Dermal Absorption and Toxicological Risk Assessment: Pitfalls Promises Dermal Absorption and Toxicological Risk Assessment: Pitfalls and Promises
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Dermal absorption and toxicological risk assessment: Pitfalls Promises Dermal absorption and toxicological risk assessment: Pitfalls and Promises Harrie Buist Harrie Buist DERMAL ABSORPTION AND TOXICOLOGICAL RISK ASSESSMENT: PITFALLS AND PROMISES Harrie Buist Thesis committee Promotors Prof. Dr R.A. Woutersen Professor of Translational Toxicology Wageningen University Prof. Dr I.M.C.M. Rietjens Professor of Toxicology Wageningen University Co-promotor Dr J.J.M. van de Sandt Head of the Department of Metabolic Health Research TNO, Leiden Other members Prof. Dr B.J. Blaauboer, Utrecht University Dr C. de Heer, Dutch Central Committee on Research Involving Human Subjects, The Hague Prof. Dr G.F. Wiegertjes, Wageningen University Prof. em. F.M. Williams, Newcastle University, United Kingdom This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in Food Technology, Agrobiotechnology, Nutrition and Health Sciences). DERMAL ABSORPTION AND TOXICOLOGICAL RISK ASSESSMENT: PITFALLS AND PROMISES Harrie Buist Thesis submitted in fulfilment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. Dr A.P.J. Mol, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Friday 13 May 2016 at 4 p.m. in the Aula. Harrie Buist Dermal absorption and toxicological risk assessment: pitfalls and promises 200 pages. PhD thesis, Wageningen University, Wageningen, NL (2016) With references, with summary in English ISBN 978-94-6257-727-5 Dermal absorption and toxicological risk assessment - Pitfalls and promises Contents page 5 Contents 1 Introduction 11 1.1 Background 12 1.1.1 Importance of the dermal route of exposure in risk assessment 12 1.1.2 Skin structure 13 1.1.3 The process of dermal absorption 15 1.1.4 Methods to estimate dermal absorption 16 1.1.5 Factors influencing absorption 33 1.2 Objectives and outline of this thesis 39 1.2.1 Objective 39 1.2.2 Outline 40 1.3 References 41 2 Relative absorption and dermal loading of chemical substances: Consequences for risk assessment 51 2.1 Abstract 52 2.2 Introduction 52 2.3 Materials and methods 53 2.4 Results 54 2.5 Discussion and conclusions 65 2.5.1 Relation between dermal loading and relative absorption 65 2.5.2 Consequences for risk assessment 65 2.6 Conclusions 66 Acknowledgments 66 Appendix A. Supplementary data 67 2.7 References 67 3 The influence of repeated exposure to biocides on the skin barrier: A literature study 73 3.1 Abstract 74 3.2 Introduction 74 3.3 Methods 75 3.3.1 Literature scan on dermal absorption after repeated exposure 75 3.3.2 Inventory of biocides admitted in the Netherlands 75 3.4 Results 76 3.5 Discussion and conclusions 88 page 6 Dermal absorption and toxicological risk assessment - Pitfalls and promises Acknowledgements 90 3.6 References 90 4 Effects of single and repeated exposure to biocidal active substances on the barrier function of the skin in vitro 95 4.1 Abstract 96 4.2 Introduction 96 4.3 Materials and methods 99 4.3.1 Selection of biocidal active substances 99 4.3.2 In vitro skin permeability assay 100 4.4 Results 102 4.5 Discussion and conclusions 105 4.5.1 Characteristics of the test system 105 4.5.2 Influence of biocide exposure on skin permeability 106 Acknowledgments 107 4.6 References 107 5 Dermatokinetics of didecyldimethylammonium chloride and the influence of some commercial biocidal formulations on its dermal absorption in vitro 111 5.1 Abstract 112 5.2 Introduction 112 5.3 Materials and methods 113 5.3.1 In vitro experiments 113 5.3.2 Statistics 115 5.4 Results 115 5.5 Discussion and conclusions 117 Acknowledgments 121 5.6 References 121 6 New in vitro dermal absorption database and the prediction of dermal absorption under finite conditions for risk assessment purposes 123 6.1 Abstract 124 6.2 Introduction 124 6.3 Materials and methods 126 6.3.1 In vitro dermal absorption experiments 126 page 7 Contents 6.3.2 Selection of the chemicals 128 6.3.3 Calculation of kp and lag time in in vitro infinite dose experiments 128 6.3.4 Calculation of experimentally determined relative absorption 129 6.3.5 Prediction of absorption in vitro under finite dose conditions 130 6.3.6 Correction factor (f) for steady state distribution into the stratum corneum 130 6.3.7 Log KOW 132 6.3.8 QSPRs for kp 132 6.3.9 Statistical analysis 133 6.4 Results and discussion 133 6.4.1 Measured and predicted kp values 133 6.4.2 Prediction of absorption 133 6.5 Conclusions 138 Acknowledgments 139 6.6 References 139 6.7 Glossary (including abbreviations) 141 7 General discussion 143 7.1 Introduction 144 7.2 Dermal loading and absorption 144 7.3 Skin irritants/corrosives and absorption 146 7.4 Repeated dermal exposure and absorption 150 7.5 Formulations and absorption 152 7.6 Prediction of dermal absorption for risk assessment 153 7.7 Application