4.0 Scenarios
4.1 Life Stages
4.2 Scenario 1
Model Flow Diagram 1
4.3 Scenario 2
Model Flow Diagram 2
4.4 Scenario 3
Model Flow Diagram 3
4.5 Scenario 4
Model Flow Diagram 4
4.6 Process Flow
4.7 Gap Analysis
4.7 Exposure-Specific Model and Process Flow Diagrams and Associated Gap Analysis
This section of the report describes the gap analysis that was conducted based on the four example exposure scenarios associated with the CCEF. A gap analysis provides a list of research needs associated with the specific topic of interest. In this case, the gap analysis will provide the research needs for the framework, models, algorithms, and databases associated with the four exposure scenarios developed to define the design of the CCEF. The gap analysis consists of a three-step process in evaluating the Modeling and Process Flow Diagrams developed for the design of the CCEF. The three steps of the gap analysis are to define: 1) what exists, 2) what is needed, and 3) what process is required to achieved the needs.
The gap analysis is focused on the main components of the CCEF and will be discussed based on these components. These four components are: Source, Transport, Exposure, and Impacts. The Exposure and Impacts components were combined in this analysis because they are so closely linked. The gap analysis will be provided for each component based on each compound and scenario of interest. The results of this analysis will be input to the Qualitative Sensitivity analysis and prioritization of research needs that will be discussed in the following sections.
4.7.1 Gap Analysis of Source Component
The source component of the CCEF involves the release of a contaminant from its initial matrix. The primary mechanisms for release to the air are diffusion/volatilization or combustion. We have listed the gaps in models for relevant scenarios and indicated potential sources or research studies needed to fill these gaps for the source component of the CCEF.
1. Fugitive VOC Emissions from Mixing Vessel: Scenario 3
(Sources or Research Needs: We expect that algorithms already exist and may be available from sources such as handbooks by the American Petroleum Institute or EPA.)
2. Aerosolization of Contaminant During Auto Fueling: Scenario 4
(Sources or Research Needs: We expect that algorithms, or data to develop algorithms, for personal exposure may be available from the South Coast Air Quality Management District, California Air Resources Board, or EPA.)
3. Release of Contaminant (in breathing zone from Internal Combustion Engine (auto, lawn mower, and trimmer): Scenario 4
(Sources or Research Needs: We expect that algorithms, or data to develop algorithms, for personal exposure may be available from the South Coast Air Quality Management District, California Air Resources Board, EPA, lawn mower manufacturers, or auto manufacturers.)
4. Source Emissions During Auto Servicing: Scenario 4
(Sources or Research Needs: Filling this gap requires data on frequency of servicing personal automobiles at home and observation or personal logs of typical activities and use of protective gear during auto servicing by individuals.)
5. Splash Frequency and Volume to Skin During Fueling: Scenario 4
(Sources or Research Needs: Filling this gap requires laboratory studies of splash characteristics and frequency logs for fueling automobiles, lawn mowers, and trimmers.)
6. Splash Frequency and Volume to Skin During Painting: Scenario 1 & 4
(Sources or Research Needs: Filling this gap requires laboratory studies of splash characteristics and frequency logs for number of splashes during painting of a typical room by a nonprofessional.)
7. Spill Frequency and Volume During Fueling: Scenario 4
(Sources or Research Needs: Filling this gap requires spill frequency and volume logs for fueling automobiles, lawn mowers, and trimmers.)
8. Spill Frequency and Volume During Painting: Scenario 1 & 4
(Sources or Research Needs: Filling this gap requires spill frequency and volume logs for painting of a typical room by a nonprofessional.)
4.7.2 Gap Analysis of Transport Component
For the CCEF, we focused on micro-environmental models for transport indoors or near source outdoors. Indoor models evaluated transport within and between rooms or other small spaces and fate and partitioning of vapor on to aerosols or particles (dust), walls, floors, and sinks (e.g., furniture, carpet, clothing, blankets). Transport for this component of the CCEF ends when it reaches the human body and does not include movement within the body. Ingestion and hand-to-mouth transfer were considered part of the exposure component of the CCEF. We have listed the gaps in models for relevant scenarios and indicated potential sources or research studies needed to fill these gaps for the transport component of the CCEF.
1. Partitioning Between Vapor and Particle (Aerosol) Phases in Air: Scenarios 1-4
(Sources or Research Needs: We expect there may be some algorithms for partitioning of vapor to particulates. Controlled laboratory partitioning studies are needed for a wide variety of combinations of contaminants and types of particles.)
