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 edited by
Agnieszka Gajewicz | Tomasz Puzyn

Computational Nanotoxicology
Challenges and Perspectives
Computational Nanotoxicology
Computational Nanotoxicology
Challenges and Perspectives

edited by
Agnieszka Gajewicz
Tomasz Puzyn
Published by
Jenny Stanford Publishing Pte. Ltd.
Level 34, Centennial Tower
3 Temasek Avenue
Singapore 039190

Email: [email protected]
Web: www.jennystanford.com

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library.

Computational Nanotoxicology: Challenges and Perspectives

Copyright © 2020 by Jenny Stanford Publishing Pte. Ltd.
All rights reserved. This book, or parts thereof, may not be reproduced in any form
or by any means, electronic or mechanical, including photocopying, recording
or any information storage and retrieval system now known or to be invented,
without written permission from the publisher.

For photocopying of material in this volume, please pay a copying fee through
the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923,
USA. In this case permission to photocopy is not required from the publisher.

ISBN 978-981-4800-64-8 (Hardcover)

ISBN 978-1-000-68088-1 (eBook)
 Contents

Preface xv

1. Modeling of Nanomaterials for Safety Assessment:

From Regulatory Requirements to Supporting
Scientific Theories 1
Lara Lamon, David Asturiol, Karin Aschberger,
Jos Bessems, Kirsten Gerloff, Andrea-Nicole Richarz,
and Andrew Worth
1.1 Introduction 2
1.2 Information Requirements for Risk Assessment:
Legal Provisions and Guidance 3
1.2.1 Chemical Substances under REACH 4
1.2.2 Cosmetic Products 7
1.2.3 Biocidal Products 8
1.2.4 Plant Protection Products 9
1.2.5 Food Production 9
1.3 Risk Assessment 10
1.4 Properties That Drive NM Behavior
(Fate and Toxicity) 13
1.4.1 Theories Underlying Environmental
and Biological Fate 22
1.5 Understanding NMs’ Fate and Toxicity 26
1.5.1 Theories Underlying Environmental
and Biological Fate 26
1.5.1.1 Agglomeration and
aggregation kinetics in fluid
media 27
1.5.1.2 DLVO theory 27
1.5.1.3 Smoluchowski–Friedlander
theory 30
1.5.1.4 Fractal approaches 33
1.5.2 Human Kinetics 34
1.5.2.1 Preabsorption processes 34
1.5.2.2 Absorption 37
vi Contents

1.5.2.3 Distribution 39
1.5.2.4 Metabolism/Dissolution/
Transformation/Bio-nano
interaction 39
1.5.2.5 Excretion 41
1.5.2.6 Elimination (sum of
solubilization and excretion) 42
1.5.3 Toxicodynamics 42
1.6 Standard Test Guideline Methods for Toxicity
Testing 46
1.7 Alternative Approaches to Animal Testing 49
1.7.1 Adverse Outcome Pathways 50
1.7.2 In silico Methods 51
1.7.2.1 Supervised and unsupervised
methods 51
1.7.2.2 QSAR/QSPR 54
1.7.2.3 Validation of QSARs for
regulatory purposes 58
1.7.2.4 Expert systems 58
1.7.2.5 Applicability of QSAR/QSPR
approaches to NMs 59
1.7.2.6 Physiologically based kinetic
modeling 60
1.7.3 In vitro Methods 64
1.7.4 Grouping and Read-Across 69
1.7.5 Weight of Evidence 71
1.7.6 Integrated Approaches to Testing
and Assessment 73
1.8 Concluding Remarks 75

2. Current Developments and Recommendations in

Computational Nanotoxicology in View of Regulatory
Applications 99
Andrea-Nicole Richarz, Lara Lamon,
David Asturiol, and Andrew P. Worth
2.1 Introduction 100
2.2 Computational Nanotoxicology Research
Project Landscape 101
2.2.1 European Nanosafety Research
Activities 101
 Contents vii

