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Directly administered antiretroviral therapy (DAART) is one approach to improving adherence to among human immunodeficiency virus (HIV)-infected drug users. We evaluated the essential features of a community-based DAART intervention in a randomized, controlled trial of DAART versus self-administered therapy. Of the initial 72 subjects, 78% were racial minorities, and 32% were women. Social and medical comorbidities among subjects included homelessness (35% of subjects), lack of interpersonal support (86%), major depression (57%), and alcoholism (36%). At baseline, the median CD4+ cell count was 403 cells/mL and the median HIV-1 RNA load was 146,333 copies/mL (log10 5.31 copies/mL). During the prior 6 months, 33% of subjects had missed a medical appointment, and 47% had visited an emergency department. Although most subjects (67%) preferred to take their own medications, 76% would accept DAART if it were made compulsory. A methadone clinic was the DAART venue acceptable to the fewest subjects (36%), and a mobile syringe-exchange program was acceptable to the most subjects (83%). Adherence was higher for supervised than for unsupervised medication administration (P<.0001), a finding that supports use of daily supervision of once-daily regimens. Moreover, DAART should incorporate enhanced elements such as convenience, flexibility, confidentiality, cues and reminders, responsive pharmacy and medical services, and specialized training for staff.

The so-called hard alpha-keratins, such as quill and hair, have a composite structure in which intermediate filaments (IF) are embedded in a sulfur-rich matrix. Recent studies of these trichocyte keratin IF have revealed that substantial changes in the molecular architecture take place when oxidation of the cysteine residues occurs as part of the terminal differentiation/keratinization process. Recent cryoelectron microscope studies suggest that the IF has a tubular structure prior to keratinization, but transmission electron micrographs of thin sections of fully keratinized fibers exhibit a "ring-core" structure. In the present contribution we develop a generic model for the IF in the reduced state based on cross-linking studies and discuss two possibilities for the way in which this structure may be modified during the keratinization process.

Early electron microscope studies of developing wool and hair established that trichocyte (hard alpha-) keratin fibers have a composite structure in which filaments, subsequently shown to belong to the class of intermediate filaments (IF), were embedded in a matrix of sulfur-rich proteins. These studies also showed that the IF aggregate in a variety of ways to form what have been termed macrofibrils. Assembly into sheets appears to be an important initial factor in aggregation, and in the present contribution the structural principles governing sheet formation are formulated and specific models for the interaction between neighboring IF in a sheet are proposed, based on existing X-ray diffraction, electron microscope, and crosslinking data. All of the trichocyte keratins so far examined by electron microscopy exhibit similar filament/matrix textures and the mechanism of sheet formation proposed here is likely to have general applicability.

The effect of different grades of hydroxyethyl cellulose (HEC) and hydroxypropyl methllcellulose (HPMC) on the film-formation and taste-masking ability for ibuprofen granules was evaluated. Three batches of coated ibuprofen granules were prepared using a roto-granulator, each with a different coating composition. Two grades of HEC [MW300,000 (H) and MW90,000 (L)] were combined with three different grades of HPMC [MW 11,000 (L), MW 25,000 (M) and MW 35,000 (H)] to prepare the coating solutions. Mechanical strength and physical properties of the polymer films were evaluated. Films made from HPMC (L)/HEC (H), HPMC (M)/HEC (H), and HPMC (H)/HEC (H) were stronger and more flexible than the HPMC (L) HEC (L) films. The assay, dissolution, particle size distribution, and environmental scanning electron microscopy (ESEM) data of the three batches of the coated ibuprofen granules were similar.

