Dropwort-induced metabolic reprogramming restrains YAP/TAZ/TEAD oncogenic axis in mesothelioma.

BACKGROUND: Over the past decade, newly designed cancer therapies have not significantly improved the survival of patients diagnosed with Malignant Pleural Mesothelioma (MPM). Among a limited number of genes that are frequently mutated in MPM several of them encode proteins that belong to the HIPPO tumor suppressor pathway. METHODS: The anticancer effects of the top flower standardized extract of Filipendula vulgaris (Dropwort) were characterized in "in vitro" and "in vivo" models of MPM. At the molecular level, two "omic" approaches were used to investigate Dropwort anticancer mechanism of action: a metabolomic profiling and a phosphoarray analysis. RESULTS: We found that Dropwort significantly reduced cell proliferation, viability, migration and in vivo tumor growth of MPM cell lines. Notably, Dropwort affected viability of tumor-initiating MPM cells and synergized with Cisplatin and Pemetrexed in vitro. Metabolomic profiling revealed that Dropwort treatment affected both glycolysis/tricarboxylic acid cycle as for the decreased consumption of glucose, pyruvate, succinate and acetate, and the lipid metabolism. We also document that Dropwort exerted its anticancer effects, at least partially, promoting YAP and TAZ protein ubiquitination. CONCLUSIONS: Our findings reveal that Dropwort is a promising source of natural compound(s) for targeting the HIPPO pathway with chemo-preventive and anticancer implications for MPM management.

A Monte Carlo t Test to Evaluate Mesothelioma and Radiation in the US Transuranium and Uranium Registries.

A cluster of nine mesothelioma cases was observed among 341 registrants' deaths in the US Transuranium and Uranium Registries. Descriptive analysis showed that mesothelioma cases had the highest average cumulative external radiation dose compared with lung cancer, other cancer, and noncancer deaths. Further analysis indicated that the mesothelioma cluster was very different demographically from lung cancer, other cancer, and noncancer deaths. Therefore, an internally matched case-control approach was applied to evaluate the differences in an average cumulative external radiation dose between mesothelioma deaths and other causes of death. A Monte Carlo t test was used to examine the statistical significance of the differences. The results showed that there were no significant statistical differences in an average cumulative external radiation dose between mesothelioma and lung cancer, other cancers, or noncancers for the internally matched cases and controls.

Comments on the causation of malignant mesothelioma: rebutting the false concept that recent exposures to asbestos do not contribute to causation of mesothelioma.

The Collegium Ramazzini is an international scientific society that examines critical issues in occupational and environmental medicine with a view towards action to prevent disease and promote health. The Collegium derives its name from Bernardino Ramazzini, the father of occupational medicine, a professor of medicine of the Universities of Modena and Padua in the late 1600s and the early 1700s. The Collegium is comprised of 180 physicians and scientists from 35 countries, each of whom is elected to membership. The Collegium is independent of commercial interests.

[Active research, registration, and prevention of tumors of professional origin]. / Ricerca attiva, registrazione e prevenzione dei tumori di origine professionale.

Occupational cancer is an important public health concern in Italy and in many industrialized countries. The difficulties in monitoring and the complexity in retrieving occupational cancer cases have required the enrolment of a national epidemiologic sureveillance system at national scale with active search methods. A structured system for the registration of occupational cancer cases is normed by the Decree No. 81/2008, that accounts for the previous legislative procedures and experiences. Research activities and prevention of occupational cancer should be integrated with insurance policies to the purpose of an efficient protection of workers health.

Peritoneal mesothelioma: the site of origin matters.

The etiology, gender distribution, pathology, natural history, and treatment options for mesothelioma (MM) differ substantially depending on the site of origin. Peritoneal mesothelioma (MPeM) is a rare disease, comprising only approximately 10% to 15% of the 2,500 cases of MM diagnosed in the United States each year. Patients with MPeM are younger than patients with pleural MM, and a higher proportion, mostly women, are long-term survivors. Most MPeM is caused by asbestos exposure. Germ-line mutations of BAP1 (BRCA associated protein 1) can predispose to MM, uveal melanoma, and potentially other cancers. MPeM can be challenging to diagnose, and cytology is rarely helpful. Review by an experienced pathologist using a panel of at least two positive and two negative immunohistochemical stains is essential. The three major pathologic subtypes are epithelial, sarcomatoid, and biphasic. Most cases are epithelial; the others have a dismal prognosis. Two indolent subtypes of borderline malignant potential-well-differentiated papillary mesothelioma and benign multicystic mesothelioma-are more common in the peritoneum and are treated surgically. In highly selected patients receiving treatment at experienced referral centers, an aggressive locoregional strategy that combines cytoreductive surgery to remove all gross disease and hyperthermic intraperitoneal chemotherapy to treat residual microscopic tumors yields a 3-year survival of 60% and a median survival approaching 5 years, far better than expected from historic controls. This approach also provides durable palliation of malignant ascites in nearly all patients. Pemetrexed is the only U.S. Food and Drug Administration (FDA)-approved systemic chemotherapy for pleural MM. Largely on the basis of data from pharmaceutical registry studies, the activity of pemetrexed-based chemotherapy appears to be similar in pleural MM and MPeM.

Compensation of pleural mesothelioma in France: data from the French National Mesothelioma Surveillance Programme.

BACKGROUND: The aim of this study was to determine the rates of compensation awarded to patients presenting with pleural mesothelioma and factors linked to such compensation in France. METHODS: The study population consisted of 2,407 patients presenting with pleural mesothelioma, recorded by the National Mesothelioma Surveillance Programme between January 1, 1999 and December 31, 2009. Analysis of claims for recognition as "occupational disease" (OD) and claims for compensation by the Compensation Fund for Asbestos Victims (FIVA) were analyzed. RESULTS: Approximately 30% of subjects presenting with pleural mesothelioma, affiliated to the General National Health Insurance fund, neither sought recognition as an OD nor claimed for FIVA compensation. Gender, age at diagnosis, type of health insurance, and socio-professional category influence the likelihood of patients presenting with mesothelioma seeking compensation for this disease. CONCLUSIONS: Results show an under-compensation of pleural mesothelioma as OD and by the FIVA in France.

[Mortality results in SENTIERI Project]. / Risultati dell'analisi della mortalità nel Progetto SENTIERI.

SENTIERI Project (Mortality study of residents in Italian polluted sites) studies mortality of residents in 44 sites of national interest for environmental remediation (Italian polluted sites, IPS). The epidemiological evidence of the causal association between causes of death and exposures was a priori classified into one of these three categories: Sufficient (S), Limited (L) and Inadequate (I). In these sites various environmental exposures are present. Asbestos (or asbestiform fibres as in Biancavilla) has been the motivation for defining six sites as IPSs (Balangero, Emarese, Casale Monferrato, Broni, Bari-Fibronit, Biancavilla). In five of these, increases in malignant neoplasm or pleura mortality are detected; in four of them, results are consistent in both genders. In six other sites (Pitelli, Massa Carrara, Aree del Litorale Vesuviano, Tito, "Aree industriali della Val Basento", Priolo), where other sources of environmental pollution in addition to asbestos are reported, mortality from malignant neoplasm of pleura is increased in both genders in Pitelli, Massa Carrara, Priolo, "Litorale vesuviano". In the time span 1995-2002, a total of 416 extra cases of malignant neoplasm of pleura are detected in the twelve asbestos-polluted sites. Asbestos and pleural neoplasm represent an unique case. Unlike mesothelioma, most causes of death analyzed in SENTIERI have multifactorial etiology; furthermore, in most IPSs multiple sources of different pollutants are present, sometimes concurrently with air pollution from urban areas: in these cases, drawing conclusions on the association between environmental exposures and specific health outcomes might be complicated. Notwithstanding these difficulties, in a number of cases an etiological role could be attributed to some environmental exposures. The attribution could be possible on the basis of increases observed in both genders and in different age classes, and the exclusion of a major role of occupational exposures was thus allowed. For example, a role of emissions from refineries and petrochemical plants was hypothesized for the observed increases in mortality from lung cancer and respiratory diseases in Gela and Porto Torres; a role of emissions from metal industries was suggested to explain increased mortality from respiratory diseases in Taranto and in Sulcis-Iglesiente-Guspinese. An etiological role of air pollution in the raise in congenital anomalies and perinatal disorders was suggested in Falconara Marittima, Massa-Carrara, Milazzo and Porto Torres. A causal role of heavy metals, PAH's and halogenated compounds was suspected for mortality from renal failure in Massa Carrara, Piombino, Orbetello, "Basso bacino del fiume Chienti" and Sulcis-Iglesiente-Guspinese. In Trento-Nord, Grado and Marano, and "Basso bacino del fiume Chienti" increases in neurological diseases, for which an etiological role of lead, mercury and organohalogenated solvents is possible, were reported. The increase for non-Hodgkin lymphomas in Brescia was associated with the widespread PCB pollution. Mortality for causes of death with a priori Sufficient or Limited evidence of association with the environmental exposure exceeds the expected figures, with a SMR of 115.8% for men (90% IC 114.4-117.2; 2 439 extra deaths) and 114.4% for women (90% CI 112.4-116.5; 1 069 extra deaths). These excesses are also observed when analysis is extended to all the causes of death (i.e. with no restriction to the ones with a priori Sufficient or Limited evidence): for a total of 403 692 deaths (both men and women), an excess of 9 969 deaths is observed, with an average of about 1 200 extra deaths per year. Most of these excesses are observed in IPSs located in Southern and Central Italy. The procedures and results of the evidence evaluation are presented in a 2010 Supplement of Epidemiology & Prevention devoted to SENTIERI.

[Pulmonary concentration of asbestos fibers in steel workers with pleural mesothelioma]. / Concentrazione polmonare di fibre di amianto in lavoratori siderurgici affetti da mesotelioma pleurico.

The asbestos fibre burden of the lung has been used in the past as a biological indicator of cumulative exposure to the mineral so much so that in 1997 reference limits even for non-occupationally exposed people have been proposed. This kind of analysis was performed on groups of workers of different type of industries and allowed to achieve a qualitative-quantitative estimate of past exposure to asbestos, even in absence of exposure estimates by environmental monitoring. An important example is the steel industry where asbestos was widely used in the past, but for which there are not available exposure estimates of workers. Among the mesothelioma cases collected by the Mesothelioma Registry of the Province of Brescia from 1980 to present there are 55 workers who spent at least 5 years in steel industry, on a total of 289 cases classified as asbestos exposed (19%). For 8 subjects who worked in steel mills and production of electrical steel pipes, of which 4 in the same plant, lung tissue samples were available for the asbestos fibres burden analysis (7 samples coming from autopsies and 1 from extra-pleural pneumonectomy). In all cases the diagnosis was given with histological analyses supplemented with immunohistochemistry. In 7 cases autopsied the diagnosis was confirmed. The work histories have been reconstructed in detail through the interview process, inclusive of details of duties performed. The asbestos fibre burden analyses showed a range of concentrations between 260,000 and 11,000,000 ff per grams of dry tissue; the concentration of amphiboles was much higher than that of chrysotile. The highest body burden was detected in the maintenance workers of the same plant in witch a cluster of malignant mesothelioma was observed. In conclusion, this study illustrates the results of asbestos fibres burden analyses in subjects where exposure to asbestos is sure but not quantifiable. The results showed also that these concentrations can reach values that overlap with those found in asbestos-cement workers and in asbestos-textile workers. These data suggest to consider the cases of mesothelioma occurred in the steel workers at least as "possible" exposure, even in the absence of adequate information on the circumstances of contact with asbestos. This study, although based on a small number of cases, is the only one ever held in Italy on workers in this sector.

Retinol supplementation and mesothelioma incidence in workers earlier exposed to blue asbestos (Crocidolite) at Wittenoom, Western Australia.

