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A M Jarabek

Publications and source records attributed to A M Jarabek.

At least 19 recordsLinked to original sources
PubMed2001

Mass transport analysis: inhalation rfc methods framework for interspecies dosimetric adjustment.

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.

Algorithms↗
PubMed2001

Nasal tissue dosimetry-issues and approaches for "Category 1" gases: a report on a meeting held in Research Triangle Park, NC, February 11-12, 1998.

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 studies and several background presentations to assess the manner in which chemical-specific and mode-of-action data can be incorporated into nasal dosimetry models. The round table had representation from the U.S. EPA, academia, and industry. This article outlines the presentations and topical areas discussed at the round table and notes recommendations made by participants to extend models for nasal dosimetry and to develop improved data for modeling. The contributions of several disciplines-toxicology, engineering, and physiologically based pharmacokinetic (PBPK) modeling-were evident in the discussions. The integration of these disciplines in creating opportunities for dosimetry model applications in risk assessments has several advantages in the breadth of skills upon which to draw in model development. A disadvantage is in the need to provide venues and develop cross-discipline dialogue necessary to ensure the understanding of cultural attitudes, terminology, and methods. The round-table discussions were fruitful in achieving such enhanced understanding and communication. Subsequent elaboration of these models will benefit from the interactions of these groups at the round table. The round-table discussions have already led to model improvements-as noted in several recently published articles. Participants emphasized several generic data needs in relation to nasal vapor uptake studies in human subjects, to broader discussion of tissue diffusion models, and to extensions to other classes of gases. The round-table articles that are published separately in this issue and the discussions, captured in this overview, provide a glimpse of the state of the science in nasal dosimetry modeling and a clear indication of the growth of and continuing opportunities in this important research area.

Animals↗
PubMed2000

Workshop to identify critical windows of exposure for children's health: immune and respiratory systems work group summary.

Fetuses, infants, and juveniles (preadults) should not be considered simply "small adults" when it comes to toxicological risk. We present specific examples of developmental toxicants that are more toxic to children than to adults, focusing on effects on the immune and respiratory systems. We describe differences in both the pharmacokinetics of the developing immune and respiratory systems as well as changes in target organ sensitivities to toxicants. Differential windows of vulnerability during development are identified in the context of available animal models. We provide specific approaches to directly investigate differential windows of vulnerability. These approaches are based on fundamental developmental biology and the existence of discrete developmental processes within the immune and respiratory systems. The processes are likely to influence differential developmental susceptibility to toxicants, resulting in lifelong toxicological changes. We also provide a template for comparative research. Finally, we discuss the application of these data to risk assessment.

Child↗
PubMed1998

The EPA health risk assessment of methylcyclopentadienyl manganese tricarbonyl (MMT).

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.

Administration, Inhalation↗
PubMed1997

Upper respiratory tract surface areas and volumes of laboratory animals and humans: considerations for dosimetry models.

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.

Acrolein↗
PubMed1996

Rat to human extrapolation of HCFC-123 kinetics deduced from halothane kinetics: a corollary approach to physiologically based pharmacokinetic modeling.

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 Fisher 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 mode 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.

Animals↗
PubMed1995

Benchmark Dose Workshop: criteria for use of a benchmark dose to estimate a reference dose.

The purpose of the Benchmark Dose Workshop was to assess the feasibility and implications of replacing the no observed adverse effect level (NOAEL) with a benchmark dose (BMD) when deriving reference doses and concentrations (RfDs and RfCs). The workshop participants supported the use of the BMD method to remove many of the limitations inherent in using the NOAEL approach. Participants endorsed in general the use of a BMD for all quantal noncancer health effects and endorsed in particular the BMD for assessing developmental toxicity based on data presented at the workshop. The discussions of implementation recognized the need to demonstrate that changing from a NOAEL to a BMD gives the risk manager more certain information on which to base decisions. Most participants agreed that the current NOAEL-derived RfDs and RfCs are sufficiently protective and should only be changed as data become available for estimating a BMD. It was recognized that to achieve general acceptance of the BMD approach, it will have to be applied to a variety of endpoints.

Animals↗
PubMed1995

The application of dosimetry models to identify key processes and parameters for default dose-response assessment approaches.

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.

Animals↗
PubMed1995

Understanding mechanisms of inhaled toxicants: implications for replacing default factors with chemical-specific data.

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.

Administration, Inhalation↗
PubMed1994

Mechanistic insights aid the search for CFC substitutes: risk assessment of HCFC-123 as an example.

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.

Air Pollutants↗
PubMed1991

Sensitivity analysis for physiologically based pharmacokinetic models.

