Non-carcinogens, risk assessment

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

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

In health risk assessments, non carcinogenic risks are estimated via Hazard Indices . A general equation for a liazard index (HI) is as follows ... 

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). 

Mutagenicity and carcinogenicity are generally considered to be non-threshold effects, unless a non-genotoxic mechanism can be established with a NOEL (or NOAEL or LOAEL). Risk assessment is based on establishing whether exposure is prevented. A similar process of preventing exposure also applies for skin and respiratory sensitisers, since there is no means of identifying a dose or concentration below which adverse effects will not occur in someone already sensitised to a particular substance. 

The EPA makes decisions about clean-up of abandoned hazardous waste sites under the so-called Superfund law. Risk assessment outcomes are one guide to the decision process. The agency has declared that, for carcinogenic contaminants, clean-up must reach lifetime risks somewhere in the range of one in 10 000 to one-in-one million most decisions seem to aim at risks of one in 100 000 or lower. Hazard index values for non-carcinogens are not expected to exceed one. Costs and technical feasibility figure heavily in these decisions. 

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. 

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. 

The health risk to local residents associated specifically with exposure to POPs contamination in the local marine environment was assessed by (a) comparing the levels of POPs contamination in marine fish and shellfish sampled in the local waters with relevant Food Safety Standards/Action Levels and (b) evaluating the non-carcinogenic and carcinogenic risks of individual POPs intake via consumption of locally caught seafood and incidental ingestion of seawater during recreational activities. 

The effects of genotoxic compounds are considered non-threshold. Thus, risk assessment for a given exposure is usually performed by a linear or sub-linear extrapolation from the high dose effects observed in animals to the lower human exposure. Since the outcome of the extrapolation depends on the model applied and extrapolation over different orders of magnitude is error prone, the European Food and Safety Authority (EFSA 2005) recommended to avoid this extrapolation and proposed the MOE approach. This approach uses the benchmark dose, or the T25 calculated from a carcinogenicity study and compares this with human exposure. A MOE of 10,000 and more is considered to be of minor concern. The advantage is that neither a debatable extrapolation from high to low doses needs to be performed nor are hypothetical cancer cases calculated. For details of the different approaches see, SCHER, SCCP, SCENIHR (2008). 

The ICH addressed several main questions. These included Would the use of rats, but not mice, result in loss of information on carcinogenicity that would be relevant to human risk assessment and Has a positive result in mice (but not in rats) correctly prevented a non-genotoxic drug from being marketed ... 

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. 

The risk models described herein for carcinogens are not yet much used outside the United States. Carcinogens tend either simply to be banned, where it is possible to do so, or are treated the way non-carcinogens are treated in the United States. The discussion of risk assessment as applied to non-cancer forms of toxicity is thus applicable to carcinogens in countries outside the U.S.A. 

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