Combinatorial × computational × cheminformatics (C3) approach to characterization of congeneric libraries of organic pollutants.

Congeners are molecules based on the same carbon skeleton but are different by the number of substituents and/or a substitution pattern. Examples are 1-chloronaphthalene, 1,4-dichloronaphthalene, and 1,3,8-trichloronaphthalene. Various persistent organic pollutants (POPs) exist in the environment as families of congeners. Very large numbers of possible congeners make their experimental characterization and risk assessment unfeasible. Computational high-throughput and quantitative structure-property relationship (QSPR) modeling has been limited by the lack of tools and approaches facilitating analysis of such POP families. We present a comprehensive approach that enables modeling of extremely large congeneric libraries. The approach involves three steps: (1) combinatorial generation of a library of congeners, (2) quantum chemical characterization of each structure at the PM6 semiempirical level to obtain molecular descriptors, and (3) analysis of the information generated in step 2. In steps 1-3, we employ combinatorial, computational, and cheminformatics techniques, respectively. Therefore, this hybrid approach is named "Combinatorial × Computational × Cheminformatics", or just abbreviated as C(3) (or C-cubed) approach. We demonstrate the usefulness of this approach by generating and characterizing Br- and Cl-substituted congeneric families of 23 typical POPs. The analysis of the resulting set of 1 840 951 congeners that includes Cl-, Br-, and mixed Br/Cl-substituted species, proves that, based on structural similarities defined by the molecular descriptors' values, the existing QSPR models developed originally for Cl- and Br-substituted congeners can be applied also to mixed Br/Cl-substituted ones. Thus, the C(3) approach may serve as a tool for exploring structural applicability domains of the existing QSPR models for congeneric sets.

Exposure to organochlorine pesticides is independent risk factor of hepatocellular carcinoma: a case--control study.

Primary hepatocellular carcinoma (HCC) is highly prevalent in China. Although hepatitis B virus (HBV) and aflatoxin B1 (AFB1) are considered the major risk factors, among the high-risk cohorts only a small fraction develops liver cancer. Therefore, we investigated if organochlorine pesticides (OCPs) exposure contributed to HCC risk in the Xiamen population. The questionnaire database was built from 346 HCC cases and 961 healthy controls during 2007-2009. The serum levels of α-, ß-, γ-, δ-HCH, p, p'-DDT, p, p'-DDE, o, p'-DDT and p, p'-DDD were measured by gas chromatography-tandem mass spectrometer and statistical analysis was done using SPSS16. Significantly, we observed p, p'-DDT, p, p'-DDE, and at first time ß-HCH displayed quartile dose-dependent HCC risk trends; p, p'-DDT showed positive (i.e., synergistic) interactions with HBV, diabetes mellitus, AFB1 and polycyclic aromatic hydrocarbon (PAH) exposure, but negative (i.e., antagonistic) interaction with heavy drinking; p, p'-DDE had positive interaction with PAH but negative interaction with HBV and p, p'-DDT; and ß-HCH was positively interacted with p, p'-DDT but negatively interacted with heavy drinking and diabetes. p, p'-DDT, p, p'-DDE and ß-HCH were independent HCC risk factors. Because of their synergistic interactions with other factors, the high level exposure combined with common AFB1 and HBV exposure in the investigated area may greatly enhance the risk of HCC.

Chlorinated hydrocarbon contaminants in feces of river otters from the southern Pacific coast of Canada, 1998-2004.

Chlorinated hydrocarbon contaminants in coastal river otters (Lontra canadensis) were evaluated by sampling feces (scats) collected on the south coast of British Columbia, Canada. A broad survey of industrialized areas of the Strait of Georgia region was conducted in 1998, and a subsequent survey of working harbours in 2004. Samples from 1998 were analyzed for polychlorinated biphenyls (PCBs), organochlorine (OC) pesticides, and polychlorinated dioxins (PCDDs) and furans (PCDFs), while in 2004, chemistry was confined to summation operatorPCBs and OC pesticides. Concentrations of OC pesticides were low in both years, with only dichlorodiphenyldichloroethylene (DDE; range: 0.01-2.12 mg/kg lw) and hexachlorocyclobenzene (HCB; range: 0.003-0.25 mg/kg lw) detected in all samples. In 1998, octachlorodibenzo-p-dioxin (OCDD) and other higher chlorinated PCDD/Fs were found in most samples, with OCDD ranging from 120 ng/kg lw in Clayoquot Sound to 19,100 ng/kg lw in a pooled sample from two latrines in Nanaimo. PCBs were present in all samples. In 1998 geometric mean concentrations of the sum of 59 PCB congeners ranged from 0.49 mg/kg lw in Nanaimo to 12.3 mg/kg lw in Victoria Harbour. Six years later, mean summation operatorPCBs remained elevated (geometric mean 9.5 mg/kg lw) in Victoria Harbour. Geometric mean concentrations of summation operatorPCBs from Victoria Harbour in 1998 and 2004 were >9 mg/kg lw, a published adverse effect level for reproduction. At some latrines in both Victoria and Esquimalt Harbours, concentrations of TCDD-toxic equivalents exceeded 1500 ng/kg lw, a value for health effects in otters that we derived using published information. As shown in previous studies, analysis of scats provides an efficient and non-intrusive approach to assessing contaminant threats to otter populations, and to documenting spatial trends in residues.

