<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Monica L. Vermillion Maier</style></author><author><style face="normal" font="default" size="100%">Siddens, Lisbeth K</style></author><author><style face="normal" font="default" size="100%">Jamie Pennington</style></author><author><style face="normal" font="default" size="100%">Sandra Uesugi</style></author><author><style face="normal" font="default" size="100%">Susan C Tilton</style></author><author><style face="normal" font="default" size="100%">Vertel, Emily A</style></author><author><style face="normal" font="default" size="100%">Kim A Anderson</style></author><author><style face="normal" font="default" size="100%">Lane G Tidwell</style></author><author><style face="normal" font="default" size="100%">Ted J Ognibene</style></author><author><style face="normal" font="default" size="100%">Kenneth Turteltaub</style></author><author><style face="normal" font="default" size="100%">Jordan Smith</style></author><author><style face="normal" font="default" size="100%">Williams, David E</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Benzo[a]pyrene toxicokinetics in humans following dietary supplementation with 3,3&#039;-diindolylmethane (DIM) or Brussels sprouts.</style></title><secondary-title><style face="normal" font="default" size="100%">Toxicol Appl Pharmacol</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Toxicol Appl Pharmacol</style></alt-title></titles><dates><year><style  face="normal" font="default" size="100%">2023</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2023 Jan 12</style></date></pub-dates></dates><pages><style face="normal" font="default" size="100%">116377</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;Utilizing the atto-zeptomole sensitivity of UPLC-accelerator mass spectrometry (UPLC-AMS), we previously demonstrated significant first-pass metabolism following escalating (25-250 ng) oral micro-dosing in humans of [C]-benzo[a]pyrene ([C]-BaP). The present study examines the potential for supplementation with Brussels sprouts (BS) or 3,3&#039;-diindolylmethane (DIM) to alter plasma levels of [C]-BaP and metabolites over a 48-h period following micro-dosing with 50 ng (5.4 nCi) [C]-BaP. Volunteers were dosed with [C]-BaP following fourteen days on a cruciferous vegetable restricted diet, or the same diet supplemented for seven days with 50 g of BS or 300 mg of BR-DIM® prior to dosing. BS or DIM reduced total [C] recovered from plasma by 56-67% relative to non-intervention. Dietary supplementation with DIM markedly increased T and reduced C for [C]-BaP indicative of slower absorption. Both dietary treatments significantly reduced C values of four downstream BaP metabolites, consistent with delaying BaP absorption. Dietary treatments also appeared to reduce the T and the plasma AUC() for Unknown Metabolite C, indicating some effect in accelerating clearance of this metabolite. Toxicokinetic constants for other metabolites followed the pattern for [C]-BaP (metabolite profiles remained relatively consistent) and non-compartmental analysis did not indicate other significant alterations. Significant amounts of metabolites in plasma were at the bay region of [C]-BaP irrespective of treatment. Although the number of subjects and large interindividual variation are limitations of this study, it represents the first human trial showing dietary intervention altering toxicokinetics of a defined dose of a known human carcinogen.&lt;/p&gt;
</style></abstract></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Monica L. Vermillion Maier</style></author><author><style face="normal" font="default" size="100%">Siddens, Lisbeth K</style></author><author><style face="normal" font="default" size="100%">Jamie Pennington</style></author><author><style face="normal" font="default" size="100%">Sandra Uesugi</style></author><author><style face="normal" font="default" size="100%">Labut, Edwin M</style></author><author><style face="normal" font="default" size="100%">Vertel, Emily A</style></author><author><style face="normal" font="default" size="100%">Kim A Anderson</style></author><author><style face="normal" font="default" size="100%">Lane G Tidwell</style></author><author><style face="normal" font="default" size="100%">Susan C Tilton</style></author><author><style face="normal" font="default" size="100%">Ted J Ognibene</style></author><author><style face="normal" font="default" size="100%">Kenneth Turteltaub</style></author><author><style face="normal" font="default" size="100%">Jordan Smith</style></author><author><style face="normal" font="default" size="100%">Williams, David E</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Impact of phenanthrene co-administration on the toxicokinetics of benzo[a]pyrene in humans. UPLC-accelerator mass spectrometry following oral microdosing.