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). Risk assessment of these exposures demands estimation of internal dose, especially to address intra-human variability across life stages. Dosimetry models have proven to effectively translate particle exposures to internal dose metrics relevant to evaluation of their effects in the respiratory tract. We used the open-access multiple path particle dosimetry (MPPD v3.04) model to estimate inhaled particle deposition in different regions of the respiratory tract for children of various age groups from three months to eighteen years old adults. Mass concentration data for input into the MPPD model were calculated using particle size distribution and density data from experimental FDM® 3D printer emissions tests using both ABS and PLA. The impact of changes in critical parameters that are principal determinants of inhaled dose, including: sex, age, and exposure duration, was examined using input parameter values available from the International Commission on Radiological Protection. Internal dose metrics used included regional mass deposition, mass deposition normalized by pulmonary surface area, surface area of deposited particles by pulmonary surface area, and retained regional mass. Total mass deposition was found to be highest in the 9-year-old to 18-year-old age groups with mass deposition by pulmonary surface area highest in 3-month-olds to 9-year-olds and surface area of deposited particles by pulmonary surface area to be highest in 9-year-olds. Clearance modeling revealed that frequent 3D printer users are at risk for an increased cumulative retained dose.

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. We construct an AEP transport and transformation model and then quantify external exposure pathways for humans, fishes, and small herbivorous mammals at the hypothetical site. A Monte Carlo approach was used to address parameter variability. Source apportionment was quantified for each species, and published pharmacokinetic models were used to estimate internal target site exposure from external exposures. Published dose-response data for a multispecies AOP network were used to interpret AEP results in the context of species-specific effects. This work demonstrates (1) the construction, analysis, and application of a quantitative AEP model, (2) the utility of AEPs for organizing mechanistic exposure data and highlighting data gaps, and (3) the advantages provided by a source-to-outcome construct for leveraging exposure data and to aid transparency regarding assumptions.

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. In recent years, attention has expanded to other types of elongate mineral particles (EMPs) that may share similar geometry with asbestos fibers but which may differ in mineralogy. Inhalability, dimensions and orientation, and density are major determinants of the aerodynamic behavior for fibers and other EMPs; and the resultant internal dose is recognized as being the critical link between exposure and pathogenesis. Insufficient data are available to fully understand the role of specific physicochemical properties on the potential toxicity across various types of fiber materials. While additional information is required to assess the potential health hazards of EMPs, dosimetry models are currently available to estimate the initially deposited internal dose, which is an essential step in linking airborne exposures to potential health risks. Based on dosimetry model simulations, the inhalability and internal dose of EMPs were found to be greater than that of spherical particles having the same mass or volume. However, the complexity of the dependence of internal dose on EMPs dimensions prevented a straightforward formulation of the deposition-dimension (length or diameter) relationship. Because health outcome is generally related to internal dose, consideration of the factors that influence internal dose is important in assessing the potential health hazards of airborne EMPs.

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 this work, we used a case study focused on the perchlorate anion (ClO4-) to highlight the value of the AOP framework for cross-species data integration. Computational models and dose-response data were used to evaluate the effects of ClO4- in 12 species and revealed a dose-response concordance across KEs and taxa. The aggregate exposure pathway (AEP) tracks stressors from sources to the exposures and serves as a complement to the AOP. We discuss how the combined AEP-AOP construct helps to maximize the use of existing data and advances CRA by (1) organizing toxicity and exposure data, (2) providing a mechanistic framework of KEs for integrating data across human health and ecological end points, (3) facilitating cross-species dose-response evaluation, and (4) highlighting data gaps and technical limitations.

