Proof of Hazard and Proof of Safety in Toxicological Studies Using Simultaneous Confidence Intervals for Differences and Ratios to Control

Abstract

Simultaneous confidence interval for differences or ratios to control are described for both the proof of hazard and the proof of safety for the typical design in toxicology including several doses and a control. For most endpoints the direction of harmfulness is a priori known; therefore one-sided confidence intervals for Gaussian distributed endpoints, proportions, and poly-k-adjusted tumor rates are used. Special packages in the software R are provided to estimate these confidence intervals. Real data examples are given to demonstrate the estimation of the confidence intervals and their interpretation for selected toxicological studies.

Key Words:

• Proof of hazard
• Proof of safety
• Regulatory toxicology
• Simultaneous confidence intervals

Parts of the presented work were supported by the EC grant EU-2006/S237-252824 ANOVA technique for ratios.