Insights into the complementarity of natural disaster insurance purchases and risk reduction behavior.

While flooding is the costliest natural disaster risk, public-sector investments provide incomplete protection. Moreover, individuals are in general reluctant to voluntarily invest in measures which limit damage costs from natural disasters. The moral hazard hypothesis argues that insured individuals take fewer other preparedness measures based on their assumption that their losses will be covered anyway. Conversely, the advantageous selection hypothesis argues that individuals view insurance and other risk reduction measures as complements. This study offers a comprehensive assessment of factors related to the separate uptake of natural disaster insurance and the flood-proofing of homes as well as why people may take both of these measures together. We use data from a survey conducted in Paris, France, in 2018, after several flood events, for a representative sample of 2976 residents facing different levels of flood risk. We perform both main effects regressions and interaction analyses to reveal that home adaptation to flooding is positively associated with comprehensive insurance coverage, which includes financial protection against natural disasters. Furthermore, actual and perceived risks, as well as awareness of official information on flood risk, are found to explain some of the relationship between home adaptation and comprehensive insurance purchase. We suggest several recommendations to policymakers based on these insights which aim to address insurance coverage gaps and the failure to take disaster risk reduction measures. In particular, groups in socially vulnerable situations may benefit from subsidized insurance, low interest loans, and decision aids to implement costly adaptation measures.

Drivers of natural disaster risk-reduction actions and their temporal dynamics: Insights from surveys during an imminent hurricane threat and its aftermath.

To improve preparedness for natural disasters, it is imperative to understand the factors that enable individual risk-reduction actions. This study offers such insights using innovative real-time (N = 871) and repeated (N = 255) surveys of a sample of coastal residents in Florida regarding flood preparations and their drivers during an imminent threat posed by Hurricane Dorian and its aftermath. Compared with commonly employed cross-sectional surveys, our methodology better represents relationships between preparedness actions undertaken during the disaster threat and their drivers derived from an extended version of Protection Motivation Theory (PMT). The repeated survey allows for examining temporal dynamics in these drivers. Our results confirm the importance of coping appraisals and show that risk perceptions relate more strongly to emergency protection decisions made during the period of the disaster threat than to decisions made well before. Moreover, we find that several personal characteristics that we add to the standard PMT framework significantly relate to undertaking preparedness actions, especially locus of control and social norms. Significant changes in key explanatory variables occur following the disaster threat, including a decline in risk perception, a potential learning effect in coping appraisals, and a decline in risk aversion. Our results confirm the advantage of the real-time and repeated survey approach in understanding both short- and long-term disaster preparedness actions.

Behavioral biases and heuristics in perceptions of COVID-19 risks and prevention decisions.

This study adds to an emerging literature on the factors associated with individual perceptions of COVID-19 risks and decision-making processes related to prevention behaviors. We conducted a survey in the Netherlands (N = 3600) in June-July 2020 when the first peak of COVID-19 infections, hospitalizations, and deaths had passed, and lockdown measures had been eased. Dutch policies relied heavily on individual prevention behaviors to mitigate a second infection wave. We examine whether biases and heuristics that have been observed in how people perceive and respond to other risks also apply to the newly emergent risks posed by COVID-19. The results indicate that people simplify risk using threshold models and that risk perceptions are related with personal experiences with COVID-19 and experiences of close others, supporting the availability heuristic. We also observe that prevention behavior is more strongly associated with COVID-19 risk perceptions and feelings toward the risk than with local indicators of COVID-19 risks, and that prevention behavior is related with herding. Support for government lockdown measures is consistent with preferences that may contribute to the not-in-my-term-of-office bias. In addition, we offer insights into the role of trust, worry, and demographic characteristics in shaping perceptions of COVID-19 risks and how these factors relate with individual prevention behaviors and support for government prevention measures. We provide several lessons for the design of policies that limit COVID-19 risks, including risk communication strategies and appeals to social norms. Perhaps more importantly, our analysis allows for learning lessons to mitigate the risks of future pandemics.

Magnetic Control of MOF Crystal Orientation and Alignment.

