Assessing Toxicological Risks in Our World: Latest Findings

TUESDAY, MARCH 12 | 11 A.M. MST

Muna Nahar, Ph.D., Manager, Chemical Regulation & Food Safety

Abstract: "Alternatives assessment frameworks formalize approaches to selecting chemical replacements while avoiding regrettable substitutions. While the alternatives assessment field is relevant to all chemical use settings, it is particularly important with regard to consumer products. Consumer product safety is getting more attention from the public in recent years with terms like 'clean beauty' and 'green' products trending in the media. Product safety assessment is a diverse field with many players, but when it comes to questions of human health and environmental impacts, alternatives assessment provides a way forward for formulators, regulators, and advocates to collaborate and create safer products. Using alternatives assessment ensures that products contain the safest available ingredients, thereby simultaneously promoting public health and increasing consumer trust. Individual alternatives assessment frameworks weigh considerations differently. The 2014 National Research Council report A Framework to Guide Selection of Chemical Alternatives formalized the field of alternatives assessment and noted that while much of the existing assessments use Globally Harmonized System of Classification and Labelling of Chemicals criteria to evaluate hazard, other novel data streams also should be considered."

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MONDAY, MARCH 11 | 9:15 A.M. MST

Authors: Megan Arnold, Ph.D., Senior Scientist, Health Sciences; Brian Head, Ph.D., Senior Scientist, Chemical Regulation & Food Safety; Melissa Badding, Ph.D., DABT, Senior Managing Scientist, Health Sciences

Abstract: "Since the release of ISO 10993-18:2020 Biological evaluation of medical devices - Part 18: Chemical characterization of medical device materials within a risk management process, large numbers of extractable organic compound constituents from medical devices that exceed the analytical evaluation threshold (AET) have required toxicological risk assessments, creating a substantial burden on the risk assessor. To streamline these assessments, toxicologists can use a variety of approaches and available in silico tools to screen the extractable compounds for inclusion in the toxicological risk assessment. Our case-study compares two different screening approaches that can be employed in toxicological risk assessments of commonly encountered extractable medical device constituents from a theoretical dataset for an implanted medical device with tissue/bone contact comprising ultra-high molecular weight polyethylene with long-term (>30 day) patient contact."

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TUESDAY, MARCH 12 | 9:15 A.M. MST

Jacob Kremer, Ph.D., Scientist, Health Sciences

Abstract: "A common approach for assessing exposure to household air pollution is evaluating carbon monoxide (CO) measurements averaged over 24 hours. CO exposures over the 15-minute, 60-minute, and 8-hour CO World Health Organization Air Quality Guidelines (WHO AQGs) may have health implications that differ from exposures over the 24-hour AQG. We investigated real-time sub-daily CO exposures among pregnant women enrolled in the Household Air Pollution Intervention Network (HAPIN) study, a randomized controlled trial of a liquefied petroleum gas stove and fuel intervention in Guatemala, India, Peru, and Rwanda."

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MONDAY, MARCH 11 | 2:15 P.M. MST

Melissa Badding, Ph.D., DABT, Senior Managing Scientist, Health Sciences

Abstract: "The Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) Core Study, conducted by FDA NCTR and published in 2018, represents one of the largest and most comprehensive experimental animal studies of oral BPA exposure. The CLARITY-BPA Core Study was performed in Sprague Dawley rats exposed in utero daily until postnatal day 21 (stop-dose arm) or for a lifetime (continuous-dose arm). Many toxicity endpoints were evaluated across all major organs and tissues. While the Core Study authors concluded that 'Several observations at 25,000 µg BPA/kg bw/day may be treatment related,' a No-Observed-Adverse-Effect Level (NOAEL) for this study has not been proposed in the published reports or by any other group thereafter."

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MONDAY, MARCH 11 | 9:15 A.M. MST

Rekha Balachandran, Ph.D., Senior Scientist, Health Sciences; Melissa Badding, Ph.D., DABT, Senior Managing Scientist, Health Sciences; Megan Arnold, Ph.D., Senior Scientist, Health Sciences

Abstract: "This case study aims to evaluate the differences between toxicological risk assessment outcomes for medical device constituents that are commonly encountered extractables from a medical device when assessed using the original ISO 10993-17:2002 standard and its recently updated version, the ISO 10993-17:2023 'Biological Evaluation of Medical Devices - Part 17: Toxicological Risk Assessment of Medical Device Constituents.' The updated standard includes key new approaches that fundamentally change our approach in conducting toxicological risk assessments for medical devices. These changes include introduction of Toxicological Screening Limits (TSLs) to determine which organic constituents should be the focus of the risk assessment and calculation of the worst-case estimated exposure dose (EED) of constituents, as well as changes to the derivation of the tolerable intake (TI), improved guidance on the cancer risk TI, and risk acceptance criteria to evaluate the margin of safety (MOS) for constituents. The purpose of this update is to streamline the risk assessment process, making it more efficient without sacrificing stringent safety standards. In this case study, we attempt to better elucidate how the updated ISO 10993-17:2023 standard impacts the toxicological assessment of medical devices compared to the original standard."

