%0 Journal Article %J Toxics %D 2022 %T Leveraging Multiple Data Streams for Prioritization of Mixtures for Hazard Characterization. %A Rivera, Brianna N %A Christine C Ghetu %A Yvonne Chang %A Truong, Lisa %A Robyn L Tanguay %A Kim A Anderson %X

There is a growing need to establish alternative approaches for mixture safety assessment of polycyclic aromatic hydrocarbons (PAHs). Due to limitations with current component-based approaches, and the lack of established methods for using whole mixtures, a promising alternative is to use sufficiently similar mixtures; although, an established framework is lacking. In this study, several approaches are explored to form sufficiently similar mixtures. Multiple data streams including environmental concentrations and empirically and predicted toxicity data for cancer and non-cancer endpoints were used to prioritize chemical components for mixture formations. Air samplers were analyzed for unsubstituted and alkylated PAHs. A synthetic mixture of identified PAHs was created (Creosote-Fire Mix). Existing toxicity values and chemical concentrations were incorporated to identify hazardous components in the Creosote-Fire Mix. Sufficiently similar mixtures of the Creosote-Fire Mix were formed based on (1) relative abundance; (2) toxicity values; and (3) a combination approach incorporating toxicity and abundance. Hazard characterization of these mixtures was performed using high-throughput screening in primary normal human bronchial epithelium (NHBE) and zebrafish. Differences in chemical composition and potency were observed between mixture formation approaches. The toxicity-based approach (Tox Mix) was the most potent mixture in both models. The combination approach (Weighted-Tox Mix) was determined to be the ideal approach due its ability to prioritize chemicals with high exposure and hazard potential.

%B Toxics %V 10 %8 2022 Oct 29 %G eng %N 11 %R 10.3390/toxics10110651 %0 Journal Article %J Arch Toxicol %D 2018 %T Comparative developmental toxicity of a comprehensive suite of polycyclic aromatic hydrocarbons. %A Mitra Geier %A Chlebowski, Anna C %A Truong, Lisa %A Staci M Simonich %A Kim A Anderson %A Robyn L Tanguay %K Animals %K Cytochrome P-450 CYP1A1 %K Embryo, Nonmammalian %K Larva %K Polycyclic Aromatic Hydrocarbons %K Toxicity Tests %K Zebrafish %X

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants that occur in complex mixtures. Several PAHs are known or suspected mutagens and/or carcinogens, but developmental toxicity data is lacking for PAHs, particularly their oxygenated and nitrated derivatives. Such data are necessary to understand and predict the toxicity of environmental mixtures. 123 PAHs were assessed for morphological and neurobehavioral effects for a range of concentrations between 0.1 and 50 µM, using a high throughput early-life stage zebrafish assay, including 33 parent, 22 nitrated, 17 oxygenated, 19 hydroxylated, 14 methylated, 16 heterocyclic, and 2 aminated PAHs. Additionally, each PAH was evaluated for AHR activation, by assessing CYP1A protein expression using whole animal immunohistochemistry (IHC). Responses to PAHs varied in a structurally dependent manner. High-molecular weight PAHs were significantly more developmentally toxic than the low-molecular weight PAHs, and CYP1A expression was detected in five distinct tissues, including vasculature, liver, skin, neuromasts and yolk.

%B Arch Toxicol %V 92 %P 571-586 %8 2018 Feb %G eng %N 2 %R 10.1007/s00204-017-2068-9 %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 Journal Article %J Toxicol Appl Pharmacol %D 2013 %T Comparative developmental toxicity of environmentally relevant oxygenated PAHs. %A Knecht, Andrea L %A Goodale, Britton C %A Truong, Lisa %A Simonich, Michael T %A Swanson, Annika J %A Matzke, Melissa M %A Kim A Anderson %A Katrina M Waters %A Robyn L Tanguay %K Abnormalities, Drug-Induced %K Animals %K Biological Markers %K Embryo, Nonmammalian %K Environmental Pollutants %K Extracellular Space %K Gene Expression Regulation, Developmental %K Immunohistochemistry %K Mitochondria %K Oxidation-Reduction %K Oxidative Stress %K Oxygen Consumption %K Polycyclic Hydrocarbons, Aromatic %K Real-Time Polymerase Chain Reaction %K RNA %K Teratogens %K Zebrafish %X

Oxygenated polycyclic aromatic hydrocarbons (OPAHs) are byproducts of combustion and photo-oxidation of parent PAHs. OPAHs are widely present in the environment and pose an unknown hazard to human health. The developing zebrafish was used to evaluate a structurally diverse set of 38 OPAHs for malformation induction, gene expression changes and mitochondrial function. Zebrafish embryos were exposed from 6 to 120h post fertilization (hpf) to a dilution series of 38 different OPAHs and evaluated for 22 developmental endpoints. AHR activation was determined via CYP1A immunohistochemistry. Phenanthrenequinone (9,10-PHEQ), 1,9-benz-10-anthrone (BEZO), xanthone (XAN), benz(a)anthracene-7,12-dione (7,12-B[a]AQ), and 9,10-anthraquinone (9,10-ANTQ) were evaluated for transcriptional responses at 48hpf, prior to the onset of malformations. qRT-PCR was conducted for a number of oxidative stress genes, including the glutathione transferase(gst), glutathione peroxidase(gpx), and superoxide dismutase(sod) families. Bioenergetics was assayed to measure in vivo oxidative stress and mitochondrial function in 26hpf embryos exposed to OPAHs. Hierarchical clustering of the structure-activity outcomes indicated that the most toxic of the OPAHs contained adjacent diones on 6-carbon moieties or terminal, para-diones on multi-ring structures. 5-carbon moieties with adjacent diones were among the least toxic OPAHs while the toxicity of multi-ring structures with more centralized para-diones varied considerably. 9,10-PHEQ, BEZO, 7,12-B[a]AQ, and XAN exposures increased expression of several oxidative stress related genes and decreased oxygen consumption rate (OCR), a measurement of mitochondrial respiration. Comprehensive in vivo characterization of 38 structurally diverse OPAHs indicated differential AHR dependency and a prominent role for oxidative stress in the toxicity mechanisms.

%B Toxicol Appl Pharmacol %V 271 %P 266-75 %8 11/2013 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23684558?dopt=Abstract %R 10.1016/j.taap.2013.05.006