New approach methodologies (NAMs) for the assessment of cleaning products for respiratory irritation: workshop report.

The use of new approach methodologies (NAMs) to assess respiratory irritation depends on several factors, including the specifics of exposure methods and cell/tissue-based test systems. This topic was examined in the context of human health risk assessment for cleaning products at a 1-day public workshop held on 2 March 2023, organized by the American Cleaning Institute (ACI). The goals of this workshop were to (1) review NAMs for evaluation of respiratory irritation, (2) examine different perspectives on current challenges and suggested solutions, and (3) publish a manuscript of the proceedings.

Advancing New Approach Methodologies (NAMs) for Tobacco Harm Reduction: Synopsis from the 2021 CORESTA SSPT-NAMs Symposium.

New approach methodologies (NAMs) are emerging chemical safety assessment tools consisting of in vitro and in silico (computational) methodologies intended to reduce, refine, or replace (3R) various in vivo animal testing methods traditionally used for risk assessment. Significant progress has been made toward the adoption of NAMs for human health and environmental toxicity assessment. However, additional efforts are needed to expand their development and their use in regulatory decision making.

Human exposure to metals in consumer-focused fused filament fabrication (FFF)/ 3D printing processes.

Fused filament fabrication (FFF) or 3D printing is a growing technology used in industry, cottage industry and for consumer applications. Low-cost 3D printing devices have become increasingly popular among children and teens. Consequently, 3D printers are increasingly common in households, schools, and libraries.

Ozone Responsive Gene Expression as a Model for Describing Repeat Exposure Response Trajectories and Interindividual Toxicodynamic Variability In Vitro.

Inhaled chemical/material exposures are a ubiquitous part of daily life around the world. There is a need to evaluate potential adverse effects of both single and repeat exposures for thousands of chemicals and an exponentially larger number of exposure scenarios (eg, repeated exposures). Meeting this challenge will require the development and use of in vitro new approach methodologies (NAMs); however, 2 major challenges face the deployment of NAMs in risk assessment are (1) characterizing what apical outcome(s) acute assays inform regarding the trajectory to long-term events, especially under repeated exposure conditions, and (2) capturing interindividual variability as it informs considerations of potentially susceptible and/or vulnerable populations.

3D Printer Particle Emissions: Translation to Internal Dose in Adults and Children.

Desktop fused deposition modeling (FDM®) three-dimensional (3D) printers are becoming increasingly popular in schools, libraries, and among home hobbyists. FDM® 3D printers have been shown to release ultrafine airborne particles in large amounts, indicating the potential for inhalation exposure and consequent health risks among FDM® 3D printer users and other room occupants including children. These particles are generated from the heating of thermoplastic polymer feedstocks during the FDM® 3D printing process, with the most commonly used polymers being acrylonitrile butadiene styrene (ABS) and poly-lactic acid (PLA).

Community Approaches for Integrating Environmental Exposures into Human Models of Disease.

Background: A critical challenge in genomic medicine is identifying the genetic and environmental risk factors for disease. Currently, the available data links a majority of known coding human genes to phenotypes, but the environmental component of human disease is extremely underrepresented in these linked data sets. Without environmental exposure information, our ability to realize precision health is limited, even with the promise of modern genomics.

Organizing mechanism-related information on chemical interactions using a framework based on the aggregate exposure and adverse outcome pathways.

This paper presents a framework for organizing and accessing mechanistic data on chemical interactions. The framework is designed to support the assessment of risks from combined chemical exposures. The framework covers interactions between chemicals that occur over the entire source-to-outcome continuum including interactions that are studied in the fields of chemical transport, environmental fate, exposure assessment, dosimetry, and individual and population-based adverse outcomes.

A Quantitative Source-to-Outcome Case Study To Demonstrate the Integration of Human Health and Ecological End Points Using the Aggregate Exposure Pathway and Adverse Outcome Pathway Frameworks.

