We have recently observed that androgens prevent the estrogen-dependent augmentation of cytoplasmic progesterone receptor (PRc) in MCF-7 human breast cancer cells and now report the results of studies that further characterize this new example of sex steroid antagonism. Using a single saturating dose assay to monitor changes in MCF-7 PRc concentration, we have observed that androgens are capable of inhibiting both the estrogenic induction and the ongoing stimulation of PRc synthesis, but have no apparent effect upon basal concentrations of this receptor. Both testosterone and dihydrotestosterone (DHT) demonstrate similar degrees of antiestrogenic activity at concentrations between 10(-10)--10(-8) M. Furthermore, a 10(-8)-M concentration of either androgen completely inhibits the stimulation of PRc synthesis by 10(-11)--10(-8) M 17 beta-estradiol (E2). This inhibitory effect is maintained during the continued presence of either testosterone or DHT, but rapidly disappears after the withdrawal of androgen from the culture medium. The specific nuclear binding of 17 beta-[3H]estradiol over time appears to be similar in cultures incubated in the presence and absence of 10(-8) M DHT. This observation suggests that androgens do not inhibit estrogen action by interfering with the formation, activation, nuclear binding, or nuclear processing of estrogen-receptor complexes. The estrogenic stimulation of PRc is not diminished by the 5 beta-epimer of DHT, and the inhibitory activity of DHT itself is blocked by several different antiandrogens. These findings provide substantial support for the concept that the antiestrogenic effect of androgens is mediated by an androgen receptor mechanism. These results may provide new insights into the clinically apparent antagonistic effects of estrogens and androgens upon both normal and malignant human breast tissues.

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The goals of this project were to evaluate and compare the efficiency and reproducibility of three methods for sampling lead-containing dust in homes. Lead-containing dust was generated in a 1-m3 chamber and uniformly deposited onto surfaces typically found in the home (painted wood, unpainted wood, varnished wood, linoleum, and carpet). Trials with three levels of lead concentrations were performed for each surface. Replicate, side-by-side, surface samples were collected using the Occupational Safety and Health Administration (OSHA) wipe method, the Department of Housing and Urban Development (HUD) wipe method, and a vacuum-filter method. Samples were digested with nitric acid and analyzed using graphite furnace atomic absorption spectroscopy per National Institute of Occupational Safety and Health Method 7105. Recovery for the HUD method was consistently the highest on most surfaces (linoleum, 89.9 to 108.9%; painted wood, 71.2 to 153.7%; unpainted wood, 25.3 to 76.0%; varnished wood, 8.7 to 165.6%). On carpet the vacuum method had a significantly higher recovery (26.2 to 47.8%). For all sampling methods the percent recovery depended on type of surface and lead concentration. The reproducibility of percent recovery for the HUD (pooled coefficient of variation [CV] = 0.22) and OSHA (pooled CV = 0.27) methods was lower than that of the vacuum method (pooled CV = 0.46), though not statistically significant. Reproducibility for all methods did not vary significantly over surface type or lead concentration. Overall, the HUD method yielded the most accurate measurements, with recoveries closest to 100%. It was also more durable than the OSHA method, where Whatman filters were observed to tear.

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Difluoromethylidene bisphosphonate (F2MBP) is one of the many bisphosphonates known to inhibit bone resorption in vitro and in vivo. We have developed an analytical method, employing anion exchange and postcolumn indirect fluorescence detection, by which F2MBP can be quantified in bone samples. The objective of this study was to relate the concentration of F2MBP in embryonic bones treated in organ culture to the physiological effects of the compound, such as bone resorption (i.e., the amount of 45Ca released into the medium from prelabeled bones) and viability of the osteoclast population (i.e., the incidence of abnormal osteoclasts). Osteoclasts in bones treated with F2MBP exhibited morphological features of apoptosis, such as nuclear fragmentation. Both the number and percentage of these abnormal cells increased with dose of F2MBP and duration of incubation. The decrease in normal osteoclasts was correlated with the decreased amount of 45Ca released into the medium. Bones treated with F2MBP for only the first 5 min of the 48-h incubation period had similar numbers of abnormal osteoclasts and amounts of 45Ca released, as had bones incubated with F2MBP continuously for 48 h. The uptake of F2MBP into the bone was rapid. Bones treated with F2MBP for 6 h were similar to bones treated with F2MBP for the entire 48-h incubation period, both in F2MBP concentration and the 45Ca release ratios. These relationships between concentrations of F2MBP within bone and osteoclast activity and viability implicate apoptosis in the mechanism by which this bisphosphonate inhibits bone resorption.

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This research project was conducted in collaboration with the Iowa Department of Public Health to evaluate whether property owners who follow recommended procedures for lead-based paint removal/repair can do the work safely and effectively. This study included 29 homes where a lead-based paint hazard had been identified and lead-based paint was removed or repaired (hazard reduction). Exposure evaluation included pre-project surface dust wipe sampling, air monitoring during lead-based paint removal, post-project surface dust wipe sampling, and pre- and post-project blood samples from adult study participants. The comparison of surface dust wipe samples taken before and after lead paint hazard reduction was used to evaluate the effectiveness of lead paint hazard reduction. The lead loadings on window sill surfaces in the work area were significantly lower after completion of the project (p = 0.04), and the lead-based paint removal did not contaminate the adjoining living area. The proportion of homes with surface dust lead loading exceeding Department of Housing and Urban Development (HUD) clearance standard was 73 percent pre-project and 38 percent post-project. Personal airborne exposures during lead removal activities (geometric mean = 59.3 micrograms/m3) reinforce the need for respiratory protection and good hygiene. There was no difference in adult pre-/post-blood levels, indicating that participants did remove lead in a safe manner with respect to their own exposures. The results indicate that hazard reduction can be done effectively when recommended procedures for the removal of lead-based paint are followed.