A plea for risk assessment of endocrine disrupting chemicals

Some recent EU Regulations have focused on the potential risks posed by the presence of endocrine disrupters (ED) into the environment. However there are conflicting opinions on how to assess the risk from exposure to these molecules that can reversibly modulate hormonal activity, endocrine active substances (EAS) rather than causing irreversible damage (ED).The present paper attempts to discuss that perturbation of normal endocrine homeostasis in itself may not be an adverse effect, since the endocrine system is naturally dynamic and responsive to various stimuli as part of its normal function and it is modulated according to the characteristic trend of the dose–response curve.EDs should be evaluated using a weight-of-evidence (WoE) approach. If a chemical meets the criteria to be defined as an ED in experimental animals, the relevance of observed effects to the human then needs to be addressed.Hazard-based risk management is therefore not justified since does not meet the criteria for a sound scientifically based assessment.     

ECETOC florence workshop on risk assessment of endocrine substances,including the potency concept

The European regulation on plant protection products (1107/2009) and the Biocidal Products Regulation (EC Regulation 528/2012) only support the marketing and use of chemicals if they do not cause endocrine disruption in humans or wildlife species. Also, substances with endocrine properties are subject to authorization under the European regulation on the registration, evaluation, authorization and restriction of chemicals (REACH; 1907/2006).     

Outline on risk assessment programme of existing substances in the European Union

Various programmes have been developed by national and international organisations to improve chemical safety of existing substances. The European Union Programme came into force on 4 June 1993. This programme gives a legal requirement that the manufacturer or the importer has to deliver data on substances produced or imported. The risk assessment process in the EU provides that every member state formally selects priority substances. To perform the risk characterisation for a priority substance, exposure assessment and the dose (concentration)-response (effect) assessment are conducted. Comparing the information on exposure to the effects identified by a hazard identification of the substance the risk assessor has to decide whether there is or there is no need for further information or testing or whether there is need for limiting the risks. The draft risk assessment report is sent to the OECD as European contribution to the programme on existing substances for discussion with OECD-member countries. A final decision on the substance is performed by the member states of the European Union.     

About hazard and risk assessment: Regulatory approaches in assessing safety in the European Union chemicals legislation

Hazard classification and labelling is the main and basic requirement for all industrial and consumer chemicals in the European Union, if they are not regulated under more specific legislation such as drugs, food ingredients or cosmetics. The first approach in hazard classification is hazard identification describing the hazardous properties of chemicals. Refinements in the classification criteria include the assessment of toxic potency (hazard characterisation) where feasible and the possibility to set higher or lower specific concentration limits for classification. In the past only a minor portion of the classified chemicals underwent a risk assessment including exposure assessment and risk characterisation. Risk assessment will become more frequent with the implementation of REACH. However, as risk assessment is rather labour-intensive even under REACH risk assessment will be performed in a targeted approach for a selected number of chemical substances while hazard classification and labelling will remain the basic approach for all chemicals.     

Refinement of the ECETOC approach to identify endocrine disrupting properties of chemicals in ecotoxicology

To use and implement an assessment scheme for the evaluation of endocrine disrupting properties of chemicals in ecotoxicology, the types of effect need to be agreed. Effects that merit further consideration in this context should fulfil the following three criteria: caused by an endocrine mode of action, be adverse, and be relevant at the population level to reflect the protection goal of ecotoxicological assessments. Thereafter, a comparison of effect values, regardless of the causative mechanisms, should be made, firstly to determine if endocrine toxicity generates the lowest endpoint within a taxon, and secondly if it is the lowest endpoint compared to that of other taxa living in the same compartment. These comparisons inform on two levels of specificity and determine if endocrine-mediated side-effects determine the ecotoxicological profile of a chemical. Various quantitative measures for the assessment of potency are also presented, which could assist in determining how to handle substances in the risk assessment when a regulatory concern is identified. Finally, derogation criteria should be defined for compounds that were designed as endocrine disruptors for non-vertebrates and those for which there is ‘negligible exposure’. This paper discusses and provides proposals on how to apply these concepts for assessment of substances.     

Assessment of user safety, exposure and risk to veterinary medicinal products in the European Union

Safety is an important part of veterinary drug assessment while user safety is a critical part of the overall safety assessment. In the European Union (EU), user safety is addressed through preclinical studies and by relationships with exposure but a key part of the process is the user safety assessment. EU user safety guidelines are available and these make certain recommendations but in places they lack detail and clarity. This paper seeks to examine the relevant factors that lie behind user risk assessments for veterinary medicinal products in general while focusing on EU requirements, the determination of risk management and risk communication strategies and how this relates to user safety assessment and pharmacovigilance responsibilities.     

