Human & Experimental Toxicology

Greene, Robert M ;Pisano, M Michele

doi: 10.1191/0960327105ht492oapmid: 15727050

Members of the transforming growth factor (TGF) family have emerged as critical contributors to the choreography of cellular and tissue interactions underlying morphogenesis of the orofacial region. The TGFs β, and their downstream effector molecules, the Smads, play a pivotal role in normal as well as abnormal development of first branchial arch structures. Components of the TGFβ signal transduction machinery are discussed in relation to regulation of transcription, cell division and tissue differentiation in developing orofacial tissue, as evidence for a functional linkage between the TGFβ and retinoic acid signal transduction pathways during orofacial development.

Joshi, Seema ;Husain, M M ;Chandra, Ramesh ;Hasan, S K ;Srivastava, R C

doi: 10.1191/0960327105ht493oapmid: 15727051

L-histidine, L-cysteine, reduced glutathione (GSH) and other bioligands, which are ubiquitously present in biological systems, are recognized as antioxidants. Studies have shown that nickel (II) complexed with these ligands catalyzes the disproportionation of H2O2, leading to the generation of hydroxyl radicals (OH•). However, none of the studies could provide information regarding effective concentrations at which these ligands act either as pro-oxidant or antioxidant. Therefore, the observed paradoxical behaviour of biological antioxidants in nickel-induced oxidative response was evaluated. Benzoic acid (BA) is hydroxylated by OH• radical to form highly fluorescent dihydroxy benzoate (OH-BA). We used this model to study the effect of nickel complexes of L-histidine, GSH or L-cysteine on the hydroxylation of BA. The concentration-dependent effect of L-histidine, GSH and L-cysteine, or nickel on the hydroxylation of BA was studied. The hydroxylation of BA was significantly enhanced up to 1:0.5 molar ratio (Ni:hist or GSH). However, beyond 1:0.5 molar ratios, histidine/GSH inhibited the hydroxylation and complete inhibition was observed at 1:1 molar ratios. Sorbitol and caffeic acid, considered as scavengers of hydroxyl radicals, inhibited nickel-induced hydroxylation of BA. The present study demonstrates paradoxical behaviour of these bioligands. They act as pro-oxidant at lower ligand ratios and as antioxidant at higher ligand ratios. The redox properties of nickel complexes with histidine, GSH or cysteine reported here may be crucial for the toxicity of nlckel.

Kim, Eun-Joo ;Kim, Ki-Suk ;Shin, Won-Ho

doi: 10.1191/0960327105ht494oapmid: 15727052

Inhibition of the potassium current IKr, and QT prolongation has been known to be associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of DW-286a, a new class of fluoroquinolone antibiotics reported to prolong the QT interval. To investigate the electrophysiological safety of DW-286a, we used conventional microelectrode recording techniques in isolated guinea pig papillary muscles, whole-cell patch clamp techniques in human ether-á-go-go related gene (hERG)-transient transfected Chinese hamster ovary cells, and in vivo electrocardiogram (ECG) measurements in Sprague-Dawley (SD) rats by the use of a telemetry system. DW-286a at 300 μM significantly (P <0.01) prolonged action potentials at 50% repolarization (APD50) and 90% repolarization (APD90). For IHERG, the IC50 value was 89.00±37.85 μM with a Hill coefficient (nH) of −0.97 ±0.49. However, when DW-286a was orally administered to conscious SD rats at a high dose (1000 mg/kg), no significant effect on ECG in vivo was detected. From a previous study, we know that concentration at 19.8 μM is the antimicrobial end-point of DW-286a. Therefore, our data suggest that in the electrophysiological aspect, it can be thought that the effective concentrations of DW-286a are between 19.8 and 100 μM (concentration in serum).

Sudakin, D L

doi: 10.1191/0960327105ht496oapmid: 15727053

The manufacture and application of aluminium phosphide fumigants pose risks of inhalation exposure to phosphine gas. This article presents a case report of suspected inhalation exposure to phosphine gas in a manufacturing facility for aluminium phosphide fumigants, which was associated with acute dyspnoea, hypotension, bradycardia and other signs of intoxication. These symptoms resolved within several hours after removal from exposure. A review of the data on human exposures to phosphide fumigants identifies both pesticide applicators and individuals in the vicinity of application to be at risk of accidental exposure and injury from phosphine inhalation. More recent reports have identified risks of phosphine gas inhalation in association with the clandestine production of methamphetamine. Toxicodynamic effects of phosphine result from the inhibition of cytochrome c oxidase and subsequent generation of reactive oxygen species. There remain unanswered questions relating to the toxicokinetics of phosphine, as well as the assessment of human exposure utilizing biomarkers. As initial signs and symptoms of intoxication from phosphine gas may be nonspecific and transient, there is a need for improved recognition of the potential hazards associated with phosphide fumigants and phosphine gas.

Battershill, Jon M

doi: 10.1191/0960327105ht495oapmid: 15727054

Published studies on the utility of toxicogenomic approaches (transcriptomics, proteomics and metabonomics) in screening for toxicological mechanisms and evaluation of dose response effects have been reviewed. The information supports the use of transcriptomics to screen for specific toxicological mechanisms for which there is an a priori hypothesis, although in some areas such as mutagenicity testing, toxicogenomics appear to have limited value for identifying mutagens. Data from such screening approaches cannot be used to exclude the possibility of toxicity. Targeted transcriptomics might be valuable for screening for specific mechanisms of toxicity considered to be irrelevant for assessing risk to humans, which would help to reduce the need for detailed testing of some chemicals. An integrated approach is suggested where data from more than one toxicogenomic approach could be used as an adjunct to conventional toxicology to assess dose-response in toxicological tests. An outline preliminary proposal for use by regulators is suggested although it is noted that more data are required before this could be formally used in a decision-making process.