The reproducibility of toxicologic test methods, including alternative tests, is a key scientific and regulatory concern. In the present work, historic rabbit eye irritation data were used to determine the intra- and interlaboratory reproducibility of the low volume eye test (LVET). The standard Draize eye irritation test was used as the basis for comparison. The LVET and Draize tests had similar degrees of intra- and interlaboratory reproducibility as determined by examination of their coefficients of variation, although the variability in LVET results was directionally lower. Results from 70 parallel Draize and LVET tests indicated a strong positive association between results from the two tests, for corneal, iridial, conjunctival, and maximum average scores (MAS). Correlation coefficients were 0.60, 0.73, 0.69, and 0.73, respectively (P

The up-and-down procedure (UDP), fixed-dose procedure (FDP) and conventional LD50 tests were compared to determine their consistency in chemical hazard classification for acute oral toxicity according to the European Economic Community (EEC) system. There was consistent classification for 23 out of 25 cases between the UDP and the conventional LD50 results, in 16 out of 20 cases between the FDP and the conventional LD50, and in seven out of 10 cases between the UDP and the FDP. The UDP needed only between six and 10 animals of one sex (fewer than either the LD50 or the FDP). Available literature indicates that the sexes are usually similar in their acute toxicity responses and that of females are often more sensitive than males when acute toxicity differences do exist, thus obviating the need for both sexes to be tested in most cases. Unlike the FDP, the UDP also estimates an LD50, thus providing data directly applicable to all current hazard classification systems based on acute oral toxicity.

Guinea pigs were exposed once a week for 10 weeks by intratracheal exposure to solutions of 3, 1, 0.3, or 0.1 micrograms of the enzyme protein, Subtilisn Carlsberg (Alcalase), in 250 micrograms of a detergent base. Other groups of guinea pigs were exposed by inhalation (6 hr per day, 4 days a week) to 1 mg/m3 of the aerosolized detergent base containing either 3.5, 1.1, 0.3, or 0.1% Alcalase protein. Evaluations of gross respiratory responses immediately following each intratracheal exposure revealed a significant dose response in respiratory symptoms measurable after the fourth exposure and continuing throughout the study. In the inhalation experiment, during Weeks 4 through 10, animals were observed to have respiratory symptoms which were dependent upon both the dose of enzyme and on total exposure to the enzyme/detergent atmosphere. For both intratracheal and inhalation routes of exposure, the initial appearance of respiratory symptoms coincided with the first appearance of measurable serum allergic antibodies specific to Alcalase. The allergic antibody levels increased with time and dosage by both routes of exposure, and the antibody titers generated by the intratracheal administration of antigen were comparable to those generated by the inhalation route of exposure. These results indicate that the intratracheal technique is appropriate for the evaluation of the respiratory allergic response to a protein.

Although the Draize eye irritation test has provided important and useful information for eye safety assessments, considerable effort has been directed toward refining the assay procedure, reducing the number of animals used, and replacing this assay with alternative methods. The low-volume eye test (LVET) is a refinement of the Draize eye irritation test that uses 1/10 the volume of test substance placed directly on the cornea. The level and duration of eye irritation in the LVET are less than those in the Draize procedure, which means that it is a less stressful test. Furthermore, LVETs are more predictive of human response. Statistical studies have been conducted to determine the effects of reducing the number of animals used in the Draize test. These results suggested that a three-animal test would provide essentially the same information as the six-animal test. A similar analysis has not been performed on results from the LVET. Accordingly, the present study was undertaken to evaluate previously existing LVET data to determine if the number of animals used in a LVET can be decreased as has been shown for the Draize test. The results of the analysis are consistent with the findings of earlier evaluations of classical Draize data. Three-animal subsets from 119 six-animal LVETs provided the correct classification greater than 92% of the time for three different classification schemes. Furthermore, the discrepancies between the three-animal subsets and the six-animal maximum average score tended to be smaller than those observed for the Draize test.(ABSTRACT TRUNCATED AT 250 WORDS)

Groups of young, sexually mature Fischer-344 rats (n = 25/sex) obtained from commercial breeders were examined ophthalmologically and histopathologically to determine the prevalence and severity of corneal basement membrane lesions (corneal dystrophy) and basement membrane changes in select nonocular tissues. Results disclosed a high incidence of corneal basement membrane dystrophy in rats of both sexes from all breeders; however, severity levels were significantly increased in rats obtained from one breeder when compared to others. Furthermore, rats that displayed the most advanced corneal lesions also exhibited more severe basement membrane changes in other organs, especially renal tubules and vascular internal laminae. These findings suggest that both ocular and nonocular dystrophic changes may have been linked through common physiologic (or genetic) mechanisms. Animals that displayed basement membrane lesions were not considered to represent compromised biologic test systems.

Two 2-year feeding studies were carried out in Fischer 344 rats with olestra, a mixture of the hexa-, hepta- and octaesters of sucrose formed with long-chain fatty acids. Olestra was fed at 0, 0.99, 4.76 or 9.09% (w/w) of the diet in the first study, and at 0 or 9.09% (w/w) of the diet in the second. Daily observations, feed consumption and body weights, ophthalmoscopic examinations, organ weights, serum chemistry, haematology, urinalysis and histopathological evaluations revealed no evidence of any adverse effects associated with olestra ingestion. Relative to controls, there was a higher incidence of basophilic liver foci in olestra-fed female rats at 12 months. At 24 months, foci were observed in most animals in all groups but were more numerous in olestra-fed females. The foci were not associated with hepatic tumours, alterations in liver function, or increases in liver weight and therefore not considered to represent a toxic response to olestra. Isolated statistically significant differences in mortality, mononuclear cell leukaemia, and pituitary adenomas were observed but were not considered to be related to olestra ingestion since they were not reproducible across the two studies, generally not dose responsive, not consistent between sexes, and the incidences were within the ranges for historical and contemporary laboratory controls. The results of the two studies show that olestra was not toxic or carcinogenic when fed to rats at up to 9% of the diet for 24 months.

The acute oral toxicity data for 10 compounds, generated by using two alternative methods in rats, the up-and-down method and the fixed-dose procedure, were compared with those obtained from the classical LD50 test. In this evaluation, both alternative methods offered a reduction in animal use, while providing adequate information to rank the compounds according to the EEC classification for acute oral toxicity. In addition to the ranking, these alternative methods also provided useful information on signs of toxicity and gross autopsy findings, although the results varied depending on the method used. Of the three methods, the up-and-down method required the fewest animals. Although the up-and-down method used only females, the LD50 values obtained were in good agreement with those obtained by the classical method, which used both sexes. It is concluded that the up-and-down method and the fixed-dose procedure are acceptable alternative methods to the classical LD50 test, and the choice of method depends on the type of toxicity information required.

Quantitation of food consumption is necessary when determining mutation responses to multiple chemical exposures in the sex-linked recessive lethal assay in Drosophila. One method proposed for quantitating food consumption by Drosophila is to measure the incorporation of 14C-leucine into the flies during the feeding period (Thompson and Reeder: Environmental Mutagenesis 10:357-365, 1987). Three sources of variation in the technique of Thompson and Reeder have been identified and characterized. First, the amount of food consumed by individual flies differed by almost 30% in a 24 hr feeding period. Second, the variability from vial to vial (each containing multiple flies) was around 15%. Finally, the amount of food consumed in identical feeding experiments performed over the course of 1 year varied nearly 2-fold. The use of chemical consumption values in place of exposure levels provided a better means of expressing the combined mutagenic response. In addition, the kinetics of food consumption over a 3 day feeding period for exposures to cyclophosphamide which produce lethality were compared to non-lethal exposures. Extensive characterization of lethality induced by exposures to cyclophosphamide demonstrate that the lethality is most likely due to starvation, not chemical toxicity.

A review of epidemiology literature revealed that only studies conducted in Africa and Asia included data adequate to permit quantitative assessment of the dose-response relationship between aflatoxin exposure levels and liver cancer rates. Although these studies were judged adequate, their direct use to predict risks in U.S. populations may be questioned since hepatitis B virus (HBV) infections are far more common in the studied areas than in the U.S. Recent research indicates that, if aflatoxin contributes to the development of liver cancer, it almost always does so in the presence of HBV infection. The African/Asian data do not permit us to estimate the potency of aflatoxin in the absence of HBV. Recognizing this, these data can only be used to establish upper limits for the predicted excess lifetime risk for liver cancer in the U.S. When used in conjunction with aflatoxin exposure estimates for the Southeast U.S., these data predict a liver cancer rate, due to aflatoxin alone, far above that actually observed due to all causes; this provides an indication of the conservatism of this approach. Data from the Southeast U.S. may be used to estimate an excess lifetime risk for liver cancer of 2.17 x 10(-6) x (aflatoxin intake, ng/kg/day).

