Evaluation of the Uncertainty Factor for Subchronic-to-Chronic Extrapolation: Statistical Analysis of Toxicity Data

Pieters, Moniek N.; Kramer, Hester; Slob, Wout

doi:10.1006/rtph.1997.1196

Cited by 73 publications

(28 citation statements)

References 8 publications

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“…Swartout (22) observed an average ratio of two and a value of 17 for the 95th percentile. As described previously, Pieters, Kramer, and Slob (15) observed for 149 cases a median ratio of 1.7 and S ᐉnU S ϭ 1.72, giving a 95th percentile of 29. An uncertainty factor of 10 for the prediction of chronic doses from subchronic studies appears to be inadequate to provide 95% coverage for that single factor.…”

Section: Multiplicity Of Uncertainty Factorsmentioning

confidence: 79%

Percentiles of the Product of Uncertainty Factors for Establishing Probabilistic Reference Doses

Gaylor

Kodell

2000

Risk Analysis

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Exposure guidelines for potentially toxic substances are often based on a reference dose (RfD) that is determined by dividing a no-observed-adverse-effect-level (NOAEL), lowest-observed-adverse-effect-level (LOAEL), or benchmark dose (BD) corresponding to a low level of risk, by a product of uncertainty factors. The uncertainty factors for animal to human extrapolation, variable sensitivities among humans, extrapolation from measured subchronic effects to unknown results for chronic exposures, and extrapolation from a LOAEL to a NOAEL can be thought of as random variables that vary from chemical to chemical. Selected databases are examined that provide distributions across chemicals of inter- and intraspecies effects, ratios of LOAELs to NOAELs, and differences in acute and chronic effects, to illustrate the determination of percentiles for uncertainty factors. The distributions of uncertainty factors tend to be approximately lognormally distributed. The logarithm of the product of independent uncertainty factors is approximately distributed as the sum of normally distributed variables, making it possible to estimate percentiles for the product. Hence, the size of the products of uncertainty factors can be selected to provide adequate safety for a large percentage (e.g., approximately 95%) of RfDs. For the databases used to describe the distributions of uncertainty factors, using values of 10 appear to be reasonable and conservative. For the databases examined the following simple "Rule of 3s" is suggested that exceeds the estimated 95th percentile of the product of uncertainty factors: If only a single uncertainty factor is required use 33, for any two uncertainty factors use 3 x 33 approximately 100, for any three uncertainty factors use a combined factor of 3 x 100 = 300, and if all four uncertainty factors are needed use a total factor of 3 x 300 = 900. If near the 99th percentile is desired use another factor of 3. An additional factor may be needed for inadequate data or a modifying factor for other uncertainties (e.g., different routes of exposure) not covered above.

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Section: Multiplicity Of Uncertainty Factorsmentioning

confidence: 79%

Percentiles of the Product of Uncertainty Factors for Establishing Probabilistic Reference Doses

Gaylor

Kodell

2000

Risk Analysis

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“…The ratios were generally in the range of approximately 2 to 5, with a majority of the ratios less than 10. The investigators arrived at different conclusions: Nessel et al (103) recommended that the UF S should be reduced to a default value of 3, based on their results of the ratio calculations, while Pieters et al (105) supported the continued usage of the default value of 10 for the UF S . The subchronic to chronic ratios show that the default UF S of 10 provides an uncertainty value that can be expected to provide a reasonable level of conservation when chemical-specific data are unavailable.…”

Section: Discussionmentioning

confidence: 97%

The Application of Non-Default Uncertainty Factors in the U.S. EPA's Integrated Risk Information System (IRIS). Part I: UF_L, UF_S, and “Other Uncertainty Factors”

Stedeford

Zhao

Dourson

et al. 2007

Journal of Environmental Science and Health, Part C

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The United States Environmental Protection Agency's Integrated Risk Information System (IRIS) includes hazard identification and dose-response assessment values developed by Agency scientists. Uncertainty factors (UFs) are used in the development of IRIS values to address the lack of information in five main areas. The standard UFs account for interspecies uncertainty (UF(A)) and intraspecies variability (UF(H)). The UF(A) addresses uncertainty related to the extrapolation of data from animals to humans, whereas the UF(H) addresses variability amongst individuals (i.e., intrahuman). Additional UFs have been employed to account for database incompleteness, extrapolations from a lowest-observed-adverse-effect level in the absence of a no-observed-adverse-effect level (UF(L)), and subchronic-to-chronic extrapolation (UF(S)). A sixth UF designated as "other uncertainty factors" (UF(O)) has also been applied in place of the UF(L) to account for uncertainty with the adversity of points of departure obtained using benchmark dose modeling. This review will discuss how UF(L), UF(S), and UF(O) have been applied in IRIS assessments, along with the rationale used to describe the choice of UF values that deviate from the standard default of 10.

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“…Previous analyses have evaluated ratios of NOAELs for chronic (1-2 years) versus subacute (3-6 weeks) and subchronic (10-26 weeks) exposures to animals (Kramer et al, 1996;Pieters et al, 1998). Phase 1 clinical trials (exposure 30 days) are more representative of a subacute exposure.…”

Section: Discussionmentioning

confidence: 99%

Application of the threshold of toxicological concern concept when applied to pharmaceutical manufacturing operations intended for short-term clinical trials

Bercu

Dolan

2013

Regulatory Toxicology and Pharmacology

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Evaluation of the Uncertainty Factor for Subchronic-to-Chronic Extrapolation: Statistical Analysis of Toxicity Data

Cited by 73 publications

References 8 publications

Percentiles of the Product of Uncertainty Factors for Establishing Probabilistic Reference Doses

Percentiles of the Product of Uncertainty Factors for Establishing Probabilistic Reference Doses

The Application of Non-Default Uncertainty Factors in the U.S. EPA's Integrated Risk Information System (IRIS). Part I: UF_L, UF_S, and “Other Uncertainty Factors”

Application of the threshold of toxicological concern concept when applied to pharmaceutical manufacturing operations intended for short-term clinical trials

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Evaluation of the Uncertainty Factor for Subchronic-to-Chronic Extrapolation: Statistical Analysis of Toxicity Data

Cited by 73 publications

References 8 publications

Percentiles of the Product of Uncertainty Factors for Establishing Probabilistic Reference Doses

Percentiles of the Product of Uncertainty Factors for Establishing Probabilistic Reference Doses

The Application of Non-Default Uncertainty Factors in the U.S. EPA's Integrated Risk Information System (IRIS). Part I: UFL, UFS, and “Other Uncertainty Factors”

Application of the threshold of toxicological concern concept when applied to pharmaceutical manufacturing operations intended for short-term clinical trials

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Product

Resources

About

The Application of Non-Default Uncertainty Factors in the U.S. EPA's Integrated Risk Information System (IRIS). Part I: UF_L, UF_S, and “Other Uncertainty Factors”