Molecular circuits, biological switches, and nonlinear dose-response relationships.
Signaling motifs (nuclear transcriptional receptors, kinase/phosphatase cascades, G-coupled protein receptors, etc.) have composite dose-response behaviors in relation to concentrations of protein receptors and endogenous signaling molecules. "Molecular circuits" include the biological components and their interactions that comprise the workings of these signaling motifs. Many of these molecular circuits have nonlinear dose-response behaviors for endogenous ligands and for exogenous toxicants, acting as switches with "all-or-none" responses over a narrow range of concentration. In turn, these biological switches regulate large-scale cellular processes, e.g., commitment to cell division, cell differentiation, and phenotypic alterations. Biologically based dose-response (BBDR) models accounting for these biological switches would improve risk assessment for many nonlinear processes in toxicology. These BBDR models must account for normal control of the signaling motifs and for perturbations by toxic compounds. We describe several of these biological switches, current tools available for constructing BBDR models of these processes, and the potential value of these models in risk assessment.
Andersen
Melvin E
ME
Quantitative and Computational Toxicology Group, Center for Environmental Toxicology and Technology, Foothills Campus, Colorado State University, Fort Collins, Colorado, USA. mandersen@ciit.org
Yang
Raymond S H
RS
French
C Tenley
CT
Chubb
Laura S
LS
Dennison
James E
JE
D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic; D004305:Dose-Response Relationship, Drug; D004703:Endocrine System / Q000187:drug effects; D004785:Environmental Pollutants / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008962:Models, Theoretical; D010641:Phenotype; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects*; D018675:Toxicity Tests; D015262:Xenobiotics / Q000009:adverse effects*
D004785:Environmental Pollutants; D015262:Xenobiotics