Computational Nanotoxicology

Challenges and Perspectives

Agnieszka Gajewicz, Tomasz Puzyn, Agnieszka Gajewicz, Tomasz Puzyn

• Publisher: Jenny Stanford Publishing
• Year: 2019
• Print ISBN: 9789814800648
• eBook ISBN: 9781000681420
• Topic: Medizin
• Subtopic: Biotechnologie in der Medizin

The development of computational methods that support human health and environmental risk assessment of engineered nanomaterials (ENMs) has attracted great interest because the application of these methods enables us to fill existing experimental data gaps. However, considering the high degree of complexity and multifunctionality of ENMs, computational methods originally developed for regular chemicals cannot always be applied explicitly in nanotoxicology. This book discusses the current state of the art and future needs in the development of computational modeling techniques for nanotoxicology. It focuses on (i) computational chemistry (quantum mechanics, semi-empirical methods, density functional theory, molecular mechanics, molecular dynamics), (ii) nanochemoinformatic methods (quantitative structure–activity relationship modeling, grouping, read-across), and (iii) nanobioinformatic methods (genomics, transcriptomics, proteomics, metabolomics). It reviews methods of calculating molecular descriptors sufficient to characterize the structure of nanoparticles, specifies recent trends in the validation of computational methods, and discusses ways to cope with the uncertainty of predictions. In addition, it highlights the status quo and further challenges in the application of computational methods in regulation (e.g., REACH, OECD) and in industry for product development and optimization and the future directions for increasing acceptance of computational modeling for nanotoxicology.

Chapter 1

Modeling of Nanomaterials for Safety Assessment: From Regulatory Requirements to Supporting Scientific Theories

Lara Lamon, David Asturiol, Karin Aschberger, Jos Bessems, Kirsten Gerloff, Andrea-Nicole Richarz, and Andrew Worth

European Commission, Joint Research Centre, Ispra, Italy
[email protected]

In this chapter, we describe different theories relevant to understanding the behavior, fate, and effects of manufactured nanomaterials (NMs). In the first part, background information on regulatory requirements related to NMs is reported, along with an overview of risk assessment as an approach to address risks posed by exposure to NMs. The second part is dedicated to the identification of key physicochemical properties that are relevant for characterizing and understanding the behavior (fate and biological effects) of NMs. An understanding of the scientific basis of NM behavior is important in the development and application of standard and alternative approaches to animal testing.

1.1 Introduction

Manufactured nanomaterials (NMs) are being increasingly included in a variety of goods and products because of their novel physical and chemical characteristics [1]. There are concerns, however, that the very same characteristics may also lead to environmental and human health risks. In the European Union (EU), NMs have been defined in legal terms. Legally binding definitions are included in the Cosmetic Products Regulation (EC) 1223/2009, the Biocidal Products Regulation (EU) 528/2012/EC, and Regulation (EU) 1169/2011 on Provisions of Food Information to the Consumers (FIC Regulation). In addition, in 2011, the EC adopted a recommendation (2011/696/EU) on the definition of the term “nanomaterial” with the goal to promote consistency in the interpretation of said term for legislative and policy purposes in the EU [2]. This definition is broadly applicable across different regulatory sectors but not legally binding. The EC definition applies to all particulate NMs regardless of their origin: natural, incidental, or manufactured. It refers to a size range of 1–100 nm and also establishes a threshold of 50% or more particles <100 nm in the number size distribution, which in specific cases can be lowered to 1%. This size range has been proposed in several definitions, including ISO/TS 12805:2011 by the International Organization for Standardization (ISO).

The NM definition in the Biocidal Products Regulation is based on the EC definition, while the definitions for cosmetic products and food were implemented previously and contain some relevant differences. Although the size range is comparable (<100 nm) the main difference is the restriction to intentionally manufactured (or produced) materials, which is further restricted for cosmetic products to insoluble or biopersistent materials. This size range has been proposed in several definitions, including ISO/TS 12805:2011 by the ISO. The revision of the EC definition foresees the consequent harmonization in cosmetic products and food regulations [3].

To evaluate and manage the environmental and health impacts of NMs, chemical risk assessment (CRA) is applied to assess the potential risks caused by NMs. CRA is a process by which scientific and regulatory principles are applied in a systematic approach to address qualitatively and/or quantitatively the likelihood that humans or environmental species may be harmed due to potential exposure to chemicals. Regulation 1907/2006 concerning the Registration, Authorisation and Restriction of Chemicals (REACH) [4, 5] requests registrants to demonstrate the safe use of chemical substances, including those in nanoform. REACH aims to ensure chemical safety while promoting innovation and competitiveness as well as reducing the use of in vivo testing through the use of nonanimal alternatives, such as in silico, in vitro, and in chemico methods; read-across; and weight of evidence.

