Dispelling urban myths about default uncertainty factors in chemical risk assessment - Sufficient protection against mixture effects?

© 2013 Martin et al.; licensee BioMed Central LtdThis article has been made available through the Brunel Open Access Publishing Fund.Assessing the detrimental health effects of chemicals requires the extrapolation of experimental data in animals to human populations. This is achieved by applying a default uncertainty factor of 100 to doses not found to be associated with observable effects in laboratory animals. It is commonly assumed that the toxicokinetic and toxicodynamic sub-components of this default uncertainty factor represent worst-case scenarios and that the multiplication of those components yields conservative estimates of safe levels for humans. It is sometimes claimed that this conservatism also offers adequate protection from mixture effects. By analysing the evolution of uncertainty factors from a historical perspective, we expose that the default factor and its sub-components are intended to represent adequate rather than worst-case scenarios. The intention of using assessment factors for mixture effects was abandoned thirty years ago. It is also often ignored that the conservatism (or otherwise) of uncertainty factors can only be considered in relation to a defined level of protection. A protection equivalent to an effect magnitude of 0.001-0.0001% over background incidence is generally considered acceptable. However, it is impossible to say whether this level of protection is in fact realised with the tolerable doses that are derived by employing uncertainty factors. Accordingly, it is difficult to assess whether uncertainty factors overestimate or underestimate the sensitivity differences in human populations. It is also often not appreciated that the outcome of probabilistic approaches to the multiplication of sub-factors is dependent on the choice of probability distributions. Therefore, the idea that default uncertainty factors are overly conservative worst-case scenarios which can account both for the lack of statistical power in animal experiments and protect against potential mixture effects is ill-founded. We contend that precautionary regulation should provide an incentive to generate better data and recommend adopting a pragmatic, but scientifically better founded approach to mixture risk assessment. © 2013 Martin et al.; licensee BioMed Central Ltd.Oak Foundatio

Comparison of the benefits of cochlear implantation versus contra-lateral routing of signal hearing aids in adult patients with single-sided deafness: study protocol for a prospective within-subject longitudinal trial

Background Individuals with a unilateral severe-to-profound hearing loss, or single-sided deafness, report difficulty with listening in many everyday situations despite having access to well-preserved acoustic hearing in one ear. The standard of care for single-sided deafness available on the UK National Health Service is a contra-lateral routing of signals hearing aid which transfers sounds from the impaired ear to the non-impaired ear. This hearing aid has been found to improve speech understanding in noise when the signal-to-noise ratio is more favourable at the impaired ear than the non-impaired ear. However, the indiscriminate routing of signals to a single ear can have detrimental effects when interfering sounds are located on the side of the impaired ear. Recent published evidence has suggested that cochlear implantation in individuals with a single-sided deafness can restore access to the binaural cues which underpin the ability to localise sounds and segregate speech from other interfering sounds. Methods/Design The current trial was designed to assess the efficacy of cochlear implantation compared to a contra-lateral routing of signals hearing aid in restoring binaural hearing in adults with acquired single-sided deafness. Patients are assessed at baseline and after receiving a contra-lateral routing of signals hearing aid. A cochlear implant is then provided to those patients who do not receive sufficient benefit from the hearing aid. This within-subject longitudinal design reflects the expected care pathway should cochlear implantation be provided for single-sided deafness on the UK National Health Service. The primary endpoints are measures of binaural hearing at baseline, after provision of a contra-lateral routing of signals hearing aid, and after cochlear implantation. Binaural hearing is assessed in terms of the accuracy with which sounds are localised and speech is perceived in background noise. The trial is also designed to measure the impact of the interventions on hearing- and health-related quality of life. Discussion This multi-centre trial was designed to provide evidence for the efficacy of cochlear implantation compared to the contra-lateral routing of signals. A purpose-built sound presentation system and established measurement techniques will provide reliable and precise measures of binaural hearing. Trial registration Current Controlled Trials http://www.controlled-trials.com/ISRCTN33301739 (05/JUL/2013

Genetic Variation in the Familial Mediterranean Fever Gene (MEFV) and Risk for Crohn's Disease and Ulcerative Colitis

