Trifluoroiodomethane (CF3I) (2019).

Trifluoroiodomethane (CF3I) is a colorless and odorless gas used primarily as a fire suppressant. CF3I has low acute inhalation toxicity. The no-observed adverse effect level (NOAEL) of CF3I for cardiac sensitization in dogs was 2000 ppm. The potential effects of 4-week inhalation exposure in both rats and mice have been examined. In rats, the NOAEL was 10,000 ppm, and in mice, the NOAEL was 10,000 ppm. In a subchronic inhalation study in rats, the lowest observed adverse effect level (LOAEL) was 20,000 ppm for thyroid-related effects; the study NOAEL (for non-thyroid-related effects) was 20,000 ppm. In a reproductive/developmental inhalation toxicity study in rats, 20,000 ppm CF3I produced minimal general toxicity and no indication of reproductive or developmental toxicity. The LOAEL for parental toxicity (based on thyroid hormone effects) was 2000 ppm; excluding thyroid effects, the parental NOAEL was 7000 ppm CF3I. The observed effects on the thyroid in rats were considered of less relevance to human risk assessment than the other observed systemic effects because of known species-specific differences in sensitivity to thyroid hormone perturbations. There are no chronic toxicity or carcinogenicity studies available. CF3I had mixed results in various in vitro and in vivo genotoxicity assays. The NOAEL of 7000 ppm from the reproductive/developmental inhalation study was used as the point of departure (POD) for workplace environmental exposure level (WEEL) value development. This POD was adjusted to account for interindividual variability, duration of exposure, and database limitations. The resulting 8-h time-weighted average WEEL value of 500 ppm is expected to provide a significant margin of safety against any potential adverse health effects in workers exposed to CF3I. A 15-min short-term exposure limit of 1500 ppm was also established to protect workers from potential cardiac effects produced by acute, high-dose inhalation of CF3I.

Distribution of Organohalogen and Synthetic Musk Compounds in Breast Adipose Tissue of Breast Cancer Patients in Ulster County, New York, USA.

We determined the concentrations of 98 halogenated organic compounds and synthetic musks in breast fat tissues of 50 breast cancer patients (age range: 34-77 years) collected during 1996-1998 in Ulster County, New York, USA. Polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated biphenyl 153 (PBB-153), polybrominated diphenyl ethers (PBDEs), and synthetic musk compounds (SMCs) were analyzed in breast fat tissues, and 46 analytes were found at a detection frequency of ≥ 65% and at concentrations in the decreasing order of OCPs > PCBs > SMCs > PBDEs > PBB-153. PCBs (median: 323 ng/g wet wt) and dichlorodiphenyltrichloroethanes (DDTs, median: 293 ng/g wet wt) were the major compounds found in breast fat tissues. Among PCB congeners, hexa- and hepta-chlorobiphenyls (60% of total PCBs) were the abundant ones. p,p'-DDE accounted for more than 99% of the total DDT concentrations. The concentrations of SMCs and PBDEs were 1-2 orders of magnitude lower than those of PCBs and DDTs. 1,3,4,6,7,8-Hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-r-2-benzopyran (median: 33 ng/g wet wt) was the most abundant SMC, whereas BDE-47 (median: 4.5 ng/g wet wt) was the most dominant PBDE congener present in breast tissues. A significant correlation (p < 0.05) between women's age and concentrations of DDTs, chlordanes, hexachlorobenzene and PCBs in breast tissues was found. Concentrations of PCBs, PBDEs, OCPs, and SMCs were not significantly different between malignant and benign tumor cases. This study adds baseline information on target tissue burdens of persistent organic contaminants in breast cancer patients.

Characterization of Brain-Penetrant Pyrimidine-Containing Molecules with Differential Microtubule-Stabilizing Activities Developed as Potential Therapeutic Agents for Alzheimer's Disease and Related Tauopathies.