Previous studies have reported that striking variations in hepatocellular vacuolization occurs in rabbits and the magnitude of vacuolization correlated independently with weight and sex. The current study evaluated the effects of feed restriction and gonadectomy on this hepatocellular vacuolization. For 28 days, rabbits were fed either ad libitum (ad lib group), 100% of the National Research Council's recommended feed intake required for growth (100% group), or 50% of the NRC recommended feed intake required for growth (50% group). Feed consumption, weight gain, final body weight, absolute liver weight, and relative liver weight were not significantly different between the ad lib and 100% groups. Values for these parameters for both groups were significantly greater than for the 50% group. Rabbits in the 50% group had significantly less hepatocellular vacuolization than rabbits in the 100% group. Hepatocellular vacuolization in the 100% group did not differ from rabbits fed ad libitum. Hepatocellular vacuolization in the ad lib group was greater than in the 50% group but this difference was not significant. Ovariectomy and orchiectomy did not significantly alter hepatocellular vacuolization in either female or male rabbits, respectively, that were fed ad libitum for 28 days. However, intact females had significantly greater hepatocellular vacuolization than either intact or orchiectomized males. Conversely, hepatocellular vacuolization in ovariectomized females was not significantly different from that in intact and orchiectomized males. There were no significant differences in feed consumption, weight gain, final body weight, and absolute and relative liver weights among these intact and gonadectomized groups. Results of these studies indicate feed consumption can affect the degree of hepatocellular vacuolization in rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Sections of thymus from New Zealand white rabbits used as controls in 28-day and 91-day percutaneous toxicity studies conducted at different laboratories were morphometrically assessed. Measurements of total thymic area, medullary area, and cortical area were greater for 28-day vs 91-day studies conducted at a given laboratory, but varied from one laboratory to another. Relative thymic measurements (percent medulla, percent cortex, and medulla:cortex ratio) were similar for studies conducted at each laboratory and from one laboratory to another regardless of study duration. A decrease in thymic size occurred between approximately 16 and 25 weeks of age (i.e., 28-day studies vs 91-day studies) due to proportionally equivalent decreases in both the cortical and medullary areas. The consistency of the relative measurements can be used to assist in distinguishing changes in thymic size due to aging from changes in size due to stress or toxicity which would be expected to differentially affect the cortical and medullary areas. Appreciation of the normal variation in thymic size is needed when evaluating results of toxicity testing in rabbits. Data are provided as to the degree of normal variation of rabbit thymic size expected within and across percutaneous toxicity studies, with considerations for interpreting such data.

Neonates of animals and humans exhibit a paradoxical ventilatory response to hypoxia characterized by an initial increase in minute ventilation followed by a late, sustained decrease. Exogenous adenosine analogues cause respiratory depression, and the xanthine derivative aminophylline, a competitive inhibitor of adenosine receptors, decreases the amount of hypoxic ventilatory depression in the newborn piglet. Other xanthine derivative such as enprofylline are weak adenosine antagonists. The purpose of this report is to test the hypothesis that enprofylline would not reverse ventilatory depression caused by hypoxia, supporting the suggestion that adenosine contributes to hypoxic ventilatory depression. To confirm the weak adenosine antagonism of enprofylline, L-N6-(phenylisopropyl)adenosine (PIA) was administered to six newborn piglets until respiratory depression was achieved. Either aminophylline or enprofylline was then administered. Aminophylline, but not enprofylline, reversed the respiratory depression caused by PIA. In seven additional piglets, respiratory depression was first produced by 10% oxygen breathing and the ability of saline, aminophylline, and enprofylline to reverse the decrease in ventilation was evaluated. The administration of either saline or enprofylline produced little change in minute ventilation (9.8% +/- 3.7% and -11.7% +/- 7.7%, respectively), whereas aminophylline consistently produced an increase (43.5% +/- 7.3% [P less than 0.001]). Both aminophylline and enprofylline increased heart rate (P less than 0.01), whereas saline produced no significant change. Blood pressure was increased by enprofylline but not by aminophylline or saline. These findings suggest that, in the anesthetized newborn piglet, adenosine contributes to ventilatory depression caused by hypoxia.

