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Bromochloromethane (BCM) is a volatile compound and a by-product of disinfection of water by chlorination. Physiologically based pharmacokinetic (PBPK) models are used in risk assessment applications. An updated PBPK model for BCM is generated and applied to hypotheses testing calibrated using vapor uptake data. The two different metabolic hypotheses examined are (1) a two-pathway model using both CYP2E1 and glutathione transferase enzymes and (2) a two-binding site model where metabolism can occur on one enzyme, CYP2E1. Our computer simulations show that both hypotheses describe the experimental data in a similar manner. The two pathway results were comparable to previously reported values (Vmax = 3.8mg/hour, Km = 0.35 mg/liter, and kGST = 4.7 /hour). The two binding site results were Vmax1 = 3.7mg/hour, Km1 = 0.3mg/hour, CL2 = 0.047 liter/hour. In addition, we explore the sensitivity of different parameters for each model using our obtained optimized values. [ABSTRACT FROM AUTHOR]

Carbon tetrachloride (CCl4) is a toxic chemical that was once used in degreasers and detergents, and some remnants of the chemical may be present in the water supply. Physiologically-based pharmacokinetic (PBPK) modeling can assist in understanding resulting internal doses of CCl4 after exposure, but the pharmacokinetic parameters describing the metabolism of CCl4 are not well characterized. The goal of this study was to provide insights into how to more accurately estimate these values in rats using PBPK modeling and data from previous studies. Three different PBPK models were constructed to describe CCl4 exposure in rats via inhalation, oral ingestion, and venous injection. Each of these models was compared to data, and sensitivity analysis was performed for each model to determine whether the available data could be used to accurately determine the metabolic parameters of interest. These parameter sensitivities were so low that optimization to the available data yielded physiologically unrealistic results. Model sensitivities were analyzed for different doses and routes of exposure in order to find experimental conditions that would allow for greater identifiability of the metabolic parameters. Data were simulated from these models at optimal conditions with varying levels of noise from a normal distribution. Optimizations were then performed to confirm that the original values could be obtained. The experiments developed are left as suggestions for investigators who wish to further pursue estimating these metabolic parameters. [ABSTRACT FROM AUTHOR]

Physiologically based pharmacokinetic (PBPK) models were developed in order to translate external concentrations into internal dose estimates, but most PBPK models were developed for younger adults. A set of physiological parameters for ages 65, 75, and 85 of both genders were developed and were used with previously established human PBPK models of exposure to toluene and perchloroethylene (PERC) in order to investigate internal dose changes with increasing age. The predicted compartmental concentrations of toluene and PERC for aged adults were lower than predicted concentrations for younger adults, and this suggests that body composition changes with aging do not increase internal doses of inhaled toxicants alone after acute exposure. Hence, susceptibility to either toxicant was not expected to increase solely based on the physiological changes associated with aging. Predictions for a metabolite of PERC, however, were similar in magnitude across ages, which may lead to enhanced susceptibility if metabolic capacity changes with aging. [ABSTRACT FROM AUTHOR]

Dermal uptake is an important and complex exposure route for a wide range of chemicals. Dermal exposure can occur due to occupational settings, pharmaceutical applications, environmental contamination, or consumer product use. The large range of both chemicals and scenarios of interest makes it difficult to perform generalizable experiments, creating a need for a generic model to simulate various scenarios. In this study, a model consisting of a series of four well-mixed compartments, representing the source solution (vehicle), stratum corneum, viable tissue, and receptor fluid, was developed for predicting dermal absorption. The model considers experimental conditions including small applied doses as well as evaporation of the vehicle and chemical. To evaluate the model assumptions, we compare model predictions for a set of 26 chemicals to finite dose in-vitro experiments from a single laboratory using steady-state permeability coefficient and equilibrium partition coefficient data derived from in-vitro experiments of infinite dose exposures to these same chemicals from a different laboratory. We find that the model accurately predicts, to within an order of magnitude, total absorption after 24 h for 19 of these chemicals. In combination with key information on experimental conditions, the model is generalizable and can advance efficient assessment of dermal exposure for chemical risk assessment., Competing Interests: Declaration of competing interest This manuscript is being submitted exclusively to Chemosphere and this research and the results have not been published previously, and if accepted this paper will not be published elsewhere. None of the authors have financial and personal relationships with other people or organizations that could inappropriately influence our work. All authors have approved this manuscript in its submitted version. The research and manuscript have been reviewed, cleared, and approved by U.S. Environmental Protection Agency. Daniel A. Vallero, Ph.D. Corresponding Author., (Published by Elsevier Ltd.)