The microtubule (MT)-stabilizing protein tau disengages from MTs and forms intracellular inclusions known as neurofibrillary tangles in Alzheimer's disease and related tauopathies. Reduced tau binding to MTs in tauopathies may contribute to neuronal dysfunction through decreased MT stabilization and disrupted axonal transport. Thus, the introduction of brain-penetrant MT-stabilizing compounds might normalize MT dynamics and axonal deficits in these disorders. We previously described a number of phenylpyrimidines and triazolopyrimidines (TPDs) that induce tubulin post-translational modifications indicative of MT stabilization. We now further characterize the biologic properties of these small molecules, and our results reveal that these compounds can be divided into two general classes based on the cellular response they evoke. One group composed of the phenylpyrimidines and several TPD examples showed a bell-shaped concentration-response effect on markers of MT stabilization in cellular assays. Moreover, these compounds induced proteasome-dependent degradation of α- and ß-tubulin and caused altered MT morphology in both dividing cells and neuron cultures. In contrast, a second group comprising a subset of TPD molecules (TPD+) increased markers of stable MTs in a concentration-dependent manner in dividing cells and in neurons without affecting total tubulin levels or disrupting MT architecture. Moreover, an example TPD+ compound was shown to increase MTs in a neuron culture model with induced tau hyperphosphorylation and associated MT deficits. Several TPD+ compounds were shown to be both brain penetrant and orally bioavailable, and a TPD+ example increased MT stabilization in the mouse brain, making these compounds potential candidate therapeutics for neurodegenerative tauopathies such as Alzheimer's disease.

Bioaccumulation of highly hydrophobic organohalogen flame retardants from sediments: application of toxicokinetics and passive sampling techniques.

Highly hydrophobic organohalogen flame retardants (HHOFRs) are found ubiquitously in the environment; therefore, a better understanding of their bioavailability is needed. In the current study, bioaccumulation testing using the oligochaete, Lumbriculus variegatus, and passive sampling (solid-phase microextraction (SPME)) were performed to study the bioaccumulation potential of HHOFRs, including decabromodiphenyl ether (deca-BDE), decabromodiphenyl ethane (DBDPE), and dechlorane plus (DP), in laboratory-spiked and field-collected sediments. The HHOFRs were bioavailable to L. variegatus even though their biota-sediment accumulation factors were low (0.016 ± 0.002 to 0.48 ± 0.082 g organic carbon/g lipid, syn-DP > anti-DP > deca-BDE > DBDPE). Hydrophobicity and stereoisomerism affected HHOFR bioavailability. Meanwhile, HHOFR concentrations on the SPME fibers (Cf) correlated with those in biota (Cb), suggesting the potential application of SPME in bioavailability prediction for those compounds. The log Cf to log Cb correlation for deca-BDE and DP had a greater intercept than that for polychlorinated biphenyls (data obtained from the literature) although the slopes were similar, while data for DBDPE fell on the regression line for PCBs, implying some uncertainty in application of SPMEs across chemical classes. The increasing sorptive ability of proteins for HHOFRs in comparison to the less-brominated BDEs suggested that protein-binding should be considered when estimating bioaccumulation potential of HHOFRs in benthic invertebrates.

Molecular biomarker-based biokinetic modeling of a PCE-dechlorinating and methanogenic mixed culture.

Bioremediation of chlorinated ethenes via anaerobic reductive dechlorination relies upon the activity of specific microbial populations--most notably Dehalococcoides (DHC) strains. In the lab and field Dehalococcoides grow most robustly in mixed communities which usually contain both fermenters and methanogens. Recently, researchers have been developing quantitative molecular biomarkers to aid in field site diagnostics and it is hoped that these biomarkers could aid in the modeling of anaerobic reductive dechlorination. A comprehensive biokinetic model of a community containing Dehalococcoides mccartyi (formerly D. ethenogenes) was updated to describe continuously fed reactors with specific biomass levels based on quantitative PCR (qPCR)-based population data (DNA and RNA). The model was calibrated and validated with subsets of chemical and molecular biological data from various continuous feed experiments (n = 24) with different loading rates of the electron acceptor (1.5 to 482 µeeq/L-h), types of electron acceptor (PCE, TCE, cis-DCE) and electron donor to electron acceptor ratios. The resulting model predicted the sum of dechlorination products vinyl chloride (VC) and ethene (ETH) well. However, VC alone was under-predicted and ETH was over predicted. Consequently, competitive inhibition among chlorinated ethenes was examined and then added to the model. Additionally, as 16S rRNA gene copy numbers did not provide accurate model fits in all cases, we examined whether an improved fit could be obtained if mRNA levels for key functional enzymes could be used to infer respiration rates. The resulting empirically derived mRNA "adjustment factors" were added to the model for both DHC and the main methanogen in the culture (a Methanosaeta species) to provide a more nuanced prediction of activity. Results of this study suggest that at higher feeding rates competitive inhibition is important and mRNA provides a more accurate indicator of a population's instantaneous activity than 16S rRNA gene copies alone as biomass estimates.

