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["AnySifter",null,null,null,null,null,"Query run: oecd AND estrogen AND toxicity"]
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["PMID","oecd","estrogen","valid","Total","Pub Yr","Title","Review","Authors","LinkPMID","tiab"]
[{"$f":"HYPERLINK(\"https://www.ncbi.nlm.nih.gov/pubmed/\" & J4,J4)","v":12948898},{"$f":"(LEN($K4) - LEN(SUBSTITUTE(LOWER($K4),LOWER(B$3),\"\")))/LEN(B$3)","v":1},15,2,{"$f":"SUM(B4:D4)","v":18},2003,"The OECD program to validate the rat uterotrophic bioassay. Phase 2: dietary phytoestrogen analyses.",0," Owens, Ashby, Odum, Onyon",12948898,"The OECD program to validate the rat uterotrophic bioassay. Phase 2: dietary phytoestrogen analyses.    Abstract:   Many commercial laboratory diets have detectable levels of isoflavones (e.g., phytoestrogens such as genistein [GN]) that have weak estrogenic activity both in vitro and in vivo. During validation studies of the uterotrophic bioassay, diet samples from 20 participating laboratories were collected and analyzed for three major phytoestrogens: GN, daidzein (DN), and coumestrol (CM). Soy phytoestrogens GN and DN were found at total phytoestrogen levels from 100 to 540 microg/g laboratory diet; a forage phytoestrogen, CM, ranged from nondetectable to 4 microg/g laboratory diet. The phytoestrogen levels were compared with both baseline uterine weights of the control groups and with the relative uterine weight increase of groups administered two weak estrogen agonists: bisphenol A (BPA) and nonylphenol (NP). The comparison uses a working assumption of additivity among the phytoestrogens, despite several significant qualifications to this assumption, to estimate total genistein equivalents (TGE). Some evidence was found that phytoestrogen levels in the diet gt; 325-350 microg/g TGE could diminish the responsiveness of the uterotrophic bioassay to weak agonists. This was especially true for the case of the intact, immature female version of the uterotrophic bioassay, where higher food consumption relative to body weight leads to higher intakes of dietary phytoestrogens versus ovariectomized adults. This dietary level is sufficient in the immature female to approach a biological lowest observable effect level for GN of 40-50 mg/kg/day. These same data, however, show that low to moderate levels of dietary phytoestrogens do not substantially affect the responsiveness of the assay with weak estrogen receptor agonists such as NP and BPA. Therefore, laboratories conducting the uterotrophic bioassay for either research or regulatory purposes may routinely use diets containing levels of phytoestrogens lt; 325-350 microg/g TGE without impairing the responsiveness of the bioassay."]
[15598176,3,8,6,17,2003,"A critical assessment of the OECD collaborative study to validate the uterotrophic assay for the detection of oestrogenic and anti-oestrogenic chemicals.",0," Combes",15598176,"A critical assessment of the OECD collaborative study to validate the uterotrophic assay for the detection of oestrogenic and anti-oestrogenic chemicals.    Abstract:   The design and execution of a recently completed validation study on the rat uterotrophic assay for detecting oestrogens and anti-oestrogens, managed by the OECD, are critically assessed with respect to internationally agreed criteria for the validation of new in vitro and in vivo toxicity test methods. It is concluded that, while the design of the study did not take account of several important criteria for validation, the uterotrophic assay appears to reliably detect the strong and weak oestrogenic substances used in the study, which act via binding to the oestrogen receptor in vivo. However, the reliability of the assay has not been substantiated for detecting anti-oestrogens that act as antagonists, due to the involvement of an insufficient number of experiments and test chemicals. Moreover, the data do not permit an assessment of the accuracy of the prediction of oestrogenicity, and the protocols have not been sufficiently optimised with regard to controlling variables. This problem has been exacerbated by a wish to introduce as much flexibility as possible into the protocols during the formal validation phase of the study, rather than during a separate prevalidation stage. In addition, the choice between surgically treated and/or immature animals, and details of housing and husbandry conditions that are necessary for increasing the sensitivity and efficiency of the assay, need to be clarified. The assay also lacks a well-defined prediction model by which the overall relevance of the data to toxicity, and especially to human hazard, can be assessed, and no performance criteria have been established. The results of this analysis of the study indicate that it would be premature to produce an OECD test guideline for the uterotrophic assay at this time, before some of the above issues have been satisfactorily resolved."]
[16326438,5,8,3,16,2005,"Validation study of OECD rodent uterotrophic assay for the assessment of estrogenic activity in Sprague-Dawley immature female rats.",0," Kim, Kang, Kang, Kim, Moon, Kim, Ki, Park, Lee, Yoo, Han",16326438,"Validation study of OECD rodent uterotrophic assay for the assessment of estrogenic activity in Sprague-Dawley immature female rats.    Abstract:   The Organization for Economic Cooperation and Development (OECD) is developing a screening and testing method to identify estrogenic/antiestrogenic compounds. Based on these demands, phase 1 study for OECD uterotrophic assay was undertaken. The OECD is in the process of validating the assay results from international participating laboratories, which carried out this study with established environmental estrogenic compounds using designed protocols. The aim of this study was to provide data for validating the OECD uterotrophic assay using Sprague-Dawley immature female rats when testing with weak or partial estrogenic compounds. Ethinyl estradiol (EE) at 0.3 or 1 microg/kg/d, a positive control used in the present study, significantly increased both uterine wet and blotted weights. In the case of weak estrogenic compounds, the uterine wet weights were significantly increased by bisphenol A (BPA) at 300 mg/kg/d, nonylphenol (NP) at 80 mg/kg/d, genistein (GN) at 35 mg/kg/d, and methoxychlor (MXC) at 500 mg/kg/d. In addition, the increase in uterine blotted weights also showed a similar pattern to that of uterine wet weights. However, both 1,1,1-trichloro-2,2-bis(p-chlorphenyl)ethane (o,p-DDT) and dibutyl phthalate (DBP) did not affect uterus (wet and blotted) weights at doses of 100 and 500 mg/kg/d. These results suggest that the increase in uterine weights should be considered useful as a sensitive endpoint for detecting weak estrogenic compounds in 3-d rodent uterotrophic assay. However, further combination studies using surrogate biomarkers may be needed to improve the sensitivity of this assay for the detection of weak estrogenic compounds, such as o,p-DDT."]
[12029382,4,8,0,12,2002,"Sensitive detection of the endocrine effects of the estrogen analogue ethinylestradiol using a modified enhanced subacute rat study protocol (OECD Test Guideline no. 407).",0," Andrews, Freyberger, Hartmann, Eiben, Loof, Schmidt, Temerowski, Folkerts, Stahl, Kayser",12029382,"Sensitive detection of the endocrine effects of the estrogen analogue ethinylestradiol using a modified enhanced subacute rat study protocol (OECD Test Guideline no. 407).    Abstract:   Groups of five male and female Wistar rats were treated by gavage with 0, 0.01, 0.05 or 0.2 mg/kg body weight of the known synthetic estrogen ethinylestradiol for 28-32 days according to a modified enhanced OECD Test Guideline no. 407 in order to investigate which of the current and/or additional parameters would detect effects on the endocrine system reliably and sensitively and to provide data on intra-laboratory variability. Two identical studies (A and B) were run concurrently. The modified enhanced protocol requests the additional determination of triiodothyronine, thyroxine and thyroid-stimulating hormone (TSH), of the stage of the estrous cycle to ensure necropsy of all females in diestrus, of the number and morphology of cauda epididymal spermatozoa, and of additional organ weights (ovaries, uterus, thyroid, and male accessory reproductive organs), and histopathology of additional organs (pituitary, epididymides, coagulation glands, pancreas, and vagina). There were no treatment-related mortalities, clinical signs or changes in behavioral parameters. In male rats, 0.2 mg/kg was the maximum tolerated dose (MTD) resulting in reduced body weight gain. The only treatment-related alteration in hematological parameter was prolonged blood clotting time in high-dose females of both studies. Changes in clinical chemistry observed in study A were elevated alkaline phosphatase activity (high-dose females) and triglyceride levels (mid- and high-dose females and high-dose males). Changes in thyroid hormones and TSH of treated animals showed high variability with no clear dose-dependency, and could not be clearly related to estrogenic activity. In accordance to a suppression of the hypothalamic-pituitary-gonadal axis, decreased relative organ weights of the male accessory reproductive organs were obtained in both studies at the high dose. Corresponding histological changes were degeneration of the testicular germinal epithelium and atrophy of Leydig cells and of all accessory sex glands. Atrophy of the coagulating gland (study A) and seminal vesicles (study B) was also seen at 0.05 mg/kg. A marked increase in relative adrenal weight in male rats, accompanied by decreased vacuolization of zona fasciculata cells observed in both studies at the high dose seems to reflect an activation of the hypothalamic-pituitary-adrenal axis. The male mammary gland was sensitively affected. Increased numbers of small basophilic over large acidophilic cells indicated an estrogen-mediated feminisation and were detected at the low (study A) or mid dose (study B). Co-mitogenic properties of estrogens in rat liver were reflected by increased relative liver weights in females at the mid and high dose of study A and also at the high dose in study B. No treatment-related changes in endocrine organ weights were observed in treated females. Histological changes in the ovaries were increased numbers of apoptotic corpora lutea (from mid dose, study B) and of early stage follicles at the high dose in both studies. Classical direct estrogenic effects on the uterus, i.e. an increased height of luminal and glandular epithelium and increased granulocytic infiltration of the endometrium, were observed even at the low dose in both studies. Uterine findings occurring with a greater variability were dilation, squamous metaplasia of glands and thickened walls. Although females were necropsied in diestrus, as diagnosed by vaginal cytology, typical signs of estrogenic action in the vagina such as keratinization (indicative of estrus in normally cycling rats), mucification (indicative of proestrus), or thickened epithelia were observed in both studies even at the lowest dose. This unexpected discrepancy between vaginal cytology and vaginal and uterine morphology of treated females was considered to be treatment-related as it was not observed in the controls. Studies on liver enzymes that were performed outside the scope of the enhanced protocol showed that ethinylestradiol at 0.2 mg/kg decreased the activity of the sex-specific testosterone-dependent liver enzyme CYP2C11 in male rats. A simulation of doubling group size (to ten animals) by combining both studies did not increase the sensitivity of detection of endocrine-mediated effects above the level already obtained by histopathological examination of groups containing five animals. Only some of the enhancements to the current OECD Test Guideline no. 407 evaluated in this study (additional organs weights and additional histopathological investigations) were helpful in detecting the endocrine-mediated effects of ethinylestradiol, while other enhancements did not contribute towards this aim. Spermatology was completely insensitive at the MTD and measurement of thyroid hormones and TSH did not contribute to increased sensitivity. Vaginal cytology appeared to be an unreliable procedure for estrous cycle staging in estrogen-treated animals. Ongoing investigations, according to the modified version of the enhanced OECD Test Guideline no. 407 protocol, into the interference of ten compounds with the endocrine system by different mechanisms will result in the identification of the most appropriate enhancements."]
[20890769,4,0,7,11,2011,"The OECD validation program of the H295R steroidogenesis assay: Phase 3. Final inter-laboratory validation study.",0," Hecker, Hollert, Cooper, Vinggaard, Akahori, Murphy, Nellemann, Higley, Newsted, Laskey, Buckalew, Grund, Maletz, Giesy, Timm",20890769,"The OECD validation program of the H295R steroidogenesis assay: Phase 3. Final inter-laboratory validation study.    Abstract:    UNLABELLEDBACKGROUND, GOALS, AND SCOPE: In response to increasing concerns regarding the potential of chemicals to interact with the endocrine system of humans and wildlife, various national and international programs have been initiated with the aim to develop new guidelines for the screening and testing of these chemicals in vertebrates. Here, we report on the validation of an in vitro assay, the H295R steroidogenesis assay, to detect chemicals with the potential to inhibit or induce the production of the sex steroid hormones testosterone (T) and 17β-estradiol (E2) in preparation for the development of an Organization for Economic Cooperation and Development (OECD) test guideline.  METHODS : A previously optimized and pre-validated protocol was used to assess the potential of 28 chemicals of diverse structures and properties to validate the H295R steroidogenesis assay. These chemicals are comprised of known endocrine-active chemicals and quot;negativequot; chemicals that were not expected to have effects on the targeted endpoints, as well as a number of test chemicals with unknown modes of action at the level of the steroidogenic pathway. A total of seven laboratories from seven countries participated in this effort. In addition to effects on hormone production, confounding factors, such as cell viability and possible direct interference of test substances with antibody-based hormone detection assays, were assessed. Prior to and during the conduct of exposure experiments, each laboratory had to demonstrate that they were able to conduct the assay within the margin of predefined performance criteria.  RESULTS : With a few exceptions, all laboratories met the key quality performance parameters, and only 2% and 7% of all experiments for T and E2, respectively, were excluded due to exceedance of these parameters. Of the 28 chemicals analyzed, 13 and 14 tested affected production of T and E2, respectively, while 11 and 8 did not result in significant effects on T and E2 production, respectively. Four and six chemicals produced ambiguous results for effects on T and E2 production, respectively. However, four of these cases each for T and E2 were associated with only one laboratory after a personnel change occurred. Significant interference of test chemicals with some of the antibody-based hormone detection systems occurred for four chemicals. Only one of these chemicals, however, significantly affected the ability of the detection system to categorize the chemical as affecting E2 or T production.  DISCUSSION AND CONCLUSIONS : With one exception, the H295R steroidogenesis assay protocol successfully identified the majority of chemicals with known and unknown modes of interaction as inducers or inhibitors of T and E2 production. Thus it can be considered a reliable screen for chemicals that can alter the production of sex steroid hormones. One of the remaining limitations associated with the H295R steroidogenesis assay protocol is the relatively small basal production of E2 and its effect on quantifying the decreased production of this hormone with regard to the identification of weak inhibitors. An initial comparison of the data produced in this study with those from in vivo studies from the literature demonstrated the potential of the H295R steroidogenesis assay to identify chemicals affecting hormone homeostasis in whole organisms. Particularly promising was the lack of any false negatives during the validation and the very low number of false positives (1 out of 28 chemicals for each T and E2).  PERSPECTIVES : Based on the results obtained during this validation study and the accordingly revised test protocols, an OECD draft test guideline was developed and submitted to the OECD working group of the national coordinators of the test guidelines program (WNT) for comments in December 2009."]
[17112243,2,6,3,11,2006,"QSAR prediction of estrogen activity for a large set of diverse chemicals under the guidance of OECD principles.",0," Liu, Papa, Gramatica",17112243,"QSAR prediction of estrogen activity for a large set of diverse chemicals under the guidance of OECD principles.    Abstract:   A large number of environmental chemicals, known as endocrine-disrupting chemicals, are suspected of disrupting endocrine functions by mimicking or antagonizing natural hormones, and such chemicals may pose a serious threat to the health of humans and wildlife. They are thought to act through a variety of mechanisms, mainly estrogen-receptor-mediated mechanisms of toxicity. However, it is practically impossible to perform thorough toxicological tests on all potential xenoestrogens, and thus, the quantitative structure--activity relationship (QSAR) provides a promising method for the estimation of a compounds estrogenic activity. Here, QSAR models of the estrogen receptor binding affinity of a large data set of heterogeneous chemicals have been built using theoretical molecular descriptors, giving full consideration to the new OECD principles in regulation for QSAR acceptability, during model construction and assessment. An unambiguous multiple linear regression (MLR) algorithm was used to build the models, and model predictive ability was validated by both internal and external validation. The applicability domain was checked by the leverage approach to verify prediction reliability. The results obtained using several validation paths indicate that the proposed QSAR model is robust and satisfactory, and can provide a feasible and practical tool for the rapid screening of the estrogen activity of organic compounds."]
[12487363,1,8,2,11,2002,"Critical review and evaluation of the uterotrophic bioassay for the identification of possible estrogen agonists and antagonists: in support of the validation of the OECD uterotrophic protocols for the laboratory rodent. Organisation for Economic Co-operation and Development.",1," Owens, Ashby",12487363,"Critical review and evaluation of the uterotrophic bioassay for the identification of possible estrogen agonists and antagonists: in support of the validation of the OECD uterotrophic protocols for the laboratory rodent. Organisation for Economic Co-operation and Development.    Abstract:   A current issue for regulatory agencies is endocrine-related modes of action such as those mediated by the estrogen, androgen, and thyroid nuclear receptors. At the national and international levels, the consensus recommendation for the assessment of such modes of action is a tiered series of in vitro and in vivo protocols. The tiered framework begins with screens for structural alerts and then moves to rapid, mechanistic in vitro screening assays, and then to in vivo screening bioassays. The objective of these screens is to identify substances that may warrant testing for endocrine-mediated adverse effects. The final framework tier as needed is to test these substances in long-term bioassays for adverse endocrine-mediated reproductive and/or developmental effects. The subject of this review, the rodent uterotrophic bioassay, is intended to be a rapid in vivo screening bioassay for possible estrogen agonists and based on the response of the estrogen-sensitive uterus. The central metric of bioassay is a statistically significant increase in the weight of the uterus after 3 consecutive days of test substance administration. The extensive background literature is summarized in this review on the mode of action underlying the bioassay and the uterine response to estrogens. The review includes the bioassays history of development and how its employment has changed and evolved over time. The review describes two major uterotrophic bioassay versions, the intact, immature female and the mature, ovariectomized female, and the protocol factors likely to influence relevance, reproducibility, and reliability of bioassay. The emphasis of the review is the ability of the uterotrophic bioassay to identify the substances of current interest: weak estrogen agonists with binding affinities relative to the natural 17beta-estradiol in the log 0 to log -3 range. Using selected model substances having RBAs in this target range, the bioassays performance in a hierarchical, tiered approach is evaluated, including the predictive capability of the uterotrophic bioassay based on available reproductive and developmental testing data. The review concludes that the uterotrophic bioassay is reliable and can identify substances that may act via an estrogen-mode of action, supporting the validity of the uterotrophic bioassay and its regulatory use as an in vivo mechanistic screening bioassay for estrogen agonists and antagonists."]
