ISO/TR 22019:2019

Nanotechnologies — Considerations for performing toxicokinetic studies with nanomaterials

This document describes the background and principles for toxicokinetic studies relevant for nanomaterials. Annex A shows the definitions for terminology with respect to toxicokinetics as used in OECD TG 417:2010.

Nanotechnologies - Considérations pour réaliser des études toxico cinétiques de nanomatériaux

General Information

• Status: Published
• Publication Date: 21-May-2019
• ICS: 07.120 - Nanotechnologies
• Technical Committee: ISO/TC 229 - Nanotechnologies
• Drafting Committee: ISO/TC 229/WG 3 - Health, Safety and Environmental Aspects of Nanotechnologies
• Current Stage: 6060 - International Standard published
• Completion Date: 22-May-2019

Standards Content (Sample)

TECHNICAL ISO/TR
REPORT 22019
First edition
2019-05
Nanotechnologies — Considerations
for performing toxicokinetic studies
with nanomaterials
Nanotechnologies - Considérations pour réaliser des études toxico
cinétiques de nanomatériaux
Reference number
ISO/TR 22019:2019(E)
©
ISO 2019

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ISO/TR 22019:2019(E)

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Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Abbreviations. 3
5 Importance of toxicokinetic information for risk assessment of nanomaterials .3
5.1 General . 3
5.2 Possible use of toxicokinetic information . 4
5.3 Key toxicokinetic issues for nanomaterials . 5
6 Factors influencing the toxicokinetics of nanomaterials . 5
6.1 Dissolution rate . 5
6.2 Physical chemical properties determinant for toxicokinetic behavior . 6
7 Analytical challenges .10
7.1 General .10
7.2 Analysis of element .10
7.3 Analysis of element radiolabel or fluorescence label .11
7.4 Determination of particles .12
7.5 Limit of detection .13
8 Issues relevant for dosing conditions .13
8.1 General .13
8.2 Dose metrics .14
9 Absorption of nanomaterials .15
9.1 General .15
9.2 Skin .15
9.3 Gastrointestinal (GI) tract .16
9.4 Respiratory tract.18
10 Distribution .22
10.1 General .22
10.2 Organ distribution . .22
10.3 Transport across the placenta, BBB and to reproductive organs .23
11 Metabolism/degradation .24
12 Excretion .24
13 Conclusions .25
Annex A (informative) Definitions as used in OECD Test Guideline 417:2010 .29
Annex B (informative) Quantitation methods for nanomaterials, advantages and challenges .32
Bibliography .39
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Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
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ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
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.org/iso/foreword .html.
This document was prepared by Technical Committee ISO/TC 229, Nanotechnologies.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www .iso .org/members .html.
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Introduction
Nanomaterials (NMs) are a family of chemicals that, like any other chemicals, can exert a range of
toxicities. Toxicokinetics can support the safety evaluation of compounds including NMs by identifying
potential target organs, and especially for NMs, the potential for persistence in organs (including
cellular uptake and compartmentalization). Also, toxicokinetic information can be used to evaluate if
a NM behaves differently from a similar NM or bulk material with the same chemical composition, e.g.
with regard to barrier penetration. As for all studies with NMs, a proper characterization of the NM
dispersions or aerosols used in the toxicokinetic studies is essential.
Importance of toxicokinetic information for risk assessment (of nanomaterials)
Toxicokinetics describes the absorption, distribution, metabolism and excretion (ADME) of foreign
compounds in the body with time. It links the external exposure with the internal dose and is thus a
key aspect for toxicity. If a NM is absorbed by the body through any of the potential exposure routes
(oral, respiratory, dermal) it can enter into the blood or lymph circulation. Subsequent distribution
to internal organs determines potential target tissues and potential toxicity. Alternatively, NMs can
be intravenously administered (e.g. as nanomedicine) thus directly entering the blood circulation,
potentially resulting in wide spread tissue distribution. Toxicokinetics therefore aids in the design of
targeted toxicity studies and in identifying potential target organs and can thus also provide relevant
information for justification or waiving of toxicity studies. In addition, toxicokinetic information can be
useful as basis for grouping and read-across of NMs. Risk assessments based on internal concentrations,
determined using toxicokinetic information, can be more realistic than risk assessments based
on external doses, as nanoparticles (NPs) can show specific tissue distribution and accumulation.
Toxicokinetic studies can be used to build toxicokinetic models, especially physiologically based
pharmacokinetic (PBPK) models, which then can be used to extrapolate experimental toxicity data to
other species, tissues, exposure routes, exposure durations and doses. Due to the accumulation of some
NPs, the ability to extrapolate to longer exposure durations is of special importance for NMs.
Why a technical report specifically for nanomaterials?
