An approach for the delineation of a generic cut-off value for local respiratory tract irritation by irritating or corrosive substances as a pragmatic tool to fulfill REACH requirements

Under the current European legislation for the Registration, Evaluation, Authorisation and restriction of Chemicals (REACHs) a Derived No Effect Level (DNEL) has to be delineated for acute and chronic inhalation effects. The majority of available experimental studies are performed by the oral route of exposure. Route to route extrapolation poses particular problems for irritating or corrosive substances but the necessity for additional animal studies with inhalation exposure needs to be balanced with the regulatory information requirements. Existing occupational exposure limits (OEL) as surrogate for cut-off limits representing safe exposure under working conditions were grouped under certain criteria for substances that are legally classified in Europe as irritating or corrosive. As a result, it was shown that the OEL for irritating substances in this dataset is not lower than 10 mg/m³ and for corrosives not lower than 1 mg/m³. Under certain conditions these generic limits could be applied as a pragmatic, but still sufficiently reliable and protective upper cut-off limit approach to avoid additional animal tests with irritating or corrosive chemicals. The respective systemic toxicity profiles and physical–chemical properties need to be considered. Specific exclusion criteria for the discussed concept apply.     

Review of REACH Annex IV – Establishing the minimum risk of a substance based on its intrinsic properties

Registration is the main mechanism in REACH that ensures the safety of substances. However, some substances are exempted from Registration, such as those included in Annex IV. Annex IV lists substances that are exempted from Registration on the basis that ‘sufficient information is known about these substances that they are considered to cause minimum risk because of their intrinsic properties’. As part of the follow up to the co-decision process on REACH, the Commission was mandated to review Annex IV. To enable consideration of whether additional substances should be added to Annex IV and whether substances currently in the Annex should remain, the Commission, together with stakeholders, operationalised the core concepts of minimum risk and sufficient information in the form of criteria. These criteria consider the intrinsic properties of the substance and are based on the classification criteria in Annex VI of Directive 67/548/EEC but were set at a level ‘well below’ the classification criteria to correspond with a minimum risk level. As a result of the review, Annex IV has been recently amended. This paper looks at how the agreed criteria demonstrate minimum risk and concludes that, although developed in the frame of REACH registration, they could be more widely used in the sound management of chemicals.     

Using Biomonitoring Equivalents to interpret human biomonitoring data in a public health risk context

Increasingly sensitive analytical tools allow measurement of trace concentrations of chemicals in human biological media in persons from the general population. Such data are being generated by biomonitoring programs conducted by the US Centers for Disease Control and other researchers. However, few screening tools are available for interpretation of such data in a health risk assessment context. This review describes the concept and implementation of Biomonitoring Equivalents (BEs), estimates of the concentration of a chemical or metabolite in a biological medium that is consistent with an existing exposure guidance value such as a tolerable daily intake or reference dose. The BE approach integrates available pharmacokinetic data to convert an existing exposure guidance value into an equivalent concentration in a biological medium. Key concepts regarding the derivation and communication of BE values resulting from an expert workshop held in 2007 are summarized. BE derivations for four case study chemicals (toluene, 2,4‐dichlorophenoxyacetic acid, cadmium and acrylamide) are presented, and the interpretation of biomonitoring data for these chemicals is presented using the BE values. These case studies demonstrate that a range of pharmacokinetic data and approaches can be used to derive BE values; fully developed physiologically based pharmacokinetic models, while useful, are not required. The resulting screening level evaluation can be used to classify these compounds into relative categories of low, medium and high priority for risk assessment follow‐up. Future challenges related to the derivation and use of BE values as tools in risk management are discussed. Copyright © 2008 John Wiley & Sons, Ltd.     

Human exposure to bisphenol A by biomonitoring: methods, results and assessment of environmental exposures

Human exposure to bisphenol A is controversially discussed. This review critically assesses methods for biomonitoring of bisphenol A exposures and reported concentrations of bisphenol A in blood and urine of non-occupationally ("environmentally") exposed humans. From the many methods published to assess bisphenol A concentrations in biological media, mass spectrometry-based methods are considered most appropriate due to high sensitivity, selectivity and precision. In human blood, based on the known toxicokinetics of bisphenol A in humans, the expected very low concentrations of bisphenol A due to rapid biotransformation and the very rapid excretion result in severe limitations in the use of reported blood levels of bisphenol A for exposure assessment. Due to the rapid and complete excretion of orally administered bisphenol A, urine samples are considered as the appropriate body fluid for bisphenol A exposure assessment. In urine samples from several cohorts, bisphenol A (as glucuronide) was present in average concentrations in the range of 1-3 microg/L suggesting that daily human exposure to bisphenol A is below 6 microg per person (<0.1 microg/kg bw/day) for the majority of the population.     

