Category Archives: THE WISDOM OF RUSSELL AND BURCH

On Replacing the Concept of Replacement

Michael Balls

Russell and Burch saw failure to accept the correlation
between humanity and efficacy as an example of rationalisation,
a psychological defence mechanism

While wondering what I could discuss in this column I looked, as I often do, in the abridged version1 of The Principles of Humane Experimental Technique,2 at Russell and Burch’s introduction of what I call the humanity criterion. It is part of their discussion of the sociological factors which are among the Factors Governing Progress. This is how part of page 101 of the abridged version reads:

In fact, really informative experiments must be as humane as would be conceivable possible, for science and exploration are indissolubly linked to the social activity of cooperation, which will find its expression in relation to other animals, no less than to our fellow humans. Conscious good will and the social operational method are useless as safeguards against the mechanism of rationalisation (in the pathological sense of the term – i.e. the mechanism of defence by which unacceptable thoughts or actions are given acceptable reasons to justify them to oneself and to others, while, at the same tie, unwittingly hiding the true, but unconscious, motives for them).

The bold type indicates my explanation, and I have to admit that, six years after preparing the abridged version of The Principles, I now found it difficult to see what Russell and Burch had intended to convey. I therefore looked back at the original book, and found this paragraph on pages 156−157:

In efficacy, or yield of information, the advantages of humane technique apply almost universally. The correlation between humanity and efficacy has appeared so often in this book that we need not labour the point. There is, however, a more fundamental aspect of this correlation, specially important in research. Science means the operational method — telling somebody else how to see what you saw. This method is one of the greatest of all human evolutionary innovations. It has, however, one drawback. It prevents permanent acceptance of false information, but it does not prevent wastage of time and effort. The activity of science is the supreme expression of the human exploratory drive, and as such it is the subject to the same pathology. The scientist is liable, like all other individuals, to block his exploration on some front where his reactions to childhood social experiences are impinged upon. When this happens to the experimental biologist, we can predict the consequence with certainty. Instead of really exploring, he will, in his experiments, act out on his animals, in a more or less symbolic and exaggerated way, some kind of treatment which he once experienced in social intercourse with his parents. He can rationalise this as exploration, and hence fail to notice the block. But in fact such acting out invariably occurs precisely when real exploration is blocked, and must be relinquished before real exploration can begin again. Hence, such experiments will be utterly wasteful, misleading, and uninformative. The treatment of the animals, for one thing, will inevitably be such as to impair their use as satisfactory models. The interpretation of the results will be vitiated by projection. Really informative experiments, must in fact be as humane as would be conceivably possible, for science and exploration are indissolubly linked to the social activity of cooperation, which will find its expression in relation to other animals no less than to our fellow humans. Conscious goodwill and the social operational method are useless as safeguards against the mechanism of rationalisation (in the pathological sense of the term).

Here, the underlining indicates what I omitted from the abridged version, and I now wonder why I did so. These words clearly reflect Russell’s interest in psychology — he later became a psychotherapist, and undoubtedly will have been influenced by discussions with his psychotherapist wife, Claire Russell. They could be seen as an explanation why some scientists did not appreciate the essential link between humanity and efficacy, and why Russell thought they needed what was offered by the Three Rs and the humanity criterion.

It is not clear what is meant by “the social operational method”, and consulting Google leads to only one hit — The Principles itself! “Conscious goodwill” is probably meant to contrast with unconscious rationalisation.  Perhaps what Russell meant is that, however sincere the intention may appear to be, support for the Three Rs is useless, unless it leads to active and practical commitment to their development and application.

We are often confronted with rationalisation, the pseudo-rational justification of irrational acts,3 and its relative, intellectualisation, a different defence mechanism (or way of making excuses), “where reasoning is used to block confrontation with an unconscious conflict and its associated emotional stress, where thinking is used to avoid feeling. It involves removing one’s self, emotionally, from a stressful event. Intellectualisation is one of Freud’s original defence mechanisms. Freud believed that memories have both conscious and unconscious aspects, and that intellectualisation allows for the conscious analysis of an event in a way that does not provoke anxiety.”4

I am not a psychoanalyst, and I think it would be unwise, even dangerous, were I to seek to delve into the underlying reasons why some scientists are so keen to run to animal experimentation as the first resort and to do so little to make possible its replacement. Nevertheless, I can say, without fear of contradiction, that this is another great example of how Russell and Burch’s wonderful book continues to give us food for thought and calls for action.

Professor Michael Balls
E-mail: michael.balls@btopenworld.com

References
1 Balls, M. (2009). The Three Rs and the Humanity Criterion, 131pp. Nottingham, UK:  FRAME.
2 Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, xiv + 238pp. London, UK: Methuen.
3 Anon. (2015). Rationalization (psychology). San Francisco, CA, USA: Wikipedia Foundation, Inc. Available at: https://en.wikipedia.org/wiki/Rationalization_(psychology) (Accessed 26.08.15).
4 Anon. (2015). Intellectualization. San Francisco, CA, USA: Wikipedia Foundation, Inc. Available at: https://en.wikipedia.org/wiki/Intellectualization (Accessed 26.08.15).

The Principles of Humane Experimental Technique is now out of print, but the full text can be found at http://altweb.jhsph.edu/pubs/books/humane_exp/het-toc. The abridged version, The Three Rs and the Humanity Criterion, can be obtained from
FRAME.

Download a pdf copy of this post by clicking here.

Previous Wisdom of Russell & Burch posts from Michael Balls:

The Concept, Sources and Incidence of Inhumanity and its Diminution or Removal Through Implementation of the Three Rs.
The Wages of Inhumanity.
Fidelity and Discrimination.
Reduction.
Refinement. 
Replacement. 
The Factors Governing Progress. 
UFAW and Major Charles Hume. 
The Toxicity Testing Problem. 
The Use of Lower Organisms.
The Analysis of Direct Inhumanity.
William Russell: Polymath, Wordsmith, Classicist and Humourist .
Rex Leonard Burch: Humane Scientist and Gentle Man.
On the Proper Application of Appropriate Statistical Methods. 
Comparative Substitution. 
The Three Rs: The Way Forward .
The Choice of Procedures .
Rationalisation and Intellectualisation.

 

Rationalisation and Intellectualisation

Michael Balls

Russell and Burch saw failure to accept the correlation
between humanity and efficacy as an example of
rationalisation, a psychological defence mechanism

While wondering what I could discuss in this column I looked, as I often do, in the abridged version1 of The Principles of Humane Experimental Technique,2 at Russell and Burch’s introduction of what I call the humanity criterion. It is part of their discussion of the sociological factors which are among the Factors Governing Progress. This is how part of page 101 of the abridged version reads:
In fact, really informative experiments must be as humane as would be conceivable possible, for science and exploration are indissolubly linked to the social activity of cooperation, which will find its expression in relation to other animals, no less than to our fellow humans. Conscious good will and the social operational method are useless as safeguards against the mechanism of rationalisation (in the pathological sense of the term — i.e. the mechanism of defence by which unacceptable thoughts or actions are given acceptable reasons to justify them to oneself and to others, while, at the same tie, unwittingly hiding the true, but unconscious, motives for them).

The bold type indicates my explanation, and I have to admit that, six years after preparing the abridged version of The Principles, I now found it difficult to see what Russell and Burch had intended to convey. I therefore looked back at the original book, and found this paragraph on pages 156−157:
In efficacy, or yield of information, the advantages of humane technique apply almost universally. The correlation between humanity and efficacy has appeared so often in this book that we need not labour the point. There is, however, a more fundamental aspect of this correlation, specially important in research. Science means the operational method — telling somebody else how to see what you saw. This method is one of the greatest of all human evolutionary innovations. It has, however, one drawback. It prevents permanent acceptance of false information, but it does not prevent wastage of time and effort. The activity of science is the supreme expression of the human exploratory drive, and as such it is the subject to the same pathology. The scientist is liable, like all other individuals, to block his exploration on some front where his reactions to childhood social experiences are impinged upon. When this happens to the experimental biologist, we can predict the consequence with certainty. Instead of really exploring, he will, in his experiments, act out on his animals, in a more or less symbolic and exaggerated way, some kind of treatment which he once experienced in social intercourse with his parents. He can rationalise this as exploration, and hence fail to notice the block. But in fact such acting out invariably occurs precisely when real exploration is blocked, and must be relinquished before real exploration can begin again. Hence, such experiments will be utterly wasteful, misleading, and uninformative. The treatment of the animals, for one thing, will inevitably be such as to impair their use as satisfactory models. The interpretation of the results will be vitiated by projection. Really  informative experiments, must in fact be as humane as would be conceivably possible, for science and exploration are indissolubly linked to the social activity of cooperation, which will find its expression in relation to other animals no less than to our fellow humans. Conscious goodwill and the social operational method are useless as safeguards against the mechanism of rationalisation (in the pathological sense of the term).

