Quantitative dose—response assessment

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. 

QUANTITATIVE DOSE-RESPONSE ASSESSMENT GENERAL ASPECTS... 

The quantitative dose-response assessment involves two different challenges, namely to determine the relationship between doses and the frequency of cases of cancer (i.e., potency evaluation), and to determine what statistical risk is tolerable or acceptable. This section gives a very short overview of some general aspects related to the quantitative dose-response assessment. The currently used approach by the WHO, the US-EPA, and the EU, as well as new approaches for the risk assessment of compounds that are both genotoxic and carcinogenic, are presented in Sections 6.3 and 6.4, respectively. 

QUANTITATIVE DOSE-RESPONSE ASSESSMENT CURRENTLY USED APPROACHES... 

As shown previously, PBPK models allow the conversion of potential dose or exposure concentration to tissue dose, which can then be used for risk characterization purposes. The choice of an internal dose metric is based principally on an understanding of the mode of action of the chemical species of concern. The internal dose metric (sometimes called the biologically effective dose) is often used in place of the applied dose in quantitative dose-response assessments, in order to reduce the uncertainty inherent in using the applied dose to derive risk values. 

Altliough the technical conununity has come a long way in understanding how to do a better job in luizard identification, dose-response assessment, and exposure assessment portions of risk assessment, it lias only begun to understand how to best cluiractcrize hcaltli risks and how to present tliese risks most appropriately to both the public and decision makers. Tlie next tliree sections specifically address tlicse issues. Tliis section deals witli qualitative risk assessment while tlie next two sections deal witli quantitative risk assessment. 

Dose-response assessment is the process of obtaining quantitative information about the probability of human illness following exposure to a hazard it is the translation of exposure into harm. Dose-response curves have been determined for some hazards. The curves show the relationship of dose exposure and the probabihty of a response. Since vahdated dose-response relationships are scarce, various other inputs are used to underpin the hazard characterization phase of risk assessment. 

Hazard characterization (or dose-response assessment) is the qualitative and, as far as possible, quantitative description of the inherent properties of an agent or situation having the potential to cause adverse effects. This step should include a dose-response assessment that describes the severity of adverse effects (the responses) related to the amount and condition of exposure to an agent (the dose). 

In the absence of human data, or when the available human data are insufficiently quantitative, or are insufficiently sensitive to rule out risks, animal data will be used for hazard identification and dose-response assessment. 

Extracts that exhibited significant inhibitory activity, defined as >50% inhibition of CPE at 100 (xg/mL, were advanced into secondary screening, which includes confirmation of activity observed during the primary screen using an expanded range of concentrations (dose response), plaque inhibition assay, and a one-step growth inhibition and testing of additional influenza viruses. As shown in Fig. 1.2a, the quantitative dose response assay was used to assess the potency of the most two... 

The concept of the Benchmark Dose (BMD), a benchmark is a point of reference for a measurement, in health risk assessment of chemicals was first mentioned by Crump (1984) as an alternative to the NOAEL and LOAEL for noncancer health effects in the derivation of the ADI/TDI these terms are addressed in detail in Chapter 5. The BMD approach provides a more quantitative alternative to the dose-response assessment than the NOAEL/LOAEL approach. The goal of the BMD approach is to define a starting point of depariure (POD) for the establishment of a tolerable exposure level (e.g., ADI/TDI) that is more independent of the study design. In this respect, the BMD approach is not... 

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. ... 

The first step of the dose-response assessment is the evaluation of the data within the range of observation. If there are sufficient quantitative data and adequate understanding of the carcinogenic process, a biologically based model may be developed to relate dose and response data. Otherwise, as a default procedure, a standard model can be used to curve-fit the data. For each mmor response, a POD from the observed data is estimated to mark the beginning of extrapolation to lower doses. The POD is an estimated dose (expressed in human-equivalent terms) near the lower end of the observed range, without significant extrapolation to lower doses. 

Risk characterization is the qualitative and/or quantitative estimation, including attendant uncertainties, of the severity and probability of known and potential adverse effects of a substance in a given population it is based on hazard identification, dose-response assessment and exposure assessment (OECD/IPCS, 2001), as described above. 

Hertzberg RC, Teuschler LK. 2002. Evaluating quantitative formulas for dose-response assessment of chemical mixtures. Environ Hlth Perspect 110 965-970. 

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)... 

Because the literature describes several limitations in the use of NOAELs (Gaylor 1983 Crump 1984 Kimmel and Gaylor 1988), the evaluative process considers other methods for expressing quantitative dose-response evaluations. In particular, the BMD approach originally proposed by Crump (1984) is used to model data in the observed range. That approach was recently endorsed for use in quantitative risk assessment for developmental toxicity and other noncancer health effects (Barnes et al. 1995). The BMD can be useful for interpreting dose-response relationships because it accounts for all the data and, unlike the determination of the NOAEL or LOAEL, is not limited to the doses used in the experiment. The BMD approach is especially helpful when a NOAEL is not available because it makes the use of a default uncertainty factor for LOAEL to NOAEL extrapolation unnecessary. 

ASSESSMENT OF RISKS TO HUMANS EXPOSED TO PESTICIDES 2 The Four Steps in Risk Assessment 2 Hazard Identification 2 Dose-Response Assessment 3 Margin of Safety Approach 3 Quantitative Risk Assessment 3 Exposure Assessment 4 Risk Characterization 4 RISK MANAGEMENT 5 ADVANCES IN DATA INTERPRETATION 5 Probabilistic Approaches 5 Recognition of the Tier Approach 5 Aggregate Exposure 6 Cumulative Exposure 6 Impact of New Scientific Advances 7 Post-Registration Monitoring 7 HARMONIZATION OF REGULATORY APPROACHES SUMMARY 9... 

A risk assessment is defined as a qualitative and quantitative process conducted by EPA to characterize the nature and magnitude of risks to public health from exposure to hazardous substances, pollutants, or contaminants released from specific sites. Risk assessments include the following components hazard identification, dose-response assessment, exposure assessment, and risk characterization. Statistical and biological models are used in quantitative risk... 

Risk characterization provides for both qualitative and quantitative descriptions of risk. The step involves integrating the results of the hazard identification, dose-response assessment, and exposure assessment to characterize risk. Often, a direct comparison between exposure criteria developed in the first two steps and the results of the exposure assessment (concentration in the environmental media or the estimated dose, as appropriate) provide a basis for determining whether risks are acceptable. Typically, if criteria are exceeded, the risk is not acceptable. What is defined as acceptable, as well as the way risk is expressed, is often a... 

Metallic Mercury. Ocular effects observed following acute exposure included red, burning eyes and conjunctivitis (Bluhm et al. 1992a Sexton et al. 1976). Workers chronically exposed to mercury have also exhibited a peculiar grayish-brown or yellow haze on the outer surface of their lenses (Atkinson 1943 Bidstrup et al. 1951 Locket and Nazroo 1952). These case studies contained insufficient quantitative data for dose-response assessment. 

In summary, having established an animal MOA and human relevance for this MOA, it is appropriate to address dose-response assessment, human exposure analysis, and risk characterization. Thus, the purpose of the human relevance framework is to establish which chemicals (or chemical mixtures) should be considered for a quantitative risk assessment and which do not require further consideration because they present a minimal risk or no risk to humans. Several thoroughly worked examples are presented in Meek et al. (2003). 

Frequently, however, a quantitative approach is applied on the basis of (i) problem formulation and hazard identification, (ii) dose-response assessment,... 

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