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 (0.5, 3.5, or 25.0 mg/m(3) targets), or AM (3.5 mg/m(3) target) for 10 days and assessed for markers of lung inflammation, injury, and cell proliferation. Short-term results guided concentration levels for a stop-exposure study in which rats were exposed to air, LA (1.0, 3.3, or 10.0 mg/m(3)), or AM (3.3 mg/m(3)) 6 h/day, 5 days/week for 13 weeks, and assessed 1 day, 1, 3, and 18 months post-exposure. Fibers were relatively short; for 10 mg/m(3) LA, mean length of all structures was 3.7 µm and 1% were longer than 20 µm. RESULTS: Ten days exposure to 25.0 mg/m(3) LA resulted in significantly increased lung inflammation, fibrosis, bronchiolar epithelial cell proliferation and hyperplasia, and inflammatory cytokine gene expression compared to air. Exposure to 3.5 mg/m(3) LA resulted in modestly higher markers of acute lung injury and inflammation compared to AM. Following 13 weeks exposure, lung fiber burdens correlated with exposure mass concentrations, declining gradually over 18 months. LA (3.3 and 10.0 mg/m(3)) and AM produced significantly higher bronchoalveolar lavage markers of inflammation and lung tissue cytokines, Akt, and MAPK/ERK pathway components compared to air control from 1 day to 3 months post-exposure. Histopathology showed alveolar inflammation and interstitial fibrosis in all fiber-exposed groups up to 18 months post-exposure. Positive dose trends for incidence of alveolar epithelial hyperplasia and bronchiolar/alveolar adenoma or carcinoma were observed among LA groups. CONCLUSIONS: Inhalation of relatively short LA fibers produced inflammatory, fibrogenic, and tumorigenic effects in rats which replicate essential attributes of asbestos-related disease in exposed humans. Fiber burden, inflammation, and activation of growth factor pathways may persist and contribute to lung tumorigenesis long after initial LA exposure. Fiber burden data are being used to develop a dosimetry model for LA fibers, which may provide insights on mode of action for hazard assessment.

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. While fibrosis takes weeks or months to develop in vivo, an in vitro test system may more rapidly predict fibrogenic potential by monitoring pro-fibrotic mediators (e.g., cytokines and growth factors). Therefore, the workshop discussions focused on the necessary specifications related to the development and evaluation of such an in vitro system. Recommendations were made for designing a system using lung-relevant cells co-cultured at the air-liquid interface to assess the pro-fibrogenic potential of aerosolized MWCNTs, while considering human-relevant dosimetry and NM life cycle transformations. The workshop discussions provided the fundamental design components of an air-liquid interface in vitro test system that will be subsequently expanded to the development of an alternative testing strategy to predict pulmonary toxicity and to generate data that will enable effective risk assessment of NMs.

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. Use of dosimetry principles and tools can improve the accuracy of risk assessment, and reduce the uncertainty, by providing reliable estimates of the internal dose at the target tissue. This is accomplished through specific measurement data or predictive models, when available, or the use of basic dosimetry principles for broad classes of materials. Accurate dose estimation is essential not only for dose-response assessment, but also for interspecies extrapolation and for risk characterization at given exposures. Inhalation dosimetry is the focus of this paper since it is a major route of exposure in the workplace. Practical examples of dose estimation and OEL derivation are provided for inhaled gases and particulates.

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. All three chemicals produce liver tumors in rats. AFB1 and VCl also produce liver tumors in humans, but Tam induces human uterine tumors, only. To support a mutagenic MOA, the chemical-induced adducts must be characterized, shown to be pro-mutagenic, be present in the tumor target tissue, and produce mutations of the class found in the tumor. The adducts formed by AFB1 and VCl support a mutagenic MOA for their carcinogenicity. However, the data available for Tam shows a mutagenic MOA for liver tumors in rats, but its carcinogenicity in humans is most likely via a different MOA.

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. Because the operation of 3D printers is associated with the release of inhalable particles and volatile organic compounds (VOCs), there are concerns of possible health implications, particularly for use in schools and residential environments that may not have adequate ventilation such as classrooms bedrooms and garages, etc. Along with the growing consumer market for low-cost printers and printer pens, there is also an expanding market for a range of specialty filaments with additives such as inorganic colorants, metal particles and nanomaterials as well as metal-containing flame retardants, antioxidants, heat stabilizers and catalysts. Inhalation of particulate-associated metals may represent a health risk depending on both the metal and internal dose to the respiratory tract. Little has been reported, however, about the presence, speciation, and source of metals in the emissions; or likewise the effect of metals on emission processes and toxicological implications of these 3D printer generated emissions. This report evaluates various issues including the following: metals in feedstock with a focus on filament characteristics and function of metals; the effect of metals on the emissions and metals detected in emissions; printer emissions, particle formation, transport, and transformation; exposure and translation to internal dose; and potential toxicity on inhaled dose. Finally, data gaps and potential areas of future research are discussed within these contexts.

