Concern-Driven Safety Assessment of Nanomaterials - Safety of Nanomaterials along Their Lifecycle - page 369

16.4.2 a ssessment of nm h uman h ealth h azards
Hazard assessment within Tier 2 of the integrated approach focuses on identifying
the basic toxicological concerns related to a given NM. Tier 3 provides options to
study specific end points of concern in more detail (Figure 16.4). Tiers 2 and 3 each
consist of three parts, the “toxicity domain,” the decision-making process, and the
description of options for testing within each domain. Depending on the concerns
determined for a given NM, testing can encompass basic and specific tests using
noncellular and then cellular systems determining relevant MOA and toxicity path-
ways, and short-term and long-term in vivo testing approaches, if necessary.
At present, four toxicity domains are defined in Tier 2 for which information
should become available (Figure 16.4), that is, local effects at the point of primary
contact, genotoxicity, biokinetics, and short-term toxicity (including inflammation
and cytotoxicity). Within each domain, a number of options for testing, grouping,
or waiving will be available, from which the need for further testing, and its pri-
oritization, can be determined. Confirmation of a concern will not necessarily lead
to further testing, but may lead to the decision to stop the development of the given
application or to apply specific risk management measures.
The process of decision making should facilitate an integrated combination of
tests serving to obtain the maximum amount of information with the minimum
resources (including animals) possible. After each tier, risk assessment is performed,
that is, the data and information on hazard and exposure obtained so far are com-
bined to characterize the risk (in a qualitative, semiquantitative, or quantitative way,
in absolute or relative terms). The decision to proceed to branches of the subsequent
tier(s) is based on risk considerations taking into account not only the output (i.e.,
acceptability or unacceptability of the risk) but also its associated uncertainty level.
In each tier, the information of preceding tiers is used as guidance on how informa-
tion should be obtained.
To ensure that meaningful test results are obtained when using cellular test sys-
tems, it is of paramount importance that the dosages applied in vitro encompass those
applied in vivo taking into account the specific diffusion and sedimentation proper-
ties of NMs depending on their levels of dispersion and agglomeration (Teeguarden
et al. 2007; Castranova et al. 2012; Sauer et al. 2013). Also the physicochemical
characteristics representative of in vivo situations should be taken into consideration
in in vitro tests.
16.4.3 a ssessment of nm B iokinetiCs
Determining the biokinetic behavior of NM forms an essential part of Tier 2 of the
testing strategy and might be the first domain to be addressed in this tier (Figure 16.4).
This covers NM absorption/uptake, distribution, corona formation, and elimination/
deposition (“ADCE,” used by analogy to ADME, absorption, distribution, metabo-
lism, and excretion): For the majority of insoluble NM, metabolism, unlike corona
formation, appears to play a negligible role.
NMs may potentially cross portals of entry into the body or internal barriers.
NMs with different physicochemical characteristics may differ considerably in