Evaluation of skin and respiratory doses and urinary excretion of alkylphosphates in workers exposed to dimethoate during treatment of olive trees.

This article describes a study of exposure to dimethoate during spraying of olive trees in Viterbo province in central Italy. Airborne concentrations of dimethoate were in the range 1.5 to 56.7 nmol/m(3). Total skin contamination was in the range 228.4 to 3200.7 nmol/d and averaged 96.0% +/- 3.6% of the total potential dose. Cotton garments afforded less skin protection than waterproof ones, which were in turn associated with higher skin contamination than disposable Tyvek overalls. Total potential doses and estimated absorbed doses, including their maxima, were below the acceptable daily intake of dimethoate, which is 43.6 nmol/kg body weight (b.w.). Urinary excretion of alkylphosphates was significantly higher than in the general population, increasing with exposure and usually showing a peak in the urine sample collected after treatment. Metabolite concentrations were influenced by the type of individual protection used: minimum levels were associated with the closed cabin and maximum levels with absence of any respiratory or hand protection. Urinary alkylphosphates showed a good correlation with estimated absorbed doses and are confirmed as sensitive biologic indicators of exposure to phosphoric esters.

Use of a toxicokinetic model in the analysis of cancer mortality in relation to the estimated absorbed dose of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD).

We performed an analysis of All cancer and Lung cancer mortality in relation to estimated absorbed dose of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) in the cohort of chemical workers at 12 US plants assembled by the US National Institute for Occupational Safety and Health (NIOSH) (n = 5172). Estimates of cumulative exposure to TCDD were based on a minimal physiologic toxicokinetic model (MPTK) that accounts for inter- and intra-individual variations in body mass index (BMI) over time. Population-level parameters related to liver elimination and background (input or concentration) of TCDD were estimated from separate data with repeated measures of serum TCDD (US Air Force Health Study). An occupational TCDD input parameter was estimated based on one-point-in-time TCDD data available for a subset (n = 253) of the NIOSH cohort. Model-based time-dependent cumulative dose estimates (area under the curve (AUC) of the lipid-adjusted serum TCDD concentration over time) were obtained for members of the full cohort with recorded body height and weight (n = 4049), as this information is required by the MPTK model to compute dose. Missing-value problems arose in the estimation of the occupational input parameter (n = 42) and in TCDD-dose calculation in the full cohort (n = 886) and they were handled with multiple imputation methods. Risk-regression analyses were based on Cox log-linear models including age at entry, year of entry and duration of employment as categorical covariates in addition to the logarithm of cumulative TCDD dose in ppt-years. Risk sets were stratified on birth cohort. Estimates of the unlagged exposure coefficient in these models were 0.1249 [95% confidence interval (CI) 0.0144, 0.2354] for All cancer and 0.2158 (95% CI 0.02376, 0.4078) for lung cancer. A 10-year lag produced an increase in the estimate for all cancer (0.1539, 95% CI 0.0387, 0.2691), whereas, the estimate for lung cancer was not affected much (0.2125, 95% CI 0.0138, 0.4112). At a dose level of 100 times the background the estimates obtained with a 10-year lag translate into a relative risk of 2.03 (95% CI 1.19-3.45) for all cancer and of 2.66 (95% CI 1.07-6.64) for lung cancer. Higher estimates of the exposure coefficients were obtained after imputation of missing values. This increase in risk seemed due to the inclusion of short-term workers, who may exhibit a higher mortality for reasons other than dioxin exposure.

[Infantile leukemia and exposure to 50/60 Hz magnetic fields: review of epidemiologic evidence in 2000]. / Leucemia infantile ed esposizione a campi magnetici a 50/60 Hz: una rassegna delle evidenze epidemiologiche al 2000.

We review the epidemiological evidence on childhood leukemia and residential exposure to 50/60 Hz magnetic fields. The possibility of carcinogenic effects of power frequency magnetic fields (ELF-EMF), at levels below units of micro tesla (microT), was first raised in 1979 by a case-control study on childhood cancer carried out in Denver, USA. In that study, excess risks of total cancer and leukemia were observed among children living in homes with "high or very high current configuration", as categorised on the basis of proximity to electric lines and transformers. Many other epidemiological studies have been published since then, characterised by improved--although still not optimal--methods of exposure assessment. At the end of 2000, the epidemiological evidence to support the association between exposure to extremely-low-frequency magnetic fields and the risk of childhood leukemia is less consistent than what was observed in the mid 90s. At the same time, a growing body of experimental evidence has accumulated against both a direct and a promoting carcinogenic effect of ELF-EMF. Such "negative" experimental evidence hampers a causal interpretation of the "positive" epidemiological studies.

