Hormesis outperforms threshold model in National Cancer Institute antitumor drug screening database.

Which dose-response model best explains low-dose responses is a critical issue in toxicology, pharmacology, and risk assessment. The present paper utilized the U.S. National Cancer Institute yeast screening database that contains 56,914 dose-response studies representing the replicated effects of 2189 chemically diverse possible antitumor drugs on cell proliferation in 13 different yeast strains. Multiple evaluation methods indicated that the observed data are inconsistent with the threshold model while supporting the hormetic model. Hormetic response patterns were observed approximately four times more often than would be expected by chance alone. The data call for the rejection of the threshold model for low-dose prediction, and they support the hormetic model as the default model for scientific interpretation of low-dose toxicological responses.

[1]  M. Leider Goodman & Gilman's The Pharmacological Basis of Therapeutics , 1985 .

[2]  E J Calabrese,et al.  Hormesis: A Highly Generalizable and Reproducible Phenomenon With Important Implications for Risk Assessment , 1999, Risk analysis : an official publication of the Society for Risk Analysis.

[3]  Edward J Calabrese,et al.  Drug development and hormesis: changing conceptual understanding of the dose response creates new challenges and opportunities for more effective drugs. , 2006, Current opinion in drug discovery & development.

[4]  J. Timbrell Casarett and Doull's Toxicology: The Basic Science of Poisons , 1981 .

[5]  G. Casella,et al.  Statistical Inference , 2003, Encyclopedia of Social Network Analysis and Mining.

[6]  E. Calabrese,et al.  The frequency of U-shaped dose responses in the toxicological literature. , 2001, Toxicological sciences : an official journal of the Society of Toxicology.

[7]  L. Goodman,et al.  The Pharmacological Basis of Therapeutics , 1941 .

[8]  N. Ellison Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th Edition , 2002 .

[9]  William R. Greco,et al.  Parabolic growth patterns in 96-well plate cell growth experiments , 1999, In Vitro Cellular & Developmental Biology - Animal.

[10]  K S Crump,et al.  A new method for determining allowable daily intakes. , 1984, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[11]  Gerry Leversha Statistical inference (2nd edn), by Paul H. Garthwaite, Ian T. Jolliffe and Byron Jones. Pp.328. £40 (hbk). 2002. ISBN 0 19 857226 3 (Oxford University Press). , 2003, The Mathematical Gazette.

[12]  E. Calabrese,et al.  The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview. , 2005, Toxicology and applied pharmacology.

[13]  Edward J Calabrese,et al.  The hormetic dose-response model is more common than the threshold model in toxicology. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[14]  X. Guitart,et al.  Applied Pharmacology , 1937, The Indian Medical Gazette.

[15]  W. Bowman Mode of Action of Drugs , 1964, Nature.

[16]  E. Calabrese Paradigm lost, paradigm found: the re-emergence of hormesis as a fundamental dose response model in the toxicological sciences. , 2005, Environmental pollution.

[17]  E. Calabrese Hormesis: from marginalization to mainstream: a case for hormesis as the default dose-response model in risk assessment. , 2004, Toxicology and applied pharmacology.

[18]  A. Hayes Principles and methods of toxicology , 1982 .

[19]  S. Holbeck,et al.  Update on NCI in vitro drug screen utilities. , 2004, European journal of cancer.

[20]  Mark J. Reasor,et al.  Principles of Toxicology , 2003 .

[21]  E J Calabrese,et al.  Hormesis: U-shaped dose responses and their centrality in toxicology. , 2001, Trends in pharmacological sciences.

[22]  A. Freedman Handbook of Experimental Pharmacology, vol 14. , 1972 .