Here, the underlining indicates what I omitted from the abridged version, and I now wonder why I did so. These words clearly reflect Russell’s interest in psychology — he later became a psychotherapist, and undoubtedly will have been influenced by discussions with his psychotherapist wife, Claire Russell. They could be seen as an explanation why some scientists did not appreciate the essential link between humanity and efficacy, and why Russell thought they needed what was offered by the Three Rs and the humanity criterion.

It is not clear what is meant by “the social operational method”, and consulting Google leads to only one hit — The Principles itself! “Conscious goodwill” is probably meant to contrast with unconscious rationalisation. Perhaps what Russell meant is that, however sincere the intention may appear to be, support for the Three Rs is useless, unless it leads to active and practical commitment to their development and application.

We are often confronted with rationalisation, the pseudo-rational justification of irrational acts,3 and its relative, intellectualisation, a different defence mechanism (or way of making excuses), “where reasoning is used to block confrontation with an unconscious conflict and its associated emotional stress, where thinking is used to avoid feeling. It involves removing one’s self, emotionally, from a stressful event. Intellectualisation is one of Freud’s original defence mechanisms. Freud believed that memories have both conscious and unconscious aspects, and that intellectualisation allows for the conscious analysis of an event in a way that does not provoke anxiety.”4

I am not a psychoanalyst, and I think it would be unwise, even dangerous, were I to seek to delve into the underlying reasons why some scientists are so keen to run to animal experimentation as the first resort and to do so little to make possible its replacement. Nevertheless, I can say, without fear of contradiction, that this is another great example of how Russell and Burch’s wonderful book continues to give us food for thought and calls for action.

Professor Michael Balls
E-mail: michael.balls@btopenworld.com

References
1 Balls, M. (2009). The Three Rs and the Humanity Criterion, 131pp. Nottingham, UK:  FRAME.
2 Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, xiv + 238pp. London, UK: Methuen.
3 Anon. (2015). Rationalization (psychology). San Francisco, CA, USA: Wikipedia Foundation, Inc. Available at: https://en.wikipedia.org/wiki/Rationalization_(psychology) (Accessed 26.08.15).
4 Anon. (2015). Intellectualization. San Francisco, CA, USA: Wikipedia Foundation, Inc. Available at: https://en.wikipedia.org/wiki/Intellectualization
(Accessed 26.08.15).
The Principles of Humane Experimental Technique is now out of print, but the full text can be found at http://altweb.jhsph.edu/pubs/books/humane_exp/het-toc. The abridged version, The Three Rs and the Humanity Criterion, can be obtained from
FRAME.

The Three Rs: The Way Forward

Michael Balls

It is now 20 years since Russell and Burch
last met to discuss, with others,
the way forward for the Three Rs concept

 

Sitting at my computer, faced with the challenge of deciding what I could say in Wisdom 16, I suddenly realised that it was almost 20 years, to the day, since Bill Russell and Rex Burch met in Sheringham, a small seaside town in Norfolk, UK, for the first scientific meeting they had attended together since the publication of The Principles in 1959 (Figure 1). Sadly, it was also to be the last such meeting, as Rex died a few months later.

Rex Burch and Bill Russell 31 May 1995 and Ecvam Workshop report

 

The meeting took place on 31 May to 3 June 1995, in the form of an e, which I chaired in partnership with Alan Goldberg of CAAT. Our reason for being in Sheringham was that Rex was too ill to go more than a few miles from home, so Alan and I decided that we would invite some of those committed to the Three Rs, to travel to meet him. The other participants included Claire Russell, and some of our colleagues from Germany, Italy, The Netherlands, the UK and the USA (Figure 2).

Workshop participants May 1995

 

An opening ceremony was held in the council chamber of Sheringham Town Hall, where Rex had rented space for his microbiology laboratory since the early 1970s. All the participants made a brief statement, and Bill sang a song, as he always did on special occasions. These opening proceedings were recorded on videotape. The rest of the workshop took place at the Links Country House Hotel in West Runton, about a mile from where I now live.

The principal aims of the workshop were to discuss the current status of the Three Rs and to make recommendations aimed at achieving greater acceptance of the concept of humane experimental technique, and, in the interests of both scientific excellence and the highest standards of animal welfare, the more active implementation of reduction alternatives, refinement alternatives and replacement alternatives.

The report of the workshop was published in the November/December 1995 issue of ATLA.1 It reviewed the origins and evolution of the Three Rs concept as originally outlined in The Principles,2 the selection of appropriate animal species, reduction alternatives, refinement alternatives and replacement alternatives, education and training, and certain special considerations (vaccines and immunobiologicals, transgenic animals, special protection for selected animals, benefit and suffering, and the setting of targets). It concluded with 58 conclusions and recommendations, which were preceded by the following remarks: The workshop participants unanimously reaffirmed the principles put forward by Russell & Burch, that humane science is good science and that this is best achieved by vigorous application of the Three Rs: reduction alternatives, refinement alternatives and replacement alternatives.

Thus, the only acceptable animal experiment is one which uses the smallest possible number of animals and causes the least possible pain or distress which is consistent with the achievement of a justifiable scientific purpose, and which is necessary because there is no other way of achieving that purpose. Any proposed experiments on animals should be subjected to prior and effective expert review by an ethics committee or an equivalent body. The Three Rs should be seen as a challenge and as an opportunity for reaping benefits of every kind — scientific, economic and humanitarian — not as a threat.

Many of the conclusions and recommendations are as relevant today as they were in 1995. The workshop was a memorable occasion in many other ways. It was run according to the ECVAM tradition — five days of hard work, interspersed with good food and good wine, with a determination to have the words of detailed conclusions and recommendations down on paper by the end. One of my lasting memories will be witnessing the pleasure shown by Bill and Rex, as they took the opportunity to sit and talk quietly together after a gap of more than 30 years. All I have to show of that is one out-of-focus photograph, taken during the final reception and dinner at Blickling Hall, on 2 June 1995 (Figure 3).

Bill Russell and Rex Burch 2 June 1995

Many developments of many kinds have taken place since 1995, but, as Roman Kolar spells out in the latest issue of ATLA,3 there is still much to be achieved, if the aims of the workshop and of The Three Rs Declaration of Bologna,4 to which it led, are to be achieved, resulting in the revolution in biomedical research and its application which was proposed in The Principles. For my own part, I am concerned that stating allegiance to the Three Rs concept has become a convenient smokescreen, to which lip service can be paid, whilst little is actually permitted to change. I have therefore proposed that the focus should now be more squarely on humane science, which avoids the problem of seeming conflicts between human benefit and animal welfare,5 and I am rather confident that Bill and Rex would approve.

Professor Michael Balls
c/o FRAME
Russell & Burch House
96–98 North Sherwood Street
Nottingham NG1 4EE
UK
E-mail: michael.balls@btopenworld.com

References
1 Balls, M., Goldberg, A.M., Fentem, J.H., Broadhead, C.L., Burch, R.L., Festing, M.F.W., Frazier, J.M., Hendriksen, C.F.M., Jennings, M., van der Kamp, M.D.O., Morton, D.B., Rowan, A.N., Russell, C., Russell, W.M.S., Spielmann, H., Stephens, M.L., Stokes, W.S., Straughan, D.W., Yager, J.D., Zurlo, J. & van Zutphen, B.F.M. (1995). The Three Rs: The way forward. The report and recommendations of ECVAM Workshop 11. ATLA 23, 838-866.
2 Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, xiv + 238pp. London, UK: Methuen.
3 Kolar, R. (2015). How long must they suffer? Success and failure of our efforts to end the animal tragedy in laboratories. ATLA 43, 129-143.
4 Anon. (2000). The Three Rs Declaration of Bologna. ATLA 28, 1-5.
5 Balls, M. (2014). Animal experimentation and alternatives: Time to say goodbye to the Three Rs and hello to humanity? ATLA 42, 27-333.

