A consistent approach for the application of pharmacokinetic modeling in cancer and noncancer risk assessment.

Physiologically based pharmacokinetic modeling provides important capabilities for improving the reliability of the extrapolations across dose, species, and exposure route that are generally required in chemical risk assessment regardless of the toxic end point being considered. Recently, there has been an increasing focus on harmonization of the cancer and noncancer risk assessment approaches used by regulatory agencies. Although the specific details of applying pharmacokinetic modeling within these two paradigms may differ, it is possible to identify important elements common to both.

[Clinical and biochemical aspects of accidental poisoning with tetraethyl lead in a 2.5 year old patient--long term observation].

The paper describes an accidental, acute toxic exposure of a 2.5-year-old girl to tetraethyl lead. The authors discuss the clinical picture and treatment within the acute phase of intoxication as well as during the ambulatory follow-up of chronic sequelae of the exposure.

Comparative contents of dietary fiber, total phenolics, and minerals in persimmons and apples.

Dietary fibers, major phenolics, main minerals, and trace elements in persimmons and apples were analyzed and compared in order to choose a preferable fruit for an antiatherosclerotic diet. Fluorometry and atomic absorption spectrometry following microwave digestion were optimized for the determination of major phenolics and minerals. Total, soluble, and insoluble dietary fibers, total phenols, epicatechin, gallic and p-coumaric acids, and concentrations of Na, K, Mg, Ca, Fe, and Mn in whole persimmons, their pulps, and peels were significantly higher than in whole apples, pulps, and peels (P < 0.

Evaluating noncancer effects of trichloroethylene: dosimetry, mode of action, and risk assessment.

Alternatives for developing chronic exposure limits for noncancer effects of trichloroethylene (TCE) were evaluated. These alternatives were organized within a framework for dose-response assessment--exposure:dosimetry (pharmacokinetics):mode of action (pharmacodynamics): response. This framework provides a consistent structure within which to make scientific judgments about available information, its interpretation, and use.

Chlamydia pneumoniae activates nuclear factor kappaB and activator protein 1 in human vascular smooth muscle and induces cellular proliferation.

Background: Observational data strongly suggest an association between Chlamydia pneumoniae and atherosclerotic cardiovascular disease. However, few studies have mechanistically linked C. pneumoniae to vascular remodeling.

In vivo kinetics of trichloroacetate in male Fischer 344 rats.

Trichloroacetate (TCA) is a toxicologically important metabolite of the industrial solvents trichloroethylene and tetrachloroethylene, and a by-product of the chlorination of drinking water. Tissue disposition and elimination of 14C-TCA were investigated in male Fischer 344 rats injected iv with 6.1, 61, or 306 micromol TCA/kg body weight.

Family approach for estimating reference concentrations/doses for series of related organic chemicals.

The family approach for related compounds can be used to evaluate hazard and estimate reference concentrations/doses using internal dose metrics for a group (family) of metabolically related compounds. This approach is based upon a simple four-step framework for organizing and evaluating toxicity data: 1) exposure, 2) tissue dosimetry, 3) mode of action, and 4) response. Expansion of the traditional exposure-response analysis has been increasingly incorporated into regulatory guidance for chemical risk assessment.

Interleukin-1beta deficiency results in reduced NF-kappaB levels in pregnant mice.

Interleukin (IL)-1beta-deficient (IL-1beta(-/-)) mice were assessed for cytokine production during pregnancy. A significant reduction in nuclear factor (NF)-kappaB p65 protein content was observed in the uteri and spleens of pregnant IL-1beta(-/-) mice, as demonstrated by immunohistochemistry and Western immunoblot analysis. In addition, electromobility gel shift assay revealed less DNA binding activity of NF-kappaB p65-containing complex in pregnant IL-1beta(-/-) mice.

Inhibition of PARS attenuates endotoxin-induced dysfunction of pulmonary vasorelaxation.

Endotoxin (Etx) causes excessive activation of the nuclear repair enzyme poly(ADP-ribose) synthase (PARS), which depletes cellular energy stores and leads to vascular dysfunction. We hypothesized that PARS inhibition would attenuate injury to mechanisms of pulmonary vasorelaxation in acute lung injury. The purpose of this study was to determine the effect of in vivo PARS inhibition on Etx-induced dysfunction of pulmonary vasorelaxation.

Dichloroacetate (DCA) dosimetry: interpreting DCA-induced liver cancer dose response and the potential for DCA to contribute to trichloroethylene-induced liver cancer.

Pharmacokinetic studies with dichloroacetate (DCA) provide insights into the likelihood that trichloroethylene-induced liver cancers arise from formation of DCA as a metabolite and the mode of action by which DCA induces liver cancer. A simple physiologically based pharmacokinetic model was developed to analyze DCA blood concentration data from mice unexposed to or pre-treated with DCA. The large first pass metabolism of DCA in the liver is significantly reduced by DCA pretreatment.

Biological regulation of receptor-hormone complex concentrations in relation to dose-response assessments for endocrine-active compounds.

Some endocrine-active compounds (EACs) act as agonists or antagonists of specific hormones and may interfere with cellular control processes that regulate gene transcription. Many mechanisms controlling gene expression are universal to organisms ranging from unicellular bacteria to more complex plants and animals. One mechanism, coordinated control of batteries of gene products, is critical in adaptation of bacteria to new environments and for development and tissue differentiation in multi-cellular organisms.

Liposomal delivery of purified inhibitory-kappaBalpha inhibits tumor necrosis factor-alpha-induced human vascular smooth muscle proliferation.

Vessel injury results in the elaboration of various cytokines, including tumor necrosis factor-alpha (TNF-alpha), which may influence vascular smooth muscle cell (VSMC) function and contribute to atherogenesis. We tested the hypothesis that TNF-alpha-induced VSMC proliferation requires activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which could be prevented by delivery of the NF-kappaB inhibitory peptide, IkappaBalpha. TNF-alpha induced concentration-dependent human VSMC proliferation, and neutralizing antibody to interleukin-6 reduced TNF-alpha-induced VSMC proliferation by 65%.

Utilization of endoscopic inoculation in a mouse model of intrauterine infection-induced preterm birth: role of interleukin 1beta.

A novel murine model of intrauterine infection/inflammation-induced preterm birth based on direct endoscopic intracervical inoculation is described. Using this model, we investigated infection-induced premature pregnancy loss in normal and interleukin (IL) 1beta-deficient mice. Seventy-four CD-1, HS, C57BL/6J wild type (IL-1beta+/+), and C57BL/6J IL-1beta-deficient (IL-1beta-/-) mice were inoculated intracervically using a micro-endoscope, at a time corresponding to 70% of average gestation.

Dose-response characteristics of uterine responses in rats exposed to estrogen agonists.

Assays for uterine response have played major roles in developing an understanding of estrogen-mediated processes and for identifying compounds with hormonal activity. Data from assays measuring increases in uterine wet weight in rats were evaluated in terms of their dose-response characteristics. Analysis using a Hill equation found inconsistent estimates for the ED50 (concentration giving half-maximal response) and n (steepness of response) among the assays.

Interleukin-10 stabilizes inhibitory kappaB-alpha in human monocytes.

Interleukin-10 (IL-10) protects animals from lethal endotoxemia. This beneficial effect is mediated, in part, by inhibition of inflammatory cytokine production, including tumor necrosis factor-alpha (TNF-alpha). Evidence suggests that IL-10 may inhibit activation of the transcription factor nuclear factor-kappaB (NF-kappaB) through an unknown mechanism.

A model for pharmacokinetics and physiological feedback among hormones of the testicular-pituitary axis in adult male rats: a framework for evaluating effects of endocrine active compounds.

The testicular-hypothalamic-pituitary axis controls reproductive functions in males. A description of the basic physiological interactions in adult rats among testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) was developed, permitting simulation of hormone levels in testes and blood. This model was used to simulate hormone levels in intact, castrate, ethane dimethanesulfonate-treated, and antiandrogen-treated rats.

Interleukin 18 stimulates HIV type 1 in monocytic cells.

The cytokine interleukin (IL) 18 (formerly interferon gamma-inducing factor) induces the T helper type 1 response. In the present studies, IL-18 increased HIV type 1 (HIV-1) production from 5- to 30-fold in the chronically infected U1 monocytic cell line. Inhibition of tumor necrosis factor (TNF) activity by the addition of TNF-binding protein reduced IL-18-stimulated HIV-1 production by 48%.

Endocrine active compounds: from biology to dose response assessment.

Endocrine active compounds (EACs) alter signaling processes responsible for regulation and coordination of physiological functions during development and adulthood. The potential that adverse effects of these compounds have gone unrecognized has focused attention on their toxicology. The primary response to this concern has been development of additional hazard identification methods.

The limited role of myocardial fluorine-18 fluorodeoxyglucose imaging in candidates for cardiac transplantation: a planar imaging study.

This study compares the incidence and extent of hibernating myocardium (defined by myocardial perfusion/metabolism mismatch) in 28 cardiac transplant candidates with ischaemic cardiomyopathy and in 16 other patients with coronary artery disease (CAD) undergoing viability assessment. It then reviews the impact of myocardial perfusion metabolism imaging on management decisions in the transplant candidates at 6 months after scintigraphy. Each patient underwent a planar myocardial thallium-201 and fluorine-18 fluorodeoxyglucose scan on a modified gamma camera.

The use of biochemical and molecular parameters to estimate dose-response relationships at low levels of exposure.

Biomarkers based on alterations in molecular and biochemical parameters may be useful in chemical risk assessment for establishing the presence of an exposure, ranking relative risks among exposed individuals, and estimating risks at low levels of exposure. Because it is unlikely that the relation between toxic responses and the degree of alteration in the biomarker is equivalent at all doses, quantification of risks at low levels is not necessarily more accurate using these biomarkers for extrapolation. The application of response biomarkers for risk evaluation at low levels of exposure is discussed in relation to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a compound that causes induction of cytochromes CYP1A1 and CYP1A2 in liver and other tissues.

Trichloroethylene health risk assessment: a new and improved process.

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.

Pharmacodynamic model of the rat estrus cycle in relation to endocrine disruptors.

Several strains of laboratory rats have a high background incidence of mammary tumors and develop a persistent, anovulatory estrus condition at about 12 mo of age. The increased tumor incidence is believed to be associated with elevated estradiol (E2) and prolactin during the period of persistent estrus. A pharmacodynamic estrus cycle (PD-EC) model for the Sprague-Dawley rats has been developed in an attempt to analyze the physiological basis of early-onset persistent estrus and to examine the potential sites of interactions in the hypothalamic-pituitary-ovarian axis for endocrine-modulating xenobiotics that accelerate the onset of persistent estrus.

Isolation, characterization, and functional studies of rat liver iron regulatory protein 1.

Ferritin mRNAs are translationally regulated by the binding of either of two cytosolic proteins, iron regulatory protein 1 (IRP1) or IRP2, to the iron responsive element (IRE) located in their 5' untranslated region (UTR). Rat liver IRP1 was purified by anion exchange, gel filtration, and affinity chromatography using a concatemerized version of the IRE. Two bands with M(r) of 95,000 and 100,000 were observed by reducing SDS-PAGE.