Comparison of in vivo derived and scaled in vitro metabolic rate constants for several volatile organic compounds (VOCs).

Metabolic rate parameters estimation using in vitro data is necessary due to numbers of chemicals for which data are needed, trend towards minimizing laboratory animal use, and limited opportunity to collect data in human subjects. We evaluated how well metabolic rate parameters derived from in vitro data predict overall in vivo metabolism for a set of environmental chemicals for which well validated and established methods exist. We compared values of VmaxC derived from in vivo vapor uptake studies with estimates of VmaxC scaled up from in vitro hepatic microsomal metabolism studies for VOCs for which data were available in male F344 rats.

The Impact of Scaling Factor Variability on Risk-Relevant Pharmacokinetic Outcomes in Children: A Case Study Using Bromodichloromethane (BDCM).

Biotransformation rates extrapolated from in vitro data are used increasingly in human physiologically based pharmacokinetic (PBPK) models. This practice requires use of scaling factors, including microsomal content (mg of microsomal protein/g liver, MPPGL), enzyme specific content, and liver mass as a fraction of body weight (FVL). Previous analyses indicated that scaling factor variability impacts pharmacokinetic (PK) outcomes used in adult population dose-response studies.

The impact of variation in scaling factors on the estimation of internal dose metrics: a case study using bromodichloromethane (BDCM).

A rate for hepatic metabolism (V) determined in vitro must be scaled for in vivo use in a physiologically based pharmacokinetic (PBPK) model. This requires the use of scaling factors such as mg of microsomal protein per gram of liver (MPPGL) and liver mass (FVL). Variation in MPPGL and FVL impacts variation in V, and hence PBPK model-derived estimates of internal dose used in dose response analysis.

Development of a human physiologically based pharmacokinetic (PBPK) model for dermal permeability for lindane.

Lindane is a neurotoxicant used for the treatment of lice and scabies present on human skin. Due to its pharmaceutical application, an extensive pharmacokinetic database exists in humans. Mathematical diffusion models allow for calculation of lindane skin permeability coefficients using human kinetic data obtained from in vitro and in vivo experimentation as well as a default compound-specific calculation based on physicochemical characteristics used in the absence of kinetic data.

Development and application of a human PBPK model for bromodichloromethane to investigate the impacts of multi-route exposure.

As a result of its presence in water as a volatile disinfection byproduct, bromodichloromethane (BDCM), which is mutagenic, poses a potential health risk from exposure via oral, dermal and inhalation routes. We developed a refined human physiologically based pharmacokinetic (PBPK) model for BDCM (including new chemical-specific human parameters) to evaluate the impact of BDCM exposure during showering and bathing on important measures of internal dose compared with oral exposure. The refined model adequately predicted data from the published literature for oral, dermal and bathing/showering exposures.

Estimating Potential Increased Bladder Cancer Risk Due to Increased Bromide Concentrations in Sources of Disinfected Drinking Waters.

Public water systems are increasingly facing higher bromide levels in their source waters from anthropogenic contamination through coal-fired power plants, conventional oil and gas extraction, textile mills, and hydraulic fracturing. Climate change is likely to exacerbate this in coming years. We estimate bladder cancer risk from potential increased bromide levels in source waters of disinfecting public drinking water systems in the United States.

Improving in vitro to in vivo extrapolation by incorporating toxicokinetic measurements: a case study of lindane-induced neurotoxicity.

Approaches for extrapolating in vitro toxicity testing results for prediction of human in vivo outcomes are needed. The purpose of this case study was to employ in vitro toxicokinetics and PBPK modeling to perform in vitro to in vivo extrapolation (IVIVE) of lindane neurotoxicity. Lindane cell and media concentrations in vitro, together with in vitro concentration-response data for lindane effects on neuronal network firing rates, were compared to in vivo data and model simulations as an exercise in extrapolation for chemical-induced neurotoxicity in rodents and humans.

Comparison of trihalomethanes in tap water and blood: a case study in the United States.

Background: Epidemiological studies have used various measures to characterize trihalomethane (THM) exposures, but the relationship of these indicators to exposure biomarkers remains unclear.

Objectives: We examined temporal and spatial variability in baseline blood THM concentrations and assessed the relationship between these concentrations and several exposure indicators (tap water concentration, water-use activities, multiroute exposure metrics).

Methods: We measured water-use activity and THM concentrations in blood and residential tap water from 150 postpartum women from three U.

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.

Integrated disinfection by-products research: salmonella mutagenicity of water concentrates disinfected by chlorination and ozonation/postchlorination.

Although chemical disinfection of drinking water is a highly protective public health practice, the disinfection process is known to produce toxic contaminants. Epidemiological studies associate chlorinated drinking water with quantitatively increased risks of rectal, kidney, and bladder cancer. One study found a significant exposure-response association between water mutagenicity and relative risk for bladder and kidney cancer.

Disposition of bromodichloromethane in humans following oral and dermal exposure.

Exposure to bromodichloromethane (BDCM), one of the most prevalent disinfection byproducts in drinking water, can occur via ingestion of water and by dermal absorption and inhalation during activities such as bathing and showering. The objectives of this research were to assess BDCM pharmacokinetics in human volunteers exposed percutaneously and orally to (13)C-BDCM and to evaluate factors that could affect disposition of BDCM. Among study subjects, CYP2E1 activity varied fourfold; 20% had the glutathione S-transferase theta 1-1 homozygous null genotype; and body fat ranged from 7 to 22%.

In vitro biotransformation and genotoxicity of the drinking water disinfection byproduct bromodichloromethane: DNA binding mediated by glutathione transferase theta 1-1.