2.2.2 Related International Activities 123

2.3 Challenges and Needs for the Development
and Use of Computational Methods 125
2.4 Progress against the Challenges and Needs 128
2.4.1 Results from EU FP7-Funded
Research Projects 128
2.4.2 Horizon 2020 Research Projects 132
2.4.3 Other Activities 135
2.5 Conclusions from the Research Landscape
Review 136
2.5.1 Conclusions on the Needs Addressed 136
2.5.2 Recommendations for Nanosafety
Research 137
2.6 Overall Conclusions on the Availability and
Applicability of Computational Approaches
for Nanosafety Assessment 138
2.6.1 Inherent Scientific Uncertainties 140
2.6.2 Data Quality and Variability 140
2.6.3 Model Landscape and Regulatory
Relevance 142
2.6.4 Model Accessibility and Visibility 142
2.6.5 Practicality of Performing
Read-Across for Nanomaterials 144
2.6.6 Need for Infrastructure 145

3. Physicochemical Properties of Nanomaterials from

in silico Simulations: An Introduction to Density
Functional Theory and Beyond 157
Laura Escorihuela, Alberto Fernández, Robert Rallo,
and Benjamí Martorell
3.1 Introduction 158
3.2 Classic Density Functional Theory:
Jacob’s Ladder 161
3.2.1 Local Density Approximation 163
3.2.2 GGA and Meta-GGA 163
3.2.3 Hybrid Functionals 165
3.2.4 The Limits of Classic DFT 166
3.3 Beyond Classic DFT 168
3.3.1 DFT+U 168
3.3.2 GW 170
viii Contents

3.3.3 Density Functional Tight Binding 171

3.3.4 LS-DFT 174
3.3.5 Time-Dependent DFT 175
3.3.6 Implicit Solvation Models 176
3.4 Concluding Remarks 180

4. Bionano Interactions: A Key to Mechanistic

Understanding of Nanoparticle Toxicity 189
David Power, Stefano Poggio, Hender Lopez, and
Vladimir Lobaskin
4.1 Introduction 190
4.2 Advanced Descriptors of the Bionano Interface 190
4.2.1 Protein Corona 190
4.2.2 Nanoparticle Descriptors and QSARs 192
4.2.3 Biomolecule Descriptors 193
4.2.4 Interaction Descriptors 194
4.3 Multiscale Modeling of the Bionano Interface 194
4.3.1 General Methodology 194
4.3.2 Coarse-Grained Protein Model 196
4.3.3 Coarse-Grained Nanoparticles 197
4.3.4 Generation of Surface Pair Potentials 198
4.3.5 Generation of the Core Potential 201
4.3.6 Calculation of the Adsorption Energy 202
4.3.7 From United-Atom to United–Amino
Acid Description 203
4.4 Application of the Method 204
4.4.1 Protein Descriptors 204
4.4.2 Bionano Interface Descriptors 205
4.4.3 United–Amino Acid Model 208
4.5 Conclusions 210

5. From Modeling Nanoparticle–Membrane Interactions

toward Nanotoxicology 217
Karandeep Singh, Qingfen Yu, Sabyasachi Dasgupta,
Gerhard Gompper, and Thorsten Auth
5.1 Particles at Membranes 218
5.1.1 Penetration vs. Wrapping 218
5.1.2 Chemically Specific vs. Generic Models 219
5.1.3 Nanoparticle-Wrapping Endpoints 220
 Contents ix

5.2 The Helfrich Model 222

5.3 Predicting Wrapping 223
5.3.1 Spherical Nanoparticles 225
5.3.2 Nonspherical Nanoparticles 226
5.3.3 Soft Nanoparticles 228
5.3.4 Dosage Effects: Cooperative Wrapping 229
5.3.5 Multicomponent Biological
Membranes 231
5.3.6 Actual and Spontaneous Membrane
Curvature 232
5.4 Experimental Validation 234
5.5 Toward Nanotoxicology 236

