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Partition coefficients (PCs) are used in physiologically based pharmacokinetic (PBPK) models to estimate the free concentration of a chemical in specific blood or organs. Biological PC(tissue:blood) (tissue to blood) values were determined for a series of nonvolatile herbicides, insecticides, and fungicides in liver, brain, skin, fat, kidneys, and muscle of male Sprague-Dawley rats using two different analytical methods. The free phase concentration (in phosphate-buffered saline) of a given chemical was measured in the presence and absence of tissue (including blood) and used to calculate the PC, defined as the ratio of the concentration of the chemical in saline to the concentration in the tissue. PCs were determined for 13 compounds with aqueous solubility ranging from 20 to 4100 mg/L, molecular weights from 187.3 to 342.2 g/mol, and log K (ow) values from -0.18 to 3.9. An ultrafiltration high-performance liquid chromatography (HPLC) method was implemented for compounds with log K (ow) near 0.1 or less and a negligible depletion solid-phase microextraction (nd-SPME) method for compounds with higher log K (ow). PC(tissue:saline) coefficients of variation were 0.13 (n = 3 compounds) on average for the HPLC method and 0.29 (n = 10 compounds) for the nd-SPME method. Presented here is one of the most comprehensive data sets of biological partition coefficients for herbicides, insecticides, and fungicides.

The pharmacokinetic behavior of the majority of jet fuel constituents has not been previously described in the framework of a physiologically based pharmacokinetic (PBPK) model for inhalation exposure. Toxic effects have been reported in multiple organ systems, though exposure methods varied across studies, utilizing either vaporized or aerosolized fuels. The purpose of this work was to assess the pharmacokinetics of aerosolized and vaporized fuels, and develop a PBPK model capable of describing both types of exposures. To support model development, n-tetradecane and n-octane exposures were conducted at 89 mg/m(3) aerosol+vapor and 1000-5000 ppm vapor, respectively. Exposures to JP-8 and S-8 were conducted at ~900-1000 mg/m(3), and ~200 mg/m(3) to a 50:50 blend of both fuels. Sub-models were developed to assess the behavior of representative constituents and grouped unquantified constituents, termed "lumps", accounting for the remaining fuel mass. The sub-models were combined into the first PBPK model for petroleum and synthetic jet fuels. Inhalation of hydrocarbon vapors was described with simple gas-exchange assumptions for uptake and exhalation. For aerosol droplets systemic uptake occurred in the thoracic region. Visceral tissues were described using perfusion and diffusion-limited equations. The model described kinetics at multiple fuel concentrations, utilizing a chemical "lumping" strategy to estimate parameters for fractions of speciated and unspeciated hydrocarbons and gauge metabolic interactions. The model more accurately simulated aromatic and lower molecular weight (MW) n-alkanes than some higher MW chemicals. Metabolic interactions were more pronounced at high (~2700-1000 mg/m(3)) concentrations. This research represents the most detailed assessment of fuel pharmacokinetics to date.

Toxicity and exposure evaluations remain the two of the key components of human health assessment. While improvement in exposure assessment relies on a better understanding of human behavior patterns, toxicity assessment still relies to a great extent on animal toxicity testing and human epidemiological studies. Recent advances in computer modeling of the dose-response relationship and distribution of xenobiotics in humans to important target tissues have advanced our abilities to assess toxicity. In particular, physiologically based pharmacokinetic (PBPK) models are among the tools than can enhance toxicity assessment accuracy. Many PBPK models are available to the health assessor, but most are so difficult to use that health assessors rarely use them. To encourage their use these models need to have transparent and user-friendly formats. To this end the Agency for Toxic Substances and Disease Registry (ATSDR) is using translational research to increase PBPK model accessibility, understandability, and use in the site-specific health assessment arena. The agency has initiated development of a human PBPK tool-kit for certain high priority pollutants. The tool kit comprises a series of suitable models. The models are recoded in a single computer simulation language and evaluated for use by health assessors. While not necessarily being state-of-the-art code for each chemical, the models will be sufficiently accurate to use for screening purposes. This article presents a generic, seven-compartment PBPK model for six priority volatile organic compounds (VOCs): benzene (BEN), carbon tetrachloride (CCl(4)), dichloromethane (DCM), perchloroethylene (PCE), trichloroethylene (TCE), and vinyl chloride (VC). Limited comparisons of the generic and original model predictions to published kinetic data were conducted. A goodness of fit was determined by calculating the means of the sum of the squared differences (MSSDs) for simulation vs. experimental kinetic data using the generic and original models. Using simplified solvent exposure assumptions for oral ingestion and inhalation, steady-state blood concentrations of each solvent were simulated for exposures equivalent to the ATSDR Minimal Risk Levels (MRLs). The predicted blood levels were then compared to those reported in the National Health and Nutrition Examination Survey (NHANES). With the notable exception of BEN, simulations of combined oral and inhalation MRLs using our generic VOC model yielded blood concentrations well above those reported for the 95th percentile blood concentrations for the U.S. populations, suggesting no health concerns. When the PBPK tool kit is fully developed, risk assessors will have a readily accessible tool for evaluating human exposure to a variety of environmental pollutants.

