Carcinogenic risk estimation

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. 

As a rule, the level of precision of a risk estimate cannot exceed the precision of the exposure and effects data from which it is obtained. In the following we will focus upon carcinogenic risk estimation, for which it will often be possible to achieve at least interval estimates of risk. 

There have been a number of recent survey articles and theoretical papers describing the available models for low-dose extrapolation. Through a literature review the most prominent models have been selected and discussed below. However, there are other models, less commonly used, that were not mentioned here for the sake of brevity. The models addressed below represent a good cross-section of the different features and capabilities that are pertinent to carcinogenic risk estimation. 

Reitz RH, Fox TR, Quast JF. 1982. Mechanistic considerations for carcinogenic risk estimation Chloroform. Environ Health Perspect 46 163-168. 

Reitz RH, Gehring PJ, Park CN. 1978. Carcinogenic risk estimation for chloroform An alternative to EPA s procedures. Food Cosmet Toxicol 16 511-514. 

Reitz RH, Quast JF, Scott WT, et al. 1980. Pharmacokinetics and macromolecular effects of chloroform in rats and mice. Implications for carcinogenic risk estimation. Water chlorination environmental impact and health effects 3 983-993. 

Ames, Bruce N., and Lois Swirsky Gold. 1988. Carcinogenic Risk Estimation. Science 240 (May 20) 1045-47. 

The evaluation of the carcinogenic potential of a chemical exposure in humans must be based on analyses of all relevant data. Human epidemiologic and cfinical smdies, as well as accidental-exposure reports are considered and used to evaluate the carcinogenic potential of a substance. In the absence of human data, long-term bioassay data from controlled animal studies are used to derive theoretical excess carcinogenic risk estimates for exposed humans. The selection of data for estimating risk is based on the species and strain considered to resemble the human response most closely to provide the most accurate estimates. 

The pharmacokinetic threshold has significance far beyond the specialized endeavor of carcinogenic risk estimation. Since virtually any toxic response is a function of the concentration X time product of the toxic chemical in the sensitive tissue, the relationship between steady state concentrations and administered dose levels is crucial in interpreting and predicting any toxic response as a function of exposure level. In particular, when otherwise efficient defense mechanisms or detoxification pathways are overwhelmed at sufficiently high dose levels dramatic nonlinear increases in toxicity may arise (, ). ... 

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

For carcinogens, risks are estimated as the incremental probability of an indii idual developing ameer o er a lifetime as a result of exposure to the potential carcinogen. The slope factor (SF) converts estimated daily intakes averaged over a lifetime of exposure directly to incremental risk of an individual developing cancer. 

Monte Carlo simulation, an iterative technique which derives a range of risk estimates, was incorporated into a trichloroethylene risk assessment using the PBPK model developed by Fisher and Allen (1993). The results of this study (Cronin et al. 1995), which used the kinetics of TCA production and trichloroethylene elimination as the dose metrics relevant to carcinogenic risk, indicated that concentrations of 0.09-1.0 pg/L (men) and 0.29-5.3 pg/L (women) in drinking water correspond to a cancer risk in humans of 1 in 1 million. For inhalation exposure, a similar risk was obtained from intermittent exposure to 0.07-13.3 ppb (men) and 0.16-6.3 ppb (women), or continuous exposure to 0.01-2.6 ppb (men) and 0.03-6.3 ppb (women) (Cronin et al. 1995). 

If linear (dose) models without thresholds are to be used for carcinogen (or other) risk assessment, estimation of exposure at specified levels becomes irrelevant to risk assessment or, at least, its use is nonintuitive. For example, a carcinogen risk analysis may be based on a linear, nonthreshold health effects model. The total health risk would thus be proportional to the long-term exposure summed for all affected people for the identified period, and exposure of many people at low concentrations would be equivalent to exposure of a few to high concentrations. The atmospheric dispersion that reduces concentrations would also lead to exposure of more people therefore, increments... 

In order to extrapolate laboratory animal results to humans, an interspecies dose conversion must be performed. Animals such as rodents have different physical dimensions, rates of intake (ingestion or inhalation), and lifespans from humans, and therefore are expected to respond differently to a specified dose level of any chemical. Estimation of equivalent human doses is usually performed by scaling laboratory doses according to observable species differences. Unfortunately, detailed quantitative data on the comparative pharmacokinetics of animals and humans are nonexistent, so that scaling methods remain approximate. In carcinogenic risk extrapolation, it is commonly assumed that the rate of response for mammals is proportional to internal surface area... 

Federal Register. Scientific Bases for Identification of Potential Carcinogens and Estimation of Risk Request for Comments on Report, Federal Register, 44, 1979, pp. 39858-39879. 

Verified inhalation and oral slope factors were unavailable from U.S. EPA for dimethylhydrazine. A cancer assessment based upon the carcinogenic potential (withdrawn cancer slope factors) of dimethylhydrazine revealed that AEGL values for a theoretical excess lifetime 10 4 carcinogenic risk exceeded the AEGL-2 values that were based on noncancer endpoints. Because the risk for dimethylhydrazine exposure was estimated from nonverified sources and because AEGLs are applicable to rare events or single once-in-a-lifetime expo... 

Albert, R. E. et al., "The Carcinogen Assessment Group s Method for Determining the Unit Risk Estimate for Air Pollutants," U.S. Environmental Protection Agency, 1980. 

EPA. 1988a. Integrated Risk Information System (IRIS). Risk estimates for carcinogenicity for 1,2-diphenylhydrazine. Online. (Verification date 3/1/88). US Environmental Protection Agency, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office. Cincinnati, OH. 

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