in regulatory risk assessment 157 7.8 Future perspectives 162 7.8.1 Dermal loading and relative absorption 162 7.8.2 Skin corrosive/irritant substances 162 7.8.3 Repeated dermal exposure 162 7.8.4 Vehicles and formulations 163 7.8.5 Prediction of dermal absorption 164 7.9 General conclusions 165 Acknowledgements 166 7.10 References 166 page 8 Dermal absorption and toxicological risk assessment - Pitfalls and promises 8 Summary 169 9 Glossary and abbreviations 175 9.1 Glossary 176 9.2 Abbreviations 182 9.3 References 185 Acknowledgements 187 Curriculum vitae 191 List of publications 193 Overview of completed training activities 197 page 9 Dermal absorption and toxicological risk assessment - Pitfalls and promises 1 Introduction page 11 Chapter 1 Introduction 1.1 Background 1.1.1 Importance of the dermal route of exposure in risk assessment Dermal contact is an important exposure route, as people are exposed to a variety of substances and products via the dermal route, either directly or indirectly while at work, at home or in public space (WHO, 2013). Under occupational conditions, dermal exposure occurs mainly as a result of splashes, spills or drifts, during the application itself or from contact with contaminated surfaces. Pesticides, organic solvents and metalworking fluids are seen to be important contributors to adverse health effects due to occupational exposure via the dermal route (WHO, 2013). In non-occupational settings, cosmetics, clothing and household products are the most relevant commodities with respect to dermal exposure, because of their conditions of use. For example, the use of cosmetics and clothing results in repeated direct skin contact, often of a large body surface area over a prolonged period of time (WHO, 2013). In the context of dermal exposure, three different types of toxicological effects can be distinguished: local effects, sensitization and systemic effects (WHO, 2013). Local effects are effects that occur at the portal of entry without the toxic compound becoming systemically available (ECHA, 2012a). Examples of local effects are skin irritation and skin tumours. By definition, absorption is of no relevance for these effects, although penetration of one or more skin layers may be relevant, e.g. in the case of tumours of the dermis, which lies immediately below the epidermis (see section 1.1.2 for more details on skin anatomy). In the latter case, comparative dermal penetration data (between tested animal and human), preferably including skin distribution, may be of importance in risk assessment in order to extrapolate animal dermal toxicity data to human exposure conditions. Sensitizing effects are allergic responses in susceptible individuals, in which, after a first initialising (sensitising) dermal exposure, subsequent dermal exposures may cause allergic contact dermatitis or atopic dermatitis, characterised by symptoms such as erythema, oedema, and vesiculation (ECHA, 2012b). At first contact (the induction phase of skin sensitization), a chemical allergen enters the viable epidermis, after passing the stratum corneum, and forms a stable association with a protein (“haptenation”), which leads to the local secretion of proinflammatory cytokines and other signal proteins (Kimber et al., 2011). The signal proteins activate Langerhans cells, which take up the haptenated allergen and move it from the epidermis to draining lymph nodes, where they initiate the cellular interactions leading to sensitization. Adverse health effects now may be initiated by renewed exposure of the sensitized person to this allergen, as allergen-specific T-cells gather at the place the chemical entered the viable epidermis, become activated and initiate page 12 Dermal absorption and toxicological risk assessment - Pitfalls and promises the immune reactions that lead to the symptoms of allergic contact dermatitis (elicitation phase). Both in the induction and the elicitation phase, the chemical allergen only needs to pass the stratum corneum and reach the viable epidermis to induce the adverse effect, without the need to become systemically available. In general, skin penetration data are not used in risk assessment with respect to skin sensitization, as in most cases the available data do not allow a quantitative assessment (ECHA, 2012). For sensitizers for which dose response data are available (mainly Local Lymph Node Assays aimed at establishing EC3- values), the contribution of the degree of epidermal bioavailability to their potency is not clear (Jaworska et al., 2013), which hampers the extrapolation of animal sensitization data to human exposure conditions or the distinction between one human exposure condition and another. Systemic effects are effects that normally occur away from the portal of entry, after a substance has passed a physiological barrier like the skin, and has become systemically available (ECHA, 2012), i.e. has entered systemic circulation.