The International Academy of Toxicologic Pathology (IATP) Satellite Symposium on Pathology Working Groups (PWGs) in Toxicologic Pathology, organized in the United Kingdom, addressed the value and importance of PWGs and expert working groups in assuring the accurate evaluation of chronic/carcinogenicity studies. These specialized panels of expert pathologists play a crucial role in confirming data quality and accurate interpretation in support of human safety and risk decisions of xenobiotics. While not every carcinogenicity bioassay may require a PWG to evaluate the quality and accuracy of study interpretation, it was the consensus of the workshop that it can be a highly valuable addition to traditional peer review. Performing a PWG should be given serious consideration, especially when it is anticipated that the chronic/carcinogenicity study will be used for making significant regulatory or business decisions.

Globally, regulatory authorities face the challenge of integrating advances in science and technology into existing frameworks for agrochemical risk assessment. Addressing this challenge is critical to meeting the demands of food safety and quality for a growing population. To support this shift, the Health and Environmental Sciences Institute (HESI) convened a multi-stakeholder committee of international scientists. Through a problem formulation-led strategy, the committee developed the Transforming the Evaluation of Agrochemicals (TEA) conceptual model to guide the adoption of new methods, best practices, and technologies into regulatory practice for agrochemical safety. The core of the model incorporates the well-established tiered approach routinely used for identifying and characterizing hazards and assessing exposures; however, the model strategically identifies three sequential elements: exposure-led, adaptability, and inclusion of new science. The central core is then surrounded by layers with additional elements, namely: fit-for-purpose over time, adapt to global need, adapt to local need, create incentives, data sharing and transparency, and build trust. Collectively, these ten elements and their intersections result in a novel, TEA conceptual model with elements that have not been simultaneously implemented in any regulatory data package to date. In providing guiding principles, two examples of regulatory applications, and a concise summary of how this model supports an opportunity to go beyond next generation risk assessments focused primarily on alternative approaches to animal testing, we demonstrate the utility of the TEA conceptual model as a tool and mechanism supporting a structured and systematic application towards the intended transformation of agrochemical evaluations.

The United States Environmental Protection Agency (USEPA) has long championed the use of the most modern toxicity testing approaches to meet its pesticide registration mandates, often collaborating with stakeholders to develop and implement innovative approaches that strengthen environmental and human health protections. Despite these efforts, the adoption of 21st-century testing approaches in pesticide registration has been slowed by various factors, including limited resources, inefficient processes for establishing confidence in new methods, and the retention of outdated data requirements codified in the Code of Federal Regulations. This paper provides a brief overview of the current USEPA legislative landscape for pesticide toxicity testing, describes the progress and remaining challenges in using new testing approaches to fulfill regulatory requirements, and highlights opportunities to address these challenges and enhance protection of human health and the environment.

Environmental context Pesticides are critical to agriculture and food production but require ecological risk assessments. Although most risk assessments require data from vertebrate animal testing, we have developed an approach to assess risk to fish, birds and mammals using other means. This approach could help to ensure protection of the environment while minimising animal testing.Rationale Recent directives to reduce animal testing have implications for ecological risk assessment, as several vertebrate tests are used to support these assessments. Therefore, a modern approach was devised to address these key knowledge needs without the use of chemical-specific vertebrate testing.Methodology An ecological risk assessment for a novel acetyl-coenzyme A carboxylase (ACCase) inhibitor herbicide was conducted using alternative lines of evidence. For fish, chemical toxicity distributions were constructed to quantify the probability of effects, and these distributions were compared with exposure estimates for a representative use in soybeans. The effect distributions were further refined based on invertebrate toxicity and partitioning behaviour. For birds and mammals, a joint probability curve was constructed by integrating chemical toxicity distributions and Kenaga exposure distributions.Results The lines of evidence presented in this predictive risk assessment suggest the intended use of a new ACCase inhibitor is unlikely to affect fish, birds, or mammals. Exposure was unlikely to exceed effect estimates, regardless of whether they were derived based on chemical-read across, invertebrate toxicity, or partitioning behaviour.Discussion Key knowledge needs for ecological risk assessment can be informed by lines of evidence that do not require animal testing. The present study demonstrates such an approach by comparing predicted exposure and effects, which are expected to be protective. This predictive approach can be extended to other active ingredients and chemical classes, as well as other taxonomic groups of interest. Future research should aim to integrate new approach methods in a predictive risk assessment framework.