This article has briefly summarized the cost of noise control for two standards under consideration by OSHA. Readers are encouraged to find ways to protect the hearing of workers in any way it can be done.

Both nonequilibrium and equilibrium models were proposed to explain the optimal biological response to a set of congeners with respect to the oil-water partition coefficient (P). A detailed analysis of the kinetic model proposed by Hansch demonstrates the bilinear form of the model, with the initial slope of the logarithm of the concentration for 50% receptor binding versus log P having a slope of greater than one. This result is in contrast to the equilibrium model for an initial slope of less than one. Thus, a criterion is established for deciding whether equilibrium or nonequilibrium processes apply.

Ten materials have been tested in parallel both by the "classical" method for acute oral toxicity (LD50) and by the up-and-down method. Materials tested included laundry and dishwashing detergents, a shampoo, a flavor, potassium hydroxide, and caffeine. All testing was done in Sprague-Dawley rats. Excellent agreement was seen between the two methods. The classical method typically used 40 to 50 animals while the up-and-down method required only six to nine animals per material.

Ethylenediaminetetra(methylenephosphonic acid), EDITEMPA, was tested for oral toxicity in rats in a 13-wk feeding study (at doses of 0, 5, 50 and 500 mg/kg/day) and in a chronic feeding study (at doses of 0, 4, 20 and 100 mg/kg/day). EDITEMPA was also tested for genotoxicity in the Ames, mouse lymphoma, unscheduled DNA synthesis, and in vivo cytogenetics assays. Additionally, absorption, distribution and excretion (ADE) studies were conducted following administration of [14C]EDITEMPA to rats by gavage and via the feed and drinking-water. The principal finding in the 13-wk study was mild anaemia in male and female rats given 500 mg/kg/day, which was resolved during a 9-wk recovery period. In the chronic study, there was no substantial evidence of any treatment-related toxicity or carcinogenicity. Differences in survival of control and treated females (noted late in the study) were interpreted to represent unusually good survival in controls; however, a compound-related increase in mortality could not be completely ruled out. Tests for genotoxicity were all negative. ADE studies revealed that [14C]EDITEMPA was poorly absorbed from the gastro-intestinal tract and that most of the absorbed dose was rapidly excreted by the kidneys or sequestered in bone. The gavage route of administration led to four- to six-fold increases in bone EDITEMPA levels as compared with administration in the feed and drinking-water, respectively. These results suggest that no significant toxicity or carcinogenicity concerns arise from EDITEMPA when it is administered in the feed at the concentrations tested. Reversible anaemia was seen only at very high doses and was interpreted as being secondary to EDITEMPA's ability to interfere with iron absorption and utilization. Localization of EDITEMPA in bone indicated a high degree of affinity for mineralizing tissues, consistent with its chelating properties. There was, however, no effect on bone resorption or mineralization. A comparison of human drinking-water levels of 3500 ppm EDITEMPA (based on a no-effect level of 100 mg/kg/day in rats) with the estimated worst-case exposure in humans of 0.01 ppm suggested a safety margin greater than 1 x 10(5).

Marked variation in hepatocellular vacuolization was present in New Zealand white rabbits used as controls in 28-day and 91-day percutaneous studies conducted at 5 different laboratories. Vacuoles in hepatocytes of alcohol-fixed and formalin-fixed livers contained periodic acid-Schiff (PAS)-positive material which was removed with diastase digestion, indicating the presence of glycogen. The magnitude of hepatocyte vacuolization was subjectively assessed by light microscopy using 5 histologic grades. Quantitative measurements of hepatocyte perimeter and lobule radius for representative liver sections of each histologic grade corroborated the different grades used. Factors associated significantly with the degree of vacuolization were sex (females were affected more severely than males), body weight, relative liver weight, and the laboratory conducting the study. Also apparent were variations in mean severity of hepatocyte vacuolization between studies conducted at the same laboratory, and variation in severity of vacuolization within individual studies. Duration of the study and season had no significant association with the degree of vacuolization. Marked variation of hepatocellular vacuolization due to glycogen accumulation must be recognized when evaluating results of toxicity testing in rabbits.