[26139245,1,9,0,10,2016,"Development of a recombinant human ovarian (BG1) cell line containing estrogen receptor α and β for improved detection of estrogenic/antiestrogenic chemicals.",0," Brennan, Bassal, He, Denison",26139245,"Development of a recombinant human ovarian (BG1) cell line containing estrogen receptor α and β for improved detection of estrogenic/antiestrogenic chemicals.    Abstract:   Estrogenic endocrine-disrupting chemicals are found in environmental and biological samples, commercial and consumer products, food, and numerous other sources. Given their ubiquitous nature and potential for adverse effects, a critical need exists for rapidly detecting these chemicals. The authors developed an estrogen-responsive recombinant human ovarian (BG1Luc4E2) cell line recently accepted by the US Environmental Protection Agency (USEPA) and Organisation for Economic Co-operation and Development (OECD) as a bioanalytical method to detect estrogen receptor (ER) agonists/antagonists. Unfortunately, these cells appear to contain only 1 of the 2 known ER isoforms, ERα but not ERβ, and the differential ligand selectivity of these ERs indicates that the currently accepted screening method only detects a subset of total estrogenic chemicals. To improve the estrogen screening bioassay, BG1Luc4E2 cells were stably transfected with an ERβ expression plasmid and positive clones identified using ERβ-selective ligands (genistein and Br-ERβ-041). A highly responsive clone (BG1LucERβc9) was identified that exhibited greater sensitivity and responsiveness to ERβ-selective ligands than BG1Luc4E2 cells, and quantitative reverse-transcription polymerase chain reaction confirmed the presence of ERβ expression in these cells. Screening of pesticides and industrial chemicals identified chemicals that preferentially stimulated ERβ-dependent reporter gene expression. Together, these results not only demonstrate the utility of this dual-ER recombinant cell line for detecting a broader range of estrogenic chemicals than the current BG1Luc4E2 cell line, but screening with both cell lines allows identification of ERα- and ERβ-selective chemicals."]
[22467034,3,7,0,10,2012,"Evaluation of in vitro screening system for estrogenicity: comparison of stably transfected human estrogen receptor-α transcriptional activation (OECD TG455) assay and estrogen receptor (ER) binding assay.",0," Lee, Kim, Kim, Kang, Kim, Jung, Kim, Han, Yoon, Rhee",22467034,"Evaluation of in vitro screening system for estrogenicity: comparison of stably transfected human estrogen receptor-α transcriptional activation (OECD TG455) assay and estrogen receptor (ER) binding assay.    Abstract:   The estrogenic activity of industrial chemicals, di(2-ethylhexyl) phthalate (DEHP), di(n-butyl) phthalate (DBP), benzylbutyl phthalate (BBP), diethyl phthalate (DEP), tetrabromobisphenol A (TBBPA), bisphenol A (BPA), and nonylphenol (NP), was compared using OECD test guideline 455(TG455), stably transfected transcriptional activation (STTA) and estrogen receptor (ER) binding assays. The estrogenic activity of BBP, BPA and NP were approximately 180,000-fold (PC(50), 4.32 x 10(-6 )M), 5,000-fold (PC(50), 1.26 x 10(-7) M) and 120,000-fold (PC(50), 2.92 x 10(-6 )M) less than 17β-estradiol (PC(50), 2.43 x 10(-11)M), whereas DEHP, DBP and DEP did not show any estrogenicity activity in the STTA assay. Moreover, binding affinities to human ERα of BBP, BPA, and NP were approximately 200,000-fold (IC(50), 4.91 x 10(-4) M), 8000-fold (IC(50), 1.92 x 10(-5) M) and 1400-fold (IC(50), 3.34 x 10(-6) M) less than 17β-estradiol (IC(50), 2.45 x 10(-9) M) in competitive human ERα binding assay. The relative potencies of STTA assay were very similar to ER binding, E-screen, and Yeast screening assays. Therefore, our results suggested that OECD test guideline TG455 may be useful as a screening test for potential endocrine disruptors."]
[20981862,2,5,3,10,2010,"Validation of the intact rat weanling uterotrophic assay with notes on the formulation and analysis of the positive control chemical in vehicle.",0," Tyl, Marr, Brown, Dolbow, Myers",20981862,"Validation of the intact rat weanling uterotrophic assay with notes on the formulation and analysis of the positive control chemical in vehicle.    Abstract:   The intact female weanling version in the Organization for Economic Cooperation and Development (OECD) uterotrophic assay Test Guideline (TG) 440 is proposed as an alternative to the adult ovariectomized female version, because it does not involve surgical intervention (vs the ovariectomized version) and detects direct/indirect-acting estrogenic/anti-estrogenic substances (vs the ovariectomized version which detects only direct-acting estrogenic/anti-estrogenic substances binding to the estrogen receptor). This validation study followed OECD TG 440, with six female weanling rats (postnatal day 21) per dose group and six treatment groups. Females were weighed and dosed once daily by oral gavage for three consecutive days, with one of six doses of 17α-ethinyl estradiol in corn oil at 5 ml kg⁻¹ at 0 and 0.1-10 µg kg⁻¹ per day. On postnatal day 24, the juvenile females were euthanized by CO₂ asphyxiation, weighed, livers weighed and uteri weighed wet and blotted. The presence or absence of vaginal patency was recorded. Absolute and relative (to terminal body weight) uterine wet and blotted weights and uterine luminal fluid weights were significantly increased at 3.0 and 10.0 (both P lt; 0.01) µg kg⁻¹ per day, and increased to ~140% of control values at 1.0 µg kg⁻¹ per day (not statistically significantly). In vivo body weights, weight changes, feed consumption, liver weights and terminal body weights were unaffected. Vaginal patency was not acquired in any female at any dose, although vaginal puckering was observed in one female at 10.0 µg kg⁻¹ per day. Therefore, this intact weanling uterotrophic assay is validated in our laboratory for use under US and European endocrine toxicity testing programs/legislation."]
[12628315,3,6,0,9,2003,"Lack of estrogenic or (anti-)androgenic effects of d-phenothrin in the uterotrophic and Hershberger assays.",0," Yamada, Ueda, Yoshioka, Kawamura, Seki, Okuno, Mikami",12628315,"Lack of estrogenic or (anti-)androgenic effects of d-phenothrin in the uterotrophic and Hershberger assays.    Abstract:   Synthetic pyrethroids are among the most common insecticides and pesticides currently in use worldwide. Recently, d-phenothrin, a synthetic pyrethroid, is suspected to have endocrine activities through the estrogen and androgen receptors. However, no study has been conducted to evaluate its potential for hormonal activity using an in vivo test specifically focused on estrogenic and androgenic activities. In this study, we evaluated the interaction of d-phenothrin (0, 100, 300 or 1000 mg/kg per day, p.o.) with estrogen- or androgen-mediated mechanisms using in vivo short-term assays. While internationally standardized protocols for the uterotrophic and Hershberger assays have not yet been fully developed, both are widely used and are being considered by the OECD as short-term screening assays for hormonal activity. The highest dose level tested for d-phenothrin was a limit dose (1000 mg/kg per day) designated in the current draft protocol by the OECD, and in fact there was no excessive systemic toxicity in both assays; slightly increased liver weight but no change of serum androgen levels in accessing anti-androgenicity. Potential estrogenic effect of d-phenothrin was evaluated by means of 3-day uterotrophic assay using immature Crj:CD(SD)IGS rats (20 days of age). No increase in uterine weight (wet or blotted) was observed following oral exposure to d-phenothrin. Reference control ethynyl estradiol (0.001 mg/kg per day) showed a significant effect in this assay protocol. A 10-day Hershberger assay using castrated peripubertal male rats measures the androgenic or anti-androgenic effects of the test chemicals on several accessory glands/tissues (the ventral prostate, dorso-lateral prostate, seminal vesicles with coagulating glands, levator ani plus bulbocavernosus muscles, glans penis and Cowpers glands). d-Phenothrin was administered by oral gavage for 10 days to castrated male Crj:CD(SD)IGS rats (7 weeks of age, rats were castrated at 6 weeks of age) with or without co-administration of 0.2 mg/kg per day testosterone propionate (subcutaneous injection on the dorsal surface). Reference controls of methyltestosterone and p,p-DDE (100 mg/kg per day) provided significant effects in this assay protocol, whereas d-phenothrin did not show any androgenic or anti-androgenic effects. It is concluded that, based on the results of these two reliable in vivo assays, d-phenothrin exhibits no potential to cause adverse estrogenic or (anti-)androgenic effects even at dose of 1000 mg/kg per day, the limit dose designated in the current draft protocol by the OECD."]
[11833800,2,7,0,9,2002,"Utility of a juvenile fathead minnow screening assay for detecting (anti-)estrogenic substances.",0," Panter, Hutchinson, Länge, Lye, Sumpter, Zerulla, Tyler",11833800,"Utility of a juvenile fathead minnow screening assay for detecting (anti-)estrogenic substances.    Abstract:   The European Chemical Industrys aquatic research program for endocrine disrupters includes the development of an in vivo juvenile fathead minnow (Pimephales promelas) screening assay. Working within the Organization for Economic Cooperation and Developments (OECD, Paris, France) tiered approach to endocrine disrupter evaluation in fish, the juvenile fish screening protocol was adapted from the OECD test guideline 204. Six chemicals, with different (anti-)estrogenic potencies, were used to develop the in vivo juvenile fish screening protocol: diethylstilbestrol, 17alpha-ethynylestradiol, genistein, methoxychlor, 4-tert-pentylphenol, and ZM189,154 (a novel pharmaceutical antiestrogen). Mixed-sex juvenile fathead minnows were exposed to individual chemicals (with chemical analyzes) and sampled after 4, 7, 14, and 21 d of exposure. Wet weight, total length, condition factor, and whole-body homogenate concentrations of vitellogenin (VTG) were determined. Estrogens and antiestrogens were detected in this screen by virtue of the VTG response (an elevation or suppression, respectively) after 14 d. The study showed that the use of VTG concentrations in mixed-sex juvenile fish provides a sensitive and robust assay for the detection of both estrogenic and antiestrogenic chemicals, with widely divergent potencies."]
[11564613,2,4,3,9,2001,"The OECD program to validate the rat uterotrophic bioassay to screen compounds for in vivo estrogenic responses: phase 1.",0," Kanno, Onyon, Haseman, Fenner-Crisp, Ashby, Owens",11564613,"The OECD program to validate the rat uterotrophic bioassay to screen compounds for in vivo estrogenic responses: phase 1.    Abstract:   The Organisation for Economic Co-operation and Development has completed the first phase of an international validation program for the rodent uterotrophic bioassay. This uterotrophic bioassay is intended to identify the in vivo activity of compounds that are suspected agonists or antagonists of estrogen. This information could, for example, be used to help prioritize positive compounds for further testing. Using draft protocols, we tested and compared two model systems, the immature female rat and the adult ovariectomized rat. Data from 19 participating laboratories using a high-potency reference agonist, ethinyl estradiol (EE), and an antagonist, ZM 189,154, indicate no substantive performance differences between models. All laboratories and all protocols successfully detected increases in uterine weights using EE in phase 1. These significant uterine weight increases were achieved under a variety of experimental conditions (e.g., strain, diet, housing protocol, bedding, vehicle). For each protocol, there was generally good agreement among laboratories with regard to the actual EE doses both in producing the first significant increase in uterine weights and achieving the maximum uterine response. Furthermore, the Hill equation appears to model the dose response satisfactorily and indicates general agreement based on calculated effective dose (ED)(10) and ED(50) within and among laboratories. The feasibility of an antagonist assay was also successfully demonstrated. Therefore, both models appear robust, reproducible, and transferable across laboratories for high-potency estrogen agonists such as EE. For the next phase of the OECD validation program, both models will be tested against a battery of weak, partial estrogen agonists."]
[24114741,1,6,1,8,2014,"Towards an integrated in vitro strategy for estrogenicity testing.",0," Wang, Aarts, de Haan, Argyriou, Peijnenburg, Rietjens, Bovee",24114741,"Towards an integrated in vitro strategy for estrogenicity testing.    Abstract:   In order to define an in vitro integrated testing strategy (ITS) for estrogenicity, a set of 23 reference compounds representing diverse chemical classes were tested in a series of in vitro assays including proliferation and reporter gene assays. Outcomes of these assays were combined with published results for estrogen receptor (ER) binding assays and the OECD validated BG1Luc ER transcriptional activation (TA) assay and compared with the outcomes of the in vivo uterotrophic assay to investigate which assays most accurately predict the in vivo uterotrophic effect and to identify discrepancies between the in vitro assays and the in vivo uterotrophic assay. All in vitro assays used revealed a reasonable to good correlation (R(2)  = 0.62-0.87) with the in vivo uterotrophic assay but the combination of the yeast estrogen bioassay with the U2OS ERα-CALUX assay seems most promising for an ITS for in vitro estrogenicity testing. The main outliers identified when correlating data from the different in vitro assays and the in vivo uterotrophic assay were 4-hydroxytamoxifen, testosterone and to a lesser extent apigenin, tamoxifen and kepone. Based on the modes of action possibly underlying these discrepancies it becomes evident that to further improve the ITS and ultimately replace animal testing for (anti-)estrogenic effects, the selected bioassays have to be combined with other types of in vitro assays, including for instance in vitro models for digestion, bioavailability and metabolism of the compounds under investigation."]
[20872646,3,2,3,8,2010,"Environmental effect assessment for sexual endocrine-disrupting chemicals: Fish testing strategy.",0," Knacker, Boettcher, Frische, Rufli, Stolzenberg, Teigeler, Zok, Braunbeck, Schäfers",20872646,"Environmental effect assessment for sexual endocrine-disrupting chemicals: Fish testing strategy.    Abstract:   Current standard testing and assessment tools are not designed to identify specific and biologically highly sensitive modes of action of chemicals, such as endocrine disruption. This information, however, can be important to define the relevant endpoints for an assessment and to characterize thresholds of their sublethal, population-relevant effects. Starting a decade ago, compound-specific risk assessment procedures were amended by specifically addressing endocrine-disrupting properties of substances. In 2002, the Conceptual Framework, agreed upon by OECDs Task Force on Endocrine Disrupters Testing and Assessment, did not propose specific testing strategies, and appropriate testing methods had not yet been developed and approved. In the meantime, the OECD Test Guidelines Programme has undertaken important steps to revise established and to develop new test methods, which can be used to identify and quantify effects of endocrine-disrupting chemicals on mammals, birds, amphibians, fish, and invertebrates. For fish testing of endocrine-disrupting chemicals, the first Test Guidelines have recently been adopted by the OECD and validation of further test systems is under progress. Based on these test systems and the experience gained during their validation procedures, we propose a 3-step fish testing strategy: 1) Weight-of-evidence approach for identifying potential sexual endocrine-disrupting chemicals; even after advanced specification of systematic criteria, this step of establishing initial suspicion will still require expert judgment; 2) in vivo evaluation of sexual endocrine-disrupting activity in fish by applying in vivo fish screening assays; sufficient data are available to diagnose the aromatase-inhibition and estrogen-receptor agonist mechanisms of action by indicative endpoints (biomarkers), whereas the ability of the respective biomarkers in the screening assay to identify the estrogen-receptor antagonists and androgen-receptor agonists and antagonists requires further validation; 3) characterization of sexual endocrine-mediated adverse effects including threshold concentrations; in cases when the most sensitive population-relevant endpoints and the most sensitive time window for exposure are known for the mechanisms of action, the fish full life-cycle or 2-generation test, which are the normal definitive tests, might be abbreviated to, e.g., the fish sexual development test. In the European Union, the measurement of indicative endpoints in the definitive test might be crucial for the authorization procedure under REACH and plant-protection products. The results of the definitive tests can be used in existing schemes of compound-specific environmental risk assessments."]
[20525538,1,7,0,8,2010,"Estrogen-like effects of cadmium in vivo do not appear to be mediated via the classical estrogen receptor transcriptional pathway.",0," Ali, Penttinen-Damdimopoulou, Mäkelä, Berglund, Stenius, Akesson, Håkansson, Halldin",20525538,"Estrogen-like effects of cadmium in vivo do not appear to be mediated via the classical estrogen receptor transcriptional pathway.    Abstract:    BACKGROUND : Cadmium (Cd), a ubiquitous food contaminant, has been proposed to be an endocrine disruptor by inducing estrogenic responses in vivo. Several in vitro studies suggested that these effects are mediated via estrogen receptors (ERs).  OBJECTIVE : We performed this study to clarify whether Cd-induced effects in vivo are mediated via classical ER signaling through estrogen responsive element (ERE)-regulated genes or if other signaling pathways are involved.  METHODS : We investigated the estrogenic effects of cadmium chloride (CdCl2) exposure in vivo by applying the Organisation for Economic Co-operation and Development (OECD) rodent uterotrophic bioassay to transgenic ERE-luciferase reporter mice. Immature female mice were injected subcutaneously with CdCl2 (5, 50, or 500 µg/kg body weight) or with 17α-ethinylestradiol (EE2) on 3 consecutive days. We examined uterine weight and histology, vaginal opening, body and organ weights, Cd tissue retention, activation of mitogen-activated protein kinase (MAPK) pathways, and ERE-dependent luciferase expression.  RESULTS : CdCl2 increased the height of the uterine luminal epithelium in a dose-dependent manner without increasing the uterine wet weight, altering the timing of vaginal opening, or affecting the luciferase activity in reproductive or nonreproductive organs. However, we observed changes in the phosphorylation of mouse double minute 2 oncoprotein (Mdm2) and extracellular signal-regulated kinase (Erk1/2) in the liver after CdCl2 exposure. As we expected, EE2 advanced vaginal opening and increased uterine epithelial height, uterine wet weight, and luciferase activity in various tissues.  CONCLUSION : Our data suggest that Cd exposure induces a limited spectrum of estrogenic responses in vivo and that, in certain targets, effects of Cd might not be mediated via classical ER signaling through ERE-regulated genes."]
[17904329,1,7,0,8,2008,"Relationship between the results of in vitro receptor binding assay to human estrogen receptor alpha and in vivo uterotrophic assay: comparative study with 65 selected chemicals.",0," Akahori, Nakai, Yamasaki, Takatsuki, Shimohigashi, Ohtaki",17904329,"Relationship between the results of in vitro receptor binding assay to human estrogen receptor alpha and in vivo uterotrophic assay: comparative study with 65 selected chemicals.    Abstract:   For screening chemicals possessing endocrine disrupting potencies, the uterotrophic assay has been placed in a higher level in the OECD testing framework than the ER binding assay to detect ER-mediated activities. However, there are no studies that can demonstrate a clear relationship between these assays. In order to clarify the relationship between the in vitro ER binding and in vivo uterotrophic assays and to determine meaningful binding potency from the ER binding assay, we compared the results from these assays for 65 chemicals spanning a variety of chemicals classes. Under the quantitative comparison between logRBAs (relative binding affinities) and logLEDs (lowest effective doses), the log RBA was well correlated with both logLEDs of estrogenic and anti-estrogenic compounds at r(2)=0.67 (n=28) and 0.79 (n=23), respectively. The RBA of 0.00233% was found to be the lowest ER binding potency to elicit estrogenic or anti-estrogenic activities in the uterotrophic assay, accordingly this value is considered as the detection limit of estrogenic or anti-estrogenic activities in the uterotrophic assay. The usage of this value as cutoff provided the best concordance rate (82%). These findings are useful in a tiered approach for identifying chemicals that have potential to induce ER-mediated effects in vivo."]