Most metal-organic frameworks (MOFs) possess anisotropic properties, the full exploitation of which necessitates a general strategy for the controllable orientation of such MOF crystals. Current methods largely rely upon layer-by-layer MOF epitaxy or tuning of MOF crystal growth on appropriate substrates, yielding MOFs with fixed crystal orientations. Here, the dynamic magnetic alignment of different MOF crystals (NH2 -MIL-53(Al) and NU-1000) is shown. The MOFs were magnetized by electrostatic adsorption of iron oxide nanoparticles, dispersed in curable polymer resins (Formlabs 1+ clear resin/ Sylgard 184), magnetically oriented, and fixed by resin curing. The importance of crystal orientation on MOF functionality was demonstrated whereby magnetically aligned NU-1000/Sylgard 184 composite was excited with linearly polarized 405 nm light, affording an anisotropic fluorescence response dependent on the polarization angle of the excitation beam relative to NU-1000 crystal orientation.

Right Ventricular Mass is Associated with Exercise Capacity in Adults with Repaired Tetralogy of Fallot.

The relationship between exercise capacity and right ventricular (RV) structure and function in adult repaired tetralogy of Fallot (TOF) is poorly understood. We therefore aimed to examine the relationships between cardiac MRI and cardiopulmonary exercise test variables in adult repaired TOF patients. In particular, we sought to determine the role of RV mass in determining exercise capacity. Eighty-two adult repaired TOF patients (age at evaluation 26 ± 10 years; mean age at repair 2.5 ± 2.8 years; 23.3 ± 7.9 years since repair; 53 males) (including nine patients with tetralogy-type pulmonary atresia with ventricular septal defect) were prospectively recruited to undergo cardiac MRI and cardiopulmonary exercise testing. As expected, these repaired TOF patients had RV dilatation (indexed RV end-diastolic volume: 153 ± 43.9 mL/m(2)), moderate-severe pulmonary regurgitation (pulmonary regurgitant fraction: 33 ± 14 %) and preserved left (LV ejection fraction: 59 ± 8 %) and RV systolic function (RV ejection fraction: 51 ± 7 %). Exercise capacity was near-normal (peak work: 88 ± 17 % predicted; peak oxygen consumption: 84 ± 17 % predicted). Peak work exhibited a significant positive correlation with RV mass in univariate analysis (r = 0.45, p < 0.001) and (independent of other cardiac MRI variables) in multivariate analyses. For each 10 g higher RV mass, peak work was 8 W higher. Peak work exhibits a significant positive correlation with RV mass, independent of other cardiac MRI variables. RV mass measured on cardiac MRI may provide a novel marker of clinical progress in adult patients with repaired TOF.

Potential new therapeutic modality revealed through agent-based modeling of the neuromuscular junction and acetylcholinesterase inhibition.

BACKGROUND: One of the leading causes of death and illness within the agriculture industry is through unintentionally ingesting or inhaling organophosphate pesticides. OP intoxication directly inhibits acetylcholinesterase, resulting in an excitatory signaling cascade leading to fasciculation, loss of control of bodily fluids, and seizures. METHODS: Our model was developed using a discrete, rules-based modeling approach in NetLogo. This model includes acetylcholinesterase, the nicotinic acetylcholine receptor responsible for signal transduction, a single release of acetylcholine, organophosphate inhibitors, and a theoretical novel medical countermeasure. We have parameterized the system considering the molecular reaction rate constants in an agent-based approach, as opposed to apparent macroscopic rates used in differential equation models. RESULTS: Our model demonstrates how the cholinergic crisis can be mitigated by therapeutic intervention with an acetylcholinesterase activator. Our model predicts signal rise rates and half-lives consistent with in vitro and in vivo data in the absence and presence of inhibitors. It also predicts the efficacy of theoretical countermeasures acting through three mechanisms: increasing catalytic turnover of acetylcholine, increasing acetylcholine binding affinity to the enzyme, and decreasing binding rates of inhibitors. CONCLUSION: We present a model of the neuromuscular junction confirming observed acetylcholine signaling data and suggesting that developing a countermeasure capable of reducing inhibitor binding, and not activator concentration, is the most important parameter for reducing organophosphate (OP) intoxication.

Quantitative structure-activity relationships for organophosphates binding to acetylcholinesterase.

