Towards internationally acceptable standards for food additives and contaminants based on the use of risk analysis

Internationally acceptable norms need to incorporate sound science and consistent risk management principles in an open and transparent manner, as set out in the Agreement on the Application of Sanitary and Phytosanitary Measures (the SPS Agreement). The process of risk analysis provides a procedure to reach these goals. The interaction between risk assessors and risk managers is considered vital to this procedure. This paper reports the outcome of a meeting of risk assessors and risk managers on specific aspects of risk analysis and its application to international standard setting for food additives and contaminants. Case studies on aflatoxins and aspartame were used to identify the key steps of the interaction process which ensure scientific justification for risk management decisions. A series of recommendations were proposed in order to enhance the scientific transparency in these critical phases of the standard setting procedure.     

The risk assessment paradigm and its application for trichothecenes

Risk analysis for trichothecene mycotoxins and other food contaminants, which are to a significant extent unavoidable, presents considerable challenges. Risk assessment is constrained by uncertainties associated with the lack of adequate data, and risk management must consider the fact that mycotoxin contamination can have serious impacts on trade and food sufficiency. These factors necessitate good communication between the risk assessors and risk managers in formulating the questions to be addressed by the risk assessment. Risk assessment must be an iterative process, since the problem formulation and the risk assessment may need to be revised to reflect new data and theories. In addition to providing advice to risk managers, risk assessment should provide a blueprint for future research by illustrating what observations will influence a prediction. The international risk assessments completed for deoxynivalenol, T-2 and HT-2 toxins, and nivalenol have noted a number of issues regarding the lack of adequate intake data for exposure assessment and significant gaps in toxicological studies for hazard characterizations. Addressing these uncertainties would provide risk managers with better guidance for control measures.     

Occupational exposure limits: a comparative study

Occupational exposure limits (OELs) are used as an important regulatory instrument to protect workers' health from adverse effects of chemical exposures. The OELs mirror the outcome of the risk assessment and risk management performed by the standard setting actor. In this study we compared the OELs established by 18 different organisations or national regulatory agencies. The OELs were compared with respect to: (1) what chemicals have been selected and (2) the average level of exposure limits for all chemicals. Our database contains OELs for a total of 1341 substances; of these 25 substances have OELs from all 18 organisations while more than one-third of the substances are only regulated by one organisation. The average level of the exposure limits has declined during the past 10 years for 6 of the 8 organisations in our study for which historical data were available; it has increased for Poland and remained nearly unchanged for Sweden. The average level of OELs differs substantially between organisations; the US OSHA exposure limits are (on average) nearly 40 % higher than those of Poland. The scientific or policy-related motivations for these differences remain to be analysed.     

Principles and practices of health risk assessment under current EU regulations

Risk assessments serve as the foundation of regulatory decision-making on whether to take actions to reduce (or otherwise manage) a toxicological or ecotoxicological risk or not. To understand the complex process that leads from the generation of scientific data, via risk assessment to risk management decision-making, close studies of the scientific basis and risk assessment methods must be undertaken. This paper consists of two main parts. In the first part the principles of the European Union process for risk assessments, as defined by legislations and official guidelines, are briefly outlined. In the second part the actual workings of this system are exemplified by the results from case studies of the risk assessment processes for trichloroethylene and for acrylamide. The analysis and comparison of these two cases illustrates: (1) that generation of a large amount of data does not ensure consensus among risk assessors, (2) that controversy can regard different levels of detail, (3) that controversy can arise at different organizational and theoretical levels, (4) that risk assessments may be subject to (public) criticism even if the experts agree, and (5) that "scientific" controversies have a significant policy component.     