[12948897,1,4,3,8,2003,"The OECD program to validate the rat uterotrophic bioassay. Phase 2: coded single-dose studies.",0," Kanno, Onyon, Peddada, Ashby, Jacob, Owens",12948897,"The OECD program to validate the rat uterotrophic bioassay. Phase 2: coded single-dose studies.    Abstract:   The Organisation for Economic Co-operation and Development has completed phase 2 of an international validation program for the rodent uterotrophic bioassay. This portion of phase 2 assessed the reproducibility of the assay with a battery of positive and negative test substances. Positive agonists of the estrogen receptor included the potent reference estrogen 17-ethinyl estradiol (EE), and the weak estrogen agonists bisphenol A, genistein, methoxychlor, nonylphenol, and o,p -DDT. The negative test substance or nonagonist was n-dibutylphthalate. The test substances were coded, and prescribed doses of each test substance were administered in 16 laboratories. Two versions of the uterotrophic assay, the intact immature and the adult ovariectomized female rat, were tested and compared using four standardized protocols covering both sc and po administration. Assay reproducibility was compared using a) EE doses identical to those used in phase 1 and in parallel dose-response studies, b) single doses of the weak agonists identical to one of five doses from the dose-response studies, and c) a single dose of the negative test substance. The results were reproducible and in agreement both within individual laboratories and across the participating laboratories for the same test substance and protocol. The few exceptions are examined in detail. The reproducibility was achieved despite a variety of different experimental conditions (e.g., variations in animal strain, diet, housing protocol, bedding, vehicle, animal age). In conclusion, both versions of the uterotrophic bioassay and all protocols appear robust, reproducible, and transferable across laboratories and able to detect weak estrogen agonists. These results will be submitted along with other data for independent peer review to provide support for the validation of the uterotrophic bioassay."]
[12948895,1,2,5,8,2003,"The OECD program to validate the rat uterotrophic bioassay: an overview.",0," Owens, Koëter",12948895,"The OECD program to validate the rat uterotrophic bioassay: an overview.    Abstract:   The Organisation for Economic Co-operation and Development has undertaken an international validation program for the rodent uterotrophic bioassay. This validation program comprised two major parts. The first part was the development of a detailed background review document compiling the existing data on the bioassays history, the molecular and physiologic basis for the bioassays mechanistic relevance to detect estrogen agonists and antagonists, a review of important bioassay protocol parameters, and a review of the data generated by in vitro assays, previous uterotrophic bioassays, and developmental and reproductive assays to assess and support the overall predictivity of the uterotrophic bioassay. The second part was an extensive multiyear effort managed by a validation management group to demonstrate the operating characteristics of four protocols. The effort was conducted in two phases. The phase 1 results with the reference agonist ethinyl estradiol (EE) and antagonist ZM 189,154 has been published previously. This Environmental Health Perspectives mini-monograph is devoted to the phase 2 work using five weak estrogen agonists, bisphenol A, genistein, methoxychlor, nonylphenol, and o,p -DDT, as well as the negative substance dibutylphthalate. These data show that all protocols successfully detected increases in uterine weights when a sufficient dose level of the weak agonists was administered, whether the substances were known or provided as coded doses to the laboratory. The data with both the reference EE and all five weak agonists are reproducible over time and under a variety of different experimental conditions (e.g., animal strain, diet, housing, bedding, vehicle, animal age). In conclusion, all protocols now have sufficient data to support their validity."]
[16522518,2,3,2,7,2006,"Assessment of in vivo assays for endocrine disruption.",1," Clode",16522518,"Assessment of in vivo assays for endocrine disruption.    Abstract:   The United States Environmental Protection Agency (USEPA) has developed a screening and testing programme to detect endocrine-disrupting chemicals. This programme is organized into two phases: a tier 1 screening battery and, for those chemicals that are positive in this phase, a tier 2 testing battery. Similarly, the Organization for Economic Cooperation and Development (OECD) has set up a task force to identify, prioritize and validate test methods for the detection of endocrine disrupters. This chapter describes the mammalian in vivo assays recommended by these organizations. The tier 1 screening recommended by both agencies comprises the uterotrophic assay for the detection of oestrogens and anti-oestrogens, and the Hershberger assay for the detection of anti-androgens. Both of these assays are nearing the end of a comprehensive validation process and show consistency across testing laboratories. A further assay recommended by the USEPA is the female pubertal assay, designed to assess steroidogenesis, anti-thyroid activity and anti-oestrogenicity, while the OECD recommends an enhanced version of their standard regulatory test guideline number 407, the 28-day rat toxicity test. The tier 2 test recommended by both agencies is an enhanced version of the two-generation regulatory study. This is a large time- and animal-consuming study, and in order to obtain the maximum information regarding the potential for endocrine-disrupting activity of a chemical, it should be modified depending on the results of the tier 1 assays."]
[16494248,{"$f":"(LEN($K24) - LEN(SUBSTITUTE(LOWER($K24),LOWER(B$3),\"\")))/LEN(B$3)","v":1},6,0,7,2006,"Estrogenic endpoints in fish early life-stage tests: luciferase and vitellogenin induction in estrogen-responsive transgenic zebrafish.",0," Bogers, Mutsaerds, Druke, De Roode, Murk, Van Der Burg, Legler",16494248,"Estrogenic endpoints in fish early life-stage tests: luciferase and vitellogenin induction in estrogen-responsive transgenic zebrafish.    Abstract:   This study incorporated specific endpoints for estrogenic activity in the early life-stage (ELS) test, as described in Guideline 210 of the Organization for Economic Cooperation and Development and traditionally used for toxicity screening of chemicals. A transgenic zebrafish model expressing an estrogen receptor-mediated luciferase reporter gene was exposed to ethinylestradiol (EE2), and luciferase activity as well as vitellogenin (VTG) was measured. Concentrations of EE2 were tested at 1, 3, or 10 ng/L for 30 d from fertilization or during only the last 4 d with dimethylsulfoxide (DMSO) as presolvent (0.01%). Exposure to EE2 induced no toxic effects. Mean body weights were significantly higher in groups exposed for 30 d in the presence of DMSO, but condition factors were not affected. Significant luciferase and VTG induction occurred following 30-d exposure (3 and 10 ng EE2/L), while only VTG levels were affected in the 4-d exposure (10 ng EE2/L). This study demonstrated the usefulness of incorporating estrogenic endpoints in the OECD ELS test, fitting the requirements for screening estrogenic activity of chemicals. Quantitative measurement of both VTG and luciferase activity proved to be rapid and sensitive. Additional value of using transgenic zebrafish lies in combining VTG measurement with the more mechanistic approach of luciferase induction in one experiment."]
[12948896,1,2,4,7,2003,"The OECD program to validate the rat uterotrophic bioassay. Phase 2: dose-response studies.",0," Kanno, Onyon, Peddada, Ashby, Jacob, Owens",12948896,"The OECD program to validate the rat uterotrophic bioassay. Phase 2: dose-response studies.    Abstract:   The Organisation for Economic Co-operation and Development has completed phase 2 of an international validation program for the rodent uterotrophic bioassay. The purpose of the validation program was to demonstrate the performance of two versions of the uterotrophic bioassay, the immature female rat and the adult ovariectomized rat, in four standardized protocols. This article reports the dose-response studies of the validation program; the coded single-dose studies are reported in an accompanying paper. The dose-response study design used five selected weak estrogen agonists, bisphenol A, genistein, methoxychlor, nonylphenol, and o,p -DDT. These weak agonists were administered in a prescribed series of doses to measure the performance and reproducibility of the protocols among the participating laboratories. All protocols successfully detected increases in uterine weights when the weak agonists were administered. Within each protocol, there was good agreement and reproducibility of the dose response among laboratories with each substance. Substance-specific variations were observed in the influence of the route of administration on the uterine response, the potency as related to the dose producing the first statistically significant increase in uterine weights, and the maximum increase in uterine weight. Substantive performance differences were not observed between the uterotrophic bioassay versions or among the standardized protocols, and these were judged to be qualitatively equivalent. It is noteworthy that these results were reproducible under a variety of different experimental conditions (e.g., animal strain, diet, housing, bedding, vehicle, animal age), indicating that the bioassays performance as a screen is robust. In conclusion, both the intact, immature, and adult OVX versions, and all protocols appear to be reproducible and transferable across laboratories and are able to detect weak estrogen agonists."]
[11566572,1,4,2,7,2001,"Endocrine disrupters--testing strategies to assess human hazard.",1," Baker",11566572,"Endocrine disrupters--testing strategies to assess human hazard.    Abstract:   During the last decade an hypothesis has been developed linking certain chemicals (natural and synthetic) to observed and suspected adverse effects on reproduction in both wildlife and humans. The issue of endocrine disruption originally focused on chemicals that mimic the action of the natural hormone oestrogen. However, the concern is now encompassing effects on the whole endocrine system. In response to public awareness, regulatory agencies (including the US EPA) and the OECD are formulating potential testing strategies and have begun the process of validating defined tests to systematically assess chemicals for their endocrine-disrupting activities. In order to investigate chemicals that have the potential to cause endocrine disruption, a large number of in vitro and in vivo assays have been identified. In vitro test systems (particularly when used in combination) offer the possibility of providing an early screen for large numbers of chemicals and can be useful in characterising the mechanism of action and potency. In vitro assays in widespread use for the screening/characterisation of endocrine disrupting potential include hormone receptor ligand binding assays (determination of the ability of a chemical to bind to the hormone receptor), cell proliferation assays (analysis of the ability of a chemical to stimulate growth of oestrogen sensitive cells), reporter gene assays in yeast or mammalian cells (analysis of the ability of a chemical to stimulate the transcription of a reporter gene construct in cell culture), and the analysis of the regulation of endogenous oestrogen sensitive genes in cell lines. However, in vitro assays do not always reliably predict the outcome in vivo due to differences in metabolic capabilities of the test systems used and the diverse range of mechanisms by which endocrine disrupting chemicals may act. Therefore a complementary battery of short- and long-term in vitro and in vivo assays (that assess both receptor and non-receptor mediated mechanisms of action) seems the most appropriate way at present of assessing the potential endocrine disrupting activities of chemicals. At Unilever we have used a combination of in vitro assays (receptor binding, reporter gene and cell proliferation assays) together with short-term in vivo tests (uterotrophic assay in immature rodents) to examine the oestrogenic potential of a large number of chemicals. An evaluation of the advantages and limitations of these methods is provided. Finally, any potential test system needs to be validated and standardized before the information generated can be for the identification of hazard, and possibly for risk assessment purposes."]
[23037998,1,5,0,6,2012,"Ovariectomized mouse uterotrophic assay of 36 chemicals.",0," Ohta, Takagi, Ohmukai, Marumo, Ono, Matsushima, Inoue, Ono, Kanno",23037998,"Ovariectomized mouse uterotrophic assay of 36 chemicals.    Abstract:   The concern over endocrine disruptors prompted international establishment of a strategic framework for the identification of the estrogenic compounds. OECD has launched the Conceptual Framework tool box containing various screening and testing methods including the uterotrophic assay. The (anti)estrogenicity of 36 chemicals suspected to be estrogen-receptor interactive by in silico and/or in vitro screening in the Extended Scheme for Endocrine Disruptor Screening and Testing of the Ministry of Health, Labour and Welfare, Japan, were monitored by the uterotrophic assay using C57BL/6J ovariectomized adult female mice after a 7-day exposure by oral gavage (po) and subcutaneous injection (sc). Ethynyl estradiol was used as reference for agonist and antagonist detection. In addition, Bisphenol A (sc) and Genistein (po) were tested for the comparison to rat assays. Among the 36, 2-[Bis(4-hydroxy-phenyl)methyl]benzylalcohol, 2,2,4,4-Tetrahydroxybenzophenone, 2,4-Dihydroxybenzophenone, 3,3,5-Triiodothyroacetic acid, New fuchsin and alpha-Naphtholbenzein, showed both estrogenic agonistic and antagonistic activities; first two showed U-shaped dose-response in antagonistic studies. N,N-Diphenyl-p-phenylenediamine, 2,2-Dihydroxy-4,4-dimethoxybenzophenone, n-Butyl 4-hydroxybenzoate, and Reserpine were agonistic by sc. Benzo [a] pyrene, Benz [a] anthracene, Dibenz [a,h] anthracene, 2-(2H-Benzotriazol-2-yl)-4,6-di(t-pentyl)phenol, Rosemarinic acid, meta-Thymol, 6-Gingerol, Colchicine, Malachite green base, Fenbuconazole, and Lead acetate were antagonistic. The rest, i.e. n-Heptyl 4-hydroxybenzoate, Tetrazolium violet, Pravastatin sodium salt, Physostigmine, salicylate (1:1), Nordihydroguaiaretic acid, o-Cresolphthalein, 1,3-Dinitrobenzene, C.I. Pigment orange, Tetrabromobis-phenol-A, 2-Hydroxy-4-methoxybenzophenone, Ethylparaben, Propyl p-hydroxybenzoate, Kaempferol, 2-(2-Benzotriazolyl)-p-cresol and Phenolphthalein were negative for both effects. Taking together with in silico/ in vitro screening, the result suggested that the ovariectomized mouse uterotrophic bioassay has sufficient performance comparable to rat for the screening of (anti)estrogenicity of various chemicals."]
[16860000,3,2,1,6,2006,"Detection of endocrine disrupters: evaluation of a Fish Sexual Development Test (FSDT).",0," Holbech, Kinnberg, Petersen, Jackson, Hylland, Norrgren, Bjerregaard",16860000,"Detection of endocrine disrupters: evaluation of a Fish Sexual Development Test (FSDT).    Abstract:   Managed by the Organisation for Economic Co-operation and Development (OECD), a comprehensive work is carried out in numerous laboratories to develop test guidelines for the detection of endocrine disrupting chemicals in humans, and various animal species. Development of tests to detect chemicals with endocrine disrupting properties in fish is a part of that work. A Fish Sexual Development Test (FSDT) (an extension of the existing OECD TG 210, fish early life stage toxicity test), proposed as an international test guideline for the detection of endocrine disrupting chemicals, was evaluated by water exposure of juvenile zebrafish to the three natural estrogens: estrone, 17beta-estradiol, and estriol and the synthetic androgen trenbolone (trenbolone acetate). As endpoints, vitellogenin induction and histological changes including changes in sex ratios were investigated. The sex ratio was significantly altered towards females from 49 ng/l estrone, 54 ng/l 17beta-estradiol and 22 microg/l estriol, respectively. An all male population was observed from exposure to 9.7 ng/l trenbolone and above. Significant vitellogenin induction in whole body homogenate was measured after exposure to 14 ng/l estrone, 54 ng/l 17beta-estradiol and 0.6 mug/l estriol, respectively. Significant vitellogenin reduction was measured after exposure to 193 ng/l trenbolone or higher. The present results provide strong evidence that the FSDT is a sensitive test toward estrogenic and especially androgenic exposure and the validation of the FSDT as an OECD test guideline should continue."]
[16586070,1,5,0,6,2006,"A dose-response study on the estrogenic activity of benzophenone-2 on various endpoints in the serum, pituitary and uterus of female rats.",0," Schlecht, Klammer, Wuttke, Jarry",16586070,"A dose-response study on the estrogenic activity of benzophenone-2 on various endpoints in the serum, pituitary and uterus of female rats.    Abstract:   The tetrahydroxylated biphenyl-ketone 2,2,4,4-tetrahydroxybenzophenone (BP2), one of twelve benzophenone-derived UV-filters, is used in cosmetic products and in packaging materials to protect these products from light induced damage. Recently published studies showed that BP2 exerts estrogenic activity; thus, it is an endocrine active chemical. We present data from a pharmacodynamic dose-response experiment with five dosages of BP2 applied per gavage to adult ovariectomized (ovx) rats for 5 days. Estradiol-valerate (E2) served as a control compound. The uterotrophic assay, proposed by the OECD, was modified to have a broader view on endocrine activity outside the urogenital tract to prevent that undesirable actions in other organs regulated by estrogens are missed. The gene expression levels of marker genes of estrogenic action were measured by semi-quantitative RT-PCR. Metabolic parameters were assessed by determination of the serum concentrations of leptin, cholesterol, high- and low-density lipoproteins, and triglycerides in the serum. Administration of BP2 at dosages of 10-1,000 mg/kg bodyweight led to changes of these parameters comparable to the changes in the E2 group with 0.6 mg/kg bodyweight. For the observed estrogenic activities of BP2, the quot;no observed adverse effect levelsquot; were determined. Additionally, the data were further analyzed using the benchmark approach. If BP2 is transcutaneously absorbed in the human, the obtained threshold values would suggest refraining from the further use of BP2 as UV-filter in cosmetic products although additional toxicological studies should be conducted to clarify possible adverse effects."]
[16291569,1,5,0,6,2006,"Endocrine disruptors in the marine environment: mechanisms of toxicity and their influence on reproductive processes in fish.",1," Goksøyr",16291569,"Endocrine disruptors in the marine environment: mechanisms of toxicity and their influence on reproductive processes in fish.    Abstract:   Recent research demonstrated how endocrine-disrupting chemicals (EDCs) may disturb wildlife populations and possibly also represent a human health risk. Much of the focus has been on (anti-)estrogenic and (anti-)androgenic effects, and these effects are thought to be mediated through the estrogen (ER) and androgen (AR) receptors, respectively. The seriousness of the problem has led international bodies such as the Organization for Economic Cooperation and Development (OECD) and the European Union (EU) to initiate large research programs and developments toward new guidelines and regulations. EDCs have both synthetic and natural sources. The mechanisms of action of EDCs can be divided into: (1) agonistic/antagonistic effect (quot;hormone mimicsquot;), (2) disruption of production, transport, metabolism, or secretion of natural hormones, and (3) disruption of production and/or function of hormone receptors. However, the number of nuclear hormone receptors being potential targets for EDCs has increased dramatically the last decade, opening up new avenues for possible endocrine disruptor effects. In studies with Atlantic salmon, data showed that 4-nonylphenol, a model xenoestrogen previously used in large volumes, for example, in paints and detergents, acts as an estrogen mimic, as a steroid metabolism disruptor, and by modulating estrogen receptor (ER) levels, indicating that one single compound exerts all of these three mechanisms, depending on the dose given to the organism. A hypothesis explaining this observation is that the nature of the effect of an EDC is determined by dose-dependent routing and cross-talk between different classes of nuclear receptors."]
