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  1. Article ; Online: Dose Addition Models Accurately Predict the Subacute Effects of a Mixture of Perfluorooctane Sulfonate and Perfluorooctanoic Acid on Japanese Quail (Coturnix japonica) Chick Mortality.

    Gray, L Earl / Conley, Justin M / Bursian, Steven J

    Environmental toxicology and chemistry

    2023  Volume 43, Issue 1, Page(s) 97–104

    Abstract: Biomonitoring data have consistently demonstrated that fish, wildlife, and humans are exposed to multiple per- and polyfluoroalkyl substances (PFAS) in drinking water and foods. Despite ubiquitous exposure to mixtures of PFAS, there is a lack of in vivo ... ...

    Abstract Biomonitoring data have consistently demonstrated that fish, wildlife, and humans are exposed to multiple per- and polyfluoroalkyl substances (PFAS) in drinking water and foods. Despite ubiquitous exposure to mixtures of PFAS, there is a lack of in vivo PFAS mixture research that addresses whether these chemicals act in a cumulative, dose-additive (DA) manner or whether they behave independently. For this reason, there is a critical need for mixtures studies designed to evaluate the cumulative toxicity and potential chemical interactions to support the assessment of human and ecological risks and also to define appropriate regulatory actions. Our primary objective was to evaluate the previously published Japanese quail chick mortality concentration-response data for perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and the mixture of PFOS + PFOA and to use statistical modeling to determine whether the effects of the mixtures were accurately predicted by either DA or response addition modeling. In addition, we wanted to compare different DA models to determine whether one model produced more accurate predictions than the others. Our results support the hypothesis of cumulative effects on shared endpoints from PFOA and PFOS co-exposure and DA approaches for predictive estimates of cumulative effects. Given the limited number of in vivo studies that have been executed with enough individual PFAS and PFAS mixture concentration-response data to test the hypothesis of DA for PFAS mixtures, this re-analysis of the data is an important contribution to our understanding of how PFAS mixtures act. The analysis will provide support for regulatory agencies as they begin to implement PFAS cumulative hazard assessments in higher vertebrates. Environ Toxicol Chem 2024;43:97-104. © 2023 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
    MeSH term(s) Animals ; Humans ; Coturnix ; Alkanesulfonic Acids/toxicity ; Fluorocarbons/toxicity ; Fluorocarbons/analysis
    Chemical Substances perfluorooctane (6P60ZBK0QL) ; perfluorooctanoic acid (947VD76D3L) ; perfluorooctane sulfonic acid (9H2MAI21CL) ; Alkanesulfonic Acids ; Fluorocarbons
    Language English
    Publishing date 2023-11-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 46234-2
    ISSN 1552-8618 ; 0730-7268
    ISSN (online) 1552-8618
    ISSN 0730-7268
    DOI 10.1002/etc.5758
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Maternal and Neonatal Effects of Maternal Oral Exposure to Perfluoro-2-methoxyacetic Acid (PFMOAA) during Pregnancy and Early Lactation in the Sprague-Dawley Rat.

    Conley, Justin M / Lambright, Christy S / Evans, Nicola / Bangma, Jacqueline / Ford, Jermaine / Hill, Donna / Medlock-Kakaley, Elizabeth / Gray, L Earl

    Environmental science & technology

    2024  Volume 58, Issue 2, Page(s) 1064–1075

    Abstract: Perfluoro-2-methoxyacetic acid (PFMOAA) is a short-chain perfluoroalkyl ether carboxylic acid that has been detected at high concentrations (∼10 μg/L) in drinking water in eastern North Carolina, USA, and in human serum and breastmilk in China. Despite ... ...