The Principles of Humane Experimental Technique is now out of print, but the full text can be found at http://altweb.jhsph.edu/pubs/books/humane_exp/het-toc.
An abridged version, The Three Rs and the Humanity Criterion, by Michael Balls (2009), can be obtained from FRAME.

Download a pdf of this article here:

Wisdom 16

Comparative Substitution

Michael Balls

The scientifically-justifiable choice of species is a crucial issue in animal
experimentation, which should not be based on ignorance and habit,
or 
on slavish compliance with political expectations
and regulatory requirements

 

 

The Principles of Humane Experimental Technique1 was published a year after it was written, and Russell and Burch added an Addendum, because they felt that year had “seen much activity in several parts of the field”.

One point they made in the Addendum was that “the comparative substitution of lower for higher animals raises difficult issues”, but, “where great severity is concerned … we must be glad to see lower forms substituted for mammals”. Unfortunately, they said nothing more about the “difficult issues” to which they referred, and I wish I had asked them about it, while I had the chance to do so.

The discussion on comparative substitution in the chapter on Replacement in the main part of the book focuses on the use of non-sentient material (plants, micro-organisms), degenerate metazoan endoparasites and free-living metazoan invertebrates. They regarded such use as a “limited gain”, and considered that “to shed obsessional tears over the fate of these organisms would bring the whole concept of humanity into contempt”. They preferred to concentrate on “the wholly desirable progress and prospects of replacement proper”, i.e. the use of any scientific methods which “replace methods which use conscious living vertebrates”.

Russell and Burch considered that not enough was being done with lower vertebrates, and saw the predominant use of mammals as “yet another expression of the high-fidelity fallacy”.2 Here, Russell’s experiences as a zoology student at Oxford came to the fore, since “our ignorance of the behaviour of common laboratory mammals is offset by a wealth of knowledge about that of numerous lower vertebrate species”. He had worked on mating behaviour in Xenopus laevis, the South African clawed toad, alongside the Nobel-prizewinning work of Tinbergen and his colleagues on the behaviour of birds and fish. In a section on The Choice of Species, Russell and Burch argued that, in terms of humanity, the “subtle matching of procedure to species, and species to objectives, is more significant that it appears at first sight”. They said that “a formal or informal training in zoology has again and again proved its value in the progress of medical research”, and lamented attempts to “correct the mistaken choice of a wrong species by forcing it to conform to the requirements of the investigation”.

They marvelled at “the present large-scale choice of laboratory species”, but regretted that, “out of the almost astronomical number of vertebrate species, only a minute selection are employed … this includes about 20 mammal species, three bird species, about four reptile species, half a dozen or so amphibians, and half a dozen or so fish”. Of the mammalian species, they said, “only about half the species are used in numbers over 1,000 per annum, the overwhelming bulk being made up of the four chief species (mouse, rat, guinea-pig and rabbit), and, of these, more than two-thirds are mice”.

Lack of sufficient understanding of the animals used for experimental purposes is still rife today. For example, the customary feeding ad libitum of caged rats and mice fundamentally alters their endocrinological, neurological and behavioural status. In real life, they spend most of their time searching for food, not eating it, while keeping alert because of the threat of predators. Also, the feminisation of male fish and amphibians by so-called endocrine disruptors, was taken as a warning of threats to human masculinity, whereas it is a normal part of the adaptability of these lower vertebrates. Even worse are attempts to genetically humanise laboratory animals, in order to make them better models for humans, without sufficient understanding of the cascade of complications likely to result from the consequent distortions of the very nature of the animals concerned.

Russell and Burch said rather little about choosing between the higher mammals, except to say that they were pleased to note that the Indian Government had “imposed salutary regulations” on the shipment of monkeys to provide kidney cells for vaccine production, and that the Medical Research Council had “issued recommendations on humane shipment”, which had been “adopted by all the British airlines concerned with livestock transport”. They welcomed “such action being taken on behalf of animals, which, although our near relatives, receive none of the privileges accorded by the Home Office to cats, dogs and the equidae” (the commonest animals to be encountered in Victorian England, when the Cruelty to Animals Act 1876 became law).
Over the years, I have had many discussions with veterinarians about whether there should be a hierarchy of laboratory mammals in the terms of the need to justify their use, with rats and mice near the bottom, and dogs and non-human primates at the top, or whether all the species should be afforded the same standards of consideration and care. I take the former view, and that is the position laid down in the Animals (Scientific Procedures) Act 1986, as amended to comply with Directive 2010/63/EU.

But what about the substitution of one species high in the hierarchy with another species high in the hierarchy. This point arose when somebody occupying a high position in the Three Rs movement, commenting on our study on the use of tests in dogs for predicting human toxicology and drug safety,3 warned us that “dropping the dog on the basis of your existing evidence could result in an increase in the use of nonhuman primates”. That would present advocates of the routine use of a second, ‘high-fidelity’, nonrodent species in toxicity testing with a dilemma and a challenge. How could they justify replacing pointless tests in one highly-protected species with pointless tests in another highly-protected species?

Professor Michael Balls
c/o FRAME
Russell & Burch House
96–98 North Sherwood Street
Nottingham NG1 4EE
UK
E-mail: michael.balls@btopenworld.com

References
1 Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, xiv + 238pp. London,
UK: Methuen.
2 Balls, M. (2013). The wisdom of Russell and Burch. 3. Fidelity and discrimination. ATLA 41, P42–P43.
3 Bailey, J., Thew, M. & Balls, M. (2013). An analysis on the use of dogs in predicting human toxicology and drug safety. ATLA 41, 335–330.
The Principles of Humane Experimental Technique is now out of print, but the full text can be found at http://altweb.jhsph.edu/pubs/books/humane_exp/het-toc. An abridged version, The Three Rs and the Humanity Criterion, can be obtained from FRAME.

Download a pdf of this article. Comparative Substitution

On the Proper Application of Appropriate Statistical Methods

Michael Balls

The proper application of appropriate statistical
methods is crucial to relevant and
reliable biomedical research and testing

As I said in an earlier contribution in this series,1 although Russell and Burch stated that “reduction, of all the modes of progress” [i.e. the Three Rs], “is the one most obviously, immediately, and universally advantageous in terms of efficiency”, I have always found their Chapter 5, on Reduction and Strategy in Research,2 the most difficult part of The Principles of Humane Experimental Technique to understand.

Russell and Burch were strongly committed to the proper design and analysis of experiments, and, in particular, to the proper application of statistical methods. They rightly said that statistical advice is important at the outset, since “every time any particle of statistical method is properly used, fewer animals are employed than would otherwise have been necessary”. However, from where that advice is sought, and when and how it is applied, is crucial. As Russell and Burch put it, “statisticians are justly indignant, if asked to cope with the results of bad design. Of course, it is an elementary principle for any experimenter, not himself a statistician, to seek advice before experimenting.” I heeded that advice, and at ECVAM, I had the privilege of working with excellent statisticians, notably Graeme Archer and Sebastian Hoffmann. I have also benefited from consultation with others, such as Michael Festing and David Lovell, being in agreement with Russell and Burch that “toxicity testing is the scene of some confused thought”. Nevertheless, as Editor of ATLA, I am still regularly confronted by the misuse of Student’s t-test when comparing data from several experimental groups with one control, when Fisher’s analysis of variance should have been used instead.

