Estimation and analysis of the concentration-response surfaces associated with multiple-agent combinations

Richard P. Solana, Vernon M. Chinchilli, John Wilson, Walter H. Carter, Richard A. Carchman

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Chinese hamster cells (V-79) were treated with ethylnitrosourea (ENU) and cis-diamminedichloroplatinum(II) (DDP) alone and in combination. Sister chromatid exchanges (SCEs) were quantified as measures of genotoxicity of the two agents. The combination experiment employed a factorial design in which cells were treated, in various concentration combinations, with both agents simultaneously. Response surface methodology, using a polynomial model based on a negative binomial distribution of SCE events, was employed for analysis of the interactions of the two genotoxic agents. The negative binomial distribution, a generalization of the Poisson distribution, is required since SCEs are discrete variables which, under the conditions of these experiments, have a distribution which exhibits extra-Poisson variability. The model of the ENU DDP combinations indicated an increasingly less-than-additive effect resulting from increasing concentrations of each agent in the combination. The analysis of these experiments demonstrates the usefulness of a powerful statistical procedure for evaluating the biological effects resulting from exposure to multiple cytotoxic agents. The methodology can be used with many other types of endpoints and is not limited by the number of treatment agents.

Original languageEnglish (US)
Pages (from-to)231-238
Number of pages8
JournalToxicology and Applied Pharmacology
Volume85
Issue number2
DOIs
StatePublished - Sep 15 1986

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Pharmacology

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