The appropriate use of human biomonitoring data to model population chemical exposures is challenging, especially for rapidly metabolized chemicals, such as agricultural chemicals. The objective of this study is to demonstrate a novel approach integrating model predicted dietary exposures and biomonitoring data to potentially inform regulatory risk assessments. We use lambda-cyhalothrin as a case study, and for the same representative U.S. population in the National Health and Nutrition Examination Survey (NHANES), an integrated exposure and pharmacokinetic model predicted exposures are calibrated to measurements of the urinary metabolite 3-phenoxybenzoic acid (3PBA), using an approximate Bayesian computing (ABC) methodology. We demonstrate that the correlation between modeled urinary 3PBA and the NHANES 3PBA measurements more than doubled as ABC thresholding narrowed the acceptable tolerance range for predicted versus observed urinary measurements. The median predicted urinary concentrations were closer to the median measured value using ABC than using current regulatory Monte Carlo methods.

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.

Objective: Evaluate tolerability/safety of extended ozanimod 0.92 mg/day treatment in adults with relapsing multiple sclerosis (RMS) or moderately to severely active ulcerative colitis (UC). Background: Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator, is approved for treatment of RMS or moderately to severely active UC. Design/Methods: The RMS population included patients treated with ozanimod 0.92 mg in DAYBREAK (NCT02576717; 10/16/2015 through 2/1/2022), an ongoing open-label extension (OLE) trial of patients from phase 1–3 ozanimod studies. The UC population included pooled patients treated with ozanimod 0.92 mg in phase 2 (NCT01647516), phase 3 (NCT02435992), and respective OLE trials through May 5, 2022. Safety outcomes included treatment-emergent adverse events (TEAEs) and TEAEs of special interest based on association with S1P modulation. Results: Mean (SD) ozanimod exposure during DAYBREAK among 2494 patients with RMS was 56.4 (15.9) months (11,732.2 patient-years [PY]); exposure in 1158 UC patients was 28.4 (23.3) months (2714.9 PY) (MS/UC combined: 14,447.1 PY). TEAEs occurred in 88.2% of RMS and 74.6% of UC patients. Serious TEAEs were reported in 14.1% and 17.3%, and TEAEs leading to ozanimod discontinuation in 3.6% and 9.3%, respectively. The most common TEAS were nasopharyngitis (20.6%; exposure-adjusted incidence rate [IR] 51.0/1000 PY), headache (16.9%; 40.3/1000 PY), and upper respiratory infection (11.9%; 27.3/1000 PY) in RMS patients, and lymphopenia (12.3%; 53.6/1000 PY), anemia (8.4%; 35.0/1000 PY), lymphocyte count decreased (7.9%; 33.2/1000 PY), and nasopharyngitis (7.9%; 33.2/1000 PY) in UC patients. In MS and UC, respectively, IRs/1000 PY were 229.3 and 194.6 for any infection, 8.4 and 15.2 for serious infection, 13.5 and 11.8 for opportunistic infection, and 3.3 and 6.2 for malignancy. Alanine aminotransferase levels >5× upper limit of normal occurred in 0.8% and 2.3% of RMS and UC patients. Conclusions: Long-term ozanimod 0.92 mg/day was generally well tolerated and safe for most patients with RMS or moderately to severely active UC. Disclosure: The institution of Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Atara. The institution of Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for EMD Serono. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. The institution of Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for TG Therapeutics. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Autobahn. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avotres. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gossamer Bio. Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Horizon. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neuron23. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boston Pharma. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Hexal/Sandoz. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Siemens. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Therini. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic AG. The institution of Dr. Cree has received research support from Genentech. Dr. Cree has received publishing royalties from a publication relating to health care. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for Abbvie. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for Alimentiv. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for Applied Molecular Transport. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for AstraZeneca. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for Athos Therapeutics. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for Bristol Myers Squibb. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for Celltrion. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for Dr Falk Pharma. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for Eli Lilly. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for Enthera. Prof. Danese has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ferring Pharmaceuticals Inc. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for Gilead. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for Inotrem. Prof. Danese has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for Johnson & Johnson. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for Morphic. Prof. Danese has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer. Prof. Danese has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda. Prof. Danese has received personal compensation in the range of $0-$499 for serving as a Consultant for Teladoc Health. Douglas C. Wolf has nothing to disclose. Prof. Alekseeva has nothing to disclose. Dr. Charles has received personal compensation for serving as an employee of Bristol Myers Squibb. Dr. Charles has stock in Bristol Myers Squibb. AnnKatrin Petersen has nothing to disclose. Dr. Sheffield has received personal compensation for serving as an employee of BMS. Mr. Cheng has received personal compensation for serving as an employee of Bristol Myers Squibb. Dr. Riolo has received personal compensation for serving as an employee of Bristol Myers Squib. Diego Silva has received personal compensation for serving as an employee of BMS. Diego Silva has received stock or an ownership interest from BMS. Dr. Lublin has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche/Genentech. Dr. Lublin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Lublin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurogene. Dr. Lublin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Lublin has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medimmune/Viela Bio/Horizon. Dr. Lublin has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Receptos/Celgene/BMS. Dr. Lublin has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic. Dr. Lublin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Labcorp. Dr. Lublin has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neuralight. Dr. Lublin has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Entelexo. Dr. Lublin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Janssen. Dr. Lublin has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avotres. Dr. Lublin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. Dr. Lublin has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. Dr. Lublin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for EMD Serono. Dr. Lublin has received personal compensation in the range of $100,000-$499,999 for serving as an Expert Witness for Multiple entities. Dr. Lublin has stock in Avotres. Dr. Lublin has stock in Neuralight. The institution of Dr. Lublin has received research support from Brainstorm. The institution of Dr. Lublin has received research support from biogen. The institution of Dr. Lublin has received research support from NIH. Dr. Rubin has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Abbvie. Dr. Rubin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alimentiv, Inc. Dr. Rubin has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Altrubio. Dr. Rubin has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Arena Pharmaceuticals. Dr. Rubin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Aslan Pharmaceuticals. Dr. Rubin has received personal compensation in the range of $0-$499 for serving as a Consultant for Athos Therapeutics. Dr. Rubin has received personal compensation in the range of $0-$499 for serving as a Consultant for Bellatrix Pharmaceuticals. Dr. Rubin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boehringer Ingelheim, Ltd. Dr. Rubin has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Bristol-Myers Squibb. Dr. Rubin has received personal compensation in the range of $0-$499 for serving as a Consultant for Celgene Corp/Syneos. Dr. Rubin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ClostraBio. Dr. Rubin has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Connect BioPharma. Dr. Rubin has received personal compensation in the range of $0-$499 for serving as a Consultant for Datos Health, Ltd. Dr. Rubin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EcoR1. Dr. Rubin has received personal compensation in the range of $0-$499 for serving as a Consultant for Evinature, Ltd. Dr. Rubin has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech/Roche. Dr. Rubin has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Gilead Sciences. Dr. Rubin has received personal compensation in the range of $0-$499 for serving as a Consultant for Ironwood Pharmaceuticals. Dr. Rubin has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Iterative Scopes. Dr. Rubin has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Janssen Pharmaceuticals. Dr. Rubin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kaleido Biosciences. Dr. Rubin has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Lilly, Eli & Co. Dr. Rubin has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Pfizer. Dr. Rubin has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Prometheus Biosciences. Dr. Rubin has received personal compensation in the range of $0-$499 for serving as a Consultant for Reistone Biopharma. Dr. Rubin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Seres Therapeutics, Inc. Dr. Rubin has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Takeda Pharmaceuticals. Dr. Rubin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Target RWE. Dr. Rubin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Techlab, Inc. Dr. Rubin has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Trellus Health. Dr. Rubin has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for AGA. Dr. Rubin has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Stephanie Freeman Attorney. Dr. Rubin has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Helper Broom LLC. Dr. Rubin has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Joseph Camarra Attorney. Dr. Cohen has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Convelo. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mylan. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PSI. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gossamer Bio. Dr. Cohen has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Sage.