Russell and Burch pointed out that “the science of statistics has been connected historically with three large-scale human activities: biological research, insurance, and gambling”. The connection with biology and medicine began at the beginning of the 20th century, and “has been associated especially with life insurance and two branches of biology — experimental agriculture and the theory of genetics and evolution”. They gave particular recognition to Sir Ronald Fisher (1890–1962), “who, more than anyone else is responsible for bringing statistical methods into experimental biology”. He introduced many concepts and methods, including biometrical genetics, and he was the first to use the term “variance” in statistics (i.e. how far a number in a set is from the mean value), an issue of great concern to Russell and Burch. Fisher introduced the concept of the analysis of variance, which was a considerable advance over the correlation methods used up to then, and is now a basic statistical tool in fundamental and applied biomedical research.3

Fisher had a glittering career, including a long and fruitful collaboration on ecological genetics with E.B. Ford, who taught genetics at Oxford to, among many others, William Russell and me. I remember Fisher coming to give a seminar in about 1958, and, on seeing him have a highly complicated discussion with Ford, in public, feeling that I was in the presence of two of the greatest minds of the 20th century. The outcome of their collaboration was “the general recognition that the force of natural selection was often much stronger than had been appreciated before, and that many ecogenetic situations (such as polymorphism) were not selectively neutral, but were maintained by the force of selection”.3 If I understand properly what that means, it may indicate that biomedical scientists should be more willing to take human polymorphism into account, especially when trying to translate the results of experiments on animals into meaningful conclusions about human beings. As Russell and Burch put it, researchers should take great care to avoid the high-fidelity fallacy.

Despite his eminence, Fisher did have what could now be seen as his weaknesses. For example, he was opposed to Bayesian statistics, and he had some thoughts on eugenics which would not fit very well with the prevailing ethos of the 21st century. Also, he was opposed to the conclusion in the 1956 report by Richard Doll and Austin Hill that smoking causes lung cancer. “He compared the correlations in their studies to a correlation between the import of apples and the rise of divorce, in order to show that correlation does not imply causation.”3

Fisher might have been wrong on smoking and cancer, but his point about correlation and causation is still widely ignored today, especially by certain scientists, broadcasters and journalists, who time and again tell us of links between what we eat or don’t eat, or what we do or don’t do, and the awful fates of various kinds which await us as a result. Often, the correlation they are referring to is mere coincidence.4

Thinking that a correlation between two sets of data implies causation becomes especially dangerous when this is plausible, such as the postulated link between cooking in aluminium saucepans and dementia. The correlation–causation fallacy is discussed in a wonderful book on seeing the world through numbers, The Tiger That Isn’t, by Michael Blastland and Andrew Dilnot,5 and some amusing examples of meaningless correlations in US affairs have recently been given by Joe Arrigo.6 For example, the correlations between: suicides by hanging and spending on science; the marriage rate in Kentucky and deaths by drowning after falling from fishing boats; the per capita consumption of cheese and deaths from becoming entangled in bed-sheets; the per capita consumption of sour cream and deaths after falling from wheelchairs; and crude oil imports from Norway and drivers killed by collision with trains.

A good example of the plausibility problem came to my attention as I was writing this piece, in an article published in The Times on 23 December 2014, by Kat Lay, entitled Heart patients more likely to survive if doctor away.7 It referred to a study at Harvard Medical School, Boston, USA, published online by JAMA Internal Medicine on 22 December 2014,8 which indicated that, while 60% of high-risk heart attack and cardiac arrest patients died in teaching hospitals within 30 days of admission when senior doctors were away at cardiology conferences, 70% died when they were present. The survival rates of low-risk patients were not affected, nor were the survival rates of high-risk or low-risk patients in non-teaching hospitals. All kinds of plausible reasons for the difference are being suggested. For example, fewer high-tech, and possibly more risky, treatments (such as percutaneous coronary intervention) may be applied when the leading doctors are away at scientific meetings. That implies that the harms of sophisticated techniques might outweigh the benefits, or, as Anupam Jena, senior author of the report, said: “The evidence suggests that a less-is-more approach might be best for higher-risk patients with these conditions”,9 but proving cause, rather than mere correlation or coincidence, will not be easy.

Mark Twain popularised the saying, often attributed to Benjamin Disraeli, that “There are three kinds of lies: lies, damned lies and statistics”, which is often used to cast doubt on the persuasive power of numbers or to cast doubt on the statistics used to prove an opponent’s point.10 That saying is, of course, nonsense, and exposes the weakness of those who use it.

In two other memorable books, both by Joel Best, Damned Lies and Statistics: Untangling Numbers from the Media, Politicians, and Activists11 and More Damned Lies and Statistics: How Numbers Confuse Public Issues,12the author considers the simple premise that vast quantities of statistics are bandied about in all walks of life, and we frequently rely on them to form our own opinions, though we don’t understand how the numbers work. There are four kinds of people when thinking about statistics: awestruck, naïve, cynical, and critical — Best considers most people to be naïve, and that this can lead to poor policies and poor decisions, and his aim is to turn them all into critical thinkers.

Russell and Burch had a critical view of statistics, i.e. they had a balanced and sensible approach in exercising careful judgement and judicious evaluation, as they recognised that the proper application of appropriate statistical methods is crucial to relevant and reliable biomedical research and testing. We should all have the wisdom to do likewise.

Michael Balls
E-mail: michael.balls@btopenworld.com

References
1 Balls, M. (2013). The Wisdom of Russell and Burch. 4. Reduction. ATLA 41, P24–P25.
2 Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, xiv + 238pp. London, UK: Methuen.
3 Anon. (2014). Ronald Fisher. Wikipedia, 8pp. Available at: http://en.wikipedia.org/wiki/Ronald_Fisher
4 Gerbis, N. (undated). 10 Correlations that are not causations. How Stuff Works. Available at: http://
science.howstuffworks.com/innovation/sciencequestions/
10-correlations-that-are-not-causations.htm
5 Blastland, M. & Dilnot, A. (2007). The Tiger That Isn’t, 184pp. London, UK: Profile Books Ltd.
6 Arrigo, J. (2014). Joe Arrigo Perspective: Meaningless Correlations, 5pp. Available at: http://www.joearrigo.com/2014/05/14/meaningless-correlations/
7 Lay, K. (2014). Heart patients more likely to survive if doctor away. The Times, 23.12.14, p. 22.
8 Jena, A.B., Prasad, V., Goldman, D.P. & Romley, J. (2014). Mortality and treatment patterns among patients hospitalized with acute cardiovascular conditions during dates of national cardiology meetings.
JAMA Internal Medicine, doi:10.1001/jamainternmed.
2014.6781
9 Anon. (2014). Patient outcomes when cardiologists are away at national meetings. Eureka Alert, 22.12.14. Available at: http://www.eurekalert.org/
pub_releases/2014-12/tjnj-pow121814.php 10 Anon. (2014). Lies, damned lies, and statistics. Wikipedia, 3pp. Available at: http://en.wikipedia.org/wiki/Lies,_damned_lies,_and_statistics
11 Best, J. (2001). Damned Lies and Statistics: Untangling Numbers from the Media, Politicians, and Activists, 219pp. Oakland, CA, USA: University of California Press.
12 Best, J. (2004). More Damned Lies and Statistics: How Numbers Confuse Public Issues, 217pp. Oakland, CA, USA: University of California Press.

Download a PDF of this article: CLICK HERE

The Principles of Humane Experimental Technique is now out of print, but the full text can be found at http://altweb.jhsph.edu/pubs/books/humane_exp/het-toc. An abridged version, The Three Rs and the Humanity Criterion, by Michael Balls (2009), can be obtained from FRAME.