Organophosphates are a group of pesticides and chemical warfare nerve agents that inhibit acetylcholinesterase, the enzyme responsible for hydrolysis of the excitatory neurotransmitter acetylcholine. Numerous structural variants exist for this chemical class, and data regarding their toxicity can be difficult to obtain in a timely fashion. At the same time, their use as pesticides and military weapons is widespread, which presents a major concern and challenge in evaluating human toxicity. To address this concern, a quantitative structure-activity relationship (QSAR) was developed to predict pentavalent organophosphate oxon human acetylcholinesterase bimolecular rate constants. A database of 278 three-dimensional structures and their bimolecular rates was developed from 15 peer-reviewed publications. A database of simplified molecular input line entry notations and their respective acetylcholinesterase bimolecular rate constants are listed in Supplementary Material, Table I. The database was quite diverse, spanning 7 log units of activity. In order to describe their structure, 675 molecular descriptors were calculated using AMPAC 8.0 and CODESSA 2.7.10. Orthogonal projection to latent structures regression, bootstrap leave-random-many-out cross-validation and y-randomization were used to develop an externally validated consensus QSAR model. The domain of applicability was assessed by the William's plot. Six external compounds were outside the warning leverage indicating potential model extrapolation. A number of compounds had residuals >2 or <-2, indicating potential outliers or activity cliffs. The results show that the HOMO-LUMO energy gap contributed most significantly to the binding affinity. A mean training R (2) of 0.80, a mean test set R (2) of 0.76 and a consensus external test set R (2) of 0.66 were achieved using the QSAR. The training and external test set RMSE values were found to be 0.76 and 0.88. The results suggest that this QSAR model can be used in physiologically based pharmacokinetic/pharmacodynamic models of organophosphate toxicity to determine the rate of acetylcholinesterase inhibition.

Evaluation of Human Performance Aiding Live Synthetically Engineered Bacteria in a Gut-on-a-Chip.

Synbiotics are a new class of live therapeutics employing engineered genetic circuits. The rapid adoption of genetic editing tools has catalyzed the expansion of possible synbiotics, exceeding traditional testing paradigms in terms of both throughput and model complexity. Herein, we present a simplistic gut-chip model using common Caco2 and HT-29 cell lines to establish a dynamic human screening platform for a cortisol sensing tryptamine producing synbiotic for cognitive performance sustainment. The synbiotic, SYN, was engineered from the common probiotic E. coli Nissle 1917 strain. It had the ability to sense cortisol at physiological concentrations, resulting in the activation of a genetic circuit that produces tryptophan decarboxylase and converts bioavailable tryptophan to tryptamine. SYN was successfully cultivated within the gut-chip showing log-phase growth comparable to the wild-type strain. Tryptophan metabolism occurred quickly in the gut compartment when exposed to 5 µM cortisol, resulting in the complete conversion of bioavailable tryptophan into tryptamine. The flux of tryptophan and tryptamine from the gut to the vascular compartment of the chip was delayed by 12 h, as indicated by the detectable tryptamine in the vascular compartment. The gut-chip provided a stable environment to characterize the sensitivity of the cortisol sensor and dynamic range by altering cortisol and tryptophan dosimetry. Collectively, the human gut-chip provided human relevant apparent permeability to assess tryptophan and tryptamine metabolism, production, and transport, enabled host analyses of cellular viability and pro-inflammatory cytokine secretion, and succeeded in providing an efficacy test of a novel synbiotic. Organ-on-a-chip technology holds promise in aiding traditional therapeutic pipelines to more rapidly down select high potential compounds that reduce the failure rate and accelerate the opportunity for clinical intervention.

Individual hurricane evacuation intentions during the COVID-19 pandemic: insights for risk communication and emergency management policies.

The U.S. 2020 hurricane season was extraordinary because of a record number of named storms coinciding with the COVID-19 pandemic. This study draws lessons on how individual hurricane preparedness is influenced by the additional risk stemming from a pandemic, which turns out to be a combination of perceptions of flood and pandemic risks that have opposite effects on preparedness behavior. We conducted a survey in early June 2020 of 600 respondents in flood-prone areas in Florida to obtain insights into households' risk perceptions and preparedness for the upcoming hurricane season under COVID-19. The results show that concerns over COVID-19 dominated flood risk perceptions and negatively impacted people's evacuation intentions. Whereas hotel costs were the main obstacle to evacuating during Hurricane Dorian in 2019 in the same geographic study area, the main evacuation obstacle identified in the 2020 hurricane season is COVID-19. Our statistical analyses investigating the factors influencing evacuation intentions show that older individuals are less likely to evacuate under a voluntary order, because they are more concerned about the consequences of becoming infected by COVID-19. We observe similar findings based on a real-time survey we conducted in Florida with another group of respondents under the threat of Hurricane Eta at the end of the hurricane season in November 2020. We discuss the implications of our findings for risk communication and emergency management policies that aim to improve hurricane preparedness when dealing with additional health risks such as a pandemic, a situation that may be exacerbated under the future climate. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11069-021-05064-2.

