Cancer risk assessment dose-response relationships

Health problems experienced in Taiwan have been the subject of much research since their initial discovery in the early 1960s and have formed the basis of many epidemiological risk assessments over the last 30 years. Taiwan is the classic area for the identification of black-foot disease (e.g. Chen et al., 1985 Tseng et al., 1968) and other peripheral vascular disorders but cardiovascular disease, neurological problems, diabetes and internal cancers have also been described from the area. A clear dose-response relationship has been found for many of the disorders, including blackfoot disease and bladder cancer (e.g. Chen et al., 1985). 

In the evaluation of carcinogenicity of chemicals, data obtained from human and animal studies are analyzed for hazard identification and dose-response relationships. The results are used in combination with exposure assessment and risk characterization for the assessment of cancer risks of the chemicals to humans. 

Dose-response models describe a cause-effect relationship. There are a wide range of mathematical models that have been used for this purpose. The complexity of a dose-response model can range from a simple one-parameter equation to complex multicompartment pharmacokinetic/pharmacodynamic models. Many dose-response models, including most cancer risk assessment models, are population models that predict the frequency of a disease in a population. Such dose-response models typically employ one or more frequency distributions as part of the equation. Dose-response may also operate at an individual level and predict the severity of a health outcome as a function of dose. Particularly complex dose-response models may model both severity of outcome and population variability, and perhaps even recognize the influence of multiple causal factors. 

Toxicity assessment includes characterization of the toxicity of a chemical, development of a dose-response relationship, and ultimately the development of exposure criteria. Toxicity values express a dose that is associated with either a given risk of cancer occurring over a lifetime of exposure (e.g., slope factors and unit risks) or a dose that is not expected to cause harm (e.g., RfDs). Some toxicity values are used as the basis for developing exposure criteria (RfDs) and some can be used as exposure criteria (e.g., RfCs). US EPA has developed toxicity values for many chemicals commonly associated with environmental contamination. Verified US EPA criteria are available in the Integrated Risk Information System (IRIS). 

The extent to which hormetic information may be nsefnl in cancer risk assessment deserves consideration. At present, it is nnclear how hormetic dose-responses might influence the MOA information necessary for a departnre from the linearity assnmption. In practice, the hormetic relationships may provide a nsefnl backdrop for nnderstanding that carcinogenic thresholds can exist, bnt it still may not be... 

Over the past decade there has been a movement to harmonize cancer and noncancer risk assessment (Gaylor 1997 Bogdanffy et al. 2001) based on the premise that cancer and noncancer events share similar pharmacokinetic dependencies and overlapping MOAs and thus have similar dose-response relationships. The benchmark dose approach lends itself to the evaluation of both linear and nonlinear dose-response. In fact, one of the stated purposes of EPA s formalization of the benchmark dose process was to provide a standardized approach to chemical dose-response assessment, regardless of whether the chemical is a carcinogen. 

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. 

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