Dermal absorption and toxicological risk assessment : pitfalls and promises

Buist, Harrie

doi:10.18174/370088

“…The latter objection is mitigated by a versatile and complex skin model, the Finite Dose Skin Permeation Model (FDSP) made available on the Internet by the US Centers for Disease Control and Prevention (CDC). Unfortunately, it did not perform well with an external validation data set (Buist, ).…”

Section: Appendix D – Evaluation Of Literature On Qsar For Skin Absormentioning

confidence: 99%

Guidance on dermal absorption

Buist¹,

Craig²,

Dewhurst³

et al. 2017

EFS2

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The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. AbstractThis guidance on the assessment of dermal absorption has been developed to assist notifiers, users of test facilities and Member State authorities on critical aspects related to the setting of dermal absorption values to be used in risk assessments of active substances in Plant Protection Products (PPPs). It is based on the 'scientific opinion on the science behind the revision of the guidance document on dermal absorption' issued in 2011 by the EFSA Panel on Plant Protection Products and their Residues (PPR). The guidance refers to the EFSA PPR opinion in many instances. In addition, the first version of this guidance, issued in 2012 by the EFSA PPR Panel, has been revised in 2017 on the basis of new available data on human in vitro dermal absorption for PPPs and wherever clarifications were needed. Basic details of experimental design, available in the respective test guidelines and accompanying guidance for the conduct of studies, have not been addressed but recommendations specific to performing and interpreting dermal absorption studies with PPPs are given. Issues discussed include a brief description of the skin and its properties affecting dermal absorption. To facilitate use of the guidance, flow charts are included. Guidance is also provided, for example, when there are no data on dermal absorption for the product under evaluation. Elements for a tiered approach are presented including use of default values, data on closely related products, in vitro studies with human skin (regarded to provide the best estimate), data from experimental animals (rats) in vitro and in vivo, and the so called 'triple pack' approach. Various elements of study design and reporting that reduce experimental variation and aid consistent interpretation are presented. A proposal for reporting data for assessment reports is also provided. The issue of nanoparticles in PPPs is not addressed. Data from volunteer studies have not been discussed since their use is not allowed in EU for risk assessment of PPPs.

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“…The latter objection is mitigated by a versatile and complex skin model, the Finite Dose Skin Permeation Model (FDSP) made available on the Internet 39 by the US Centers for Disease Control and Prevention (CDC). Unfortunately, it did not perform well with an external validation data set (Buist, 2016).…”

Section: Methodsmentioning

confidence: 96%

Guidance on Dermal Absorption

2012

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The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. AbstractThis guidance on the assessment of dermal absorption has been developed to assist notifiers, users of test facilities and Member State authorities on critical aspects related to the setting of dermal absorption values to be used in risk assessments of active substances in Plant Protection Products (PPPs). It is based on the 'scientific opinion on the science behind the revision of the guidance document on dermal absorption' issued in 2011 by the EFSA Panel on Plant Protection Products and their Residues (PPR). The guidance refers to the EFSA PPR opinion in many instances. In addition, the first version of this guidance, issued in 2012 by the EFSA PPR Panel, has been revised in 2017 on the basis of new available data on human in vitro dermal absorption for PPPs and wherever clarifications were needed. Basic details of experimental design, available in the respective test guidelines and accompanying guidance for the conduct of studies, have not been addressed but recommendations specific to performing and interpreting dermal absorption studies with PPPs are given. Issues discussed include a brief description of the skin and its properties affecting dermal absorption. To facilitate use of the guidance, flow charts are included. Guidance is also provided, for example, when there are no data on dermal absorption for the product under evaluation. Elements for a tiered approach are presented including use of default values, data on closely related products, in vitro studies with human skin (regarded to provide the best estimate), data from experimental animals (rats) in vitro and in vivo, and the so called 'triple pack' approach. Various elements of study design and reporting that reduce experimental variation and aid consistent interpretation are presented. A proposal for reporting data for assessment reports is also provided. The issue of nanoparticles in PPPs is not addressed. Data from volunteer studies have not been discussed since their use is not allowed in EU for risk assessment of PPPs.

