04.03 Safety and Toxicity

New drugs undergo extensive safety and toxicity testing in animals. This testing was increased after the thalidomide disaster. Thalidomide was developed as a hypnotic (calming) and anti-emetic drug in the 1950s. It was used as a hypnotic and extensively to prevent morning sickness. For severe morning sickness, it was more beneficial than any other drugs available at the time. Limited toxicity testing in rats had suggested it was safe in pregnancy. To women who took thalidomide during pregnancy, 10,000 children were born with phocomelia, which is the absence of arms or legs with hands or feet attached to body trunk. Obviously, when it was shown that thalidomide was the causative agent, it was withdrawn and litigation followed, costing the pharmaceutical company responsible to pay millions in compensation.

What was learnt from the thalidomide disaster? The animal rights movement claimed that the thalidomide disaster showed that the testing of drugs in animals was not predictive of toxicity in humans, and should be abandoned. Toxicity testing should be in humans.

There is another interpretation. Birth defects are rare in rats. Rats are more likely to reabsorb defective foeti. Closer analysis of toxicity testing of thalidomide showed lower litter numbers, which probably indicated the potential to cause birth defects in humans. More extensive toxicity in animals probably would have prevented the thalidomide tragedy. More extensive toxicity in animals is now undertaken.

This preclinical safety and toxicity testing takes two to five years, and involves the collection and analysis of lots of data. This testing is closely supervised by an independent Animal Ethics Committee that works to minimise the number of animals used, and the harm done to animals. Acute toxicity of single doses and chronic toxicity of repeated doses of drugs is often tested on mice. The effects of drugs on reproductive function and teratogenicity (ability to cause birth defects) are tested in a variety of animal species. For drugs that are going to be used long term in chronic illness, the carcinogenic potential has to be tested in animals longterm. Mutagenic potential is undertaken in bacteria.