The effects of urban green space and road proximity to indoor traffic-related PM2.5, NO2, and BC exposure in inner-city schools.

BACKGROUND: Since there are known adverse health impacts of traffic-related air pollution, while at the same time there are potential health benefits from greenness, it is important to examine more closely the impacts of these factors on indoor air quality in urban schools. OBJECTIVE: This study investigates the association of road proximity and urban greenness to indoor traffic-related fine particulate matter (PM2.5), nitrogen dioxide (NO2), and black carbon (BC) in inner-city schools. METHODS: PM2.5, NO2, and BC were measured indoors at 74 schools and outdoors at a central urban over a 10-year period. Seasonal urban greenness was estimated using the Normalized Difference Vegetation Index (NDVI) with 270 and 1230 m buffers. The associations between indoor traffic-related air pollution and road proximity and greenness were investigated with mixed-effects models. RESULTS: The analysis showed linear decays of indoor traffic-related PM2.5, NO2, and BC by 60%, 35%, and 22%, respectively for schools located at a greater distance from major roads. The results further showed that surrounding school greenness at 270 m buffer was significantly associated (p < 0.05) with lower indoor traffic-related PM2.5: -0.068 (95% CI: -0.124, -0.013), NO2: -0.139 (95% CI: -0.185, -0.092), and BC: -0.060 (95% CI: -0.115, -0.005). These associations were stronger for surrounding greenness at a greater distance from the schools (buffer 1230 m) PM2.5: -0.101 (95% CI: -0.156, -0.046) NO2: -0.122 (95% CI: -0.169, -0.075) BC: -0.080 (95% CI: -0.136, -0.026). These inverse associations were stronger after fully adjusting for regional pollution and meteorological conditions. IMPACT STATEMENT: More than 90% of children under the age of 15 worldwide are exposed to elevated air pollution levels exceeding the WHO's guidelines. The study investigates the impact that urban infrastructure and greenness, in particular green areas and road proximity, have on indoor exposures to traffic-related PM2.5, NO2, and BC in inner-city schools. By examining a 10-year period the study provides insights for air quality management, into how road proximity and greenness at different buffers from the school locations can affect indoor exposure.

Perimenarchal air pollution exposure and menstrual disorders.

STUDY QUESTION: What is the association between perimenarchal exposure to total suspended particulate (TSP) in air, menstrual irregularity phenotypes and time to menstrual cycle regularity? SUMMARY ANSWER: Exposures to TSP during high school are associated with slightly increased odds of menstrual irregularity and longer time to regularity in high school and early adulthood. WHAT IS KNOWN ALREADY: The menstrual cycle is responsive to hormonal regulation. Particulate matter air pollution has demonstrated hormonal activity. However, it is not known if air pollution is associated with menstrual cycle regularity. STUDY DESIGN, SIZE, DURATION: Cross sectional study of 34 832 of the original 116 430 women (29.91%) enrolled in 1989 from the Nurses' Health Study II (NHSII). The follow-up rate for this analytic sample was 97.76% at the 1991 survey. PARTICIPANTS/MATERIALS, SETTING, METHODS: Annual averages of TSP were available for each year of high school attendance. We created three case definitions including high school menstrual irregularity and androgen excess. The time to menstrual cycle regularity was reported by participants as <1 year, 1-2 years, 3-4 years, 5 years or longer, or never on the baseline questionnaire. Odds ratios and 95% confidence intervals (CI) were calculated for 45 µg/m3 increases in TSP exposure, adjusted for risk factors for menstrual irregularity. MAIN RESULTS AND THE ROLE OF CHANCE: In multivariable adjusted models, we observed that for every 45 µg/m3 increase in average high school TSP there was an increased odds (95%CI) of 1.08 (1.03-1.14), 1.08 (1.02-1.15) and 1.10 (0.98-1.25) for moderate, persistent, and persistent with androgen excess irregularity phenotypes, respectively. TSP was also associated with a longer time to cycle regularity, with stronger results among women with older ages at menarche and those living in the Northeast or the West. LIMITATIONS, REASONS FOR CAUTION: The outcomes of menstrual regularity and time to cycle regularity were retrospectively assessed outcomes and may be susceptible to recall bias. There is also the potential for selection bias, as women had to live until 2011 to provide addresses. WIDER IMPLICATIONS OF THE FINDINGS: Temporal exposure to air pollution in the adolescent and early adulthood window may be especially important, given its association with phenotypes of menstrual irregularity. The data from this study agrees with existing literature regarding air pollution and reproductive tract diseases. STUDY FUNDING/COMPETING INTEREST(S): Shruthi Mahalingaiah: Reproductive Scientist Development Program HD000849, and a research grant from the Boston University Department of Obstetrics and Gynecology, Stacey Missmer: R01HD57210 from the National Institute of Child Health and Human Development and the Massachusetts Institute of Technology Center for Environmental Health Sciences Translational Pilot Project Program, R01CA50385 from the National Cancer Institute, Jaime Hart and Francine Laden: 5R01ES017017 from the National Institute for Environmental Health Sciences, Jaime Hart: P30 ES00002 from the National Institute for Environmental Health Sciences at the National Institute of Health, The Nurses' Health Study II is supported by infrastructure grant UM1CA176726 from the National Cancer Institute, NIH, U.S. Department of Health and Human Services The authors have no conflicts of interest to declare.

