Benzo[a]pyrene (BaP) metabolites predominant in human plasma following escalating oral micro-dosing with [14C]-BaP

Environment International

Jamie M. Pennington¹  Lisbeth K. Siddens²  Susan C. Tilton²  Kim A. Anderson²  Jordan N. Smith³  Kenneth W. Turteltaub⁴  David E. Williams⁴  Lane G. Tidwell⁵  Monica L. Vermillion Maier⁵  Ted J. Ognibene⁵  Sandra L. Uesugi⁵ 

[1] Corresponding author at: Department of Environmental and Molecular Toxicology, ALS 1007, Oregon State University, Corvallis, OR 97331, USA.;Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA;NIEHS Superfund Research Program, Oregon State University, Corvallis, OR 97331, USA;Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA;Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA;

关键词: Benzo[a]pyrene;    Polycyclic aromatic hydrocarbons;    Human carcinogen dosing;    Accelerator mass spectrometry;    Toxicokinetics in humans;   

DOI  :  

来源: DOAJ

【 摘 要 】

Benzo[a]pyrene (BaP) is formed by incomplete combustion of organic materials (petroleum, coal, tobacco, etc.). BaP is designated by the International Agency for Research on Cancer as a group 1 known human carcinogen; a classification supported by numerous studies in preclinical models and epidemiology studies of exposed populations. Risk assessment relies on toxicokinetic and cancer studies in rodents at doses 5–6 orders of magnitude greater than average human uptake. Using a dose–response design at environmentally relevant concentrations, this study follows uptake, metabolism, and elimination of [14C]-BaP in human plasma by employing UPLC - accelerator mass spectrometry (UPLC-AMS). Volunteers were administered 25, 50, 100, and 250 ng (2.7–27 nCi) of [14C]-BaP (with interceding minimum 3-week washout periods) with quantification of parent [14C]-BaP and metabolites in plasma measured over 48 h. [14C]-BaP median Tmax was 30 min with Cmax and area under the curve (AUC) approximating dose-dependency. Marked inter-individual variability in plasma pharmacokinetics following a 250 ng dose was seen with 7 volunteers as measured by the Cmax (8.99 ± 7.08 ng × mL−1) and AUC0-48hr (68.6 ± 64.0 fg × hr−1 × mL−1). Approximately 3–6% of the [14C] recovered (AUC0-48 hr) was parent compound, demonstrating extensive metabolism following oral dosing. Metabolite profiles showed that, even at the earliest time-point (30 min), a substantial percentage of [14C] in plasma was polar BaP metabolites. The best fit modeling approach identified non-compartmental apparent volume of distribution of BaP as significantly increasing as a function of dose (p = 0.004). Bay region tetrols and dihydrodiols predominated, suggesting not only was there extensive first pass metabolism but also potentially bioactivation. AMS enables the study of environmental carcinogens in humans with de minimus risk, allowing for important testing and validation of physiologically based pharmacokinetic models derived from animal data, risk assessment, and the interpretation of data from high-risk occupationally exposed populations.

【 授权许可】

Unknown