Associations between complex OHC mixtures and thyroid and cortisol hormone levels in East Greenland polar bears.

The multivariate relationship between hair cortisol, whole blood thyroid hormones, and the complex mixtures of organohalogen contaminant (OHC) levels measured in subcutaneous adipose of 23 East Greenland polar bears (eight males and 15 females, all sampled between the years 1999 and 2001) was analyzed using projection to latent structure (PLS) regression modeling. In the resulting PLS model, most important variables with a negative influence on cortisol levels were particularly BDE-99, but also CB-180, -201, BDE-153, and CB-170/190. The most important variables with a positive influence on cortisol were CB-66/95, α-HCH, TT3, as well as heptachlor epoxide, dieldrin, BDE-47, p,p'-DDD. Although statistical modeling does not necessarily fully explain biological cause-effect relationships, relationships indicate that (1) the hypothalamic-pituitary-adrenal (HPA) axis in East Greenland polar bears is likely to be affected by OHC-contaminants and (2) the association between OHCs and cortisol may be linked with the hypothalamus-pituitary-thyroid (HPT) axis.

A kinetic model for human blood concentrations of gaseous halocarbon fire-extinguishing agents.

A simple kinetic model for calculating the blood concentration history of humans exposed to time-varying concentrations of gaseous, halocarbon fire-extinguishing agents is described. The kinetic model was developed to extend experimental physiologically based pharmacokinetic (PBPK) models for arterial blood concentration of halocarbons, obtained from constant concentration exposure of dogs to time-varying exposure conditions for humans. In the present work, the simplified kinetic model was calibrated using published PBPK-derived arterial concentration histories for constant concentration exposure to several common fire-extinguishing agents. The calibrated kinetic model was then used to predict the blood concentration histories of humans exposed to time-varying concentrations of these fire-extinguishing agents in ventilated compartments and the results were compared with PBPK-derived data for the agents. It was found that the properly calibrated kinetic model predicts human arterial blood concentration histories for time-varying exposures as well as the PBPK models. Consequently, the kinetic model represents an economical methodology for calculating safe human exposure limits for time-varying concentrations of gaseous halocarbon fire-extinguishing agents when only PBPK-derived human arterial blood concentration histories for constant exposure conditions are available.

Contaminant pattern and bioaccumulation of legacy and emerging organhalogen pollutants in the aquatic biota from an e-waste recycling region in South China.

Legacy pollutants, polychlorinated biphenyls (PCBs), dichlorodiphenyl trichloroethane and its metabolites (DDTs), and some emerging organhalogen pollutants, such as polybrominated diphenyl ethers (PBDEs), hexabromobenzene (HBB), pentabromotoluene (PBT), 2,3,4,5,6-pentabromoethyl benzene (PBEB), 1,2-bis (2,4,6-tribromophenoxy) ethane (BTBPE), and dechlorane plus (DP), were detected in an aquatic food chain (invertebrates and fish) from an e-waste recycling region in South China. Polychlorinated biphenyls, DDTs, PBDEs, and HBB were detected in more than 90% of the samples, with respective concentrations ranging from not detected (ND)-32,000 ng/g lipid weight, ND-850 ng/g lipid weight, 8 to 1,300 ng/g lipid weight, and 0.28 to 240 ng/g lipid weight. Pentabromotoluene, PBEB, BTBPE, and DP were also quantifiable in collected samples with a concentration range of ND-40 ng/g lipid weight. The elevated levels of PCBs and PBDEs in the organisms, compared with those in non-e-waste regions in South China, suggest that these two kinds of pollutants derived mainly from e-waste recycling practices. Hexabromobenzene was significantly correlated with PBDEs, implying that HBB come from the release of e-waste along with PBDEs and/or the pyrolysis of BDE209. Most of the compounds whose trophic magnification factor (TMF) could be calculated were found to biomagnify (TMF > 1). Hexabromobenzene was also found, for the first time, to biomagnify in the present food web, with a TMF of 2.1.

