Toxicity, general dose/response

Figure 23.2 shows a generalized dose-response curve. The dose corresponding to the mid-point (inflection point) of the resulting S-shaped curve is the statistical estimate of the dose that would kill 50 % of the subjects. It is designated as LD50 and is commonly used to express toxicities. 

In addition to the effect of biological variabihty in group response for a given exposure dose, the magnitude of the dose for any given individual also determines the severity of the toxic injury. In general, the considerations for dose—response relationship with respect to both the proportion of a population responding and the severity of the response are similar for local and systemic effects. However, if metabohc activation is a factor in toxicity, then a saturation level may be reached. 

Although acute lethal toxicity has been used as an example, the principles discussed apply ia general to other forms of toxicity capable of being quantitated ia terms of dose—response relationships. 

The results of the studies reviewed here show that the neurotoxic effects of MDMA generalize to the primate. Further, they indicate that monkeys are considerably more sensitive than rats to the serotonin-depleting effects of MDMA, and that the dose-response curve of MDMA in the monkey is much steeper than in the rat. Perhaps as a consequence of this, the toxic effects of MDMA in the monkey involve serotonergic nerve fibers as well as cell bodies, whereas in the rat, only nerve fibers are affected. The present studies also show that the toxic dose of MDMA in the monkey... 

Group comparison tests for proportions notoriously lack power. Trend tests, because of their use of prior information (dose levels) are much more powerful. Also, it is generally believed that the nature of true carcinogenicity (or toxicity for that matter), manifests itself as dose-response. Because of the above facts, evaluation of trend takes precedence over group comparisons. In order to achieve optimal test statistics, many people use ordinal dose levels (0,1,2..., etc.) instead of the true arithmetic dose levels to test for trend. However, such a decision should be made a priori. The following example demonstrates the weakness of homogeneity tests. 

Exposures in the population of interest will generally reveal that incurred dose is only a small fraction, and sometimes a very tiny fraction, of that at which toxic responses has been or can be directly measured, in either epidemiology or animal studies. Occupational populations (Table 8.1, Scenario C) may be exposed at doses close to those for which data are available, but general population exposures are usually much smaller. Thus, to estimate risk it will be necessary to incorporate some form of extrapolation from the available dose-response data to estimate toxic response (risk) in the range of doses expected to be incurred by the population that is the subject of the risk assessment. 

The more classical approach to assess the presence of marine biotoxins in seafood is the in vivo mouse bioassay. It is based on the administration of suspicious extracted shellfish samples to mice, the evaluation of the lethal dose and the toxicity calculation according to reference dose response curves, established with reference material. It provides an indication about the overall toxicity of the sample, as it is not able to differentiate among individual toxins. This is a laborious and time-consuming procedure the accuracy is poor, it is nonspecific and generally not acceptably robust. Moreover, the mouse bioassay suffers from ethical implications and it is in conflict with the EU Directive 86/609 on the Protection of Laboratory Animals. Despite the drawbacks, this bioassay is still the method of reference for almost all types of marine toxins, and is the official method for PSP toxins. 

Other dose-response relationships may also be seen for certain compounds such as, e.g., essential metals, where symptoms of dehciency may occur if the intake is too low, whereas toxic symptoms may occur if the intake is too high. For such compounds, the dose-response curve is generally U-shaped as illustrated in Figure 4.2. It should be noted that the right part of the U-shaped curve representing the toxic effects in reality is the typical S-shape observed for toxic effects in general. 

For threshold carcinogens, it is possible to identify a NOAEL for the underlying toxicity responsible for tumor formation. The following general guidance is provided for the dose-response assessment for non-genotoxic (threshold) carcinogens (EC 2003). The dose-response assessment for the relevant tumor types is performed in a two-step process. 

In general, the use of LOAEL/NOAEL ratios to estimate a NOAEL from a LOAEL is questionable as these ratios reflect more the applied intervals between the dose levels in the studies (dose spacing, which is dependent on the study design), rather than the steepness of the dose-response relationship, i.e., the inherent toxicity. It has also been pointed out that there is no guarantee whatsoever that at one dose interval lower (extrapolation from a LOAEL to a NOAEL), the effect would be statistically nonsignificant. 

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