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...
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: Research Design, Life Sciences, Risk assessment, Manganese, Progesterone, and 15 moreHumans, Case Study, Animals, Reference Data, Zinc, Vinyl acetate, Decision making process, Risk Assessment, Acetaminophen, Formaldehyde, Decision Maker, Environmental Protection Agency, Ethylene Glycol, ENVIRONMENTAL SCIENCE AND MANAGEMENT, 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
Research Interests: Polymorphism, Monte Carlo Simulation, Population Genetics, Toxicology, Humans, and 15 moreAnimals, Glutathione, Detoxification, Phenotype, Enzyme, Genotype, Public health systems and services research, Xenobiotics, Substrate Specificity, Genetic Polymorphism, Enzyme activity, Glutathione Transferase, Population Study, Epidemiologic Studies, and Monte Carlo Method
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: Genetics, Polymorphism, Monte Carlo Simulation, Population Genetics, Kinetics, and 15 moreMonte Carlo, Health Risk Assessment, Humans, African American, Mice, Animals, Detoxification, Enzyme, Ethnic Group, Genetic Polymorphism, Enzyme activity, Population Study, PBPK Model, Monte Carlo Method, and Allele Frequency
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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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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An attempt was made to build an integrated series of pharmacokinetic models for low-molecular-weight alkylating agents in efforts to expand the understanding of risk assessment for various occupational carcinogens. The purpose was to... more
An attempt was made to build an integrated series of pharmacokinetic models for low-molecular-weight alkylating agents in efforts to expand the understanding of risk assessment for various occupational carcinogens. The purpose was to allow for better assessment of biologically effective doses of activated metabolites delivered to target tissues and to arrive at a better translation of such units between species. The approach to pharmacokinetic modeling of ethylene oxide was defined, and specific results were presented. Longer elimination was predicted to increase internal dose, so that greater internal doses would be expected in man compared to rodents. Lower respiration per body weight in man would decrease absorption rate, offsetting the higher predicted internal dose. In terms of human cancer risk, it is stated that substantial data are available showing carcinogenic response of rats and mice to ethylene oxide. Equations are presented showing the risk resulting for different sites, species, and sexes using the measure of delivered dose in a multistage model. Implications for overall human cancer risk from 45 years 8 hours per day occupational exposure to 1 part per million ethylene oxide were presented. Doses used in analysis did not yield markedly divergent estimates of human risk. The authors conclude that, for a simple direct-acting alkylator like ethylene oxide, traditional approaches for dose and risk projection across species are supported by pharmacokinetic-based analysis.
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Research Interests: Genetics, Risk, Risk assessment, Multidisciplinary, Molecular Epidemiology, and 15 moreHumans, Mice, Animals, Risk factors, Dose Response Relationship, Rats, Biological markers, Risk Factors, Risk Assessment, Curve fitting, Formaldehyde, Biological Assay, Predictive value of tests, Statistical Science, and Nose Neoplasms
Some issues in conflict regarding the proposed OSHA standard for occupational exposure to noise are examined. These include material impairment, the extent of possible hearing loss, nonauditory effects, and the nature of social and... more
Some issues in conflict regarding the proposed OSHA standard for occupational exposure to noise are examined. These include material impairment, the extent of possible hearing loss, nonauditory effects, and the nature of social and economic costs benefits of regulation at 85 dBA and 90 dBA exposure limits. A preliminary analysis of the methodology and difficulties in arriving at cost benefit
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This paper first reviews in plain language some basic concepts and methods for estimating inter-individual variability in susceptibility from human data. A scale is offered to allow different variability findings to be understood and... more
This paper first reviews in plain language some basic concepts and methods for estimating inter-individual variability in susceptibility from human data. A scale is offered to allow different variability findings to be understood and compared. Then the accumulated results of different variability analyses, information on how much variability has been observed and how often, is summarized in the form of a series of box plots. Data are presented on pharmacodynamic variability for various non-cancer effects, variability in susceptibility to infectious organisms, and variability in susceptibility to carcinogenesis by genetically-acting agents.
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To assess the role of smoking on low birth weight (LBW). From Massachusetts for 1998, 79,904 birth certificates were reviewed. Birth weight, gestational age, plurality and maternal race were analyzed in relation to the... more
To assess the role of smoking on low birth weight (LBW). From Massachusetts for 1998, 79,904 birth certificates were reviewed. Birth weight, gestational age, plurality and maternal race were analyzed in relation to the mother's smoking status during the pregnancy. The etiologic fraction (EF) was calculated for smoking and LBW for the group as a whole as well as for various subgroups. A total of 11.7% of women acknowledged smoking during pregnancy. The overall LBW rate was 6.83%. The relative risk (RR) of LBW among smokers was 1.58. For all births the EF for smoking was 6.4% (95% CI: 5.4-7.3). For singleton pregnancies it was 10.9% (95% CI: 9.6-12.1) (14% for singleton whites and 7.2 for singleton blacks). At term, the EF of smoking on LBW was 13.4% (95% CI: 11.5-15.3), with an EF of 16.7% (95% CI: 14.5-18.7) for term singletons (21.4% among whites and 14.6% among blacks). Among very LBW infants, smoking accounted for 1.7% (95% CI:--0.5-3.8) of the outcome (5.8% among singletons). When stratifying for the effect of smoking, the rate of LBW was 6.38% among nonsmokers, 9.5% (RR 1.48, 1.38-1.61) among light smokers, 11.67% (RR 1.82, 1.63-2.05) among moderate smokers and 11.72% (RR 1.84, 1.33-2.54) among heavy smokers. Sixty percent of the overall population effect of smoking on LBW was in the category of light smokers. The amount of LBW attributable to smoking was 6.4% in this sample. Among those who smoked, LBW was 58% more likely than among nonsmokers, and 60% of the overall population effect of smoking on LBW was noted among light smokers.
