scholarly journals Introduction: Endocrine Disruptors—Exposure Assessment, Novel End Points, and Low-Dose and Mixture Effects

2007 ◽  
Vol 115 (Suppl 1) ◽  
pp. 7-7 ◽  
Author(s):  
Andreas Kortenkamp
Keyword(s):  
Exposure Assessment ◽  
Endocrine Disruptors ◽  
Low Dose ◽  
End Points ◽  
Mixture Effects

Mixture Effects of 3 Mechanistically Different Steroidogenic Disruptors (Prochloraz, Genistein, and Ketoconazole) in the H295R Cell Assay

2015 ◽  
Vol 34 (6) ◽  
pp. 534-542 ◽  
Author(s):  
Frederik Knud Nielsen ◽  
Cecilie Hurup Hansen ◽  
Jennifer Anna Fey ◽  
Martin Hansen ◽  
Bent Halling-Sørensen ◽  
...  
Keyword(s):  
Cell Line ◽  
Endocrine Disruptors ◽  
Mixture Toxicity ◽  
Concentration Addition ◽  
Mixture Effects ◽  
Modes Of Action ◽  
Cell Assay ◽  
17Β Estradiol ◽  
H295r Cells ◽  
The Individual

Mixture effects of 3 model endocrine disruptors, prochloraz, ketoconazole, and genistein, on steroidogenesis were tested in the adrenocortical H295R cell line. Seven key steroid hormones (pregnenolone, progesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone, and 17β-estradiol) were analyzed using gas chromatography and tandem mass spectrometry (GC-MS/MS) to investigate the effects throughout the steroidogenic pathway. Current modeling approaches often rely on models assuming compounds acting independently and that the individual effects in some way can be summarized to predict a mixture effect. In H295R cells with an intact steroidogenic pathway, such assumptions may not be feasible. The purpose of this study was therefore to evaluate whether effects of a mixture with differing modes of action followed or deviated from additivity (concentration addition) and whether the H295R cell line was suitable for evaluating mixture toxicity of endocrine disruptors with different modes of action. The compounds were chosen because they interfere with steroidogenesis in different ways. They all individually decrease the concentrations of the main sex steroids downstream but exert different effects upstream in the steroidogenic pathway. Throughout the study, we observed lowest observed effect concentrations of mixtures at levels 2 to 10 times higher than the predicted EC50, strongly indicating antagonistic effects. The results demonstrate that chemical analysis combined with the H295R cell assay is a useful tool also for studying how mixtures of endocrine disruptors with differing modes of action interfere with the steroidogenic pathway and that existing models like concentration addition are insufficient in such cases. Furthermore, for end points where compounds exert opposite effects, no relevant models are available.

The low-dose issue and stochastic responses to endocrine disruptors

2010 ◽  
Vol 31 (1) ◽  
pp. 84-88 ◽  
Author(s):  
Yoko Hirabayashi ◽  
Tohru Inoue
Keyword(s):  
Endocrine Disruptors ◽  
Low Dose ◽  
Stochastic Responses

scholarly journals Randomized Open-Label Phase II Study of Decitabine in Patients With Low- or Intermediate-Risk Myelodysplastic Syndromes

2013 ◽  
Vol 31 (20) ◽  
pp. 2548-2553 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Stefan Faderl ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Phase Ii ◽  
Low Dose ◽  
De Novo ◽  
Phase Ii Study ◽  
Cytogenetic Response ◽  
Open Label ◽  
End Points ◽  
Improvement Rate ◽  
Transfusion Independence ◽  
Open Label Phase

Purpose This open-label, randomized phase II trial assessed efficacy and tolerability of two low-dose regimens of subcutaneous (SC) decitabine in patients with low- or intermediate-1–risk myelodysplastic syndrome (MDS). Patients and Methods Patients received decitabine 20 mg/m2 SC per day for 3 consecutive days on days 1, 2, and 3 every 28 days (schedule A) or 20 mg/m2 SC per day once every 7 days on days 1, 8, and 15 every 28 days (schedule B) for up to 1 year. Primary efficacy end point was overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points were HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death. Results Efficacy and safety populations were identical: schedule A, n = 43; schedule B, n = 22. Median time from MDS diagnosis to treatment was 3.6 months; 89% had de novo MDS. The trial was terminated early on achievement of protocol-defined OIR superiority of schedule A over schedule B; OIR was 23% for schedule A (seven CRs, three HIs) and 23% for schedule B (one mCR, one PR, three HIs). No differences were observed in secondary end points. Median OS was not reached; approximately 70% of patients were alive at 500 days. Patients in schedule A (67%) and schedule B (59%) were RBC/platelet independent on study. The most frequent drug-related adverse events overall were neutropenia (28% v 36%), anemia (23% v 18%), and thrombocytopenia (16% v 32%). Conclusion In this phase II study, low-dose decitabine showed promising results in patients with low- or intermediate-1–risk MDS.

