Exploitation of the menshutkin reaction for the controlled assembly of halogen bonded architectures incorporating 1,2-diiodotetrafluorobenzene and 1,3,5-Triiodotrifluorobenzene

1,4-Diazabicyclo[2.2.2]octane (DABCO) forms well-defined co-crystals with 1,2-diiodotetrafluorobenzene (1,2-DITFB), [(1,2-DITFB)2DABCO], and 1,3,5-triiodotrifluorobenzene, [(1,3,5-TITFB)2DABCO]. Both systems exhibited lower-than-expected supramolecular connectivity, which inspired a search for polymorphs in alternative crystallization solvents. In dichloromethane solution, the Menshutkin reaction was found to occur, generating chloride anions and quaternary ammonium cations through the reaction between the solvent and DABCO. The controlled in situ production of chloride ions facilitated the crystallization of new halogen bonded networks, DABCO–CH2Cl[(1,2-DITFB)Cl] (zigzag X-bonded chains) and (DABCO–CH2Cl)3[(1,3,5-TITFB)2Cl3]·CHCl3 (2D pseudo-trigonal X-bonded nets displaying Borremean entanglement), propagating with charge-assisted C–I···Cl– halogen bonds. The method was found to be versatile, and substitution of DABCO with triethylamine (TEA) gave (TEA-CH2Cl)3[(1,2-DITFB)Cl3]·4(H2O) (mixed halogen bond hydrogen bond network with 2D supramolecular connectivity) and TEA-CH2Cl[(1,3,5-TITFB)Cl] (tightly packed planar trigonal nets). The co-crystals were typically produced in high yield and purity with relatively predictable supramolecular topology, particularly with respect to the connectivity of the iodobenzene molecules. The potential to use this synthetic methodology for crystal engineering of halogen bonded architectures is demonstrated and discussed.

Nephrotoxicity and nephrocarcinogenicity of dinitrotoluene : new aspects to be considered

Technical dinitrotoluene (DNT) is a mixture of 2,4- and 2,6-DNT. In humans, industrial or environmental exposure can occur orally, by inhalation, or by skin contact. The classification of DNT as an 'animal carcinogen' is based on the formation of malignant tumors in kidneys, liver, and mammary glands of rats and mice. Clear signs of toxic nephropathy were found in rats dosed with DNT, and the concept was derived of an interrelation between renal toxicity and carcinogenicity. Recent data point to the carcinogenicity of DNT on the urinary tract of exposed humans. Between 1984 and 1997, 6 cases of urothelial cancer and 14 cases of renal cell cancer were diagnosed in a group of 500 underground mining workers in the copper mining industry of the former GDR and having high exposures to explosives containing technical DNT. The incidences of both urothelial and renal cell tumors in this group were 4.5 and 14.3 times higher, respectively, than anticipated on the basis of the cancer registers of the GDR. The genotyping of all identified tumor patients for the polymorphic enzymes NAT2, GSTM1, and GSTT1 identified the urothelial tumor cases as exclusively 'slow acetylates'. A group of 161 miners highly exposed to DNT was investigated for signs of subclinical renal damage. The exposures were categorized semi-quantitatively into 'low', 'medium', 'high', and 'very high'. A straight dose-dependence of the excretion of urinary biomarker proteins with the ranking of exposure was seen. Biomarker excretion (alpha1-microglobulin, glutathione S-transferases alpha and pi) indicated that DNT-induced damage was directed toward the tubular system. New data on DNT-exposed humans appear consistent with the concept of cancer initiation by DNT isomers and the subsequent promotion of renal carcinogenesis by selective damage to the proximal tubule. The differential pathways of metabolic activation of DNT appear to apply to the proximal tubule of the kidney and to the urothelium of the renal pelvis and lower urinary tract as target tissues of carcinogenicity.

Species differences in the glutathione transferase GSTT1-1 activity towards the model substrates methyl chloride and dichloromethane in liver and kidney

Glutathione transferase (GST) GSTT1-1 is involved in the biotransformation of several chemicals widely used in industry, such as butadiene and dichloro methane DCM. The polymorphic hGSTT1-1 may well play a role in the development of kidney tumours after high and long-term occupational exposure against trichloroethylene. Although several studies have investigated the association of this polymorphism with malignant diseases little is known about its enzyme activity in potential extrahepatic target tissues. The known theta-specific substrates methyl chloride (MC) dichloromethane and 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) were used to assay GSTT1-1 activity in liver and kidney of rats, mice, hamsters and humans differentiating the three phenotypes (non-conjugators, low conjugators, high conjugators) seen in humans. In addition GSTT1-1 activity towards MC and DCM was determined in human erythrocytes. No GSTT1-1 activity was found in any tissue of non-conjugators (NC). In all organs high conjugators (HC) showed twofold higher activity towards MC and DCM than low conjugators (LC). The activity in human samples towards EPNP was too close to the detection limit to differentiate between the three conjugator phenotypes. GSTT1-1 activity towards MC was two to seven-times higher in liver cytosol than in kidney cytosol. The relation for MC between species was identical in both organs: mouse > HC > rat > LC > hamster > NC. In rats, mice and hamsters GSTT1-1 activity in liver cytosol towards DCM was also two to seven-times higher than in the kidney cytosol. In humans this activity was twice as high in kidney cytosol than in liver cytosol. The relation between species was mouse > rat > HC > LC > hamster > NC for liver, but mouse > HC > LC/rat > hamster/NC for kidney cytosol. The importance to heed the specific environment at potential target sites in risk assessment is emphasized by these results.

Misleading conduct arising from public statements : establishing the knowledge base of the target audience

Despite the very substantial body of primary sources and secondary literature on Australia’s much-litigated statutory provisions proscribing misleading or deceptive conduct, the courts have provided little in the way of assistance about how to establish the knowledge base of the target audience at whom the public statement was directed. The purpose of this case note is to compare and contrast two recent decisions of the High Court of Australia that highlight the difficulties faced by applicants in attempting to establish a contravention of the relevant legislation where conduct is directed at a segment of the public or the public as a whole.