Noncancer Risk Assessment

Baird, S.J.S., J.T. Cohen, J.D. Graham, A.I. Shylakter, and J.S. Evans. 1996. Noncancer risk assessment Alternatives to current Practice. Hum. Ecol. Risk Assess. 2 79-102. 

Clewell, H.J., M.E. Andersen, and H.A. Barton. 2002a. A consistent approach for the application of pharmacokinetic modeling in cancer and noncancer risk assessment. Environ. Health Perspect. 110 85-93. 

Dourson, M.L., S.P. Pelter, and D. Robinson. 1996. Evolution of science-based uncertainty factors in noncancer risk assessment. Regul. Toxicol. Pharmacol. 24 108-120. 

Renwick, A.G. and N.R. Lazarus. 1998. Human variability and noncancer risk assessment—An analysis of the default uncertainty factor. Regul. Toxicol. Pharmacol. 27 3-20. 

Both qualitative and quantitative evaluations of uncertainty provide useful information in a risk assessment. The techniques of quantitative uncertainty analysis are evolving rapidly. An approach was recently proposed for estimating distribution of uncertainty in noncancer risk assessments (Baird et al., 1996). 

Borton, H. A., M. E. Anderson, and H. J. Clewell. Harmonization Developing consistent guidelines for applying mode of action and dosimetry information for applying mode of action and dosimetry information to cancer and noncancer risk assessment. Hum. Ecol. Risk Assess. 4 75-115, 1998. 

Renwick, A.G., and N.R. Lazarus. 1998. Human variability and noncancer risk assessment An analysis of the default uncertainty factor. Regul. Toxicol. Pharmacol. 27(1 Part l) 3-20. Reidy, C.A., J.T. Johnson, and M.J. Olson. 1990. Metabolism in vitro of fluorocarbon R-134a. 

Cicmanec, J.L., Dourson, M.L., Hertzberg, R.C. (1996). Noncancer risk assessment present and emerging issues. In Toxicology and Risk Assessment Principles, Methods, and Applications (A.M. Fan, L.W. Chang, eds), pp. 293-310. Marcel Dekker, New York, NY. 

Whenever possible, data on humans is used to conduct noncancer risk assessment, thereby avoiding the problems inherent with interspecies extrapolation. If sufficient data on sensitive individuals exist, the safe dose can be estimated directly, that is, without the need of an UF. If adequate data on sensitive humans do not exist, an uncertainty is encountered that must be addressed, most often with a 10-fold factor. This UF assumes that variability in response from one human to the next occurs and that this variability may not have been detected in the study, usually due to small sample size. This factor may also assume that subpopulations of humans exist that are more sensitive to the toxicity of the chemical than the average population. 

Haber LT, Dollarhide JS, Maier A, and Dourson ML (2001) Noncancer risk assessment Principles and practice in environmental and occupational settings. In Bingham E, Cohrssen E, and Powell CH (eds.) Fatty s Toxicology, 5th edn. New York Wiley. 

L. T. Haber, J. S. Dollarhide, A. Maier and M. L. Dourson, Noncancer Risk Assessment Principles and Practice in Environmental and Occupational Settings, Patty s Toxicology, 5(1), 169-232 (2001a). 

In the United States, the ERA is the lead agency on major waste sites, but there are thousands of smaller sites across the United States, for which states often take the lead. Because it is not possible to do a comprehensive cancer and noncancer risk assessment for each site (abandoned gas stations with petroleum hydrocarbon in the soil, for instance), the risk assessment process has been simplified with predefined cleanup standards for most common contaminants. These are often called Rreliminary Remediation Goals (RRGs) (ERA 2007). These may be modified by individual states to meet their own exposure or risk standards (CleanupLevels 2008). 

Once the BMD is identified, the one-sided lower 95th confidence interval on the BMD called the BMDL (benchmark dose lower bound) is used as the POD. Similar to noncancer risk assessment, the POD is then divided by uncertainty factors to account for potential interspecies differences, intraindividual variability, and so on. The current risk assessment paradigm has accepted that, by accounting for uncertainty through use of the BMDL and other uncertainty factors, the resulting dose is either below a toxic threshold or so low as to constitute a virtually safe dose (Bogdanffy et al. 2001). 

Over the past decade there has been a movement to harmonize cancer and noncancer risk assessment (Gaylor 1997 Bogdanffy et al. 2001) based on the premise that cancer and noncancer events share similar pharmacokinetic dependencies and overlapping MOAs and thus have similar dose-response relationships. The benchmark dose approach lends itself to the evaluation of both linear and nonlinear dose-response. In fact, one of the stated purposes of EPA s formalization of the benchmark dose process was to provide a standardized approach to chemical dose-response assessment, regardless of whether the chemical is a carcinogen. 

Use of this proposed approach represents a significant paradigm shift in noncancer risk assessment and is inconsistent with basic biological principles. Earlier in this chapter we discussed the fact that it is unlikely for many carcinogens to operate with a linear dose-response. Although it is possible for a single molecule to interact with DNA to increase cancer risk, carcinogenesis is not a multistep process, and protective controls are in place to limit tumor formation. 

Under this same line of reasoning, it is even less likely for a single-molecule interaction to increase the risk of noncancer effects. As noted earlier, biological systems have several levels of redundancy, such that insults to one cell or even many cells is not sufficient to lead to a loss of function. In response to the assertion that noncancer risk assessment should default to a linear approach, Rhomberg (2009) has commented that there are still fundamental differences between carcinogenicity... 

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