Pharmacokinetics and Tolerability of LC28-0126, a Novel Necrosis Inhibitor, After Multiple Ascending Doses: A Phase I Randomized, Double-blind, Placebo-controlled Study in Healthy Male Subjects.

PURPOSE: LC28-0126 is a reactive oxygen species scavenger being developed for the treatment of various conditions caused by oxidative stress, such as oral mucositis, graft-versus-host disease, and lethal reperfusion injury in acute myocardial infarction. The aim of this study was to assess the tolerability and pharmacokinetic properties of LC28-0126 with multiple IV administrations in healthy male subjects. METHODS: A dose-block-randomized, double-blind, placebo-controlled, multiple ascending-dose study was conducted. Subjects received 3-, 10-, 20-, or 30-mg doses of LC28-0126 or inactive control vehicle, infused over 30 min, once daily for 7 days. Blood and urine samples were collected for pharmacokinetics assessment. Tolerability was assessed by the documentation of adverse events, including abnormal findings on physical examination, vital sign measurements, blood oxygen saturation monitoring, 12-lead ECG, continuous ECG monitoring, and clinical laboratory testing. FINDINGS: A total of 32 subjects completed the study. After multiple dosing, the plasma concentration of LC28-0126 showed a steep decrease after infusion, followed by slow elimination. Systemic exposure of LC28-0126 was increased proportionally to doses ranging from 3 to 30 mg. The accumulation ratios were 2.58-2.79 on multiple dosing. The fractions excreted unchanged in urine were found to be <5%. All reported drug-related adverse events were injection-site reactions, and no serious adverse events were reported. IMPLICATIONS: Multiple administrations of LC28-0126 exhibited a dose-proportional pharmacokinetic profile and were well tolerated at a dose range of 3-30 mg. ClinicalTrials.gov identifier: NCT03196804.

Haloacetonitriles: metabolism and toxicity.