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We have argued that accurate identification of the microorganism will form a cornerstone of the assessment of potential hazard. Appropriate methodology for identification exists, and is continually under development and refinement.... more
We have argued that accurate identification of the microorganism will form a cornerstone of the assessment of potential hazard. Appropriate methodology for identification exists, and is continually under development and refinement. Organizations such as the American Type Culture Collection will perform certified identifications for relatively low cost. Thus there appears to be little reason that an organism should not be identified insofar as current microbiology allows prior to submission for PMN review. We suggest that a complete microbiological characterization be considered an essential element of an acceptable PMN. To accomplish this, however, current institutional arrangements for the protection of trade secret information needed in the process of identification may need to be improved. An accurate identification of the strain will often provide access to important information with which to evaluate its ecology, pathogenicity, biochemistry, and genetics. Specialized texts, the scientific literature, and professional consultation are ready sources of such information. However, a major effort should be made to establish a data base that can specifically address the needs of biohazard evaluation. This could be done, in part, by collecting information about the construction, and about the behavior in the environment of genetically-engineered microorganisms that are now under development and will soon be tested or used. Identification information may also eventually be useful for the formulation of hypotheses about possible modes of harm or about relative safety, based on phylogenetic relationships. This is a very difficult undertaking at present, however. Microbial taxonomy is currently in a process of radical reevaluation as new macromolecular sequence information reveals previously unsuspected phylogenetic relationships, and disturbs categorizations based on older types of traits such as morphology, etc. This means that both inferences about relative safety and about possible modes of harm from taxonomic relationships must be highly tentative based on current information. Regulatory authorities may wish to consider requesting confirmatory DNA hybridization data or other macromolecular sequence comparisons in cases where strong arguments related to safety must be made from taxonomic information in relatively poorly studied groups of organisms. Detailed strain histories would provide valuable information for safety evaluations.(ABSTRACT TRUNCATED AT 400 WORDS)
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Fetal growth restriction is one of the most common findings in animal toxicology studies of reproductive/developmental effects for environmental chemicals. Projection of the possible implications of such effects for human health requires... more
Fetal growth restriction is one of the most common findings in animal toxicology studies of reproductive/developmental effects for environmental chemicals. Projection of the possible implications of such effects for human health requires a mathematical model of how human birth weight distributions can be expected to change under the influence of a non-specific toxic exposure. The present analysis draws on recent U.S. national aggregate data from birth certificates on the birth weights of over ten million babies born to mothers who do and do not report cigarette smoking during pregnancy. These data are analyzed empirically both by straightforward interpolation of percentiles and by fitting to a mixture distribution of lognormals. The percentile interpolations of the aggregate data indicate differential effects between the higher and lower ends of the birth weight distribution. Specifically, the lighter end, which is at greater baseline risk of adverse effects (e.g., infant mortality,...
This case study illustrates how a very simple dynamic modeling approach can extract information of interest for both toxic mechanism research and risk assessment from a series of dose/time/response data. The technique is applicable for... more
This case study illustrates how a very simple dynamic modeling approach can extract information of interest for both toxic mechanism research and risk assessment from a series of dose/time/response data. The technique is applicable for effects that are thought to result from damage processes that are reversible, at least at low doses and times of exposure. The data sets analyzed provided information on some specific manifestation of acrylamide neurotoxicity produced by different combinations of acrylamide dose rate and duration of exposure. Assuming that responses occur when a specific amount of axonal damage accumulates, and that the repair of damage depends directly on the amount of damage present, the dose-related change in the time required to produce a specific type of effect can be used to estimate: (1) The rate of repair of the incipient damage - and differences in repair rates for different individuals within species, and among different species, and (2) The dose of acrylami...
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Behavioral end points for neurotoxicity risk assessment have been developed and examined over the past three decades. They are now ready to move from simple qualitative guidelines, such as exemplified by reference doses, to more... more
Behavioral end points for neurotoxicity risk assessment have been developed and examined over the past three decades. They are now ready to move from simple qualitative guidelines, such as exemplified by reference doses, to more quantitative models, such as benchmark doses, based on dose-response information. Risk assessors, confronted by a wider array of methodologies and data than in the past, should be offered guidance in interpretation because now they have to deal with unaccustomed questions and problems. These include reversibility, susceptible populations, multiple end points, and the details of dose-response and dose-effect distributions.
