RESUMEN
BACKGROUND: Vemurafenib is a targeted therapy approved for the treatment of patients with metastatic melanoma harbouring the BRAF V600E mutation. Photosensitivity has been reported in over 50% of patients and has been demonstrated to involve at least the broadband UVA spectrum in most patients. Erythrocyte protoporphyrin levels have also been reported as elevated in some patients. OBJECTIVES: We report the results of monochromator phototesting in one patient recorded before and while taking vemurafenib. Analysis of porphyrin levels was also conducted. RESULTS: After one month of vemurafenib therapy the patient demonstrated markedly increased light sensitivity in the UVA spectrum between 335 ± 27 nm, 365 ± 27 nm and 400 ± 27 nm. However responses in the UVB (305 ± 5 nm) and blue light (430 ± 27 nm) regions were normal. There was no abnormal immediate erythemal response. Pre-vemurafenib baseline phototesting was normal, as was repeat testing two months later when the patient was taking high doses of systemic steroid. No abnormal porphyrins were detected and the antinuclear antibody test was normal. In parallel studies, HaCaT keratinocytes incubated with vemurafenib were killed by UVA but not by visible (blue) light and did not show evidence of detectable intracellular porphyrin in the presence of the drug. CONCLUSION: These data confirm vemurafenib induced UVA photosensitivity with a probable phototoxic mechanism not mediated via enhanced porphyrin.
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Dermatitis Fototóxica/etiología , Indoles/efectos adversos , Melanoma/tratamiento farmacológico , Sulfonamidas/efectos adversos , Línea Celular , Clorpromazina/efectos adversos , Cromatografía Líquida de Alta Presión , Dexametasona/uso terapéutico , Eritema/inducido químicamente , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Humanos , Indoles/uso terapéutico , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Queratinocitos/patología , Queratinocitos/efectos de la radiación , Masculino , Melanoma/patología , Persona de Mediana Edad , Porfirinas/metabolismo , Prednisolona/uso terapéutico , Protoporfirinas/metabolismo , Sulfonamidas/uso terapéutico , Rayos Ultravioleta/efectos adversos , VemurafenibAsunto(s)
Anilidas/efectos adversos , Antineoplásicos/efectos adversos , Compuestos de Bifenilo/efectos adversos , Proteínas Hedgehog/antagonistas & inhibidores , Piridinas/efectos adversos , Adulto , Anciano , Alopecia , Carcinoma Basocelular/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
We report the case of a male patient presenting with eosinophilia, pulmonary oedema and eosinophilic fasciitis (EF). He had the classic clinical appearance and magnetic resonance imaging of EF. Cytogenetic analysis of the bone marrow revealed a previously undescribed pericentric inversion of chromosome 5. Overall, the presentation was consistent with a diagnosis of chronic eosinophilic leukaemia, not otherwise specified (CEL-NOS). Dermatologists should consult a haematologist in cases of EF, in order to rule out possible haematological malignancies.
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Inversión Cromosómica , Cromosomas Humanos Par 5/genética , Eosinofilia/genética , Fascitis/genética , Síndrome Hipereosinofílico/genética , Anciano , Médula Ósea , Eosinofilia/patología , Fascitis/patología , Humanos , Cariotipo , MasculinoRESUMEN
BACKGROUND: Podoconiosis is a common cause of lymphoedema in barefoot workers in Ethiopia and other countries. It has severe consequences for patients' physical function, quality of life and economic status. AIMS: To investigate stratum corneum (SC) hydration and transepidermal water loss (TEWL) in patients with podoconiosis compared with controls. METHODS: In total, 55 patients and 20 controls were recruited. For each study subject, SC and TEWL measurements were taken, along with foot and lower leg circumferences. Measurements were compared between the patient and control groups. RESULTS: Foot circumferences tended to be higher in patients with podoconiosis, with the mean foot:leg circumference ratio being 1·19 (95% confidence interval 1·11-1·28) times that for controls (P = 0·001). There was no detectable difference between patients and controls in TEWL values (P > 0·05); however, SC hydration was significantly lower in patients vs. controls for the foot (P = 0·004) and lower leg (P = 0·046) sites. CONCLUSIONS: Patients with podoconiosis have significantly lower SC hydration in the skin of their lower legs and feet than controls, which may lead to cracking and splitting, and increased risk of lymphoedema and infection.
