Dose-response represents the relationship between exposures and the correlated changes in body function or health and is an essential concept in toxicology. In general, the higher the dose, the more severe the response. The dose-response relationship is based on observed data from experimental animal, human clinical, or cell studies.
Knowledge of the dose-response relationship establishes:
- Causality – that the chemical has induced the observed effects.
- Threshold effect – the lowest dose where an induced effect occurs.
- Slope of the dose–response – the rate at which injury builds up.
For some metals, dose–response relationships are influenced by essentiality. Essential elements are required for normal human function, but adverse effects occur both when intake is too low (deficiency) and when it is too high (toxicity). Between these extremes, the body maintains balance through homeostatic mechanisms. Risk assessment therefore considers background physiological concentrations, population variability in requirements, and the impact of speciation and bioavailability on internal dose. Essentiality must be addressed when deriving Derived No-Effect Levels (DNELs) or Derived Minimal Effect Levels (DMELs) under REACH.
Models
Benchmark Dose Tools (U.S. EPA)
Benchmark dose methods are used for dose-response analyses to support chemical risk assessments and regulatory actions.
Includes:
- The Benchmark dose (BMD) software
- Multistage Weibull Time - to - tumour model
- Categorical Regression (CatReg) software
Guidance
HERAG- Health Risk Assessment Guidance for Metals - Fact Sheets 7. (2007)
HERAG is a Human Health risk assessment guidance targeting metal substances, therefore taking the metal specificities into account contrary to most of the other risk assessment guidances.
The critical concepts are presented in a series of eight independently reviewed HERAG fact sheets. These fact sheets were written to reflect the lessons learned from the metal substances risk assessments conducted under the previous EU legislation (2000-2008). It is hoped that these latest concepts will enable regulators and scientists to create new or adapt local, national or regional risk assessment systems accordingly.
Fact sheets:
Presentations
Benchmark Dose Modeling – Introduction (Allen Davis, Jeff Gi0, Jay Zhao, U.S. EPA)
- U.S. EPA Benchmark Dose Technical Guidance
- Other sources of BMD Guidance
- Review of Key Terminology
- Characterizing Non-cancer Hazards in Risk Assessments
- Calculation of the RfC/RfD
- Limitations of Using a NOAEL
- Study Conducted with 100 Animals/Dose
- A Brief History of the BMD Method
- Benchmark Dose – Key Terminology
- Calculation of the RfC/RfD Using a BMDL
- Advantages of BMD Approach
- Study Conducted with 100 Animals/Dose
- Study Conducted with 10 Animals/Dose
- Challenges in the Use of the BMD Method
- Are the Data Worth Modeling? (Study/Endpoint Criteria)
- Comparison of NOAELs and BMDLs
Publications
Benchmark dose (BMD) modeling: current practice, issues, and challenges.(Haber LT, Dourson ML, Allen BC, Hertzberg RC, Parker A, Vincent MJ, Maier A, Boobis AR.Critical reviews in toxicology, 2018 ).
Multimedia
ToxTutor-Dose Response (U.S. National Library of Medicine)
This educational website gives insights on the dose responses principles using an interactive approach.