Associations between ozone and morbidity using the Spatial Synoptic Classification system.

BACKGROUND: Synoptic circulation patterns (large-scale tropospheric motion systems) affect air pollution and, potentially, air-pollution-morbidity associations. We evaluated the effect of synoptic circulation patterns (air masses) on the association between ozone and hospital admissions for asthma and myocardial infarction (MI) among adults in North Carolina. METHODS: Daily surface meteorology data (including precipitation, wind speed, and dew point) for five selected cities in North Carolina were obtained from the U.S. EPA Air Quality System (AQS), which were in turn based on data from the National Climatic Data Center of the National Oceanic and Atmospheric Administration. We used the Spatial Synoptic Classification system to classify each day of the 9-year period from 1996 through 2004 into one of seven different air mass types: dry polar, dry moderate, dry tropical, moist polar, moist moderate, moist tropical, or transitional. Daily 24-hour maximum 1-hour ambient concentrations of ozone were obtained from the AQS. Asthma and MI hospital admissions data for the 9-year period were obtained from the North Carolina Department of Health and Human Services. Generalized linear models were used to assess the association of the hospitalizations with ozone concentrations and specific air mass types, using pollutant lags of 0 to 5 days. We examined the effect across cities on days with the same air mass type. In all models we adjusted for dew point and day-of-the-week effects related to hospital admissions. RESULTS: Ozone was associated with asthma under dry tropical (1- to 5-day lags), transitional (3- and 4-day lags), and extreme moist tropical (0-day lag) air masses. Ozone was associated with MI only under the extreme moist tropical (5-day lag) air masses. CONCLUSIONS: Elevated ozone levels are associated with dry tropical, dry moderate, and moist tropical air masses, with the highest ozone levels being associated with the dry tropical air mass. Certain synoptic circulation patterns/air masses in conjunction with ambient ozone levels were associated with increased asthma and MI hospitalizations.

Quantitative structure-activity relationships for organophosphates binding to trypsin and chymotrypsin.

Organophosphate (OP) nerve agents such as sarin, soman, tabun, and O-ethyl S-[2-(diisopropylamino) ethyl] methylphosphonothioate (VX) do not react solely with acetylcholinesterase (AChE). Evidence suggests that cholinergic-independent pathways over a wide range are also targeted, including serine proteases. These proteases comprise nearly one-third of all known proteases and play major roles in synaptic plasticity, learning, memory, neuroprotection, wound healing, cell signaling, inflammation, blood coagulation, and protein processing. Inhibition of these proteases by OP was found to exert a wide range of noncholinergic effects depending on the type of OP, the dose, and the duration of exposure. Consequently, in order to understand these differences, in silico biologically based dose-response and quantitative structure-activity relationship (QSAR) methodologies need to be integrated. Here, QSAR were used to predict OP bimolecular rate constants for trypsin and α-chymotrypsin. A heuristic regression of over 500 topological/constitutional, geometric, thermodynamic, electrostatic, and quantum mechanical descriptors, using the software Ampac 8.0 and Codessa 2.51 (SemiChem, Inc., Shawnee, KS), was developed to obtain statistically verified equations for the models. General models, using all data subsets, resulted in R(2) values of .94 and .92 and leave-one-out Q(2) values of 0.9 and 0.87 for trypsin and α-chymotrypsin. To validate the general model, training sets were split into independent subsets for test set evaluation. A y-randomization procedure, used to estimate chance correlation, was performed 10,000 times, resulting in mean R(2) values of .24 and .3 for trypsin and α-chymotrypsin. The results show that these models are highly predictive and capable of delineating the complex mechanism of action between OP and serine proteases, and ultimately, by applying this approach to other OP enzyme reactions such as AChE, facilitate the development of biologically based dose-response models.

Characterization of an engineered live bacterial therapeutic for the treatment of phenylketonuria in a human gut-on-a-chip.

