Biologically based dose-response modeling

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

Lau C, Andersen ME, Crawford-Brown DJ, Kavlock RJ, Kimmel CA, Knudsen , Muneoka K, Rogers JM, Setzer RW, Smith G, Tyl R (2000) Evaluation of biologically based dose-response modeling for developmental toxicity A workshop report. Regul Toxicol Pharmacol, 31(2 Pt 1) 190-199. 

Shuey DL, Lau C, Logsdon RR, Zucker RM, Elstein KH, Narotsky MG, Setzer RW, Kavlock RJ, Rogers JM (1994) Biologically-based dose-response modeling in developmental toxicology biochemical and cellular sequelae of 5-fluorouracil exposure in the developing rat. Toxicol Appl Pharmacol, 126 129-144. 

Much of the research efforts in risk assessment are therefore aimed at reducing the need to use these default uncertainty factors, although the risk assessor is limited by data quality of the chemical of interest. With sufficient data and the advent of sophisticated and validated physiologically based pharmacokinetic models and biologically based dose-response models (Conolly and Butterworth, 1995), these default values can be replaced with science-based factors. In some instances there may be sufficient data to be able to obtain distributions rather than point estimates. 

Conolly, R. B., and B. E. Butterworth. Biologically based dose response model for hepatic toxicity a mechanistically based replacment for traditional estimates of noncancer risk. Toxicol. Lett. 82-83 901-906, 1995. 

Biologically based dose-response models are considered a major advance for evaluating dose-response relationships (Shuey et al., 1994 IPCS, 2000). Although considerable work remains in developing such models, they should provide information on the potential for chemicals to alter critical signalling pathways, define... 

Physiologically based pharmacokinetic (PBPK) modelling sometimes constitutes a basis for replacement of default components of uncertainty for toxicokinetics and a portion of toxicodynamics. Where data are sufficient, a full biologically based dose-response model addresses additional uncertainties with respect to both interspecies differences and interindividual variability in both kinetics and dynamics. 

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... 

Leroux BG, Leisenring WM, Moolgavkar SH, et al. 1996. A biologically-based dose-response model for developmental toxicology. Risk Analysis 16 (4) 449-458. 

All of these considerations indicate that the biology behind the shape of the tumor dose-response curve is much more complex than a simple conclusion that mutagenic activity = linear dose-response. Ultimately, biologically based dose-response models and use of biomarker data may make it possible to extend the tumor dose-response curve to low doses based on biological data, rather than presumptions about the shape of the dose-response curve. In the shorter term, it is important to recognize that the biology is complex, and linear extrapolation from tumor data is a health-protective science policy decision. 

Slikker, W.Jr, Scallet, A.C., and Gaylor, D.W., Biologically-based dose-response model for neurotoxicity risk assessment, Toxicol. Lett, 102/103, 429, 1998. 

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. 

Physiologically Based Pharmacokinetic (PBPK) models and Biologically Based Dose-Response (BBDR) models are finding increasing use in risk assessment... 

Use of a biologically based dose-response (BBDR) model that can capture multiple MOAs, which may dominate in different portions of the dose-response curve [e.g., the formaldehyde assessment by The Hamner Institutes for Health Sciences, formerly Chemical Institute of Industrial Toxicology (CUT 2009)], which has been used in regulatory settings (Conolly et al. 2004). 

---