A considerable body of published literature, including many national and international guidelines,
exists on the use of toxicokinetic methods to study the fate of chemicals in the body. In addition, OECD
Test Guideline (TG) 417 on Toxicokinetics (latest update dated 2010) gives an extensive description for
evaluation of the toxicokinetic profile of chemicals but excludes NMs specifically. ISO 10993-16:2017
Biological evaluation of medical devices — Part 16: Toxicokinetic study design for degradation products
and leachables, provides an overview for toxicokinetic studies for leachables of medical devices.
Furthermore, the European Medicines Agency’s ICH S3A (Toxicokinetics: A Guidance for Assessing
Systemic Exposure in Toxicology Studies) and ICH S3B (Pharmacokinetics: Repeated Dose Tissue
Distribution Studies) give guidance on the design and conduct of toxicokinetic studies to assist in the
development of new drugs.
Guidelines also exist on toxicokinetic modelling, especially the development and application of
physiologically-based pharmacokinetic (PBPK) models. For example, the United States Food and
Drug Administration’s Draft Physiologically Based Pharmacokinetic Analyses — Format and Content
Guidance for Industry, provides the standard content and format of PBPK study reports while the United
States Environmental Protection Agency’s Approaches for the Application of Physiologically Based
Pharmacokinetic (PBPK) Models and Supporting Data in Risk Assessment, addresses the application
and evaluation of PBPK models for risk assessment purposes. The European Medicines Agency (EMA)
has published a “Guideline on the qualification and reporting of physiologically based pharmacokinetic
[1]
(PBPK) modelling and simulation” in 2016 . WHO has published the “Characterization and application
[2]
of physiologically based pharmacokinetic models in risk assessment” .
As stated, the current OECD toxicokinetics TG 417 explicitly states that the guideline is not intended
[3]
for the testing of NMs , as the toxicokinetics of NMs are different from dissolved ions/molecules and
large particles. This was confirmed in a report on preliminary review of OECD Test Guidelines for their
[4]
applicability to NMs . Additionally, the PBPK models described in the current and mentioned guidance
documents are not suitable for NMs, as the processes governing the distribution of NPs is different from
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those of the dissolved (molecular/ionic) substances addressed by the current guidance documents (e.g.
Reference [5]).
New guidelines or specific additions to existing guidelines about the case of NMs are thus necessary.
A review of the current knowledge on the specific toxicokinetic characteristics of NMs and the issues
around toxicokinetic testing is a practical preparative step to ensure the best possible understanding of
testing needed to obtain relevant information on toxicokinetics of NMs.
How are nanomaterials different from dissolved ions/molecules and large particles?
Nanomaterials (NMs) present a unique family of chemicals that, by their particulate nature and
reduction in size, acquire specific physical chemical properties not present for their bulk or soluble
counterparts, that might or might not be accompanied by specific toxicity as discussed previously in
many reports (e.g. References [6], [7], [8], [9], [10]).
Toxicokinetics of NPs is of special interest because, in comparison to larger sized particles, the small
size of NPs could enable an increased rate of translocation beyond the portal of entry, to the lymphatic
[11]
fluid and blood circulation, from where they can reach potentially all internal organs . In addition,
[12]
smaller sized NPs can show a more widespread organ distribution than larger sized particles . For
the same reason, transport across barriers such as the blood-brain barrier and placenta can occur (e.g.
References [13] and [14]).
Other notable differences between the toxicokinetic behaviour of dissolved molecular/ionic substances
and NMs can be understood within the context of the principles that govern the absorption, distribution,
metabolism and excretion (ADME) of a substance. For dissolved molecular/ionic substances,
toxicokinetics is driven by 1) passive transport, which includes simple diffusion and filtration or 2)
special transport, which includes active transport, carrier-mediated transporter systems and facilitated
diffusion through cellular membranes, enzymatic metabolism and passive or active excretion. For NMs,
toxicokinetics involves aggregation, agglomeration, protein corona formation, active cellular uptake,
[15]
distribution through macrophages, and for certain NMs degradation, and excretion . In addition, the
surface chemistry/composition affects the toxicokinetics of NPs by its potential of binding a variety
of biomolecules on the surface (also designated the “protein” corona). As excretion is often limited,
bioaccumulation can occur similar to other poorly metabolized molecules. Thus, the requirements for
the testing and modelling of the toxicokinetics of NMs can differ significantly from those identified
for dissolved substances. In this respect, especially the potential for accumulation and persistence in
organs needs to be evaluated, for example in repeated dose and prolonged toxicokinetic studies.
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TECHNICAL REPORT ISO/TR 22019:2019(E)