The haloacetonitriles (HANs) exist in drinking water exclusively as byproducts of disinfection. HANs are found in drinking water more often, and in higher concentrations, when surface water is treated by chloramination. Human exposure occurs through consumption of finished drinking water; oral and dermal contact also occurs, and results from showering, swimming and other activities. HANs are reactive and are toxic to gastrointestinal tissues following oral administration. Such toxicity is characterized by GSH depletion, increased lipid peroxidation, and covalent binding of HAN-associated radioactivity to gut tissues. The presence of GSH in cells is an important protective mechanism against HAN toxicity; depletion of cellular GSH results in increased toxicity. Some studies have demonstrated an apparently synergistic effect between ROS and HAN administration, that may help explain effects observed in GI tissues. ROS are produced in gut tissues, and in vitro evidence indicates that ROS may contribute to the degradation and formation of reactive intermediates from HANs. The rationale for ROS involvement may involve HAN-induced depletion of GSH and the role of GSH in scavenging ROS. In addition to effects on GI tissues, studies show that HAN-derived radiolabel is found covalently bound to proteins and DNA in several organs and tissues. The addition of antioxidants to biologic systems protects against HAN-induced DNA damage. The protection offered by antioxidants supports the role of oxidative stress and the potential for a threshold in han-induced toxicity. However, additional data are needed to substantiate evidence for such a threshold. HANs are readily absorbed from the GI tract and are extensively metabolized. Elimination occurs primarily in urine, as unconjugated one-carbon metabolites. Evidence supports the involvement of mixed function oxidases, the cytochrome P450 enzyme family and GST, in HAN metabolism. Metabolism represents either a detoxification or bioactivation process, depending on the particular HAN and the enzyme involved. HANs can inhibit CYP2E1-mediated metabolism, an effect which may be dependent on a covalent interaction with the enzyme. In addition, HAN compounds inhibit GST-mediated conjugation, but this effect is reversible upon dialysis, indicating that the interaction does not represent covalent binding. No subchronic studies of HAN toxicity are available in the literature. However, studies show that HANs produce developmental toxicity in experimental animals. The nature of developmental toxicity is affected by the type of administration vehicle, which renders interpretation of results more difficult. Skin tumors have been found following dermal application of HANs, but oral studies for carcinogenicity are negative. Pulmonary adenomas were increased following oral administration of HANs, but the A/J strain of mice employed has a characteristically high background rate of such tumors. HANs interact with DNA to produce unscheduled DNA repair, SCE and reverse mutations in Salmonella. HANs did not induce micronuclei or cause alterations in sperm head morphology in mice, but did induce micronuclei in newts. Thus, there is concern for the potential carcinogenicity of HANs. It would be valuable to delineate any relationship between the apparent threshold for micronuclei formation in newts and the potential mechanism of toxicity involving HAN-induced oxidative stress. Dose-response studies in rodents may provide useful information on toxicity mechanisms and dose selection for longer term toxicity studies. Additional studies are warranted before drawing firm conclusions on the hazards of HAN exposure. Moreover, additional studies on HAN-DNA and HAN-protein interaction mechanisms, are needed. Such studies can better characterize the role of metabolism in toxicity of individual HANs, and delineate the role of oxidative stress, both of which enhance the capacity to predict risk. Most needed, now, are new subchronic (and chronic) toxicity studies; the results of such well-planned, controlled, conducted, interpreted and published investigations would be valuable in establishing margins of safety for HANs in human health risk assessment.

Studies on the pharmacokinetics and metabolism of a gamma-secretase inhibitor BMS-299897, and exploratory investigation of CYP enzyme induction.

BMS-299897 is a gamma-secretase inhibitor that was effective in reducing amyloid beta-peptide (A beta) in transgenic mice and guinea pigs. Therefore, pharmacokinetic and drug metabolism studies were conducted in animals to support its clinical development. The compound appeared to have low to intermediate total body clearance and was orally bioavailable (24-100%). The oral absorption of BMS-299897 from solid dosage forms appeared to be dissolution rate-limited. BMS-299897 was distributed into extravascular space (V(ss) >or= 1.3 l kg(-1)), including brain (brain-to-plasma ratio = 0.13-0.50). BMS-299897 appeared to be a P-glycoprotein (P-gp) substrate as the brain-to-plasma ratio was two-fold higher in the mdr1a knockout mouse as compared with the wild-type. Apparent autoinduction by BMS-299897 was observed in murine and rat efficacy and toxicity studies. In vitro, BMS-299897 was a weaker inducer of cytochrome P450 3A4 (CYP3A4) and a weaker transactivator of human pregnane X receptor (hPXR) as compared with rifampicin. Induction of human UGT1A and UGT2B was evaluated in primary human hepatocytes, but the results were inconclusive. A low potential for autoinduction in humans was predicted at a clinical dose of 250 mg and the prediction was consistent with the findings from a clinical multiple-dose study with BMS-299897 in probable Alzheimer's patients.

Cevipabulin (TTI-237): preclinical and clinical results for a novel antimicrotubule agent.

Antimitotic agents are among the most effective drugs for the treatment of solid tumors and metastatic cancer. These drugs promote cell death by interfering with the crucial structural and regulatory function of microtubules in cells. Most of the agents of clinical relevance are natural products or semisynthetic derivatives thereof, and they fall into two major classes: microtubule stabilizers such as the taxanes, which enhance tubulin polymerization, and microtubule destabilizers such as the Vinca alkaloids, which lead to the depolymerization of existing microtubules. While these drugs are effective in inhibiting the progression of certain types of tumors, their utility is limited in part by incomplete tumor responses and/or significant side effects. In addition, inherent resistance is encountered in many tumor types, or acquired resistance may occur as a result of multiple cycles of therapy. Cevipabulin (TTI-237) is a novel, small synthetic molecule with an unusual biological mode of action. It appears to bind at the vinca site, but exhibits some properties similar to those of taxane-site ligands, such as enhancing tubulin polymerization. The compound works against a variety of tumors, including those resistant to paclitaxel and vincristine. Furthermore, cevipabulin is stable and water-soluble, and can be administered i.v. or p.o. in saline. It can be synthesized in bulk quantities efficiently. Based on these properties, cevipabulin was selected for clinical development.

Organohalogen contaminants in striped dolphins (Stenella coeruleoalba) from Japan: present contamination status, body distribution and temporal trends (1978-2003).

Organohalogen contaminants including PCBs, DDTs, CHLs, HCHs, HCB, PBDEs and HBCDs were determined in striped dolphins (Stenella coeruleoalba) found stranded at Gogo-shima (n=6, 2003) and collected from Taiji (n=15, 1978-1992) in Japan. All target compounds were significantly detected in all the specimens, indicating ubiquitous contamination of oceanic cetaceans in northwest Pacific Ocean. Examination of body distribution of organohalogens in the six specimens from Gogo-shima showed no significant difference in concentrations among the analyzed tissues, except for brain, which had lower levels possibly due to the existence of blood-brain barrier. For evaluating temporal trends, archived blubber samples of adult male stripped dolphins collected in 1978, 1979, 1986 and 1992 were analyzed. Concentrations of PCBs, DDTs and HCHs did not change significantly during 1978-2003. In contrast, remarkable increasing trends of PBDEs and HBCDs were observed, suggesting growing consumption in Japan and surrounding countries in recent years.

Persistent organohalogen contaminant burdens in Antarctic krill (Euphausia superba) from the eastern Antarctic sector: a baseline study.

A baseline for persistent organohalogen compound (POC) accumulation in the Antarctic keystone species, Antarctic krill (Euphausia superba) has been established for a 50 degrees longitudinal range of the eastern Antarctic sector. Samples of adult krill, caught from 12 sites distributed between 30 degrees and 80 degrees E (60-70 degrees S), were analysed for >100 organohalogen compounds including chlorinated pesticides, polychlorinated biphenyls (PCBs), polybrominated organic compounds and polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs). Organochlorine pesticides dominated measured krill contaminant burdens with hexachlorobenzene (HCB) as the single most abundant compound quantified. Krill HCB concentrations were comparable to those detected at this trophic level in both the Arctic and temperate northwest Atlantic, lending support for the hypothesis that HCB will approach global equilibrium at a faster rate than other POCs. Para, para'-dichlorodiphenylethene (p,p'-DDE) was detected at notable concentrations. Measurements of DDT and its degradation products provide an important baseline for monitoring the temporal and geographical influence of renewed, DDT usage for malaria-control in affected southern hemisphere countries. In contrast to the Arctic, PCBs did not feature prominently in contaminant burdens of Antarctic krill. The major commercial polybrominated diphenyl ether (PBDE) congeners -99 and -47 were quantified at low background levels with clear concentration spikes observed at around 70 degrees E , in the vicinity of modern, active research stations. The likelihood that local anthropogenic activities are supplementing low PBDE levels, delivered otherwise primarily via long range environmental transport, is discussed. The suspected naturally occurring brominated organic compound, 2,4,6-tribromoanisole (TBA), was a ubiquitous contaminant in all samples whereas the only PCDD/Fs quantifiable were trace levels of octachlorodibenzo-p-dioxin (OCDD) and 1,2,3,4,7,8/1,2,3,4,7,9-hexachlorodibenzofuran (HxCDF). With the aims of; i) Generating a robust and broadly applicable POC auditing platform for the scarcely studied eastern Antarctic sector; ii) Determining the compounds accumulating in Antarctic krill for further toxicity evaluation studies and iii) Establishing a baseline for Antarctic predator exposure to POCs, this study represents one of the most comprehensive reports of POC contamination of the Antarctic food web to date.

