Journal of Exposure Science & Environmental Epidemiology, 2019
Consumer product categorizations for use in predicting human chemical exposure provide a bridge b... more Consumer product categorizations for use in predicting human chemical exposure provide a bridge between product composition data and consumer product use pattern information. Furthermore, the categories reflect other factors relevant to developing consumer product exposure scenarios, such as microenvironment of use (e.g., indoors or outdoors), method of application/form of release (e.g., spray versus liquid), release to various media, removal processes (e.g., rinse-off or wipe-off), and route-specific exposure factors (dermal surface areas of application, fraction of release in respirable form). While challenging, developing harmonized product categories can generalize the factors described above allowing for rapid parameterization of route-specific exposure scenario algorithms for new chemical/product applications and efficient utilization of new data on product use or composition. This can be accomplished via mapping product categories to likewise categorized release and use patterns or exposure factors. Here, hierarchical product use categories (PUCs) for consumer products that provide such mappings are presented and crosswalked with other internationally harmonized product categories for consumer exposure assessment. The PUCs were defined by applying use and exposure scenario information to the products in EPA's Chemical and Products Database (CPDat). This paper demonstrates how these PUCs are being used to rapidly parameterize algorithms for scenario-specific use, fate, and exposure in a probabilistic aggregate model of human exposure to chemicals used in consumer products. The PUCs provide a generic representation of consumer products for use in exposure assessment and *
Phthalates are used in a wide range of consumer goods, resulting in exposures to specific phthala... more Phthalates are used in a wide range of consumer goods, resulting in exposures to specific phthalates that vary over time in accordance with changes in product use and how phthalates are utilized. We investigated trends in estimates of daily intake dose and several cumulative risk metrics, including the Hazard Quotient (HQ), Hazard Index (HI), and Maximum Cumulative Ratio (MCR) for six phthalates from 2005 to 2014 using metabolite biomonitoring data collected from spot urine samples under the National Health and Nutrition Examination Survey (NHANES). Over this period, there was a 2.2-fold decrease in the mean HI (0.34 to 0.15) and a 7.2-fold decrease in the percentage of participants with an HI > 1 (5.7% to 0.8%), indicating an overall decrease in combined exposure to these phthalates. Children (aged 6-11 years) had higher mean HI values than either adolescents (aged 12-19 years) or adults (aged 20+ years) during this period. MCR values were generally low and inversely correlated with HI. This indicated that a single phthalate usually drove the hazards for highly exposed individuals. However, the average value of MCR increased 1.2-fold (1.7-2.1) over this period indicating an increasing need to consider exposures to multiple phthalates in this group.
Toxicology in vitro : an international journal published in association with BIBRA, Jan 5, 2017
In vitro chemical safety testing methods offer the potential for efficient and economical tools t... more 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 concent...
Integrative testing strategies (ITS) for potential endocrine activity can use tiered in silico an... more Integrative testing strategies (ITS) for potential endocrine activity can use tiered in silico and in vitro models. Each component of an ITS should be thoroughly assessed. We used the data from three in vitro ToxCast binding assays to assess OASIS, a quantitative structure-activity relationship (QSAR) platform covering both estrogen (ER) and androgen receptor (AR) binding. For stronger binders (described here as AC50 < 1 µM), we also examined the relationship of QSAR predictions of ER or AR binding to the results from 18 ER and 10 AR transactivation assays, 72 ER-binding reference compounds as well as the in vivo uterotrophic assay. NovaScreen binding assay data for ER (human, bovine and mouse) and AR (human, chimp and rat) were used to assess the sensitivity, specificity, concordance and applicability domain of two OASIS QSAR models. The binding strength relative to the QSAR-predicted binding strength was examined for the ER data. The relationship of QSAR predictions of binding ...
