%0 Journal Article %J Toxicol Appl Pharmacol %D 2023 %T Benzo[a]pyrene toxicokinetics in humans following dietary supplementation with 3,3'-diindolylmethane (DIM) or Brussels sprouts. %A Monica L. Vermillion Maier %A Siddens, Lisbeth K %A Jamie Pennington %A Sandra Uesugi %A Susan C Tilton %A Vertel, Emily A %A Kim A Anderson %A Lane G Tidwell %A Ted J Ognibene %A Kenneth Turteltaub %A Jordan Smith %A Williams, David E %X

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'-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.

%B Toxicol Appl Pharmacol %P 116377 %8 2023 Jan 12 %G eng %R 10.1016/j.taap.2023.116377 %0 Journal Article %J Sci Total Environ %D 2023 %T Diffusive fluxes of persistent organic pollutants between Arctic atmosphere, surface waters and sediments. %A Ian L Moran %A Lane G Tidwell %A Michael L Barton %A Molly Kile %A Miller, Pamela %A Diana Rohlman %A Seguinot-Medina, Samarys %A Ungwiluk, Bobby %A Waghiyi, Vi %A Kim A Anderson %X

Arctic communities are disproportionately exposed to pollutants from sources including global atmospheric transport and formerly used defense sites (FUDS). The effects of climate change and increasing development in the Arctic have the potential to exacerbate this problem. Yupik People of Sivuqaq, or St Lawrence Island, Alaska are one such community with documented exposures to pollutants from FUDS, and their traditional lipid-rich foods such as blubber and rendered oils of marine mammals. Troutman Lake, adjacent to the Yupik community of Gambell, Alaska, was used as a disposal site during the decommission of the adjacent FUDS, leading to community concern about exposure to military pollution and intrusion from historic local dump sites. In collaboration with a local community group, this study utilized passive sampling devices deployed in Troutman Lake. Air, water and sediment deployed samplers were analyzed for unsubstituted and alkylated polycyclic aromatic hydrocarbons (PAHs), brominated and organophosphate flame retardants and polychlorinated biphenyls (PCBs). PAH concentrations were low and comparable to other remote/rural locations. PAHs were generally in deposition from the overlying atmosphere into Troutman Lake. Of the flame retardants, brominated diphenyl ether-47 was detected in all surface water samplers while triphenyl phosphate was detected in all environmental compartments. Both were at concentrations equivalent or lower than other remote locations. Of particular interest, we measured higher atmospheric concentrations of tris(2-chloroethyl) phosphate (TCEP) (0.75-2.8 ng/m) than previously reported in the literature for remote Arctic sites (<0.017-0.56 ng/m). TCEP was found to be in deposition to Troutman Lake at magnitudes from 290 to 1300 ng/m/day. No PCBs were detected in this study. Our findings demonstrate the relevance of both modern and legacy chemicals from local and global sources. These results help us to understand the fate of anthropogenic contaminants in dynamic Arctic systems providing valuable data for communities, policy makers and scientists.

%B Sci Total Environ %P 164566 %8 2023 Jun 01 %G eng %R 10.1016/j.scitotenv.2023.164566 %0 Journal Article %J Chem Biol Interact %D 2023 %T Impact of phenanthrene co-administration on the toxicokinetics of benzo[a]pyrene in humans. UPLC-accelerator mass spectrometry following oral microdosing. %A Monica L. Vermillion Maier %A Siddens, Lisbeth K %A Jamie Pennington %A Sandra Uesugi %A Labut, Edwin M %A Vertel, Emily A %A Kim A Anderson %A Lane G Tidwell %A Susan C Tilton %A Ted J Ognibene %A Kenneth Turteltaub %A Jordan Smith %A Williams, David E %X

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 h following a dose of [C]-BaP (50 ng, 5.4 nCi) or the same dose of [C]-BaP plus Phe (1250 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.

%B Chem Biol Interact %V 382 %P 110608 %8 2023 Jun 25 %G eng %R 10.1016/j.cbi.2023.110608 %0 Journal Article %J Environ Int %D 2022 %T Benzo[a]pyrene (BaP) metabolites predominant in human plasma following escalating oral micro-dosing with [C]-BaP. %A Monica L. Vermillion Maier %A Siddens, Lisbeth K %A Jamie Pennington %A Sandra Uesugi %A Kim A Anderson %A Lane G Tidwell %A Susan C Tilton %A Ted J Ognibene %A Kenneth Turteltaub %A Jordan Smith %A Williams, David E %X

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 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 h. [C]-BaP median T was 30 min with C 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 C (8.99 ± 7.08 ng × mL) and AUC (68.6 ± 64.0 fg × hr × 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 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 = 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.

