Abstract
Hazard assessment, based on new approach methods (NAM), requires the use of batteries of assays, where individual tests may be contributed by different laboratories. A unified strategy for such collaborative testing is presented. It details all procedures required to allow test information to be usable for integrated hazard assessment, strategic project decisions and/or for regulatory purposes. The EU-ToxRisk project developed a strategy to provide regulatorily valid data, and exemplified this using a panel of > 20 assays (with > 50 individual endpoints), each exposed to 19 well-known test compounds (e.g. rotenone, colchicine, mercury, paracetamol, rifampicine, paraquat, taxol). Examples of strategy implementation are provided for all aspects required to ensure data validity: (i) documentation of test methods in a publicly accessible database; (ii) deposition of standard operating procedures (SOP) at the European Union DB-ALM repository; (iii) test readiness scoring accoding to defined criteria; (iv) disclosure of the pipeline for data processing; (v) link of uncertainty measures and metadata to the data; (vi) definition of test chemicals, their handling and their behavior in test media; (vii) specification of the test purpose and overall evaluation plans. Moreover, data generation was exemplified by providing results from 25 reporter assays. A complete evaluation of the entire test battery will be described elsewhere. A major learning from the retrospective analysis of this large testing project was the need for thorough definitions of the above strategy aspects, ideally in form of a study pre-registration, to allow adequate interpretation of the data and to ensure overall scientific/toxicological validity.
Highlights
Animal-free new approach methods (NAM) are increasingly used for the characterization of chemical hazards
Three sets of criteria were used to assemble the assays for cross-systems testing study of the (CSY): (i) readiness level and throughput; (ii) use of cells representative of four target organs or for developmental and reproductive toxicity (DART)
A special case was the set of U-2 OS cell-based reporter assays, which allowed determination of viability and of 26 functional endpoints related to toxicity pathways
Summary
Animal-free new approach methods (NAM) are increasingly used for the characterization of chemical hazards. This makes it necessary to define the conditions, under which the information from such assays can be considered ‘valid’, i.e. robust, reproducible, transparent and linked to a set of measures of uncertainty at all levels of data generation. Hundreds of NAM are available to researchers, some highly complex, such as microphysiological systems (Marx et al 2016), others being inexpensive and allowing high throughput (Adler et al 2011; Bal-Price et al 2018; Judson et al 2017; Leist et al 2012b; Liu et al 2017; Richard et al 2016; Zimmer et al 2012). Most of the available methods do often not fulfill the requirements of regulators, as their technical background, reliability, and predictivity are not well documented
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