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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.

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.

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.

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.

Modernizing risk assessment methods that underlie risk management decisions developed to protect public and environmental health will require interdisciplinary dialog and communication. Alignment of exposures across traditional data streams such as data from in vivo laboratory animal and epidemiological or clinical studies, as well as integration of novel data types from emerging testing technologies and new methods of analysis, will improve causal inference. We propose a mechanistic scaffold that supports a source-to-outcome structure and an associated workflow pipeline which facilitates needed data curation and transparency regarding operational assumptions. The scaffold and workflow components enhance the utility and repurposing of data with the flexibility to support regulatory decision-making in a fit-for-purpose fashion. Efficient use of data based on this scaffold across various modeling approaches will promote “one health” characterization to improve, promote, and protect the health of all species and the environment. Associated data standards to facilitate leveraging and sharing of data will increase communication and collaboration across different disciplines to enable that end.

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

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., in vitro to in vivo extrapolation (IVIVE). Currently available IVIVE approaches need to be refined before they can be utilized for regulatory decision-making. To explore the capabilities and limitations of IVIVE within this context, the U.S. Environmental Protection Agency Office of Research and Development and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods co-organized a workshop and webinar series. Here, we integrate content from the webinars and workshop to discuss activities and resources that would promote inclusion of IVIVE in regulatory decision-making. We discuss properties of models that successfully generate predictions of in vivo doses from effective in vitro concentration, including the experimental systems that provide input parameters for these models, areas of success, and areas for improvement to reduce model uncertainty. Finally, we provide case studies on the uses of IVIVE in safety assessments, which highlight the respective differences, information requirements, and outcomes across various approaches when applied for decision-making.

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. Environmental Protection Agency (EPA) issued under Clean Air Act (CAA) section 211(b) an Alternative Tier 2 Test Rule that required development of scientific information intended to help resolve uncertainties in exposure or health risk estimates associated with MMT use. Among the uncertainties identified were: the chemical forms of Mn emitted in automotive exhaust; the relative toxicity of different Mn species; the potential for exposure among sensitive subpopulations including females, the young and elderly; differences in sensitivity between test species and humans; differences between inhalation and oral exposures; and the influence of dose rate and exposure duration on tissue accumulation of Mn. It was anticipated that development of specific sets of pharmacokinetic (PK) information and models regarding Mn could help resolve many of the identified uncertainties and serve as the best foundation for available data integration. The results of the test program included development of several unique Mn datasets, and a series of increasingly sophisticated Mn physiologically-based pharmacokinetic (PBPK) models. These data and models have helped address each of the uncertainties originally identified in the Test Rule. The output from these PBPK models were used by the Agency for Toxic Substances and Disease Registry (ATSDR) in 2012 to inform the selection of uncertainty factors for deriving the manganese Minimum Risk Level (MRL) for chronic exposure durations. The EPA used the MRL in the Agency’s 2015 evaluation of potential residual risks of airborne manganese released from ferroalloys production plants. This resultant set of scientific data and models likely would not exist without the CAA section 211(b) test rule regulatory procedure.

