Mechanisms and shapes of causal exposure-response functions for asbestos in mesotheliomas and lung cancers.

This paper summarizes recent insights into causal biological mechanisms underlying the carcinogenicity of asbestos. It addresses their implications for the shapes of exposure-response curves and considers recent epidemiologic trends in malignant mesotheliomas (MMs) and lung fiber burden studies. Since the commercial amphiboles crocidolite and amosite pose the highest risk of MMs and contain high levels of iron, endogenous and exogenous pathways of iron injury and repair are discussed.

Updating the biologically based dose-response model for the nasal carcinogenicity of inhaled formaldehyde in the F344 rat.

Chronic inhalation of formaldehyde by F344 rats causes nasal squamous cell carcinoma (SCC). This outcome is well-characterized: including dose-response and time course data for SCC, mechanistic endpoints, and nasal dosimetry. Conolly et al.

PBPK modeling to evaluate maximum tolerated doses: A case study with 3-chloroallyl alcohol.

A physiologically based pharmacokinetic (PBPK) model for 3-chloroallyl alcohol (3-CAA) was developed and used to evaluate the design of assays for the genotoxicity of 3-CAA. Model development was supported by read across from a published PBPK model for ethanol. Read across was motivated by the expectation that 3-CAA, which like ethanol is a primary alcohol, is metabolized largely by hepatic alcohol dehydrogenases.

A Physiologically Based Pharmacokinetic (PBPK) Modeling Framework for Mixtures of Dioxin-like Compounds.

Humans are exposed to persistent organic pollutants, such as dioxin-like compounds (DLCs), as mixtures. Understanding and predicting the toxicokinetics and thus internal burden of major constituents of a DLC mixture is important for assessing their contributions to health risks. PBPK models, including dioxin models, traditionally focus on one or a small number of compounds; developing new or extending existing models for mixtures often requires tedious, error-prone coding work.

Relative contributions of endogenous and exogenous formaldehyde to formation of deoxyguanosine monoadducts and DNA-protein crosslink adducts of DNA in rat nasal mucosa.

Understanding the dose-response for formaldehyde-induced nasal cancer in rats is complicated by (1) the uneven distribution of inhaled formaldehyde across the interior surface of the nasal cavity and, (2) the presence of endogenous formaldehyde (endoF) in the nasal mucosa. In this work, we used computational fluid dynamics (CFD) modeling to predict flux of inhaled (exogenous) formaldehyde (exogF) from air into tissue at the specific locations where DNA adducts were measured. Experimental work has identified DNA-protein crosslink (DPX) adducts due to exogF and deoxyguanosine (DG) adducts due to both exogF and endoF.

Case Study in 21st-Century Ecotoxicology: Using In Vitro Aromatase Inhibition Data to Predict Reproductive Outcomes in Fish In Vivo.

To reduce the use of intact animals for chemical safety testing, while ensuring protection of ecosystems and human health, there is a demand for new approach methodologies (NAMs) that provide relevant scientific information at a quality equivalent to or better than traditional approaches. The present case study examined whether bioactivity and associated potency measured in an in vitro screening assay for aromatase inhibition could be used together with an adverse outcome pathway (AOP) and mechanistically based computational models to predict previously uncharacterized in vivo effects. Model simulations were used to inform designs of 60-h and 10-21-day in vivo exposures of adult fathead minnows (Pimephales promelas) to three or four test concentrations of the in vitro aromatase inhibitor imazalil ranging from 0.

Pregnancy-specific physiologically-based toxicokinetic models for bisphenol A and bisphenol S.

Predictions from physiologically based toxicokinetic (PBTK) models can help inform human health risk assessment for potentially toxic chemicals in the environment. Bisphenol S (BPS) is the second most abundant bisphenol detected in humans in the United States, after bisphenol A (BPA). We have recently demonstrated that BPS, much like BPA, can cross the placental barrier and disrupt placental function.

Embracing Systems Toxicology at Single-Cell Resolution.

As systems biology expands its multi-omic spectrum to increasing resolutions, distinguishing cells based on single-cell profiles becomes feasible. Unlike traditional bulk assays that average cellular responses and blur the distinct identities of responsive cells, single-cell technologies enable sensitive detection of small cellular changes and precise identification of those cells perturbed by toxicants. Among the suite of omic technologies that continue to expand and become affordable, single-cell RNA sequencing (scRNA-seq) is at the cutting edge and leading the way to transform systems toxicology.

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.

Development of a Novel AOP for Cyp2F2-Mediated Lung Cancer in Mice.

Traditional methods for carcinogenicity testing rely heavily on the rodent bioassay as the standard for identification of tumorigenic risk. As such, identification of species-specific outcomes and/or metabolism are a frequent argument for regulatory exemption. One example is the association of tumor formation in the mouse lung after exposure to Cyp2F2 ligands.

Building and Applying Quantitative Adverse Outcome Pathway Models for Chemical Hazard and Risk Assessment.

