Towards a mechanism-based approach for the prediction of nongenotoxic carcinogenic potential of agrochemicals

Abstract

Chemical substances are subjected to assessment of genotoxic and carcinogenic effects before being marketed to protect man and the environment from health risks. For agrochemicals, the long-term rodent carcinogenicity study is currently required from a regulatory perspective. Although it is the current mainstay for the detection of nongenotoxic carcinogens, carcinogenicity studies are shown to have prominent weaknesses and are subject to ethical and scientific debate. A transition toward a mechanism-based weight-of-evidence approach is considered a requirement to enhance the prediction of carcinogenic potential for environmental (agro)chemicals. The resulting approach should make optimal use of innovative (computational) tools and be less animal demanding. To identify the various mode of actions (MOAs) underlying the nongenotoxic carcinogenic potential of agrochemicals, we conducted an extensive analysis of 411 unique agrochemicals that have been evaluated for carcinogenicity by the United States Environmental Protection Agency (US EPA) and the European Chemicals Agency (ECHA). About one-third of these substances could be categorized as nongenotoxic carcinogens with an average of approximately two tumor types per substance, observed in a variety of organs. For twothird of the tumor cases, an underlying MOA (network) could be identified. This analysis demonstrates that a limited set of MOA (networks) is underlying nongenotoxic carcinogenicity of agrochemicals, illustrating that the transition toward a MOA-driven approach appears manageable. Ultimately the approach should cover relevant MOAs and its associated key events; this will also facilitate the evaluation of the human relevance. This manuscript describes the results of the analysis while identifying knowledge gaps and necessities to achieve a mechanism-based weight-of-evidence approach.

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 ).…”

Application of humanized mice to toxicology studies: Evaluation of the human relevance of the mode of action for rodent liver tumor formation by activators of the constitutive androstane receptor (CAR)

“…Since liver is the most common site of tumor formation in rodent carcinogenicity studies of non-genotoxic compounds 3 , 21 , 22 , 23 , evaluation of the human relevance of chemical-induced liver tumor production in rodents is very important to correctly protect humans from health risks. To avoid misclassifying chemicals as possible human carcinogens due to the limitations of long-term bioassays, it has become imperative to undertake an MOA analysis 24 .…”

“…For example, a recent analysis of 411 unique agrochemicals that have been evaluated for carcinogenicity by the US.EPA and the European Chemicals Agency (ECHA) identified 170 chemicals as non-genotoxic carcinogens. These chemicals produced 340 cases of treatment-related tumor formation, of which MOAs or MOA networks could be identified in 224 instances 3 . 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 2 , 3 , 4 , 42 .…”

“…Therefore, the safety evaluation of chemicals is mainly dependent on animal testing. While these animal studies provide valuable information on possible hazards of test chemicals, considering the differences between human and rodent physiology, the predictive value of these rodent studies has limitations 1 , 2 , 3 , 4 , 5 . In vitro study systems, such as human precision-cut liver slices, hepatic microsomes, or primary hepatocytes, have been widely used and potentially provide useful information for predicting actual human in vivo metabolic profiles of test chemicals 6 .…”