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.

3T3 Cells↗

PubMedDate not supplied

Neoplastic transformation of BALB/3T3 cells by metals and the quest for induction of a metastatic phenotype.

In the mouse embryo cell line BALB/3T3 Clone A31-1-1, dose-dependent morphologic neoplastic transformation was obtained with NaAsO2, Na2HAsO4, CdCl2, and K2CrO4. Cellular uptake was four fold higher for As3+ than for As5+, and As5- was metabolized to As3+ in cytosol. Cytotoxicity and transformation rates were four fold higher for As3+ than As5+, but when correlated to cellular As burden they were equivalent. As3+ appears responsible for the transforming activity. The foci transformed by metals (or by other carcinogens) gave rise to tumorigenic cell lines (sc sarcomas in nude mice), none of which, however, induced metastases when tested by sc or by iv injection in nude mice. Thus carcinogens change this aneuploid cell line from a preneoplastic stage to the expression of malignant growth but not of metastatic activity. Metastatic and type IV collagenolytic activities can be induced by transfection of the c-Ha-ras oncogene and inhibited by the Ad2-E1a gene (so far shown in other cell types). It remains to be seen whether metal or other carcinogens can induce the nonmetastatic phenotype to become metastatic. The molecular mechanisms of metal carcinogenesis, studied in cell culture systems, in combination with other factors or oncogenes, may reveal the effect of individual metal carcinogens on discrete steps of the complex process of carcinogenesis.

Animals↗

PubMedDate not supplied

Split-dose exposure to N-methyl-N'-nitro-N-nitrosoguanidine in BALB/3T3 C1 a31-1-1 cells: evidence of DNA repair by alkaline elution without changes in cell survival, mutation and transformation rates.

Dose fractionation of a direct-acting chemical carcinogen, the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), was studied for its concurrent effects on survival, DNA damage and repair, ouabain resistance (Ouar) mutations and neoplastic transformation, in the mouse embryo cell line BALB/3T3 C1A31-1-1. MNNG doses of 0.5, 1 and 2 micrograms/ml were added to the cells either as a single exposure or in two equal fractions separated by 1, 3 or 5 h intervals. No significant difference in cytotoxicity was found when single and split-dose treatments were compared. No recovery from sublethal damage was therefore found in this cell line by split-dose administration of MNNG, although such an effect was found when the same cell line was treated with single and split doses of X-rays. Repair of DNA damage as measured by alkaline elution was studied up to 24 h after a single MNNG exposure (0.5 micrograms/ml). DNA repair was rapid during the first 5 h after treatment and slow thereafter. DNA damage detected after split doses of MNNG at 1 and 5 h intervals was significantly lower than after a corresponding single dose. With both single and split doses, rejoining of single-strand breaks (ssb) was nearly complete after 24 h of repair time. Ouar mutation and neoplastic transformation frequencies were determined for single and split doses of MNNG with the second treatment being given during (1 h) or after (5 h) the period of rapid DNA repair. No significant differences in either effect were detected for dose splitting at any tested dose.

Animals↗

PubMedDate not supplied

Identification and definition of chemical carcinogens: review of criteria and research needs.

Advances in carcinogenesis research have greatly improved the methods for detection, investigation, and definition of occupational carcinogens. A basis of scientific criteria has been developed for carcinogen identification and evaluation. Research, legislative, and regulatory initiatives in the United States are reviewed. The 1979 Report of the Working Group on Occupational Carcinogenesis, Occupational Cancer Task Force, National Cancer Institute, is added as an appendix. A detailed discussion is given of the 1979 report of the Interagency Regulatory Liaison Group entitled "Scientific bases for identification of potential carcinogens and estimation of risks." Two separate approaches are considered, i.e., the qualitative determination that a substance poses a carcinogenic hazard and the quantitative estimation of risk. The qualitative criteria are reviewed in the present paper. The need for critical data evaluation and the judgmental nature of the process are emphasized. Research needs arising from the analysis of these criteria are discussed. Laboratory research contributions to the identification and characterization of carcinogens are summarized, including development and study of organ target models for carcinogenesis in animals; studies of human target tissues and cells in culture; studies of transformation, initiation, and promotion of epidermal cells in culture; studies of transplacental carcinogenesis; and studies of molecular mechanisms.

Animals↗

PubMedDate not supplied

The problem of extrapolating from observed carcinogenic effects to estimates of risk for exposed populations.

A review is presented of the complex problems involved in the quantitative estimation of cancer risk for populations exposed to carcinogens on the basis of evidence provided either by epidemiologic studies or by experimental data. Strain and species differences among experimental animals and wide interindividual differences among human subjects are discussed. Examples from quantitative laboratory studies on carcinogenic risk factors are discussed to illustrate research approaches in this field, especially in measurements of carcinogen interactions with animal and human target tissues, in human tissue-mediated mutagenesis of mammalian cells, and in studies of combined effects of different carcinogens. The scientific criteria for the quantitative estimation of carcinogenic risk, developed by the Interagency Regulatory Liaison Group, are reviewed, and related research needs are indicated. The implications for regulatory policy, as outlined by the U.S. Regulatory Council, are discussed. Precise and reliable quantitative estimates of cancer risk often appear not to be obtainable and, in such cases, nonquantitative risk assessments have been recognized as appropriate.

Carcinogens↗

PubMedDate not supplied

The histogenesis of experimental silicosis. I--Methods for the histological evaluation of experimentally induced dust lesions. (2). 1960.

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Animals↗