60 Years of the 3Rs symposium: Lessons learned and the road ahead.

When The Principles of Humane Experimental Technique was published in 1959, authors William Russell and Rex Burch had a modest goal: to make researchers think about what they were doing in the laboratory - and to do it more humanely. Sixty years later, their groundbreaking book was celebrated for inspiring a revolution in science and launching a new field: The 3Rs of alternatives to animal experimentation. On November 22, 2019, some pioneering and leading scientists and researchers in the field gathered at the Johns Hopkins Bloomberg School of Public Health in Bal-timore for the 60 Years of the 3Rs Symposium: Lessons Learned and the Road Ahead. The event was sponsored by the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), the Foundation for Chemistry Research and Initiatives, the Alternative Research & Development Foundation (ARDF), the American Cleaning Institute (ACI), the International Fragrance Association (IFRA), the Institute for In Vitro Sciences (IIVS), John "Jack" R. Fowle III, and the Society of Toxicology (SoT). Fourteen pres-entations shared the history behind the groundbreaking publication, international efforts to achieve its aims, stumbling blocks to progress, as well as remarkable achievements. The day was a tribute to Russell and Burch, and a testament to what is possible when people from many walks of life - science, government, and industry - work toward a common goal.

William Russell and Rex Burch published their book The Principles of Humane Experimental Technique in 1959. The book encouraged researchers to replace animal experiments where it was possible, to refine experiments with animals in order to reduce their suffering, and to reduce the number of animals that had to be used for experiments to the minimum. Sixty years later, a group of pioneering and leading scientists and researchers in the field gathered to share how the publi­cation came about and how the vision inspired international collaborations and successes on many different levels including new laws. The paper includes an overview of important milestones in the history of alternatives to animal experimentation.

Alternatives to Laboratory Animals: Trends in Replacement and the Three Rs.

The significance of contributions in volumes 11-46 (1983 to 2018) of Alternatives to Laboratory Animals in relation to the reduction, refinement and replacement of animal experimentation in biomedical research and testing is reviewed and discussed by the journal's former editor-in-chief, with particular emphasis on the development and production of the journal itself, FRAME, the European Centre for the Validation of Alternative Methods and other organisations. The role of the journal in promoting the principles of humane research (as spelled out by William Russell and Rex Burch) and highlighting a range of important issues and focus topics is explored. These include: botulinum toxin potency testing; ethical issues; the use of human volunteers, and human cells and tissues; the use of non-human primates (especially chimpanzees) and dogs as laboratory animals; toxicity testing in relation to cosmetics, pharmaceuticals and chemicals; UK and EU politics and legislation; and test validation and invalidation. The review concludes by identifying some of the issues that still need to be discussed and some of the questions that urgently need to be addressed.

It's Time to Include Harm to Humans in Harm-Benefit Analysis - But How to Do It, That is the Question.

The Three Rs (reduction, refinement, replacement) concept put forward by Russell and Burch now appears to be widely accepted. However, their warnings concerning reliance on animals as models for humans, the insurmountable problem of species differences and the impact of human variation, have been downplayed or even ignored. Schemes for harm-benefit analysis have been introduced, but the focus has largely been on harm to the animals, rather than on the direct and indirect benefit to humans, which is much more difficult to evaluate. Greater recognition should be given to the direct or indirect harm to humans resulting from the current over-reliance of biomedical research and testing on data obtained from animal experiments. That will be hard to achieve in the current climate, given the vigorous defence of animal experimentation by those with vested interests, confusion over responsibilities for regulating animal experimentation, hierarchies of regulatory authorities which require or limit experiments on animals, and exaggerated claims about the current availability of new approach methodologies (NAMs) and relevant and reliable strategies for their use. Those who defend animal experimentation at almost any cost must bear part of the responsibility for the human harms which result. Meanwhile, much greater effort should be put into the development, validation and application of new approaches not involving animals.

It's Time to Reconsider The Principles of Humane Experimental Technique.