Exposure to environmental contaminants can lead to adverse outcomes in both human and nonhuman receptors. The Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) frameworks can mechanistically inform cumulative risk assessment for human health and ecological end points by linking together environmental transport and transformation, external exposure, toxicokinetics, and toxicodynamics. This work presents a case study of a hypothetical contaminated site to demonstrate a quantitative approach for implementing the AEP framework and linking this framework to AOPs.

The evaluation of inhalation studies for exposure quality: A case study with formaldehyde.

The inherent complexity of generating and monitoring a test article in an inhalation chamber can make inhalation toxicity testing challenging. Poor study design, human error, and electrical and mechanical problems can adversely affect an inhalation exposure and undermine a study's results. We have developed a process for evaluating seven key elements of exposure quality in inhalation chamber studies: 1) test article characterization, 2) generation method, 3) chamber sampling and analytical method, 4) chamber concentrations, 5) particle size characteristics, 6) chamber type, and 7) controls.

Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity.

New approaches are needed to assess the effects of inhaled substances on human health. These approaches will be based on mechanisms of toxicity, an understanding of dosimetry, and the use of in silico modeling and in vitro test methods. In order to accelerate wider implementation of such approaches, development of adverse outcome pathways (AOPs) can help identify and address gaps in our understanding of relevant parameters for model input and mechanisms, and optimize non-animal approaches that can be used to investigate key events of toxicity.

Dosimetry of inhaled elongate mineral particles in the respiratory tract: The impact of shape factor.

Inhalation exposure to some types of fibers (e.g., asbestos) is well known to be associated with respiratory diseases and conditions such as pleural plaques, fibrosis, asbestosis, lung cancer, and mesothelioma.

Alternative approaches for acute inhalation toxicity testing to address global regulatory and non-regulatory data requirements: An international workshop report.

Inhalation toxicity testing, which provides the basis for hazard labeling and risk management of chemicals with potential exposure to the respiratory tract, has traditionally been conducted using animals. Significant research efforts have been directed at the development of mechanistically based, non-animal testing approaches that hold promise to provide human-relevant data and an enhanced understanding of toxicity mechanisms. A September 2016 workshop, "Alternative Approaches for Acute Inhalation Toxicity Testing to Address Global Regulatory and Non-Regulatory Data Requirements", explored current testing requirements and ongoing efforts to achieve global regulatory acceptance for non-animal testing approaches.

A Case Study Application of the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) Frameworks to Facilitate the Integration of Human Health and Ecological End Points for Cumulative Risk Assessment (CRA).

Cumulative risk assessment (CRA) methods promote the use of a conceptual site model (CSM) to apportion exposures and integrate risk from multiple stressors. While CSMs may encompass multiple species, evaluating end points across taxa can be challenging due to data availability and physiological differences among organisms. Adverse outcome pathways (AOPs) describe biological mechanisms leading to adverse outcomes (AOs) by assembling causal pathways with measurable intermediate steps termed key events (KEs), thereby providing a framework for integrating data across species.

In vitro to in vivo extrapolation for high throughput prioritization and decision making.

In vitro chemical safety testing methods offer the potential for efficient and economical tools to provide relevant assessments of human health risk. To realize this potential, methods are needed to relate in vitro effects to in vivo responses, i.e.

Interpreting Mobile and Handheld Air Sensor Readings in Relation to Air Quality Standards and Health Effect Reference Values: Tackling the Challenges.

The US Environmental Protection Agency (EPA) and other federal agencies face a number of challenges in interpreting and reconciling short-duration (seconds to minutes) readings from mobile and handheld air sensors with the longer duration averages (hours to days) associated with the National Ambient Air Quality Standards (NAAQS) for the criteria pollutants-particulate matter (PM), ozone, carbon monoxide, lead, nitrogen oxides, and sulfur oxides. Similar issues are equally relevant to the hazardous air pollutants (HAPs) where chemical-specific health effect reference values are the best indicators of exposure limits; values which are often based on a lifetime of continuous exposure. A multi-agency, staff-level Air Sensors Health Group (ASHG) was convened in 2013.

Manganese testing under a clean air act test rule and the application of resultant data in risk assessments.

