Applications of Sensitivity Analysis to a Physiologically Based Pharmacokinetic Model for Carbon Tetrachloride in Rats

Evans, Marina V.; Crank, William D.; Yang, Huimin; Simmons, Jane Ellen

doi:10.1006/taap.1994.1177

Cited by 60 publications

(28 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The muscle was used to represent the slowly perfused tissue compartment, and the liver was used to represent both the liver and the richly perfused tissue compartments in the PBPK model. Measured hamster tissue:air partition coefficients did not differ significantly from those reported for the rat (Gargas et al, 1986;Evans et al, 1994 (Gargas et al, 1986) and 343:47 (Uemitsu, 1986), thus confirming the technique in our laboratory.…”

Section: Partition Coefficientssupporting

confidence: 84%

“…However, these species-specific unit risks vary by 2 orders of magnitude, from 3.4 × 10 for CCl 4 in Sprague-Dawley rats to be 0.3 mg/L and 2.7 mg/hour/kg BW, respectively, based on evaluation of uptake curves from nose-only inhalation exposures. More recently, a re-evaluation of gas uptake data from Evans et al (1994) found a K m and V max of 1.16 mg/L and 0.32 mg/hour/kg BW for young (65-72 day old) F344 rats (Simmons et al, 1999).…”

Section: A Backgroundmentioning

confidence: 99%

See 1 more Smart Citation

Improved Risk Estimates for Carbon Tetrachloride

Benson¹,

Springer²

1999

View full text Add to dashboard Cite

Section: Partition Coefficientssupporting

confidence: 84%

Section: A Backgroundmentioning

confidence: 99%

Improved Risk Estimates for Carbon Tetrachloride

Benson¹,

Springer²

1999

View full text Add to dashboard Cite

“…Incorporation of agespecific input parameters into the same basic PBPK model structure as described originally by Ramsey and Andersen (1984) and used in our laboratory (Evans et al, 1994;Evans & Simmons, 1996), will improve the utility of PBPK models in helping understand the influence of age on the pharmacokinetic behavior of chemicals. Similarly, incorporation of strainspecific information for those input parameters that vary with strain will allow PBPK models to be used to understand strain differences in susceptibility to toxicity.…”

Section: Discussionmentioning

confidence: 99%

Organ Weights and Fat Volume in Rats as a Function of Strain and Age

Schoeffner

Warren²,

Muralidara³

et al. 1999

Journal of Toxicology and Environmental Health, Part A

View full text Add to dashboard Cite

The Fischer 344 (F344) rat and the Sprague-Dawley (SD) rat are used commonly to evaluate potential adverse health effects resulting from environmental exposure to chemicals. They are also the most common rat strain/stock used in physiologically based pharmacokinetic (PBPK) modeling. Accurate characterization of model input parameters will improve the usefulness of PBPK model predictions. Thus, organ (i.e., liver, kidneys, spleen, stomach, small intestine, large intestine, heart, lungs, brain) weights and body fat were measured in male SD rats of different ages (4 to 40 wk) and in young (9 to 10 wk) and old (22 to 23 mo) male F344 rats. Comparison of age-matched (9 to 10 wk) F344 and SD rats revealed that the SD rats weighed significantly more and had significantly higher absolute organ weights. These significant differences usually disappeared when organ weights were expressed as a percentage of body weight (relative organ weight). Percent body fat was significantly lower in the age-matched SD rats (6.48%) than in their F344 counterparts (8.67%). As expected, both body weight and absolute organ weights were significantly higher in old than in young F344 rats. However, these differences were largely reversed when relative organ weights were considered, with most relative organ weights significantly lower in the old F344 rats. Body fat as a percentage of body weight was 14.02% in the old F344 rats. When SD rats of various ages were examined, relative organ weights declined between the ages of 4 and 14 wk. In contrast, significant differences in percent body fat were not detected among the SD rats of different ages and weights examined in this study (4 to 40 wk, approximately 75 to approximately 450 g). In summary, values for physiological input parameters are provided that should prove useful in development and implementation of more accurate PBPK models.

show abstract

“…As in the analysis conducted with chloroform (Tan et al, 2006), a log-normalized sensitivity coefficient (LSC) for each model parameter was calculated to indicate the percent change in model output per unit change (71%) in each parameter (Clewell et al, 1994;Evans et al, 1994). If the absolute value of an LSC (|LSC|) is near or larger than 1, the specific parameter evaluated is considered to have significant model output sensitivity.…”

Section: Model Evaluation -Individual Models For Chloroform Bdcm Dbmentioning

confidence: 99%

Reverse dosimetry: interpreting trihalomethanes biomonitoring data using physiologically based pharmacokinetic modeling

Tan¹,

Liao²,

Clewell³

2006

J Expo Sci Environ Epidemiol

137

View full text Add to dashboard Cite

Biomonitoring data provide evidence of exposure of environmental chemicals but are not, by themselves, direct measures of exposure. To use biomonitoring data in understanding exposure, physiologically based pharmacokinetic (PBPK) modeling can be used in a reverse dosimetry approach to assess a distribution of exposures possibly associated with specific blood or urine levels of compounds. Reverse dosimetry integrates PBPK modeling with exposure pattern characterization, Monte Carlo analysis, and statistical tools to estimate a distribution of exposures that are consistent with biomonitoring data in a population. The present study used an existing PBPK model for chloroform as a generic framework to develop PBPK models for other trihalomethanes (THMs). Using Monte Carlo sampling techniques, probabilistic information about pharmacokinetics and exposure patterns was included to estimate distributions of THMs concentrations in blood in relation to various exposure patterns in a diverse population. In addition, the possibility of inhibition of hepatic metabolism among THMs was evaluated under the scenarios of household exposure. These studies demonstrated how PBPK modeling can be used as a tool to estimate a population distribution of exposures that could have resulted in particular biomonitoring results. When toxicity level is known, this tool can also be used to estimate proportion of population above levels associated with health risk.

show abstract

Applications of Sensitivity Analysis to a Physiologically Based Pharmacokinetic Model for Carbon Tetrachloride in Rats

Cited by 60 publications

References 0 publications

Improved Risk Estimates for Carbon Tetrachloride

Improved Risk Estimates for Carbon Tetrachloride

Organ Weights and Fat Volume in Rats as a Function of Strain and Age

Reverse dosimetry: interpreting trihalomethanes biomonitoring data using physiologically based pharmacokinetic modeling

Contact Info

Product

Resources

About