Inhaled aerosols whether beneficial or harmful express their effects depending on the amount initially deposited in the body (i.e. the deposition dose), with clearance mechanisms including dissolution, mucociliary transport and translocation then determining retained dose in the respiratory tract. The many regions of the respiratory tract differ in their shapes, cellular makeups, defenses, and pathologies. As a result, predicting, measuring, and simulating initial deposition doses and subsequent events for deposited particles, vapors and gases presents formidable challenges. Interest in supplementing and in some cases replacing laboratory animals in inhalation studies with in vitro cellular exposures, challenges researchers with both designing exposure systems and defining the internal doses to exposed cells. Addressing these challenges requires the cooperation and collaboration of many specialists that do not normally meet at discipline-specific conferences. To address that historical limitation, research related to the dosimetry of inhaled aerosols has been addressed at a series of three issue oriented international conferences. This paper addresses the research-related needs and recommendations from the third, October 2019 conference held in Irvine, CA, USA. Conference participants were invited to submit suggestions related to research. This paper includes those suggestions plus some offered by e-mail after the conference. Over 40 submitted suggestions are organized into several categories. Sample suggestions include; 1. research-related activities should address an identified health related problem; 2. in vitro aerosol systems require development in order to have better-defined doses to cells and to represent actual in vivo exposures; 3. additional knowledge on respiratory tract anatomy is needed for several species and for the variations within humans and other species; 4. dosimetric models should be expanded in scope, and should improve their usability by non-modelers; and 5. there is value in introducing newcomers to the field of inhaled aerosols. Collaborations among several disciplines are emphasized in order to advance inhaled dosimetry models and their applications to laboratory and real-life inhalation exposures. The suggestions reported here are a snapshot in time from experts from a variety of disciplines. The categories represent the major topic areas discussed at the meeting, but within each area the recommendations are not prioritized. As such, they do not carry the approval of any research institutions, research funding agencies, private entities, or regulatory agencies. The authors are solely responsible for the contents of this paper.

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. This paper describes the AOPs and the toolbox of in vitro and in silico models that can be used to assess the key events leading to toxicity following inhalation exposure. Because the optimal testing strategy will vary depending on the substance of interest, here we present a decision tree approach to identify an appropriate non-animal integrated testing strategy that incorporates consideration of a substance's physicochemical properties, relevant mechanisms of toxicity, and available in silico models and in vitro test methods. This decision tree can facilitate standardization of the testing approaches. Case study examples are presented to provide a basis for proof-of-concept testing to illustrate the utility of non-animal approaches to inform hazard identification and risk assessment of humans exposed to inhaled substances.

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.

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 endpoints 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. 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 twelve 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 endpoints, 3) facilitating cross-species dose-response evaluation, and 4) highlighting data gaps and technical limitations.

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. The importance of using integrated approaches that combine existing data with in vitro and/or computational approaches to generate new data was discussed. Approaches were also proposed to develop a strategy for identifying and overcoming obstacles to replacing animal tests. Attendees noted the importance of dosimetry considerations and of understanding mechanisms of acute toxicity, which could be facilitated by the development of adverse outcome pathways. Recommendations were made to (1) develop a database of existing acute inhalation toxicity data; (2) prepare a state-of-the-science review of dosimetry determinants, mechanisms of toxicity, and existing approaches to assess acute inhalation toxicity; (3) identify and optimize in silico models; and (4) develop a decision tree/testing strategy, considering physicochemical properties and dosimetry, and conduct proof-of-concept testing. Working groups have been established to implement these recommendations.

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.

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/m3 targets), or AM (3.5 mg/m3 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/m3), or AM (3.3 mg/m3) 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/m3 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/m3 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/m3 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/m3) 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. Electronic supplementary material The online version of this article (doi:10.1186/s12989-016-0130-z) contains supplementary material, which is available to authorized users.

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.

