Benchmark concentrations for methylmercury obtained from the Seychelles Child Development Study.
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Methylmercury is a neurotoxin at high exposures, and the developing fetus is particularly susceptible. Because exposure to methylmercury is primarily through fish, concern has been expressed that the consumption of fish by pregnant women could adversely affect their fetuses. The reference dose for methylmercury established by the U.S. Environmental Protection Agency was based on a benchmark analysis of data from a poisoning episode in Iraq in which mothers consumed seed grain treated with methylmercury during pregnancy. However, exposures in this study were short term and at much higher levels than those that result from fish consumption. In contrast, the Agency for Toxic Substances and Disease Registry (ATSDR) based its proposed minimal risk level on a no-observed-adverse-effect level (NOAEL) derived from neurologic testing of children in the Seychelles Islands, where fish is an important dietary staple. Because no adverse effects from mercury were seen in the Seychelles study, the ATSDR considered the mean exposure in the study to be a NOAEL. However, a mean exposure may not be a good indicator of a no-effect exposure level. To provide an alternative basis for deriving an appropriate human exposure level from the Seychelles study, we conducted a benchmark analysis on these data. Our analysis included responses from batteries of neurologic tests applied to children at 6, 19, 29, and 66 months of age. We also analyzed developmental milestones (age first walked and first talked). We explored a number of dose-response models, sets of covariates to include in the models, and definitions of background response. Our analysis also involved modeling responses expressed as both continuous and quantal data. The most reliable analyses were considered to be represented by 144 calculated lower statistical bounds on the benchmark dose (BMDLs; the lower statistical bound on maternal mercury hair level corresponding to an increase of 0.1 in the probability of an adverse response) derived from the modeling of continuous responses. The average value of the BMDL in these 144 analyses was 25 ppm mercury in maternal hair, with a range of 19 to 30 ppm. (+info)
Predictors of weaning outcome in chronic obstructive pulmonary disease patients.
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Several threshold values for predicting weaning outcome from mechanical ventilation have been proposed. These values, however, have been obtained in nonhomogeneous patient populations. The aim of the present study was to determine the threshold values in chronic obstructive pulmonary disease (COPD) patients and compare them to those reported for nonhomogeneous patient populations. The initial weaning trial included 81 COPD patients. Fifty-three of them underwent a successful weaning trial, whereas 28 failed it. The latter were enrolled into the present investigation, and were restudied during a subsequent successful trial. The weaning indices used were those reported in the literature. The threshold values obtained were within 10% of those reported for a nonhomogeneous patients population only for tidal volume and effective compliance. The classification error was <20% for maximal inspiratory pressure (MIP), occluded inspiratory pressure swing (deltaPI)/MIP, rapid and shallow breathing (respiratory frequency/tidal volume), and compliance, rate, oxygenation, pressure index (CROP), whereas the area under the receiver operating characteristic curves was >0.9 only for deltaPI/MIP and CROP. In conclusion, the threshold values obtained in chronic obstructive pulmonary disease patients who failed the first weaning attempt differed from those previously reported. Although a gold standard weaning index is not available for chronic obstructive pulmonary disease patients, the occluded inspiratory pressure swing/ maximal inspiratory pressure and compliance, rate, oxygenation, pressure index may be candidates for such a role. (+info)
Ovarian antibodies, FSH and inhibin B: independent markers associated with unexplained infertility.
