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

Adaptation of cortical activity to sustained pressure stimulation on the fingertip

Background Tactile adaptation is a phenomenon of the sensory system that results in temporal desensitization after an exposure to sustained or repetitive tactile stimuli. Previous studies reported psychophysical and physiological adaptation where perceived intensity and mechanoreceptive afferent signals exponentially decreased during tactile adaptation. Along with these studies, we hypothesized that somatosensory cortical activity in the human brain also exponentially decreased during tactile adaptation. The present neuroimaging study specifically investigated temporal changes in the human cortical responses to sustained pressure stimuli mediated by slow-adapting type I afferents. Methods We applied pressure stimulation for up to 15 s to the right index fingertip in 21 healthy participants and acquired functional magnetic resonance imaging (fMRI) data using a 3T MRI system. We analyzed cortical responses in terms of the degrees of cortical activation and inter-regional connectivity during sustained pressure stimulation. Results Our results revealed that the degrees of activation in the contralateral primary and secondary somatosensory cortices exponentially decreased over time and that intra- and inter-hemispheric inter-regional functional connectivity over the regions associated with tactile perception also linearly decreased or increased over time, during pressure stimulation. Conclusion These results indicate that cortical activity dynamically adapts to sustained pressure stimulation mediated by SA-I afferents, involving changes in the degrees of activation on the cortical regions for tactile perception as well as in inter-regional functional connectivity among them. We speculate that these adaptive cortical activity may represent an efficient cortical processing of tactile information.open

A Toolkit for Dermal Risk Assessment and Management: An Overview

The European Research project RISKOFDERM (QLK4-CT-1999-01107) has two major goals. One is the development of a conceptual model for dermal risk assessment for regulatory purposes, such as the registration of new chemicals. The other goal is to develop a simple-to-use toolkit for assessment and management of health risks from occupational dermal exposure. This toolkit was constructed by analysing the major determinants of dermal hazard and dermal exposure. The results were combined in the form of a decision-tree that leads the user of the toolkit through a number of questions on the hazardous properties of the chemical in use, and on the exposure situation. The toolkit translates the information given by the user into broad data categories of hazard and exposure that lead to a rough estimate of health risk from dermal exposure. This is done separately for local skin effects and skin allergy on the one hand, and systemic effects after skin penetration on the other hand. After going through the decision-tree, the user is advised to act to control the risk, and to read general information on dermal exposure and a statement describing the uncertainty of the risk estimate produced by the toolkit. The final version of the toolkit will be available for use on portable or stationary computers and runs the decision algorithms in the background so that the non-expert user only will see the judgements, the recommendations and the general information. The toolkit will be evaluated before release by experts on the various elements included in the toolkit and by field experts in its practical use. The toolkit is an attempt to adapt elements of exact science to a situation where the necessary input data are of limited quality and are only estimates. The toolkit does not claim to give precise answers based on imprecise information. The purpose is to enable the user to estimate the order of magnitude of hazard, exposure and risk, and to encourage the user to deal with the issues of dermal hazard, exposure and control

A Toolkit for Dermal Risk Assessment: Toxicological Approach for Hazard Characterization

The toxicological background for hazard assessment using a simple to use toolkit for assessment and management of health risks from occupational dermal exposure is presented. Hazard assessment is intended to answer the following questions: (i) is the substance under consideration capable of damaging the skin; (ii) is the substance under consideration capable of leading to systemic health effects after having penetrated the skin; (iii) to what extent may the substance become systemically available; (iv) is the hazard influenced by the concentration? Local effects (like irritation or corrosion) and systemic effects (like drowsiness or liver damage) are treated separately, taking into account their possible interrelations. Hazard assessment is performed on the basis of easily available risk phrases, which give a short characterization of the inherent toxicity of a pure chemical or preparation. The information provided by risk phrases and possibly additional data is transformed into a one-dimensional ranking system of intrinsic toxicity (IT) scores. IT scores are expressed in broad categories like low, moderate, high or extreme. This ranking provides plausible information on the relevance of potential skin contact to health effects

Ueberpruefung der Datenlage im Hinblick auf eine Verbesserung der Dosis-Wirkungsbeziehung als Basis zur Quantifizierung von Sicherheitsfaktoren Endbericht

Extrapolation factors are used to substitute lacking experimental data by plausible assumptions. All substance specific data should be taken into account to avoid the use of uncertainty factors or to modify default assumptions. If default assumptions are used, the size of the factors should be scientifically supported. The usually applied default values of 10 (or a multiple of 10) result in different statistical safety and are not equally suitable for extrapolation purposes: for time extrapolation in average a factor of 2 to 3 should be sufficient to extrapolate from subchronic to chronic exposure time. To derive a 'no adverse effect level' (NAEL) from a 'lowest observed effect level' (LOAEL) default values should be avoided and benchmark procedures should be applied where possible. Interspecies extrapolations may be described best by scaling according to the caloric demand, but deviations from allometric principles may be additionally integrated by an extra factor. Intraspecies variability is sufficiently covered by a factor of 10, if just toxicokinetic variability for healthy adults is to be respected. Further integration of toxicodynamic variations (and maybe special risk groups) calls for additional factors. If 90-percentiles of the distributions have to be integrated to derive the uncertainty factor, larger factors would have to be chosen. Additional investigations will have to be carried out regarding the size of the intraspecies factor, the factor specific for local effects and for the total extrapolation factor. (orig.)SIGLEAvailable from TIB Hannover: RN 8908(97-033) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekUmweltbundesamt, Berlin (Germany); Bundesministerium fuer Umwelt, Naturschutz und Reaktorsicherheit, Bonn (Germany)DEGerman

Erfassung und Bewertung von Daten zur biologischen Verfuegbarkeit altlastenrelevanter Stoffe sowie toxikologische Stoffberichte zu metallischen Einzelverbindungen Abschlussbericht

Available from TIB Hannover: RN 8908(97-073,1) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEUmweltbundesamt, Berlin (Germany); Bundesministerium fuer Umwelt, Naturschutz und Reaktorsicherheit, Bonn (Germany)DEGerman