Showing papers on "Toxicity published in 1987"

Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays.

Abstract: Four widely used in vitro assays for genetic toxicity were evaluated for their ability to predict the carcinogenicity of selected chemicals in rodents. These assays were mutagenesis in Salmonella and mouse lymphoma cells and chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Seventy-three chemicals recently tested in 2-year carcinogenicity studies conducted by the National Cancer Institute and the National Toxicology Program were used in this evaluation. Test results from the four in vitro assays did not show significant differences in individual concordance with the rodent carcinogenicity results; the concordance of each assay was approximately 60 percent. Within the limits of this study there was no evidence of complementarity among the four assays, and no battery of tests constructed from these assays improved substantially on the overall performance of the Salmonella assay. The in vitro assays which represented a range of three cell types and four end points did show substantial agreement among themselves, indicating that chemicals positive in one in vitro assay tended to be positive in the other in vitro assays.

Lethal toxicity of lipopolysaccharide and tumor necrosis factor in normal and D-galactosamine-treated mice.

Abstract: The toxic properties of human recombinant tumor necrosis factor (TNF) were investigated in mice made hypersensitive to endotoxin by treatment with D-galactosamine. C3H/TifF mice treated with D-galactosamine were rendered sensitive to the lethal effects of submicrogram amounts of TNF. In the absence of D-galactosamine, TNF caused approximately 80% lethality with 500 micrograms. The duration of sensitization to TNF lasted up to 8 h after D-galactosamine administration, that towards LPS, up to 4 h. As with LPS, with TNF sensitization could be inhibited by uridine administered up to 2 h after D-galactosamine/TNF, showing that the early biochemical alterations in the liver known to be necessary for sensitization to LPS are also necessary for sensitization to TNF. In contrast to LPS, the toxicity of TNF was expressed also in D-galactosamine-treated endotoxin-resistant C3H/HeJ mice. The susceptibility of these mice to TNF was identical to that of endotoxin sensitive mice. In the absence of D-galactosamine the toxicity of TNF in C3H/HeJ mice was comparable to that obtained in C3H/TifF mice, being lethal with amounts of the order of 500 micrograms. The present results support the hypothesis that TNF is a mediator of lethal toxicity of endotoxin.

Central Nervous System Toxicity after Liver Transplantation

Abstract: We describe severe central nervous system (CNS) toxicity, manifested by confusion, cortical blindness, quadriplegia, seizures, and coma, associated with cyclosporine treatment in three patients undergoing liver transplantation. CT and magnetic resonance studies disclosed a severe, diffuse disorder of the white matter. All side effects and radiographic findings were reversed with discontinuation or a reduction in the dose of cyclosporine. We also observed an inverse association between CNS side effects and total serum cholesterol levels after transplantation. A retrospective analysis of 54 liver transplantations performed in 48 patients revealed that 13 patients had symptoms of CNS toxicity associated with the use of cyclosporine. These patients' total serum cholesterol levels in the first week after transplantation were reduced as compared with those in patients without symptoms (mean +/- SE, 94 +/- 4 mg per deciliter vs. 132 +/- 6, or 2.44 +/- 0.10 mmol per liter vs. 3.43 +/- 0.16). We conclude that cyclosporine therapy for immunosuppression in liver transplantation may cause a syndrome of encephalopathy, seizures, and white-matter changes and that this is most likely to occur in patients with low total serum cholesterol levels after transplantation.

Glutathione, a first line of defense against cadmium toxicity.