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TUESDAY, MARCH 12 | 11:45 A.M. MST

Anne Loccisano, Ph.D., DABT, Managing Scientist, Health Sciences; Brent Kerger, Ph.D., DABT, Principal Scientist, Health Sciences

Abstract: "Historical paint stripper products contained methylene chloride (MC) as a key component to solubilize dried paints or epoxy materials, but concerns for neurological and cardiac toxicity from its metabolism to carbon monoxide (CO) led to discontinued use in consumer products. The purpose of the current study is to illustrate the application and utility of exposure simulation studies to estimate MC emission rates, near-field/far-field modeling techniques to estimate upper bound exposures, and physiologically based pharmacokinetic (PBPK) models to estimate internal dose of CO during paint stripper use."

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MONDAY, MARCH 11 | 11:45 A.M. MST

Brent Kerger, Ph.D., DABT, Principal Scientist, Health Sciences; Anne Loccisano, Ph.D., DABT, Managing Scientist, Health Sciences; Gabor Mezei, M.D., Ph.D., Principal Scientist, Health Sciences

Abstract: "Occupational exposure to amphibole forms of commercial asbestos (e.g., crocidolite and amosite) are causally associated with malignant mesothelioma (MM) at sufficiently high cumulative doses based on consistent epidemiological data. No such causal relationship has been consistently demonstrated for exposure to the more prevalent and less potent chrysotile form of asbestos or for mixed fiber asbestos exposures from US background air. Familial genetic predisposition to MM has been documented under two pedigrees involving specific germline mutations impairing the breast cancer (BRCA) type 1-associated protein 1 (BAP1) tumor suppressor gene on chromosome 3 (3p21.1) with an autosomal dominant inheritance pattern. Recent studies simulating these human BAP1 mutations in a genetically modified mouse model have hypothesized that low level/background asbestos exposures may trigger MM in persons with these mutations. The purpose of the current study is to illustrate application of quantitative cancer contribution analysis methods to assess the attributable causal fractions for MM from low level cumulative exposure to asbestos, age at onset, and genetic predisposition in Caucasian females with these BAP1 germline mutations."

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MONDAY, MARCH 11 | 9:15 A.M. MST

Elaine Freeman, DABT, Senior Managing Scientist, Chemical Regulation & Food Safety; Kyle Wilson, Senior Scientist, Chemical Regulation & Food Safety

Abstract: "The Organisation for Economic Co-operation and Development (OECD) is an international standards-making body that collaborates with multiple stakeholders to establish evidence-based guidance. To keep pace in developing guidance for use of new approach methodologies (NAMs), the Working Party on the Hazard Assessment (WPHA) was revised to enhance the activity of the development and the application of Integrated Approaches to Testing and Assessment (IATA). Subsequently, the OECD launched the IATA Case Studies Project with the intention of building experience with IATA through case studies that demonstrate their use to fulfill regulatory needs for product safety assessment. Following the submission of an IATA case study to the OECD, expert reviewers from international regulatory authorities and other stakeholders provide feedback to authors outlining (1) the strongest aspects of the case study; (2) areas of uncertainty; (3) areas in need of further development and guidance; and (4) the possibility of use for implementation of the case study in regulatory context. Given this opportunity, case studies from the Rethinking chronic toxicity and Carcinogenicity Assessment for Agrochemicals Project (ReCAAP) were developed and submitted to the OECD IATA Case Study Project."

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WEDNESDAY, MARCH 13 | 9:15 A.M. MST

Elaine Freeman, DABT, Senior Managing Scientist, Chemical Regulation & Food Safety;

Abstract: "The serendipity berry plant (Dioscoreophyllum cumminsii (Stapf) Diels) is the source of a naturally sweet protein referred to as monellin. The safety of serendipity berry sweet protein (SBSP) containing single polypeptide monellin protein (MON) expressed in Komagataella phaffii (formerly Pichia pastoris) and produced via precision fermentation was examined comprehensively through GLP studies conducted to assess the safety profile of SBSP including its mutagenic, clastogenic, and toxicologic potential."

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TUESDAY, MAR. 12 | 2:15-4:15 P.M. MST

Elaine Freeman, DABT, Senior Managing Scientist, Chemical Regulation and Food Safety 

Abstract: "Thyroid hormone homeostasis is a critical component in the evaluation of endocrine- and developmental (neuro)toxicity human health risk assessment in regulatory decision-making. Benalaxyl-M, a European approved fungicide currently undergoing registration renewal, is known to increase thyroid hormone clearance via uridine diphosphate-glucuronosyltransferase (UDP-GT) induction in rats. This rat-specific mode of action (MoA) is known to be not relevant to humans. To protect public health, the human relevant parameters should also be investigated. This research evaluated the functions of two critical proteins directly contributing to thyroid hormone synthesis in the presence of benalaxyl-M, namely thyroid peroxidase (TPO) and sodium/iodide symporter (NIS), via in vitro new approach methods (NAMs). Specifically, additional cytotoxicity investigation was utilized in the NIS assay, demonstrating different sensitivities between cytotoxicity markers. The combination of cytotoxicity analysis and the MoA investigation provides additional understanding in the interpretation of NAMs and provide further reliability on NAMs in order to replace and reduce animal use."

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WEDNESDAY, MARCH 13 | 10:40 A.M.

Craig Llewellyn Ph.D., Principal Scientist, Chemical Regulation & Food Safety

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