Assessing human carcinogenicity risk of agrochemicals without the rodent cancer bioassay

Abstract

The rodent cancer bioassays are conducted for agrochemical safety assessment yet they often do not inform regulatory decision-making. As part of a collaborative effort, the Rethinking Carcinogenicity Assessment for Agrochemicals Project (ReCAAP) developed a reporting framework to guide a weight of evidence (WOE)-based carcinogenicity assessment that demonstrates how to fulfill the regulatory requirements for chronic risk estimation without the need to conduct lifetime rodent bioassays. The framework is the result of a multi-stakeholder collaboration that worked through an iterative process of writing case studies (in the form of waivers), technical peer reviews of waivers, and an incorporation of key learnings back into the framework to be tested in subsequent case study development. The example waivers used to develop the framework were written retrospectively for registered agrochemical active substances for which the necessary data and information could be obtained through risk assessment documents or data evaluation records from the US EPA. This exercise was critical to the development of a framework, but it lacked authenticity in that the stakeholders reviewing the waiver already knew the outcome of the rodent cancer bioassay(s). Syngenta expanded the evaluation of the ReCAAP reporting framework by writing waivers for three prospective case studies for new active substances where the data packages had not yet been submitted for registration. The prospective waivers followed the established framework considering ADME, potential exposure, subchronic toxicity, genotoxicity, immunosuppression, hormone perturbation, mode of action (MOA), and all relevant information available for read-across using a WOE assessment. The point of departure was estimated from the available data, excluding the cancer bioassay results, with a proposed use for the chronic dietary risk assessment. The read-across assessments compared data from reliable registered chemical analogues to strengthen the prediction of chronic toxicity and/or tumorigenic potential. The prospective case studies represent a range of scenarios, from a new molecule in a well-established chemical class with a known MOA to a molecule with a new pesticidal MOA (pMOA) and limited read-across to related molecules. This effort represents an important step in establishing criteria for a WOE-based carcinogenicity assessment without the rodent cancer bioassay(s) while ensuring a health protective chronic dietary risk assessment.

Keywords: agrochemical; carcinogenicity; new approach methods; regulatory toxicology; risk assessment; rodent cancer bioassay; weight of evidence.

FIGURE 1

Reporting framework for the weight of evidence assessment. This workflow was used to identify and select the relevant and reliable lines of evidence used to make an informed decision in developing a waiver rationale of the chronic/carcinogenicity studies in rats and mice without having the knowledge of the outcome of the bioassays. Adapted from Hilton et al., 2022.

FIGURE 2

RISK21^® graph for predicted chronic exposure to the new active substances. The RISK21® plots evaluating the available exposure and hazard data for the safety assessment of the (A). SDHI fungicide, (B). ACCase inhibitor insecticide, and (C). GABA-Cl insecticide. The yellow line in the RISK21® tool represents the margin of exposure between the 90-day toxicity study NOAEL (as an estimate of toxicity) and the registrant’s modeled exposure values (as estimates of exposure) generated in US EPA’s DEEM dietary risk software. The Health and Environmental Science Institute (HESI) provide RISK21® tools, which are available online through the following link: https://risk21.org/webtool/.