International regulatory needs for development ofan IATA for non-genotoxic carcinogenic chemical substances

Uncertainties of testing methods: What do we (want to) know about carcinogenicity?

“…As far as available also human reference data and mechanistic information is used to support validation (OECD, 2005;Hartung et al, 2004). With advancing in vitro toxicology that targets increasingly complex endpoints, like earlier skin sensitization integrated approaches to testing and assessment (IATA) (OECD, 2012a) or most recently non-genotoxic carcinogenicity (Jacobs et al, 2016), it is not just individual methods that need validation, but an optimum combination of several in silico and in vitro methods. In the most recent OECD terminology, such a combination of methods that includes a prediction model integrating various in silico and/or in vitro method read-outs is called a defined approach (OECD, At present, for current chemical risk assessment for human health purposes, the RCB constitutes the in vivo "reference" data and is considered to be the current "gold standard" for the identification of carcinogens.…”

“…Usually very limited information on MoA/AOP from standard animal studies may lead to false conclusions for human hazard assessment (for instance atrazine, DEHP etc., discussed in Jacobs et al, 2016).…”

“…Current toxicological practice is already in the throes of change, with the rapid expansion of work on AOPs and IATAs under the auspices of the OECD (e.g., Jacobs et al, 2016 and references therein, http://www.oecd.org/chemicalsafety/testing/ adverse-outcome-pathways-molecular-screening-and-toxicogenomics.htm), and the consequent advancement in our mechanistic understanding of AOPs.…”

“…With more and more chemicals being tested, also more chemicals may be expected to appear to be "positive" for the one or other critical effect. In this case, further sub-categorizing between "positives" may be necessary in order to focus regulation on the most critical chemicals (Jacobs et al, 2016). -Testing an increasing amount of substances with the same in vitro approach may increase data availability from similar testing strategies and thus allow a better comparison of chemicals and their potency (compared to the current situation where we have high variability of -largely animal -test designs).…”

“…However, similar MoAs may lead to various apical adverse effects: For example, receptor mediated effects and cellular stress response pathways may trigger organ toxicity, carcinogenicity (see e.g., figures for multistep carcinogenesis in Jacobs et al, 2016), but also developmental toxicity and other toxicities. Therefore, we may consider redefining adversity on a molecular and cellular level (Fig.…”