The nature of the exposure-response relationship has a profound influence on risk analyses. Sever... more The nature of the exposure-response relationship has a profound influence on risk analyses. Several arguments have been proffered as to why all exposure-response relationships for both cancer and noncarcinogenic endpoints should be assumed to be linear at low doses. We focused on three arguments that have been put forth for noncarcinogens. First, the general "additivity-to-background" argument proposes that if an agent enhances an already existing disease-causing process, then even small exposures increase disease incidence in a linear manner. This only holds if it is related to a specific mode of action that has nonuniversal properties-properties that would not be expected for most noncancer effects. Second, the "heterogeneity in the population" argument states that variations in sensitivity among members of the target population tend to "flatten out and linearize" the exposure-response curve, but this actually only tends to broaden, not linearize, the dose-response relationship. Third, it has been argued that a review of epidemiological evidence shows linear or no-threshold effects at low exposures in humans, despite nonlinear exposure-response in the experimental dose range in animal testing for similar endpoints. It is more likely that this is attributable to exposure measurement error rather than a true nonthreshold association. Assuming that every chemical is toxic at high exposures and linear at low exposures does not comport to modern-day scientific knowledge of biology. There is no compelling evidence-based justification for a general low-exposure linearity; rather, case-specific mechanistic arguments are needed.
Computer Methods and Programs in Biomedicine, 2012
There are numerous programs ongoing to analyze environmental exposure of humans to xenobiotic che... more There are numerous programs ongoing to analyze environmental exposure of humans to xenobiotic chemicals via biomonitoring measurements (e.g.: EU ESBIO, COPHES; US CDC NHANES; Canadian Health Measures Survey). The goal of these projects is to determine relative trends in exposure to chemicals, across time and subpopulations. Due to the lack of data, there is often little information correlating biomarker concentrations with exposure levels and durations. As a result, it can be difficult to utilize biomonitoring data to evaluate if exposures adhere to or exceed hazard/exposure criteria such as the Derived No-Effect Level values under the EU REACH program, or Reference Dose/Concentration values of the US EPA. A tiered approach of simple, arithmetic pharmacokinetic (PK) models, as well as more standardized mean-value, physiologically-based (PBPK) models, have therefore been developed to estimate exposures from biomonitoring results. Both model types utilize a user-friendly Excel spreadsheet interface. QSPR estimations of chemical-specific parameters have been included, as well as accommodation of variations in urine production. Validation of each model's structure by simulations of published datasets and the impact of assumptions of major model parameters will be presented.
This publication contains the collective views of an international group of experts and does not ... more This publication contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the World Health Organization.
Prioritizing the potential risk posed to human health by chemicals requires tools that can estima... more Prioritizing the potential risk posed to human health by chemicals requires tools that can estimate exposure from limited information. In this study chemical structure and physicochemical properties were used to predict the probability that a chemical might be associated with any of four exposure pathways leading from sources-consumer (nearfield), dietary, far-field industrial, and far-field pesticide-to the general population. The balanced accuracies of these source-based exposure pathway models range from 73-81%, with the error rate for identifying positive chemicals ranging from 17-36%. We then used exposure pathways to organize predictions from thirteen different exposure models as well as other predictors of human intake rates. We created a consensus, meta-model using the Systematic Empirical Evaluation of Models (SEEM) framework in which the predictors of exposure were combined by pathway and weighted according to predictive ability for chemical intake rates inferred from human biomonitoring data for 114 chemicals. The consensus model yields an R 2 of ~0.8. We extrapolate to predict relevant pathway(s), median intake rate, and credible interval for 479,926 chemicals, mostly with
Acute and chronic exposure to benzene vapors poses a number of health hazards to humans. To evalu... more Acute and chronic exposure to benzene vapors poses a number of health hazards to humans. To evaluate the probability that a specific degree of exposure will produce an adverse effect, risk assessment methods must be used. This paper reviews much of the published information and evaluates the various risk assessments for benzene that have been conducted over the past 20 years. There is sufficient evidence that chronic exposure to relatively high concentrations of benzene can produce an increased incidence of acute myelogenous leukemia (AML). Some studies have indicated that benzene may cause other leukemias, but due to the inconsistency of results, the evidence is not conclusive. To predict the leukemogenic risk for humans exposed to much lower doses of benzene than those observed in most epidemiology studies, a model must be used. Although several models could yield plausible results, to date most risk assessments have used the linear-quadratic or conditional logistic models. These appear to be the most appropriate ones for providing the cancer risk for airborne concentrations of 1 ppb to 10 ppm, the range most often observed in the community and workplace. Of the seven major epidemiology studies that have been conducted, there is a consensus that the Pliofilm cohort (rubber workers) is the best one for estimating the cancer potency because it is the only one with good exposure and incidence of disease data. The current EPA, OSHA, and ACGIH cancer potency estimates for benzene are based largely on this cohort. A retrospective exposure assessment and an analysis of the incidence of disease in these workers were completed in 1991. All of these issues are discussed and the implications evaluated in this paper. The range of benzene exposures to which Americans are commonly exposed and the current regulatory criteria are also presented.
