Factors affecting the chemical durability of glass used in the pharmaceutical industry.

Delamination, or the generation of glass flakes in vials used to contain parenteral drug products, continues to be a persistent problem in the pharmaceutical industry. To understand all of the factors that might contribute to delamination, a statistical design of experiments was implemented to describe this loss of chemical integrity for glass vials. Phase I of this study focused on the effects of thermal exposure (prior to product filling) on the surface chemistry of glass vials. Even though such temperatures are below the glass transition temperature for the glass, and parenteral compounds are injected directly into the body, data must be collected to show that the glass was not phase separating. Phase II of these studies examined the combined effects of thermal exposure, glass chemistry, and exposure to pharmaceutically relevant molecules on glass delamination. A variety of tools was used to examine the glass and the solution contained in the vial including: scanning electron microscopy and dynamic secondary ion mass spectroscopy for the glass; and visual examination, pH measurements, laser particle counting, and inductively coupled plasma-optical emission spectrometry for the analysis of the solution. The combined results of phase I and II showed depyrogenation does not play a significant role in delamination. Terminal sterilization, glass chemistry, and solution chemistry are the key factors in the generation of glass flakes. Dissolution of silica may be an effective indicator that delamination will occur with a given liquid stored in glass. Finally, delamination should not be defined by the appearance of visible glass particulates. There is a mechanical component in the delamination process whereby the flakes must break away from the interior vial surface. Delamination should be defined by the observation of flakes on the interior surface of the vial, which can be detected by several other analytical techniques.

The management and outcome of patients with germ-cell tumours treated in the Edinburgh Cancer Centre between 1988 and 2002.

AIMS: The aim of this retrospective analysis was to review the outcome of patients with germ-cell tumours treated in the Edinburgh Cancer Centre over the past 15 years, and to see whether there had been any changes over three 5-year cohorts. MATERIALS AND METHODS: Patients referred with gonadal and extra-gonadal primary germ-cell tumours, between 1988 and 2002, were identified from the departmental database, and survival by stage and prognostic group was analysed. RESULTS AND CONCLUSIONS: The proportion of patients with stage I seminoma has significantly increased. The good prognosis of patients with early stage disease is confirmed, with the outcome for some groups of patients being better than expected. There is a non-significant trend to improved results over the three 5-year cohorts. The outcome for patients with stage IV seminoma is worse than would be expected, but numbers are small. The poor prognosis of patients with non-seminomatous germ-cell tumours who fall into the International Germ Cell Consensus Classification (IGCCC) poor-prognostic group is confirmed. Failure of patients with metastatic non-seminomatous germ-cell tumours to achieve a complete response to initial therapy is shown to be a poor prognostic indicator.

Gonopodium development in normal male and 11-ketotestosterone-treated female mosquitofish (Gambusia affinis): a quantitative study using computer image analysis.

Mature male mosquitofish possess a highly modified anal fin called a gonopodium that develops from an unmodified female-like anal fin under the influence of endogenous androgens at sexual maturity. Although females do not normally develop gonopodia, their anal fins can be induced to develop into gonopodium-like structures by the administration of androgens. We used computer image analysis techniques to quantify the morphological changes in the anal fins of normal male and female mosquitofish during growth and development and the changes that occur in females exposed to an androgen, 11-ketotestosterone. The mosquitofish anal fin is a useful bioassay system for quantifying the effects of known or suspected environmental androgens.

Pulmonary effects of sulfur oxides on the surface of copper oxide aerosol.

The authors have developed a system that generates copper oxide aerosol similar to the primary emissions from smelters. The surface of the ultrafine copper oxide aerosol is coated with a layer of sulfur oxides consisting of sulfate, S(VI), and sulfite, S(IV). Guinea pigs were exposed to this sulfur oxide layered copper oxide aerosol, and pulmonary mechanical functions were measured by using the Amdur-Mead method. The concentration of sulfur oxides on the aerosol was determined by using a flame photometric detector system. Although sulfuric acid was not found in this system, S(IV) at concentrations as low as 0.36 mumol/m3 delivered as a surface layer caused prolonged changes in pulmonary mechanical functions.

Pulmonary function of guinea pigs exposed to freshly generated ultrafine zinc oxide with and without spike concentrations.

