Censoring Trace-Level Environmental Data: Statistical Analysis Considerations to Limit Bias.

Trace-level environmental data typically include values near or below detection and quantitation thresholds where health effects may result from low-concentration exposures to one chemical over time or to multiple chemicals. In a cook stove case study, bias in dibenzo[a,h]anthracene concentration means and standard deviations (SDs) was assessed following censoring at thresholds for selected analysis approaches: substituting threshold/2, maximum likelihood estimation, robust regression on order statistics, Kaplan-Meier, and omitting censored observations. Means and SDs for gas chromatography-mass spectrometry-determined concentrations were calculated after censoring at detection and calibration thresholds, 17% and 55% of the data, respectively. Threshold/2 substitution was the least biased. Measurement values were subsequently simulated from two log-normal distributions at two sample sizes. Means and SDs were calculated for 30%, 50%, and 80% censoring levels and compared to known distribution counterparts. Simulation results illustrated (1) threshold/2 substitution to be inferior to modern after-censoring statistical approaches and (2) all after-censoring approaches to be inferior to including all measurement data in analysis. Additionally, differences in stove-specific group means were tested for uncensored samples and after censoring. Group differences of means tests varied depending on censoring and distributional decisions. Investigators should guard against censoring-related bias from (explicit or implicit) distributional and analysis approach decisions.

Global optimization of the Michaelis-Menten parameters using physiologically-based pharmacokinetic (PBPK) modeling and chloroform vapor uptake data in F344 rats.

Objective: To quantify metabolism, a physiologically based pharmacokinetic (PBPK) model for a volatile compound can be calibrated with the closed chamber (i.e. vapor uptake) inhalation data. Here, we introduce global optimization as a novel component of the predictive process and use it to illustrate a procedure for metabolic parameter estimation.Materials and methods: Male F344 rats were exposed in vapor uptake chambers to initial concentrations of 100, 500, 1000, and 3000 ppm chloroform. Chamber time-course data from these experiments, in combination with optimization using a chemical-specific PBPK model, were used to estimate Michaelis-Menten metabolic constants. Matlab® simulation software was used to integrate the mass balance equations and to perform the global optimizations using MEIGO (MEtaheuristics for systems biology and bIoinformatics Global Optimization - Version 64 bit, R2016A), a toolbox written for Matlab®. The cost function used the chamber time-course data and least squares to minimize the difference between data and simulation values.Results and discussion: The final values estimated for Vmax (maximum metabolic rate) and Km (affinity constant) were 1.2 mg/h and a range between 0.0005 and 0.6 mg/L, respectively. Also, cost function plots were used to analyze the dose-dependent capacity to estimate Vmax and Km within the experimental range used. Sensitivity analysis was used to assess identifiability for both parameters and show these kinetic data may not be sufficient to identify Km.Conclusion: In summary, this work should help toxicologists interested in optimization techniques understand the overall process employed when calibrating metabolic parameters in a PBPK model with inhalation data.

Predictive Analysis Using Chemical-Gene Interaction Networks Consistent with Observed Endocrine Activity and Mutagenicity of U.S. Streams.

In a recent U.S. Geological Survey/U.S. Environmental Protection Agency study assessing more than 700 organic compounds in 38 streams, in vitro assays indicated generally low estrogen, androgen, and glucocorticoid receptor activities, with 13 surface waters with 17ß-estradiol-equivalent (E2Eq) activities greater than a 1-ng/L estimated effects-based trigger value for estrogenic effects in male fish. Among the 36 samples assayed for mutagenicity in the Salmonella bioassay (reported here), 25% had low mutagenic activity and 75% were not mutagenic. Endocrine and mutagenic activities of the water samples were well correlated with each other and with the total number and cumulative concentrations of detected chemical contaminants. To test the predictive utility of knowledge-base-leveraging approaches, site-specific predicted chemical-gene (pCGA) and predicted analogous pathway-linked (pPLA) association networks identified in the Comparative Toxicogenomics Database were compared with observed endocrine/mutagenic bioactivities. We evaluated pCGA/pPLA patterns among sites by cluster analysis and principal component analysis and grouped the pPLA into broad mode-of-action classes. Measured E2eq and mutagenic activities correlated well with predicted pathways. The pPLA analysis also revealed correlations with signaling, metabolic, and regulatory groups, suggesting that other effects pathways may be associated with chemical contaminants in these waters and indicating the need for broader bioassay coverage to assess potential adverse impacts.