2. Particle Resuspension from Floors: Scenarios 1, 3, & 4
(Sources or Research Needs: There is a major gap in models or algorithms for particle resuspension from floors. Controlled laboratory studies are needed to determine resuspension of different types of particulates with different indoor air currents and simulated human activity.)
3. Contaminant Inhalation and Release by Mainstream Cigarette Smoking: Scenarios 3 & 4
(Sources or Research Needs: Models or algorithms already exist for mainstream cigarette smoking, which can be located by a literature search or from review articles on smoking release, such as the article at http://ehpnet1.niehs.nih.gov/docs/1999/Suppl-2/375-381ott/abstract.html. The reference for this review article is Ott, W.R. 1999. Mathematical Models for Predicting Indoor Air Quality from Smoking Activity. Environmental Health Perspectives Volume 107, Supplement 2, May 1999)
4.7.3 Gap Analysis of Exposure and Impact Components
There are several approaches that can be taken when choosing exposure models, algorithms, and databases for estimating human health exposure and impacts using microenvironmental modeling scenarios; however, the choice is most frequently made based on the available data and/or models. A gap analysis of the approaches to modeling exposures and health impacts from chemical concentrations in the environment in humans follows:4.7.3.1. Physiologically Based Pharmacokinetic and Pharmacodynamic Models: The best approach to predicting blood and tissue concentrations as a function of time following an administered dose (exposure) as well as interaction of the bioactive form of the compound with the target tissue(s) is to use a combination of a Physiologically Based Pharmacokinetic (PBPK) model and a Physiologically Based Pharmacodynamic (PBPD) model. PBPK modeling refers to the development of mathematical descriptions of the uptake and disposition (absorption, distribution, metabolism and excretion) of chemicals based on quantitative interrelationships among the critical biological determinants of these processes (Krishnan and Andersen, 1994). PBPD modeling refers to developing mathematical descriptions of interactions of the actual toxicant with its receptor to produce the observed toxic effect. These models are specific to species, compound, exposure route, and life stage. Because their bases lie in the use of physiological parameters such as blood flow, respiration rate, kidney filtration rates, etc., in addition to chemical-specific parameters, i.e. binding constants, solubilities, etc., they aid in extrapolation of data from a laboratory animal model such as a rat to the human.
Unfortunately, a full suite of these types of models applicable to the conditions described in the four exposure scenarios implemented in this study does not exist. In lieu of a well-defined PBPK and PBPD model for each scenario, a hierarchy of alternatives may be employed.
4.7.3.2. PBPK model, no PBPD model: If PBPD models are not available, compound- and exposure-specific bioavailability data obtained from toxicokinetic studies can be used to estimate body, organ, and tissue concentrations. For instance, a PBPK model may be used to provide target tissue concentrations of a toxicant for a given dose, which can then be plotted against experimental data to extrapolate dose to effect relationships without specific knowledge of how the toxicant interacts with the receptor (i.e. PBPK model without a PBPD model). There is research being conducted to generate compound-specific bioavailability data for specific exposure pathways and routes, but there are many gaps that need to be filled to complete the suite of exposure scenarios being evaluated for this study.
4.7.3.3. Neither PBPK or PBPD models available: If compound- and exposure-specific bioavailability data are not available, bioavailability models for surrogate compounds and/or alternate exposure routes can be used to estimate body, organ, or tissue concentrations. Reference doses (Rfd) or cancer slope factors may also be used to predict health effects.
4.7.3.4. Generic bioavailability models: If no appropriate surrogate compounds or exposure-specific bioavailability models are available, default generic bioavailability models can be used to provide a very rough estimate of body, organ, or tissue concentrations. These are very generic and conservative models but can be used if no other models or chemical-specific data exist.
The tiered approach for addressing the exposure component of the framework ensures that the best available information and models are used while filling as many data gaps as possible when completing the exposure scenarios. Below is the list of 18 specific research gaps identified in the exposure scenarios.
Scenario 1
1. PBPK/PBPD Model for 2-Butoxyethanol for Residential Exposure of Pregnant Mother. Source or Research Needs: PBPK/PBPD model for pregnant mother needs to be developed and validated. See American Chemistry Council Exposure Technical Implementation Panel Developmental Dosimetry/Lactation Model Review for existing models. Adopt initial parameter from related chemical (2-methoxyethanol). Refine and include information from 2-butoxyethanol specific studies on developmental dosimetry that already exists for male adult and rats/mice as a starting point.
2. PBPK/PBPD Model for 2-Butoxyethanol for Residential Exposure of Fetus (-0.75 to 0.0 years old). Source or Research Needs: See above for exposure of pregnant mother. PBPK/PBPD model for fetus also needs to be developed and validated. Existing PBPK/PBPD model for male adult rats/mice may be used as a starting point to develop fetus model with subsequent extrapolation to the human.
