Nitrogen dioxide (NO2) is a common oxidant air pollutant. Animal studies have suggested that NO2 exposure causes a decrease in the numbers of some splenic lymphocyte subtypes and impairs lymphocyte-dependent immune responses. To investigate whether ambient levels of NO2 alter circulating and bronchoalveolar lavage fluid (BALF) human lymphocytes, we studied five healthy nonsmoking adult volunteers. In each subject, blood and bronchoalveolar lavage fluid was obtained and then, more than 2 weeks later, volunteers were exposured to 0.60 ppm NO2 for 2 hr with intermittent light to moderate exercise on 4 separate days within a 6-day period. We measured standard tests of pulmonary function (airway resistance, thoracic gas volume, maximal expiratory flow) and had the subjects rate the severity of respiratory symptoms before and after each NO2 exposure. Circulating and BALF lymphocytes were labeled with fluorochrome-conjugated monoclonal antibodies to human lymphocyte antigens and a flow cytometer was used to count lymphocyte subtypes. Neither any single day's exposure nor all four exposures caused a change in symptoms or in the results of tests of pulmonary function. The total number of circulating lymphocytes obtained after NO2 exposure was slightly greater than at baseline (1792 +/- 544 vs 1598 +/- 549 cells/mm3 at baseline; P = not significant) but the proportions of lymphocyte subtypes did not differ. In the BALF obtained after NO2 exposure and in the baseline state, the total number of lymphocytes and the percentages of T cells (CD 3), B cells (CD 20), T cytotoxic-suppressor cells (CD 8), T helper-inducer cells (CD 4), and large granular lymphocytes (CD 57) also did not differ after NO2 exposure. A slightly but significantly greater proportion of natural killer cells (CD 16) was found in the BALF obtained after NO2 exposure (7.2 +/- 3.1 vs 4.2 +/- 2.4% of total lymphocytes). We conclude that repeated exposures of healthy nonsmoking adults to 0.60 ppm NO2 are not associated with clinically significant symptoms, changes in airway caliber, or alterations in circulating and BALF lymphocyte subtypes. We suggest that brief, daily exposures to NO2 at levels higher than those achieved in urban atmosphere are unlikely to provoke acute respiratory impairment in healthy, nonsmoking adults.
Cardiopulmonary and metabolic responses of three groups, each consisting of five adult males (aged 20–25), were determined before, during, and after a 2-hr exposure to 0.62 ± 0.12 ppm NO2 at 25°C and 45% RH. The three groups exercised during exposure at 40% of V̇O2 max for either 15, 30, or 60 min for Groups A, B, and C, respectively. During the exercise periods the ventilation was about 33 liter/min, a fourfold increase over the resting level. There were no physiologically significant cardiovascular, metabolic, or pulmonary function changes which could be attributed to exposure to this level of NO2 (0.62 ppm). There were no differences between the groups in their response despite the fact that Groups A and B received more NO2 as a result of 28% and 84% greater ventilations, respectively.
A rat model of chronic pulmonary infection (CPI) initiated by Pseudomonas aeruginosa embedded in agar beads was used to test the effect of ozone on lysosomal enzyme levels in alveolar macrophages (AM). CPI was induced by intratracheal instillation of a 0.1-ml suspension of infected beads into the left lung. Ten days after infection half the rats were exposed to atmospheres of air and half to 0.64 ppm ozone for 4 weeks. Enzyme levels were measured using a scanning cytospectrophotometer linked to PDP/11 computer. Measurement of lysozyme in individual rat AM in situ showed a significant decrease in cell size and enzyme content in ozone-exposed uninfected animals. Cell size and enzyme content of ozone-exposed animals with CPI were further reduced, suggesting a synergistic effect between ozone exposure and chronic infection.
