Risk assessment of carcinogens

Substance Biological monitoring guidance values Monitoring schedule 

Butan-2-one 70 4mol butan-2-one/l in urine (HGV) Post shift 

Carbon monoxide 30 ppm carbon monoxide in end-tidal breath (HGV) Post shift 

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Risk assessment of carcinogens is a two-step process involving first, a qualitative assessment of the data from the hazard identification stage (see above) and second, a quantitation of the risk for definite or probable human carcinogens. 

Farris GM, Miller GK, Wollenberg GK, Molon-Noblot S, Chan C, Prahalada S. Recombinant rat and mouse growth hormones risk assessment of carcinogenic potential in 2-year bioassays in rats and mice. Toxicol Sci 2007 97 548-61. 

The first section of this chapter provides a discussion of hazard assessment, classification of potentially dangerous substances, and the process of risk assessment. A summary of the mandatory and voluntary initiatives for regulating chemicals and biocides in the United States and Europe is also included together with information on the regulatory aspects of hazard communication. The second section deals with the scientific aspects of hazard identification and risk assessment of carcinogenic chemicals within the regulatory context. 

Kroes, R. (1987). Contribution of toxicology towards risk assessment of carcinogens. Arch Toxicol 60, 224-228. 

The potential for a compound to induce carcinogenicity is a crucial consideration when establishing hazard and risk assessment of chemicals and pharmaceuticals in humans [53]. To date, the standard approach to assess carcinogenicity at a regulatory level is the 2-year bioassay in rodents. According to the recent REACH... 

Toxicity and exposure studies indicate PFOA is immunosuppressive and can cause developmental problems and other adverse effects in laboratory animals, such as rodents [Lau et al (2004), Lau et al (2006)]. In 2005 the US Environmental Protection Agency (EPA) released a draft risk assessment of its potential human health effects [U S. EPA (2005)]. A subsequent review by the EPA science advisory board concluded that there is sufficient evidence to classify PFOA as likely human carcinogenic. 

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. 

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. 

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 ... 

ECETOC. 2002. The use ofTZS estimates and alternative methods in the regulatory risk assessment of nonthreshold carcinogens in the European Union. Technical Report No. 83. Brussels ECETOC. 

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/... 

Sanner, T., E. Dybing, M.I. Willems, and E.D. Kroese. 2001. A simple method for quantitative risk assessment of non-threshold carcinogens based on the dose descriptor T25. Pharmacol Toxicol. 88 331-341. 

Factorial designs, in which n chemicals are tested at x dose levels (x treatment groups) have been suggested by the US-EPA (US-EPA 1986) as a statistical approach for risk assessment of chemical mixmres. A 2 factorial design has been used to describe interactions between the carcinogenic activity of five polycyclic aromatic hydrocarbons at two dose levels (Nesnow 1994) and a 5 design to identify nonadditive effects of three chemicals on developmental toxicity at five dose levels (Narotsky et al. 1995). 

Use of Response/Effect Addition in the Risk Assessment of Mixtures OF Carcinogenic Polycyclic Aromatic Hydrocarbons... 

Krewski, D., T. Thorslund, and J. Withey. 1989. Carcinogenic risk assessment of complex mixtures. Toxicol. Ind. Health 5 851-867. 

Assessment of the carcinogenic risk to humans from a review of animal data is complicated by the results of pharmacokinetic studies that have associated methylene chloride carcinogenicity with a specific metabolic pathway. This glutathione S-mediated pathway appears to proceed slowly in humans compared with mice and only at high exposure doses. Therefore, extrapolation from high dose to low dose and between species may not provide accurate risk assessment of human exposure. 

Table 7.18. Non-carcinogenic risk assessment of POPs to the residents of Hong Kong in 2003...

Results of assessment of carcinogenic risks associated with exposure of local residents to POPs contamination in the local marine environment are presented in Table 7.22. The calculated cancer risks of POPs all fell well within the 1 x 10 4-1 x 10-6 range, indicating there was no unacceptable cancer risk of toxicological concern associated specifically with a lifetime exposure of local residents to the current level of POPs contamination in the local marine environment via dietary intake of locally caught seafood (marine fish and shellfish) and incidental ingestion of seawater during recreational activities. 

Table 7.21. Human non-carcinogenic risk assessment of POPs pollution in the marine environment of Hong Kong in 2000-2004...

Rozman K, Roth WL, Greim H, et al. 1993. Relative potency of chlorinated dibenzo-p-dioxins (CDDs) in acute, subchronic and chronic (carcinogenicity) toxicity studies Implications for risk assessment of chemical mixtures. Toxicology 77(l-2) 39-50. 

Gibb HJ, Chen CW, Hiremath CB. 1988. Carcinogen risk assessment of chromium compounds. Washington, DC Office of Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency. EPA-600/D-880129. 

TABLE 19.4a Examples of communication of human carcinogenic risk without preclinical assessment of carcinogenic risk... 

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