Rex Leonard Burch: Humane Scientist and Gentle Man

Michael Balls

Rex Burch played a vital role in collecting background information
about practical animal experimentation, and was the first person
to use the term ‘alternatives’ in that context. The senior author of
The Principles, William Russell, greatly valued their collaboration

 

Whereas The Principles of Humane Experimental Technique1 reveals a great deal about its first author, it gives us very little insight into the character and contributions of its second author, Rex Burch. As a result, his role in the origins of the Three Rs concept could be underestimated. Happily, that can be avoided, not least because his co-author, William Russell, was solicitous in ensuring that his partner received the credit properly due to him.2 In addition, a few of us had the privilege of knowing Rex,3-5 and he recorded his own thoughts in a report produced under contract to ECVAM and published in ATLA.6

Soon after the UFAW project began, Russell informed Charles Hume that he would need some assistance, and the UFAW Council somewhat reluctantly agreed to the appointment of Burch. The plan was that Burch would “discuss with existing research workers, their techniques and attitudes to modifications, in terms of humaneness, and the idea of replacement techniques which did not require animals”. 6 To facilitate this, a letter of introduction was prepared (not without a struggle2) and sent to 20 individuals in December 1954. The response was positive, so Burch was able to begin his visits. He carried a tape recorder with him, then sent the interview tapes to Russell, who had their contents transcribed and placed in the records on which their eventual report and The Principles would be based.

Rex Burch in the lab

Russell later commented that, “As fieldwork for our project, Rex travelled widely over Britain, interviewing well over a hundred experimentalists, and every single one of them was cooperative. This shows, I think, not only the goodwill in the British scientific community, but the confidence Rex must have inspired by his friendly approach and his real understanding of the issues. These interviews were, of course, vitally important for our project, but I feel that there was more to them than that. Rex sowed many seeds, and helped to channel the goodwill of scientists into the more systematic approach to humane technique which has produced so many advances in recent years.”4 That was an immense achievement, since it must not be forgotten that, in those days, before the publication of The Principles with its introduction of the Three Rs concept, there was virtually no activity in the middle ground between the pro-vivisectionists and the anti-vivisectionists. There were only two positions on animal experimentation — for or against.

Burch’s success in gaining the confidence of research scientists undoubtedly stemmed from his own considerable experience in laboratory work, even though he was only 28 years old when he joined the UFAW project. He put it like this,6 in his own words: “In the early part of the Second World War, I worked in the North Riding Laboratory of Pathology and Public Health at Scarborough in North Yorkshire. One of my duties was to test milk for tubercle bacilli, and I had a constant stock of 200 guinea-pigs for this purpose. After their intraperitoneal injection of a centrifuged deposit of the milk sample (two guinea-pigs were used for each sample, one being killed after three weeks, the other after six weeks), their inguinal glands were examined for tubercle bacilli. My concern, before taking charge of this work, was about the humane killing. I was shown the method — a short, sharp blow to the nape of the neck with a specially made wooden instrument, which certainly caused instant death. I was made to practice on dead animals, and my first live guinea-pig did die instantly. From here I joined the army, serving in the Middle East and still using guinea-pigs for this diagnostic work. After the war, I read medicine at Guy’s Hospital Medical School in London (UK), but had to abort my studies and find paid work. I was offered work in the research department of Boots Pure Drug Company, where a large variety of laboratory animals were used. My appointment was that of an assistant in tropical medicine. At an early stage, disease broke out in a large mouse unit which supplied the various laboratories, and all of the mice had to be destroyed. I suggested that there should be a diagnostic laboratory for all of the laboratory animals, in order to provide early warning of disease. Within a matter of days, the Head of Research instructed me to set up such a unit. This work gave me wide experience in animal husbandry and experimental procedures, because I became deeply involved with work in the breeding units and with all those working experimentally in different disciplines. After a few years, I resigned from my appointment to set up my own research unit and breeding unit, in Huntingdonshire. My bank manager soon made me aware that there was a Professor Alastair Worden, only a few miles away, carrying out what he thought was similar work to my own. I soon made my acquaintance with Alastair Worden and, at our first meeting, he invited me to carry out histological and microbiological work for him on a casual basis. In the course of what seemed a comparatively short time, he told me that UFAW was appointing a very talented zoologist from Oxford University, Dr William Russell, to carry out a laboratory animal survey.” Worden knew that Russell needed an assistant, and suggested that Burch should contact Hume about the possibility of an appointment.

It is clear that, in 1954, Burch had greater, and wider, experience in practical laboratory work than his senior partner. Nevertheless, Burch’s crucial role in the project was not recognised at first, even by UFAW’s President, Edward Hindle FRS, who refused to support his application for membership of the Institute of Biology. Happily, largely as a result of Russell’s vigorous support, Burch became an MIBiol in mid-1959, at the time of the publication of The Principles. He was elected a Fellow of the Institute in 1987.2

For many years, there was confusion about when the term ‘alternatives’ was first used in relation to experiments on living animals. For a long while, the credit was given to Terry Hegarty, a FRAME Trustee and the son of FRAME’s Founder Chairman, Dorothy Hegarty. However, on a visit to the Russell Archive at the University of Nottingham, I discovered that the fact is that it was Burch himself who first used the term ‘alternatives’ in the context of the Three Rs — in October 1954, even before he had joined William Russell to work on the UFAW project! The story is as follows.2 Russell produced a draft of the letter of introduction to be sent to heads of university departments and research institutions, which was amended by Burch. In a sentence in which Russell wrote, “Mr. Burch is on a fact-finding mission, and with the information we hope to be able to suggest improvements in routine methods of research…”, Burch crossed out “improvements”, and suggested, as indicated in a footnote, that “some possible alternatives” should be used instead. Russell rejected that suggestion, crossed out “to suggest possible alternatives to techniques used at present” and suggested that “to produce a review of progress in the development of humane techniques” should be used. His position was supported by Charles Hume, Head of UFAW, who said, “The only thing that worries me a little is the reference to suggesting possible alternatives. Of course we do hope to do this, but if we say so bluntly I fear there may be a counter action — ‘Who are you to tell me how to do my job?’, I would suggest deleting the line ‘to suggest …at present’ and substituting something of this sort: ‘to present a review of progress in the development of humane techniques’.”

Happily, this temporary difficulty did not have a lasting effect on the excellent relationship between Russell and Burch, which was crucial to the development of the Three Rs concept. However, the publication of The Principles was not without controversy, largely because Russell rejected any external attempts to edit his text, but correspondence with Hume again bears witness to his respect for Burch. The original agreement with Methuen, publishers of The Principles, was that 80% of any royalties would go to UFAW and 20% would go to Russell, as its author, who would also own the copyright. Russell asked that his 20% should be shared equally with Burch, whereupon Hume impatiently commented that 10% of not very much would not be very much.2

Friday 5 August 1994, was a very special day for me, as I went to Sheringham, Norfolk, UK, to meet Rex Burch for the first time. As I said later,4 “I was totally captivated by his enthusiasm, his genuine excitement about the activities of FRAME and ECVAM, and his kindness. Within a few minutes, I felt as if I had known him for many years, and I knew that I would never forget him for the rest of my life”. That meeting had two important practical consequences. Firstly, the ECVAM contract, which led to a fascinating article in ATLA, The Progress of Humane Experimental Technique since 1959: A Personal View.6 That is the closest we will ever get to the autobiography he had hoped to write. It tells of his life before the UFAW project, gives his perspective on what went on between 1954 and 1959, and comments briefly on what had happened since the publication of The Principles.

Secondly, since Rex was too ill to travel far from home, I went back to Ispra, and arranged with Alan Goldberg that we should organise a workshop on the Three Rs, to be held in Sheringham, and with Russell and Burch as special participants. This was the first and, sadly, the last scientific meeting which the two authors of The Principles had attended since 1959. It resulted in a report with 58 far-reaching recommendations,7and it was a memorable event of very special significance to Rex Burch, humane scientist and gentle man.
Professor Michael Balls
c/o FRAME
Russell & Burch House
96–98 North Sherwood Street
Nottingham NG1 4EE
UK
E-mail: michael.balls@btopenworld.com

References
1 Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, xiv + 238pp. London,UK: Methuen.
2 Balls, M. (2009). The origins and early days of the Three Rs concept. ATLA 37, 255–265.
3 Balls, M. (1994). A day with Rex Burch. FRAME News 36, 1.
4 Russell, W.M.S., Sainsbury, D., Self, K. & Balls, M. (1996). Editorial. Rex Leonard Burch (1926–1996). ATLA 24, 313–316.
5 Goldberg, A. (2010). The Principles of Humane Experimental Technique: Is it relevant today? ALTEX
27, Special Issue, 25–27.
6 Burch, R.L. (1995). The progress of humane experimental technique since 1959: A personal view. ATLA
23, 776–783. Reprinted in ATLA 37, 269–275.
7 Balls, M., Goldberg, A.M., Fentem, J.H., Broadhead, C.L., Burch, R.L., Festing, M.F.W., Frazier, J.M., Hendriksen, C.F.M., Jennings, M., van der Kamp, M.D.O., Morton, D.B., Rowan, A.N., Russell, C., Russell, W.M.S., Spielmann, H., Stephens, M.L., Stokes, W.S., Straughan, .W., Yager, J.D., Zurlo, J. & van Zutphen, B.F.M. (995). The Three Rs: The way forward. The report and recommendations of ECVAM workshop 11. ATLA 23, 838–866.
The Principles of Humane Experimental Technique is now out of print, but the full text can be found at
http://altweb.jhsph.edu/pubs/books/humane_exp/het-toc. An abridged version, The Three Rs and the
Humanity Criterion, by Michael Balls (2009), can be obtained from FRAME.