To determine the influence of mouthpiece breathing on respiratory responses to sulfur dioxide (SO2), 23 young adult asthmatic volunteers were exposed in a chamber to 0.75 ppm SO2 during heavy exercise, once with breathing unencumbered and once while they wore noseclips and mouthpieces. These conditions (more severe than in typical ambient exposures) were deliberately chosen to produce significant physiological and clinical responses. Similar exposures to clean air served as controls. Exposure studies were separated by 1-week intervals and order was randomized. The protocol consisted of 10 min on a bicycle ergometer (mean load 650 kg-m/min, mean ventilation 40 liter/min), preceded and followed by response testing (body plethysmography, symptom questionnaires, and forced expiratory function tests; the last were performed only postexposure). During clean-air exposures, specific airway resistance (SRaw) and symptoms increased significantly, but no meaningful differences between mouthpiece breathing and unencumbered breathing were observed. Exposures to SO2 under these relatively severe conditions produced greater increases in SRaw than clean-air exposures regardless of the mode of breathing, but the excess increase was significantly greater with mouthpiece than with unencumbered breathing. Symptom changes and postexposure forced expiratory function showed qualitatively the same pattern of decrements with SO2 ad did SRaw, but the excess responses attributable to mouthpiece breathing did not attain statistical significance. Mouthpiece breathing can compromise upper-respiratory defenses against SO2 to the extent that responses are greater than with more natural breathing. The mode of breathing should be taken in account when applying laboratory human exposure data to air-quality risk assessment.
Cytoplasmic inclusions known as Lewy bodies, a hallmark of Parkinson's disease (PD) pathology, may protect against cytotoxic proteins. Since the ubiquitin-proteasome system (UPS) degrades cytotoxic proteins, dysfunction in the UPS may contribute to PD etiology. Our goal in this study was to screen pesticides for proteasome inhibition and investigate (i) whether ambient exposures to pesticides that inhibit the UPS increase PD risk and (ii) whether genetic variation in candidate genes of the UPS pathway modify those increased risks. We assessed 26S UPS activity in SK-N-MC(u) cells by fluorescence. We recruited idiopathic PD cases (n=360) and population-based controls (n=816) from three counties in California with considerable commercial agriculture. We determined ambient pesticide exposure by our validated GIS-based model utilizing residential and workplace address histories. We limited effect measure modification assessment to Caucasians (287 cases, 453 controls). Eleven of 28 pesticides we screened inhibited 26S UPS activity at 10µM. Benomyl, cyanazine, dieldrin, endosulfan, metam, propargite, triflumizole, and ziram were associated with increased PD risk. We estimated an odds ratio of 2.14 (95% CI: 1.42, 3.22) for subjects with ambient exposure to any UPS-inhibiting pesticide at both residential and workplace addresses; this association was modified by genetic variation in the s-phase kinase-associated protein 1 gene (SKP1; interaction p-value=0.005). Our results provide evidence that UPS-inhibiting pesticides play a role in the etiology of PD and suggest that genetic variation in candidate genes involved in the UPS pathway might exacerbate the toxic effects of pesticide exposures.
One etiologic model for narcolepsy suggests that some environmental toxin selectively and irreversibly destroys hypocretin-producing cells in individuals with human leukocyte antigen (HLA) DQB1(*)0602. Between 2001 and 2005, the authors conducted a population-based case-control study in King County, Washington to examine narcolepsy risk in relation to toxins found in jobs, hobbies, and other non-vocational activities. Sixty-seven cases and 95 controls were enrolled; all were between ages 18 and 50 and positive for HLA DQB1(*)0602. All were administered in-person interviews about jobs, hobbies or other non-vocational activities before age 21. All analyses were adjusted for African-American race and income. Risk increased significantly for jobs involving heavy metals (odds ratio [OR]=4.7; 95% confidence interval [CI]: 1.5, 14.5) and for highest levels of exposure to woodwork (OR: 3.0; 95% CI: 1.0, 8.9), fertilizer (OR=3.1; 95% CI: 1.1, 9.1), and bug or weed killer (OR=4.5; 95% CI: 1.5, 13.4). Associations were of borderline significance for activities involving ceramics, pesticides, and painting projects. Significant dose-response relationships were evident for jobs involving metals (p<0.03), paints (p<0.03), and bug or weed killer (p<0.02). Additional studies are needed to replicate these findings and continue the search for specific toxins that could damage hypocretin neurons in genetically susceptible people.
