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Evaluation of subchronic toxicity data using the benchmark dose approach
L A Gephart1, W F Salminen, M J Nicolich
1Toxicology and Environmental Sciences Division, ExxonMobil Biomedical Sciences, Inc., 1545 Route 22 East, Annandale, New Jersey 08801-0971, USA. lagepha@erenj.com
Regulatory Toxicology and Pharmacology : RTP
|March 22, 2001
Summary
The benchmark dose (BMD) methodology offers advantages over the NOAEL approach for toxicological risk assessment. Careful consideration of variables is crucial for accurate BMD estimation and regulatory application.
Area of Science:
- Toxicology
- Risk Assessment
- Biostatistics
Background:
- The no-observable-adverse-effect level (NOAEL) is a traditional point estimate in toxicology.
- Dose-response modeling, using methods like the benchmark dose (BMD), offers potential advantages.
- However, BMD estimation involves numerous variables that can influence results.
Purpose of the Study:
- To evaluate the benchmark dose (BMD) methodology using toxicological data.
- To examine the impact of various parameters on BMD estimates.
- To compare BMD results with traditional NOAEL values.
Main Methods:
- Applied the benchmark dose (BMD) methodology (Crump, 1984) to 90-day toxicological data and fabricated datasets.
- Calculated BMDs for discrete and continuous endpoints using maximum likelihood estimates (MLEs) and lower confidence limits (LCLs).
- Manipulated datasets by removing dose groups to assess data form impact on BMD.
Main Results:
- For discrete endpoints, BMDs were generally within an order of magnitude of the NOAEL.
- MLEs for discrete endpoints were typically higher than NOAELs, while LCLs were lower.
- BMD estimates showed insensitivity to data points beyond two dose groups from the NOAEL/LOAEL.
- Continuous data yielded highly variable ratios of MLEs and LCLs to NOAELs, with no clear trend.
Conclusions:
- The BMD methodology utilizes dose-response characteristics, potentially improving risk assessment.
- BMD estimates can lead to more or less conservative reference doses/concentrations compared to the NOAEL approach.
- Further discussion with regulatory agencies is needed to standardize model selection and BMD application to prevent unreasonable estimates.
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