Modeling the impact of heat stress on the toxicokinetics of toluene and acetone.

Many workers can be exposed simultaneously to heat and volatile chemicals. In a controlled human exposure study, it was observed that an increase in ambient temperature was associated with increased blood concentrations for acetone and toluene. Based on the expected changes in physiological parameters that occur with an increase in ambient temperature, we aimed to develop a PBPK model for acetone and toluene that could account for the impact of temperature on the kinetics of these solvents. Changes in temperature-dependent physiological parameters (i.e. blood flows, cardiac output, alveolar ventilation) based on recent measurements in volunteers were introduced in the PBPK models to simulate observed blood concentrations for different temperature exposure conditions. Because initial simulations did not adequately predict solvent kinetics at any temperature, the most sensitive parameter (alveolar ventilation; Qp) was, therefore, optimized on experimental acetone blood concentrations to obtain a relationship with temperature. The new temperature-dependent Qp relationship gave Qp values consistent with the literature and estimated a mean increase of 19% at 30 °C (wet bulb globe temperature) compared to 21 °C. The integration of a new temperature-dependent Qp relationship in the PBPK toluene model yielded adequate simulations of the experimental data for toluene in blood, exhaled air and urine. With further validation with other solvents, the temperature-dependant PBPK model could be a useful tool to better assess the risks of simultaneous exposure to volatile chemicals and heat stress and interpret biomonitoring data in workers as well as in the general population. TRN: NCT02659410, Registration date: January 15, 2016.

Cardiopulmonary parameters and organ blood flows for workers expressed in terms of VO2 for use in physiologically based toxicokinetic modeling.

Minute ventilation rates (VE), alveolar ventilation rates (VA), cardiac outputs (Q), liver blood flow (LBF) and kidneys blood flows (KBF) for physiologically based toxicokinetic modeling and occupational health risk assessment in active workers have apparently not been determined. Minute energy expenditure rates (E) and oxygen consumption rates (VO2) in workers during exertions and their aggregate daytime activities are obtained by using open-circuit wearable devices for indirect calorimetry measurements and the doubly labeled water method respectively. Hundreds of E (in kcal/min) and VO2 (in L of O2/min) were previously reported for workers. The oxygen uptake factors of 0.2059 ± 0.0019 and 0.2057 ± 0.0018 L of O2/kcal during postprandial and fasting phases respectively enabled conversion of E into VO2. Equations determined in this study based upon more than 25 000 published measurements enable the calculation of 15 parameters in the same worker only by using the VO2 reflecting workload. These parameters, notably VE, VA, VE/VO2 VA/Q, Q, LBF and KBF were found to be interrelated. Altering one of these changes the order of magnitude of the others. Q, LBF and KBF decrease when supine adults at rest switch to an upright position. This effect of gravity diminished when VO2 increased. The fall in LBF and KBF during exertion might enhance muscle blood flow as reported previously. Taken together these equations and data may improve the accuracy of physiologically based toxicokinetic modeling as well as occupational health assessment studies in active workers exposed to xenobiotics.List of main abbreviations: AVOD: arterioveinous oxygen content difference.BMI: body mass index (in kg/m2).BSA: body surface area (in m2).BTPS: body temperature and saturated with water vapor.Bw: body weight (in kg).E: minute energy expenditure rate (in kcal/min).FGE: organ blood flow factor for the gravitational effect on blood circulation.H: oxygen uptake factor, volume of oxygen (at STPD) consumed to produce 1 kcal of energy expended.KBF: kidneys blood flow (in ml/min).LBF: liver blood flow (in ml/min).PBF: liver or kidneys blood flows expressed in terms of percentages (in %) of Qsup C values: namely PBF = (LBF or KBF/Qsup C) x 100.Q: cardiac output (in L/min or ml/min).Qsup C: cardiac output for the cohort of males or females in supination (in ml/min).STPD: standard temperature and pressure, dry air.sup: values measured when adults are in the supine position.up: values measured when adults are in the upright position.VDphys: physiological dead space at BTPS (in L).VT: tidal volume at BTPS (in L).VA: alveolar ventilation rate at BTPS (in L/min).VA/Q: ventilation-perfusion ratio (unitless).VE: minute ventilation rate at BTPS (in L/min).VO2: oxygen consumption rate (i.e. the oxygen uptake) at STPD (in L/min).VQ: ventilatory equivalent for VO2 (VE at BTPS /VO2 at STPD).

