%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 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 Generic %D 2022 %T A Novel Framework to Form Sufficiently Similar Mixtures %A Briana N Rivera %A Christine C Ghetu %A Yvonne Chang %A Kim A Anderson %A Susan C Tilton %B Risk Assessment and Mixtures Specialty Section Webinar %8 01/22 %G eng %0 Generic %D 2021 %T Current Approaches to Characterizing Chemical Mixtures %A Briana N Rivera %A Diana Rohlman %A Kim A Anderson %A Susan C Tilton %B Northwest Toxics Community Coalition %8 4/2021 %G eng %0 Audiovisual Material %D 2021 %T A Novel Approach to Forming Sufficiently Similar Mixtures from Environmental Exposure Data %A Briana N Rivera %A Christine C Ghetu %A Kim A Anderson %A Susan C Tilton %B Society of Toxicology %8 03/2021 %G eng %0 Generic %D 2020 %T A Comparative Approach to Evaluating Bioactivity of Representative Mixtures %A Briana N Rivera %A Christine C Ghetu %A Kim A Anderson %A Susan C Tilton %B Protecting Our Water Future for Human and Environmental Health %8 01/2020 %G eng %0 Generic %D 2020 %T A Comparative Approach to Evaluating Bioactivity of Representative Mixtures %A Briana N Rivera %A Christine C Ghetu %A Kim A Anderson %A Susan C Tilton %B Protecting Our Water Future for Human and Environmental Health %8 01/2020 %G eng %0 Generic %D 2020 %T A Novel Approach to Forming Sufficiently Similar Mixtures From Environmental Exposure Data %A Briana N Rivera %A Christine C Ghetu %A Kaley A Adams %A Kim A Anderson %A Susan C Tilton %B Pacific Northwest Association of Toxicologists Annual Meeting %8 11/2020 %G eng %0 Audiovisual Material %D 2020 %T A Novel Approach to Forming Sufficiently Similar Mixtures from Environmental Exposure Data %A Briana N Rivera %A Christine C Ghetu %A Kim A Anderson %A Susan C Tilton %B Superfund Research Center Annual Meeting %8 12/2020 %G eng %0 Audiovisual Material %D 2019 %T Determining Environmental Exposure Profiles of Health and Dysphagic Foals %A Briana N Rivera %A Kathleen Mullen %A Lane G Tidwell %A Renata Ivanek %A Dorothy Ainsworth %A Susan C Tilton %A Kim A Anderson %B Society of Environmental Toxicology and Chemistry North America, Toronto, ON %8 11/2019 %G eng %0 Audiovisual Material %D 2019 %T Determining Environmental Exposure Profiles of Health and Dysphagic Foals %A Briana N Rivera %A Kathleen Mullen %A Lane G Tidwell %A Renata Ivanek %A Dorothy Ainsworth %A Susan C Tilton %A Kim A Anderson %B Superfund Research Program, Seattle, WA %8 11/2019 %G eng %0 Audiovisual Material %D 2019 %T Evaluating Toxicity of Inhalation Exposure to Unconventional Natural Gas Drilling %A Briana N Rivera %A Lane G Tidwell %A Carey E Donald %A Yvonne Chang %A Kathleen Mullen %A Dorothy Ainsworth %A Kim A Anderson %A Susan C Tilton %B Society of Toxicology National Conference, Baltimore, MD %8 03/2019 %G eng %0 Audiovisual Material %D 2019 %T Evaluating Toxicity of Inhalation Exposure to Unconventional Natural Gas Drilling %A Briana N Rivera %A Lane G Tidwell %A Carey E Donald %A Yvonne Chang %A Kathleen Mullen %A Dorothy Ainsworth %A Kim A Anderson %A Susan C Tilton %B Society of Toxicology National Conference, Baltimore, MD %8 03/2019 %G eng %0 Generic %D 2019 %T How Should We Approach Forming Representative Mixtures? %A Briana N Rivera %A Kim A Anderson %A Susan C Tilton %B Environmental Health Sciences Colloquim, Corvallis OR %8 09/2019 %G eng %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 Generic %D 2019 %T Using Passive Samplers to Evaluate Inhalation Exposure %A Briana N Rivera %A Kathleen Mullen %A Lane G Tidwell %A Renata Ivanek %A Dorothy Ainsworth %A Susan C Tilton %A Kim A Anderson %B Military Health System Research Symposium, Kissimmee, FL %8 08/2019 %G eng %0 Audiovisual Material %D 2018 %T Evaluating Toxicity Associated with Inhalation Exposure to Unconventional Natural Gas Drilling %A Briana N Rivera %A Lane G Tidwell %A Yvonne Chang %A Carey E Donald %A Kathleen Mullen %A Dorothy Ainsworth %A Richard P Scott %A Kim A Anderson %A Susan C Tilton %B Environmental Public Health in the 21st Century Research Symposium %8 01/2018 %G eng %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 Journal Article %J Toxicol Appl Pharmacol %D 2018 %T Systematic developmental neurotoxicity assessment of a representative PAH Superfund mixture using zebrafish. %A Mitra Geier %A D James Minick %A Truong, Lisa %A Susan C Tilton %A Pande, Paritosh %A Kim A Anderson %A JG Teeguarden %A Robyn L Tanguay %X