</style></title><secondary-title><style face="normal" font="default" size="100%">Chem Biol Interact</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Chem Biol Interact</style></alt-title></titles><dates><year><style  face="normal" font="default" size="100%">2023</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2023 Jun 25</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">382</style></volume><pages><style face="normal" font="default" size="100%">110608</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;Current risk assessments for environmental carcinogens rely on animal studies utilizing doses orders of magnitude higher than actual human exposures. Epidemiological studies of people with high exposures (e.g., occupational) are of value, but rely on uncertain exposure data. In addition, exposures are typically not to a single chemical but to mixtures, such as polycyclic aromatic hydrocarbons (PAHs). The extremely high sensitivity of accelerator mass spectrometry (AMS) allows for dosing humans with known carcinogens with de minimus risk. In this study UPLC-AMS was used to assess the toxicokinetics of [C]-benzo[a]pyrene ([C]-BaP) when dosed alone or in a binary mixture with phenanthrene (Phe). Plasma was collected for 48&amp;nbsp;h following a dose of [C]-BaP (50&amp;nbsp;ng, 5.4&amp;nbsp;nCi) or the same dose of [C]-BaP plus Phe (1250&amp;nbsp;ng). Following the binary mixture, C of [C]-BaP significantly decreased (4.4-fold) whereas the volume of distribution (V) increased (2-fold). Further, the toxicokinetics of twelve [C]-BaP metabolites provided evidence of little change in the metabolite profile of [C]-BaP and the pattern was overall reduction consistent with reduced absorption (decrease in C). Although Phe was shown to be a competitive inhibitor of the major hepatic cytochrome P-450 (CYP) responsible for metabolism of [C]-BaP, CYP1A2, the high inhibition constant (K) and lack of any increase in unmetabolized [C]-BaP in plasma makes this mechanism unlikely to be responsible. Rather, co-administration of Phe reduces the absorption of [C]-BaP through a mechanism yet to be determined. This is the first study to provide evidence that, at actual environmental levels of exposure, the toxicokinetics of [C]-BaP in humans is markedly altered by the presence of a second PAH, Phe, a common component of environmental PAH mixtures.&lt;/p&gt;
</style></abstract></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Monica L. Vermillion Maier</style></author><author><style face="normal" font="default" size="100%">Siddens, Lisbeth K</style></author><author><style face="normal" font="default" size="100%">Jamie Pennington</style></author><author><style face="normal" font="default" size="100%">Sandra Uesugi</style></author><author><style face="normal" font="default" size="100%">Kim A Anderson</style></author><author><style face="normal" font="default" size="100%">Lane G Tidwell</style></author><author><style face="normal" font="default" size="100%">Susan C Tilton</style></author><author><style face="normal" font="default" size="100%">Ted J Ognibene</style></author><author><style face="normal" font="default" size="100%">Kenneth Turteltaub</style></author><author><style face="normal" font="default" size="100%">Jordan Smith</style></author><author><style face="normal" font="default" size="100%">Williams, David E</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Benzo[a]pyrene (BaP) metabolites predominant in human plasma following escalating oral micro-dosing with [C]-BaP.</style></title><secondary-title><style face="normal" font="default" size="100%">Environ Int</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Environ Int</style></alt-title></titles><dates><year><style  face="normal" font="default" size="100%">2022</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2022 Jan 15</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">159</style></volume><pages><style face="normal" font="default" size="100%">107045</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;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 [C]-BaP in human plasma by employing UPLC - accelerator mass spectrometry (UPLC-AMS). Volunteers were administered 25, 50, 100, and 250&amp;nbsp;ng (2.7-27 nCi) of [C]-BaP (with interceding minimum 3-week washout periods) with quantification of parent [C]-BaP and metabolites in plasma measured over 48&amp;nbsp;h. [C]-BaP median T was 30&amp;nbsp;min with C and area under the curve (AUC) approximating dose-dependency. Marked inter-individual variability in plasma pharmacokinetics following a 250&amp;nbsp;ng dose was seen with 7 volunteers as measured by the C (8.99&amp;nbsp;±&amp;nbsp;7.08&amp;nbsp;ng&amp;nbsp;×&amp;nbsp;mL) and AUC (68.6&amp;nbsp;±&amp;nbsp;64.0&amp;nbsp;fg&amp;nbsp;×&amp;nbsp;hr&amp;nbsp;×&amp;nbsp;mL). Approximately 3-6% of the [C] recovered (AUC) was parent compound, demonstrating extensive metabolism following oral dosing. Metabolite profiles showed that, even at the earliest time-point (30&amp;nbsp;min), a substantial percentage of [C] 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&amp;nbsp;=&amp;nbsp;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.&lt;/p&gt;