Hurdles of environmental risk assessment procedures for advanced therapy medicinal products: comparison between the European Union and the United States

Abstract

An environmental risk assessment (ERA) consists of an analysis of the risks to human health and the environment that a medicinal product may cause due to its release during clinical development or after entering the market. Regulators in European Union (EU) and the United States (US) require that advanced therapy medicinal products (ATMPs) that are also genetically modified organisms (GMOs) undergo an ERA in order to be approved for marketing authorization. This work aims to review the regulatory issues that need to be taken into consideration for carrying out an ERA, comparing the EU and the US. The European regulatory framework for environmental procedures and the dissimilarities in its implementation across the Member States and its implications at a logistical level are analyzed in detail. In addition, this review provides a brief insight into the non-clinical and clinical assessments that should be carried out during the development of the product in order to conduct a successful ERA, and thus facilitate its marketing authorization and post-marketing monitoring. Finally, the need for a European harmonization regarding environmental procedures for ATMPs is discussed.     

Framework for integrating human and animal data in chemical risk assessment

Although regulatory agencies formally encourage the integration of all available data in chemical risk assessment, consistent implementation of this practice has been constrained by the lack of a clear, systematic method for doing so. In this paper, we describe a methodology for evaluating, classifying and integrating human and animal data into the risk assessment process that incorporates: (1) a balanced appraisal of human and animal data, (2) relevance to different stages of the risk assessment process, and (3) accommodation for different data quality requirements. The proposed framework offers a flexible, step-wise approach for determining which set of available data best support the chemical risk assessment that involves the rating and relative ranking of human and animal data quality. The evaluation of human data incorporates seven data quality elements, nature and specificity of the lead effect; evaluation of animal data incorporates data quality and relevance to humans. Results of simulations with selected chemicals previously evaluated in a formal risk assessment generally agreed with existing regulatory guidance. Application of the proposed framework across a wider range of chemical agents will improve transparency of the risk assessment process and validity of results, while informing continuous refinements to this evolving methodology.     

Investigation of endocrine disruptor pollutants and their metabolites along the Romanian Black Sea Coast: Occurrence,distribution and risk assessment

In recent years, the occurrence of organic UV-filters (UVFs) and bisphenol derivatives (BPs) in the marine environment has raised high concerns all over the world, due to the potentially adverse impacts on marine organism and, indirectly on human health. This paper reports, for the first time in Romania, the occurrence, distribution pattern and environmental risk assessment of UVFs, BPs and their metabolites in seawater, sediment and algae collected from the Romania Black Sea coastal region. BP-3 (2-hydroxy-4-methoxy-benzophenone) was the most abundant contaminant in seawater samples, with detection frequency of 100 %. Sediment samples were dominated by ES (Ethylhexyl salicylate), with concentration values up to 5823 ng/g d.w., while for algae, concentrations of several hundreds of ng/g d.w. were determined for BP-3, BS (Benzyl salicylate) and BPE (Bisphenol E). Environmental risk assessment revealed that some UVFs and BPs detected in seawater samples were hazardous to the marine organism of the Black Sea.     

Variability in toxic response - relevance to chemical safety and risk assessment at the global level

The aim of control limits for exposure to chemicals in air, food, water, and consumer products is to protect the whole human population, including the most susceptible individuals and ‘at risk’ groups. The existence of susceptible individuals is a factor that must be taken into account when quantitative chemical risk assessments are being made, and should be covered in the risk characterization. Classically, when extrapolating data derived from animal experiments using homogeneous, healthy test species for human health risk assessment uncertainty factors are applied. For inter-species extrapolation an uncertainty factor of up to 10 is applied. While it is evident that this procedure provides reasonable protection for the great majority of the population there are outlyers who may not be protected under all conditions. Within a population, individual susceptibility is influenced by genetic and environmental factors. These have regional and national differences. Environmental factors that are important in many countries include ‘life-style’ (e.g. tobacco and alcohol consumption, diet), nutritional and health status. In the case of environmental protection similar considerations apply but the emphasis is on species rather than individuals. The International Programme on Chemical Safety, as the global programme on identifying and assessing chemical risks to human health and the environment in order to assist countries in effective management, is constantly advancing the basic science and methodology for making chemical risk assessment.     