Chlorination of Source Water Containing Iodinated X-ray Contrast Media: Mutagenicity and Identification of New Iodinated Disinfection Byproducts.

Iodinated contrast media (ICM) are nonmutagenic agents administered for X-ray imaging of soft tissues. ICM can reach µg/L levels in surface waters because they are administered in high doses, excreted largely unmetabolized, and poorly removed by wastewater treatment. Iodinated disinfection byproducts (I-DBPs) are highly genotoxic and have been reported in disinfected waters containing ICM. We assessed the mutagenicity in Salmonella of extracts of chlorinated source water containing one of four ICM (iopamidol, iopromide, iohexol, and diatrizoate). We quantified 21 regulated and nonregulated DBPs and 11 target I-DBPs and conducted a nontarget, comprehensive broad-screen identification of I-DBPs. We detected one new iodomethane (trichloroiodomethane), three new iodoacids (dichloroiodoacetic acid, chlorodiiodoacetic acid, bromochloroiodoacetic acid), and two new nitrogenous I-DBPs (iodoacetonitrile and chloroiodoacetonitrile). Their formation depended on the presence of iopamidol as the iodine source; identities were confirmed with authentic standards when available. This is the first identification in simulated drinking water of chloroiodoacetonitrile and iodoacetonitrile, the latter of which is highly cytotoxic and genotoxic in mammalian cells. Iopamidol (5 µM) altered the concentrations and relative distribution of several DBP classes, increasing total haloacetonitriles by >10-fold. Chlorination of ICM-containing source water increased I-DBP concentrations but not mutagenicity, indicating that such I-DBPs were either not mutagenic or at concentrations too low to affect mutagenicity.

Method to assess component contribution to toxicity of complex mixtures: Assessment of puberty acquisition in rats exposed to disinfection byproducts.

A method based on regression modeling was developed to discern the contribution of component chemicals to the toxicity of highly complex, environmentally realistic mixtures of disinfection byproducts (DBPs). Chemical disinfection of drinking water forms DBP mixtures. Because of concerns about possible reproductive and developmental toxicity, a whole mixture (WM) of DBPs produced by chlorination of a water concentrate was administered as drinking water to Sprague-Dawley (S-D) rats in a multigenerational study. Age of puberty acquisition, i.e., preputial separation (PPS) and vaginal opening (VO), was examined in male and female offspring, respectively. When compared to controls, a slight, but statistically significant delay in puberty acquisition was observed in females but not in males. WM-induced differences in the age at puberty acquisition were compared to those reported in S-D rats administered either a defined mixture (DM) of nine regulated DBPs or individual DBPs. Regression models were developed using individual animal data on age at PPS or VO from the DM study. Puberty acquisition data reported in the WM and individual DBP studies were then compared with the DM models. The delay in puberty acquisition observed in the WM-treated female rats could not be distinguished from delays predicted by the DM regression model, suggesting that the nine regulated DBPs in the DM might account for much of the delay observed in the WM. This method is applicable to mixtures of other types of chemicals and other endpoints.

Occurrence and Comparative Toxicity of Haloacetaldehyde Disinfection Byproducts in Drinking Water.

