Risk assessment of genotoxic carcinogens

Valid epidemiological studies are preferable for the quantitative risk assessment of genotoxic carcinogens for the purpose of deriving a tolerable intake. If such data are available, for example in the working environment, they can be used quantitatively to convert work exposure to lifetime exposure, i.e., to convert intermittent exposure to continuous exposure (see Section 5.1 for adjustment of concentrations). However, as addressed in Chapter 3, valid human data are seldom available. 

At present, there is no clear consensus on an appropriate methodology for the risk assessment of genotoxic carcinogens. A number of approaches based largely on characterization of dose-response have been adopted for the assessment of genotoxic carcinogens ... 

The available evidence indicates that Druckrey s equation [Eq. (3.10)] with n > 1 can serve as a regulatory basis for risk assessment of genotoxic and nongenotoxic carcinogens. Carlborg (1981) pointed out that this equation is implied by a Weibull model for dose-response functions in carcinogenesis, as follows. The simple form of the Weibull model is... 

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. 

EFSA. 2005. Draft opinion on a harmonized approach for risk assessment of compounds which are both genotoxic and carcinogenic. Request No EFSA-Q-2004-020, EFSA Scientific Committee, The European Food Safety Authority, 7 April 2005. Brussels EFSA. http /www.efsa.eu.int/en/... 

EFS A (2005) Opinion of the scientific committee on a request from EFSA related to a harmonised approach for risk assessment of substances which are both genotoxic and carcinogenic. The EFSA Journal 282 1-31. http //www.efsa.eu.int/science/sc commitee/sc opinions/1201/... 

Fan AM and Howd R (2001) Quantitative risk assessment of non-genotoxic carcinogens. In Choy WN (ed.) Genetic Toxicology and Cancer Risk Assessment, pp. 299-320. New York Dekker. 

Farmer, P. B., and Singh, R. (2008). Use of DNA adducts to identify human health risk from exposure to hazardous environmental pollutants The increasing role of mass spectrometry in assessing biologically effective doses of genotoxic carcinogens. Mutat Res 659, 68-76. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency or perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer end points (if derived) and the end points from which they were derived are indicated and discussed. 

This study, like that of Fisher and Allen (1993), incorporated a linear multistage model. However, the mechanism of trichloroethylene carcinogenicity appears to be non-genotoxic, and a non-linear model (as opposed to the linearized multistage model) has been proposed for use along with PBPK modeling for cancer risk assessment. The use of this non-linear model has resulted in a 100-fold increase in the virtually safe lifetime exposure estimates (Clewell et al. 1995). 

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