Engineered bacteria (synthetic biotics) represent a new class of therapeutics that leverage the tools of synthetic biology. Translational testing strategies are required to predict synthetic biotic function in the human body. Gut-on-a-chip microfluidics technology presents an opportunity to characterize strain function within a simulated human gastrointestinal tract. Here, we apply a human gut-chip model and a synthetic biotic designed for the treatment of phenylketonuria to demonstrate dose-dependent production of a strain-specific biomarker, to describe human tissue responses to the engineered strain, and to show reduced blood phenylalanine accumulation after administration of the engineered strain. Lastly, we show how in vitro gut-chip models can be used to construct mechanistic models of strain activity and recapitulate the behavior of the engineered strain in a non-human primate model. These data demonstrate that gut-chip models, together with mechanistic models, provide a framework to predict the function of candidate strains in vivo.

Use of respiratory function tests to predict survival in amyotrophic lateral sclerosis.

Respiratory function tests (RFTs) are commonly used as a measure of progression in ALS. This study assessed the ability of various RFTs to predict survival in ALS patients. Subjects with ALS had one or more measurements of seated and supine FVC, maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP). Kaplan-Meier (KM) analysis was used to determine whether patients with abnormal RFTs had shorter survival than those with normal RFTs. The sensitivity and specificity of RFTs as predictors of two-year survival were calculated from receiver operating characteristic (ROC) curves. With KM analysis, subjects with abnormal values of seated FVC, supine FVC, MIP and MEP had significantly reduced survival compared to subjects with normal values. With ROC curves, a normal supine FVC was highly predictive for two-year survival and had superior sensitivity over seated FVC. Slower rates of decline in seated or supine FVC were strong predictors of two-year survival. Our study demonstrates that respiratory function measurements are useful to predict survival in ALS patients. We show that measurements of FVC in the supine position are worth including in the assessment of respiratory function in ALS.

Perchlorate and radioiodide kinetics across life stages in the human: using PBPK models to predict dosimetry and thyroid inhibition and sensitive subpopulations based on developmental stage.

Perchlorate (ClO4(-)) is a drinking-water contaminant, known to disrupt thyroid hormone homeostasis in rats. This effect has only been seen in humans at high doses, yet the potential for long term effects from developmental endocrine disruption emphasizes the need for improved understanding of perchlorate's effect during the perinatal period. Physiologically based pharmacokinetic/dynamic (PBPK/PD) models for ClO4(-) and its effect on thyroid iodide uptake were constructed for human gestation and lactation data. Chemical specific parameters were estimated from life-stage and species-specific relationships established in previously published models for various life-stages in the rat and nonpregnant adult human. With the appropriate physiological descriptions, these kinetic models successfully simulate radioiodide data culled from the literature for gestation and lactation, as well as ClO4(-) data from populations exposed to contaminated drinking water. These models provide a framework for extrapolating from chemical exposure in laboratory animals to human response, and support a more quantitative understanding of life-stage-specific susceptibility to ClO4(-). The pregnant and lactating woman, fetus, and nursing infant were predicted to have higher blood ClO4(-) concentrations and greater thyroid iodide uptake inhibition at a given drinking-water concentration than either the nonpregnant adult or the older child. The fetus is predicted to receive the greatest dose (per kilogram body weight) due to several factors, including placental sodium-iodide symporter (NIS) activity and reduced maternal urinary clearance of ClO4(-). The predicted extent of iodide inhibition in the most sensitive population (fetus) is not significant (approximately 1%) at the U.S. Environmental Protection Agency reference dose (0.0007 mg/kg-d).

Analysis of algorithms predicting blood:air and tissue:blood partition coefficients from solvent partition coefficients for prevalent components of JP-8 jet fuel.

Algorithms predicting tissue and blood partition coefficients (PCs) from solvent properties were compared to assess their usefulness in a petroleum mixture physiologically based pharmacokinetic/pharmacodynamic model. Measured blood:air and tissue:blood PCs for rat and human tissues were sought from literature resources for 14 prevalent jet fuel (JP-8) components. Average experimental PCs were compared with predicted PCs calculated using algorithms from 9 published sources. Algorithms chosen used solvent PCs (octanol:water, saline or water:air, oil:air coefficients) due to the relative accessibility of these parameters. Tissue:blood PCs were calculated from ratios of predicted tissue:air and experimental blood:air values (PCEB). Of the 231 calculated values, 27% performed within +/- 20% of the experimental PC values. Physiologically based equations (based on water and lipid components of a tissue type) did not perform as well as empirical equations (derived from linear regression of experimental PC data) and hybrid equations (physiological parameters and empirical factors combined) for the jet fuel components. The major limitation encountered in this analysis was the lack of experimental data for the selected JP-8 constituents. PCEB values were compared with tissue:blood PCs calculated from ratios of predicted tissue:air and predicted blood:air values (PCPB). Overall, 68% of PCEB values had smaller absolute % errors than PCPB values. If calculated PC values must be used in models, a comparison of experimental and predicted PCs for chemically similar compounds would estimate the expected error level in calculated values.