Survey Non-Response in COVID-19 Times: The Case of the Labour Force Survey.

During the COVID-19 pandemic, labour-force survey non-response rates have surged in many countries. We show that in the case of the Canadian Labour Force Survey (LFS), the bulk of this increase is due to the suspension of in-person interviews following the adoption of telework within Federal agencies, including Statistics Canada. Individuals with vulnerabilities to the COVID-19 economic shock have been harder to reach and have been gradually less and less represented in the LFS during the pandemic. We present evidence suggesting that the decline in employment and labour-force participation have been underestimated over the March-July 2020 period. We argue that these non-response issues are moderate when analyzing aggregate outcomes, but that researchers should exert caution when gauging the robustness of estimates for subgroups. We discuss practical implications for research based on the LFS, such as the consequences for panels and the choice of public-use versus master files of the LFS.

Pendant la pandémie de COVID-19, le taux de non-réponse aux enquêtes auprès de la population active a explosé dans beaucoup de pays. Nous montrons que dans le cas de l'Enquête canadienne sur la population active (EPA), le gros de cette hausse s'explique par la suspension des entrevues en personne qui a suivi l'adoption du télétravail dans les agences fédérales, y compris à Statistique Canada. Les personnes vulnérables au choc économique de la COVID-19 ont été plus difficiles à joindre et ont été de moins en moins représentées dans l'EPA au cours de la pandémie. Nous montrons, preuves à l'appui, que la diminution de l'emploi et de la participation à la main-d'œuvre est sous-estimée pour la période de mars à juillet 2020. Nous soutenons que la gravité de ces problèmes de non-réponses est modérée quand il s'agit d'analyser des résultats agrégés mais que la prudence s'impose dans l'évaluation de la robustesse des estimations pour les sous-groupes. Nous présentons les conséquences pratiques de cette situation pour les travaux qui reposent sur l'EPA, telles que les effets sur les panels et le choix entre données à grande diffusion et fichiers principaux de l'EPA.

Cardiopulmonary values and organ blood flows before and during heat stress: data in nine subjects at rest in the upright position.

Physiological changes associated with thermoregulation can influence the kinetics of chemicals in the human body such as alveolar ventilation (VA) and redistribution of blood flow to organs. In this study, the influence of heat stress on various physiological parameters was evaluated in nine male volunteers during sessions of exposure to wet-bulb globe temperatures (WBGT) of 21, 25, and 30 °C for 4 h. Skin and core temperatures and more than 20 cardiopulmonary parameters were measured. Liver, kidneys, brain, skin, and muscles blood flows were also determined based on published measurements. Results show that most subjects (eight out of nine) have been affected by the inhalation of hot and dry air at the WBGT of 30 °C. High respiratory rates, superficial tidal volumes, and low VA values were notably observed. The skin blood flow increased by 2.16-fold, whereas the renal blood flow and liver blood flow decreased by about by 11% and 18%, respectively. A complete set of key cardiopulmonary parameters in healthy male adults before and during heat stress was generated for use in physiologically based pharmacokinetic modeling. A toxicokinetic studies are ongoing to evaluate the impact of heat stress on the absorption, biotransformation and excretion rates of volatile xenobiotics.

Physiological daily inhalation rates for health risk assessment in overweight/obese children, adults, and elderly.

