Concern-Driven Safety Assessment of Nanomaterials - Safety of Nanomaterials along Their Lifecycle - page 371

tier to tier to collect or generate information. During the initial tier, as a rule, exist-
ing information is gathered and used to derive a preliminary assessment as a basis
to identify relevant concerns. As necessary, the IATA proceeds through a number of
tiers where additional information on exposure, kinetics, and hazard is considered
to refine the assessment and derive a more comprehensive conclusion. Based on the
information of the previous tiers, not all tests of a tier have to be performed but
the tests targeted toward the relevant concerns can be selected. The assessment can
stop at any given tier as soon as sufficient certainty on the conclusion to be drawn
is obtained. Although advancing to higher tiers, the total amount of data and their
complexity increase, the uncertainty is progressively reduced, and the assessment
becomes more and more realistic and detailed. This difference between tiers is based
not only on the amount and quality of the data used but also on the types of models
and tools applied to come to a conclusion.
16.5 OUTLOOK
Comprehensive application of IATA will require less testing whenever the avail-
able information is sufficient and adequate for decision making. It will further
allow obtaining more information from the selected tests, for example, on the par-
ticles' mechanism of action (Nel et al. 2013a) also by using high content screening
approaches (Damoiseaux et al. 2011). Nevertheless, the decision making process
might also imply requiring more information if additional specific concerns are rec-
ognized (e.g., immunotoxicity, cardiovascular toxicity, neurotoxicity, developmental
toxicity, and biopersistence/bioaccumulation). Hence, IATA does not imply the gen-
eration of less or less comprehensive data but rather of more relevant information.
Future research to develop integrated approaches for testing and assessment of
NMs should address the changing characteristics, biokinetics, and hazards of NMs
throughout their lifecycle. In elaborating IATA that fully integrates exposure, material
properties, ADCE, and primary and apical effect testing into a concern-driven risk
assessment strategy aiming at an efficient and effective generation of data (including
hazard testing and exposure assessment), relevant triggers for Tiers 2 and 3 of the
strategy and criteria for the decision-making process should be established.
In addition, existing testing methods should be updated and amended for the
specific needs of NM testing (e.g., including bronchoalveolar lavage and extended
[pulmonary] histopathology in in vivo inhalation studies). Likewise, a list of NMs as
performance standards for testing methods, ideally covering different toxic effects
and including positive and negative controls, remains to be defined. Specific guid-
ance is required on NM dispersion and in situ characterization, just as on methods
to study NM biokinetics (ADCE) and biopersistence, and on the application of these
data in the course of the IATA. General concepts for specific NM effects (carcino-
genicity, cardiovascular effects, epigenetic effects, immunological effects, reproduc-
tive toxicity, and developmental toxicity) remain to be developed.
Finally, for grouping to be used as an integral part of integrated approaches for
the testing and assessment of NMs, scientifically sound grouping criteria based on
available data and material properties, ADCE, as well as primary and apical effects
remain to be defined (Stone et al. 2010; Som et al. 2012). In this context, defining