title: Refined biokinetic model for humans exposed to cobalt dietary supplements and other sources of systemic cobalt exposure.
abstract: An updated biokinetic model for human exposures to cobalt (Co) was developed based on a comprehensive set of human pharmacokinetics data collected from five male and five female volunteers who ingested ∼1 mg Co/day of a Co supplement for 3 months. Three key experimental observations from the human dosing studies were incorporated into the model: (1) an increase in the measured fraction of large molecular serum protein bound Co from 95% during dosing to 99% after dosing; (2) a linear decrease in Co red blood cell concentration after dosing; and (3) Co renal clearance consistent with estimated glomerular filtration rates and free Co²⁺ concentration. The model was refined by adding compartments accounting for (1) albumin bound Co in intravascular fluid (serum); (2) albumin bound Co in extravascular fluid with physiologic exchange rates of albumin bound Co between extravascular and intravascular fluid; and (3) a novel sequential cascade of compartments representing red blood cell ages between 1 and 120 days. Reasonable agreement between the modeled and measured urine, serum, and whole blood concentrations were observed (r>0.84, slope=0.79-1.0) with gastrointestinal absorption rates between 9% and 66%. In addition, model predictions agreed well with data from several external studies representing healthy human volunteers, dialysis patients, anephric patients, a Co-poisoning incident and whole body retention studies. Our revised model considerably improves the state of knowledge on human Co kinetics, and should be helpful for evaluating elevated blood Co concentrations in currently exposed populations, such as metal-on-metal (MoM) hip implant patients.
authors.affiliation: Cardno ChemRisk, Pittsburgh, PA 15222, United States. Electronic address: ken.unice@cardno.com.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Unice
authors.affiliation: Cardno ChemRisk, Aliso Viejo, CA 92656, United States.
authors.forename: Brent D
authors.initials: BD
authors.lastname: Kerger
authors.affiliation: Cardno ChemRisk, San Francisco, CA 94105, United States.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Paustenbach
authors.affiliation: Cardno ChemRisk, Brooklyn, NY 11201, United States.
authors.forename: Brent L
authors.initials: BL
authors.lastname: Finley
authors.affiliation: Cardno ChemRisk, Boulder, CO 80301, United States.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Tvermoes
mesh_terms: D000328:Adult; D000418:Albumins; D003035:Cobalt / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D003198:Computer Simulation; D019587:Dietary Supplements; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D011485:Protein Binding; D015203:Reproducibility of Results
chemical_list: D000418:Albumins; D003035:Cobalt
keywords: Albumin binding; Cobalt; Red blood cell kinetics; Renal excretion; Renal reabsorption; Toxicokinetics