Assessment of Progress - Research Progress on Environmental Health and Safety Aspects of Engineered Nanomaterials - page 36

Chapter 3 of the first report, “Critical Questions for Understanding Human and Environmental
Effects of Engineered Nanomaterials”, posed the question (p. 91), What biologic effects occur at realistic
ENM doses and dose rates, and how do ENM properties influence the magnitude of these effects? The
report noted that a long-term goal is to develop simple in vitro assays that predict in vivo effects at the
organism level and may eventually be used for HTS assays. To address that long-term goal, it was
concluded that a key requirement should be that any in vitro assay used as a predictive tool needs to have
been validated with appropriate and pertinent in vivo data (with particular relevance to exposure routes).
The results of simple assays have been proposed for identifying potential effects and possibly establishing
a hazard scale (Rushton et al. 2010), although some comparative studies have reported a lack of
convergence between in vivo-related (inhalation or intratracheal instillation) findings and in vitro data on
the same nanoparticle test materials, perhaps partly because of mechanisms that are dose-dependent
(Slikker et al. 2004; Sayes et al. 2007, 2009; Warheit et al. 2009) or because of differential ENM
transformations that depend on the exposure vehicle (medium) used (Lowry et al. 2012a). Finally, as
currently designed, in vitro studies are limited by their inherent measurement of acute responses. Even if
they are conducted under relevant dose conditions, in vitro results generally reflect early (acute) effects of
exposures and may not predict long-term (chronic) effects.
Research activity to correlate in vivo mechanistic toxicity studies systematically at relevant
concentrations with in vitro screening assays that use relevant exposure concentrations, ENMs, cell types,
and appropriate routes of exposures (such as inhalation, oral, dermal, and intravenous exposure) is central
to progress. Some initial efforts have been proposed to address that issue in the ToxCast and NIEHS U19 9
programs. Laboratories are pursuing such research, and important insights into mechanisms of toxicity are
being generated, but these efforts are not sufficient to provide the information necessary for adequate
understanding of toxicity pathways in cell and organ systems. The committee designates this indicator as
red given the limited progress in appropriately designed studies.
 Steps toward development of models for exposure and potential ecologic effects 10
Work on modeling exposure to and effects of nanomaterials in ecosystems, including food webs,
is in its infancy. Important first steps have been taken to understand the phenomena of uptake,
bioaccumulation, and trophic transfer (Werlin et al. 2011; Unrine et al. 2012), and this mixed progress
gives this indicator a yellow rating.
However, more work is required to understand the mechanisms of biouptake. Lack of progress in
modeling the transfer of materials between organisms can be attributed in part to the relatively low
priority that this topic has received, as measured by publications, relative to work on direct health effects
(see Figure 3-3 in NRC 2012). In addition, the modeling required is predicated on fundamental discovery
concerning the mechanisms of biouptake and assimilation of ENMs in organisms. Greater focus on
modeling of biouptake, bioaccumulation, and trophic transfer is essential not only for predicting the fate
of nanomaterials in ecosystems but for interpreting the growing body of literature on nanomaterial effects
associated with ambient concentrations introduced in laboratory studies.
In addition to uptake, more information is needed on the effects of chronic, low-level realistic
exposure scenarios in complex ecologic systems. Effects of ENMs in a simplified assay may not
accurately reflect the gross effects on a system of interconnected species. Alterations in uptake in the
presence of multiple species, population and community effects, changes in interactions among
9 U19 is part the National Institute of Environmental Health Sciences Centers for Nanotechnology Health
Implications Research. It is an interdisciplinary program that comprises five U19 and three cooperative centers and
other grantees and is intended to increase understanding of how the properties of ENMs influence their interactions
with biologic systems and potential health risks.
10 The indicator originally titled “Steps toward development of models for exposure and potential effects along
the ecologic food chain” (NRC 2012, p. 182) was rephrased to broaden its scope to include all ecologic effects (both
biotic and abiotic).