Regulatory Purpose Research Articles

Predicting aquatic toxicities of chemical pesticides in multiple test species using nonlinear QSTR modeling approaches

In this study, we established nonlinear quantitative-structure toxicity relationship (QSTR) models for predicting the toxicities of chemical pesticides in multiple aquatic test species following the OECD (Organization for Economic Cooperation and Development) guidelines. The decision tree forest (DTF) and decision tree boost (DTB) based QSTR models were constructed using a pesticides toxicity dataset in Selenastrum capricornutum and a set of six descriptors. Other six toxicity data sets were used for external validation of the constructed QSTRs. Global QSTR models were also constructed using the combined dataset of all the seven species. The diversity in chemical structures and nonlinearity in the data were evaluated. Model validation was performed deriving several statistical coefficients for the test data and the prediction and generalization abilities of the QSTRs were evaluated. Both the QSTR models identified WPSA1 (weighted charged partial positive surface area) as the most influential descriptor. The DTF and DTB QSTRs performed relatively better than the single decision tree (SDT) and support vector machines (SVM) models used as a benchmark here and yielded R2 of 0.886 and 0.964 between the measured and predicted toxicity values in the complete dataset (S. capricornutum). The QSTR models applied to six other aquatic species toxicity data yielded R2 of >0.92 (DTF) and >0.97 (DTB), respectively. The prediction accuracies of the global models were comparable with those of the S. capricornutum models. The results suggest for the appropriateness of the developed QSTR models to reliably predict the aquatic toxicity of chemicals and can be used for regulatory purpose.

Classification of dermal sensitizers in pharmaceutical manufacturing

Workers in development and manufacturing of pharmaceuticals are at risk for occupational contact dermatitis (OCD) of irritative (ICD) or allergic (ACD) origin, due to contacts with reactive intermediates (IM) and drug substances (DS). We examined, if alternative methods could replace presently used animal tests for identification of ACD in pharmaceutical development and manufacturing, without apparent loss of worker health, in line with regulations. The status of alternative methods for regulatory toxicology for consumer products has recently been reviewed by the Organisation for Economic Co-operation and Development (OECD) and the European Commission’s Joint Research Center (JRC) for the European Chemicals Agency (ECHA). They concluded that prediction of skin sensitization potential, extent and quality by in vitro methods, for regulatory assessments, will depend on the regulatory purpose and level of confidence required. Some alternative methods are currently in validation. Current Globally Harmonized System (GHS) regulations on classification, labeling and packaging of substances and mixtures depend on human and animal data, whereas alternative methods may provide supportive evidence. Since the levels of workplace skin exposure to DS and IM in manufacturing of pharmaceuticals are usually not known, it is not possible to conduct quantitative risk assessments based on threshold calculations for contact sensitizers.

Mathematical model of biodegradation process of sewage due to addition of chlorides

Biodegradation plays a key role in the environmental risk assessment of organic matter. The need to assess biodegradability of organic matter for regulatory purpose can be ably supported by the development of a model for predicting the extent of improvement or inhibition of the process. A mathematical model was developed in order to describe the ratios of BOD5 exertion under varying chloride concentrations compared to those at zero additional chloride values, which indicated the best fit in a polynomial third order equation. It reflected closely both the stimulation as well as inhibition effects under varied chloride concentrations. The model was duly validated by both primary data, acquired through an organized set of controlled laboratory experiments, as well as secondary data reported in the literature. The results indicate a peak value of the ratio at 0.8 g/L, while inhibition started at 6 g/L of chloride concentration. The model can be used as an aid for the design and prediction of sewage treatment process under different salt concentrations. It may help develop strategies for the co-treatment of domestic sewage and R.O. rejects as well as high salt containing industrial wastewaters.

Addressing procedural bias in municipal planning governance: A case for incorporating citizen participation within technical advisory committees

This essay presents models of multiparty negotiation as a means to compare the conventional public meetings format of planning to a preliminary process, the technical advisory committee. A metric of market concentration, the Herfindahl-Hirschman Index, is used to quantify the structural advantages in each, and presented within the context of municipal planning processes. In doing so, this work advances several propositions: First, open meetings expand power differentials between parties, which lead to outcomes that reflect the political efficacy of participants over the regulatory purpose of government. Second, such meetings create substantial transaction costs for the public, creating a barrier to the expression of community values. Finally, preliminary processes constitute a more effective forum for citizen participation than open meetings.

