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Micronucleus (MN) expression in peripheral blood lymphocytes is well established as a standard method for monitoring chromosome damage in human populations. The first results of an analysis of pooled data from laboratories using the cytokinesis-block micronucleus (CBMN) assay and participating in the HUMN (HUman MicroNucleus project) international collaborative study are presented. The effects of laboratory protocol, scoring criteria, and host factors on baseline micronucleated binucleate cell (MNC) frequency are evaluated, and a reference range of "normal" values against which future studies may be compared is provided. Primary data from historical records were submitted by 25 laboratories distributed in 16 countries. This resulted in a database of nearly 7000 subjects. Potentially significant differences were present in the methods used by participating laboratories, such as in the type of culture medium, the concentration of cytochalasin-B, the percentage of fetal calf serum, and in the culture method. Differences in criteria for scoring micronuclei were also evident. The overall median MNC frequency in nonexposed (i.e., normal) subjects was 6.5 per thousand and the interquartile range was between 3 and 12 per thousand. An increase in MNC frequency with age was evident in all but two laboratories. The effect of gender, although not so evident in all databases, was also present, with females having a 19% higher level of MNC frequency (95% confidence interval: 14-24%). Statistical analyses were performed using random-effects models for correlated data. Our best model, which included exposure to genotoxic factors, host factors, methods, and scoring criteria, explained 75% of the total variance, with the largest contribution attributable to laboratory methods.

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Botulinum C2 toxin has histopathological activity in the mouse intestine and induces fluid accumulation in intestinal loops. The toxin caused degenerative and necrotic changes in the intestinal mucosa: intracellular vacuolization of epithelial cells, desquamation and necrosis of the villous epithelium, intercellular edema, and infiltration of lymphocytes and histiocytes. The detectable changes in the morphology of the intestinal mucosa preceded the increase in fluid accumulation in intestinal loops. Intraluminal injection of botulinum C2 toxin also induced the leakage of plasma protein into the intestinal lumen as determined by the extravasation of Evans blue. In contrast to botulinum C, toxin, cholera and Clostridium perfringens enterotoxin controls caused a very slight protein leakage, although these toxins induced marked fluid accumulation in intestinal loops. The results indicate that the mode of action of botulinum C2 toxin in eliciting the secretory response is distinguishable from those of cholera and C. perfringens enterotoxins and suggest that botulinum C2 toxin induces the secretory response by cytopathic effect(s) on the epithelial cells of the intestine.