When registering a new pesticide, 90-day oral toxicity studies performed with both rodent and non-rodent species, typically rats and dogs, are part of a standard battery of animal tests required in most countries for human health risk assessment (RA). This analysis set out to determine the need for the 90-day dog study in RA by reviewing data from 195 pesticides evaluated by the US Environmental Protection Agency (USEPA) from 1998 through 2021. The dog study was used in RA for only 42 pesticides, mostly to set the point of departure (POD) for shorter-term non-dietary pesticide exposures. Dog no-observed-adverse-effect-levels (NOAELs) were lower than rat NOAELs in 90-day studies for 36 of the above 42 pesticides, suggesting that the dog was the more sensitive species. However, lower NOAELs may not necessarily correspond to greater sensitivity as factors such as dose spacing and/or allometric scaling need to be considered. Normalizing doses between rats and dogs explained the lower NOAELs in 22/36 pesticides, indicating that in those cases the dog was not more sensitive, and the comparable rat study could have been used instead for RA. For five of the remaining pesticides, other studies of appropriate duration besides the 90-day rat study were available that would have offered a similar level of protection if used to set PODs. In only nine cases could no alternative be found in the pesticide's database to use in place of the 90-day dog study for setting safe exposure levels or to identify unique hazards. The present analysis demonstrates that for most pesticide risk determinations the 90-day dog study provided no benefit beyond the rat or other available data.

Progress in developing new tools, assays, and approaches to assess human hazard and health risk provides an opportunity to re-evaluate the necessity of dog studies for the safety evaluation of agrochemicals. A workshop was held where partic-ipants discussed the strengths and limitations of past use of dogs for pesticide evaluations and registrations. Opportunities were identified to support alternative approaches to answer human safety questions without performing the required 90-day dog study. Development of a decision tree for determining when the dog study might not be necessary to inform pesticide safety and risk assessment was proposed. Such a process will require global regulatory authority participation to lead to its acceptance. The identification of unique effects in dogs that are not identified in rodents will need further evaluation and determination of their relevance to humans. The establishment of in vitro and in silico approaches that can provide critical data on relative species sensitivity and human relevance will be an important tool to advance the decision process. Promising novel tools including in vitro comparative metabolism studies, in silico models, and high-throughput assays able to identify metabolites and mechanisms of action leading to development of adverse outcome pathways will need further development. To replace or eliminate the 90-day dog study, a collaborative, multidisciplinary, international effort that transcends organi-zations and regulatory agencies will be needed in order to develop guidance on when the study would not be necessary for human safety and risk assessment.

In 2019, the US EPA Administrator issued a directive directing the agency away from reliance on vertebrate tests by 2035, whilst maintaining high-quality human health and environmental risk assessments. There is no accepted approach to achieve this. The decade-long duration of the crop protection (CP) chemical R&D process therefore requires both the invention and application of a modernized approach to those CP chemical projects entering corporate research portfolios by the mid-2020s. We conducted problem formulation discussions with regulatory agency scientists which created the problem statement: "Develop, demonstrate, and implement a modern scientifically sound and robust strategy that applies appropriate and flexible exposure and effects characterization without chemical specific vertebrate tests to reliably address risk, uncertainties, and deficiencies in data and its interpretation with equivalent confidence as do the currently accepted test guidelines and meet the regulatory needs of the agencies". The solution must provide the knowledge needed to confidently conclude human health and environmental protective risk assessments. Exploring this led to a conceptual model involving the creation and parallel submission of a new approach without reliance on chemical-specific vertebrate tests. Assessment in parallel to a traditional package will determine whether it supports some, or all, of the necessary risk management actions. Analysis of any deficiencies will provide valuable feedback to focus development of tools or approaches for subsequent iterations. When found to provide sufficient information, it will form the technical foundation of stakeholder engagement to explore acceptance of a new approach to CP chemical risk assessment.

Regulatory science, rooted in legal requirements, provides a mechanism for identifying, assessing, and managing harm to humans and the environment from exposure to hazardous substances. A challenge for regulatory authorities is that many governing laws reflect the scientific paradigm of the mid-20th century. By the nature of legislative processes, most laws are not able to readily adapt to incorporate scientific advances that are inherent in an ever-evolving paradigm. Consequently, the issue of rigid legal frameworks has become prominent in global discussions related to the incorporation of reliable and relevant modern technology to fulfill regulatory needs. To explore this issue, we apply Thomas Kuhn's The Structure of Scientific Revolutions as a conceptual framework to help understand the natural progression of scientific paradigms (from normal science, to anomaly, to crisis, to revolution, and finally to a new normal), identify where we are now in the paradigm cycle, and to explore a path towards a revolution that enables timely implementation of the best available science to fulfil legal requirements.

Concern over substances that may cause cancer has led to various classification schemes to recognize carcinogenic threats and provide a basis to manage those threats. The least useful schemes have a binary choice that declares a substance carcinogenic or not. This overly simplistic approach ignores the complexity of cancer causation by considering neither how the substance causes cancer, nor the potency of that mode of action. Consequently, substances are classified simply as “carcinogenic”, compromising the opportunity to properly manage these kinds of substances. It will likely be very difficult, if not impossible, to incorporate New Approach Methodologies (NAMs) into binary schemes. In this paper we propose a new approach cancer classification scheme that segregates substances by both mode of action and potency into three categories and, as a consequence, provides useful guidance in the regulation and management of substances with carcinogenic potential. Examples are given, including aflatoxin (category A), trichlorethylene (category B), and titanium dioxide (category C), which demonstrate the clear differentiation among these substances that generate appropriate levels of concern and management options.

