Cancer risk assessments

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 ... 

CRUMg K.S., Hoel, D., Langley, C., and Peto, R. (1976). Fundamental carcinogenic processes and their implications for low dose risk assessment, Cancer Res., 36 2973. 

B. Butterworth, R. Conolly, and R. Morgan, A Strategy for Establishing Mode of Action of Chemical Carcinogens as a Guide for Approaches to Risk Assessment, Cancer Lett. 95 (1995) 129-46. 

Butterworth BE, Conolly RB, Morgan KT. 1995. A strategy for establishing mode of action of chemical carcinogens as a guide for approaches to risk assessments. Cancer Lett 93 129-146. 

Andersen, M. E., Krewski, D., and Withey, J. R. (1993). Physiological pharmacokinetics and cancer risk assessment. Cancer Lett 69, 1-14. 

There are many definitions of the word risk. It is a combination of uncertainty and damage a ratio of Itazards to safeguards a triplet combination of event, probability, and consequences or even a measure of economic loss or human injury in terms of both the incident likelihood and tlie magnitude of the loss or injuiy (AICliE, 1989). People face all kinds of risks eveiyday, some voluntarily and otliers involuntarily. Tlierefore, risk plays a very important role in today s world. Studies on cancer caused a turning point in tlie world of risk because it opened tlie eyes of risk scientists and healtli professionals to tlie world of risk assessments. 

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. 

To assess tlie overall potential for noncarcinogenic effects posed by more dian one chemical, a liazard index (HI) approach has been developed based on EPA s Guidelines for Healdi Risk Assessment of Chemical Mixtures. This approach assumes that simultaneous subtlu eshold exposures to several chemicals could result in an adverse healtli effect. It also assumes tliat tlie magnitude of the adverse effect will be proportional to tlie sum of the ratios of the subtlireshold exposures to acceptable exposures. The non cancer hazard index is equal to tlie sum of the hazard quotients, as described below, where E and tlie RfD represent the same exposure period (e.g., subclironic, clironic, or shorter-term). 

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 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). 

Clewell HJ, Gentry PR, Gearhart JM, et al. 1995. Considering pharmacokinetic and mechanistic information in cancer risk assessments for environmental contaminants Examples with vinyl chloride and trichloroethylene. Chemosphere 31 2561-2578. 

A number of calculators are available on the Internet to estimate a patient s risk of developing breast cancer. The National Cancer Institute (NCI) has an online version of the Breast Cancer Risk Assessment Tool that is considered to be the most authoritative and accurate standard (www.cancer.gov/ bcrisk-tool). The Breast Cancer Risk Assessment Tool was designed for health professionals to project a women s individualized risk for invasive breast cancer over a 5-year period and over her lifetime. 

It is clear that patients with febrile neutropenia represent a heterogeneous group. Some patients are at lower risk and potentially could be treated as outpatients, thereby avoiding the risk and cost of hospitalization. The Multinational Association for Supportive Care in Cancer (MASCC) has validated a risk-assessment tool that assigns a risk score to patients presenting with febrile neutropenia7 (Table 96-3). Patients with a risk-index score of 21 or greater are identified as low risk and are candidates for outpatient therapy (discussed under Treatment ). 

The exposure pathways of concern identified during the baseline risk assessment include direct contact, with the possible ingestion of contaminated soil (1 x 10 3 4 associated excess cancer risk), and potential ingestion of contaminated groundwater in the future through existing or newly installed offsite wells (2 x 11 0 2 associated excess cancer risk). 

The risk assessment has also concluded that a level of 200 mg/kg for lead in the soil will be a protective level for expected site exposures along with an excess cancer risk level for TCE-contaminated soil (56 pg/L). Based on investigations of activities at the site, the TCE-contaminated soil has not been determined to be a listed RCRA hazardous waste, as the cleaning solution records indicate the solution contained less than 10% TCE. However, the lead-contaminated soil is an RCRA hazardous waste by characteristic in this instance due to extraction procedure (EP) toxicity. None of the waste is believed to have been disposed at the site after November 19, 1980 (the effective date for most of the RCRA treatment, storage, and disposal requirements). 

The following example is based on a risk assessment of di(2-ethylhexyl) phthalate (DEHP) performed by Arthur D. Little. The experimental dose-response data upon which the extrapolation is based are presented in Table II. DEHP was shown to produce a statistically significant increase in hepatocellular carcinoma when added to the diet of laboratory mice (14). Equivalent human doses were calculated using the methods described earlier, and the response was then extrapolated downward using each of the three models selected. The results of this extrapolation are shown in Table III for a range of human exposure levels from ten micrograms to one hundred milligrams per day. The risk is expressed as the number of excess lifetime cancers expected per million exposed population. 

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