Estimating sensory irritation potency of volatile organic chemicals using QSARs based on decision tree methods for regulatory purpose.

Volatile organic compounds (VOCs) are among the priority atmospheric pollutants that have high indoor and outdoor exposure potential. The toxicity assessment of VOCs to living ecosystems has received considerable attention in recent years. Development of computational methods for safety assessment of chemicals has been advocated by various regulatory agencies. The paper proposes robust and reliable quantitative structure-activity relationships (QSARs) for estimating the sensory irritation potency and screening of the VOCs. Here, decision tree (DT) based classification and regression QSARs models, such as single DT, decision tree forest (DTF), and decision tree boost (DTB) were developed using the sensory irritation data on VOCs in mice following the OECD principles. Structural diversity and nonlinearity in the data were evaluated through the Euclidean distance and Brock-Dechert-Scheinkman statistics. The constructed QSAR models were validated with external test data and the predictive performance of these models was established through a set of coefficients recommended in QSAR literature. The performance of all three classification and regression QSAR models was satisfactory, but DTF and DTB performed relatively better. The classification and regression QSAR models (DTF, DTB) rendered classification accuracies of 98.59 and 100%, and yielded correlations (R(2)) of 0.950 and 0.971, respectively in complete data. The lipoaffinity index and SwHBa were identified as the most influential descriptors in proposed QSARs. The developed QSARs performed better than the previous studies. The developed models exhibited high statistical confidence and identified the structural properties of the VOCs responsible for their sensory irritation, and hence could be useful tools in screening of chemicals for regulatory purpose.

Risk Management And IEC 60601-1: Assessing Compliance

In December 2005, the third edition of International Electrotechnical Commission (IEC) standard 60601-1:2005 was published.1 In February 2006, the the U.S. adoption of IEC 60601-1:2005 was approved by the American National Standards Institute (ANSI; i.e., ANSI/ AAMI ES60601-1:2005).2 This article also refers to the international standards IEC 60601-1:2012 (edition 3 with Amendment 1), ISO 14971:2000, and ISO 14971:2007. Each of the following standards has been adopted as ANSI/AAMI U.S. national standards: ANSI/AAMI ES 60601-1:2005/(R)2012 and A1:2012, C1:2009/(R)2012, and A2:2010/(R)2012 and ANSI/AAMI/ISO 14971:2000 and ANSI/AAMI/ISO 14971:2007/(R)2010. Each ANSI/AAMI ES 60601-1 edition is identical to its respective IEC 60601-1 edition, with the exception of a few requirements that have been modified to comply with the U.S. National Electrical Code and relevant standards of the National Fire Protection Association. Each ANSI/AAMI/ISO 14971 edition is adopted identically without any difference to its respective ISO 14971 edition. For the purposes of this article, we will refer to the international editions of each standard. IEC 60601-1 had been under development for almost 10 years. The biggest change was the inclusion of requirements for risk management. Edition 3 required manufacturers of medical electrical equipment to implement a risk management process compliant with ISO 14971:2000 and to provide evidence related to specific risks for approximately 140 clauses in IEC 60601-1. Of note, the scope of the IEC 60601-1 series covers only electrical medical equipment. Therefore, for brevity, the term “medical device” is used in this article. Moreover, the content of the current work is specific to medical devices falling within the scope of the IEC 60601-1 series of standards. In August 2012, amendment 1 to IEC 60601-1: 2005 was published. A majority of the changes in the amendment related to risk management requirements. IEC 60601-1:2012 (edition 3.1) updated the reference to the current risk management standard, ISO 14971:2007, and reduced the number of clauses requiring risk management tasks to approximately 85. Since 2005, the inclusion of risk management in the IEC 60601-1 family of standards has been the subject of many discussions, trainings, and arguments around the world. As a result of this controversy, the standard has failed to gain traction in industry and was not required/ adopted by medical device regulatory agencies until 2012—and, at the time this article was written, some still had not adopted the standard. (Note: The use of standards for regulatory purpose differs globally. The use of the word “adopted” above is intended to indicate some form of acceptance by a regulatory agency that gives the manufacturer some benefit from declaring compliance with the standard as part of a regulatory submission.) The key questions frequently discussed include the following: • What are the requirements for risk management in IEC 60601-1? Risk Management And IEC 60601-1: Assessing Compliance