Abstract: Experimental modulation of cellular glutathione levels has been used to explore the role of glutathione in cadmium toxicity. Mice treated with buthionine sulfoximine [an effective irreversible inhibitor of gamma-glutamylcysteine synthetase (EC 6.3.2.2) that decreases cellular levels of glutathione markedly] were sensitized to the toxic effects of CdCl2. Mice pretreated with a sublethal dose of Cd2+ to induce metallothionein synthesis were not sensitized to Cd2+ by buthionine sulfoximine. Mice sensitized to Cd2+ by buthionine sulfoximine were protected against a lethal dose of Cd2+ by glutathione mono isopropyl ester (L-gamma-glutamyl-L-cysteinylglycylisopropyl ester), but not by glutathione. These results are in accord with studies that showed that glutathione mono esters (in contrast to glutathione) are efficiently transported into cells and converted intracellularly to glutathione. The findings indicate that intracellular glutathione functions in protection against Cd2+ toxicity, and that this tripeptide provides a first line of defense against Cd2+ before induction of metallothionein synthesis occurs. The experimental approach used here in which cellular levels of glutathione are decreased or increased seems applicable to investigation of other types of metal toxicity and of other glutathione-dependent biological phenomena.

Glutathione, a first line of defense against cadmium toxicity

Abstract: Experimental modulation of cellular glutathione levels has been used to explore the role of glutathione in cadmium toxicity. Mice treated with buthionine sulfoximine (an effective irreversible inhibitor of ..gamma..-glutamylcysteine synthetase (EC 6.3.2.2) that decreases cellular levels of glutathione markedly) were sensitized to the toxic effects of CdCl/sub 2/. Mice pretreated with a sublethal dose of Cd/sup 2 +/ to induce metallothionein synthesis were not sensitized to Cd/sup 2 +/ by buthionine sulfoximine were protected against a lethal dose of Cd/sup 2 +/ by glutathione mono isopropyl ester (L-..gamma..-glutamyl-L-cysteinylglycylisopropyl ester), but not by glutathione. These results are in accord with studies that showed that glutathione mono esters (in contrast to glutathione) are efficiently transported into cells and converted intracellularly to glutathione. The findings indicate that intracellular glutathione functions in protection against Cd/sup 2 +/ toxicity, and that this tripeptide provides a first line of defense against Cd/sup 2 +/ before induction of metallothionein synthesis occurs. The experiment approach used here in which cellular levels of glutathione are described or increased seems applicable to investigation of other types of metal toxicity and of other glutathione-dependent biological phenomena.

Reactive free radical generation in vivo in heart and liver of ethanol-fed rats: correlation with radical formation in vitro

Abstract: Rats fed a high-fat ethanol-containing diet for 2 weeks were found to generate free radicals in liver and heart in vivo. The radicals are believed to be carbon-centered radicals, were detected by administering spin-trapping agents to the rats, and were characterized by electron paramagnetic resonance spectroscopy. The radicals in the liver were demonstrated to be localized in the endoplasmic reticulum. Rats fed ethanol in a low-fat diet showed significantly less free radical generation. Control animals given isocaloric diets without ethanol showed no evidence of free radicals in liver and heart. When liver microsomes prepared from rats fed the high-fat ethanol diet were incubated in a system containing ethanol, NADPH, and a spin-trapping agent, the generation of 1-hydroxyethyl radicals was observed. The latter was verified by using 13C-substituted ethanol. Microsomes from animals fed the high-fat ethanol-containing diet had higher levels of cytochrome P-450 than microsomes from rats fed the low-fat ethanol-containing diet. The results suggest that the consumption of ethanol results in the production of free radicals in rat liver and heart in vivo that appear to initiate lipid peroxidation.

Fatal toxicity of antidepressant drugs in overdose.

Abstract: A fatal toxicity index (deaths per million National Health Service prescriptions) was calculated for antidepressant drugs on sale during the years 1975-84 in England, Wales, and Scotland. The tricyclic drugs introduced before 1970 had a higher index than the mean for all the drugs studied (p less than 0.001). In this group the toxicity of amitriptyline, dibenzepin, desipramine, and dothiepin was significantly higher, while that of clomipramine, imipramine, iprindole, protriptyline, and trimipramine was lower. The monoamine oxidase inhibitors had intermediate toxicity, and the antidepressants introduced since 1973, considered as a group, had significantly lower toxicity than the mean (p less than 0.001). Of these newer drugs, maprotiline had a fatal toxicity index similar to that of the older tricyclic antidepressants, while the other newly introduced drugs had lower toxicity indices, with those for mianserin, nomifensine, trazodone, and viloxazine reaching significance. Provided that these drugs are equally effective clinically, serious consideration should be given to prescribing antidepressants with a lower fatal toxicity.