The introduction of drinking water disinfection greatly reduced waterborne diseases. However, the reaction between disinfectants and natural organic matter in the source water leads to an unintended consequence, the formation of drinking water disinfection byproducts (DBPs). The haloacetaldehydes (HALs) are the third largest group by weight of identified DBPs in drinking water. The primary objective of this study was to analyze the occurrence and comparative toxicity of the emerging HAL DBPs. A new HAL DBP, iodoacetaldehyde (IAL) was identified. This study provided the first systematic, quantitative comparison of HAL toxicity in Chinese hamster ovary cells. The rank order of HAL cytotoxicity is tribromoacetaldehyde (TBAL) ≈ chloroacetaldehyde (CAL) > dibromoacetaldehyde (DBAL) ≈ bromochloroacetaldehyde (BCAL) ≈ dibromochloroacetaldehyde (DBCAL) > IAL > bromoacetaldehyde (BAL) ≈ bromodichloroacetaldehyde (BDCAL) > dichloroacetaldehyde (DCAL) > trichloroacetaldehyde (TCAL). The HALs were highly cytotoxic compared to other DBP chemical classes. The rank order of HAL genotoxicity is DBAL > CAL ≈ DBCAL > TBAL ≈ BAL > BDCAL>BCAL ≈ DCAL>IAL. TCAL was not genotoxic. Because of their toxicity and abundance, further research is needed to investigate their mode of action to protect the public health and the environment.

Improving the risk assessment of lipophilic persistent environmental chemicals in breast milk.

Lipophilic persistent environmental chemicals (LPECs) have the potential to accumulate within a woman's body lipids over the course of many years prior to pregnancy, to partition into human milk, and to transfer to infants upon breastfeeding. As a result of this accumulation and partitioning, a breastfeeding infant's intake of these LPECs may be much greater than his/her mother's average daily exposure. Because the developmental period sets the stage for lifelong health, it is important to be able to accurately assess chemical exposures in early life. In many cases, current human health risk assessment methods do not account for differences between maternal and infant exposures to LPECs or for lifestage-specific effects of exposure to these chemicals. Because of their persistence and accumulation in body lipids and partitioning into breast milk, LPECs present unique challenges for each component of the human health risk assessment process, including hazard identification, dose-response assessment, and exposure assessment. Specific biological modeling approaches are available to support both dose-response and exposure assessment for lactational exposures to LPECs. Yet, lack of data limits the application of these approaches. The goal of this review is to outline the available approaches and to identify key issues that, if addressed, could improve efforts to apply these approaches to risk assessment of lactational exposure to these chemicals.

Integrated chemical and toxicological investigation of UV-chlorine/chloramine drinking water treatment.

As the use of alternative drinking water treatment increases, it is important to understand potential public health implications associated with these processes. The objective of this study was to evaluate the formation of disinfection byproducts (DBPs) and cytotoxicity of natural organic matter (NOM) concentrates treated with chlorine, chloramine, and medium pressure ultraviolet (UV) irradiation followed by chlorine or chloramine, with and without nitrate or iodide spiking. The use of concentrated NOM conserved volatile DBPs and allowed for direct analysis of the treated water. Treatment with UV prior to chlorine in ambient (unspiked) samples did not affect cytotoxicity as measured using an in vitro normal human colon cell (NCM460) assay, compared to chlorination alone when toxicity is expressed on the basis of dissolved organic carbon (DOC). Nitrate-spiked UV+chlorine treatment produced greater cytotoxicity than nitrate-spiked chlorine alone or ambient UV+chlorine samples, on both a DOC and total organic halogen basis. Samples treated with UV+chloramine were more cytotoxic than those treated with only chloramine using either dose metric. This study demonstrated the combination of cytotoxicity and DBP measurements for process evaluation in drinking water treatment. The results highlight the importance of dose metric when considering the relative toxicity of complex DBP mixtures formed under different disinfection scenarios.

Evaluation of the Interaction-Based Hazard Index Formula Using Data on Four Trihalomethanes from U.S. EPA's Multiple-Purpose Design Study.

