toxicology

toxicology is essentially the science of poisons. It was recognized long ago that the toxicity of any substance is related to dose. The sixteenth-century iconoclast Paracelsus is credited with the statement: ‘All substances are poisons, there is none which is not a poison. The right dose differentiates a poison from a remedy.’ Toxicology had its origins in medicine and therapeutics, and to this day one of the key steps in the development of new drugs is the evaluation of the ‘therapeutic window’. This window corresponds to the range of doses where a beneficial effect is obtained but below the dose which causes unacceptable side-effects.

Throughout history the substances that have been used for medicine — as well as the poisons used to eliminate political rivals, as practised from classical times through to the Renaissance — have been almost exclusively derived from natural sources. Despite a recent emphasis on the toxicity of synthetic chemicals, arising in part from the influential writings of Rachel Carson, it is interesting to note that Nature has been endlessly inventive in its production of toxic agents. Such natural toxic substances are sometimes used as part of defence mechanisms as, for example, in the case of snake venoms. However, sometimes the toxic substances are by-products of normal metabolism by many different species. Several varieties of the mould Aspergillus produce a group of carcinogens called aflatoxins, which cause liver injury and cancer. A proper understanding of the occurrence and actions of natural toxins is vital to the maintenance of a healthy lifestyle. In a number of countries cassava is a major source of carbohydrate, but if it is not properly treated ingestion of the naturally occurring cyanogenic (cyanide-forming) glycosides can be fatal.

From the mid nineteenth century onwards the increasing use of pure chemicals as drugs paved the way for the development of toxicology as a more exact science which aimed to unravel the mechanisms of action of toxic substances. Very few drugs or toxic agents are active without some sort of metabolic activation; a chemical or physical change brought about in the body. Usually the effect of these changes is to render the substance more water soluble so that it may be excreted as rapidly as possible. In some instances metabolism results in the formation of a reactive chemical species, which binds to cellular macromolecules such as DNA or proteins. Such modifications can then lead to biological consequences, which are manifested as a frank toxic effect. However, there are protective mechanisms for dealing with such reactive species within cells; many are converted into substances that are ultimately excreted in urine.

In some cases unfortunate toxicological incidents can have beneficial consequences in the long term. For example, it was noted that soldiers returning from World War I who had been exposed to sulphur mustard had very depressed white blood cell counts. Ultimately, this observation led to the development of nitrogen mustards which, soon after World War II, began to be widely used in the treatment of cancers such as leukaemia. A rather different story relates to the discovery of a class of potent carcinogens, the nitrosamines. Several poisoning incidents in the textile industry, starting in the late 1930s, were associated with the use of dimethylnitrosamine (DMN) as a solvent for rayon. It was shown in animal models that acute administration of DMN produced a characteristic type of liver damage similar to that seen in workers. However, chronic administration of low doses of DMN produced liver tumours. It was subsequently found that many other nitrosocompounds produced tumours in different organs in many species of animals. Paradoxically, some nitrosocompounds were found to have antitumour activity and, like the nitrogen mustards described above, probably act by damaging the DNA in tumours in such a way that the cells cannot repair the damage and die.

There are sometimes great differences between species and between individuals with regard to the toxicity of a particular substance. A famous example is penicillin, which was tested for toxicity in rats before being given to humans. As rats tolerated large doses of penicillin with no ill effect, the drug was considered safe enough to be administered to humans, and the age of antibiotics was born. It was subsequently found that guinea pigs are very susceptible to toxicity from penicillin — history might have been very different if guinea pigs had been the test animal of choice. For many drugs which require metabolism to be active, or, in some cases, for toxicity to be apparent, polymorphism (occurrence in more than one form) of key metabolic enzymes can lead to spectacular differences in individual susceptibility. Debrisoquine, a drug used in the treatment of high blood pressure, was found to be very slowly metabolized by 1 in 10 Caucasian people, due to a genetic polymorphism for a particular enzyme. In affected individuals, administration of the drug caused a dramatic fall in blood pressure due to the persistence of the active drug in the circulation.

Despite much current public concern about health effects from environmental chemicals, there is little or no evidence of large numbers of cases of any disease being due to exposure to such agents. It is not that chemicals are any more or less toxic than those to which earlier generations were exposed — it is rather that contemporary exposure levels have been progressively reduced to such an extent that effects are almost undetectable. As our understanding of the mechanisms of toxicity of chemicals has improved, it is less likely that highly dangerous industrial chemicals will be present in the environment. However, as indicated above, our exposure to natural toxic agents remains a major source of concern.

Over much of its history the study of toxicology has relied upon the manifestation of some adverse health effect, in either humans or experimental animals, as an indication of the toxic effects of any particular substance. As the Human Genome Project attains one of its first goals of obtaining the complete sequence of the human genome (and as the complete sequences of the genomes of many other species have either already been, or will shortly be, completed), it is likely that approaches to toxicological questions will be quite different in the near future. Many pharmaceutical companies have led the way in the exploitation of this technology for rapid and comprehensive screening of adverse side effects of the increasing numbers of novel substances that are being examined for beneficial effects.

David Shuker

Bibliography

Klassen, C. D. (1996). Casarett and Doull's Toxicology: the basic science of poisons. McGraw Hill, New York.
Timbrell, J. A. (1991). Principles of biochemical toxicology, (2nd edn). Taylor and Francis, London.

See also drug; environmental toxicology; poisoning.