Direct calculation of delivered dose in the species of interest potentially affects the magnitude of an uncertainty factor needed to address extrapolation of laboratory animal data to equivalent human exposure scenarios, thereby improving the accuracy of human health risk estimates. Development of an inhalation reference concentration (RfC) typically involves extrapolation of an effect level observed in a laboratory animal exposure study to a level of exposure in humans that is not expected to result in an appreciable health risk. The default dose metric used for respiratory effects is the average deposited dose normalized by regional surface area. However, the most relevant dose metric is generally one that is most closely associated with the mode of action leading to the response. Critical factors in determining the best dose metric to characterize the dose-response relationship include the following: the nature of the biological response being examined; the magnitude, duration, and frequency of the intended exposure scenario; and the mechanisms by which the toxicants exert their effects. Dosimetry models provide mechanistic descriptions of these critical factors and can compute species-specific dose metrics. In this article, various dose metrics are postulated based on potential modes of action for poorly soluble particles (PSP). Dosimetry models are used to extrapolate the internal dose metric across species and to estimate the human equivalent concentration (HEC). Dosimetry models for the lower respiratory tract (LRT) of humans and rats are used to calculate deposition and retention using the principle of particle mass balance in the lower respiratory tract. Realistic asymmetric lung geometries using detailed morphometric measurements of the tracheobronchial (TB) airways in rats and humans are employed in model calculations. Various dose metrics are considered for the TB and pulmonary (P) regions. Because time is an explicit parameter incorporated in species-specific constants such as mucociliary clearance rates used in the models, the impact of the application of optimal model structures to refine adjustments and assumptions used in default risk assessment approaches to address exposure duration are discussed. HEC estimates were found for particles ranging in sizes that corresponded to existing toxicity studies of PSP (0.3 to 5 microm). A dose metric expressed as number of particles per biologically motivated normalization factors (e.g., number of ventilatory units, number of alveoli, and number of macrophages) was lower than the current default of mass normalized to regional surface area for either deposited or retained dose estimates. Retained dose estimates were lower than deposited dose estimates across all particle sizes evaluated. Dose metrics based on the deposited mass per unit area in small and large airways of the TB region indicate HECs of 1 to 5 times those of rats: that is, an equivalent exposure to humans which would achieve the same internal dose as in the rat would be 1 to 5 times greater. HEC estimates in the TB region increase with an increase in particle size for particles from 0.3 to/= 2 microm, then decrease with an increase in particle size for particles2 microm in the small airways and3 microm in the large airways. The HEC decreases with increase in particle size in the P region across all particle sizes studied, and the decrease has a more significant slope for those particles2 microm due to the limited inhalability of particles this size in rats relative to humans. Our modeling results elucidate a number of important issues to be considered in assessing current default approaches to dosimetry adjustment for inhaled PSP. Simulation of realistic, polydisperse particle distributions for the human exposure scenario results in reduced HEC estimates compared to estimates derived with the experimental particle distribution used in the laboratory animal study. Consideration should be given also to replacing the default dose metric of normalized deposited dose in the P region with normalized retained dose. Chronic effects are more likely due to retained dose and estimates calculated using retained versus deposited mass are shown to be lower across all particle sizes. Because dose metrics based on normalized particle number rather than normalized mass result in lower HEC estimates, use of inhaled mass as the default should also be revisited, if the pathogenesis suggests particle number determines the mode of action. Based on demonstrated age differences, future work should pursue the construction of "lifetime" estimates calculated by sequentially appending simulations for each specific age span.

Detection of perchlorate (ClO4-) in several drinking water sources across the U.S. has lead to public concern over health effects from chronic low-level exposures. Perchlorate inhibits thyroid iodide (I-) uptake at the sodium (Na+)-iodide (I-) symporter (NIS), thereby disrupting the initial stage of thyroid hormone synthesis. A physiologically based pharmacokinetic (PBPK) model was developed to describe the kinetics and distribution of both radioactive I- and cold ClO4- in healthy adult humans and simulates the subsequent inhibition of thyroid uptake of radioactive I- by ClO4-. The model successfully predicts the measured levels of serum and urinary ClO4- from drinking water exposures, ranging from 0.007 to 12 mg ClO4-/kg/day, as well as the subsequent inhibition of thyroid 131I- uptake. Thyroid iodine, as well as total, free, and protein-bound radioactive I- in serum from various tracer studies, are also successfully simulated. This model's parameters, in conjunction with corresponding model parameters established for the male, gestational, and lactating rat, can be used to estimate parameters in a pregnant or lactating human, that have not been or cannot be easily measured to extrapolate dose metrics and correlate observed effects in perchlorate toxicity studies to other human life stages. For example, by applying the adult male rat:adult human ratios of model parameters to those parameters established for the gestational and lactating rat, we can derive a reasonable estimate of corresponding parameters for a gestating or lactating human female. Although thyroid hormones and their regulatory feedback are not incorporated in the model structure, the model's successful prediction of free and bound radioactive I- and perchlorate's interaction with free radioactive I- provide a basis for extending the structure to address the complex hypothalamic-pituitary-thyroid feedback system. In this paper, bound radioactive I- refers to I- incorporated into thyroid hormones or iodinated proteins, which may or may not be bound to plasma proteins.