A Prospective Multicenter Single-Arm Study of Low-Dose Decitabine in Adult Patients with Immune Thrombocytopenia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3744-3744
Author(s):  
Hai Zhou ◽  
Ping Qin ◽  
Chenglu Yuan ◽  
Haiyan Zhang ◽  
Zhencheng Wang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Intravenous Immunoglobulin ◽  
Immune Thrombocytopenia ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
End Points ◽  
Thrombopoietin Receptor Agonists ◽  
Receptor Agonists ◽  
Thrombopoietin Receptor

Abstract Introduction: Approximately 30% of patients with immune thrombocytopenia (ITP) fail to respond to the first- and/or second-line treatments (corticosteroids, intravenous immunoglobulin, rituximab, splenectomy, and thrombopoietin-receptor agonists). For those patients, the management is challenging. Decitabine (DAC), a demethylating agent with a dual mechanism of action: the demethylating effect leading to cell differentiation at low dose and cytotoxic activity leading to cell death at high concentration, has been used in the management of myelodysplastic syndrome (MDS) with a considerable platelet response during the past decade. Recent studies proved that low-dose DAC was sufficient to show a therapeutic effect with no obvious cytotoxicity. Our previous and other studies have demonstrated that low-dose DAC could promote megakaryocyte maturation and platelet production. These findings suggest a possible therapeutic role of low-dose DAC in the management of ITP. We hereby present the preliminary results of a prospective, multicenter, open-labeled study evaluating the efficacy and safety of low-dose DAC for ITP patients. Methods: ITP patients, who failed to respond to corticosteroids, intravenous immunoglobulin, rituximab, and/or thrombopoietin-receptor agonists from 9 centers, were enrolled in the study. The study protocol was approved by the ethics committee on medical research of each participating site. All patients provided written informed consent in accordance with the Declaration of Helsinki. DAC was given intravenously at 3.5mg/m2 for 3 days/cycle for 3 cycles with a 4-week interval between cycles. The primary end points were complete response (CR), response (R), overall response (OR). All the criteria were consistent with the standardization of terminology, definitions and outcome criteria in immune thrombocytopenia proposed by the international working group (RodeghieroF, et al. Blood, 2009, 113:2386-2393). Secondary end points were bleeding scores, time to response (TTR), duration of response and adverse events. Adverse events were evaluated according to Common Terminology Criteria for Adverse Events, version3.0. This clinical trial was registered at http://clinicaltrials.gov as NCT 01568333. Results: A total of 20 ITP patients were recruited. The clinical characteristics were shown in Table 1. At the end of the 12th week of the initial treatment, CR was achieved in 1 patient (5%) and R was achieved in 9 patients (45%). The OR rate was 50%. During the follow-up period, 1 patient initially stabilized at R and subsequently improved to CR at the 20th week. Therefore, CR, R and OR rates were 10% (2/20), 40% (8/20) and 50% (10/20), respectively. In patients who achieved CR and R, the median (range) TTR was 22 days (8-38 days). The median (range) follow-up time was 24 weeks (13-40 weeks). The platelet counts of patients who achieved CR and R were shown in Figure 1. The follow-up of our study is in progress. Adverse events were observed in 2 patients, one had nausea and the other was mild fever. No adverse events exceeded grade 1. Conclusion: Although the sample size is small, with a relatively short follow-up period limited by now, our study suggests that low-dose DAC is effective and safe in the management of ITP patients. Disclosures No relevant conflicts of interest to declare.

LOW DOSE MIXTURE EFFECTS OF BISPHENOL A AND ISOBUTYLPARABEN FOR THE MALE REPRODUCTIVE SYSTEM

2011 ◽  
Vol 2011 (1) ◽  
Author(s):  
Yun-jung Yang ◽  
Mun-seo Park ◽  
Sang-yon Kim ◽  
Lee-so Maeng ◽  
Soon-chul Myoung ◽  
...  
Keyword(s):  
Bisphenol A ◽  
Reproductive System ◽  
Low Dose ◽  
Male Reproductive System ◽  
Mixture Effects

scholarly journals Deciphering the Impact of Early-Life Exposures to Highly Variable Environmental Factors on Foetal and Child Health: Design of SEPAGES Couple-Child Cohort