3. PBPK/PBPD Model for 2-Butoxyethanol for Residential Exposure of Child (2 to 6 years old). Source or Research Needs: PBPK/PBPD model for child needs to be developed and validated. Existing PBPK/PBPD model for male adult rats/mice may be used as a starting point to develop model for the child with subsequent extrapolation to the human.
4. PBPK/PBPD Model for 2-Butoxyethanol for Residential Exposure of Lactation Child (0.0 to 2 years old). Source or Research Needs: PBPK/PBPD model for nursing child needs to be developed and validated. Existing PBPK/PBPD model for male adult rats/mice may be used as a starting point to develop model for the nursing offspring with subsequent extrapolation to the human.
5. PBPK/PBPD Model for Ethylene Glycol for Residential Exposure of Fetus (-0.75 to 0.0 years old). (Source or Research Needs: PBPK/PBPD model for fetus based on rat embryo data has been developed but has not yet been published. Existing information for male adult (human) and rats/mice may be compared with new model. Also compare to adult human male controlled inhalation and dermal study conducted in Germany (Dr. Filser). Some of these key studies are being conducted under the guidance of the American Chemistry Council Ethylene Glycol Panel.
6. PBPK/PBPD Model for Ethylene Glycol for Residential Exposure of Lactation Child (0.0 to 2 years old). Source or Research Needs: PBPK/PBPD model for nursing child needs to be developed and validated. Information from the already existing PBPK/PBPD model for male adult (human) and rats/mice may be used as a starting point to develop the nursing child model.
7. PBPK/PBPD Model for Ethylene Glycol for Residential Exposure of Child (2 to 6 years old). Source or Research Needs: PBPK/PBPD model for child needs to be developed and validated. Scaling from existing male adult (human) and rats/mice may be used but must be validated.
8. PBPK/PBPD Model for Ethylene Glycol for Residential Exposure of Pregnant Mother. Source or Research Needs: PBPK/PBPD model for pregnant mother needs to be developed and validated. See American Chemistry Council Exposure Technical Implementation Panel Developmental Dosimetry/Lactation Model Review for existing structures. Initial parameters could be adopted from model for related chemical (2-methoxyethanol), then refine and include data from 2-butoxyethanol specific studies on developmental dosimetry. Existing information for male adult (human) and rats/mice may be used as a starting point.
Scenario 2
9. PBPK/PBPD Model for Three Phthalates: DEHP, BBP, DINP for Residential Exposure of Lactation Child (0.0 to 2 years old). Source or Research Needs: PBPK/PBPD model for nursing child needs to be developed and validated. Existing information for male adult (human) and rats/mice may be used as a starting point to develop model for nursing child.
10. PBPK/PBPD Model for Three Phthalates: DEHP, BBP, DINP for Residential Exposure of Child (2 to 6 years old). Source or Research Needs: PBPK/PBPD model for child needs to be developed and validated. Scaling with existing male adult (human) and rats/mice data may be used but must be validated.
11. PBPK/PBPD Model for Three Phthalates: DEHP, BBP, DINP for Residential Exposure of Adolescent (6 to 16 years old). Source or Research Needs: PBPK/PBPD model for adolescent needs to be developed and validated. Scaling with existing male adult (human) and rats/mice may be used but must be validated. Some phthalates have been shown to be endocrine disruptors; however, no models exist specifically for laboratory animals or humans as they go through puberty.
Scenario 3
12. PBPK/PBPD Model for Benzene, Toluene, or n-Hexane for Occupational Exposure of Adult Male (18 to 65 years old). Source or Research Needs: PBPK/PBPD models exist for male adult (human) and rats/mice, but need to be extended to PBPD model. Ideally a model should incorporate interactions between the three solvents, as well as with cigarette smoke. No models at this level of sophistication were identified in the literature. No accommodation is made for advancing age in this scenario or in published models. Such an accommodation is important as metabolic capacity and other physiological functions may change with advancing age.
13. Influence of Smoking on PBPK/PBPD Model for Mixtures of Benzene, Toluene, N-Hexane for Occupational Exposure of Adult Male (18 to 65 years old). Research is needed to understand the impacts of smoking on this exposure scenario based on 1) addition to the source, 2) alternate behavior, and 3) change in behavior.
Scenario 4
14. PBPK/PBPD Model for 2-Butoxyethanol for Backyard Exposure of Adult Male (25 to 50 years old): Source or Research Needs: Need to understand potential interactions between smoking and 2-butoxyethanol and effect these may have on PBPK/PBPD model that already exists for male adult (human) and rats/mice.
