10% Body weight (gain) change as criterion for the maximum tolerated dose: A critical analysis.

The concept of the Maximum Tolerated Dose (MTD) was introduced in the seventies for carcinogenicity testing and was defined as the highest dose inducing clear toxicity, but not mortality by causes other than cancer. As estimation of the MTD in a carcinogenicity study, the highest dose that causes a 10% decrease in body weight compared to control animals over the course of a 90-day study, was formulated as a suitable criterion. This criterion was not seen as indicator of excessive toxicity but as a means to avoid false negative outcomes in a carcinogenicity study, as tumor formation may be reduced when body weight is significantly decreased. The body weight-based MTD criterion, however, turned up in carcinogenicity test guidelines and guidance (e.g., from OECD) as the highest dose that causes a 10% decrease in body weight gain relative to controls. Moreover, the 10% decrease in body weight gain criterion for MTD also ended up in test guidelines and guidances for toxicity endpoints other than carcinogenicity, so outside the context it was intended for. A 10% decrease in body weight gain relative to controls is however not a biologically relevant effect as it corresponds to less than 3% body weight reduction relative to controls in a 90-day study, which is within the normal variation in body weight. It therefore should certainly not be considered as a condition of excessive toxicity. Using the 10% lower weight gain criterion and incorrectly associating it with excessive toxicity has major implications for top dose selection in regulatory safety studies, resulting in tests performed at doses too low to elicit toxicity. This negatively impacts the reliability of studies and their regulatory usability; moreover, it results in a waste of experimental animals, which is ethically highly undesirable. Hence, our plea is to remove this MTD criterion for top dose selection in test guidelines and guidances for toxicity endpoints other than carcinogenicity and to reinstall the original 10% decrease in body weight criterion in test guidelines and guidances for carcinogenicity.