Mosquito-borne disease presents a significant threat to urban populations, but risk can be uneven across a city due to underlying environmental patterns. Urban residents rely on social and economic processes to control the environment and mediate disease risk, a phenomenon known as everyday governance. We studied how households employed everyday governance of urban infrastructure relevant to mosquito-borne disease in Bengaluru, India to examine if and how inequalities in everyday governance manifest in differences in mosquito control. We found that governance mechanisms differed for water access and mosquitoes. Economic and social capital served different roles for each, influenced by global narratives of water and vector control., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Haber's rule as commonly interpreted in inhalation toxicology, can be stated as exposure concentration times duration equals a constant biological effect, or C x t=k. In other words, identical products of concentration and duration lead to the same effect. The goals of this paper are to develop a biological and pharmacokinetic modeling approach for chloroform, and to evaluate Haber's rule for different ages by taking into account the physiological changes due to growth and aging in rats. Three-dimensional dose-response surfaces for liver toxicity were generated for each age group of interest: adolescent, adult, and senescent rats. The three-dimensional surfaces were then characterized with a generalized description of Haber's rule for each age group. The simulations suggest that adolescent rats need higher exposure levels in order to achieve similar levels of liver damage compared to adults or senescent rats, if the comparison is made using the same exposure length. In summary, a pharmacokinetic modeling approach with a biological framework including the chemical's mode of action, was used to relate concentration, exposure duration and effect. Major advantages of this approach include: the potential ability to extrapolate to humans, the inclusion of aging in the simulations, and the ability to summarize the results using a generalized form of Haber's rule.

A kinetic model describing the hepatic methylation of arsenite [As(III)] was developed on the basis of limited data from in vitro mechanistic studies. The model structure is as follows: sequential enzymic methylation of arsenite to its monomethylated (MMA) and dimethylated (DMA) products by first-order and Michaelis-Menten kinetics, respectively; uncompetitive inhibition of the formation of DMA by As(III); and first-order reversible binding of As(III), MMA and DMA to cytosolic proteins. Numerical sensitivity analysis was used to evaluate systematically the impact of changes in input parameters on model responses. Sensitivity analysis was used to investigate the possibility of designing experiments for robust testing of the uncompetitive inhibition hypothesis, and for further refining the model. Based on the sensitivity analysis, the MMA concentration is the most important response on which to focus. The parameters V(max) and k(i) can be reliably estimated by using the same concentration time-course data at intermediate initial arsenite concentrations of 1--5microM at 30 +/- 5 minutes. K(m) must be estimated independently of V(max), since the two parameters are highly correlated at all times, and the optimal experimental conditions would include lower initial concentrations of arsenite (0.1--0.5microM) and earlier time-points (about 8--18 minutes). The use of initial arsenite concentrations much above 5microM would not yield additional useful information, because the sensitivity coefficients for MMA, protein-bound MMA, DMA and protein-bound DMA tend to become extremely small or exhibit erratic trends. Overall trends in the sensitivity analysis indicated the desirability of performing measurements at times shorter than 60 minutes. This work demonstrates that physiological modelling and sensitivity analysis can be efficient tools for experimental planning and hypothesis testing when applied in the earliest phases of kinetic model development, thus allowing more-efficient and more-directed experimentation, and minimising the use of laboratory animals.