QSTR modeling for predicting aquatic toxicity of pharmacological active compounds in multiple test species for regulatory purpose

High concentrations of pharmacological active compounds (PACs) detected in global drinking water resources and their toxicological implications in aquatic life has become a matter of concern compelling for the development of reliable QSTRs (qualitative/quantitative structure–toxicity relationships) for their risk assessment. Robust QSTRs, such as decision treeboost (DTB) and decision tree forest (DTF) models implementing stochastic gradient boosting and bagging algorithms were established by experimental toxicity data of structurally diverse PACs in daphnia using molecular descriptors for predicting toxicity of new untested compounds in multiple test species. Developed models were rigorously validated using OECD recommended internal and external validation procedures and predictive power tested with external data of different trophic level test species (algae and fish). Classification QSTRs (DTB, DTF) rendered accuracy of 98.73% and 97.47%, respectively in daphnia and 84.38%, 85.94% (algae), 78.46% and 79.23% (fish). On the other hand, the regression QSTRs (DTB, DTF) yielded squared correlation coefficient values of 0.831, 0.852 (daphnia), 0.534, 0.556 (algae) and 0.620, 0.637 (fish). QSTRs developed in this study passed the OECD validation criteria and performed better than reported earlier for predicting toxicity of PACs, and can be used for screening the new untested compounds for regulatory purpose.

Performance and data interpretation of the in vivo comet assay in pharmaceutical industry: EFPIA survey results

In genotoxicity testing of pharmaceuticals the rodent alkaline comet assay is being increasingly used as a second in vivo assay in addition to the in vivo micronucleus assay to mitigate in vitro positive results as recommended by the ICH S2(R1) guideline. This paper summarizes a survey suggested by the Safety Working Party of European Medicines Agency (EMA), and conducted by the European Federation of Pharmaceutical Industries and Associations (EFPIA) to investigate the experience among European pharmaceutical companies by conducting the in vivo comet assay for regulatory purpose. A special focus was given on the typology of the obtained results and to identify potential difficulties encountered with the interpretation of study data.The participating companies reported a total of 147 studies (conducted in-house or outsourced) and shared the conclusion on the comet assay response for 136 studies. Most of the studies were negative (118/136). Only about 10% (14/136 studies) of the comet assays showed a positive response. None of the positive comet assay results were clearly associated with organ toxicity indicating that the positive responses are not due to cytotoxic effects of the compound in the tissue examined. The number of comet assays with an equivocal or inconclusive response was rare, respectively <1% (1/147 studies) and 2% (3/147 studies). In case additional information (e.g. repeat assay, organ toxicity, metabolism, tissue exposure) would have been available for evaluation, a final conclusion could most probably have been drawn for most or all of these studies. All (46) negative in vivo comet assays submitted alongside with a negative in vivo micronucleus assay were accepted by the regulatory authorities to mitigate a positive in vitro mammalian cell assay following the current ICH S2 guidance. The survey results demonstrate the robustness of the comet assay and the regulatory acceptance of the current ICH S2 guidance.