Risk–benefit analysis of micronutrients

Traditionally, different approaches have been used to determine the recommended dietary allowances for micronutrients, above which there is a low risk of deficiency, and safe upper levels, below which there is a negligible risk of toxicity. The advice given to risk managers has been in the form of point estimates, such as the recommended dietary allowance (RDA) and the tolerable upper level (UL). In future, the gap between the two intake–response curves may become narrower, as more sensitive indicators of deficiency and toxicity are used, and as health benefits above the recommended daily allowance are taken into account. This paper reviews the traditional approaches and proposes a novel approach to compare beneficial and adverse effects across intake levels. This model can provide advice for risk managers in a form that will allow the risk of deficiency or the risk of not experiencing the benefit to be weighed against the risk of toxicity. The model extends the approach used to estimate recommended dietary allowances to make it applicable to both beneficial and adverse effects and to extend the intake–incidence data to provide a range of estimates that can be considered by the risk manager. The data-requirements of the model are the incidence of a response at one or more levels of intake, and a suitable coefficient of variation to represent the person-to-person variations within the human population. A coefficient of variation of 10% or 15% has been used for established recommended dietary allowances and a value of 15% is proposed as default for considerations of benefit. A coefficient of variation of 45% is proposed as default for considerations of toxicity, based on analyses of human variability in the fate and effects of therapeutic drugs. Using this approach risk managers, working closely with risk assessors, will be able to define ranges of intake based on a balance between the risks of deficiency (or lack of benefit) and toxicity.     

Human health risk assessment database, "the NHSRC toxicity value database": supporting the risk assessment process at US EPA's National Homeland Security Research Center

The toxicity value database of the United States Environmental Protection Agency's (EPA) National Homeland Security Research Center has been in development since 2004. The toxicity value database includes a compilation of agent property, toxicity, dose-response, and health effects data for 96 agents: 84 chemical and radiological agents and 12 biotoxins. The database is populated with multiple toxicity benchmark values and agent property information from secondary sources, with web links to the secondary sources, where available. A selected set of primary literature citations and associated dose-response data are also included. The toxicity value database offers a powerful means to quickly and efficiently gather pertinent toxicity and dose-response data for a number of agents that are of concern to the nation's security. This database, in conjunction with other tools, will play an important role in understanding human health risks, and will provide a means for risk assessors and managers to make quick and informed decisions on the potential health risks and determine appropriate responses (e.g., cleanup) to agent release. A final, stand alone MS ACESSS working version of the toxicity value database was completed in November, 2007.     

Is the acceptable daily intake as presently used an axiom or a dogma?

International scientific committees, regional scientific committees such as those of the European Union, and national regulatory agencies generally use the uncertainly factor approach for establishing acceptable or tolerable intakes of substances that exhibit thresholds of toxicity. No observed adverse effect levels (NOAELs) are identified in the critical studies to which appropriate uncertainly factors are applied to allocate acceptable daily intake (ADI). This paper discusses the different steps of the risk assessment process considered for decades worldwide a pragmatic approach to allocate safe doses, yet in need of improvements during the extrapolation phase which could increase the confidence level of the work performed by risk assessors.     

运用FMEA降低住院患者静脉用药治疗风险

目的:优化静脉用药流程,促进用药安全。方法:运用失效模式与效应分析(FMEA)方法评估住院患者静脉用药流程潜在的风险因素,并结合用药流程探讨可能造成错误的原因,提出改善住院患者用药安全的可行性方案,并持续追踪改善成效。结果:在住院患者静脉用药流程中找到40项容易导致用药错误的高风险因素,并对高风险流程进行优化改造。改造后流程得到简化,用药错误风险较前明显降低。结论:FMEA作为一种风险管理工具,能使药品管理者前瞻性地发现住院患者在执行静脉用药流程中潜在的漏洞与风险,从而降低风险,防患于未然。     

The use of mechanistic data and the handling of scientific uncertainty in carcinogen risk assessments. The trichloroethylene example

The purpose of this paper is to explore how risk assessors actually use mechanistic data in carcinogen risk assessment and to discuss how the handling of scientific uncertainty may affect the outcome of the risk assessment. The analysis is performed by comparing 29 trichloroethylene risk assessment documents in general and 2 of these, namely the ECETOC (1994, Trichloroethylene: Assessment of Human Carcinogenic Hazard, Technical Report No. 60) and the OECD/EU (1996, Initial Assessment Report for the 4th SIAM (Screening Information Data Set Initial Assessment Meeting), May 1996: Trichloroethylene, sponsor country, United Kingdom [Draft]), in more detail. It is concluded that in this example the ECETOC required less evidence for considering a carcinogenic mechanism irrelevant to humans than did the OECD/EU risk assessors. There are examples of when two risk assessors have selected different primary data for their argumentation and also examples of how one and the same primary publication was interpreted differently. Biased data selection and evaluation of primary data that correlate to the risk assessor's overall conclusions have also been identified. The general comparison of all 29 TCE risk assessment documents indicates that the assessment of scientific uncertainty in the mechanistic data affects the overall conclusions.     