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“…In short, relevant search terms and subject areas were selected and reviewed by experts in the field. For refinement, it was investigated whether a draft search strategy developed for Scopus would reveal all 27 papers that are listed in Scopus and were reviewed in a recent publication by Buist (2016). Following revision of the initial search strategy, 26 out of 27 publications were retrieved.…”

Section: Literature Searchmentioning

confidence: 99%

“…In vitro dermal absorption measurements of pesticides are usually executed under finite dose conditions, implying a mathematical model addressing finite dose conditions is needed for this conversion. Two publicly available finite dose models discussed by Buist, one of the authors of this report, in his 2016 thesis, were considered for this purpose: the Dermal Absorption Model for Extrapolation (DAME) (Buist et al, 2010;Buist, 2016) In silico tools for prediction of dermal absorption www.efsa.europa.eu/publications 12 EFSA Supporting publication 2018: EN-1493 The present document has been produced and adopted by the bodies identified above as authors. This task has been carried out exclusively by the authors in the context of a contract between the European Food Safety Authority and the authors, awarded following a tender procedure.…”

Section: Sequential Combination (Dame)mentioning

confidence: 99%

“…For lipophilicity (LogP ow ) and molecular weight (MW) experimental values were used, as provided by the EFSA dataset. The permeability coefficient k p was then transformed to %DA by feeding the predicted k p values to the DAME model (Buist et al 2010 andBuist 2016). For implementation of the DAME model please refer to section 2.5.1.…”

Section: Model Implementationmentioning

confidence: 99%

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Applicability of in silico tools for the prediction of dermal absorption for pesticides

Kneuer

¹

,

Charistou

²

,

Craig

³

et al. 2018

EFSA Supporting Publications

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Based on the “Human in vitro dermal absorption datasets” published as supporting information to the revised EFSA Guidance on Dermal Absorption, in silico models for prediction of absorption across the skin have been evaluated. For this evaluation, a systematic literature search and review was performed, identifying 288 publications describing mathematical models for prediction of dermal absorption. Eleven models potentially relevant to the regulatory assessment of pesticides and which cover a range of approaches were selected for in depth evaluation. This included three mixture models taking into account physicochemical properties of the co‐formulants such as polar surface area, hydrogen bonding or octanol‐water partition coefficients. Additional data on the pesticidal active substances and information on the composition of some of the formulations covered in the dermal absorption dataset were gathered, as these were required as input parameters for the selected models. The models were implemented with settings reflecting as much as possible realistic exposure scenarios and the experimental conditions under which the measured data were obtained. As the majority of the models predicted either maximum flux or the permeation coefficient, further combination with a model achieving translation into percentage absorption was required. This was done with and without consideration of the lag time. Only one model directly predicted percentage dermal absorption, which was a spreadsheet‐based single substance model taking into consideration several skin parameters, experimental conditions, various physicochemical properties of the active substance and the type of vehicle. Statistical analysis of model predictions revealed overall low concordance with measured values, thereby limiting regulatory acceptance. Additional analysis was performed on the results of two mixture models and the above mentioned complex single substance model which showed moderate correlation between predicted and measured data. Options to improve model performance were discussed and Bayesian random effects modelling was explored to adjust predicted percentage dermal absorption to measured data as was model combination. When taking into account observed uncertainties of predictions, one of the models may provide a Tier 2 tool to estimate dermal absorption value in the absence of adequate experimental data when the predicted values are in the range of 10 to 70%. However, further work is needed to better understand the effect of co‐formulants on dermal absorption of pesticides and to improve model predicitivity.

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Dermal absorption and toxicological risk assessment : pitfalls and promises

Cited by 4 publications

References 43 publications

Guidance on dermal absorption

Guidance on dermal absorption

Guidance on Dermal Absorption

Applicability of in silico tools for the prediction of dermal absorption for pesticides

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