Getting to Green - Research Progress on Environmental Health and Safety Aspects of Engineered Nanomaterials - page 60

annotation, curation, and provenance of the data and models in the knowledge commons. In addition, the
informatics system could be implemented with different levels of security to accommodate both open
exchanges with precompetitive data and models and privileged access for more restricted collaborative
efforts.
NANOMATERIAL INTERACTIONS IN COMPLEX SYSTEMS
RANGING FROM SUBCELLULAR SYSTEMS TO ECOSYSTEMS
As discussed in Chapter 3, the committee evaluated progress in a set of indicators related to ENM
interactions in complex systems and found some progress. The indicators included extent of initiation of
studies to relate in vitro to in vivo observations, extending research from simplified laboratory studies to
more complex assays, and going from organisms to ecosystems; steps toward development of models for
ecologic exposures and effects in complex systems; extent of refinement of a set of screening tools that
reflect toxicity pathways; adapting existing system-level tools; and identification of benchmark or
reference materials for use in development of tools for estimating exposures and doses and for providing
positive and negative controls—useful for hazard ranking of ENMs. Perhaps one of the biggest gaps is the
lack of mechanistic data—an increasing volume of toxicity data is being generated, but the ability to use
the data to predict ENM risks with any certainty is constrained because of the types of studies conducted.
Many of the published studies incorporate high-dose (overload) acute exposures to single cells or
simplified single-organism mortality assays involving a single postexposure time and do not consider that
underlying mechanisms are dose-dependent (Slikker et al. 2004). To provide more useful information,
studies need to focus on more complex experimental design issues—such as relevant dose and dosimetry;
dose response and time course characteristics; appropriate target cells, tissues, and organisms; and
examination of more biologic pathways—concomitantly with better characterization of ENM test
substances and incorporation of standardized reference materials as controls. The development and
availability of standardized reference materials or benchmark (positive and negative) controls are
essential because these materials are integral to study design. For example, use of ENM positive control
material provides a reference for comparing the effects of ENM test materials being studied, and studies
using ENM test materials and positive reference controls can facilitate comparisons of results among
research laboratories, an essential component of the validation process.
In addition, consensus on the interpretation of hazard data is more readily achieved when the
mechanism of action is known for the reference material. Useful comparisons are toxicity studies of
endocrine disruption and 2,3,7,8-tetrachlorodibenzodioxin (TCDD); mechanisms are well known for the
reference material (Eadon et al. 1986; Safe 1987, 1998; Van den Berg et al. 1998; Silva et al. 2002).
Toxicity tests of potential estrogens or dioxins are done in reference to that of estrogen or TCDD and
provide a comparison with the toxicity of the agent of interest, and they ensure that a study has a positive
control. In contrast, for the development of validated assays for ENMs, no positive controls exist, partly
because of the sparseness of information on potential mechanisms of action of ENMs. However, having
available toxicologic data for ENMs once they have been more thoroughly studied, including an
understanding of potential mechanisms, would help to advance the science. Thus, ENM reference and
benchmark materials are needed for use by all researchers. A consistent set of reference and benchmark
ENMs is also needed for each category, such as metal oxides, silver, gold, and carbon nanotubes (CNTs).