BACKGROUND AND AIMS: The familial Mediterranean fever (FMF) gene (MEFV) encodes pyrin, a major regulator of the inflammasome platform controlling caspase-1 activation and IL-1beta processing. Pyrin has been shown to interact with the gene product of NLRP3, NALP3/cryopyrin, also an important active member of the inflammasome. The NLRP3 region was recently reported to be associated with Crohn's disease (CD) susceptibility. We therefore sought to evaluate MEFV as an inflammatory bowel disease (IBD) susceptibility gene. METHODOLOGY AND RESULTS: MEFV colonic mucosal gene expression was significantly increased in experimental colitis mice models (TNBS p<0.0003; DSS p<0.006), in biopsies from CD (p<0.02) and severe ulcerative colitis (UC) patients (p<0.008). Comprehensive genetic screening of the MEFV region in the Belgian exploratory sample set (440 CD trios, 137 UC trios, 239 CD cases, 96 UC cases, and 107 healthy controls) identified SNPs located in the MEFV 5' haplotype block that were significantly associated with UC (rs224217; p = 0.003; A allele frequency: 56% cases, 45% controls), while no CD associations were observed. Sequencing and subsequent genotyping of variants located in this associated haplotype block identified three synonymous variants (D102D/rs224225, G138G/rs224224, A165A/rs224223) and one non-synonymous variant (R202Q/rs224222) located in MEFV exon 2 that were significantly associated with UC (rs224222: p = 0.0005; A allele frequency: 32% in cases, 23% in controls). No consistent associations were observed in additional Canadian (256 CD trios, 91 UC trios) and Scottish (495 UC, 370 controls) sample sets. We note that rs224222 showed marginal association (p = 0.012; G allele frequency: 82% in cases, 70% in controls) in the Canadian sample, but with a different risk allele. None of the NLRP3 common variants were associated with UC in the Belgian-Canadian UC samples and no significant interactions were observed between NLRP3 and MEFV that could explain the observed flip-flop of the rs224222 risk allele. CONCLUSION: The differences in association levels observed between the sample sets may be a consequence of distinct founder effects or of the relative small sample size of the cohorts evaluated in this study. However, the results suggest that common variants in the MEFV region do not contribute to CD and UC susceptibility.Journal ArticleResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Towards a general framework for including noise impacts in LCA

Industrial Ecolog

[Proposal for the human toxicologically based C-values. Concerning a supplement on report 725201005.]

This report is an addendum to report no 725201005, in which human toxicological guideline values and daily intakes for man are derived based on of a search of the toxicological literature in order to derive C-values for soil. Maximum tolerable risk levels for the total intake of genotoxic carcinogens and toxicologically tolerable daily intakes for threshold compounds have been determined for the following compounds or groups of chemically related compounds: sulfides, anthracene, naphthalene, PAH (total), chlorinated PAH, oxidized PAH, mineral oil, and tetrahydrothiophene. In addition, the maximum tolerable risk level for benzene has been revised

Screening van chemische stoffen ; de toepassing van het Uniforme Beoordelingssysteem Stoffen, USES 1.0