Inhalation Toxicity Studies With 1,3-Butadiene 3 Two Year Toxicity/Carcinogenicity Study in Rats

Abstract: Groups of 110 male and 110 female CD (Sprague-Dawley) rats were exposed to atmospheres containing 0 (control), 1000 or 8000 ppm v/v butadiene for 6 hr/day and 5 days/week. Ten of each sex from each group were killed at 52 weeks. The study was terminated when it was predicted that survival would drop to 20% to 25% (105 weeks for females and 111 weeks for males). High dose rats had wet, ruffled fur and showed slight incoordination during the first exposure each week. During the second year, mortality in both treated female groups was increased because of humanitarian sacrifice of animals with large subcutaneous masses, while increased mortality in the high dose males was accompanied by an increase of the severity of nephropathy. Body weight was slightly lower than controls in both sexes at the high dose, but statistically significant only over the first 12 weeks. There were no effects in hematological analyses or tests of neuromuscular function that definitely could be associated with treatment. Liver weigh...

Prevention of lethal and renal toxicity of cis-diamminedichloroplatinum(II) by induction of metallothionein synthesis without compromising its antitumor activity in mice.

Abstract: The participation of renal metallothionein (MT) in the toxicity and antitumor activity of cis-diamminedichloroplatinum(II) (cis-DDP) in male mice was examined. Preinduction of MT in the kidney by the s.c. administration of bismuth compounds decreased the lethality and renal and gastrointestinal toxicity caused by a single s.c. injection of cis-DDP. In the present study a correlation between the protective effect of pretreatment with bismuth nitrate against cis-DDP toxicity and the preinduced MT levels in the kidney was observed. Bismuth nitrate pretreatment showed no effect on the antitumor activity of cis-DDP against several transplantable tumors, probably because it induces MT in the kidney but not in tumor tissues. The fact that p.o. preadministration of bismuth subnitrate, an antidiarrheal drug, also depressed the lethal toxicity of cis-DDP is promising for its prompt application in medical attention. Thus, bismuth pretreatment allows higher doses of cis-DDP with no apparent toxicity, resulting in more efficient utilization of this anticancer drug.

Fish acute toxicity syndromes and their use in the QSAR approach to hazard assessment.

Abstract: Implementation of the Toxic Substances Control Act of 1977 creates the need to reliably establish testing priorities because laboratory resources are limited and the number of industrial chemicals requiring evaluation is overwhelming. The use of quantitative structure activity relationship (QSAR) models as rapid and predictive screening tools to select more potentially hazardous chemicals for in-depth laboratory evaluation has been proposed. Further implementation and refinement of quantitative structure-toxicity relationships in aquatic toxicology and hazard assessment requires the development of a "mode-of-action" database. With such a database, a qualitative structure-activity relationship can be formulated to assign the proper mode of action, and respective QSAR, to a given chemical structure. In this review, the development of fish acute toxicity syndromes (FATS), which are toxic-response sets based on various behavioral and physiological-biochemical measurements, and their projected use in the mode-of-action database are outlined. Using behavioral parameters monitored in the fathead minnow during acute toxicity testing, FATS associated with acetylcholinesterase (AChE) inhibitors and narcotics could be reliably predicted. However, compounds classified as oxidative phosphorylation uncouplers or stimulants could not be resolved. Refinement of this approach by using respiratory-cardiovascular responses in the rainbow trout, enabled FATS associated with AChE inhibitors, convulsants, narcotics, respiratory blockers, respiratory membrane irritants, and uncouplers to be correctly predicted.