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Premature menopause and unexplained infertility are associated with ovarian antibodies, a marker of ovarian autoimmunity. In premature menopause, FSH is also elevated while in unexplained infertility FSH concentrations are often normal. The relationship of ovarian antibodies and FSH and inhibin B, as markers of follicle function, was investigated in unexplained infertility. Ovarian antibodies were determined by immunoassay in comparison to normal controls (n = 12); 51.9% were positive at two SD (P < 0.05) and 38.5% were positive at three SD above the control mean (P < 0.01). In this study three SD above the control mean was considered positive. In unexplained infertility, three out of 10 (30%) had elevated day 3 FSH (>10 mIU/ml) and ovarian antibodies, while 17/42 (40%) had normal FSH (<10 mIU/ml) and ovarian antibodies. In women with normal FSH, two out of seven (29%) had low inhibin B concentrations (<33 pg/ml) and ovarian antibodies, and 15/35 (43%) had normal inhibin B concentrations (> 33 pg/ml) and ovarian antibodies. Similarly, when women with and without ovarian antibodies were compared there was no difference in mean FSH or mean inhibin B concentrations. Thus, unlike other endocrine autoimmune disorders, hormone concentrations are not predictors of potential ovarian autoimmunity. This suggests that in unexplained infertility ovarian antibodies are an independent marker of potential ovarian failure, and may precede changes in regulatory hormones. (+info)
Occupational exposure to mercury. What is a safe level?
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QUESTION: One of my pregnant patients, a dental hygienist, uses mercury in her workplace, but appears to have no symptoms of mercury toxicity. She has heard that mercury might affect her fetus. What should I recommend to her? What is a safe level of mercury in the air for pregnant women? ANSWER: Testing for levels of mercury in whole blood and, preferably, urine is useful for confirming exposure. Currently, mercury vapour concentrations greater than 0.01 mg/m3 are considered unsafe. Also, women of childbearing age should avoid contact with mercury salts in the workplace. (+info)
Predicting residue solvent accessibility from protein sequence by considering the sequence environment.
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The solvent accessibility of each residue is predicted on the basis of the protein sequence. A set of 338 monomeric, non-homologous and high-resolution protein crystal structures is used as a learning set and a jackknife procedure is applied to each entry. The prediction is based on the comparison of the observed and the average values of the solvent-accessible area. It appears that the prediction accuracy is significantly improved by considering the residue types preceding and/or following the residue whose accessibility must be predicted. In contrast, the separate treatment of different secondary structural types does not improve the quality of the prediction. It is furthermore shown that the residue accessibility is much better predicted in small than in larger proteins. Such a discrepancy must be carefully considered in any algorithm for predicting residue accessibility. (+info)
Biological monitoring and exposure to mercury.
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Occupational health professionals' interest in controlling mercury (Hg) exposure, and the use of biological monitoring in this context, has been ongoing for a number of years. Evidence from urinary Hg results in a number of UK firms who have undertaken some form of biological monitoring or occupational health surveillance suggest that exposure has decreased over the last 10-15 years. This decrease precedes the establishment in the UK of an advisory biological monitoring guidance value (HGV) for urinary Hg and the production of updated medical guidance from the Health & Safety Executive on Hg exposure (MS12 1996). This latter document recommends a urinary sampling interval for urinary Hg of between 1 and 3 months, which is consistent with the reported toxicokinetics of Hg excretion, but we highlight that urinary Hg represents integrated exposure over many previous months. Mercury is a recognized nephrotoxin and MS12 1996 mentions the use of regular dipstick protein estimations. We review our experience of investigating proteinuria and enzymuria in a large-scale cross-sectional occupational study. The incidence of Hg-induced renal disease is probably very rare at current exposure levels. Therefore acceptance of a high false-positive rate of proteinuria not related to Hg exposure needs to be considered in any urinary protein testing regime of Hg workers. The establishment of an HGV for urinary Hg has raised questions about the uncertainty associated with a urinary Hg result, including factors such as diurnal variation, whether urine correction by creatinine or specific gravity is preferable and the possibility of non-occupational sources of Hg contributing significantly towards breaching the HGV. Correction of urinary Hg results by creatinine or specific gravity and the use of a fixed sampling time, such as the beginning or end of the day, substantially reduce the uncertainty in a urinary Hg measurement. But even with good laboratory precision, an individual with a true urinary Hg excretion of 20 nmol/mmol creatinine could supply urine samples of between 14 and 26 nmol/mmol creatinine. The influence of dietary sources in the UK contributing to urinary Hg values approaching or exceeding the HGV is unlikely. The use of tribal or ethnic cosmetics and remedies needs to be considered if a urinary Hg result looks inappropriately high, as some such preparations have been found to contain Hg and can be absorbed through the skin. The ability of excessive chewers or teeth grinders who have a large number of dental amalgam fillings to breach the urinary HGV in the absence of substantial occupational Hg exposure has been reported in a few Scandanavian studies. We report here a likely case of this phenomenon. Since the establishment of the HGV, our biological monitoring Hg data from a number of industry sectors using inorganic or metallic Hg have suggested that a minority of samples (13%) are still greater than the HGV. (+info)
Proposed occupational exposure limits for select ethylene glycol ethers using PBPK models and Monte Carlo simulations.
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Methoxyethanol (ethylene glycol monomethyl ether, EGME), ethoxyethanol (ethylene glycol monoethyl ether, EGEE), and ethoxyethyl acetate (ethylene glycol monoethyl ether acetate, EGEEA) are all developmental toxicants in laboratory animals. Due to the imprecise nature of the exposure data in epidemiology studies of these chemicals, we relied on human and animal pharmacokinetic data, as well as animal toxicity data, to derive 3 occupational exposure limits (OELs). Physiologically based pharmacokinetic (PBPK) models for EGME, EGEE, and EGEEA in pregnant rats and humans have been developed (M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 53-62; M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 63-73). These models were used to calculate estimated human-equivalent no adverse effect levels (NAELs), based upon internal concentrations in rats exposed to no observed effect levels (NOELs) for developmental toxicity. Estimated NAEL values of 25 ppm for EGEEA and EGEE and 12 ppm for EGME were derived using average values for physiological, thermodynamic, and metabolic parameters in the PBPK model. The uncertainties in the point estimates for the NOELs and NAELs were estimated from the distribution of internal dose estimates obtained by varying key parameter values over expected ranges and probability distributions. Key parameters were identified through sensitivity analysis. Distributions of the values of these parameters were sampled using Monte Carlo techniques and appropriate dose metrics calculated for 1600 parameter sets. The 95th percentile values were used to calculate interindividual pharmacokinetic uncertainty factors (UFs) to account for variability among humans (UF(h,pk)). These values of 1.8 for EGEEA/EGEE and 1.7 for EGME are less than the default value of 3 for this area of uncertainty. The estimated human equivalent NAELs were divided by UF(h,pk) and the default UFs for pharmacodynamic variability among animals and among humans to calculate the proposed OELs. This methodology indicates that OELs (8-h time-weighted average) that should protect workers from the most sensitive adverse effects of these chemicals are 2 ppm EGEEA and EGEE (11 mg/m(3) EGEEA, 7 mg/m(3) EGEE) and 0.9 ppm (3 mg/m(3)) EGME. These recommendations assume that dermal exposure will be minimal or nonexistent. (+info)
Exercise and outdoor ambient air pollution.
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OBJECTIVES: To establish by literature survey: (a) levels at which air pollutants are considered damaging to human health and to exercisers in particular; (b) the current ambient levels experienced in the United Kingdom; (c) whether athletes are especially at risk. METHODS: Six major urban air pollutants were examined: carbon monoxide (CO); nitrogen oxides (NO(X)); ozone (O(3)); particulate matter (PM(10)); sulphur dioxide (SO(2)); volatile organic compounds (VOCs). RESULTS: CO is detrimental to athletic performance. NO(2) is of concern to human health, but outdoor levels are low. O(3) poses a potentially serious risk to exercising athletes. Decrements in lung function result from exposure, and there is evidence that athletic performance may be affected. Detrimental effects may occur at low ambient levels, but there is no scientific consensus on this matter. PM(10) is causing concern in the scientific community. Blood lead accumulation during exercise indicates that personal exposure to toxic compounds associated with PM(10) may be magnified. Generally, outdoor ambient levels of SO(2) are too low to cause a problem to the athlete, except the asthmatic athlete. The few studies on exposure of exercisers to VOCs are reviewed. CONCLUSIONS: Athletes and exercisers should avoid exercising by the road side even though levels of the more noxious air pollutants have been controlled in the United Kingdom. O(3) is particularly damaging to athletes; it reaches its highest concentrations on hot bright days in rural areas. (+info)