A collaboration between the UK’s National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), pharmaceutical multinationals and contract research organisations (CROs) has come up with recommendations for improving animal welfare in short-term toxicity studies.

Based on an analysis of data from 151 studies, the 15 pharmaceutical companies and CROs concluded that the maximum tolerated dose of a drug candidate could be determined in short-term toxicity studies without exceeding a bodyweight loss of 10% in rats and dogs.

Bodyweight loss is used as a measure of animal welfare. Data sharing on 151 compounds in the review led by NC3Rs and AstraZeneca showed that the upper limit for bodyweight loss ranged from 15% to 25% in practice.

Detailed analysis of the data, however, indicated there was little scientific value in exceeding bodyweight-loss limits of 10% in rats and dogs to determine the maximum tolerated dose in future drug dosing decisions, NC3Rs noted.  

Bodyweight loss above these limits “has been found to almost always be associated with additional clinical signs,” the Centre said.

Previously there has been little regulatory or cross-industry agreement on how the maximum tolerated dose should be defined.

Alert system

The review and its findings were published in the journal Regulatory Toxicology and Pharmacology.

Along with the new recommended limits, an alert system has been developed to determine when the maximum-tolerated dose is reached.

While bodyweight loss is used as an objective measurement in the alert system, the presence of other clinical signs has been incorporated to add value.

“Acting as an honest broker in this way has proven successful to identify an objective methodology to minimise animal suffering in short-term toxicity studies,” commented study author Dr Kathryn Chapman, head of innovation and translation at NC3Rs.

“Defining the maximum tolerated dose is crucially important for this in addition to making it easier to select an appropriate dose for future studies.”

Co-author Dr Sally Robinson of AstraZeneca, said the findings could potentially be applied across a broader spectrum than pharmaceuticals, “delivering even greater animal welfare benefits in short-term toxicity studies, which often have the highest severity limits”.