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Toxys is a Dutch biotech company that provides innovative in vitro toxicity screening solutions to rapidly identify hazardous and potential carcinogenic properties of novel compounds during the early phases of product and drug development.

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Regulatory

Regulatory

ToxTracker can contribute to a mechanism-based, animal-free, cancer hazard and risk assessment of chemicals.ToxTracker can be particularly useful in an Adverse Outcome Pathway (AOP) approach for both genotoxic and non-genotoxic carcinogens by reveal genotoxic modes of action and a number of non-genotoxic modes of action, such as oxidative stress and protein damage.

ToxTracker in the regulatory context

ToxTracker is used to identify genotoxic properties of compounds. It separates DNA damage, oxidative stress, protein damage and cellular stress. Currently ToxTracker is not part of the recommended battery of genotoxic assays in the OECD guidelines, however as the assay provides different endpoints and insight into the toxic mode-of-action (MOA) the results might still be useful for selection of compounds and dossier building.

Shift to MOA assays (like ToxTracker) in regulatory endpoints

A paradigm shift is observed from single endpoint assays to assays that provide insight into MOA, as recommended by ICH and Tox21.  ToxTracker perfectly fits into the need for MOA information instead of testing in a standard battery of tests.

“In regulatory assessment of carcinogenic or germ cell mutagenic risk, it is becoming increasingly important to understand mode of action, and not just rely on weight of negative evidence from in vivo genotoxicity studies to overrule positive in vitro genotoxicity results. To this end, there is increasing demand for integrated mechanism-based assays like ToxTracker as essential components in the development of safe and specific drugs or products.”

David Kirkland, Kirkland Consultancy

Steps taken by Toxys to regulatory acceptance of ToxTracker
  • In 2016 an ECVAM application has been submitted
  • An draft OECD SPSF has been submitted for discussion, the definitive document will be submitted by the Dutch representatives in December 2017
  • The assay has been extensively validated using the ECVAM and Toxcast compound libraries, please see publications
  • In 2016 Toxys has become a member of ILSI Hesi and is part of a specialised workgroup on MOA assays
ToxTracker suggested as part of “An integrative test strategy for cancer hazard”

In an extensive review paper in Critical Reviews in Toxicology by Mirjam Luijten and Jan van Benthem from the Dutch national institute for health and the environment RIVM, a strategy that includes ToxTracker was proposed for a regulatory carcinogenicity hazard screening strategy. The ToxTracker assay can be particularly useful in a weight of evidence approach where the ability of the assay to provide mechanistic insight into the genotoxicity of substances has clear benefits over the conventional in vitro genotoxicity assays.

Given the current context, how can ToxTracker help me with my compounds

Our customers apply the assay in several variations in the screening strategy, which also varies widely over the different industries. Here we will explain the most common use strategies for the assay.

  1. Early non-regulatory preclinical development phase of pharmaceuticals. ToxTracker can be applied as early genotoxicity screen in parallel or as alternative to AmesII/MPF, GreenScreen HC, flow micronucleus. ToxTracker can predict with high accuracy the outcomes the regulatory in vitro battery of genotoxicity tests (positive in mutation or chromosome damage tests).
  2. ToxTracker can be applied as follow-up of the regulatory in vitro battery of genotoxicity assays to provide insight into MOA of genotoxic compounds. This information can be used in a weight of evidence approach during hazard assessment of novel compounds.
  3. As prescreen or as mechanistic follow up of the regulatory in vitro genotoxicity tests for cosmetic ingredients and final products.
  4. Mechanistic studies and read across approaches for retesting of marketed chemicals under REACH and novel substances.
  5. In vitro indicator test for a number of non-genotoxic mechanisms of toxicity that are associated with increased carcinogenicity hazard.