Groups of eight human volunteers and eight albino rabbits, under controlled laboratory conditions, were exposed in one eye without subsequent rinsing to the same concentrations and volumes of four prototype consumer products: fabric softener, shampoo, hand soap, and laundry detergent. Dose volume was 0.10 or 0.01 ml. The dose concentrations were selected to produce moderate effects with recovery within 24 to 48 hr. Two irritation scales were employed with both human and animal subjects: the Draize scale by a technician and a medical scale used with slit lamp examination by an ophthalmologist. Eyes were examined by both graders before and after dosing at specified intervals until recovery. Mean and maximum irritation scores are presented for each grading time, method, and exposure, as are the mean hours to recovery (clearing) for each exposure. Recovery times for human eyes were consistent with those reported previously for accidental human exposures to similar materials. Correlation coefficients for time to clear, comparing human vs rabbit for each dose volume-species combination across the four test products, were 0.72, 0.1 ml-human vs 0.01 ml-rabbit; 0.66, 0.01 ml-human vs 0.01 ml-rabbit; 0.40, 0.01 ml-human vs 0.1 ml-rabbit; 0.35, 0.1 ml-human vs 0.1 ml-rabbit. Thus, recovery time obtained under conditions of the "Low-Volume" test (0.01 ml-rabbit) better correlates with human eye recovery time (either dose volume) than does recovery time under Draize test conditions (0.10 ml-rabbit).(ABSTRACT TRUNCATED AT 250 WORDS)

Aminophylline reduces hypoxic ventilatory depression in newborn piglets and can enhance the release of catecholamines (CATs), which in turn may stimulate ventilation. To determine if the effect of aminophylline on ventilation was due to the release of CATs, we measured plasma CATs and ventilation in two groups of spontaneously breathing newborn piglets less than 4 days old, treated with either aminophylline (n = 7) or normal saline solution (n = 6) during both normoxia and hypoxia. The piglets were anesthetized with ketamine and xylazine and intubated, and the femoral artery was catheterized. Epinephrine and norepinephrine were measured before and 30 minutes after treatment with aminophylline (15 mg/kg) or normal saline. The animals were exposed to 10% oxygen and the CATs again measured after 5 minutes of hypoxia. Respiratory rate, expiratory flow integrated to minute ventilation (VE), heart rate, and blood pressure were continuously recorded. CATs were assayed by high-pressure liquid chromatography with electrochemical detection. Treatment with aminophylline during normoxia was associated with an increase in tidal volume. During hypoxia, treatment with aminophylline prevented a fall in VE and respiratory rate seen in the normal saline group. Epinephrine and norepinephrine increased during hypoxia, but there was no difference between the groups at 5 minutes. In our model the increase in CATs observed during hypoxia was not enhanced by aminophylline. This is consistent with the hypothesis that some mechanism other than catecholamine release is responsible for the effect of aminophylline in reducing neonatal hypoxic respiratory depression.

An up-and down method for acute toxicity (LD50) testing has been developed and statistically evaluated. Compared with the "classical" procedure, this method permits a major reduction in the number of animals used. In the up-and-down procedure, animals are dosed one at a time. If an animal survives, the dose for the next animal is increased; if it dies, the dose is decreased. A survey of 48 acute toxicity tests in rats showed that the great majority of the animals that ultimately died did so within 1 or 2 days. Because of this, it suffices to observe each animal for 1 or 2 days before dosing the next animal. It is recommended, however, that surviving animals be monitored for delayed death for a total of 7 days. The procedure for estimating the LD50 takes into account all deaths, and may be performed using widely available computer program packages. Testing in females alone is recommended, based on the observation that they were generally more sensitive in the survey of 48 studies; selective follow-up in males may sometimes be indicated. The procedure has been tested, by simulation, on 10 of the survey studies. It produced excellent agreement with the original studies. The 95% confidence interval for the LD50 averaged +/- 32% by the up-and-down method, compared with +/- 15% for conventional studies using 40 to 50 animals. The up-and-down procedure will require only 6 to 10 animals, provided that the initial estimate of the LD50 is within a factor of 2 of the true LD50. The method cannot be recommended for testing materials where deaths beyond 2 days postdosing are the rule.