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Pharmacokinetic models were developed of the uptake of ethoxyethanol (EE), metabolism of EE via ethoxyacetaldehyde to ethoxyacetic acid (EAA), and urinary excretion of EAA. The performance of these models was tested with data on EE... more
Pharmacokinetic models were developed of the uptake of ethoxyethanol (EE), metabolism of EE via ethoxyacetaldehyde to ethoxyacetic acid (EAA), and urinary excretion of EAA. The performance of these models was tested with data on EE exposure, and preshift and postshift urinary EAA excretion/gram creatinine in a group of 36 painters studied over several successive days. The less simple model resulted
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The one second forced expiratory volume (FEV1) was used as a predictor of excess general mortality and as an indicator of progressive deterioration to respiratory impairment as a result of exposure to coal dust. Data on 1,362 coal miners... more
The one second forced expiratory volume (FEV1) was used as a predictor of excess general mortality and as an indicator of progressive deterioration to respiratory impairment as a result of exposure to coal dust. Data on 1,362 coal miners who had never smoked were used. The adequacy of nine different linear regression models for representing the effects of coal dust,
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The "irritation signaling" model proposed that a long term contribution to chronic bronchitis might result from the repeated delivery of "signals" resulting from temporary localized acidification of the bronchial... more
The "irritation signaling" model proposed that a long term contribution to chronic bronchitis might result from the repeated delivery of "signals" resulting from temporary localized acidification of the bronchial epithelium by the action of individual particles. This led to a prediction that the effectiveness of particles in inducing changes in mucus secreting cell numbers/types should depend on the number of particles deposited that contained a particular amount of acid--implying that particles below a certain size cutoff (and therefore lacking a minimum amount of acid) should be ineffective; and that particle potency per unit weight should be greatest at the cutoff and decline strongly above the cutoff. Since the development of this hypothesis both epidemiological observations and some experimental studies have tended to reinforce the notion that acid particles can make a contribution to relatively long lasting bronchitic-like changes, and enhance the desirabil...
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... Douglas O. Johns1, Elizabeth Oesterling Owens1, Chad M. Thompson2, Babasaheb Sonawane2, Dale Hattis3, and Kannan Krishnan4 1National Center for ... density, tissue composi-tion, and tissue blood flow rates which are presented in ICRP... more
... Douglas O. Johns1, Elizabeth Oesterling Owens1, Chad M. Thompson2, Babasaheb Sonawane2, Dale Hattis3, and Kannan Krishnan4 1National Center for ... density, tissue composi-tion, and tissue blood flow rates which are presented in ICRP (2003), Leggett and Williams ...
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Research Interests: Science, Multidisciplinary, Humans, Mice, United States, and 4 moreAnimals, Carcinogens, Formaldehyde, and Public Policy
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N-Acetyltransferases (NAT) are key enzymes in the conjugation of certain drugs and other xenobiotics with an arylamine structure. Polymorphisms in NAT2 have long been recognized to modulate toxicity produced by the anti-tubercular drug... more
N-Acetyltransferases (NAT) are key enzymes in the conjugation of certain drugs and other xenobiotics with an arylamine structure. Polymorphisms in NAT2 have long been recognized to modulate toxicity produced by the anti-tubercular drug isoniazid, with molecular epidemiologic studies suggesting a link between acetylator phenotype and increased risk for bladder cancer. Recent evidence indicates that the other major NAT isozyme, NAT1, is also polymorphic. The current analysis characterizes the main polymorphisms in both NAT2 and NAT1 in terms of their effect on enzyme activity and frequency in the population. Multiple NAT2 alleles (NAT2*5, *6, *7, and *14) have substantially decreased acetylation activity and are common in Caucasians and populations of African descent. In these groups, most individuals carry at least one copy of a slow acetylator allele, and less than 10% are homozygous for the wild type (fast acetylator) trait. Incorporation of these data into a Monte Carlo modeling framework led to a population distribution of NAT2 activity that was bimodal and associated with considerable variability in each population assessed. The ratio of the median to the first percentile of NAT2 activity ranged from 7 in Caucasians to 18 in the Chinese population. This variability indicates the need for more quantitative approaches (e.g., physiologically based pharmacokinetic [PBPK] modeling) to assess the full distribution of internal dose and adverse responses to aromatic amines and other NAT2 substrates. Polymorphisms in NAT1 are generally associated with relatively minor effects on acetylation function, with Monte Carlo analysis indicating less interindividual variability than seen in NAT2 analysis.
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The U.S. Environmental Protection Agency (EPA) practice of risk assessment is moving toward more thoroughly considering... more
The U.S. Environmental Protection Agency (EPA) practice of risk assessment is moving toward more thoroughly considering children's unique susceptibilities and exposure potential. Childhood is assessed as a sequence of life stages that reflects the fact that as humans develop, windows of susceptibility may appear that lead to enhanced sensitivity to exposure of environmental agents, while changes in behavior and physiology may increase exposure and dose. The U.S. EPA developed guidance in the past few years that addresses some aspects of increased susceptibility and exposure and dose. However, when it comes to considering inhalation exposure, dose, and risk, current U.S. EPA practice does not explicitly address children. The purpose here is to begin studying the adequacy of practice for children's health and to explore possible next steps in developing new methods to more accurately assess life-stage-specific differences. The existing guidelines and policies used to address potentially unique susceptibilities of children for inhaled environmental chemicals were considered, as well as what may be learned from examples of approaches that have been applied by state agencies (such as the California Environmental Protection Agency) or in the literature, to incorporate potentially unique susceptibilities and exposures to children. Finally, there is a discussion of possible approaches for considering inhalation exposure and susceptibility in U.S. EPA risk assessments.
