%0 Journal Article %J Toxicol Appl Pharmacol %D 2019 %T Toxicokinetics of benzo[a]pyrene in humans: Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing. %A Erin Madeen %A Siddens, Lisbeth K %A Sandra Uesugi %A McQuistan, Tammie %A Corley, Richard A %A Jordan Smith %A Katrina M Waters %A Susan C Tilton %A Kim A Anderson %A Ted J Ognibene %A Kenneth Turteltaub %A Williams, David E %X

Benzo[a]pyrene (BaP), is a known human carcinogen (International Agency for Research on Cancer (IARC) class 1). The remarkable sensitivity (zepto-attomole C in biological samples) of accelerator mass spectrometry (AMS) makes possible, with de minimus risk, pharmacokinetic (PK) analysis following [C]-BaP micro-dosing of humans. A 46 ng (5 nCi) dose was given thrice to 5 volunteers with minimum 2 weeks between dosing and plasma collected over 72 h. [C]-BaP PK analysis gave plasma T and C values of 1.25 h and 29-82 fg/mL, respectively. PK parameters were assessed by non- compartment and compartment models. Intervals between dosing ranged from 20 to 420 days and had little impact on intra-individual variation. DNA, extracted from peripheral blood mononuclear cells (PBMCs) of 4 volunteers, showed measurable levels (LOD ~ 0.5 adducts/10 nucleotides) in two individuals 2-3 h post-dose, approximately three orders of magnitude lower than smokers or occupationally-exposed individuals. Little or no DNA binding was detectable at 48-72 h. In volunteers the allelic variants CYP1B1, or and GSTM1 or had no impact on [C]-BaP PK or DNA adduction with this very limited sample. Plasma metabolites over 72 h from two individuals (one CYP1B1 and one CYP1B1) were analyzed by UPLC-AMS. In both individuals, parent [C]-BaP was a minor constituent even at the earliest time points and metabolite profiles markedly distinct. AMS, coupled with UPLC, could be used in humans to enhance the accuracy of pharmacokinetics, toxicokinetics and risk assessment of environmental carcinogens.

%B Toxicol Appl Pharmacol %V 364 %P 97-105 %8 2019 Feb 01 %G eng %R 10.1016/j.taap.2018.12.010 %0 Journal Article %J Food Chem Toxicol %D 2018 %T Pharmacokinetics of [C]-Benzo[a]pyrene (BaP) in humans: Impact of Co-Administration of smoked salmon and BaP dietary restriction. %A Hummel, Jessica M %A Erin Madeen %A Siddens, Lisbeth K %A Sandra Uesugi %A McQuistan, Tammie %A Kim A Anderson %A Kenneth Turteltaub %A Ted J Ognibene %A Bench, Graham %A Krueger, Sharon K %A Stuart Harris %A Jordan Smith %A Susan C Tilton %A Baird, William M %A Williams, David E %K Adult %K Aged %K Animals %K Benzo(a)pyrene %K Carbon Radioisotopes %K Carcinogens %K Cooking %K Female %K Fish Products %K Food Safety %K Humans %K Male %K Middle Aged %K Polycyclic Aromatic Hydrocarbons %K Salmon %K Young Adult %X

Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), is a known human carcinogen. In non-smoking adults greater than 95% of BaP exposure is through diet. The carcinogenicity of BaP is utilized by the U.S. EPA to assess relative potency of complex PAH mixtures. PAH relative potency factors (RPFs, BaP = 1) are determined from high dose animal data. We employed accelerator mass spectrometry (AMS) to determine pharmacokinetics of [C]-BaP in humans following dosing with 46 ng (an order of magnitude lower than human dietary daily exposure and million-fold lower than animal cancer models). To assess the impact of co-administration of food with a complex PAH mixture, humans were dosed with 46 ng of [C]-BaP with or without smoked salmon. Subjects were asked to avoid high BaP-containing diets and a 3-day dietary questionnaire given to assess dietary exposure prior to dosing and three days post-dosing with [C]-BaP. Co-administration of smoked salmon, containing a complex mixture of PAHs with an RPF of 460 ng BaP, reduced and delayed absorption. Administration of canned commercial salmon, containing very low amounts of PAHs, showed the impacts on pharmacokinetics were not due to high amounts of PAHs but rather a food matrix effect.

%B Food Chem Toxicol %V 115 %P 136-147 %8 2018 May %G eng %R 10.1016/j.fct.2018.03.003