5-Fluorouracil toxicity to the ocular surface epithelium.

The antimetabolite, 5-fluorouracil (5-FU), has been used to control proliferation of retinal pigment epithelial cells and fibrocytes, and is currently the subject of a multicenter clinical trial of its value in the control of scarring after glaucoma operations. To evaluate possible ocular surface toxicity, the effect of 5-FU on the mitotic rate and differentiation of the ocular surface epithelium in rabbits was measured. 5-FU was instilled into eyes with 10-mm diameter central epithelial wounds and into nonwounded eyes at a dose of 9 mg per day for 4 days. Saline treated control wounded eyes healed within 4 days (n = 5) while 40% (4 of 10) of the 5-FU treated wounded eyes had defects at 4 days. The normal mitotic rate of the corneal epithelium was 1.0 +/- 0.3 (n = 4) tritiated thymidine labeled cells per 100 basal corneal epithelial cells after 2.5 hr incubation. Saline treated control wounded eyes had an increased mitotic rate, 7.1 +/- 1.3 (n = 5) labeled cells per 100 basal corneal epithelial cells after 2.5 hr incubation. Topical 5-FU decreased both of those rates to about 1% of normal. The normal conjunctival epithelial mitotic rate was 1.8 +/- 0.4 (n = 4) labeled cells per 60 basal cells after per 2.5 hr incubation. This rate was the same in wounded eyes, but was decreased in eyes treated with 5-FU. Thus, 5-FU (9 mg/day topically) has serious toxic effects to ocular surface epithelium which must be carefully considered if this drug is to be used clinically.

Delayed nonexpulsive suprachoroidal hemorrhage.

Eight cases of delayed nonexpulsive suprachoroidal hemorrhage occurred after filtering operations in aphakic eyes. Sustained hypotonia resulting in serous choroidal detachments, scleral infolding, or both was observed prior to the hemorrhage in seven of the eight eyes. The prognosis was related to the extent of the hemorrhage and possibly to whether or not surgical drainage was performed. Only one of the five patients with massive hemorrhages recovered visual acuity better than hand motions; that patient had undergone prompt surgical drainage of the suprachoroidal blood.

Wound healing after filtering surgery in owl monkeys.

We performed posterior lip sclerectomies in 29 owl monkey eyes to determine the natural history of wound healing after filtering surgery without adjunctive antimetabolite therapy. We noted three phases of wound healing during clinical and histologic examination: early healing (days 2 to 6), intermediate healing (days 7 to 9), and late healing (days 10 to 14). In the early healing phase, all limbal fistulas except one remained open gonioscopically, but by day 6, fibroblasts had proliferated along the walls of the opening. Proliferation and migration of fibroblasts continued during the intermediate healing phase to completely occlude four and to partially occlude two of the ten fistulas in the eyes studied during this time. In the late healing phase, the limbal fistula was completely closed by granulation tissue in four of five eyes and was slitlike open in one eye. In this model of filtering surgery, wound healing at the sclerectomy site with obliteration of the limbal opening by proliferating fibroblasts occurred within the first 14 postoperative days. We believe that the short-term effects of newer treatments designed to alter wound healing after filtering surgery may be assessed in this model, which is characterized by predictable and prompt wound healing.

The influence of simulated light scattering on automated perimetric threshold measurements.

The effect of light scattering by ocular media opacities on OCTOPUS and Humphrey perimeter threshold measurements was simulated with randomly ordered sequences of six ground-glass diffusers in the right eyes of five subjects. Threshold measurements were performed at 0 degrees, 5 degrees, 10 degrees, 15 degrees, 20 degrees, and 25 degrees nasally along the 180 degrees meridian with the F4 program on an OCTOPUS perimeter, and with twice-repeated profiles on a Humphrey perimeter. The reduction in differential light sensitivity correlated well with the 2.7-dB to 16.7-dB reduction in stimulus intensity caused by the 46% to 98% scattering of incident light by the diffusers. Contrast sensitivity in the presence of a glare source (Miller-Nadler glare test) was also affected by the diffusers, such that a 75% contrast target was not visible through the strongest diffuser whereas a 5% contrast target was visible without a diffuser. Conversely, the diffusers had very little effect on visual acuity measurements that were performed with projected high-contrast targets in a darkened room. Our data suggest that even minimal light scattering, such as might be caused by a cataract that has a relatively insignificant effect on visual acuity, may influence threshold measurements.

Topical fluorouracil. Pharmacokinetics in normal rabbit eyes.

