Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 9 (2010) / Chapter Skim
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7 PBPK Modeling White Paper: Addressing the Use of PBPK Models to Support Derivation of Acute Exposure Guideline Levels1
7 PBPK Modeling White Paper: Addressing the Use of PBPK Models to Support Derivation of Acute Exposure Guideline Levels1
Pages 381-446
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From page 381... ...
Therefore, the PBPK White Paper does not describe the entire methodology; rather, it describes the additional steps when PBPK modeling is undertaken within the existing risk assessment paradigm. As in any methodology, every facet of the method cannot be explicitly stated in a manner that is universally applicable to all chemicals.
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From page 382... ...
and the AEGL Subcommittee of the Committee on Toxicology, National Academy of Sciences, this White Paper has been prepared to describe an approach for integrating the use of PBPK modeling into the development of AEGL values. PBPK modeling serves as a useful adjunct to risk assessment of systemically acting chemicals by improving the basis of, or entirely allowing for, extrapolation of pharmacokinetics between animals and humans, extrapolation between various exposure scenarios (e.g., what exposure concentration for 10 minutes [min]
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From page 383... ...
The rationale for using PBPK modeling in these other types of risk assessments applies as well in the assessment of acute exposure risks. The difference between a PBPK-based and a traditional dose-response assessment is that the PBPK method relies on an internal measure of exposure rather than an external one.
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From page 384... ...
PBPK modeling is advocated and frequently used in modern risk assessments, but there are times when it is not appropriate. There are no set criteria, but in general PBPK models can be used for AEGL risk assessment when: Existing PBPK models are available for a given chemical.
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From page 385... ...
2. DESCRIPTION OF PBPK MODELING In this section, PBPK models are described in a general manner.
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From page 386... ...
Unfortunately, the computation burden in these models is such that the model could be solved only at steady state. In the 1950s and 1960s, PBPK models were described for additional drugs, including the chemotherapeutic methotrexate.
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From page 387... ...
for up to 8 h. Based on PBPK model for toluene used for setting AEGL values for toluene.
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From page 388... ...
For many chemicals, PBPK models can be constructed with only a few
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From page 389... ...
The use of PBPK modeling has been compared with results of using the ten Berge empirical equation for inhalation exposure to toluene. The specific results of this analysis are presented in Appendix A
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From page 390... ...
– clearance, where Qi = blood flow to tissue i, CA = arterial blood concentration, CVi = chemical concentration in the venous blood leaving tissue i, and
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From page 391... ...
. Additional quantities are then calculated: CT = AT/VT concentration in each tissue compartment and CVi = CT/PT concentration in venous blood leaving tissue, where CT = chemical concentration in each tissue, AT = amount in each tissue, VT = volume of each tissue, and PT = partition coefficient between the tissue and blood.
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From page 392... ...
. Several authors as well as the National Academy of Sciences have advocated using PBPK modeling in AEGL development (Bruckner et al.
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From page 393... ...
4. CRITERIA FOR USE OF PBPK MODELING IN AEGL DEVELOPMENT Several issues must be addressed when PBPK models are being considered for use in AEGL development.
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From page 394... ...
The AEGL development team should include someone with PBPK modeling experience to help in this evaluation. The determination should weigh the following factors: Is there a basis to expect that PBPK modeling may yield more reliable and realistic AEGL values than other approaches?
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From page 395... ...
Data sets that are representative and relevant for the AEGL development process and that include data from laboratories other than those connected with the model's developers should be used and justified. Other considerations for data set selection include the following: Do the data involve exposures in the range of interest (likely range of AEGL values)
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From page 396... ...
Optimized parameter values should be within the range of existing measurements or estimates and should be reasonable when compared with values for similar compounds. Human parameter values for partition coefficients and metabolism are preferred to animal values when using the human versions of the models.
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From page 397... ...
Evaluation of PBPK models has been discussed elsewhere (Clark et al.
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From page 398... ...
5. APPLICATION OF PBPK MODELING TO THE AEGL DEVELOPMENT PROCESS Figure 7-3 describes the process by which PBPK modeling can be used in AEGL development as a series of sequential steps.