William Russell: Polymath, Wordsmith, Classicist and Humourist

Michael Balls

Reading the The Principles of Humane Experimental Technique is a very special
privilege, not only because of the importance of the messages it conveys,
but because of the unique character and qualities of its principal author

The Principles of Humane Experimental Technique1 was based on a report submitted to the Universities Federation for Animal Welfare (UFAW) in 1956, and was completed in 1958. Rex Burch had left UFAW’s employment in 1956, but it is likely that it was always the intention that William Russell would write the text of the book. He owned the copyright, but always insisted that Burch be regarded as a full co-author and should share the meagre royalties that were received.2

Methuen & Co. were reluctant to publish it at all, possibly because of the resistance of its author to  suggestions for modifying its length or content.2 At one point, in 1957, Charles Hume, the founder of UFAW and the originator of the project, intervened, telling Russell that, while the book “contains factual matter of great importance and also original thinking which is quite fundamental” … “the style is high-falutin’, complicated and obscure, and too long-winded. The references to psychoanalysis are of great interest to psychoanalysts, but hardly interesting to readers who have no knowledge of psychoanalysis, who will be in the majority. Many of the sentences have to be read more than once before the readers can construe them and see the point.” He suggested that the book should “be revised, little by little over the next year or two … one thinks of improvements in one’s bath, and then again the whole thing matures — and maturation means simplification and abridgement, rather than proliferation”.

I have read the complete Principles at least 30 times, and I have some sympathy with what Hume was trying to say, not least because I edited a number of Russell’s later manuscripts. This included the first joint Russell & Burch publication since 1959,3  which was submitted to ATLA along with a letter, which said, “We don’t want the wording fiddled with and split infinitives introduced”. It was because The Principles is not an easy read that, to mark its 50th anniversary, I produced the abridged version, with explanations of some of the most difficult passages and concepts.4

Nevertheless, that having been said, in addition to the importance of The Principles in terms of the Three Rs, it also represents a remarkable legacy, left to us by a unique scientist, who was also a polymath, wordsmith, classicist and humourist. In this brief comment, I would like to give some illustrations of what made William Russell so very special.

A polymath is somebody who excels in a wide variety of subjects or fields. Russell was an author, classicist, composer, entertainer, linguist, philosopher, pianist, psychologist, psychotherapist, raconteur, singer, sociologist and soldier.5 His publications covered animal behaviour, comparative sociology, demography, ecology, ethology, evolution, folklore, genetics, geography, history, human behaviour, mythology, primate sociology, science fiction, statistics, population control, and zoology.

A wordsmith is a skilled user of words. I have been an author and editor for more than 50 years, but I could not claim to approach his skill in using the English language. For example, two words, in particular, made me immediately reach for my dictionary — adumbrate and limn. Adumbrate can be used to mean “represent in outline”, “foreshadow” and “overshadow”. Russell clearly meant the first of these, when he wrote, “An attempt has been made to adumbrate the outlines of such a theory [of replacement]”. Limn means to depict in painting or in words, and Russell wrote, “We have sought only to limn the barest of outlines [on humane experimental technique]”. I also appreciate his use of the “bludgeon of stress” to describe the unnecessarily severe procedures used in some studies on animal behaviour.

After he returned from the Second World War, Russell had been expected to go to Oxford University to read Classics, but he changed his mind and studied Zoology instead. Nevertheless, his classicist leanings come to the surface at various points in The Principles. In a section on Choice of Species, he makes the following comment: “This subtle matching of procedure to species, and species in turn to objectives, is more significant than appears at first sight for the humanity of technique. For the only alternative is to try to correct the mistaken choice of a wrong species by forcing it to conform to the requirements of the investigation. This results in just those roundabout methods we should guard against, and is
all too liable to end in gross inhumanity. It is the method of Procrustes, and Procrustes would have been less deservedly unpopular if he had selected his guests instead of dissecting them.”

Procrustes was a cruel figure in Greek mythology. He invited guests into his stronghold, where he had an adjustable bed, so he could make sure that his guests were either too long or too short for it. He amputated the excess length of the former, and stretched the latter on a rack!

Russell referred to refinement as “protean in its aspects”, which means displaying great diversity. Proteus was a Greek god of rivers and oceans, who knew all things — past, present, and future — but was reluctant to divulge what he knew. He would try to escape enquirers by assuming all sorts of shapes, but, if caught while asleep and bound, he would return to his proper shape, give the desired answer, and, on being released, plunge into the sea.

Another historical, although not strictly classical, reference is used to illustrate the point that we cannot extend the concept of inhumanity to non-sentient material, in which “we include higher plants, microorganisms, and the more degenerate metazoan endoparasites, in which nervous and sensory systems are almost atrophied. To shed obsessional tears over the fate of these organisms would bring the whole concept of humanity into contempt by Samuel Butler’s famous reductio ad absurdum — the Erewhonian philosopher who inquired whether salt can feel”.

Erewhon is the title of a book by Butler, published in 1872, which is a satire of Victorian society. Erewhon is a fictional country and its name is based on Nowhere backwards, albeit with the letters “h” and “w” transposed. In the book, among many other adventures, the narrator visits the Colleges of Unreason and meets, among others, the Professor of Worldly Wisdom, who was also the President of the Society for the Suppression of Useless Knowledge. The Professor of Botany there contended that “vegetables are only animals under another name”, so, “if it was sinful to kill and eat animals, it was not less sinful to do the like by vegetables or their seeds”.

Russell was well known as a humourist to all those who met him or witnessed his performances at, for example, the world congresses on the Three Rs, held in Utrecht in 1996 and in Bologna in 1999. The Principles is essentially a serious a book, but Russell’s sense of humour comes through at various points. For example, in referring to discrepancies between his analysis of data from the 1952 Laboratory Animals Bureau Survey and the published figures, he says, “I seem to have produced rather more rabbits from the common hat, and my conjuring skill is further attested by the transformation of 108 canaries into 78 ducks”. Later on, in a discussion on the use of lower vertebrates, including birds, instead of  mammals, he says that, “In its recruiting campaign, experimental psychiatry would be ill-advised to look the humblest gift-finch in the beak”. This is an analogy with “don’t look a gift-horse in the mouth”, where it is considered ungrateful to look inside the mouth of a horse given as a gift, although this is a common practice in judging the age and state of health of horses.

