Hall (1790–1857)

Marshall Hall, an English neurophysiologist and contemporary of Magendie, pioneered animal welfare from within science. In 1831, he proposed that physiologic procedures be regulated in a way that took into consideration the su ffering of animals [19]. He called for the formation of a society for physiological research, which would regulate animal experimentation, for he said, "every experiment ... is necessarily attended by pain or su ffering of a bodily or mental kind". In 1835, in his "Principles of Investigation in Physiology," he outlined five principles to govern animal experimentation, the fourth of which stated (in the days before anaesthesia) that "justifiable experiments should be carried out with the least possible infliction of su ffering, often through the use of lower, less sentient animals, such as frogs and fish or even newly dead animals". (The other points were that: (1) an experiment should never be performed if the necessary information could be obtained by observation; (2) no experiment should be performed without a clearly defined and obtainable objective; (3) scientists should be well-informed about the work of their predecessors and peers to avoid unnecessary experimental repetition; (4) *vide supra*; and (5) every experiment should be performed under circumstances that would provide the clearest possible results, thereby diminishing the need for repetition of experiments.)

### Morton (1819–1868), Glover (1815–1859), Simpson (1811–1870) and Snow (1813–1858)

The birth of medical anaesthesia based upon N2O and ether in the United States did not depend on animal experimentation, although Morton tested ether on animals [23] and then patients, before administering a convincing anaesthetic at the Massachusetts General Hospital on 16 October 1846.

In the UK, Simpson's eventual "discovery" and promotion of chloroform in 1847 [24] relied as much on what could be remembered after self-administration as it did upon his own animal studies. That said, Simpson's pioneering had been eased by others establishing the compound's pharmacological properties through animal testing—namely Robert Glover, whose studies of bromine, iodine and chlorine compounds, including chloroform and dichlorethane culminated in a thesis entitled 'On the Physiological and Medicinal Properties of Bromine and its Compounds'. Published in 1842, this was the first to describe chloroform's anaesthetic e ffects. Among various experiments, Glover injected 30 and 60 minims (1.6 and 3.6 mL) of chloroform into the jugular vein of two dogs, causing immediate unconsciousness, loss of the eyelid reflex, insensitivity of the paws to painful stimuli and marked motor weakness, a state from which the dogs quickly recovered. Glover did not test chloroform by inhalation, although he described its smell on his animals' breath [25].

Despite Simpson's inclination to test newly discovered halogenated organic molecules on himself, it is probable that animal testing saved his life. Having recently synthesized ethylene dibromide, Wemyss Reid (the Professor of Chemistry at the University of Edinburgh) suggested to Simpson that it should be tested on rabbits first. Simpson had intended to inhale ethylene dibromide himself but surrendered the opportunity on discovering the two rabbits so treated had died overnight. It was subsequently discovered that the inhalation of ethylene dibromide causes pulmonary congestion; it is currently used as a soil fumigant to kill nematode worms [26].

John Snow—Simpson's Yorkshire-born contemporary—was described by Waters (1936) as "the first anaesthetist" because his research spanned basic science and clinical medicine and he answered fundamental questions with respect to anaesthetic safety [27]. Snow also recognised the importance of accuracy in anaesthetic delivery and patient monitoring. Investigating ether (and later chloroform), Snow performed numerous studies on animals, including birds and fish, in which his renowned attention to detail—at least on one occasion—lapsed. Whilst demonstrating ether anaesthesia on a thrush to an audience of Military Surgeons, he became distracted and killed the bird [28]. Snow's published description of the event reveals the legitimacy of Waters' accolade.

*"This thrush was only in the vapour for about a minute, and it is dead. It had ceased to breathe before I took it out of the jar. It is a result I did not intend, and it has arisen from my going on with the lecture, and looking at my notes, instead of directing my whole attention to the animal".*