The interaction-based hazard index (HIINT), a mixtures approach to characterizing toxicologic interactions, is demonstrated and evaluated by statistically analyzing data on four regulated trihalomethanes (THMs). These THMs were the subject of a multipurpose toxicology study specifically designed to evaluate the HIINT formula. This HIINT evaluation uses single, binary and quaternary mixture THM data. While this research is considered preliminary, the results provide insights on the application of HIINT when toxicology mixture data are available and on improvements to the method. The results for relative liver weight show the HIINT was generally not conservative but did adjust the additive hazard index (HI) in the correct direction, predicting greater than dose-additivity, as seen in the mixture data. For the liver serum enzyme endpoint alanine aminotransferase, the results were mixed, with some indices giving an estimated effective dose lower than the observed mixture effective dose and others higher; in general, the HIINT adjusted the HI in the correct direction, predicting less than dose-additivity. In addition, a methodological improvement was made in the calculation of maximum interaction magnitude. Suggested refinements to the HIINT included mixture-specific replacements for default parameter values and approaches for supplementing the usual qualitative discussions of uncertainty with numerical descriptions.

Evaluation of a Proportional Response Addition Approach to Mixture Risk Assessment and Predictive Toxicology Using Data on Four Trihalomethanes from the U.S. EPA's Multiple-Purpose Design Study.

In this study, proportional response addition (Prop-RA), a model for predicting response from chemical mixture exposure, is demonstrated and evaluated by statistically analyzing data on all possible binary combinations of the four regulated trihalomethanes (THMs). These THMs were the subject of a multipurpose toxicology study specifically designed to evaluate Prop-RA. The experimental design used a set of doses common to all components and mixtures, providing hepatotoxicity data on the four single THMs and the binary combinations. In Prop-RA, the contribution of each component to mixture toxicity is proportional to its fraction in the mixture based on its response at the total mixture dose. The primary analysis consisted of 160 evaluations. Statistically significant departures from the Prop-RA prediction were found for seven evaluations, with three predications that were greater than and four that were less than the predicted response; interaction magnitudes (n-fold difference in response vs. prediction) ranged from 1.3 to 1.4 for the former and 2.6 to 3.8 for the latter. These predictions support the idea that Prop-RA works best with chemicals where the effective dose ranges overlap. Prop-RA does not assume the similarity of toxic action or independence, but it can be applied to a mixture of components that affect the same organ/system, with perhaps unknown toxic modes of action.

Comprehensive assessment of a chlorinated drinking water concentrate in a rat multigenerational reproductive toxicity study.

Some epidemiological studies report associations between drinking water disinfection byproducts (DBPs) and adverse reproductive/developmental effects, e.g., low birth weight, spontaneous abortion, stillbirth, and birth defects. Using a multigenerational rat bioassay, we evaluated an environmentally relevant "whole" mixture of DBPs representative of chlorinated drinking water, including unidentified DBPs as well as realistic proportions of known DBPs at low-toxicity concentrations. Source water from a water utility was concentrated 136-fold, chlorinated, and provided as drinking water to Sprague-Dawley rats. Timed-pregnant females (P0 generation) were exposed during gestation and lactation. Weanlings (F1 generation) continued exposures and were bred to produce an F2 generation. Large sample sizes enhanced statistical power, particularly for pup weight and prenatal loss. No adverse effects were observed for pup weight, prenatal loss, pregnancy rate, gestation length, puberty onset in males, growth, estrous cycles, hormone levels, immunological end points, and most neurobehavioral end points. Significant, albeit slight, effects included delayed puberty for F1 females, reduced caput epidydimal sperm counts in F1 adult males, and increased incidences of thyroid follicular cell hypertrophy in adult females. These results highlight areas for future research, while the largely negative findings, particularly for pup weight and prenatal loss, are notable.

Developmental toxicity evaluations of whole mixtures of disinfection by-products using concentrated drinking water in rats: gestational and lactational effects of sulfate and sodium.