Sudden cardiac death in adults with congenitally corrected transposition of the great arteries.

BACKGROUND: Congenitally corrected transposition of the great arteries (ccTGA) is a rare congenital heart disease. There have been only few reports of sudden cardiac death (SCD) in patients with ccTGA and reasonable ventricular function. METHODS: A retrospective review of the medical records of all patients attending our adult congenital heart centre, with known ccTGA. RESULTS: From a database of over 3500 adult patients with congenital heart disease, we identified 39 (∼1%) with ccTGA and 'two-ventricle' circulations. 65% were male. The mean age at diagnosis was 12.4±11.4 years and the mean age at last time of review was 34.3±11.3 years. 24 patients (56%) had a history of surgical intervention. 8 (19%) had had pacemaker implantation and 2 had had a defibrillator implanted for non-sustained ventricular tachycardia (NSVT). In 544 years of patient follow-up, there had been five cases of SCD in our population; 1 death per 109 patient-years. Two of these patients had had previously documented supraventricular or NSVT. However, they were all classified as New York Heart Association (NYHA) class I or II, and systemic (right) ventricular function had been recorded as normal, mildly or mildly-moderately impaired, at most recent follow-up. CONCLUSIONS: Our experience suggests the need for improved risk stratification and/or surveillance for malignant arrhythmia in adults with ccTGA, even in those with reasonable functional class on ventricular function.

PBPK model for radioactive iodide and perchlorate kinetics and perchlorate-induced inhibition of iodide uptake in humans.

Detection of perchlorate (ClO4-) in several drinking water sources across the U.S. has lead to public concern over health effects from chronic low-level exposures. Perchlorate inhibits thyroid iodide (I-) uptake at the sodium (Na+)-iodide (I-) symporter (NIS), thereby disrupting the initial stage of thyroid hormone synthesis. A physiologically based pharmacokinetic (PBPK) model was developed to describe the kinetics and distribution of both radioactive I- and cold ClO4- in healthy adult humans and simulates the subsequent inhibition of thyroid uptake of radioactive I- by ClO4-. The model successfully predicts the measured levels of serum and urinary ClO4- from drinking water exposures, ranging from 0.007 to 12 mg ClO4-/kg/day, as well as the subsequent inhibition of thyroid 131I- uptake. Thyroid iodine, as well as total, free, and protein-bound radioactive I- in serum from various tracer studies, are also successfully simulated. This model's parameters, in conjunction with corresponding model parameters established for the male, gestational, and lactating rat, can be used to estimate parameters in a pregnant or lactating human, that have not been or cannot be easily measured to extrapolate dose metrics and correlate observed effects in perchlorate toxicity studies to other human life stages. For example, by applying the adult male rat:adult human ratios of model parameters to those parameters established for the gestational and lactating rat, we can derive a reasonable estimate of corresponding parameters for a gestating or lactating human female. Although thyroid hormones and their regulatory feedback are not incorporated in the model structure, the model's successful prediction of free and bound radioactive I- and perchlorate's interaction with free radioactive I- provide a basis for extending the structure to address the complex hypothalamic-pituitary-thyroid feedback system. In this paper, bound radioactive I- refers to I- incorporated into thyroid hormones or iodinated proteins, which may or may not be bound to plasma proteins.

PBPK predictions of perchlorate distribution and its effect on thyroid uptake of radioiodide in the male rat.