The effect of hydralazine on the tumor cytotoxicity of the hypoxic cell cytotoxin RSU-1069: evidence for therapeutic gain.

Abstract: The effect of the vasodilator hydralazine on both the tumor and systemic toxicity of RSU-1069 has been evaluated in C57B1 mice bearing Lewis lung tumors. The results obtained indicate that both hydralazine and RSU-1069 are cytotoxic to the Lewis lung tumor on their own. However, administration of hydralazine (5 mg/kg PO) at times up to either 3 hr before or 3 hr after RSU-1069 (0.1 mg/g IP) results in a level of cell killing greater than expected from additive effects. This potentiation by hydralazine was observed with doses of RSU-1069 from 0.01 to 0.1 mg/g. The results obtained using excision assays were confirmed using in situ growth delay as the endpoint. Growth delay (+/- s.e.m.) values for tumors to double in volume of 1.5 (+/- 1.2), 2.0 (+/- 1.3) and 6.0 (+/- 0.9) were obtained for hydralazine (5 mg/kg PO) alone, RSU-1069 (0.1 mg/g IP) alone and for hydralazine administered at the same time as RSU-1069 respectively. In contrast to the potentiating effect of hydralazine on the tumor cytotoxicity of RSU-1069, it had no significant effect on the systemic toxicity of RSU-1069 as measured by LD50/30d. No detailed studies to examine the mechanism responsible for the potentiation of tumor cytotoxicity have been performed in the present study. However, the results obtained would be consistent with previous reports that vasodilators such as hydralazine can selectively reduce tumor blood flow and thus oxygenation. Such reduced tumor oxygenation would increase the cytotoxic effects of RSU-1069 which is known to be more toxic to cells at reduced oxygen levels.

Cerebellar toxicity with high-dose cytosine arabinoside.

Abstract: CNS dysfunction, especially impaired cerebellar function, is the dose-limiting toxicity associated with high-dose cytosine arabinoside, which precludes doses of greater than 48 g/m2. Four hundred eighteen patients between the ages of 2 and 74 years with leukemia or lymphoma received 36 to 48 g/m2 cytosine arabinoside either alone or with anthracycline antibiotics, 4'-(9-acridinylamino) methane sulfon-m-anisidine (m-AMSA), or total body irradiation. In only 35 of 418 patients (8%) did severe cerebellar toxicity develop; it was irreversible or fatal in four (1%) patients. The age of the patient was a critical factor in the incidence of severe cerebellar toxicity. Patients greater than 50 years old had a statistically significant greater incidence of cerebellar toxicity compared with younger patients (26/137, 19%, v 9/281, 3%; P less than .0005, chi 2). Neither the diagnosis, disease status, sex, nor the regimen altered the incidence of severe cerebellar toxicity (when corrected for age). A second course of ...

Investigation of the relationship between invertebrate predation and biochemical composition, energy content, spicule armament and toxicity of benthic sponges at McMurdo Sound, Antarctica