In the 1990's, the proposed use of methylcyclopentadienyl manganese tricarbonyl (MMT) as an octane-enhancing gasoline fuel additive led to concerns for potential public health consequences from exposure to manganese (Mn) combustion products in automotive exhaust. After a series of regulatory/legal actions and negotiations, the U.S.

Expert consensus on an in vitro approach to assess pulmonary fibrogenic potential of aerosolized nanomaterials.

The increasing use of multi-walled carbon nanotubes (MWCNTs) in consumer products and their potential to induce adverse lung effects following inhalation has lead to much interest in better understanding the hazard associated with these nanomaterials (NMs). While the current regulatory requirement for substances of concern, such as MWCNTs, in many jurisdictions is a 90-day rodent inhalation test, the monetary, ethical, and scientific concerns associated with this test led an international expert group to convene in Washington, DC, USA, to discuss alternative approaches to evaluate the inhalation toxicity of MWCNTs. Pulmonary fibrosis was identified as a key adverse outcome linked to MWCNT exposure, and recommendations were made on the design of an in vitro assay that is predictive of the fibrotic potential of MWCNTs.

Persistent effects of Libby amphibole and amosite asbestos following subchronic inhalation in rats.

Background: Human exposure to Libby amphibole (LA) asbestos increases risk of lung cancer, mesothelioma, and non-malignant respiratory disease. This study evaluated potency and time-course effects of LA and positive control amosite (AM) asbestos fibers in male F344 rats following nose-only inhalation exposure.

Methods: Rats were exposed to air, LA (0.

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation.

The purpose of this article is to provide an overview and practical guide to occupational health professionals concerning the derivation and use of dose estimates in risk assessment for development of occupational exposure limits (OELs) for inhaled substances. Dosimetry is the study and practice of measuring or estimating the internal dose of a substance in individuals or a population. Dosimetry thus provides an essential link to understanding the relationship between an external exposure and a biological response.

An organizational approach for the assessment of DNA adduct data in risk assessment: case studies for aflatoxin B1, tamoxifen and vinyl chloride.

The framework analysis previously presented for using DNA adduct information in the risk assessment of chemical carcinogens was applied in a series of case studies which place the adduct information into context with the key events in carcinogenesis to determine whether they could be used to support a mutagenic mode of action (MOA) for the examined chemicals. Three data-rich chemicals, aflatoxin B1 (AFB1), tamoxifen (Tam) and vinyl chloride (VCl) were selected for this exercise. These chemicals were selected because they are known human carcinogens and have different characteristics: AFB1 forms a unique adduct and human exposure is through contaminated foods; Tam is a pharmaceutical given to women so that the dose and duration of exposure are known, forms unique adducts in rodents, and has both estrogenic and genotoxic properties; and VCl, to which there is industrial exposure, forms a number of adducts that are identical to endogenous adducts found in unexposed people.

Meeting report: mode(s) of action of asbestos and related mineral fibers.

Background: Although asbestos in general is well known to cause a range of neoplastic and non-neoplastic human health effects, not all asbestos fiber types have the same disease-causing potential, and the mode of action (MOA) of specific types of asbestos and related fibers for various health outcomes are not well understood.

Objectives: A workshop was held to discuss the state of the science of the MOA for asbestos-related disease. The objective was to review the range of asbestos-induced health effects (including those at sites remote to the respiratory tract).

Creating context for the use of DNA adduct data in cancer risk assessment: I. Data organization.

The assessment of human cancer risk from chemical exposure requires the integration of diverse types of data. Such data involve effects at the cell and tissue levels. This report focuses on the specific utility of one type of data, namely DNA adducts.

Hormesis and adaptive cellular control systems.

Hormetic dose response occurs for many endpoints associated with exposures of biological organisms to environmental stressors. Cell-based U- or inverted U-shaped responses may derive from common processes involved in activation of adaptive responses required to protect cells from stressful environments. These adaptive pathways extend the region of cellular homeostasis and are protective against ultimate cell, organ, and system toxicity.