    Abstract Perfluoro-2-methoxyacetic acid (PFMOAA) is a short-chain perfluoroalkyl ether carboxylic acid that has been detected at high concentrations (∼10 μg/L) in drinking water in eastern North Carolina, USA, and in human serum and breastmilk in China. Despite documented human exposure there are almost no toxicity data available to inform risk assessment of PFMOAA. Here we exposed pregnant Sprague-Dawley rats to a range of PFMOAA doses (10-450 mg/kg/d) via oral gavage from gestation day (GD) 8 to postnatal day (PND) 2 and compared results to those we previously reported for perfluorooctanoic acid (PFOA) and hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX). Newborn pups displayed reduced birthweight (≥30 mg/kg), depleted liver glycogen concentrations (all doses), hypoglycemia (≥125 mg/kg), and numerous significantly altered genes in the liver associated with fatty acid and glucose metabolism similar to gene changes produced by HFPO-DA. Pup survival was significantly reduced at ≥125 mg/kg, and at necropsy on PND2 both maternal and neonatal animals displayed increased liver weights, increased serum aspartate aminotransferase (AST), and reduced serum thyroid hormones at all doses (≥10 mg/kg). Pups also displayed highly elevated serum cholesterol at all doses. PFMOAA concentrations in serum and liver increased with maternal oral dose in both maternal and F1 animals and were similar to those we reported for PFOA but considerably higher than HFPO-DA. We calculated 10% effect levels (ED10 or EC10) and relative potency factors (RPF; PFOA = index chemical) among the three compounds based on maternal oral dose and maternal serum concentration (μM). Reduced pup liver glycogen, increased liver weights and reduced thyroid hormone levels (maternal and pup) were the most sensitive end points modeled. PFMOAA was ∼3-7-fold less potent than PFOA for most end points based on maternal serum RPFs, but slightly more potent for increased maternal and pup liver weights. PFMOAA is a maternal and developmental toxicant in the rat producing a constellation of adverse effects similar to PFOA and HFPO-DA.
    MeSH term(s) Pregnancy ; Humans ; Female ; Rats ; Animals ; Rats, Sprague-Dawley ; Liver Glycogen ; Fluorocarbons/toxicity ; Lactation ; Thyroid Hormones ; Maternal Exposure ; Caprylates ; Propionates
    Chemical Substances perfluoro-2-methoxyacetic acid ; ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate ; Liver Glycogen ; perfluorooctanoic acid (947VD76D3L) ; Fluorocarbons ; Thyroid Hormones ; Caprylates ; Propionates
    Language English
    Publishing date 2024-01-01
    Publishing country United States
    Document type Journal Article
    ISSN 1520-5851
    ISSN (online) 1520-5851
    DOI 10.1021/acs.est.3c08559
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: In vitro activity of a panel of per- and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, and estrogen receptor assays.

    Evans, Nicola / Conley, Justin M / Cardon, Mary / Hartig, Phillip / Medlock-Kakaley, Elizabeth / Gray, L Earl

    Toxicology and applied pharmacology

    2022  Volume 449, Page(s) 116136

    Abstract: Data demonstrate numerous per- and polyfluoroalkyl substances (PFAS) activate peroxisome proliferator-activated receptor alpha (PPARα), however, additional work is needed to characterize PFAS activity on PPAR gamma (PPARγ) and other nuclear receptors. We ...

    Abstract Data demonstrate numerous per- and polyfluoroalkyl substances (PFAS) activate peroxisome proliferator-activated receptor alpha (PPARα), however, additional work is needed to characterize PFAS activity on PPAR gamma (PPARγ) and other nuclear receptors. We utilized in vitro assays with either human or rat PPARα or PPARγ ligand binding domains to evaluate 16 PFAS (HFPO-DA, HFPO-DA-AS, NBP2, PFMOAA, PFHxA, PFOA, PFNA, PFDA, PFOS, PFBS, PFHxS, PFOSA, EtPFOSA, and 4:2, 6:2 and 8:2 FTOH), 3 endogenous fatty acids (oleic, linoleic, and octanoic), and 3 pharmaceuticals (WY14643, clofibrate, and the metabolite clofibric acid). We also tested chemicals for human estrogen receptor (hER) transcriptional activation. Nearly all compounds activated both PPARα and PPARγ in both human and rat ligand binding domain assays, except for the FTOH compounds and PFOSA. Receptor activation and relative potencies were evaluated based on effect concentration 20% (EC
    MeSH term(s) Animals ; Fatty Acids ; Female ; Fluorocarbons/toxicity ; Ligands ; Male ; PPAR alpha/genetics ; PPAR gamma ; Rats ; Receptors, Estrogen
    Chemical Substances Fatty Acids ; Fluorocarbons ; Ligands ; PPAR alpha ; PPAR gamma ; Receptors, Estrogen
    Language English
    Publishing date 2022-06-22
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 204477-8
    ISSN 1096-0333 ; 0041-008X
    ISSN (online) 1096-0333
    ISSN 0041-008X
    DOI 10.1016/j.taap.2022.116136
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Dose additive maternal and offspring effects of oral maternal exposure to a mixture of three PFAS (HFPO-DA, NBP2, PFOS) during pregnancy in the Sprague-Dawley rat.

