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ToxSci Advance Access published online on November 4, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh007
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received May 6, 2003; accepted September 28, 2003
© 2003 Society of Toxicology

Risk Assessment

Non-Monotonic Dose-Response Relationships: Mechanistic Basis, Kinetic Modeling, and Implications for Risk Assessment

Rory B. Conolly 1 and Werner K. Lutz 2*

1 CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709
2 Department of Toxicology, University of Würzburg, 97078 Würzburg, Germany

* To whom correspondence should be addressed. E-mail: lutz{at}toxi.uni-wuerzburg.de.


  Abstract

Dose-response curves for the first interaction of a chemical with a biochemical target molecule are usually monotonic, i.e., increase or decrease over the entire dose range. However, for reactions of a complex biological system to a toxicant, non-monotonic (bi-phasic) dose-effect relationships can be observed, showing a decrease at low dose followed by an increase at high dose, or vice versa. We present four examples to demonstrate that non-monotonic dose-response relationships can result from superimposition of monotonic dose responses of component biological reactions. Examples include (i) a membrane receptor model with receptor subtypes of different ligand affinity and opposing downstream effects (adenosine receptors A1 vs. A2), (ii) androgen receptor-mediated gene expression driven by homodimers, but not mixed-ligand dimers, (iii) repair of background DNA damage by enzymatic activity induced by adducts formed by a xenobiotic, (iv) rate of mutation as a consequence of DNA damage times rate of cell division, the latter being modulated by cell-cycle delay at low-level DNA damage and cell-cycle acceleration due to regenerative hyperplasia at cytotoxic dose levels. Quantitative analyses based on biological models are shown, and factors that affect the degree of non-monotonicity are identified. It is noted that threshold-type dose-response curves could in fact be non-monotonic. Our analysis should promote a scientific discussion of bi-phasic dose responses and the concept termed "hormesis", and of default procedures for low-dose extrapolation in toxicological risk assessment.

Key Words: Dose-response relationship, hormesis, mechanisms, models .


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