The purpose of this study was to determine the effects of maturation and aging on cardiac output, the distribution of cardiac output, tissue blood flow (determined by using the radioactive-microsphere technique), and body composition in conscious juvenile (2-mo-old), adult (6-mo-old), and aged (24-mo-old) male Fischer-344 rats. Cardiac output was lower in juvenile rats (51 +/- 4 ml/min) than in adult (106 +/- 5 ml/min) or aged (119 +/- 10 ml/min) rats, but cardiac index was not different among groups. The proportion of cardiac output going to most tissues did not change with increasing age. However, the fraction of cardiac output to brain and spinal cord tissue and to skeletal muscle was greater in juvenile rats than that in the two adult groups. In addition, aged rats had a greater percent cardiac output to adipose tissue and a lower percent cardiac output to cutaneous and reproductive tissues than that in juvenile and adult rats. Differences in age also had little effect on mass-specific perfusion rates in most tissues. However, juvenile rats had lower flows to the pancreas, gastrointestinal tract, thyroid and parathyroid glands, and kidneys than did adult rats, and aged rats had lower flows to the white portion of rectus femoris muscle, spleen, thyroid and parathyroid glands, and prostate gland than did adult rats. Body mass of juvenile rats was composed of a lower percent adipose mass and a greater fraction of brain and spinal cord, heart, kidney, liver, and skeletal muscle than that of the adult and aged animals. Relative to the young adult rats, the body mass of aged animals had a greater percent adipose tissue mass and a lower percent skeletal muscle and skin mass. These data demonstrate that maturation and aging have a significant effect on the distribution of cardiac output but relatively little influence on mass-specific tissue perfusion rates in conscious rats. The old-age-related alterations in cardiac output distribution to adipose and cutaneous tissues appear to be associated with the increases in percent body fat and the decreases in the fraction of skin mass, respectively, whereas the decrease in the portion of cardiac output directed to reproductive tissue of aged rats appears to be related to a decrease in mass-specific blood flow to the prostate gland.

Linoleic acid hydroperoxide (LoaOOH) formed during free radical attack on long-chain unsaturated fatty acids is an important source of biomembrane damage and is implicated in the onset of atherosclerosis, hepatic diseases, and food rancidity. LoaOOH is toxic to wild-type Saccharomyces cerevisiae at a very low concentration (0.2 mM) relative to other peroxides. By using isogenic mutant strains, the possible roles of glutathione (gsh1 and gsh2), glutathione reductase (glr1), respiratory competence ([rho0] petite), and yAP-1p-mediated expression (yap1) in conferring LoaOOH resistance have been examined. Respiration-related processes were essential for maximal toxicity and adaptation, as evidenced by the fact that the [rho0] petite mutant was most resistant to LoaOOH but could not adapt. Furthermore, when respiration was blocked by using inhibitors of respiration and mutants defective in respiratory-chain components, cells became more resistant. An important role for reduced glutathione and yAP-1 in the cellular response to LoaOOH was shown, since the yap1 and glr1 mutants were more sensitive than the wild type. In addition, total glutathione peroxidase activity increased following treatment with LoaOOH, indicating a possible detoxification role for this enzyme. Yeast also showed an adaptive response when pretreated with a nonlethal dose of LoaOOH (0.05 mM) and subsequently treated with a lethal dose (0.2 mM), and de novo protein synthesis was required, since adaptation was abolished upon treatment of cells with cycloheximide (25 microg ml-1). The wild-type adaptive response to LoaOOH was independent of those for the superoxide-generating agents paraquat and menadione and also of those for the organic hydroperoxides cumene hydroperoxide and tert-butyl hydroperoxide. Pretreatment with LoaOOH induced resistance to hydrogen peroxide, while pretreatment of cells with malondialdehyde (a lipid peroxidation product) and heat shock (37 degrees C) gave cross-adaptation to LoaOOH, indicating that yeast has effective overlapping defense systems that can detoxify fatty acid hydroperoxides directly or indirectly.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic member of a class of planar and halogenated chemicals. Improvements in exposure assessment of TCDD require scientific information on the distribution of TCDD in target tissues and cellular responses induced by TCDD. Since 1980, several physiologically based pharmacokinetic (PBPK) models for TCDD and related compounds have been reported. Some of these models incorporated the induction of a hepatic binding protein in response to interactions of TCDD, the Ah receptor, and DNA binding sites and described the TCDD disposition in a biological system for certain data sets. Due to the limitations of the available experimental data, different values for the same physical parameters of these models were obtained from the different studies. The inconsistencies of the parameter values limit the application of PBPK models to risk assessment. Therefore, further refinement of previous models is necessary. This paper develops an improved PBPK model to describe TCDD disposition in eight target tissues. The interaction of TCDD with the Ah receptor and with hepatic inducible CYP1A2 were also incorporated into the model. This model accurately described the time course distribution of TCDD following a single oral dose of 10 microg/kg, as well as the TCDD concentration on Day 3 after six different doses, 0.01, 0.1, 0.3, 1, 10, and 30 microg TCDD/kg, in target tissues. This study extends previous TCDD models by illustrating the validity and the limitation of the model and providing further confirmation of the potential PBPK model for us in optimal experimental design and extrapolation across doses and routes of exposure. In addition, this study demonstrated some critical issues in PBPK modeling., (Copyright 1997 Academic Press.)

