Magnitude and mechanistic determinants of the interspecies toxicokinetic uncertainty factor for organic chemicals

Pelekis, Michael; Krishnan, Kannan

doi:10.1016/j.yrtph.2004.07.004

Cited by 10 publications

(4 citation statements)

References 19 publications

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“…Physiological modeling methods have previously been applied in the determination of the interspecies UF. (24) Thus, U/V can be accounted for quantitatively along the exposure-tissue dose-tissue response continuum, making the use of UFs unnecessary. In a fully probabilistic noncancer risk assessment framework, the UFs will be transparent to the risk manager.…”

Section: Discussionmentioning

confidence: 99%

Probabilistic Framework for the Estimation of the Adult and Child Toxicokinetic Intraspecies Uncertainty Factors

Pelekis¹,

Nicolich²,

Gauthier³

2003

Risk Analysis

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Human health risk assessments use point values to develop risk estimates and thus impart a deterministic character to risk, which, by definition, is a probability phenomenon. The risk estimates are calculated based on individuals and then, using uncertainty factors (UFs), are extrapolated to the population that is characterized by variability. Regulatory agencies have recommended the quantification of the impact of variability in risk assessments through the application of probabilistic methods. In the present study, a framework that deals with the quantitative analysis of uncertainty (U) and variability (V) in target tissue dose in the population was developed by applying probabilistic analysis to physiologically-based toxicokinetic models. The mechanistic parameters that determine kinetics were described with probability density functions (PDFs). Since each PDF depicts the frequency of occurrence of all expected values of each parameter in the population, the combined effects of multiple sources of U/V were accounted for in the estimated distribution of tissue dose in the population, and a unified (adult and child) intraspecies toxicokinetic uncertainty factor UFH-TK was determined. The results show that the proposed framework accounts effectively for U/V in population toxicokinetics. The ratio of the 95th percentile to the 50th percentile of the annual average concentration of the chemical at the target tissue organ (i.e., the UFH-TK) varies with age. The ratio is equivalent to a unified intraspecies toxicokinetic UF, and it is one of the UFs by which the NOAEL can be divided to obtain the RfC/RfD. The 10-fold intraspecies UF is intended to account for uncertainty and variability in toxicokinetics (3.2x) and toxicodynamics (3.2x). This article deals exclusively with toxicokinetic component of UF. The framework provides an alternative to the default methodology and is advantageous in that the evaluation of toxicokinetic variability is based on the distribution of the effective target tissue dose, rather than applied dose. It allows for the replacement of the default adult and children intraspecies UF with toxicokinetic data-derived values and provides accurate chemical-specific estimates for their magnitude. It shows that proper application of probability and toxicokinetic theories can reduce uncertainties when establishing exposure limits for specific compounds and provide better assurance that established limits are adequately protective. It contributes to the development of a probabilistic noncancer risk assessment framework and will ultimately lead to the unification of cancer and noncancer risk assessment methodologies.

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Section: Discussionmentioning

confidence: 99%

Probabilistic Framework for the Estimation of the Adult and Child Toxicokinetic Intraspecies Uncertainty Factors

Pelekis¹,

Nicolich²,

Gauthier³

2003

Risk Analysis

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“…For systemic effects of volatile organics the RfC methodology describes a default dosimetry adjustment to derive a human equivalent concentration (HEC) based upon the blood:air partition coefficients in animals and humans (U.S. EPA, 1994). Analyses for volatile organics show that blood:air PCs as well as hepatic extraction ratio (comprising blood flow to the liver and liver metabolism) and fraction of cardiac output reaching liver are key determinants for steady-state blood concentrations and interspecies extrapolation (Chiu & White, 2006;Pelekis & Krishnan, 2004). This implicates the blood:air and tissue:blood PCs as critical parameters in PBPK models and further justifies the need for accurate and age-specific values.…”

Section: Discussionmentioning

confidence: 99%

Age-Dependent Partition Coefficients for a Mixture of Volatile Organic Solvents in Sprague-Dawley Rats and Humans

Mahle¹,

Gearhart²,

Grigsby³

et al. 2007

Journal of Toxicology and Environmental Health, Part A

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The absorption, distribution, metabolism, and excretion of volatile organic compounds (VOCs) are critically determined by a few chemical-specific factors, notably their blood and tissue partition coefficients (PC) and metabolism. Age-specific values for PCs in rats have rarely been reported or utilized in pharmacokinetic modeling for predicting dosimetry in toxicity studies with rats progressing through their lifestages. A mixture of six VOCs (benzene, chloroform, methyl ethyl ketone, methylene chloride, trichloroethylene, and perchloroethylene) was used to determine blood:air and tissue:air PCs in rats at three different ages (postnatal d 10, 60 d, and 2 yr) and blood:air PCs in pediatric and adult human blood. No differences with age in human blood:air PCs for the six compounds were observed. Rat blood:air PCs increased with age varying with compound. Tissue:air PCs showed tissue-specific changes with age. Water-soluble methyl ethyl ketone showed no age-dependent differences. Partition coefficients, particularly the blood:air PC, are key determinants of the rodent and human blood concentrations; age-appropriate values improve the accuracy of pharmacokinetic model predictions of population variability and age-specific exposures.

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“…We retrieved 101 in vivo data of K AB measured in rats from one review and several papers in the literature [10,11,12,13,14,15] …”

Section: Methodsmentioning

confidence: 99%

“…We retrieved 101 in vivo data of K AB measured in rats from one review and several papers in the literature. [10,11,12,13,14,15] The dataset contains organic chemicals belonging to different categories and uses: drugs (e. g. Nitrazepam, Lomefloxacin), plant protection products (e. g. Molinate, Deltamethrin), polychlorinated biphenyls (PCBs, e. g. 2,2',3,4,5'-Pentachlorobiphenyl, 3,3',4,4'-Tetrachlorobiphenyl), volatile organic compounds (VOCs).…”

Section: Data Collection and Curationmentioning

confidence: 99%

Prediction of the Partition Coefficient between Adipose Tissue and Blood for Environmental Chemicals: From Single QSAR Models to an Integrated Approach

Cappelli

Manganelli

Toma

et al. 2020

Molecular Informatics

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The adipose tissue:blood partition coefficient is a key‐endpoint to predict the pharmacokinetics of chemicals in humans and animals, since other organ:blood affinities can be estimated as a function of this parameter. We performed a search in the literature to select all the available rat in vivo data. This approach resulted into two improvements to existing models: a homogeneous definition of the endpoint and an expanded data collection. The resulting dataset was used to develop QSAR models as a function of linear and non‐linear algorithms. Several applicability domain definitions were assessed and the definition corresponding to a good balance between performance and coverage was retained. We assessed the pertinence of combining single models into integrated approaches to increase the accuracy in predictions. The best integrated model outperformed the single models and it was characterized by an external mean absolute error (MAE) equal to 0.26, while preserving an adequate coverage (84 %). This performance is comparable to experimental variability and it highlights the pertinence of the integrated model.

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Magnitude and mechanistic determinants of the interspecies toxicokinetic uncertainty factor for organic chemicals

Cited by 10 publications

References 19 publications

Probabilistic Framework for the Estimation of the Adult and Child Toxicokinetic Intraspecies Uncertainty Factors

Probabilistic Framework for the Estimation of the Adult and Child Toxicokinetic Intraspecies Uncertainty Factors

Age-Dependent Partition Coefficients for a Mixture of Volatile Organic Solvents in Sprague-Dawley Rats and Humans

Prediction of the Partition Coefficient between Adipose Tissue and Blood for Environmental Chemicals: From Single QSAR Models to an Integrated Approach

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