Toxicology and Epidemiology: Improving the Science with a Framework for Combining Toxicological and Epidemiological Evidence to Establish Causal Inference

Historically, toxicology has played a significant role in verifying conclusions drawn on the basis of epidemiological findings. Agents that were suggested to have a role in human diseases have been tested in animals to firmly establish a causative link. Bacterial pathogens are perhaps the oldest examples, and tobacco smoke and lung cancer and asbestos and mesothelioma provide two more recent examples. With the advent of toxicity testing guidelines and protocols, toxicology took on a role that was intended to anticipate or predict potential adverse effects in humans, and epidemiology, in many cases, served a role in verifying or negating these toxicological predictions. The coupled role of epidemiology and toxicology in discerning human health effects by environmental agents is obvious, but there is currently no systematic and transparent way to bring the data and analysis of the two disciplines together in a way that provides a unified view on an adverse causal relationship between an agent and a disease. In working to advance the interaction between the fields of toxicology and epidemiology, we propose here a five-step "Epid-Tox” process that would focus on: (1) collection of all relevant studies, (2) assessment of their quality, (3) evaluation of the weight of evidence, (4) assignment of a scalable conclusion, and (5) placement on a causal relationship grid. The causal relationship grid provides a clear view of how epidemiological and toxicological data intersect, permits straightforward conclusions with regard to a causal relationship between agent and effect, and can show how additional data can influence conclusions of causalit

Toxicology and Epidemiology: Improving the Science with a Framework for Combining Toxicological and Epidemiological Evidence to Establish Causal Inference

Historically, toxicology has played a significant role in verifying conclusions drawn on the basis of epidemiological findings. Agents that were suggested to have a role in human diseases have been tested in animals to firmly establish a causative link. Bacterial pathogens are perhaps the oldest examples, and tobacco smoke and lung cancer and asbestos and mesothelioma provide two more recent examples. With the advent of toxicity testing guidelines and protocols, toxicology took on a role that was intended to anticipate or predict potential adverse effects in humans, and epidemiology, in many cases, served a role in verifying or negating these toxicological predictions. The coupled role of epidemiology and toxicology in discerning human health effects by environmental agents is obvious, but there is currently no systematic and transparent way to bring the data and analysis of the two disciplines together in a way that provides a unified view on an adverse causal relationship between an agent and a disease. In working to advance the interaction between the fields of toxicology and epidemiology, we propose here a five-step “Epid-Tox” process that would focus on: (1) collection of all relevant studies, (2) assessment of their quality, (3) evaluation of the weight of evidence, (4) assignment of a scalable conclusion, and (5) placement on a causal relationship grid. The causal relationship grid provides a clear view of how epidemiological and toxicological data intersect, permits straightforward conclusions with regard to a causal relationship between agent and effect, and can show how additional data can influence conclusions of causality

Die Notverordnungen des kroatischen Präsidenten aus den Jahren 1991 und 1992

U radu se razmatraju uredbe iz nužde koje je donio predsjednik Republike Franjo Tuđman u drugoj polovici 1991. i početkom 1992. godine u vrijeme otvorene agresije na Republiku Hrvatsku. Glavnina uredbi donesena je 10. rujna 1991., a do kraja 1991. godine donesene su gotovo sve uredbe iz nužde. Uredbama su regulirani klasični državni resori poput pravosuđa, unutarnjih poslova i vojske, no velik dio uredbi regulirao je i javne službe te gospodarstvo.At the beginning, this paper gives a brief notional historical overview of emergency decrees, after which follows a reconstruction of events in 1990 that led to the introduction of articles 17 and 101 of the Constitution of the Republic of Croatia as Constitutional decrees relating to states of emergency. The central part of the paper deals with emergency decrees passed by the Croatian President Franjo Tuđman at the time of the open aggression against the Republic of Croatia in the second half of 1991 and the beginning of 1992. In this section, using sources, especially the minutes of the Commission for Constitutional Matters of the Croatian Partliament and the minutes of the plenary sessions of the Croatian Parliament, and also relevant literature, the paper sheds light on the circumstances under which the decrees were passed and approved by the Croatian Parliament, and thus provides a new interpretation of the decrees. After discussing the circumstances under which the decrees were passed, the author deals with various aspects of the decrees\u27 content, first noting the basic characteristics of the decrees, and then classifying them according to fields, such as: internal affairs, defense and justice, and also those covering public services and the economy. While discussing particular decrees the author sets out only the main provisions of the decrees with a view to presenting their basic characteristics, such as the limitation of constitutional rights and the centralisation of public services and of the economy. In the last part of the paper, the author analyzes the constitutionality of the decrees and their lifting. The question of whether the Parliament could convene is paramount in considering the constitutionality of the decrees, since this is important in establishing whether the President of the Republic had the power to pass decrees limiting constitutional rights. The author also considers the decision of the Constitutional Court to approve the constitutionality of the decrees. The lifting of the decrees is analyzed with special consideration given to the circumstances leading to this.Am Anfang dieser Arbeit wird eine kurze begriffshistorische Übersicht über die Notverordnungen präsentiert, wonach rekonstruiert wird, wie die den Ausnahmezustand regelnden Artikel 17 und 101 der Verfassung der Republik Kroatien von 1990 zustande kamen. Der zentrale Teil dieser Arbeit befasst sich mit den Notverordnungen, die der damalige kroatische Staatspräsident Franjo Tuđman während des offenen Angriffskrieges gegen die Republik Kroatien in der zweiten Hälfte des Jahres 1991 und Anfang 1992 erließ. Dabei wird versucht, anhand des Quellenstudiums, vor allem der Niederschriften zur Arbeit der parlamentarischen Kommission für Verfassungsfragen, der Protokolle zu den Plenarsitzungen des Parlaments der Republik Kroatien (Sabor), aber auch unter Rückgriff auf die entsprechende Literatur die Umstände des Erlasses der Notverordnungen sowie ihrer Bestätigung durch den Sabor zu beleuchten und auf diese Weise einen Beitrag zur Reinterpretation der betreffenden Verordnungen zu leisten. Nach einer dementsprechenden Klärung werden die inhaltlichen Aspekte der Verordnungen dargestellt, indem zunächst deren Hauptmerkmale bestimmt werden und danach eine Zuordnung zum Bereich des Inneren, der Verteidigung und der Justiz beziehungsweise zum Bereich der öffentlichen Aufgaben und der Wirtschaft erfolgt. Innerhalb der Darstellung einzelner Verordnungen versuchen wir, lediglich ihre wesentlichen Bestimmungen zu präsentieren, an denen die wichtigsten Merkmale wie die Beschränkung der Verfassungsrechte und die Zentralisierung der öffentlichen Aufgaben und der Wirtschaft deutlich werden. Im letzten Teil der Arbeit werden die Verfassungskonformität der Verordnungen und das Ende ihrer Gültigkeit analysiert. Die Verfassungsmäßigkeit der Verordnungen wird in erster Linie unter dem Aspekt untersucht, ob das Parlament hätte zusammentreten können, wovon schließlich die Zuständigkeit des Präsidenten der Republik für das Erlassen von verfassungsrechtsbeschränkenden Verordnungen abhing. Ebenfalls wird die Entscheidung des Verfassungsgerichts besprochen, in der es den Verordnungen Verfassungsmäßigkeit bescheinigt. Die Aufhebung der Verordnungen wird hinsichtlich der dafür verantwortlichen Umstände analysiert