Resources for global risk assessment: the International Toxicity Estimates for Risk (ITER) and Risk Information Exchange (RiskIE) databases

The rate of chemical synthesis and use has outpaced the development of risk values and the resolution of risk assessment methodology questions. In addition, available risk values derived by different organizations may vary due to scientific judgments, mission of the organization, or use of more recently published data. Further, each organization derives values for a unique chemical list so it can be challenging to locate data on a given chemical. Two Internet resources are available to address these issues. First, the International Toxicity Estimates for Risk (ITER) database (www.tera.org/iter) provides chronic human health risk assessment data from a variety of organizations worldwide in a side-by-side format, explains differences in risk values derived by different organizations, and links directly to each organization's website for more detailed information. It is also the only database that includes risk information from independent parties whose risk values have undergone independent peer review. Second, the Risk Information Exchange (RiskIE) is a database of in progress chemical risk assessment work, and includes non-chemical information related to human health risk assessment, such as training modules, white papers and risk documents. RiskIE is available at http://www.allianceforrisk.org/RiskIE.htm, and will join ITER on National Library of Medicine's TOXNET (http://toxnet.nlm.nih.gov/). Together, ITER and RiskIE provide risk assessors essential tools for easily identifying and comparing available risk data, for sharing in progress assessments, and for enhancing interaction among risk assessment groups to decrease duplication of effort and to harmonize risk assessment procedures across organizations.     

中西药复方制剂的风险管理

目的:研究中西药复方制剂存在的风险并为构建风险管理体系提出相应建议。方法:统计中国药典2010年版一部中的中西药复方制剂,检索和查阅相关文献、法律法规、药品标准、标签和说明书,分析存在的问题,探讨可能造成此类制剂风险的原因。结果:中西药复方制剂存在组方缺乏足够的科学依据,产品研发过程中安全性评价不足,产品推广过度宣传,说明书中不良反应信息不完善,使用过程中存在超剂量服用等问题,其潜在风险较大。结论:风险管理对于中西药复方制剂的用药安全十分重要,要从监督管理和专业技术两方面着手构建并完善其风险管理体系。     

Health risk assessment of chemicals – A commentary on requirements for the provision of training

Today, only a limited number of training courses specifically in human health risk assessment are available in Europe and although some basic training in health risk assessment is part of most toxicology university programmes, the preparation is often not enough. The purpose of this commentary is to present provision of training program in risk assessment based on common European criteria, easily adopted by institutions across Europe and focusing on risk assessment methodology and procedure. It is worth mentioning that the following paper does not deal with microbiological risk assessment and ecotoxicological risk assessment but mainly with chemical risk assessment. The project focuses on understanding the profile and training requirements of risk assessors in order to design a modular training program covering a range of disciplines in risk assessment and providing a model to establish guidelines for the training and recognition of risk assessors in accordance to a well-defined and properly acknowledged training standard.     

Safety assessment, detection and traceability, and societal aspects of genetically modified foods. European Network on Safety Assessment of Genetically Modified Food Crops (ENTRANSFOOD). Concluding remarks.

The most important results from the EU-sponsored ENTRANSFOOD Thematic Network project are reviewed, including the design of a detailed step-wise procedure for the risk assessment of foods derived from genetically modified crops based on the latest scientific developments, evaluation of topical risk assessment issues, and the formulation of proposals for improved risk management and public involvement in the risk analysis process.     

The use and evaluation of primary data in 29 trichloroethylene carcinogen risk assessments

This paper reports the results from a detailed study on how risk assessments of chemicals are actually made. The study is performed by comparing 29 cancer risk assessments made of one and the same chemical substance, namely, trichloroethylene. In this paper, the conclusions that are drawn in these risk assessment documents are described, and differences between the conclusions are explored. This is made within the framework of a proposed cancer risk assessment index. The selection of scientific data for risk assessment purposes is analyzed and the different risk assessors' interpretations and evaluations of individual primary data are compared. It is concluded that the data sets utilized by the trichloroethylene risk assessors are surprisingly incomplete and that biased data selection may have influenced some of the risk assessors' conclusions. Different risk assessors often interpret and evaluate one and the same study in different ways. There are also indications of both interpretation bias and evaluation bias for some of the risk assessors.     

