Rethinking chronic toxicity and carcinogenicity assessment for agrochemicals project (ReCAAP): A reporting framework to support a weight of evidence safety assessment without long-term rodent bioassays.

Rodent cancer bioassays have been long-required studies for regulatory assessment of human cancer hazard and risk. These studies use hundreds of animals, are resource intensive, and certain aspects of these studies have limited human relevance. The past 10 years have seen an exponential growth of new technologies with the potential to effectively evaluate human cancer hazard and risk while reducing, refining, or replacing animal use. To streamline and facilitate uptake of new technologies, a workgroup comprised of scientists from government, academia, non-governmental organizations, and industry stakeholders developed a framework for waiver rationales of rodent cancer bioassays for consideration in agrochemical safety assessment. The workgroup used an iterative approach, incorporating regulatory agency feedback, and identifying critical information to be considered in a risk assessment-based weight of evidence determination of the need for rodent cancer bioassays. The reporting framework described herein was developed to support a chronic toxicity and carcinogenicity study waiver rationale, which includes information on use pattern(s), exposure scenario(s), pesticidal mode-of-action, physicochemical properties, metabolism, toxicokinetics, toxicological data including mechanistic data, and chemical read-across from similar registered pesticides. The framework could also be applied to endpoints other than chronic toxicity and carcinogenicity, and for chemicals other than agrochemicals.

Minimum datasets to establish a CAR-mediated mode of action for rodent liver tumors.

Methods for investigating the Mode of Action (MoA) for rodent liver tumors via constitutive androstane receptor (CAR) activation are outlined here, based on current scientific knowledge about CAR and feedback from regulatory agencies globally. The key events (i.e., CAR activation, altered gene expression, cell proliferation, altered foci and increased adenomas/carcinomas) can be demonstrated by measuring a combination of key events and associative events that are markers for the key events. For crop protection products, a primary dataset typically should include a short-term study in the species/strain that showed the tumor response at dose levels that bracket the tumorigenic and non-tumorigenic dose levels. The dataset may vary depending on the species and the test compound. As examples, Case Studies with nitrapyrin (in mice) and metofluthrin (in rats) are described. Based on qualitative differences between the species, the key events leading to tumors in mice or rats by this MoA are not operative in humans. In the future, newer approaches such as a CAR biomarker signature approach and/or in vitro CAR3 reporter assays for mouse, rat and human CAR may eventually be used to demonstrate a CAR MoA is operative, without the need for extensive additional studies in laboratory animals.

Current and future use of genomics data in toxicology: opportunities and challenges for regulatory applications.

Toxicogenomics is the application of toxicology, genetics, molecular biology and environmental health to describe the response of organisms to environmental stimuli. The field of toxicogenomics has developed over the past 15 years mainly due to advances in toxicology, molecular genetics and cell biology. Its prospective use to resolve crucial data gaps and data inconsistencies could improve risk assessment by providing additional data to increase the understanding of mechanisms and modes of action (MOA) and enhance the reliability of dose-response extrapolation. Thus, toxicogenomics holds promise for advancing the scientific basis of risk assessments. However, one of the current issues is how genomic/transcriptional data is being used to further describe a MOA for oncogenicity and, in turn, its potential uses in cancer risk assessment. This commentary identifies how toxicogenomics could be used on a case by case basis to add information to a MOA addressing both the opportunities and challenges this technology holds. In addition, some pitfalls to avoid in the generation and interpretation of toxicogenomic data and validation issues that need to be addressed before toxicogenomics can be used in the risk assessment process and regulatory decisions are discussed.

Implementing a globally harmonized risk assessment-based approach for regulatory decision-making of crop protection products.

A global, harmonized evaluation system for crop protection chemicals based on exposure and risk will improve the ability to inform risk management decisions and better support innovation. This would be achieved through harmonized risk assessment-based regulatory decision-making realized through the application of the best available science, via integration of new methods and traditional data to create tailored exposure-driven risk assessments. A requirement to achieve success is a structure that encourages direct communication between the regulatory community and the regulated industry, which would enable a more rapid incorporation of new technologies and advancing science. An approach that emulates the International Conference of Harmonization (ICH) for pharmaceuticals would bring together regulatory authorities and the regulated industry along with relevant experts from academia and Non-Governmental Organizations to discuss scientific and technical advances and their implementation. These discussions would also encourage the elimination of outmoded practices that no longer serve a purpose resulting in more uniform testing requirements and best practices for data evaluation to support safe use and scientifically defensible human health and environmental risk assessments. New and developing technologies offer exciting opportunities to improve the current toxicity testing paradigms to provide better solutions and diminish animal testing. Implementation of a harmonized approach will increase the speed, efficiency and accuracy of regulatory decision-making for human health and environmental protection while increasing the efficiency of providing safe and effective innovative products to the agriculture community. © 2020 Society of Chemical Industry.

Diuron-induced rat bladder epithelial cytotoxicity.

Diuron, a substituted urea herbicide, is carcinogenic to the rat urinary bladder at high dietary levels (2500 ppm). To further elucidate the mode of action, this study aimed to determine the time course and sequence of bladder cytotoxic and proliferative changes induced by diuron treatment of male Wistar rats. Rats were randomized into two groups (control and 2500 ppm diuron) and treated for 28 days. Ten rats from each group were terminated on each of study days 1, 3, 7, or 28. Scanning electron micro scopy (SEM) showed urothelial cell swelling beginning on day 1, and by day 28, showed extensive necrosis, exfoliation and piling up of cells suggestive of hyperplasia. No difference in the bromo deoxyuridine labeling index was detected. In a second experiment, rats were randomized into control and diuron-treated groups and treated for 7 days or 8 weeks. After 7 days, transmission electron microscopy showed cell degenerative changes and distention of the cytoplasm, organelles, and nuclei characteristic of cytolysis. This resulted in protrusion of the superficial cells into the lumen, corresponding to the cell swelling observed previously by SEM. After 8 weeks, bladders in the diuron-treated group showed an increased incidence of simple hyperplasia by light microscopy (6/10, p < 0.05) compared with controls (0/10) and a significantly different SEM classification. In summary, our results support the hypothesis that urothelial cytotoxicity followed by regenerative cell proliferation are the sequential key events that occur with high-dose diuron exposure in rats.