TITLE

UNIVERSALITY OF J-SHAPED AND U-SHAPED DOSE-RESPONSE RELATIONS AS EMERGENT PROPERTIES OF STOCHASTIC TRANSITION SYSTEMS

AUTHOR(S)
Cox Jr., Louis Anthony (Tony)
PUB. DATE
July 2005
SOURCE
Dose-Response;2005, Vol. 3 Issue 3, p353
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Dose-response data for many chemical carcinogens exhibit multiple apparent concentration thresholds. A relatively small increase in exposure concentration near such a threshold disproportionately increases incidence of a specific tumor type. Yet, many common mathematical models of carcinogenesis do not predict such threshold-like behavior when model parameters (e.g., describing cell transition rates) increase smoothly with dose, as often seems biologically plausible. For example, commonly used forms of both the traditional Armitage-Doll and multistage (MS) models of carcinogenesis and the Moolgavkar-Venzon-Knudson (MVK) two-stage stochastic model of carcinogenesis typically yield smooth dose-response curves without sudden jumps or thresholds when exposure is assumed to increase cell transition rates in proportion to exposure concentration. This paper introduces a general mathematical modeling framework that includes the MVK and MS model families as special cases, but that shows how abrupt transitions in cancer hazard rates, considered as functions of exposure concentrations and durations, can emerge naturally in large cell populations even when the rates of cell-level events increase smoothly (e.g., proportionally) with concentration. In this framework, stochastic transitions of stem cells among successive events represent exposure-related damage. Cell proliferation, cell killing and apoptosis can occur at different stages. Key components include: 1. An effective number of stem cells undergoing active cycling and hence vulnerable to stochastic transitions representing somatically heritable transformations. (These need not occur in any special linear order, as in the MS model.) 2. A random time until the first malignant stem cell is formed. This is the first order-statistic, T = min{T1, T2, … , Tn} of n random variables, interpreted as the random times at which each of n initial stem cells or their progeny first become malignant. 3. A random time for a normal stem cell to complete a full set of transformations converting it to a malignant one. This is interpreted very generally as the first passage time through a network of stochastic transitions, possibly with very many possible paths and unknown topology. In this very general family of models, threshold-like (J-shaped or multi-threshold) dose-response nonlinearities naturally emerge even without cytotoxicity, as consequences of stochastic phase transition laws for traversals of random transition networks. With cytotoxicity present, U-shaped as well as J-shaped dose-response curves can emerge. These results are universal, i.e., independent of specific biological details represented by the stochastic transition networks.
ACCESSION #
22124867

 

Related Articles

  • Integration of Physicochemical and Pharmacokinetic Parameters in Lead Optimization: A Physiological Pharmacokinetic Model Based Approach. Benjamin, Biju; Barman, Tarani Kanta; Chaira, Tridib; Paliwal, Jyoti K. // Current Drug Discovery Technologies;Sep2010, Vol. 7 Issue 3, p143 

    No abstract available.

  • Dose-Response Thresholds for Progressive Diseases. Cox, Louis Anthony (Tony) // Dose-Response;2012, Vol. 10 Issue 2, p233 

    Many diseases, including cancers, heart diseases, and lung diseases, can usefully be viewed as arising from disruption of feedback control systems that normally maintain homeostasis of tissues and cell populations. Excessive exposure can destabilize feedback control loops, leading to sustained...

  • Phytotchemical Phytotoxins and Hormesis - A Commentary. Duke, Stephen O. // Dose-Response;2011, Vol. 9 Issue 1, p76 

    No abstract available.

  • New Confidence. Potera, Carol // Environmental Health Perspectives;May2014, Vol. 122 Issue 5, pA138 

    The article discusses the optimization of the benchmark dose (BMD) modeling as an accurate method for conducting chemical risk assessments. Topics discussed include use of no-observed-adverse-effect-level (NOAEL) obtained from animal experiments, uses experimental data as the basis for plotting...

  • A new mathematical approach for qualitative modeling of the insulin-TOR-MAPK network. Nijhout, H. Frederik; Callier, Viviane // Frontiers in Physiology;Sep2013, Vol. 4, p1 

    In this paper we develop a novel mathematical model of the insulin-TOR-MAPK signaling network that controls growth. Most data on the properties of the insulin and MAPK signaling networks are static and the responses to experimental interventions, such as knockouts, overexpression, and hormonal...

  • UNDERESTIMATION OF RISK DUE TO EXPOSURE MISCLASSIFICATION. Grandjean, Philippe; Budtz-Jørgensen, Esben; Keiding, Niels; Weihe, Pal // International Journal of Occupational Medicine & Environmental H;Jan2004, Vol. 17 Issue 1, p131 

    Exposure misclassification constitutes a major obstacle when developing dose-response relationships for risk assessment. A non-differentional error results in underestimation of the risk. If the degree of misclassification is known, adjustment may be achieved by sensitivity analysis. The purpose...

  • A mathematical model for quantifying training. Hayes, Philip R.; Quinn, Mike D. // European Journal of Applied Physiology;Aug2009, Vol. 106 Issue 6, p839 

    A systems modelling approach has been used to quantify the dose-response nature of training. Considerable attention has been focused on the modelling process with little work on the determination of the training impulse (TRIMP) scores. Currently, the methods employed to calculate TRIMPs are...

  • Hormesis in Aging and Neurodegeneration--A Prodigy Awaiting Dissection. Mao, Lei; Franke, Jacqueline // International Journal of Molecular Sciences;Jul2013, Vol. 14 Issue 7, p13109 

    Hormesis describes the drug action of low dose stimulation and high dose inhibition. The hormesis phenomenon has been observed in a wide range of biological systems. Although known in its descriptive context, the underlying mode-of-action of hormesis is largely unexplored. Recently, the hormesis...

  • CANCER RISK ASSESSMENT: PRESENT AND FUTURE. Szymczak, Wieslaw; Szadkowska-StaŃczyk, Irena // International Journal of Occupational Medicine & Environmental H;Jul2005, Vol. 18 Issue 3, p207 

    Risk assessment is a process based on available scientific information about properties of a given agent, and its effect on biological processes to evaluate potential adverse consequences of exposure to that particular agent. Occupational cancer risk assessment might be considered as a more...

Share

Read the Article

Courtesy of VIRGINIA BEACH PUBLIC LIBRARY AND SYSTEM

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics