Chapter 18. Biological Studies on the Carcinogenic Mechanisms of Quartz

Saffiotti, Umberto; Daniel, Lambert N.; Mao, Yan; Williams, A. Olufemi; Kaighn, M. Edward; Ahmed, Nadera; Knapton, Alan

doi:10.1515/9781501509711-021

Cited by 9 publications

(10 citation statements)

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“…The MQZ sample reached maximum frequency at 25 pg/cm2 (confirmed in seven replicate tests), whereas the HFMQZ sample reached it at 50 pg/cm2 in the present test and at 25 pg/cm2 in a replicate test. When tested in vivo in long-term bioassays in F344 rats of both sexes, treated with a single intratracheal instillation of 12 mg quartz in 0.3 ml saline, MQZ and HFMQZ induced similar high incidences of lung tumors, with comparable tumor frequencies observed at three time intervals, and with the same distribution of tumor types, mostly adenocarcinomas of alveolar origin [12,13]. It appears, therefore, that the mechanisms responsible for the markedly different effects of MQZ and HFMQZ, observed for DNA damage and production of hydroxyl radical in vitro, are superseded by other mechanisms in the process of carcinogenesis in living cells and tissues.…”

Section: Discussionmentioning

confidence: 92%

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Neoplastic transformation by quartz in the BALB/3T3/A31‐1‐1 cell line and the effects of associated minerals

Saffiotti

Ahmed

1995

Teratog Carcinog Mutagen

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Quartz, the most common form of crystalline silica, was tested quantitatively for neoplastic transformation in the mouse embryo cell line, BALB/3T3/A31-1-1. Five quartz dust samples of respirable size [Min-U-Sil 5 (MQZ); hydrofluoric-acid-etched MQZ (HFMQZ); Chinese standard quartz (CSQZ); DQ12; and F600] all induced significant levels of neoplastic transformation, showing dose-dependent increases in the frequency of morphologically transformed foci at lower tested doses and a plateau level of response at higher doses. The plateau levels reached by the five tested samples did not differ substantially (maximum transformation frequencies per 10(5) cells ranging from 53.2 for MQZ to 28.3 for HFMQZ). F600 had minimal cytotoxicity but transforming activity comparable to the other samples. Cells from all tested transformed foci, when injected s.c. in nude mice, grew as sarcomas. Cytogenetic analysis showed that all tested silica-transformed cell lines had acquired one to five additional marker chromosomes, of types not seen in untreated control lines, indicative of induced chromosomal translocations and amplification. Increased expression of one or more of five genes (p53, myc, H-ras, K-ras, and abl) was observed in several quartz-transformed cell lines. No transforming activity was found for hematite and anatase (both nontoxic), and for rutile (more toxic than MQZ). Combined exposure (1:1 w/w per unit culture area) of each of these dusts with MQZ showed that hematite and anatase inhibited MQZ toxicity as well as transformation, whereas rutile markedly enhanced MQZ toxicity but not MQZ-induced transformation.

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Section: Discussionmentioning

confidence: 92%

“…The role of surface impurities, especially iron, was considered in the comparison of samples MQZ and HFMQZ, since HF etching removed iron impurities from MQZ, as shown by x-ray fluorescence spectra [12]. In the assay for DNA damage in vitro [17], MQZ caused more rapid DNA breakage than HFMQZ [Daniel et al, unpublished observations].…”

Section: Discussionmentioning

confidence: 99%

Neoplastic transformation by quartz in the BALB/3T3/A31‐1‐1 cell line and the effects of associated minerals

Saffiotti

Ahmed

1995

Teratog Carcinog Mutagen

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“…Silica administration in different experimental animals has produced a wide range of pulmonary responses. For example, it has been shown that rats are highly susceptible to silica as compared with mice (43,44). Differences in susceptibility were also observed in different strains of the same species.…”

Section: What Is the Relationship Between Downregulated Tnf-␣ And Thementioning

confidence: 99%

Soluble Tumor Necrosis Factor (TNF) Receptors p55 and p75 and Interleukin-10 Downregulate TNF- α Activity during the Lung Response to Silica Particles in NMRI Mice

