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

Probabilistische assessment factoren voor de humane risicobeoordeling - Een practische gids

This report is a practical guide for the application of probabilistic distributions of default assessment factors in human health risk assessments. RIVM and TNO developed the use of probabilistic assessment factors as a first step towards further national and international harmonisation. Consensus was reached on the nature of distributions of several human assessment factors. The proposed distributions will be applied in risk assessments of new and existing substances and pesticides, produced at RIVM and TNO. A format for this analysis is presented in this report.Dit rapport is een practische gids voor de toepassing van probabilistische verdelingen van default assessment factoren in risicobeoordelingen voor de mens. RIVM en TNO ontwikkelden het gebruik van probabilistische assessment factoren als eerste stap naar nationale en internaitonale harmonisatie. Er was overeenstemming over de aard van de verdelingen van verschillende humane assessment factoren. De voorgestelde verdelingen zullen worden toegepast in RIVM- en TNO-risicobeoordelingen van nieuwe en bestaande stoffen en bestrijdingsmiddelen. Een voorbeeld van een dergelijke analyse is toegevoegd

Probabilistische assessment factoren voor de humane risicobeoordeling - Een practische gids

Dit rapport is een practische gids voor de toepassing van probabilistische verdelingen van default assessment factoren in risicobeoordelingen voor de mens. RIVM en TNO ontwikkelden het gebruik van probabilistische assessment factoren als eerste stap naar nationale en internaitonale harmonisatie. Er was overeenstemming over de aard van de verdelingen van verschillende humane assessment factoren. De voorgestelde verdelingen zullen worden toegepast in RIVM- en TNO-risicobeoordelingen van nieuwe en bestaande stoffen en bestrijdingsmiddelen. Een voorbeeld van een dergelijke analyse is toegevoegd.This report is a practical guide for the application of probabilistic distributions of default assessment factors in human health risk assessments. RIVM and TNO developed the use of probabilistic assessment factors as a first step towards further national and international harmonisation. Consensus was reached on the nature of distributions of several human assessment factors. The proposed distributions will be applied in risk assessments of new and existing substances and pesticides, produced at RIVM and TNO. A format for this analysis is presented in this report.RIV

Oral-to-inhalation route extrapolation in occupational health risk assessment: A critical assessment

Due to a lack of route-specific toxicity data, the health risks resulting from occupational exposure are frequently assessed by route-to-route (RtR) extrapolation based on oral toxicity data. Insight into the conditions for and the uncertainties connected with the application of RtR extrapolation has not been clearly described in a systematic manner. In our opinion, for a reliable occupational health risk assessment, it is necessary to have insight into the accuracy of the routinely applied RtR extrapolation and, if possible, to give a (semi-)quantitative estimate of the possible error introduced. Therefore, experimentally established no-observed-adverse-effect-levels for inhalation studies were compared to no-adverse-effect-levels predicted from oral toxicity studies by RtR extrapolation. From our database analysis it can be concluded that the widely used RtR extrapolation methodology based on correction for differences in (estimates of) absorption is not generally reliable and certainly not valid for substances inducing local effects. More experimental data are required (from unpublished data or new experiments) to get insight into the reliability of RtR extrapolation and the possibility to derive an assessment factor to account for the uncertainties. Moreover, validated screening methods to predict/exclude the occurrence of local effects after repeated exposure are warranted. Especially, in cases where chemical exposure by inhalation or skin contact cannot be excluded route-specific toxicity studies should be considered to prevent from inadequate estimates of human health risks. © 2003 Elsevier Inc. All rights reserved

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Assessment factors for human health risk assessment : a discussion paper

The general goal of this discussion paper is to contribute toward the further harmonization of human health risk assessment. It first discusses the development of a formal, harmonized set of assessment factors. The status quo with regard to assessment factors is reviewed, that is, the type of factors to be identified, the range of values assigned, as well as the presence or absence of a scientific basis for these values. Options are presented for a set of default values and probabilistic distributions for assessment factors based on the state of the art. Methods of combining default values or probabilistic distributions of assessment factors are also described. Second, the effect parameter, the no-observed-adverse-effect level (NOAEL), is discussed. This NOAEL as selected from the toxicological database may be a poor substitute for the unknown, true no-adverse-effect level (NAEL). New developments are presented with respect to the estimation of the NAEL. The already widely discussed Benchmark Dose concept can be extended to obtain an uncertainty distribution of the Critical Effect Dose (CED). This CED distribution can be combined with estimated uncertainty distributions for assessment factors. In this way the full distribution of the Human Limit Value will be derived and not only a point estimate, whereas information on dose-response relations is taken into account. Finally, a strategy is proposed for implementation of the new developments into human health risk assessments