First in vivo evaluation of a potential SPECT brain radiotracer for the gonadotropin releasing hormone receptor.

OBJECTIVES: In vivo evaluations of a gonadotropin releasing hormone-receptor single photon emission computed tomography radiotracer for non-invasive detection of gonadotropin releasing homone-receptors in brain. RESULTS: We have used a simple, robust and high-yielding procedure to radiolabel an alpha-halogenated bioactive compound with high radiochemical yield. Literature findings showed similar alpha-halogenated compounds suitable for in vivo evaluations. The compound was found to possess nano molar affinity for the gonadotropin releasing hormone-receptor in a competition dependent inhibition study. Furthermore, liquid chromatography-mass spectrometry analysis in saline, human and rat serum resulted in 46%, 52% and 44% stability after incubation for 1 h respectively. In addition, rat brain single photon emission computed tomography and biodistribution studies gave further insight into the nature of the compound as a radiotracer.

Incorporation of acute dynamic ventilation changes into a standardized physiologically based pharmacokinetic model.

A seven-compartment physiologically based pharmacokinetic (PBPK) model incorporating a dynamic ventilation response has been developed to predict normalized internal dose from inhalation exposure to a large range of volatile gases. The model uses a common set of physiologic parameters, including standardized ventilation rates and cardiac outputs for rat and human. This standardized model is validated against experimentally measured blood and tissue concentrations for 21 gases. For each of these gases, body-mass-normalized critical internal dose (blood concentration) is established, as calculated using exposure concentration and time duration specified by the lowest observed adverse effect level (LOAEL) or the acute exposure guideline level (AEGL). The dynamic ventilation changes are obtained by combining the standardized PBPK model with the Toxic Gas Assessment Software 2.0 (TGAS-2), a validated acute ventilation response model. The combined TGAS-2P model provides a coupled, transient ventilation and pharmacokinetic response that predicts body mass normalized internal dose that is correlated with deleterious outcomes. The importance of ventilation in pharmacokinetics is illustrated in a simulation of the introduction of Halon 1301 into an environment of fire gases.

Kinetic assessment of persistent halogenated xenobiotics in cell culture models: comparison of mono- and poly-halogenated compounds.

We evaluated the suitability of single and multiple cell type cultures as model systems to characterise cellular kinetics of highly lipophilic compounds with potential ecotoxicological impact. Confluent mono-layers of human skin fibroblasts, rat astrocytoma C6 cells, non-differentiated and differentiated mouse 3T3 cells were kept in culture medium supplemented with 10% foetal calf serum. For competitive uptake experiments up to four different cell types, grown on glass sectors, were exposed for 3h to (14)C-labelled model compounds, dissolved either in organic solvents or incorporated into unilamellar lecithin liposomes. Bromo-, or chloro-benzenes, decabromodiphenylether (DBP), and dichlorodiphenyl ethylene (DDE) were tested in rather high concentration of 20 microM. Cellular toxicity was low. Compound levels were related to protein, DNA, and triglyceride contents. Cellular uptake was fast and dependent on physico-chemical properties of the compounds (lipophilicity, molecular size), formulation, and cell type. Mono-halogenated benzenes showed low and similar uptake levels (=low accumulation compounds). DBP and DDE showed much higher cellular accumulations (=high accumulation compounds) except for DBP in 3T3 cells. Uptake from liposomal formulations was mostly higher than if compounds were dissolved in organic solvents. The extent of uptake correlated with the cellular content of triglycerides, except for DBP. Uptake competition between different cell types was studied in a sectorial multi-cell culture model. For low accumulation compounds negligible differences were found among C6 cells and fibroblasts. Uptake of DDE was slightly and that of DBP highly increased in fibroblasts. Well-defined cell culture systems, especially the sectorial model, are appropriate to screen for bioaccumulation and cytotoxicity of (unknown) chemical entities in vitro.

