University of Georgia, 206 Environmental Health Science Building, Athens, Georgia
ABSTRACT
The article highlighted in this issue is "Physiological Modeling of Inhalation Kinetics of Octamethylcyclotetrasiloxane in Humans during Rest and Exercise," by Micaela B. Reddy, Melvin E. Andersen, Paul E. Morrow, Ivan D. Dobrev, Sudarsanan Varaprath, Kathleen P. Plotzke, and Mark J. Utell (pp. 4356).
In the featured article, Reddy et al. report on the development and validation of a human physiologically based pharmacokinetic (PBPK) model for octamethylcyclotetrasiloxane (D4). D4 is used as a silicone fluid (MW = 296) in the manufacturing of high molecular weight silicone polymers and as an additive in personal care products and in high-performance cleaning products. This human PBPK model for inhaled D4 relies heavily on information gained from PBPK modeling efforts carried out earlier with rats (Andersen et al., 2001). Recent metabolism and toxicology studies with D4 also have been reported in the literature (Varaprath et al., 1999
, Varaprath et al., 2000
, McKim et al., 2001
), which have helped in the development of the human PBPK model. The next step for characterizing D4 toxicity in humans is dose-response analyses of the critical toxic effects of D4 using the rat and human PBPK models.
This PBPK modeling paper is refreshing and worthy of public comment because the paper is written in an easy-to-follow manner similar to a detective story. In this case the authors describe how PBPK modeling was used to develop circumstantial evidence about the kinetic behavior of D4. D4 is not a prototypical chemical for PBPK model development, and difficulties were encountered in model development. D4 is readily metabolized and cleared from the body and has a low blood:air partition coefficient value (near 1.0) and high lipophilicity (fat:blood partition coefficient = 490). D4 appears to reversibly sequester on lipoproteins in blood and is unavailable for exchange in the lung. The authors observed that breath levels of D4 dropped rapidly after inhalation exposure to D4, compared to a slower decline in blood levels. D4 also exhibits diffusion-limited properties in deep fat and slowly perfused tissues. The authors initially used a classical PBPK model structure (Ramsey and Andersen, 1984) to obtain insights into the kinetic behavior of D4 (Fig. 1, p. 47). Failure of the initial PBPK model led to advances in the thinking about the kinetics of D4 and subsequent changes in model structure (Fig. 2, p. 48) consistent with the rodent studies. They have clearly conveyed their model failures and successes by showing comparisons of initial model simulations (model failure) and the new or refined model simulations (model success). This is important because the reader has a much better appreciation for D4 kinetics when one can see both simulations. Failure to predict observations should provide the modeler with a sense of wonderment and trigger the question, "What is going on with this chemical?" The reader is provided with hypotheses about what is going on with D4. In addition, the authors philosophy of starting simple with model structure and adding complexity to model structure as needed, was important to their success.
The authors present rationale for the new model structure and discuss the mathematical equations in a fashion germane to the biology of the body. Their ability to discuss the mathematical equations in terms of the biological consequences strengthens the paper. This writing style provides a "reader-friendly" means for discussing mathematics and biology in the same context. Deciphering modeling papers can be difficult, even for scientists involved in PBPK modeling. The writing style of this paper is excellent, in that a complex modeling project is presented in an easy-to-read manner. This includes the discussion of how formal optimizations were conducted for parameterization of model constants.
Another important aspect of this paper is that the human PBPK model for D4 is part of a larger research strategy for D4. PBPK modeling studies with D4 in rats and humans were envisioned along with conducting toxicologic studies with laboratory animals. The authors used PBPK model findings in rats for understanding how to structure the human PBPK model. Thus, biological plausibility of the model structure is increased. In addition, the potential utility of the models increase as more toxicologic data is collected in rodents, and the PBPK models are exercised to extrapolate internal measures of dose from rat to human.
In summary, the biological determinants that are responsible for the unusual kinetic behavior of D4 remain to be elucidated empirically. However, the hypotheses generated by the PBPK kinetic analyses suggest plausible explanations for the kinetic behavior of D4. These authors have demonstrated with D4 that PBPK models can play an important role in discovery, in identification of experimental needs, and serve as a tool for hypothesis generation. Furthermore, the D4 research findings may be important for understanding the kinetic behavior of other chemicals that may behave similar to D4 such as selected hydrocarbons found in gasoline and jet fuels.
NOTES
1 For correspondence via e-mail: jw.sher{at}uga.edu.
REFERENCES
Andersen, M. E., Sarangapani, R., Reitz, R. H., Dobrev, I. D., and Plotzke, K. P. (2001). Physiologically modeling reveals novel pharmacokinetic behavior for inhaled octamethylcyclotetrasiloxane in rats. Toxicol. Sci. 60, 214231.
McKim, J. M., Kolesar, G. B., Jean, P. A., Meeker, L. S., Wilga, P. C., Schoonhoven, R., Swenberg, J. A., Goodman, J. I., Gallavan, R. H., and Meeks, R. G. (2001). Repeated inhalation exposure to octamethylcyclotetrasiloxane produces hepatomegly, transient hepatic hyperplasia, and sustained hypertrophy in female Fischer 344 rats in a manner similar to phenobarbital. Toxicol. Appl. Pharmacol. 172, 8392.[CrossRef][ISI][Medline]
Ramsey, J. C. and Andersen, M. E. (1984). A physiologically based description of the inhaled pharmacokinetics of styrene in rats and humans. Toxicol. Appl. Pharmacol. 73, 159173.[ISI][Medline]
Varaprath, S., Salyers, K. L., Plotzke, K. P., and Nanavati, S. (1999). Identification of metabolites of octamethylcyclotetrasiloxane (D4) in rat urine. Drug Metabol. Dispos. 27, 12671273.
Varaprath, S., Seaton, M., McNett, D. A., Cao, L., and Plotzke, K. P. (2000). Quantitative determination of octamethylcyclotetrasiloxane (D4) in extracts of biological matrices by gas chromatography-mass spectrometry. Int. J. Environ. Anal. Chem. 77, 203219.[ISI]
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