The present study evaluates the sensitivity of pharmacokinetic model output to variability in the biochemical and metabolic input parameters. Pharmacokinetic models of three chemicals are chosen for analysis: styrene, methylchloroform, and methylene chloride. Results show that model sensitivities are time-, dose-, and species-dependent and that the most sensitive parameters are the maximum Michaelis-Menten metabolism rate Vmax and the blood/air and fat/air partition coefficients. For humans, the muscle/air partition coefficient is also important. Model output is insensitive to the Michaelis-Menten parameter Km (except for low doses) and to other tissue/air partition coefficients.

Administration, Inhalation↗
PubMed1990

Cold air challenge and platinum skin reactivity in platinum refinery workers. Bronchial reactivity precedes skin prick response.

An investigation of a platinum refinery operation consisted of an administered questionnaire, spirometry, skin prick testing with platinum salts and common aeroallergens, serum total IgE, radioallergosorbent test for platinum salts, and measurement of nonspecific airway hyperresponsiveness by cold air challenge testing. Among 136 employees examined, there were 107 current and 29 medically terminated workers; 23 (17 percent) subjects had a positive platinum salts prick skin test and 19 (14 percent) displayed a positive cold air challenge. RAST binding for platinum salts IgE antibodies showed a high level of agreement with platinum skin prick test results. A proportion (63 percent) of the population (74 current and 12 terminated workers) underwent repeat platinum skin testing one year later. Among current workers, there was conversion of the platinum skin test from negative to a positive test in five employees, with three conversions occurring in workers who showed only a positive cold air challenge test the year before. Platinum skin sensitivity, asthma symptoms, and nonspecific airway hyperresponsiveness persisted for years after termination of exposure in some medically terminated workers presumably because of a delay in removal from work of employees who became sensitized to platinum salts. It is suggested that proper surveillance for occupational asthma involves the use of several testing procedures. Prompt removal from work of individuals found to become sensitized to platinum salts is important in this industry.

Adult↗
PubMed1990

The U.S. Environmental Protection Agency's inhalation RfD methodology: risk assessment for air toxics.

The U.S. Environmental Protection Agency (U.S. EPA) has advocated the establishment of general and scientific guidelines for the evaluation of toxicological data and their use in deriving benchmark values to protect exposed populations from adverse health effects. The Agency's reference dose (RfD) methodology for deriving benchmark values for noncancer toxicity originally addressed risk assessment of oral exposures. This paper presents a brief background on the development of the inhalation reference dose (RfDi) methodology, including concepts and issues related to addressing the dynamics of the respiratory system as the portal of entry. Different dosimetric adjustments are described that were incorporated into the methodology to account for the nature of the inhaled agent (particle or gas) and the site of the observed toxic effects (respiratory or extrarespiratory). Impacts of these adjustments on the extrapolation of toxicity data of inhaled agents for human health risk assessment and future research directions are also discussed.

Administration, Inhalation↗
PubMed1990

The U.S. Environmental Protection Agency's risk assessment guidelines.

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.

Animals↗
PubMed1990

Research on risk assessment and risk management: future directions.

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.

Dose-Response Relationship, Drug↗
PubMed1989

Estimating equivalent human concentrations of no observed adverse effect levels: a comparison of several methods.

Four methods for intra- and inter-species dose extrapolation for inhalation reference doses are discussed. Dichloromethane is used as an example to illustrate quantitative differences in the methods. The methods include a procedure recommended by the U.S. EPA in 1980, 2 approaches to using physiologically-based pharmacokinetic (PB-PK) models that depend on the extent of knowledge of the values of physiological parameters, and a proposed method based on the concepts inherent to PB-PK models but requiring significantly less data on physiological parameters.

Administration, Inhalation↗
PubMed1989

Inhalation reference dose (RfDi): an application of interspecies dosimetry modeling for risk assessment of insoluble particles.

Accurate extrapolation of animal toxicity data for human health risk assessment requires determination of the effective dose to the target tissue and the sensitivity of the target tissue to that dose. The methodology for deriving reference doses [the U.S. Environmental Protection Agency's (EPA) benchmark values for gauging systemic toxicity] for oral exposures has not included dosimetry modeling. Dosimetry data facilitate evaluation of concentration-response data with respect to the dose-response relationships used in quantitative risk assessment. Extension of this methodology to derivation of inhalation reference doses (RfDi) should account for the dynamics of the respiratory system as the portal of entry. Predictive physiologically based modeling of the inhalation of reactive gases has recently been demonstrated (Overton and Miller 1988). Models that describe the deposition of hygroscopic particles and account for chemical factors that affect clearance mechanisms and gas uptake are under development. This paper presents a method for calculating a dosimetric adjustment factor based on the values for the initial deposited dose of insoluble particles in an animal species and in humans. The ratio of these two values serves as a scaling factor that can be applied in the R f D methodology to account for the dosimetric differences in the inhaled deposited dose. This application for insoluble particles illustrates the feasibility of interspecies dosimetry calculations for extrapolating the toxicological results of inhaled agents to human exposure conditions for more accurate risk estimation.

Aerosols↗