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A new approach to evaluating carcinogenic risk.

¹Department of Food Microbiology and Toxicology, University of Wisconsin, Madison 53706.

Proceedings of the National Academy of Sciences of the United States of America

|February 1, 1992

Summary

Redefining the maximum tolerated dose (MTD) to exclude chemically induced cell proliferation offers enhanced protection. New MTDs, excluding mitogenesis, would inform safer acceptable daily exposure levels for chemicals.

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Area of Science:

Toxicology
Risk Assessment
Carcinogenesis

Background:

Current carcinogenic risk assessments extrapolate from high-dose rodent studies.
A significant issue is that ~50% of tested substances induce cancer at their maximum tolerated dose (MTD).
The current MTD definition is criticized for potentially stimulating cell proliferation, increasing cancer risk.

Purpose of the Study:

To propose a revised definition of MTD that excludes chemically induced mitogenesis.
To establish a new framework for determining acceptable daily exposure levels for chemicals based on a revised MTD.

Main Methods:

Consider chemically induced mitogenesis as an undesirable toxic effect during MTD determination.
Define a substance's true MTD as the highest dose that does not induce mitogenesis.
Apply a safety factor of 100 (1% of the no-observed-effect level) to the revised MTD for acceptable daily exposure.

Main Results:

Substances not inducing cancer at the revised MTD would have their acceptable daily exposure set at 1% of this MTD.
Chemicals inducing cancer at the revised MTD would continue to be regulated under current practices.

Conclusions:

A revised MTD definition excluding mitogenesis provides an added layer of protection.
This approach aims to improve the accuracy and safety of chemical risk assessments and establish safer exposure limits.

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