Superfund sites often consist of complex mixtures of polycyclic aromatic hydrocarbons (PAHs). It is widely recognized that PAHs pose risks to human and environmental health, but the risks posed by exposure to PAH mixtures are unclear. We constructed an environmentally relevant PAH mixture with the top 10 most prevalent PAHs (SM10) from a Superfund site derived from environmental passive sampling data. Using the zebrafish model, we measured body burden at 48 hours post fertilization (hpf) and evaluated the developmental and neurotoxicity of SM10 and the 10 individual constituents at 24 hours post fertilization (hpf) and 5 days post fertilization (dpf). Zebrafish embryos were exposed from 6 to 120 hpf to (1) the SM10 mixture, (2) a variety of individual PAHs: pyrene, fluoranthene, retene, benzo[a]anthracene, chrysene, naphthalene, acenaphthene, phenanthrene, fluorene, and 2-methylnaphthalene. We demonstrated that SM10 and only 3 of the individual PAHs were developmentally toxic. Subsequently, we constructed and exposed developing zebrafish to two sub-mixtures: SM3 (comprised of 3 of the developmentally toxicity PAHs) and SM7 (7 non-developmentally toxic PAHs). We found that the SM3 toxicity profile was similar to SM10, and SM7 unexpectedly elicited developmental toxicity unlike that seen with its individual components. The results demonstrated that the overall developmental toxicity in the mixtures could be explained using the general concentration addition model. To determine if exposures activated the AHR pathway, spatial expression of CYP1A was evaluated in the 10 individual PAHs and the 3 mixtures at 5 dpf. Results showed activation of AHR in the liver and vasculature for the mixtures and some individual PAHs. Embryos exposed to SM10 during development and raised in chemical-free water into adulthood exhibited decreased learning and responses to startle stimulus indicating that developmental SM10 exposures affect neurobehavior. Collectively, these results exemplify the utility of zebrafish to investigate the developmental and neurotoxicity of complex mixtures.

%B Toxicol Appl Pharmacol %8 2018 Apr 06 %G eng %R 10.1016/j.taap.2018.03.029 %0 Audiovisual Material %D 2018 %T Using passive samplers and 3D bronchial epithelium to determine toxicity associated with natural gas drilling %A Briana N Rivera %A Lane G Tidwell %A Carey E Donald %A Kathleen Mullen %A Dorothy Ainsworth %A Richard P Scott %A Kim A Anderson %A Susan C Tilton %B Center for Genome Research and Biocomputing Fall Conference %8 10/2018 %G eng %0 Audiovisual Material %D 2018 %T Using passive samplers and 3D bronchial epithelium to determine toxicity associated with natural gas drilling %A Briana N Rivera %A Lane G Tidwell %A Carey E Donald %A Kathleen Mullen %A Dorothy Ainsworth %A Richard P Scott %A Kim A Anderson %A Susan C Tilton %B Pacific Northwest Association of Toxicologists (PANWAT), Bothell, Wa %8 10/2018 %G eng %0 Journal Article %J Toxicol Appl Pharmacol %D 2013 %T Structurally distinct polycyclic aromatic hydrocarbons induce differential transcriptional responses in developing zebrafish. %A Goodale, Britton C %A Susan C Tilton %A Corvi, Margaret M %A Glenn R Wilson %A Janszen, Derek B %A Kim A Anderson %A Katrina M Waters %A Robyn L Tanguay %K Animals %K Embryo, Nonmammalian %K Polycyclic Hydrocarbons, Aromatic %K Structure-Activity Relationship %K Transcription, Genetic %K Zebrafish %X

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment as components of fossil fuels and by-products of combustion. These multi-ring chemicals differentially activate the aryl hydrocarbon receptor (AHR) in a structurally dependent manner, and induce toxicity via both AHR-dependent and -independent mechanisms. PAH exposure is known to induce developmental malformations in zebrafish embryos, and recent studies have shown cardiac toxicity induced by compounds with low AHR affinity. Unraveling the potentially diverse molecular mechanisms of PAH toxicity is essential for understanding the hazard posed by complex PAH mixtures present in the environment. We analyzed transcriptional responses to PAH exposure in zebrafish embryos exposed to benz(a)anthracene (BAA), dibenzothiophene (DBT) and pyrene (PYR) at concentrations that induced developmental malformations by 120 h post-fertilization (hpf). Whole genome microarray analysis of mRNA expression at 24 and 48 hpf identified genes that were differentially regulated over time and in response to the three PAH structures. PAH body burdens were analyzed at both time points using GC-MS, and demonstrated differences in PAH uptake into the embryos. This was important for discerning dose-related differences from those that represented unique molecular mechanisms. While BAA misregulated the least number of transcripts, it caused strong induction of cyp1a and other genes known to be downstream of the AHR, which were not induced by the other two PAHs. Analysis of functional roles of misregulated genes and their predicted regulatory transcription factors also distinguished the BAA response from regulatory networks disrupted by DBT and PYR exposure. These results indicate that systems approaches can be used to classify the toxicity of PAHs based on the networks perturbed following exposure, and may provide a path for unraveling the toxicity of complex PAH mixtures.

%B Toxicol Appl Pharmacol %V 272 %P 656-70 %8 11/2013 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23656968?dopt=Abstract %R 10.1016/j.taap.2013.04.024