Determining aggregate and cumulative risks from exposures to pesticides presents a number of chal... more Determining aggregate and cumulative risks from exposures to pesticides presents a number of challenges. The analysis must capture the correlations in residues that occur from both additive and exclusionary processes in the use of pesticides. The analysis also requires a quantitative mechanism for evaluating risks associated with exposures to mixtures of pesticides. This paper presents an analysis of aggregate exposures and risks associated with exposures to a pesticide, Alpha, and the cumulative exposure to and risk from three pesticides, Alpha, Beta, and Gamma. The cumulative risks are evaluated by determining the systemic (absorbed) doses that result from inhalation, dermal, and oral exposures to the pesticides. A 'relative toxicity' model is used to evaluate cumulative risks. The assessment of cumulative exposure was performed using the LifeLine Version 1.0. The model simulates pesticide exposure using an individual-based approach where daily exposures are evaluated for each person, season, and location.
Exposure to chemicals is influenced by associations between the individual’s location and activit... more Exposure to chemicals is influenced by associations between the individual’s location and activities as well as demographic and physiological characteristics. Currently, many exposure models simulate individuals by drawing distributions from population-level data or use exposure factors for single individuals. The Residential Population Generator (RPGen) binds US surveys of individuals and households and combines the population with physiological characteristics to create a synthetic population. In general, the model must be supported by internal consistency; i.e., values that could have come from a single individual. In addition, intraindividual variation must be representative of the variation present in the modeled population. This is performed by linking individuals and similar households across income, location, family type, and house type. Physiological data are generated by linking census data to National Health and Nutrition Examination Survey data with a model of interindiv...
Users may download and print one copy of any publication from the public portal for the purpose... more Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Journal of Exposure Science & Environmental Epidemiology, 2018
Exposure to a chemical is a critical consideration in the assessment of risk, as it adds real-wor... more Exposure to a chemical is a critical consideration in the assessment of risk, as it adds real-world context to toxicological information. Descriptions of where and how individuals spend their time are important for characterizing exposures to chemicals in consumer products and in indoor environments. Herein we create an agent-based model (ABM) that simulates longitudinal patterns in human behavior. By basing the ABM upon an artificial intelligence (AI) system, we create agents that mimic human decisions on performing behaviors relevant for determining exposures to chemicals and other stressors. We implement the ABM in a computer program called the Agent-Based Model of Human Activity Patterns (ABMHAP) that predicts the longitudinal patterns for sleeping, eating, commuting, and working. We then show that ABMHAP is capable of simulating behavior over extended periods of time. We propose that this framework, and models based on it, can generate longitudinal human behavior data for use in exposure assessments.
Quantitative data on product chemical composition is a necessary parameter for characterizing nea... more Quantitative data on product chemical composition is a necessary parameter for characterizing near-field exposure. This data set comprises reported and predicted information on more than 75,000 chemicals and more than 15,000 consumer products. The data's primary intended use is for exposure, risk, and safety assessments. The data set includes specific products with quantitative or qualitative ingredient information, which has been publicly disclosed through material safety data sheets (MSDS) and ingredient lists. A single product category from a refined and harmonized set of categories has been assigned to each product. The data set also contains information on the functional role of chemicals in products, which can inform predictions of the concentrations in which they occur. These data will be useful to exposure and risk assessors evaluating chemical and product safety.