Mortality among rubber chemical manufacturing workers.

BACKGROUND: A retrospective cohort mortality study evaluated ischemic heart disease (IHD) among workers in the "rubber chemicals" manufacturing department of a Western New York plant. A previous study at the plant found elevated chest pain and angina among workers in this department. METHODS: Mortality experience of workers employed from 1946-1988 was followed through December 31, 1994. Mortality was compared to U.S. population rates and to local Niagara county rates by using the NIOSH life table analysis system. Poisson regression was used to examine patterns of IHD within the cohort. RESULTS: The standardized mortality ratio (SMR) for IHD among workers in the rubber chemicals department was 1.51 (U.S. rates) and 1.19 (Niagara county rates). Increased mortality from IHD in the rubber chemicals department was most pronounced at younger ages (< 50, SMR = 2.4); workers in a second chemical production department also had an elevated (but not statistically significant) SMR of 1.5 for IHD. CONCLUSIONS: IHD mortality among workers in the rubber chemicals department was elevated, particularly among those under 50 years of age. Potential occupational risk factors for IHD include the rotating shift pattern for employees assigned to two chemical production departments and chemical exposures present in the rubber chemicals department.

[Proton magnetic resonance spectrometry for the non-invasive exploration of human brain metabolism: current and future clinical applications]. / La spectrométrie de résonance magnétique du proton dans l'exploration non invasive du métabolisme cérébral humain: applications cliniques actuelles et futures.

Magnetic resonance spectrometry (MRS) is now a routine investigation method in neurology. In some situations, its diagnostic sensitivity is better than MRI. In this review, we propose a critical analysis of the large body of literature on brain MRS concerning a wide range of pathologies and many different protocols. The diagnostic value of MRS is not fully determined in all neurological diseases, but the specific properties of MRS (detection of neuron-specific and glial-specific metabolites, quantitative data, reversibility of metabolic lesions) make it a high-performance tool for quantifying neuron, glial and membrane abnormalities. After reviewing the methodological advances in MRS and discussing restrictions on interpretation of spectral data, we describe variations in metabolic patterns detected by MRS in different groups of diseases. The currently reasonable indications for MRS exploration are presented as well as new avenues for research. Based on MRS data, we propose a metabolic definition of encephalopathy which could be useful in better understanding the role of MRS in modern neurology.

In vivo brain proton MR spectroscopy in a case of molybdenum cofactor deficiency.

A 20-day-old infant with molybdenum cofactor deficiency, a rare encephalopathy, was investigated using cerebral MRI and proton MR spectroscopy. Images demonstrated extensive white-matter destruction with large cavities. The short-echo-time MR spectrum acquired in the parieto-occipital area was characterised by global loss of signal and accumulation of lactate. No additional signal in relation to the pathophysiology of the disease was detected. The brain metabolic abnormalities observed in this patient may reflect destruction of white matter and the presence of large cavities.

Brain metabolic impairment in non-cerebral and cerebral forms of X-linked adrenoleukodystrophy by proton MRS: identification of metabolic patterns by discriminant analysis.

Cerebral metabolism in six children with X-linked adrenoleukodystrophy (X-ALD) was studied using 1H magnetic resonance spectroscopy (MRS), and the status of the patients was monitored for evaluating disease progression. Spectra were abnormal even in patients with no cerebral impairment. Four different metabolic patterns were identified, and a metabolic classification of the disease was proposed, from grade 0 to grade III. The evolution of the disease toward grade II appears to be systematic, but many patients did not evolve from this grade to grade III, which is the metabolic mark of severe progressive forms. Metabolic data of X-ALD were processed using discriminant analysis, which provides a classification accuracy of 95.2%. Proton cerebral MRS together with discriminant analysis may be useful during the follow-up in X-ALD for monitoring the evolution of the disease and the effects of therapy.

Uncertainty in estimating exposure using a toxicokinetic model. The example of 2,3,7,8-tetrachlorodibenzo-p-dioxin.

