A pharmacokinetic model to study the excretion of trichloroethylene and its metabolites after an inhalation exposure.

Sato, Akio; Nakajima, Tamie; Fujiwara, Yoshitaka; Murayama, Ninzo

doi:10.1136/oem.34.1.56

Cited by 30 publications

(33 citation statements)

References 28 publications

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“…Parameter pairs for which correlation coefficients were higher than 0.5 are in bold face. (36)(37)(38)(39)(40)(41)(42)(43). These additional data sets might be useful for external validation of the model.…”

Section: Preictions Ofcancer Dose Metricsmentioning

confidence: 99%

Statistical analysis of Clewell et al. PBPK model of trichloroethylene kinetics.

Bois

2000

Environ Health Perspect

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A physiologically based pharmacokinetic model for trichloroethylene (TCE) in rodents and humans was calibrated with published toxicokinetic data sets. A Bayesian statistical framework was used to combine previous information about the model parameters with the data likelihood, to yield posterior parameter distributions. The use of the hierarchical statistical model yielded estimates of both variability between experimental groups and uncertainty in TCE toxicokinetics. After adjustment of the model by Markov chain Monte Carlo sampling, estimates of variability for the animal or human metabolic parameters ranged from a factor of 1.5-2 (geometric standard deviation [GSDI). Uncertainty was of the same order as variability for animals and higher than variability for humans. The model was used to make posterior predictions for several measures of cancer risk. These predictions were affected by both uncertainties and variability and exhibited GSDs ranging from 2 to 6 in mice and rats and from 2 to 10 for humans. The recent development of a comprehensive physiologically based pharmacokinetic (PBPK) model of trichloroethylene (TCE) disposition and metabolism in mice, rats, and humans (1) offers us the opportunity to examine issues of variability and uncertainty for that solvent. In particular, uncertainties in prediction of various cancer dose metrics deserve to be computed, since they could be directly used as input for improved risk assessments.PBPK modeling provides a strong mechanistic basis for prediction of disposition and metabolism of toxicants. Yet much uneasiness remains with the use of these models in toxicology (2). Similarly, as discussed in a recent review and an accompanying commentary, PBPK modeling has not seen the development it promised for therapeutic compounds (3,4). The reason for this essentially lies in the lack of statistical methods for calibrating these models. Because of individual variability and uncertainty, many parameters are difficult to measure accurately even for inbred animal strains. Using input parameters or presenting results in the form of a single value can therefore be very misleading (5). In the absence of rigorous statistical treatment, inference presented by PBPK modeling is largely empirical, hypotheses are left unvalidated, and predictions lack realistic measures of uncertainty. This state of affairs is unfortunate, when considering the consequences (for public health and national welfare) of the decisions made using these models.Obviously, correct statistical treatment of PBPK models is difficult, since these are large nonlinear models with relatively small data sets and a high degree of uncertainty and biological variability (6). It is also essential to respect the fundamental specificity of PBPK models, i.e., their high prior information content, which they provide through the opportunity to use physiological information on parameter values. Yet, although several parameters have physiological meaning and a narrow range of possible values, others-often specific of the com...

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Section: Preictions Ofcancer Dose Metricsmentioning

confidence: 99%

Statistical analysis of Clewell et al. PBPK model of trichloroethylene kinetics.

Bois

2000

Environ Health Perspect

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“…As a consequence of differences in blood flow and overall metabolic rate, species differences exist in the fraction of administered dose of TCE that is available for conversion (163) 9.2 (164) SD, Sprague-Dawley. Blood samples were taken by cardiac puncture and were analyzed by gas chromatography.…”

mentioning

confidence: 99%

Metabolism of trichloroethylene.

Lash

Fisher

Lipscomb

et al. 2000

Environ Health Perspect

247

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A major focus in the study of metabolism and disposition of trichloroethylene (TCE) is to identify metabolites that can be used reliably to assess flux through the various pathways of TCE metabolism and to identify those metabolites that are causally associated with toxic responses. Another important issue involves delineation of sex-and species-dependent differences in biotransformation pathways. Defining these differences can play an important role in the utility of laboratory animal data for understanding the pharmacokinetics and pharmacodynamics of TCE in humans. Sex-, species-, and strain-dependent differences in absorption and distribution of TCE may play some role in explaining differences in metabolism and susceptibility to toxicity from TCE exposure. The majority of differences in susceptibility, however, are likely due to sex-, species-, and strain-dependent differences in activities of the various enzymes that can metabolize TCE and its subsequent metabolites. An additional factor that plays a role in human health risk assessment for TCE is the high degree of variability in the activity of certain enzymes. TCE undergoes metabolism by two major pathways, cytochrome P450 (P450)-dependent oxidation and conjugation with glutathione (GSH). Key P450-derived metabolites of TCE that have been associated with specific target organs, such as the liver and lungs, include chloral hydrate, trichloroacetate, and dichloroacetate. Metabolites derived from the GSH conjugate of TCE, in contrast, have been associated with the kidney as a target organ. Specifically, metabolism of the cysteine conjugate of TCE by the cysteine conjugate ,B Iyase generates a reactive metabolite that is nephrotoxic and may be nephrocarcinogenic. Although the P450 pathway is a higher activity and higher affinity pathway than the GSH conjugation pathway, one should not automatically conclude that the latter pathway is only important at very high doses. A synthesis of this information is then presented to assess how experimental data, from either animals or from in vitro studies, can be extrapolated to humans for risk assessment.

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“…Partition coefficients of organic solvents into blood, water and o il at 37 ·C (46,47 vapor for each tissue. Table 2 shows the partition coefficients of tr ichloroethylene into the va rious body tissues of rat s (53). The coefficients between blood and tissues were almost unit y for all tissues other than fat.…”

Section: Principles Of Pharmacokinetics For Organic Solvent Vaporsmentioning

confidence: 99%

“…When inhaled, the vapors in lung alveoli diffu se into the blood according Table 2. Partition coefficients of trichloroethylene in various body t issues of rats and humans (53).…”

Section: Principles Of Pharmacokinetics For Organic Solvent Vaporsmentioning

confidence: 99%

Pharmacokinetics of organic solvent vapors in relation to their toxicity.

Sato¹,

Nakajima²

1987

Scand J Work Environ Health

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SATO A, NAKAJIMA T. Pharmacokinetics of organic solvent vapors in relation to their toxicit y. Scand J Work Environ Health 13 (1987) 81-93 . The volatility and Iipophilicity by which organi c solvents are distinct from other chemicals constitut e a characteristic pharmacokinetic feature . They enter a living body by inhalation, preferentially distribute in the adipose tissue, and are eliminated by both expirat ion and metabolic degradation. Th is review article is centered on experiment al studies conducted by the authors and their co-workers, and it deals with (i) pharmacokinetic principl es, (ii) partition coefficients in relation to toxicity, (iii) significance of metabolism in the developmen t of organic solvent toxicity, and (iv) environmental factors that alt er the metabolism and toxicity of solvents.

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A pharmacokinetic model to study the excretion of trichloroethylene and its metabolites after an inhalation exposure.

Cited by 30 publications

References 28 publications

Statistical analysis of Clewell et al. PBPK model of trichloroethylene kinetics.

Statistical analysis of Clewell et al. PBPK model of trichloroethylene kinetics.

Metabolism of trichloroethylene.

Pharmacokinetics of organic solvent vapors in relation to their toxicity.

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