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Dietary exposure to acrylamide is common as a result of its formation during the cooking of carbohydrate foods. This leads to widespread human exposure in adults and children alike. Acrylamide is neurotoxic and is metabolized by... more
Dietary exposure to acrylamide is common as a result of its formation during the cooking of carbohydrate foods. This leads to widespread human exposure in adults and children alike. Acrylamide is neurotoxic and is metabolized by cytochrome P-450 (CYP) 2E1 to a mutagenic epoxide, glycidamide. This article describes a modeling framework for assessing acrylamide and glycidamide dosimetry in rats and human adults and children. The challenges in building a physiologically based toxicokinetic (PBTK) model that is compatible with existing rat and human data are described, with an emphasis on calibration against the hemoglobin adduct database. This exploratory PBTK model was adapted to children by incorporating life-stage-specific parameters consistent with children's changing physiology and metabolic capacity for processes involved in acrylamide disposition in terms of CYP2E1, glutathione conjugation, and epoxide hydrolase. Monte Carlo analysis was used to simulate the distribution of internal doses to gain an initial understanding of the range of child/adult differences possible. This analysis suggests modest dosimetry differences between children and adults, with area-under-the-curve (AUC) doses for the 99th percentile child up to fivefold greater than the median adult for both acrylamide and glycidamide. Early life immaturities tended to exert a greater effect on acrylamide than glycidamide dosimetry because immaturities in CYP2E1 and glutathione counteract one another for glycidamide AUC, but both lead to greater acrylamide dose. The analysis points toward glutathione conjugation parameters as being particularly influential and uncertain in early life, making this a key area for future research.
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In the USA a small proportion of fishery products are contaminated with appreciable amounts of potentially hazardous contaminants. However, risks to consumers are not generally high. Inorganic contaminants with the greatest potential for... more
In the USA a small proportion of fishery products are contaminated with appreciable amounts of potentially hazardous contaminants. However, risks to consumers are not generally high. Inorganic contaminants with the greatest potential for toxicity are antimony, arsenic, cadmium, lead, mercury, selenium and sulfites. Among organic compounds, polychlorinated biphenyls, dioxins, several chlorinated hydrocarbon insecticides, certain processing-related and aquaculture-related contaminants pose potential risks for consumers. Log-normal distributions appear to provide good descriptions of the pattern of variation of contaminant concentrations among different geographic areas, and some contaminants (mostly organic) appear to be much more variable than others. This variability offers a solution for reduction of exposure through restricting the harvest of aquatic organisms from specific sites, and by excluding certain species. It is recommended that: (i) existing State and Federal regulations and environmental monitoring be strengthened and enforced to minimize contamination of the aquatic environment; (ii) a program of shared responsibility be instituted, where Federal agencies develop a set of monitoring and inspection practices and state agencies assume responsibility for primary control, site closures and advisories issue; (iii) research and public education by government agencies and health professionals be expanded to determine actual risks and approaches to manage them; (iv) mandatory labeling be considered for specific contaminants; (v) a better system requiring international agreements be developed in order to minimize the differences among various national regulatory approaches.
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ABSTRACT The publication of the National Research Council's (NRC's) report Risk Assessment in the Federal Government: Managing the Process, called the “Red Book,” marked a crystallization of the Risk Analysis paradigm. We... more
ABSTRACT The publication of the National Research Council's (NRC's) report Risk Assessment in the Federal Government: Managing the Process, called the “Red Book,” marked a crystallization of the Risk Analysis paradigm. We offer an outsider's perspective on not only what was gained in this process, but also what was lost (or at least temporarily lost sight of)—the alternative framing of risk issues under the rubrics of policy and decision analysis. More recently, with increasing demands for analyses that juxtapose expected positive and negative consequences of available policy choices, and a newer NRC report on assessing the benefits of air pollution controls, a policy and decision analysis framework may be making a comeback from its long exile from the center of risk and policy discussions. The framework can be usefully informed by progress made in the use and methods of risk assessment.
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Existing risk assessment procedures for carcinogens are intended to be “conservative” in the uncertainty dimension—giving estimates that are expected to be higher than true risks for typical people. However, these procedures do not... more
Existing risk assessment procedures for carcinogens are intended to be “conservative” in the uncertainty dimension—giving estimates that are expected to be higher than true risks for typical people. However, these procedures do not consider the likely variability in susceptibility among individual people. This paper updates previous estimates of the likely extent of this variability for metabolically activated, genetically-acting carcinogens based
Research Interests: Genetics, Monte Carlo Simulation, Ecology, Risk Management, Risk assessment, and 13 moreDNA repair, Glutathione, Detoxification, Long Tail, Three Dimensional, Risk Assessment, Ecological Applications, Distributed Transactional Management, Cancer Risk, Confidence Limit, ENVIRONMENTAL SCIENCE AND MANAGEMENT, Expected Value, and Risk estimation
This paper surveys some recent available observations in humans on interindividual variability in exposure-related parameters, pharmacokinetics, and pharmacodynamics. Overall, I think two inferences are warranted. First, the drug and... more
This paper surveys some recent available observations in humans on interindividual variability in exposure-related parameters, pharmacokinetics, and pharmacodynamics. Overall, I think two inferences are warranted. First, the drug and epidemiological literatures do contain information that can shed new light on the extent of variability in the doses associated with different non-cancer responses. These data are waiting to be systematically extracted and analyzed. Second, I think it is likely that with more systematic measurement and analysis of interindividual variability we are likely to find that there are systematic tendencies for some kinds of responses to some categories of agents to occur at more variable exposures/doses than others. If we gather and analyze additional data of this type, we may be able to recommend adaptive modifications to the ten-fold safety factor tuned to these differences.