Because the nose acts as a filter to prevent penetration of toxic particles and gases to the lower respiratory tract, the route of breathing, oral vs. nasal, may be an important determinant of toxicant dose to the lungs. Using respiratory inductance plethysmography and a nasal mask fitted with flowmeter, we measured the nasal contribution to breathing at rest and during exercise (to 60% maximum workload) in healthy young adults (men/women = 11/11 and Caucasian/African-American = 11/11). We found that the nasal contribution to breathing is less during submaximal exercise in the Caucasians vs. African-Americans (e.g., at 60% maximum workload, mean nasal-to-total ventilation ratio = 0.40 ± 0.21 and 0.65 ± 0.24, respectively, P < 0.05). This difference is likely due to the African-Americans' ability to achieve higher maximal inspiratory flows through their nose than the Caucasians. Men also had a lesser nasal contribution to breathing during exercise compared with women. This is likely due to greater minute ventilations at any given percentage of maximum workload in men vs. women.

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.

Substantial improvements in dose response modeling for risk assessment may result from recent and continuing advances in biological research, biochemical techniques, biostatistical/mathematical methods and computational power. This report provides a ranked set of recommendations for proposed research to advance the state of the art in dose response modeling. The report is the result of a meeting of invited workgroup participants charged with identifying five areas of research in dose response modeling that could be incorporated in a national agenda to improve risk assessment methods. Leading topics of emphasis are interindividual variability, injury risk assessment modeling, and procedures to incorporate distributional methods and mechanistic considerations into now-standard methods of deriving a reference dose (RfD), reference concentration (RfC), minimum risk level (MRL) or similar dose-response parameter estimates.

Three organizations, the Basic Acrylic Monomer Manufacturers (BAMM), Methacrylate Producers Association (MPA), and Vinyl Acetate Toxicology Group (VATG), have sponsored development of physiologically based pharmacokinetic (PBPK) models for nasal tissue dosimetry with, respectively, acrylic acid (AA), methyl methacrylate (MMA), and vinyl acetate (VA). These compounds cause lesions in nasal epithelial tissues and are classified as "Category 1" gases within the U.S. EPA (1994) classification scheme. The National Center for Environmental Assessment in the U.S. EPA Office of Research and Development also has continuing interests in refining its methods for dosimetry adjustments when data on mode of action are available for Category 1 gases. A round-table discussion was held in Research Triangle Park, NC, on 11-12 February 1998, to develop a broader appreciation of the key processes and parameters required in developing nasal tissue dosimetry models. The discussions at the round table drew on these three case s...

In 1994, the U.S. Environmental Protection Agency introduced dosimetry modeling into the methods used to derive an inhalation reference concentration (RfC). The type of dosimetric adjustment factor (DAF) applied had to span the range of physicochemical characteristics of the gases listed on the Clean Air Act Amendments in 1991 as hazardous air pollutants (HAPs) and accommodate differences in available data with respect to their toxicokinetic properties. A framework was proposed that allowed for a hierarchy of dosimetry model structures, from optimal to rudimentary, and a category scheme that provided for limiting model structures based on physicochemical and toxicokinetic properties. These limiting cases were developed from restricting consideration to specific properties relying on an understanding of the generalized system based on mass transport theory. Physiochemical characteristics included the solubility and reactivity (e.g., propensity to dissociate, oxidize, or serve as a metabolic substrate) of the gas and were used as major determinants of absorption. Dosimetric adjustments were developed to evaluate portal of entry (POE) effects as well as remote (systemic) effects relevant to the toxicokinetic properties of the gas of interest. The gas categorization scheme consisted of defining three gas categories: (1) gases that are highly soluble and/or reactive, absorbing primarily in the extrathoracic airways; (2) gases that are moderately soluble and/or reactive, absorbing throughout the airways, as well as accumulating in the bloodstream; and (3) gases that have a low water solubility and are lipid soluble such that they are primarily absorbed in the pulmonary region and likely to act systemically. This article presents the framework and the mass transport theory behind the RfC method. Comparison to compartmental approaches and considerations for future development are also discussed.

