Dale Hattis
Clark University, George Perkins Marsh Institute, Faculty Member
A key element of risk assessment is accounting for the full range of variability in response to environmental exposures. Default dose-response methods typically assume a 10-fold difference in response to chemical exposures between average... more
A key element of risk assessment is accounting for the full range of variability in response to environmental exposures. Default dose-response methods typically assume a 10-fold difference in response to chemical exposures between average (healthy) and susceptible humans, despite evidence of wider variability. Experts and authoritative bodies support using advanced techniques to better account for human variability due to factors such as in utero or early life exposure and exposure to multiple environmental, social, and economic stressors.This review describes: 1) sources of human variability and susceptibility in dose-response assessment, 2) existing US frameworks for addressing response variability in risk assessment; 3) key scientific inadequacies necessitating updated methods; 4) improved approaches and opportunities for better use of science; and 5) specific and quantitative recommendations to address evidence and policy needs.Current default adjustment factors do not sufficien...
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Acknowledgment: This research is supported by a cooperative agreement with the US Environmental Protection Agency--CR 829746-01. However, the conclusions are those of the authors and do not necessarily reflect the views of the US... more
Acknowledgment: This research is supported by a cooperative agreement with the US Environmental Protection Agency--CR 829746-01. However, the conclusions are those of the authors and do not necessarily reflect the views of the US Environmental Protection Agency. We also gratefully acknowledge the assistance of Hugh Barton of USEPA in suggesting some additions and modifications to the data originally presented in USEPA (2003), and the helpful review of technical statistical issues by Woodrow Setzer and Paul White of USEPA. Abbreviations: UCL—Upper Confidence Limit
Clewell et al. presented a risk assessment for chloroprene that incorporates physiologically based pharmacokentic (PBPK) modeling to opine that the inhalation-based cancer risk from exposure to chl...
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This paper describes a methodology used to incorporate specific mechanism-related information into carcinogenesis risk assessment. We are developing a coordinated series of pharmacokinetic models to aid in quantitative risk assessments of... more
This paper describes a methodology used to incorporate specific mechanism-related information into carcinogenesis risk assessment. We are developing a coordinated series of pharmacokinetic models to aid in quantitative risk assessments of inhalation exposure to two-carbon alkylating agents. We have applied our system to perchloroethylene and ethylene oxide. Human, rat, and mouse multi-compartment pharmacokinetic models were developed on the Apple Macintosh using the STELLA modeling system. The interactive and easy to use STELLA provides a powerful tool in the study of dynamic behavior and underlying feedback mechanisms of a structure. The models allow the systematic exploration of the causal relationships between external ambient exposure and steps in the pathway to carcinogenesis, including tissue absorption and metabolism. Simulations run on the models were used to study the relative hazards of high and low doses under acute and chronic exposure conditions. In addition, the models were used to assess the sensitivity of risk of carcinogenesis to changes in physiological variables and different levels of activity.
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... of the artificial sweetener aspartame.1 Dose-dependent increases in total malignant tumors, lympho-mas/leukemias, and mammary car-cinomas were ... The European Food Safety Authority (EFSA) reviewed the study and concluded for various... more
... of the artificial sweetener aspartame.1 Dose-dependent increases in total malignant tumors, lympho-mas/leukemias, and mammary car-cinomas were ... The European Food Safety Authority (EFSA) reviewed the study and concluded for various reasons that aspartame was not ...
