Center for Environmental Toxicology & Technology
Colorado State University
1690 Campus Delivery – Foothills Campus
Fort Collins, CO 80523-1690
January 15, 2003
RE: submission for 2003 BMSS Best Poster Competition
Dear Dr. Fisher,
For the 2003 Biological Modeling Specialty Section Best Poster Competition, I would
like to submit the poster entitled, “Physiological Modeling of the Dermal Absorption of
Octamethylcyclotetrasiloxane (D4),” by myself, R. J. Looney, M. J. Utell, M. L. Jovanovic, J. M.
McMahon, D. A. McNett, I. D. Dobrev, K. P. Plotzke and M. E. Andersen (abstract number
1842.) A Microsoft PowerPoint file containing the poster is attached to the e-mail containing
this letter. As a postdoctoral trainee in toxicology at the Center for Environmental Toxicology &
Technology (CETT) at Colorado State University, I believe that I qualify for the competition.
D4 is a lipophilic (logKo/w  5), semi-volatile (vapor pressure  0.68 mmHg at 20C)
compound used in some personal care products and as an intermediate in the manufacture of
high molecular weight silicone polymers. Studies on human dermal absorption of D4 through
axilla skin in vivo and through abdominal skin in vitro have been completed. In this poster, a
mathematical model describing the dermal absorption of D4 is presented in combination with a
previously developed inhalation physiologically based pharmacokinetic (PBPK) model. The
dermal absorption model includes volatilization of D4 from the skin surface, evaporation of D4
out of the skin after the skin surface had been cleared of chemical, and potential for storage in a
deep skin compartment. Concentrations of D4 in exhaled air and blood plasma from human, in
vivo, dermal exposures were used to estimate critical model parameters.
Typically, dermal absorption models do not include evaporation of chemical back out of
the skin following an exposure, but an in vivo dermal absorption study of D4 in the rat, in which
F344 female rats were exposed to three dose levels of D4, provided evidence that this model
structure was appropriate. During this study, the amount of D4 absorbed (defined as the amount
of chemical that has passed through the skin into the viable skin layers and blood) decreased
significantly with time. However, there were no corresponding increases in the amount that
penetrated (defined as the amount of chemical that has passed into the blood). Thus, some D4
had to be eliminated from the skin by evaporation before penetration into systemic circulation
occurred. Often, the amount absorbed (particularly in vitro) is used as an estimate of the amount
penetrated for lipophilic materials. However, for semi-volatile chemicals that can eliminate from
skin by evaporation, the amount penetrated may be significantly less than the amount absorbed.
By adding the dermal exposure route in a human D4 inhalation PBPK model, it was
possible to perform several calculations relevant to the pharmacokinetic study of human, in vivo,
dermal absorption of D4. Model calculations indicated that all of the applied D4 would be
cleared from the skin within 5 minutes due to evaporation of neat D4 and dermal absorption, and
more than 90% of the applied dose evaporated from the skin surface before it could be absorbed
into the skin. Additionally, the majority of the D4 that had initially absorbed into the skin was
eliminated from the skin by back diffusion and evaporation before penetration into systemic
blood could occur. About 0.3% of the applied dose of D4 penetrated the axilla skin in 24 h.
Model calculations indicated that the maximum D4 plasma concentration was more than 100
mg/L. It is important to recognize, however, that the peak D4 plasma concentration probably
occurred before the earliest samples were collected at one hour after the application of D4.
Because data were unavailable at early times when peak blood concentrations and D4
evaporation occurred, model predictions at early times require confirmation. In future work, we
will improve our confidence in model predictions at early times by acquiring more data pertinent
to that period (e.g., by measuring the rate of D4 evaporation).
This poster is part of a research program here at CETT studying the pharmacokinetics of
cyclic siloxanes. Recently, a PBPK model for human inhalation exposures to D4 was developed
(Reddy et al. In press, 2003). The model structure was based on our experience in modeling D4
pharmacokinetics in the rat (Andersen et al. 2001). After inhalation exposures of rats to D4, the
ratio of the concentration of D4 in the venous blood to the concentration of D4 in exhaled breath,
Cv/Cex, increased with time. To describe this behavior, the PBPK model included a pool of
unavailable D4 that was produced in the liver, moved through the blood, and was cleared in the
fat. This model structure was successfully adopted to describe human inhalation kinetics of D4.
In this poster, we used a similar approach to determine an appropriate model structure by
studying the dermal absorption of D4 in the rat, and then applying the acquired knowledge to
choose an appropriate model structure for human dermal exposures. Because the ratio Cv/Cex
also increased with time following the human, in vivo, dermal exposures, sequestration of D4 in
blood lipids appears to be equally important for describing D4 kinetics following dermal and
inhalation exposures.
In summary, the work presented in our poster is significant for several reasons. Because
of the unusual properties of D4, it was possible to demonstrate that for semi-volatile chemicals
that can eliminate from the skin by back diffusion and evaporation, the amount penetrated may
be significantly less than the amount initially absorbed. Additionally, the use of a PBPK model
to quantify the outcome of a human, in vivo, dermal exposure to D4 was illustrated. Finally, we
demonstrated the use of rat studies for improving our understanding of human pharmacokinetics.
Thank you for providing this opportunity for the recognition of graduate and postdoctoral
students attending the Society of Toxicology meeting. If you have any questions, I can be
reached by telephone at 970-491-3481, by FAX at 970-491-8304, or by electronic mail at
mreddy@colostate.edu.
Sincerely,
Micaela B. Reddy, Ph.D.
Postdoctoral Trainee in Toxicology
References
Andersen, M. E., Sarangapani, R., Reitz, R. H., Dobrev, I. D., Gallavan, R. H. and Plotzke, K. P.
(2001). Physiological modeling reveals novel pharmacokinetic behavior of inhaled
octamethylcyclotetrasiloxane. Toxicol. Sci., 60, 214-231.
Reddy, M. B., Andersen, M. E., Morrow, P. E., Dobrev, I. D., Varaprath, S., Plotzke, K. P. and
Utell, M. J. (In press, 2003.) Physiological modeling of inhalation kinetics of
octamethylcyclotetrasiloxane (D4) in humans during rest and exercise. Toxicol. Sci.