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. A virtual symposium was held during the 2021 Cooperation Centre for Scientific Research Relative to Tobacco (CORESTA) Smoke Science and Product Technology (SSPT) conference (titled "Advancing New Alternative Methods for Tobacco Harm Reduction"), with the goals of introducing the concepts and potential application of NAMs in the evaluation of potentially reduced-risk (PRR) tobacco products. At the symposium, experts from regulatory agencies, research organizations, and NGOs shared insights on the status of available tools, strengths, limitations, and opportunities in the application of NAMs using case examples from safety assessments of chemicals and tobacco products. Following seven presentations providing background and application of NAMs, a discussion was held where the presenters and audience discussed the outlook for extending the NAMs toxicological applications for tobacco products. The symposium, endorsed by the CORESTA In Vitro Tox Subgroup, Biomarker Subgroup, and NextG Tox Task Force, illustrated common ground and interest in science-based engagement across the scientific community and stakeholders in support of tobacco regulatory science. Highlights of the symposium are summarized in this paper.

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. To address these questions, we used a primary human bronchial epithelial cell air-liquid interface model exposed to ozone (O3), a model oxidant and ubiquitous environmental chemical. Here we report that O3-induced proinflammatory gene induction is attenuated in repeated exposures thus demonstrating that single acute exposure outcomes do not reliably represent the trajectory of responses after repeated or chronic exposures. Further, we observed 10.1-, 10.3-, 14.2-, and 7-fold ranges of induction of interleukin (IL)-8, IL-6, heme oxygenase 1, and cyclooxygenase 2 transcripts, respectively, within in our population of 25 unique donors. Calculation of sample size estimates that indicated that 27, 24, 299, and 13 donors would be required to significantly power similar in vitro studies to identify a 2-fold change in IL-8, IL-6, HMOX1, and cyclooxygenase 2 transcript induction, respectively, to inform considerations of the uncertainty factors to reflect variability within the human population for in vitro studies.

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. The framework proposes to organize data using a semantic triple of a chemical (subject), has impact (predicate), and a causal event on the source-to-outcome continuum of a second chemical (object). The location of the causal event on the source-to-outcome continuum and the nature of the impact are used as the basis for a taxonomy of interactions. The approach also builds on concepts from the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP). The framework proposes the linking of AEPs of multiple chemicals and the AOP networks relevant to those chemicals to form AEP-AOP networks that describe chemical interactions that cannot be characterized using AOP networks alone. Such AEP-AOP networks will aid the construction of workflows for both experimental design and the systematic review or evaluation performed in risk assessments. Finally, the framework is used to link the constructs of existing component-based approaches for mixture toxicology to specific categories in the interaction taxonomy.

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. Achieving integration of gene, phenotype, and environment will require extensive translation of data into a standard, computable form and the extension of the existing gene/phenotype data model. The data standards and models needed to achieve this integration do not currently exist. OBJECTIVES: Our objective is to foster development of community-driven data-reporting standards and a computational model that will facilitate the inclusion of exposure data in computational analysis of human disease. To this end, we present a preliminary semantic data model and use cases and competency questions for further community-driven model development and refinement. DISCUSSION: There is a real desire by the exposure science, epidemiology, and toxicology communities to use informatics approaches to improve their research workflow, gain new insights, and increase data reuse. Critical to success is the development of a community-driven data model for describing environmental exposures and linking them to existing models of human disease. https://doi.org/10.1289/EHP7215.

