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Basic Analytical Toxicology
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Related articles in Web of Science Google Scholar. These methods are not yet ready for practical use in occupational health, but rapid progress in this line of research would suggest that such methods will become available within a few years. A marker of susceptibility, whether inherited or induced, is an indicator that the individual is particularly sensitive to the effect of a xenobiotic or to the effects of a group of such compounds.
Most attention has been focused on genetic susceptibility, although other factors may be at least as important.
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Hypersusceptibility may be due to an inherited trait, the constitution of the individual, or environmental factors. Several relevant enzymes appear to be controlled by a single gene. For example, oxidation of foreign chemicals is mainly carried out be a family of enzymes belonging to the P family. Other enzymes make the metabolites more water soluble by conjugation e.
The activity of these enzymes is genetically controlled and varies considerably. As mentioned above, the activity can be determined by administering a small dose of a drug and then determining the amount of the metabolite in the urine.
Some of the genes have now been characterized, and techniques are available to determine the genotype. Important studies suggest that a risk of developing certain cancer forms is related to the capability of metabolizing foreign compounds. Many questions still remain unanswered, thus at this time limiting the use of these potential susceptibility biomarkers in occupational health.
Other inherited traits, such as alpha 1 -antitrypsin deficiency or glucosephosphate dehydrogenase deficiency, also result in deficient defence mechanisms in the body, thereby causing hypersusceptibility to certain exposures. Most research related to susceptibility has dealt with genetic predisposition. Other factors play a role as well and have been partly neglected. For example, individuals with a chronic disease may be more sensitive to an occupational exposure.
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Also, if a disease process or previous exposure to toxic chemicals has caused some subclinical organ damage, then the capacity to withstand a new toxic exposure is likely to be less. Biochemical indicators of organ function may in this case be used as susceptibility biomarkers. Perhaps the best example regarding hypersusceptibility relates to allergic responses.
If an individual has become sensitized to a particular exposure, then specific antibodies can be detected in serum. Even if the individual has not become sensitized, other current or past exposures may add to the risk of developing an adverse effect related to an occupational exposure. A major problem is to determine the joint effect of mixed exposures at work. In addition, personal habits and drug use may result in an increased susceptibility.
For example, tobacco smoke usually contains a considerable amount of cadmium. Thus, with occupational exposure to cadmium, a heavy smoker who has accumulated substantial amounts of this metal in the body will be at increased risk of developing cadmium-related kidney disease. Biomarkers are extremely useful in toxicological research, and many may be applicable in biological monitoring. Nonetheless, the limitations must also be recognized.
Many biomarkers have so far been studied only in laboratory animals.
Toxicokinetic patterns in other species may not necessarily reflect the situation in human beings, and extrapolation may require confirmatory studies in human volunteers. Also, account must be taken of individual variations due to genetic or constitutional factors. In some cases, exposure biomarkers may not at all be feasible e.
Other chemicals may be stored in, or may affect, organs which cannot be accessed by routine procedures, such as the nervous system. The route of exposure may also affect the distribution pattern and therefore also the biomarker measurement and its interpretation. For example, direct exposure of the brain via the olfactory nerve is likely to escape detection by measurement of exposure biomarkers.
As to effect biomarkers, many of them are not at all specific, and the change can be due to a variety of causes, including lifestyle factors. Perhaps in particular with the susceptibility biomarkers, interpretation must be very cautious at the moment, as many uncertainties remain about the overall health significance of individual genotypes.
In occupational health, the ideal biomarker should satisfy several requirements. First of all, sample collection and analysis must be simple and reliable. For optimal analytical quality, standardization is needed, but the specific requirements vary considerably. Major areas of concern include: preparation of the in- dividual, sampling procedure and sample handling, and measurement procedure; the latter encompasses technical factors, such as calibration and quality assurance procedures, and individual- related factors, such as education and training of operators.
For documentation of analytical validity and traceability, reference materials should be based on relevant matrices and with appropriate concentrations of toxic substances or relevant metabolites at appropriate levels. For biomarkers to be used for biological monitoring or for diagnostic purposes, the responsible laboratories must have well-documented analytical procedures with defined performance characteristics, and accessible records to allow verification of the results. At the same time, nonetheless, the economics of characterizing and using reference materials to supplement quality assurance procedures in general must be considered.
Thus, the achievable quality of results, and the uses to which they are put, have to be balanced against the added costs of quality assurance, including reference materials, manpower and instrumentation.
Another requirement is that the biomarker should be specific, at least under the circumstances of the study, for a particular type of exposure, with a clear-cut relationship to the degree of exposure. Otherwise, the result of the biomarker measurement may be too difficult to interpret.
For proper interpretation of the measurement result of an exposure biomarker, the diagnostic validity must be known i. In this area, metals serve as a paradigm for biomarker research.
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Recent research has demonstrated the complexity and subtlety of dose-response relationships, with considerable difficulty in identifying no-effect levels and therefore also in defining tolerable exposures. However, this kind of research has also illustrated the types of investigation and the refinement that are necessary to uncover the relevant information.
For most organic compounds, quantitative associations between exposures and the corresponding adverse health effects are not yet available; in many cases, even the primary target organs are not known for sure. In addition, evaluation of toxicity data and biomarker concentrations is often complicated by exposure to mixtures of substances, rather than exposure to a single compound at the time. Before the biomarker is applied for occupational health purposes, some additional considerations are necessary. First, the biomarker must reflect a subclinical and reversible change only.
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Second, given that the biomarker results can be interpreted with regard to health risks, then preventive efforts should be available and should be considered realistic in case the biomarker data suggests a need to reduce the exposure. Third, the practical use of the biomarker must be generally regarded as ethically acceptable. Industrial hygiene measurements may be compared with applicable exposure limits. Likewise, results on exposure biomarkers or effect biomarkers may be compared to biological action limits, sometimes referred to as biological exposure indices.
The scientific basis should, if possible, include dose-response relationships supplemented by information on variations in susceptibility within the population at risk. In some countries, workers and members of the general public are involved in the standard-setting process and provide important input, particularly when scientific uncertainty is considerable.
One of the major uncertainties is how to define an adverse health effect that should be prevented—for example, whether adduct formation as an exposure biomarker by itself represents an adverse effect i. Difficult questions are likely to arise when deciding whether it is ethically defensible, for the same compound, to have different limits for adventitious exposure, on the one hand, and occupational exposure, on the other.
The information generated by the use of biomarkers should generally be conveyed to the individuals examined within the physician-patient relationship. Ethical concerns must in particular be considered in connection with highly experimental biomarker analyses that cannot currently be interpreted in detail in terms of actual health risks. For the general population, for example, limited guidance exists at present with regard to interpretation of exposure biomarkers other than the blood-lead concentration.
Also of importance is the confidence in the data generated i.