    Conley, Justin M / Lambright, Christy S / Evans, Nicola / Farraj, Aimen K / Smoot, Jacob / Grindstaff, Rachel D / Hill, Donna / McCord, James / Medlock-Kakaley, Elizabeth / Dixon, Aaron / Hines, Erin / Gray, L Earl

    The Science of the total environment

    2023  Volume 892, Page(s) 164609

    Abstract: Simultaneous exposure to multiple per- and polyfluoroalkyl substances (PFAS) is common in humans across the globe. Individual PFAS are associated with adverse health effects, yet the nature of mixture effects after exposure to two or more PFAS remains ... ...

    Abstract Simultaneous exposure to multiple per- and polyfluoroalkyl substances (PFAS) is common in humans across the globe. Individual PFAS are associated with adverse health effects, yet the nature of mixture effects after exposure to two or more PFAS remains unclear. Previously we reported that oral administration of hexafluoropropylene oxide-dimer acid (HFPO-DA, or GenX), Nafion byproduct 2 (NBP2), or perfluorooctane sulfonate (PFOS) individually during pregnancy produced maternal and F1 effects. Here, we hypothesized that responses to the combined exposure to these three PFAS would be dose additive. Pregnant Sprague-Dawley rats were exposed to a fixed-ratio equipotent mixture where the top dose contained each PFAS at their ED50 for neonatal mortality (100 % dose = PFOS 3 mg/kg; NBP2 10 mg/kg; HFPO-DA 110 mg/kg), followed by a dilution series (33.3, 10, 3.3, and 1 %) and vehicle controls (0 % dose). Consistent with the single chemical studies, dams were exposed from gestation day (GD)14-18 or from GD8-postnatal day (PND2). Fetal and maternal livers on GD18 displayed multiple significantly upregulated genes associated with lipid and carbohydrate metabolism at all dose levels, while dams displayed significantly increased liver weight (≥3.3 % dose) and reduced serum thyroid hormones (≥33.3 % dose). Maternal exposure from GD8-PND2 significantly reduced pup bodyweights at birth (≥33.3 % dose) and PND2 (all doses), increased neonatal liver weights (≥3.3 % dose), increased pup mortality (≥3.3 % dose), and reduced maternal bodyweights and weight gain at the top dose. Echocardiography of adult F1 males and females identified significantly increased left ventricular anterior wall thickness (~10 % increase), whereas other cardiac morphological, functional, and transcriptomic measures were unaffected. Mixture effects in maternal and neonatal animals conformed to dose addition using a relative potency factor (RPF) analysis. Results support dose addition-based cumulative assessment approaches for estimating combined effects of PFAS co-exposure.
    MeSH term(s) Pregnancy ; Rats ; Animals ; Humans ; Male ; Female ; Adult ; Maternal Exposure/adverse effects ; Rats, Sprague-Dawley ; Prenatal Exposure Delayed Effects/chemically induced ; Fluorocarbons/toxicity ; Alkanesulfonic Acids/toxicity
    Chemical Substances ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate ; perfluorosulfonic acid (39464-59-0) ; perfluorooctane sulfonic acid (9H2MAI21CL) ; Fluorocarbons ; Alkanesulfonic Acids
    Language English
    Publishing date 2023-06-02
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 121506-1
    ISSN 1879-1026 ; 0048-9697
    ISSN (online) 1879-1026
    ISSN 0048-9697
    DOI 10.1016/j.scitotenv.2023.164609
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Dose additive maternal and offspring effects of oral maternal exposure to a mixture of three PFAS (HFPO-DA, NBP2, PFOS) during pregnancy in the Sprague-Dawley rat