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Making use of quantitative estimates of risk involves sometimes painful choices about risk control options and ethical and social policies for additional control and/or acceptance of remaining risks. Out of the history of these choices in... more
Making use of quantitative estimates of risk involves sometimes painful choices about risk control options and ethical and social policies for additional control and/or acceptance of remaining risks. Out of the history of these choices in the U.S., we have drawn four broad categories of risk control criteria: The first of these is entirely qualitative; the last three can be informed by different kinds of quantitative analyses. The analyses differ in the implications of variability and uncertainty, among other factors. These suggested criteria should not be seen as a kind of formula to be programmed into a computer in place of human decision making. Rather, we hope they will contribute to an evolving language that can accurately represent our advancing technical understanding of the facts and frankly and compassionately convey our maturing understanding of the relevant value questions.
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Consideration of needs for public health interventions and new research requires comparative assessments of the health benefits that are likely to result from alternative uses of limited regulatory and technical resources. This paper... more
Consideration of needs for public health interventions and new research requires comparative assessments of the health benefits that are likely to result from alternative uses of limited regulatory and technical resources. This paper briefly examines regulatory and research priorities in the light of recent information on the carcinogenic hazards of vinyl chloride and alkyl and vinyl halides related to vinyl chloride, the respiratory-system hazards of poly (vinyl chloride), and the reproductive hazards of vinyl chloride. Specific suggestions are made for relatively promising types of efforts in these areas.
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Research Interests: Aging, Environmental Health, Kidney diseases, Liver diseases, Environmental Sciences, and 12 moreHumans, Aged, Environmental Risk Assessment, Xenobiotics, Adverse Drug Reaction, Age Factors, Polypharmacy, Environmental Pollutants, Environmental Exposure, Nervous System Diseases, Age Groups, and Pharmaceutical preparations
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Research Interests: Environmental Science, Environmental Health, Environmental Monitoring, Public Health, Environmental Sciences, and 15 moreHumans, Country of Origin, Public Education, Health Professionals, Eating, Polychlorinated Biphenyl, Human health, Fish Products, Food Contamination, Risk Assessment, Mechanism of action, International Agreements, Lognormal Distribution, Environmental Exposure, and health status indicators
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Characterizing variability in the extent and nature of responses to environmental exposures is a critical aspect of human health risk assessment. Our goal was to explore how next-generation human health risk assessments may better... more
Characterizing variability in the extent and nature of responses to environmental exposures is a critical aspect of human health risk assessment. Our goal was to explore how next-generation human health risk assessments may better characterize variability in the context of the conceptual framework for the source-to-outcome continuum. This review was informed by a National Research Council workshop titled "Biological Factors that Underlie Individual Susceptibility to Environmental Stressors and Their Implications for Decision-Making." We considered current experimental and in silico approaches, and emerging data streams (such as genetically defined human cells lines, genetically diverse rodent models, human omic profiling, and genome-wide association studies) that are providing new types of information and models relevant for assessing interindividual variability for application to human health risk assessments of environmental chemicals. One challenge for characterizing variability is the wide range of sources of inherent biological variability (e.g., genetic and epigenetic variants) among individuals. A second challenge is that each particular pair of health outcomes and chemical exposures involves combinations of these sources, which may be further compounded by extrinsic factors (e.g., diet, psychosocial stressors, other exogenous chemical exposures). A third challenge is that different decision contexts present distinct needs regarding the identification-and extent of characterization-of interindividual variability in the human population. Despite these inherent challenges, opportunities exist to incorporate evidence from emerging data streams for addressing interindividual variability in a range of decision-making contexts.
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Research Interests: Genetics, Monte Carlo, Disease susceptibility, Environmental Sciences, Humans, and 15 moreMice, Female, Animals, Male, Growth and development, Carcinogens, Age Factors, Body Weight, Biological Assay, Environmental Protection Agency, Confidence Limit, Monte Carlo Method, Data Uncertainty, Arithmetic mean, and guidelines as topic
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Biomarkers have a number of different uses in risk assessment, including (1) a variety of applications as dosimeters, (2) as an aid in quantifying inter-individual variability in susceptibility; and (3) as intermediate effect parameters... more
Biomarkers have a number of different uses in risk assessment, including (1) a variety of applications as dosimeters, (2) as an aid in quantifying inter-individual variability in susceptibility; and (3) as intermediate effect parameters that can help the analyst predict outcomes that are difficult to measure directly. This paper focuses primarily on applications of the first and second types, which are most frequently found in assessing risks from inorganic compounds.