Risk assessment of local dermal effects and skin sensitisation under the EU Chemicals Regulation REACH: a proposal for a qualitative, exposure scenario specific, approach

Within the framework of REACH, an assessment regarding local dermal effects and skin sensitisation should be performed for substances. Quantitative hazard information for these effects is often not available. Furthermore, it is difficult to relate the way in which animals are exposed in dermal toxicity studies directly to dermal exposure in practice. In the absence of quantitative information, a qualitative assessment for dermal effects is the most reasonable option. The qualitative approach as proposed in the REACH guidance recommends only general risk management measures (RMM) for three categories with a low, moderate and high identified hazard, without specifying which RMM are needed for a specific exposure scenario. We propose to differentiate frequency of exposure based on differences in activities and to compare measured and estimated local skin exposure levels with rules of thumb for evaluation of control of risks per hazard category. For workers, specific RMM regimes are assigned to each combination of hazard category and process category (PROC). For consumers, a strategy in which RMM are arranged from product-integrated measures to the use of personal protective equipment (PPE) is presented. Our approach may be transferred into automated assessment tools like Chesar and CEFIC GES.     

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.     

REACH exposure assessment of anticorrosive paint products--determination of exposure from application and service life to the aquatic environment

The European Community Regulation on the registration, evaluation, authorisation and restriction of chemicals (REACH) introduced exposure scenarios describing safe use quantitatively, and enhancing the importance of scientific based exposure assessments. This paper presents methods to determine exposure from the airless spray application of anti-corrosive paint and leaching of painted articles submerged in seawater, to establish whether it is possible to test these exposures in a reproducible and feasible way. The paper also presents results from using the methods in order to assess how well the default values recommended under REACH coincide with the tested values and corresponding values available in literature. The methods used were feasible under laboratory conditions. The reproducibility of the application study was shown to be good and all analyses of the leaching showed concentrations below detection limit. More replicates will be required to validate the reproducibility of the growth inhibition tests. Measured values for the present overspray scenario were between, and the leaching values below, values from REACH guidelines and emission scenario documents. Further development of the methods is recommended.     

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.     

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.     

Derivation of endogenous equivalent values to support risk assessment and risk management decisions for an endogenous carcinogen: Ethylene oxide

An approach is presented for ethylene oxide (EO) to derive endogenous equivalent (EE) values, which are endogenous levels normally found within the body expressed in terms of exogenous exposures. EE values can be used to support risk assessment and risk management decisions for chemicals such as EO that have both endogenous and exogenous exposure pathways. EE values were derived using a meta-analysis of data from the published literature characterizing the distribution for an EO biomarker of exposure, hemoglobin N-(2-hydroxyethyl)-valine (HEV), in unexposed populations. These levels are compared to the those reported in exposed populations (smokers, workers). Correlation between the biomarker of exposure and external exposures of EO were applied to this distribution to determine corresponding EE values, which range from 0.13 to 6.9 ppb for EO in air. These values are orders of magnitude higher than risk-based concentration values derived for EO using default methods, and are provided as a pragmatic, data-driven alternative approach to managing the potential risks from exogenous exposures to EO.     

Human health safety evaluation of cosmetics in the EU: A legally imposed challenge to science

As stated in the European legislation, cosmetic products present on the European market must be safe for the consumer. Safety evaluation of the products is carried out by a qualified safety assessor who needs to consider potential exposure scenarios next to the physicochemical and toxicological profiles of all composing ingredients. Whereas, until recently, the tools to determine the toxicological profile of cosmetic ingredients mainly consisted of animal experiments, they have now been narrowed down substantially by the legally imposed animal testing ban on cosmetic ingredients, taken up in the Cosmetic Products Directive (76/768/EEC). This Directive, however, is not a stand-alone piece of European legislation, since as well directly as indirectly it is influenced by a complex web of related legislations. Vertical legislations deal with different categories of chemicals, including dangerous substances, biocides, plant protection products, food additives, medicinal products, and of course also cosmetics. Horizontal legislative texts, on the contrary, cover more general fields such as protection of experimental animals, consumer product safety, misleading of consumers, specific provisions for aerosols, and others. Experience has learnt that having a general overview of these related legislations is necessary to understand their impact on the cosmetic world in general terms and on cosmetic safety evaluation in particular. This goes for a variety of concerned parties, including national and European regulators/agencies, contract laboratories, raw material suppliers, cosmetic companies, research and educational centers. They all deal with a number of aspects important for the quality and toxicity of cosmetics and their ingredients.This review summarises the most relevant points of the legislative texts of different types of product categories and emphasises their impact on the safety evaluation of cosmetics.     