[15746892,1,4,1,6,2004,"Development of vitellogenin assay for endocrine disrupters using medaka (Oryzias latipes).",0," Nozaka, Abe, Matsuura, Sakamoto, Nakano, Maeda, Kobayashi",15746892,"Development of vitellogenin assay for endocrine disrupters using medaka (Oryzias latipes).    Abstract:   An enzyme-linked immunosorbent assay (ELISA) was developed for the detection of the egg yolk precursor vitellogenin (VTG) in the liver of medaka (Oryzias latipes) and was employed to establish an in vivo testing system for estrogen and estrogenic compounds using liver homogenates. Results of 3-month-old fish exposed to three reference chemicals (ethynylestradiol, methyltestosterone and flutamide) recommended by Organisation for Economic Co-operation and Development (OECD) for the validation showed the induction and decrease of vitellogenic responses, making the assay using the liver VTG of medaka a possible screening method for not only estrogens but also androgens. In addition, 21-day exposure of male fish to 4-tert-octylphenol and 4-nonylphenol produced concentration-dependent inductions of liver vitellogenin, with the lowest observed effect concentrations of 64.1 microg/L and 22.5 microg/L, respectively, while no significant VTG responses were observed in male and female fish exposed to tributyltin chloride and dibutyl phthalate. This study demonstrates that the VTG assay using liver homogenates from small fish such as medaka can be used as a screening method for environmental estrogens. This is because the sensitivity of the VTG response in medaka may be almost the same as that of other fish using blood samples."]
[12802581,5,1,0,6,2003,"Tamoxifen: 28-day oral toxicity study in the rat based on the Enhanced OECD Test Guideline 407 to detect endocrine effects.",0," Kennel, Pallen, Barale-Thomas, Espuña, Bars",12802581,"Tamoxifen: 28-day oral toxicity study in the rat based on the Enhanced OECD Test Guideline 407 to detect endocrine effects.    Abstract:   The main objective of this 28-day oral gavage toxicity study in the rat was to investigate which of the current and/or additional parameters of the OECD Test Guideline 407 would reliably and sensitively detect the endocrine-mediated effects of the nonsteroidal antiestrogen tamoxifen. In addition, as this study was performed using two subgroups of five animals of each sex run concurrently, it enabled an assessment of the intralaboratory reproducibility while also assessing the potential value of using ten animals of each sex per group instead of using the standard five animals of each sex per group stipulated by the current guideline. Tamoxifen was administered daily by gavage to groups of 7-week-old Wistar rats for at least 28 days at dose levels of 5, 30, or 200 microg/kg body weight. Additional parameters specified in the enhanced OECD Test Guideline 407 were spermatozoa enumeration and morphology of the cauda epididymis, hormonal analysis of the thyroid-stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4) levels, monitoring of the estrous cycle during week 4 of treatment to ensure females were in diestrus on the day of terminal sacrifice, organ weight of ovary, uterus, thyroid gland, prostate gland (ventral and dorsolateral parts), seminal vesicles with coagulation glands and pituitary gland, and microscopic investigation of the pituitary gland, vagina, mammary gland, seminal vesicles with coagulating glands, epididymis, and prostate gland (ventral and dorsolateral parts). Overall, 200 microg/kg per day was considered to be the Maximum Tolerated Dose (MTD) in both sexes, resulting in a marked reduction of body weight gain, together with slight effects on clinical signs, hematology, plasma chemistry, and microscopic changes in some endocrine tissues. Five micrograms per kilogram per day represented the No Observed Adverse Effect Level (NOAEL) in males and the No Observed Effect Level (NOEL) in females. At the intermediate dose level (30 microg/kg per day), the current OECD Test Guideline 407 was appropriate to detect the specific endocrine-related changes induced by tamoxifen in females, based on the histopathology findings observed in the ovary and the uterus. The additional parameters which were found to be changed in females (thyroid hormone levels, ovary and uterus weights, and histopathology of vagina) provided supplementary information further confirming tamoxifen-mediated endocrine effects. In males, when data from the current Test Guideline 407 were considered at the intermediate dose level, specific endocrine effects were only indicated on the basis of the histopathology findings observed in the prostate gland. The additional parameters examined which were found to be changed (prostate gland and seminal vesicle weights, and histopathology of seminal vesicle and mammary gland) were necessary to confirm the specific tamoxifen-mediated endocrine effects. Hence, amongst the additional parameters contained in the enhanced OECD Test Guideline 407, organ weights and histopathological examination of endocrine-related organs were the most helpful in confirming the detection of tamoxifen-mediated endocrine effects. The reproducibility evaluation showed that a group size of five animals of each sex consistently allowed the detection of endocrine effects with the current Test Guideline in both sexes at the high dose level and in females at the intermediate dose level. Doubling the animal number from five to ten of each sex per dose level did not notably increase the sensitivity of detection of endocrine-mediated effects."]
[23811024,3,2,0,5,2013,"Organic solvents impair life-traits and biomarkers in the New Zealand mudsnail Potamopyrgus antipodarum (Gray) at concentrations below OECD recommendations.",0," Lecomte, Noury, Tutundjian, Buronfosse, Garric, Gust",23811024,"Organic solvents impair life-traits and biomarkers in the New Zealand mudsnail Potamopyrgus antipodarum (Gray) at concentrations below OECD recommendations.    Abstract:   Potamopyrgus antipodarum is a gastropod mollusk proposed for use in the development of reproduction tests within the Organization for Economic Cooperation and Development (OECD). Numerous chemicals, including endocrine disrupters, are relatively water-insoluble, and water-miscible solvents are currently used for testing them. OECD recommends a maximum concentration of 100 μll(-1). As several studies highlighted effects of lower concentrations of solvents, this study assessed the effects of 20 μll(-1) acetone, ethanol, methanol and dimethylsulfoxide (DMSO) on juvenile and adult snails during 42 days. Ethanol decreased juvenile growth, while acetone increased the rate of embryonic development. All solvents increased estradiol-like levels in adult snails. DMSO only increased mRNA expression of vitellogenin-like gene, while acetone, ethanol and methanol decreased mRNA expression of three nuclear receptor (estrogen receptor-like, ecdysone-induced protein and chicken ovalbumin upstream promoter transcription factor) genes as well as of genes encoding proteins involved in genomic (prohibitin-2) and non-genomic (striatin) pathways of estrogens activity in vertebrates. This study highlights the confounding effects of low concentrations of solvents and recommends avoiding their use. Where solvent use is inevitable, their concentrations and type should be investigated for suitability for the measured endpoints prior to use in chemical testing strategies."]
[22348781,0,4,1,5,2012,"Two-generation reproduction toxicity study in rats with methoxychlor.",0," Aoyama, Hojo, Takahashi, Shimizu-Endo, Araki, Takeuchi-Kashimoto, Saka, Teramoto",22348781,"Two-generation reproduction toxicity study in rats with methoxychlor.    Abstract:   A two-generation reproduction toxicity study was conducted in rats with a reference estrogenic pesticide, methoxychlor, to validate the sensitivity and competency of current guidelines recommended by the United States Environmental Protection Agency; Japanese Ministry of Agriculture, Forestry and Fisheries; and Organisation for Economic Co-operation and Development for predicting reproductive toxicity of the test compound based on estrogenic endocrine disrupting effects. Both sexes of SD rats were exposed to methoxychlor in the diet at concentrations of 0, 10, 500 and 1500 ppm for two successive generations. The present study has successfully detected estrogenic activities and reproductive toxicities of methoxychlor, as well as its systemic toxicity. Body weights, body weight gains and food consumption of both sexes of animals were suppressed significantly in the 500 and 1500 ppm groups. Typical reproductive toxicities observed in females of these groups included, but were not limited to, prolonged estrous cycle, reduced fertility, decreased numbers of implantation sites and newborns, decreased ovary weights and/or increased incidences of cystic ovary. Uterine weights of weanlings increased significantly in these groups, suggesting that the sensitivity of this parameter for predicting estrogenic ability of the test compound is comparable to that of the uterotrophic assay. Reproductive toxicities of methoxychlor seemed less potent in males than in females. Methoxychlor delayed preputial separation and significantly reduced sperm counts and reproductive organ weights of males of the 500 and/or 1500 ppm groups; however, most males that failed to impregnate females in the same group showed normal fertility when they were re-mated with untreated females. Neither systemic nor reproductive toxicities appeared in the 10 ppm group."]
[17508203,4,1,0,5,2007,"Uterotrophic assay, Hershberger assay, and subacute oral toxicity study of 4,4 -[1-[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenyl]ethylidene]bis[phenol] based on the OECD draft protocols.",0," Yamasaki, Miyata, Muroi, Ehara, Higashihara, Houshuyama, Oshima, Minobe",17508203,"Uterotrophic assay, Hershberger assay, and subacute oral toxicity study of 4,4 -[1-[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenyl]ethylidene]bis[phenol] based on the OECD draft protocols.    Abstract:   We performed an uterotrophic assay, the Hershberger assay, and a 28-day repeated-dose toxicity study (enhanced OECD test guideline No. 407) of 4,4 -[1-[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenyl]ethylidene]bis[phenol] based on the OECD draft protocols. In the uterotrophic assay, female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and the uterine weight of rats given the 1,000 mg/kg dose of the test chemical plus ethinyl estradiol decreased. In the Hershberger assay, the test chemical was orally administered at doses of 0, 100, 300, and 1,000 mg/kg day to castrated male SD rats for ten consecutive days beginning on postnatal day 56, and no changes were observed. On the other hand, when the test chemical was orally administered at doses 0, 100, 300, and 1,000 mg/kg day for at least 28 days, a decrease in LH values in rats of both sexes and a decrease in FSH and estradiol values in female rats were detected in the 1,000 mg/kg group, and abnormal estrous cycles, uterine glandular atrophy, persistence of ovarian corpora lutea, vaginal epithelial mucification, and mammary glandular hyperplasia were also observed in one female rat in the 1,000 mg/kg group. Therefore, the uterotrophic assay used in this study showed that the chemical has the estrogen-antagonist properties, and some potentially endocrine-mediated effects were detected in growing rats based on the results of the enhanced OECD test guideline No. 407. However, the changes were observed in rats given a high dose of the chemical, 1,000 mg/kg day."]
[{"$f":"HYPERLINK(\"https://www.ncbi.nlm.nih.gov/pubmed/\" & J36,J36)","v":17219090},1,4,0,{"$f":"SUM(B36:D36)","v":5},2007,"Prosobranch snails as test organisms for the assessment of endocrine active chemicals--an overview and a guideline proposal for a reproduction test with the freshwater mudsnail Potamopyrgus antipodarum.",1," Duft, Schmitt, Bachmann, Brandelik, Schulte-Oehlmann, Oehlmann",17219090,"Prosobranch snails as test organisms for the assessment of endocrine active chemicals--an overview and a guideline proposal for a reproduction test with the freshwater mudsnail Potamopyrgus antipodarum.    Abstract:   Recently, prosobranch snails have been recommended as promising candidates for test organisms for the assessment of endocrine active chemicals. Three prosobranch snail species, the freshwater mudsnail Potamopyrgus antipodarum, the freshwater ramshorn snail Marisa cornuarietis, and the marine netted whelk Nassarius reticulatus are portrayed and their respective biotests are presented together with results of laboratory experiments and biological effect monitoring surveys in the field. All characterized species are highly sensitive toward xeno-androgens [triphenyltin (TPT), tributyltin (TBT), methyltestosterone (MT) and fenarimol (FEN)], and xeno-estrogens [bisphenol A (BPA), octylphenol (OP), ethinylestradiol], and show effects at environmentally relevant, rather low concentrations in laboratory experiments. For exposure to the xeno-androgen TPT, EC(10) values range between 15.9 and 29.0 ng as Sn/L (sediment 0.03 mug as Sn/kg), for TBT, EC(10) values are found between 3.42 and 37.8 ng as Sn/L (sediment 2.98 microg as Sn/kg) and effect concentrations for FEN are calculated as 18.6 ng/L (EC(10)) and 0.19 microg/kg (EC(50) sediment; EC(10) not calculable). Exposure to xeno-estrogens yielded EC(10 )values of 13.9 ng/L (0.19 microg/kg) for BPA, a NOEC of lt;1 microg/L (EC(10) of 0.004 microg/kg) for OP and a NOEC of 1 ng/l (EC(10) sediment of 2.2 microg/kg) for ethinylestradiol. Responses to androgens comprised the development of imposex and the reduction of fertility or embryo production, effects of estrogens included the stimulation of egg production and embryo production, and the increased weight of glands. Also, biological effect monitoring studies with P. antipodarum and N. reticulatus in several rivers or estuarine areas revealed the capacity of the biotests to detect an androgenic or estrogenic potential of sediment samples. A comparison of the three test species with regard to sensitivity and practical aspects in routine application favors the freshwater mudsnail P. antipodarum for a standardized procedure, and this reproduction test will be introduced into the OECD guideline program for standardization in the near future."]
[14751673,1,4,0,5,2004,"Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals.",0," Yamasaki, Sawaki, Noda, Muroi, Takakura, Mitoma, Sakamoto, Nakai, Yakabe",14751673,"Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals.    Abstract:   We performed the Hershberger assay of 12 chemicals based on the OECD draft protocol. The chemicals tested by the Hershberger assay were phthalic acid di-n-hexyl ester, phthalic acid di-n-amyl ester, phthalic acid di-n-propyl ester, diethylstilbestrol, 17beta-estradiol, tamoxifen, 5alpha-dihydrotestosterone, dichlorodiphenyldichloroethane, cyproterone acetate, 6alpha-methyl-17alpha-hydroxy-progesterone, atrazine, and spironolactone. Phthalic acid di-n-hexyl ester, phthalic acid di-n-amyl ester, and phthalic acid di-n-propyl ester are phthalates; diethylstilbestrol and 17beta-estradiol are estrogenic chemicals; tamoxifen is partial estrogen receptor antagonist with mainly estrogenic properties; 5alpha-dihydrotestosterone is an androgen derivatives; dichlorodiphenyldichloroethane is a reference androgen antagonistic chemical; cyproterone acetate, 6alpha-methyl-17alpha-hydroxy-progesterone, and spironolactone have an androgenic steroid structure and are known as androgen antagonistic chemicals; and atrazine is a reference endocrine disruptor. We also subjected these chemicals to the receptor binding assay for androgen. A clear androgen agonistic effect was detected in 5alpha-dihydrotestosterone, and an androgen antagonistic effect was observed in five chemicals: cyproterone acetate, spironolactone, 6alpha-methyl-17alpha-hydroxy-progesterone, phthalic acid di-n-amyl ester, and dichlorodiphenyldichloroethane. By contrast, diethylstilbestrol, 17beta-estradiol, tamoxifen, 5alpha-dihydrotestosterone, dichlorodiphenyldichloroethane, cyproterone acetate, 6alpha-methyl-17alpha-hydroxy-progesterone, and spironolactone were positive in the receptor binding assay for androgen. Three estrogenic chemicals, diethylstilbestrol, 17beta-estradiol, and tamoxifen, were negative in the Hershberger assay with receptor binding affinity. On the other hand, the Hershberger assays of three phthalates were performed at the same dosages, and the results showed androgen antagonistic affinity only in the assay of phthalic acid di-n-amyl ester without receptor binding affinity."]
[27821304,1,2,1,4,2017,"A novel enzyme-linked immunosorbent assay based on anti-lipovitellin monoclonal antibodies for quantification of zebrafish (Danio rerio) vitellogenin.",0," Wang, Wang, Tian, Zhang, Ru",27821304,"A novel enzyme-linked immunosorbent assay based on anti-lipovitellin monoclonal antibodies for quantification of zebrafish (Danio rerio) vitellogenin.    Abstract:   Vitellogenin (Vtg) in zebrafish (Danio rerio) is a recommended biomarker endpoint for detecting estrogenic activity of chemicals under the OECD test guidelines. The present paper reports the development of a sensitive and rapid enzyme-linked immunosorbent assay (ELISA) for the quantification of zebrafish Vtg based on monoclonal antibodies (MAbs) against lipovitellin (Lv), the major yolk protein derived from Vtg. The purified Lv was used to immunize mice and the spleen cells of mice were fused with myeloma cells. Two high-affinity MAbs (H3A8 and H4D9) were screened from hybridoma cells. Western blot analysis revealed that two MAbs were highly specific to zebrafish Vtg and recognized different antigenic epitopes because MAb H3A8 detected a main band of 143kDa in purified Vtg, while MAb H4D9 reacted with two clear bands of purified Vtg at 117 and 102kDa. Using MAb H3A8 as the coating antibody, HRP-labeled MAb H4D9 or HRP-labeled PAbs as the detecting antibody, two sandwich ELISAs for Vtg quantification were developed. The sandwich ELISA developed using HRP-labeled MAb H4D9 had a working range of 1.95-250ng/mL, with a detection limit of 0.78ng/mL, which was lower than that of the assay based on HRP-labeled PAbs. Parallelism between Lv standard curves and dilution curves of whole-body homogenates (WBH) from E2-treated male zebrafish confirmed the validity of the ELISAs for quantifying zebrafish Vtg. Finally, the usefulness of two assays for detecting estrogenic activity was verified by quantifying Vtg inductions in zebrafish exposed to 17β-estradiol."]
[25461902,1,3,0,4,2015,"Structural features of endocrine active chemicals--A comparison of in vivo and in vitro data.",0," Lewin, Escher, van der Burg, Simetska, Mangelsdorf",25461902,"Structural features of endocrine active chemicals--A comparison of in vivo and in vitro data.    Abstract:   Studies on reproductive toxicity need high numbers of test animals. Therefore, we investigated whether chemical structural features (SF) in combination with in vitro data on specific adverse outcome pathways (AOPs) may be used for predicting reproductive toxicity of untested chemicals. Using the OECD Toolbox and expert judgment, we identified 89 structure groups for 275 chemicals for which the results of prenatal developmental toxicity or multigeneration studies were present in the Fraunhofer database on Fertility and Developmental Toxicity in experimental animals (FeDTex) database. Likewise, we evaluated 220 chemicals which had been tested in reporter gene assays on endocrine ((anti)estrogenic and (anti)androgenic) properties in the CALUX(®) test battery. There was a large spread of effect levels for substances within the chemical structure groups for both, in vivo and in vitro results. The groups of highest concern (diphenyl derivatives, planar conjugated systems with fused rings, phenols and organophosphates) correlated quite well, however, between the in vivo and in vitro data on estrogenic activity. For the 56 chemicals represented in both databases, lowest effect doses in vivo correlated well with the estrogenic activity in vitro. These results suggest that a panel of assays covering relevant AOPs and data on metabolism and toxicokinetics may allow prediction of relative reproductive or development toxicity potency within the identified chemical structure groups."]