A Human Effectiveness and Risk Characterization for Electromuscular Incapacitation (EMI) reflects... more A Human Effectiveness and Risk Characterization for Electromuscular Incapacitation (EMI) reflects the results from three workshops (data gathering/sharing, peer consultation, and independent external review) evaluating two EMI devices: the M26 and X26 TASERs. The intended effect of these devices is electromuscular disruption. Key potential unintended effects included ocular injury, seizures, ventricular fibrillation, or fall injuries. The likelihood of these effects were determined, based on an analysis of the TASER International Database (scrubbed to minimize false positives) and modeling. The probability of inducing a complete EMD ranges from 74% to 52% depending on distance to the target. Probability estimates were up to 0.04% for eye "strikes and 0.15% for fall injuries depending on distance to the target. Ventricular fibrillation (VF) is not expected to occur in an otherwise healthy adult population. Key data gaps include the biological basis for TASER effects and appropriate dosimetry. The results support the conclusion that the M26 and X26 TASERs are generally effective for their intended use.
This paper uses the maximum cumulative ratio (MCR) as part of a tiered approach to evaluate and p... more This paper uses the maximum cumulative ratio (MCR) as part of a tiered approach to evaluate and prioritize the risk of acute ecological effects from combined exposures to the plant protection products (PPPs) measured in 3 099 surface water samples taken from across the United States. Assessments of the reported mixtures performed on a substance-by-substance approach and using a Tier One cumulative assessment based on the lowest acute ecotoxicity benchmark gave the same findings for 92.3% of the mixtures. These mixtures either did not indicate a potential risk for acute effects or included one or more individual PPPs that had concentrations in excess of their benchmarks. A Tier Two assessment using a trophic level approach was applied to evaluate the remaining 7.7% of the mixtures. This assessment reduced the number of mixtures of concern by eliminating the combination of endpoint from multiple trophic levels, identified invertebrates and nonvascular plants as the most susceptible no...
Toxicological sciences : an official journal of the Society of Toxicology, Jan 2, 2015
There is great interest in assessing the in vivo toxicity of chemicals using non-animal alternati... more There is great interest in assessing the in vivo toxicity of chemicals using non-animal alternatives. However, acute mammalian toxicity is not adequately predicted by current in silico or in vitro approaches. Mechanisms of acute toxicity are likely conserved across invertebrate, aquatic and mammalian species, suggesting that dose-response concordance would be high and in vitro mechanistic data could predict responses in multiple species under conditions of similar bioavailability. We tested this hypothesis by comparing acute toxicity between rat, daphnia and fish, and by comparing their respective acute data to inhibition of mitochondria membrane potential (MMP) using US Environmental Protection Agency ToxCast in vitro high-throughput screening (HTS) data. Logarithmic scatter plots of acute toxicity data showed a clear relationship between fish, daphnia and intravenous rat but not oral rat data. Similar plots versus MMP showed a well-delineated upper boundary for fish, daphnia and i...
This report presents the findings of a multi-year assessment of the releases of polychlorinated b... more This report presents the findings of a multi-year assessment of the releases of polychlorinated biphenyls (PCBs) from the Oak Ridge Reservation (ORR) and the potential for adverse effects in the local populations. PCBs were used and released from the ORR, and large numbers of individuals received doses by multiple routes of exposure. These routes included exposure to PCBs in air, water, sediments, biota (fish and turtles), and possibly from the sale and use of contaminated surplus oil. For many individuals, the exposures resulted in dose rates that are of little toxicological concern. However, for the farm families that lived along East Fork Poplar Creek (EFPC), and for persons who ate fish from Watts Bar and the Clinch River, the exposures could have resulted in both carcinogenic and noncarcinogenic effects. An accurate evaluation of exposures to the farm families is not possible due to the absence of relevant measurements of PCBs in the soils of the farms. However, sufficient data were available to assess the risks to anglers and their families. A conservative estimate of the carcinogenic risks posed by the ORR releases to consumers of fish from Watts Bar Reservoir and the Clinch River range from less than 1 in a 1,000,000 to 2 in 10,000. Based on these risk estimates and the number of anglers using the fisheries, three or less excess cases of cancer would be expected to occur in the populations of consumers of fish from Watts Bar Reservoir and Clinch River since the ORR began operations in the 1940s. Because the estimates are conservative, the actual risks and expected number of cases are likely to be smaller and could be zero.