The rodent cancer bioassay has been the standard approach to fulfill regulatory requirements for assessing human carcinogenic potential of agrochemicals, food additives, industrial chemicals, and pharmaceuticals. Decades of research have described the limitations of the rodent cancer bioassay leading to international initiatives to seek alternatives and establish approaches that modernize carcinogenicity assessment. Biologically relevant approaches can provide mechanistic information and increased efficiency for evaluating hazard and risk of chemical carcinogenicity to humans. The application of human-relevant mechanistic understanding to support new approaches to carcinogenicity assessment will be invaluable for regulatory decision-making. The present work outlines the challenges and opportunities that authorities should consider as they come together to build a roadmap that leads to global acceptance and incorporation of fit-for-purpose, scientifically defensible new approaches for human-relevant carcinogenicity assessment of agrochemicals.

The US Environmental Protection Agency (USEPA) and other regulatory authorities have been working to utilize in vitro studies with human cells and in silico modelling to reduce the use of vertebrate animals for evaluating chemical risk. Using the Source-to-Outcome framework, a novel mathematical procedure was developed to estimate the human equivalent concentration (HEC) for inhalation risk assessment based upon the relevant aerosol characterization, respiratory dosimetry modelling, and endpoints derived from an in vitro assay using human respiratory epithelial tissue. The procedure used the retained doses at the various areas of the inhalation tract estimated from a computational fluid-particle dynamics (CFPD) model coupled with a simple clearance model. The effect of exposure was derived from an in vitro assay. The magnitude of exposure and the particle size distributions (PSDs) of the external aerosol droplets were obtained from Unit Exposure values published by the USEPA and published monitoring studies, respectively. The Source-to-Outcome approach incorporates external and internal exposure metrics with the toxicity pathway. The information was then integrated to conduct a risk assessment for agricultural operators exposed to products containing chlorothalonil (CTN), a broad-spectrum fungicide. The HECs for three different PSDs considered in this work ranged from 0.043 to 0.112 mg-CTN/L for nasal and oral breathing. These were compared with the estimated average daily exposure concentration for six representative application scenarios. The resulting margins of exposure (MOEs) ranged from 230 to 70,000 depending on the application scenario. This New Assessment Method (NAM) that combined human in silico and human in vitro methods, eliminated the typical uncertainties associated with extrapolation from rodent studies, with their associated interspecies toxicokinetics and toxicodynamics differences. The intraspecies toxicodynamics and toxicokinetics, are still relevant and may need to be used in an inhalation risk assessment. The NAM presented in this work is not chemical-specific and may be applied to conduct an inhalation risk assessment for workers as well as bystanders who could be exposed to aerosol particles of any cytotoxic respiratory irritant.

Abstract The present agrochemical safety evaluation paradigm is long‐standing and anchored in well‐established testing and evaluation procedures. However, it does not meet the present‐day challenges of rapidly growing populations, food insecurity, and pressures from climate change. To transform the current framework and apply modern evaluation strategies that better support sustainable agriculture, the Health and Environmental Sciences Institute (HESI) assembled a technical committee to reframe the safety evaluation of crop‐protection products. The committee is composed of international experts from regulatory agencies, academia, industry and nongovernmental organizations. Their mission is to establish a framework that supports the development of fit‐for‐purpose agrochemical safety evaluation that is applicable to changing global, as well as local needs and regulatory decisions, and incorporates relevant evolving science. This will be accomplished through the integration of state‐of‐the‐art scientific methods, technologies and data sources, to inform safety and risk decisions, and adapt them to evolving local and global needs. The project team will use a systems‐thinking approach to develop the tools that will implement a problem formulation and exposure driven approach to create sustainable, safe and effective crop protection products, and reduce, replace and refine animal studies with fit‐for‐purpose assays. A new approach necessarily will integrate the most modern tools and latest advances in chemical testing methods to guarantee the robust human and environmental safety and risk assessment of agrochemicals. This article summarizes the challenges associated with the modernization of agrochemical safety evaluation, proposes a potential roadmap, and seeks input and engagement from the broader community to advance this effort. © 2022 Health and Environmental Sciences Institute (HESI). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

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.