A single 6-hr exposure to inhaled methanol (MeOH) has been shown to enhance carbon tetrachloride (CCl4) hepatotoxicity. The objective of the present study was to use gas uptake data and the development of a physiologically based pharmacokinetic model (PBPK) to determine in vivo changes in CCl4 metabolism resulting from MeOH pretreatment. Adult male F344 rats (167-197 g) were exposed to 10,000 ppm MeOH (constant concentration) via inhalation for 6 hr. Individual rats were exposed using gas uptake techniques to CCl4 alone or to CCl4 either 24 or 48 hr after initiation of MeOH pretreatment. The following initial concentrations were used for CCl4: 0, 25, 100, 250, and 1000 ppm with exposures lasting 6 hr. Vmax (metabolic rate) was estimated from gas uptake data and Km (Michaelis constant) was assumed constant after methanol pretreatment. For CCl4 alone, Vmax was 0.11 mg/hr (Vmaxc = 0.37 mg/hr/kg) and Km was 1.3 mg/liter. Vmax was 0.48 mg/hr (Vmaxc = 1.6 mg/hr/kg) for the 24-hr MeOH + CCl4 group and Vmax was 0.18 mg/hr (Vmaxc = 0.6 mg/hr/kg) for the 48-hr MeOH + CCl4 group. For CCl4 alone, serum markers of hepatotoxicity alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) were increased significantly only at 1000 ppm CCl4. Both serum markers of hepatotoxicity in the 24-hr MeOH + CCl4 group increased as a function of CCl4 concentration when compared with 0 ppm CCl4 controls. The maximum increase occurred at 1000 ppm CCl4, where ALT and SDH increased by 392- and 286-fold, respectively. At 100, 250, and 1000 ppm CCl4, ALT and SDH values for the 24-hr MeOH + CCl4 groups were significantly increased relative to control (0 ppm CCl4), CCl4 alone, and 48-hr MeOH + CCl4. ALT and SDH levels in the 48-hr MeOH + CCl4 groups were not statistically different from the respective CCl4 alone groups.

Comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (3D-QSAR) paradigm, has been used to analyze the metabolic rates, as intrinsic clearance, of a series of chlorinated volatile organic compounds (VOCs). A comparison between 3D-QSAR and conventional Hansch-type QSAR is provided. To develop predictive 3D-QSARs for metabolism, the standard CoMFA model based on steric and electrostatic potential fields must be supplemented with hydropathic and molecular orbital information also in the form of three-dimensional fields. A mechanistic interpretation of chlorinated VOC metabolism by cytochrome P450 isozymes is provided as a rationalization for the inclusion of multiple fields in the CoMFA 3D-QSAR model. Models of this type have practical utility in the development of generalized physiologically-based pharmacokinetic models, as well as the rational, structure-based, design and/or selection of compounds for use in the in vivo and in vitro metabolic studies.