Exposure to particulate matter air pollution and risk of multiple sclerosis in two large cohorts of US nurses.

BACKGROUND: Air pollution is thought to raise the risk of neurological disease by promoting neuroinflammation, oxidative stress, glial activation and cerebrovascular damage. Multiple Sclerosis is a common auto-immune disorder, primarily affecting young women. We conducted, to a large prospective study of particulate matter (PM) exposure and multiple sclerosis (MS) risk in two prospective cohorts of women: the Nurses Health Study (NHS) and the Nurses Health Study II (NHS II). METHODS: Cumulative average exposure to different size fractions of PM up to the onset of MS was estimated using spatio-temporal models. We used multivariable Cox proportional hazards models to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of MS associated with each size fraction of PM independently. Participants were followed from 1998 through 2004 in NHS and from 1988 through 2007 for NHS II. We conducted additional sensitivity analyses stratified by smoking, region of the US, and age, as well as analyses restricted to women who did not move during the study. Analyses were adjusted for age, ancestry, smoking, body mass index at age 18, region, tract level population density, latitude at age 15, and UV index. RESULTS: We did not observe significant associations between air pollution and MS risk in our cohorts. Among women in the NHS II, the HRs comparing the top vs. bottom quintiles of PM was 1.11 (95% Confidence Intervals (CI): 0.74, 1.66), 1.04 (95% CI: 0.73, 1.50) and 1.09 (95% CI: 0.73, 1.62) for PM10 (≤10µm in diameter), PM2.5 (≤2.5µm in diameter), and PM2.5-10 (2.5 to 10µm in diameter) respectively, and tests for linear trends were not statistically significant. No association between exposure to PM and risk of MS was observed in the NHS. CONCLUSIONS: In this study, exposure to PM air pollution was not related to MS risk.

Clinical factors associated with C-reactive protein in chronic spinal cord injury.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: Determine clinical factors associated with plasma C-reactive protein (CRP) in persons with chronic spinal cord injury (SCI). SETTING: Veterans Affairs Medical Center in Boston, MA, USA. METHODS: Participants provided a blood sample, completed a respiratory health questionnaire and underwent dual X-ray absorptiometry (DXA) to assess total and regional body fat. Linear regression models were used to assess cross-sectional associations with plasma CRP. RESULTS: In multivariable models, factors associated with a higher CRP included a greater BMI, urinary catheter use, a respiratory illness in the past week and non-white race. Mean CRP also increased with decreasing mobility (motorized wheelchair >hand-propelled wheelchair >walk with an assistive device >walk independently). Results were similar when adjusting for percentage android, gynoid, trunk or total fat mass in place of BMI. Level and completeness of SCI was not associated with CRP in multivariable models. CONCLUSIONS: Clinical characteristics common in chronic SCI are associated with plasma CRP. These factors are more important than the level and completeness of SCI and some are potentially modifiable.

Adult air pollution exposure and risk of infertility in the Nurses' Health Study II.

STUDY QUESTION: Is there an association between air pollution exposures and incident infertility? SUMMARY ANSWER: Increased exposure to air pollution is associated with an increased incidence of infertility. WHAT IS KNOWN ALREADY: Exposures to air pollution have been associated with lower conception and fertility rates. However, the impact of pollution on infertility incidence is unknown. STUDY DESIGN, SIZE, DURATION: Prospective cohort study using data collected from 116 430 female nurses from September 1989 to December 2003 as part of the Nurses' Health Study II cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertility was defined by report of attempted conception for ≥12 months without success. Participants were able to report if evaluation was sought and if so, offer multiple clinical indications for infertility. After exclusion, 36 294 members were included in the analysis. Proximity to major roadways and ambient exposures to particulate matter less than 10 microns (PM10), between 2.5 and 10 microns (PM2.5-10), and less than 2.5 microns (PM2.5) were determined for residential addresses for the 36 294 members between the years of 1993 and 2003. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using multivariable adjusted Cox proportional hazard models with time-varying covariates. MAIN RESULTS AND THE ROLE OF CHANCE: Over 213 416 person-years, there were 2508 incident reports of infertility. Results for overall infertility were inconsistent across exposure types. We observed a small increased risk for those living closer to compared to farther from a major road, multivariable adjusted HR = 1.11 (CI: 1.02-1.20). This was consistent for those reporting primary or secondary infertility. For women living closer to compared to farther from a major road, for primary infertility HR = 1.05 (CI: 0.94-1.17), while for secondary infertility HR = 1.21 (CI: 1.07-1.36). In addition, the HR for every 10 µg/m(3) increase in cumulative PM2.5-10 among women with primary infertility was 1.10 (CI: 0.96-1.27), and similarly was 1.10 (CI: 0.94-1.28) for those with secondary infertility. LIMITATIONS, REASONS FOR CAUTION: Within the 2 year window of infertility diagnosis, we do not have the exact date of diagnosis or the exact timing of the start of attempting conception. As infertility status and subtypes of infertility were prospectively collected biennially, we were unable to tightly examine the timing of exposures on incidence of infertility. In terms of exposure quantification, we used ambient air pollution exposures as a proxy for personal exposures, potentially leading to exposure misclassification. However, several studies suggest that ambient measurements are an acceptable surrogate for individual level exposures in most populations. WIDER IMPLICATIONS OF THE FINDINGS: We observed an association between all size fractions of PM exposure, as well as traffic-related air pollution, and incidence of infertility. Of note, the strongest association was observed between cumulative average exposures over the course of follow-up and the risk of infertility, suggesting that chronic exposures may be of greater importance than short-term exposures. STUDY FUNDING/COMPETING INTERESTS: The work for this paper was supported by the following: S.M.: Reproductive Scientist Development Program HD000849, and the Building Interdisciplinary Research Careers in Women's Health HD043444, the Boston University CTSI 1UL1TR001430, and a research grant from the Boston University Department of Obstetrics and Gynecology, S.A.M.: R01HD57210 from the National Institute of Child Health and Human Development and the Massachusetts Institute of Technology Center for Environmental Health Sciences Translational Pilot Project Program, R01CA50385 from the National Cancer Institute, J.E.H. and F.L.: 5R01ES017017 from the National Institute for Environmental Health Sciences, 5 P42 ES007381 from the National Institute of Environmental Health at the National Institute of Health. L.V.F.: T32HD060454 in reproductive, perinatal, and pediatric epidemiology from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The Nurses' Health Study II is additionally supported by infrastructure grant UM1CA176726 from the National Cancer Institute, NIH, U.S. Department of Health and Human Services. The authors have no actual or potential competing financial interests to disclose.