    Conley, Justin M. / Lambright, Christy S. / Evans, Nicola / Farraj, Aimen K. / Smoot, Jacob / Grindstaff, Rachel D. / Hill, Donna / McCord, James / Medlock-Kakaley, Elizabeth / Dixon, Aaron / Hines, Erin / Gray, L. Earl

    Science of the Total Environment. 2023 Sept., v. 892 p.164609-

    2023  

    Abstract: Simultaneous exposure to multiple per- and polyfluoroalkyl substances (PFAS) is common in humans across the globe. Individual PFAS are associated with adverse health effects, yet the nature of mixture effects after exposure to two or more PFAS remains ... ...

    Abstract Simultaneous exposure to multiple per- and polyfluoroalkyl substances (PFAS) is common in humans across the globe. Individual PFAS are associated with adverse health effects, yet the nature of mixture effects after exposure to two or more PFAS remains unclear. Previously we reported that oral administration of hexafluoropropylene oxide-dimer acid (HFPO-DA, or GenX), Nafion byproduct 2 (NBP2), or perfluorooctane sulfonate (PFOS) individually during pregnancy produced maternal and F1 effects. Here, we hypothesized that responses to the combined exposure to these three PFAS would be dose additive. Pregnant Sprague-Dawley rats were exposed to a fixed-ratio equipotent mixture where the top dose contained each PFAS at their ED50 for neonatal mortality (100 % dose = PFOS 3 mg/kg; NBP2 10 mg/kg; HFPO-DA 110 mg/kg), followed by a dilution series (33.3, 10, 3.3, and 1 %) and vehicle controls (0 % dose). Consistent with the single chemical studies, dams were exposed from gestation day (GD)14–18 or from GD8-postnatal day (PND2). Fetal and maternal livers on GD18 displayed multiple significantly upregulated genes associated with lipid and carbohydrate metabolism at all dose levels, while dams displayed significantly increased liver weight (≥3.3 % dose) and reduced serum thyroid hormones (≥33.3 % dose). Maternal exposure from GD8-PND2 significantly reduced pup bodyweights at birth (≥33.3 % dose) and PND2 (all doses), increased neonatal liver weights (≥3.3 % dose), increased pup mortality (≥3.3 % dose), and reduced maternal bodyweights and weight gain at the top dose. Echocardiography of adult F1 males and females identified significantly increased left ventricular anterior wall thickness (~10 % increase), whereas other cardiac morphological, functional, and transcriptomic measures were unaffected. Mixture effects in maternal and neonatal animals conformed to dose addition using a relative potency factor (RPF) analysis. Results support dose addition-based cumulative assessment approaches for estimating combined effects of PFAS co-exposure.
    Keywords adults ; blood serum ; byproducts ; carbohydrate metabolism ; echocardiography ; environment ; lipids ; liver ; maternal exposure ; neonatal mortality ; oral administration ; perfluorooctane sulfonic acid ; pregnancy ; progeny ; rats ; transcriptomics ; weight gain ; Cumulative effects ; Dose addition ; Relative potency factor ; Thyroid ; Birthweight
    Language English
    Dates of publication 2023-09
    Publishing place Elsevier B.V.
    Document type Article ; Online
    ZDB-ID 121506-1
    ISSN 1879-1026 ; 0048-9697
    ISSN (online) 1879-1026
    ISSN 0048-9697
    DOI 10.1016/j.scitotenv.2023.164609
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  6. Article ; Online: Cross-species conservation of endocrine pathways: a critical analysis of tier 1 fish and rat screening assays with 12 model chemicals.