Nanotechnologies — Considerations for performing
toxicokinetic studies with nanomaterials
1 Scope
This document describes the background and principles for toxicokinetic studies relevant for
nanomaterials.
Annex A shows the definitions for terminology with respect to toxicokinetics as used in OECD TG
417:2010.
2 Normative references
There are no normative references in this document.
3 Terms and definitions
For the purposes of this document, the terms and definitions given in the ISO 80004 series
Nanotechnologies Vocabulary and the following apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at http: //www .iso .org/obp
— IEC Electropedia: available at http: //www .electropedia .org/
3.1
agglomerate
collection of weakly or medium strongly bound particles (3.12) where the resulting external surface
area is similar to the sum of the surface areas of the individual components
Note 1 to entry: The forces holding an agglomerate together are weak forces, for example van der Waals forces or
simple physical entanglement.
Note 2 to entry: Agglomerates are also termed secondary particles and the original source particles are termed
primary particles.
[SOURCE: ISO 26824:2013, 1.2]
3.2
aggregate
particle (3.12) comprising strongly bonded or fused particles where the resulting external surface area
is significantly smaller than the sum of surface areas of the individual components
Note 1 to entry: The forces holding an aggregate together are strong forces, for example covalent or ionic bonds,
or those resulting from sintering or complex physical entanglement, or otherwise combined former primary
particles.
Note 2 to entry: Aggregates are also termed secondary particles and the original source particles are termed
primary particles.
[SOURCE: ISO 26824:2013, 1.3, modified — Note 1 adapted.]
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3.3
nanoscale
length range approximately from 1 nm to 100 nm
Note 1 to entry: Properties that are not extrapolations from larger sizes are predominantly exhibited in this
length range.
[SOURCE: ISO/TS 80004-1: 2015, 2.1]
3.4
nanotechnology
application of scientific knowledge to manipulate and control matter predominantly in the nanoscale
(3.3) to make use of size- and structure-dependent properties and phenomena distinct from those
associated with individual atoms or molecules, or extrapolation from larger sizes of the same material
Note 1 to entry: Manipulation and control includes material synthesis.
[SOURCE: ISO/TS 80004-1: 2015, 2.3]
3.5
nanomaterial
material with any external dimension in the nanoscale (3.3) or having internal structure or surface
structure in the nanoscale
Note 1 to entry: This generic term is inclusive of nano-object (3.6) and nanostructured material (3.8).
Note 2 to entry: See also 3.6 to 3.11.
[SOURCE: ISO/TS 80004-1: 2015, 2.4]
3.6
nano-object
discrete piece of material with one, two or three external dimensions in the nanoscale (3.3)
Note 1 to entry: The second and third external dimensions are orthogonal to the first dimension and to each other.
[SOURCE: ISO/TS 80004-1: 2015, 2.5]
3.7
nanostructure
composition of inter-related constituent parts in which one or more of those parts is a nanoscale
(3.3) region
Note 1 to entry: A region is defined by a boundary representing a discontinuity in properties.
[SOURCE: ISO/TS 80004-1: 2015, 2.6]
3.8
nanostructured material
material having internal nanostructure (3.7) or surface nanostructure
Note 1 to entry: This definition does not exclude the possibility for a nano-object (3.6) to have internal structure
or surface structure. If external dimension(s) are in the nanoscale (3.3), the term nano-object is recommended.
[SOURCE: ISO/TS 80004-1: 2015, 2.7]
3.9
nanoparticle
nano-object (3.6) with all external dimensions in the nanoscale (3.3) where the lengths of the longest
and the shortest axes of the nano-object do not differ significantly
Note 1 to entry: If the dimensions differ significantly (typically by more than 3 times), terms such as nanofibre
(ISO/TS 80004-2:2017, 4.5) or nanoplate (ISO/TS 80004-2:2017 4.6) may be preferred to the term nanoparticle.
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[SOURCE: ISO/TS 80004-2:2017, 4.4, modified — Note 1 to entry has been changed for clarification. ]
3.12
particle
minute piece of matter with defined physical boundaries
Note 1 to entry: A physical boundary can also be described as an interface.
Note 2 to entry: A particle can move as a unit.
Note 3 to entry: This general particle definition applies to nano-objects (3.6).
[SOURCE: ISO 26824:2013, 1.1]
3.13
substance
single chemical element or compound, or a complex structure of compounds
[SOURCE: ISO 10993-9:2009, 3.6]
4 Abbreviations
AAS Atomic Absorption Spectrometry
ADME Absorption, Distribution, Metabolism, Excretion
AUC Area under the Curve
BALF Bronchoalveolar lavage fluid
ICP-MS Inductively Coupled Plasma – Mass Spectrometry
IV Intravenous
IVIVE in vitro in vivo extrapolation
MPS mononuclear phagocytic system
MWCNT Multi Walled Carbon Nanotubes
NM(s) Nanomaterial(s)
NP(s) Nanoparticle(s)
PBPK Physiologically Based Pharmacokinetic (model)
SSA Specific Surface Area
TG Test Guideline
5 Importance of toxicokinetic information for risk assessment of nanomaterials
5.1 General
Toxicokinetic studies are important to obtain insight in the toxicologically relevant target organs
