Quantitative Risk Carcinogens

Where Risk = a unilless probability (c.g., 2x 10 ) of an individual developing cancer 

CDl = chronic daily inliUre averaged over 70 years (mg/kg-day) 

Howci cr, this linear equation is valid only at low risk levels (i.e., below estimated risks of 0.01). For situations where chemical intakes might be liigh (i.e., risk above 0.01), an altcrmilc equation should be used. The one-liit equation, which is consistent with the linear low-dose model given above and described below, should be used instead. 

Because the slope factor is often an upper 95 percentile confidence limit of the probability of response based on experimental animal data used in tlie multistage model, tlie carcinogenic risk estimate will generally be an upper-bound estimate. Tliis means tliat tlie EPA is reasonably confident tliat tlie true risk will not exceed the risk estimate derived tlirough use of tliis model and is likely to be less than tliat predicted. 

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Section 13.2 Qualitative Risk Scenarios Section 13.3 Quantitative Risk Non-carcinogens Section 13.4 Quantitative Risk Carcinogens Section 13.5 Risk Uncertainties/Liinitations Section 13.6 Risk-Based Decision Making Section 13.7 Public Perception of Risk... 

J.P. Leape. "Quantitative Risk Assessments in Regulation of Environmental Carcinogens." Harvard Environmental Law Review, 4, 1980, p. 86. 

DK NFA. 1990. Quantitative Risk Analysis of Carcinogens. Sphorg, Denmark National Eood Agency of Denmark, Institute of Toxicology, Ministry of Health. 

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 most widely used of the many mathematical models proposed for extrapolation of carcinogenicity data from animal studies to low-dose human exposures (i.e., low-dose extrapolation) is the LMS model. This has, in effect, become the default approach for quantitative risk assessment and has been used by, e.g., the US-EPA for many years as well as by the WHO in relation to derivation of drinking-water guideline values for potential carcinogens (WHO 1996) (see Section 9.2.1.2 for drinking-water guideline values). 

The 95% confidence limits of the estimate of the linear component of the LMS model, /, can also be calculated. The 95% upper confidence limit is termed qi and is central to the US-EPA s use of the LMS model in quantitative risk assessment, as qi represents an upper bound or worst-case estimate of the dose-response relationship at low doses. It is considered a plausible upper bound, because it is unlikely that the tme dose-response relationship will have a slope higher than qi, and it is probably considerably lower and may even be zero (as would be the case if there was a threshold). Lfse of the qj as the default, therefore, may have considerable conservatism incorporated into it. The values of qi have been considered as estimates of carcinogenic potency and have been called the unit carcinogenic risk or the Carcinogen Potency Factor (CPF). 

In 1996, the US-EPA published their Proposed Guidelines for Carcinogen Risk Assessment (US-EPA 1996). These Proposed Guidelines were a revision of the 1986 Guidelines for Carcinogen Risk Assessment (US-EPA 1986) and introduced, among others, a new approach for the quantitative risk assessment. A revised draft Guidelines was launched in 1999 (US-EPA 1999) and the final version was published in 2005 (US-EPA 2005). 

Within the EU chemical s regulation, a more simple approach based on the dose descriptor T25 has been proposed as a basis for quantitative risk characterization of non-threshold carcinogens. 

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. 

Nesnow S. 1994. Mechanistic linkage between DNA adducts, mutations in oncogenes, and tumorigenicity of carcinogenic aromatic hydrocarbons in strain A/J mice. In Chemical mixtures and quantitative risk assessment. Abstract of the second annual HERL symposium, Nov. 7-10., Raleigh, North Carolina Health Effects Research Laboratory, U.S. Environmental Protection Agency. 

The Monographs represent the first step in carcinogenic risk assessment, which involves examination of all relevant information in order to assess the strength of the available evidence that certain exposures could alter the incidence of cancer in humans. The second step is quantitative risk estimation. Detailed, quantitative evaluations of epidemiological data may be made in the Monographs, but without extrapolation beyond the range of the data available. Quantitative extrapolation from experimental data to the human situation is not undertaken. 

The fundamental question of risk assessment for potential human carcinogens requires definition of substances that exceed an evidentiary threshold. Once the scientific evidence establishes a substantial basis for conclusion of known or potential human cancer, it is then in order to determine a procedure for risk quantification. Quantitative risk assessments must always be read with the qualitative evidence of the likelihood of carcinogenicity. 

Perhaps one of the most politically sensitive areas is that of oncogenicity. Many arguments on the quantitation of carcinogenicity have included hip-shooting and emotional controversy. It is still hoped that evidence of carcinogenicity will not be the only step upon which regulations are based. Potency and risk of actual exposure from use patterns will hopefully be critically considered. If this can be accomplished, better delineation of impacts of the risk and benefits should result (19). 

FDA (U.S. Food and Drug Administration). 1990. Carcinogenic risk assessment for dioxins and furans in fish contaminated by bleached-paper mills. Report of the Quantitative Risk Assessment Committee. Washington, DC Food and Drug Administration. 

If carcinogenicity data are unavailable or inconclusive, the next step (Level 4) is to test for mutagenicity in the mouse. In many cases, the presence or absence of mutagenicity in the short-term tests and in the mouse may be sufficient evidence for a decision. In the most difficult cases, a quantitative risk estimate may be needed. 

Although sophisticated mathematical models are often relied upon for quantitative risk assessments, assessments have also been made on more qualitative evaluation of animal test data. In part this is because mathematical models are often based on assumptions on mutation rates and not all carcinogens are primary mutagens. 

When an agent is classified as a human or probable human carcinogen, it is then subjected to a quantitative risk assessment. For those designated as possible human carcinogen, the risk assessor can determine on a case-by-case basis whether a quantitative risk assessment is warranted. 

In the US, quantitative risk assessments are conducted for carcinogenicity. The risk assessment is performed by multiplying the chronic dietary exposure estimate by the qi. ... 

In the United States, some state and federal regulatory agencies conduct quantitative risk assessments on known or suspect carcinogens for continuous or long-term human exposure by extrapolating downward in linear fashion from an npper confidence limit on theoretical excess risk (FDA 1985 EPA 1986). The values derived for a specified acceptable theoretical excess risk to the U.S. human population, based on a lifetime of exposure to a carcinogenic substance, have been used extensively for regulatory purposes. 

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. 

In certain cases, the FDA has applied a negligible risk concept for food additives. This is demonstrated in the case of dimethyl dicarbamate, a yeast inhibitor for use in beverages (FDA 2000). The additive evenmaUy decomposes to methanol and carbon dioxide, but in the presence of ammonium ions (not uncommon in certain beverages) a carcinogenic chemical may also be formed in small amounts. The FDA used formal quantitative risk assessment procedures to estimate the upper-bound limit of carcinogenic risk to humans posed by urethane generated by decomposition of the additive. It was concluded that the potential risk was sufficiently low that the additive would be safe for the requested use, and the FDA s final rule approved its use (56 FR 40502 1988). 

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