title: A tissue dose-based comparative exposure assessment of manganese using physiologically based pharmacokinetic modeling-The importance of homeostatic control for an essential metal.
abstract: A physiologically-based pharmacokinetic (PBPK) model (Schroeter et al., 2011) was applied to simulate target tissue manganese (Mn) concentrations following occupational and environmental exposures. These estimates of target tissue Mn concentrations were compared to determine margins of safety (MOS) and to evaluate the biological relevance of applying safety factors to derive acceptable Mn air concentrations. Mn blood concentrations measured in occupational studies permitted verification of the human PBPK models, increasing confidence in the resulting estimates. Mn exposure was determined based on measured ambient air Mn concentrations and dietary data in Canada and the United States (US). Incorporating dietary and inhalation exposures into the models indicated that increases in target tissue concentrations above endogenous levels only begin to occur when humans are exposed to levels of Mn in ambient air (i.e. >10μg/m3) that are far higher than those currently measured in Canada or the US. A MOS greater than three orders of magnitude was observed, indicating that current Mn air concentrations are far below concentrations that would be required to produce the target tissue Mn concentrations associated with subclinical neurological effects. This application of PBPK modeling for an essential element clearly demonstrates that the conventional application of default factors to "convert" an occupational exposure to an equivalent continuous environmental exposure, followed by the application of safety factors, is not appropriate in the case of Mn. PBPK modeling demonstrates that the relationship between ambient Mn exposures and dose-to-target tissue is not linear due to normal tissue background levels and homeostatic controls.
authors.affiliation: Ramboll Environ US Corporation, 3701 Armand St., Monroe, LA 71201, United States. Electronic address: rgentry@ramboll.com.
authors.forename: P Robinan
authors.initials: PR
authors.lastname: Gentry
authors.affiliation: Ramboll Environ US Corporation, 3701 Armand St., Monroe, LA 71201, United States.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Van Landingham
authors.affiliation: Ramboll Environ US Corporation, 3701 Armand St., Monroe, LA 71201, United States.
authors.forename: William G
authors.initials: WG
authors.lastname: Fuller
authors.affiliation: Ramboll Environ US Corporation, Amherst, MA, United States.
authors.forename: Sandra I
authors.initials: SI
authors.lastname: Sulsky
authors.affiliation: Ramboll Environ US Corporation, 3701 Armand St., Monroe, LA 71201, United States.
authors.forename: Tracy B
authors.initials: TB
authors.lastname: Greene
authors.affiliation: ScitoVation, RTP, NC, United States.
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
authors.affiliation: ScitoVation, RTP, NC, United States.
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.affiliation: Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Harry A
authors.initials: HA
authors.lastname: Roels
authors.affiliation: NIPERA, Durham, NC, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Afton Chemical Corporation, Richmond, VA, United States.
authors.forename: Athena M
authors.initials: AM
authors.lastname: Keene
mesh_terms: D002170:Canada / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000009:adverse effects; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects*; D008345:Manganese / Q000009:adverse effects / Q000493:pharmacokinetics*; D008954:Models, Biological; D009749:Nutrition Surveys / Q000379:methods; D016273:Occupational Exposure / Q000009:adverse effects; D052638:Particulate Matter / Q000009:adverse effects / Q000493:pharmacokinetics; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D014131:Trace Elements / Q000009:adverse effects / Q000493:pharmacokinetics*; D014481:United States / Q000453:epidemiology
chemical_list: D052638:Particulate Matter; D014131:Trace Elements; D008345:Manganese
keywords: MOS; Manganese; Margin of safety; PBPK; Pharmacokinetics