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From page 399... ...
Second, the 700-ppm exposure was preceded by exposures at 100, 300, and 500 ppm and a break, confounding the assessment of the POD. PBPK modeling was used to determine the internal DM for the exposure at the NOAEL.
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From page 400... ...
. When PBPK modeling is used to perform the internal dose calculations for extrapolation, the EPA supports an appropriate reduction in the pharmacokinetic portion of the interspecies UF (EPA 2006)
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From page 401... ...
When the UFs are applied to the DM, they reduce the target tissue dose before modeling is used to determine human equivalent concentrations , thereby reducing the extent of the high-dose extrapolation of the human model. For these reasons, Option 1 is the default choice of method.
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From page 402... ...
79-01-6) Proposed Acute Exposure Guideline Levels (AEGLs)
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From page 403... ...
2005. Duration adjustment of acute exposure guideline level values for trichloroethylene using a physiologically-based pharmacokinetic model.
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From page 404... ...
2004. Develop ment of acute exposure guideline levels for airborne exposures to hazardous sub stances.
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From page 405... ...
2001. Standing Operating Procedures for Developing Acute Exposure Guidelines Levels for Hazardous Substances.
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From page 406... ...
. The method reduces the uncertainty inherent in extrapolating rat toxicity data to humans and extrapolating toxicity data across time-scales by using validated PBPK models to perform the extrapolation based on an internal measure of dose.
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From page 407... ...
Second, the model is validated by showing model performance against rat and human data sets obtained from the literature. Third, recommended AEGL values are derived.
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From page 408... ...
. The PBPK models have been optimized to provide CV as model output under the exposure conditions indicated for this assessment.
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From page 409... ...
are linked by the arterial and venous blood supply. The CA is set equal to the concentration in a small volume of lung blood, which is assumed to be in equilibrium with the exhaled air concentration.
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From page 410... ...
For validation studies, actual or assumed body weights are used. Validation studies include relevant studies in which venous blood and other data are provided.
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From page 411... ...
When AEGL values were calculated, 70 kg was also used as the human body weight. Several studies have shown that the blood concentrations of several small molecular weight organic solvents are highly dependent on physiologic parameters, which in turn are highly dependent on workload (Droz and Fernandez 1977; Johanson 1986; Kumagai et al.
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From page 412... ...
e This study. The principal effects of exercise on an organic solvent's pharmacokinetics involve alveolar ventilation, cardiac output, and blood flow to tissues.
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From page 413... ...
The value selected for the rat PB in this model (18) has been used in numerous toluene PBPK models for rats and lies in the middle of three published values; it appears to allow a successful description of rat blood data (see below)
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From page 414... ...
or decreasing the affinity constant (Km) improved the model at some exposure levels but did not achieve a reasonable fit at others.
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From page 415... ...
data. Output from the PBPK model with the second linear metabolic pathway included, based on six exposure levels (4 h and 3 h postexposure)
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From page 416... ...
The upper curve in each group included a single enzyme and the lower curve also included a linear pathway representing other CYPs.
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From page 417... ...
. Using the same model as described above, a reasonable fit was obtained for CV in rats after 4 h of exposure to lower levels of toluene.
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From page 418... ...
emphasis was placed on data sets that included exposure during exercise; (3) emphasis was placed on high exposure levels.
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From page 419... ...
1000 100 10 1 Arterial Blood Toluene, mg/L 0.1 0 5 10 15 20 25 Time , hrs. FIGURE A-5 PBPK Model and data from van Asperen et al.
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From page 420... ...
In the postexposure phase, the fit was not good. However, the venous blood data do not track well with the exhaled air data in the final stage of the experiment, so experimental issues may be present with this part of the data.
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From page 421... ...
. The upper curve and data are toluene concentrations in exhaled air and the lower curve is toluene CV.
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From page 422... ...
The first half hour was at 75 W and the second half hour was at 150 W of work. The upper curve is exhaled air and the lower curve is CV.
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From page 423... ...
The upper curve is the concentration of toluene in exhaled air and the lower curve is CV.
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From page 424... ...
