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15. 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 Technique
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 ani-
mals raises difficult issues”, but, “where great sever-
ity 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 endopara-
sites 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 human-
ity 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 con-
scious living vertebrates”.
Russell and Burch considered that not enough was
being done with lower vertebrates, and saw the pre-
dominant use of mammals as “yet another expression
of the high-fidelity fallacy”.
Here, Russell’s experi-
ences 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, along-
side 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 endocrino-
logical, 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 disrup-
tors, was taken as a warning of threats to human
masculinity, whereas it is a normal part of the adapt-
ability 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 con-
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
ATLA 43, P11–P12, 2015 P11
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 common-
est 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 hier-
archy 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 hier-
archy. 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,
warned us that
“dropping the dog on the basis of your existing evi-
dence could result in an increase in the use of non-
human primates”. That would present advocates of
the routine use of a second, ‘high-fidelity’, non-
rodent species in toxicity testing with a dilemma and
a challenge. How could they justify replacing point-
less tests in one highly-protected species with point-
less tests in another highly-protected species?
Professor Michael Balls
Russell & Burch House
96–98 North Sherwood Street
Nottingham NG1 4EE
Russell, W.M.S. & Burch, R.L. (1959). The Principles of
Humane Experimental Technique, xiv + 238pp. London,
UK: Methuen.
Balls, M. (2013). The wisdom of Russell and Burch. 3.
Fidelity and discrimination. ATLA 41, P42–P43.
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
het-toc. An abridged version, The Three Rs and the
Humanity Criterion, can be obtained from FRAME.
ISSN 0261 1929 ©2015 FRAME FRAME Charity Registration Number 259464
Submissions for consideration for publication in PiLAS are welcome.
Please send articles to, or by post to Susan Trigwell, FRAME, Russell and Burch
House, 96–98 North Sherwood Street, Nottingham NG1 4EE, UK. Instructions to Authors are available
from the above, or from the PiLAS website, All articles considered for publication
will be peer-reviewed.
ResearchGate has not been able to resolve any citations for this publication.
Full-text available
Dogs remain the main non-rodent species in preclinical drug development. Despite the current dearth of new drug approvals and meagre pipelines, this continues, with little supportive evidence of its value or necessity. To estimate the evidential weight provided by canine data to the probability that a new drug may be toxic to humans, we have calculated Likelihood Ratios (LRs) for an extensive dataset of 2,366 drugs with both animal and human data, including tissue-level effects and Medical Dictionary for Regulatory Activities (MedDRA) Level 1-4 biomedical observations. The resulting LRs show that the absence of toxicity in dogs provides virtually no evidence that adverse drug reactions (ADRs) will also be absent in humans. While the LRs suggest that the presence of toxic effects in dogs can provide considerable evidential weight for a risk of potential ADRs in humans, this is highly inconsistent, varying by over two orders of magnitude for different classes of compounds and their effects. Our results therefore have important implications for the value of the dog in predicting human toxicity, and suggest that alternative methods are urgently required.
The wisdom of Russell and Burch. 3. Fidelity and discrimination
  • M Balls
Balls, M. (2013). The wisdom of Russell and Burch. 3. Fidelity and discrimination. ATLA 41, P42-P43.