A prospective whole-mixture approach to assess risk of the food and chemical exposome.

Many widely used chemicals result in ubiquitous human exposure from multiple sources, including diet. Legislation mainly deals with the toxicological evaluation of single substances owing to a methodological and conceptual lack of alternatives, and does so within defined silos subject to over 40 distinct regulations in the EU alone. Furthermore, much of the research and many of the initiatives concerned with the assessment and evaluation of chemical mixtures and their potential effects on human health rely on retrospective analysis. Here we propose an approach for the prospective identification, assessment and regulation of mixtures relevant to human health. We address two distinct aspects of toxicology-which chemicals actually do occur together, and how potential mixture-related health hazards can be predicted-with an adapted concept of the exposome and large-scale hazard screens. The proactive use of the likelihood of co-exposure, together with the new approach of methods-based testing, may be a timely and feasible way of identifying those substances and mixtures where hazards may have been overlooked and regulatory action is needed. Ideally, we would generate co-exposure patterns for specific consumer groups, depending on lifestyle and dietary habits, to assess the specific risk of identified mixtures.

Overview on legislation and scientific approaches for risk assessment of combined exposure to multiple chemicals: the potential EuroMix contribution.

This article reviews the current legislative requirements for risk assessment of combined exposure to multiple chemicals via multiple exposure routes, focusing on human health and particularly on food-related chemicals. The aim is to identify regulatory needs and current approaches for this type of risk assessment as well as challenges of the implementation of appropriate and harmonized guidance at international level. It provides an overview of the current legal requirements in the European Union (EU), the United States and Canada. Substantial differences were identified in the legal requirements for risk assessment of combined exposure to multiple chemicals and its implementation between EU and non-EU countries and across several regulatory sectors. Frameworks currently proposed and in use for assessing risks from combined exposure to multiple chemicals via multiple routes and different durations of exposure are summarized. In order to avoid significant discrepancies between regulatory sectors or countries, the approach for assessing risks of combined exposure should be based on similar principles for all types of chemicals. OECD and EFSA identified the development of harmonized methodologies for combined exposure to multiple chemicals as a key priority area. The Horizon 2020 project "EuroMix" aims to contribute to the further development of internationally harmonized approaches for such risk assessments by the development of an integrated test strategy using in vitro and in silico tests verified for chemical mixtures based on more appropriate data on potential combined effects. These approaches and testing strategies should be integrated in a scientifically based weight of evidence approach to account for complexity and uncertainty, to improve risk assessment.

Application of omics data in regulatory toxicology: report of an international BfR expert workshop.

Advances in omics techniques and molecular toxicology are necessary to provide new perspectives for regulatory toxicology. By the application of modern molecular techniques, more mechanistic information should be gained to support standard toxicity studies and to contribute to a reduction and refinement of animal experiments required for certain regulatory purposes. The relevance and applicability of data obtained by omics methods to regulatory purposes such as grouping of chemicals, mode of action analysis or classification and labelling needs further improvement, defined validation and cautious expert judgment. Based on the results of an international expert workshop organized 2014 by the Federal Institute for Risk Assessment in Berlin, this paper is aimed to provide a critical overview of the regulatory relevance and reliability of omics methods, basic requirements on data quality and validation, as well as regulatory criteria to decide which effects observed by omics methods should be considered adverse or non-adverse. As a way forward, it was concluded that the inclusion of omics data can facilitate a more flexible approach for regulatory risk assessment and may help to reduce or refine animal testing.

Assessment of three approaches for regulatory decision making on pesticides with endocrine disrupting properties.

Recent EU legislation has introduced endocrine disrupting properties as a hazard-based "cut-off" criterion for the approval of active substances as pesticides and biocides. Currently, no specific science-based approach for the assessment of substances with endocrine disrupting properties has been agreed upon, although this new legislation provides interim criteria based on classification and labelling. Different proposals for decision making on potential endocrine disrupting properties in human health risk assessment have been developed by the German Federal Institute for Risk Assessment (BfR) and other regulatory bodies. All these frameworks, although differing with regard to hazard characterisation, include a toxicological assessment of adversity of the effects, the evaluation of underlying modes/mechanisms of action in animals and considerations concerning the relevance of effects to humans. Three options for regulatory decision making were tested upon 39 pesticides for their applicability and to analyze their potential impact on the regulatory status of active substances that are currently approved for use in Europe: Option 1, based purely on hazard identification (adversity, mode of action, and the plausibility that both are related); Option 2, based on hazard identification and additional elements of hazard characterisation (severity and potency); Option 3, based on the interim criteria laid down in the recent EU pesticides legislation. Additionally, the data analysed in this study were used to address the questions, which parts of the endocrine system were affected, which studies were the most sensitive and whether no observed adverse effect levels were observed for substance with ED properties. The results of this exercise represent preliminary categorisations and must not be used as a basis for definitive regulatory decisions. They demonstrate that a combination of criteria for hazard identification with additional criteria of hazard characterisation allows prioritising and differentiating between substances with regard to their regulatory concern. It is proposed to integrate these elements into a decision matrix to be used within a weight of evidence approach for the toxicological categorisation of relevant endocrine disruptors and to consider all parts of the endocrine system for regulatory decision making on endocrine disruption.