Update of risk assessments of main marine biotoxins in the European Union

This review is an up-to-date compilation of the available literature, including scientific papers, reviews, and EFSA’s opinions, on toxicity and risk assessment data on the main marine biotoxins of importance in the European Union, including the legislated ones and the ones of recent appearance which are not legislated. Information about the hazard identification and hazard characterisation of okadaic acid, dynophysistoxins, pectenotoxins, yessotoxins, azaspiracids, domoic acid, saxitoxins, tetrodotoxins, brevetoxins, ciguatoxins, cyclic imines and palytoxins is reviewed and presented in the form of a collection of risk assessments. It is concluded that the importance of having an appropriate exposure assessment reiterates the urgency of establishing a database with representative and comparable data on exposure to food items possiby containing marine biotoxins. It is also concluded that a revision of the present regulation of marine biotoxins in the EU legislation could be considered, as some regulated toxins have been shown not to pose a risk for EU’s population (as yessotoxin) and some non regulated toxins have been shown to be harmful and/or to occur in the EU (as tetrodotoxin, palytoxin, and some cyclic imines) while they are not regulated.     

Chironomids: suitable test organisms for risk assessment investigations on the potential endocrine disrupting properties of pesticides

Selecting an appropriate invertebrate assay has been a primary goal of national and international testing programs for endocrine disrupting chemicals. The available information on the endocrine system, its hormones and their modes of action in controlling physiological processes in invertebrates is limited and the selection of appropriate test species still presents a challenge. This paper outlines the development of a higher-tier full life cycle (FLC) test for pesticides with the non-biting midge Chironomus riparius (Insecta, Diptera, Chironomidae). As an insect, C. riparius represents the species’ richest and ecologically one of the most important groups of invertebrates. In addition, the endocrine system of insects is one of the best studied among the invertebrates. Acute and chronic tests with Chironomus spp. are commonly used for testing and risk assessment of agrochemicals. A chironomid FLC test protocol has been developed and its suitability investigated in an inter-laboratory comparison. The protocol used is based on existing OECD and US-EPA test methods. To verify the suitability of the test to generate endpoints that encompass adverse effects on the arthropod endocrine system, a juvenile hormone analog was selected as positive control substance. Results have demonstrated that the proposed chironomid FLC can be performed in separate laboratories and that the selected arthropod juvenile hormone mimic causes effects. However, the observed toxicity is not proof of an endocrine disruptive mechanism and could equally be evoked by other compounds. Contrary to a screening assay, which aims at revealing a substance’s mode-of-action, the FLC test generates robust, population-relevant endpoints that can be used in the risk assessment of agrochemicals. Since the initial results presented in this paper are encouraging we propose to complete the validation of this assay under OECD with high priority.     

欧盟药品上市后安全性研究监管体系分析与思考

效益风险评估贯穿于药品整个的生命周期。为保障药品全生命周期最佳效益风险比,识别并针对药品风险因素采取适宜的风险最小化措施,积极开展药品上市后安全性研究尤为重要。欧洲药品管理局（European Medicines Agency,EMA）为了量化药品的安全隐患,基于评估药物的效益风险状况并支持监管决策而开展上市后安全性研究（postauthorisation safety study,PASS）,为保障其顺利开展而形成一套成熟的体系及监管流程。通过分析EMA开展PASS的制度及流程,提出建立健全监管体系、制定PASS指南及实施细则以及建立共享平台是丰富完善我国上市后安全评价体系的有效方式。     

Alternative methods to safety studies in experimental animals: role in the risk assessment of chemicals under the new European Chemicals Legislation (REACH)

During the last two decades, substantial efforts have been made towards the development and international acceptance of alternative methods to safety studies using laboratory animals. In the EU, challenging timelines for phasing out of many standard tests using laboratory animals were established in the seventh Amending Directive 2003/15/EC to Cosmetics Directive 76/768/EEC. In continuation of this policy, the new European Chemicals Legislation (REACH) favours alternative methods to conventional in vivo testing, if validated and appropriate. Even alternative methods in the status of prevalidation or validation, but without scientific or regulatory acceptance may be used under certain conditions. Considerable progress in the establishment of alternative methods has been made in some fields, in particular with respect to methods predicting local toxic effects and genotoxicity. In more complex important fields of safety and risk assessment such as systemic single and repeated dose toxicity, toxicokinetics, sensitisation, reproductive toxicity and carcinogenicity, it is expected that the development and validation of in silico methods, testing batteries (in vitro and in silico) and tiered testing systems will have to overcome many scientific and regulatory obstacles which makes it extremely difficult to predict the outcome and the time needed. The main reasons are the complexity and limited knowledge of the biological processes involved on one hand and the long time frame until validation and regulatory acceptance of an alternative method on the other. New approaches in safety testing and evaluation using "Integrated Testing Strategies" (ITS) (including combinations of existing data, the use of chemical categories/grouping, in vitro tests and QSAR) that have not been validated or not gained wide acceptance in the scientific community and by regulatory authorities will need a thorough justification of their appropriateness for a given purpose. This requires the availability of knowledge and experience of experts in toxicology. The challenging deadlines for phasing out of in vivo tests in the Cosmetics Amending Directive 2003/15/EC appear unrealistic. Likewise, we expect that the application of validated alternative methods will only have a small or moderate impact on the reduction of in vivo tests under the regimen of REACH, provided that at least the same level of protection of human health as in the past is envisaged. As a consequence, under safety aspects, it appears wise to consider established in vivo tests to be indispensable as basic tools for hazard and risk assessment with respect to systemic single and repeated dose toxicity, sensitisation, carcinogenicity and reproductive toxicity, especially regarding quantitative aspects of risk assessment such as NOAELs, LOAELs and health-related limit values derived from them. Based on the overall evaluation in this review, the authors are of the opinion that in the short- and mid-term, the strategy of the development of alternative methods should be more directed towards the refinement or reduction of in vivo tests. The lessons learnt during these efforts will provide a substantial contribution towards the replacement initiatives in the long-term.     

