Factor Rationale
10 Suitable human data 100 Chronic data in animals At least 1000 Limited animal data
any human data that are available must be included and are of great importance. Often, however, we find that these data are of limited use for a variety of reasons, such as co-exposures in the workplace, or the reports being of unsatisfactory scientific rigor.
Nevertheless, well-conducted positive epidemiological studies in humans will always outweigh analogous studies from experimental animals. Furthermore, other data may be used, such as those from cells relating to the genotoxic effects of the chemical in question. It is also important that data relating to the mechanism of toxicity are considered when making conclusions. The appropriateness of the study and quality of the data are other important factors that must not be overlooked. Overall, all the available information must be considered in order to arrive at an acceptable value for the exposure standard.
The process for setting exposure standards for workplace chemicals has been somewhat different to that used for chemicals found in other settings over the last 50 years or so. Many workplace chemicals had been in use when the standards were first set, so information was already available on their effects in exposed humans. Thus the setting of exposure limits often relied heavily on this information. Furthermore, little toxicological data from experimental animals was available for consideration because detailed animal testing has only been required in recent years. By comparison, animal data have been a requirement for many years before registration and marketing of pesticide residues. Thus, standard’s setting for pesticide residues has relied more heavily on animal data gathered before any human exposure. It should be the end result of toxicological testing, of course, that positive human toxicity data for that chemical are never obtained. This view sometimes seems to arouse condescension in committee colleagues during meetings to decide on acceptable practices for using chemicals in the workplace. For example, should not a genotoxic aromatic amine with clear and strong evidence of causing urinary bladder cancer in dogs be treated as if it were a human carcinogen? In asserting that it should be, one often hears that there is no supporting human data. The author’s response is ‘Aren’t we fortunate that this is so?’. It is interesting to consider the IARC list of Group 1 carcinogens (proven human carcinogens) in this context where many are related to occupational (as compared to environmental) exposures (IARC 1987).
Over recent years the process of setting standards for exposure to workplace chemicals has received considerable criticism (Castleman and Ziem 1988; Halton 1988; Roach and Rappaport 1990). One reason for this has been the use of uncertainty factors to a much lesser extent than has been applied to other chemical groups. Nevertheless, it should be appreciated that the process began because there was a clear void that required attention, and this gap was filled due to the efforts particularly of the American Conference of Governmental Industrial Hygienists (ACGIH). This does not mean that the process should remain unchanged, as more and newer chemicals are brought into the workplace, or existing ones are re-evaluated. There are now increasing requirements for toxicological information to be provided about new chemicals before they may be brought into the workplace. However, it should also be recognised that the extent of this information is not as great as that required for pesticides, for example.
Role in biological monitoring for chemical exposure
Biological monitoring is the measurement of a substance, its metabolites, or its effects in body tissues, fluids or exhaled air of exposed persons. While biological monitoring itself is not a preventive measure, consideration of biological monitoring is an interesting exercise because it is a topic that clearly exemplifies the interdisciplinary nature of protecting workers from the deleterious effects of exposure to chemicals.
There has been increasing attention to biological monitoring in recent years, as evidenced by the publications of world bodies (Elinder et al. 1994; WHO 1996) and journals dedicated to the topic (such as Biomarkers). The WHO documents are useful reference materials for those wanting further general information and for specific details on measurements of particular substances. The textbook by Lauwerys and Hoet (1993)
also contains information on the biological monitoring of a number of individual substances. Advances with newer, more generally applicable techniques may also provide assistance to the monitoring, and therefore management, of exposed workers in the future. Examples from the author’s (former) laboratory include detection of DNA adducts, especially by 32P-postlabelling (Qu et al. 1997a) and use of serum bile acids as a sensitive indicator of exposure to organic solvents (Neghab and Stacey 2000).
There is usually a relationship between workplace air levels of substances and the actual levels in the workers. Determination of the air levels is largely the domain of the occupational hygienist, while information about levels in the body requires the biological component. Information from experimental animals is very useful, if not essential, with regard to the latter, especially in the initial considerations of what may be the most suitable entity to determine. Thus the involvement of the occupational toxicologist is required. Then we have the issue of biological exposure and biological effect. A metabolite of a chemical in the urine can be considered an index of exposure, but is cholinesterase depression in serum or red blood cells an indicator of exposure or of effect? It is a biological effect, but it is used as a marker of exposure at the early stages of its depression. DNA adducts are certainly related to exposure and provide a measure of internal dose at a critical site, but do we have sufficient information at this time to consider them as an effect as such? The three disciplines of occupational toxicology, medicine and hygiene meet here. Lastly, when there is evidence of organ dysfunction related to chemical exposure we move into the domain of the occupational physician.
These inter-relationships are represented schematically in Figure 1.1.
When resolving problems such as evidence of an adverse health effect, it is appropriate for the occupational physician to consult a hygienist for advice on ventilation controls and/or a toxicologist for advice on the toxicity of alternatives, for example. Thus a team approach is very much called for to obtain the best end result. The same view is promulgated by Thorne (2001).
Comparison with chemicals in the general environment
Having referred to pesticides above it is interesting to compare exposure to chemicals in the environment to that in the workplace. Exposure in a workplace is often to higher concentrations of the chemicals than in the environment, although the duration of the exposure will be limited to the time at work while exposure in the environment could be for 24 hours a day, 7 days a week. Another difference is the size of the exposed population; it is limited to the particular workforce in the occupational setting, while environmental exposure includes larger numbers depending on the spread of the chemical in question. It is perhaps easier to investigate occupational toxicological problems because of the generally higher concentrations and a more easily defined exposed population. Then it must be considered that there may be exposure to the chemical in both the workplace and the environment as well as to multiple chemicals. Perhaps passive smoking or exposure to diesel emissions may be suitable examples. It is of interest to consider recent studies of DNA adducts in this regard. Hemminki et al. (1990) found that workers at the site and people in the surrounding community had similar levels of adducts while those in a rural population had much lower levels. However, Qu et al. (1997b)
found higher levels of DNA adducts associated with work practices involving higher exposures to diesel engine emissions.