title: Development of an integrated multi-species and multi-dose route PBPK model for volatile methyl siloxanes - D4 and D5.
abstract: There are currently seven published physiologically based pharmacokinetic (PBPK) models describing aspects of the pharmacokinetics of octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) for various exposure routes in rat and human. Each model addressed the biological and physico-chemical properties of D4 and D5 (highly lipophilic coupled with low blood: air partition coefficient and high liver clearance) that result in unique kinetic behaviors as well differences between D4 and D5. However, the proliferation of these models resulted in challenges for various risk assessment applications when needing to determine the optimum model for estimating dose metrics. To enhance the utility of these PBPK models for risk assessment, we integrated the suite of structures into one coherent model capable of simulating the entire set of existing data equally well as older more limited scope models. In this paper, we describe the steps required to develop this integrated model, the choice of physiological, partitioning and biochemical parameters for the model, and the concordance of the model behavior across key data sets. This integrated model is sufficiently robust to derive relevant dose metrics following individual or combined dermal and inhalation exposures of workers, consumer or the general population to D4 and D5 for route-to-route, interspecies and high to low dose extrapolations for risk assessment.
authors.affiliation: Dow Corning Corporation, Health and Environmental Sciences, 2200 West Salzburg Road, Auburn, MI 48611, USA. Electronic address: tami.mcmullin@state.co.us.
authors.forename: Tami S
authors.initials: TS
authors.lastname: McMullin
authors.affiliation: The Hamner Institutes for Health Sciences, 6 Davis Drive, P.O. Box 12137, Research Triangle Park, NC 27709-2137, USA.
authors.forename: Yuching
authors.initials: Y
authors.lastname: Yang
authors.affiliation: The Hamner Institutes for Health Sciences, 6 Davis Drive, P.O. Box 12137, Research Triangle Park, NC 27709-2137, USA. Electronic address: jcampbell@thehamner.org.
authors.forename: Jerry
authors.initials: J
authors.lastname: Campbell
authors.affiliation: The Hamner Institutes for Health Sciences, 6 Davis Drive, P.O. Box 12137, Research Triangle Park, NC 27709-2137, USA. Electronic address: hclewell@thehamner.org.
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
authors.affiliation: Dow Corning Corporation, Health and Environmental Sciences, 2200 West Salzburg Road, Auburn, MI 48611, USA. Electronic address: kathy.plotzke@dowcorning.com.
authors.forename: Kathy
authors.initials: K
authors.lastname: Plotzke
authors.affiliation: The Hamner Institutes for Health Sciences, 6 Davis Drive, P.O. Box 12137, Research Triangle Park, NC 27709-2137, USA. Electronic address: mandersen@thehamner.org.
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D005260:Female; D006801:Humans; D019570:Inhalation Exposure; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D051381:Rats; D018570:Risk Assessment; D012833:Siloxanes / Q000493:pharmacokinetics*; D012867:Skin / Q000378:metabolism; D014018:Tissue Distribution; D014835:Volatilization
chemical_list: D012833:Siloxanes; C114768:decamethylcyclopentasiloxane; C024064:octamethylcyclotetrasiloxane
keywords: Cyclic volatile methyl siloxane; D4; D5; Decamethylcyclopentasiloxane; Kinetics; Octamethylcyclotetrasiloxane; PBPK; Pharmacokinetics; Physiologically based pharmacokinetic model; Risk assessment; Siloxane