European medicines and feed additives regulation are not in compliance with environmental legislation and policy

Environmental legislations for water and soil aim at the protection of quality of these compartments. This legislation has major consequences for product registration, amongst others the setting of environmental quality standards. A thorough risk assessment at registration of all products is crucial for the proper operationalisation of the environmental policy. A regulatory problem arises when the registration procedure is harmonised at a European level by the communautarian authority, while the authorities at the national level are responsible for maintaining the desired environmental quality. This problem can be tackled in two ways: firstly, the environmental risk assessment (ERA) should be based on common principles based on EU regulations and policy that steer the national authorities; secondly, the ERA should be developed under the supervision of competent authorities. Both options are not reflected in the forging of the ERA for medicines and feed additives. The formalisation of the contents and the procedure is not transparent nor open to input by scientists and other interested parties; the formalisation has no legal status, and European legislation cannot provide common protection goals in a global setting. The VICH Phase I and the EMEA Phase II guidance do not contain all communautarian environmental quality criteria, nor clear acceptability standards, nor harmonised methodology. Assessments are not made for all products, and the decision-making principles and practical procedures are not operational. It is therefore unlikely that any result of an ERA can be taken into consideration at registration, which undermines the legitimacy of the process. Both applicants and assessors are uncertain how to perform the risk assessment. The current developments may ultimately not only compromise product availability but also fail to protect the environment.     

An exposure-response database for detailed toxicity data

Risk assessment for human health effects often depends on evaluation of toxicological literature from a variety of sources. Risk assessors have limited resources for obtaining raw data, performing follow-on analyses or initiating new studies. These constraints must be balanced against a need to improve scientific credibility through improved statistical and analytical methods that optimize the use of available information. Computerized databases are used in toxicological risk assessment both for storing data and performing predictive analyses. Many systems provide primarily either bibliographic information or summary factual data from toxicological studies; few provide adequate information to allow application of dose-response models. The Exposure-Response database (ERDB) described here fills this gap by allowing entry of sufficiently detailed information on experimental design and results for each study, while limiting data entry to the most relevant. ERDB was designed to contain information from the open literature to support dose-response assessment and allow a high level of automation in performance of various types of dose-response analyses. Specifically, ERDB supports emerging analytical approaches for dose-response assessment, while accommodating the diverse nature of published literature. Exposure and response data are accessible in a relational multi-table design, with closely controlled standard fields for recording values and free-text fields to describe unique aspects of the study. Additional comparative analyses are made possible through summary tables and graphic representations of the data contained within ERDB.     

A framework for fit-for-purpose dose response assessment

The NRC report Science and Decisions: Advancing Risk Assessment made several recommendations to improve chemical risk assessment, with a focus on in-depth chronic dose–response assessments conducted by the U.S. Environmental Protection Agency. The recommendations addressed two broad elements: improving technical analysis and utility for decision making. To advance the discussions in the NRC report, in three multi-stakeholder workshops organized by the Alliance for Risk Assessment, available and evolving risk assessment methodologies were considered through the development and application of case studies. A key product was a framework (http://www.allianceforrisk.org/Workshop/Framework/ProblemFormulation.html) to guide risk assessors and managers to various dose–response assessment methods relevant to a range of decision contexts ranging from priority setting to full assessment, as illustrated by case studies. It is designed to facilitate selection of appropriate methodology for a variety of problem formulations and includes a variety of methods with supporting case studies, for areas flagged specifically by the NRC committee for consideration – e.g., susceptible sub-populations, population variability and background. The framewok contributes to organization and communication about methodologies for incorporating increasingly biologically informed and chemical specific knowledge into dose–response analysis, which is considered critical in evolving fit-for-purpose assessment to address relevant problem formulations.     

Susceptibility and risk: an overview

This symposium on susceptibility and risk was the third in a series designed to bring together experts from diverse disciplines to discuss contemporary issues in risk assessment. The topic in 1996 was especially challenging since susceptibility is influenced by a myriad of factors including environmental, genetic, social and political elements. The delineation of the relative contribution of various ‘susceptibility' factors has major implications for risk management options that may be applied in a regulatory context (risk prevention and risk reduction) or by the individual (risk avoidance). Current approaches to account for susceptibility in risk assessments (e.g. application of an uncertainty factor) have frequently been challenged as to their scientific basis and thus need periodic re-examination or update to maintain a credible foundation for the assessment process. The goal of this symposium was to gain a better understanding of the dimensions of the problem and to explore the directions that the risk assessment process might follow to better quantify the contribution of susceptibility in risk calculations.