the required information about the toxic mechanisms and effects of chemicals, while the other three are primarily involved in using and evaluating the information for particular purposes. A toxicologist may work in any of these divisions or, as is often the case, across these divisions. Needless to say a mix of expertise brings advantages to activities in any particular area. It should also be appreciated that others have used different terms, such as testing, research and safety evaluation (Malmfors 1981), but the meaning is essentially the same.
Descriptive toxicology involves the undertaking of experiments or test procedures to provide standard toxicological data for the assessment of the safety of a chemical. This includes various protocols from acute to chronic toxicity testing (which will be detailed later), Thus the outcome is data that describe the toxicity of the chemical under test.
Mechanistic toxicology involves the study of mechanisms by which chemicals exert their toxic effects. While it seems this has been regarded by some in the past as an academic pursuit it is becoming increasingly realised just how important it is to understand the mechanism of action if a meaningful risk assessment for humans is to be undertaken.
Informational toxicology involves the collection, collation and dissemination of toxicological information. It increasingly includes some interpretation and summarising of data as seen, for example, in the provision of material safety data sheets for chemicals, This area of information provision has been overlooked by others, but it is one of
developing importance and visibility particularly in the application of toxicological knowledge. It is crucial that those involved in the area have an adequate background in toxicology so that their efforts are not thwarted by misinterpretation of often complex material. This is becoming more so as the ready availability of databases over the Internet continues to develop.
Risk assessment toxicology involves review of the results of descriptive and mechanistic studies, combined with study of potential exposures to make probabilistic estimations of risk in exposed populations. It provides for a better understanding of the impact of toxic materials on exposed populations.
Regulatory toxicology involves the evaluation of the available data for an agent and decision making about its application. A clear example of this is the setting of workplace exposure standards. As outlined earlier, tasks like this bring another dimension to toxicology in that there is much more scope for subjectivity and opinion to have an influence on outcome (IPCS 1994). The final decision may often be based on factors in addition to the toxicological information. This is not to say that the toxicological information is disregarded, but that recognition of socioeconomic factors as well as differing opinions among experts have been involved in the final decision on how a chemical may or may not be used.
Other terms that are intimately involved in toxicology and the application of data also require attention, as follows:
■ Toxicity is the intrinsic property of an agent to adversely affect an organism
■ Hazard is the potential for the toxicity of an agent to be realised in a particular situation
■ Risk is the probability that a hazard will be realised
■ Safety is the probability that a hazard will not be realised.
Again one may find that others define these terms a little differently, so it is worth explaining them further by way of example. Consider a chemical that has a known acute toxicity in that ymg/kg will result in death. It is to be used in a factory for the production of a certain material in a fully enclosed process. Before it is delivered to the factory it presents no hazard to the workers at that plant. Once it is delivered there is potential for exposure during procedures such as handling, for accident during operation, during maintenance procedures, and so on. Thus there is a certain hazard now present. However, the toxicity of the chemical (its inherent properties) belong to the chemical itself and remain unchanged irrespective of whether it is in the supply house, on the delivery truck, or at the plant. Risk is when one quantifies the likelihood of a hazard being realised—that is, an estimate of the likelihood of an event occurring is given in numerical terms.
Consideration of these terms highlights a very important aspect of toxicology whereby for a toxic response to be manifest exposure must occur. That is, not only is the toxicity of the chemical of importance but so are the conditions under which it is used, which relate to the exposure that occurs. If there is no exposure there can be no toxicological effects.
Empirical truisms in toxicology
Two fundamental aspects of toxicology are critical to its functionality and application.
They are usually described as basic assumptions, or tenets, but empirical truisms may better represent their origins. These are the relationship between dose and response, or effect, and the validity of extrapolating of data from experimental animals to humans.
Dose response and dose effect
As the dose of a chemical is increased, the response or effect also increases. The first formal recognition of this relationship is attributed to Paracelsus (also known as Philippus Theophrastus Aureolus von Hohenheim) from the 16th century. Interestingly, his reason for espousing the relationship was to justify his use of a remedy of recognised toxicity for treatment of the Great Pox. As justification for using this poisonous remedy he informed those concerned about its use that it was the dose that was important in determining whether or not a toxic reaction occurred. Thus he was indicating that if the appropriate dose was given the therapeutic benefit could be obtained, without the toxicity being expressed. The obvious relationship to concerns over exposures to workplace chemicals is that it should be possible to determine an exposure level below which a response or effect would not be seen. Thus an acceptable exposure level should be attainable. It is worth noting at this stage that this is an area of uncertainty and debate for carcinogenic effects of chemicals.
The terms ‘response’ and ‘effect’ require some clarification because they are used differently in different areas of occupational health. ‘Response’ is used to mean the proportion of a population showing a specified change. ‘Effect’ is the actual magnitude of the change in the parameter. An example will help to explain the difference: if there is evidence of liver damage in response to exposure to different levels of a particular agent, the data could be presented as the number of individuals as compared to the total with a serum alanine aminotransferase level over, say, 100IU/l at the different exposure levels—
this would be the response. Alternatively, the data could be presented as the actual enzyme measurements at the different exposure levels, say, 95 or 870IU/l—this would be the effect. These terms will be used differently and often interchangeably by others. This is most probably related to the use in pharmacology of the terms quantal response and graded response which are equivalent to response and effect, respectively, as defined above.
The relationship between dose and response or effect is often depicted graphically using log (dose) against response or effect arithmetically, or using a probit scale. Return to arithmetic versus arithmetic is also useful in dealing with extrapolation from high to low dose levels. Examples of plots using these scales are shown in Figure 2.2. Use of the log scales has facilitated calculation of values such as the dose calculated to cause lethality in half the exposed population (LD50), the dose calculated to cause a certain toxic outcome in 1% of those exposed (TD1) and so on. However, they have not proved useful when it is necessary to extrapolate from the high doses used experimentally in small numbers of animals to the low doses experienced by humans, where it is desirable
to be able to predict response rates of down to 0.0001%. This remains a contentious issue in contemporary toxicology and is of primary concern when dealing with endpoints such as carcinogenicity as there is debate about the existence of a threshold for this event. The existence of a threshold means that there is a dose below which there will be no effect.
However, when there may be no threshold there is a need to extrapolate to very low exposure levels and the shape of the curve is unknown at this point. Figure 2.3 illustrates some possible alternatives. In order that experimental data can be accurate from a statistical point of view huge numbers of experimental animals would be required—tens or hundreds of thousands for each chemical. The only alternative that seems to be available currently is to continue to use the high-dose protocol and extrapolate cautiously due to the added uncertainty. If known, factors relating to nonlinear kinetics due to saturation of metabolic pathways must be incorporated into the evaluation process as these may be important in allowing a more accurate determination of appropriate exposure levels.