    Ankley, Gerald T / Gray, L Earl

    Environmental toxicology and chemistry

    2013  Volume 32, Issue 5, Page(s) 1084–1087

    Abstract: Many structural and functional aspects of the vertebrate hypothalamic-pituitary-gonadal (HPG) axis are known to be highly conserved, but the significance of this from a toxicological perspective has received comparatively little attention. High-quality ... ...

    Abstract Many structural and functional aspects of the vertebrate hypothalamic-pituitary-gonadal (HPG) axis are known to be highly conserved, but the significance of this from a toxicological perspective has received comparatively little attention. High-quality data generated through development and validation of Tier 1 tests for the U.S. Environmenal Protection Agency Endocrine Disruptor Screening Program (EDSP) offer a unique opportunity to compare responses of mammals versus fish to chemicals that may affect shared pathways within the HPG axis. The present study focuses on data generated with model chemicals that act (primarily) as estrogen receptor agonists (17α-ethynylestradiol, methoxychlor, bisphenol A), androgen receptor agonists (methyltestosterone, 17β-trenbolone), androgen receptor antagonists (flutamide, vincolozolin, p,p'-DDE), or inhibitors of different steroidogenic enzymes (ketoconazole, fadrozole, fenarimol, prochloraz). All 12 chemicals had been tested in the EDSP fish short-term (21 d) reproduction assay and in one or more of the four in vivo Tier 1 screens with rats (uterotrophic, Hershberger, male and female pubertal assays). There was a high concordance between the fish and rat assays with respect to identifying chemicals that impacted specific endocrine pathways of concern. Although most chemicals were detected as positive in both rat and fish assays, eliminating data from one class of vertebrate or the other would weaken the battery. For example, the effects of competitive inhibitors of steroid hormone synthesis were far more obvious in the fish assay, whereas the activity of androgen receptor antagonists was clearer in mammalian assays. The observations are significant both to the cross-species extrapolation of toxicity of HPG-active substances and the optimization of screening and testing frameworks for endocrine-disrupting chemicals.
    MeSH term(s) Androgens/toxicity ; Animals ; Biological Assay/methods ; Biological Assay/standards ; Endocrine Disruptors/toxicity ; Endocrine System/physiology ; Environmental Pollutants/toxicity ; Female ; Fishes ; Male ; Rats ; Risk Assessment ; Species Specificity
    Chemical Substances Androgens ; Endocrine Disruptors ; Environmental Pollutants
    Language English
    Publishing date 2013-04
    Publishing country United States
    Document type Journal Article
    ZDB-ID 46234-2
    ISSN 1552-8618 ; 0730-7268
    ISSN (online) 1552-8618
    ISSN 0730-7268
    DOI 10.1002/etc.2151
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: A mixture of 15 phthalates and pesticides below individual chemical no observed adverse effect levels (NOAELs) produces reproductive tract malformations in the male rat.

    Conley, Justin M / Lambright, Christy S / Evans, Nicola / Cardon, Mary / Medlock-Kakaley, Elizabeth / Wilson, Vickie S / Gray, L Earl

    Environment international

    2021  Volume 156, Page(s) 106615

    Abstract: Humans carry residues of multiple synthetic chemicals at any given point in time. Research has demonstrated that compounds with varying molecular initiating events (MIE) that disrupt common key events can act in concert to produce cumulative adverse ... ...