The 1990 Clean Air Act Amendments require that health risk from exposure to vinyl acetate be assessed. Vinyl acetate is a nasal carcinogen in rats, but not mice, and induces olfactory degeneration in both species. A biologically based approach to extrapolating risks of inhalation exposure from rats to humans was developed, which incorporates critical determinants of interspecies dosimetry. A physiologically based pharmacokinetic (PBPK) model describing uptake and metabolism of vinyl acetate in rat nose was validated against nasal deposition data collected at three airflow rates. The model was also validated against observations of metabolically derived acetaldehyde. Modifying the rat nose model to reflect human anatomy created a PBPK model of the human nose. Metabolic constants from both rats and humans specific for vinyl acetate and acetaldehyde metabolism enabled predictions of various olfactory tissue dosimeters related to the mode of action. Model predictions of these dosimeters in rats corresponded well with observations of vinyl acetate toxicity. Intracellular pH (pHi) of olfactory epithelial cells was predicted to drop significantly at airborne exposure concentrations above the NOAEL of 50 ppm. Benchmark dose methods were used to estimate the ED10 and LED10 for olfactory degeneration, the precursor lesion thought to drive cellular proliferation and eventually tumor development at excess cellular acetaldehyde levels. A concentration x time adjustment was applied to the benchmark dose values. Human-equivalent concentrations were calculated by using the human PBPK model to predict concentrations that yield similar cellular levels of acetic acid, acetaldehyde, and pHi. After the application of appropriate uncertainty factors, an ambient air value of 0.4 to 1.0 ppm was derived. The biologically based approach supports a workplace standard of 10 ppm.

This paper describes the U.S. Environmental Protection Agency's assessment of potential health risks associated with the possible widespread use of a manganese (Mn)-based fuel additive, methylcyclopentadienyl manganese tricarbonyl (MMT). This assessment was significant in several respects and may be instructive in identifying certain methodological issues of general relevance to risk assessment. A major feature of the inhalation health risk assessment was the derivation of Mn inhalation reference concentration (RfC) estimates using various statistical approaches, including benchmark dose and Bayesian analyses. The exposure assessment component used data from the Particle Total Exposure Assessment Methodology (PTEAM) study and other sources to estimate personal exposure levels of particulate Mn attributable to the permitted use of MMT in leaded gasoline in Riverside, CA, at the time of the PTEAM study; on this basis it was then possible to predict a distribution of possible future exposure levels associated with the use of MMT in all unleaded gasoline. Qualitative as well as quantitative aspects of the risk characterization are summarized, along with inherent uncertainties due to data limitations.

