Mechanistic biomarkers

Some biomarkers only provide a measure of exposure others also provide a measure of toxic effect. Biomarkers of the latter kind are of particular interest and importance and will be referred to as mechanistic biomarkers in the present text. Some mechanistic biomarker assays directly measure effects at the site of action as described in Section 2.4 (see Chapter 4, Table 4.2, for examples). Inhibition of acetylcholinesterase is one example. Others measure secondary effects on the operation of nerves or the endocrine system (examples given in Table 4.2 and Chapters 15 and 16). 

Some biomarker responses provide evidence only of exposure and do not give any reliable measure of toxic effect. Other biomarkers, however, provide a measure of toxic effects, and these will be referred to as mechanistic biomarkers. Ideally, biomarker assays of this latter type monitor the primary interaction between a chemical and its site of action. However, other biomarkers operating down stream from the original toxic lesion also provide a measure of toxic action (see Figure 14.3 in Chapter 14), as, for instance, in the case of changes in the transmission of action potential... 

In the field, effects of chemicals upon individuals may be measured by the use of mechanistic biomarkers. This approach has recently been strengthened by new technologies arising in the field of genomics. Free-living or deployed organisms may be sampled in order to measure responses to environmental chemicals. 

Thus, it is often not possible to measure the combined effects of members of one group of pollutants with a single mechanistic biomarker assay. The situation... 

Four examples will now be given of such mechanistic biomarker assays that can give integrative measures of toxic action by pollutants, all of which have been described earlier in the text. Where the members of a group of pollutants share a common mode of action and their effects are additive, TEQs can, in principle, be estimated from their concentrations and then summated to estimate the toxicity of the mixture. In these examples, toxicity is thought to be simply related to the proportion of the total number sites of action occupied by the pollutants and the toxic effect additive where two or more compounds of the same type are attached to the binding site. 

Particular attention is given to the development of new mechanistic biomarker assays and bioassays that can be used as indices of the toxicity of mixtures. These biomarker assays are typically based on toxic mechanisms such as brain acetylcholinesterase inhibition, vitamin K antagonism, thyroxin antagonism, Ah-receptor-mediated toxicity, and interaction with the estrogenic receptor. They can give integrative measures of the toxicity of mixtures of compounds where the components of the mixture share the same mode of action. They can also give evidence of potentiation as well as additive toxicity. 

Because of their wide-ranging and holistic character, assays of behavioral effects have been used as screening procedures when testing for neurotoxicity (see, for example, Iversen 1991, Tilson 1993). They can provide sensitive indications of neurotoxic disturbances, which can then be traced back to their ultimate cause by using mechanistic biomarker assays. 

In a similar way, an integrated biomarker approach has a role when carrying out experiments in mesocosms. Under these controlled conditions, behavioral effects of neurotoxic pollutants, acting singly or in combination, can be monitored and compared with data on predator-prey relationships and effects at the population level. The employment of mechanistic biomarker assays can facilitate comparisons between results obtained in mesocosms and other data obtained in the field or in laboratory tests. Here is one way of attempting to answer the difficult question— how comparable are mesocosms to the real world ... 

THE DEVELOPMENT OF MORE SOPHISTICATED METHODS OF TOXICITY TESTING MECHANISTIC BIOMARKERS... 

At the practical level, an ideal mechanistic biomarker should be simple to use, sensitive, relatively specific, stable, and usable on material that can be obtained by nondestructive sampling (e.g., blood or skin). A tall order, no doubt, and no biomarker yet developed has all of these attributes. However, the judicious use of combinations of biomarkers can overcome the shortcomings of individual assays. The main point to emphasize is that the resources so far invested in the development of biomarker technology for environmental risk assessment has been very small (cf the investment in biomarkers for use in medicine). Knowledge of toxic mechanisms of organic pollutants is already substantial (especially of pesticides), and it grows apace. The scientific basis is already there for technological advance it all comes down to a question of investment. 

With improvements in scientific knowledge and related technology, there is an expectation that more environmentally friendly pesticides will continue to be introduced, and that ecotoxicity testing procedures will become more sophisticated. There is much interest in the introduction of better testing procedures that work to more ecologically relevant end points than the lethal toxicity tests that are still widely used. Such a development should be consistent with the aims of organizations such as FRAME and ECVAM, which seek to reduce toxicity testing with animals. Mechanistic biomarker assays have the potential to be an important part of... 

Mechanistic biomarker A biomarker that provides a measure of a toxic effect (some biomarkers only measure exposure). In the simplest case, this involves the direct measurement of the operation of a mechanism of toxicity (e.g., of acetylcholinesterase inhibition). 

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