Jet Fuel 8 (JP-8) is a major fuel source used by US and NATO military. JP-8 is a complex mixture of aliphatic and aromatic isomers of hydrocarbons. Tissue/blood partition coefficient (PC) values are chemical-specific parameters used in modeling the kinetic behavior of chemicals. The partition coefficient values for n-alkanes tend to increase with the increasing carbon number, but less is known about the trend for isomers of n-alkanes. PC values were obtained for the n-alkane nonane (C9) and five of its isomers, namely 3-methyloctane, 4-ethylheptane, 2,3-dimethylheptane, 2,2,4-trimethylhexane, 2,2,4,4-tetramethylpentane. The blood:air and tissue:air PC values correlated with the published log octanol/water (O:W) PC values for n-nonane and its isomers. Experimentally determined blood:air and tissue:air PC values for n-nonane with the largest O:W value were greatest and smallest for the isomer 2,2,4,4-tetramethylpentane with the lowest O:W value. As expected the fat tissue had the highest PC values and muscle the lowest for n-nonane and its isomers. For each tissue, a linear relationship was observed between the tissue/blood PC values for the isomers of n-nonane and n-nonane. This suggests that tissue/blood PC values for all isomers of an alkane could be estimated using data collected from only a sub-set of alkanes of equal carbon number. These reported tissue/blood PC values will support the development of a jet fuel physiologically-based pharmacokinetic (PBPK) model.

Jet Propellant 8 (JP-8) is a kerosene-based jet fuel used in the military and is composed of hundreds of hydrocarbons. A PBPK model was developed to assess the metabolic interactions of JP-8 vapor on two prominent constituents of JP-8 vapor, m-xylene (XYL) and ethylbenzene (EBZ). A limited number of rats were exposed to JP-8 vapor in a Leach chamber for 4 h to 380, 1100, or 2700 mg/m3 (total hydrocarbon). Several individual hydrocarbons were monitored in the chamber atmosphere, including XYL, EBZ, and the total hydrocarbon concentration. Blood and liver were harvested and analyzed by a novel headspace SPME/GC-MS method that allowed for identification of individual hydrocarbons and low limits of detection. The PBPK model was able to describe the metabolic interactions between XYL, EBZ, and a lumped aromatic fraction of JP-8 vapor estimated to be 18 to 25% of the fuel vapor. Competitive inhibition of XYL and EBZ metabolism was observed for JP-8 vapor inhalation exposures of 1100 and 2700 mg/m3. Future inhalation studies with jet fuel include aerosol exposures and expansion of the PBPK models to include other hydrocarbons such as n-alkanes and upper respiratory tract dosimetry of aerosol droplets.

The primary aim of the Acute Exposure Guideline Level (AEGL) program is to develop scientifically credible limits for once-in-a-lifetime or rare acute inhalation exposures to high-priority, hazardous chemicals. The program was developed because of the need of communities for information on hazardous chemicals to assist in emergency planning, notification, and response, as well as the training of emergency response personnel. AEGLs are applicable to the general population, including children, the elderly, and other potentially susceptible subpopulations. AEGLs are the airborne concentrations of chemicals above which a person could experience notable discomfort or irritation (AEGL-1); serious, long-lasting health effects (AEGL-2); and life-threatening effects or death (AEGL-3). AEGLs are determined for five exposure periods (10 and 30 min and 1, 4, and 8 h). Physiologically based pharmacokinetic (PBPK) models can be very useful in the interspecies and time scaling often required here. PBPK models are used for the current article to predict AEGLs for trichlorethylene (TCE), based on the time course of TCE in the blood and/or brain of rats and humans. These AEGLs are compared to values obtained by standard time-scaling methods. Comprehensive toxicity assessment documents for each chemical under consideration are prepared by the National Advisory Committee for AEGLs, a panel comprised of representatives of federal, state, and local governmental agencies, as well as industry and private-sector organizations. The documents are developed according to National Research Council (NRC) guidelines and must be reviewed by the NRC Subcommittee on Acute Exposure Guideline Levels before becoming final. AEGLs for 18 chemicals have been published, and it is anticipated that 40 to 50 chemicals will be evaluated annually.