Abstract: The biochemical and energetic composition, spicule content, and toxicity of benthic sponges was investigated in McMurdo Sound, Antarctica from October through December 1984. The predominant organic constituent of sponges was soluble and insoluble protein. Levels of total protein ranged from 17.0 to 55.9% dr. wt. Levels of lipid and carbohydrate were low, ranging from 2.1 to 9.6 and 0.6 to 3.5% dr. wt, respectively. Levels of ash were high and variable (32 t0 79% dr. wt), reflecting species-specific differences in spicule contents. Calculated energy contents of sponges were low, with a mean of 9.8±3.5 kJ g-1 dr. wt; ranging from 5.1 kJ g-1 dr. wt in Sphaerotylus antarcticus to 17.4 kJ g-1 dr. wt in Dendrilla membranosa. Insoluble protein accounted for the greatest contribution to the energetic composition of the sponges, while lipid and carbohydrate combined contributed to less than 25% of the overall energy. Normalized spicule volumes of sponges ranged from 0.15 to 0.38 cm3 g-1 dr. wt. Ichthyotoxicity assays indicated that 9 (56%) of 16 antarctic sponge species were toxic. The most highly toxic species were Mycale acerata and Leucetta leptorhapsis. The high incidence of toxicity in antarctic sponges indicates that the current hypothesis suggesting a simple inverse relationship between toxicity and latitude in marine sponges is invalid. There was little correspondence between the energetic composition or spicule contents of the sponges and feeding patterns (electivity indices) of sponge-eating predators. Although the asteroid Perknaster fuscus antarcticus specializes on the highly toxic, fast-growing M. acerata, most antarctic sponge-eating predators appear to be generalists which feed on the more abundant, non- to mildly-toxic, sponge species. This feeding strategy is based on exploitation of low energy, sedentary prey, which require a minimal energy output to harvest.

Pharmacology and toxicity of high-dose ketoconazole.

Abstract: One hundred sixty patients were entered in two multicenter protocols to receive 400 to 2,000 mg of ketoconazole once daily for nonmeningeal or meningeal coccidiodomycosis. For 24 h after administration of all doses, mean concentrations in serum exceeded MICs for Coccidioides immitis (trough concentrations, greater than 1 microgram/ml). Mean peak concentrations occurred 4 to 6 h after administration, ranging from 7 to 17 micrograms/ml for doses of 400 to 2,000 mg. Incremental increases in peak concentrations in serum were greatest at doses of less than or equal to 1,200 mg. To investigate whether long-term therapy altered concentrations in serum, serial data were studied by several methods. The results suggested a trend to increased levels in serum with prolonged therapy, but were not statistically significant. All 168 cerebrospinal fluid (CSF) samples from meningitis patients contained less than or equal to 2.9 micrograms/ml, and only 6 contained greater than 1 microgram/ml. There was no apparent relation between dose, time after dose, site of CSF sampling, or concurrent inflammation and CSF ketoconazole concentration. Neither concentration in serum, toxicity, nor outcome correlated with dose, calculated in milligrams per kilogram at the fixed doses (400-mg increments) under study. Likewise, at the various doses, concentration in serum did not correlate with outcome or toxicity, suggesting that individual drug disposition was not an important factor in outcome or toxicity. Toxicity was reversible, and principal side effects were nausea and vomiting (50%), gynecomastia (21%), decreased libido (13%), alopecia (8%), elevated liver function tests (5%), pruritus (5%), and rash (4%). Gastrointestinal and endocrinologic toxicity were dose related and increased at doses greater than 800 mg. The cumulative percent toxicity requiring discontinuation of drug was 6, 17, 23, and 56% at 400-, 800-, 1,200-, and 1,600-mg doses. Doses of >400 mg are thus markedly more toxic, and efficacy data for nonmeningeal disease have not demonstrated that they are more efficacious.

Angio-oedema and urticaria associated with angiotensin converting enzyme inhibitors.