Do you mind if I don't smoke? Products, purpose and indeterminacy in US – Measures Affecting the Production and Sale of Clove Cigarettes

AbstractThe AB Report in US–Clove Cigarettes confirmed the Panel's conclusions that imported clove cigarettes were ‘like’ US menthol cigarettes, and accorded ‘less favourable treatment’ for the purpose of national treatment under Article 2.1 TBT, but it employed significantly different logic. The AB's reasoning extends earlier GATT jurisprudence into the TBT, applying competition-oriented analysis to the question of product definition, while reserving consideration of regulatory purpose to the comparison of treatment. We consider this emphasis from the perspectives of legal and economic indeterminacy, which we find run in parallel to each other. In the particular questions of the appeal, the AB's decisions are sensible from both perspectives, but ultimately do not add significantly to determinacy. We find it impossible to ignore regulatory purpose in discrimination cases, and we provide a novel economic model for analysing regulatory utility in this respect. In our view, there is not much economic difference in analysing regulatory purpose separately from more observable market considerations, but this sequencing does add political logic, analytical focus and formal transparency, all of which may enhance the legitimacy of WTO dispute settlement rulings, although ideally, further specification from the WTO Membership regarding the methodological content of the national treatment discipline would be preferred.

Transformation and regulation: a century of continuity in nursery school and welfare policy rhetoric

This article explores policy development for under-fives and its implementation in nursery schools in the first two decades of the twentieth century and draws parallels with current policy initiatives such as Sure Start and the ‘Troubled Families’ programme. It interrogates how discourse on British racial health shaped policy and presents a fresh perspective which builds on existing accounts by examining contemporary rhetoric in the context of practice in two London nursery schools. Central to the debate was the effectiveness of existing provision in Public Elementary Schools on the bodies and minds of young children and the ability of working-class families, or more properly, mothers, to care for their children. Two central themes are identified, of transformation and regulation, and the article demonstrates how these were evident in the language used by nursery school teachers to describe their task, the practices they implemented and their conception of achievement. The article concludes that attempts by the nursery schools to transform lives through provision of education and welfare also served as a regulatory mechanism for both the children and their families and this has resonance with current initiatives which espouse rhetoric of social transformation but embody a regulatory purpose.

Voices - Raising the NMC fee will help protect the public, says Mark Addison

Without a sufficient and sustainable income, the Nursing and Midwifery Council (NMC) will be unable to fulfil its core regulatory purpose of protecting the public.

Will they like me? Adolescents’ emotional responses to peer evaluation

Relative to children and adults, adolescents are highly focused on being evaluated by peers. This increased attention to peer evaluation has implications for emotion regulation in adolescence, but little is known about the characteristics of the evaluatee and evaluator that influence emotional reactions to evaluative outcomes. The present study used a computer-based social evaluation task to examine predictors of adolescents’ emotional responses to feedback from unknown peers. Nine-to-seventeen-year-olds (N = 36) completed the “chatroom task” and indicated the degree to which each peer would be interested in interacting with them and how good they felt after receiving acceptance and rejection feedback from peers. We examined whether adolescents’ age and gender impacted their emotional responses to being accepted or rejected by peers of different age groups (i.e., early or middle adolescence) and genders. We also tested whether expectations about peers’ interest was associated with variability in adolescents’ emotional responses to the evaluative outcome. Upon being accepted by middle adolescent male peers, females in the middle relative to early years of adolescence reported greater well-being, whereas males reported similar levels of well-being regardless of their own age. Following acceptance from middle adolescent female peers, females reported greater well-being than males. Adolescents with high expectations for being liked by peers felt better after being accepted versus rejected relative to those with low expectations. For adolescents with low expectations, acceptance and rejection were associated with similar levels of well-being. Adolescents’ emotional responses to peer evaluation are influenced by specific individual characteristics and antecedent preparation for evaluation that may serve an emotion regulatory purpose.

High throughput and miniaturised systems for biodegradability assessments

The society demands safer products with a better ecological profile. Regulatory criteria have been developed to prevent risks for human health and the environment, for example, within the framework of the European regulation REACH (Regulation (EC) No 1907, 2006). This has driven industry to consider the development of high throughput screening methodologies for assessing chemical biodegradability. These new screening methodologies must be scalable for miniaturisation, reproducible and as reliable as existing procedures for enhanced biodegradability assessment. Here, we evaluate two alternative systems that can be scaled for high throughput screening and conveniently miniaturised to limit costs in comparison with traditional testing. These systems are based on two dyes as follows: an invasive fluorescent dyes that serves as a cellular activity marker (a resazurin-like dye reagent) and a noninvasive fluorescent oxygen optosensor dye (an optical sensor). The advantages and limitations of these platforms for biodegradability assessment are presented. Our results confirm the feasibility of these systems for evaluating and screening chemicals for ready biodegradability. The optosensor is a miniaturised version of a component already used in traditional ready biodegradability testing, whereas the resazurin dye offers an interesting new screening mechanism for chemical concentrations greater than 10 mg/l that are not amenable to traditional closed bottle tests. The use of these approaches allows generalisation of high throughput screening methodologies to meet the need of developing new compounds with a favourable ecological profile and also assessment for regulatory purpose.