Exposure of guinea pigs 3 hr/day for 5 consecutive days to freshly formed ultrafine zinc oxide (ZnO) (count median diameter: 0.05 micron; geometric standard deviation: 2.0) at a concentration of 7 mg/m3 produced a gradual decrease in total lung capacity and vital capacity over the course of the exposure period. The carbon monoxide (CO) diffusing capacity (DLCO) was not affected until the fourth day, when it dropped abruptly to 30% below control levels. Wet-lung weight/body weight ratios and wet-lung/dry-lung weight ratios increased, indicating the presence of edema. Exposures to 2.7 mg/m3 ZnO, using the same 3 hr/day, 5 day time frame, did not alter any parameters measured. In 2 experiments a single high peak of ZnO (25-34 mg/m3) occurred. In one experiment exposure was stopped, but pulmonary function measurements were made as scheduled; in the other case, exposures to ZnO were continued. In both, lung volumes were decreased abruptly and to a greater extent than when peaks were absent. Continued exposure caused greater decrements in total lung capacity (TLC) and vital capacity (VC) as well as decrements in functional residual capacity (FRC) and residual volume (RV) than were observed when exposure was stopped. Peak exposures reduced DLCO to 45%-60% below control. These values rose to 25%-30% below control with or without continued exposure. Airway resistance increased and compliance decreased following peak exposures. When exposure was stopped, these changes were reversible; with continued exposure they still were different from control levels on the fifth day.(ABSTRACT TRUNCATED AT 250 WORDS)

Copper oxide aerosol: generation and characterization.

Effluent gases from high temperature systems such as fossil fuel combustion and pyrometallurgical processes contain inorganic material which has the potential to interact with sulfur dioxide (SO2) on the surface of particles to form an irritant aerosol. The submicron fraction of this inorganic material is especially important as the fine particles may penetrate deep into the lung and cause serious health effects. A laboratory furnace was designed to produce a submicrometer copper oxide aerosol to stimulate emissions from copper smelters and other pyrometallurgical operations. The ultimate aim of this research is to investigate the interaction of SO2 and the copper oxide aerosol at different temperatures and humidities in order to determine the reaction products and their potential health effects upon inhalation. The initial work, as presented in this paper, was to reproducibly generate a submicrometer copper oxide aerosol and to characterize it in terms of size, morphology and composition. Two experimental regimes were set up. One admitted filtered air, without water vapor, into the furnace, and the other admitted filtered air and water vapor. The size and morphology of the aerosols were determined using an electrical aerosol analyzer and transmission electron microscopy. The particles appear as chain aggregates with a count median diameter of 0.026 micron when no water vapor was added and 0.031 micron when water vapor was added into the furnace. Composition of the aerosol was determined using x-ray photoelectron spectroscopy. The aerosol, with or without water in the furnace, consists of a mixture of copper(I) oxide and copper(II) hydroxide.

Nephrotoxicity of sodium arsenate in dogs.

Nephrotoxicity of sodium arsenate was evaluated in dogs to determine the pathophysiologic basis for renal lesions caused by this heavy metal. Examination of biopsy specimens indicated that the low dose of the As salt (0.73 mg/kg of body weight) produced histologic changes consisting of mild degeneration and vacuolation of renal tubular epithelium. Vacuolation involved mainly the ascending thick portion of the nephron. Clinical pathologic changes were not demonstrable at this dosage level according to glomerular filtration rate (creatinine clearance), fractional reabsorption of sodium, potassium, and chloride; plasma osmolar and free water clearance; and urinalysis. The medium dose (7.33 mg/kg) resulted in alterations determined by urinalysis, but did not markedly affect other clinical pathologic measurements. Histopathologic changes were equal to or greater than those seen with the low dose. Tubular necrosis was observed in the cortical portion of the nephron and the ascending thick limb. The high dose (14.66 mg/kg) consistently produced marked changes in all parameters evaluated. Clinical pathologic alterations were compatible with acute tubular necrosis involving all segments of the nephron. Histologically, moderate glomerular sclerosis and severe tubular necrosis were observed. During recovery from the high dose of As, a gradual compensatory healing process was observed that was evident in all clinical pathologic parameters and was confirmed from sequential renal biopsy specimens.

Metabolism and renal handling of sodium arsenate in dogs.

Renal handling of sodium arsenate was studied in 5 dogs. Using a low dose (0.73 mg/kg of body weight) of sodium arsenate given IV, variable arsenite concentrations were detected in plasma and urine. Using a medium dose (7.33 mg/kg), the renal tubule cells were determined to be the probable sites of reabsorption of arsenate, reduction of arsenate to arsenite, and secretion or diffusion of the latter into urine. However, using a high dose (14.66 mg/kg), despite a similar pattern of reduction of arsenate to arsenite, marked reabsorption of arsenite into plasma took place instead of secretion or diffusion into urine. Because of reabsorption, the amount of arsenite in plasma (18.4 +/- 3.5% of the total As) was about 3 times higher than that measured during the medium dose experiment (6.0 +/- 1.0%). During the clearance experiments which lasted 110 minutes, only 40% to 45% of the arsenate infused was excreted in urine, and a minimal amount of dimethylarsinic acid (DMAA) was detected. In contrast, by the next day, DMAA was the major metabolite excreted in urine. This excretion of As as DMAA was partly due to delayed excretion of 55% to 60% As that was stored in the body and was subsequently metabolized.

Occupational exposures to pesticides containing organoarsenicals in California.

The only organic arsenicals used in agriculture are methanearsonic acid (MSMA) and its sodium and ammonium salts and dimethylarsinic acid (cacodylic acid) and its sodium salt. They have an oral LD50 in the rat of 700-1,000 mg/kg and are classified as toxicity category 3 pesticides. During the three-year period 1975, 1976 and 1977 in California there were 34 reports by physicians of injury due to exposure to pesticides containing organic arsenicals of which nine resulted in systemic symptoms and the remainder being eye and skin irritations. There appeared to be prompt recovery from these exposures. They were caused primarily by use of faulty equipment, not using due care in its operation, poor work practices and improper use of protective equipment. There is no evidence that this group of chemicals is carcinogenic in animals or man.

Tissue distribution and binding of radioactivity in mouse after intravenous administration of [14C]3-chloro-p-toluidine.

The avicide [14C]3-chloro-p-toluidine (CPT) HCL, ring labeled, was injected intravenously to mice. The radioactivity associated with this compound was found to be unevenly distributed in different parts of the body. It leaves the plasma, as well as many tissues, with 2 elimination rate constants, the fast and the slow. The faster component of the [14C]CPT decay curve of the plasma was similar to the faster components of the decay curves of brain, lung, heart, intestine, testicle and kidney. The retention half-life of the radioactivity for the slower component of the decay curve varied a great deal from tissue to tissue, being shortest (14.55 h) in the intestine and longest (326 h) in the adipose tissue. Of the 10 tissues examined, a substantial amount of [14C]CPT radioactivity was found to be covalently bound only to liver, kidney, lung and RBC protein. There was no cause and effect relationship between the covalent binding of radioactivity and the tissue pathology, since no remarkable histopathological lesions were found in the liver and kidney of treated mice. The tissue retention of [14C]CPT radioactivity did not parrallel the covalent binding of the compound to tissue protein. The covalent binding of [14C]CPT radioactivity to RBC was suggestive of the conversion of the parent compound into a reactive metabolite responsible for the generation of methemoglobin in mice. The percent distribution of radioactivity in subcellular fractions of liver and kidney correlated with the amount of protein associated with subcellular fractions. The 102 000 g supernatant fraction of the liver contained the highest proportion of radioactivity, both in terms of absolute percent radioactivity as well as specific activity (dpm/mg of protein). This was also true for the 102 000 g supernatant fraction of the kidney. The majority of radioactivity in the 102 000 g supernatant fraction of liver appears to be bound to one or more polypeptide sized proteins with a mol. wt. of approx. 1000--2000.

Organophosphate pesticide poisoning.

