A comprehensive view on mechanistic approaches for cancer risk assessment of non-genotoxic agrochemicals

Integration of data across toxicity endpoints for improved safety assessment of chemicals: the example of carcinogenicity assessment

“…Human relevant information on biomarkers of disease, SNPs (singlenucleotide polymorphisms) and susceptibility risk factors for disease was also included. Percent ratio for ToxCast data was calculated on the basis of selected assays as reported by Chiu et al 2018 that uses targeted tools and test methods (Luijten et al 2020;Heusinkveld et al 2020). This approach could even go one step further if the classification of chemicals is based on a generic level of concern, rather than specific endpoints, as illustrated by Da Silva et al (2020).…”

“…The identification of specific mechanisms and modes of action can help the selection of studies to be performed. The latter is also at the basis of the ongoing project promoted by the European Partnership for Alternative Approaches to Animal Testing (EPAA) that aims to develop a mechanism-based approach to cancer risk assessment for agrochemicals that uses targeted tools and test methods (Luijten et al 2020 ; Heusinkveld et al 2020 ). This approach could even go one step further if the classification of chemicals is based on a generic level of concern, rather than specific endpoints, as illustrated by Da Silva et al ( 2020 ).…”

“…For the exercise described in this paper, we defined our scenario, carcinogenicity endpoint and, we made use of the ten key characteristics (KCs) of carcinogens (Smith et al 2016 ) to build a matrix to organise the information in a structured way. This scenario was chosen as the opportunity to integrate information across systemic health endpoints that are particularly relevant to the evaluation of the carcinogenic potential of substances and, it complements with a number of ongoing activities in different sectors such as, pharmaceuticals, agrochemicals and industrial chemicals (Jacobs et al 2020 ; Krewski et al 2020 ; Luijten et al 2020 ; Sistare et al 2011 ; van der Laan et al 2016 ). The study was completed with the analysis of three different publicly available toxicological dossiers for the pesticide Linuron, and industrial chemicals 1,2-dichloroethane and hydroquinone, which served as a proof of concept.…”

Critical evaluation of the human relevance of the mode of action for rodent liver tumor formation by activators of the constitutive androstane receptor (CAR)

“…Analysis of tumor data demonstrates that the liver is the most common site of tumor formation in both the mouse and rat (Huff et al 1991;Gold et al 2001;Thoolen et al 2010). The potential usefulness and difficulties of such long-term bioassays for human risk assessment have been evaluated in many publications (Cohen 2004(Cohen , 2010(Cohen , 2017Cohen and Arnold 2011;Osimitz et al 2013;Goodman 2018;Cohen et al 2019;Doe et al 2019;Heusinkveld et al 2020;Luijten et al 2020). Such bioassays have two fundamental assumptions: first, rodent carcinogens are human carcinogens (i.e.…”

“…For example, a recent analysis of 411 unique agrochemicals that have been evaluated for carcinogenicity by US.EPA and the European Chemicals Agency (ECHA) identified 170 chemicals as nongenotoxic carcinogens, which produced 340 cases of treatment-related tumor formation, of which MOAs or MOA networks could be identified in 224 instances (Heusinkveld et al 2020). The further development of innovative test methods and enhanced understanding of carcinogenic processes will permit a better understanding of tumor formation in rodents and an evaluation of the relevance of such rodent tumors to humans (Rooney et al 2018;Cohen et al 2019;Heusinkveld et al 2020;Luijten et al 2020).…”