Regional differences regarding risk of developing rheumatoid arthritis in Stockholm County, Sweden: results from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study.

OBJECTIVES: Rheumatoid arthritis (RA) is a complex disease that is associated with genetic and environmental factors. We have investigated geospatial variation in the risk of developing RA within Stockholm County, Sweden, with respect to established environmental risk factors for RA, as well as serologically defined subgroups of RA. METHOD: Information regarding geographical location for 1432 cases and 2529 controls from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, living in Stockholm County at RA symptom onset, or matched date for controls, was used to estimate geospatial variation in risk. We used generalized additive models (GAMs) to create a risk surface, calculate odds ratios (ORs), and adjust for potential confounding by smoking, education level, and RA within family. We performed a stratified analysis based on the presence/absence of anti-citrullinated peptide antibodies (ACPA). RESULTS: We found significant spatial variation in the odds of developing RA in Stockholm County. After adjustment for smoking, education level, and family history of RA, this geospatial variation remained. The stratified analysis showed areas with higher ORs for ACPA-positive RA and ACPA-negative RA, after adjusting for smoking, education level, and having a family history of RA. Living in the city of Stockholm was associated with decreased risk of RA. CONCLUSIONS: The risk of developing RA in Stockholm County is not distributed evenly and there are areas of increased risk that could not be explained by known factors. Further investigations of local exposures or social factors are warranted.

Chronic obstructive pulmonary disease mortality in railroad workers.

BACKGROUND: There is little information describing the risk of non-malignant respiratory disease and occupational exposure to diesel exhaust. METHODS: US railroad workers have been exposed to diesel exhaust since diesel locomotives were introduced after World War II. In a retrospective cohort study we examined the association of chronic obstructive pulmonary disease (COPD) mortality with years of work in diesel-exposed jobs. To examine the possible confounding effects of smoking, multiple imputation was used to model smoking history. A Cox proportional hazards model was used to estimate an incidence rate ratio, adjusted for age, calendar year, and length of follow-up after leaving work (to reduce bias due to a healthy worker survivor effect). RESULTS: Workers in jobs with diesel exhaust exposure had an increased risk of COPD mortality relative to those in unexposed jobs. Workers hired after the introduction of diesel locomotives had a 2.5% increase in COPD mortality risk for each additional year of work in a diesel-exposed job. This risk was only slightly attenuated after adjustment for imputed smoking history. CONCLUSIONS: These results support an association between occupational exposure to diesel exhaust and COPD mortality.

Urinary naphthalene and phenanthrene as biomarkers of occupational exposure to polycyclic aromatic hydrocarbons.