Dichloroacetic acid (DCA) is a small, polar compound that individuals are exposed to as a result of drinking water consumption. The occurrence of DCA in drinking water is of concern because DCA has been shown to cause cancer in laboratory animals. To date, no validated LC/MS/MS methods are available for quantitative analysis of DCA. In addition, most methods use a derivatizing reagent that can artificially inflate the levels of DCA. Presented in this paper, is a validated LC/MS/MS method for the analysis of DCA in drinking water. An amino column was used with ion‐exchange hydrophilic interaction chromatography (HILIC).

Decane, a 10-carbon n-alkane and one of the highest vapor phase constituents of jet propellent-8 (JP-8), was selected to represent the semivolatile fraction for the initial development of a physiologically based pharmacokinetic (PBPK) model for JP-8. Rats were exposed to decane vapors at time-weighted average concentrations of 1200, 781, or 273 ppm in a 32-L Leach chamber for 4 h. Time-course samples for 1200 ppm and end-of-exposure samples for 781 and 273 ppm decane exposures were collected from blood, brain, liver, fat, bone marrow, lung, skin, and spleen. The pharmacokinetics of decane could not be described by flow-limited assumptions and measured in vitro tissue/air partition coefficients. A refined PBPK model for decane was then developed using flow-limited (liver and lung) and diffusion-limited (brain, bone marrow, fat, skin, and spleen) equations to describe the uptake and clearance of decane in the blood and tissues. Partition coefficient values for blood/air and tissue/blood were estimated by fitting end-of-exposure pharmacokinetic data and assumed to reflect the available decane for rapid exchange with blood. A portion of decane is speculated to be sequestered in "deep" pools in the body, unavailable for rapid exchange with blood. PBPK model predictions were adequate in describing the tissues and blood kinetics. For model validation, the refined PBPK model for decane had mixed successes at predicting tissue and blood concentrations for lower concentrations of decane vapor, suggesting that further improvements in the model may be necessary to extrapolate to lower concentrations.

NASA and DoD use ammonium perchlorate (NH4ClO4) salt as an oxidizer in solid rocket propellants. Perchlorate salts are used in several applications such as flares, pyrotechnics, explosives, batteri...

Healthy male and female human volunteers were exposed to 50 ppm or 100 ppm trichloroethylene (Tri) by inhalation for 4 h. Blood and urine samples were taken at various times before, during, and after the exposure period for analysis of glutathione (GSH), related thiols and disulfides, and GSH-derived metabolites of Tri. The GSH conjugate of Tri, S-(1,2-dichlorovinyl)glutathione (DCVG), was found in the blood of all subjects from 30 min after the start of the 4-h exposure to Tri to 1 to 8 h after the end of the exposure period, depending on the dose of Tri and the sex of the subject. Male subjects exposed to 100 ppm Tri exhibited a maximal content of DCVG in the blood at 2 h after the start of the exposure of 46.1 +/- 14.2 nmol/ml (n = 8), whereas female subjects exposed to 100 ppm Tri exhibited a maximal content of DCVG in the blood at 4 h after the start of the exposure of only 13.4 /- 6.6 nmol/ml (n = 8). Pharmacokinetic analysis of blood DCVG concentrations showed that the area under the curve value was 3.4-fold greater in males than in females, while the t1/2 values for systemic clearance of DCVG were similar in the two sexes. Analysis of the distribution of individual values indicated a possible sorting, irrespective of gender, into a high- and a low-activity population, which suggests the possibility of a polymorphism. The mercapturates N-acetyl-1,2-DCVC and N-acetyl-2,2-DCVC were only observed in the urine of 1 male subject exposed to 100 ppm Tri. Higher contents of glutamate were generally found in the blood of females, but no marked differences between sexes were observed in contents of cyst(e)ine or GSH or in GSH redox status in the blood. Urinary GSH output exhibited a diurnal variation with no apparent sex- or Tri exposure-dependent differences. These results provide direct, in vivo evidence of GSH conjugation of Tri in humans exposed to Tri and demonstrate markedly higher amounts of DCVG formation in males, suggesting that their potential risk to Tri-induced renal toxicity may be greater than that of females.