6. Descriptors in Nano-QSAR/QSPR Modeling 245

Ewelina Wyrzykowska, Karolina Jagiello,
Bakhtiyor Rasulev, and Tomasz Puzyn
6.1 Nano-QSAR/QSPR Modeling: Benefits and
Challenges 246
6.2 Idea of Descriptors 248
6.2.1 Size Aspect 250
6.2.2 Chemical Composition Aspect 252
6.2.3 Surrounding Aspect 253
6.3 The First Nano-QSAR Model and Its
Recalculations 255
6.3.1 Quantum-Mechanical Descriptors 255
6.3.2 SMILES-Based Optimal Descriptors 258
6.3.3 Improved SMILES-Based Optimal
Descriptors 259
6.3.4 Periodic Table Descriptors 262
6.3.5 SiRMS Descriptors 265
6.3.6 Liquid Drop Model Descriptors 268
6.3.7 Metal–Ligand Binding Characteristic 270
6.3.8 Full-Particle Descriptors 271
6.4 Other Nanodescriptors 276
6.4.1 Perturbation Approach 277
6.4.2 Image Descriptors 282
6.4.3 Reusing Toxicity Measurements 285
6.4.4 Mixture Descriptors 287
6.5 Summary and Future Perspectives 290
x Contents

7. Nano-QSAR for Environmental Hazard Assessment:

Turning Challenges into Opportunities 303
Willie Peijnenburg, Guangchao Chen, and
Martina Vijver
7.1 Introduction 304
7.1.1 General 304
7.1.2 Safety Concerns 305
7.1.3 Toxicity of ENMs 306
7.1.4 Environmental Risk Assessment and
Safe-by-Design Development of ENMs 308
7.1.5 Handling Nanosafety with the Aid of
Computational Toxicology 310
7.2 Inventory of Existing Toxicity Data of
Metal-Based ENMs 312
7.2.1 Need for Reliable Experimental Data 312
7.2.2 Overview of Experimental Data 313
7.2.3 Suitability of Experimental Data for
QSAR Modeling 316
7.3 Recent Advances toward the Development of
QSARs for Metallic ENMs 318
7.3.1 Representation of the Intrinsic
Properties of ENMs 318
7.3.2 Overview of Models and Modeling
Approaches 321
7.3.2.1 General considerations 321
7.3.2.2 Sources of data actually
used for modeling 325
7.3.2.3 Existing nano-QSARs 340
7.3.2.4 Interpretation of mechanisms
of ENM biological activities
using the models developed 355
7.4 Conclusions and Outlook 363

8. Read-Across to Fill Toxicological Data Gaps:

Good Practice to Ensure Success with Nanoparticles 381
Mark T.D. Cronin, Steven J. Enoch, Judith C. Madden,
and Andrea-Nicole Richarz
8.1 Introduction 382
8.2 Why and When Read-Across Is Used to
Predict Toxicity 383
 Contents xi

8.2.1 Ethics 383

8.2.2 Cost 383
8.2.3 Compliance with Regulatory Pressures 384
8.2.4 Expectation of Common Properties
within a Group 385
8.2.5 The Necessity for Alternatives due
to the Difficulty of Testing 385
8.2.6 Lack of Data for New Nanoparticles
and New Toxicological Problems 386
8.2.7 Opportunities to Utilize New Methods
and Techniques 386
8.3 Good Practice in Read-Across: Ensuring
Success 387
8.3.1 Proper Definition of Structure 387
8.3.2 Understanding How Structure Affects
Toxicology and Mechanism of Action:
Appropriate Grouping 388
8.3.3 High-Quality Experimental Data to
Anchor the Read-Across 389
8.3.4 Use Appropriate Computational
Tools for Read-Across 390
8.3.5 Justification of Nanoparticle
Similarity and Read-Across Hypothesis 391
8.3.6 Inclusion of Toxicokinetics for Members
of a Category 391
8.3.7 Identifying and Defining Uncertainties 392
8.3.8 Assessing and Increasing Confidence 393
8.3.9 Description and Documentation of the
Read-Across Prediction 394
8.4 Conclusions 394