An important goal in toxicology is the development of new ways to increase the speed, accuracy, and applicability of chemical hazard and risk assessment approaches. A promising route is the integration of in vitro assays with biological pathway information. We examined how the adverse outcome pathway (AOP) framework can be used to develop pathway-based quantitative models useful for regulatory chemical safety assessment.

Bridging the Data Gap From Toxicity Testing to Chemical Safety Assessment Through Computational Modeling.

Chemical toxicity testing is moving steadily toward a human cell and organoid-based approach for reasons including scientific relevancy, efficiency, cost, and ethical rightfulness. Inferring human health risk from chemical exposure based on testing data is a challenging task, facing various data gaps along the way. This review identifies these gaps and makes a case for the approach of computational dose-response and extrapolation modeling to address many of the challenges.

An updated analysis of respiratory tract cells at risk for formaldehyde carcinogenesis.

Study of the mode of action (MOA) relating exposure to a given chemical with an associated adverse outcome is an iterative process with each iteration driven by new understandings of the relevant biology. Here, we revisit a previously described, MOA-based clonal growth model of the human respiratory tract cancer risk associated with formaldehyde inhalation. Changes reflect a better understanding of populations of cells at risk of carcinogenic transformation in the pharynx, larynx and respiratory bronchiolar portions of the human respiratory tract and inclusion of basal cells in the pool of cells at risk.

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.

Quantitative Adverse Outcome Pathways and Their Application to Predictive Toxicology.

A quantitative adverse outcome pathway (qAOP) consists of one or more biologically based, computational models describing key event relationships linking a molecular initiating event (MIE) to an adverse outcome. A qAOP provides quantitative, dose-response, and time-course predictions that can support regulatory decision-making. Herein we describe several facets of qAOPs, including (a) motivation for development, (b) technical considerations, (c) evaluation of confidence, and (d) potential applications.

Editor's Highlight: Computational Modeling of Plasma Vitellogenin Alterations in Response to Aromatase Inhibition in Fathead Minnows.

In vertebrates, conversion of testosterone into 17β-estradiol (E2) is catalyzed by cytochrome P450 (CYP) 19A aromatase. An important role of E2 in oviparous vertebrates such as fish is stimulation of hepatic synthesis of the glycolipoprotein vitellogenin (VTG), an egg yolk precursor essential to oocyte development and larval survival. In fathead minnows (FHMs) (Pimephales promelas) exposed to the aromatase inhibitor fadrozole, plasma VTG levels do not change in concert with plasma E2 levels.

Developing a Gene Biomarker at the Tipping Point of Adaptive and Adverse Responses in Human Bronchial Epithelial Cells.

Determining mechanism-based biomarkers that distinguish adaptive and adverse cellular processes is critical to understanding the health effects of environmental exposures. Shifting from in vivo, low-throughput toxicity studies to high-throughput screening (HTS) paradigms and risk assessment based on in vitro and in silico testing requires utilizing toxicity pathway information to distinguish adverse outcomes from recoverable adaptive events. Little work has focused on oxidative stresses in human airway for the purposes of predicting adverse responses.

Computational model of the fathead minnow hypothalamic-pituitary-gonadal axis: Incorporating protein synthesis in improving predictability of responses to endocrine active chemicals.

There is international concern about chemicals that alter endocrine system function in humans and/or wildlife and subsequently cause adverse effects. We previously developed a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows exposed to a model aromatase inhibitor, fadrozole (FAD), to predict dose-response and time-course behaviors for apical reproductive endpoints. Initial efforts to develop a computational model describing adaptive responses to endocrine stress providing good fits to empirical plasma 17β-estradiol (E2) data in exposed fish were only partially successful, which suggests that additional regulatory biology processes need to be considered.

Molecular signaling network motifs provide a mechanistic basis for cellular threshold responses.

Background: Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations.

A new method for generating distributions of biomonitoring equivalents to support exposure assessment and prioritization.

Biomonitoring data are now available for hundreds of chemicals through state and national health surveys. Exposure guidance values also exist for many of these chemicals. Several methods are frequently used to evaluate biomarker data with respect to a guidance value.

Effects of endogenous formaldehyde in nasal tissues on inhaled formaldehyde dosimetry predictions in the rat, monkey, and human nasal passages.

Formaldehyde is a nasal carcinogen in rodents at high doses and is an endogenous compound that is present in all living cells. Due to its high solubility and reactivity, quantitative risk estimates for inhaled formaldehyde have relied on internal dose estimates in the upper respiratory tract. Dosimetry calculations are complicated by the presence of endogenous formaldehyde concentrations in the respiratory mucosa.

Uncertainties in estimating health risks associated with exposure to ionising radiation.

The information for the present discussion on the uncertainties associated with estimation of radiation risks and probability of disease causation was assembled for the recently published NCRP Report No. 171 on this topic. This memorandum provides a timely overview of the topic, given that quantitative uncertainty analysis is the state of the art in health risk assessment and given its potential importance to developments in radiation protection.