Journal of Exposure Science & Environmental Epidemiology, 2019
Consumer product categorizations for use in predicting human chemical exposure provide a bridge b... more Consumer product categorizations for use in predicting human chemical exposure provide a bridge between product composition data and consumer product use pattern information. Furthermore, the categories reflect other factors relevant to developing consumer product exposure scenarios, such as microenvironment of use (e.g., indoors or outdoors), method of application/form of release (e.g., spray versus liquid), release to various media, removal processes (e.g., rinse-off or wipe-off), and route-specific exposure factors (dermal surface areas of application, fraction of release in respirable form). While challenging, developing harmonized product categories can generalize the factors described above allowing for rapid parameterization of route-specific exposure scenario algorithms for new chemical/product applications and efficient utilization of new data on product use or composition. This can be accomplished via mapping product categories to likewise categorized release and use patterns or exposure factors. Here, hierarchical product use categories (PUCs) for consumer products that provide such mappings are presented and crosswalked with other internationally harmonized product categories for consumer exposure assessment. The PUCs were defined by applying use and exposure scenario information to the products in EPA's Chemical and Products Database (CPDat). This paper demonstrates how these PUCs are being used to rapidly parameterize algorithms for scenario-specific use, fate, and exposure in a probabilistic aggregate model of human exposure to chemicals used in consumer products. The PUCs provide a generic representation of consumer products for use in exposure assessment and *
Phthalates are used in a wide range of consumer goods, resulting in exposures to specific phthala... more Phthalates are used in a wide range of consumer goods, resulting in exposures to specific phthalates that vary over time in accordance with changes in product use and how phthalates are utilized. We investigated trends in estimates of daily intake dose and several cumulative risk metrics, including the Hazard Quotient (HQ), Hazard Index (HI), and Maximum Cumulative Ratio (MCR) for six phthalates from 2005 to 2014 using metabolite biomonitoring data collected from spot urine samples under the National Health and Nutrition Examination Survey (NHANES). Over this period, there was a 2.2-fold decrease in the mean HI (0.34 to 0.15) and a 7.2-fold decrease in the percentage of participants with an HI > 1 (5.7% to 0.8%), indicating an overall decrease in combined exposure to these phthalates. Children (aged 6-11 years) had higher mean HI values than either adolescents (aged 12-19 years) or adults (aged 20+ years) during this period. MCR values were generally low and inversely correlated with HI. This indicated that a single phthalate usually drove the hazards for highly exposed individuals. However, the average value of MCR increased 1.2-fold (1.7-2.1) over this period indicating an increasing need to consider exposures to multiple phthalates in this group.
Toxicology in vitro : an international journal published in association with BIBRA, Jan 5, 2017
In vitro chemical safety testing methods offer the potential for efficient and economical tools t... more 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 concent...
Integrative testing strategies (ITS) for potential endocrine activity can use tiered in silico an... more Integrative testing strategies (ITS) for potential endocrine activity can use tiered in silico and in vitro models. Each component of an ITS should be thoroughly assessed. We used the data from three in vitro ToxCast binding assays to assess OASIS, a quantitative structure-activity relationship (QSAR) platform covering both estrogen (ER) and androgen receptor (AR) binding. For stronger binders (described here as AC50 < 1 µM), we also examined the relationship of QSAR predictions of ER or AR binding to the results from 18 ER and 10 AR transactivation assays, 72 ER-binding reference compounds as well as the in vivo uterotrophic assay. NovaScreen binding assay data for ER (human, bovine and mouse) and AR (human, chimp and rat) were used to assess the sensitivity, specificity, concordance and applicability domain of two OASIS QSAR models. The binding strength relative to the QSAR-predicted binding strength was examined for the ER data. The relationship of QSAR predictions of binding ...
