It is frequently pointed out that regulatory guidelines are not rigid requirements to be universally applied. But whatever the intention, they do tend to be treated as minimum requirements if only because research directors fear to risk holding up their expensive coordinated programmes with disagreements that result in their having to go back to the laboratory, with consequent delay and financial loss.
Knowledge of the mode of action of a potential new drug obviously greatly enhances prediction from animal studies of what will happen in man. Whenever practicable such knowledge should be obtained; sometimes this is quite easy, but sometimes it is impossible. Many drugs have been introduced safely without such knowledge, the later acquisition of which has not always made an important difference to their use, e.g. antimicrobials. Pharmacological studies are integrated with those of the toxicologist to build up a picture of the undesired as well as the desired drug effects.
In pharmacological testing the investigators know what they are looking for and choose the experiments to gain their objectives.
In toxicological testing the investigators have less clear ideas of what they are looking for; they are screening for risk, unexpected as well as predicted, and certain major routines must be done. Toxicity testing is therefore liable to become mindless routine to meet regulatory requirements to a greater extent than are the pharmacological studies. The predictive value of special toxicology (above) is particularly controversial.
All drugs are poisons if enough is given and the task of the toxicologist is to find out whether, where and how a compound acts as a poison to animals, and to give an opinion on the significance of the data in relation to risks likely to be run by human beings. This will remain a nearly impossible task until molecular explanations of all effects can be provided. Toxicologists are in an unenviable position. When a useful drug is safely introduced they are considered to have done no more than their duty. When an accident occurs they are invited to explain how this failure of prediction came about. When they predict that a chemical is unsafe in a major way for man, this prediction is never tested.
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