A total of 118 workers from a 120-person grape picking crew became ill in early September 1976. Of these (108 men and 10 women), 85 received medical attention and three of the 85 were admitted to hospital. The symptoms were typical for organophosphate poisoning. Average plasma and red cell cholinesterase values for the affected workers were depressed more than 60 percent. Most were treated with atropine and some were also treated with 2-PAM (pralidoxime). The exposure to residues of the organophosphate pesticides dialifor (Torak((R))) and phosalone (Zolone((R))) occurred in one grower's vineyards near Madera, California. It appeared that workers had been allowed into recently-treated areas before the expiration of the required 30-day safety interval for dialifor, and that excessive skin exposure to residues of this pesticide had resulted. The clinical management of these cases and the occupational surveillance of the workplace became quite complex. The grower sustained significant losses of grapes during the period in which some of his vineyards were under quarantine and he had to pay substantial medical expenses as well as a fine for violating state regulations concerning the proper use of pesticides. Organophosphate pesticides decay more slowly under hot, dry weather conditions than they do when rainfall is frequent. California has imposed a number of specific safety intervals to be observed after the application of these pesticides to certain crops. If, in violation of these regulations, workers are permitted to enter fields too soon, poisoning can occur.

Hexachlorobenzene II. Effects on growing lambs of prolonged low-level oral exposure to hexachlorobenzene (HCB).

Fifty growing male (castrated) lambs were exposed to hexachlorobenzene in the diet at levels of 0, 0.01, 0.1 and 1.0 ppm for 90 days. They were then moved to clean quarters and the study continued for an additional 210 days. Growth rates, certain plasma enzyme activities and hepatic microsomal enzyme activities were studied to detect subclinical effects related to the exposure. A 19-day acute exposure at 100 ppm was done and the same parameters except for growth rate, measured. Hematocrit and plasma protein concentrations were also monitored. No significant changes were seen in the growth rates (90 days exposure), in the plasma enzymes alkaline phosphatase, glutamic oxaloacetic transaminase, glucose 6-phosphate dehydrogenase or succinic dehydrogenase, or in the hematocrit or plasma protein concentrations after either the 90-day or 19-day exposures. However, in vivo metabolism of antipyrine was increased in both the 1.0 ppm (90-day) and the 100 ppm (19-day), but was significantly increased (p less than 0.01) in only the 100-ppm exposure. Additionally, hepatic microsomal N-demethylase was increased significantly by the 90-day exposure at 1.0 ppm and the 19-day exposure at 100 ppm, but the hepatic microsomal O-demethylase was significantly increased only after the 1.0-ppm exposure. Histopathologic examination of tissues (brain, lung, myocardium, large and small intestines, liver, kidneys, adrenals, mesenteric lymph nodes) collected from animals sacrificed at 90 days and at the termination of the study (300 days) revealed no lesions suggestive of harmful HCB exposure.

Hexachlorobenzene I. Uptake, distribution and excretion of hexachlorobenzene (HCB) in growing lambs.

The uptake, distribution, and excretion of hexachlorobenzene (HCB) was studied in young male (castrated) lambs. Lambs were exposed for 90 days at a dietary concentration of 0, 0.01, 0.1 and 1.0 ppm. Tissue concentration of HCB were monitored by periodic omental biopsy and by post-slaughter collection of tissues at 90 and at 300 days. Blood samples were collected by venipuncture each time that biopsies or sacrifice occurred. Findings of the 300 days duration study were: (1) the growth rate of the exposed lambs was unaffected by the exposure to the dietary HCB, (2) adipose tissue concentrations reached a level approximately ten times that in the diet at the end of the 90-day exposure period, (3) HCB concentration was higher in the omental fat than in the perirenal fat at 90 days but not at 300 days, (4) a good portion of the apparent decresae in HCB in the fat following cessation of exposure is due to dilution (by increasing carcass fat), (5) the apparent half-life of HCB was approximately 90 days and was not dose-dependent at the exposure rates studied, and (6) the highest HCB concentrations in other tissues were in the brain and liver. The study demonstrated that the omental biopsy provides an excellent means of estimating body fat burden of this lipid soluble pesticide, although it tends to provide an overestimate during actual dietary exposure. The finding that the bioconcentration of and the depletion from the adipose tissues were independent of dose enables prediction of the degree to which food animals might become contaminated if allowed to feed on HCB-contaminated pastures or feed stuffs, and of the time which will be required for such residues to decrease to negligible levels. This predictive ability is of obvious benefit to both the food animal producer and the consumer. Since the HCB is apparently much more stable in the body than is indicated by the depletion half-life of 90 days in these growing lambs, it follows that environmental contamination of grazing lands or animal feeds is of far greater consequence for adult animals which would not be likely to experience the growth dilution of carcass residues.