Uncertainty Factors Used to Ensure Protection of Public Health. Based on Chapter 14-4: Toxicity Assessment

Chapter 14 of LaGrega et.al.’s Hazardous Waste Management pointed out that various approaches to dose-response assessments and hazard characterizations are utilized for threshold versus non-threshold endpoints. Carcinogens exhibit a non-threshold effect where the carcinogenic potency is determined by the slope factor, defined as the 95% upper bound confidence limit of the dose-response curve from a lifetime exposure to a chemical. Non-carcinogens exhibit a threshold effect, whereby Reference Doses (RfDs) or concentrations (RfCs) are used as estimates of a daily exposure to an agent that fails to induce any adverse health impact in humans. Unfortunately, the majority of chemicals of concern do not have human toxicological indices and thus, surrogate data or rodent NOAELS (No Observable Adverse Effect Levels) are used to determine these important RfC’s by dividing the NOAEL by uncertainty or safety factors.

The EPA adopted the term “uncertainty factor” to reflect true scientific uncertainties in the establishment of acceptable intakes. In principle, dividing by the uncertainty factors allows for interspecies variability (such as using mice data for human extrapolation) and intraspecies variability (such as different genetic predispositions or chemical sensitivities among human populations). Additional uncertainty factors may be required if there are experimental inadequacies (such as inadequate numbers of study animals), or an LOAEL (Lowest Observable Adverse Effect Levels) is used instead of an NOAEL. Each factor is normally assigned a default value of 10.

In today’s world, decisions and actions are often demanded or required even when there is a high level of uncertainty in the available toxicological data. As a result, most risk assessments are actually scientific hypotheses that are not testable with any practical epidemiological study. To account for these uncertainties, The EPA has taken a protective approach to ensure all uncertainty factors are considered when calculating the toxicological indices so risks are overestimated rather than underestimated.

Though the public may be skeptical in accepting these estimated values instead of absolute, proven values, the policy decision to act before science is certain is the right approach and the only way to adequately protect the public until more advanced models are available. From my readings, there definitely appears to be an increasing need to integrate biologically and mechanistically based data (such as that derived by physiologically based pharmacokinetic (PB-PK) modeling) to refine this risk-assessment process. Though this modeling started to be used in risk assessments in the mid 1980’s, the complexity seems to have limited the use to chemicals of very high concern such as polychlorinated biphenyls and other persistent molecules. I hope we start to see more widespread use of this, and other advanced modeling techniques, to more accurately predict dose responses and relieve public fears of “uncertain” estimates.

References:

Anderson, M.E. (1999). Physiologically based pharmacokinetic (PB-PK) models in the study of the disposition and biological effects of xenobiotics and drugs. Toxicology Letters, 82, 341-348. doi:10.1016/0378-4274(95)03487-0.

Dorne, J.L.C.M. & Renwick,A.G. (2005). The Refinement of Uncertainty/Safety Factors in Risk Assessment by the Incorporation of Data on Toxicokinetic Variability in Humans. Toxicological Sciences, 86(1), 20–26. doi:10.1093/toxsci/kfi160.

Greim, H. & Snyder R. (2008). Toxicology and Risk Assessment: A Comprehensive Introduction. West Sussex, England: John Wiley & Sons Ltd. Pages 5-6.

Klassen, C.D. (2008). Casarett and Doull’s Toxicology: The Basic Science of Poisons. McGraw-Hill eBook. DOI: 10.1036/0071470514.

LaGrega et al (2001). Hazardous Waste Management, 2nd edition. Pages 884-887.
Rodricks, J.V. (2007). Calculated Risks: The Toxicity and Human Health Risks of Chemicals in our Environment. Cambridge, UK: Cambridge University Press. Pages 231-249.