Obstacles in Haemocompatibility Testing

ISO 10993-4 is an international standard describing the methods of testing of medical devices for interactions with blood for regulatory purpose. The complexity of blood responses to biomaterial surfaces and the variability of blood functions in different individuals and species pose difficulties in standardisation. Moreover, in vivo or in vitro testing, as well as the clinical relevance of certain findings, is still matter of debate. This review deals with the major remaining problems, including a brief explanation of surface interactions with blood, the current ISO 10993 requirements for testing, and the role of in vitro test models. The literature is reviewed on anticoagulation, shear rate, blood-air interfaces, incubation time, and the importance of evaluation of the surface area after blood contact. Two test categories deserve further attention: complement and platelet function, including the effects on platelets from adhesion proteins, venipuncture, and animal derived- blood. The material properties, hydrophilicity, and roughness, as well as reference materials, are discussed. Finally this review calls for completing the acceptance criteria in the ISO standard based on a panel of test results.

Microscale Obstacle Resolving Air Quality Model Evaluation with the Michelstadt Case

Modelling pollutant dispersion in cities is challenging for air quality models as the urban obstacles have an important effect on the flow field and thus the dispersion. Computational Fluid Dynamics (CFD) models with an additional scalar dispersion transport equation are a possible way to resolve the flowfield in the urban canopy and model dispersion taking into consideration the effect of the buildings explicitly. These models need detailed evaluation with the method of verification and validation to gain confidence in their reliability and use them as a regulatory purpose tool in complex urban geometries. This paper shows the performance of an open source general purpose CFD code, OpenFOAM for a complex urban geometry, Michelstadt, which has both flow field and dispersion measurement data. Continuous release dispersion results are discussed to show the strengths and weaknesses of the modelling approach, focusing on the value of the turbulent Schmidt number, which was found to give best statistical metric results with a value of 0.7.

US - Clove Cigarettes and US - Tuna II (Mexico): Implications for the Role of Regulatory Purpose under Article III:4 of the GATT

The resolution of the issue of what role regulatory purpose might play in adjudicating the consistency of origin-neutral measures under the GATT National Treatment rule is essential to the resolution of the tension between trade liberalization and domestic autonomy with respect to the use of domestic policy instruments. As far as internal non-fiscal measures are concerned, the Appellate Body has yet to clarify its position on whether purpose should be considered in the step of determining ‘less favourable treatment’ under Article III:4. The Appellate Body’s recent decisions in US – Clove Cigarettes and US – Tuna II (Mexico) indicate that it continues to be reluctant to assign purpose a role under Article III:4, despite its explicit consideration of purpose in assessing ‘less favourable treatment’ under the National Treatment provision of the Agreement on Technical Barriers to Trade. These decisions also suggest that, in examining the policy claims raised in these two cases, the Appellate Body has employed its approach to ‘arbitrary or unjustifiable discrimination’ in the context of the Chapeau of GATT Article XX.

Determination of florfenicol residue in rainbow trout muscles by HPLC in Chaharmahal va Bakhtiari Province, Iran

Florfenicol residues in cultured rainbow trout muscles were determined using high-performance liquid chromatography with a regulatory surveillance purpose. A total of 40 randomly selected rainbow trout fish were collected to evaluate florfenicol residue. According to the results, concentrations of the antibiotic in fish muscle were in the range of 0.4–3.6 μg g−1 (mean = 0.8). The results show that 14 of 40 studied samples (35 %) contained florfenicol, and the concentration of florfenicol in five samples (12.5 %) was higher than maximum allowable level (1 mg kg−1). The results of this study prove the hypothesis that fish farmers use this antibiotic in large scale.

