Genotoxicity of iron compounds in Salmonella typhimurium and L5178Y mouse lymphoma cells.

The mutagenic activity of elemental and salt forms of iron (Fe), including compounds currently being used in dietary supplements and for food fortification, were evaluated for mutagenicity in Salmonella typhimurium and L5178Y mouse lymphoma cells. Except for the weak response obtained with ferrous fumarate, none of the compounds induced a mutagenic response in Salmonella. In the mouse lymphoma assay, responses were related to the Fe compound and/or reduction of ferric (Fe+3) to ferrous (Fe+2). Responses with the elemental forms of Fe were divergent. Electrolytic Fe with a relatively larger particle size and irregular shape was negative. The smaller-sized carbonyl Fe, which after 4 hr attached to and was taken up by the cells, induced mutagenic responses both with and without S9. With ferric chloride (FeCl3) and ferric phosphate (FePO4), there was an increase in mutant frequency only with S9. With the Fe+2 compounds, ferrous sulfate (FeSO4) and ferrous fumarate (FeC4H2O4), positive responses were observed without S9. The Fe chelate, sodium Fe(III)EDTA was positive in both the presence and absence of S9. The lowest effective doses (LED) for induction of mutagenicity were identified for these compounds and an LED ratio calculated. The LED ratio ranges from 1 for FeSO4 to 30 for carbonyl Fe, which are similar to oral LD50 values obtained in animal studies.

Use of unscheduled DNA synthesis in freshly isolated human intestinal mucosal cells for carcinogen detection.

Mucosal cells freshly isolated from human intestine with pronase retain the capacity to undergo DNA repair synthesis (unscheduled DNA synthesis) during a 2-hr exposure to the carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine, and the procarcinogen, aflatoxin B1. This procedure combining the use of human intestinal mucosal cells and the measurement of unscheduled DNA synthesis may provide a highly relevant and convenient test system for the detection of cell-specific, direct-acting, and activation-dependent chemical carcinogens. The use of whole-cell preparations in such in vitro studies may be of additional significance in view of growing evidence for artefactual metabolism by subcellular fractions.

Possible use of short-term tests for carcinogens in experimental epidemiology.

This brief overview pointed out the feasibility of applying the recently developed short-term bioassays for carcinogens/mutagens to the field of epidemiology. The simplicity and economy of these test systems permitted their adaptation for large-scale screening for intrinsic and extrinsic carcinogens with an eye to detecting subpopulations with elevated sensitivity to particular carcinogens.

The search for relevant short term bioassays for chemical carcinogens: the tribulation of a modern Sisyphus.

Based on a good correlation between carcinogenicity and mutagenic activity several rapid microbial bioassays for chemical carcinogens have been recently developed. We would like to suggest, that these microbial tests should be followed by bioassays using cultured human cells of the "average" man, and of persons with elevated cancer risk or increased susceptibility to carcinogenic agents. The main objective of using DNA repair (unscheduled uptake of 3HTdR) and DNA fragmentation (shift in sedimentation profiles) of cultured human cells was to design a test system that can simulate conditions found in man and thus provide information relevant to the human population. A trial on 98 different carcinogens, precarcinogens and noncarcinogens showed the suitability of DNA repair synthesis as a rapid, economic and relevant assay for detection of chemical carcinogens. To check the adaptability of DNA repair synthesis of human cells as a bioassay for chemical carcinogens we examined carcinogenic nitrosation products which are formed from the interaction of nitrite and nitrosatable compounds, carcinogenic or mutagenic photosensitizing chemicals, and the effect of complex interactions. Organotropic carcinogens can be detected by measuring DNA fragmentation and DNA repair in various target organs following the in vivo application of chemical carcinogens. The pros and cons of several bioassays and their usefulness in judging a carcinogenic or mutagenic hazard to human populations is discussed.

DNA repair synthesis of cultured human cells as a rapid bioassay for chemical carcinogens.

The feasibility of detection of carcinogenic chemicals using DNA repair synthesis of cultured human fibroblasts as measured by an unscheduled 3HTdR incorporation has been explored. Of 64 chemicals tested, 29 were proximate or ultimate carcinogens, 15 were precarcinogens that required metabolic activation, 16 were non-oncogenic compounds and 4 were of unknown carcinogenicity. All directly acting carcinogens triggered a DNA repair synthesis, whereas no unscheduled 3HTdR incorporation was observed following the application of the 16 non-oncogenic compounds. As a rule, the precarcinogens (without metabolic activation) do not elicit DNA repair synthesis. However, longer exposures and higher concentrations of the precarcinogens 2-AAF, aflatoxin B1 and sterigmatocystin gave unscheduled 3HTdR uptake. The results suggest the suitability of using repair synthesis as endpoint, and cultured human cells as subjects in a prescreening programme for chemical carcinogens.