Anatomic variability of groin innervation.

Inguinal hernia repairs are very common yet fairly complex surgical procedures.Variations in the anatomical course of the inguinal nerves require that diligence is taken in their proper recognition. Inadvertent surgical injury to these nerves is associated with long term postoperative pain and complications. The aim of the present study was to highlight the complexity and variation in the innervation of the inguinal region in order to increase proper nerve identification during surgical interventions. Bilateral dissection of the inguinal and posterior abdominal regions in one human male cadaver revealed an atypical anatomic topography of the groin innervation. This unusual case was observed at the Jagiellonian University Anatomy Department during routine cadaveric preparations. The left ilioinguinal nerve was absent. The left genital branch of the genitofemoral nerve arose higher than expected from the lumbar plexus and supplied the groin region, which is typically innervated by the ilioinguinal nerve. Furthermore, the left lateral cutaneous femoral nerve and the right genital branch of the genitofemoral nerve also followed uncharacteristic courses. Awareness of topographical nerve variations during inguinal hernia repair will help surgeons identify and preserve important nerves, thus decreasing the incidence of chronic postoperative pain.

Assessment strategies and decision criteria for pesticides with endocrine disrupting properties relevant to humans.

There is growing concern that environmental substances with a potential to modulate the hormonal system may have harmful effects on human health. Consequently, a new EU regulation names endocrine disrupting properties as one of the cut-off criteria for the approval of plant protection products, although it currently fails to provide specific science-based measures for the assessment of substances with such properties. Since specific measures are to be presented by the European Commission in 2013 the development of assessment and decision criteria is a key challenge concerning the implementation of this new EU regulation. Proposals of such decision criteria for substances with potential endocrine disrupting properties in human health risk assessment were developed by the German Federal Institute for Risk Assessment (BfR) and discussed at an expert workshop in November 2009. Under consideration of the requirements laid down within the new plant protection product legislation and the scientific discussions during the workshop, a conceptual framework on evaluation of substances for endocrine disrupting properties in a regulatory context is presented in this paper. Central aspects of the framework include assessment of adversity of effects, establishment of a mode/mechanism of action in animals, considerations concerning the relevance of effects to humans and two options for a regulatory decision.

[Plant protection products and their residues : Aspects of consumer safety in context of the new EU regulations]. / Pflanzenschutzmittel und ihre Rückstände : Aspekte der Verbrauchersicherheit im Kontext neuer EU-Verordnungen.

The law regulating plant protection products (PPP) in the European Union (EU) was fundamentally revised through the introduction of Regulation (EC) No. 1107/2009 which is due to enter into force on 14 June 2011. EU-wide harmonized maximum residue levels (MRLs) for the active substances of PPP in foods are laid down in Regulation (EC) No. 396/2005 and apply since entry into force of the regulation on 1 September 2008. The goal of both regulations is to strengthen the level of consumer protection. PPP are subject to a strict assessment of active substances, which is regulated at the EU level as well as an authorization procedure in the EU Member States. Prior to application for authorization of a PPP, the active substance(s) it contains must be included in a positive list. Tests regarding the toxicity and residue behavior of PPP must be conducted by the applicant, and the respective documents must be submitted to the authorities for evaluation. Following review of the required data, toxicological threshold values are derived, consumer exposure is assessed, and the risk to health is evaluated. The goal of this evaluation is to ensure that the use of PPP according to good plant protection practice does not have any harmful effects on human health.

Bifocal esophageal and rectal cancer palliatively treated with argon plasma coagulation.

Primary multiple neoplasms make a serious diagnostic and therapeutic problem. They occur infrequently; however, they must be considered in the diagnosis as the detection of simultaneous neoplastic foci requires change of therapeutic approach. We present a case of a patient with synchronous esophageal and rectal cancer treated at the Department of Surgery. Because of the advanced neoplastic process and concomitant diseases, the patient was qualified for minimally invasive procedures with recanalization using argon plasma coagulation to avoid injuring palliative procedures and to improve quality of life. The patient died of the primary disease without symptoms of gastrointestinal tract obstruction.

Amyand's hernia: a report of two cases.

In 2000-2001 two patients with acute appendicitis in the right inguinal hernia (Amyand's hernia) and the symptoms of incarcerated hernia were operated on in emergency. One patient with the symptoms of local peritonitis was subjected to hernioplasty and appendectomy. The second underwent midline inferior laparotomy, because of diffuse peritonitis with appendectomy and hernioplasty. Both patients were operated by Shouldice's method. None of the patients developed recurrent disease. The presented cases point to the necessity of considering acute appendicitis in the differential diagnosis of incarcerated right inguinal hernia.

Harmonisation of rat fetal skeletal terminology and classification. Report of the Third Workshop on the Terminology in Developmental Toxicology. Berlin, 14-16 September 2000.