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Human exposure to synthetic endocrine disrupting chemicals (S-EDCs) is generally negligible as compared to natural compounds with higher or comparable endocrine activity : How to evaluate the risk of the S-EDCs?

publishe

Human exposure to synthetic endocrine disrupting chemicals (S-EDCs) is generally negligible as compared to natural compounds with higher or comparable endocrine activity : how to evaluate the risk of the S-EDCs?

Theoretically, both synthetic endocrine disrupting chemicals (S-EDCs) and natural (exogenous and endogenous) endocrine disrupting chemicals (N-EDCs) can interact with endocrine receptors and disturb hormonal balance. However, compared to endogenous hormones, S-EDCs are only weak partial agonists with receptor affinities several orders of magnitude lower. Thus, to elicit observable effects, S-EDCs require considerably higher concentrations to attain sufficient receptor occupancy or to displace natural hormones and other endogenous ligands. Significant exposures to exogenous N-EDCs may result from ingestion of foods such as soy-based diets, green tea and sweet mustard. While their potencies are lower as compared to natural endogenous hormones, they usually are considerably more potent than S-EDCs. Effects of exogenous N-EDCs on the endocrine system were observed at high dietary intakes. A causal relation between their mechanism of action and these effects is established and biologically plausible. In contrast, the assumption that the much lower human exposures to S-EDCs may induce observable endocrine effects is not plausible. Hence, it is not surprising that epidemiological studies searching for an association between S-EDC exposure and health effects have failed. Regarding testing for potential endocrine effects, a scientifically justified screen should use in vitro tests to compare potencies of S-EDCs with those of reference N-EDCs. When the potency of the S-EDC is similar or smaller than that of the N-EDC, further testing in laboratory animals and regulatory consequences are not warranted.publishe

The EU chemicals strategy for sustainability : in support of the BfR position

The EU chemicals strategy for sustainability (CSS) asserts that both human health and the environment are presently threatened and that further regulation is necessary. In a recent Guest Editorial, members of the German competent authority for risk assessment, the BfR, raised concerns about the scientific justification for this strategy. The complexity and interdependence of the networks of regulation of chemical substances have ensured that public health and wellbeing in the EU have continuously improved. A continuous process of improvement in consumer protection is clearly desirable but any initiative directed towards this objective must be based on scientific knowledge. It must not confound risk with other factors in determining policy. This conclusion is fully supported in the present Commentary including the request to improve both, data collection and the time-consuming and bureaucratic procedures that delay the publication of regulations.publishe

Corrigendum to “Critique of the “Comment” etitled “Pyrethroid exposure: not so harmless after all” by Demeniex et al. (2020) published in the lancet diabetes endocrinology"

The authors regret that the letter inaccurately refers to “the lancet diabetes endocrinology” and “The Lancet” while it should read: “The Lancet Diabetes & Endocrinology”. The correct title of the letter should read: “Critique of the “Comment” entitled: “Pyrethroid exposure: Not so harmless after all” by Demeneix et al. (2020) published in The Lancet Diabetes & Endocrinology”. The authors wish to clarify that the comment was published in The Lancet Diabetes & Endocrinology and not The Lancet. The authors also wish to clarify that The Lancet Diabetes & Endocrinology chose not to publish their criticism of the article because the correspondence content published in The Lancet Diabetes & Endocrinology is only accepted within 8 weeks of publication of the original item