Priority setting is a sequential process and can be regarded a first step in the risk management of substances. It is used to extract, from the many thousands of substances, those that are expected to be the most riskful to man and the environment and therefore deserve the highest attention from regulators. The Uniform System for the Evaluation of Substances, USES 1.0, has been developed as a tool for screening and risk assessment in accordance with Action point 41 of the Netherlands National Environmental Policy Plan 1990-1994. In this report, USES 1.0 has been applied as a screening system for existing, organic substances to meet the objective of this action point. A total of 100 substances have been screened, all of which occur on the 1992 list of "Attention Substances" of the Ministry of Housing, Spatial Planning and the Environment. The report analyses USES 1.0. with respect to its application as a screening tool, especially within the scope of the Netherlands Chemical Substances Act - involving screening of Attention Substances - and the EU Council Regulation (EEC) No. 793/93 on the evaluation and control of existing substances. Although the results of any screening system are difficult to evaluate in view of the lack of absolute standards, an attempt was made on the basis of recently published expert based conclusions on the degree of priority of the Attention Substances. The results obtained with USES 1.0 in many ways are found to be compatible with these conclusions. USES 1.0 therefore can be considered acceptable as a tool for the screening of substances such as the Attention Substances. The basis of the priority setting process of the European Commission is the "IPS" screening system. This report also compares this method with that of USES 1.0. The comparison is complicated by differences in input values. Roughly 50 to 60% of the 35 substances compared rank similarly with both priority setting tools, 15 to 20% receives lower rankings with USES 1.0 than with IPS and 20 to 30% receives higher rankings with USES 1.0. Possible explanations for the differences found are discussed.Prioritering is een stapsgewijs proces en kan worden beschouwd als het begin van het risicomanagement voor stoffen. Uit vele duizenden stoffen worden via prioritering die stoffen geselecteerd die als de meest risicovolle beschouwd kunnen worden en daarom de meeste aandacht van het beleid zouden moeten verdienen. Het Uniforme Beoordelingssysteem Stoffen, USES 1.0, is ontwikkeld om als hulpmiddel te fungeren in de prioritering en risicobeoordeling van stoffen. Dit is in overeenstemming met Actiepunt 41 uit het Nationaal Milieubeleidsplan 1990-1994. Als verdere uitwerking van dit actiepunt is in dit rapport USES 1.0 toegepast als een systeem voor de eerste prioritering van bestaande, organische stoffen. In totaal zijn 100 stoffen getest die allemaal voorkomen op de "Aandachtstoffenlijst" uit 1992 van het ministerie van VROM. Dit rapport analyseert de toepassing van USES 1.0 als instrument in de screening van stoffen, met name in het kader van de Wet Milieugevaarlijke Stoffen en EU Verordening (EEG) Nr. 793/93 inzake de beoordeling en de beperking van de risico's van bestaande stoffen. Hoewel de resultaten van elk prioriteringsinstrument voor stoffen lastig te evalueren zijn gezien het ontbreken van een absolute standaard, is toch een poging hiertoe gedaan op basis van conclusies over de prioriteit van aandachtstoffen zoals vermeld in het onlangs gepubliceerde RIVM-rapport "Aandachtstoffen in het Nederlandse Milieubeleid - Overzicht 1994. In vele opzichten zijn de resultaten zoals die met USES 1.0 zijn verkregen in overeenstemming met deze conclusies die zijn getoetst door een adviesgroep van de deskundigen. USES 1.0 kan daarom beschouwd worden als een aanvaardbaar instrument voor de screening van stoffen zoals bijvoorbeeld de aandachtstoffen. De basis van het prioriteringsproces van de Europese Commissie is het "Informal Working Group on Priority Setting" (IPS) systeem. Dit rapport vergelijkt deze methode met die in USES 1.0. Van de 35 vergeleken stoffen krijgt 50 tot 60% ongeveer even hoge prioriteit met beide systemen, 15 tot 20% krijgt met USES 1.0 een duidelijk lagere prioriteit dan met IPS en 20 tot 30% een hogere

Screening van chemische stoffen ; de toepassing van het Uniforme Beoordelingssysteem Stoffen, USES 1.0