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ABSTRACT
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This paper discusses the merits and disadvantages of a specific proposal for a numerical calculation of the reference dose (RfD) with explicit recognition of both uncertainty and variability. It is suggested that the RfD be the lower... more
This paper discusses the merits and disadvantages of a specific proposal for a numerical calculation of the reference dose (RfD) with explicit recognition of both uncertainty and variability. It is suggested that the RfD be the lower (more restrictive) value of: The daily dose rate that is expected (with 95% confidence) to produce less than 1/100,000 incidence over background of a minimally adverse response in a standard general population of mixed ages and genders, or The daily dose rate that is expected (with 95% confidence) to produce less than a 1/1000 incidence over background of a minimally adverse response in a definable sensitive subpopulation. Developing appropriate procedures to make such estimates poses challenges. To be a viable replacement for current RfDs, a numerical definition needs to be A plausible representation of the risk management values that both lay people and "experts" believe are intended to be achieved by current RfDs, (while better representing the "truth" that current RfDs cannot be expected to achieve zero risk with absolute confidence for a mixed population with widely varying sensitivities), Estimable with no greater amount of chemical specific information than is traditionally collected to estimate current RfD values, Subjected to a series of comparisons with existing RfDs to evaluate overall implications for current regulatory values, A more flexible value in the sense of facilitating the development of procedures to allow the incorporation of more advanced technical information--e.g., defined data on human distributions of sensitivity; information on comparative pharmacokinetic and/or pharmacodynamics in humans vs. test species, etc. The discussion evaluates the straw man proposal in the light of each of these points, and assesses the risks and uncertainties inherent in present RfDs by applying existing distributional information on various uncertainty factors to 18 of 20 randomly-selected entries from IRIS. The analysis here suggests that current RfDs seem to meet the 1/100,000 risk criterion with only somewhat better than 50% confidence. However, the current RfDs appear to generally fall short of the goal of meeting this risk criterion with 95% confidence, typically by an order of magnitude in dose or somewhat more. The single most important uncertainty is the extent of human interindividual variability in the doses of specific chemicals that cause adverse responses. Our major conclusion is that with some important assumptions, it is currently feasible to both specify quantitative probabilistic performance objectives for RfDs and to make tentative assessments about whether specific current RfDs for real chemicals seem to meet those objectives. Similarly it is also possible to make preliminary estimates of how much risk is posed by exposures in the neighborhood of current RfDs, and what the uncertainties are in such estimates. It is therefore possible to harmonize cancer and noncancer risk assessments by making quantitative noncancer risk estimates comparable to those traditionally made for carcinogenic risks. The benefits from this change will be an increase in the candor of public discussion of the possible effects of exposures to chemicals posing non-cancer risks, and encouragement for the collection of better scientific information related to toxic risks in people--particularly the extent and distributional form of interindividual differences among people in susceptibility.
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Some issues in conflict regarding the proposed OSHA standard for occupational exposure to noise are examined. These include material impairment, the extent of possible hearing loss, nonauditory effects, and the nature of social and... more
Some issues in conflict regarding the proposed OSHA standard for occupational exposure to noise are examined. These include material impairment, the extent of possible hearing loss, nonauditory effects, and the nature of social and economic costs benefits of regulation at 85 dBA and 90 dBA exposure limits. A preliminary analysis of the methodology and difficulties in arriving at cost benefit
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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...
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ABSTRACT
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Children's risks from environmental toxicant exposure can be affected by pharmacokinetic factors that affect the internal dose of parent chemical or active... more
Children's risks from environmental toxicant exposure can be affected by pharmacokinetic factors that affect the internal dose of parent chemical or active metabolite. There are numerous physiologic differences between neonates and adults that affect pharmacokinetics including size of lipid, and tissue compartments, organ blood flows, protein binding capacity, and immature function of renal and hepatic systems. These factors combine to decrease the clearance of many therapeutic drugs, which can also be expected to occur with environmental toxicants in neonates. The net effect may be greater or lesser internal dose of active toxicant depending upon how the agent is distributed, metabolized, and eliminated. Child/adult pharmacokinetic differences decrease with increasing postnatal age, but these factors should still be considered in any children's age group, birth through adolescence, for which there is toxicant exposure. Physiologically based pharmacokinetic (PBPK) models can simulate the absorption, distribution, metabolism, and excretion of xenobiotics in both children and adults, allowing for a direct comparison of internal dose and risk across age groups. This review provides special focus on the development of hepatic cytochrome P-450 enzymes (CYPs) in early life and how this information, along with many factors unique to children, can be applied to PBPK models for this receptor population. This review describes a case study involving the development of neonatal PBPK models for the CYP1A2 substrates caffeine and theophylline. These models were calibrated with pharmacokinetic data in neonates and used to help understand key metabolic differences between neonates and adults across these two drugs.
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Research Interests: Metabolism, Pharmacokinetics, Risk assessment, Adolescent, Drug Use, and 19 moreHumans, Child, Toxicity, Regression Analysis, Infant, Medline, Enzyme, Clearance, Newborn Infant, Shell Half-Life, Adult, Xenobiotics, Age Factors, Xenobiotic, Risk Assessment, Database, Toxicokinetics, Age Groups, and Nino
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Glutathione transferases (GST) catalyze the conjugation of glutathione (GSH) with electrophiles, many of which may otherwise interact with protein or DNA. In select cases such as halogenated solvents, GST-mediated conjugation may lead to... more
Glutathione transferases (GST) catalyze the conjugation of glutathione (GSH) with electrophiles, many of which may otherwise interact with protein or DNA. In select cases such as halogenated solvents, GST-mediated conjugation may lead to a more toxic or mutagenic metabolite. Polymorphisms that exert substantial effects on GST function were noted in human populations for several isozymes. This analysis focuses on three well-characterized isozymes, GSTM1, T1, and P1, in which polymorphisms were extensively studied with respect to DNA adducts and cancer in molecular epidemiologic studies. The current review and analysis focused upon how polymorphisms in these GST contributed to population variability in GST function. The first step in developing this review was to characterize the influence of genotype on phenotype (enzyme function) and the frequency of the polymorphisms across major population groups for all three GST. This information was then incorporated into Monte Carlo simulations to develop population distributions of enzyme function. These simulations were run separately for GSTM1, T1, and P1, and also for the combination of these isozymes, to assess the possibility of overlapping substrate specificity. Monte Carlo simulations indicated large interindividual variability for GSTM1 and T1 due to the presence of the null (zero activity) genotype, which is common in all populations studied. Even for GSTM1 or T1 non-null individuals, there was considerable interindividual variability with a bimodal distribution of enzyme activity evident. GSTP1 polymorphisms are associated with somewhat less variability due to the absence of null genotypes. However, in all cases simulated, the estimated variability is sufficiently large to warrant consideration of GST function distributions in assessments involving GST-mediated activation or detoxification of xenobiotics. Ideally, such assessments would involve physiologically based toxicokinetic (PBTK) modeling to assess population variability in internal dose.