Physiological daily inhalation rates reported in our previous study for normal-weight subjects 2.6-96 years old were compared to inhalation data determined in free-living overweight/obese individuals (n = 661) aged 5-96 years. Inhalation rates were also calculated in normal-weight (n = 408), overweight (n = 225), and obese classes 1, 2, and 3 adults (n = 134) aged 20-96 years. These inhalation values were based on published indirect calorimetry measurements (n = 1,069) and disappearance rates of oral doses of water isotopes (i.e., (2)H2 O and H2 (18)O) monitored by gas isotope ratio mass spectrometry usually in urine samples for an aggregate period of over 16,000 days. Ventilatory equivalents for overweight/obese subjects at rest and during their aggregate daytime activities (28.99 ± 6.03 L to 34.82 ± 8.22 L of air inhaled/L of oxygen consumed; mean ± SD) were determined and used for calculations of inhalation rates. The interindividual variability factor calculated as the ratio of the highest 99th percentile to the lowest 1st percentile of daily inhalation rates is higher for absolute data expressed in m3 /day (26.7) compared to those of data in m3/kg-day (12.2) and m3/m2-day (5.9). Higher absolute rates generally found in overweight/obese individuals compared to their normal-weight counterparts suggest higher intakes of air pollutants (in µg/day) for the former compared to the latter during identical exposure concentrations and conditions. Highest absolute mean (24.57 m3/day) and 99th percentile (55.55 m3 /day) values were found in obese class 2 adults. They inhale on average 8.21 m3 more air per day than normal-weight adults.

Derivation of cardiac output and alveolar ventilation rate based on energy expenditure measurements in healthy males and females.

Physiologically based pharmacokinetic modeling and occupational exposure assessment studies often use minute ventilation rates (VE), alveolar ventilation rates (VA) and cardiac outputs (Q) that are not reflective of the physiological variations encountered during the aggregate daytime activities of individuals from childhood to adulthood. These variations of VE, VA and Q values were determined for healthy normal-weight individuals aged 5-96 years by using two types of published individual data that were measured in the same subjects (n = 902), namely indirect calorimetry measurements and the disappearance rates of oral doses of deuterium (²H) and heavy-oxygen (¹8O) in urine monitored by gas-isotope-ratio mass spectrometry. Arteriovenous oxygen content differences (0.051-0.082 ml of O2 consumed ml⁻¹ of blood) and ratios of the physiological dead space to the tidal volume (0.232-0.419) were determined for oxygen consumption rates (0.157-0.806 l min⁻¹) required by minute energy expenditures ranging from 0.76 to 3.91 kcal min⁻¹. Generally higher values for the 2.5th up to the 99th percentile for VE (0.132-0.774 l kg⁻¹ min⁻¹, 4.42-21.69 l m⁻² min⁻¹), VA (0.093-0.553 l kg⁻¹ min⁻¹, 3.09-15.53 l m⁻² min⁻¹), Q (0.065-0.330 l kg⁻¹ min⁻¹, 2.17 to 9.46 l m⁻² min⁻¹) and ventilation-perfusion ratios (1.12-2.16) were found in children and teenagers aged 5-<16.5 years compared with older individuals. The distributions of cardiopulmonary parameters developed in this study should be useful in facilitating a scientifically sound characterization of the inter-individual differences in the uptake and health risks of lipophilic air pollutants, particularly as they relate to younger children.

Correlation of intercentromeric distance, mosaicism, and sexual phenotype: molecular localization of breakpoints in isodicentric Y chromosomes.

Isodicentric chromosomes are among the structural abnormalities of the Y chromosome that are commonly identified in patients. The simultaneous 45,X cell line that is generated in cell division due to instability of the isodicentric Y chromosome [idic(Y)] has long been hypothesized to explain the variable sexual development of these patients, although gonads have been studied in only a subset of cases. We report here on the molecular localization of breakpoints in ten patients with an idic(Y). Breakpoints were mapped by FISH using BACs; gonads and fibroblasts were also analyzed when possible to evaluate the level of mosaicism. First, we demonstrate great tissue variability in the distribution of idic(Y). Second, palindromes and direct repeats were near the breakpoint of several idic(Y), suggesting that these sequences play a role in the formation of idic(Y). Finally, our data suggest that intercentromeric distance has a negative influence on the stability of idic(Y), as a greater proportion of cells with breakage or loss of the idic(Y) were found in idic(Y) with a greater intercentromeric distance. Females had a significantly greater intercentromeric distance on their idic(Y) than did males. In conclusion, our study indicates that the Y chromosome contains sequences that are more prone to formation of isodicentric chromosomes. We also demonstrate that patients with an intercentromeric distance greater than 20 Mb on their idic(Y) are at increased risk of having a female sexual phenotype.

