| 1. |
- Schug, Thaddeus T., et al.
(författare)
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Designing Endocrine Disruption Out of the Next Generation of Chemicals
- 2013
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Ingår i: Green Chemistry. - : Royal Society of Chemistry. - 1463-9262 .- 1463-9270. ; 15:1, s. 181-198
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Tidskriftsartikel (refereegranskat)abstract
- A central goal of green chemistry is to avoid hazard in the design of new chemicals. This objective is best achieved when information about a chemical's potential hazardous effects is obtained as early in the design process as feasible. Endocrine disruption is a type of hazard that to date has been inadequately addressed by both industrial and regulatory science. To aid chemists in avoiding this hazard, we propose an endocrine disruption testing protocol for use by chemists in the design of new chemicals. The Tiered Protocol for Endocrine Disruption (TiPED) has been created under the oversight of a scientific advisory committee composed of leading representatives from both green chemistry and the environmental health sciences. TiPED is conceived as a tool for new chemical design, thus it starts with a chemist theoretically at "the drawing board." It consists of five testing tiers ranging from broad in silico evaluation up through specific cell- and whole organism-based assays. To be effective at detecting endocrine disruption, a testing protocol must be able to measure potential hormone-like or hormone-inhibiting effects of chemicals, as well as the many possible interactions and signaling sequellae such chemicals may have with cell-based receptors. Accordingly, we have designed this protocol to broadly interrogate the endocrine system. The proposed protocol will not detect all possible mechanisms of endocrine disruption, because scientific understanding of these phenomena is advancing rapidly. To ensure that the protocol remains current, we have established a plan for incorporating new assays into the protocol as the science advances. In this paper we present the principles that should guide the science of testing new chemicals for endocrine disruption, as well as principles by which to evaluate individual assays for applicability, and laboratories for reliability. In a 'proof-of-principle' test, we ran 6 endocrine disrupting chemicals (EDCs) that act via different endocrinological mechanisms through the protocol using published literature. Each was identified as endocrine active by one or more tiers. We believe that this voluntary testing protocol will be a dynamic tool to facilitate efficient and early identification of potentially problematic chemicals, while ultimately reducing the risks to public health.
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| 2. |
- Day, Louise T., et al.
(författare)
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"Every Newborn-BIRTH" protocol : observational study validating indicators for coverage and quality of maternal and newborn health care in Bangladesh, Nepal and Tanzania
- 2019
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Ingår i: Journal of Global Health. - : International Global Health Society. - 2047-2978 .- 2047-2986. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: To achieve Sustainable Development Goals and Universal Health Coverage, programmatic data are essential. The Every Newborn Action Plan, agreed by all United Nations member states and >80 development partners, includes an ambitious Measurement Improvement Roadmap. Quality of care at birth is prioritised by both Every Newborn and Ending Preventable Maternal Mortality strategies, hence metrics need to advance from health service contact alone, to content of care. As facility births increase, monitoring using routine facility data in DHIS2 has potential, yet validation research has mainly focussed on maternal recall surveys. The Every Newborn - Birth Indicators Research Tracking in Hospitals (EN-BIRTH) study aims to validate selected newborn and maternal indicators for routine tracking of coverage and quality of facility-based care for use at district, national and global levels.Methods: EN-BIRTH is an observational study including >20000 facility births in three countries (Tanzania, Bangladesh and Nepal) to validate selected indicators. Direct clinical observation will be compared with facility register data and a pre-discharge maternal recall survey for indicators including: uterotonic administration, immediate newborn care, neonatal resuscitation and Kangaroo mother care. Indicators including neonatal infection management and antenatal corticosteroid administration, which cannot be easily observed, will be validated using inpatient records. Trained clinical observers in Labour/Delivery ward, Operation theatre, and Kangaroo mother care ward/areas will collect data using a tablet-based customised data capturing application. Sensitivity will be calculated for numerators of all indicators and specificity for those numerators with adequate information. Other objectives include comparison of denominator options (ie, true target population or surrogates) and quality of care analyses, especially regarding intervention timing. Barriers and enablers to routine recording and data usage will be assessed by data flow assessments, quantitative and qualitative analyses.Conclusions: To our knowledge, this is the first large, multi-country study validating facility-based routine data compared to direct observation for maternal and newborn care, designed to provide evidence to inform selection of a core list of indicators recommended for inclusion in national DHIS2. Availability and use of such data are fundamental to drive progress towards ending the annual 5.5 million preventable stillbirths, maternal and newborn deaths.
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| 3. |
- Gore, Andrea C., et al.
(författare)
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EDC-2 : The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals
- 2015
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Ingår i: Endocrine reviews. - : Oxford University Press. - 0163-769X .- 1945-7189. ; 36:6, s. E1-E150
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Forskningsöversikt (refereegranskat)abstract
- The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.
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| 4. |
- Gore, Andrea C., et al.
