Responses at high doses may distort the benchmark dose in animal studies

The FSVO compared the two methods (NOAEL and BMD) currently used to determine the safe dose for humans of substances that are potentially hazardous to health. The research found that NOAEL is preferable to BMD in certain situations.

Potentially hazardous substances are subjected to an official toxicological risk assessment. This involves comparing the expected exposure, for example via the consumption of contaminated food, with the safe dose for humans.

Two methods are currently used to derive a dose considered safe for humans: NOAEL (No Observed Adverse Effect Level) and BMD (Benchmark Dose). Both methods are based on the same results of animal studies. However, they differ in the way in which a safe dose is derived from these data.

Using simulated animal studies, the FSVO has now compared fundamental aspects of the NOAEL and BMD methods. In this research the FSVO concludes that, in certain situations, NOAEL is preferable to BMD.

NOAEL is simple and transparent

In animal studies, different doses of a chemical are administered to groups of animals. At the end of the study, the animals are examined and the highest dose at which no adverse effects are observed (NOAEL) is identified. The NOAEL is divided by a safety factor to give the acceptable daily intake (ADI) considered safe for humans. This means that one of the doses tested in the study is the NOAEL, which becomes the basis for the ADI.

BMD is mathematically complicated

Using the same study data as for the NOAEL method, the BMD method models a dose-response relationship according to statistical criteria. This mathematical dose-response model is then used to calculate the dose (BMD) corresponding to a predefined effect level, for example the dose at which 10% of the animals show an effect. As in the NOAEL method, the BMD is divided by a safety factor to give the ADI and thus derive the dose considered acceptable for humans.

Conceptual weaknesses of BMD

The main advantage of BMD over NOAEL is generally considered to be that the former includes information on all dose groups tested in the study in order to derive the safe dose. In contrast, the NOAEL method uses only the information on the dose group corresponding to the NOAEL. However, because its mathematical dose-response model is influenced by all dose groups, the BMD approach implicitly assumes that all dose group results are relevant for deriving the safe dose for humans. This critical assumption disregards the fact that high-dose phenomena often play no role at lower doses, from which the safe dose for humans is generally derived.

This research uses simulated animal studies to show that the main factor strongly influencing the BMD and thus the safe dose for humans is the response at high doses, even though this may be irrelevant for assessing responses at low doses. The NOAEL method focuses on biological arguments, whereas the BMD method focuses on mathematical analysis of the data. According to these findings, BMD is not fundamentally superior to NOAEL, as is often claimed.

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Last modification 17.06.2020

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