Assessment of Progress - Research Progress on Environmental Health and Safety Aspects of Engineered Nanomaterials - page 35

doses (based on exposure data) and on time-course assessment to gauge the persistence of measured end
points. The cell types used should simulate in vivo point-of-entry exposure routes. Selection of relevant
doses for cell types of secondary organs should be based on results of biokinetic studies. In the aggregate,
those integrated components are necessary for developing science-based in vivo predictability and
extrapolation. With regard to acute-hazard ranking, HTS assays can be powerful, but present approaches
for short-term and long-term hazard assessments and corresponding risk characterization have serious
limitations. Furthermore, only a few long-term in vivo studies have examined more sensitive end points,
such as reproduction and growth, and few funded studies other than those supported through EPA-NSF
funded centers have examined ecosystem effects.
Some other subjects that remain underrepresented are toxicity mechanisms and pathways
examined under realistic exposure conditions, exposure to mixtures of contaminants, genotoxicity, and
ecosystem effects of ENM exposures. Therefore, the committee designates progress in these fields as
yellow.
 Extent of adaptation of existing system-level tools (such as individual species tests,
microcosms, and organ-system models) to support studies of nanomaterials in such systems
In its first report, the committee noted inadequate activity in this indicator. Specific studies would
contribute to a better understanding of system-level effects that can be induced by ENMs in an organism
or in the environment. Adaptation of existing system-level tools to support studies of isolated organ
systems—isolated perfused heart or lung, explant models (isolated vessels, including coronary vessels
and aorta, and muscle), in vitro double- and triple-cell models, and complete constructs of airway
epithelium—have been developed and used in nanotoxicologic research, either through exposure of live
organisms to ENMs or through exposure of the isolated model systems directly (Nurkiewicz et al. 2008).
Such models are useful for exploring mechanisms of specific effects, preferably if appropriate doses have
been selected for exposure of the organism or the explant.
Whole-organism environmental studies have been adapted to be used in nanotoxicology (Lovern
and Klaper 2006; Bai et al. 2010; Galloway et al. 2010; H. Wang et al. 2009; S. Wang et al. 2011).
Specific projects that are addressing systemwide effects of ENM exposures include studies of the use of
microcosms and mesocosms to examine organism and ecosystem-level effects (Priester et al. 2012;
Colman et al. 2013). Those studies demonstrate that steps toward meeting this objective have been
initiated, but progress is confined to a few studies, and system-level effects remain largely unknown. The
committee therefore determined that this indicator is yellow.
 Development of a set of screening tools that reflect important characteristics or toxicity
pathways of the complex systems described above 8
As noted in the committee's first report, hazard-identification studies of a variety of ENMs have
used both in vivo and in vitro methods. Development of a set of reliable and validated screening tools is
critical in that adequate testing of individual ENMs used in commerce, each with different functionalities
and applications, is not practical. In general, results obtained from in vivo studies may have limited value
for assessing health risks due to use of higher doses of ENMs than might be expected from real-world
exposures and a focus primarily on acute responses. However, implementation of a spectrum of in vitro
investigations may ultimately hold promise for revealing important mechanistic insights into toxicity
pathways. Optimizing the relevance of in vitro studies to toxicity considerations would require
experimental designs that involve dose-response behavior over a full range of doses (very low to high) in
relevant cell types, including time-course assessments and validation of findings with corresponding in
vivo systems.
8 This indicator was originally phrased as “Extent of refinement of a set of screening tools that reflect important
characteristics or toxicity pathways of the complex systems described above” (NRC 2012, p. 182).