Toxicology of methyl bromide.

Methyl bromide is widely used as an insecticidal fumigant in food supplies, warehouses, barges, buildings, and furniture. Its popularity as a fumigant is largely attributable to its high toxicity to many pests, the variety of settings in which it can be applied, its ability to penetrate the fumigated substances, and its rapid dissipation following application. Because of its frequent use around humans and human-related activities and its high acute toxicity, methyl bromide-related fatal accidents have occurred. The primary route for human exposure to methyl bromide is inhalation. In California, the most frequent cause of death from methyl bromide exposure in recent years has been unauthorized entry into structures under fumigation. The most frequently reported lesions included pulmonary edema, congestion, and hemorrhage. In recent years, a great deal of effort has been given to the characterization of the toxicity of methyl bromide because of its commercial value and its direct and indirect economic importance. Methyl bromide is acutely very toxic. Subchronically and chronically, the principal target site for methyl bromide appears to be the central nervous system. However, there was no evidence for carcinogenic activity of methyl bromide following the normal environmental exposure routes of inhalation or oral intake through residue on foods. Methyl bromide is clearly genotoxic in vitro and in vivo, as evidenced by the positive results from various tests. The mechanism of toxicity for methyl bromide is currently uncertain, although its alkylating property as well as the possibility of forming a reactive intermediate through metabolic transformation remain attractive hypotheses.

No evidence of carcinogenicity of D-mannitol and propyl gallate in F344 rats or B6C3F1 mice.

Chronic toxicity and carcinogenicity studies were conducted on D-mannitol and propyl gallate in F344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were maintained on diets containing either 0, 2.5 or 5.0% D-mannitol or 0, 0.6 or 1.2% propyl gallate for 103 wk. D-Mannitol had no effect on survival or mean body weight of rats and mice, and feed consumption was approximately the same in control and treated groups in each species. Gastric fundal gland dilation occurred at a higher incidence in treated female rats than in controls. A mild nephrosis characterized by focal vacuolization of the renal tubular epithelium was observed in an increased incidence in treated mice. No significant increase in tumour incidence was observed in any of the treated groups in comparison with the corresponding controls. Survival of rats and mice given propyl gallate was similar to that of the controls. Mean body weights were lower in chemically exposed animals, and more so for females. Male rats exposed to propyl gallate showed an increased incidence of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate gland. Tumours of the preputial gland, islet-cell tumours of the pancreas, and phaeochromocytoma of the adrenal gland occurred at a significantly (P less than 0.05) higher incidence in the low-dose male rats. Malignant lymphoma occurred with a positive trend in male mice (control 1/50, low dose 3/49 and high dose 8/50), and the incidence in the high-dose group was significantly (P less than 0.05) higher than in the control group. However, since the incidence in the control group was much less than the historical control rate (36/398 or 9%) in this laboratory, this apparent increase was not considered to be related to propyl gallate administration. Under the conditions of these studies, neither D-mannitol nor propyl gallate was considered to be carcinogenic to F344 rats or B6C3F1 mice of either sex.

Bent DNA: visualization of a base-paired and stacked A-B conformational junction.

A model for the junction of contiguous DNA segments having A-DNA and B-DNA conformations is generated using a computerized linked-atom, least-squares model building program. The junction region comprises one base pair and the two neighboring internucleotide linkages and exhibits full hydrogen-bonded base-pairing, full base-stacking, and unexceptional stereochemistry. In addition, the junction has a mixed sugar ring pucker with the junction base pair adopting C2-endo and C3-endo furanose sugar rings in the complementary strands. Since the junction is fully base-stacked, the differences in base tilt between A-DNA and B-DNA result in a bend of 26 degrees in the duplex at the junction. The results of this study indicate: 1) a correlation of the B leads to A transition with several features of the initiation of RNA transcription, 2) possible structural roles of alternating AT and GC sequences in protein recognition, and 3) the possibility of dynamic conformational discontinuities in a DNA helix.

Stereochemical model for proflavin intercalation in A-DNA.

Linked-atom molecular modelling was employed to determine the steric and torsional requirements for intercalation of proflavine into a double-stranded region of DNA compatible with adjacent regions of cohelical A-DNA. The optimum intercalation conformation is characterized by the dihedral angles xi and psi becoming trans, with all sugars retaining the characteristics C3'-endo pucker. This extended conformation results in virtually no helical unwinding, suggesting it may be an appropriate model for an intercalative intermediary in mutagenesis by virtue of its similarity to standard helical DNA.

Visualization of planar drug intercalations in B-DNA.

A computerized linked-atom modeling system was developed to examine the stereochemical requirements for intercalation of planar drugs into DNA. All classes of conformational possibilities for extending the polynucleotide backbone were examined for their ability to accommodate insertion of a drug into a base-paired region of DNA compatible with adjacent regions of B-DNA while stacking interactions, steric strain and non-bonded interatomic contacts were optimised. One conformation was found which proved superior to all others in ability to satisfy these criteria: an extension of the backbone by characteristic changes in two torsion angles to trans values, plus a change in one sugar puckering to C3'-endo to relieve strain in an adjacent residue. The turn angle distributed over three polynucleotides for this most general mode of intercalation is 90 degrees, equivalent to a helical unwinding of -18 degrees for B-DNA.