Due to perchlorate's (ClO4-) ability to competitively inhibit thyroid iodide (I-) uptake through the sodium-iodide symporter (NIS), potential human health risks exist from chronic exposure via drinking water. Such risks may include hypothyroidism, goiter, and mental retardation (if exposure occurs during critical periods in neurodevelopment). To aid in predicting perchlorate's effect on normal I- kinetics, we developed a physiologically-based pharmacokinetic (PBPK) model for the adult male rat. The model structure describes simultaneous kinetics for both anions together with their interaction at the NIS, in particular, the inhibition of I- uptake by ClO4-. Subcompartments and Michaelis-Menten (M-M) kinetics were used to describe active uptake of both anions in the thyroid, stomach, and skin. Separate compartments for kidney, liver, plasma, and fat were described by passive diffusion. The model successfully predicts both 36ClO4- and 125I- kinetics after iv doses of 3.3 mg/kg and 33 mg/kg, respectively, as well as inhibition of thyroid 125I- uptake by ClO4- after iv doses of ClO4- (0.01 to 3.0 mg/kg). The model also predicts serum and thyroid ClO4- concentrations from 14-day drinking water exposures (0.01 to 30.0 mg ClO4-/kg/day) and compensation of perchlorate-induced inhibition of radioiodide uptake due to upregulation of the thyroid. The model can be used to extrapolate dose metrics and correlate observed effects in perchlorate toxicity studies to other species and life stages, such as rat gestation (Clewell et al., 2003). Because the model successfully predicts perchlorate's interaction with iodide, it provides a sound basis for future incorporation of the complex hypothalamic-pituitary-thyroid feedback system.

Predicting fetal perchlorate dose and inhibition of iodide kinetics during gestation: a physiologically-based pharmacokinetic analysis of perchlorate and iodide kinetics in the rat.

Perchlorate (ClO4-) disrupts endocrine homeostasis by competitively inhibiting the transport of iodide (I-) into the thyroid. The potential for health effects from human exposure to ClO4- in drinking water is not known, but experimental animal studies are suggestive of developmental effects from ClO4- induced iodide deficiency during gestation. Normal hormone-dependent development relies, in part, on synthesis of hormones in the fetal thyroid from maternally supplied iodide. Although ClO4- crosses the placenta, the extent of inhibition in the fetal thyroid is unknown. A physiologically-based pharmacokinetic (PBPK) model was developed to simulate ClO4- exposure and the resulting effect on iodide kinetics in rat gestation. Similar to concurrent model development for the adult male rat, this model includes compartments for thyroid, stomach, skin, kidney, liver, and plasma in both mother and fetus, with additional compartments for the maternal mammary gland, fat, and placenta. Tissues with active uptake are described with multiple compartments and Michaelis-Menten (M-M) kinetics. Physiological and kinetic parameters were obtained from literature and experiment. Systemic clearance, placental-fetal transport, and M-M uptake parameters were estimated by fitting model simulations to experimental data. The PBPK model is able to reproduce maternal and fetal iodide data over five orders of magnitude (0.36 to 33,000 ng/kg 131I-), ClO4- distribution over three orders of magnitude (0.01 to 10 mg/kg-day ClO4-) and inhibition of maternal thyroid and total fetal I- uptake. The model suggests a significant fetal ClO4- dose in late gestation (up to 82% of maternal dose). A comparison of model-predicted internal dosimetrics in the adult male, pregnant, and fetal rat indicates that the fetal thyroid is more sensitive to inhibition than that of the adult.

Assessment of dermal absorption and penetration of components of a fuel mixture (JP-8).

Occupational and environmental multi-chemical exposures are extremely common. Methods for assessment of the risks from dermal exposures to complex mixtures vary depending on the information available. The composition of a volatile mixture (such as JP-8 jet fuel) can change radically, depending on the phase of the mixture - vapor, liquid or aerosol. Assessing the absorption (into the skin) and penetration (through the skin) of components of the mixture can reduce uncertainty in the risk assessment process. Permeability coefficients of the 12 individual components that could be detected to penetrate the skin could be used to assess the toxicity of each individual component in the JP-8. The penetration of each of these components is related to and can be predicted from molecular weight and octanol water partition coefficients of that component. The composition of the components that penetrate the skin would be different from the composition of JP-8 because the permeability of the components differs by two orders of magnitude. Concentrations of the aliphatic chemicals found in the skin correlated well with carbon number. The JP-8 jet fuel is used as an example of how component data on absorption and penetration can be integrated into an assessment (McDougal et al., Toxicol Sci 2000; 55: 247-255). The component approach shows promise for estimating systemic toxicity of mixtures. Local toxicity (irritation, sensitization, etc.) may be better understood in the future when quantitative information becomes available about the duration and magnitude of chemical exposures required to cause local effects.