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Elefantiasis/fisiopatología , Epidermis/fisiología , Pérdida Insensible de Agua/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , Femenino , Pie , Humanos , Linfedema/fisiopatología , Masculino , Persona de Mediana Edad , Desequilibrio Hidroelectrolítico/fisiopatología , Adulto JovenRESUMEN
BACKGROUND/PURPOSE: Topical photodynamic therapy (PDT) is increasingly being used to treat skin cancers. Knowledge of the detailed characteristics of 5-aminolaevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence in diseased and normal skin is incomplete. Understanding the characteristics of PpIX fluorescence in normal skin may facilitate optimization of PDT regimes while minimizing side effects in the surrounding normal skin. We investigated the characteristics of ALA-induced PpIX fluorescence in normal skin. METHODS: ALA was applied to the arm, back and leg skin of 21 healthy volunteers for 1-6 h, and PpIX fluorescence was measured for up to 24 h after ALA application using a fluorescent spectrometer. The effect of tape stripping on fluorescence was also examined. RESULTS: Considerable inter-subject variation was observed in the time to reach peak PpIX fluorescence. Intra-subject variation in the time to peak fluorescence was dependent on ALA application time. Six hours after ALA application, no significant difference was observed in the degree of fluorescence achieved irrespective of ALA application times ranging between 1 and 6 h. PpIX fluorescence was reduced on the leg and increased by tape stripping. CONCLUSIONS: Marked inter- and intra-subject variation in ALA-induced PpIX fluorescence occurs in normal human skin. ALA application time, body site and the state of the stratum corneum are all determinants of PpIX fluorescence within subjects and these factors need to be taken into account in optimization of PDT regimes.
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Ácido Aminolevulínico/farmacología , Protoporfirinas/farmacología , Piel/efectos de los fármacos , Adulto , Femenino , Fluorescencia , Humanos , Masculino , Persona de Mediana Edad , Valores de ReferenciaRESUMEN
Components of the innate immune system serve to protect the host from invading pathogens prior to the generation of a directed immune response, and influence the manner in which the directed immune response develops. The pulmonary surfactant system consists of a complex array of proteins and lipids that reduce surface tension of the alveoli, and appears to play an essential role in innate immunity. Investigators have recently gained insight into the interactions between components of the surfactant system and the respiratory pathogen Mycobacterium tuberculosis. It is likely that pulmonary surfactant and other innate immune determinants play significant roles in the pathogenesis of tuberculosis.
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Surfactantes Pulmonares/fisiología , Tuberculosis Pulmonar/inmunología , Animales , Proteínas del Sistema Complemento/fisiología , Perros , Células Epiteliales/fisiología , Humanos , Inmunidad Innata/fisiología , Inmunoglobulinas/fisiología , Macrófagos Alveolares/fisiología , Unión Proteica/fisiología , Conejos , Porcinos , Tuberculosis Pulmonar/patologíaRESUMEN
The allocation of funding for new anticancer treatments within the UK has not kept pace with demand. Clinicians find themselves restricted in the use of licensed drugs which they feel are in the best interests of individual patients. Against this, health authorities have a duty to ensure that scarce resources are used equitably to meet the needs of the local population as a whole. Differential levels of funding for new treatments across the country have led to concerns about rationing by postcode. This paper outlines an approach to the prioritization of new treatment for advanced cancer developed jointly by clinicians and health authorities in South London. The approach involves evidence reviews and consensus meetings. Existing and new treatments are rated on a four-point 'relative effectiveness scale', which takes account of the impact of the treatment on quality of life and on survival. The strength of evidence supporting each effectiveness rating is also classified. Health Authorities have used these ratings to determine overall funding levels, while leaving decisions on individual patients to the relevant Trusts.