Postoperative subconjunctival fluorouracil injections may be a useful adjunct to standard glaucoma filtering surgery in eyes that are at high risk of failure. Topical administration would be preferable to subconjunctival administration; however, there are no data on the ocular penetration of topically applied fluorouracil. Consequently, we investigated the pharmacokinetics of topically administered fluorouracil labeled with carbon 14 in normal rabbit eyes. One drop (approximately 2.4 mg) of fluorouracil resulted in the following concentrations at 0.5 and six hours, respectively: 17.3 and 0.9 micrograms/g of conjunctiva; 24.3 and 1.3 micrograms/g of cornea; 14.6 and 0.2 micrograms/mL of aqueous; 0.8 and 0.5 microgram/g of lens; 1.1 and 0.3 microgram/g of vitreous; and 0.2 and less than 0.1 microgram/mL of serum. Three drops (approximately 7.2 mg) of fluorouracil resulted in the following concentrations at 0.5 and eight hours, respectively: 589.8 and 1.3 micrograms/g of conjunctiva; 502.9 and 1.8 micrograms/g of cornea; 199.6 and 0.8 micrograms/mL of aqueous; 6.2 and 0.5 micrograms/g of lens; 6.8 and 0.5 micrograms/g of vitreous; and 1.3 and 0.2 microgram/mL of serum. Since a fluorouracil concentration of 0.2 microgram/mL inhibits rabbit conjunctival fibroblast proliferation in cell culture by 50%, these data suggest that topically applied fluorouracil achieves sufficient levels in the ocular compartments and tissues to have potential therapeutic applications.

Topical fluorouracil. II. Postoperative administration in an animal model of glaucoma filtering surgery.

Unilateral posterior lip sclerectomies were performed in ten owl monkeys. Five milligrams of fluorouracil was injected subconjunctivally in each operated eye immediately after surgery. Three drops (approximately 2.4 mg/drop) of fluorouracil were instilled ten minutes apart in each operated eye twice daily on postoperative days 1 through 7 and once daily on postoperative days 8 through 15, 17, 19, and 21. One monkey died on the seventh postoperative day; its death could not be attributed to systemic fluorouracil toxicity. All of the operated eyes had filtering blebs after the full course of fluorouracil, but seven also had corneal epithelial defects. By the seventh postoperative week, two of the operated eyes manifested moderately severe corneal opacification. Ten weeks postoperatively, the electroretinographic a- and b-wave amplitudes averaged 17% and 12% less, respectively, in the seven operated eyes without clinically significant corneal opacification than in the unoperated fellow eyes. Only two eyes had blebs after the 12th postoperative week. Histopathologic examination was performed on five eyes, of which only two revealed patent sclerostomies. Although topical fluorouracil appears to delay bleb scarring, the corneal findings suggest that it may be more toxic than subconjunctival fluorouracil.

The influence of decreased retinal illumination on automated perimetric threshold measurements.

Decreased retinal illumination (such as can be caused by pupillary constriction or light absorption by ocular media opacities) was simulated with a randomly ordered series of neutral density filters in front of the right eyes of five subjects with dilated pupils. Threshold measurements were performed on Humphrey and Octopus perimeters at 0, 5, 10, 15, 20, and 25 degrees nasally along the 180-degree meridian. A 0.6-log unit neutral density filter, which reduces retinal illumination the equivalent of halving the pupillary diameter, decreased the mean Humphrey thresholds by 1.1 +/- 0.8 decibels (dB) (mean +/- standard deviation) and the mean Octopus thresholds by 1.7 +/- 1.4 dB. Statistically significant (P less than or equal to .05, Dunnett's test) threshold depressions were observed at all eccentricities with a 1.5-log unit neutral density filter on the Humphrey perimeter (-4.5 +/- 0.7 dB) and with a 1.0-log unit neutral density filter on the Octopus perimeter (-3.5 +/- 1.0 dB).

An evaluation of a local exhaust ventilation control system for a foundry casting-cleaning operation.

A study was conducted to evaluate the effectiveness of a local exhaust ventilation system for a foundry casting-cleaning operation in which a worker cleaned gray iron castings using a variety of handheld chipping and grinding tools. The operation originally had an exhaust system consisting only of an exhaust duct terminating approximately 1 m (3 ft) above the floor and 2 m (6 ft) from the casting-cleaning workstation. An earlier evaluation of this original control system found time-weighted average exposures to respirable silica ranging from 124 to 160 micrograms/m3. The local exhaust ventilation system evaluated in this present study consisted of a downdraft booth outfitted with a turntable for manipulating the castings. The modified local exhaust ventilation system was installed at this facility and connected to the existing plant exhaust ventilation system through the original ductwork. A direct-reading instrument was used to measure the operator's respirable aerosol exposure concentrations during a single day both before and after the installation of the new workstation. The same worker was sampled both times. The operator's activities were recorded on videotape so that the exposures associated with the various tools could be determined. While day-to-day variability could not be accounted for, depending on the type of tool used the local exhaust ventilation system reduced exposures by 59 to 79% during casting cleaning by the sampled worker when compared with the original configuration. These reductions were statistically significant.