Research Interests: Polymorphism, Monte Carlo Simulation, Population Genetics, Toxicology, Humans, and 15 moreAnimals, Glutathione, Detoxification, Phenotype, Enzyme, Genotype, Public health systems and services research, Xenobiotics, Substrate Specificity, Genetic Polymorphism, Enzyme activity, Glutathione Transferase, Population Study, Epidemiologic Studies, and Monte Carlo Method
Cytochrome P-450 2D6 (CYP2D6) is involved in the metabolism of many therapeutic drugs even though the enzyme represents a small proportion of the total CYP content of human liver. In vivo phenotyping with probe drug substrates such as... more
Cytochrome P-450 2D6 (CYP2D6) is involved in the metabolism of many therapeutic drugs even though the enzyme represents a small proportion of the total CYP content of human liver. In vivo phenotyping with probe drug substrates such as debrisoquine and dextromethorphan showed a clear separation between poor metabolizers (PM) and extensive metabolizers (EM). This polymorphism may affect susceptibility to environmental disease, as suggested by molecular epidemiologic studies that found an association between CYP2D6 metabolizer phenotype and cancer risk; however, this association is not consistent. There are only a few examples of CYP2D6 involvement in toxicant mechanism of action, but this has not been extensively studied. Gene probe studies documented a number of genetic polymorphisms that underlie CYP2D6 metabolizer phenotypes. The EM group carries the wild-type (*1) or active (*2) variant alleles, while the PM group carries the *3, *4, *5, or *6 alleles, all of which code for a protein that has lower or null CYP2D6 activity. The current analysis characterizes (a) influence of genotype on phenotype based upon in vivo metabolism studies of probe drugs and (b) frequency of the major genotypes in different population groups is also characterized. These data were then incorporated into Monte Carlo modeling to simulate population distributions of CYP2D6 activity. This analysis reproduced the bimodal distributions commonly seen in phenotyping studies of Caucasians and found extensive population variability in enzyme activity, as indicated by the 9- to 56-fold difference between the PM modal median and the total population median CYP2D6 activity. This substantial degree of interindividual variability in CYP function indicates that assessments involving CYP2D6 substrates need to consider the full distribution of enzyme activity in refining estimates of internal dose in health assessments of xenobiotics.
Research Interests: Polymorphism, Population Genetics, Toxicology, Monte Carlo, Molecular Epidemiology, and 12 moreHumans, Phenotype, Enzyme, Public health systems and services research, Genetic Polymorphism, Genetic variation, Enzyme activity, Mechanism of action, Epidemiologic Studies, Cancer Risk, Monte Carlo Method, and Pharmaceutical preparations
Paraoxonase-1 (PON1) is a serum esterase that hydrolyzes the activated oxon form of several organophosphates. The central role of PON1 in detoxification of organophosphate (OP) pesticides was demonstrated in knockout mouse studies,... more
Paraoxonase-1 (PON1) is a serum esterase that hydrolyzes the activated oxon form of several organophosphates. The central role of PON1 in detoxification of organophosphate (OP) pesticides was demonstrated in knockout mouse studies, suggesting that human variability in PON1 needs to be considered in health risk assessments involving exposure to these pesticides. The current analysis focused on two genetic loci in which polymorphisms demonstrated to affect PON1 activity. Detailed kinetic studies and population studies found that the *192Q (wild type) allele is more active toward some substrates (such as sarin, soman, and diazoxon) and less active toward others (such as paraoxon or chlorpyrifos) relative to the variant *192R allele. Another allele that affects activity is *55M; PON1 enzyme quantity, rather than specific activity or substrate preference, is altered. The *192R variant occurs commonly with a frequency of 25-64% across the populations analyzed. The *55M allele is less common, occurring in 5-40% of individuals depending upon the ethnic group studied. These activity and allele frequency data were incorporated into Monte Carlo simulations in which the frequency of both variant alleles was simultaneously modeled in Caucasian, African American, and Japanese populations. The resulting Monte Carlo activity distributions were bimodal for the substrate paraoxon with approximately fourfold differences between low- and high-activity modal medians. Differences in activity between total population median and 1st percentile were five- to sixfold. When sarin metabolic variability was simulated, the population distributions were unimodal. However, there was an even greater degree of interindividual variability (median to 1st percentile difference >20-fold). These results show that the combined effects of two PON1 allelic variants yielded a population distribution that is associated with a considerable degree of interindividual variability in enzyme activity. This indicates that assessments involving PON1 substrates need to evaluate polymorphism-related variability in enzyme activity to display the distribution of internal doses and adverse responses. This may best be achieved via physiologically based pharmacokinetic (PBPK) models that input PON1 activity distributions, such as those generated in this analysis, to simulate the range of oxon internal doses possible across the population.