Fertile white Leghorn chicken eggs were exposed via intravitelline injections to dosages of 5.0, 10.0, or 20 mg 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT) in olive oil prior to incubation. Control embryos received only the olive oil vehicle. Eggs were placed in a forced-draft incubator for either 5 or 12 days. Embryos were removed and their gonadal areas prepared for histological or histochemical evaluation. Histological examination of DDT-exposed 5-day embryos revealed no significant differences in the number of primordial germ cells aggregating in the gonadal area and in the localization of acid and alkaline phosphatase activity. Embryos exposed to DDT for 12 days revealed significant alterations in both ovaries and testes. The testes of DDT-exposed embryos consisted of mostly stroma with fewer seminiferous cords than controls while ovaries of exposed embryos contained a larger number of distended medullary cords as well as a difference in the distribution of these cords when compared to controls. There was an increased alkaline phosphatase activity in the stromal cells of female gonads. Increased amounts of alkaline phosphatase activity found in the stroma at 12 days might be due to a DDT-induced stimulation of these cells to differentiate more rapidly. Acid phosphatase activity was found in the secondary sex cords of control 12-day ovaries, but was much reduced or absent in those of pesticide-exposed embryos. These results indicate that a single dosage of DDT administered to a chick embryo prior to incubation does not affect early stages of gonadal development but that effects on both ovaries and testes occur 12 days following exposure.
Recent data suggest that prenatal exposure to p,p'-DDE may reduce height and increase body mass index (BMI) in childhood, thus potentially raising the risk of adult health problems. The association between prenatal DDE exposure and growth was evaluated in 788 boys from Chiapas, an area of Mexico where DDT was recently used. The median DDE levels in maternal serum at birth (2002-2003) were 2.7 microg/g lipid. 2633 measurements of height (cm) and weight (kg) were obtained in 2004-2005. The median age of the children during follow-up was 18 months (quartiles 14 and 22 months). Height and body mass index (kg/m(2)) were age-standardized and expressed as standard deviation scores (SDS). Multivariate random-effect models for longitudinal data were fitted and predicted height and BMI SDS were estimated from the adjusted models. Overall, associations between prenatal DDE level and height or BMI SDS at any given age were not observed. For example, the predicted values showed that children with the highest exposure (DDE: >9.00 microg/g) compared to those least exposed (DDE: <3.01 microg/g) grew similarly and they had a BMI SDS similar to the referent group. The results do not support the prior findings of an association of DDE exposure with childhood height or BMI.
Dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs) are persistent organochlorine compounds bioaccumulating in human tissues. Body burden of organochlorines may be influenced by individual characteristics such as age, weight variations, breastfeeding, dietary habits and place of residence.
To assess the current serum concentrations of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE), the main DDT breakdown product, and of PCBs in women from two French administrative areas (Ille-et-Vilaine and Côte d'Or). To identify determinants of the current serum levels among individual characteristics related to intake, metabolism, and excretion of organochlorines.
We measured serum p,p'-DDE and PCB levels in 1055 general population women who were recruited in 2005-2007 to serve as controls in a case-control study on breast cancer. Associations between organochlorine levels and age, current body mass index (BMI), BMI change during the last 10 years, dietary habits, breastfeeding history, residence area and education were assessed in multivariate analyses.
Median concentrations of p,p'-DDE and total PCBs were 85 and 240ng/g lipid, respectively. Based on multivariate analyses, the main predictors of high p,p'-DDE levels included age and frequent consumption of saltwater fish in women below 50 years, and high BMI in older women. Total PCB levels increased markedly with age. Among older women, other important predictors of high PCB levels included frequent consumption of saltwater fish and low BMI. Our results are also suggestive of an inverse association between PCB levels and BMI gain during the last ten years. Women in Côte d'Or had significantly higher PCB levels than women in Ille-et-Vilaine.
The patterns of associations between determinants and serum organochlorine concentrations suggest that human PCB contamination is still ongoing in France. The most important predictors of serum p,p'-DDE and PCB concentrations among French women include age, body mass index, dietary habits, and place of residence.