The nature of the exposure-response relationship has a profound influence on risk analyses. Sever... more The nature of the exposure-response relationship has a profound influence on risk analyses. Several arguments have been proffered as to why all exposure-response relationships for both cancer and noncarcinogenic endpoints should be assumed to be linear at low doses. We focused on three arguments that have been put forth for noncarcinogens. First, the general "additivity-to-background" argument proposes that if an agent enhances an already existing disease-causing process, then even small exposures increase disease incidence in a linear manner. This only holds if it is related to a specific mode of action that has nonuniversal properties-properties that would not be expected for most noncancer effects. Second, the "heterogeneity in the population" argument states that variations in sensitivity among members of the target population tend to "flatten out and linearize" the exposure-response curve, but this actually only tends to broaden, not linearize, the dose-response relationship. Third, it has been argued that a review of epidemiological evidence shows linear or no-threshold effects at low exposures in humans, despite nonlinear exposure-response in the experimental dose range in animal testing for similar endpoints. It is more likely that this is attributable to exposure measurement error rather than a true nonthreshold association. Assuming that every chemical is toxic at high exposures and linear at low exposures does not comport to modern-day scientific knowledge of biology. There is no compelling evidence-based justification for a general low-exposure linearity; rather, case-specific mechanistic arguments are needed.
Computer Methods and Programs in Biomedicine, 2012
There are numerous programs ongoing to analyze environmental exposure of humans to xenobiotic che... more There are numerous programs ongoing to analyze environmental exposure of humans to xenobiotic chemicals via biomonitoring measurements (e.g.: EU ESBIO, COPHES; US CDC NHANES; Canadian Health Measures Survey). The goal of these projects is to determine relative trends in exposure to chemicals, across time and subpopulations. Due to the lack of data, there is often little information correlating biomarker concentrations with exposure levels and durations. As a result, it can be difficult to utilize biomonitoring data to evaluate if exposures adhere to or exceed hazard/exposure criteria such as the Derived No-Effect Level values under the EU REACH program, or Reference Dose/Concentration values of the US EPA. A tiered approach of simple, arithmetic pharmacokinetic (PK) models, as well as more standardized mean-value, physiologically-based (PBPK) models, have therefore been developed to estimate exposures from biomonitoring results. Both model types utilize a user-friendly Excel spreadsheet interface. QSPR estimations of chemical-specific parameters have been included, as well as accommodation of variations in urine production. Validation of each model's structure by simulations of published datasets and the impact of assumptions of major model parameters will be presented.
This publication contains the collective views of an international group of experts and does not ... more This publication contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the World Health Organization.
Prioritizing the potential risk posed to human health by chemicals requires tools that can estima... more Prioritizing the potential risk posed to human health by chemicals requires tools that can estimate exposure from limited information. In this study chemical structure and physicochemical properties were used to predict the probability that a chemical might be associated with any of four exposure pathways leading from sources-consumer (nearfield), dietary, far-field industrial, and far-field pesticide-to the general population. The balanced accuracies of these source-based exposure pathway models range from 73-81%, with the error rate for identifying positive chemicals ranging from 17-36%. We then used exposure pathways to organize predictions from thirteen different exposure models as well as other predictors of human intake rates. We created a consensus, meta-model using the Systematic Empirical Evaluation of Models (SEEM) framework in which the predictors of exposure were combined by pathway and weighted according to predictive ability for chemical intake rates inferred from human biomonitoring data for 114 chemicals. The consensus model yields an R 2 of ~0.8. We extrapolate to predict relevant pathway(s), median intake rate, and credible interval for 479,926 chemicals, mostly with
Acute and chronic exposure to benzene vapors poses a number of health hazards to humans. To evalu... more Acute and chronic exposure to benzene vapors poses a number of health hazards to humans. To evaluate the probability that a specific degree of exposure will produce an adverse effect, risk assessment methods must be used. This paper reviews much of the published information and evaluates the various risk assessments for benzene that have been conducted over the past 20 years. There is sufficient evidence that chronic exposure to relatively high concentrations of benzene can produce an increased incidence of acute myelogenous leukemia (AML). Some studies have indicated that benzene may cause other leukemias, but due to the inconsistency of results, the evidence is not conclusive. To predict the leukemogenic risk for humans exposed to much lower doses of benzene than those observed in most epidemiology studies, a model must be used. Although several models could yield plausible results, to date most risk assessments have used the linear-quadratic or conditional logistic models. These appear to be the most appropriate ones for providing the cancer risk for airborne concentrations of 1 ppb to 10 ppm, the range most often observed in the community and workplace. Of the seven major epidemiology studies that have been conducted, there is a consensus that the Pliofilm cohort (rubber workers) is the best one for estimating the cancer potency because it is the only one with good exposure and incidence of disease data. The current EPA, OSHA, and ACGIH cancer potency estimates for benzene are based largely on this cohort. A retrospective exposure assessment and an analysis of the incidence of disease in these workers were completed in 1991. All of these issues are discussed and the implications evaluated in this paper. The range of benzene exposures to which Americans are commonly exposed and the current regulatory criteria are also presented.