Research Interests: Italy, Humans, Child, United States, Female, and 15 moreAnimals, Male, Occupational and environmental health, Carcinogens, ENVIRONMENTAL AND OCCUPATIONAL HEALTH, Rats, Public Administration and Policy, Adult, Public health systems and services research, Neoplasms, Reproducibility of Results, Aspartame, Biological Assay, United States Food and Drug Administration, and Child preschool
Dietary Reference Intakes (DRIs) are used in Canada and the United States in planning and assessing diets of apparently healthy individuals and population groups. The approaches used to establish DRIs on the basis of classical nutrient... more
Dietary Reference Intakes (DRIs) are used in Canada and the United States in planning and assessing diets of apparently healthy individuals and population groups. The approaches used to establish DRIs on the basis of classical nutrient deficiencies and/or toxicities have worked well. However, it has proved to be more challenging to base DRI values on chronic disease endpoints; deviations from the traditional framework were often required, and in some cases, DRI values were not established for intakes that affected chronic disease outcomes despite evidence that supported a relation. The increasing proportions of elderly citizens, the growing prevalence of chronic diseases, and the persistently high prevalence of overweight and obesity, which predispose to chronic disease, highlight the importance of understanding the impact of nutrition on chronic disease prevention and control. A multidisciplinary working group sponsored by the Canadian and US government DRI steering committees met ...
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Research Interests: Polymorphism, Monte Carlo Simulation, Molecular Epidemiology, Enzymes, Humans, and 12 moreAnimals, Glutathione, Enzyme, Public health systems and services research, Blood Flow, Xenobiotics, Genetic Polymorphism, Health risk, Enzyme activity, Aldehyde Dehydrogenase, PBPK Model, and Monte Carlo Method
Research Interests: Metabolism, Drug interactions, Low Dose, Animals, Male, and 14 moreModel development, Neurotoxins, Shell Half-Life, Rats, Rat, Wistar Rats, Interaction effect, Ketone, Experimental Data, Area Under the Curve, Toxicokinetics, Methyl Ethyl Ketone, Area Under Curve, and Pharmacology and pharmaceutical sciences
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Research Interests: Pharmacokinetics, Health, Peer Review, Health Risk Assessment, Humans, and 15 moreGender Difference, Heart Disease, Aged, Public health systems and services research, Cardiac Output Monitoring, Blood Flow, Genetic Polymorphism, Chronic obstructive pulmonary disease, Body Weight, Risk Assessment, Reference Values, Renal disease, PBPK Model, Glomerular Filtration Rate, and Cardiac output
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Research Interests: Engineering, Risk, Evaluation, Risk assessment, Exposure Assessment, and 15 moreEnvironmental Sciences, Humans, Carcinogens, Theoretical Models, Risk Assessment, Environmental Pollutants, Residence Time, Tetrachloroethylene, Laundering, Carcinogen, Environmental Exposure, Approximation Method, Air Pollutants, Solvents, and Random Allocation
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Research Interests: Polymorphism, Population Genetics, Enzyme Inhibitors, Gene expression, Health Risk Assessment, and 13 moreHumans, Animals, Phenotype, Enzyme, Public health systems and services research, Xenobiotics, Genetic Polymorphism, Body Weight, Enzyme activity, Trichloroethylene, Epidemiologic Studies, PBPK Model, and Enzyme Induction
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Co-exposure to methyl ethyl ketone (MEK) potentiates the neurotoxicity of n-hexane in humans as well as in animals. This effect is associated with increased persistence of 2,5-hexanedione (2,5-HD) in blood, probably due to inhibition of... more
Co-exposure to methyl ethyl ketone (MEK) potentiates the neurotoxicity of n-hexane in humans as well as in animals. This effect is associated with increased persistence of 2,5-hexanedione (2,5-HD) in blood, probably due to inhibition of 2,5-HD phase II biotransformation by MEK. There is no previous quantitative toxicokinetic model to describe this interaction. In this study we constructed a toxicokinetic model to depict the inhibition of 2,5-HD metabolism and elimination by MEK. Experimental data on 2,5-HD blood concentrations in rats from a published study were used to estimate model parameters. Three different inhibition mechanisms were evaluated: competitive, uncompetitive, and noncompetitive inhibition. Extrapolation from high to low doses was made to assess the interactive effects of MEK on 2,5-HD beyond experimental conditions. The models developed successfully described the toxicokinetic behavior of 2,5-HD when inhibited by MEK. The competitive inhibition model yielded a much...