9. Computational Methods of Interspecies Nanotoxicity

Extrapolation: A Step toward the Future 401
Supratik Kar, Shinjita Ghosh, and Jerzy Leszczynski 401

9.1 Introduction 402

9.2 Nanotoxicity 405
9.2.1 Carbon NMs 407
9.2.2 Metal Oxide NMs 407
9.3 Role of Computational Methods in
Nanotoxicity Predictions 408
xii Contents

9.4 Interspecies Model: Extrapolation through

Toxicity–Toxicity Correlation 410
9.5 Fundamental of i-QSTR Correlation 412
9.6 Necessity of Interspecies Extrapolation 415
9.7 Computational Interspecies Nanotoxicity
Models 417
9.8 Species and Endpoints for an Interspecies
Model 421
9.9 Future Direction 421
9.10 Conclusion 426

10. On Error Measures for Validation and Uncertainty

Estimation of Predictive QSAR Models 437
Supratik Kar Kunal Roy, and Jerzy Leszczynski
10.1 Introduction 438
10.2 Concept and Significance of Validation of
QSAR Models 441
10.3 Validation Strategies 442
10.3.1 Internal Validation or Cross-Validation 442
10.3.2 External Validation 443
10.3.3 True External Validation 444
10.3.4 Double Cross-Validation 444
10.3.5 Data Randomization or Y-Scrambling 445
10.3.6 Bias and Variance in Prediction Errors 445
10.4 Validation Metrics 448
10.4.1 Metrics for Classification-Based QSAR
Models 448
10.4.2 Metrics for Regression-Based QSAR
Models 453
10.5 Model Uncertainty Aspects 462
10.5.1 Derivation of Uncertainty in QSAR
Predictions: Mathematical Formalization 462
10.6 Prediction Confidence and Conformal
Predictions 464
10.6.1 Conformal Prediction Errors in
Regression 465
10.6.2 Conformal Prediction Errors in
Classification 467
10.7 Randomization: Assessment of Chance
Correlation 469
 Contents xiii

10.7.1 Randomization Metrics cRp2 470

10.7.2 Q2yrand and R2yrand 470
10.8 Applicability Domain and Reliability
of Predictions 471
10.9 Open-Source Software Tools for QSAR Model
Development and Validation 479
10.10 Conclusion 488

11. Green Toxicology Meets Nanotoxicology:

The Process of Sustainable Nanomaterial
Development and Use 495
Alexandra Maertens and Thomas Hartung
11.1 Green Toxicology 496
11.2 Green Toxicology Principles Applied to
Nanomaterials 497
11.2.1 Principle 1: Design Benign 497
11.2.2 Principle 2: Test Early, Fail Safe 499
11.2.3 Principle 3: Avoid Exposure and
thus Testing Needs 500
11.2.4 Principle 4: Make Testing Sustainable 501
11.2.5 Principle 5: Adopt Test Strategies
That Are Not Mature Enough for
Regulatory Use 502
11.2.6 Principle 6: Green Toxicology as
Twenty-First-Century Toxicology 502
11.3 Going Forward 503

12. Issues for and Examples of Computational Design

of “Safe-by-Design” Nanomaterials 507
David A. Winkler
12.1 Introduction 508
12.2 Biocorona: Biologically Relevant Entity 510
12.3 System Complexity, Reproducibility, Data
Generation, and Curation 513
12.3.1 Complexity of Nanoparticle–Biology
Interactions 513
12.3.2 Experimental Issues 514
12.3.3 Data Availability, Reliability, and
Processing Issues 515
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