Frank N. Dost

Methane formation in vivo from N-isopropyl α(2-methylhydrazino)-ρ-toluamide hydrochloride, a tumor-inhibiting methylhydrazine derivative

Abstract N -isopropyl-α(2-methylhydrazino)-ρ-toluamide hydrochloride (MIH), a cytotoxic agent with both antitumor and carcinogenic properties, was found to be rapidly degraded in vivo . 14 C and 3 H N -methyl labeled MIH were given intraperitoneally to rats (20 and 200 mg/kg) and, in 8 hr, 7–10 per cent of the methyl group was converted to respired methane and 11–22 per cent to respiratory CO 2 . A comparison of the rate of methane and CO 2 formation from MIH and monomethylhydrazine (MMH) suggests that MMH may be an intermediate in MIH metabolism.

Studies on the toxicity of hexachlorophene in the rat

Abstract Acute and subacute toxic effects of hexachlorophene (HCP) were studied in Wistar rats. The ip LD50 of HCP ranged between 21.8 mg/kg in mature rats and 40.0 mg/kg in weanlings. The oral LD50 varied similarly with age from 57.6 to 87.0 mg/kg, respectively. HCP was slightly less toxic to male rats than to females. Signs of intoxication were general lethargy, posterior paralysis, increased respiration rate, hyperthermia and diarrhea. Maximum body temperatures were attained approximately 1.5 hr after ip injection. In subacute studies, HCP was fed to weanling rats at dietary concentrations from 12.5 to 400 ppm HCP for a 16-week period. Animals on the 400 ppm diet, ingesting an average of 28.9 mg HCP/kg/day, developed severe posterior paralysis during the first few days of the study, and died within 10 days. No drug related mortality was observed in the other groups. Paralysis was also observed initially in rats fed the 200 ppm HCP diet (average intake 23.6 mg/kg/day) but by the second week, these animals had apparently recovered. Rats fed diets containing 100 and 200 ppm HCP (average intake 7.73 and 14.9 mg/kg/day) developed significant histopathologic changes in the brain, characterized by extensive vacuolization and edema of the myelinated areas. Significant growth depression and reduced plasma alkaline phosphatase activities were also found at 8 and 16 weeks in rats receiving the 200 ppm diet. The minimum “no effect” intake of HCP under the conditions of this study was between 3.7 mg/kg/day and something less than 7.7 mg/kg/day.

Acute toxicology of components of vegetation smoke

Only in recent times, systematic attention has been paid to the occupational health of forest firefighters and workers who manage prescribed fire. Two parts of the effort to learn the impact on worker health are medical observation of those workers, and study of occupational hygiene. It is also necessary to learn what components of smoke are most likely to affect firefighters, and to learn something of the manner in which those substances might compromise health; this review is a step toward that end. The number of possible products of vegetation combustion is almost limitless, and every fuel and condition of burning produces a unique pattern. Nonetheless, it is possible and practical to select a limited number of products that are most likely to be involved in the acute toxicity of smoke. Two products that are almost certainly important are formaldehyde and acrolein. Both appear to occur in all smoke. The toxicology of both is well studied; in particular both are powerful mucosal irritants. Estimates of exposure suggest strongly that concentrations are high enough in smoke to contribute some or all of the irritant activity. There seems to be a reasonable prospect that free radical precursors with half-lives in the tens of minutes are produced when cellulosic materials burn. If so, they will reach the respiratory tract, and liberate free radicals that react immediately on or in pulmonary cells. Ozone is not produced in the fire, but the various hydrocarbons of smoke are substrates for reactions that eventually produce ozone, and that production may continue for miles down-plume. Some measured plume concentrations approach the threshold for human health effects. The effects of the best known component, the particulate material, are unknown in isolation from all of the other substances in smoke. In spite of that ignorance, particulate loading is the principal index of smoke pollution for regulatory purposes, and sometimes is incorrectly used to represent smoke emissions regardless of source. The need to understand health impacts of these components of smoke seems obvious. Perhaps less obvious is the need to use such knowledge in management of both prescribed burning and wildfire. To some extent, it is possible to either manage fire itself to alter emission patterns, or control exposures in certain situations. Whether that should be done to protect worker health can only be judged if enough is known about health effects to direct the management decisions.

The metabolic fate of monomethylhydrazine and unsymmetrical dimethylhydrazine

Abstract The respiratory and urinary excretion of intraperitoneally administered unsymmetrieal dimethylhydrazine (UDMH) and monomethylhydrazine (MMH) and their metabolites by rats has been studied by means of radiotracer techniques. Animals given a very low dose of UDMH- 14 C metabolized almost 30 per cent of the compound to respiratory 14 CO 2 in 10 hr. The conversion of a convulsive dose of UDMH- 14 C to 14 CO 2 amounted to slightly more than 13 per cent at the end of 20 hr. At the various doses of UDMH- 14 C used, at least 50 per cent of the administered radioactivity appeared in the urine in a 2-day period. Rats given 0.12 m-mole MMH- 14 C/kg i.p. respired approximately 45% of the 14 C during the following 24 hr. Of the respired radioactivity, 20% to 25% was 14 CO 2 ; the remainder was 14 CH 4 . At the subconvulsive doses, 40 per cent of the administered radioactivity in MMH- 14 C was excreted in urine. The percentage of urinary excretion of 14 C from higher doses of MMH- 14 C was less, but the net amount excreted was slightly higher.