This chapter describes regulatory information requirements for NMs, with a special focus on REACH, as well as the scientific and technical basis for understanding their behavior (fate and effects). The REACH regulation (Section 1.2) and the risk assessment approach (Section 1.3) are briefly introduced, and an overview is given (Section 1.4) of key physicochemical (PC) properties that are relevant for characterizing and understanding the behavior (fate and biological effects) of NMs. This chapter also touches on the scientific basis of NM behavior (Section 1.5), since this understanding is important in the development and application of standard (Section 1.6) and alternative approaches to animal testing (Section 1.7).

1.2 Information Requirements for Risk Assessment: Legal Provisions and Guidance

In the EU, substance- and sector-specific pieces of legislation provide a binding framework to ensure the safety of substances and products on the market (manufactured or imported). NMs are implicitly covered or explicitly addressed (e.g., cosmetics and biocidal products), depending on the applications and applicable legislation. The “substance” definition of REACH applies to chemicals irrespective of size, shape, and physical state, and thus its provisions apply also to NMs, even if there are currently no provisions that explicitly refer to NMs [5, 6].

1.2.1 Chemical Substances under REACH

According to the Second Regulatory Review on Nanomaterials [7], REACH sets the best possible framework for the risk management of NMs when they occur as substances or mixtures. More specific requirements may be introduced through the possible revision of some of the REACH annexes.

The provisions of REACH contain extensive obligations for manufacturers to generate and assess data on chemicals (including PC properties, manufacture, uses, and hazardous properties) and to demonstrate that risks can be adequately controlled during their use. All chemicals manufactured or imported in quantities higher than 1 ton/year (t/y) have to be registered with basic information requirements. In addition, for all chemicals manufactured or imported in quantities higher than 10 t/y, a chemical safety assessment has to be performed and documented in the chemical safety report.

Under REACH, different forms of one substance (e.g., solids, suspensions, powders, and NMs) are considered within a single registration of a substance [7]. However, the registrant must ensure the safety of all included forms and provide adequate information to address the different forms in the registration. This means that more than one endpoint study for different forms may be required or different forms within one registration may have different hazard classifications. The REACH approach to hazard assessment and risk characterization, with its built-in flexibility, makes it suitable for NMs [7]. On the basis of REACH Implementation Project on Nanomaterials (RIPoN) reports [8], the European Chemicals Agency (ECHA) has published specific guidance for NMs [9, 10, 11]. In addition, ECHA has set up an NMs working group to give advice on scientific and technical issues in relation to NMs under REACH.

The information collected or generated under REACH is used, for example, for priority setting, classification and labeling, chemical safety assessment, and PBT/vPvB¹ assessment. It needs to be adequate for both classification and labeling and for chemical safety assessment if the latter is required (triggered by classification or PBT assessment). REACH Article 10 defines the information requirements to be submitted for registration, and Annex I outlines the general provisions for assessing substances and preparing chemical safety reports. Annexes VII to X more specifically detail the standard information requirements. Information on intrinsic properties is mainly dependent on the tonnage at which the substance is brought on the market. Column 2 of each of these annexes (VII to X) defines the specific rules for adaptation of the standard information requirements as defined in Column 1, that is, when a specific step (test) does not need to be conducted or further studies may be considered if...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• Preface
• 1. Modeling of Nanomaterials for Safety Assessment: From Regulatory Requirements to Supporting Scientific Theories
• 2. Current Developments and Recommendations in Computational Nanotoxicology in View of Regulatory Applications
• 3. Physicochemical Properties of Nanomaterials from in silico Simulations: An Introduction to Density Functional Theory and Beyond
• 4. Bionano Interactions: A Key to Mechanistic Understanding of Nanoparticle Toxicity
• 5. From Modeling Nanoparticle–Membrane Interactions toward Nanotoxicology
• 6. Descriptors in Nano-QSAR/QSPR Modeling
• 7. Nano-QSAR for Environmental Hazard Assessment: Turning Challenges into Opportunities
• 8. Read-Across to Fill Toxicological Data Gaps: Good Practice to Ensure Success with Nanoparticles
• 9. Computational Methods of Interspecies Nanotoxicity Extrapolation: A Step toward the Future
• 10. On Error Measures for Validation and Uncertainty Estimation of Predictive QSAR Models
• 11. Green Toxicology Meets Nanotoxicology: The Process of Sustainable Nanomaterial Development and Use
• 12. Issues for and Examples of Computational Design of “Safe-by-Design” Nanomaterials
• Index