Abstract: All reports from the United Kingdom of suspected adverse reactions to captopril and enalapril received by the Committee on Safety of Medicines from the dates they were first sold (May 1981 and January 1985, respectively) up to January 1986 were examined. Enalapril-Thirteen patients developed angio-oedema (table); one also developed urticaria. The reaction occurred after the first dose in six patients and within five days in the remainder. No formal rechallenge tests were described though the reaction occurred acutely after each oftwo doses taken by one patient. Angio-oedema resolved within one to two days after the drug was stopped in 12 patients; two patients were treated with steroids. Urticaria alone was reported in seven patients (four men) aged 46-80 (mean 59) after daily doses of 5-20 mg. Four patients had hypertension, and three with heart failure received concomitant diuretic treatment. The reaction occurred after the first dose in one patient, within four days in three, and within 10, 14, and 16 days in the remainder. Drug withdrawal resulted in the resolution of signs in all patients within one to seven days. Captopril-Six patients developed angio-oedema (table); three also developed urticaria. The reaction occurred two to 28 days after treatment started and resolved within one to four days after drug withdrawal in four patients. The outcome in the two other patients was unknown. Urticaria alone was reported in 17 patients (14 women) aged 53-78 (mean 64). Fifteen were being treated for hypertension and two for heart failure, with daily doses of 25-150 mg. The reaction occurred one hour after the first dose in one, after three days in two, and after 8-60 (mean 31) days in the remaining patients. The signs resolved within six days after drug withdrawal in 16 patients but persisted for two to four weeks after treatment was stopped in two others. A positive result ofrechallenge was reported for two patients. Comment

Corticosteroid toxicity in neuro-oncology patients

Abstract: Hospital charts from 59 patients with intracranial malignancy or epidural spinal cord compression were reviewed to establish the frequency of clinically important corticosteroid toxicities and to determine treatment or patient characteristics which were predictive for toxicity. Thirty patients (51%) developed at least one steroid toxicity and eleven (19%) required hospital admission for diagnosis and/or management of steroid-related complications. In this retrospective analysis the duration of steroid therapy and the total administered dose predicted for toxicity. Patients with toxicity also had a significant fall in the serum albumin level. Important corticosteroid toxicity occurs frequently in neuro-oncology patients. Further research should be directed at developing non-toxic alternatives to corticosteroids.

Use of respiratory‐cardiovascular responses of rainbow trout (Salmo gairdneri) in identifying acute toxicity syndromes in fish: Part 1. pentachlorophenol, 2,4‐dinitrophenol, tricaine methanesulfonate and 1‐octanol

Abstract: An in vivo fish model was adapted to monitor respiratory-cardiovascular responses of spinally transected rainbow trout exposed to acutely toxic aqueous concentrations of two uncouplers of oxidative phosphorylation, pentachlorophenol (PCP) and 2,4-dinitrophenol (DNP), and two narcotics, tricaine methanesulfonate (MS-222) and 1-octanol. The most evident toxic response to the uncouplers was a rapid 150 to 200% increase in ventilation volume (VG) and oxygen consumption (VO2) over the entire survival period. This caused an initial increase in total arterial oxygen (TaO2) content of the blood, which then fell slowly as the tissues used more and more oxygen to generate ATP. Arterial blood pressure (BPa) and other blood measurements did not change appreciably in response to PCP, yet DNP caused increases in hematocrit (Hct) and hemoglobin (Hb) and slight decreases in total arterial carbon dioxide (TaCO2) and arterial pH (pHa). In contrast to the uncouplers, the response of the respiratory-cardiovascular system of trout to toxic levels of narcotics was a dramatic slowing of all respiratory-cardiovascular functions. While VG and VO2 decreased 40 to 50% from predose levels, oxygen utilization (U) increased 20 to 30%. Ventilation rate (VR) declined initially and then increased slowly until death occurred, but remained within the control range. As respiration declined TaCO2 significantly decreased, as did pHa. In response to hypoxia, Hct increased substantially, and Hb increased slightly only in the 1-octanol exposure. A rapid 40 to 50% drop in heart rate (reflex bradycardia) was also observed. The final phase of toxicity caused by both uncouplers and narcotics appeared to eventually produce acute tissue hypoxia, with a generalized loss of respiratory-cardiovascular coordination, and finally respiratory paralysis. Individual principal component analyses of the cardiovascular-respiratory responses of fish exposed to the first two principal components explained 68 to 76% of the variation in the 18 parameters analyzed. A two-dimensional diagram of the first two principal components illustrated this multivariate response and the increased variability in the responses of exposed fish as compared with control fish. The general sets of responses described for these two fish acute toxicity syndromes have provided the initial information necessary to group similar responses caused by other chemicals into a fish uncoupler syndrome, a fish narcosis syndrome or some new syndrome.