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. Emphasis is placed on the appreciation that such DNA adduct data cannot be used in isolation in the risk assessment process but must be used in an integrated fashion with other information. As emerging technologies provide even more sensitive quantitative measurements of DNA adducts, integration that establishes links between DNA adducts and accepted outcome measures becomes critical for risk assessment. The present report proposes an organizational approach for the assessment of DNA adduct data (e.g., type of adduct, frequency, persistence, type of repair process) in concert with other relevant data, such as dosimetry, toxicity, mutagenicity, genotoxicity, and tumor incidence, to inform characterization of the mode of action. DNA adducts are considered biomarkers of exposure, whereas gene mutations and chromosomal alterations are often biomarkers of early biological effects and also can be bioindicators of the carcinogenic process.

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. For each study evaluated, exposure deficiencies are documented, and a study is given an overall rating (Robust, Adequate, or Poor) for the quality of its exposure characterization and documentation. In combination with the systematic consideration of experimental features other than exposure, these ratings can inform the utility of a study for use in hazard identification and/or exposure-response analysis. Exposure quality evaluations of 204 formaldehyde inhalation studies are presented as a case study. Of these, 34% were rated Robust because they had comprehensive exposure documentation and no serious deficiencies in the key elements of exposure quality. Another 19% of studies with minor uncertainties or limitations were rated Adequate. Conversely, 47% of the studies were rated Poor due to multiple serious exposure deficiencies. This formaldehyde case study illustrates the need to carefully consider the exposure quality of inhalation toxicity studies when their results are used to support hazard and risk assessments.

Nasal contribution to breathing and fine particle deposition in children versus adults.

Both the route of breathing, nasal versus oral, and the effectiveness of the nose to filter inhaled, fine particles may differ between children and adults. This study compared (1) the nasal contribution to breathing at rest and during mild to moderate exercise in children (age 6-10 yr) versus young adults and (2) the nasal deposition efficiency (NDE) of fine particles (1 and 2 microm MMAD, GSD < 1.2) under resting and light exercise breathing conditions in the same children and adults. Nasal contribution to breathing was assessed by respiratory inductance plethysmography and a nasal mask with flow meter during incremental exercise on a bicycle ergometer. Fine particle deposition fractions for nasal and oral breathing were assessed by inhalation of monodisperse carnauba wax particles and laser photometry to determine inhaled/exhaled concentrations. There was a trend for children to have a lesser nasal contribution to breathing at rest and during exercise, but the differences from adults were not statistically significant. Children did, however, have significantly decreased NDE for 2-microm particles under light exercise breathing conditions compared to adults, suggesting less efficient nasal filtering for larger particles and higher flow conditions. These results suggest that the lungs of children may be exposed to higher concentrations of inhaled, ambient particles than adults.

Focusing on children's inhalation dosimetry and health effects for risk assessment: an introduction.

Substantial effort has been invested in improving children's health risk assessment in recent years. However, the body of scientific evidence in support of children's health assessment is constantly advancing, indicating the need for continual updating of risk assessment methods. Children's inhalation dosimetry and child-specific adverse health effects are of particular concern for risk assessment. When focusing on this topic within children's health, key issues for consideration include (1) epidemiological evidence of adverse effects following children's exposure to air pollution, (2) ontogeny of the lungs and effects on dosimetry, (3) estimation and variability of children's inhalation rates, and (4) current risk assessment methodologies for addressing children. In this article, existing and emerging information relating to these key issues are introduced and discussed in an effort to better understand children's inhalation dosimetry and adverse health effects for risk assessment. While much useful evidence is currently available, additional research and methods are warranted for improved children's health risk assessment.

Modeling approaches for estimating the dosimetry of inhaled toxicants in children.

Risk assessment of inhaled toxicants has typically focused upon adults, with modeling used to extrapolate dosimetry and risks from lab animals to humans. However, behavioral factors such as time spent playing outdoors may lead to more exposure to inhaled toxicants in children. Depending on the inhaled agent and the age and size of the child, children may receive a greater internal dose than adults because of greater ventilation rate per body weight or lung surface area, or metabolic differences may result in different tissue burdens. Thus, modeling techniques need to be adapted to children in order to estimate inhaled dose and risk in this potentially susceptible life stage. This paper summarizes a series of inhalation dosimetry presentations from the U.S. EPA's Workshop on Inhalation Risk Assessment in Children held on June 8-9, 2006 in Washington, DC. These presentations demonstrate how existing default models for particles and gases may be adapted for children, and how more advanced modeling of toxicant deposition and interaction in respiratory airways takes into account children's anatomy and physiology. These modeling efforts identify child-adult dosimetry differences in respiratory tract regions that may have implications for children's vulnerability to inhaled toxicants. A decision framework is discussed that considers these different approaches and modeling structures including assessment of parameter values, supporting data, reliability, and selection of dose metrics.

