PubMed · 6714106
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M S Huuskonen, J Järvisalo, H Koskinen, J Nickels, J Pasanen, A Tossavainen. 1984. [Fiber minerals causing disease].. https://pubmed.ncbi.nlm.nih.gov/6714106/
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Crocidolite asbestos is a known human carcinogen containing 27% iron by weight. It has previously been shown that iron was mobilized intracellularly from crocidolite after treatment of human lung epithelial cells (A549) and that the toxicity of the fibers was directly related to how much mobilized iron was in the < 10,000 MW (low-molecular-weight, LMW) fraction [C. C. Chao, L.G. Lund, K. R. Zinn, and A. E. Aust (1994) Arch. Biochem. Biophys. 314, 384-391]. The data here show that iron mobilization from crocidolite began immediately after treatment of the A549 cells and increased linearly with time. However, the synthesis of ferritin, an iron storage protein, did not begin until after 4 h of treatment, reaching a sustained maximum after 12 h. Mobilized iron was preferentially incorporated into the nonferritin-protein fraction up to 7 h after treatment, when the amount of iron mobilized was low and before significant accumulation of newly synthesized ferritin had occurred. This suggested that these cultured cells needed additional iron for synthesis of iron-requiring proteins and that iron mobilized from crocidolite could be utilized directly for this purpose. Subsequent to this, additional mobilized iron was incorporated into newly synthesized ferritin. Even though iron from crocidolite was incorporated into newly synthesized ferritin or into other proteins, the amount of iron from crocidolite in the LMW fraction remained constant during the 24 h. Thus, it appeared that synthesis of ferritin may not have fully protected the cells from the toxic effects of iron mobilized from crocidolite.
In epidemiologic studies, analysis of the relationship between exposure intensity and risk is complicated by the fact that exposures often take place over extended periods, during which intensities can vary substantially. To relate exposure to outcome, it is necessary to combine information about duration, intensity and timing into a summary measure of exposure. If the aim of the exposure-response analysis is to estimate the risk associated with differing exposure intensities, the results depend on the manner in which one incorporates intensity into the summary exposure metric. Most metrics used to summarize exposure, such as the cumulative exposure index, are time-weighted summations of intensity. They are thus based on the assumption that for any fixed time point, the effect of a unit of exposure is proportional to its intensity. This paper describes an approach for constructing and fitting summary measures of exposure that one can use to incorporate alternative assumptions about the effect of exposure intensity, as well as effects relating to the timing of exposure. Data from a study of lung cancer mortality in asbestos miners and millers serve to illustrate the method. Exposure metrics based on various functions of intensity and time of exposure are constructed and fitted to the data using conditional logistic regression. The results demonstrate how the choice of a function for quantification of exposure can affect the exposure-response analysis and the risk estimates it yields.
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