The effects of cadmium on the excretion and metabolism of DDT in rats were investigated. The excretion of DDT after a single parenteral administration was modified by the addition of a small amount of cadmium. The time pattern of DDT retention in the whole body was explained by a three-compartment model. An increased level of lipid content in the liver induced by cadmium was accompanied by a relative increase of DDT residue in the liver. This indicates that the effect of cadmium on the metabolism of DDT is mainly due to the change of lipid content in the liver. Since the effect of the cadmium was long-lasting, a significant elevation in the metabolic rate of DDT and a low level of DDT concentration in adipose tissue was observed after the dose of cadmium.
The oral administration of dieldrin (1.25, 2.50, or 5.00 mg/kg daily × 5) significantly reduced the total uptake and subsequent metabolism of labeled androgens in the mouse anterior prostate gland. The in vivo metabolism of testosterone-1,2-3H to dihydrotestosterone-3H (DHT-3H), androstanediol-3H, or androstenedione-3H by the mouse prostate gland was lowered by pretreatment with dieldrin. Similarly, the in vitro metabolism of testosterone-1,2-3H to these aforementioned radiometabolites was reduced by dieldrin at a treatment level of 5 mg/kg (daily × 5). This highest-dose regimen also reduced the formation of the metabolites of testosterone in mouse hepatic microsomes. Varying concentrations of dieldrin (4 × 10−7, 4 × 10−6, or 2 × 10−5m) in vitro effectively decreased the formation of DHT-H3 in the mouse anterior prostate gland and of androstanediol-3H in the rat ventral prostate gland.
This study was initiated to investigate the possible perinatal carcinogenic effects of the colon carcinogen 1,2-dimethylhydrazine (DMH) in Fischer F344 inbred rats. Pregnant female animals during their 16-18th day of gestation were administered the chemical by intraperitoneal injections, and beginning at 4 months postparturition, the antitumor cell-mediated immunity (CMI) was delineated in the dams and pups as an indirect measure of carcinogenesis. The CMI status was established by the ability of peripheral blood lymphoid cells obtained from the rats to injure and kill target tumor cells derived from an X-ray-induced rat small bowel adenocarcinoma cell line with the degree of damage being reflected in the quantity of loss of radioiodinated peripheral and integral membrane proteins from the target cells. A significant antitumor CMI was observed in the exposed offsprings although there was no apparent difference between the immunoresponsiveness observed in either the males or the female siblings. Unexpectedly, the mothers exhibited little such antitumor cellular immunity following the carcinogenic insult; even though all previous investigations of adult animals always demonstrated such an immunological response following exposure to the quantities of DMH that were administered (0.1 to 20 mg per kg body wt). As a consequence, these findings tentatively implied that the state of pregnancy alters a female's response to chemical carcinogenic insults and may actually serve as a device for protection from environmentally caused cancer. The threshold detection level for DMH exposure utilizing immune measurements was found to be approximately 10 times smaller for the perinatal susceptibility to the chemical insult intimating that such tests might usefully be incorporated in those bioassays utilized for determining the cancer-causing potential of weak carcinogens. Our findings now suggest that DMH may indeed be a perinatal carcinogen and that immune responsiveness may be readily employed for identifying such substances. However, the definitive studies of actually identifying cancer following such in utero exposures remain to be accomplished.