A developmental toxicity bioassay was used in three experiments to evaluate water concentrates for suitability in multigenerational studies. First, chlorinated water was concentrated 135-fold by reverse osmosis; select lost disinfection by-products were spiked back. Concentrate was provided as drinking water to Sprague-Dawley and F344 rats from gestation day 6 to postnatal day 6. Maternal serum levels of luteinizing hormone on gestation day 10 were unaffected by treatment for both strains. Treated dams had increased water consumption, and increased incidences of polyuria, diarrhea, and (in Sprague-Dawley rats) red perinasal staining. Pup weights were reduced. An increased incidence of eye defects was seen in F344 litters. Chemical analysis of the concentrate revealed high sodium (6.6 g/l) and sulfate (10.4 g/l) levels. To confirm that these chemicals caused polyuria and osmotic diarrhea, respectively, Na2SO4 (5-20 g/l) or NaCl (16.5 g/l) was provided to rats in drinking water. Water consumption was increased at 5- and 10-g Na2SO4/l and with NaCl. Pup weights were reduced at 20-g Na2SO4/l. Dose-related incidences and severity of polyuria and diarrhea occurred in Na2SO4-treated rats; perinasal staining was seen at 20 g/l. NaCl caused polyuria and perinasal staining, but not diarrhea. Subsequently, water was concentrated ∼120-fold and sulfate levels were reduced by barium hydroxide before chlorination, yielding lower sodium (≤1.5 g/l) and sulfate (≤2.1 g/l) levels. Treatment resulted in increased water consumption, but pup weight and survival were unaffected. There were no treatment-related clinical findings, indicating that mixtures produced by the second method are suitable for multigenerational testing.

Environmental exposure to metals and the development of tauopathies, synucleinopathies, and TDP-43 proteinopathies: A systematic evidence map protocol.

BACKGROUND: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are incurable and expected to increase in prevalence in the upcoming decades. Environmental exposure to metals has been suggested as a contributing factor to the development of neurodegenerative disease. This systematic evidence map will identify and characterize the epidemiological and experimental data available on the intersection of eighteen metals of environmental concern (i.e., aluminum, antimony, arsenic, barium, beryllium, cadmium, chromium, cobalt, copper, lead, manganese, mercury, nickel, palladium, radium, silver, vanadium, and zinc) and three neurodegenerative disease clusters (i.e., tauopathies, synucleinopathies, and TDP-43 proteinopathies). We aim to describe the type and amount of evidence available (or lack thereof) for each metal and neurodegenerative disease combination and highlight important knowledge gaps and knowledge clusters for future research. METHODS: We will conduct a thorough search using two databases (MEDLINE and Web of Science Core Collection) and grey literature resources. Pre-defined criteria have been developed to identify studies which evaluate at least one of the selected metals and neurodegenerative disease-relevant outcomes (e.g., neuropathology, cognitive function, motor function, disease mortality). At each phase of review, studies will be evaluated by two reviewers. Studies determined to be relevant will be extracted for population, exposure, and outcome information. We will conduct a narrative review of the included studies, and the extracted data will be available in a database hosted on Tableau Public. CONCLUSION: This protocol documents the decisions made a priori to data collection regarding these objectives.

Genomic comparisons between hepatocarcinogenic and non-hepatocarcinogenic organophosphate insecticides in the mouse liver.

Short-term biomarkers of toxicity have an increasingly important role in the screening and prioritization of new chemicals. In this study, we examined early indicators of liver toxicity for three reference organophosphate (OP) chemicals, which are among the most widely used insecticides in the world. The OP methidathion was previously shown to increase the incidence of liver toxicity, including hepatocellular tumors, in male mice. To provide insights into the adverse outcome pathway (AOP) that underlies these tumors, effects of methidathion in the male mouse liver were examined after 7 and 28 day exposures and compared to those of two other OPs that either do not increase (fenthion) or possibly suppress liver cancer (parathion) in mice. None of the chemicals caused increases in liver weight/body weight or histopathological changes in the liver. Parathion decreased liver cell proliferation after 7 and 28 days while the other chemicals had no effects. There was no evidence for hepatotoxicity in any of the treatment groups. Full-genome microarray analysis of the livers from the 7 and 28 day treatments demonstrated that methidathion and fenthion regulated a large number of overlapping genes, while parathion regulated a unique set of genes. Examination of cytochrome P450 enzyme activities and use of predictive gene expression biomarkers found no consistent evidence for activation of AhR, CAR, PXR, or PPARα. Parathion suppressed the male-specific gene expression pattern through STAT5b, similar to genetic and dietary conditions that decrease liver tumor incidence in mice. Overall, these findings indicate that methidathion causes liver cancer by a mechanism that does not involve common mechanisms of liver cancer induction.