[23524272,1,3,0,4,2013,"Chlorpyrifos: weight of evidence evaluation of potential interaction with the estrogen, androgen, or thyroid pathways.",1," Juberg, Gehen, Coady, LeBaron, Kramer, Lu, Marty",23524272,"Chlorpyrifos: weight of evidence evaluation of potential interaction with the estrogen, androgen, or thyroid pathways.    Abstract:   Chlorpyrifos was selected for EPAs Endocrine Disruptor Screening Program (EDSP) based on widespread use and potential for human and environmental exposures. The purpose of the program is to screen chemicals for their potential to interact with the estrogen, androgen, or thyroid pathways. A battery of 11 assays was completed for chlorpyrifos in accordance with test guidelines developed for EDSP Tier 1 screening. To determine potential endocrine activity, a weight-of-evidence (WoE) evaluation was completed for chlorpyrifos, which included the integration of EDSP assay results with data from regulatory guideline studies and the published literature. This WoE approach was based on the OECD conceptual framework for testing and assessment of potential endocrine-disrupting chemicals and consisted of a systematic evaluation of data, progressing from simple to complex across multiple levels of biological organization. The conclusion of the WoE evaluation is that chlorpyrifos demonstrates no potential to interact with the estrogen, androgen, or thyroid pathways at doses below the dose levels that inhibit cholinesterase. Therefore, regulatory exposure limits for chlorpyrifos, which are based on cholinesterase inhibition, are sufficient to protect against potential endocrine alterations. Based on the results of this WoE evaluation, there is no scientific justification for pursuing additional endocrine testing for chlorpyrifos."]
[22203403,1,3,0,4,2012,"Acute and chronic toxicity of benzotriazoles to aquatic organisms.",0," Seeland, Oetken, Kiss, Fries, Oehlmann",22203403,"Acute and chronic toxicity of benzotriazoles to aquatic organisms.    Abstract:    PURPOSE : Resulting from their intensive use as corrosion inhibitors in aircraft deicing and anti-icing fluids (ADAF) and for silver protection in dishwasher detergents benzotriazoles (BTs) are widespread in European surface waters. The current study aimed on an ecotoxicological characterization of 1H-benzotriazole (1H-BT) and 5-methyl-1H-benzotriazole (5MBT).  METHODS : Acute and chronic OECD guideline tests were conducted with primary producers (Desmodesmus subspicatus, Lemna minor) and two daphnia species (Daphnia magna, Daphnia galeata) to characterize the hazard of these chemicals. Additionally, the estrogenic activity of both BTs was analyzed in vitro using a recombinant yeast estrogen screen (YES).  RESULTS : Both BTs revealed significant effects in acute and chronic experiments, but exhibited no estrogenic activity in the YES. The algal growth test displayed an inhibited cell number increase with effect concentration (EC) values of EC(10) 1.18 and 2.86 mg l(-1) for 1H-BT and 5MBT, respectively. In the Lemna test, EC(10) values were 3.94 mg l(-1) (1H-BT) and 2.11 mg l(-1) (5MBT). D. magna was also affected with EC(50) (48 h) values of 107 mg l(-1) for 1H-BT and 51.6 mg l(-1) for 5MBT. D. galeata was more sensitive with an EC(50) (48 h) of 14.7 mg 1H-BT l(-1) and 8.13 mg 5MBT l(-1). In the 21-day reproduction tests with D. magna, the EC(10) for 5MBT was 5.93 mg l(-1) while 1H-BT showed no adverse effects. D. galeata turned out to be more sensitive in the chronic study with EC(10) values of 0.97 mg l(-1) for 1H-BT and 0.40 mg l(-1) for 5 MBT.  CONCLUSION : Because BTs are regularly found in the aquatic environment at lower μg l(-1) concentrations reflecting their persistence and poor elimination during wastewater treatment processes, a preliminary risk assessment was conducted. There is little indication that BTs pose a risk for aquatic ecosystems at current exposure levels during most of the year. However, it cannot be excluded that in winter with a higher usage of ADAFs environmental concentrations may well exceed the level that is considered safe for aquatic organisms."]
[22093917,1,3,0,4,2012,"Comparison of endocrine-mediated effects of two bisphenol A related compounds, 2,2-bis(4-cyanatophyenyl)propane and 4,4-cyclohexylidenebisphenol, based on subacute oral toxicity studies using rats.",0," Yamasaki, Okuda",22093917,"Comparison of endocrine-mediated effects of two bisphenol A related compounds, 2,2-bis(4-cyanatophyenyl)propane and 4,4-cyclohexylidenebisphenol, based on subacute oral toxicity studies using rats.    Abstract:   The purpose of this study was to compare endocrine-mediated effects of bisphenol A related compounds, 2,2-bis(4-cyanatophyenyl)propane and 4,4-cyclohexylidenebisphenol with reference to OECD Test Guideline No. 407. Rats were orally gavaged with 0, 4, 20, and 100 mg/kg/day of 2,2-bis(4-cyanatophyenyl)propane, and 0, 30, 100, and 300 mg/kg/day of 4,4-cyclohexylidenebisphenol for at least 28 days beginning at 8 weeks of age. Endocrine-mediated effects were not observed in rats given 2,2-bis(4-cyanatophyenyl)propane. Male accessory sex organ weights decreased in the 4,4-cyclohexylidenebisphenol 300 mg/kg group and serum T4 values increased in all male groups treated with this compound. Our results suggest that endocrine-mediated changes caused by the present bisphenol related compound can be divided into estrogenic or thyroid hormonal effects, and estrogenic effects observed in the repeated-dose study were related to their estrogenic potency confirmed by uterotrophic assay."]
[17628788,3,1,0,4,2007,"Subacute oral toxicity study of bisphenol F based on the draft protocol for the quot;Enhanced OECD Test Guideline no. 407quot;.",0," Higashihara, Shiraishi, Miyata, Oshima, Minobe, Yamasaki",17628788,"Subacute oral toxicity study of bisphenol F based on the draft protocol for the quot;Enhanced OECD Test Guideline no. 407quot;.    Abstract:   Since bisphenol F (4,4-dihydroxydiphenylmethane) has been reported to exhibit estrogen agonistic properties in the uterotrophic assay, we performed a 28-day repeated-dose toxicity study (enhanced OECD test guideline No. 407) on bisphenol F based on the OECD draft protocols to determine whether it has endocrine-mediated properties. Bisphenol F was orally administered at doses 0, 20, 100 and 500 mg/kg per day for at least 28 days, but no clear endocrine-mediated changes were detected, and it was concluded to have no endocrine-mediated effects in young adult rats. On the other hand, the main effect of bisphenol F was concluded to be liver toxicity based on clinical biochemical parameters and liver weight, but without histopathological changes. The no-observed-effect level for bisphenol F is concluded to be under 20 mg/kg per day since decreased body weight accompanied by decreased serum total cholesterol, glucose, and albumin values were observed in the female rats given 20 mg/kg per day or higher doses of bisphenol F."]
[16489464,{"$f":"(LEN($K44) - LEN(SUBSTITUTE(LOWER($K44),LOWER(B$3),\"\")))/LEN(B$3)","v":3},1,0,4,2006,"Repeated 28-day oral toxicity study of vinclozolin in rats based on the draft protocol for the quot;Enhanced OECD Test Guideline No. 407quot; to detect endocrine effects.",0," Shin, Moon, Kim, Kang, Ki, Choi, Han",16489464,"Repeated 28-day oral toxicity study of vinclozolin in rats based on the draft protocol for the quot;Enhanced OECD Test Guideline No. 407quot; to detect endocrine effects.    Abstract:   We performed a 28-day repeated-dose toxicity study of vinclozolin, a widely used fungicide, based on the draft protocol of the quot;Enhanced OECD Test Guideline 407quot; (Enhanced TG407) to investigate whether vinclozolin has endocrine-mediated properties according to this assay. Seven-week-old SD rats were administered with vinclozolin daily by oral gavage at dose rates of 0, 3.125, 12.5, 50 and 200 mg/kg/day for at least 28 days. The vinclozolin-treated male rats showed a reduction of epididymis and accessory sex organ weights and an alteration of hormonal patterns. A slight prolongation of the estrous cycle and changes in the estrogen/testosterone ratio and luteinizing hormone level were observed in vinclozolin-treated female rats. Thyroxin concentrations were decreased and thyroid-stimulating hormone concentrations were increased in both sexes; however, there were no compound-related microscopic lesions in the thyroid gland or changes in the thyroid weight. The endocrine-related effects of vinclozolin could be detected by the parameters examined in the present study based on the OECD protocol, suggesting the Enhanced TG407 protocol should be a suitable screening test for the detection of endocrine-mediated effects of chemicals."]
[16483677,1,3,0,4,2006,"Development of chronic tests for endocrine active chemicals. Part 1. An extended fish early-life stage test for oestrogenic active chemicals in the fathead minnow (Pimephales promelas).",0," Panter, Hutchinson, Hurd, Bamforth, Stanley, Duffell, Hargreaves, Gimeno, Tyler",16483677,"Development of chronic tests for endocrine active chemicals. Part 1. An extended fish early-life stage test for oestrogenic active chemicals in the fathead minnow (Pimephales promelas).    Abstract:   An extended early-life stage test (based on OECD test guideline 210) was developed to allow the evaluation of a weak environmental oestrogen, 4-tert-pentyphenol (4TPP), on sexual differentiation and gonadal development. Fathead minnow (Pimephales promelas) embryos were exposed to three concentrations of 4TPP (56, 180 and 560 microg l(-1)) in a flow-through system, at 25+/-1 degrees C, for lt;107 days post-hatch (dph). In addition, some embryos were exposed to 180 microg 4TPPl(-1) until 30 or 60 dph, after which they were exposed to dilution water only until 107 dph. At 30, 60 and 107 dph fish were evaluated for growth and gonadal development (via histology), and at 107 dph fish were also evaluated for secondary sexual characteristics (SSC), gonadosomatic index (GSI) and plasma vitellogenin (VTG). There were no effects of 4TPP on hatching success or survival, however, there was a delay in the time taken for embryos to hatch (560 microg 4TPPl(-1)). No treatment-related effects were observed on fish growth, with the exception of at 107 dph when the condition factor in female fish was reduced in all 4TPP continuous exposure treatments. Plasma VTG was only elevated in female fish exposed to 180 microg 4TPPl(-1) and inhibition of gonadal growth (GSI) occurred only in females exposed to 560 microg 4TPPl(-1). Histological examination of the gonads revealed delays and disruption in male sexual differentiation and development (180 microg 4TPPl(-1)) and no testicular tissue was observed in any fish exposed to 560 microg 4TPPl(-1). Mixed gonads (predominately testes with a scattering of primary oocytes) were present in fish exposed to all doses of 180 microg 4TPPl(-1) at 107 dph. Feminisation of the reproductive ducts (formation of an ovarian like cavity) occurred in the testis of all males exposed to 180 microg l(-1), regardless of length of 4TPP exposure. Results indicate that the period of 30-60 dph appears to be the sensitive window for disruption of formation of the reproductive duct and this effect is not reversible when the fish are transferred to dilution water. The data also show that this integrative test is suitable for the detection of a weak environmental oestrogen and comparisons of these results with that of a fish full life-cycle, in medaka, indicate that this test could be a suitable surrogate for a fish full life-cycle."]
[14551668,1,2,1,4,2004,"Development of quantitative vitellogenin-ELISAs for fish test species used in endocrine disruptor screening.",0," Nilsen, Berg, Eidem, Kristiansen, Brion, Porcher, Goksøyr",14551668,"Development of quantitative vitellogenin-ELISAs for fish test species used in endocrine disruptor screening.    Abstract:   The yolk protein precursor vitellogenin (Vtg) in plasma has proved to be a simple and sensitive biomarker for assessing exposure of fish to environmental estrogens. Within international bodies such as the Organization for Economic Cooperation and Development (OECD) work is ongoing to develop screening and testing programmes for endocrine disrupting effects of new chemicals, and in the focus of this development are the fish test species common carp (Cyprinus carpio), fathead minnow (Pimephales promelas), zebrafish (Danio rerio) and Japanese medaka (Oryzias latipes). In this study we have developed quantitative enzyme linked immunosorbent assays (ELISAs) for Vtg in common carp/fathead minnow, zebrafish and Japanese medaka. The assays were developed using a combination of monoclonal and polyclonal fish Vtg antibodies in a sandwich format, using stabilized Vtg from the test species as a standard. The carp Vtg ELISA has a working range of 1-63 ng/mL, a minimal detection limit of 0.6 ng/mL, and may also be used for quantification of Vtg in fathead minnow. In fathead minnow whole-body homogenate samples, the practical detection limit is 400 ng/mL due to the matrix effect. The zebrafish Vtg ELISA has a working range of 0.5-63 ng/mL, a minimal detection limit of 0.4 ng/mL, and a practical detection limit of 200 ng/mL in whole-body homogenate samples. The medaka Vtg ELISA has a working range of 0.25-16 ng/mL, a minimal detection limit of 0.1 ng/mL, and a practical detection limit of 125 ng/mL in whole-body homogenate samples. The intra- and inter-assay variations were below 20% for all assays. The assays were evaluated with sets of representative samples spanning the wide dynamic range of Vtg-levels found in fish exposed to environmental estrogens, and all three assays are currently undergoing international inter-laboratory validation."]
[12373451,2,1,1,4,2002,"A repeated 28-day oral dose toxicity study of genistein in rats, based on the Enhanced OECD Test Guideline 407 for screening endocrine-disrupting chemicals.",0," Okazaki, Okazaki, Nakamura, Kitamura, Hatayama, Wakabayashi, Tsuda, Katsumata, Nishikawa, Hirose",12373451,"A repeated 28-day oral dose toxicity study of genistein in rats, based on the Enhanced OECD Test Guideline 407 for screening endocrine-disrupting chemicals.    Abstract:   In association with the international validation project to establish an OECD Enhanced Test Guideline 407, we performed a 28-day repeated-dose toxicity study of genistein, which is known as a phytoestrogen. Attention was paid to the sensitivity of certain additional parameters, such as histopathology observations and organ weights of endocrine related organs, sperm characteristics, serum hormone levels and estrous cycle, for detecting endocrine-related effects of endocrine-disrupting chemicals based on the existing TG 407. Seven-week-old Crj:CD(SD)IGS rats were assigned to one of four groups, each consisting of ten males and ten females, and genistein was administered once daily by gavage at doses of 0 (control), 120, 400 or 1000 mg/kg body weight per day. Male rats were killed on the day after the 28th administration. Female rats were killed on the day of the diestrus stage during the 4 days after the 28th administration. Endocrine-disrupting effects of genistein were detected in females by histopathology. The changes included vacuolation and mucinification of the vaginal epithelium in the 400 and 1000 mg/kg groups; however, the incidences of the lesion were very low. Although increased serum prolactin levels were recorded in the males of the 1000 mg/kg group, we could not determine whether this was indeed induced by genistein. General toxicological effects of genistein were detected in blood chemistry, such as increased triglycerides and total protein and a decreased albumin/globulin ratio, as well as increased liver weight and glycogen deposition in the periportal hepatocytes. Based on these results, the no-observed-adverse-effect level (NOAEL) in the present study was estimated to be 120 mg/kg per day. In particular, endocrine-related effects were most sensitively detected by histopathology examination of sexual organs. However, the findings indicate that chemicals with weak endocrine-disrupting potential like genistein must be evaluated taking into consideration the results of other test systems."]
[12052007,1,3,0,4,2002,"Lack of (anti-) androgenic or estrogenic effects of three pyrethroids (esfenvalerate, fenvalerate, and permethrin) in the Hershberger and uterotrophic assays.",0," Kunimatsu, Yamada, Ose, Sunami, Kamita, Okuno, Seki, Nakatsuka",12052007,"Lack of (anti-) androgenic or estrogenic effects of three pyrethroids (esfenvalerate, fenvalerate, and permethrin) in the Hershberger and uterotrophic assays.    Abstract:   Synthetic pyrethroids are among the most common pesticides and insecticides currently in use worldwide. Recently, chemicals classified as synthetic pyrethroids are suspected as being endocrine disrupting chemicals. However, no study has been conducted to assess their potential hormonal activities using in vivo test specifically focused on endocrine disruption. In the present study, we evaluated the interaction of three pyrethroids (esfenvalerate, fenvalerate, and permethrin) with androgen receptor (AR)- and estrogen receptor (ER)-mediated mechanisms using in vivo short-term assays. While internationally standardized protocols for the Hershberger and uterotrophic assays have not yet been fully developed, both are widely used and are being considered by OECD as short-term screening assays for hormonal activity. A 5-day Hershberger assay using castrated male rats measures agonistic and androgenic ability of the test chemicals to AR of several accessory glands/tissues (the ventral prostate, dorsolateral prostate, seminal vesicles with coagulating glands, and levator ani plus bulbocavernosus muscles). Esfenvalerate (5, 10, or 20 mg/kg/day), fenvalerate (20, 40, or 80 mg/kg/day), or permethrin (25, 50, or 75 mg/kg/day) was administered by oral gavage for 5 days to castrated male Crj:CD(SD)IGS rats (1 week after the castration, 11 weeks of age) with or without coadministration of 0.25 mg/kg/day testosterone propionate (subcutaneous injection on the dorsal surface). The highest dose levels tested for each chemical were considered the maximum level that could be used without causing excessive systemic toxicity. None of esfenvalerate, fenvalerate, and permethrin showed any androgenic or antiandrogenic effects. Reference control of p,p-DDE and methyltestosterone (100 mg/kg/day) provided significant effects in this assay protocol. Potential effects of these pyrethroids mediated through the ER were evaluated by means of 3-day uterotrophic assay using ovariectomized Crj:CD(SD)IGS rats (2 weeks after the ovariectomy, 8 weeks of age). No increase in weight of uterus (wet or blotted) was observed following oral exposure to esfenvalerate (5, 10, or 20 mg/kg/day), fenvalerate (20, 40, or 80 mg/kg/day), or permethrin (37.5, 75, or 150 mg/kg/day), respectively. Again, the highest dose levels tested for each chemical were considered the maximum level that could be used without causing excessive systemic toxicity. Reference controls consisting of ethynyl estradiol (0.03 mg/kg/day) and methoxychlor (125 mg/kg/day) both showed a significant effect in this assay protocol. It is concluded that, based on the results of these two reliable in vivo assays, none of esfenvalerate, fenvalerate, or permethrin exhibit any potential to cause adverse (anti-) androgenic or estrogenic effects at dose levels below that of those causing excessive systemic toxicity."]
