Concern-Driven Safety Assessment of Nanomaterials - Safety of Nanomaterials along Their Lifecycle - page 360

and cardiovascular systems (Castranova et al. 2012; Nel et al. 2013b; Shvedova et al.
2013). On the molecular level, NMs can interact with biological macromolecules,
membranes, and intracellular organelles, which are oftentimes in a comparable size
range as the NMs. Thereby, NMs can interfere, for example, with the native function
of proteins or bind to functional sites of DNA, RNA, ribosomes, mitochondria, or
the endoplasmic reticulum (Yanamala et al. 2013). The adverse outcomes of these
molecular initiating events have not yet been fully described.
Figure 16.2 provides an overview of the steps of a source-to-adverse-outcome path-
way for NMs taking into account their release, uptake, surface properties and states of
agglomeration, biodistribution, and possible early and apical biological effects. Early
biological effects can—initially—be investigated in vitro. However, in order to assess
if this can result in an apical effect, information on the external and internal exposure
is required. External exposure refers to the level and physicochemical form of a NM
exposure outside the body and is thus related to the various lifecycle stages, used
amounts, and release of the NM (referred to as dispersion in Figure 16.2). Internal

INFORMATION BOX 16.2 DEFINITIONS RELATED
TO ADVERSE OUTCOME PATHWAYS

During the molecular initiating event , a substance interacts with a specific
biological target tissue, which results in a cellular response. This is the initial
point of chemical-biological interaction.
Toxicity pathways describe the sequence of the respective molecular initiat-
ing event and the resulting cellular effect.
Modes of action (MOA) link toxicity pathways to organ or organ system
effects. The MOA action differs from mechanism of action, with the mode
of action requiring a less detailed understanding of the molecular basis to the
toxic effect.
Early biological effects summarize molecular initiating events and cellular
responses.
Apical toxic effects are the clinically manifested adverse effects in an
organism; they are the outcome of a cogent early biological effect.
Adverse outcome pathways (AOP) describe the steps linking the molecular
initiating event to an adverse outcome at the organism—or population—level
that is directly relevant for a given risk assessment context.
Source-to-[adverse-]outcome pathways relate to the comprehensive under-
standing of the effects of a substance from its release through to its effects on
the organism/individual or population level.

Source: Ankley et al., Env Toxicol Chem , 29, 730-741, 2010, OECD (2012a), Proposal

for a template, and guidance on developing and assessing the completeness of
adverse outcome pathways, 17 pp; available at: http://www.oecd.org/env/ehs/
testing/49963554.pdf, OECD. (2012b). Appendix I, Collection of working
definitions, OECD, Paris, France; available at: http://www.oecd.org/env/ehs/
testing/49963576.pdf.