Carcinogens, genotoxic, related

Ethylene oxide is used in the manufacture of raw materials and can be used to sterilize the surface of finished products and containers. Unfortunately, ethylene oxide is a genotoxic carcinogen and its use is not accepted without justification. In any event, tight controls are required on residues of ethylene oxide and its halohydrin-related substances. For raw materials the amount of these residues is limited to 1 and 50 pig/g, respectively for finished products 1 and 50 pg/g, respectively (with any affected ingredients subject to the control limits for raw materials) and for containers, based on simulated use, 1 and 50 pg/mL container volume, respectively. 

Harwood M, Danielewska-Nikiel B, Borselleca JF, Flamm GW, Williams GM and Lines TC. 2007. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol 45 2179-2205. 

Many sites of exposure to bile in the body are associated with the development of cancer, e.g. the oesophagus, gallbladder and bile duct, pancreas, small intestine and colon (reviewed in ref. 2). One explanation for increased cancer at these sites could be that bile acids stimulate carcinogenesis via DNA-damaging effects. This chapter provides an overview of research conducted in relation to establishing the genotoxic and carcinogenic effects of bile acids. 

Renwick considered that in relation to carcinogenicity for non-genotoxic chemicals and teratogenicity, the application of an extra factor for nature of toxicity is difficult to justify scientifically. He concluded that if a safety factor for nature of toxicity is to be used then logically it should be apphed to the NOAEL for the toxicity, which resulted in its use. For example, in relation to teratogenicity, a factor for nature of toxicity should be applied to the NOAEL for teratogenicity and not for maternal toxicity or some other endpoint. For carcinogenicity, the extra factor should be applied only to the NOAEL for the detection of tumors in those studies where this effect was the rationale for the use of an extra factor. In relation to a steep dose-response, it was concluded that this, in reality, concerns the precision of the NOAEL and therefore relates to the adequacy of the database rather than nature of toxicity. 

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. 

The WHO considers in its drinking-water quality guidelines, in relation to genotoxic carcinogens, that a lifetime cancer risk for consumers of less than 10 represents a tolerable risk (WHO 1996). Guideline values associated with excess lifetime cancer risks of 10 and 10 are also presented for the genotoxic carcinogens to emphasize the fact that each country should select its own appropriate risk level. 

In relation to their air quality guidelines, the WHO has estimated the risk associated with lifetime exposure to a certain concentration of a genotoxic carcinogen by linear extrapolation and the carcinogenic potency expressed as the incremental unit risk estimate. However, the guideline sections for carcinogenic pollutants also provide the concentration in air associated with an excess cancer risk of 10 ", 10 , and 10 , calculated from the unit risk, in order to support authorities in the decision-making process. 

Some EU Member States have also applied similar lifetime cancer risk estimates in judging tolerable risk levels. There is as yet no EU harmonized view on such default risk estimates at a policy level, although the starting point for the derivation of limit values for the general population in relation to the EU directives on ambient air and drinking water quality is the 10 lifetime risk for genotoxic carcinogens. 

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/... 

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