    Abstract Humans carry residues of multiple synthetic chemicals at any given point in time. Research has demonstrated that compounds with varying molecular initiating events (MIE) that disrupt common key events can act in concert to produce cumulative adverse effects. Congenital defects of the male reproductive tract are some of the most frequently diagnosed malformations in humans and chemical exposures in utero can produce these effects in laboratory animals and humans. Here, we hypothesized that in utero exposure to a mixture of pesticides and phthalates, each of which produce male reproductive tract defects individually, would produce cumulative effects even when each chemical is present at a no observed adverse effect level (NOAEL) specific for male reproductive effects. Pregnant Sprague-Dawley rats were exposed via oral gavage to a fixed-ratio dilution mixture of 5 pesticides (vinclozolin, linuron, procymidone, prochloraz, pyrifluquinazon), 1 pesticide metabolite (dichlorodiphenyldichloroethylene (DDE)), and 9 phthalates (dipentyl, dicyclohexyl, di-2-ethylhexyl, dibutyl, benzyl butyl, diisobutyl, diisoheptyl, dihexyl, and diheptyl) during the critical window of rat fetal masculinization (gestation day 14-18). The top dose (100% dose) contained each compound at a concentration 2-fold greater than the individual chemical NOAEL followed by a dilution series that represented each chemical at NOAEL, NOAEL/2, NOAEL/4, NOAEL/8, NOAEL/15, NOAEL/100, NOAEL/1000. Reduced fetal testis gene expression occurred at NOAEL/15, reduced fetal testis testosterone production occurred at NOAEL/8, reduced anogenital distance, increased nipple retention, and delayed puberty occurred at NOAEL/4, and severe effects including genital malformations and weight reductions in numerous reproductive tissues occurred at NOAEL/2. This study demonstrates that these phthalates and pesticides acted cumulatively to produce adverse effects at doses below which any individual chemical had been shown to produce an effect alone and even though they have different MIEs.
    MeSH term(s) Animals ; Female ; Genitalia, Male ; Male ; No-Observed-Adverse-Effect Level ; Pesticides/toxicity ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Reproduction ; Testis
    Chemical Substances Pesticides
    Language English
    Publishing date 2021-05-14
    Publishing country Netherlands
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 554791-x
    ISSN 1873-6750 ; 0160-4120
    ISSN (online) 1873-6750
    ISSN 0160-4120
    DOI 10.1016/j.envint.2021.106615
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  8. Article ; Online: Cumulative effects of antiandrogenic chemical mixtures and their relevance to human health risk assessment.

    Howdeshell, Kembra L / Hotchkiss, Andrew K / Gray, L Earl

    International journal of hygiene and environmental health

    2016  Volume 220, Issue 2 Pt A, Page(s) 179–188

    Abstract: Toxicological studies of defined chemical mixtures assist human health risk assessment by establishing how chemicals interact with one another to induce an effect. This paper reviews how antiandrogenic chemical mixtures can alter reproductive tract ... ...

    Abstract Toxicological studies of defined chemical mixtures assist human health risk assessment by establishing how chemicals interact with one another to induce an effect. This paper reviews how antiandrogenic chemical mixtures can alter reproductive tract development in rats with a focus on the reproductive toxicant phthalates. The reviewed studies compare observed mixture data to mathematical mixture model predictions based on dose addition or response addition to determine how the individual chemicals in a mixture interact (e.g., additive, greater, or less than additive). Phthalate mixtures were observed to act in a dose additive manner based on the relative potency of the individual phthalates to suppress fetal testosterone production. Similar dose additive effects have been reported for mixtures of phthalates with antiandrogenic pesticides of differing mechanisms of action. Overall, data from these phthalate experiments in rats can be used in conjunction with human biomonitoring data to determine individual hazard indices, and recent cumulative risk assessments in humans indicate an excess risk to antiandrogenic chemical mixtures that include phthalates only or phthalates in combination with other antiandrogenic chemicals.
    MeSH term(s) Androgen Antagonists/toxicity ; Animals ; Drug Interactions ; Humans ; Models, Biological ; Risk Assessment
    Chemical Substances Androgen Antagonists
    Language English
    Publishing date 2016-11-19
    Publishing country Germany
    Document type Journal Article ; Review ; Research Support, N.I.H., Intramural
    ZDB-ID 2009176-X
    ISSN 1618-131X ; 1438-4639
    ISSN (online) 1618-131X
    ISSN 1438-4639
    DOI 10.1016/j.ijheh.2016.11.007
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  9. Article ; Online: Corrigendum to "Validation of an automated counting procedure for phthalate-induced testicular multinucleated germ cells" [Toxicol. Lett. 290 (2018) 55-61].

