The 'scientific basis' for the selection of a rodent and non-rodent species
The choice of rodents for the study of human toxicity can be traced back to the 1940s. The late Professor Dennis Parke, a former chief advisor on food safety to Unilever Corporation and advisor to the FDA (US Food and Drug Administration), reviewed how the humble rat came to be chosen, and whether or not the use of this animal as a 'standard' model was a sound choice:
"The wild rat was readily available and became the experimental animal, and this is how the drug safety industry began. Later on, inbred strains of rats were developed to enhance the uniformity of response, but there was little or no consideration at that time as to whether or not the rat was a scientifically appropriate surrogate species for man" (7).
The rodent model
The following two tables illustrate some of the species differences between rats and humans, rats and mice, and between different types of rats. There does not appear to be any biological trend or logical pattern that scientists can follow.
Tables 2 and 3 illustrate a clear lack of concordance with respect to several animal species, including humans. The similarity between rats and humans in regard to the lethal dose of caffeine proves to be the exception, rather than the rule. More significantly, the animal data can only be correlated with human data in retrospect, i.e. only afterhuman exposure. Human data of lethal overdose are obtained from suicide attempts and accidental poisonings. For rare chemicals, the human values remain unknown.
|Chemical||Humans LDLO* (mg/kg)||Rat LD50 (mg/kg)||Mouse LD50 (mg/kg)||Rabbit LD50 (mg/kg)||Dog LD50 (mg/kg)|
|*(LO = lethal overdose) Source: Adapted from Christenson and Luginbuhl 1975; Sunshine 1979. In: The Cruel Deception, Robert Sharpe 1988, Thorsons.|
|Drug||Lethal dose (LD50)|
|Young rat||Adult rat|
|Digitoxin (cardiac glycoside)||
|Young rat||Adult rat|
|200g rat||600g rat|
|female rat||male rat|
|Hopkin strain||Norway strain|
|Thiourea (industrial chemical)||4mg/kg||1830mg/kg|
|*Note the massive anomalies throughout the above table - and, in particular,the difference in lethal dose simply on the basis of age within the same species. Source: Zbinden G., Flury-Roversi M. (1981) Significance of the LD50-test for the toxicological evaluation of chemical substances, Archives of Toxicology, 47, 77-99.|
Selection of a non-rodent species
The regulatory requirement for testing in two animal species (rodent and non-rodent) would appear to be as arbitrary as it is unscientific. Whereas the selection of a rodent as the first species is considered by both industry and regulatory authorities to be 'standard practice' (based on habit and considerations of convenience), the selection of the second species is much less so.
Although drug manufacturers are required to submit 'good data' to the regulatory authorities, the regulators are quite content to allow the company developing a new chemical product to choose its own testing strategy. Thus, the choice of a second, non-rodent species becomes something of a lottery - a beagle dog or a non-human primate (macaques or marmosets) may be just as acceptable as a minipig, or even a ferret (8). Given the unpredictable results of animal testing, as evidenced in the preceding tables, this laissez faireattitude on the part of the regulatory authorities is clearly not in keeping with their role of protectors of public health.
Dogs remain popular for purposes of regulatory toxicology because they are docile, easy to handle, and have been used so extensively that there is a vast amount of data on them. Ferrets would be more popular if they were not so awkward to inject or to take blood samples from. Minipigs are increasingly popular, but they can grow quite heavy - making them much more expensive than marmoset monkeys to dose with valuable test chemicals.
Indeed, there has been an increasing trend over the last few years to use marmosets. An enlightening paper (9) published by the Association of the British Pharmaceutical Industry (ABPI) makes a valiant attempt to pretend that the choice of marmoset is rooted in science, but it is abundantly clear that the real reasons are considerations of cost and convenience for researchers. Marmosets weigh around 400g and are thus comparatively cheap to dose with valuable test compounds. Their small size also makes them easy to incarcerate in small cages or in inhalation chambers.
There is the added attraction of a relatively long lifespan (though short by human standards). This means that they can be used in chronic (long-term) toxicity studies - lasting up to several years. Marmosets are, furthermore, easy to breed in captivity, allowing drug companies, or their contract testing firms, to keep in-house colonies and avoid the controversy associated with importing macaques or other monkeys from abroad (e.g. China, journeys from which can last up to 58 hours). Their use also seems - so far - to have attracted less controversy than that of companion animals such as dogs.
As more firms opt for marmosets, their use is likely to increase further as there will be more data for comparisons. UK regulators (notably, the Medicines and Healthcare products Regulatory Agency) accept marmoset toxicity data quite readily, without querying their use. This is despite Home Office regulations stating that the use of non human primates is permissible only when there is no alternative animal 'model'. Whatever animal species is chosen, it is impossible to know whether it is a good 'model' for humans until we discover how humans react to the substance in question - by which point the animal data is clearly unnecessary!
It must be concluded that rodents, dogs and, increasingly, marmosets have become the species of choice for medical drug testing, simply because they are readily available and convenient to use.