To facilitate the development of regional respiratory tract dosimetry comparisons between laboratory animal species and humans, published surface area (SA) and volume (VOL) data for the upper respiratory tract (URT) were reviewed. The review of the literature revealed that (1) different studies used different techniques to prepare specimens and make measurements, (2) different areas of the URT were measured, and (3) URT surface areas and volumes have been reported for a limited number of individual subjects within a species but for a relatively wide range of species. The published data are summarized in tables in this article. New measurements made in an F344 rat and in a female human subject are also presented. Despite the differences in experimental protocols, it was possible to fit allometric scaling equations to the data: In(SA, cm2) = -0.34 + 0.52 In(body weight, g) and In(VOL, cm3) = 1.70 + 0.78 In(body weight, g). Separate scaling equations were also fitted for rats alone. To illustrate the use of these scaling equations in quantitative human health risk assessment, two dose metrics (fractional absorption/cm2 URT SA and fractional absorption/g body weight) for predicted URT uptake in laboratory animals and humans were calculated for acrolein and epichlorohydrin. Expressed as an animal-to-human ratio, the 95% confidence interval for URT SA could change the predicted dose ratio by up to a factor of 2. Additional studies are needed to describe the entire URT (from the nares through the larynx) quantitatively and to decrease variability in scaling equation predictions as well as to develop additional species-specific scaling equations. Three-dimensional imaging techniques provide a noninvasive method to obtain URT surface areas and volumes in humans and the larger laboratory animals. Comparisons of magnetic resonance image (MRI) and computed tomography (CT) scans made as part of this study suggest that the greater clarity of the mucosal-air interface in the CT image provides better resolution for the study of anatomic features. Because there is no radiation exposure associated with MRI imaging, however, it is more safely used than CT scans in making repeated measurements in a subject to elucidate changes in URT geometry associated with normal nasal cycling or other physiological changes.

Important data for human risk assessment of inhaled chlorine are provided by a recent rodent cancer bioassay (Wolf et al., 1995) and a chronic inhalation toxicity study in rhesus monkeys (Klonne et al., 1987). To improve interspecies comparisons based upon these data sets, the tissues from these studies were reexamined to (a) map the location of responses to assess the potential role of local chlorine dosimetry, (b) generate quantitative data on selected endpoints to compliment subjective scores, and (c) further characterize the responses in relation to interspecies differences and potential human health risks. Chlorine-induced lesions, which were confined to the respiratory tract, exhibited both similarities and differences among rodents and primates. At equivalent airborne concentrations (∼2.5 ppm), chlorine-induced responses were less severe in rhesus monkeys, but extended more distally in the respiratory tract to involve the trachea, while treatment-induced lesions were confined to the nose in...

Assessing risk of inhaled materials is a challenging endeavor because of the profound interspecies differences in respiratory tract anatomy, physiology, and biochemistry. Recent advances in the availability of mechanistic data and mathematical models for describing dosimetry behavior of particles and gases has lead to improvements in default approaches to risk assessment of inhaled materials. An overview of some of the more well-understood differences between species in factors controlling dosimetry and response, and the default approach of the U.S. Environmental Protection Agency that accounts for many of these factors, are presented. The default methodology also creates a framework which inhalation toxicologists can use to direct research at reducing uncertainty in risk assessments that might otherwise be handled through default uncertainty factors. The optimal approach to risk assessment is to develop chemical-specific mode of action and dosimetry data that can be used quantitatively to replace the entire default approach. The toxicology of vinyl acetate and recent efforts to develop data to supplant assumptions made in the default approach are presented. The conclusion is drawn that the future of inhalation toxicity risk assessment lies in reducing uncertainties associated with interspecies extrapolation and that to do this effectively requires approaches to toxicology that are outside of routine testing paradigms, and are aimed at elucidating mechanisms of action through hypothesis-driven research.

Uncertainty factors are applied in methods developed by the Environmental Protection Agency (EPA) to derive dose‐response estimates. The uncertainty factors are applied to account for uncertainties in defined extrapolations from the laboratory animal experimental data conditions to a dose‐response estimate appropriate for the assumed human scenario. The conceptual difference between these uncertainty factors and safety factors is best illustrated by how uncertainty factors can be modified as scientific data inform our understanding of the key factors that influence chemical disposition and toxicity. Mechanistic data help describe the major factors influencing chemical disposition and toxicant‐target tissue interactions, and should increase the accuracy of exposure‐dose‐response assessment. Mechanistic data on the determinants of inhaled chemical disposition were used to construct default dosimetry adjustments applied by the EPA in its inhalation Reference Concentration (RfC) methods. Because thes...