[11102288,2,1,1,4,2000,"Ecological risk assessment of endocrine disruptors.",1," Hutchinson, Brown, Brugger, Campbell, Holt, Länge, McCahon, Tattersfield, van Egmond",11102288,"Ecological risk assessment of endocrine disruptors.    Abstract:   The European Centre for Ecotoxicology and Toxicology of Chemicals proposes a tiered approach for the ecological risk assessment of endocrine disruptors, integrating exposure and hazard (effects) characterization. Exposure assessment for endocrine disruptors should direct specific tests for wildlife species, placing hazard data into a risk assessment context. Supplementing the suite of mammalian screens now under Organization for Economic Cooperation and Development (OECD) validation, high priority should be given to developing a fish screening assay for detecting endocrine activity in oviparous species. Taking into account both exposure characterization and alerts from endocrine screening, higher tier tests are also a priority for defining adverse effects. We propose that in vivo mammalian and fish assays provide a comprehensive screening battery for diverse hormonal functions (including androgen, estrogen, and thyroid hormone), whereas Amphibia should be considered at higher tiers if there are exposure concerns. Higher tier endocrine-disruptor testing should include fish development and fish reproduction tests, whereas a full life-cycle test could be subsequently used to refine aquatic risk assessments when necessary. For avian risk assessment, the new OECD Japanese quail reproduction test guideline provides a valuable basis for developing a test to detecting endocrine-mediated reproductive effects; this species could be used, where necessary, for an avian life-cycle test. For aquatic and terrestrial invertebrates, data from existing developmental and reproductive tests remain of high value for ecological risk assessment. High priority should be given to research into comparative endocrine physiology of invertebrates to support data extrapolation to this diverse fauna."]
[28128023,1,2,0,3,2017,"Hypothesis-driven weight-of-evidence analysis of endocrine disruption potential: a case study with triclosan.",0," Mihaich, Capdevielle, Urbach-Ross, Slezak",28128023,"Hypothesis-driven weight-of-evidence analysis of endocrine disruption potential: a case study with triclosan.    Abstract:   Triclosan is an antimicrobial agent used in a range of consumer products, such as deodorants, oral care, clothing, and household items. As with many consumer products, triclosan can be rinsed down the drain and transported to wastewater treatment plants. While most is eliminated during activated sludge sewage treatment by biodegradation and adsorption, some triclosan enters the aquatic environment and may expose wildlife. Given the potential for exposure to both humans and wildlife, resolving whether triclosan is endocrine active is important due to growing concerns about potential adverse public health and environmental effects of endocrine-disrupting substances. A weight of evidence (WoE) analysis focusing on specific hypotheses related to interaction with estrogen, androgen, and thyroid hormone pathways, and steroidogenesis was applied to triclosan. This WoE procedure involved systematic consideration of each endpoint, focused on screening level studies in the US Endocrine Disruptor Screening Program, as well as those in levels 1 through 5 of the OECD Conceptual Framework. This was followed by a semiquantitative relevance weighting of each endpoint to a given hypothesis to reach scientifically justified conclusions. Use of all relevant and reliable information and consistent observations in multiple studies strengthen support for or against each mode of action hypothesis. Using data from multiple animal species and in vitro systems, this systematic and transparent WoE assessment indicated that triclosan is not acting as an agonist or antagonist within the estrogen, androgen, thyroid, or steroidogenic pathways and is not impacting endocrine pathways as a lead or primary mode of toxicity."]
[27130971,1,2,0,3,2016,"Linking the response of endocrine regulated genes to adverse effects on sex differentiation improves comprehension of aromatase inhibition in a Fish Sexual Development Test.",0," Muth-Köhne, Westphal-Settele, Brückner, Konradi, Schiller, Schäfers, Teigeler, Fenske",27130971,"Linking the response of endocrine regulated genes to adverse effects on sex differentiation improves comprehension of aromatase inhibition in a Fish Sexual Development Test.    Abstract:   The Fish Sexual Development Test (FSDT) is a non-reproductive test to assess adverse effects of endocrine disrupting chemicals. With the present study it was intended to evaluate whether gene expression endpoints would serve as predictive markers of endocrine disruption in a FSDT. For proof-of-concept, a FSDT according to the OECD TG 234 was conducted with the non-steroidal aromatase inhibitor fadrozole (test concentrations: 10μg/L, 32μg/L, 100μg/L) using zebrafish (Danio rerio). Gene expression analyses using quantitative RT-PCR were included at 48h, 96h, 28days and 63days post fertilization (hpf, dpf). The selection of genes aimed at finding molecular endpoints which could be directly linked to the adverse apical effects of aromatase inhibition. The most prominent effects of fadrozole exposure on the sexual development of zebrafish were a complete sex ratio shift towards males and an acceleration of gonad maturation already at low fadrozole concentrations (10μg/L). Due to the specific inhibition of the aromatase enzyme (Cyp19) by fadrozole and thus, the conversion of C19-androgens to C18-estrogens, the steroid hormone balance controlling the sex ratio of zebrafish was altered. The resulting key event is the regulation of directly estrogen-responsive genes. Subsequently, gene expression of vitellogenin 1 (vtg1) and of the aromatase cyp19a1b isoform (cyp19a1b), were down-regulated upon fadrozole treatment compared to controls. For example, mRNA levels of vtg1 were down-regulated compared to the controls as early as 48 hpf and 96 hpf. Further regulated genes cumulated in pathways suggested to be controlled by endocrine mechanisms, like the steroid and terpenoid synthesis pathway (e.g. mevalonate (diphospho) decarboxylase (mvd), lanosterol synthase (2,3-oxidosqualene-lanosterol cyclase; lss), methylsterol monooxygenase 1 (sc4mol)) and in lipid transport/metabolic processes (steroidogenic acute regulatory protein (star), apolipoprotein Eb (apoEb)). Taken together, this study demonstrated that the existing Adverse Outcome Pathway (AOP) for aromatase inhibition in fish can be translated to the life-stage of sexual differentiation. We were further able to identify MoA-specific marker gene expression which can be instrumental in defining new measurable key events (KE) of existing or new AOPs related to endocrine disruption."]
[24950493,1,2,0,3,2014,"Investigating apical adverse effects of four endocrine active substances in the freshwater gastropod Lymnaea stagnalis.",0," Giusti, Lagadic, Barsi, Thomé, Joaquim-Justo, Ducrot",24950493,"Investigating apical adverse effects of four endocrine active substances in the freshwater gastropod Lymnaea stagnalis.    Abstract:   The hermaphroditic gastropod Lymnaea stagnalis is proposed as a candidate species for the development of OECD guidelines for testing of the reprotoxicity of chemicals, including endocrine active substances (EASs). Up to now, only a few putative EASs have been tested for their reproductive toxicity in this species. In this study, we investigate the effects of four EASs with different affinities to the vertebrate estrogen and androgen receptors (chlordecone as an estrogen; cyproterone acetate, fenitrothion and vinclozolin as anti-androgens) on the reproduction of L. stagnalis in a 21-day semi-static test. Testosterone and 17α-ethinylestradiol (EE2) were used as the reference compounds. The tested EASs had no significant effect on growth and survival at the tested concentration ranges (ng to μg/L). Classical reproduction endpoints (i.e., oviposition and fecundity) were not responsive to the tested chemicals, except for chlordecone and 17α-ethinylestradiol, which hampered reproduction from 19.6 μg/L and 17.6 μg/L, respectively. The frequency of polyembryonic eggs, used as an additional endpoint, demonstrated the effects of all compounds except EE2. The molecular pathways, which are involved in such reproduction impairments, remain unknown. Our results suggest that egg quality is a more sensitive endpoint as compared to other reproductive endpoints commonly assessed in mollusk toxicity tests."]
[24831966,1,2,0,3,2014,"Bisphenol A--Why an adverse outcome pathway framework needs to be applied.",1," FitzGerald, Wilks",24831966,"Bisphenol A--Why an adverse outcome pathway framework needs to be applied.    Abstract:   Bisphenol A (BPA) is one of the most widely used and extensively studied chemicals. Numerous studies have reported in vitro effects or animal adverse findings at BPA doses lower than the no observed adverse effect levels (NOAELs) established in regulatory toxicity studies and used for human health risk assessment. Intensive discussions on the adequacy and relevance of test systems have not satisfactorily resolved whether positive or negative animal and/or in vitro findings are more relevant for human health risk assessment purposes. BPA imperfectly mimics endogenous estrogens at membrane-bound estrogen receptors in the fM-nM concentration range, and may have downstream pleiotropic effects such as human seminoma proliferation and mammary gland hyperplasia after in utero exposure which are not detectable in regulatory toxicology studies. We argue that a structured approach like the OECD Adverse Outcome Pathway (AOP) framework is needed to help researchers in designing relevant studies, and risk assessors in evaluating them. The huge amount of experimental data generated for BPA has highlighted data gaps in basic biology and the shortcomings of current approaches to hazard characterization and risk assessment. Establishing AOPs for BPA, and other endocrine active chemicals, will require major scientific as well as training investments by all responsible stakeholders."]
[23485653,3,0,0,3,2013,"The influence of study design and sex-differences on results from developmental neurotoxicity studies of bisphenol A: implications for toxicity testing.",1," Beronius, Johansson, Rudén, Hanberg",23485653,"The influence of study design and sex-differences on results from developmental neurotoxicity studies of bisphenol A: implications for toxicity testing.    Abstract:   Developmental neurotoxicity (DNT) of bisphenol A (BPA) has been investigated in a large number of studies. However, there are discrepancies in the results reported between the studies. The aim of this study was to identify and analyze factors that may contribute to these differences and to assess whether there are sex-differences in the sensitivity of certain endpoints or tests used in DNT-studies. Forty-four DNT studies of BPA were identified from the open literature. Details about study design and results from each study, as well as the criteria for DNT testing according to the standardized OECD test guideline (TG) 426, were collected in a database. This enabled systematic and detailed comparisons between studies as well as to the criteria and recommendations stated in TG 426. Multivariate analyses were also used to investigate how different factors of the study design contributed to differences in study results. The analyses showed behavioral effects were often observed for endpoints that are not required according to OECD TG 426, such as anxiety-related, social and sexual behaviors, especially at very low doses and in female offspring. On the other hand relatively few studies observed any effects on motor activity, which is commonly used in screening for neurotoxic effects in regulatory testing. However, varied and to some extent seemingly contradictory results have been reported in these studies, especially for endpoints related to motor activity and anxiety and exploration. Many studies were also poorly reported, limiting these analyses. No strong conclusions could be drawn from the multivariate analyses. A few factors of study design, such as the size of the dose and number of dose levels used and the use of litter or individual pup as statistical unit seemed to have some influence on study results. In conclusion, this analysis suggests that DNT-studies conducted according to the standardized OECD TG 426 may overlook sensitive effects of BPA, and possibly other potential endocrine disruptors, especially in female offspring."]
[22768806,1,1,1,3,2012,"Screening for modulatory effects on steroidogenesis using the human H295R adrenocortical cell line: a metabolomics approach.",0," Rijk, Peijnenburg, Blokland, Lommen, Hoogenboom, Bovee",22768806,"Screening for modulatory effects on steroidogenesis using the human H295R adrenocortical cell line: a metabolomics approach.    Abstract:   The recently OECD validated H295R steroidogenesis assay provides an in vitro alternative to evaluate the potential interference of exogenous compounds with endogenous steroid hormone synthesis. Currently, this assay is used for a simple negative-positive screening of compounds using testosterone and estradiol levels as end points, measured with specific enzyme immunoassays (EIAs) or targeted liquid chromatography (LC) and gas chromatography (GC)-mass spectrometry (MS) methods. However, recent developments in LC-MS and bioinformatics allow for more comprehensive approaches to evaluate changes in steroid profiles. In the current work, the H295R cell model was combined with a metabolomics approach to monitor changes in metabolite profiles in both a targeted and untargeted way. H295R cells were exposed for 48 h to model compounds, i.e., forskolin, abiraterone, prochloraz, ketoconazole, trilostane, formestane, aminoglutethimide, fadrozole, etomidate, and metyrapone, known to affect steroidogenesis. After exposure, the levels of 9 natural steroids were determined by a quantitative targeted GC-MS/MS method and compared to a metabolomics method using Ultra Performance Liquid Chromatography-Time-of-Flight-Mass Spectrometry (UPLC-ToF-MS). Like the EIAs, both methods were suited for negative-positive screening, but the MS methods also generated specific fingerprints, allowing chemical class prediction of the compound under investigation. Although the targeted GC-MS/MS was more sensitive, which was an advantage regarding analysis of the estrogens 17β-estradiol and estrone, the untargeted UPLC-ToF-MS was able to evaluate effects on the synthesis of the corticosteroids. Moreover, untargeted comparison of the aligned chemical profiles allowed identification of all m/z-values that are differential between exposed and nonexposed H295R cells. In conclusion, application of a comprehensive metabolite profiling methodology not only provides a tool to screen compounds for steroidogenic modulating properties, but also allows chemical class prediction. As such, steroid profiling methodologies in conjunction with the H295R assay can contribute to the prioritization of chemicals for additional safety testing."]
[21944693,1,2,0,3,2012,"Freshwater mudsnail (Potamopyrgus antipodarum) estrogen receptor: identification and expression analysis under exposure to (xeno-)hormones.",0," Stange, Sieratowicz, Horres, Oehlmann",21944693,"Freshwater mudsnail (Potamopyrgus antipodarum) estrogen receptor: identification and expression analysis under exposure to (xeno-)hormones.    Abstract:   Molluscs are raising attention as ecotoxicological test organisms due to their high diversity and ecological importance. The ovoviviparous prosobranch gastropod Potamopyrgus antipodarum (freshwater mudsnail) responds very sensitively to xenobiotics and has therefore been proposed as OECD standard test organism. Endocrine disrupting chemicals influence the reproduction of P. antipodarum, which can be assessed by embryo numbers in the brood pouch. However, the knowledge about the endocrine system of P. antipodarum is rather limited. The aim of this study was to identify an estrogen receptor in the endocrine system of P. antipodarum and to investigate if this receptor is differentially expressed under exposure to (xeno-)hormones (17α-ethinylestradiol, bisphenol A and 17α-methyltestosterone). The DNA-binding domain of the identified ER-like transcript has an amino acid identity of 92 percent compared to the ER of the gastropod Nucella lapillus (84 percent to human ERα) and 83 percent in the ligand binding domain (38 percent to human ERα). Furthermore, the P. antipodarum ER is transcriptionally regulated as shown by quantitative real-time PCRs of (xeno-)hormone exposed snails. 17α-ethinylestradiol and bisphenol A exposure resulted in a transitory ER-mRNA increase while17α-methyltestosterone caused a transitory reduction of ER-mRNA. In addition the solvent dimethyl sulfoxide had also a modulating effect on the receptor."]
[19344930,1,2,0,3,2009,"Evaluation of biodegradation of nonylphenol ethoxylate and lignin by combining toxicity assessment and chemical characterization.",0," Pessala, Keränen, Schultz, Nakari, Karhu, Ahkola, Knuutinen, Herve, Paasivirta, Ahtiainen",19344930,"Evaluation of biodegradation of nonylphenol ethoxylate and lignin by combining toxicity assessment and chemical characterization.    Abstract:   The aerobic biodegradation of commercial nonylphenol ethoxylate (NPE) mixture and alkali lignin was studied using the OECD headspace test accompanied by the simultaneous measurement of ecotoxicity directly from the biodegradation liquors and by the follow-up of the chemical composition of the studied chemicals. NPE degradation was dependent on the inoculum source: approximately 40% of NPE was mineralized into CO(2) during the 4-week experiment when inoculum from Helsinki City wastewater treatment plant (WWTP) was used, and only 12% was mineralized when inoculum from Jyväskylä City WWTP was used. Chemical analyses revealed a shift in the ethoxylate chain length from longer to shorter soon after the beginning of the NPE biodegradation tests. At the same time also toxicity (reverse electron transport assay, RET) and estrogenic activity (human estrogen receptor yeast) measured directly from the biodegradation liquors decreased. In case of alkali lignin, approximately 11% was mineralized in the test and chemical analysis showed in maximum a 30% decrease in lignin concentration. Toxicity of lignin biodegradation liquors started to decrease in the beginning of the test, but became more toxic towards the end of the test again. Especially RET assay proved to be sensitive enough for measuring toxicity changes directly from biodegradation liquors, although a concentrating treatment of the liquors is recommended for a more detailed characterization and identification of toxic metabolites."]
[18973785,1,2,0,3,2009,"Genotoxic and endocrine activities of bis(hydroxyphenyl)methane (bisphenol F) and its derivatives in the HepG2 cell line.",0," Cabaton, Dumont, Severin, Perdu, Zalko, Cherkaoui-Malki, Chagnon",18973785,"Genotoxic and endocrine activities of bis(hydroxyphenyl)methane (bisphenol F) and its derivatives in the HepG2 cell line.    Abstract:   Human can be exposed to bis(hydroxyphenyl)methane (bisphenol F or BPF) and its derivatives as environment and foods contaminants. This study was investigated to identify and to compare toxic potency of BPF, BFDGE, and two of BPF metabolites using in vitro methods. BPF did not induce any genic mutation in bacteria when the Ames test was performed according to the OECD guideline. In contrast, using Human cell lines and Comet assay, we demonstrated that BPF and Bisphenol F Diglycidyl Ether (BFDGE) were effective on HepG2 cell DNA fragmentation at non-cytotoxic concentrations. DHB was also positive but at higher concentrations, near its limit of solubility. Neither BPF, nor DHB induced a positive response in the micronucleus assay. The increase of micronuclei observed when cells were exposed to BFDGE was mostly due to a cytotoxic effect. Concerning endocrine activities, BPF increased the luciferase activity in HepG2 cells transiently transfected with a concentration dependant pattern, DHB also induced a positive response but at highest concentrations. Estrogenic responses in the HepG2 cells differed with the estrogen receptor (ER) involved. Using MDA-kb2 cell line stably transfected with pMMTV-neo-Luc, only BPF was anti-androgenic at the highest concentration (10(-5)M). Then, we demonstrated using human cell lines, especially HepG2, BPF was the most toxic compound in term of genotoxicity and endocrine activities compared to DHB and BPF-OH, the free metabolites identified in rat urine when BPF was administrated to rats."]