Non-toxic potentiation of cancer chemotherapy by combined C and K3 vitamin pre-treatment.

Abstract: The influence on the survival of ascitic liver tumor (TLT)-bearing mice of combined vitamins C and K3 administered before or after a single i.p. dose of 6 different cytotoxic drugs, all commonly used in human cancer therapy, was investigated. Combined i.p. administration of these vitamins produced a distinct chemotherapy-potentiating effect for all drugs examined, especially when injected before chemotherapy. This potentiating treatment did not increase the general and organ toxicity that accompanies cancer chemotherapy. The possible generation of peroxides followed by membrane lipid alteration, DNase activation and DNA destruction by combined vitamin C and K3 in catalase-deficient cancer cells might be involved in the mechanisms of this selective potentiation.

Univariate and multivariate analyses of risk factors predisposing to auditory toxicity in patients receiving aminoglycosides.

Abstract: Risk factors predisposing to auditory toxicity of aminoglycosides were analyzed from records of 187 patients enrolled in three prospective randomized trials comparing the toxicity of netilmicin, tobramycin, and amikacin. Patients were eligible if they received three or more days of therapy and at least two serial audiograms were available. The overall auditory toxicity rate was 9.6% (18 of 187). Auditory toxicity was detected in 4.4, 10.8, and 23.5% of patients given netilmicin, tobramycin, and amikacin, respectively (P = 0.05). In the univariate analysis, patients who developed auditory toxicity were significantly older (P = 0.01) and had a significantly higher (P = 0.04) percentage of trough levels of netilmicin or tobramycin above 2 mg/liter or amikacin above 5 mg/liter. In the final logistic regression model, only age was retained as independently influencing the development of auditory toxicity (P less than 0.00001). Conversely, factors that did not add significantly to the prediction of auditory toxicity were aminoglycoside serum levels, total aminoglycoside dose, duration of therapy, sex, peak temperature, presence of bacteremia, shock, liver cirrhosis, dehydration, previous otic pathology or renal failure, and development of renal toxicity. At least in certain populations, age is the most important predisposing factor for the development of auditory toxicity in patients receiving aminoglycosides.

Toxicity of intravesical BCG and its management in patients with superficial bladder tumors.

Abstract: Toxicity of bacillus Calmette-Guerin (BCG) Pasteur strain, given in a dose of 120 mg once a week for 6 weeks, was retrospectively evaluated in a study of 107 patients with recurrent superficial bladder cancer. Only six patients had no symptoms of toxicity. Severe cystitis (ten patients) was most likely to occur in those with decreased bladder compliance before treatment. Systemic symptoms resembling those of influenza (flu) were severe in six patients. Potentially serious complications occurred in six patients. Overall, toxic reactions were mild and self limited, and toxicity often could be easily managed by a reduction in the BCG dose (17 patients), temporary interruption of treatment (five patients), or cessation (four patients). Late occurrence of bladder granulomas (32 patients) and cystoscopic appearance of significant cystitis (55 patients) did not correlate with posttreatment voiding symptoms, and these changes were temporary and confined to the first 6 months after treatment. There were no cases of late bladder contracture, and none of the patients free of voiding symptoms before treatment had such symptoms afterward. Extravesical granulomas were observed in 37 patients and were the cause of obstruction of the urinary tract in nine. Pretreatment skin reactivity did not correlate with toxicity, and concurrent percutaneous administration of BCG had no effect on toxicity. BCG has a cumulative effect, so increased toxicity is to be expected during long-term administration. BCG toxicity is primarily a response of the cell-mediated immune system, and transient local or systemic infection appears to be important. This fact suggests that immunosuppression is a relative contraindication to BCG use.