Absence of DNA damage in multiple organs after oral exposure to fluoride in Wistar rats.
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Administration, Oral↗
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Measurement of genotoxic activity in multiple tissues following inhalation exposure to dimethylnitrosamine.
Chemically-induced DNA repair was measured as unscheduled DNA synthesis (UDS) in selected tissues isolated from rats following in vivo exposure to inhaled dimethylnitrosamine (DMN). UDS was evaluated in epithelial cells from rat nasal turbinates and trachea, in hepatocytes and in pachytene spermatocytes from the same treated animal. At nominal concentrations of 500 and 1000 ppm of DMN in air, chemically-induced DNA repair was observed in the epithelial cells of the upper respiratory system. DMN also entered the circulation, as evidenced by a strong DNA-repair response in hepatocytes. No DNA repair was observed in pachytene spermatocytes indicating either that DMN or its active metabolites did not reach the testes in sufficient concentration to induce DNA repair or that the testes lacked the capability to metabolically activate the compound. These results illustrate the potential of this approach to assess the organ-specific genotoxicity of environmental chemicals.
Animals↗
Increase in cerivastatin systemic exposure after single and multiple dosing in cyclosporine-treated kidney transplant recipients.
OBJECTIVE: The mutual drug-drug interaction potential of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor cerivastatin and cyclosporine (INN, ciclosporin) in kidney transplant recipients receiving individual immunosuppressive treatment was evaluated with respect to pharmacokinetic behavior of either drug and tolerability of concomitant use. METHODS: Plasma and urine concentrations of cerivastatin and its major metabolites were determined after administration of 0.2 mg single-dose cerivastatin to 12 kidney transplant recipients (9 men and 3 women) who were receiving stable individual cyclosporine treatment (mainly 200 mg twice a day). These results were compared with the single-dose pharmacokinetic results obtained from a healthy control group (n = 12, age-comparable men). Cerivastatin steady-state pharmacokinetics were evaluated in the same patients during continued immunosuppressive treatment 4 to 6 weeks later, after a 7-day treatment of 0.2 mg cerivastatin once a day. Cyclosporine steady-state concentration-time profiles were determined in blood with monoclonal (EMIT [enzyme multiplied immunoassay technique] assay, parent drug specific) and polyclonal antibodies (FPIA [fluorescence polarization immunoassay] assay, cyclosporine plus metabolites) during cerivastatin cotreatment and compared with predosing data. RESULTS: Coadministration of 0.2 mg cerivastatin once a day to the kidney transplant recipients treated with individual doses of cyclosporine and other immunosuppressive agents resulted in a 3- to 5-fold increase in cerivastatin and metabolites plasma concentrations. Cerivastatin and metabolites elimination half-lives were unaffected, and no accumulation occurred during multiple-dosing conditions. Cerivastatin had no influence on steady-state blood concentrations of cyclosporine or cyclosporine metabolites in these patients. The concomitant use of both drugs was well tolerated. CONCLUSIONS: Cerivastatin and metabolites plasma concentrations were significantly increased in kidney transplant recipients treated with cyclosporine and other immunosuppressive agents. Displacement from the main site for cerivastatin distribution-the liver-by cyclosporine-inhibited liver transport processes may explain the decrease in both metabolic clearance and volume of distribution for cerivastatin and metabolites.
Adult↗
Megaloblastic haemopoiesis after multiple short-term exposure to nitrous oxide.
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5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
Mechanical impedance of the sitting human body in single-axis compared to multi-axis whole-body vibration exposure.
OBJECTIVE: The study was aimed to investigate the mechanical impedance of the sitting human body and to compare data obtained in laboratory single-axis investigations with multi-axis data from in vehicle measurements. DESIGN: The experiments were performed in a laboratory for single-axis measurements. The multi-axis exposure was generated with an eight-seat minibus where the rear seats had been replaced with a rigid one. The subjects in the multi-axis experiment all participated in the single-axis experiments. BACKGROUND: There are quite a few investigations in the literature describing the human response to single-axis exposure. The response from the human body can be expected to be affected by multi-axis input in a different way than from a single-axis exposure. The present knowledge of the effect of multiple axis exposure is very limited. METHODS: The measurements were performed using a specially designed force and accelerometer plate. This plate was placed between the subject and the hard seat. RESULTS: Outcome shows a clear difference between mechanical impedance for multi-axis exposure compared to single-axis. This is especially clear in the x-direction where the difference is very large. CONCLUSIONS: The conclusion is that it seems unlikely that single-axis mechanical impedance data can be directly transferred to a multi-axis environment. This is due to the force cross-talk between different directions.