According to the 1983 NAS paradigm that serves as the basis for current health risk assessment procedures, risk characterization requires the comparison of an exposure estimate against a dose-response estimate. The types of exposure scenarios required under various regulations can be categorized as acute, subchronic, and chronic. Toxicity testing studies can also be so categorized, but such categories are defined by the exposure duration and not the underlying mechanism of action or its appropriate dose metric. Considerations of underlying mechanisms and temporal relationships of toxicity challenge current default assumptions and extrapolation approaches for derivation of dose-response estimates. This article discusses the duration adjustments used in current health risk assessment procedures and highlights the attendant assumptions. Comprehensive dosimetry model structures integrate mechanistic and temporal determinants of the exposure-dose-response continuum. Analysis of dosimetry model structur...

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). We sought to identify existing knowledge gaps and define what research is needed to address these gaps and advance asbestos research. Discussion: Discussions centered on areas of uncertainty in the field, including the ways asbestos is defined and characterized, the role of different fiber characteristics (e.g., length and mineralogy) in disease, and the impact of low-dose exposures on human health. Studying the dosimetry and mode of action of multiple fiber types would enhance our understanding of asbestos-related disease. To better elucidate the MOA of specific asbestos fibers, the risk assessor requires data as to specific characteristics of asbestos in determining fiber toxicity (e.g., surface area, mineral type), which may inform efforts to assess and control exposures and prevent adverse human health outcomes for the diverse range of fiber types. Specific research aims were defined for these topics and for overarching issues to be addressed, including the use of standardized terminology, test materials, and better experimental models to aid in data extrapolation to humans. Conclusion: To resolve these and other issues, participants agreed that diverse scientific disciplines must coordinate to better understand the MOA leading to the various asbestos-related disease end points.

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.

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. However, the activation of stress responses carries a significant energetic cost to the cell, leading to alterations of a variety of basal cellular functions in adapted or stressed cells. This tradeoff of resources between the unstressed and adapted states may lead to U-or inverted U-shaped dose response curves for some precursor endpoints. We examine this general hypothesis with chlorine, a prototype oxidative stressor, using a combination of cellular studies with gene expression analysis of response pathways and with computational modeling of activation of control networks. Discrete cellular states are expected as a function of exposure concentration and duration. These cellular states include normal functioning state, adaptive and stressed states at mild to intermediate exposures, and overt toxicity in the presence of an overwhelming concentration of stressors. These transitions can be used to refine default risk assessment practices that do not currently accommodate adaptive responses.

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 concentrations50 ppm (90 day exposure) and respiratory and olfactory nasal tumors at concentrationsor = 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.

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).

This paper has been reviewed by the Office of Health and Environmental Assessment, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The U.S. EPA has increasingly relied upon quantitative health risk assessments as the basis for management decisions about public health protection. Full utilization of risk assessment in management applications, however, is limited by uncertainties in the resultant accuracy of the risk estimates. This paper will discuss a research strategy to address the uncertainties in the risk assessment process and describe parallel issues to address in the risk management area. An attendant need for effective communication of complex scientific concepts is also identified.

This paper has been reviewed by the Office of Health and Environmental Assessment, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. In 1983, the U.S. National Academy of Sciences (U.S. NAS) proposed a framework for the processes of risk assessment and risk management in government agencies (U.S. NAS, 1983). Using the U.S. NAS scheme as an organizing principle, the U.S. Environmental Protection Agency (U.S. EPA) published guidelines pertaining to risk assessment in five areas: estimating exposures, chemical mixtures, mutagenicity, suspect developmental toxicity and carcinogenicity. These guidelines were developed to promote high technical quality and consistent practice of risk assessment Agencywide. This paper will discuss the historical development of the guidelines and their role in the work performed by the Agency. Each of the five (5) guidelines is outlined and anticipated revisions discussed. Related assessment activities and new subject areas are also presented.

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.

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.