OBJECTIVES: The study investigated the utility of unmetabolised naphthalene (Nap) and phenanthrene (Phe) in urine as surrogates for exposures to mixtures of polycyclic aromatic hydrocarbons (PAHs). METHODS: The report included workers exposed to diesel exhausts (low PAH exposure level, n = 39) as well as those exposed to emissions from asphalt (medium PAH exposure level, n = 26) and coke ovens (high PAH exposure level, n = 28). Levels of Nap and Phe were measured in urine from each subject using head space-solid phase microextraction and gas chromatography-mass spectrometry. Published levels of airborne Nap, Phe and other PAHs in the coke-producing and aluminium industries were also investigated. RESULTS: In post-shift urine, the highest estimated geometric mean concentrations of Nap and Phe were observed in coke-oven workers (Nap: 2490 ng/l; Phe: 975 ng/l), followed by asphalt workers (Nap: 71.5 ng/l; Phe: 54.3 ng/l), and by diesel-exposed workers (Nap: 17.7 ng/l; Phe: 3.60 ng/l). After subtracting logged background levels of Nap and Phe from the logged post-shift levels of these PAHs in urine, the resulting values (referred to as ln(adjNap) and ln(adjPhe), respectively) were significantly correlated in each group of workers (0.71 < or = Pearson r < or = 0.89), suggesting a common exposure source in each case. Surprisingly, multiple linear regression analysis of ln(adjNap) on ln(adjPhe) showed no significant effect of the source of exposure (coke ovens, asphalt and diesel exhaust) and further suggested that the ratio of urinary Nap/Phe (in natural scale) decreased with increasing exposure levels. These results were corroborated with published data for airborne Nap and Phe in the coke-producing and aluminium industries. The published air measurements also indicated that Nap and Phe levels were proportional to the levels of all combined PAHs in those industries. CONCLUSION: Levels of Nap and Phe in urine reflect airborne exposures to these compounds and are promising surrogates for occupational exposures to PAH mixtures.

Inhibition of compensatory renal growth by the N-terminus of a sheep-derived peptide.

The N-terminal sequence of a novel sheep-derived peptide with growth inhibitory activity has been obtained. The N-terminal fragment was chemically synthesised and designated EPL001. The kidney was chosen as the first mammalian system in which to study EPL001 since kidney growth can be accurately quantified following a surgical reduction in renal mass. Cell proliferation was measured in mouse collecting duct kidney (MCDK) cells stimulated with insulin-like growth factor I (IGF-I). Compensatory renal growth (CRG) was induced in Wistar rats and either EPL001 or an EPL001 antibody delivered by continuous renal tissue infusion. Mouse monoclonal antibodies to EPL001 were generated for immunoneutralisation, rabbit polyclonal antibodies were generated for immunohistochemistry. EPL001 had no apparent effect on IGF-I stimulated cell proliferation in MCDK cells in vitro, yet provoked a dose-dependent inhibition of CRG in vivo. An EPL001 antibody potentiated CRG, in the absence of exogenous EPL001, consistent with an inhibitory role in kidney growth for an endogenous peptide containing the EPL001 sequence. Tubular staining for epitopes to the EPL001 sequence was detected in normal human kidney sections and enhanced in renal cell carcinoma. Results support the presence of growth inhibitory activity in the N-terminus of a sheep-derived peptide with evidence for both its presence and endogenous activity in the kidney. Attempts to further characterise its structure and activity are ongoing.

Occupational exposure to volatile organic compounds and aldehydes in the U.S. trucking industry.

Diesel exhaust is a complex chemical mixture that has been linked to lung cancer mortality in a number of epidemiologic studies. However, the dose-response relationship remains largely undefined, and the specific components responsible for carcinogenicity have not been identified. Although previous focus has been on the particulate phase, diesel exhaust includes a vapor phase of numerous volatile organic compounds (VOCs) and aldehydes that are either known or suspected carcinogens, such as 1,3-butadiene, benzene, and formaldehyde. However, there are relatively few studies that quantify exposure to VOCs and aldehydes in diesel-heavy and other exhaust-related microenvironments. As part of a nationwide assessment of exposure to diesel exhaust in the trucking industry, we collected measurements of VOCs and aldehydes at 15 different U.S. trucking terminals and in city truck drivers (with 6 repeat site visits), observing average shift concentrations in truck cabs and at multiple background and work area locations within each terminal. In this paper, we characterize occupational exposure to 18 different VOCs and aldehydes, as well as relationships with particulate mass (elemental carbon in PM < 1 microm and PM2.5) across locations to determine source characteristics. Our results show that occupational exposure to VOCs and aldehydes varies significantly across the different sampling locations within each terminal, with significantly higher exposures noted in the work environments over background levels (p < 0.01). A structural equation model performed well in predicting terminal exposures to VOCs and aldehydes as a function of job, background levels, weather conditions, proximity to a major road, and geographic location (R2 = 0.2-0.4 work area; R2 = 0.5-0.9 background).