Determining aggregate and cumulative risks from exposures to pesticides presents a number of chal... more Determining aggregate and cumulative risks from exposures to pesticides presents a number of challenges. The analysis must capture the correlations in residues that occur from both additive and exclusionary processes in the use of pesticides. The analysis also requires a quantitative mechanism for evaluating risks associated with exposures to mixtures of pesticides. This paper presents an analysis of aggregate exposures and risks associated with exposures to a pesticide, Alpha, and the cumulative exposure to and risk from three pesticides, Alpha, Beta, and Gamma. The cumulative risks are evaluated by determining the systemic (absorbed) doses that result from inhalation, dermal, and oral exposures to the pesticides. A 'relative toxicity' model is used to evaluate cumulative risks. The assessment of cumulative exposure was performed using the LifeLine Version 1.0. The model simulates pesticide exposure using an individual-based approach where daily exposures are evaluated for each person, season, and location.
Exposure to chemicals is influenced by associations between the individual’s location and activit... more Exposure to chemicals is influenced by associations between the individual’s location and activities as well as demographic and physiological characteristics. Currently, many exposure models simulate individuals by drawing distributions from population-level data or use exposure factors for single individuals. The Residential Population Generator (RPGen) binds US surveys of individuals and households and combines the population with physiological characteristics to create a synthetic population. In general, the model must be supported by internal consistency; i.e., values that could have come from a single individual. In addition, intraindividual variation must be representative of the variation present in the modeled population. This is performed by linking individuals and similar households across income, location, family type, and house type. Physiological data are generated by linking census data to National Health and Nutrition Examination Survey data with a model of interindiv...
Users may download and print one copy of any publication from the public portal for the purpose... more Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Journal of Exposure Science & Environmental Epidemiology, 2018
Exposure to a chemical is a critical consideration in the assessment of risk, as it adds real-wor... more Exposure to a chemical is a critical consideration in the assessment of risk, as it adds real-world context to toxicological information. Descriptions of where and how individuals spend their time are important for characterizing exposures to chemicals in consumer products and in indoor environments. Herein we create an agent-based model (ABM) that simulates longitudinal patterns in human behavior. By basing the ABM upon an artificial intelligence (AI) system, we create agents that mimic human decisions on performing behaviors relevant for determining exposures to chemicals and other stressors. We implement the ABM in a computer program called the Agent-Based Model of Human Activity Patterns (ABMHAP) that predicts the longitudinal patterns for sleeping, eating, commuting, and working. We then show that ABMHAP is capable of simulating behavior over extended periods of time. We propose that this framework, and models based on it, can generate longitudinal human behavior data for use in exposure assessments.
Quantitative data on product chemical composition is a necessary parameter for characterizing nea... more Quantitative data on product chemical composition is a necessary parameter for characterizing near-field exposure. This data set comprises reported and predicted information on more than 75,000 chemicals and more than 15,000 consumer products. The data's primary intended use is for exposure, risk, and safety assessments. The data set includes specific products with quantitative or qualitative ingredient information, which has been publicly disclosed through material safety data sheets (MSDS) and ingredient lists. A single product category from a refined and harmonized set of categories has been assigned to each product. The data set also contains information on the functional role of chemicals in products, which can inform predictions of the concentrations in which they occur. These data will be useful to exposure and risk assessors evaluating chemical and product safety.