%B Environ Int %V 159 %P 107045 %8 2022 Jan 15 %G eng %R 10.1016/j.envint.2021.107045 %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 %0 Audiovisual Material %D 2012 %T Evaluating polycyclic aromatic hydrocarbon (PAH) exposure from traditional Native American food smoking practices %A Cardenas, Andres %A Harding, Anna %A Stuart Harris %A Staci M Simonich %A Kim A Anderson %A Harper, Barbara %A Stone, Dave %A Jai, Y %A Motorkyn, O %A Sandra Uesugi %A Norman D Forsberg %A Sudakin, Dan %B National Institute of Environmental Health Sciences Core Centers Meeting, Boston, MA %8 2012 %G eng %0 Generic %D 2011 %T Walking in two worlds: Tribal-university partnerships, capacity building, technology transfer, and developing cultural sensitivity in toxicology and environmental health research %A Sandra Uesugi %A Harding, Anna %A Stuart Harris %A Harper, Barbara %A Staci M Simonich %A Kim A Anderson %A Stone, Dave %A Jai, Y %A Hirsch, Naomi %A Cardenas, Andres %A Sudakin, Dan %B Pacific Northwest Association of Toxicologists Meeting, North Bonneville, WA %8 2011 %G eng %0 Generic %D 2005 %T Atmospheric Deposition of Semi-Volatile Organic Compounds in National Parks of the Pacific Northwest %A Hageman, K J %A Usenko, S %A Cambell, D H %A Glenn R Wilson %A Schmedding, D %A Staci M Simonich %B Puget Sound/Georgia Basin Research Conference, Seattle, WA %8 03/2005 %G eng %0 Journal Article %J Environ Sci Technol %D 2005 %T Trace analysis of semivolatile organic compounds in large volume samples of snow, lake water, and groundwater. %A Usenko, Sascha %A Hageman, Kimberly J %A Schmedding, Dave W %A Staci M Simonich %K Chemistry Techniques, Analytical %K Environmental Monitoring %K Organic Chemicals %K Pesticides %K Snow %K Soil Pollutants %K Solubility %K Volatilization %K Water %K Water Pollutants, Chemical %X

An analytical method was developed for the trace analysis of a wide range of semivolatile organic compounds (SOCs) in 50-L high-elevation snow and lake water samples. The method was validated for 75 SOCs from seven different chemical classes (polycyclic aromatic hydrocarbons, organochlorine pesticides, amides, triazines, polychlorinated biphenyls, thiocarbamates, and phosphorothioates) that covered a wide range of physical-chemical properties including 7 orders of magnitude of octanol-water partition coefficient (log K(ow) = 1.4-8.3). The SOCs were extracted using a hydrophobically and hydrophilically modified divinylbenzene solid-phase extraction device (modified Speedisk). The average analyte recovery from 50 L of reverse osmosis water, using the modified Speedisk, was 99% with an average relative standard deviation of 4.8%. Snow samples were collected from the field, melted, and extracted using the modified Speedisk and a poly(tetrafluoroethylene) remote sample adapter in the laboratory. Lake water was sampled, filtered, and extracted in situ using an Infiltrex 100 fitted with a 1-microm glass fiber filter to trap particulate matter and the modified Speedisk to trap dissolved SOCs. The extracts were analyzed by gas chromatographic mass spectrometry with electron impact ionization and electron capture negative ionization using isotope dilution and selective ion monitoring. Estimated method detection limits for snow and lake water ranged from 0.2 to 125 pg/L and 0.5-400 pg/L, respectively. U.S. historic and current-use pesticides were identified and quantified in snow and lake water samples collected from Rocky Mountain National Park, CO. The application of the analytical method to the analysis of SOCs in large-volume groundwater samples is also shown.

%B Environ Sci Technol %V 39 %P 6006-15 %8 2005 Aug 15 %G eng %N 16 %R 10.1021/es0506511 %0 Audiovisual Material %D 2004 %T Semi-volatile Organic Compounds in Lake Water from High Elevation or High Latitude Perched Lakes in National Parks in the Western U.S. %A Usenko, S %A Hageman, K J %A Schmedding, D %A Glenn R Wilson %A Staci M Simonich %B Fourth SETAC World Congress, Portland, OR %8 11/2004 %G eng %0 Generic %D 2004 %T Semi-Volatile Organic Compounds in Snow and Lake Water from National Parks of the Western United States %A Hageman, K J %A Usenko, S %A Glenn R Wilson %A Schmedding, D %A Cambell, D H %A Staci M Simonich %B SETAC Europe, Prague, Czechoslovakia %8 04/2004 %G eng %0 Generic %D 2004 %T Semi-Volatile Organic Compounds in Snow Collected at National Parks in the Western United States %A Hageman, K J %A Cambell, D H %A Glenn R Wilson %A Schmedding, D %A Usenko, S %A Staci M Simonich %B Fourth SETAC World Congress, Portland, OR %8 11/2004 %G eng %0 Generic %D 2004 %T Semi-Volatile Organic Compounds in Snow from National Parks of the Western United States %A Hageman, K J %A Usenko, S %A Glenn R Wilson %A Schmedding, D %A Staci M Simonich %B SETAC Europe Workshop, Milano, Italy %8 06/2004 %G eng %0 Audiovisual Material %D 2003 %T A Method for the Measurement of Anthropogenic Semi-Volatile Organic Compounds in High Elevation Snow and Lake Water %A Usenko, S %A Schmedding, D %A Glenn R Wilson %A Staci M Simonich %B Society of Environmental Toxicology and Chemistry, Austin TX %8 11/2003 %G eng