The Principles conveys very useful messages. Perhaps we should be more concerned about worldly wisdom and useless knowledge, especially when animals are used as models of humans. The problem is that we rarely know whether or not the models are relevant and reliable. Russell referred to an oft quoted remark attributed to Lord Kelvin, who so said, “If ye canna mak’ a model, ye dinna understan’ it” [if you can’t make a model, you don’t understand it], which could also be paraphrased as, “If ye dinna understan’ it, ye canna mak’ a model” [if you don’t understand it, you can’t make a model]. Lord Kelvin (1824–1907)6 was a physicist and mathematician, but the problem is much worse in our world of biomedical
research and testing. Why is that? Because we rarely have sufficient understanding of what we are trying to model (e.g. carcinogenesis, embryotoxicity, Alzheimer’s disease, Parkinson’s disease) or of the model we are trying to use (e.g. the rat, mouse, rabbit, dog, macaque). That is the point that Russell made, very forcefully, in his excellent and vitally important discussion of fidelity and discrimination, and the danger of the high-fidelity fallacy.6

References and Notes
1 Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, xiv + 238pp. London, UK: Methuen.
2 Balls, M. (2009). The origins and early days of the Three Rs concept. ATLA 37, 255–265.
3 Russell, W.M.S. & Burch, R.L. (1995). Prefatory note. ATLA 23, 11–13.
4 Balls, M. (2009). The Three Rs and the Humanity Criterion, 19 + 131pp. Nottingham, UK: FRAME.
5 Paskal, C. (2006). Bill Russell: The singing scientific detective. ATLA 34, 470–472.
6 It is not surprising that Russell quoted Lord Kelvin, who, like Russell himself, was a polymath. William Thomson, first Baron Kelvin of Largs, was one of the most famous scientists of his time. He was Professor of Natural Philosophy at the University of Glasgow for 53 years, having been appointed in 1846, at the age of 22. He was as famous for his inventions as for his academic work on mathematical physics and electrical engineering. His research on the nature of heat led him to formulate the second law of thermodynamics. He proposed an absolute scale of temperature, now known as the Kelvin Scale, worked on planning a Trans-Atlantic Telegraph cable, and invented the Kelvin Compass. He was the first scientist to be elevated to the peerage, and is buried in Westminster Abbey, next to Isaac Newton. Further information can be found at: http://special.lib.gla.ac.uk/exhibns/Kelvin/kelvinindex.html
7 Balls, M. (2013). The Wisdom of Russell and Burch. 3. Fidelity and discrimination. ATLA 41, P42–P43.
The Principles of Humane Experimental Technique is now out of print, but the full text can be found at http://altweb.jhsph.edu/pubs/books/humane_exp/het-toc. The abridged version, The Three Rs and the Humanity Criterion, can be obtained from FRAME.

The Analysis of Direct Inhumanity

The incidence, character and severity of direct inhumanity
should be seen as separate, but indivisible,
parts of the same whole concept.

 

In the first Wisdom of Russell and Burch comment in PiLAS,1 their concept of inhumanity, its sources, diminution or removal were discussed. In the outstanding Chapter 4 of The Principles of Humane Experimental Technique,2 they distinguished between direct inhumanity, “the infliction of distress as an unavoidable consequence of the procedure employed”, and contingent inhumanity, “the infliction of distress as an incidental and inadvertent by-product of the use of the procedure, which is not necessary for its success”.

They saw the avoidance of contingent inhumanity as mainly a matter of good husbandry, diligent care and common sense, but correctly saw the diminishing or removal of direct inhumanity, defined as unavoidable, as a completely different matter.

They outlined “three obvious ways of classifying procedures in terms of their direct inhumanity”,
namely, “incidence (e.g. in control and experimental groups), severity (e.g. the severity of a procedure in those animals that are affected), and special character (e.g. post-operative pain and distress, effects of particular pathogens, or death due to various types of toxic chemical)”, as follows:

“The incidence of direct inhumanity is a convenient concept in connection with assay, toxicity testing, or diagnosis. A procedure may be such that it causes no (or negligible) distress to some or most of the animals used, while likely or even certain to cause distress in a certain (often unpredictable) proportion, as a necessary consequence of the nature and object of the procedure. Incidence is an important factor to be considered in weighing the inhumanity of a procedure as a whole. Often, incidence is total — that is, all animals treated are likely and expected to react similarly and specifically to the treatment. A special case of incidence is the distinction between experimental and control groups in many types of experiments. Sometimes the experimental group is more likely to suffer (as in the study of the effects of particular operations), sometimes the controls (as in chemotherapy or immunisation experiments, where the unassisted group is expected to succumb).”

“The special character of procedures is often a unifying factor among experiments of extremely diverse objects. We might distinguish here such effects as general postoperative pain and stress, specific effects of widespread operations (such as adrenalectomy), modes of death due to various groups of poisons, general and specific effects of groups of pathogens, etc. We might note a special sort of semicontingent inhumanity — a component of a procedure which is irrelevant or harmful to its success, but more or less indispensable to its performance. For instance, pyrogen tests often involve nothing more serious than a rise in temperature which would not even send most humans to bed. But, for their performance, animals are often restrained for periods of over an hour, and this may impose some distress.”

“This analysis might form a starting point for the third dimension of classification — the severity of a procedure in those animals which are affected.”

The problem of severity was addressed in detail in Chapter 2 of The Principles, and is such a huge issue that it deserves to be considered separately in a future issue of PiLAS.
Russell and Burch went on to say that incidence, character, and severity are at least partly independent
variables, and that “a cross-classification will ultimately be required along all three dimensions”. I think that what they mean by this, is that we should see them as separate, but indivisible, parts of the same whole concept.

Significantly, they then turned to a “consideration of the ways in which [direct] inhumanity can be and
is being diminished or removed”. These ways, they said, “can be discussed under the three broad headings
of Replacement, Reduction, and Refinement, [which] have conveniently been referred to as the Three Rs of humane technique”. Convenient in 1959, maybe, but now essential — for ethical, scientific and legal reasons — that the individual Rs are also seen as separate, but indivisible, parts of the same whole. For example:
— Replacement can be partial, rather than total, contributing to a Reduction in the number of animals
needed for a particular purpose, and/or to Refinement (by, for example, screening out the most toxic chemicals, so that extreme severity is unlikely in animals used to test those chemicals at lower doses);
— a step-wise procedure can be used as a Refinement, obviating the need to test at certain doses, thus leading to a Reduction in the overall number of animals required;
— Refinement can also be used to make it clear where Replacement is needed and/or is possible;
and finally
— recognising the limitations in the use of animal models for certain purposes, can result in
Reduction, leading to Replacement. Replacement will occur when the need for more directly-relevant human alternatives is necessary, and intellectual energy and other resources are released to encourage them to be made available and implemented.

 

References
1 Anon. (2012). The Wisdom of Russell and Burch. 1. The concept, sources and incidence of inhumanity and its diminution or removal through implementation of the Three Rs. ATLA 40, P15–P16.
2Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, xiv + 238pp. London, UK: Methuen.

The Principles of Humane Experimental Technique is now out of print, but the full text can be found at http://altweb.jhsph.edu/pubs/books/humane_exp/het-toc. An abridged version, The Three Rs and the Humanity Criterion, by Michael Balls (2009), can be obtained from FRAME.

The Use of Lower Organisms

Lower organisms can be particularly useful as high discrimination models in fundamental research, but cannot offer the high fidelity required when specific questions are asked about humans in health and disease, and about their responses to drugs and other chemicals.

In The Principles of Humane Experimental Technique,1 Russell and Burch discussed comparative substitution as a form of replacement by organisms which were not of humanitarian concern. This included non-sentient material, such as higher plants, micro-organisms, and the more degenerate metazoan endoparasites, “in which nervous and sensory systems are almost atrophied”.

They accepted that “a more difficult question arises when we consider the free-living metazoan invertebrates”, but they “arbitrarily excluded them from consideration as objects of humanitarian concern”. They commented that “to shed obsessional tears over the fate of these organisms would bring the whole concept of humanity into contempt by Samuel Butler’s famous reductio ad absurdum” (disproof of a proposition by showing that it leads to absurd or untenable conclusions), and his satirical piece about the fictional country where a professor of botany contended that “vegetables are only animals under another name”, and that, if it is “sinful to kill and eat animals”, it is no less sinful to eat “vegetables or their seeds”!