健康管理对社区慢性病高危人群的干预效果评估

目的探讨健康管理对慢性非传染性疾病高危人群生活行为方式的干预效果。方法将400例45～69岁的慢性病高危人群随机分成两组,研究组200例应用健康管理系统实施疾病风险评估和饮食、运动量化干预管理,对照组200例给予社区健康服务中心普通随访管理。观察两组1年后的饮食结构、运动状况、体格检查指标等变化情况。结果研究组饮食结构、运动、体质指数、腰围、血压、血糖、血脂等均有不同程度改善,尤其是饮食、运动、体质指数及血脂改善率均明显高于对照组（P〈0.05）。研究组管理前后饮食、运动、体质指数、腰围及血脂指标间的差异有统计学意义（P〈0.05）。结论健康管理能促进慢性病高危人群改变其不良的生活行为方式,有效预防慢性病的发生、发展。     

Determination of free and total bisphenol A in human urine to assess daily uptake as a basis for a valid risk assessment

Bisphenol A (BPA) is widely distributed and exhibits weak estrogenic activity. In contrast to BPA, the corresponding glucuronide metabolite is not estrogenic. Therefore, free and total BPA were determined in human urine samples to assess the significance of free BPA for risk assessment. In only 10% of 474 samples from 287 subjects was free BPA detected in a range from 相似文献   

Human health risk assessment of endosulfan. Part III: Occupational handler exposure and risk

The United States Environmental Protection Agency (USEPA) and the California Department of Pesticide Regulation (CDPR) have authority to regulate pesticides, respectively, within the United States and within the state of California. Both agencies are obligated to protect human and environmental health within the geographical boundaries where they have authority. Risk assessment of pesticidal active ingredients is conducted by both USEPA and CDPR, yet the agencies have different legal mandates that influence how they conduct assessments. Exposure estimates are key inputs into the risk assessment. Both agencies released draft risk assessments for endosulfan in the same time frame, and while some exposure estimates were similar, many differed considerably. This paper focuses on the differences in exposure estimates for individuals involved in endosulfan applications (handler exposures). Although CDPR and USEPA relied on the same data sets for their exposure estimates for most handler scenarios, CDPR estimates were in some cases more than an order of magnitude higher than estimates from USEPA. Reasons underlying these disparities, and their effects on risk estimates and resulting regulatory decisions, are discussed in this paper. Additionally, because of differences in legal mandates, CDPR estimated exposures for scenarios lacking data, whereas USEPA did not.     

胸外科护理风险管理研究进展

胸外科患者存在病情复杂、危重症多、病种繁多、治疗性操作多、患者病情变化快等特点,护理人员工作时面对的潜在风险较大,如果不能采取预见性的护理措施很容易导致不良事件的发生,护理人员针对胸外科存在的风险点制定针对性的管控措施,抓好护理管理工作中的关键环节,对保证护理安全、提高护理质量具有重要的意义.本文探讨风险管理在胸外科的...     

Exposure-triggered reproductive toxicity testing under the REACH legislation: a proposal to define significant/relevant exposure

Under the new REACH legislation, toxicological testing is required in relation to annual tonnages produced or imported. Requirements for toxicological information increase when production volume increases. The respective information requirements are laid down in the REACH Annexes VII-X. Concerning human toxicology, certain toxicological tests may be waived under specific conditions. Aside from waiving criteria such as technical feasibility, exposure plays a decisive role in the waiving process with the consequence that toxicological testing will not be required in case of "no relevant exposure", "limited exposure", "no exposure" or "no significant exposure" (as expressed in the documents). However, up to now criteria are lacking which precisely define these terms. Attempts have been made to establish cut-off criteria between "non-relevant" and "relevant" (detrimental) exposure based on external exposure concentrations and the threshold of toxicological concern (TTC) principle. In this paper we make a proposal and describe a strategy how to define the currently insufficiently described terms "relevant/significant" exposure. We propose to define relevant/significant exposure based on an endpoint-specific TTC approach, starting from a comparison of the tentative external exposure to the specific TTC. This can be followed by a refinement of exposure estimates and may culminate in the experimental determination of internal and target tissue exposure. This strategy enables a well-founded assessment of what "no relevant exposure" is and safeguards an appropriate level of protection of the general population. The feasibility of the approach is demonstrated for reproductive toxicity endpoints.