1,2-Cyclohexane dicarboxylic acid, diisononyl ester (DINCH) is a complex mixture of nine carbon branched-chain isomers. It has been used in Europe since 2002 as a plasticizer to replace phthalates such as di(2-ethylhexyl)phthalate (DEHP) and diisononyl phthalate (DINP). Urinary concentrations of the oxidative metabolites of DINCH, namely cyclohexane-1,2-dicarboxylic acid-monocarboxy isooctyl ester (MCOCH); cyclohexane-1,2-dicarboxylic acid-mono(oxo-isononyl) ester (MONCH); and cyclohexane-1,2-dicarboxylic acid-mono(hydroxy-isononyl) ester (MHNCH), can potentially be used as DINCH exposure biomarkers. The concentrations of MCOCH, MONCH and MHNCH were measured by online solid phase extraction-high performance liquid chromatography-tandem mass spectrometry in urine collected in 2000 (n=114), 2001 (n=57), 2007 (n=23), 2009 (n=118), 2011 (n=94) and 2012 (n=121) from convenience groups of anonymous U.S. adult volunteers with no known DINCH exposure. None of the DINCH metabolites were detected in samples collected in 2000 and 2001. Only one sample collected in 2007 had measureable concentrations of DINCH metabolites. The detection rate for all three metabolites increased from 2007 to 2012. The presence of oxidative metabolites of DINCH in urine suggests that these oxidative metabolites can be used as DINCH biomarkers for exposure assessment even at environmental exposure levels.
The possible maternal hepatic and reproductive effects of 1,2,4-trichlorobenzene (TCB) were assessed in rats given 0, 36, 120, 360, and 1200 mg/kg/day of TCB on Days 9-13 of gestation. The animals were sacrificed on Day 14 of pregnancy. Maternal deaths (2/9 rats, 6/6 rats) were recorded in the 360 and 1200 mg/kg/day treatment groups and body weight gain was significantly decreased in the 360 mg/kg/day TCB group. Maternal liver weight, liver/body weight ratio, and hepatic microsomal protein content were unaffected by TCB treatment. Although Day 14 NADPH-cytochrome c reductase activity was affected only at 360 mg/kg/day TCB, the maternal hepatic microsomal cytochrome P-450 content was significantly increased by administration of both 120 and 360 mg/kg/day of TCB. Hepatic microsomal aminopyrine N-demethylase, ethoxyresorufin O-deethylase, and UDP-glucuronyl transferase activity towards p-nitrophenol were also increased at 120 and 360 mg/kg TCB. Glutathione S-transferase activity to 1-chloro-2,4-dinitrobenzene and 1,2 dichloro-4-nitrobenzene were both increased by pretreatment with TCB. Although pretreatment with 360 mg/kg/day TCB did not increase resorptions, embryolethality, or teratogenicity, embryonic development was significantly retarded by all four growth criteria used (head length, crown-rump length, somite number, and protein content).
Interactions between dietary calcium (Ca) and lead (Pb) which influence serum levels of the vitamin D hormone, 1,25-dihydroxyvitamin D (1,25(OH)2D), intestinal Ca and Pb absorption, and body Pb retention were investigated in chicks. In a 5 x 5 (levels of Ca and Pb) design, response surface modeling was used to describe and compare the various interactions. Lead ingestion and Ca deficiency alone or in combination generally increased serum 1,25(OH)2D levels over most of the range of dietary Ca and Pb. However, in severe Ca deficiency, Pb ingestion resulted in marked decreases in hormone concentration. Overall similarities in response profiles for 1,25(OH)2D, intestinal Ca absorption and calbindin-D suggest that major interactions between Pb and Ca are mediated via changes in circulating 1,25(OH)2D concentration, rather than direct effects on the intestine. The response profiles for Ca and Pb absorption differed, in part, suggesting that intestinal transport of the two cations may not be identical. Kidney and bone Pb content also differed in response to varying Ca and Pb levels, providing evidence for additional tissue-specific interactions not related to 1,25(OH)2D. The present study provides a comprehensive basis on which to interpret the results of previous clinical and experimental results.