A PBPK model for evaluating the impact of aldehyde dehydrogenase polymorphisms on comparative rat and human nasal tissue acetaldehyde dosimetry.

Acetaldehyde is an important intermediate in the chemical synthesis and normal oxidative metabolism of several industrially important compounds, including ethanol, ethyl acetate, and vinyl acetate. Chronic inhalation of acetaldehyde leads to degeneration of the olfactory and respiratory epithelium in rats at concentrations > 50 ppm (90 day exposure) and respiratory and olfactory nasal tumors at concentrations > or = 750 ppm, the lowest concentration tested in the 2-yr chronic bioassay. Differences in the anatomy and biochemistry of the rodent and human nose, including polymorphisms in human high-affinity acetaldehyde dehydrogenase (ALDH2), are important considerations for interspecies extrapolations in the risk assessment of acetaldehyde. A physiologically based pharmacokinetic model of rat and human nasal tissues was constructed for acetaldehyde to support a dosimetry-based risk assessment for acetaldehyde (Dorman et al., 2008). The rodent model was developed using published metabolic constants and calibrated using upper-respiratory-tract acetaldehyde extraction data. The human nasal model incorporates previously published tissue volumes, blood flows, and acetaldehyde metabolic constants. ALDH2 polymorphisms were represented in the human model as reduced rates of acetaldehyde metabolism. Steady-state dorsal olfactory epithelial tissue acetaldehyde concentrations in the rat were predicted to be 409, 6287, and 12,634 microM at noncytotoxic (50 ppm), and cytotoxic/tumorigenic exposure concentrations (750 and 1500 ppm), respectively. The human equivalent concentration (HEC) of the rat no-observed-adverse-effect level (NOAEL) of 50 ppm, based on steady-state acetaldehyde concentrations from continual exposures, was 67 ppm. Respiratory and olfactory epithelial tissue acetaldehyde and H(+) (pH) concentrations were largely linear functions of exposure in both species. The impact of presumed ALDH2 polymorphisms on human olfactory tissue concentrations was negligible; the high-affinity, low-capacity ALDH2 does not contribute significantly to acetaldehyde metabolism in the nasal tissues. The human equivalent acetaldehyde concentration for homozygous low activity was 66 ppm, 1.5% lower than for the homozygous full activity phenotype. The rat and human acetaldehyde PBPK models developed here can also be used as a bridge between acetaldehyde dose-response and mode-of-action data as well as between similar databases for other acetaldehyde-producing nasal toxicants.

3-chlorotyrosine and 3,5-dichlorotyrosine as biomarkers of respiratory tract exposure to chlorine gas.

Modification of tyrosine by reactive chlorine can produce both 3-chlorotyrosine (CY) and 3,5-dichlorotyrosine (dCY). Both of these amino acids have proven to be promising biomarkers for assessing the extent of myeloperoxidase-catalyzed chlorine stress in a number of adverse physiological conditions. To date, there has been no application of these biomarkers for determining the extent of exposure to environmentally present gaseous chlorinating chemicals. In this manuscript, we present a method using selective ion monitoring gas chromatography for the simultaneous analysis of both CY and dCY in nasal tissue excised from Fisher 344 rats exposed to varying concentrations of chlorine gas. Using this method, we were able to demonstrate the following: 1. a dose-dependent increase in the conversion of tyrosine to CY and dCY in the respiratory epithelium tissue; 2. preferential formation of CY and dCY in the respiratory and transitional epithelium versus the olfactory epithelium of the nasal cavity of the rat; and 3. similar rates of formation for CY and dCY when exposed to chlorine gas based on a strong [CY] versus [dCY] correlation (slope = 1.001, r(2) = 0.912).