Driver exposure to combustion particles in the U.S. Trucking industry.

A large study of combustion particle exposures for drivers of diesel-powered trucks was conducted in collaboration with an epidemiologic study of lung cancer outcomes for workers in the trucking industry. Three components of diesel exhaust combustion particles (PM(2.5), elemental carbon, and organic carbon) were measured inside the driver cabs of diesel-powered trucks from 36 different trucking terminals across the United States between 2001 and 2005. In-cab particle exposures for drivers assigned to both short and long distance trips were observed, as well as information on the smoking status of the driver, truck characteristics such as age and model, and weather conditions during the sampling session. This article summarizes these findings and describes the relationship between exhaust particles and various determinants of exposure. The results suggest that in-cab particle exposures are positively related to smoking, ambient particle concentrations, truck age, and open windows, with other significant modifying factors such as weather. This study represents the largest and most comprehensive exposure assessment of drivers in the trucking industry, encompassing a 4-year period of observations on diesel and exhaust particle exposures nationwide. The results are relevant not only to the occupational group of truck drivers being examined but also to the general population that live, commute, or work within proximity to diesel-fueled traffic or trucking terminals.

Modeling particle exposure in U.S. trucking terminals.

Multi-tiered sampling approaches are common in environmental and occupational exposure assessment, where exposures for a given individual are often modeled based on simultaneous measurements taken at multiple indoor and outdoor sites. The monitoring data from such studies is hierarchical by design, imposing a complex covariance structure that must be accounted for in order to obtain unbiased estimates of exposure. Statistical methods such as structural equation modeling (SEM) represent a useful alternative to simple linear regression in these cases, providing simultaneous and unbiased predictions of each level of exposure based on a set of covariates specific to the exposure setting. We test the SEM approach using data from a large exposure assessment of diesel and combustion particles in the U.S.trucking industry. The exposure assessment includes data from 36 different trucking terminals across the United States sampled between 2001 and 2005, measuring PM2.5 and its elemental carbon (EC), organic carbon (OC) components, by personal monitoring, and sampling at two indoor work locations and an outdoor "background" location. Using the SEM method, we predict the following: (1) personal exposures as a function of work-related exposure and smoking status; (2) work-related exposure as a function of terminal characteristics, indoor ventilation, job location, and background exposure conditions; and (3) background exposure conditions as a function of weather, nearby source pollution, and other regional differences across terminal sites. The primary advantage of SEMs in this setting is the ability to simultaneously predict exposures at each of the sampling locations, while accounting for the complex covariance structure among the measurements and descriptive variables. The statistically significant results and high R2 values observed from the trucking industry application supports the broader use of this approach in exposure assessment modeling.

Pituitary-related weight changes affecting the liver, uterus and adrenal glands of rats treated with hexoestrol and clomiphene in high doses.

The synthetic oestrogen hexoestrol, administered at 60 mg/kg/day for 4 days to female rats in 3 studies, caused the following mean changes in the relative weights of some of the principal organs: liver (+37%), spleen (-11%), adrenals (+43%), kidneys (+3%), pituitary (+23%), uterus (+49%), and ovaries (+13%). The heart weights showed no consistent changes. The mean relative organ weights of hypophysectomized, hexoestrol-treated rats did not differ significantly from those of untreated hypophysectomized controls. The latter animals had lower organ weights than sham-operated controls. Pretreatment with clomiphene citrate at dose levels of 20-60 mg/kg/day prevented in a dose-dependent manner most of the organ weight changes induced by hexoestrol. The exception was the adrenal weight, which was increased. Compared with controls, the mean relative organ weights of rats receiving clomiphene alone at 60 mg/kg/day differed as follows: liver (-18%), spleen (-17%), heart (-16%), adrenals (+7%), kidneys (-11%), pituitary (-13%), uterus (-25%), and ovaries (-4%). The changes affecting the liver, spleen, heart, kidneys and uterus were significant. Rats immunised with a monkey antiserum to rat growth hormone and treated with hexoestrol had significantly lower relative liver weights than did animals treated with hexoestrol alone. No other significant differences were observed. It is tentatively concluded that there is a mediating or co-operative pituitary influence involved in the significant hepatic, uterine and adrenal weight gains caused by hexoestrol. Clomiphene may act centrally to affect these organ weight changes and, indeed, may act at this level to (mainly) anti-organotrophic effect even in the absence of exogenous oestrogen. In the case of the hexoestrol-induced liver enlargement, the role of pituitary growth hormone is worth further investigation.

Endocrine pathology of estrogens: species differences.

The clinical uses of estrogens are associated with serious adverse effects, so the experimental toxicology of these compounds is under continuous review. Structurally different estrogens have qualitatively similar effects in animals when given in amounts way above the rodent uterotrophic dose. Toxicity still tends, however, to be related to estrogenic potency. Carnivores are more susceptible than rodents. Changes in reproductive, mammary and endocrine tissues are consistent with hyperestrogenism. Growth rate is decreased in rats and mice, but weight gains have been reported in other species. The weights of the liver, spleen, thymus and other organs are changed. Liver damage can occur. Susceptibility declines in the order cat, ferret, rat and mouse, dog. Clotting changes seen in the rat are secondary to liver damage. Moderate doses elicit anemia in rats, but lethal bone marrow depression in dogs and ferrets. Death is associated with hemorrhage. Antiestrogens modify aspects of estrogen toxicity in the rat, but not in the ferret. The predictive value of animal studies for humans has been disappointing. Interspecies variations at the hypothalamic-pituitary axis appear to have an important bearing on the differential activities of estrogens and antiestrogens across the species.

Subacute toxicity of diethylstilboestrol and hexoestrol in the female rat, and the effects of clomiphene pretreatment.

Two groups, each of ten female rats, were orally dosed with the synthetic oestrogens diethylstilboestrol (DES; 6 mg/kg day) and hexoestrol (60 mg/kg/day) for 6 wk. A further group of ten animals received clomiphene citrate (2 mg/kg/day) and DES (6 mg/kg/day), while two groups, each of ten animals, acted as controls. One animal treated with DES died within the 42-day study period. Its death was associated with a bleeding disorder related to severe liver damage. The remaining treated animals showed little overt toxicity. The major haematological finding in the treated animals that survived was a moderate, stable, normocytic, normochromic anaemia. The terminal bone marrows of these animals showed a modest degree of erythroid hypoplasia. There were stimulatory and other changes in the reproductive tract and there were gains in the liver, adrenal and pituitary weights. These effects were more marked in the rats treated with hexoestrol, the gains in the relative organ weights being particularly striking: liver, 51%, adrenals, 210%, uterus, 79% and pituitary, 500%. The oestrogens caused reductions in body weight (18% in both cases) and appetite, a modest degree of fatty change in the liver, and alterations in the serum proteins. The Thrombotest clotting times of the hexoestrol-treated rats were prolonged. Clomiphene citrate decreased the adverse effects of DES on appetite and body weight, and sharply decreased the gains in the pituitary and uterine weights from 243 to 80% and 59 to 14%, respectively. The toxic effects of the oestrogens in the rat were more closely related to the dose administered than to their hormonal potency. Oestrogens are less toxic to the rat than they are to the cat, dog and ferret, and the toxic effects are in many respects qualitatively different.

(-)[125I]pindolol binding to human peripheral lung beta-receptors.

Beta-adrenergic receptors in human peripheral lung were characterized by biochemical and radioligand assays employing binding of the beta-antagonist (-)[125I]pindolol to plasma membrane preparations. The specific binding of (-)[125I]pindolol reached equilibrium by 45 min with an initial rate constant of 0.0282 min-1. Binding was reversible with a kinetic dissociation rate constant of 0.0146 min-1. The calculated kinetic Kd (dissociation constant) was 430 pM which agreed very well with the Kd of 394 pM obtained by Scatchard analyses of equilibrium binding data. Computer analyses of equilibrium binding experiments revealed a similar Kd of 336 +/- 24 pM. The binding capacities calculated by computer analyses (155 +/- 7 fmol/mg protein) and Scatchard analyses (113 fmol/mg protein) were also in close agreement. By all three methods (kinetic, Scatchard, and computer analyses), the data were most compatible with a single (-)[125I]pindolol binding site. Analyses of equilibrium binding data from ten different human lungs revealed values for the Kd ranging from 79 to 360 pM (mean, 136 pM), and for the receptor concentration ranging from 58 to 196 fmol/mg protein (mean, 118 fmol/mg protein). The displacement of (-)[125I]pindolol binding by various agents exhibited stereoselectivity and the expected rank order of potency predicted for interactions with beta-receptors. Isoproterenol induced a rapid and dose-related increase in cyclic AMP that was prevented by specific beta-antagonists. Approximately 70% of the beta-receptors were found to be of the beta 2-subtype by both radioligand binding and biochemical assays. Thus, (-)[125I]pindolol appears to be an excellent ligand for characterizing human lung beta-receptors since accurate and reproducible results can be obtained with this radioligand using limited tissue sample quantities.

Vitamin K-dependent blood clotting changes in female rats treated with oestrogens.

Hexoestrol, diethylstilboestrol and ethinyloestradiol administered orally at a dose of 60 mg/kg/day to groups of five rats caused decreases in vitamin K-dependent blood clotting as measured by the Thrombotest reaction. These changes were self-limiting over a twenty-day study period and were not associated with external signs of bleeding. Pretreatment with testosterone and vitamin K1 did not significantly affect the clotting changes, but the antioestrogen clomiphene citrate exacerbated these, in several cases to lethal effect. Death was associated with haemorrhage. Hexoestrol-treated rats receiving clomiphene citrate in a sub-experiment did not show the increase in liver weight seen in animals given hexoestrol alone. In another sub-experiment, the level of clotting factor VII activity in the plasma of rats receiving hexoestrol at 60 mg/kg/day for four days was shown to be about half that of controls. There was probably no abnormal clotting inhibitor activity. It was deduced that the reduction in factor VII activity was more likely to be due to a decrease in synthesis as a result of liver dysfunction than changes in vitamin K availability. Clomiphene citrate may exacerbate the liver-dependent clotting disorders induced by oestrogens by preventing an adaptive increase in liver mass. It is concluded that the rat is a poor model species for investigating the blood clotting disorders seen in humans treated with oestrogens.

Laboratory experiments on planetary and stellar convection performed on spacelab 3.

Experiments on thermal convection in a rotating, differentially heated hemispherical shell with a radial buoyancy force were conducted in an orbiting microgravity laboratory. A variety of convective structures, or planforms, were observed, depending on the magnitude of the rotation and the nature of the imposed heating distribution. The results are compared with numerical simulations that can be conducted at the more modest heating rates, and suggest possible regimes of motion in rotating planets and stars.

Endocrine factors in haematological changes seen in dogs and ferrets given oestrogens.

High doses of oestrogens in the dog and ferret cause myeloid hyperplasia in the bone marrow superseded by hypoplasia affecting all cell lines. In the peripheral blood after an initial leucocytosis, there is thrombocytopenia, anaemia and leucopenia. These effects, which are ultimately lethal, do not occur in cats, rats and monkeys, and their cause is unknown. It is speculated that they may be due to endocrine derangements possibly affecting the pituitary-adrenal axis and that species differences in oestrogen toxicity may be due to species differences in endocrinology.