Identification of developmentally toxic drinking water disinfection byproducts and evaluation of data relevant to mode of action.

Reactions between chemicals used to disinfect drinking water and compounds present in source waters produce chemical mixtures containing hundreds of disinfection byproducts (DBPs). Although the results have been somewhat inconsistent, some epidemiological studies suggest associations may exist between DBP exposures and adverse developmental outcomes. The potencies of individual DBPs in rodent and rabbit developmental bioassays suggest that no individual DBP can account for the relative risk estimates reported in the positive epidemiologic studies, leading to the hypothesis that these outcomes could result from the toxicity of DBP mixtures. As a first step in a mixtures risk assessment for DBP developmental effects, this paper identifies developmentally toxic DBPs and examines data relevant to the mode of action (MOA) for DBP developmental toxicity. We identified 24 developmentally toxic DBPs and four adverse developmental outcomes associated with human DBP exposures: spontaneous abortion, cardiovascular defects, neural tube defects, and low birth weight infancy. A plausible MOA, involving hormonal disruption of pregnancy, is delineated for spontaneous abortion, which some epidemiologic studies associate with total trihalomethane and bromodichloromethane exposures. The DBP data for the other three outcomes were inadequate to define key MOA steps.

Concentration, chlorination, and chemical analysis of drinking water for disinfection byproduct mixtures health effects research: U.S. EPA's Four Lab Study.

The U.S. Environmental Protection Agency's "Four Lab Study" involved participation of researchers from four national Laboratories and Centers of the Office of Research and Development along with collaborators from the water industry and academia. The study evaluated toxicological effects of complex disinfection byproduct (DBP) mixtures, with an emphasis on reproductive and developmental effects that have been associated with DBP exposures in some human epidemiologic studies. This paper describes a new procedure for producing chlorinated drinking water concentrate for animal toxicology experiments, comprehensive identification of >100 DBPs, and quantification of 75 priority and regulated DBPs. In the research reported herein, complex mixtures of DBPs were produced by concentrating a natural source water with reverse osmosis membranes, followed by addition of bromide and treatment with chlorine. By concentrating natural organic matter in the source water first and disinfecting with chlorine afterward, DBPs (including volatiles and semivolatiles) were formed and maintained in a water matrix suitable for animal studies. DBP levels in the chlorinated concentrate compared well to those from EPA's Information Collection Rule (ICR) and a nationwide study of priority unregulated DBPs when normalized by total organic carbon (TOC). DBPs were relatively stable over the course of the animal studies (125 days) with multiple chlorination events (every 5-14 days), and a significant portion of total organic halogen was accounted for through a comprehensive identification approach. DBPs quantified included regulated DBPs, priority unregulated DBPs, and additional DBPs targeted by the ICR. Many DBPs are reported for the first time, including previously undetected and unreported haloacids and haloamides. The new concentration procedure not only produced a concentrated drinking water suitable for animal experiments, but also provided a greater TOC concentration factor (136×), enhancing the detection of trace DBPs that are often below detection using conventional approaches.

Analysis of proportional data in reproductive and developmental toxicity studies: Comparison of sensitivities of logit transformation, arcsine square root transformation, and nonparametric analysis.

