Basic toxicological considerations

Toxicology, the science concerning the studies of harmful effects of chemicals of both natural and industrial origin on living organisms, has the prime objective of investigating the possible risk to all forms of life from chemical substances. 

The aim of toxicological investigations is to establish the risk of chemicals to human and animal health, in order to recognize possible hazards in time to take preventive steps. 

In addition to acute and chronic toxic effects (especially carcinogenic, mutagenic, embryo-toxic and teratogenic effects), examination of the degradability or persistence of a chemical compound, together with the possibility of its bioaccumulation in the food chain are very much in the foreground of product environmental protection. 

The acute toxic effect of a substance is generally determined by animal experiments, usually on the rat. Substances which cause death when administered in a maximum oral dose of 25 mg/kg of body weight (LD) are classed as highly toxic. Toxic substances are those which have a lethal effect in applications between 25 to 200 mg/kg. Less toxic, harmful substances cause death by doses between 200 and 2,000 mg/kg body weight. Substances with acute toxicity ratings above 2,000 mg/kg are classed as non-toxic. 

Parallel to the examination of acute toxicity, the determination of chronic and sub-chronic toxicity (long-term effect) is playing an increasingly important role in the study of environmental effects. 

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Residue Reviews (vol. 1 in 1962) for basically detailed review articles concerned with any aspects of residues of pesticides and other chemical contaminants in the total environment, including toxicological considerations and consequences. 

The expectation of combined effects from mixture exposure is most often founded in the basic principles of toxicology and pharmacology (Loewe and Muischnek 1926a Bliss 1939 Plackett and Hewlett 1952). The first strictly pharmacological ideas formulated (Loewe and Muischnek 1926a) were supplemented by biometrical considerations. Later, Bliss (1939), a biologist and a biometrician, provided the first consistent framework, as depicted in Table 5.2 (Plackett and Hewlett 1952). In this framework, the main ideas focused on the presence or absence of interactions (commonly referred to as interactive and noninteractive joint action) with respect to responses observed in test organisms, and the presence of the same or a different mode of action. 

There must be considerable overlap here between the basic pharmacodynamic and pharmacological experimentation, which has shown why the intended product may be of therapeutic value and the mechanisms of that desired activity, and the range of investigations that it is necessary and worthwhile to apply in the types of preclinical studies usually labeled as toxicology, here including pharmacokinetics. 

Most toxicological test procedures were never intended for vaccines. However, the requirement to test the pharmacokinetics, pharmacodynamics and reproductive toxicity for human vaccines means, that at least the basic rationale of these studies also applies to vaccines. The test methods may vary considerably. 

The major concern is that of skin sensitisation. When a material comes in contact with the skin, it may react with a protein present in the skin to form a modified protein and this could become an antigen as far as the immune system is concerned. If this happens, the immune system will produce antibodies to combat the antigen. If the immune system over-reacts, an allergic reaction will result and a rash will break out on the skin. Thus, skin sensitisers do not produce a reaction on the first contact with the skin, but only after repeated exposure. Fortunately, we now know the basic features of molecular structure which are associated with skin sensitisation and can design molecules which will not behave in this way. This is a good example of the importance of safety SARs to the discovery chemist. Of course, predictions are not the ultimate test and therefore many companies, especially in the pharmaceutical industry, invest considerable amount in the development of rapid in vitro screens to detect any adverse toxicological effects. 

The following information presents the very basics of toxicology necessary to support health and safety considerations for plasma processing. This discussion is necessarily brief and the reader is referred to the references for additional information. In the workplace, and for applications that are natural extensions of the workplace, the reader is urged to seek out a toxicologist many occupational toxicology j udgments must be made on a case-specific basis. 

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