Acceleration↗
Pregnancy failure in laboratory mice after multiple short-term exposure to strange males.
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Animals↗
Approaches to community concerns: applied public health.
Public health workers are challenged to address community health concerns believed to be related to environmental exposures. The challenge is heightened when there are multiple potential exposures and numerous health concerns. In a community in Washington State, we employed different approaches depending on the specificity of diagnosis and the relation of the disease to environmental exposures. For diseases with specific diagnoses and questionable associations with environmental exposures, we began by determining whether rates of disease were higher than expected. Different approaches were needed for three different health concerns. Major limitations were estimating community population counts and obtaining comparison rates from published literature. Despite limitations, epidemiologic data developed at a relatively low cost were useful in assisting the community in understanding its health status.
Aged↗
Workshop on harmonization of serving multiple needs with occupational exposure databases, session II.
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Databases, Factual↗
Mixed-effect models for evaluating multiple measures of atrazine exposure among custom applicators.
The exposure of custom (or commercial) applicators to the herbicide atrazine was measured in environmental (hand wash and dermal patch) and biological (urine and saliva) samples. Surrogate exposure data, such as amount of atrazine sprayed, were also collected. A systematic sampling design was used that included both spray and nonspray days. Fifteen applicators were sampled 5 to 7 days each during a 6-week spring spray season for a total of 89 sampled days. Mixed-effect regression modeling was used to examine the relationship among the surrogate, environmental, and biological atrazine exposure measures. Surrogate measures of atrazine application (either kg of atrazine sprayed or spray atrazine [yes/no]) were significantly associated with increased levels of atrazine or atrazine equivalents (eq) in hand wash, thigh patch, 4-6 p.m. saliva, and 24-hour urine samples. Two days of spraying information (day of sampling and day before sampling) were needed to optimally estimate atrazine biomarkers in the biological samples, whereas only 1 day of spraying information (day of sampling) was needed to estimate atrazine levels in the environmental samples. Thigh and hand atrazine exposures were significantly associated with increased atrazine and atrazine eq. levels in the 4-6 p.m. saliva and 24-hour urine samples, respectively. Levels of 4-6 p.m. salivary atrazine were also significantly associated with increased levels of 24-hour urinary atrazine eq. Atrazine levels in the 4-6 p.m. saliva samples tracked most closely with evening and next morning urinary atrazine eq. Number of days into the study at the time of sample collection predicted urinary and salivary atrazine levels independent of other fixed effects. These results indicate that either surrogate, environmental, or biological exposure measures can be used in appropriately specified models to estimate urinary and salivary atrazine biomarker levels.
Air Pollutants, Occupational↗
Acute multiple mononeuropathy after accidental exposure to oven microwaves.
A patient accidentally exposed to oven microwaves developed an acute and severe dystrophy and sympathetic reflex of the right hand, a peripheral neuropathy of the digits of the left hand, and a sensory injury of the trigeminal nerve in the right side of the face. The physiopathological involvement in the injury of the peripheral nerve and the failure of analgesia with carbamazepine are emphasized. In this causalgia, relief from pain and modification of the autonomic disorders can be achieved by a sympathetic block.
Adult↗
Influence of Exposure to Single versus Multiple Toxins of Bacillus thuringiensis subsp. israelensis on Development of Resistance in the Mosquito Culex quinquefasciatus (Diptera: Culicidae).
The impending widespread use of transgenic crop plants encoding a single insecticidal toxin protein of Bacillus thuringiensis has focused attention on the perceived risk of rapid selection of resistance in target insects. We have used Bacillus thuringiensis subsp. israelensis toxins as a model system and determined the speed and magnitude of evolution of resistance in colonies of the mosquito Culex quinquefasciatus during selection for 28 consecutive generations with single or multiple toxins. The parental strain was synthesized by combining approximately 500 larvae from each of 19 field collections obtained from the states of California, Oregon, Louisiana, and Tennessee. At least 10,000 larvae were selected in each generation of each line at an average mortality level of 84%. The susceptibilities of the parental and selected lines were compared in parallel tests in every third generation by using fresh suspensions of toxin powders. The normal toxin complement of B. thuringiensis subsp. israelensis consists of four toxins, CryIVA, CryIVB, CryIVD, and CytA. Resistance became evident first in the line that was selected with a single toxin (CryIVD), attaining the highest level (resistance ratio [RR], >913 at 95% lethal concentration) by generation F(inf28) when the study was completed. Resistance evolved more slowly and to a lower level (RR, >122 by F(inf25)) in the line selected with two toxins (CryIVA+CryIVB) and lower still (RR, 91 by F(inf28)) in the line selected with three toxins (CryIVA+CryIVB+ CryIVD). Resistance was remarkably low (RR, 3.2) in the line selected with all four toxins. The results reveal the importance of the full complement of toxins found in natural populations of B. thuringiensis subsp. israelensis as an effective approach to resistance management.
Journal Article↗
Interpreting the human phase response curve to multiple bright-light exposures.
Czeisler and his colleagues have recently reported that bright light can induce strong (Type O) resetting of the human circadian pacemaker. This surprising result shows that the human clock is more responsive to light than has been previously thought. The interpretation of their results is subtle, however, because of an unconventional aspect of their experimental protocol: They measured the phase shift after three cycles of the bright-light stimulus, rather than after the usual single pulse. A natural question is whether the apparent Type O response could reflect the summation of three weaker Type 1 responses to each of the daily light pulses. In this paper I show mathematically that repeated Type 1 resetting cannot account for the observed Type O response. This finding corroborates the strong resetting reported by Czeisler et al., and supports their claim that bright light induces strong resetting by crushing the amplitude of the circadian pacemaker. Furthermore, the results indicate that back-to-back light pulses can have a cooperative effect different from that obtained by simple iteration of a phase response curve (PRC). In this sense the resetting response of humans is similar to that of Drosophila, Kalanchoe, and Culex, and is more complex than that predicted by conventional PRC theory. To describe the way in which light resets the human circadian pacemaker, one needs a theory that includes amplitude resetting, as pioneered by Winfree and developed for humans by Kronauer.
Circadian Rhythm↗
The performance of culture-based methods and microscopy for quantification of noninfectious airborne microorganisms in epidemiological studies of highly contaminated work environments.
Airborne levels of microorganisms traditionally have been measured by culture-based methods. Culture-based methods are suitable for the detection of infectious agents, but their suitability for the detection of microorganisms with toxic and allergic effects is less clear, because these effects do not depend on viability of the organisms. During the last 15 years several noncultural methods have been developed for the quantification of airborne microorganisms, including microscopic methods. Microscopy may be expected to provide more valid exposure estimates of microorganisms than culture-based methods, because live and dead microorganisms can be detected. However, their validity may also depend on the ability to differentiate between species. The literature was searched for epidemiological studies in which exposure-response analyses were carried out using culture-based methods and/or microscopy. The influence of several factors on exposure-response associations were considered: design; population size; analytical method; sampling method; exposure levels; outcome; and confounder adjustment. Thirteen studies were found, including a total of 49 exposure-response analyses, and 45% of the analyses showed associations. It was found that the potential of microscopic methods to uncover exposure-response associations was only marginally better than that of culture-based methods (47 and 44%, respectively). Exposure-response associations were more often found with fungi (70%) than with gram-negative bacteria (50%) or total bacteria (22%), perhaps because fungal exposure is more strongly associated to respiratory outcomes than exposure to bacteria. But the shortcomings of the measurement methods may also be important. Further development of measurement methods for bacteria is therefore needed. The complex composition of bioaerosols in many work environments necessitate the assessment of exposure to multiple agents and multivariate statistical analysis of exposure-response associations.
Air Pollution, Indoor↗
Renal and neurologic effects of cadmium, lead, mercury, and arsenic in children: evidence of early effects and multiple interactions at environmental exposure levels.
Lead, cadmium, mercury, and arsenic are common environmental pollutants in industrialized countries, but their combined impact on children's health is little known. We studied their effects on two main targets, the renal and dopaminergic systems, in > 800 children during a cross-sectional European survey. Control and exposed children were recruited from those living around historical nonferrous smelters in France, the Czech Republic, and Poland. Children provided blood and urine samples for the determination of the metals and sensitive renal or neurologic biomarkers. Serum concentrations of creatinine, cystatin C, and beta2-microglobulin were negatively correlated with blood lead levels (PbB), suggesting an early renal hyperfiltration that averaged 7% in the upper quartile of PbB levels (> 55 microg/L; mean, 78.4 microg/L). The urinary excretion of retinol-binding protein, Clara cell protein, and N-acetyl-beta-d-glucosaminidase was associated mainly with cadmium levels in blood or urine and with urinary mercury. All four metals influenced the dopaminergic markers serum prolactin and urinary homovanillic acid, with complex interactions brought to light. Heavy metals polluting the environment can cause subtle effects on children's renal and dopaminergic systems without clear evidence of a threshold, which reinforces the need to control and regulate potential sources of contamination by heavy metals. Key words: arsenic, biomarkers, cadmium, dopaminergic, heavy metals, interactions, lead, mercury, renal.
Arsenic↗
Study of some biochemical changes among workers occupationally exposed to phenol, alone or in combination with other organic solvents.
The present study was aimed for the effects of exposure to multiple organic solvent vapors in comparison with single exposure to phenol. It included 20 workers exposed to phenol alone and 32 workers of combined exposure to phenol, benzene, toluene and methyl ethyl ketone. A control group of 30 subjects was also included. The levels of transaminases, total proteins, prothrombin time, bleeding time, clotting time, fasting blood sugar, serum creatinine and some trace elements (copper, zinc, iron, magnesium, manganese and calcium) were determined in blood together with a complete blood picture. Urine samples were analyzed for phenol, hippuric acid and methyl ethyl ketone. The effects of combined exposure did not differ from that of exposure to phenol alone concerning the majority of the tested parameters. Only the levels of platelets count, prothrombin time, eosinophils, copper and iron have been affected by combined exposure in a probably additive manner.
Adult↗
Hemorrhagic disease in white-tailed deer in Texas: a case for enzootic stability.
Although antibodies to viruses in both the epizootic hemorrhagic disease virus (EHDV) and bluetongue virus (BTV) sero-groups have been reported from white-tailed deer (Odocoileus virginianus) in Texas (USA), there are few reports of hemorrhagic disease (HD) in these populations. To understand the extent and diversity of exposure to the North American EHDV and BTV serotypes in these deer populations, we serologically tested 685 white-tailed deer collected from November 1991 through March 1992 throughout their range in Texas. Overall, 574 (84%) of deer had antibodies to EHDV or BTV. Prevalence estimates varied according to ecological region, from 57% in the Gulf Prairies to 100% in the northwest Edwards Plateau. Based on serum neutralization tests, the deer had evidence of previous exposures to multiple EHDV and BTV serotypes, with evidence of exposure to two to five serotypes detected in each ecological region. The apparent lack of HD in relation to this high antibody prevalence cannot be explained, but may be related to enzootic stability in which a near perfect host-virus relationship exists.
Age Distribution↗
kappa-Opioid tolerance and dependence in cultures of dopaminergic midbrain neurons.
Repeated cocaine exposure upregulates kappa opioids and their receptors in the mesocorticolimbic system; the ensuing kappa-mediated dysphoria appears to contribute to addiction and withdrawal. As a potential rehabilitation strategy to reverse cocaine-induced kappa sensitization, the present study used tritiated dopamine release assays to examine the induction of kappa-opioid tolerance in cultured mesencephalic neurons. Administration of the kappa agonist U69,593 inhibited tetrodotoxin-sensitive, spontaneous (EC(50) = 1.5 nM), and potassium-stimulated (EC(50) = 10 nM) release. These effects were blocked by pertussis toxin and by the kappa antagonist nor-binaltorphimine. The 2 d agonist exposure (1 microM) caused a shift in the U69,593 dose-response curve that was greater in the potassium-stimulated paradigm (140-fold) than in the spontaneous release assay (sixfold). These results were attributable to the attenuation of kappa-receptor signaling mechanisms and to dependence. In the stimulated release assay, attenuation of kappa signaling caused by 4 hr of U69,593 exposure recovered with a half-life of 1.1 hr, whereas attenuation after 144 hr of exposure recovered slowly (t(1/2) = 20 hr). In the spontaneous release assay, attenuation of kappa-opioid signaling occurred slowly (t(1/2) = 22 hr), and resensitization after a 144 hr exposure was rapid (t(1/2) < 1 hr). kappa-Opioid dependence was observed after 144 hr of U69,593 exposure. Thus multiple mechanisms of adaptation to kappa-opioid exposure occur in mesocorticolimbic neurons. These data support the idea that the administration of kappa opioids might facilitate drug rehabilitation.
Analgesics↗
[Neoformed multiple hepatic angiomas after exposure to vinyl chloride monomer: report of a case].
The paper describes the case of a 60 years old man with previous protracted exposure to CVM. After a latency of 20 years, the man developed two hepatic hemangiomas, one characterized by rapid growth (4 cm of diameter in 1 year) and surgically removed. On the basis of the anamnestic data (15 years in a PVC polymerization factory in the reactor vessels department) considering the degree and duration of exposure to CVM, an occupational origin of the hepatic hemangiomas is probable. The ability of CVM to induce sclerosis, necrosis and endothelial hyperplasy in the liver tissue may represent the primum movens of hemangiomas.
Carcinogens↗