In the 60 years since the publication of The Principles of Humane Experimental Technique, the Three Rs (Reduction, Refinement, Replacement) proposed by William Russell and Rex Burch have gradually been accepted throughout the world as ways of facing up to the ethical and scientific dilemmas involved in animal experimentation. However, the scale of animal use and the use of animals as models of humans has continued, seemingly almost unchallenged in much of the scientific community, despite the warnings about models, species differences and human variation spelled out in the The Principles. In this Comment, it is proposed that it is time to move away from the animal welfare focus of the Three Rs, in favour of a wider concept of humanity, which also embraces human welfare. In addition, since less than 10% of new drugs successfully pass from preclinical testing, which is highly reliant on animal procedures, to acceptance for clinical use, it is argued that the aim should not be to directly replace animal testing with non-animal methods with similar aims and which produce similar results, but to take advantage of developments in cell and molecular biology and in computer science, to devise new, different, appropriate, specific and intelligent stand-alone preclinical testing strategies that are applicable to particular human situations.

Clinical impact of high-profile animal-based research reported in the UK national press.

OBJECTIVES: We evaluated animal-based biomedical 'breakthroughs' reported in the UK national press in 1995 (25 years prior to the conclusion of this study). Based on evidence of overspeculative reporting of biomedical research in other areas (eg, press releases and scientific papers), we specifically examined animal research in the media, asking, 'In a given year, what proportion of animal research "breakthroughs"' published in the UK national press had translated, more than 20 years later, to approved interventions?' METHODS: We searched the Nexis media database (LexisNexis.com) for animal-based biomedical reports in the UK national press. The only restrictions were that the intervention should be specific, such as a named drug, gene, biomedical pathway, to facilitate follow-up, and that there should be claims of some clinical promise. MAIN OUTCOME MEASURES: Were any interventions approved for human use? If so, when and by which agency? If not, why, and how far did development proceed? Were any other, directly related interventions approved? Did any of the reports overstate human relevance? RESULTS: Overspeculation and exaggeration of human relevance was evident in all the articles examined. Of 27 unique published 'breakthroughs', only one had clearly resulted in human benefit. Twenty were classified as failures, three were inconclusive and three were partially successful. CONCLUSIONS: The results of animal-based preclinical research studies are commonly overstated in media reports, to prematurely imply often-imminent 'breakthroughs' relevant to human medicine.

Recent efforts to elucidate the scientific validity of animal-based drug tests by the pharmaceutical industry, pro-testing lobby groups, and animal welfare organisations.

BACKGROUND: Even after several decades of human drug development, there remains an absence of published, substantial, comprehensive data to validate the use of animals in preclinical drug testing, and to point to their predictive nature with regard to human safety/toxicity and efficacy. Two recent papers, authored by pharmaceutical industry scientists, added to the few substantive publications that exist. In this brief article, we discuss both these papers, as well as our own series of three papers on the subject, and also various views and criticisms of lobby groups that advocate the animal testing of new drugs. MAIN TEXT: We argue that there still remains no published evidence to support the current regulatory paradigm of animal testing in supporting safe entry to clinical trials. In fact, the data in these recent studies, as well as in our own studies, support the contention that tests on rodents, dogs and monkeys provide next to no evidential weight to the probability of there being a lack of human toxicity, when there is no apparent toxicity in the animals. CONCLUSION: Based on these data, and in particular on this finding, it must be concluded that animal drug tests are therefore not fit for their stated purpose. At the very least, it is now incumbent on-and we very much encourage-the pharmaceutical industry and its regulators to commission, conduct and/or facilitate further independent studies involving the use of substantial proprietary data.

The Emergence and Early Fate of the Three Rs Concept.

In the 60th year since the publication of The Principles of Humane Experimental Technique by W.M.S. Russell and R.L. Burch, we visited the W.M.S. and Claire Russell Archive at the University of Nottingham to discover, or confirm, answers to certain questions: the origins of the UFAW project which led to its writing; the relationship between Russell and Burch; the project plan; the origin of the Three Rs (Replacement, Reduction, Refinement) concept; the drafting, publication and response to the appearance of the book; and the future careers of its authors. We report on our findings, though many other questions have yet to be answered.

Electronic cigarettes: can dependable public health policies be developed and applied without relevant and reliable risk assessments?

The use of electronic cigarettes is being encouraged as a way of escaping from the harm resulting from conventional tobacco smoking, while scant attention is being paid to the long-term risks of inhaling electronic cigarette vapour. More information is needed for an acceptable risk assessment, from integrated non-animal testing and sound clinical investigations.

Replacing animal use in education and training.

In the USA, the general public want the use of animals in medical training to cease, but, at least in Australia, some teachers want it to continue, even when effective non-animal alternatives are available.