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Background: We analyze the scientific basis and methodology used by the German MAK Commission in their recommendations for exposure limits and carcinogen classification of "granular biopersistent particles without known specific toxicity" (GBS). These recommendations are under review at the European Union level. We examine the scientific assumptions in an attempt to reproduce the results. MAK's human equivalent concentrations (HECs) are based on a particle mass and on a volumetric model in which results from rat inhalation studies are translated to derive occupational exposure limits (OELs) and a carcinogen classification., Methods: We followed the methods as proposed by the MAK Commission and Pauluhn 2011. We also examined key assumptions in the metrics, such as surface area of the human lung, deposition fractions of inhaled dusts, human clearance rates; and risk of lung cancer among workers, presumed to have some potential for lung overload, the physiological condition in rats associated with an increase in lung cancer risk., Results: The MAK recommendations on exposure limits for GBS have numerous incorrect assumptions that adversely affect the final results. The procedures to derive the respirable occupational exposure limit (OEL) could not be reproduced, a finding raising considerable scientific uncertainty about the reliability of the recommendations. Moreover, the scientific basis of using the rat model is confounded by the fact that rats and humans show different cellular responses to inhaled particles as demonstrated by bronchoalveolar lavage (BAL) studies in both species., Conclusion: Classifying all GBS as carcinogenic to humans based on rat inhalation studies in which lung overload leads to chronic inflammation and cancer is inappropriate. Studies of workers, who have been exposed to relevant levels of dust, have not indicated an increase in lung cancer risk. Using the methods proposed by the MAK, we were unable to reproduce the OEL for GBS recommended by the Commission, but identified substantial errors in the models. Considerable shortcomings in the use of lung surface area, clearance rates, deposition fractions; as well as using the mass and volumetric metrics as opposed to the particle surface area metric limit the scientific reliability of the proposed GBS OEL and carcinogen classification.

We analyzed the so-called "19-dust-studies" (19-DS) that reported lifetime lung tumor occurrence in female rats following repetitive, short-term intratracheal instillation (ITI) of 19 different insoluble dusts. In the 19-DS, lung instillation of up to 120mg/rat of granular, biopersistent, low-specific-toxicity particles (GBP) caused about half of the rats to develop lung tumors, but the relevance of these data to deriving exposure limits for GBP is uncertain. Specific drawbacks to using the 19-DS for risk assessment include: (1) Delivery, via ITI, of a worker's estimated lifetime lung dose causes "lung overload" in rats, and is not equivalent to lifetime inhalation exposure; (2) The response of rats to insoluble-particle "lung overload" is stereotyped and unique to that species; (3) The 19-DS did not include low-dose studies, and the dose-response showed saturation at the high levels; (4) When the lung-overload threshold is exceeded, rats develop lung tumors from ongoing inflammation (as opposed to particle-specific toxicity); that is, the dramatically increased dose-delivery rate evokes mechanisms not relevant to gradual exposure; and (5) workers historically exposed to potentially lung-overloading burdens of inhaled dust (e.g., coal workers, underground miners using diesel equipment) do not exhibit an established lung-cancer excess. Our critical review of the data from the 19-DS suggests that the reported results for GBP are not a reliable basis for predicting human lung cancer risk, e.g., for the typical inhaled-dose conditions for which worker exposure limits to GBP are promulgated.

Background: Mineral dusts that contain crystalline silica have been associated directly or indirectly with the development of pneumoconiosis or silicosis, non-malignant respiratory diseases, lung cancer, and other diseases. The health impacts on workers with silica mixed dust exposure in tin mines and dose-response relationships between cumulative dust exposure and the mortality from lung cancer are investigated., Methods: A cohort of 7,837 workers registered in the employment records in 4 Chinese tin mines between 1972 and 1974 was identified for this study and the mortality follow-up was traced through 1994. Of the cohort, the cause of death was ascertained for 1,061 (97%) of the 1,094 deceased workers. Standardized mortality ratios (SMRs) were calculated for all workers, non-exposed workers, and dust-exposed workers with different exposure levels, silicotics, and non-silicotics based on Chinese national rates., Results: The mortality from all causes in four tin mines was nearly the same as the national mortality. Malignant neoplasm, cerebrovascular disease, and cardiovascular disease accounted for 68.6% of all deaths. Mortality excess from lung cancer, liver cancer, all malignant diseases, and non-malignant respiratory diseases was observed among dust-exposed workers; a 50-fold excess of pneumoconiosis was observed. There was an upward trend for SMRs of lung cancer was noted from no exposure to low, medium, and high exposure levels (SMRs=1.29, 2.65, 2.66, 3.33). The shape of the exposure-response curve for risk of lung cancer at high exposure levels was inconsistent in these four mines., Conclusions: The findings indicated a positive dose-response relation between exposure to cumulative dust and the mortality of lung cancer. High arsenic content in dust particles, together with crystalline silica, may play an important role in causing increased mortality from lung cancer., (Copyright (c) 2005 Wiley-Liss, Inc.)

Objective: To evaluate the biological and toxicity of tin mine particles mixed with crystalline silica using an in vitro test, and to compare to the pathogenesis of pneumoconiosis and lung cancer., Methods: Respirable particle samples were sampled from four tin mines, in which elevated mortality of pneumoconiosis and lung cancer were reported in miners exposed to particles. Alveolar macrophages (AM) are considered as the target cells of primary dust effects. The samples were then measured in 15, 30, 60 and 120 microg particle per 106 AM for cytoxicity with the release of glucuronidase, lactate dehydrogenase, for reactive oxygen damage with H2O2 release, and for ability to induce fibrosis using the secretion of tumor necrosis factor-alpha (TNF-(alpha) in guinea pig and/or rat am. pure quartz (dq12) and corundum were used as controls., Results: The results showed the samples from tin mines caused a higher cytoxicity when compared to corundum, yet lower when compared to quartz. However, reactive oxygen species release induced by the samples were significantly higher than that induced by quartz and corundum. Beside particle samples induced higher TNF-alpha secretion than corundum, samples from Limu tin mine also induced greatly higher TNF-alpha levels than that induced by pure quartz, even in the lowest concentration. The results from epidemiological research show that high incidence of silicosis among tin miners. And standardize mortality from all cancer (SMR = 1.58, 95% CI: 1.39-1.76) and lung cancer (SMR = 3.17, 95% CI: 2.59-3.76) are higher than national average level., Conclusion: The results from in vitro test may reasonable interpret high risk of pneumoconiosis and lung cancer in tin miners. The in vitro multidimensional reaction patterns of AM can be used to screen workplace particles for adverse effects to health.

Epidemiological research has demonstrated the relationship between exposure to quartz dust and an elevated risk of pneumoconiosis and possible elevated risk of cancer. The current study was designed to evaluate the biological responses of workplace particles containing crystalline silica using an in vitro cell test. Respirable particle samples were sampled from four tin mines, where the standardized mortality ratio (SMR) for pneumoconiosis was 51.6 and SMR for lung cancer was 2.2 in dust-exposed miners. Alveolar macrophages (AM) are considered as the target cells for primary dust effects. The samples were then measured at 15, 30, 60 and 120 microg particle per 10(6) AM for cytoxicity with the release of glucuronidase, lactate dehydrogenase, for reactive oxygen damage with H(2)O(2) release, and for ability to induce fibrosis using the secretion of tumor necrosis factor-alpha (TNF-alpha). Pure quartz (DQ12) and corundum were used as controls. The results showed the samples from tin mines caused a higher cytoxicity when compared to corundum, yet lower when compared to quartz. However, reactive oxygen species release (148-177 nmol/3 x 10(5) AM in high concentration of 120 microg/10(6) AM) induced by the samples were significantly higher than that induced by quartz (57 nmol/3 x 10(5) AM) and corundum (62 nmol/3 x 10(5) AM). Furthermore, particle samples induced higher TNF-alpha secretion than corundum, the samples from Limu tin mine induced much higher TNF-alpha levels than that induced by DQ12 quartz. The results from the in vitro tests help elucidate the degree of hazard of dust particles in tin mines. The in vitro reaction patterns of AM also constitute a powerful tool to monitor biological and pathogenic responses of humans following dust particle exposure.

Exposure of rats to quartz (or various other particles) can lead to the development of lung tumors. At the moment, the mechanisms involved in particle-induced tumor formation are not clarified. However, it is suggested that inflammation, in conjunction with the production of reactive oxygen species (ROS) and an enhancement of epithelial cell proliferation, may play a key role in the development of lung tumors. ROS induces 8-oxoguanine (8-oxoGua) and other mutagenic DNA oxidation products, which can be converted to mutations in proliferating cells. Mutation formation in cancer-related genes is a critical event with respect to tumor formation. In this study we investigated the effects of quartz (DQ12) and of the nontumorigenic dust corundum on the induction of 8-oxoGua in the DNA of rat lung cells, as well as on cell proliferation and pulmonary inflammation. Wistar rats were exposed by intratracheal instillation to quartz (2.5 mg/rat) or corundum (2.5 mg/rat) suspended in physiological saline; control animals exposed to physiological saline or left untreated. Measurements were carried out 7, 21, and 90 days after the exposures. 8-oxoGua levels were determined in lung tissue sections at the single cell level by immunocytological assay using a rabbit anti-8-oxoGua antibody. After exposure to quartz, 8-oxoGua levels were significantly increased at all time points of investigation. Additionally, we observed inflammation and an enhanced cell proliferation. Exposure to corundum had no adverse effects on the lung; neither increased 8-oxoGua levels nor enhanced cell proliferation or inflammation were detected. These observations support the suggestion that inflammation associated with increased 8-oxoGua levels in lung cells and increased cell proliferation is an important determinant for particle-induced development of lung tumors in the rat.