Russell and Burch made frequent references to studies with fish, amphibians and birds, particularly those concerned with animal behaviour, including flight and fight responses. However, they also drew particular attention to “the trivial use of lower vertebrates, which make up less than 5% of the total” number of animals used. They saw this as “yet another expression of the high-fidelity fallacy”, and argued that “all the arguments we adduced for the use of discriminative models apply with no less force to the choice of [lower] vertebrate species than to that of absolute replacement” (i.e. the use of nonsentient organisms, tissue culture and non-living physical and chemical systems). An understanding of the application of the Three Rs principles to higher organisms (i.e. mammals) and lower organisms (i.e. non-mammals) is heavily dependent on an appreciation of Russell and Burch’s distinction between fidelity and discrimination.2

Fidelity models have a high general similarity to what is being modelled (e.g. old world monkeys and humans), whereas discrimination models involve a high specific similarity to what is being modelled, while lacking many other similarities. The problem, which they call the high-fidelity fallacy, arises when a fidelity model is used in attempts to predict precisely what will happen in what is being modelled, such as when rats, mice, dogs or macaques are used to predict whether candidate drugs will work in humans, without unacceptable side-effects. The use of discrimination models is less demanding and less likely to be fallacious, since the questions asked are better targeted (e.g. will this treatment damage cell membranes or DNA, or inhibit DNA, RNA or protein synthesis, or mitochondrial functions). Another way of expressing the distinction is to draw the contrast between fundamental and applied research.

It cannot be denied that many types of organism undoubtedly have value as discrimination models at the fundamental research level, including plants such as onion (Allium cepa) and garlic (Allium sativum), bacteria such as Escherichia coli, fungi such as yeasts (Saccharomyces cerevisiae), slime moulds such as Dictyostelium discoideum, coelenterates such as hydra (Hydra magnipapillata), nematode roundworms such as Caenorhabditis elegans, insects such as Drosophila melanogaster, and lower vertebrates, including fish such as the zebrafish (Danio rerio) and amphibians such as the South African clawed toad (Xenopus laevis). These organisms are being extensively used in fundamental research on cell and molecular biology, cell death, ageing, developmental biology, immunobiology and neurobiology. However, they cannot tell us precisely what happens in humans, in health or disease, or after exposure to drugs and other chemicals. Hence, although some pharmacotoxicological test systems involving lower organisms and aimed at predicting effects in humans have been proposed, they are unlikely to provide solutions to the problems currently facing the pharmaceutical industry (lack of efficacy or unacceptable side-effects, discovered late in drug development), because the differences between these organisms and humans are too great for tackling other than certain highly specific questions which may apply to many different kinds of organisms. That is why so much effort is currently being invested in the search for relevant and reliable, more-directly human-oriented systems, which will combine high fidelity and high discrimination.

Russell and Burch’s Principles was, of course, primarily focused on “the intimate relationship between humanity and efficiency in [animal] experimentation”, and they were rightly concerned about how their concept of inhumanity and its diminution or removal applied to lower animals, as well as to mammals. By chance, as I was thinking about this, I received a copy of a new book by Robert Hubrecht, a zoologist who is CEO and Scientific Director of the Universities Federation for Animal Welfare, the organisation which employed Russell and Burch to do the research which led to The Principles. Entitled The Welfare of Animals Used in Research,3 the book provides a highly-detailed, wide-ranging, thoughtful, thought-provoking and up-to-date analysis of the kinds of issues raised by the principles and application of the Three Rs, based on his own long experience.

Hubrecht discusses the reasons for using animals in research, legislative and other controls, and the moral imperative — the need to reduce any animal harm to a minimum. In a chapter on species choice and animal welfare, he discusses consciousness/sentience, and the relationship between neurological complexity and the capacity to suffer, with reference to invertebrates and lower vertebrates, as well as mammals. Later on, he argues that, “rather than attempting to develop some scale of suffering so that an animal lower on the scale is always used in preference to one higher up, a much more rigorous approach is to evaluate the impact of the proposed study on the candidate species”. He describes this as an “evolutionary approach, which requires a deep understanding of the needs and adaptations of each species. Here, as in many other parts of the book, Hubrecht’s training as a zoologist shines through, and I am convinced that another zoologist, Bill Russell, would have been very supportive of what he has to say.

As for me, while I haven’t yet had time to read the book in detail, and I doubt whether I will agree with absolutely everything it says, I am content to endorse the remark of Paul Flecknell on the back cover, that: “This book should be read by all those involved in the use of animals in research and by anyone who has interests or concerns as to how this type of research is conducted”.

References
1 Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, xiv + 238pp. London, UK: Methuen.
2 Balls, M. (2013). The wisdom of Russell and Burch. 3. Fidelity and discrimination. ATLA 41, P12–P13.
3 Hubrecht, R.C. (2014). The Welfare of Animals Used in Research, vii + 271pp. Chichester, West Sussex, UK: Wiley Blackwell.

The Toxicity Testing Problem

The field of toxicity testing is an urgent humanitarian problem,
for it regularly involves a finite and large incidence of distress
which is often considerable and sometimes acute.

Michael Balls

In the latter part of Chapter 5 of The Principles of Humane Experimental Technique,1 on Replacement, Russell and Burch described the question of progress in the field of toxicity testing as a particularly serious problem, since “this is one use [of animals] which is an urgent humanitarian problem, both numerically and in terms of severity, for it regularly involves a finite and large incidence of distress which is often considerable and sometimes acute.”

They recognised the widely-held view that toxicity testing must be conducted with mammals, on the basis of agreement with the high-fidelity argument, because of “the importance rightly attached to the need for safeguarding human patients against the toxic side-effects of drugs”. However, they were also careful to point out that high-fidelity arguments cut both ways. Other mammals may be superficially similar to humans, but “the mechanisms of excretion and detoxification in non-human mammalian species frequently differ from our own”. This objection, they said, “is met in practice by erring on the side of caution, and by using more than one mammalian species; it cannot be fully met, for there may always be metabolic peculiarities specific to man”. Put more forcefully, it can be argued that toxicity testing in laboratory animals is an obvious example of the risks inherent in the high-fidelity fallacy, especially when the insistence on the use of a rodent species and a non-rodent species is based on the misperception that using two inadequate models is better than using only one.

In a particularly important paragraph, they refer to dosage: A very large number of substances are toxic at a high enough dosage, so “the important concept is the therapeutic index of a drug — that is, the ratio between its toxic dose and its therapeutically effective dosage. If this ratio is great, the [use of the] drug or preparation is prudent, since it allows for the wide variations between human individual patients in sensitivity to the toxic effects”. Toxicity testing would be a less serious humanitarian problem, if more care were to be taken to administer only rational doses of chemical and products in general, based on reasonable estimations of likely exposure.

Russell and Burch made a distinction between bioassay and toxicity testing: bioassay being “the detection and quantitative estimation of a known activity or principle in a relatively impure preparation, usually, though not invariably, assessed by comparison with a preparation of standard purity and potency”; while toxicity testing “may mean the assessment of various unknown or unpredictable special activities with the general property in common of toxicity in higher animals”.

They made a further useful distinction between two types of toxicity testing. The first of these, somewhat akin to bioassay, is routine testing for specific toxic effects which are well-known. They saw this as an activity where in vitro methods could be particularly useful.

The second type of testing particularly applies to new chemicals or drugs, where “the kind of toxic effect which may arise is virtually unknown”. This is the focus of insistence that high-fidelity mammalian models must be used, to reveal the unexpected, whereas non-animal in silico and in vitro, i.e. alternative, methods are designed to answer specific questions.

Their comment, that “in theory, we should be able to classify all the ways in which toxic and lethal symptoms are produced”, must be considered embarrassing in 2014 — 55 years after The Principles was published — since, despite all the efforts of toxicologists and other scientists, the suffering of huge numbers of laboratory animals, considerable damage to many patients and to the environment, and all the associated costs, we are very far from achieving that goal. We lack sufficient understanding of the main mechanisms involved in inducing toxic effects, and effective ways of predicting the likelihood of their occurrence in particular circumstances. It is true that there are hopeful signs that human-relevant and human-focused, non-animal testing strategies will eventually become available for the efficacy and toxicity testing of new medicines, but the continuation of stubborn and powerful defence of the need to rely on rodents, dogs and non-human primates represents a ball and chain around the ankle of progress. Chapter 5 of The Principles should be required reading for all concerned.

Reference

1 Russell, W.M.S. & Burch, R.L. (1959). The Principles of Humane Experimental Technique, xiv + 238pp. London, UK: Methuen.