The initial efforts of the Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV) and the Free University of Berlin to standardise terminology in the field of developmental toxicology began in 1995. Procedures were undertaken to harmonise the terminology used by the International Federation of Teratology Societies (IFTS) and the International Programme on Chemical Safety (IPCS). This article reflects these activities and is a report on the Third Workshop on the Terminology in Developmental Toxicology held in September 2000. This Workshop served as a forum to discuss the results of a survey on the classification of skeletal anomalies that had been previously sent to scientists active in the field. Although high agreement was reached among the evaluators for several terms, the use of a number of terms was rather variable. Therefore, the discussions at the workshop among the experts from research institutions, regulatory agencies, and industry were mainly focussed on those terms for which there was disagreement and/or uncertainties and the possible reasons. Pictures provided by the participants for the illustration of "grey zone" anomalies constituted the basis for detailed discussions. In many of the cases with lower agreement, decisions were facilitated by the provision of the corresponding picture. The main reasons for lower agreement were imprecise terms, insufficient knowledge on postnatal consequences, theoretical terms that are unlikely to occur in isolation, and the possibility of observing a range of severity that might be decisive for the classification of either a malformation or variation. The attendees concluded that "grey-zone" anomalies will never disappear completely and that for the assessment, the grade of severity and/or the frequency of the observation can be decisive for the terminology chosen. A Joint IPCS/IFTS Project was proposed to further consensus of terminology and classification and to link these anomalies to pictures at different skeletal sites. In order to support the harmonisation of regulatory decisions, it was proposed to establish a "Clearinghouse" System under the umbrella of the IPCS. The Clearinghouse could be contacted either by the regulatory authorities or by any company to clarify their queries, particularly with regard to registration or authorisation processes. Finally, it was recommended to also carry out a similar survey on "soft tissue anomalies" and "external findings." The results of this survey will be discussed at a Joint IPCS/IFTS Workshop in Berlin in 2002.

[A case of acute appendicitis with abdominal actinomycosis]. / Ostre zapalenie wyrostka robaczkowego wspólistniejace z promienica brzuszna.

The authors presented a rare case of acute appendicitis with abdominal actinomycosis. Diagnostic and therapeutic procedures for accidentally found abdominal actinomycosis were discussed based on current literature.

[Neurofibroma of the small intestine as a cause of massive bleeding from the gastrointestinal tract]. / Neurofibroma jelita cienkiego przyczyna masywnego krwawienia z przewodu pokarmowego.

Two cases of neoplastic tumors of small intestine, operated on because of acute abdominal signs, were described. In both cases, before ultimate surgical treatment, chronic gastro-intestinal bleeding and ileus were observed. None of routine diagnostic procedures (endoscopy and angiography) diagnosed the disease. It was the radiological contrast examination of small bowel, that solved the problem. For the reason, that neoplastic tumors of small intestine are extremely rare and symptoms are not specific, results of treatment were described. Also the mistakes in diagnostic process were analysed. Malignant lesions are very rare and they are not symptomatic, those are the reasons of delayed surgical treatment. Moreover, they are more common in older age (over 60), that makes the invasive diagnostics even more difficult because of general condition and additional loads, e.g. atherosclerosis or circulatory and respiratory failure. Literature survey underlines the fact, that difficulties in the diagnostics process lead to developing of advanced stages of neoplastics disease, which are treated because of massive bleeding ileus. Often patients are hospitalized many times before the ultimate surgery, but are discharged without right diagnosis. Therefore the retrospective analysis of our cases can be useful in future for the proper interpretation of clinical signs.

[Hemangiopericytoma localized in the peritoneum]. / Haemangiopericytoma o wewnatrzotrzewnowej lokalizacji.

The authors present a rare case of intraperitoneal haemangiopericytoma. Diagnostic and therapeutic procedures were discussed based on current literature.

[Defense mechanisms in the peritoneum]. / Mechanizmy odpornosciowe otrzewnej.

There are many specialised defence mechanisms connected with immunity of peritoneal cavity. These are absorbtion of bacteria and their toxins from peritoneum, phagocytosis, opsonization, activation of the complement and separation of infection in the peritoneal cavity. A very important role in defence mechanisms of peritoneal cavity play GALT and PALT. Among many cells of the immune system mastocytes and gamma delta T cells have important role in induction and regulation of immune mechanisms in the peritoneal cavity. Lymphocytes T gamma delta release many cytokines and chemokines what allows them to play their protecting role during peritonitis. Released cytokines (especially IFN-gamma) activate macrophages to produce and secret many proinflammatory cytokines and factors. On the other hand mast cells play their role in defence of peritoneal cavity via TNF-alpha and histamine release and inhibition of fibrynolysis.

Standard values for reproductive and clinical chemistry parameters of Japanese quail.

Historical control data of Japanese quail collected from reproduction studies conducted at the Federal Institute for Health Protection of Consumers and Veterinary Medicine between 1988 and 1994 are presented in this paper. Reproductive and clinical chemistry data from control animals of 10 ecotoxicological studies are summarized and discussed to develop a normal data base of this species. The data obtained were compared to the control reproductive parameters of bob-white quail and mallard ducks available in the literature. For a long time these two species have been most used in avian reproductive toxicology studies. In summary, the data obtained indicate that Japanese quail appears to be more appropriate to be used for the determination of reproductive effects of pesticides on birds.