Semi-synthesis of polymyxin B (2-10) and colistin (2-10) analogs employing the Trichloroethoxycarbonyl (Troc) group for side chain protection of alpha,gamma-diaminobutyric acid residues.

Improved strategies for the chemical conversion of natural polymyxin B and colistin to their N-terminal analogs are reported. First, the protection of the side chains of five L-alpha,gamma-diaminobutyric acid (Dab) residues in natural polymyxin B and colistin was achieved with trichloroethoxycarbonyl (Troc), then the resulting pentakis(N gamma-Troc)-polymyxin B and pentakis(N gamma)Troc)-colistin were treated with trifluoroacetic acid (TFA) : methanesulfonic acid (MSA) : dimethylformamide (DMF) : H2O (10 : 30 : 55 : 5) at 40 degrees C in order to remove N alpha-alkanoyl-Dab(Troc)-OH selectively. The new key compounds, tetrakis(N gamma-Troc)-polymyxin B (2-10) and tetrakis(N gamma-Troc)-colistin (2-10), were obtained in 19% and 15% yields, respectively, which is higher than previous reports using trifluoroacetyl (Tfa) for tetrakis(N gamma-Tfa)-polymyxin B (2-10) and tetrakis(N gamma-Tfa)-colistin (2-10), respectively. Acylation of tetrakis(N gamma-Troc)-polymyxin B (2-10) and tetrakis(N gamma-Troc)-colistin (2-10) with various hydrophobic acids bearing aliphatic or aromatic ring structures, followed by the deprotection of Troc by Zn in AcOH, produced polymyxin B (2-10) and colistin (2-10) analogs which were used for structure-activity relationship studies. It was found that cyclohexylbutanoyl-, 4-biphenylacetyl-, and 1-adamantaneacetyl-polymyxin B (2-10) showed potent antimicrobial activity equal to that of polymyxin B against three Gram-negative bacterial strains. The lipopolysacharide (LPS) binding activity of cyclohexylbutanoyl-, 4-biphenylacetyl-, and cyclododecanecarbonyl-polymyxin B (2-10) increased greatly in comparison with that of polymyxin B (2-10). The various N alpha-acylated polymyxin B (2-10) analogs showed slightly higher antimicrobial and LPS binding activities than the corresponding N alpha-acylated colistin (2-10) analogs.

Review of the toxicity of chemical mixtures containing at least one organochlorine.

An analysis of current research on mixture toxicity was conducted by critically reviewing published journal articles. The scope was limited to complex mixtures (more than two components) where at least one component was a chlorinated organic chemical. Although the basics of dose-response are widely accepted for mixtures, a number of technical issues, including dose metrics and the unquantified influence of toxicity modifying factors, confound data interpretation and restrict the ability to establish reliable determinations of the presence, nature, and extent of additivity. Lack of knowledge about dose level influences and species-specific variations contribute further interpretational limitations. Within this context, available data indicates that most tested mixtures are near or below simple dose/concentration additivity. Exceptions (both positive and negative) tend to occur when tested mixtures have only a few components or where sensitive whole organism or sub-organismal changes are used as the response metric. Available information does not routinely identify the presence of chlorine as a marker either of a particular type of toxicity or consistently greater potency. The most profound difficulty is the problem of clearly defining when and why similarity and dissimilarity of toxic action is expected for a particular mixture. This impediment largely results from the lack of a generally accepted, technical classification for mode/mechanism of toxic action coupled with the lack of a generally accepted classification scheme for mode/mechanism of toxicity interactions.

New carbonimidic dichlorides from the Australian sponge Ulosa spongia and their possible taxonomic significance.

Five sesquiterpene carbonimide dichlorides (1-5) have been isolated from the dichloromethane extract of the Australian sponge Ulosa spongia. The structures of the two new compounds, ulosins A (1) and B (2), were elucidated by employing spectroscopic techniques (NMR, MS, UV, and IR). The chemotaxonomic significance of our data is discussed.

Organochlorine formation in magnesium electrowinning cells.

The formation of organochlorines during the electrolytic production of magnesium was investigated using a laboratory-scale electrolytic cell having a graphite anode, a liquid aluminium alloy cathode, and a molten chloride electrolyte. The cell was operated at current densities ranging from 3000 to 10,000 A m(-2) and at temperatures ranging from 660 degrees C to 750 degrees C. Organochlorines were adsorbed from the cell off-gases onto silica gel, extracted with hexane, and determined by gas chromatography. All compounds identified were fully chlorinated aliphatic and aromatic compounds, the major components being hexachlorobutadiene, hexachlorobenzene, hexachloroethylene, and octachlorostyrene. The total amount of organochlorines per tonne of magnesium produced decreased with electrolysis time and with current density and increased with operating temperature; it was also dependent on the type of graphite employed. The output of organochlorines varied from 5 to 20 g t(-1) of magnesium.