[16989909,1,2,0,3,2006,"Development of chronic tests for endocrine active chemicals. Part 2: an extended fish early-life stage test with an androgenic chemical in the fathead minnow (Pimephales promelas).",0," Bogers, De Vries-Buitenweg, Van Gils, Baltussen, Hargreaves, van de Waart, De Roode, Legler, Murk",16989909,"Development of chronic tests for endocrine active chemicals. Part 2: an extended fish early-life stage test with an androgenic chemical in the fathead minnow (Pimephales promelas).    Abstract:   The Endocrine Modulators Study Group (EMSG) of the European Chemical Industry has proposed an extended fish early-life stage (ELS) test based on OECD test guideline 210 in combination with a fish pair-breeding reproduction study as a possible alternative for fish full life cycle testing. In this paper the androgen methyldihydrotestosterone (MDHT) was tested in an extended ELS test with fathead minnow supplementary to such a test with the weak estrogen 4-tert-pentylphenol (4TPP). Main endpoints were secondary sexual characteristics (SSC), plasma vitellogenin (VTG) induction and gonadal development. Early blastula embryos were exposed to 0, 0.10, 0.32 and 1.0 microgMDHTl(-1) for up to 114 days post-hatch (dph). A batch of fish exposed to 1.0 microg l(-1) was transferred to clean water after 30 or 63 dph for the remainder of the study. Ethinylestradiol (EE2) was included as estrogenic reference substance at 0.01 microg l(-1). Exposure to MDHT had no significant effect on hatching success or survival, but significantly increased the condition factor of fish exposed for 63 and 114 dph (up to 150% of the control). At 63 dph MDHT exposure induced appearance of tubercles on the snout (a male SSC) of more than 80% of fish. Compared to the controls, plasma VTG was not detectable or significantly lower in fish exposed to MDHT at 0.10 microg/l, but not significantly affected at higher MDHT concentrations. Both lower levels of MDHT significantly inhibited the development of female gonads as of 30 dph. Fish exposed to MDHT at 0.32 and 1.0 microg l(-1) showed higher incidences of mixed sex gonads (10-25%) and smaller testes or dysplasia of gonadal tissue. Dysplasia was present in 80% of the fish continuously exposed to 1.0 microg l(-1) up to 114 dph, but reversible when fish were transferred to dilution water. Results indicate that suppression of ovarian development was the most sensitive endpoint for MDHT exposure after 30 dph. Other endpoints (e.g., growth and SSC) required exposure during at least up to 63 dph to yield a significant effect. Androgenic effects on VTG production required even longer exposure, i.e., until sufficient number of females had matured."]
[16710696,3,0,0,3,2006,"Repeated 28-day oral toxicity study of ketoconazole in rats based on the draft protocol for the quot;Enhanced OECD Test Guideline No. 407quot; to detect endocrine effects.",0," Shin, Moon, Kang, Kim, Kim, Park, Kim, Jeung, Han",16710696,"Repeated 28-day oral toxicity study of ketoconazole in rats based on the draft protocol for the quot;Enhanced OECD Test Guideline No. 407quot; to detect endocrine effects.    Abstract:   We performed a 28-day repeated-dose toxicity study of ketoconazole, a widely used an antimycotic drug, based on the draft protocol of the quot;Enhanced OECD Test Guideline 407quot; (Enhanced TG407) to investigate whether ketoconazole has endocrine-mediated properties according to this assay. Seven-week-old SD rats were administered with ketoconazole daily by oral gavage at doses of 0, 6.25, 25 or 100 mg kg(-1) day(-1) for at least 28 days. The ketoconazole-treated male rats showed reduction of epididymis and accessory sex organ weights, spermatid retention in the seminiferous tubules, decrease of testosterone and increases of estradiol, luteinizing hormone (LH) and follicular stimulating hormone (FSH). A prolongation of the estrous cycle and increases of estradiol, LH and FSH were observed in the treated female rats. Thyroxin and triiodothyronine were decreased and thyroid-stimulating hormone was increased in both sexes; however, there were no compound-related microscopic lesions in the thyroid gland or changes in the thyroid weight. The endocrine-related effects of ketoconazole could be detected by the parameters examined in the present study based on the Organization for Economic Cooperation and Development (OECD) protocol, suggesting that the Enhanced TG407 protocol should be a suitable screening test for detection of endocrine-mediated effects of chemicals."]
[25978955,1,1,0,2,2015,"Acute and sub-acute oral toxicity of Brazilian red propolis in rats.",0," da Silva, Andrade, Bullé Rêgo, Azevedo Dória, Santos Lima, da Silva, de Souza Araújo, de Albuquerque Júnior, Cordeiro Cardoso, Zanardo Gomes",25978955,"Acute and sub-acute oral toxicity of Brazilian red propolis in rats.    Abstract:    ETHNOPHARMACOLOGICAL RELEVANCE : Propolis is a bee product widely used in folk medicine due to its numerous pharmacological properties. However, samples from different regions can differ in chemical composition, effectiveness, and side effects. Despite the widespread use of Brazilian red propolis, which is an isoflavone-rich variety, its toxicity has not been carefully studied.  AIMS OF THE STUDY : To assess the acute and sub-acute toxicity of the hydroethanolic extract of red propolis (HERP) administered orally to rats.  MATERIALS AND METHODS : HERP for the acute (300mg/kg) and sub-acute (10, 100 and 200mg/kg) toxicity studies was administered orally to rats according to OECD Guidelines 420 and 407, respectively. Clinical signs were identified, and hematological and biochemical analyses were performed. Water and food uptake as well as body and organ weights of animals were recorded.  RESULTS AND CONCLUSIONS : The acute study revealed no lethal effects at 300mg/kg of HERP, but toxic signs were observed, as HERP had an LD50 of more than 300mg/kg, indicating a warning. The most toxic signals in sub-acute studies were observed in males at a dose of 200mg/kg HERP. These results suggest estrogen-like activity, possibly from the isoflavones in HERP."]
[21737193,1,0,1,2,2011,"Reproductive toxicity of bisphenol A and cadmium in Potamopyrgus antipodarum and modulation of bisphenol A effects by different test temperature.",0," Sieratowicz, Stange, Schulte-Oehlmann, Oehlmann",21737193,"Reproductive toxicity of bisphenol A and cadmium in Potamopyrgus antipodarum and modulation of bisphenol A effects by different test temperature.    Abstract:   An OECD initiative for the development of mollusc-based toxicity tests for endocrine disrupters and other chemicals has recommended three test species with respective test designs for further standardisation. Preparing a subsequent pre-validation study we performed a reproduction test with Potamopyrgus antipodarum, determining the concentration range of the selected test substances, bisphenol A (BPA) and cadmium (Cd). At 16 °C, the recommended test temperature, the number of embryos in the brood pouch was increased by BPA and decreased by Cd (NOEC: 20 μg BPA/L and 1 μg Cd/L). Coinstantaneous BPA tests at 7 °C and 25 °C demonstrated a temperature dependency of the response, resulting in lower NOECs (5 μg/L respectively). As expected, reproduction in control groups significantly varied depending on temperature. Additional observations of the brood stock showed seasonal fluctuations in reproduction under constant laboratory conditions. The recommended temperature range and test conditions have to be further investigated."]
[21212042,2,0,0,2,2010,"2-Aminoanthracene, diethylstilboestrol and vinblastine tested in the in vitro mammalian cell micronucleus test at British American Tobacco UK in support of the OECD draft Test Guideline 487.",0," Massey, Hinchliffe",21212042,"2-Aminoanthracene, diethylstilboestrol and vinblastine tested in the in vitro mammalian cell micronucleus test at British American Tobacco UK in support of the OECD draft Test Guideline 487.    Abstract:   Reference genotoxic compounds 2-aminoanthracene, diethylstilboestrol and vinblastine were tested in the in vitro micronucleus assay using Chinese hamster V79 derived cells in the laboratories of British American Tobacco in the UK. The work was conducted in support of the cytotoxicity measures recommended in the 2007 version of the OECD Test Guideline 487. The three compounds were positive in the assay in the presence and absence of the cytokinesis blocking agent cytochalasin B at concentrations that did not exceed the recommended cytotoxic limits determined by relative population doubling, relative increase in cell counts, relative cell counts and cytokinesis block proliferation index. Consequently, this work supports the hypothesis that relative population doubling, relative increase in cell counts and relative cell counts are appropriate measures of cytotoxicity for the non-cytokinesis blocked in vitro micronucleus assay."]
[20692362,{"$f":"(LEN($K64) - LEN(SUBSTITUTE(LOWER($K64),LOWER(B$3),\"\")))/LEN(B$3)","v":2},0,0,2,2010,"Comparison of different methods for an accurate assessment of cytotoxicity in the in vitro micronucleus test without cytokinesis block.",0," Hynes",20692362,"Comparison of different methods for an accurate assessment of cytotoxicity in the in vitro micronucleus test without cytokinesis block.    Abstract:   A European collaborative study was conducted in order to investigate the different measurements of cytotoxicity assessment in the in vitro micronucleus test. Relative population doubling and relative increase in cell counts were the measurements of cytotoxicity assessed in this study. The test chemicals, etoposide, benzo[a]pyrene, cytosine arabinoside and diethylstilboestrol were tested in this in vitro micronucleus assay, in mouse lymphoma L5178Y cells, without cytokinesis block. This study was conducted in support of the toxicity measurements recommended in the draft OECD Test Guideline 487. Etoposide, benzo[a]pyrene and cytosine arabinoside produced positive responses at concentrations where approximately 50% toxicity was observed measured by relative population doubling and relative increase in cell counts. Diethylstilboestrol was negative at all concentrations tested. These results are in concordance with the principles of the draft OECD Test Guideline 487."]
[20348020,2,0,0,2,2010,"Cytosine arabinoside, vinblastine, diethylstilboestrol and 2-aminoanthracene tested in the in vitro human TK6 cell line micronucleus test (MNvit) at Institut Pasteur de Lille in support of OECD draft test guideline 487.",0," Nesslany, Marzin",20348020,"Cytosine arabinoside, vinblastine, diethylstilboestrol and 2-aminoanthracene tested in the in vitro human TK6 cell line micronucleus test (MNvit) at Institut Pasteur de Lille in support of OECD draft test guideline 487.    Abstract:   The reference genotoxic agents Cytosine arabinoside, Vinblastine, Diethylstilboestrol and 2-Aminoanthracene were tested in the in vitro micronucleus assay, in human lymphoblastoid TK6 cells, without cytokinesis block, at the laboratories of Institut Pasteur de Lille, France. This was done in support of the toxicity measures recommended in the late 2007 version of the draft OECD Test Guideline 487 for the testing of chemicals. All four reference agents were positive in the assay at concentrations giving approximately 50% toxicity or less as assessed by draft Test Guideline 487 recommended measures, relative population doublings and relative increase in cell counts. Accordingly, this work supports the premise that relative population doublings and relative increase in cell counts are appropriate measures of toxicity for the non-cytokinesis blocked in vitro micronucleus assay."]
[19666138,2,0,0,2,2010,"Vinblastine and diethylstilboestrol tested in the in vitro mammalian cell micronucleus test (MNvit) at Swansea University UK in support of OECD draft Test Guideline 487.",0," Johnson, Jenkins, Thomas, Doak",19666138,"Vinblastine and diethylstilboestrol tested in the in vitro mammalian cell micronucleus test (MNvit) at Swansea University UK in support of OECD draft Test Guideline 487.    Abstract:   The known aneugens vinblastine and diethylstilboestrol (DES) were tested in the in vitro micronucleus assay, with and without cytokinesis block in Chinese hamster CHO cells, at the laboratories of Swansea University, Swansea, UK. These experiments were carried out to determine the suitability of the cell death and cytostasis measures used in the assay, as recommended in the draft OECD Test Guideline 487, 2007. Both compounds were positive in the assay without cytokinesis block at concentrations giving approximately 50% or less cell death and cytostasis, using relative population doublings and relative increase in cell counts. Moreover, both compounds were positive in the assay with cytokinesis block at concentrations giving approximately 50% cell death and cytostasis, using replicative index. Vinblastine was also positive for mitotic slippage, causing micronuclei in mononucleate cells with cytokinesis block. Relative population doublings and relative increase in cell counts were appropriate measures of cell death and cytostasis for the non-cytokinesis block in vitro micronucleus assay. In the cytokinesis blocked micronucleus assay, replicative index and cytokinesis block proliferation index were suitable cell death and cytostasis measures."]
[17881226,2,0,0,2,2008,"Application of the OECD 301F respirometric test for the biodegradability assessment of various potential endocrine disrupting chemicals.",0," Stasinakis, Petalas, Mamais, Thomaidis",17881226,"Application of the OECD 301F respirometric test for the biodegradability assessment of various potential endocrine disrupting chemicals.    Abstract:   The biodegradability of several potential endocrine disrupting compounds, namely 4-n-nonylphenol (4-n-NP), nonylphenol monoethoxylate (NP1EO), nonylphenol diethoxylate (NP2EO), bisphenol A (BPA), triclosan (TCS), di-(2-ethylhexyl)-phthalate (DEHP), perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) was evaluated in this study, using OECD method 301F (manometric respirometry test) and activated sludge as inoculum. According to the results, 4-n-NP and BPA meet the strict definition of ready biodegradability and they are not expected to be persistent during the activated sludge process. Partial biodegradation was observed for DEHP (58.7+/-5.7%, n=3), TCS (52.1+/-8.5%, n=3) and NP1EO (25.9+/-8.1%, n=3), indicating their possible biodegradation in wastewater treatment systems, while no biodegradation was observed for NP2EO, PFOA and PFNA. Experiments in the co-presence of a readily biodegradable compound showed the absence of co-metabolic phenomena during 4-n-NP, BPA and TCS biodegradation. Using first order kinetics to describe biodegradation of the target compounds, half-lives of 4.3+/-0.6, 1.3+/-0.2, 1.8+/-0.5, 6.9+/-2.6 days were calculated for 4-n-NP, BPA, TCS and DEHP, respectively. Toxicity tests using marine bacterium Vibrio fischeri showed that biodegradation of 4-n-NP, NP1EO, BPA and TCS is a simultaneous detoxification process, while possible abiotic or biotic transformations of NP2EO, DEHP, PFOA and PFNA during respirometric test resulted to significant increase of their toxicities."]
[{"$f":"HYPERLINK(\"https://www.ncbi.nlm.nih.gov/pubmed/\" & J68,J68)","v":12062934},2,0,0,{"$f":"SUM(B68:D68)","v":2},2002,"Changes of serum alpha 2u-globulin in the subacute oral toxicity study of ethynyl estradiol and bisphenol A based on the draft protocol for the Enhanced OECD Test Guideline No. 407.",0," Yamasaki, Takeyoshi, Noda, Takatsuki",12062934,"Changes of serum alpha 2u-globulin in the subacute oral toxicity study of ethynyl estradiol and bisphenol A based on the draft protocol for the Enhanced OECD Test Guideline No. 407.    Abstract:   To investigate the usefulness of serum alpha 2u-globulin changes as a new parameter for detecting endocrine-mediated effects, we performed a 28-day repeated-dose toxicity study using the administration of bisphenol A (BPA) or ethynyl estradiol (EE) in male rats, based on the draft protocol of the Enhanced OECD Test Guideline 407 (enhanced TG 407). BPA at doses of 0, 40, 200 and 1000 mg/kg per day or EE at doses of 0, 15, 75 and 375 microg/kg per day were orally administered to SD rats. The highest dose of BPA was reduced to 600 mg/kg per day from the second week of the study onwards because a male rat given 1000 mg/kg per day of BPA died within the first week, showing toxic clinical signs. In the assay using BPA, a reduction in the level of alpha 2u-globulin was detected in the group receiving a dose of 600 mg/kg per day. Reductions in the absolute and relative ventral prostate weights were only observed in the 600 mg/kg per day group. In the assay using EE, the alpha 2u-globulin level decreased significantly in the 375 microg/kg per day group. A reduction in the absolute and relative dorsolateral prostate weights was also observed in the 75 and 375 microg/kg per day groups, morphologically abnormal sperm were observed in the 375 microg/kg per day group. Furthermore, atrophic changes in the prostate and seminal vesicle and degenerative changes in the testis were observed in the 375 microg/kg per day group. Although the alpha 2u-globulin level was reduced in this assay using BPA and EE, further studies are necessary before this assay becomes a useful method for detecting endocrine-mediated effects."]
[11914775,2,0,0,2,2002,"Subacute oral toxicity study of ethynylestradiol and bisphenol A, based on the draft protocol for the quot;Enhanced OECD Test Guideline no. 407quot;.",0," Yamasaki, Sawaki, Noda, Imatanaka, Takatsuki",11914775,"Subacute oral toxicity study of ethynylestradiol and bisphenol A, based on the draft protocol for the quot;Enhanced OECD Test Guideline no. 407quot;.    Abstract:   We performed a 28-day repeated-dose toxicity study of ethynylestradiol (EE) and bisphenol A (BPA) based on the draft protocol of the quot;Enhanced OECD Test Guideline no. 407quot;, and assessed the sensitivity of a list of parameters for detecting endocrine-related effects of endocrine disruption. Doses of EE at 0, 10, 50 or 200 microg/kg per day, or BPA at 0, 40, 200 or 1000 mg/kg per day were orally administered to Sprague-Dawley rats. The highest dose of BPA was decreased to 600 mg/kg per day from the second week of administration because a male rat given 1000 mg/kg BPA had died within 1 week with toxic clinical signs. In the assay using EE, the decrease of prostate, seminal vesicle and pituitary weights, increase of the testis weight, atrophic changes of the prostate, seminal vesicle and mammary gland, and degenerative changes in the testes were detected in male rats in the 50 and/or 200 microg/kg groups. In females of the 200 microg/kg group, decrease of the ovary weight, increase of the uterine weight, atrophy of the ovary, hypertrophy or squamous metaplasia of the uterine epithelial cells and mucification in the vagina were observed. Furthermore, diestrous, estrous or the unknown stage was prolonged in the 50 and 200 microg/kg groups of rats. Endocrine-mediated effects of EE were not detected in general observations, hematology, serum biochemistry, or hormonal or spermatological examinations. In the assay using BPA, the diestrous stages were prolonged at the highest dose, but changes related to endocrine effects were not detected in other examinations. Thus, among the parameters tested, the weight of endocrine-linked organs and their histopathological assessment and estrous cycle stage allowed the detection of the endocrine-related effect of EE, whereas the estrous cycle stage was only a useful parameter to detect the effect of BPA."]