This paper deals with sources of uncertainty in the use of a minimal physiological toxicokinetic model to obtain dose estimates for a dose-response analysis of cancer in an occupational cohort. Toxicokinetic models make it possible to construct exposure parameters that are more closely related to the individual dose than traditional measures of exposures to toxic agents. However, the process introduces a wide array of sources of uncertainty. Selecting a model structure to describe the kinetics of a toxic agent implies necessarily making simplifications and assumptions that influence the range of applicability of the model. Once a model has been selected, the value of certain model parameters (constants) must be assigned, for example, from anthropometric data. The question then arises of how sensitive the model predictions are to variations in the values of these constants. Other model parameters, typically those describing the kinetics of the agent, are next estimated from actual data. There may be limitations in the data concerning, for example, sparseness (too few observations per subject) or missing values. The methods used for parameter estimation carry their own set of assumptions that need to be appropriate to the situation at hand. In summary, the dioxin example is used to characterize the sources of uncertainty at different levels, such as model structure, methods and data used for parameter estimation, estimation of occupational exposure, and imputation of missing values in exposure indices derived from the kinetic model.

Localized proton magnetic resonance spectroscopy of the brain in children infected with human immunodeficiency virus with and without encephalopathy.

Twenty children older than 2 y infected with human immunodeficiency virus (HIV) were examined by in vivo proton magnetic resonance spectroscopy (1H MRS) to study their cerebral metabolism and to identify metabolic profiles in relation with different stages of the disease. Patients were rated regarding their clinical and immunologic status according to the Centers for Disease Control classification and were divided into two groups: without encephalopathy (E-, n = 15) and with progressive encephalopathy (E+, n = 5). The acquisition was performed in the centrum semiovale using the short echo stimulated echo acquisition mode 20-ms sequence. The MRS profile was abnormal in all HIV-infected children compared with healthy age-matched controls (n = 7), even when magnetic resonance images were normal. A significant increase of the proportion of the lipid signals (ANOVA, p < 0.05) was found in all HIV-infected children. In addition, a significant decrease of the proportion of the N-acetylaspartate signal and a significant increase of the proportion of the myo-inositol signal (ANOVA, p < 0.05) characterized the E+ group. The principal component analysis performed on eight variables on 30 spectra confirms that the spectra of HIV-infected children differ from control spectra. The E+ group and the E- group are clearly separated on the map of subjects on the principal plane. The E- group lies in an intermediate position between the E+ group and the control group. The evolution of metabolic alterations in the brain of HIV-infected children can clearly be monitored by 1H MRS and associated with the occurrence of an encephalopathy.

[Brain proton magnetic resonance spectroscopy. Indications for diagnosis and follow-up of HIV-related encephalopathy in the adult]. / Spectroscopie de résonance magnétique cérébrale du proton. Indications dans le diagnostic et le suivi de l'encéphalopathie liée au VIH chez l'adulte.

UNLABELLED: NONINVASIVE EXPLORATION: Proton localized magnetic resonance spectroscopy (MRS) is a noninvasive human neurochemistry method based on the magnetic resonance phenomenon. ADVANTAGES: This exploration of brain metabolism, performed without any injection, detects neuronal, glial, and membrane markers, and can be performed after an MRI examination without moving the patient. INDICATIONS: In vivo brain MRS plays a major role (i) in early diagnosis of HIV-related encephalopathy, (ii) in differential diagnosis of HIV-related encephalopathy versus psychiatric symptoms or occurring in AIDS patients, (iii) in differential diagnosis of HIV-related encephalopathy versus other brain lesions related to AIDS, and (iv) in the follow-up of patient response to therapy. In these indications, MRS is frequently more reliable than neuropsychologic testing and more sensitive than MRI.

Brain metabolic profiles obtained by proton MRS in two forms of mitochondriopathies: Leber's hereditary optic neuropathy and chronic progressive external ophthalmoplegia.

The status of brain metabolism has been evaluated using monovoxel short echo time (20 ms) 1H magnetic resonance spectroscopy in 6 patients with two forms of mitochondrial disorders without clinical cerebral involvement: 2 patients with Leber's hereditary optic neuropathy (LHON) and 4 patients with chronic progressive external ophthalmoplegia (CPEO). Patients with LHON displayed normal spectra. In all patients with CPEO, the brain metabolic profiles were abnormal, with no single uniform pattern. No typical cerebral metabolic profile was found even when these disorders were classified either by syndrome or by biochemical defect. No lactate signal was detected. The metabolic alterations observed in CPEO patients contrasted with the absence of clinical signs of encephalopathy. The absence of a typical metabolic profile reflects the large variability in the clinical expression of biochemical defects in mitochondriopathies, and the lack of convergence between genetic deletions, biochemical anomalies and clinical syndromes.

