Dose-response assessment threshold

As has been emphasized so many times in the preceding chapters, these various manifestations of toxicity all display dose-response characteristics, where by response we refer to the incidence or severity of specific adverse health effects. As we demonstrated in earlier chapters, toxic responses increase in incidence, in severity, and sometimes in both, as dose increases. Moreover, just below the range of doses over which adverse effects can be observed, there is usually evidence for a threshold dose, what we have called the no-observed adverse effect level (NOAEL). The threshold dose must be exceeded before adverse effects become observable (Chapter 3). Deriving from the literature on toxic hazards, descriptions of the dose-response relationships for those hazards comprise the dose-response assessment step of the four-step process. 

Any test of skin sensitizing capabUity that includes dose-response assessment can be used to assess potency. Even though potency cannot be directly derived from human elicitation data, a low ehcitation threshold is suggestive of a high potency. Where possible, attempts should be made to use clinical data for quantitative risk assessment. ... 

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. 

The first step, extrapolation of data from experimental animals to the human simation, is similar to the interspecies extrapolation described in detail for threshold effects (Section 5.3). The second step, evaluation of a carcinogen s mechanism(s) or mode of action(s), is very important for the choice of model for the risk assessment, i.e., non-threshold or threshold this issue is addressed in Section 4.9. The third step, quantitative dose-response assessment, is the main focus of this chapter and is addressed in more detail in the following text. 

Dose-Response Assessment for Chemicals That Cause Deterministic Effects. For hazardous chemicals that cause deterministic effects and exhibit a threshold in the dose-response relationship, the purpose of the dose-response assessment is to identify the dose of a substance below which it is not likely that there will be an adverse response in humans. Establishing dose-response relationships for chemicals that cause deterministic effects has proved to be complex because (1) multiple responses are possible, (2) the dose-response assessment is usually based on data from animal studies, (3) thousands of such chemicals exist, and (4) the availability and quality of data are highly variable. As a consequence, the scientific community has needed to devise and adhere to a number of methods to quantify the most important (low or safe dose) part of the dose-response relationship. 

Dose-Response Assessment for Chemicals That Cause Stochastic Effects. For hazardous chemicals that do not have a threshold in the dose-response relationship, which is currently believed to... 

Although dose-response assessments for deterministic and stochastic effects are discussed separately in this Report, it should be appreciated that many of the concepts discussed in Section 3.2.1.2 for substances that cause deterministic effects apply to substances that cause stochastic effects as well. The processes of hazard identification, including identification of the critical response, and development of data on dose-response based on studies in humans or animals are common to both types of substances. Based on the dose-response data, a NOAEL or a LOAEL can be established based on the limited ability of any study to detect statistically significant increases in responses in exposed populations compared with controls, even though the dose-response relationship is assumed not to have a threshold. Because of the assumed form of the dose-response relationship, however, NOAEL or LOAEL is not normally used as a point of departure to establish safe levels of exposure to substances causing stochastic effects. This is in contrast to the common practice for substances causing deterministic effects of establishing safe levels of exposure, such as RfDs, based on NOAEL or LOAEL (or the benchmark dose) and the use of safety and uncertainty factors. 

For food allergens, validated animal models for dose-response assessment are not available and human studies (double-blind placebo-controlled food challenges [DBPCFCs]) are the standard way to establish thresholds. It is practically impossible to establish the real population thresholds this way. Such population threshold can be estimated, but this is associated with major statistical and other uncertainties of low dose-extrapolation and patient recruitment and selection. As a matter of fact, uncertainties are of such order of magnitude that a reliable estimate of population thresholds is currently not possible. The result of the dose-response assessment can also be described as a threshold distribution rather than a single population threshold. Such distribution can effectively be used in probabilistic modeling as a tool in quantitative risk assessment (see Section 15.2.5)... 

Dose-response assessment follows the hazard identification in the risk assessment process. In dose-response assessment, an adverse effect is presumed to either exhibit a threshold or not in the dose-response curve. Depending on the nature of this curve, different approaches are employed to estimate the risk posed by the potential toxic agent. 

Additional difficulties arise when making dose-response assessments. First, one must select what measure of dose to use. A common measure is milligrams of chemical per kilogram of body weight per day. Then there is appUcation of a scaling factor between species. Procedures make an adjustment for absorption rates, because several factors affect absorption. Also, there is an extrapolation from high to low doses. Not all extrapolations are linear or linear over a range of dose rates. There may be a need also to make an adjustment for threshold effects. For some substances, there are no-observable-effect levels (NOELs) or lowest-observed-effect levels (LOELs). 