Research Interests: Genetics, Polymorphism, Monte Carlo Simulation, Population Genetics, Kinetics, and 18 moreMonte Carlo, Health Risk Assessment, Humans, African American, Mice, Animals, Detoxification, Enzyme, Specific Activity, Public health systems and services research, Ethnic Group, Xenobiotics, Genetic Polymorphism, Enzyme activity, Population Study, PBPK Model, Monte Carlo Method, and Allele Frequency
Cytochrome P-450 2E1 (CYP2E1) is a key enzyme in the metabolic activation of a variety of toxicants including nitrosamines, benzene, vinyl chloride, and halogenated solvents such as trichloroethylene. CYP2E1 is also one of the enzymes... more
Cytochrome P-450 2E1 (CYP2E1) is a key enzyme in the metabolic activation of a variety of toxicants including nitrosamines, benzene, vinyl chloride, and halogenated solvents such as trichloroethylene. CYP2E1 is also one of the enzymes that metabolizes ethanol to acetaldehyde, and is induced by recent ethanol ingestion. There is evidence that interindividual variability in the expression and functional activity of this cytochrome (CYP) may be considerable. Genetic polymorphisms in CYP2E1 were identified and linked to altered susceptibility to hepatic cirrhosis induced by ethanol and esophageal and other cancers in some epidemiological studies. Therefore, it is important to evaluate how such polymorphisms affect CYP2E1 function and whether it is possible to construct a population distribution of CYP2E1 activity based upon the known effects of these polymorphisms and their frequency in the population. This analysis is part of the genetic polymorphism database project described in the lead article in this series and followed the approach described in that article (Ginsberg et al., 2009, this issue). Review of the literature found that there are a variety of CYP2E1 variant alleles but the functional significance of these variants is still unclear. Some, but not all, studies suggest that several upstream 5' flanking mutations affect gene expression and response to inducers such as ethanol or obesity. None of the coding-region variants consistently affects enzyme function. Part of the reason for conflicting evidence regarding genotype effect on phenotype may be due to the wide variety of exposures such as ethanol or dietary factors and physiological factors including body weight or diabetes that modulate CYP2E1 expression. In conclusion, evidence is too limited to support the development of a population distribution of CYP2E1 enzyme activity based upon genotypes. Health risk assessments may best rely upon data reporting interindividual variability in CYP2E1 function for input into physiologically based pharmacokinetic (PBPK) models involving CYP2E1 substrates.
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
Standard approaches for computing population exposures due to specific sources of air pollutants are relatively complex. In many cases, more simple and approximate methods would be useful. This paper develops an approach, based on the... more
Standard approaches for computing population exposures due to specific sources of air pollutants are relatively complex. In many cases, more simple and approximate methods would be useful. This paper develops an approach, based on the concept of exposure efficiency, that may be used for estimating the impact of a source (or source class) on the integrated population exposure. The approach is illustrated by an example, which uses the concept of exposure efficiency to examine the impact of perchloroethylene emissions from dry cleaners in the United States. The paper explores the geographic variability of exposure efficiency by evaluating it for each of 100 randomly selected dry cleaners. For perchloroethylene, which has a long atmospheric residence time, the site-to-site variability in exposure efficiency is found to be relatively small. This suggests that simple exposure assessments, based on generic distributional characterizations of exposure efficiency, may be used in risk assessments without introducing appreciable uncertainty. For many compounds, like perchloroethylene, the uncertainty inherent in the estimation of cancer potency or source emissions would dominate these small errors.
Research Interests: Engineering, Risk assessment, Exposure Assessment, Environmental Sciences, Humans, and 12 moreUnited States, Carcinogens, Theoretical Models, Risk Assessment, Environmental Pollutants, Residence Time, Tetrachloroethylene, Laundering, Environmental Exposure, Approximation Method, Air Pollutants, and Solvents
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Research Interests: Early Intervention, Environmental Health, Tobacco, Environmental Sciences, Pregnancy, and 13 moreHumans, Child, Smoking Cessation, Minority Groups, New York City, Female, Developmental disabilities, Economic Impact, Smoke, Indoor air pollution, Developmental delay, Environmental Tobacco Smoke, and Cohort Studies
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For more than three decades chronic studies in rodents have been the benchmark for assessing the potential long-term toxicity, and particularly the carcinogenicity, of chemicals. With doses typically administered for about 2 years (18... more
For more than three decades chronic studies in rodents have been the benchmark for assessing the potential long-term toxicity, and particularly the carcinogenicity, of chemicals. With doses typically administered for about 2 years (18 months to lifetime), the rodent bioassay has been an integral component of testing protocols for food additives, pesticides, pharmaceuticals, industrial chemicals, and all manner of byproducts and environmental contaminants. Over time, the data from these studies have been used to address an increasing diversity of questions related to the assessment of human health risks, adding complexity to study design and interpretation. An earlier ILSI RSI working group developed a set of principles for the selection of doses for chronic rodent studies (ILSI, 1997). The present report builds on that work, examining some of the issues that arise and offering new perspectives and approaches for putting the principles into practice. Dose selection is considered both from the prospective viewpoint of the choosing of dose levels for a study and from the retrospective interpretation of study results in light of the doses used. A main theme of this report is that the purposes and objectives of chronic rodent studies vary and should be clearly defined in advance. Dose placement, then, should be optimized to achieve study objectives. For practical reasons, most chronic studies today must be designed to address multiple objectives, often requiring trade-offs and innovative approaches in study design. A systematic approach to dose selection should begin with recognition that the design of chronic studies occurs in the context of a careful assessment of the accumulated scientific information on the test substance, the relevant risk management questions, priorities and mandates, and the practical limitations and constraints on available resources. A stepwise process is described. The aim is to increase insofar as possible the utility of an expensive and time-consuming experiment. The kinds of data that are most commonly needed for dose selection and for understanding the dose-related results of chronic rodent studies, particularly carcinogenicity studies, are discussed as "design/interpretation…