ibayashi, Y., Tokuda, Y., Golub, S. H., Fahey, J. L., and Sarna, G. P. 1990. A pilot study of intralymphatic interleukin-2.1. Cytotoxic and surface marker changes of peripheral blood lymphocytes. / Biological Response Model, 9, 71-80. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically-based dose-response model which quantitatively describes the relationship between target tissue dose and toxic end points. These models advance the importance of physiologically based models in that they clearly describe the biological effect (response) produced by the system following exposure to an exogenous substance. 

The in vivo relevance and biological importance of in vitro observations about mast cell function, as well as the contributions of mast cells towards the expression of particular biological responses (such as various models of anaphylaxis) in vivo, can be assessed using c-kit mutant mice (e.g., WBB6Fi-FCit or mice) that virtually lack mast cell populations. Mice with mutations of c-kit [6,11] or mutations that affect KIT expression [12-14] have other abnormalities of phenotype besides a mast cell deficiency. However, the mast cell deficiency of these mice can be selectively repaired by the adoptive transfer of genetically compatible, in vitro-derived... 

Despite the work of Overton and Meyer, it was to be many years before structure-activity relationships were explored further. In 1939 Ferguson [10] postulated that the toxic dose of a chemical is a constant fraction of its aqueous solubility hence toxicity should increase as aqueous solubility decreases. Because aqueous solubility and oil-water partition coefficient are inversely related, it follows that toxicity should increase with partition coefficient. Although this has been found to be true up to a point, it does not continue ad infinitum. Toxicity (and indeed, any biological response) generally increases initially with partition coefficient, but then tends to fall again. This can be explained simply as a reluctance of very hydrophobic chemicals to leave a lipid phase and enter the next aqueous biophase [11]. An example of this is shown by a QSAR that models toxicity of barbiturates to the mouse [12] ... 

Ensure that the biological response data are appropriate for modeling. 

We consequently became interested in developing a dose-dependent quantitative model using tso as the relative biological response. This model is shown as equation 6. 

There appears now to be ample evidence that the variations in carcinogenicity among the nitrosamines are systematically and rationally related to structure and that several Indices of carcinogenic potency can be used as indices of biological response for the generation of quantitative structure-activity models (11-17). 

Gilbert ME. 1997. Towards the development of a biologically based dose-response model of lead neurotoxicity. American Zoologist 37(4) 389-398. 

Specific culture conditions are essential to ensure that the biological model maintains unchanged, as long as possible, its intrinsic characteristics in terms of biological response and cell function. 

Fliri, A.F., Loging, W.T., Thadeio, P. and Volkmann, R.A. (2005) Biospectra analysis model proteome characterizations for linking molecular structure and biological response. Journal of Medicinal Chemistry, 48, 6918-6925. 

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. 

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