Weaver, J. E., Cardin, C. W. and Maibach, H. I., 1985. Dose-response assessments of kathon biocide (1) Diagnostic use and diagnostic threshold patch testing with sensitised humans. Contact Dermatitis 12, pp. 141-145. 

The use of in vitro, ex vivo and in vivo studies (but not necessarily extending to a rodent bioassay) can all help to achieve a better understanding of the overall biological activity, any proliferative actions, dose-response, and threshold effects of the product, together with the relationship between these and the intrinsic pharmacological activity of the product in a particular species. Clinical experience with a similar product may allow correlations to be made between in vitro mitogenic activities and proliferative activity in animal models. Such information may assist in the assessment of benefit/risk to humans. 

For all toxic effects other than carcinogenicity, a threshold in the dose-response curve is assumed. The lowest NOAEL from all available studies is assumed to be the approximate threshold for the groups of subjects (humans or animals) in which toxicity data were collected. Alternatively, a benchmark dose (BMD) may be estimated from the observed dose-response curve, and used as the point-of-departure for risk assessment (see below and Box). 

In the hazard assessment process, described in detail in Chapter 4, all effects observed are evaluated in terms of the type and severity (adverse or non-adverse), their dose-response relationship, and the relevance for humans of the effects observed in experimental animals. For threshold effects, a No- or a Lowest-Observed-Adverse-Effect Level (N/LOAEL), or alternatively a Benchmark Dose (BMD), is derived for every single effect in all the available smdies provided that data are sufficient for such an evaluation. In the last step of the hazard assessment for threshold effects, all this information is assessed in total in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). 

The 95% confidence limits of the estimate of the linear component of the LMS model, /, can also be calculated. The 95% upper confidence limit is termed qi and is central to the US-EPA s use of the LMS model in quantitative risk assessment, as qi represents an upper bound or worst-case estimate of the dose-response relationship at low doses. It is considered a plausible upper bound, because it is unlikely that the tme dose-response relationship will have a slope higher than qi, and it is probably considerably lower and may even be zero (as would be the case if there was a threshold). Lfse of the qj as the default, therefore, may have considerable conservatism incorporated into it. The values of qi have been considered as estimates of carcinogenic potency and have been called the unit carcinogenic risk or the Carcinogen Potency Factor (CPF). 

An alternative approach to a quantitative assessment is to divide the highest dose at which there is no observed increase in tumor incidence in comparison with controls by a large composite UF, for example 5000 as suggested by Wed (1972). The magnimde of the factor could be a function of the weight of evidence, e.g., numbers of species in which the mmors have been observed or namre of the mmors (WHO/IPCS 1994). The adequacy of this approach, which is sometimes used when data on dose-response are limited, must be judged by criteria similar to those used in developing a tolerable intake for threshold effects this is addressed in detail in Chapter 5. 

The lARC has concluded that epidemiological studies have established the relationship between benzene exposure and the development of acute myelogenous leukemia and that there is sufficient evidence that benzene is carcinogenic to humans. Although a benzene-leukemia association has been made, the exact shape of the dose-response curve and/or the existence of a threshold for the response is unknown and has been the source of speculation and controversy. Some risk assessments suggest exponential increases in relative risk (of leukemias) with increasing cumulative exposure to benzene. At low levels of exposure, however, a small increase in leukemia mortality cannot be distinguished from a no-risk situation. In addition to cumulative dose other factors such as multiple solvent exposure, familial connection, and individual sus-... 

A threshold also exists for quantal dose responses as well as graded, i.e., there will be a dose below which no individuals respond. However, the concept of a threshold also has to be considered in relation to the variation in sensitivity in the population, especially a human population with great variability. Thus, although there will be a dose at which the greatest number of individuals show a response (see point B in Fig. 2.5), there will be those individuals who are very much more sensitive (point A in Fig. 2.5) or those who are much less sensitive (point C in Fig. 2.5). This consideration is incorporated into risk assessment of chemicals such as food additives, contaminants, and industrial chemicals (see below). 

Although the straightforward threshold model of the dose-response relationship as described here is the one originally conceived and the one for which there is clear mechanistic justification, other dose-response relationships have been suggested. The other dose-response relationships are substantially different and lead to different predictions in relation to toxicity. This becomes particularly important in risk assessment (see below). 

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