Prioritering is een stapsgewijs proces en kan worden beschouwd als het begin van het risicomanagement voor stoffen. Uit vele duizenden stoffen worden via prioritering die stoffen geselecteerd die als de meest risicovolle beschouwd kunnen worden en daarom de meeste aandacht van het beleid zouden moeten verdienen. Het Uniforme Beoordelingssysteem Stoffen, USES 1.0, is ontwikkeld om als hulpmiddel te fungeren in de prioritering en risicobeoordeling van stoffen. Dit is in overeenstemming met Actiepunt 41 uit het Nationaal Milieubeleidsplan 1990-1994. Als verdere uitwerking van dit actiepunt is in dit rapport USES 1.0 toegepast als een systeem voor de eerste prioritering van bestaande, organische stoffen. In totaal zijn 100 stoffen getest die allemaal voorkomen op de "Aandachtstoffenlijst" uit 1992 van het ministerie van VROM. Dit rapport analyseert de toepassing van USES 1.0 als instrument in de screening van stoffen, met name in het kader van de Wet Milieugevaarlijke Stoffen en EU Verordening (EEG) Nr. 793/93 inzake de beoordeling en de beperking van de risico's van bestaande stoffen. Hoewel de resultaten van elk prioriteringsinstrument voor stoffen lastig te evalueren zijn gezien het ontbreken van een absolute standaard, is toch een poging hiertoe gedaan op basis van conclusies over de prioriteit van aandachtstoffen zoals vermeld in het onlangs gepubliceerde RIVM-rapport "Aandachtstoffen in het Nederlandse Milieubeleid - Overzicht 1994. In vele opzichten zijn de resultaten zoals die met USES 1.0 zijn verkregen in overeenstemming met deze conclusies die zijn getoetst door een adviesgroep van de deskundigen. USES 1.0 kan daarom beschouwd worden als een aanvaardbaar instrument voor de screening van stoffen zoals bijvoorbeeld de aandachtstoffen. De basis van het prioriteringsproces van de Europese Commissie is het "Informal Working Group on Priority Setting" (IPS) systeem. Dit rapport vergelijkt deze methode met die in USES 1.0. Van de 35 vergeleken stoffen krijgt 50 tot 60% ongeveer even hoge prioriteit met beide systemen, 15 tot 20% krijgt met USES 1.0 een duidelijk lagere prioriteit dan met IPS en 20 tot 30% een hogere.Priority setting is a sequential process and can be regarded a first step in the risk management of substances. It is used to extract, from the many thousands of substances, those that are expected to be the most riskful to man and the environment and therefore deserve the highest attention from regulators. The Uniform System for the Evaluation of Substances, USES 1.0, has been developed as a tool for screening and risk assessment in accordance with Action point 41 of the Netherlands National Environmental Policy Plan 1990-1994. In this report, USES 1.0 has been applied as a screening system for existing, organic substances to meet the objective of this action point. A total of 100 substances have been screened, all of which occur on the 1992 list of "Attention Substances" of the Ministry of Housing, Spatial Planning and the Environment. The report analyses USES 1.0. with respect to its application as a screening tool, especially within the scope of the Netherlands Chemical Substances Act - involving screening of Attention Substances - and the EU Council Regulation (EEC) No. 793/93 on the evaluation and control of existing substances. Although the results of any screening system are difficult to evaluate in view of the lack of absolute standards, an attempt was made on the basis of recently published expert based conclusions on the degree of priority of the Attention Substances. The results obtained with USES 1.0 in many ways are found to be compatible with these conclusions. USES 1.0 therefore can be considered acceptable as a tool for the screening of substances such as the Attention Substances. The basis of the priority setting process of the European Commission is the "IPS" screening system. This report also compares this method with that of USES 1.0. The comparison is complicated by differences in input values. Roughly 50 to 60% of the 35 substances compared rank similarly with both priority setting tools, 15 to 20% receives lower rankings with USES 1.0 than with IPS and 20 to 30% receives higher rankings with USES 1.0. Possible explanations for the differences found are discussed.DGM/SV

Initiele beoordeling van de gevaren en risico&apos;s van nieuwe stoffen voor mens en milieu