BACKGROUND: In developmental and reproductive toxicity studies, analysis of litter-based binary endpoints (e.g., incidence of malformed fetuses) is complex in that littermates often are not entirely independent of one another. It is well established that the litter, not the individual fetus, is the proper independent experimental unit in statistical analysis. Accordingly, analysis is often based on the proportion affected per litter and the litter proportions are analyzed as continuous data. Because these proportional data generally do not meet assumptions of symmetry or normality, data are typically analyzed by nonparametric methods, arcsine square root transformation, or logit transformation. METHODS: We conducted power calculations to compare different approaches (nonparametric, arcsine square root-transformed, logit-transformed, untransformed) for analyzing litter-based proportional data. A reproductive toxicity study with a control and one treated group provided data for two endpoints: prenatal loss, and fertility by in utero insemination (IUI). Type 1 error and power were estimated by 10,000 simulations based on two-sample one-tailed t tests with varying numbers of litters per group. To further compare the different approaches, we conducted additional analyses with shifted mean proportions to produce illustrative scenarios. RESULTS: Analyses based on logit-transformed proportions had greater power than those based on untransformed or arcsine square root-transformed proportions, or nonparametric procedures. CONCLUSION: The logit transformation is preferred to the other approaches considered when making inferences concerning litter-based proportional endpoints, particularly with skewed distributions. The improved performance of the logit transformation becomes increasingly pronounced as the response proportions are increasingly close to the boundaries of the parameter space.

Development of an inhalation physiologically based pharmacokinetic (PBPK) model for 2,2, 4-trimethylpentane (TMP) in male Long-Evans rats using gas uptake experiments.

2,2,4-Trimethylpentane (TMP) is a volatile colorless liquid used primarily to increase the octane rating of combustible fuels. TMP is released in the environment through the manufacture, use, and disposal of products associated with the gasoline and petroleum industry. Short-term inhalation exposure to TMP (< 4 h; > 1000 ppm) caused sensory and motor irritations in rats and mice. Like many volatile hydrocarbons, acute exposure to TMP may also be expected to alter neurological functions. To estimate in vivo metabolic kinetics of TMP and to predict its target tissue dosimetry during inhalation exposures, a physiologically based pharmacokinetic (PBPK) model was developed for the chemical in Long-Evans male rats using closed-chamber gas-uptake experiments. Gas-uptake experiments were conducted in which rats (80-90 days old) were exposed to targeted initial TMP concentrations of 50, 100, 500, and 1000 ppm. The model consisted of compartments for the closed uptake chamber, lung, fat, kidney, liver, brain, and rapidly and slowly perfused tissues. Physiological parameters were obtained from literature. Partition coefficients for the model were experimentally determined for air/blood, fat, liver, kidney, muscle, and brain using vial equilibration methods. Common to other hydrocarbons, metabolism of TMP via oxidative reactions is assumed to mainly occur in the liver. The PBPK model simulations of the closed chamber data were used to estimate in vivo metabolic parameters for TMP in male Long-Evans rats.

Per- and polyfluoroalkyl substances in source and treated drinking waters of the United States.

Contaminants of emerging concern (CECs), including per- and polyfluoroalkyl substances (PFAS), are of interest to regulators, water treatment utilities, the general public and scientists. This study measured 17 PFAS in source and treated water from 25 drinking water treatment plants (DWTPs) as part of a broader study of CECs in drinking water across the United States. PFAS were quantitatively detected in all 50 samples, with summed concentrations of the 17 PFAS ranging from <1 ng/L to 1102 ng/L. The median total PFAS concentration was 21.4 ng/L in the source water and 19.5 ng/L in the treated drinking water. Comparing the total PFAS concentration in source and treated water at each location, only five locations demonstrated statistically significant differences (i.e. P < 0.05) between the source and treated water. When the perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) concentrations in the treated drinking water are compared to the existing US Environmental Protection Agency's PFOA and PFOS drinking water heath advisory of 70 ng/L for each chemical or their sum one DWTP exceeded the threshold. Six of the 25 DWTPs were along two large rivers. The DWTPs within each of the river systems had specific PFAS profiles, with the three DWTPs from one river being dominated by PFOA, while three DWTPs on the second river were dominated by perfluorobutyric acid (PFBA).