[11876503,1,1,0,2,2002,"Uterotrophic and Hershberger assays for n-butylbenzene in rats.",0," Yamasaki, Sawaki, Noda, Takatsuki",11876503,"Uterotrophic and Hershberger assays for n-butylbenzene in rats.    Abstract:   We performed the uterotrophic and Hershberger assays proposed by the OECD to investigate the estrogenic and androgenic effects of n-butylbenzene (nBB). For the uterotrophic assay, nBB was injected subcutaneously at doses of 0, 40, 200, 1000 and 2000 mg/kg to 19-day-old rats for 3 days. In some rats, ethynylestradiol (EE) was also injected subcutaneously at a dose of 0.6 microg/kg after the administration of nBB. There were essentially no differences in the uterine wet or blotted weights between the control and any of the nBB-treated groups, or between the control and any of the nBB plus EE-treated groups. For the Hershberger assay, nBB was administered orally at doses of 0, 200 and 600 mg/kg to 56-day-old castrated rats for 10 days. In some rats, 0.4 mg/kg testosterone propionate (TP) was also administered by subcutaneous injection after the administration of nBB. Doses of 0, 200 and 600 mg/kg nBB were also administered orally to non-castrated rats. The weights of the accessory sex organs of the castrated rats showed no significant differences between the control and any of the nBB-treated groups or between the control and the nBB plus TP-treated groups. No significant differences in the weights of the accessory sex organs of the non-castrated rats were observed between the control and the nBB-treated groups. These findings suggest that nBB does not have any endocrine-disrupting properties on in vivo screening tests."]
[27241388,0,1,0,1,2016,"Development of the Larval Amphibian Growth and Development Assay: Effects of benzophenone-2 exposure in Xenopus laevis from embryo to juvenile.",0," Haselman, Sakurai, Watanabe, Goto, Onishi, Ito, Onoda, Kosian, Korte, Johnson, Iguchi, Degitz",27241388,"Development of the Larval Amphibian Growth and Development Assay: Effects of benzophenone-2 exposure in Xenopus laevis from embryo to juvenile.    Abstract:   The Larval Amphibian Growth and Development Assay (LAGDA) is a globally harmonized chemical testing guideline developed by the U.S. Environmental Protection Agency in collaboration with Japans Ministry of Environment to support risk assessment. The assay is employed as a higher tiered approach to evaluate effects of chronic chemical exposure throughout multiple life stages in a model amphibian species, Xenopus laevis. To evaluate the utility of the initial LAGDA design, the assay was performed using a mixed mode of action endocrine disrupting chemical, benzophenone-2 (BP-2). X. laevis embryos were exposed in flow-through conditions to 0, 1.5, 3.0 or 6.0 mg l(-1) BP-2 until 2 months post-metamorphosis. Overt toxicity was evident throughout the exposure period in the 6.0 mg l(-1) treatment due to elevated mortality rates and observed liver and kidney pathologies. Concentration-dependent increases in severity of thyroid follicular cell hypertrophy and hyperplasia occurred in larval tadpoles indicating BP-2-induced impacts on the thyroid axis. Additionally, gonads were impacted in all treatments with some genetic males showing both testis and ovary tissues (1.5 mg l(-1) ) and 100% of the genetic males in the 3.0 and 6.0 mg l(-1) treatments experiencing complete male-to-female sex reversal. Concentration-dependent vitellogenin induction occurred in both genders with associated accumulations of protein in the livers, kidneys and gonads, which was likely vitellogenin and other estrogen-responsive yolk proteins. This is the first study that demonstrates the endocrine effects of this mixed mode of action chemical in an amphibian species and demonstrates the utility of the LAGDA design for supporting chemical risk assessment. Copyright © 2016 John Wiley amp; Sons, Ltd."]
[23219663,1,0,0,1,2013,"Endocrine-active compound evaluation: qualitative and quantitative histomorphological assessment of zebrafish gonads after bisphenol-A exposure.",0," Molina, Lora, Blanco, Monterde, Ayala, Moyano",23219663,"Endocrine-active compound evaluation: qualitative and quantitative histomorphological assessment of zebrafish gonads after bisphenol-A exposure.    Abstract:   There is great social concern about the risk involved from exposure to BPA as an endocrine disrupter in humans, as well as the possible repercussion of this chemical on the environment. In this study, the short-term effects of BPA at a gonadal level were assessed by means of different biomarkers in a model animal organism in vogue, the zebrafish (Danio rerio). For this purpose, 60 female zebrafish aged 16 weeks were used. These were exposed for 14 days in aquariums (following OECD Directive no.204) to BPA concentrations of 1, 10, 100 and 1000 μg/L, in addition to a control batch. After the exposure period, the zebrafish were sacrificed and samples taken for a histopathological study by light and electron microscopy and morphometric analysis. During the fourteen days of exposure, water samples were taken from the aquariums to analyze the BPA levels. The BPA concentration in the fish and the water was determined by LC-MS/MS. The gonads of the zebrafish exposed to the BPA had a normal external appearance and there were no variations in their size or body weight. An accumulation of BPA was produced in the zebrafish tissues, and this increased as the BPA concentration to which the fish were exposed did. In the histopathological and morphometric studies, multiple alterations were observed in the zebrafish ovaries, particularly highlighting the vacuolization of the follicular cytoplasm, a great degeneration of all the cell components, and an important increase in the percentage of atretic follicles as from concentrations of 100 and 1000 μg/L of BPA, verified by morphometry. These data indicate that morphological endpoints are sufficiently sensitive to individuate early effects of environmental concentration of BPA on gonads after two weeks of exposure."]
[22796587,1,0,0,1,2012,"Dermal penetration of bisphenol A in human skin contributes marginally to total exposure.",0," Demierre, Peter, Oberli, Bourqui-Pittet",22796587,"Dermal penetration of bisphenol A in human skin contributes marginally to total exposure.    Abstract:   Bisphenol A (BPA) is ubiquitous and many exposure scenarios have been described during the last decades. While oral uptake is considered as the major route of exposure, the contribution of skin penetration has been recently discussed. In the present study, the dermal penetration rate of BPA has been determined in human skin in an in vitro test method according to the OECD Test Guideline 428. This analysis resulted in penetration of 8.6% and a total amount of bio-available BPA of 9.3% of the dose applied after 24h incubation under realistic exposure conditions. This confirms that the systemic exposure to BPA via the skin contributes in a negligible way to total systemic BPA exposure."]
[20470846,1,0,0,1,2010,"Weight factors in an Integrated Testing Strategy using adjusted OECD principles for (Q)SARs and extended Klimisch codes to decide on skin irritation classification.",0," Hulzebos, Gerner",20470846,"Weight factors in an Integrated Testing Strategy using adjusted OECD principles for (Q)SARs and extended Klimisch codes to decide on skin irritation classification.    Abstract:   The Integrated Assessment Scheme (IAS) defines weight factors for each piece of toxicological information under REACH in an Integrated Testing Strategy. This IAS is illustrated on skin irritation for Classification and Labelling (Camp;L) for five substances and using mostly (Q)SAR models. The models are the BfR Rulebase, Derek for Windows and TOPKAT, read across and pH-rules. The weight factors derived in the IAS show that for peracetic-acid and pentabromodiphenylether the Camp;L decision could be easily made. For bisphenol A additional information on read across was used to finalise a decision on Camp;L, while for methylphenyl-diisocyanate additional expert judgement was needed. For allylheptanoate only the TOPKAT prediction was in the applicability domain, which was insufficient on its own. Therefore, other non guideline testing information was used and in vitro testing results. The above examples on skin irritation information show how the IAS can aid in the decision making process and how it adds to the ToxRTool and the ITS of Hoffmann et al. on the same endpoint and similar methods."]
[18184636,1,0,0,1,2008,"Two-generation reproductive toxicity evaluation of dietary 17beta-estradiol (E2; CAS No. 50-28-2) in CD-1 (Swiss) mice.",0," Tyl, Myers, Marr, Sloan, Castillo, Veselica, Seely, Dimond, Van Miller, Shiotsuka, Stropp, Waechter, Hentges",18184636,"Two-generation reproductive toxicity evaluation of dietary 17beta-estradiol (E2; CAS No. 50-28-2) in CD-1 (Swiss) mice.    Abstract:   No information exists on reproductive/developmental effects in mice exposed to dietary 17beta-estradiol (E2) over multiple generations. Therefore, under OECD Test Guideline 416 with enhancements, CD-1 mice (F0 generation, 25 mice/sex/group) were exposed to dietary E2 at 0, 0.001, 0.005, 0.05, 0.15, or 0.5 ppm ( approximately 0, 0.2, 1, 10, 30, or 100 mug E2/kg body weight/day) for 8 weeks prebreed, 2 weeks mating, approximately 3 weeks gestation, and 3 weeks lactation. At weaning, selected F1 offspring (F1 parents; 25/sex/group) and extra retained F1 males (one per litter) were exposed to the same dietary concentrations and durations as the F0 generation; study termination occurred at F2 weaning; F1/F2 weanlings (up to three per sex per litter) were necropsied with organs weighed. At 0.5 ppm, effects were increased F1/F2 perinatal loss, prolonged F0/F1 gestational length, reduced numbers of F2 (but not F1) litters/group, reduced F1/F2 litter sizes, accelerated vaginal patency (VP) and delayed preputial separation (PPS), increased uterus + cervix + vagina weights (UCVW) in F0/F1 adults and F1/F2 weanlings, and decreased testes and epididymides weights (TEW) in F1/F2 weanlings. At 0.15 ppm, effects were increased UCVW in F0/F1 adults and F1/F2 weanlings, accelerated VP, delayed PPS, and reduced TEW in F1/F2 weanlings. At 0.05 ppm, UCVW were increased in F1/F2 weanlings, and PPS was delayed only in extra retained F1 males. There were no biologically significant or treatment-related effects on F0/F1 parental body weights, feed consumption, or clinical observations, or on F0/F1 estrous cyclicity, F0/F1 andrology, or F1/F2 anogenital distance at any dose. The no observable effect level was 0.005 ppm E2 ( approximately 1 mug/kg/day). Therefore, the mouse model is sensitive to E2 by oral administration, with effects on reproductive development at doses of 10- 100 mug/kg/day."]
[16732769,1,0,0,1,2006,"Two-generation reproduction toxicity study in rats with 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (p,p-DDT).",0," Hojo, Aoyama, Takahashi, Shimizu, Araki, Takizawa, Sakasai, Kuwahara, Saka, Teramoto",16732769,"Two-generation reproduction toxicity study in rats with 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (p,p-DDT).    Abstract:   DDT, an organochlorine pesticide, has been cited as a representative chemical suspected of having endocrine disrupting effects. In this study, the potential endocrine disrupting activities of p,p-DDT, a major component of DDT, were investigated in rats in a 2-generation reproduction toxicity study in accordance with the most current test guidelines of the Ministry of Agriculture, Forestry and Fisheries in Japan, Organization for Economic Cooperation and Development (OECD) and United States Environmental Protection Agency (USEPA) with some modifications and additions. p,p-DDT was given to parental rats at dietary levels of 0, 5, 50 or 350 ppm. Systemic toxicities in the parental animals consisted of tremors and subsequent deaths (females only) and/or pathological alterations of the liver (both sexes of animals) of the 2 higher dose groups. Reproductive and postnatal developmental toxicities were not evident up to the highest dose level except for the decreased pup viability index on postnatal day 21 in the 350 ppm group. Changes in serum estradiol and progesterone levels and/or a delay in male sexual maturation were noted in the 2 higher dose groups in a dose-dependent fashion, suggesting alterations of endogenous endocrine functions. However, these changes never resulted in substantial reproductive disorders."]
[12007857,1,0,0,1,2002,"Developmental toxicity but no immunotoxicity in the rat after prenatal exposure to diethylstilbestrol.",0," Piersma, Verhoef, Sweep, de Jong, van Loveren",12007857,"Developmental toxicity but no immunotoxicity in the rat after prenatal exposure to diethylstilbestrol.    Abstract:   Studies with dioxins and PCBs have shown that the developing immune system may be especially vulnerable to xenobiotics during the perinatal period. However, current guidelines for reproductive toxicity testing do not include immune parameters. In the present study, we have explored the usefulness of including immune parameters within the prenatal developmental toxicity study in rats, using the treatment protocol as described in the OECD 414 developmental toxicity test guideline. In addition, the experimental protocol was enhanced by including ten dose groups to facilitate dose-response analysis. Diethylstilbestrol (DES) was used as the model compound, as it is known to be toxic both for embryofetal development and for the immune system. The results show developmental toxicity in terms of decreased fetal survival and decreased pup body weight in the presence of reduced maternal food consumption and reduced body weight gain. However, immune parameters, including histopathology, hematology, and antibody responses to sheep red blood cells (SRBC) in pups at 4 weeks of age were uncompromised. It is speculated that rather than the prenatal exposure protocol used here, the generation study design with both pre- and postnatal exposure may be preferable as a general screen to detect developmental immunotoxic injury after xenobiotic exposure."]
[23886749,0,0,0,0,2013,"Toxicity of new generation flame retardants to Daphnia magna.",0," Waaijers, Hartmann, Soeter, Helmus, Kools, de Voogt, Admiraal, Parsons, Kraak",23886749,"Toxicity of new generation flame retardants to Daphnia magna.    Abstract:   There is a tendency to substitute frequently used, but relatively hazardous brominated flame retardants (BFRs) with halogen-free flame retardants (HFFRs). Consequently, information on the persistence, bioaccumulation and toxicity (PBT) of these HFFRs is urgently needed, but large data gaps and inconsistencies exist. Therefore, in the present study the toxicity of a wide range of HFFRs to the water flea Daphnia magna was investigated. Our results revealed that four HFFRs were showing no effect at their Sw (saturated water concentration) and three had a low toxicity (EC50gt;10 mg L(-1)), suggesting that these compounds are not hazardous. Antimony trioxide had a moderate toxicity (EC50=3.01 mg L(-1), 95% CL: 2.76-3.25) and triphenyl phosphate and the brominated reference compound tetra bromobisphenol A were highly toxic to D. magna (EC50=0.55 mg L(-1), 95% CL: 0.53-0.55 and EC50=0.60 mg L(-1), 95% CL: 0.24-0.97 respectively). Aluminum trihydroxide and bisphenol A bis(diphenyl phosphate) caused limited mortality at Sw (26 and 25% respectively) and have a low solubility (lt;10 mg L(-1)). Hence, increased toxicity of these compounds may be observed when for instance decreasing pH could increase solubility. By testing all compounds under identical conditions we provided missing insights in the environmental hazards of new generation flame retardants and propose as best candidates for BFR replacements: APP, ALPI, DOPO, MHO, MPP, ZHS and ZS."]

{"sheet":"Abstract","index":1,"n_rows":5,"n_cols":4,"rows_kept":5,"cut":false,"hidden":false,"merged":[[0,0,0,1]]}
["Abstract with highlights"]
["Article:",{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & C2,C2)","v":15598176},15598176,"Pub Yr: 2003"]
[]
["Title:","A critical assessment of the OECD collaborative study to validate the uterotrophic assay for the detection of oestrogenic and anti-oestrogenic chemicals.",null,"Authors:  Combes"]
["Title and Abstract:","A critical assessment of the OECD collaborative study to validate the uterotrophic assay for the detection of oestrogenic and anti-oestrogenic chemicals.    Abstract:   The design and execution of a recently completed validation study on the rat uterotrophic assay for detecting oestrogens and anti-oestrogens, managed by the OECD, are critically assessed with respect to internationally agreed criteria for the validation of new in vitro and in vivo toxicity test methods. It is concluded that, while the design of the study did not take account of several important criteria for validation, the uterotrophic assay appears to reliably detect the strong and weak oestrogenic substances used in the study, which act via binding to the oestrogen receptor in vivo. However, the reliability of the assay has not been substantiated for detecting anti-oestrogens that act as antagonists, due to the involvement of an insufficient number of experiments and test chemicals. Moreover, the data do not permit an assessment of the accuracy of the prediction of oestrogenicity, and the protocols have not been sufficiently optimised with regard to controlling variables. This problem has been exacerbated by a wish to introduce as much flexibility as possible into the protocols during the formal validation phase of the study, rather than during a separate prevalidation stage. In addition, the choice between surgically treated and/or immature animals, and details of housing and husbandry conditions that are necessary for increasing the sensitivity and efficiency of the assay, need to be clarified. The assay also lacks a well-defined prediction model by which the overall relevance of the data to toxicity, and especially to human hazard, can be assessed, and no performance criteria have been established. The results of this analysis of the study indicate that it would be premature to produce an OECD test guideline for the uterotrophic assay at this time, before some of the above issues have been satisfactorily resolved."]

{"sheet":"Notes","index":2,"n_rows":3,"n_cols":8,"rows_kept":3,"cut":false,"hidden":false,"merged":[]}
[null,"My Notes"]
["Chemical","PMID ","DOI","Note ","Title","LinkDOI","LinkID","Link"]
[null,{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & G3,G3)","v":16326438},null,"test","Validation study of OECD rodent uterotrophic assay for the assessment of estrogenic activity in Sprague-Dawley immature female rats.",null,16326438]

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["Log of activity"]
["Date","Records Returned","Query Used"]
["2017-03-01T14:32:04",75,"oecd AND estrogen AND toxicity"]
["2017-03-01T13:53:52",100,"oecd AND estrogen"]
["2017-02-28T15:28:00",35,"atrazine AND (noel OR loel OR loael or reference dose)"]
["2017-02-28T15:26:50",12,"atrazine AND (noel OR loel OR loael)"]
["2017-02-28T15:25:16",6,"ddt AND (noel OR loel OR loael)"]
["2017-02-28T11:16:57",96,"judson[au] AND 2016"]
["2017-02-09T12:02:08",1024,"retinoid AND limb"]
["2017-02-09T12:00:58",1024,"retinoid AND limb"]
["2017-02-09T11:59:49",162,"retinoid AND cyp26"]
["2017-02-09T11:44:45",2833,"retinoid AND (bone OR teeth)"]
["2017-02-09T11:38:08",162,"retinoid AND cyp26"]
["2017-01-31T12:51:08",2327,"\"ames test\"[tiab]"]
["2017-01-31T12:29:47",3011,"\"guideline animal studies\" OR \"guideline animal study\""]
["2017-01-31T12:26:08",17,"toxrefdb "]
["2017-01-31T11:08:38",1665,"heart AND embryo AND development AND (defect OR malformation)"]
["2017-01-31T11:06:24",319,"heart AND embryo AND development AND septal"]
["2017-01-31T11:03:00",1841,"(cleft palate OR palate) AND embryo"]