Skip Navigation

Industry Evidence Sets Animal Welfare Benchmark for Short-term Toxicity Studies

10% upper limit of bodyweight loss sufficient to determine maximum-tolerated dose.

The maximum-tolerated dose of a drug candidate can be determined in short-term toxicity studies without exceeding a bodyweight loss of 10 per cent in rats and dogs, according to a review by 15 pharmaceutical companies and contract research organisations published in Regulatory Toxicology and Pharmacology.

Led by the UK's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) and AstraZeneca, data from short-term toxicity studies of up to seven days in duration was collected from a multinational industry collaboration. The evidence sets out a new upper limit of bodyweight loss to be used as a primary endpoint for selecting the highest dose of a drug that can be tolerated in animals to reduce the likelihood of major adverse effects.

The maximum-tolerated dose is usually determined by parameters such as bodyweight loss, clinical signs and a change in food consumption. However, such assessments are often subjective with little regulatory or cross-industry agreement on how the maximum-tolerated dose should be defined. Bodyweight loss is one of the few objective measurements used in short-term toxicity studies. It is used as a measure of animal welfare, with the greater the weight loss the greater the potential for suffering.

To date there has been no evidence-based guidance on the upper limit for bodyweight loss. In this NC3Rs-industry collaboration, data sharing on 151 compounds has shown the upper limit for bodyweight loss ranges from 15 to 25 per cent in practice. Detailed analysis of the data however has shown that there is little scientific value in exceeding bodyweight loss limits of 10 per cent in rats and dogs to determine the maximum-tolerated dose for future dosing decisions. 
Bodyweight loss above these limits has been found to almost always be associated with additional clinical signs.

Along with the new recommended limits, an alert system has been developed to determine when the maximum-tolerated dose has been reached. While bodyweight loss is used here as an objective measurement, the presence of other clinical signs is also incorporated to add value to this practical advice. These standardised assessment criteria will minimise the adverse effects experienced by thousands of animals used in pharmaceutical development each year.

Study author Dr Kathryn Chapman, Head of Innovation and Translation, NC3Rs, said:

"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. 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, AstraZeneca, said:

"We have shared data across global pharmaceutical companies and developed an evidence base to support significant refinement in short-term toxicity studies where high doses of potential new medicines are given. The outcome from this novel approach can potentially be applied more broadly than the pharmaceutical industry delivering even greater animal welfare benefits in short-term toxicity studies which often have the highest severity limits."

Co-author Dr Vicente Nogués, Head of Operations for Preclinical Safety, Novartis Institute for Biomedical Research, said:

"Novartis has gained confidence that the conclusions of this investigation, based on the analysis of a considerable historical database throughout the pharmaceutical industry, will help to improve overall decision making during animal study conduct along the 3Rs; this without harming the ultimate objective of the preclinical studies."

Maximum-tolerated dose studies are important from both a scientific and ethical perspective. They are used to make decisions on the progression of potential candidate drugs across a range of therapeutic areas. They also set the dose level for subsequent studies that allow for regulatory approval.

This approach to re-assessing bodyweight loss has the potential to be translated to other research areas including pharmacology and efficacy studies and short-term toxicity studies with chemicals.

See NC3Rs website for more information.

New ALTEX: 1/2016

ALTEX 2.16 cover

Support ALTWEB, Make a Gift
Online Humane Science Course


Promoting Dialogue Between In Vivo, In Vitro, and In Silico
May 18, 2016
Milan, Italy

SOT In Vitro and Alternatives Methods Speciality Section Grad Student and Postdoc Webinar
May 18, 2016
11am EDT

Mucosal Immunity and In Vitro Science
May 19, 2016
Milan, Italy

CAAT Academy: In Silico Modeling and Tools Under REACH 
May 20, 2016
Hosted by ROCAM in Cluj, Romania
Registration and Information

ACTC 2016 Conference
May 30-June 1, 2016
Barcelona, Spain

Kirkstall Workshop
June 2-3, 2016
Barcelona, Spain

CAAT Academy: Animal-free Pyrogenicity and Endotoxin Testing Under the New EU Pharmacopeia Chapter 5.1.10
June 8th, 2016
Konstanz, Germany 
17th International Conference on QSAR in Environmental and Health Sciences (QSAR 2016)
June 13-17, 2016
Miami Beach, Florida

17th Annual Congress of EUSAAT/20th European Congress on Alternatives to Animal Testing
August 24-27, 2016
University of Linz, Austria

ESTIV 2016 Congress: In Vitro Toxicology for Human Safety Assessment
October 17-20, 2016
Juan-les-Pins, France

AALAS 67th Annual Meeting
October 30-November 3, 2016
Charlotte, NC

10th World Congress on Alternatives and Animal Use in the Life Sciences
August 20-24, 2017
Seattle, Washington

More Meetings...