Metabolic fate of hydrazine

Studies of the disposition of hydrazine administered to mammals have not succeeded in accounting for more than a modest fraction of the dose, nor have the excretory products been completely identified. We have utilized 15N-labeled hydrazine and conventional methods to account for about 75% of single doses of about 0.5 LD50 (1 mmol/kg). In 48 h, about 30% appeared in urine as hydrazine and about 20% emerged as a derivative that is acid-hydrolyzable to hydrazine. About 25% was converted to N2 gas, most of which appeared less than 30 min after administration. The percentage converted to N2 at 4 h increased only slightly with dose between 0.5 and 2.0 mmol/kg. Disappearance of hydrazine from blood was biphasic with half-times of 0.74 and 26.9 h.

Fluoride impairment of glucose utilization: nature of effect in rats during and after continuous NaF infusion.

Intravenous infusion of 6 mg of fluoride/kg/hr for 3 hr caused a sharp decrease in formation of respiratory 14 CO 2 from [ 14 C]glucose, regardless of position of the label. Oxidation of [1- 14 C]fructose was not impaired, indicating that triose metabolism was not hindered; this information, along with the similarity in depression of metabolism of all labels indicated that glycolysis was not impaired. Glycogen deposition was decreased. The data suggest that the interference caused by fluoride at the observed concentrations is located at or prior to phosphorylation of glucose.

Fluoride distribution in rats during and after continuous infusion of Na18F.

Rats were given Na18F as a radiotracer for fluoride ion at varying chemical dose rates by continuous iv infusion for 3 hr. Blood fluoride was assessed six to seven times over the infusion period, at the end of which the animals were sacrificed for determination of tissue fluoride distribution. Data indicate that at sublethal dose rates blood fluoride concentration approaches a steady state proportional to the rate of fluoride infusion. Blood, kidney, and lung contained the highest fluoride concentration at doses up to 3.6 mg of F/kg/hr, but at 6 mg/kg/hr the fluoride of liver, spleen, and hollow organs increased sharply indicating this dose exceeded the amount readily processed by the fluoride excretory mechanisms of the body. Another group of animals was infused for 3 hr with 6 mg of F/kg/hr, a dose which approaches the acute LD50. Tissue fluoride distribution was determined at various intervals during both fluoride accumulation and depletion phases. During infusion the fluoride concentration of blood and other tissues was high, with highest accumulation in bone. Of soft tissues, lung contained the greatest amount of fluoride, and brain, testes, and fat pads the least. During the depletion phase, tissue fluoride concentrations decreased sharply, while bone fluoride remained constant and substantial amounts remained in lung.

Toxicology of nitrogen trifluoride

Abstract One hour of exposure to 1% nitrogen trifluoride (NF3) in air was usually lethal to rats, probably as a result of methemoglobin (MHb) formation and consequent failure of oxygen transport. After ip administration of NF3 the LD50 was about 8.2 ml (0.37 mmole)/kg, and death did not occur until at least 1 hr after MHb began to decrease. NF3 apparently did not influence the rate at which high concentrations of MHb were reduced, but residual concentrations of MHb or a derivative spectrally similar to MHb persisted at concentrations of as much as 5% for several days. Total hemoglobin (Hb) was increased for at least 7 days following NF3 inhalation. Following NF3 intoxication, significant amounts of fluorine were firmly and persistently associated with an ammonium sulfate precipitate of erythrocyte proteins, including Hb and MHb. Spectral examination indicated that this complex is not fluoromethemoglobin.

Toxic properties of chlorine trifluoride

Abstract The toxicity of chlorine trifluoride (ClF 3 ) is based primarily on its corrosive effects on surfaces of contact. The damage caused by CIF 3 is in part a function of its diverse hydrolysis products, which may form in varying proportions in the atmosphere, in pulmonary gases or during decontamination procedures. In the vapor phase, CIF 3 may decompose to ClF, Cl 2 , ClOF, ClO 2 F, ClO 3 F, ClO 2 and HF, depending on the availability of water. Of these, Cl 2 , HF and ClO 2 are probably of greatest significance. Inhalation exposure of rats to 800 ppm ClF 3 for 15 min was always lethal and 13 min of contact was usually survived. Four-hundred ppm was usually lethal after 35 min of exposure. ClF 3 , given ip in doses up to 400 μmol/kg, was not lethal although this high dose is considerably greater than the calculated maximum inhaled dose. ClF 3 exposures resulted in severe mucosal inflammation and burning of the skin, followed by corneal ulceration. Pulmonary release of 14 CO 2 from injected [ 14 C]bicarbonate was decreased after ClF 3 inhalation, as was blood pH, indicating pulmonary impairment. Of the principal hydrolysis products considered, ClO 2 F decomposes too rapidly in the presence of water vapor for study, ClO 3 F was always lethal at exposures of 5000 ppm × 15 min and 2000 ppm × 40 min with extensive methemoglobin formation, and essentially nonlethal at 2000 ppm × 25 min and 1000 ppm × 60 min. ClO 2 lethality is comparable to that of ClF 3 on a chlorine equivalent basis. ClF 3 lethality is similarly comparable to that of HF, on a fluorine equivalent basis. Predictions are made of the behavior of ClF 3 atmospheres, and of the expected dominant products in such atmospheres under various conditions.

Peer review at a crossroads--a case study.

Prepublication peer review has been the subject of scores of editorials, articles, critiques and letters, and an occasional book. The Sixth International Conference on Peer Review and Biomedical Publication will be held in Vancouver, British Columbia, Canada next year (Rennie et al. 2007). Collectively, these efforts discuss all aspects of the mechanics of the process, its virtues and faults and the reviewers who make it all work. They address specific problems such as fraud, poor quality, plagiarism, uninvolved authors and double publication of the same data. And while misconduct leads to heated discussions off the printed page, the hard facts often surface as relatively gentle words. In a history of peer review and discussion of misconduct, Fox (1994) provides a paragraph that may provoke argument, but may also hit the mark: