Agreement between prenatal ultrasonography and fetal autopsy findings: a retrospective study of second trimester terminations of pregnancy.

OBJECTIVES: To estimate the agreement between prenatal ultrasonography observations at 16 - 21 gestational weeks and fetal autopsy findings in pregnancies terminated because of fetal anomalies. STUDY DESIGN: This 4½ year retrospective study includes consecutive fetuses that were terminated because of fetal malformation and/or chromosomal anomaly diagnosed in the second trimester. Only fetuses that had undergone fetal anatomy scanning by an obstetrician trained in fetal ultrasound before the termination and with available fetal autopsy reports were included. The cases were identified through the malformation registry database of our ultrasound unit. The sensitivity and specificity of ultrasound were calculated per organ system. When estimating the agreement between ultrasound results and autopsy findings, the cases were allocated to one of four categories according to the degree of concordance between ultrasound and autopsy findings: full agreement, near match, partial agreement and unconfirmed ultrasound findings. RESULTS: 71 of 95 pregnancy terminations due to fetal malformations met the inclusion criteria and constitute our study population. The sensitivity of ultrasonography with regard to malformations in the brain and spine was 100 % (27/27) and with regard to malformations in the internal organ system (including malformations in the urogenital and gastrointestinal systems and in the abdominal wall and diaphragm) was 91 % (30/33). The corresponding figures for malformations in the cardiovascular and skeletal organ systems were 63 % (17/27) and 71 % (25/35), respectively. The specificity was lowest for malformations in the central nervous system and internal organ system (33/38, 87 % and 39/44, 89 %, respectively). There was full agreement between the ultrasound and autopsy findings in 44 % (31/71) of all cases and a near match in 46 % (33/71) of cases. In almost 10 % (7/71) of the pregnancies, the ultrasound findings were only partially confirmed or not confirmed by autopsy. In one case the discrepancy between the ultrasound and autopsy findings suggests that the pregnant woman might have decided to terminate the pregnancy on the basis of incorrect interpretation of ultrasound findings. CONCLUSION: Even though the agreement between ultrasound and autopsy findings was acceptable from a clinical point of view, agreement with regard to the detailed description of malformations was far from perfect. The detection rates were suboptimal for the cardiovascular and skeletal organ systems.

Evaluation of immune response to artificial infections of Haemonchus contortus in Gulf Coast Native compared with Suffolk lambs.

The Gulf Coast Native (Native) breed of sheep among many others is identified as being relatively resistant to Haemonchus contortus, an abomasal nematode parasite of small ruminants. Understanding the mode of immune response that helps these breeds of sheep control infection could help design and implement appropriate control programs. In this experiment, the components of the immune response during the early infection period in resistant Native lambs were evaluated and compared with susceptible Suffolk breed of sheep. Groups (n=5) of six month old Native and Suffolk lambs were given infective larvae as one time (single) or trickle experimental infections. Fecal, blood, and serum samples were collected on days 0, 2, 7, 14 and 21 post-infection. Abomasal mucosa and regional lymph node samples were collected at the time of necropsy on days 14 and 21. There was no significant difference in number of worms recovered at necropsy but the ratio of adult versus larvae was significantly greater in single infected Suffolk than Native lambs. Native lambs had significantly greater numbers of mast cells and eosinophils in the abomasal mucosa and serum IgG production was significantly greater compared to Suffolk lambs. Native lambs also showed a trend of increased level of serum IgA and IgE compared to Suffolk lambs.

Randomized phase II study of temozolomide given every 8 hours or daily with either interferon alfa-2b or thalidomide in metastatic malignant melanoma.

PURPOSE: Temozolomide is an imidazotetrazine with a mechanism of action similar to dacarbazine and equivalent activity in melanoma. It is well tolerated and is a candidate for combination chemotherapy and schedule manipulation. In this study, we combined temozolomide with interferon alfa-2b and, separately, with thalidomide, and we administered temozolomide alone in a compressed schedule. The objectives of this randomized phase II, two-center study were to determine response rates, overall survival, and tolerability of the regimens in patients with advanced metastatic melanoma. PATIENTS AND METHODS: One hundred eighty-one patients with metastatic melanoma were randomly assigned to receive up to six 4-weekly cycles consisting of temozolomide 200 mg/m2 every 8 hours for five doses, or temozolomide 200 mg/m2 daily for days 1 to 5 plus interferon alfa-2b 5 MU (million International Units) subcutaneously three times a week, or temozolomide 150 mg/m2 (increased after one cycle to 200 mg/m2) daily on days 1 to 5 plus thalidomide 100 mg daily days 1 to 28. RESULTS: The treatment arms were well balanced for known prognostic factors. Median survival was 5.3 months for 8-hourly temozolomide, 7.7 months for temozolomide/interferon, and 7.3 months for temozolomide/thalidomide; and 1-year survivals were 18%, 26%, and 24%, respectively. Response or disease stabilization occurred in 20% of patients (95% confidence interval [CI], 10% to 33%) given 8-hourly temozolomide, 21% (95% CI, 12% to 33%) given temozolomide/interferon, and 25% (95% CI, 15% to 38%) given temozolomide/thalidomide. Grade 3 or 4 nonhematologic toxicities were similar in each arm except for infection, which was more frequent with 8-hourly temozolomide. There were fewer instances of grade 3 or 4 myelotoxicity with temozolomide/thalidomide. CONCLUSION: Of the three regimens tested, the combination of temozolomide and thalidomide seems the most promising for future study.

Identical chemotherapy schedules given on and off trial protocol in small cell lung cancer: response and survival results.

Patients who are treated within clinical trials may have a survival benefit dependent on being a trial participant. A number of factors may produce such beneficial outcome including more rigorous adherence to a peer reviewed trial protocol, management by an experienced treatment team, being treated in a specialist centre etc. The current investigation compared patients treated on and off trial with the same standard arm treatment regimen. The results could then be interpreted without the confounding factors of differing treatment regimens, treatment teams or treatment hospitals. The results demonstrated given these circumstances that survival was no different for patients participating in a randomised trial compared with a group of patients similarly treated who were not eligible for trial entry or who declined randomisation. These results were obtained by the rigorous adherence to a defined protocol with the invaluable assistance of designated lung cancer staff.

Effects of dietary genistein exposure during development on male and female CD (Sprague-Dawley) rats.

Genistein is a naturally occurring isoflavone that interacts with estrogen receptors and multiple other molecular targets. Human exposure to genistein is predominantly through consumption of soy products, including soy-based infant formula and dietary supplements. A dose range-finding study was conducted as a prelude to a multigeneration bioassay to assess potential toxicities associated with genistein consumption. Genistein was administered in a soy- and alfalfa-free diet at 0, 5, 25, 100, 250, 625, or 1250 ppm to pregnant dams starting on Gestation day 7 and continuing throughout pregnancy. Dietary exposure of the dams continued through lactation, and pups were maintained on the same dosed feed as their mother after weaning until sacrifice at Postnatal day 50. Body weight and feed consumption of the treated dams prior to parturition showed a decreasing trend with a significant reduction at the highest dose. Litter birth weight was depressed in the 1250 ppm dose group, and pups of both sexes in that dose group had significantly decreased body weights relative to controls at the time of sacrifice. The most pronounced organ weight effects in the pups were decreased ventral prostate weight in males at the 1250 ppm dose and a trend toward higher pituitary gland to body weight ratios in both sexes. Histopathologic examination of female pups revealed ductal/alveolar hyperplasia of the mammary glands at 250 to 1250 ppm. Ductal/alveolar hyperplasia and hypertrophy also occurred in males, with significant effects seen at 25 ppm and above. Abnormal cellular maturation in the vagina was observed at 625 and 1250 ppm, and abnormal ovarian antral follicles were observed at 1250 ppm. In males, aberrant or delayed spermatogenesis in the seminiferous tubules relative to controls was observed at 1250 ppm. There was a deficit of sperm in the epididymis at 625 and 1250 ppm relative to controls, although testicular spermatid head counts and epididymal spermatozoa counts did not show significant differences from controls at these doses. Both sexes showed an increase in the incidence and/or severity of renal tubal mineralization at doses of 250 ppm and above. Dietary genistein thus produced effects in multiple estrogen-sensitive tissues in males and females that are generally consistent with its estrogenic activity. These effects occurred within exposure ranges achievable in humans.

The challenge of treatment for clients with dismissing states of mind.

Thirty-four clients with serious psychopathological disorders were videotaped solving interpersonal problems with significant others or with case managers. Differential reliance on dismissing states of mind was examined in relation to behavioral ratings of clients during the interactions, and in relation to changes in clients' and partners' reports of feelings. Clients who relied more on dismissing strategies showed greater rejection of significant others, but not of case managers, compared with clients who relied more on preoccupied strategies. The partners of dismissing clients reported greater sadness following problem-solving interactions than the partners of preoccupied clients. Clients who relied more on dismissing strategies spent less time on task when interacting with their case managers than clients who relied more on preoccupied strategies, and reported more confusion following these interactions. These findings suggest that treatment is likely to provide a particularly challenging context for adults with dismissing states of mind.

A hybrid computational fluid dynamics and physiologically based pharmacokinetic model for comparison of predicted tissue concentrations of acrylic acid and other vapors in the rat and human nasal cavities following inhalation exposure.

To assist in interspecies dosimetry comparisons for risk assessment of the nasal effects of organic acids, a hybrid computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) dosimetry model was constructed to estimate the regional tissue dose of inhaled vapors in the rat and human nasal cavity. Application to a specific vapor would involve the incorporation of the chemical-specific reactivity, metabolism, partition coefficients, and diffusivity (in both air and tissue phases) of the vapor. This report describes the structure of the CFD-PBPK model and its application to a representative acidic vapor, acrylic acid, for interspecies tissue concentration comparisons to assist in risk assessment. By using the results from a series of short-term in vivo studies combined with computer modeling, regional nasal tissue dose estimates were developed and comparisons of tissue doses between species were conducted. To make these comparisons, the assumption was made that the susceptibilities of human and rat olfactory epithelium to the cytotoxic effects of organic acids were similar, based on similar histological structure and common mode of action considerations. Interspecies differences in response were therefore assumed to be driven primarily by differences in nasal tissue concentrations that result from regional differences in nasal air flow patterns relative to the species-specific distribution of olfactory epithelium in the nasal cavity. The results of simulations with the seven-compartment CFD-PBPK model suggested that the olfactory epithelium of the human nasal cavity would be exposed to tissue concentrations of acrylic acid similar to that of the rat nasal cavity when the exposure conditions are the same. Similar analysis of CFD data and CFD-PBPK model simulations with a simpler one-compartment model of the whole nasal cavities of rats and humans provides comparable results to averaging over the compartments of the seven-compartment model. These results indicate that the general structure of the hybrid CFD-PBPK model applied in this assessment would be useful for target tissue dosimetry and interspecies dose comparisons for a wide variety of vapors. Because of its flexibility, this CFD-PBPK model is envisioned to be a platform for the construction of case-specific inhalation dosimetry models to simulate in vivo exposures that do not involve significant histopathological damage to the nasal cavity.

Use of hematopoietic progenitors in whole blood to support dose-dense chemotherapy: a randomized phase II trial in small-cell lung cancer patients.

PURPOSE: Small-cell lung cancer (SCLC) is exquisitely chemosensitive, but few patients are cured by conventional chemoradiotherapy. Recent studies suggest that increased cytotoxic dose-intensity might improve survival. In this randomized phase II study, we tested the feasibility of dose intensification using sequential reinfusion of hematopoietic progenitors in whole blood. PATIENTS AND METHODS: SCLC patients with a favorable prognosis were treated with six cycles of ifosfamide, carboplatin, and etoposide (ICE), at 4-week (standard treatment) or 2-week (intensified treatment) intervals. Intensified treatment was supported by daily subcutaneous filgrastim injections and reinfusion of 750 mL of autologous blood collected immediately before each cycle. RESULTS: Fifty consecutive patients were randomized to standard (n = 25) or intensified (n = 25) ICE. A total of 94% completed at least three treatment cycles, and 70% completed six cycles; 96% of treatments were given at full dose. The planned dose-intensity was 1.0 for standard and 2.0 for intensified ICE. The median received dose-intensity for cycles 1 through 3 was 0.99 (range, 0.33 to 1.02) for the standard treatment arm and 1.80 (range, 0.99 to 1.97) for the intensified treatment arm (P <.001). Over all six cycles, the median received dose-intensity was 0.95 (range, 0.17 to 1.03) for the standard treatment arm and 1.60 (range, 0.60 to 2.01) for the intensified treatment arm (P <.001). Febrile neutropenia was more common on the standard treatment arm (84% v 56%), resulting in more days of intravenous antibiotics (median, 10 v 3 days; P =.035). Transfusion requirements were similar in the two groups. CONCLUSION: Sequential reinfusion of hematopoietic progenitors in whole blood can safely support substantial increases in dose-intensity of ICE chemotherapy for SCLC.

Clinical and quality of life outcomes in the first United Kingdom randomized trial of endobronchial brachytherapy (intraluminal radiotherapy) vs. external beam radiotherapy in the palliative treatment of inoperable non-small cell lung cancer.

BACKGROUND AND PURPOSE: A randomized controlled trial was designed to evaluate the clinical and quality of life (QL) outcomes of patients receiving endobronchial brachytherapy (EBT) or external beam radiotherapy (XRT) as a primary palliative treatment in advanced lung cancer. MATERIALS AND METHODS: Ninety-nine patients presenting de novo with lung cancer were randomized to receive EBT or XRT. Eleven key symptoms or clinical signs were assessed by clinicians and patient ratings using self-assessment questionnaires were obtained at the same time. The primary endpoints were a comparison of EBT and XRT for symptom relief and acute and late side-effects (palliation) and their effect on patients' functional status and patient-rated QL outcomes. A secondary objective was a comparison of clinician assessments with patient self-reported symptoms. RESULTS: Both treatments produced good levels of symptom relief. They were better for XRT at the expense of more acute morbidity. Late side-effects were similar. The functional status of patients was well maintained and changed similarly with time in both groups. XRT gave a better duration of palliation. Twenty-eight percent of XRT patients required EBT (at a median time of 304 days) whereas 51% of EBT patients subsequently had XRT (at a median of 125 days). There was a significant modest gain in median survival with initial XRT (287 vs. 250 days). When clinician and patient assessments were compared, doctors were found to underestimate the severity of breathlessness, anorexia, tiredness and nausea. CONCLUSIONS: Fractionated XRT is preferred to EBT as an initial treatment in better performance patients because it provides better overall and more sustained palliation with fewer retreatments and a modest gain in survival time. QL assessment is required in the evaluation of palliative treatments because clinicians frequently underestimate the incidence and severity of key symptoms.

A comparison of the inflammatory response to a polydimethylsiloxane implant in male and female Balb/c mice.

The implantation of biomaterials elicits a host response that influences the long-term behavior of implanted medical devices. This foreign body response is governed by cells of the immune system. Because sexual dimorphism in the immune system is well-established, a comparative study of the foreign body response in male and female mice was initiated. Eight-week-old male and female Balb/c mice received two subcutaneous implants in the interscapular region of a smooth peroxide-catalyzed polydimethylsiloxane (PDMS) and were sacrificed at 2, 14, 42, 70, and 105 days after implantation (n = 6 per sex per time point). Controls for each time point underwent the surgical procedure but received no implant. Tissue from the implant or surgical site was fixed, processed, and paraffin-embedded for histopathological evaluation and immunohistochemical (IHC) staining for tumor necrosis factor-alpha TNF-alpha) and interleukin-1 beta (IL-1beta). In control animals, an inflammatory response was observed at 2 days that was decreased by 14 days and absent after 42 days. At 2 and 14 days after PDMS implantation, a mild to moderate inflammatory reaction was observed around implants. The peak response was seen at 14 days, and granulation tissue, composed primarily of fibroblasts, macrophages, and neutrophils, was first observed at this time. After 105 days, the implantation site was surrounded by mature connective tissue, which had minimal numbers of macrophages and neutrophils, with severity scores that did not differ significantly in males and females. The immunostaining for TNF-alpha and IL-1beta followed similar temporal patterns, with both reaching a peak at the two week time point and remaining elevated, compared to level of expression in the controls, throughout the 105 day observation period. Staining for both cytokines in the implanted animals was generally higher in females than in males, although this difference was significant only for IL-1beta. These results suggest subtle differences between males and females in the activity of peri-implant inflammatory cells.

Differences in the response to oxidative stress and mutant frequency in CD (Sprague-Dawley) and Fisher 344 rats due to an induced inflammatory response.

In this study, the rodent air pouch model was used to examine the production and processing of oxidative DNA damage in two strains of rats commonly used in toxicity testing. An inflammatory response was induced by injecting zymosan A (50 mg) into an air pouch on male CD (Sprague-Dawley [S-D]) and Fisher 344 (F-344) rats, and the animals were then sacrificed at 1, 3, 7, 14, and 28 days (n = 6 per time point per strain). Tissues from the lining of the air pouch were collected for 8-hydroxy-2'-deoxyguanosine (8-OH-dG) analysis and for paraffin embedding. Significant (P < 0.01) increases in 8-OH-dG were observed after 1 day in the DNA from cells lining the air pouch of zymosan A-treated versus control S-D (101.5 +/- 27.1 vs. 23.1 +/- 2. 7 8-OH-dG/dG x 10(5)) and F-344 (51.4 +/- 5.3 vs. 14.4 +/- 0.6 8-OH-dG/dG x 10(5)) rats. By 28 days, 8-OH-dG levels had returned to background in S-D rats, but remained elevated in F-344 rats. The frequency of apoptosis was evaluated using the in situ end-labeling (TUNEL) assay, which revealed that zymosan A-treated S-D rats had a significantly (P < 0.05) higher frequency of apoptosis compared to zymosan A-treated F-344 rats. To examine the potential consequences of these differences in endogenously produced DNA damage and apoptosis, we measured mutations at the hprt locus in fibroblasts of the pouch lining and observed a significant (P < 0.05) increase in the mutant frequency at day 28 in F-344 rats (54.2 +/- 13.6 mutants per 10(6) cells) compared to controls (4.5 +/- 2.0 mutants per 10(6) cells). The mutant frequency was not increased in S-D rats. These data demonstrate that strain differences in the production and processing of oxidative DNA damage due to an inflammatory response may impact the long-term pathologic consequences of chronic inflammation. Environ. Mol. Mutagen. 35:336-342, 2000 Published 2000 Wiley-Liss, Inc.

Stimulated pulmonary cell hyperplasia underlies resistance to alpha-naphthylthiourea.

The rodenticide alpha-naphthylthiourea (ANTU) causes pulmonary edema and pleural effusion that leads to death via pulmonary insufficiency. Rats become resistant to the lethal effect of ANTU if they are first exposed to a small, nonlethal dose of ANTU. Young rats are also resistant to ANTU. The mechanism by which rats develop resistance by a prior, small dose exposure has yet to be determined. Growth factor induced-pulmonary hyperplasia has been demonstrated to attenuate ANTU-induced lung leak. We hypothesized that a small dose of ANTU protects against a large dose through pulmonary cell hyperplasia induced by the protective dose. Furthermore, we hypothesized that this hyperplasia is associated with altered transcription of growth factors. Male Sprague-Dawley rats (175-225 g) were treated with a low dose of ANTU (5 mg ANTU/kg; ANTU(L)) 24 h before challenge with a 100% lethal dose of ANTU (70 mg ANTU/kg; ANTU(H)) resulting in 100% protection against the lethal effect of ANTU(H). ANTU(L) protection against ANTU(H) lasted for 5 days, slowly phased out, all being lost by day 20. Injury was assessed by estimating pulmonary vascular permeability and through histopathological examination. ANTU(H) alone resulted in an increase in pulmonary edema leading to animal death. However, injury was prevented if the rats were first treated with ANTU(L). There was a stimulation of pulmonary cell hyperplasia in the lungs of ANTU(L) treated rats as measured by [3H]-thymidine and bromodeoxyuridine incorporation. Treatment with the antimitotic agent colchicine abolished ANTU(L)-induced resistance to ANTU(H). ANTU resistant rats were also resistant to the lethal effect of paraquat. Paraquat is not taken up by pneumocytes if they are undergoing hyperplasia. ANTU(L) administration resulted in an up regulation of gene transcription for keratinocyte growth factor, transforming growth factor-beta, keratinocyte growth factor receptor and epidermal growth factor receptor as determined through reverse transcription-polymerase chain reaction. A significant increase in transforming growth factor-alpha was not observed. These findings collectively suggest that ANTU(L)-induced pulmonary cell hyperplasia underlies resistance to ANTU(H). Furthermore, the stimulation of hyperplasia may be due to altered growth factor and growth factor receptor expressions.

Histopathology of nasal olfactory mucosa from selected inhalation toxicity studies conducted with volatile chemicals.

In recent years, histopathologic changes have been reported in the olfactory mucosa of rodents exposed, by inhalation, to a variety of volatile chemicals. In order to better characterize these lesions, a panel of experienced pathologists reviewed microscopic lesions of the olfactory epithelium of rats reported in 10 inhalation studies conducted with 8 different chemicals. The objectives were to determine if the olfactory epithelial lesions are morphologically similar or different for the chemicals of interest, to develop and recommend appropriate diagnostic criteria and nomenclature to characterize the morphology of these olfactory lesions, and to provide specific criteria for judging the degree of severity of the olfactory changes in these studies. The results indicated that the distribution and nature of the lesions were similar in all the examined studies in which olfactory changes were observed. Recommended standardized nomenclature and diagnostic criteria and a uniform method for scoring lesion severity based on the extent of distribution and severity of tissue damage are presented.

Application of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry extrapolation of acidic vapors in the upper airways.

This study provides a scientific basis for interspecies extrapolation of nasal olfactory irritants from rodents to humans. By using a series of short-term in vivo studies, in vitro studies with nasal explants, and computer modeling, regional nasal tissue dose estimates were made and comparisons of tissue doses between species were conducted. To make these comparisons, this study assumes that human and rodent olfactory epithelium have similar susceptibility to the cytotoxic effects of organic acids based on similar histological structure and common mode of action considerations. Interspecies differences in susceptibility to the toxic effects of acidic vapors are therefore assumed to be driven primarily by differences in nasal tissue concentrations that result from regional differences in nasal air flow patterns relative to the species-specific distribution of olfactory epithelium in the nasal cavity. The acute, subchronic, and in vitro studies have demonstrated that the nasal olfactory epithelium is the most sensitive tissue to the effects of inhalation exposure to organic acids and that the sustentacular cells are the most sensitive cell type of this epithelium. A hybrid computational fluid dynamics (CFD) and physiologically based pharmacokinetic (PBPK) dosimetry model was constructed to estimate the regional tissue dose of organic acids in the rodent and human nasal cavity. The CFD-PBPK model simulations indicate that the olfactory epithelium of the human nasal cavity is exposed to two- to threefold lower tissue concentrations of a representative inhaled organic acid vapor, acrylic acid, than the olfactory epithelium of the rodent nasal cavity when the exposure conditions are the same. The magnitude of this difference varies somewhat with the specific exposure scenario that is simulated. The increased olfactory tissue dose in rats relative to humans may be attributed to the large rodent olfactory surface area (greater than 50% of the nasal cavity) and its highly susceptible location (particularly, a projection of olfactory epithelium extending anteriorly in the dorsal meatus region). In contrast, human olfactory epithelium occupies a much smaller surface area (less than 5% of the nasal cavity), and it is in a much less accessible dorsal posterior location. In addition, CFD simulations indicate that human olfactory epithelium is poorly ventilated relative to rodent olfactory epithelium. These studies suggest that the human olfactory epithelium is protected from irritating acidic vapors significantly better than rat olfactory epithelium due to substantive differences in nasal anatomy and nasal air flow. Furthermore, the general structure of the hybrid CFD-PBPK model used for this study appears to be useful for target tissue dosimetry and interspecies dose comparisons for a wide range of inhaled vapors.

Chronic inhalation toxicity and oncogenicity of methyl methacrylate in rats and hamsters.

Male and female Fischer 344 rats were exposed to methyl methacrylate (MMA) monomer vapours at 0, 25, 100 and 400 ppm, 6 hr/day, 5 days/wk for 24 months and male and female Golden hamsters were exposed to similar vapour concentrations of MMA for 18 months. Parameters monitored throughout the study included clinical signs, individual body weights, haematology, clinical chemistry (rats only) and urinalyses (rats only). 10 rats per sex per exposure group were killed after 13 and 52 wk of exposure and all surviving rats were killed during wk 104-106. All surviving hamsters were killed at wk 78. Mortality and haematological, clinical chemistry and urinalyses parameters were not affected by MMA exposure. Body weights of male rats were not affected by exposure to MMA while body weights of female rats exposed to 400 ppm were lower than control values after wk 52. Male and female hamsters exposed to 400 ppm had body weight decreases ranging from 9 to 12% after wk 48. The nasal cavity was identified as the target organ for chronic toxicity in male and female rats exposed to 100 or 400 ppm. The microscopic nasal cavity changes occurred primarily in olfactory epithelium lining the dorsal meatus and consisted of degeneration of neuroepithelium, basal cell hyperplasia and atrophy of Bowman's glands. Hamsters did not have demonstrable nasal cavity microscopic changes. Chronic exposure to MMA vapour did not cause tumours in either rats or hamsters.

Can cytotoxic dose-intensity be increased by using granulocyte colony-stimulating factor? A randomized controlled trial of lenograstim in small-cell lung cancer.

PURPOSE: The use of granulocyte colony-stimulating factor (G-CSF) to increase cytotoxic dose-intensity was assessed in a randomized trial in better-prognosis small-cell lung cancer (SCLC). Both control and G-CSF arms were subject to the same dose-intensification strategy. PATIENTS AND METHODS: Patients with newly diagnosed SCLC and either no or one adverse prognostic factor were randomized to receive vincristine, ifosfamide, carboplatin, and etoposide (VICE) alone or with recombinant human (rHu)G-CSF (lenograstim) 5 micrograms/kg/d between cycles. Six chemotherapy cycles were given, with prophylactic cranial irradiation after cycle 1 and thoracic irradiation after cycle 3. There was no fixed dose interval. In both arms, patients were eligible for re-treatment when the WBC count was > or = 3 x 10(9)/L and platelet count was > or = 100 x 10(9)/L. No dose reductions were permitted. Dose-intensity was expressed relative to standard every-4-weeks VICE. RESULTS: Sixty-five consecutive patients in one institution were randomized to control (n = 31) or G-CSF (n = 34). WBC and neutrophil counts were consistently higher in G-CSF patients than in the control group, but there were no significant differences in the incidence of febrile neutropenia, antibiotic or transfusion requirements, or days in hospital. In both treatment arms, the median dose-intensity was greater than one for each cycle (control group, P = .0009; G-CSF group, P = .0001). The G-CSF group received a significantly higher dose-intensity than the control group, with the greatest difference in the first three cycles (1.34 v 1.17, P = .001). There were more chemotherapy-related deaths in the G-CSF group than in the control group (six v one), but this group had a better 2-year survival rate (32% with G-CSF, 95% confidence interval [CI], 16 to 48; 15% with controls, 95% CI, 2 to 27). CONCLUSION: The dose-intensity of VICE chemotherapy was increased in both groups. Patients randomized to receive G-CSF achieved a significantly higher dose-intensity than controls. Despite early toxicity, they had a better 2-year survival rate.

Chronic inhalation toxicity and carcinogenicity study of respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol in rats.

Four groups of 60 Wistar rats of each sex were exposed by inhalation to 0, 0.2, 1.0, or 6.0 mg/m3 respirable polymeric methylene diphenyl diisocyanate (polymeric MDI) aerosol (93.5% < 4.2 microns) for 6 hr a day, 5 days a week for up to 24 months. In addition, satellite groups of 10 rats/sex/group received the same treatment for 12 months. There was no adverse effect on general health, survival, body weight, or hematological or clinical chemistry parameters. Lung weights were increased in both males and females exposed to 6.0 mg polymeric MDI/m3 for 12 or 24 months. Gross examination at autopsy of males exposed to 6.0 mg polymeric MDI/m3 for 24 months revealed an increased incidence of spotted and discolored lungs. Increased incidences of degeneration and basal cell hyperplasia of the nasal olfactory epithelium, often accompanied by hyperplasia of Bowman's glands, were found in the 1.0 and 6.0 mg/m3 groups. Light and electron microscopic studies of the lungs revealed accumulations of alveolar macrophages containing polymeric MDI-associated refractile yellowish material at the level of the alveolar duct in all exposed groups. Alveolar duct epithelialization as well as fibrosis of tissues surrounding the macrophage accumulations occurred at the 1.0 and 6.0 mg/m3 exposure levels. In addition, increased incidences of calcareous deposits and localized alveolar bronchiolization were seen in the 6.0 mg/m3 group. Moreover, eight pulmonary adenomas (six in males and two in females) and one pulmonary adenocarcinoma (in a male) were observed in the 6.0 mg/m3 exposure group. The time sequence of the spectrum of pulmonary changes indicates that recurrent alveolar wall damage by polymeric MDI and/or polymeric MDI-containing alveolar macrophages leads to alveolar bronchiolization and ultimately to bronchioloalveolar tumors. No lung tumors were found in the lower concentration groups and in the control group. The incidence and distribution of other types of tumors were not influenced by polymeric MDI. It was concluded that in the present study, the "no-observed-adverse-effect level" of polymeric MDI was 0.2 mg/m3, and that chronic exposure to polymeric MDI at a level of 6.0 mg/m3 was related to the occurrence of pulmonary tumors. It was also concluded that exposure to polymeric MDI at concentrations not leading to recurrent lung tissue damage will not produce pulmonary tumors.

Neurotoxicologic examination of rats exposed to 1,1,1-trichloroethane vapor for 13 weeks.

Large evoked potential and EEG changes occurred in a pilot study in Fisher 344 rats during exposure to 2000 ppm of 1,1,1-trichloroethane (1,1,1-T; a cleaning solvent with anesthetic properties). In the main study, rats were evaluated for persistent nervous system effects the week following exposure to 0, 200, 630, or 2000 ppm 1,1,1-T for 6 h/day, 5 days/week, for 13 weeks. Rats were clinically examined regularly and were given a functional observational battery monthly (FOB, including forelimb and hindlimb grip performance testing). After 13 weeks of exposure, the rats were evaluated by FOB and by visual, auditory, somatosensory, and caudal nerve-evoked potentials. After functional testing, a subgroup of rats had histopathologic examination of brain, spinal cord, peripheral nerves, and limb muscles. There were no post-exposure treatment-related findings in any parameter (FOB observations plus 39 dependent variables) except for a slightly smaller forelimb grip performance in the 2000-ppm exposure group. There was no recognized toxicologic significance for the difference in forelimb grip performance; a lack of findings in any other clinical, evoked potential or morphologic parameter did not support a diagnosis of neurotoxicity.

Hemolytic activity of ethylene glycol phenyl ether (EGPE) in rabbits.

Studies were conducted to characterize the hemolytic effects of EGPE in rabbits following oral and dermal exposure, and to evaluate the in vitro hemolytic potential of EGPE and its major metabolite using rabbit red blood cells (RBC). Gavage administration of EGPE to female New Zealand White rabbits at 100, 300, 600, or 1000 mg/kg/day for up to 10 consecutive days (one dose/day) resulted in a dose-related intravascular hemolytic anemia. The hemolytic anemia was characterized by decreased RBC count, hemoglobin concentration, packed cell volume, hemoglobinuria, splenic congestion, renal tubule damage, and a regenerative erythroid response in the bone marrow. The hemolytic anemia was observed without alterations in RBC glutathione or methemoglobin. Phenoxyacetic acid (PAA) was identified as a major blood metabolite of EGPE. In vitro exposure of female rabbit erythrocytes indicated EGPE to be considerably more hemolytic than PAA. In a 90-day dermal study in which EGPE was applied to the skin of male and female New Zealand White rabbits 6 hr/day, 5 days/week, at doses up to 500 mg/kg/day, there was no indication of a hemolytic response. The only treatment-related effects were sporadic occurrences of slight erythema and scaling of skin at the site of test material application in high dose group male and female rabbits. However, erythema and scaling were not associated with gross or histopathologic changes and were not considered toxicologically significant.

Dermal sensitization potential and inhalation toxicological evaluation of 4-phenylcyclohexene.

4-Phenylcyclohexene (4-PCH) is a by-product formed in trace amounts during the production of styrene-butadiene latexes, which are used in carpet manufacturing. The dermal sensitization potential of 4-PCH was evaluated by using a modification of the Buehler method. The condition of the test site was evaluated 24 and 48 hr after the challenge application with no response observed in any of the guinea pigs. For the acute inhalation study, groups of five Fischer 344 rats/sex were exposed to 16 or 60 ppm 4-PCH for a single 6-hr exposure. Subsequently, groups of 10 Fischer 344 rats/sex were exposed to time-weighted average concentrations of 0, 1, 10, or 50 ppm (0, 6.6, 65, or 320 mg/m3) 4-PCH for 6 hr/day, 5 days/week for nine exposures. The highest vapor concentration, 50 ppm, was the maximum attainable during the course of the 2-week study. It was only achieved by acclimating the chamber with saturated vapor prior to each animal exposure. The following parameters were evaluated for the 2-week study: clinical signs, body weights, selected organ weights, hematology, clinical chemistry, urinalysis, and histopathology. All rats survived to the termination of the study and had no clinical or pathologic evidence of eye, skin, nasal, or respiratory tract irritation. There were no exposure-related effects identified in any of the parameters monitored. Thus, 4-PCH produced no toxicity at the highest concentration that could be generated and did not produce delayed contact hypersensitivity in guinea pigs.