Huaux

Arras

Vink

et al. 1999

Am J Respir Cell Mol Biol

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We have found reduced activity of tumor necrosis factor (TNF)-alpha accompanying resolving and fibrosing alveolitis induced in NMRI mice by mineral particles (MnO2 and SiO2, respectively), which is in apparent contradiction to the well-recognized proinflammatory and profibrotic activities of this cytokine. The objective of this study was to examine the mechanisms involved in this paradoxical response in NMRI mice. Although lung tissue messenger RNA (mRNA) levels for TNF-alpha were transiently (up to 15 d) and persistently (up to 120 d) upregulated in the resolving and fibrosing models, respectively, these changes were not accompanied by a parallel release of TNF-alpha protein, which was respectively transiently and persistently downregulated in bronchoalveolar lavage fluid and bronchoalveolar lavage cell cultures. The downregulation of the TNF-alpha protein was concurrent with the accumulation of recruited polymorphonuclear neutrophils (PMNs) in alveoli, and coculture experiments showed that PMN explanted from the lungs of mice treated with silica particles were able to downregulate the expression of TNF-alpha protein by naive alveolar macrophages. In addition, PMN depletion prevented the downregulation of TNF-alpha induced by silica, further establishing the role of PMNs in the downregulation of TNF-alpha. The possible degradation of TNF-alpha by proteolytic enzymes could be excluded. Marked increases in soluble p55 and p75 TNF receptors (sTNF-R), as well as in interleukin (IL)-10, paralleled the downregulation of TNF-alpha protein. The role of these mediators in the observed reduction of TNF-alpha activity was confirmed by immunoneutralizing the activity of p55 and p75 sTNF-R and by using IL-10-deficient animals. Because IL-10 also exerts profibrotic activity in addition to its antiinflammatory activity, the protracted overproduction of IL-10 observed in fibrosing alveolitis may help the understanding of why, in NMRI mice treated with silica particles, lung fibrosis develops in association with a downregulation of TNF-alpha.

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“…However, one study reported an increased incidence of lung tumors among mice exposed to DEP. Furthermore, asbestos and crystalline silica provide examples of particulate substances which are classified by the IARC as carcinogenic to humans [IARC, 1987[IARC, , 1997, and which are carcinogenic by inhalation in rats, but not in other common laboratory species [Reeves, 1974;Saffiotti, 1993]. Therefore, ignoring the rat lung carcinogenicity data for inhaled particles would run the risk of producing false negatives.…”

Section: Sources Of Uncertainty In the Toxicologic Assessments Of Riskmentioning

confidence: 99%

Predicted lung cancer risk among miners exposed to diesel exhaust particles

et al. 1998

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Several quantitative risk assessment models have been published for occupational and environmental exposures to diesel exhaust particles (DEP). These risk assessment models are reviewed and applied to predict lung cancer risks for miners exposed to DEP. The toxicologically based unit risk estimates varied widely (from 2 to 220 × 10−6 per μg/m3). The epidemiologically based unit risk estimates were less variable and suggest higher risks (from 100 to 920 × 10−6 per μg/m3). The wide range of risk estimates derived from these analyses reflects the strong assumptions and large uncertainties underlying these models. All of the models suggest relatively high risks (i.e., >1/1,000) for miners with long‐term exposures greater than 1,000 μg/m3. This is not surprising, given the fact that miners may be exposed to DEP concentrations similar to those that induced lung cancer in rats and mice, and substantially higher than the exposure concentrations in the positive epidemiologic studies. Am. J. Ind. Med. 34:207–219, 1998. Published 1998 Wiley‐Liss, Inc.

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Chapter 18. Biological Studies on the Carcinogenic Mechanisms of Quartz

Cited by 9 publications

References 0 publications

Neoplastic transformation by quartz in the BALB/3T3/A31‐1‐1 cell line and the effects of associated minerals

Neoplastic transformation by quartz in the BALB/3T3/A31‐1‐1 cell line and the effects of associated minerals

Soluble Tumor Necrosis Factor (TNF) Receptors p55 and p75 and Interleukin-10 Downregulate TNF- α Activity during the Lung Response to Silica Particles in NMRI Mice

Predicted lung cancer risk among miners exposed to diesel exhaust particles

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