The Unbearable Lightness of Likeness

In Some Thoughts on The Concept of ‘Likeness’ in the GATS, Mireille Cossy (of the WTO Secretariat) advocates the re-introduction of an “improved” aims-and-effects test in the GATS. Under such test “elements related to the ‘regulatory context’ of the service and/or of the supplier should play a role in relation to GATS national treatment”. One consequence of such test, Cossy argues, is that it “would almost inevitably entail the introduction of some kind of proportionality or necessity test” within the very definition of GATS national treatment. This comment raises two points. First, although Cossy follows the conventional wisdom of both WTO jurisprudence and commentators, the core of any non-discrimination principle does not lie in the threshold question of “likeness” (are two services/suppliers “comparable”?), but in the substantive test of whether the government, either de jure or de facto, favors domestic over foreign services or service suppliers (does the regulation, either in law or in effect, distinguish based on national origin). This test of what constitutes de facto discrimination – a weighing exercise which, in this author’s view, should include consideration of both the objective purpose of the regulation and its effects -- has received surprisingly little attention in international trade law. Second, Cossy’s claim that trade in services (GATS) needs “something different” than trade in goods (GATT) – i.e. that GATS national treatment should focus on regulatory purpose and protectionism (improved aims-and-effects), but that this “would be without prejudice to the approach taken under the GATT” -- is unconvincing and unrealistic. If aims-and-effects are to return, in whatever guise, they should return – and are already resurfacing -- in both GATS and GATT.

IT enabled logistics procedure redesign for high value pharmaceutical shipments

PurposeThe purpose of this paper is to introduce a method for (re)designing complex logistics networks, which interact with various governmental bodies (e.g. in FDA and USDA) for regulatory clearance and control purpose. The method (the e3‐control methodology) is demonstrated to be a useful approach to analyzing and redesigning international logistics procedures in reaction to a technological innovation in a government‐business (G2B) network.Design/methodology/approachAn action research method relying on Living Lab study was used in this research. To illustrate and better understand the application of the e3‐control methodology, the authors place the development of e3‐control as a design tool for deploying the pharmaceutical case. The authors collected data with multiple methods including workshops, semi‐structured interviews and document analysis.FindingsThe e3‐control methodology has been successfully applied in this paper to carry out a step‐by‐step redesign for an international pharmaceutical logistics network. It was found that a win‐win situation can be achieved if business and government see each other as partners and share the responsibility of carrying out government regulatory and Customs controls. In this situation, Customs administrations can be relieved from redundant control tasks, and businesses will be rewarded with simplified procedures.Originality/valueThe authors' e3‐control methodology is an innovative redesign methodology for analyzing and redesigning business logistic networks including government agencies. With this approach, one can achieve a clear overview on critical problems within the logistics chains; disclose unclear procedures and in the meanwhile take into consideration the different concerns of the partners within the network.

Indirect Expropriation and the Right to Regulate: Revisiting Proportionality Analysis and the Standard of Review in Investor-State Arbitration

International investment tribunals considering claims of indirect expropriation have increasingly taken into account the host state’s regulatory purpose in their analysis, alluding to the need for measures to achieve a balance between host state and investor interests. Some tribunals have attempted to employ proportionality analysis in their determination of claims, but their reasoning has been methodologically problematic and characterized by a stringent standard of review, diverging from the approach of other international and supranational fora hearing disputes concerning the exercise of public power affecting individual rights and interests. Investment tribunals should be more deferential in performing proportionality analysis, mindful of host state authorities’ greater democratic legitimacy and proximity to host state communities, and tribunals’ comparatively weak institutional capacity. Such an approach would entail greater deference to host states in evaluating the legitimacy of a measure’s objective, the measure’s suitability and necessity, and the ultimate balance between the interests of the host state and of the investor. An appropriately deferential use of proportionality analysis is a more coherent approach to indirect expropriation that provides greater space for host states to take measures in the public interest, yet provides sufficient scrutiny to control misuse of public power.