Pathways of Toxicity

Abstract

Summary Despite wide-spread consensus on the need to transform toxicology and risk assessment in order to keep pace with technological and computational changes that have revolutionized the life sciences, there remains much work to be done to achieve the vision of toxicology based on a mechanistic foundation. A workshop was organized to explore one key aspect of this transformation – the development of Pathways of Toxicity (PoT) as a key tool for hazard identification based on systems biology. Several issues were discussed in depth in the workshop: The first was the challenge of formally defining the concept of a PoT as distinct from, but complementary to, other toxicological pathway concepts such as mode of action (MoA). The workshop came up with a preliminary definition of PoT as “A molecular definition of cellular processes shown to mediate adverse outcomes of toxicants”. It is further recognized that normal physiological pathways exist that maintain homeostasis and these, sufficiently perturbed, can become PoT. Second, the workshop sought to define the adequate public and commercial resources for PoT information, including data, visualization, analyses, tools, and use-cases, as well as the kinds of efforts that will be necessary to enable the creation of such a resource. Third, the workshop explored ways in which systems biology approaches could inform pathway annotation, and which resources are needed and available that can provide relevant PoT information to the diverse user communities.

The need for strategic development of safety sciences

“…CAAT, with one of the authors (TH) as principal investigator, promotes the use of advanced-omics and high-throughput technologies and supports the implementation of knowledge-based frameworks such as Pathways of Toxicity and Adverse Outcome Pathways (Hartung and McBride, 2011) and thus plays a key role in implementing the NAS Tox21 vision. A key goal of the Human Toxome Project is the development of tools for identification of pathways of toxicity (Kleensang et al, 2014) from multi-omics technologies (Maertens et al 2015Pendse et al, 2016) to feed into a systems toxicology approach (Hartung et al, 2012). The combination of orthogonal omics technologies has the advantage that the tremendous signal/noise problem of any omics technology is overcome.…”

Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: Example lists and criteria for their selection and use_suppl

“…The serious limitations that apply to individual tests (see first consequence) do not apply to a test battery that aims to cover the majority of DNT adverse effects. Compounds that are defined as gold standard positive controls should be identified as hits in the test battery (or an Kleensang et al, 2014). In vitro toxicity testing is the major focus of the "biomarkers-of-toxicity" concept, which concerns the identification of measurable and predictive endpoints that can be applied to model systems.…”

Systems biology for organotypic cell cultures

“…To ensure survival under dynamic micro-environmental conditions, normal cellular physiology is highly adaptable. Perturbations to these systems (disease, drugs, or toxicants) can overcome normal adaptive mechanisms resulting in maladaption and pathology/toxicity (Kleensang et al, 2014). The progression from homeostatic cellular physiology to adaptive physiology to pathophysiology can be characterized quantitatively by measures of gene or protein expression, cellular function, or morphologic phenotype.…”