Physiologically based pharmacokinetic (PBPK) models developed from gas uptake experiments have been used to estimate metabolic parameters for volatile organic compounds. Due to the potential application of PBPK models to estimate metabolic bioactivation constants in humans, it is important to understand the complex nature of these models and the resulting estimates. Adult male F344 rats (165-205 g) were individually exposed to carbon tetrachloride (CCl4) in gas uptake systems. Three rats at each concentration were exposed for 6 hr to initial concentrations of 25, 100, 250, and 1000 ppm CCl4. Partition coefficient determinations were performed by the vial equilibration technique and used as model inputs. Computer optimizations with the means of each initial chamber concentration at each time point resulted in an estimate of Vmax of 0.11 mg/hr (Vmaxc = 0.37 mg/hr/kg) and Km of 1.3 mg/liter. To determine the effect of individual animal variation in Vmax, optimizations were also performed with the mean +/- SD, resulting in Vmax estimates of 0.09 and 0.12 mg/hr, respectively. Similar analysis resulted in Km estimates of 0.98 and 1.58 mg/liter. The results of the sensitivity analysis were concentration dependent for CCl4. These results show Vmax and Km to be most accurately detected at lower initial chamber concentrations. Results of the sensitivity analysis at the lowest concentration established the following model input hierarchy: blood to air partition > fat partition and fat volume fraction > slowly perfused partition, ventilation rate, cardiac output, fat blood flow percentage > liver blood flow percentage and slowly perfused blood flow percentage. Further sensitivity analysis determined Vmax and Km to be highly correlated when using gas uptake technology and point to the need to an independent estimate for either constant. In summary, the application of sensitivity analysis to PBPK modeling resulted in an increased understanding of factors governing the estimation of metabolic parameters.

In an artificially ventilated dog, the varying tracheal pressure causes a density fluctuation in the blood sampled from the aorta. We cross-correlated the tracheal pressure with the density to determine the time shift or delay of the latter from the former waveform for a ventilation frequency in the range of 6-30 CPM. The delay time was found to be 29% of the mean transit time (MTT) of the pulmonary vasculature and independent of the ventilation frequency. A comparison of this percentage with the reported arterial-to-capillary-to-venous fractional volumes of the lung suggested that the delay time may be the MTT time for blood flowing through the venous network of the lung and the cross-correlation may serve as an in vivo means to partition the MTT of the pulmonary vasculature at its capillaries. These results and an analysis on the deformation of the viscoelastic, pulmonary capillaries indicated that the tracheal pressure, acting primarily through the viscous part of the viscoelasticity, deforms the capillaries to produce the density fluctuation in blood outflowing from the lung.

We perfused the left lower lobe of a dog with autologous blood having a hematocrit Ha. When the vascular pressure perfusing the lobe was elevated, we observed a transient increase in the density of venous blood. Converting the density increase to a rise in hematocrit, we could calculate a volume (Vr) of red blood cells (RBC) over their normal outflow that was released by the lobe as a result of the elevation. We measured the weight gain of the lobe to determine the increase in pulmonary vascular volume, V' - V. We found that the ratio, Vr/Ha/(V' - V), is 0.11 +/- 0.02. To determine the implication of this ratio, we divided the lobular vasculature into an arterial, microvascular, and venous compartment. Due to the Fahraeus effect, the tube hematocrit in the microvascular compartment (Hc) is lower than that of two macrovascular compartments, Ha. An analysis on the balance of RBC and plasma flows through the lobe identified the volume Vr as (Vc' - Vc) (Ha - Hc) with Vc' - Vc being the volumetric increase of the lobular microvascular compartment. Based on the reported volumetric fractional change of microvascular compartment, we estimated that the microvascular (tube) hematocrit in pulmonary capillaries is 80% (ranging from 78 to 82%) of the hematocrit perfusing the lobe. Since the additional RBC volume (Vr) being released from the lobe cannot be accounted for by transcapillary filtration or capillary recruitment, we conclude from this analysis that the measurement of the transient density change in pulmonary outflow can be used to quantify the microvascular hematocrit of the lung.