The long running controversy about the relative merits of hazard-based versus risk-based approaches has been investigated. There are three levels of hazard codification: level 1 divides chemicals into dichotomous bands of hazardous and non-hazardous; level 2 divides chemicals into bands of hazard based on severity and/or potency; and level 3 places each chemical on a continuum of hazard based on severity and/or potency. Any system which imposes compartments onto a continuum will give rise to issues at the boundaries, especially with only two compartments. Level 1 schemes are only justifiable if there is no variation in severity, or potency or if there is no threshold. This is the assumption implicit in GHS/EU classification for carcinogenicity, reproductive toxicity and mutagenicity. However, this assumption has been challenged. Codification level 2 hazard assessments offer a range of choices and reduce the built-in conflict inherent in the level 1 process. Level 3 assessments allow a full range of choices between the extremes and reduce the built-in conflict even more. The underlying reason for the controversy between hazard and risk is the use of level 1 hazard codification schemes in situations where there are ranges of severity and potency which require the use of level 2 or level 3 hazard codification. There is not a major difference between level 2 and level 3 codification, and they can both be used to select appropriate risk management options. Existing level 1 codification schemes should be reviewed and developed into level 2 schemes where appropriate.

The aim of this study was to examine whether short term, repeat dose, rat studies provide sufficient information about potential carcinogenicity to enable predictions about the carcinogenic potential of agrochemicals to be made earlier in compound development. This study aimed to identify any correlations between toxicity findings obtained for short term rat studies (28 day and 90 day) and neoplastic findings obtained from 24 month rat carcinogenicity studies for agrochemical compounds (18 compounds) tested in Han Wistar and Sprague Dawley rats. The macroscopic pathology, microscopic pathology, hematology, biochemistry, organ weights, estrogen receptor activation and genotoxicity results were examined. Seven out of 18 non genotoxic compounds developed tumors in treated rats in the carcinogenicity study and of these, two compounds showed no preneoplastic findings in the affected tissues (false negatives). Of the remaining five true positives, correlations were noted between corneal opacity and keratitis (90 day study) as early indicators of squamous cell carcinoma and papilloma of the cornea of the eye (compound 1, a hydroxyphenylpyruvate dioxygenase inhibitor) and inflammation of the stomach and kidney (90 day study) and gastric squamous cell papilloma and squamous cell carcinoma and renal tubular adenoma and carcinoma, respectively (compound 12, a fungicide with multisite activity). Minor decreases in uterine weight and increases in estradiol hydroxylation activity at 28 days were associated with endometrial adenocarcinoma (compound 18, a mitochondrial complex II electron transport inhibitor). Early liver weight increases and hepatocellular centrilobular hypertrophy (28 day study) were associated with thyroid follicular adenomas (compound 11, a succinate dehydrogenase inhibitor) in female animals only. Hepatic centrilobular hypertrophy (28 day studies) correlated with thyroid adenomas in males in carcinogenicity studies (compound 2, a hydroxyphenylpyruvate dioxygenase inhibitor). In contrast, treatment related, nasopharynx tumors (compound 3, an elongase inhibitor) and uterine adenocarcinoma (compound 9, a succinate dehydrogenase inhibitor) could not be correlated with findings from the short term studies examined. Eleven compounds displayed preneoplastic findings with no tumors (false positives) and there were no compounds with no preneoplastic findings and no tumors (true negatives). This work indicates the value of examining historical, short term studies for specific, nonneoplastic findings which correlate with tumors in carcinogenicity studies, which may obviate the need for further animal carcinogenicity studies.

Paraquat dichloride (PQ) is a non-selective herbicide which has been the subject of numerous toxicology studies over more than 50 years. This paper describes the development of a physiologically-based pharmacokinetic (PBPK) model of PQ kinetics for the rat, mouse and dog, firstly to aid the interpretation of studies in which no kinetic measurements were made, and secondly to enable the future extension of the model to humans. Existing pharmacokinetic data were used to develop a model for the rat and mouse. Simulations with this preliminary model were then used to identify key data gaps and to design a new blood binding study to reduce uncertainty in critical aspects of the model. The new data provided evidence to support the model structure, and its predictive performance was then assessed against dog and rat datasets not used in model development. The PQ-specific model parameters are the same for all three species, with only the physiological parameters varying between species. This consistency across species provides a strong basis for extrapolation to other species, as demonstrated here for the dog. The model enables a wide range of PQ data to be linked together to provide a broad understanding of PQ pharmacokinetics in rodents and the dog, showing that the key aspects of PQ kinetics in these species are understood and adequately encapsulated within the model.