Assessment of Progress - Research Progress on Environmental Health and Safety Aspects of Engineered Nanomaterials - page 34

yellow to red; no indicators were denoted as green. Indicators were yellow for extent of initiation of
studies that address effects of ENMs in complex systems, adaptation of system-level tools to support
studies in these systems, and steps toward development of models for assessing ecologic exposures and
effects. Indicators were red for developing screening tools that reflect important toxicity pathways and
identifying benchmark and reference ENMs for use in studies to estimate exposure or dose.
 Extent of initiation of studies that address the impacts of nanomaterials on a variety of end
points in complex systems, such as studies that link in vitro to in vivo observations, that examine effects
on important biologic pathways, and that investigate ecosystem effects 7
The majority of toxicology studies involving ENMs have examined only a few end points,
including acute mortality and acute oxidative stress. Although valuable, these studies provide little
information that is useful for examining the effects of ENM exposures on organisms. Historical studies of
chemicals have demonstrated that evaluation of outcomes—such as reproductive, developmental, and
endocrine effects—is critical for understanding human health and ecologic impacts. In vitro analyses,
although potentially useful as an initial screen for gross effects, have not been shown to predict in vivo
effects adequately. Ecosystem effects, which are difficult to measure, are often not considered in chemical
assessments, but such information is essential for understanding changes in community and abiotic
interactions that may lead to detrimental effects. Initial model ecosystem studies on mescocosms can
begin to address changes that may occur on a larger scale due to ENM releases. In addition, molecular
studies can provide the basis to predict potential larger scale impacts. Conduct of these more complex
studies, rather than reliance on data from more simplified assays, is critical for comprehensive
understanding of the potential effects of ENMs on humans and ecosystems.
Nanotoxicology studies to determine the suitability of in vitro study results for predicting
responses in vivo had been published before the release of the committee's first report (Sayes et al. 2007;
Gerde 2008; Lu et al. 2009; Rushton et al. 2010; Han et al. 2012; Zhang et al. 2012), but the report
identified several subjects that required further in-depth study. Continuing concerns include dosimetry-
related issues and the need for further in vivo validation of effects and underlying mechanisms. The
committee also identified a dearth of exposure-assessment studies—that is, studies of workplace
exposures and consumer exposures to ENMs.
Some studies have addressed the latter subject, including workplace-exposure studies and
ecosystem studies that were conducted by EPA-NSF funded centers. NIOSH and academic institutions
(Bello et al. 2009; Methner et al. 2010; NIOSH 2012a; Tsai et al. 2012) have increased efforts to engage
with industry to perform workplace monitoring. The European NanoCare Program also includes
exposure-assessment studies (Kuhlbusch et al. 2011).
With respect to in vitro-in vivo correlations, several studies have compared results of in vitro and
in vivo toxicity testing for their predictive power. The comparisons have provided findings that
encompass good and poor concordance between in vitro and in vivo results (for example, Sayes et al.
2007; Rushton et al. 2010); this indicates a need for improved approaches to the design of comparative
studies with the goal of predicting hazards. High-throughput screening (HTS) assays allow hazard ranking
of many ENMs simultaneously on the basis of mechanistic information about cellular activation pathways
of injury (Meng et al. 2009). However, Thomas et al. (2012a, b) concluded from an evaluation of HTS
assays of numerous chemicals that these assays have little ability to predict in vivo hazards. They can,
however, be useful for setting priorities among materials for further testing (Dix et al. 2012).
Validation of the predictive value of HTS assays for assessing in vivo hazards of ENMs is
essential, including consideration of and differences between short-term, intermediate, and chronic
exposures. Study designs should focus on developing tests with relevant ENM dosimetry and realistic
7 This indicator was formerly titled “Extent of initiation of studies that address heretofore underrepresented
fields of research, such as those seeking to relate in vitro to in vivo observations, to predict ecosystem effects, or to
examine effects on the endocrine or developmental systems” in NRC (2012, p. 182).