Absorption of decabromodiphenyl ether and other organohalogen chemicals by grey seals (Halichoerus grypus).

An input-output balance study was performed for polybrominated diphenyl ethers, polychlorinated biphenyls and some organochlorine pesticides on three captive, juvenile grey seals (Halichoerus grypus). The animals were fed a diet of herring for six months, during the last three months of which this study was performed. A supplement of decabromodiphenyl ether was included in the diet during the second month of the study. Consistently high absorption (>89%) was observed for all of the chemicals studied, whereas work on other animals has generally shown high (>80%) net absorption at log K(OW) < approximately 6, dropping towards higher log K(OW), and very low absorption of decabromodiphenyl ether. The half-life of decabromodiphenyl ether in blood was estimated to be between 8.5 and 13 days. Measurable concentrations of decabromodiphenyl ether were detected in seal blubber at the end of the study, indicating that this chemical can be stored in adipose and may bioaccumulate. Current understanding of the mechanism of absorption of organohalogen chemicals and the potential for accumulation of decabromodiphenyl ether will need reassessing in the light of these results.

Gonadal transcriptome analysis of wild contaminated female European eels during artificial gonad maturation.

Since the early 1980s, the population of European eels (Anguilla anguilla) has dramatically declined. Nowadays, the European eel is listed on the red list of threatened species (IUCN Red List) and is considered as critically endangered of extinction. Pollution is one of the putative causes for the collapse of this species. Among their possible effects, contaminants gradually accumulated in eels during their somatic growth phase (yellow eel stage) would be remobilized during their reproductive migration leading to potential toxic events in gonads. The aim of this study was to investigate the effects of organic and inorganic contaminants on the gonad development of wild female silver eels. Female silver eels from two sites with differing contamination levels were artificially matured. Transcriptomic analyses by means of a 1000 candidate gene cDNA microarray were performed on gonads after 11weeks of maturation to get insight into the mechanisms of toxicity of contaminants. The transcription levels of several genes, that were associated to the gonadosomatic index (GSI), were involved in mitotic cell division but also in gametogenesis. Genes associated to contaminants were mainly involved in the mechanisms of protection against oxidative stress, in DNA repair, in the purinergic signaling pathway and in steroidogenesis, suggesting an impairment of gonad development in eels from the polluted site. This was in agreement with the fact that eels from the reference site showed a higher gonad growth in comparison to contaminated fish.

7 alpha-Methyl- and 11 beta-ethoxy-substitution of [125I]-16 alpha-iodoestradiol: effect on estrogen receptor-mediated target tissue uptake.

The 7 alpha-methyl and 11 beta-ethoxy derivatives of 16 alpha-[125I]iodoestradiol were prepared via halogen exchange with 125I of the corresponding 16 beta-bromoestradiol precursors. The 16 alpha-bromo derivatives were obtained via halogenation of the analogous 17-enol acetate, epimerization to the 16 beta-isomer, and hydride reduction. Stereochemical assignments were based on high resolution 1H NMR. To evaluate the effect of the nature and stereochemistry of the 16-halo substituent on the relative binding affinity for the estrogen receptor, the analogous 16-chloro derivatives were also prepared. The highest binding affinities were observed with the 7 alpha-methyl-16 alpha-haloestradiols, particularly the bromo and chloro derivatives while the 16 alpha-iodo derivatives gave somewhat lower values. Both the 11 beta-ethoxy and 7 alpha-methyl-16 alpha-[125I]iodoestradiols localize in the uteri of immature female rats via a receptor-mediated process. Rapid blood clearance of the 125I-labeled 7 alpha-methyl derivative results in lower 125I uptake by the uterus as well as nontarget organs as compared to the 11 beta-substituted estradiol analogs. However, uterus to blood and nontarget ratios are more favorable for the 7 alpha-methyl-16 alpha-[125I]iodoestradiol as compared to the analogous 11 beta-ethoxy derivatives suggesting that this compound substituted with 123I may be useful for the in vivo imaging of estrogen receptor-rich breast tumors by single photon emission computerized tomography.