15. PBPK/PBPD Model for 2-Butoxyethanol for Backyard Exposure of Adult Male (50 to 75 years old). Source or Research Needs: Need research on PBPK/PBPD model for aging male. Possibly the existing human male adult model can be scaled appropriately.
16. PBPK/PBPD Model for Ethylene Glycol for Backyard Exposure of Adult Male (25 to 50 years old). Source or Research Needs: Need to understand potential interactions between smoking and ethylene glycol and effect these may have on PBPK/PBPD model that already exists for male adult (human) and rats/mice.
17. PBPK/PBPD Model for Ethylene Glycol for Backyard Exposure of Adult Male (50 to 75 years old). Source or Research Needs: Need research on PBPK/PBPD model for aging male. Possibly the existing human male adult model can be scaled appropriately.
18. PBPK/PBPD Model for MTBE for Backyard Exposure of Adult Male (25 to 50 years old). Source or Research Needs: Need to understand potential interactions between smoking and 2-butoxyethanol and effect these may have on PBPK model that already exists for male adult (human) and rats/mice.
19. PBPK/PBPD Model for MTBE for Backyard Exposure of Adult Male (50 to 75 years old). Source or Research Needs: Need research on PBPK/PBPD model for aging male. Possibly the existing human male adult model can be scaled appropriately.
20. PBPK/PBPD Model for 2-butoxyethanol for Backyard Exposure of Adult Male (50 to 75 years old): Scenario 4 (Source or Research Needs: Need research on PBPK/PBPD model for geriatric male human. The existing human male adult model can be used to scale to the geriatric model)
21. PBPK/PBPD Model for Ethylene Glycol for Backyard Exposure of Adult Male (25 to 50 years old): Scenario 4 (Source or Research Needs: Need to understand how mixtures of compound and smoking has on PBPK/PBPD model that already exists for male adult and rats/mice)
22. PBPK/PBPD Model for Ethylene Glycol for Backyard Exposure of Adult Male (50 to 75 years old): Scenario 4 (Source or Research Needs: PBPK/PBPD model already exists for male adult and rats/mice)
23. PBPK/PBPD Model for MTBE for Backyard Exposure of Adult Male (25 to 50 years old): Scenario 4 (Source or Research Needs: Need to understand how smoking affects parameters of the PBPK/PBPD model that already exists for male adult and rats/mice)
24. PBPK/PBPD Model for MTBE for Backyard Exposure of Adult Male (50 to 75 years old): Scenario 4 (Source or Research Needs: Need research on PBPK/PBPD model for the aging male human. The existing human male adult model could be used to scale to the geriatric model)
4.7.4 Summary of Gap Analysis for Source, Transport, Exposure and Impacts Components
A number of research gaps were identified in the models or frequency/usage logs needed for the source and transport components of the four exposure scenarios used as examples in the CCEF. Three of the research gaps in models for the source component (i.e., fugitive VOC emissions from mixing vessel, aerosolization during auto fueling, and release of contaminant in combustion zone from internal combustion engine) may already exist as algorithms, but they were not identified as part of this study because they are not widely published. Five research gaps in frequency/usage logs needed for the source component were also not readily available (i.e., frequency of auto servicing and associated protective gear used at home, splash frequency/volume during fueling, splash frequency/volume during painting, spill frequency/volume during fueling, and spill frequency/volume during painting). Two major research gaps in models needed for the transport component of most of the example scenarios include: (1) partitioning between vapor and particle (aerosol) phases in air (Scenarios 1-4) and (2) particle resuspension from floors (Scenarios 1, 3, & 4).Currently, considerable research is underway, funded by other parts of the American Chemistry Council (i.e., Endocrine Disruptor Technical Implementation Panel and CHEMSTAR Program), as well as government agencies and universities, with the goal of generating data necessary to construct PBPK and PBPD models for many chemicals to which humans of all life stages are exposed. Due to the complexity and expense of this research, it will be several years before enough new information is available to fill in the data gaps that have been identified when designing the preceding CCEF components. Further difficulties exist in that the quality of the physiological data available for many of the parameters needed to develop the models is inadequate. This is especially true when attempting to model maternal-placental-fetal transfer and metabolism of chemical substances as well as lactational transfer. The lack of accurate physiological parameters during pregnancy and lactation not only prevents construction of a substantive model in laboratory animals, it also precludes useful extrapolation to the human. Another data gap lies in the lack of knowledge regarding the effects of exogenous compounds on physiological parameters during the onset of puberty in both laboratory animal models and humans.