Cadmium is a widespread environmental pollutant, which is associated with increased risk of osteoporosis. It has been proposed that cadmium's toxic effect on bone is exerted via impaired activation of vitamin D, secondary to the kidney effects. To test this, we assessed the association of cadmium-induced bone and kidney effects with serum 1,25-dihydroxyvitamin D (1,25(OH)(2)D); measured by enzyme immunoassay. For the assessment, we selected 85 postmenopausal women, based on low (0.14-0.39 microg/L) or high (0.66-2.1 microg/L) urinary cadmium, within a cross-sectional population-based women's health survey in Southern Sweden. We also measured 25-hydroxy vitamin D, cadmium in blood, bone mineral density and several markers of bone remodeling and kidney effects. Although there were clear differences in both kidney and bone effect markers between women with low and high cadmium exposure, the 1,25(OH)(2)D concentrations were not significantly different (median, 111 pmol/L (5-95th percentile, 67-170 pmol/L) in low- and 125 pmol/L (66-200 pmol/L) in high-cadmium groups; p=0.08). Also, there was no association between 1,25(OH)(2)D and markers of bone or kidney effects. It is concluded that the low levels of cadmium exposure present in the studied women, although high enough to be associated with lower bone mineral density and increased bone resorption, were not associated with lower serum concentrations of 1,25(OH)(2)D. Hence, decreased circulating levels of 1,25(OH)(2)D are unlikely to be the proposed link between cadmium-induced effects on kidney and bone.
Eight adult healthy male volunteers were exposed to 1.0 ppm nitric oxide (NO) with intermittent light exercise for 2 hr. No one showed any symptoms during NO exposure. A small, but significant, decrease of specific airway conductance was observed in half of the subjects. As a group, a significant reduction of the percentage increase of maximal expiratory flow at 50% of forced vital capacity while breathing a He-O/sub 2/ gas mixture as compared with air was observed among various pulmonary function tests. These results suggested that some physiological response to NO exposure might be observed in some subjects when performing exercise.
Bouwman and coauthors present data and analyses of DDT and other halogenated pollutants in environmental samples and based on their data and analyses thereof, argue against the use of DDT for malaria control. Regrettably, the analyses, presentations, and interpretations of data presented by Bouwman and coauthors are biased and erroneous.
Measurements of ultra-low ambient blood lead (PbB) concentrations (mean +/- SD = 0.13 +/- 0.06 micrograms/dL) in Northern elephant seal (Mirounga angustirostris) validate previous estimates of ultra-low PbB levels in preindustrial humans. These estimates had been unsubstantiated, since PbB levels in this range had never been measured in any organisms prior to this study. Similarities in PbB levels among these contemporary and preindustrial mammals are consistent with similarities in their measured and estimated lead exposures, respectively. The marginally higher PbB levels and rates of lead exposure in contemporary marine mammals are, also, consistent with lead isotopic composition analyses that indicate their PbB levels have been elevated from exposure to industrial lead. Consequently, these analyses substantiate concerns that current baseline PbB levels in humans, which are estimated to be two to three orders of magnitude above natural levels, may still constitute public health risks.
The retention, tissue distribution, and excretion of 103Pd in adult rats was determined following oral, intravenous (iv), and intratracheal admission. The highest retention was obtained following iv dosing, and lowest retention (less than 0.5%) occurred after oral dosing. Tissues containing the highest concentrations of 103Pd were the kidney, spleen, liver, lung, and bone. Following a single oral dose, almost all of the 103Pd was excreted in the feces due to nonabsorption, whereas after iv dosing, similar quantities were excreted in both the urine and feces. In pregnant rats following iv dosing, 103Pd did not readily move across the placental barrier, and statistically significant amounts of 103Pd were not found in all the fetuses. Furthermore, 103Pd was transferred to suckling rats via the dam's milk.
Understanding the gender similarities and differences in how organisms respond following exposure to environmental chemicals is important if we are to determine the relative risk of these agents to wildlife and human populations. In this paper, we have chosen to focus on the sex determination and differentiation of fishes, amphibians, and reptiles, because of their close association with the environment and the number of environmental factors (e.g., temperature and endocrine disrupting chemicals) that are known to affect these phenomena in these taxa. We have discussed examples of gender differences in response to exposure to endocrine disrupting chemicals and found gender similarities about as often as we found differences. We found that most studies examined either one sex exclusively, or the experimental design did not include examining the effect of sex as a variable. Given the central role of sex steroid hormones in the sex determination and sexual differentiation of fishes, amphibians, and reptiles, we recommend that future research purposefully include sex as a factor, so that risk assessment by government agencies can address the probable gender differences in effects from exposure to chemicals in the environment.