A Human Effectiveness and Risk Characterization for Electromuscular Incapacitation (EMI) reflects... more A Human Effectiveness and Risk Characterization for Electromuscular Incapacitation (EMI) reflects the results from three workshops (data gathering/sharing, peer consultation, and independent external review) evaluating two EMI devices: the M26 and X26 TASERs. The intended effect of these devices is electromuscular disruption. Key potential unintended effects included ocular injury, seizures, ventricular fibrillation, or fall injuries. The likelihood of these effects were determined, based on an analysis of the TASER International Database (scrubbed to minimize false positives) and modeling. The probability of inducing a complete EMD ranges from 74% to 52% depending on distance to the target. Probability estimates were up to 0.04% for eye "strikes and 0.15% for fall injuries depending on distance to the target. Ventricular fibrillation (VF) is not expected to occur in an otherwise healthy adult population. Key data gaps include the biological basis for TASER effects and appropriate dosimetry. The results support the conclusion that the M26 and X26 TASERs are generally effective for their intended use.
This paper uses the maximum cumulative ratio (MCR) as part of a tiered approach to evaluate and p... more This paper uses the maximum cumulative ratio (MCR) as part of a tiered approach to evaluate and prioritize the risk of acute ecological effects from combined exposures to the plant protection products (PPPs) measured in 3 099 surface water samples taken from across the United States. Assessments of the reported mixtures performed on a substance-by-substance approach and using a Tier One cumulative assessment based on the lowest acute ecotoxicity benchmark gave the same findings for 92.3% of the mixtures. These mixtures either did not indicate a potential risk for acute effects or included one or more individual PPPs that had concentrations in excess of their benchmarks. A Tier Two assessment using a trophic level approach was applied to evaluate the remaining 7.7% of the mixtures. This assessment reduced the number of mixtures of concern by eliminating the combination of endpoint from multiple trophic levels, identified invertebrates and nonvascular plants as the most susceptible no...
Toxicological sciences : an official journal of the Society of Toxicology, Jan 2, 2015
There is great interest in assessing the in vivo toxicity of chemicals using non-animal alternati... more There is great interest in assessing the in vivo toxicity of chemicals using non-animal alternatives. However, acute mammalian toxicity is not adequately predicted by current in silico or in vitro approaches. Mechanisms of acute toxicity are likely conserved across invertebrate, aquatic and mammalian species, suggesting that dose-response concordance would be high and in vitro mechanistic data could predict responses in multiple species under conditions of similar bioavailability. We tested this hypothesis by comparing acute toxicity between rat, daphnia and fish, and by comparing their respective acute data to inhibition of mitochondria membrane potential (MMP) using US Environmental Protection Agency ToxCast in vitro high-throughput screening (HTS) data. Logarithmic scatter plots of acute toxicity data showed a clear relationship between fish, daphnia and intravenous rat but not oral rat data. Similar plots versus MMP showed a well-delineated upper boundary for fish, daphnia and i...
This report presents the findings of a multi-year assessment of the releases of polychlorinated b... more This report presents the findings of a multi-year assessment of the releases of polychlorinated biphenyls (PCBs) from the Oak Ridge Reservation (ORR) and the potential for adverse effects in the local populations. PCBs were used and released from the ORR, and large numbers of individuals received doses by multiple routes of exposure. These routes included exposure to PCBs in air, water, sediments, biota (fish and turtles), and possibly from the sale and use of contaminated surplus oil. For many individuals, the exposures resulted in dose rates that are of little toxicological concern. However, for the farm families that lived along East Fork Poplar Creek (EFPC), and for persons who ate fish from Watts Bar and the Clinch River, the exposures could have resulted in both carcinogenic and noncarcinogenic effects. An accurate evaluation of exposures to the farm families is not possible due to the absence of relevant measurements of PCBs in the soils of the farms. However, sufficient data were available to assess the risks to anglers and their families. A conservative estimate of the carcinogenic risks posed by the ORR releases to consumers of fish from Watts Bar Reservoir and the Clinch River range from less than 1 in a 1,000,000 to 2 in 10,000. Based on these risk estimates and the number of anglers using the fisheries, three or less excess cases of cancer would be expected to occur in the populations of consumers of fish from Watts Bar Reservoir and Clinch River since the ORR began operations in the 1940s. Because the estimates are conservative, the actual risks and expected number of cases are likely to be smaller and could be zero.
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