Animal testing and alternative approaches for the human health risk assessment under the proposed new European chemicals regulation

During the past 20 years the EU legislation for the notification of chemicals has focussed on new chemicals and at the same time failed to cover the evaluation of existing chemicals in Europe. Therefore, in a new EU chemicals policy (REACH, Registration, Evaluation and Authorisation of Chemicals) the European Commission proposes to evaluate 30,000 chemicals within a period of 15 years. We are providing estimates of the testing requirements based on our personal experiences during the past 20 years. A realistic scenario based on an in-depth discussion of potential toxicological developments and an optimised tailor-made testing strategy shows that to meet the goals of the REACH policy, animal numbers may be significantly reduced below 10 million if industry would use in-house data from toxicity testing, which are confidential, if non-animal tests would be used, and if information from quantitative structure activity relationships (QSARs) would be applied in substance-tailored testing schemes. The procedures for evaluating the reproductive toxicity of chemicals have the strongest impact on the total number of animals bred for testing under REACH. We are assuming both an active collaboration with our colleagues in industry and substantial funding of the development and validation of advanced non-animal methods by the EU Commission, specifically in reproductive and developmental toxicity.     

Approaches in the risk assessment of genetically modified foods by the Hellenic Food Safety Authority.

Risk analysis has become important to assess conditions and take decisions on control procedures. In this context it is considered a prerequisite in the evaluation of GM food. Many consumers worldwide worry that food derived from genetically modified organisms (GMOs) may be unhealthy and hence regulations on GMO authorisations and labelling have become more stringent. Nowadays there is a higher demand for non-GM products and these products could be differentiated from GM products using the identity preservation system (IP) that could apply throughout the grain processing system. IP is the creation of a transparent communication system that encompasses HACCP, traceability and related systems in the supply chain. This process guarantees that certain characteristics of the lots of food (non-GM origin) are maintained "from farm to fork". This article examines the steps taken by the Hellenic Food Safety Authority to examine the presence of GMOs in foods. The whole integrated European legislation framework currently in place still needs to be implemented in Greece. Penalties should be enforced to those who import, process GMOs without special licence and do not label those products. Similar penalties should be enforced to those companies that issue false certificates beyond the liabilities taken by the food enterprises for farmers' compensation. We argue that Greece has no serious reasons to choose the use of GMOs due to the fact that the structural and pedologic characteristics of the Greek agriculture favour the biological and integrated cultivation more. Greece is not in favour of the politics behind coexistence of conventional and GM plants and objects to the use of GMOs in the food and the environment because the processor has a big burden in terms of money, time and will suffer a great deal in order to prove that their products are GMO free or that any contamination is adventitious or technically unavoidable. Moreover, Greece owns a large variety of genetic material that should try to protect from patenting and commercialisation. Finally, we should be aware of the requirements of movement of GMOs within borders, i.e. GMOs grown or used in other countries but which are not intended to cross into Greece, since Greece is very close to countries that are non-EU. This is where the development of a new, integrated, trustworthy and transparent food quality control system will help to satisfy the societal demands for safe and quality products. On the other hand, Greece should not be isolated from any recent scientific technological development and should assess the possible advantages for some cultivation using a case by case approach. Finally, the safety assessment of GM foods and feed has been discussed according to the risk assessment methodology applied by EFSA.     