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Antineoplásicos/economía , Financiación Gubernamental , Asignación de Recursos para la Atención de Salud , Política de Salud , Neoplasias/tratamiento farmacológico , Análisis Costo-Beneficio , Toma de Decisiones , Quimioterapia/tendencias , Economía Farmacéutica , Medicina Basada en la Evidencia , Humanos , Neoplasias/economía , Formulación de Políticas , Reino UnidoRESUMEN
Preventive therapy for patients infected with tuberculosis (TB) remains an important component of TB control. To guide physicians in applying preventive therapy, the American Thoracic Society and Centers for Disease Control (ATS/CDC) developed guidelines based on PPD reactivity and on pretest probability of infection. The guidelines have become complex, and many clinicians find them challenging to apply. The authors developed a computerized decision-support system to assist clinicians in applying the ATS/CDC guidelines. This tool, published on the World Wide Web using hypertext markup language, delivers patient-specific recommendations based on physician-delivered patient-specific information. Four local TB experts derived eight TB infection scenarios and validated the web-based tool, which was tested for effectiveness using general internal medicine residents, randomly divided into two groups. Group A (n = 12) used the web-based tool and group B (n = 17) used pre-existing understanding of the guidelines and/or written resources to determine the need for preventive therapy in the case scenarios. Group A correctly used therapy in 92/96 possible cases (95.8%), group B in only 77/136 (56.6%) (p < 0.001). Group A required a mean of three mouse-clicks and 1.5 minutes per scenario to reach their choices, and they rated the web-based tool both intuitive and effective. These data demonstrate that a computer-based decision-support system for applying TB treatment guidelines can be delivered over the Internet and provide an efficient and effective resource for clinicians.
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Toma de Decisiones Asistida por Computador , Técnicas de Apoyo para la Decisión , Internet , Guías de Práctica Clínica como Asunto , Tuberculosis Pulmonar/prevención & control , Centers for Disease Control and Prevention, U.S. , Humanos , Tuberculosis Pulmonar/diagnóstico , Estados UnidosRESUMEN
Surfactant protein-D (SP-D) is a collectin produced in the distal lung airspaces that is believed to play an important role in innate pulmonary immunity. Naive immunologic responses to Mycobacterium tuberculosis (M.tb) are especially important in the lung, since entry of this inhaled pathogen into the alveolar macrophage is a pivotal event in disease pathogenesis. Here we investigated SP-D binding to M.tb and the effect of this binding on the adherence of M. tb to human macrophages. These studies demonstrate specific binding of SP-D to M.tb that is saturable, calcium dependent, and carbohydrate inhibitable. In addition to purified SP-D, SP-D in bronchoalveolar lavage fluids from healthy donors and patients with alveolar proteinosis also binds to M.tb. Incubation of M.tb with SP-D results in agglutination of the bacteria. In contrast to its binding to M.tb, SP-D binds minimally to the avirulent Mycobacterium smegmatis. SP-D binds predominantly to lipoarabinomannan from the virulent Erdman strain of M.tb, but not the lipoarabinomannan from M. smegmatis. The binding of SP-D to Erdman lipoarabinomannan is mediated by the terminal mannosyl oligosaccharides of this lipoglycan. Incubation of M.tb with subagglutinating concentrations of SP-D leads to reduced adherence of the bacteria to macrophages (62.7% of control adherence +/- 3.3% SEM, n = 8), whereas incubation of bacteria with surfactant protein A leads to significantly increased adherence to monocyte-derived macrophages. These data provide evidence for specific binding of SP-D to M. tuberculosis and indicate that SP-D and surfactant protein A serve different roles in the innate host response to this pathogen in the lung.
