Beyond Implications and Applications: the Story of ‘Safety by Design’

Using long-term anthropological observations at the Center for Biological and Environmental Nanotechnology in Houston, Texas, the article demonstrates in detail the creation of new objects, new venues and new modes of veridiction which have reoriented the disciplines of materials chemistry and nanotoxicology. Beginning with the confusion surrounding the meaning of ‘implications’ and ‘applications’ the article explores the creation of new venues (CBEN and its offshoot the International Council on Nanotechnology); it then demonstrates how the demands for a responsible, safe or ethical science were translated into new research and experiment in and through these venues. Finally it shows how ‘safety by design’ emerged as a way to go beyond implications and applications, even as it introduced a whole new array of controversies concerning its viability, validity and legitimacy

Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/- mice

Introduction Treatment with estrogen and progesterone (E+P) mimics the protective effect of parity on mammary tumors in rodents and depends upon the activity of p53. The following experiments tested whether exogenous E+P primes p53 to be more responsive to DNA damage and whether these pathways confer resistance to mammary tumors in a mouse model of Li-Fraumeni syndrome. Methods Mice that differ in p53 status (Trp53+/+, Trp53+/-, Trp53-/-) were treated with E+P for 14 days and then were tested for p53-dependent responses to ionizing radiation. Responses were also examined in parous and age-matched virgins. The effects of hormonal exposures on tumor incidence were examined in BALB/c-Trp53+/- mammary tissues. Results Nuclear accumulation of p53 and apoptotic responses were increased similarly in the mammary epithelium from E+P-treated and parous mice compared with placebo and age-matched virgins. This effect was sustained for at least 7 weeks after E+P treatment and did not depend on the continued presence of ovarian hormones. Hormone stimulation also enhanced apoptotic responses to ionizing radiation in BALB/c-Trp53+/- mice but these responses were intermediate compared with Trp53+/+ and Trp-/- tissues, indicating haploinsufficiency. The appearance of spontaneous mammary tumors was delayed by parity in BALB/c-Trp53+/- mice. The majority of tumors lacked estrogen receptor (ER), but ER+ tumors were observed in both nulliparous and parous mice. However, apoptotic responses to ionizing radiation and tumor incidence did not differ among outgrowths of epithelial transplants from E+P-treated donors and nulliparous donors

Pregnancy in the mature adult mouse does not alter the proportion of mammary epithelial stem/progenitor cells

Introduction In humans, an early full-term pregnancy reduces lifetime breast cancer risk by up to 50% whereas a later pregnancy (>35 years old) can increase lifetime risk. Several mechanisms have been suggested, including changes in levels of circulating hormones, changes in the way the breast responds to these hormones, changes in gene expression programmes which may alter susceptibility to transformation and changes to mammary stem cell numbers or behaviour. Previous studies have shown that the mammary tissue isolated from both virgin and parous mice has the ability to repopulate a cleared mammary fat pad in transplant experiments. Limited dilution transplant assays have demonstrated that early pregnancy (at 5 weeks of age) reduces stem/progenitor cell numbers in the mouse mammary epithelium by twofold. However, the effects on stem/progenitor cell numbers in the mammary epithelium of a pregnancy in older animals have not yet been tested. Methods Mice were put through a full-term pregnancy at 9 weeks of age, when the mammary epithelium is mature. The total mammary epithelium was purified from parous 7-week post-lactation and age-matched virgin mice and analysed by flow cytometry and limiting dilution cleared fat pad transplants. Results There were no significant differences in the proportions of different mammary epithelial cell populations or numbers of CD24+/Low Sca-1- CD49fHigh cells (stem cell enriched basal mammary epithelial compartment). There was no significant difference in stem/progenitor cell frequency based on limiting dilution transplants between the parous and age-matched virgin epithelium. Conclusions Although differences between parous and virgin mammary epithelium at later time points post lactation or following multiple pregnancies cannot be ruled out, there are no differences in stem/progenitor cell numbers between mammary epithelium isolated from parous animals which were mated at 9 weeks old and virgin animals. However, a recent report has suggested that animals that were mated at 5 weeks old have a twofold reduction in stem/progenitor cell numbers. This is of interest given the association between early, but not late, pregnancy and breast cancer risk reduction in humans. However, a mechanistic connection between stem cell numbers and breast cancer risk remains to be established

Size-dependent elasticity of nanocrystalline titania

Synchrotron-based high-pressure x-ray diffraction measurements indicate that compressibility, a fundamental materials property, can have a size-specific minimum value. The bulk modulus of nanocrystalline titania has a maximum at particle size of 15 nm. This can be explained by dislocation behavior because very high dislocation contents can be achieved when shear stress induced within nanoparticles counters the repulsion between dislocations. As particle size decreases, compression increasingly generates dislocation networks hardened by overlap of strain fields that shield intervening regions from external pressure. However, when particles become too small to sustain high dislocation concentrations, elastic stiffening declines. The compressibility has a minimum at intermediate sizes

Agglomeration and sedimentation of titanium dioxide nanoparticles (n-tio2) in synthetic and real waters

The recent detection of titanium dioxide nanoparticles (n-TiO2) in wastewaters raised concerns about its fate in the aquatic environment, which is related to its mobility through water bodies. Laboratory experiments of n-TiO2 (particle size distribution: 10–65 nm) dispersed into both synthetic and real aqueous solutions under environmentally realistic concentrations (0.01, 0.1, 1 and 10 mg/l) were conducted over a time of 50 h to mimic duration of ecotoxicological tests. Agglomeration and sedimentation behaviour were measured under controlled conditions of salinity (0–35 %), ionic composition and strength, pH and dissolved organic carbon (DOC). Physico-chemical parameters and particle agglomeration in the dispersions were investigated by transmission electron microscopy, Brunauer, Emmett and Teller method and dynamic light scattering. A fluorescence spectrophotometer operating in the nephelometric mode was employed to obtain the sedimentation rates of n-TiO2. The overall results showed that agglomeration and sedimentation of n-TiO2 were affected mainly by the initial concentration. Sedimentation data fitted satisfactorily (R2 in the range of 0.74–0.98; average R2: 0.90) with a first-order kinetic equation.The settling rate constant, k, increased by approx. one order of magnitude by moving from the lowest to the highest concentration, resulting very similar especially for all dispersions at 1(k = 8 9 10-6 s-1) and 10mg/l (k = 2 9 10-5 s-1) n-TiO2, regardless the ionic strength and composition of dispersions. The implication of these results on toxicological testing is discussed