The drinking water disinfection byproduct bromodichloromethane (CHBrCl(2)) was previously shown to be mutagenic in Salmonella typhimurium that overexpress rat glutathione transferase theta 1-1 (GSTT1-1). Several experimental approaches were undertaken in this study to investigate the DNA covalent binding potential of reactive intermediates generated by GSTT1-1-mediated metabolism of CHBrCl(2). First, rodent hepatic cytosol incubations containing [(14)C]CHBrCl(2), supplemented glutathione (GSH), and calf thymus DNA resulted in approximately 3-fold (rat liver cytosol) and 7-fold (mouse liver cytosol) greater amounts of total radioactivity (RAD) associated with the purified DNA as compared to a control (absence of rodent cytosol) following liquid scintillation counting (LSC) of isolated DNA.

Analysis of in vivo and in vitro DNA strand breaks from trihalomethane exposure.

BACKGROUND: Epidemiological studies have linked the consumption of chlorinated surface waters to an increased risk of two major causes of human mortality, colorectal and bladder cancer. Trihalomethanes (THMs) are by-products formed when chlorine is used to disinfect drinking water. The purpose of this study was to examine the ability of the THMs, trichloromethane (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and tribromomethane (TBM), to induce DNA strand breaks (SB) in (1) CCRF-CEM human lymphoblastic leukemia cells, (2) primary rat hepatocytes (PRH) exposed in vitro, and (3) rats exposed by gavage or drinking water.

Bromodichloromethane inhibits human placental trophoblast differentiation.

Epidemiological data suggest an association between exposures to bromodichloromethane (BDCM), a trihalomethane found in drinking water as a result of drinking water disinfection, and an increased risk of spontaneous abortion. We previously hypothesized that BDCM targets the placenta and showed that the secretion of chorionic gonadotrophin (CG) was reduced in primary cultures of human term syncytiotrophoblasts exposed to BDCM. In the present study we extend this observation by evaluating the effects of BDCM on the morphological differentiation of mononucleated cytotrophoblast cells to multinucleated syncytiotrophoblast-like colonies.

Effect of bromodichloromethane on chorionic gonadotrophin secretion by human placental trophoblast cultures.

Bromodichloromethane (BDCM) is a trihalomethane found in drinking water as a by-product of disinfection processes. BDCM is hepatotoxic and nephrotoxic in rodents and has been reported to cause strain-specific full-litter resorption in F344 rats during the luteinizing hormone-dependent phase of pregnancy. In humans, epidemiological studies suggest an association between exposure to BDCM in drinking water and increased risk of spontaneous abortion.

[35S]-labeling of the Salmonella typhimurium glutathione pool to assess glutathione-mediated DNA binding by 1,2-dibromoethane.

Biotransformation of drugs and environmental chemicals to reactive intermediates is often studied with the use of radiolabeled compounds that are synthesized by expensive and technically difficult procedures. In general, glutathione (GSH) conjugation serves as a detoxification mechanism, and conjugation of reactive intermediates with GSH is often a surrogate marker of reactive species formation. However, several halogenated alkanes can be bioactivated by GSH to yield highly reactive GSH conjugates, some of which are DNA-reactive (e.

Induction of DNA strand breaks by trihalomethanes in primary human lung epithelial cells.

Trihalomethanes (THMs) are disinfection by-products and suspected human carcinogens present in chlorinated drinking water. Previous studies have shown that many THMs induce sister chromatid exchanges and DNA strand breaks in human peripheral blood lymphocytes in vitro. Exposure to THMs occurs through oral, dermal, or inhalation routes, with the lung being a target of exposure by the latter route, although not a target for rodent carcinogenicity.

Glutathione transferase theta 1-1-dependent metabolism of the water disinfection byproduct bromodichloromethane.

Bromodichloromethane (CHBrCl(2)), a prevalent drinking water disinfection byproduct, was previously shown to be mutagenic in Salmonella that express rat GSH transferase (GST) theta 1-1 (GST T1-1). In the present study, in vitro experiments were performed to study the kinetics of CHBrCl(2) reactions mediated by GST in different species as well as the isoform specificity and reaction products of the GST pathway. Conjugation activity of CHBrCl(2) with GSH in mouse liver cytosol was time- and protein-dependent, was not inhibited by the GST alpha, mu and pi inhibitor S-hexyl-GSH, and correlated with GST T1-1 activity toward the substrate 1,2-epoxy-3-(4'-nitrophenoxy)propane.

Evidence for the involvement of CYP1A2 in the metabolism of bromodichloromethane in rat liver.

Bromodichloromethane (BDCM) is a drinking water disinfectant by-product that has been implicated in liver, kidney and intestinal cancers in rodents and in intestinal tumors and low birth weight effects in humans. BDCM is also hepatotoxic and requires metabolic activation for both toxicity and carcinogenicity. We have recently reported that CYP1A2 may participate in that metabolism and we now report experiments to support that implication.

Assessing exposure in epidemiologic studies to disinfection by-products in drinking water: report from an international workshop.

The inability to accurately assess exposure has been one of the major shortcomings of epidemiologic studies of disinfection by-products (DBPs) in drinking water. A number of contributing factors include a) limited information on the identity, occurrence, toxicity, and pharmacokinetics of the many DBPs that can be formed from chlorine, chloramine, ozone, and chlorine dioxide disinfection; b) the complex chemical interrelationships between DBPs and other parameters within a municipal water distribution system; and c) difficulties obtaining accurate and reliable information on personal activity and water consumption patterns. In May 2000, an international workshop was held to bring together various disciplines to develop better approaches for measuring DBP exposure for epidemiologic studies.