Dit rapport is het derde in een serie die de initiele risicobeoordeling van nieuwe stoffen op het RIVM beschrijft. Deze beoordeling betreft zowel de mens als het milieu en wordt uitgevoerd in het kader van Europese Commissie (EC) Richtlijn 67/548/EEG over de evaluatie en controle van nieuwe stoffen, de hierop gebaseerde Wet Milieugevaarlijke Stoffen en de recent aangenomen EC Richtlijn 93/67/EEG over de risicobeoordeling van nieuwe stoffen. Deze laatste Richtlijn wordt ondersteund door een Technische Leidraad die de beoordeling van blootstelling en effecten en de risicokarakterisering beschrijft voor zowel mens als milieu. Dit derde rapport, Deel III, bespreekt opnieuw een aantal problemen in de beoordeling van effecten evenals een aantal teststrategieen, met name in relatie tot hetgeen hierover in de EC Technische Leidraad is geschreven. Dit rapport zal tevens ingaan op nog niet eerder besproken onderwerpen ook weer rekening houdend met de EC Technische Leidraad. Dit rapport staat niet op zichzelf en kan alleen samen met Deel I en II in deze serie gebruikt worden. Als zodanig zijn deze rapporten op de eerste plaats geschreven als een gids voor hen die op het RIVM betrokken zijn bij de beoordeling van stoffen, maar ook voor beleidsmedewerkers die belast zijn met de regulering en de algehele evaluatie van dossiers van nieuwe stoffen en voor overige geinteresseerden, bijvoorbeeld bij de industrie, particuliere organisaties en het algemene publiek. Een index van de voornaamste onderwerpen die in de drie rapporten besproken worden is toegevoegd om de toegankelijkheid te verhogen.This report is the third in a series describing the initial hazard and risk assessment process for new substances at the National Institute of Public Health and Environmental Protection (RIVM) in The Netherlands. This assessment pertains to both man and the environment and is performed within the framework of the European Commission Directive 67/548/EEC on the evaluation and control of new substances, the ensuing Dutch Chemical Substances Act, and the recently adopted European Commission Directive 93/67/EEC on the risk assessment of new substances. The latter Directive is supported by a Technical Guidance Document which describes exposure assessment, effects assessment and risk characterization for human health and the aquatic environment. This third report, Part III, is meant to revisit several hazard identification issues and testing strategies which already have been discussed in Part I and Part II, particularly in relation to this Technical Guidance Document. Secondly it will discuss subjects which were not taken up in Part I and Part II, again using the results of the Technical Guidance Document. This report cannot stand on its own and should be used together with the previous reports in this series. Altogether these reports have primarily been written as a reference guide for those involved in the hazard and risk assessment process at RIVM, but also for risk managers responsible for the regulation and the overall dossier evaluation of new substances, and for others interested in this subject, e.g. industry, non-governmental organizations and the public at large. To enhance the accessibility of this report and Parts I and II, an index to the major subjects discussed is included.DGM/SV

The assessment of human exposure to chemical substances and radiation: scoping report

De risicoschatting van stoffen en straling en de ontwikkeling van methoden daarvoor is een van de kerntaken van het RIVM. De karakterisering van het risico (risk characterization) volgt uit een vergelijking van de blootstelling met effect- of geen-effect niveaus. Het RIVM wil haar activiteiten op het terrein van de risicobeoordeling van stoffen en straling versterken. Dit geldt daarom ook voor het deelaspect van de blootstellingsschatting. Versterking betekent hier zowel ontwikkeling van nieuwe methoden als een analyse, verificatie, onderbouwing en verbetering van bestaande methoden. Versterking betekent ook het opzetten van een structuur waarin de projecten aangaande blootstellingsschatting optimaal met elkaar kunnen samenwerken. Dit rapport is het resultaat van uitvoerige discussies met RIVM-deskundigen van verschillende laboratoria. Het doel van dit rapport is een bijdrage te zijn aan de versterking van het onderzoek naar de blootstellingsschatting voor de mens op het RIVM. Allereerst worden de ontwikkelingen op het RIVM op het terrein van de risicobeoordeling en met name voor wat betreft het deelaspect blootstellingsschatting beschreven. Vervolgens wordt getracht tot een eenduidig begrippenkader te komen zodat de onderzoekers op dit terrein dezelfde taal kunnen spreken en gemakkelijk met elkaar kunnen communiceren. Kwaliteitsaspecten komen ook aan de orde. Tenslotte wordt naar de toekomst gekeken: het rapport gaat in op reeds gepland werk op het terrein van de blootstellingsschatting en op hiaten die geconstateerd kunnen worden. Hiervan uitgaand worden voorstellen gedaan voor eventuele nieuwe deelprojecten. Verwacht mag worden dat deze een rol zullen gaan spelen bij de planning voor de komende jaren.This report aims at boosting the human exposure assessment activities of the RIVM with regard to chemical substances and radiation. It is the result of thorough discussions with RIVM-experts. The report starts with an overview of past developments in the area of human exposure assessment at the RIVM and continues describing recent projects. Major developments outside the Institute are also discussed. An attempt is made to harmonise definitions which are relevant for exposure assessment, i.e. definitions on exposure, intake, uptake and dose. Important gaps in the human exposure assessment work at the RIVM are identified, leading to proposals for future work.RIV