Carcinogenic risk assessment

Arguably, risk assessment from exposure to carcinogens merits special consideration because of the low levels of exposure capable of producing an adverse response in certain individuals coupled with the often long time-lag (latency period) between exposure and onset of disease. 

Olden, K., and Klein, J.-L. (1995). Environmental health science research and human risk assessment. Mol, Carcinogen. 14, 2-9. 

Savolainen, K. M. (1997). The use of maximum tolerated dose in rodent carcinogenicity bioas says and its relevance to human risk assessment. Hum. Exp. Toxicol. 16, 190-192. 

Generally, the slope factor is a plausible upper bound estimate of the probability of a response per unit intake of a ehemieal over a lifetime. The slope factor is used in risk assessments to estimate an upper-bound lifetime probability of an individual developing cancer as a result of e.xposure to a particular level of a potential carcinogen. Slope factors should always be accompanied by the weight-of-evidence classification to indicate the strength of the evidence that the agent is a human carcinogen. Calculational details are presented below. 

The cancer risk equation described below estimates tlie incremental individual lifetime cancer risk for simultaneous exposure to several carcinogens and is based on EPA s risk assessment guidelines. Tliis equation represents an approximation of the precise equation for combining risks wliich accounts for tlie joint probabilities of tlie same individual developing cancer as a consequence of exposure to two or more carcinogens. The difference between tlie precise equation and tlie approximation described is negligible for total cancer risks less tlian 0.1. Thus, tlie simple additive equation is appropriate for most risk assessments. The cancer risk equation for multiple substances is given by ... 

The reader should note that tlie introductory comments in tine similarly titled subsections of the previous section applies to carcinogens as well. The calculation proceeds as follows. First, smn tlie cancer risks for each exposure patliway contributing to exposure of the same individual or subpopulation. For Superfimd risk assessments, cancer risks from various exposure patliways are assumed to be additive, as long as tlie risks are for tlie same individuals and time period (i.e., less-tlian-lifetime e.xposures have all been converted to equivalent lifetime exposures). Tliis smnmation procedure is described below ... 

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

The following equation can be used in risk assessment studies for carcinogens ... 

In health risk assessment, the carcinogenic risk calculation by inhalation (IR) can be calculated by ... 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency or perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer end points (if derived) and the end points from which they were derived are indicated and discussed. 

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). 

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). 

DAVIES T s and monro a (1994) The rodent carcinogenicity bioassay produces a similar frequency of tumor increases and decreases implications for risk assessment . Regulatory Toxicol Pharmacol. 20 281-301. 

U.S. EPA may list a waste as hazardous for any and all of the above reasons. The majority of listed wastes fall into the toxic waste category. To decide if a waste should be a toxic listed waste, U.S. EPA first determines whether it typically contains harmful chemical constituents. An appendix to RCRA contains a list of chemical compounds or elements that scientific studies have shown to have toxic, carcinogenic, mutagenic, or teratogenic effects on humans or other life forms. If a waste contains chemical constituents found on the appendix list, U.S. EPA then evaluates 11 other factors to determine if the wastestream is likely to pose a threat in the absence of special restrictions on its handling. These additional considerations include a risk assessment and study of past cases of damage caused by the waste. 

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... 

The Log-Probit Model. The log-probit model has been utilized widely in the risk assessment literature, although it has no physiological justification. It was first proposed by Mantel and Bryan, and has been found to provide a good fit with a considerable amount of empirical data (10). The model rests on the assumption that the susceptibility of a population or organisms to a carcinogen has a lognormal distribution with respect to dose, i.e., the logarithm of the dose will produce a positive response if normally distributed. The functional form of the model is ... 

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

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