Models carcinogenic risk assessment

Crump, K.S., and R.B.Howe. 1984. The multistage model with a time-dependent dose pattern Applications to carcinogenic risk assessment. Risk Anal 4 163-176. 

In its 1986 Guidelines for Carcinogen Risk Assessment, the US-EPA introduced the LMS model into the U.S. regulatory framework. The multistage model was chosen for regulatory... 

Crouch, E.A.C. (1983b). Carcinogenic risk assessment — the consequences of believing models, Basic Life ScL 24,653. 

Krewski, D., Withey, J.R., Ku, L.F. and Andersen, M.E. (1994) Applications of physiologic pharmacokinetic modeling in carcinogenic risk assessment. Environ. Health Perspect., 102, (Suppl 11) ... 

Maltoni C, Lefemine G, Cilibedi A, Cotti G, Carretti D (1981) Carcinogenicity bioassays of vinyl chloride monomer A model of risk assessment on an experimental basis. Environ Health Perspect, 41 3-29. 

The consideration of mode of action in carcinogen risk assessment is becoming standard practice. When data are adequate to demonstrate use of the standard default low dose extrapolation models such as the linearized multistage model is not appropriate, alternate approaches, including threshold approaches are now being used. 

By assuming TCDD Is an Initiator when the data attest to the contrary, EPA and CDC are not Incorporating all the available data Into their assessments. In EPA s "Proposed Guidelines for Carcinogen Risk Assessment" ( ), they stipulate that models used In risk assessment should reflect data on mechanism of carcinogenesis ... 

Thus, model selection, and data selection to define dose/response curves, are critical variables in assessing risk. The guidelines on carcinogenic risk assessment issued by EPA in 1984 give considerable freedom to the risk assessor on model and data selection and results on the same problem assessed by two individuals can vary widely. 

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). 

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 ... 

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