that can be considered more closely in the safety evaluation and risk assessment of NMs and/or NPs.
Furthermore, information might be obtained on relevant exposure durations (e.g. acute, chronic) to be
applied in toxicity studies based on the persistence of the NP over time. Finally, such information is
essential to enable more reliable extrapolations over species, time and exposure routes and can be used
for grouping, read-across and waiving.
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5.2 Possible use of toxicokinetic information
For dissolved substances, legislation differs in the requirement for providing kinetic information,
[16]
also between countries, but most often this information is not required by legislation . However,
toxicokinetic knowledge is essential for various purposes in the current risk assessment approach
based on animal tests:
— to predict systemic exposure and internal tissue dose (correlate given dose with target dose);
— to know whether a test, such as a genotoxicity test in bone marrow or sperm, is relevant (does the
substance reach these tissues?);
— to perform route-to-route extrapolation (see e.g. Reference [17]);
— to perform high-to-low-dose extrapolation or to select appropriate doses (see e.g. Reference [18]
and [19]);
— to verify human relevance of test results from animals (i.e. perform interspecies extrapolation; e.g.
Reference [20]);
— to enable extrapolation in time for accumulating substances, as animal tests do not cover an entire
human lifetime, while accumulation can lead to increases in concentration in a tissue that continues
lifelong (e.g. Reference [21]).
When avoiding animal tests as much as possible and performing a risk assessment based mostly on
[22]
in vitro test results, as envisioned by the 3Rs principle , kinetic information becomes even more
essential. In vitro tests do not provide for the totality of the toxicokinetics of a whole body, as animals
do: the absorption in the intestines, for example, is not included in an in vitro test with liver cells. Thus,
in vitro test results need to be supplemented with kinetic information using kinetic models, in a process
named in vitro in vivo extrapolation (IVIVE).
In addition, toxicokinetic information provides insight into potential target organs and organ burden
that might ultimately result in toxicity. This allows for improved selection and design of hazard studies,
e.g. waiving a certain systemic study if absorption and accumulation of the substances are known not
to occur, or adding additional analyses to a study that are relevant to identified target organs.
These considerations are valid for both NMs and soluble substances. Specific for non-degradable NMs
is that there is a higher potential for accumulation. In the case of accumulation, determination of the
kinetics is of greater importance for the correct estimation of a health risk, as an extrapolation in time
needs to be made. This is valid for accumulating NMs just as much as it is for accumulating substances.
Internal (or target tissue) concentrations are therefore better dose metrics for risk assessment purposes
than external doses.
Specific for NMs is also that they have a distinct distribution pattern, with high proportions in organs
of the mononuclear phagocytic system (MPS) notably in the liver and spleen. Such information can, for
[21][23]
example, warrant special attention for potential effects on liver and spleen cell populations .
Due to the many forms in which NMs can occur or be produced, of which testing all would require a large
amount of resources, grouping is of high interest for NMs. Recent papers on possibilities for grouping of
NMs describe kinetic parameters as essential pieces of information on which to base group formation
and justification: degradation (including dissolution), distribution and potential bioaccumulation or
[24][25][26]
persistence and distribution . Dissolution is actually a physico-chemical parameter that also
is dependent of the local environment (e.g. water, buffer or (simulated) body fluids), but can also be
seen as a kinetic parameter. The rate of dissolution/degradation provides insight in the toxicokinetic
behaviour of a NM. Until dissolution occurs, the kinetics of NMs are governed by the particulate nature
of the NMs, whereas after dissolution the (dissolved) ions or molecules determine the toxicokinetics.
Distribution studies are needed to assess if and to which extent the different NMs show distribution
to the same target organs, as part of a scientific justification for grouping, and to assess if the same
hazards can be considered. Accumulation is a kinetic parameter, which is not measured directly, but is
determined by all other (more basic) kinetic parameters, i.e. absorption, distribution, and elimination.
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5.3 Key toxicokinetic issues for nanomaterials
The kinetic properties of a compound include the biodistribution, biodegradation and biopersistence
and can be described by the time course for absorption, distribution, metabolism and excretion (ADME)
of a compound in the body with time. Absorption, distribution, (metabolism), and excretion can be
[3]
described as potentially sequential processes. The basic principles that are described in OECD 417
and ISO 10993-16:2017 provide a framework how to perform toxicokinetic studies. An OECD Expe
...