Identification,assessment and management of “endocrine disruptors” in wildlife in the EU substance legislation—Discussion paper from the German Federal Environment Agency (UBA)

A discussion paper was developed by a panel of experts of the German Federal Environment Agency (UBA) contributing to the on-going debate on the identification, assessment and management of endocrine disruptors with a view to protect wildlife according to the EU substance legislation (plant protection products, biocides, industrial chemicals). Based on a critical synthesis of the state-of-the-art regarding regulatory requirements, testing methods, assessment schemes, decision-making criteria and risk management options, we advise an appropriate and consistent implementation of this important subject into existing chemicals legislation in Europe. Our proposal for a balanced risk management of endocrine disruptors essentially advocates transparent regulatory decision making based on a scientifically robust weight of evidence approach and an adequate risk management consistent across different legislations. With respect to the latter, a more explicit consideration of the principle of proportionality of regulatory decision making and socio-economic benefits in the on-going debate is further encouraged.     

Occurrence and risk assessment of estrogenic compounds in the East Lake,China

Forty two surface water samples were collected in May and June of 2013 in five lakelets of the East Lake, China. Four steroid hormones (17β-estradiol (βE2), estrone (E1), 17α-estradiol (αE2) and 17α-ethinylestradiol (αEE2)) were analyzed in these samples. Determination of four estrogenic compounds was performed on high performance liquid chromatography/mass spectrometry (HPLC/MS). βE2 was detected with the highest detection frequency of 62% and its concentration range was from nd to 17.58 ng/L. The mean total concentration of four compounds increased with the order: Houhu lake (L5) (8.91 ng/L) < Niuchao lake (L1) (19.92 ng/L) < Guozheng lake (L2) (20.03 ng/L) < Tangling lake (L4) (22.65 ng/L) < Guandu lake (L3) (35.68 ng/L). Pollution sources of four compounds were mainly from municipal wastewater and water washed out from farm land fertilized with the waste of livestock or irrigated with water from livestock farm. The proportion of sample sites at high risk that compounds had effect on fish population were 58.3% in Guozheng (L2) lake, 100% in Guandu (L3) lake, and 62.5% in Tangling (L4), Niuchao (L1) and Houhu (L5) lake, respectively. The mean βE2 equivalent concentrations was at relatively high levels in L3 with 8.6 ng/L, L1 with 6.1 ng/L, L4 with 4.62 ng/L, L2 with 4.58 ng/L and L5 with 2.62 ng/L, respectively. Meanwhile, sampling sites at high risk generally were surrounded with hospitals, hotels and residential buildings where had high population density.     

The usefulness of the bioconcentration factor as a tool for priority setting in chemicals control

The implementation of the REACH system will lead to the creation of a single, uniform legislation for industrial chemicals in Europe. An important aim of this legislation is to generate toxicity data for previously untested chemicals. Testing tens of thousands of chemicals can however not be done in one step, and criteria for priority setting is therefore an essential part of the proposed REACH system. In this study we investigate potential consequences of using bioaccumulation (B) data as a tool for priority setting in chemicals control. The results of this investigation suggests that the use of data for the bioconcentration factor (BCF, as an estimation of B) at first tier will not introduce bias towards a particular type of toxicity (i.e. carcinogenicity, reproductive toxicity or mutagenicity) in the priority setting process.     

A framework for cumulative risk assessment in the 21st century

The ILSI Health and Environmental Sciences Institute (HESI) has developed a framework to support a transition in the way in which information for chemical risk assessment is obtained and used (RISK21). The approach is based on detailed problem formulation, where exposure drives the data acquisition process in order to enable informed decision-making on human health safety as soon as sufficient evidence is available. Information is evaluated in a transparent and consistent way with the aim of optimizing available resources. In the context of risk assessment, cumulative risk assessment (CRA) poses additional problems and questions that can be addressed using the RISK21 approach. The focus in CRA to date has generally been on chemicals that have common mechanisms of action. Recently, concern has also been expressed about chemicals acting on multiple pathways that lead to a common health outcome, and non-chemical other conditions (non-chemical stressors) that can lead to or modify a common outcome. Acknowledging that CRAs, as described above, are more conceptually, methodologically and computationally complex than traditional single-stressor risk assessments, RISK21 further developed the framework for implementation of workable processes and procedures for conducting assessments of combined effects from exposure to multiple chemicals and non-chemical stressors. As part of the problem formulation process, this evidence-based framework allows the identification of the circumstances in which it is appropriate to conduct a CRA for a group of compounds. A tiered approach is then proposed, where additional chemical stressors and/or non-chemical modulating factors (ModFs) are considered sequentially. Criteria are provided to facilitate the decision on whether or not to include ModFs in the formal quantitative assessment, with the intention to help focus the use of available resources to have the greatest potential to protect public health.