The goal of this study was to develop a human physiologically based pharmacokinetic (PBPK) model for the chemical HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) and its major metabolite, trifluoroacetic acid (TFA). No human kinetic data for HCFC-123 are available, thus a corollary approach was developed. HCFC-123 is a structural analog of the common anesthetic agent halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) and follows a common pathway of oxidative biotransformation, resulting in the formation of the same metabolite, TFA. In this study, halothane models for rats and humans were developed and validated. Then the corollary approach was used to develop a human HCFC-123 model from a rat HCFC-123 model. This strategy was implemented by using a previously validated PBPK model for HCFC-123/TFA in the Fischer 344 rat as a template model for halothane in rats. Model predictions were then compared to, and were in good agreement with, measured values for the concentration of halothane in rat blood and fat tissue. A human PBPK model for halothane was developed. The identical model structure (with the exception of the description for the fat compartment) that was used to describe halothane and TFA in the rat was used for describing halothane and TFA in the human. Human physiological parameters for tissue volumes and flows were taken from the literature, and human tissue partition coefficients for halothane were measured in the laboratory. Based on reported similarity in metabolism of halothane by humans and rats, metabolic constants for halothane in the rat were used in the human model, and specific parameters describing the kinetics of TFA were estimated by optimization. The model was validated against human exposure data for halothane from six published studies (expired breath concentrations of halothane and serum/urine data for TFA). A similar approach was then used to derive a human HCFC-123 model for humans from the HCFC-123 rat model. The corollary approach described here illustrates the innovative use of template model structures to aid in the development and validation of models for structural analogs with similar metabolism and activity in biologic systems. Furthermore, given that the PBPK model adequately describes the kinetics of halothane in rats and humans and of HCFC-123 in rats, use of the human PBPK model is proposed for deriving dose–response estimates of human health risks in the absence of human kinetic data.

Mathematical dosimetry models should improve the accuracy of various extrapolations required in dose-response assessment because they include explicit descriptions of the major mechanistic determinants of the exposure-dose-response continuum. The availability of these anatomic and physiologic parameters for different mammalian species (including humans) and the physicochemical parameters for individual chemicals is an important consideration in the formulation of model structures and the application of simplifying assumptions to develop default models. A framework is presented that includes iterative development of model structures as more data become available. Development of the default dosimetry adjustments for interspecies extrapolation used in the inhalation reference concentration (RfC) methods of the U.S. Environmental Protection Agency (EPA) is discussed as an example of iterative model development, a process intended to ensure that model structures are commensurate with available data. The framework also aids evaluation of different model structures and can be applied to identify key parameters. Examples are provided to illustrate how insight on the key mechanistic determinants of exposure-dose-response can guide interpretation of data in the absence of comprehensive model structures, identify gaps in the database for a given chemical, or direct data gathering for chemicals that are yet to enter production.

An international consensus on the need to reduce the use of chlorofluorocarbons (CFCs) and other ozone-depleting gases such as the halons led to the adoptions of the 1987 Montreal Protocol and Title VI of the 1990 Clean Air Act Amendments, “Protecting Stratospheric Ozone.” These agreements included major provisions for reducing and eventually phasing out production and use of CFCs and halons as well as advancing the development of replacement chemicals. Because of the ubiquitous use and benefits of CFCs and halons, an expeditious search for safe replacements to meet the legislative deadlines is of critical importance. Toxicity testing and health risk assessment programs were established to evaluate the health and environmental impact of these replacement chemicals. Development and implementation of these programs as well as the structural-activity relationships significant for the development of the replacement chemicals are described below. A dose-response evaluation for the health risk assessment of the replacement chemical HCFC-123 (2,2-dichloro-1,1,1-trifluoroethane) is also presented to show an innovative use of physiologically based pharmacokinetic (PBPK) modeling. This is based on a parallelogram approach using data on the anesthetic gas halothane, a structural analog to HCFC-123. Halothane and HCFC-123 both form the same metabolite, trifluoroacetic acid (TFA), indicative of the same metabolic oxidative pathway attributed to hepatotoxicity. The parallelogram approach demonstrates the application of template model structures and shows how PBPK modeling, together with judicious experimental design, can be used to improve the accuracy of health risk assessment and to decrease the need for extensive laboratory animal testing.