Dose-response assessment carcinogens

The TGD (EC 2003), Chapter 3.11, addresses carcinogenicity and provides guidance on data requirements, evaluation of data, and dose-response 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. 

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. 

Dose-response assessment evaluates potential risks to humans at particular exposure levels. The approach to dose-response assessment for a particular agent is based on the conclusion reached as to its potential mode(s) of action for each tumor type. If the mode of action for known carcinogens is anticipated to be a DNA-reactive and direct mutagenic activity, such substances are assessed with a linear approach. Other modes of action may be modeled with either linear or nonhnear approaches after a rigorous analysis of available data. 

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. 

Hazard or dose-response assessment the attempt to assemble the hazard and exposure information along with mathematical models to estimate an upper bound on the carcinogenic risk at a given dose. 

In spite of the differences among carcinogens, the principles of dose-response assessment that have proven to be useful for ionizing radiation appear to be applicable, within limits, to chemicals, particularly those chemicals that resemble radiation in genotoxicity, cytotoxicity, and in the stages of carcinogenesis that are affected. 

Dose-response assessments for chemical carcinogens generally are more uncertain than dose-response assessments for ionizing radiation. 

Contains information on hazard identification and dose - response assessment of over 600 hazardous substances. Covers toxicity, carcinogenicity, chemical and physical properties, and applicable regulations. Includes the reference dose as defined by US EPA, unit risk of exposure by oral and inhalation routes. Produced by the US EPA. (CIS, TOXNET available on CD as part of TOMES Plus by Micromedex and on the EPA Internet website). 

Because the dose-response assessment step is performed differently for agents considered to be carcinogens compared to those classified as noncarcinogens, the risk characterization process for these two kinds of agents differs as well. The result of the dose-response assessment for carcinogens is some measure of the potency of the agent for example, the... 

IRIS is a toxicology data file that contains data in support of human health risk assessment. It is compiled by the US EPA and contains over 500 chemical records. IRIS data, focusing on hazard identification and dose-response assessment, are reviewed by work groups of EPA scientists and represents EPA consensus. Among the key data provided in IRIS are EPA carcinogen classifications, unit risks, slope factors, oral reference doses, and inhalation reference concentrations. 

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. 

Interestingly, while much of the focus over the past several years has been applying traditionally noncancer approaches, such as the BMD analysis, to nonlinear carcinogens, a recent NRC report has advocated an alternative approach to unifying dose-response assessments for cancer and noncancer endpoints. This report reflects some of the positions summarized by White et al. (2009) discussed earlier in the context of the low-dose linearity of carcinogens. 

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