</style></abstract></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Erin Madeen</style></author><author><style face="normal" font="default" size="100%">Siddens, Lisbeth K</style></author><author><style face="normal" font="default" size="100%">Sandra Uesugi</style></author><author><style face="normal" font="default" size="100%">McQuistan, Tammie</style></author><author><style face="normal" font="default" size="100%">Corley, Richard A</style></author><author><style face="normal" font="default" size="100%">Jordan Smith</style></author><author><style face="normal" font="default" size="100%">Katrina M Waters</style></author><author><style face="normal" font="default" size="100%">Susan C Tilton</style></author><author><style face="normal" font="default" size="100%">Kim A Anderson</style></author><author><style face="normal" font="default" size="100%">Ted J Ognibene</style></author><author><style face="normal" font="default" size="100%">Kenneth Turteltaub</style></author><author><style face="normal" font="default" size="100%">Williams, David E</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Toxicokinetics of benzo[a]pyrene in humans: Extensive metabolism as determined by UPLC-accelerator mass spectrometry following oral micro-dosing.</style></title><secondary-title><style face="normal" font="default" size="100%">Toxicol Appl Pharmacol</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Toxicol. Appl. Pharmacol.</style></alt-title></titles><dates><year><style  face="normal" font="default" size="100%">2019</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2019 Feb 01</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">364</style></volume><pages><style face="normal" font="default" size="100%">97-105</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;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.&lt;/p&gt;
</style></abstract></record><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Hummel, Jessica M</style></author><author><style face="normal" font="default" size="100%">Erin Madeen</style></author><author><style face="normal" font="default" size="100%">Siddens, Lisbeth K</style></author><author><style face="normal" font="default" size="100%">Sandra Uesugi</style></author><author><style face="normal" font="default" size="100%">McQuistan, Tammie</style></author><author><style face="normal" font="default" size="100%">Kim A Anderson</style></author><author><style face="normal" font="default" size="100%">Kenneth Turteltaub</style></author><author><style face="normal" font="default" size="100%">Ted J Ognibene</style></author><author><style face="normal" font="default" size="100%">Bench, Graham</style></author><author><style face="normal" font="default" size="100%">Krueger, Sharon K</style></author><author><style face="normal" font="default" size="100%">Stuart Harris</style></author><author><style face="normal" font="default" size="100%">Jordan Smith</style></author><author><style face="normal" font="default" size="100%">Susan C Tilton</style></author><author><style face="normal" font="default" size="100%">Baird, William M</style></author><author><style face="normal" font="default" size="100%">Williams, David E</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Pharmacokinetics of [C]-Benzo[a]pyrene (BaP) in humans: Impact of Co-Administration of smoked salmon and BaP dietary restriction.</style></title><secondary-title><style face="normal" font="default" size="100%">Food Chem Toxicol</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Food Chem. Toxicol.</style></alt-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Adult</style></keyword><keyword><style  face="normal" font="default" size="100%">Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">Animals</style></keyword><keyword><style  face="normal" font="default" size="100%">Benzo(a)pyrene</style></keyword><keyword><style  face="normal" font="default" size="100%">Carbon Radioisotopes</style></keyword><keyword><style  face="normal" font="default" size="100%">Carcinogens</style></keyword><keyword><style  face="normal" font="default" size="100%">Cooking</style></keyword><keyword><style  face="normal" font="default" size="100%">Female</style></keyword><keyword><style  face="normal" font="default" size="100%">Fish Products</style></keyword><keyword><style  face="normal" font="default" size="100%">Food Safety</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Male</style></keyword><keyword><style  face="normal" font="default" size="100%">Middle Aged</style></keyword><keyword><style  face="normal" font="default" size="100%">Polycyclic Aromatic Hydrocarbons</style></keyword><keyword><style  face="normal" font="default" size="100%">Salmon</style></keyword><keyword><style  face="normal" font="default" size="100%">Young Adult</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2018</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2018 May</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">115</style></volume><pages><style face="normal" font="default" size="100%">136-147</style></pages><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;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.&lt;/p&gt;
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