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Proteínas Portadoras/metabolismo , Glicoproteínas/metabolismo , Lectinas/metabolismo , Lipopolisacáridos/metabolismo , Macrófagos/inmunología , Mycobacterium tuberculosis/metabolismo , Fagocitosis/inmunología , Surfactantes Pulmonares/metabolismo , Aglutinación/efectos de los fármacos , Aglutinación/inmunología , Adhesión Bacteriana/efectos de los fármacos , Adhesión Bacteriana/inmunología , Sitios de Unión/efectos de los fármacos , Sitios de Unión/inmunología , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Calcio/fisiología , Metabolismo de los Hidratos de Carbono , Carbohidratos/farmacología , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/farmacología , Glicoproteínas/antagonistas & inhibidores , Glicoproteínas/farmacología , Humanos , Macrófagos/microbiología , Manosa/metabolismo , Mycobacterium smegmatis/metabolismo , Mycobacterium smegmatis/patogenicidad , Mycobacterium tuberculosis/inmunología , Fagocitosis/efectos de los fármacos , Proteína D Asociada a Surfactante Pulmonar , Surfactantes Pulmonares/antagonistas & inhibidores , Surfactantes Pulmonares/farmacología , VirulenciaRESUMEN
Patients with latent tuberculosis characterized by a positive tuberculin (purified protein derivative) skin test and radiographic evidence of fibronodular changes or silicosis are at increased risk for the development of active tuberculosis. Before preventive therapy is initiated, the radiographic abnormalities must be differentiated from those representing active disease. According to recommendations from the American Thoracic Society and the Centers for Disease Control and Prevention, patients with latent tuberculosis who exhibit fibronodular changes or silicosis on chest radiographs should be given either isoniazid alone for one year or the combination of isoniazid and rifampin for four months, preferably with pyrazinamide for the first two months. Patients with similar radiographic findings and sputum or culture evidence of active tuberculosis require full multidrug therapy.
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Tuberculosis Pulmonar/diagnóstico por imagen , Algoritmos , Diagnóstico Diferencial , Humanos , Enfermedades Pulmonares/diagnóstico por imagen , Radiografía , Factores de RiesgoRESUMEN
1. Violent or aggressive behavior may be a consequence of poor frustration tolerance, ineffective individual coping, impulsivity, and real or imagined threats to the individuals territory, body space, or life. 2. It is ironic that at the same time that the numbers of elderly are increasing, available services are decreasing and the number of beds in nursing homes and rest homes are lower than in the past. 3. Nurses must look at the environment in which these patients function to develop strategies and techniques to maximize independence while decreasing aggression.
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Agresión , Enfermería Geriátrica/métodos , Trastornos Mentales/enfermería , Anciano , Anciano de 80 o más Años , Agresión/psicología , Femenino , Humanos , Masculino , Trastornos Mentales/terapia , Persona de Mediana Edad , New England , Relaciones Enfermero-Paciente , Escalas de Valoración Psiquiátrica , Esquizofrenia/enfermería , Medio SocialAsunto(s)
Síndrome de Inmunodeficiencia Adquirida/psicología , Hemofilia A/terapia , Relaciones Médico-Paciente , Revelación de la Verdad , Síndrome de Inmunodeficiencia Adquirida/etiología , Confidencialidad , Negación en Psicología , Factor VIII/efectos adversos , Factor VIII/uso terapéutico , Humanos , Medicina Interna , Mississippi , Inhabilitación MédicaRESUMEN
Groups of guinea pigs were exposed for 3 hr to 6, 13, 19, 27, or 37 ppm of methyl isocyanate (MIC). Pulmonary performance was evaluated immediately postexposure and for a period of 1 year in the animals surviving 19 or 37 ppm of MIC. At 6 and 13 ppm deterioration of pulmonary performance was observed but complete recovery occurred within a few weeks. In those animals surviving 19 or 37 ppm some recovery occurred but a long lasting impairment of pulmonary performance was observed. One year after a single exposure to MIC these animals presented a condition best described as chronic obstructive lung disease. Using flow-volume measurements during air breathing and during CO2 challenge, animals surviving at 19 or 37 ppm presented typical abnormalities associated with airflow limitation along the conducting airways. One year after exposure lung hyperinflation was also present. At this time the poor ventilatory response to CO2 was due to mechanical limitation of lung expansion during inspiration and airflow limitation during expiration. The findings were similar to humans with severe obstructive lung disease. Microscopic examination substantiated the flow-volume measurements in that the main bronchi, small bronchi, and bronchioles were found to have an increase in dense fibrous tissue, while the alveolar level was characterized by destruction of alveolar walls and an increase in septal thickness. Thus a single exposure to MIC, if the concentration is high enough, is sufficient to induce permanent pulmonary toxicity.