Metabolic and myoelectrical effects of acute hypoxaemia during isometric contraction of forearm muscles in humans: a combined 31P-magnetic resonance spectroscopy-surface electromyogram (MRS-SEMG) study.

1. Failure of muscle force during sustained fatiguing contraction is associated with myoelectrical and metabolic alterations. However, the inter-relationships between these two types of events remain unclear. The purpose of this study was to examine the effects of decreased oxygen availability during sustained contraction on myoelectrical and metabolic changes, thereby addressing the issue of fatigue. 2. 31P-Magnetic resonance spectra and surface electromyograms were simultaneously recorded in six subjects (three women and three men) performing isometric contraction of forearm flexor muscles sustained at 60% maximum value of force under aerobic or acute hypoxaemic conditions (inhalation of a gas mixture containing 12% O2). 3. The 5 min hypoxaemic rest preceding contraction did not affect the phosphocreatine level and pH value. Under both conditions of oxygen availability, the magnitude of metabolic changes remained similar and the duration of contraction was unaffected (similar workload). However, hypoxaemia significantly reduced the rate of changes in integrated surface electromyogram activity measured in the high-frequency band. Correlative analysis of magnetic resonance spectroscopy and surface electromyogram data shows that for a given surface electromyogram change, metabolic variations were always larger under hypoxaemic conditions. 4. These results suggest that hypoxaemia does not alter metabolic changes, i.e. decrease in pH and phosphocreatine during static contraction. The downward shift of the relationships between myoelectrical and metabolic changes under hypoxaemia points to the existence of a better excitation-contraction coupling in acute hypoxaemia compared with normoxia and this is indicative of an adaptative mechanism.

Estimation of occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin using a minimal physiologic toxicokinetic model.

In this study we investigated estimation of occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on a minimal physiologic toxicokinetic model in humans. Our purpose was to obtain a mathematical tool for dose-response studies based on human data. We first simplified an existing model of TCDD kinetics in humans and estimated its parameters (i.e., liver elimination and background input of TCDD) using repeated measures of serum dioxin taken in Vietnam veterans (Ranch Hand data and data from an unexposed reference group). We carried out computer simulation and estimation of the model parameters both under a nonlinear weighted least-squares model (naive pooled data approach) and under a nonlinear mixed-effects model. The best parameter estimates were obtained with log-transformed data under a mixed-effects model: liver elimination parameter kf = 0.022 days-1 (95% confidence interval [CI] = 0.020, 0.024), and background input rate input = 0.1251 pg/kg/day (95% CI = 0.071, 0.179). The dioxin kinetic model and its estimated parameters were then used to provide dose estimates for a cohort of workers with exposure to TCDD at chemical plants in the United States. First, the model was used to estimate the rate of occupational intake of TCDD in a subset of the cohort consisting of 253 subjects for whom one measure of serum TCDD was available. A model of change in body-mass index over time was also identified for this subsample. The occupational exposure rate was estimated by linear regression using the above values of kinetic parameters and assuming an initial condition for serum TCDD of 7 ppt, i.e., the average level found in unexposed workers. The estimate of the occupational exposure parameter was 232.7 pg/kg/day (95% CI 192, 273). This value can be applied to the full cohort to obtain for each cohort member the time course of serum dioxin concentration from which exposure indices can be derived. Sensitivity coefficients to model parameters (background input, kf, occupational exposure, and the assumed TCDD concentration at hire) allow for a convenient recalculation of the serum TCDD curve and of the derived exposure indices for different assumed values of the model parameters.

Work with video display terminals and the risk of reduced birthweight and preterm birth.

To determine whether the use of video display terminals (VDTs) is associated with an increased risk of reduced birthweight (RBW) and preterm birth, a cohort of telephone operators who used VDTs at work was compared to a cohort of non-VDT-users. Among 2,430 women interviewed, 713 eligible singleton live births were reported. Exposure was estimated from company records and a representative sample of electromagnetic fields was measured at the VDT workstations. For RBW (< or = 2,800 g), we found no excess risk associated with any VDT use during pregnancy (odds ratio [OR] = 0.9; 95% confidence interval [CI] = 0.5-1.7). For preterm birth (< or = 37 weeks), we similarly found no excess risk (OR = 0.7; 95% CI = 0.4-1.1). The risks estimated did not change substantially when hours working with VDTs were used as exposure variables. By contrast, increased risks were found for several known risk factors for LBW and preterm birth. We conclude that occupational VDT use does not increase the risk of RBW and preterm birth.