In an effort to develop risk‐based Soil Screening Levels (SSLs) for Total Petroleum Hydrocarbons (TPH) in weathered soils, literature reviews were conducted to identify information regarding toxicology and previously developed oral risk factors for neat petroleum products and their potential surrogates, in particular, long chain petroleum hydrocarbons (LCPHs). Oral reference doses (RfDs) were identified in the literature for hexane; nonane; gasoline; JE‐4; JP‐5; marine diesel fuel; and mineral oil. Alternative RfDss are proposed for these previously developed oral RfDs and new oral RfDss were developed for other petroleum‐related chemicals where sufficient toxicological information was available. RfDss were developed for hexane; nonane; decane; C10 ‐ C11 isoparaffinic hydrocarbon; dearomatized white spirit C11 ‐ C12; gasoline; JP‐4; JP‐5; JP‐7; JP‐8; marine diesel fuel; mineral oil; and for petroleum wax. Then risk‐based SSLs were estimated for each of these compounds using the oral RfDs and the ...

Lactational transfer of chemicals to nursing infants is a concern for occupational physicians when women who are breast-feeding return to the workplace. Some work environments, such as paint shops, have atmospheric contamination from volatile organic chemicals (VOCs). Very little is known about the extent of exposure a nursing infant may receive from the mother's occupational exposure. A physiologically based pharmacokinetic model was developed for a lactating woman to estimate the amount of chemical that a nursing infant ingests for a given nursing schedule and maternal occupational exposure. Human blood/air and milk/air partition coefficients (PCs) were determined for 19 VOCs. Milk/blood PC values were above 3 for carbon tetrachloride, methylchloroform, perchloroethylene, and 1,4-dioxane, while the remaining 16 chemicals had milk/blood PC values of less than 3. Other model parameters, such as solid tissue PC values, metabolic rate constants, blood flow rates, and tissue volumes were taken from the literature and incorporated into the lactation model. In a simulated exposure of a lactating woman to a threshold limit value concentration of an individual chemical, only perchloroethylene, bromochloroethane, and 1,4-dioxane exceeded the U.S. Environmental Protection Agency non-cancer drinking water ingestion rates for children. Very little data exists on the pharmacokinetics of lactational transfer of volatile organics. More data are needed before the significance of the nursing exposure pathway can be adequately ascertained. Physiologically based pharmacokinetic models can play an important role in assessing lactational transfer of chemicals.

Trichloroethylene (TCE), an environmental contaminant of National concern, is the focus of a new health risk assessment process incorporating the Proposed Cancer Risk Assessment Guidelines. This paper describes not only how TCE became an environmental problem for the Air Force, but also details the new Risk Assessment process envisioned by the Environmental Protection Agency's (EPA) National Center for Environmental Assessment (NCEA). Insights on epidemiological evaluations, both past and future, and their impact on the cancer classification of TCE are discussed. Examples of how physiologically based pharmacokinetics and dose-response characterization described in the new Cancer Guidelines are applied to TCE are provided. In addition, a variety of modeling techniques are discussed for the development of reference doses (oral exposure) and reference concentrations (inhalation exposures) for TCE. Finally, the role of risk communication is included. This new process provides an example of how interagency (EPA, Department of Defense. Department of Energy) and extramural (industry, academia) partnerships can provide greater gains to the nation, as a whole, than any of the parts on their own.

A “rule-of-thumb” methodology is presented to assist in assessing risk to a nursing child due to the mother's occupational inhalation exposure. The method represents an example of the use of physiologically-based pharmacokinetic modeling using state-of-the-art computational techniques. A computer model is developed to describe distribution of nonmetabolized, inhaled contaminants into a mother/child system as a function of the contaminant's blood: air and octanol: water partition coefficients. Effective dose is calculated in terms of the area under the blood concentration vs. time curve of the exposure chemical. Since low partition values yield low risk for the nursing child and high values yield high risk, the model is exercised over a range of intermediate values (blood: air = [2, 25]; octanol: water = [100, 1500]). Results are thus applicable to chemicals for which the mother's dose is a strong factor in estimating the child's risk. The most notable observation is that, for the range of partiti...