An engineer's perspective of the intervention research workshop.

As an engineer practicing in the area of engineering controls for the reduction of occupational exposures to hazardous agents, the Intervention Research Workshop studies appeared to be effective for the studied situations, yet the models may not be applicable across a wide range of intervention possibilities. A more generic model might be more appropriate, perhaps a business model. Dr. W. Edwards Deming has proposed a model for the production of goods and services. If we can view interventions as products which need to be sold to potential customers, perhaps this type of model would be more effective across a wide range of intervention strategies.

Recurrent bilateral optic neuropathy in mixed connective tissue disease.

Multiple attacks of optic neuropathy occurred in a young woman suffering from mixed connective tissue disease despite maintenance therapy with corticosteroids and cytotoxic agents.

An overview of process hazard evaluation techniques.

Since the 1985 release of methyl isocyanate in Bhopal, India, which killed thousands, the chemical industry has begun to use process hazard analysis techniques more widely to protect the public from catastrophic chemical releases. These techniques can provide a systematic method for evaluating a system design to ensure that it operates as intended, help identify process areas that may result in the release of a hazardous chemical, and help suggest modifications to improve process safety. Eight different techniques are discussed, with some simple examples of how they might be applied. These techniques include checklists, "what if" analysis, safety audits and reviews, preliminary hazard analysis (PHA), failure modes and effect analysis (FMEA), fault tree analysis (FTA), event tree analysis (ETA), and hazard and operability studies (HAZOP). The techniques vary in sophistication and scope, and no single one will always be the best. These techniques can also provide the industrial hygienist with the tools needed to protect both workers and the community from both major and small-scale chemical releases. A typical industrial hygiene evaluation of a facility would normally include air sampling. If the air sampling does detect a specific hazardous substance, the source will probably be a routine or continuous emission. However, air sampling will not be able to identify or predict the location of a nonroutine emission reliably. By incorporating these techniques with typical evaluations, however, industrial hygienists can proactively help reduce the hazards to the workers they serve.

The control of press cleaning solvent vapors in a small lithographic printing establishment.

Small businesses frequently have inadequate in-house expertise to solve a variety of safety and health problems. The National Institute for Occupational Safety and Health (NIOSH) has therefore conducted a demonstration project in the commercial lithographic printing industry, which consists largely of small companies, in an effort to establish suitable control technology for airborne solvent vapors released primarily during press cleaning operations. These solvent vapors have a number of potential adverse health effects, including narcosis, kidney and liver damage, and cancer. Also, airborne anti-offset powder is a potential allergic sensitizer and cause of occupational asthma. As a means of controlling worker exposures to the vapors and dust, a local exhaust inlet was attached to the side of the press adjacent to the paper delivery point. Tempered outside air was introduced through ceiling outlets installed to make up for the exhausted air. Measurements of press operator exposure and area concentrations of solvent vapors and area concentration of anti-offset powder were made before and after installation of the new ventilation controls. Vapor concentrations were reduced by 73 percent for the press operators. Area concentrations of the vapors were reduced by 86 percent and dust concentration by 67 percent. The ventilation system was found to be suitable for vapor and dust control, although substitution of a cleaning solution containing non-carcinogenic solvents for solutions containing carcinogens was recommended.

A hazard and operability study of anhydrous ammonia application in agriculture.

Researchers from the National Institute for Occupational Safety and Health (NIOSH) applied Hazard and Operability (HAZOP) analysis to examine hazards during the use of anhydrous ammonia by farmers. This analysis evaluated the storage, transfer, and application of anhydrous ammonia, identifying credible hazard scenarios, practical solutions, and research needs. Ninety-five findings were developed that are of use to farmers, distributors of ammonia and application equipment, and manufacturers of application equipment. The findings generally involve training, equipment design changes, preventive maintenance, and material compatibilities. The HAZOP team found that additional safety features need to be developed or implemented. The study also pointed out where correct operator procedure and preventive maintenance can prevent inadvertent releases. Other inadvertent releases are caused by incompatible materials, or by using equipment in ways other than intended. Several examples of the findings are given to emphasize the HAZOP technique and the high-risk scenarios. Strategies for dissemination to the agricultural community are presented.

5-fluorouracil and glaucoma filtering surgery: I. An animal model.

Failure of a glaucoma filtering procedure commonly results from scarring at the surgical site. Fibroblasts play an important role in the scarring process. 5-fluorouracil is an antimetabolite capable of inhibiting fibroblast proliferation. We tested the ability of 5-fluorouracil to inhibit cicatrization at the filtering site in an experimental model. Posterior lip sclerectomies were performed in each eye of ten normal owl monkeys. Postoperatively, one eye of each animal received subconjunctival injections of fluorouracil and the fellow eye received saline injections in a randomized, masked fashion. Two animals died of undetermined causes. None of the control eyes developed blebs, but six of the eight treated eyes in surviving animals developed blebs. The difference between intraocular pressures in fluorouracil-treated and control eyes was statistically significant (P less than 0.05). Signs of ocular toxicity included persistent corneal epithelial defects and delayed healing of the conjunctival incision. These results are considerably more favorable than those previously reported with experimental filtering procedures in non-human primates. Pharmacologic modulation of wound healing may decrease the risk of failure of filtering operations.

Potential problems associated with the Rustrak Ranger data logger's data storage technique.

To maximize the 8 kilobyte memory of the Rustrak Ranger data logger, a patented technique called adaptive storage was used. With adaptive storage, the data logger predicts the value of an incoming reading. Based on previously stored readings, the data logger predicts the next reading to be constant, linear, or exponential. If the reading falls outside a window surrounding the predictions, it is stored; otherwise, it is discarded. The size of the window affects the rate at which the readings are stored, and thus is adjusted so data can be collected for the specified sampling time. If the windows are made too large, there is a resultant loss in the resolution of the data. The characteristics of the instrument and the contaminant or physical agent being measured (i.e., air contaminant versus noise) also affect data resolution. In this evaluation, previously collected exposure data (air monitoring) were sent by a computer to the Rustrak Ranger for recording. To determine the effect of the sampling time on resolution, the recorded data were analyzed using two different methods. Sampling times varied from 2 to 120 minutes. These tests showed poor resolution for sampling times as short as 30 minutes, indicating that the Rustrak Ranger may not be suitable for certain types of sampling schemes. However, if used within its limitations, this data logger is a valuable tool for recording real-time industrial hygiene data.

Trabeculectomy in young patients.

The results of 117 trabeculectomies performed on 98 patients under the age of 50 years were reviewed. The success rate in primary glaucomas (29/39, 74%) was considerably higher than in secondary glaucomas (24/50, 48%) or in developmental glaucomas (6/17, 35%). Only one (9%) of 11 trabeculectomies performed for neovascular glaucoma was successful. Trabeculectomies for secondary glaucomas were significantly more often successful in eyes that had not undergone previous surgery. None of the six trabeculectomies performed on patients under the age of ten years controlled the intraocular pressure. Of the 45 trabeculectomies performed on patients aged 10 to 29 years, 17 (38%) were successful. Of the 66 trabeculectomies performed on patients aged 30 to 49 years, 43 (65%) were successful. The success rates among black, white, and hispanic patients were similar. The ability to identify patients at high risk for failure of trabeculectomy may be of value in guiding the surgical management of glaucoma.

The influence of refraction accuracy on automated perimetric threshold measurements.

The effect of refraction accuracy on the differential light threshold of a Goldmann size III (0.43 degrees diameter) stimulus was evaluated in the right eyes of five normal subjects with randomly ordered sequence of plano, +1.00-, +2.00-, +3.00-, +4.00-, +5.00-, and +6.00-diopter (D) spherical overcorrections. Threshold measurements were performed at 0 degree, 5 degrees, 10 degrees, 15 degrees, 20 degrees, and 25 degrees eccentricity nasally along the 180 degrees meridian with the F4 program on the Octopus 201 perimeter. The +1.00- through +6.00-D overcorrections decreased the threshold values by an average of 1.4, 2.9, 4.2, 5.6, 6.7, and 7.6 dB, respectively, compared with the plano overcorrection. The depression of the differential light threshold was of similar magnitude at all eccentricities within the central 25 degrees.

Reducing exposures during the pouring operations of a brass foundry.

The focus of this exposure assessment and control technology study was a brass foundry and the lead exposures of workers involved in the transportation and pouring of metal. Controls in place at the foundry included ventilation systems at the furnace and along the continuous and stationary pouring lines. Real-time measurements were made to determine which tasks were the primary exposure sources, and a hand-held aerosol monitor was used to measure real-time aerosol exposures (as a surrogate for lead) in the workers' breathing zones. Data were collected over two 30-min sampling periods while worker activities were monitored using a video camera. Analysis of the data showed that the greatest aerosol exposures occurred during the transportation of an unventilated, full ladle, resulting in an average concentration of at least twice that of the other tasks. The study concluded that the addition of exhaust ventilation such as a moveable hood and duct system during the ladle transport and pouring tasks, and the implementation of a side draft hood at the pigging area, could result in a reduction of worker exposure to aerosols during the continuous pouring operation by up to 40%. The controls and techniques suggested in this study could be applied to pouring operations throughout the industry to reduce worker exposure to metal fumes.