. A good correspondence between the data for venous blood and exhaled air was obtained at rest and at 50 W (Figures A-9 and A-10)
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From page 425... ...
The output variable used for the analysis was venous blood concentration, as it is the DM used for the risk assessment. The analysis results in a sensitivity coefficient (S)
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From page 426... ...
100 426 10 1 0.1 # CarlssonFig4Ser1CV # CarlssonFig4Ser1CXPPM cv :1 cxppm:1 Toluene in Venous Blood (mg/L) , Exhaled Air, ppm 0.01 0 0.5 1 1.5 2 2 .5 Time , hrs.
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From page 427... ...
100 10 1 0.1 # CarlssonFig4Ser2CV # CarlssonFig4Ser2CXPPM cv:1 cxppm:1 Toluene in Venous Blood (mg/L) , Exhaled Air, ppm 0.01 0 0.5 1 1.5 2 2 .5 Time, hrs.
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From page 428... ...
Upper curve is exhaled air and lower curve is CV.
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From page 429... ...
. Mean values for toluene in exhaled air for 12 subjects exposed to different levels of toluene at rest.
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From page 430... ...
At higher workloads, the approach to steady state is much faster. Results of the simulation for higher concentrations were identical.
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From page 431... ...
. The model is also differentially sensitive to some other parameters in the period of initial uptake, especially to QRC (percent of blood flow going to rapidly perfused tissue)
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From page 432... ...
The range of toluene exposures was 80 to 700 ppm. The lower bound of this range is less than the lower bound of the AEGL extrapolations, although the upper bound of validation is lower than some of the AEGL values.
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From page 433... ...
. TABLE A-7 AEGL-3 Values Determined with PBPK Model, ppm Workload 10 min 30 min 1h 4h 8h Rest 38,420 18,200 13,470 8,890 7,320 50 W 20,020 10,480 7,190 4,580 4,300 75 W 17,450 8,950 6,190 4,310 4,100 100 W 15,740 8,060 5,710 4,300 4,060 AEGL-3 AEGL recommendation after application of UF (3)
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From page 434... ...
For example, the 1-h AEGL determined above was 2,397 ppm, while applying the UF first led to an AEGL of 2,360. Comparison of PBPK-Based AEGL Values with ten Berge Approach A useful comparison can be made between the AEGL values determined using the ten Berge approach (ten Berge et al.
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From page 435... ...
Third, the PBPK modeling approach is uniquely suited for use when a critical study had a complex exposure scenario, as in the case of the Gamberale and Hultengren (1972) model.
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From page 436... ...
2004. The Acute Exposure Guideline Level (AEGL)
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From page 437... ...
2004. Develop ment of acute exposure guideline levels for airborne exposures to hazardous sub stances.
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From page 438... ...
1998. PBPK modeling of the short-term (0 to 5 min)
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From page 439... ...
439 PBPK Modeling White Paper Abbreviations AEGL acute exposure guideline level AT amount of chemical in each tissue AUC area under the curve BMD benchmark dose BW body weight CA arterial blood concentration maximum concentration Cmax CNS central nervous system CT chemical concentration in each tissue CV venous blood concentration CVi chemical concentration in the venous blood leaving tissue i CVL concentration of chemical in venous blood leaving the liver CYP cytochrome P-450 DM dose metric EPA U.S. Environmental Protection Agency h hour KFC linear metabolism rate constant Km affinity constant for the chemical median lethal concentration LC50 LOAEL lowest-observed-adverse-effect level mg/L milligram per liter min minute NAC National Advisory Committee NOAEL no-observed-adverse-effect level NRC National Research Council OSHA Occupational Safety and Health Administration PB blood-air partition coefficient PBPD physiologically based pharmacodynamic PBPK physiologically based pharmacokinetic PEL permissible exposure limits PFA fat-air coefficient PLA liver-air coefficient
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From page 440... ...