2019 ◽  
Vol 16 (20) ◽  
pp. 3888 ◽  
Author(s):  
Sarah Lyon-Caen ◽  
Valérie Siroux ◽  
Johanna Lepeule ◽  
Philippe Lorimier ◽  
Pierre Hainaut ◽  
...  
Keyword(s):  
Child Health ◽  
Pregnant Women ◽  
Exposure Assessment ◽  
Endocrine Disruptors ◽  
Early Life ◽  
Air Pollutants ◽  
Atmospheric Pollutants ◽  
Urine Samples ◽  
The Impact ◽  
Deep Phenotyping

In humans, studies based on Developmental Origins of Health and Disease (DOHaD) concept and targeting short half-lived chemicals, including many endocrine disruptors, generally assessed exposures from spot biospecimens. Effects of early-life exposure to atmospheric pollutants were reported, based on outdoor air pollution levels. For both exposure families, exposure misclassification is expected from these designs: for non-persistent chemicals, because a spot biospecimen is unlikely to capture exposure over windows longer than a few days; for air pollutants, because indoor levels are ignored. We developed a couple-child cohort relying on deep phenotyping and extended personal exposure assessment aiming to better characterize the effects of components of the exposome, including air pollutants and non-persistent endocrine disruptors, on child health and development. Pregnant women were included in SEPAGES couple-child cohort (Grenoble area) from 2014 to 2017. Maternal and children exposure to air pollutants was repeatedly assessed by personal monitors. DNA, RNA, serum, plasma, placenta, cord blood, meconium, child and mother stools, living cells, milk, hair and repeated urine samples were collected. A total of 484 pregnant women were recruited, with excellent compliance to the repeated urine sampling protocol (median, 43 urine samples per woman during pregnancy). The main health outcomes are child respiratory health using early objective measures, growth and neurodevelopment. Compared to former studies, the accuracy of assessment of non-persistent exposures is expected to be strongly improved in this new type of birth cohort tailored for the exposome concept, with deep phenotyping and extended exposure characterization. By targeting weaknesses in exposure assessment of the current approaches of cohorts on effects of early life environmental exposures with strong temporal variations, and relying on a rich biobank to provide insight on the underlying biological pathways whereby exposures affect health, this design is expected to provide deeper understanding of the interplay between the Exposome and child development and health.

Developmental exposure to low-dose estrogenic endocrine disruptors alters sex differences in exploration and emotional responses in mice

2007 ◽  
Vol 52 (3) ◽  
pp. 307-316 ◽  
Author(s):  
Laura Gioiosa ◽  
Elena Fissore ◽  
Giorgia Ghirardelli ◽  
Stefano Parmigiani ◽  
Paola Palanza
Keyword(s):  
Sex Differences ◽  
Endocrine Disruptors ◽  
Low Dose ◽  
Emotional Responses ◽  
Developmental Exposure

scholarly journals Intravenous Iron Dosing and Infection Risk in Patients on Hemodialysis: A Prespecified Secondary Analysis of the PIVOTAL Trial

2020 ◽  
Vol 31 (5) ◽  
pp. 1118-1127 ◽  
Author(s):  
Iain C. Macdougall ◽  
Sunil Bhandari ◽  
Claire White ◽  
Stefan D. Anker ◽  
Kenneth Farrington ◽  
...  
Keyword(s):  
Cardiovascular Event ◽  
Low Dose ◽  
Secondary Analysis ◽  
Maintenance Hemodialysis ◽  
High Dose ◽  
Pivotal Trial ◽  
Infection Rates ◽  
End Points ◽  
Iv Iron ◽  
Event Rates

BackgroundExperimental and observational studies have raised concerns that giving intravenous (IV) iron to patients, such as individuals receiving maintenance hemodialysis, might increase the risk of infections. The Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial randomized 2141 patients undergoing maintenance hemodialysis for ESKD to a high-dose or a low-dose IV iron regimen, with a primary composite outcome of all-cause death, heart attack, stroke, or hospitalization for heart failure. Comparison of infection rates between the two groups was a prespecified secondary analysis.MethodsSecondary end points included any infection, hospitalization for infection, and death from infection; we calculated cumulative event rates for these end points. We also interrogated the interaction between iron dose and vascular access (fistula versus catheter).ResultsWe found no significant difference between the high-dose IV iron group compared with the lose-dose group in event rates for all infections (46.5% versus 45.5%, respectively, which represented incidences of 63.3 versus 69.4 per 100 patient years, respectively); rates of hospitalization for infection (29.6% versus 29.3%, respectively) also did not differ. We did find a significant association between risk of a first cardiovascular event and any infection in the previous 30 days. Compared with patients undergoing dialysis with an arteriovenous fistula, those doing so via a catheter had a higher incidence of having any infection, hospitalization for infection, or fatal infection, but IV iron dosing had no effect on these outcomes.ConclusionsThe high-dose and low-dose IV iron groups exhibited identical infection rates. Risk of a first cardiovascular event strongly associated with a recent infection.

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