Abstract

This paper provides an assessment of the toxicological basis of the hormetic dose–response relationship including issues relating to its reproducibility, frequency, and generalizability across biological models, endpoints measured and chemical class/physical stressors and implications for risk assessment. The quantitative features of the hormetic dose response are described and placed within toxicological context that considers study design, temporal assessment, mechanism, and experimental model/population heterogeneity. Particular emphasis is placed on an historical evaluation of why the field of toxicology rejected hormesis in favor of dose response models such as the threshold model for assessing non-carcinogens and linear no threshold (LNT) models for assessing carcinogens. The paper argues that such decisions were principally based on complex historical factors that emerged from the intense and protracted conflict between what is now called traditional medicine and homeopathy and the overly dominating influence of regulatory agencies on the toxicological intellectual agenda. Such regulatory agency influence emphasized hazard/risk assessment goals such as the derivation of no observed adverse effect levels (NOAELs) and the lowest observed adverse effect levels (LOAELs) which were derived principally from high dose studies using few doses, a feature which restricted perceptions and distorted judgments of several generations of toxicologists concerning the nature of the dose–response continuum. Such historical and technical blind spots lead the field of toxicology to not only reject an established dose–response model (hormesis), but also the model that was more common and fundamental than those that the field accepted.

The quantitative features of the hormetic dose/response are described and placed within the context of toxicology.

The quantitative features of the hormetic dose/response are described and placed within the context of toxicology.

Keywords: Hormesis; U-shaped; J-shaped; Homeopathy; Dose–response; Biphasic; Risk assessment; Threshold; Linearity; History of science; History of medicine; Toxicology

Article Outline

1. Introduction

2. Definition of hormesis

3. Quantitative features of the hormetic dose response

3.1. Magnitude of stimulatory response

3.2. Width of stimulatory response

4. Dose range and hormesis

5. Frequency

6. Generalizability of hormesis

7. Reproducibility

7.1. Hormetic mechanisms

8. Evaluation of multiple endpoints

8.1. Making hormesis the default assumption in risk assessment

9. Why was hormesis rejected/marginalized by the toxicology community?

10. Integrating the causes of why hormesis was rejected and its rebirth

11. Discussion

Acknowledgements

Appendix A. Appendix

Appendix. Supplementary data

References