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Antidrepanocíticos/toxicidad , Cianatos/toxicidad , Isocianatos , Pulmón/efectos de los fármacos , Administración por Inhalación , Animales , Antidrepanocíticos/administración & dosificación , Peso Corporal/efectos de los fármacos , Dióxido de Carbono/fisiología , Cianatos/administración & dosificación , Eosina Amarillenta-(YS)/metabolismo , Cobayas , Hematoxilina/metabolismo , Histocitoquímica , Riñón/efectos de los fármacos , Riñón/metabolismo , Laringe/efectos de los fármacos , Laringe/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Pulmón/anatomía & histología , Pulmón/fisiología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Respiración/efectos de los fármacos , Respiración/fisiología , Bazo/efectos de los fármacos , Bazo/metabolismo , Factores de TiempoRESUMEN
Guinea pigs were exposed to [14C]methyl isocyanate (14CH3-NCO, 14C MIC) for periods of 1 to 6 hr at concentrations of 0.5 to 15 ppm. Arterial blood samples taken during exposure revealed immediate and rapid uptake of 14C. Clearance of 14C was then gradual over a period of 3 days. Similarly 14C was present in urine and bile immediately following exposure, and clearance paralleled that observed in blood. Guinea pigs fitted with a tracheal cannula and exposed while under anesthesia showed a reduced 14C uptake in blood indicating that most of the 14C MIC uptake in normal guinea pigs occurred from retention of this agent in the upper respiratory tract passages. In exposed guinea pigs 14C was distributed to all examined tissues. In pregnant female mice similarly exposed to 14C MIC, 14C was observed in all tissues examined following exposure including the uterus, placenta, and fetus. While the form of 14C distributed in blood and tissues has not yet been identified, these findings may help to explain the toxicity of MIC or MIC reaction products on organs other than the respiratory tract, as noted by several investigators.
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Cianatos/farmacocinética , Isocianatos , Animales , Bilis/metabolismo , Radioisótopos de Carbono , Glutatión/metabolismo , Cobayas , Masculino , Sistema Respiratorio/metabolismo , Distribución TisularRESUMEN
Effects of starvation (24 and 48 h), dexamethasone, sodium thiosulfate, atropine, and ethanol on the toxicity of methyl isocyanate (MIC) vapor, which escaped during the Bhopal accident of December 3, 1984, were studied in male Swiss-Webster mice. Toxicity to MIC appeared to be biphasic; majority of animals died between 1 and 2 d or between 7 and 21 d after exposure to 40 ppm MIC. Starvation (24 or 48 h) or an injection of 2 mg dexamethasone/kg prior to exposure inhibited the toxicity of MIC, especially during the first 6-7 d; administrations of sodium thiosulfate, alcohol, and atropine before or of dexamethasone after the exposure to MIC were ineffective. Starvation increased serum corticosterone levels. The antidotal effects of both starvation and dexamethasone might be due to suppression of the inflammatory response to MIC.
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Atropina/farmacología , Cianatos/antagonistas & inhibidores , Dexametasona/farmacología , Etanol/farmacología , Isocianatos , Inanición/fisiopatología , Tiosulfatos/farmacología , Animales , Cámaras de Exposición Atmosférica , Peso Corporal/efectos de los fármacos , Corticosterona/sangre , Cianatos/toxicidad , Inyecciones Intraperitoneales , Masculino , RatonesRESUMEN
Desmodur-N (DES-N) or hexamethylene diisocyanate trimer (HDIt), a biuret structure of hexamethylene diisocyanate, is a viscous liquid used for durable coatings and is applied by brushing or spraying. DES-N aerosol has been shown to be primarily a pulmonary irritant following a single exposure in mice. To explore the pulmonary effects of this agent further, groups of guinea pigs were exposed to concentrations ranging from 8 to 121 mg/m3 of DES-N for 3 hr. Prior to and following exposure, each animal was challenged with 10% CO2 in 20% O2 and 70% N2 to evaluate their pulmonary performance. Following a single exposure, these animals displayed a concentration-dependent increase in respiratory rate and decrease in tidal volume, as well as coughing and apnea. Their ventilatory response to 10% CO2 was abnormal and characteristic of a lung restriction response. Some airflow limitation was seen during expiration but this occurred more often during air breathing than during CO2 challenge. With daily exposures repeated for 11 consecutive days, guinea pigs began to adapt to the exposures as indicated by a return to a normal ventilatory response to CO2. This adaptation occurred within the first 5 days of exposures. From Days 6 to 11, there was a demonstrable effect, but the level of response was much less than that following the first exposure. No cumulative effect could be demonstrated with this polyisocyanate and the effect was found to be different than that for mono- or diisocyanates. Acceptable levels of exposure to this polyisocyanate for industrial workers are suggested.