440 Acute Exposure Guideline Levels POD point of departure ppm parts per million PRA rapidly perfused air coefficient PSA slowly perfused air coefficient PT partition coefficient between the tissue and blood QCC cardiac output QFC percentage of blood flow going to fat Qi blood flow to tissue i QLC fraction of QCC to liver QPC alveolar ventilation rate QRC percentage of blood flow going to rapidly perfused tissues QSC percentage of blood flow going to slowly perfused tissues S sensitivity coefficient TLV Threshold Limit Value time (of maximum concentration) Tmax TSD technical support document UF uncertainty factor VBC fraction lung blood VFC fraction fat tissue VLC fraction liver tissue maximum rate of metabolism Vmax VmaxC maximum velocity of metabolism VRC fraction rapidly perfused VSC fraction slowly perfused VT volume of each tissue W watt
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From page 441... ...
/QC) ;Chemical-specific parameters PLA = 83.6 ;Liver-air partition coefficient PFA = 1021 ;Fat-air partition coefficient PSA = 27.7 ;Slowly perfused air partition coefficient PRA = 83.6 ;Rapidly perfused air partition coefficient PB = 18 ;Blood-air partition coefficient PL = PLA/PB ;Liver-blood partition coefficient PF = PFA/PB ;Fat-blood partition coefficient PS = PSA/PB ;Slowly perfused blood partition coefficient PR = PRA/PB ;Rapidly perfused blood partition coefficient MW = 92.13 ;Molecular weight (g/mol)
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From page 442... ...
QS = QC – QF – QL – QR ;Blood flow to nonfat tissue (L/h) QR = QRC QC ;Blood flow to rapidly perfused (L/h)
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From page 443... ...
443 PBPK Modeling White Paper ;QCC = IF TIME >= 1.5 THEN QCC150 ELSE IF TIME >= 1.0 THEN QCC100 ELSE IF TIME >= 0.5 THEN QCC50 ELSE 18 ;QLC = IF TIME >= 1.5 THEN QLC150 ELSE IF TIME >= 1.0 THEN QLC100 ELSE IF TIME >= 0.5 THEN QLC50 ELSE 0.26 ;QFC = IF TIME >= 1.5 THEN QFC150 ELSE IF TIME >= 1.0 THEN QFC100 ELSE IF TIME >= 0.5 THEN QFC50 ELSE 0.09 ;QRC = IF TIME >= 1.5 THEN QRC150 ELSE IF TIME >= 1.0 THEN QRC100 ELSE IF TIME >= 0.5 THEN QRC50 ELSE 0.55 ;The following IF THEN statements implement the Carlsson Stage 3 exercise scenario (rest, 50 W, 100 W, 150 W) with QPC and QCC from QCP2004 calculations ;QPC = IF TIME >= 1.5 THEN 129 ELSE IF TIME >= 1.0 THEN 88.4 ELSE IF TIME >= .5 THEN 45 ELSE 14.7 ;QCC = IF TIME >= 1.5 THEN 46.6 ELSE IF TIME >= 1.0 THEN 37.1 ELSE IF TIME >= 0.5 THEN 26 ELSE 14.4 ;QLC = IF TIME >= 1.5 THEN 0.05 ELSE IF TIME >= 1.0 THEN .076 ELSE IF TIME >= 0.5 THEN 0.13 ELSE 0.26 ;QFC = IF TIME >= 1.5 THEN 0.03 ELSE IF TIME >= 1.0 THEN 0.03 ELSE IF TIME >= 0.5 THEN 0.03 ELSE 0.09 ;QRC = IF TIME >= 1.5 THEN 0.58 ELSE IF TIME >= 1.0 THEN 0.58 ELSE IF TIME >= 0.5 THEN 0.60 ELSE 0.55 ;The following IF THEN statements implement the Astrand et al.
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From page 444... ...
444 Acute Exposure Guideline Levels ;The following IF THEN statements implement the Astrand et al.
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From page 445... ...
;CONC = IF TIME >= 1.08 THEN 714 ELSE IF TIME >= .75 THEN 501 ELSE IF TIME >= .67 THEN 0 ELSE IF TIME >= .33 THEN 300 ELSE 100 CIX = CONC MW/24,450 ;Exposure concentration (mg/L) LENGTH = 4 ;Length of inhalation exposure (h)
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From page 446... ...
CF = AF/VF ;(mg/L) CVF = CF/PF ;Venous blood (mg/L)
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