Owing to the high rates of malignant mesothelioma in workers exposed to crocidolite earlier at Wittenoom and evidence of protection against cancer by vitamin A, a population-based cancer prevention programme providing retinol supplements (25 000 IU/day) was commenced in 1990. The former workers at Wittenoom known to be alive and living in Western Australia in June 1990 constitute the study population. The participants were classified into two groups: those who received supplemental retinol (intervention group) and those who received none (comparison group). The relative rate of mesothelioma for those receiving retinol was estimated using Cox regression, adjusting for cumulative asbestos exposure and age at first exposure to asbestos. Nine hundred and twenty-eight former Wittenoom workers received retinol at some stage of the programme, whereas 1471 workers never received retinol (comparison group). Those who received retinol were younger, had a greater exposure to asbestos and smoked less than the comparison group. There were 65 cases of mesothelioma in the retinol group and 88 in the comparison group. After adjustment, the hazard ratio was 0.99 (95% confidence interval=0.70-1.41). This result did not alter when the participants who received only retinol once or those who received beta-carotene earlier were excluded from the analysis. In conclusion, this study provides little support for possible preventive effects of retinol against mesothelioma in workers exposed to blue asbestos.

Surgical biology for the clinician: peritoneal mesothelioma: current understanding and management.

Mesothelioma is an asbestos-related tumour. Mesothelioma in the thorax occurs on the pleura and is known as pleural mesothelioma. It is the more common form of mesothelioma, accounting for 70% of cases. The other form occurs in the abdomen. It accounts for much of the remaining 30% and is known as peritoneal mesothelioma. Early diagnosis of peritoneal mesothelioma is often difficult because the early symptoms are often overlooked as being a benign ailment of the gastrointestinal tract. Therefore, diagnosis often occurs at an advanced stage when disease is widespread throughout the peritoneal cavity. Treatment approaches have evolved in the last decade from systemic chemotherapy and palliative surgery to aggressive cytoreductive surgery and perioperative intraperitoneal chemotherapy. This has led to a marked increase in survival among patients who were once classified as "preterminal." We update on the current understanding of peritoneal mesothelioma from a clinical perspective in hope that greater clinician awareness will promote best practice management of this condition.

All cause mortality and incidence of cancer in workers in bauxite mines and alumina refineries.

Bauxite is a reddish clay that is refined to produce alumina, which is then reduced to aluminium. There have been studies examining the health of workers in aluminium smelters, but not workers in bauxite mining and alumina refining. A cohort of employees of 1 large aluminium company since 1983 was assembled (n = 6,485, 5,828 men). Deaths and incident cancers to 2002 were ascertained by linkage to national and state cancer and death registries. SIRs and SMRs were calculated compared to national rates standardizing for calendar year, sex and 5-year age group. The mortality from all causes (SMR 0.68, 95% CI: 0.60-0.77), and from circulatory and respiratory diseases, all cancers combined and injury in the male cohort were lower than in the Australian male population and were similar across work groups and with duration of employment. The only significant increased mortality risk was from pleural mesothelioma. The incidence of all cancers combined was similar to the Australian rate. The cohort had a lower risk of incident lymphohaematopoietic cancer (SIR 0.50, 95% CI: 0.31-0.88) and a higher risk of melanoma (SIR 1.30, 95% CI: 1.00-1.69) although no dose-responses were seen. There was also an increased risk of mesothelioma (SIR 3.49, 95% CI: 1.82-6.71), which was associated with exposures outside the aluminium industry. This study is the first to examine cancer and mortality amongst workers in bauxite mines and alumina refineries and found little evidence for increased cancer incidence or mortality in these workers.

Eighth international mesothelioma interest group.

The eighth International Mesothelioma Interest Group (IMIG) meeting was held in Chicago, IL, United States, in 19-22 October 2006 to discuss mesothelioma - the cancer often linked to asbestos exposure. It is a very aggressive malignancy with a median survival of less than 1 year from diagnosis. Millions of people have been exposed worldwide to asbestos, especially during the second half of the twentieth century when asbestos use increased significantly. The tons of asbestos utilized in the past remain a health hazard for current and future generations because asbestos is difficult to be disposed off. This makes asbestos and mesothelioma research a public health issue in addition to a medical problem. Moreover, the very high costs of asbestos litigation have a significant impact on the whole economy. In the United States, up until 2001, defendant companies had paid 54 billion dollars in claims and estimated future liabilities ranged from 145 to 210 billion. Therefore, asbestos research is of great interest to a large audience that includes patients, millions of asbestos-exposed individuals, scientists, physicians, public health officials, politicians, unions of asbestos workers, lawyers and the public at large. During the past few years, there has been significant progress in understanding the process of mineral fiber carcinogenesis and mesothelioma pathogenesis. With improved understanding of the pathogenesis of mesothelioma, new diagnostic, preventive and therapeutic options are being developed. A total of 247 papers were presented at the IMIG: the abstracts of these presentations were published in Lung Cancer, Supplement 1, October 2006. Here, experts in different disciplines critically review some of the most exciting presentations of the IMIG meeting. The result is a comprehensive review of the research field of asbestos carcinogenesis and mesothelioma, and of the progress that has been made in recent years in both basic and clinical sciences.

Asbestos-related cancers in refinery workers in the Australian petroleum industry.

In this study of the incidence of asbestos-related cancer in the Australian petroleum industry, the authors traced a cohort of 16,543 petroleum industry workers for a total of 226,989 person-years. There were 18 cases of pleural mesothelioma; 12 occurred in refinery nonoffice workers, for whom the Standardized Incidence Ratio was 3.77 (95% confidence interval = 1.95-6.59). The incidence of lung cancer was significantly lower than that in the general male population. Lung cancer incidence was higher in maintenance workers than in nonmaintenance workers, but the excess was not statistically significant, as it was based on small numbers with wide confidence intervals. Lung cancer rates in refinery workers did not increase with duration of employment; however, they did tend to be higher in workers hired in earlier decades. Excess mesothelioma incidence in refinery workers is confirmed, but it is likely that there are few if any asbestos-related lung cancers.

Malignant pleural mesothelioma: a case report.

OBJECTIVE: The aim of this study was to discuss a case of malignant pleural mesothelioma (MPM) that presented to a chiropractic teaching clinic and review the pathophysiology of diseases associated with asbestos exposure. CLINICAL FEATURES: An 86-year-old woman had right-sided back pain at the thoracolumbar junction for 3 months; this pain prevented her from exercising on a daily basis. She was alert and oriented but in obvious distress because of her back pain. Breath sounds were decreased on the right in the posterior and lower lobes, with dull percussion and increased tactile fremitus. A significant collection of pleural effusion was seen on the right side on plain film radiographs. A chest computed tomography with contrast showed a large right-sided pleural effusion with small consolidation at the right lung base suggestive of pleural or pulmonary malignancy and highly suspicious for MPM. Further questioning about asbestos exposure revealed that her husband was a maintenance worker. An extrapleural pneumonectomy was performed, and specimens of parietal and visceral pleura were sent for pathological, which revealed a definitive diagnosis of spindle cell mesothelioma. INTERVENTION AND OUTCOME: The patient was diagnosed with MPM, and a surgical therapy option was considered because of the aggressive nature of the lesion and her advanced age. An extrapleural pneumonectomy was performed with removal of parietal and visceral pleura, right lower lobe, and right hemidiaphragm. CONCLUSION: This is an unusual case of advanced MPM that is most likely from indirect asbestos exposure.

[Cluster cases of malignant pleural mesothelioma in an oil factory]. / Cluster di casi di mesotelioma maligno della pleura in un oleificio.

BACKGROUND: The traditional occupational hazards of the productive cycle of oils are attributable to chemicals (use of solvents, pesticides and other agents), dusts, labour accidents (trauma, ignition, explosion), noise, manual lifting, work organization and hot-wet microclimate. The latest risk is due to the use of high temperatures (from 50 up to 250 degrees C) during the processes of extraction with solvent and refining. No cases are reported in literature of asbestos related disease in subjects who worked in oil factories. Nevertheless the structure and organization of the workplace, which is similar to that of sugar refineries, where cases of malignant mesothelioma have been described (moreover in workers employed in running and maintenance of the plants), led to the assumption that even in oil factories asbestos for the insulation of pipes and boilers could be present. OBJECTIVES: To describe 3 cases of Malignant Mesothelioma that occurred in workers of the same oil factory. METHODS: Since this occupational sector is not conventionally known for asbestos exposure the Local Health Unit and the Lombardy Mesothelioma Registry decided to investigate this industrial plant. RESULTS: Following examination of the archives of the Local Health Unit and inspection of the plant, an environmental asbestos contamination (pipes and boilers) was found. The 3 cases were defined as occupational disease and the required legal procedures were initiated. This underlines the importance of close cooperation with Local Health Units of occupational medicine and the Regional Mesothelioma Registry in the study and acknowledgment of cases which would otherwise not have been recognized, with consequent loss of precious information.

Update of a prospective study of mortality and cancer incidence in the Australian petroleum industry.

AIMS: To update the analysis of the cohort mortality and cancer incidence study of employees in the Australian petroleum industry. METHODS: Employees from 1981 to 1996 were traced through the Australian National Death Index and the National Cancer Statistics Clearing House. Cause specific mortality and cancer incidence were compared with those of the Australian population by means of standardised mortality ratios (SMRs) and standardised incidence ratios (SIRs). Associations between increased incidence of specific cancers and employment in the petroleum industry were tested by trends according to period of first employment, duration of employment, latency, and hydrocarbon exposure, adjusting for personal smoking history where appropriate. Total follow up time was 176 598 person-years for males and 10 253 person-years for females. RESULTS: A total of 692 of the 15 957 male subjects, and 16 of the 1206 female subjects had died by the cut off date, 31 December 1996. In males, the all-cause SMR and the SMRs for all major disease categories were significantly below unity. There was a non-significant increase of the all-cancer SIR (1.04, 95% CI 0.97 to 1.11). There was a significant increase of the incidence of melanoma (SIR 1.54, 95% CI 1.30 to 1.81), bladder cancer (SIR 1.37, 95% CI 1.00 to 1.83), and prostate cancer (SIR 1.19, 95% CI 1.00 to 1.40), and a marginally significant excess of pleural mesothelioma (SIR 1.80, 95% CI 0.90 to 3.22), leukaemia (SIR 1.39, 95%CI 0.91 to 2.02), and multiple myeloma (SIR 1.72, 95% CI 0.96 to 2.84). CONCLUSIONS: Most cases of mesothelioma are probably related to past exposure to asbestos in refineries. The melanoma excess may be the result of early diagnosis. The excess bladder cancer has not been observed previously in this industry and is not readily explained. The divergence between cancer incidence and cancer mortality suggests that the "healthy worker effect" may be related to early reporting of curable cancers, leading to increased likelihood of cure and prolonged mean survival time.

Experience from a long-term carcinogenicity study with intraperitoneal injection of biosoluble synthetic mineral fibers.

The carcinogenic potential in the intraperitoneal cavity of three newly developed biosoluble insulation glass wool fibers (M, P, and V) and one newly developed biosoluble insulation stone wool fiber (O) was investigated and compared to that of a previously developed soluble glass fiber (B). The in vitro dissolution coefficient of the three glass wool fibers ranged from 450 to 1037 ng/cm(2) x h and was 523 ng/cm(2) x h for the stone wool fiber. The in vitro dissolution coefficient of the B fiber was 580 ng/cm(2) x h. Groups of female Wistar rats (strain Crl: Wi BR) were exposed by repeated injections to doses of 0.5, 2, and 5 x 10(9) WHO fibers, which corresponds to between 41 mg to 724 mg fiber injected. In addition, 2 groups of crocidolite were used as positive controls at doses of 0.1 x 10(9) and 1 x 10(9) WHO fibers (0.5 and 5 mg). The in vitro dissolution coefficient of crocidolite is estimated to be approximately 1 ng/cm(2) x h. The protocol of the study and the size distribution of the test samples conformed to the European Commission Protocol EUR 18748 EN, and the study was executed under Good Laboratory Practice conditions. Two of the new insulation wools, fibers M and 0, showed no statistically significant tumorigenic response even at the very high dose of 5 x 10(9) WHO fibers injected. Fibers P and V showed a small tumorigenic response in the ip cavity similar in magnitude to the B fiber, which has been declared in the German fiber regulations as a noncarcinogenic fiber. The response to the soluble insulation fibers was notably different from that of the known carcinogen crocidolite, which produced 53% tumors at a comparatively low dose of 0.1 x 10(9) WHO fibers. The incidence of mesothelioma was found to be highly correlated to the incidence of intra-abdominal nodules and masses at different sites. The incidence of abdominal nodules and masses was highly correlated to the number of animals with ascites. The incidence of chronic peritonitis with fibrotic nodules at different organs also correlated with the incidence of mesotheliomas. Differences in etiology were observed between the massive doses of the highly soluble insulation wools when injected directly into the ip cavity and the lower doses of the extremely insoluble fiber crocidolite. The variability in this reaction and the impairment of animal health put into question the value of these massive doses in evaluating the carcinogenic response of soluble insulation wools. All of the fibers tested fulfilled the exoneration criteria with respect to carcinogenicity according to the European Directive 97/69/EC ("an appropriate intra-peritoneal test has not expressed signs of excessive carcinogenicity"). The dose as defined in the EC-Protocol EUR 18748 EN was 1 x 10(9) WHO fibers with a defined geometric spectrum. The influence of fiber dimensions on the ip tumor response and the difficulty in assessing the influence of the difference in background levels between this and previous studies make direct application of the German TRGS 905 criteria difficult; however, by comparison to fiber B, which in the TRGS 905 is considered as a noncarcinogenic fiber, all of the synthetic mineral fiber types tested in this study also appear to meet the intended German criteria for exoneration.

Tumorigenicity of cellulose fibers injected into the rat peritoneal cavity.

Cellulose fibers, along with many other organic fibers, are durable. Therefore, if inhaled, they have the potential to persist within the lung, and may then cause disease. Here we report the effects of injecting high-purity cellulose fibers into the abdominal cavity of rats. A respirable fraction of cellulose fiber was collected from an aerosol of a thermo-mechanically-processed wood pulp. A sample of respirable crocidolite asbestos, known to produce mesotheliomas in rats, was used as a positive control. Total doses of 10(6), 10(7), 10(8), or 10(9) WHO fibers were injected intraperitoneally as 3 weekly aliquots. A negative control was provided by phosphate-buffered saline used to suspend the fibers for injection. There were 50 rats per treatment group except for the 10(8) and 10(9) fibers crocidolite groups which were reduced to 26 rats because of the expectation of high tumor incidence in these groups. The two higher doses of crocidolite asbestos caused greatly reduced survival compared to the saline controls. With cellulose there was a much less marked effect on survival. In the highest dose cellulose group, multiple large nodules (granulomas) and widespread adhesions (bands of new tissue connecting organs to each other and to the abdominal wall) were present in all animals. Granulomas were not observed in the 10(9) fibers crocidolite group. More than 80% of animals in the 10(8) and 10(9) crocidolite asbestos groups had mesotheliomas, a type of tumor sometimes observed in people exposed to asbestos. In contrast, there were only 2 animals in the cellulose groups with mesothelioma tumors, 1 in the 10(7) and 1 in the 10(8) groups. However, 9 (18%) of the 10(9) cellulose group had malignant tumors that, in contrast to the usual pattern of mesothelioma development following treatment with mineral fibers in rats, showed no obvious involvement of mesothelial tissues, were not associated with blood-stained ascites fluid, and were thus classified as sarcomas. This study has demonstrated that a high dose of cellulose fibers is capable of producing tumors when injected into the abdominal cavity of rats.