(författare)
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Executive Summary to EDC-2 : The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals
- 2015
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Ingår i: Endocrine reviews. - : Oxford University Press. - 0163-769X .- 1945-7189. ; 36:6, s. 593-602
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Forskningsöversikt (refereegranskat)abstract
- This Executive Summary to the Endocrine Society's second Scientific Statement on environmental endocrine-disrupting chemicals (EDCs) provides a synthesis of the key points of the complete statement. The full Scientific Statement represents a comprehensive review of the literature on seven topics for which there is strong mechanistic, experimental, animal, and epidemiological evidence for endocrine disruption, namely: obesity and diabetes, female reproduction, male reproduction, hormone-sensitive cancers in females, prostate cancer, thyroid, and neurodevelopment and neuroendocrine systems. EDCs such as bisphenol A, phthalates, pesticides, persistent organic pollutants such as polychlorinated biphenyls, polybrominated diethyl ethers, and dioxins were emphasized because these chemicals had the greatest depth and breadth of available information. The Statement also included thorough coverage of studies of developmental exposures to EDCs, especially in the fetus and infant, because these are critical life stages during which perturbations of hormones can increase the probability of a disease or dysfunction later in life. A conclusion of the Statement is that publications over the past 5 years have led to a much fuller understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability. These findings will prove useful to researchers, physicians, and other healthcare providers in translating the science of endocrine disruption to improved public health.
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| 5. |
- La Merrill, Michele A, et al.
(författare)
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Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification
- 2020
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Ingår i: Nature Reviews Endocrinology. - : Nature Publishing Group. - 1759-5029 .- 1759-5037. ; 16:1, s. 45-57
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Tidskriftsartikel (refereegranskat)abstract
- Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with hormone action, thereby increasing the risk of adverse health outcomes, including cancer, reproductive impairment, cognitive deficits and obesity. A complex literature of mechanistic studies provides evidence on the hazards of EDC exposure, yet there is no widely accepted systematic method to integrate these data to help identify EDC hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we have developed ten KCs of EDCs based on our knowledge of hormone actions and EDC effects. In this Expert Consensus Statement, we describe the logic by which these KCs are identified and the assays that could be used to assess several of these KCs. We reflect on how these ten KCs can be used to identify, organize and utilize mechanistic data when evaluating chemicals as EDCs, and we use diethylstilbestrol, bisphenol A and perchlorate as examples to illustrate this approach.
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| 6. |
- vom Saal, Frederick S., et al.
(författare)
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The Conflict between Regulatory Agencies over the 20,000-Fold Lowering of the Tolerable Daily Intake (TDI) for Bisphenol A (BPA) by the European Food Safety Authority (EFSA)
- 2024
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Ingår i: Journal of Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 132:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: The European Food Safety Authority (EFSA) recommended lowering their estimated tolerable daily intake (TDI) for bisphenol A (BPA) 20,000-fold to 0.2 ng/kg body weight (BW)/day. BPA is an extensively studied high production volume endocrine disrupting chemical (EDC) associated with a vast array of diseases. Prior risk assessments of BPA by EFSA as well as the US Food and Drug Administration (FDA) have relied on industry-funded studies conducted under good laboratory practice protocols (GLP) requiring guideline end points and detailed record keeping, while also claiming to examine (but rejecting) thousands of published findings by academic scientists. Guideline protocols initially formalized in the mid-twentieth century are still used by many regulatory agencies. EFSA used a 21st century approach in its reassessment of BPA and conducted a transparent, but time-limited, systematic review that included both guideline and academic research. The German Federal Institute for Risk Assessment (BfR) opposed EFSA’s revision of the TDI for BPA.Objectives: We identify the flaws in the assumptions that the German BfR, as well as the FDA, have used to justify maintaining the TDI for BPA at levels above what a vast amount of academic research shows to cause harm. We argue that regulatory agencies need to incorporate 21st century science into chemical hazard identifications using the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) nonguideline academic studies in a collaborative government–academic program model.Discussion: We strongly endorse EFSA’s revised TDI for BPA and support the European Commission’s (EC) apparent acceptance of this updated BPA risk assessment. We discuss challenges to current chemical risk assessment assumptions about EDCs that need to be addressed by regulatory agencies to, in our opinion, become truly protective of public health. Addressing these challenges will hopefully result in BPA, and eventually other structurally similar bisphenols (called regrettable substitutions) for which there are known adverse effects, being eliminated from all food-related and many other uses in the EU and elsewhere.
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| 7. |
- Wang, Yifan, et al.
(författare)
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The BRCA1-Δ11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP inhibition and cisplatin
- 2016
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Ingår i: Cancer Research. - 0008-5472. ; 76:9, s. 2778-2790
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Tidskriftsartikel (refereegranskat)abstract
- Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo. Furthermore, spliceosome inhibitors reduced BRCA1- Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance.
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| 8. |
- Zoeller, R. Thomas, 1952-, et al.
(författare)
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Update on Activities in Endocrine Disruptor Research and Policy
- 2019
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Ingår i: Endocrinology. - : Oxford University Press. - 0013-7227 .- 1945-7170. ; 160:7, s. 1681-1683
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Tidskriftsartikel (refereegranskat)abstract
- For nearly 15 years, the Endocrine Society has engaged in a coordinated effort to engage the issue of endocrine-disrupting chemicals (EDCs). This effort is based on an effective collaboration between scientists and physician members of the Endocrine Society and a competent and professional staff that supports membership efforts to study EDC actions and translate this knowledge to regulatory agencies. This is a brief history of these important efforts to inform the broad readership of Endocrinology.
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