    Spade, Daniel J / Bai, Cathy Yue / Lambright, Christy / Conley, Justin M / Boekelheide, Kim / Gray, L Earl

    Toxicology letters

    2019  Volume 313, Page(s) 208

    Language English
    Publishing date 2019-06-26
    Publishing country Netherlands
    Document type Published Erratum
    ZDB-ID 433788-8
    ISSN 1879-3169 ; 0378-4274
    ISSN (online) 1879-3169
    ISSN 0378-4274
    DOI 10.1016/j.toxlet.2019.06.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: A mixture of 15 phthalates and pesticides below individual chemical no observed adverse effect levels (NOAELs) produces reproductive tract malformations in the male rat

    Conley, Justin M / Lambright, Christy S / Evans, Nicola / Cardon, Mary / Medlock-Kakaley, Elizabeth / Wilson, Vickie S / Gray, L. Earl

    Environment international. 2021 Nov., v. 156

    2021  

    Abstract: Humans carry residues of multiple synthetic chemicals at any given point in time. Research has demonstrated that compounds with varying molecular initiating events (MIE) that disrupt common key events can act in concert to produce cumulative adverse ... ...

    Abstract Humans carry residues of multiple synthetic chemicals at any given point in time. Research has demonstrated that compounds with varying molecular initiating events (MIE) that disrupt common key events can act in concert to produce cumulative adverse effects. Congenital defects of the male reproductive tract are some of the most frequently diagnosed malformations in humans and chemical exposures in utero can produce these effects in laboratory animals and humans. Here, we hypothesized that in utero exposure to a mixture of pesticides and phthalates, each of which produce male reproductive tract defects individually, would produce cumulative effects even when each chemical is present at a no observed adverse effect level (NOAEL) specific for male reproductive effects. Pregnant Sprague-Dawley rats were exposed via oral gavage to a fixed-ratio dilution mixture of 5 pesticides (vinclozolin, linuron, procymidone, prochloraz, pyrifluquinazon), 1 pesticide metabolite (dichlorodiphenyldichloroethylene (DDE)), and 9 phthalates (dipentyl, dicyclohexyl, di-2-ethylhexyl, dibutyl, benzyl butyl, diisobutyl, diisoheptyl, dihexyl, and diheptyl) during the critical window of rat fetal masculinization (gestation day 14–18). The top dose (100% dose) contained each compound at a concentration 2-fold greater than the individual chemical NOAEL followed by a dilution series that represented each chemical at NOAEL, NOAEL/2, NOAEL/4, NOAEL/8, NOAEL/15, NOAEL/100, NOAEL/1000. Reduced fetal testis gene expression occurred at NOAEL/15, reduced fetal testis testosterone production occurred at NOAEL/8, reduced anogenital distance, increased nipple retention, and delayed puberty occurred at NOAEL/4, and severe effects including genital malformations and weight reductions in numerous reproductive tissues occurred at NOAEL/2. This study demonstrates that these phthalates and pesticides acted cumulatively to produce adverse effects at doses below which any individual chemical had been shown to produce an effect alone and even though they have different MIEs.
    Keywords DDE (pesticide) ; environment ; gene expression ; linuron ; males ; masculinization ; maternal exposure ; no observed adverse effect level ; pesticide metabolites ; phthalates ; pregnancy ; prochloraz ; procymidone ; puberty ; rats ; testes ; testosterone ; vinclozolin
    Language English
    Dates of publication 2021-11
    Publishing place Elsevier Ltd
    Document type Article
    Note NAL-AP-2-clean
    ZDB-ID 554791-x
    ISSN 1873-6750 ; 0160-4120
    ISSN (online) 1873-6750
    ISSN 0160-4120
    DOI 10.1016/j.envint.2021.106615
    Database NAL-Catalogue (AGRICOLA)

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