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12 Issues in the Assessment of Dose Response
Pages 315-328

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From page 315...
... 12 Issues in the Assessment of Dose Response The assessment of dose-response relationships is used to predict the incidence, probability, or magnitude of an adverse health effect in an individual or population for any amount of exposure to a toxicant. Dose-response relationships can also be used to estimate an exposure concentration or range of concentrations likely to correspond to a specific probability or risk of adverse health effects (e.g., dose corresponding to 10-6 excess risk of cancer)
From page 316...
... The ability to quantify specific response levels depends on the study design, which often differs in epidemiologic and toxicologic studies. Third, the dose-response model(s)
From page 317...
... proposed the use of only LED10 values from rodent carcinogenicity studies (adjusted to achieve human-equivalent doses) as points of departure in the trichloroethylene assessment.
From page 318...
... The effects of selecting different dose metrics for adjustment to equivalent human doses from animal models may be important for both noncancer and cancer dose-response modeling. For example, EPA notes that subchronic dosing studies indicate that cumulative exposure metrics may not be appropriate for predicting the risk of liver cancer (EPA 2001b, p.
From page 319...
... Although the linear extrapolation procedure was adopted to avoid the difficulty of choosing from among alternative dose-response models that fit equally well, there appears to be little scientific basis for evaluating its performance. The claim that "the dose-response curve for [trichloroacetic acid]
From page 320...
... 320 ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE variability on the shape of the population's dose-response curve have long been recognized for the deterministic model in which each individual has a tolerance to an exposure and the tolerance values have a Gaussian, logit, or other typical distribution (Dobson 1990) , but similar results hold for many alternative models.
From page 321...
... ISSUES IN THE ASSESSMENT OF DOSE RESPONSE 321 FIGURE 12-1 Classic "hockey-stick" dose-response shape. assessment.
From page 322...
... 322 ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE FIGURE 12-2 Sigmoidal population dose-response curve with no threshold. susceptibility, the effects of exposure measurement error can distort the 12-2 apparent shape of an observed dose-response curve.
From page 323...
... Alternatively, a surrogate such as variation of rates in a key toxicodynamic step could be used to estimate population variation in susceptibility. Formal Bayesian methods similar to those applied for physiologically based pharmacokinetic modeling of trichloroethylene offer a natural unified framework for addressing population variability and uncertainty in dose-response assessment and for incorporating information from multiple sources (see Chapter 11)
From page 324...
... The committee also endorses EPA's exploration of hypothetical mechanism-based models such as the two-stage cancer model. However, for current pharmacokinetic models for trichloroethylene, the two-stage model is not well validated and should be viewed only as a plausible alternative to other nonlinear dose-response models.
From page 325...
... The central estimate should neither understate nor overstate the risk, but rather, should provide the risk manager and the public with the expected risk. Although formal quantitative uncertainty analysis techniques are commonly applied in the exposure assessment and pharmacokinetic modeling portions of environmental risk assessment, they are not yet widely used for doseresponse modeling (Presidential/Congressional Commission on Risk Assessment and Risk Management 1997)
From page 326...
... 326 ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE son 1996)
From page 327...
... ISSUES IN THE ASSESSMENT OF DOSE RESPONSE 32 the point of departure to zero dose, and characterization of uncertainty and variability in estimates of cancer and noncancer risk. Although it is preferable to use continuous dose-response models to identify a point of departure for noncancer risks, the committee recognizes that suitable data on trichloroethylene were not always available for such modeling.
From page 328...
... 328 ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE cancer. The committee recommends that toxicologic data be used to fit the primary dose-response model(s)


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