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Cianatos/farmacología , Pulmón/efectos de los fármacos , Aerosoles , Animales , Cianatos/efectos adversos , Relación Dosis-Respuesta a Droga , Cobayas , Humanos , Masculino , Concentración Máxima Admisible , Ratones , Enfermedades Profesionales/inducido químicamente , Tamaño de los Órganos/efectos de los fármacos , Pintura/efectos adversos , Respiración/efectos de los fármacos , Pruebas de Función Respiratoria , Volumen de Ventilación Pulmonar , Factores de TiempoRESUMEN
Methyl isocyanate (MIC) was evaluated for sensory and pulmonary irritation in mice. MIC was found to be both a potent sensory and pulmonary irritant in this species. From these results, a safe level of exposure for a period of 8 hr was estimated to be about 0.02 ppm for humans. Guinea pigs were also exposed to MIC for a single 3-hr exposure at a concentration of 37 ppm. During exposure to MIC, coughing was observed in all animals. Pulmonary function was evaluated immediately following exposure and intermittently on the next 35 days using CO2 challenges and flow-volume loops. Highly abnormal responses to CO2 were observed immediately after exposure in all animals. Six of the eight animals exposed to MIC died. In the two survivors, an apparent recovery was seen during the 5 days following exposure, but a worsening effect was observed at days 21 and 28, with a partial recovery at day 35. The data clearly demonstrated that the primary pulmonary effect of MIC was one of airways obstruction. Oxygen uptake and carbon dioxide output were also measured in the guinea pigs following exposure to MIC. No evidence of a cyanidelike effect was observed, in contrast to a severe depression of oxygen uptake following exposure to hydrogen cyanide.
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Cianatos/toxicidad , Isocianatos , Pulmón/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Células Receptoras Sensoriales/efectos de los fármacos , Obstrucción de las Vías Aéreas/inducido químicamente , Animales , Tos/inducido químicamente , Cianuros , Cobayas , Pulmón/fisiopatología , Masculino , Concentración Máxima Admisible , Ratones , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/inervación , Respiración/efectos de los fármacos , Factores de TiempoRESUMEN
The purpose of this study was to assess sister chromatid exchange (SCE) levels and cell cycle kinetics in various murine tissues following MIC exposure. Following exposure of mice to MIC, these parameters were measured in bone marrow and alveolar macrophages labeled with BrdUrd in vivo and in peripheral blood and spleen lymphocytes cultured in the presence of BrdUrd in vitro. Target concentrations of MIC were 2, 15, and 30 ppm (3 hr). Neither elevated SCE frequencies nor inhibition of cell cycling were evident in lipopolysaccharide (LPS)- or concanavalin A (ConA)-stimulated spleen lymphocytes, or in LPS-stimulated peripheral blood lymphocyte (PBL) cultures from mice exposed for 3 hr to MIC concentrations as high as 30.5 ppm. Inhibition of cell cycling and poor culture success rates were apparent in ConA-stimulated PBLs following MIC exposures as low as 2.3 +/- 0.4 ppm for 3 hr. At the lowest MIC dose employed, the cycling characteristics of bone marrow and alveolar macrophages were not altered, and SCE frequencies were at control levels. However, severe cell cycle inhibition was observed in these tissues at MIC concentrations of 15 ppm or greater. A marker of cytotoxicity at this dose was a high frequency (approximately 33-90%) of occurrence of first division cells containing a late-replicating Y chromosome. Despite its apparent cellular toxicity, MIC is not genotoxic as measured by SCE analysis in the tissues examined in this study.