Derivation of physiological inhalation rates in children, adults, and elderly based on nighttime and daytime respiratory parameters.

The methodology developed in our previous studies ( Brochu et al. 2006a-c ) for the determination of physiological daily inhalation rates was improved by integrating into the calculation process, both nighttime and daytime respiratory parameters, namely oxygen uptake factors (H) and ventilatory equivalents (VQ). H values during fasting (0.2057±0.0018 L of O2/kcal; mean±SD) and postprandial phases (0.2059±0.0019 L of O2/kcal) as well as VQ values for subjects at rest (27.4±4.8 to 32.2±3.1, unitless) and during the aggregate daytime activities (29.9±4.2 to 33.7±7.2) were determined and combined with published doubly labeled water measurements for the calculation of daily inhalation rates in normal-weight males and females aged 0.22-96 years (n=1235). Depending upon the unit value chosen, the highest 99th percentiles for inhalation data were found in males aged 35 to <45 years (35.40 m3/day), 2.6 to <6 months (1.138 m3/kg-day), and 10 to <16.5 years (22.29 m3/m2-day). Means and percentiles expressed in m3/kg-day as well as in m3/m2-day suggest generally higher intakes of air pollutants in children than in adults and in males than in females (in g/kg-day or g/m2-day) for identical exposure concentrations and conditions. For instance, means in boys aged 2.6 to <6 months of 10.99±3.50 m3/m2-day and 0.572±0.191 m3/kg-day are 1.3- and 2.5-folds higher, respectively, than those in adult males 65?96 years old (8.42±2.13 m3/m2-day, 0.225±0.059 m3/kg-day).

Impact of heat on biological concentrations of toluene and acetone resulting from exposure by inhalation: A pilot study.

Climatic conditions raise new concerns about the potential impact of heat on the absorption and kinetics of certain chemicals. The impact of 3 temperatures (21, 25 and 30 °C WBGT) on the toxicokinetics of toluene and acetone was therefore evaluated in five human subjects during controlled exposures in an inhalation chamber. Biological samples were collected and analyzed by GC-MS/MS. Increases between 4 and 85 % were observed for solvents concentrations in blood (30 vs 21 °C) while decreases in urine samples for acetone and o-cresol were measured at the end of the exposure period (4 h). Mean blood concentrations at 4 h are well correlated with temperature. Results suggest an increased absorption and/or a decreased elimination of volatile chemicals in the presence of heat. Higher increases of blood chemical concentrations were observed in heavier individuals. Further studies should include physiologically based toxicokinetic models to help in better understanding the mechanisms involved and their respective contribution.

Chylomicron retention disease: a long term study of two cohorts.

Lipoprotein assembly is critical for the intestinal absorption of dietary lipids and of fat-soluble vitamins. Through their inhibition of chylomicron secretion, mutations of the Sar1B gene coding for Sar1 GTPase are associated with chylomicron retention disease (CRD). The aim of this study was to describe the phenotypic expression of CRD in two clinically and genetically well characterized cohorts, and to compare their long term evolution. The study in 7 children from France (X age 11.3+/-1.7 years) and 9 from Quebec, Canada (X age 12+/-2.5 years) involved data collection from medical records for growth evaluation, neurological and ophthalmological status as well as bone density over an average follow-up period of 4.9 years for the French cohort and of 10.6 years for the Canadian one. All CRD patients presented within the first few months of life with diarrhea and failure to thrive. Severe hypocholesterolemia coupled with normal triglycerides was associated with low LDL and HDL-cholesterol, as well as with low apolipoproteins A-I and B. Varying degrees of essential fatty acid and of vitamin E deficiency were observed. The earlier diagnosis in the Canadian cohort (1.3+/-0.04 years) than in the French one (6.3+/-1.3 years) was unrelated with the severity of presenting symptoms. The fact that the disease had more impact on growth and bone density in the latter group may be related to delayed diagnosis of the disease. Vitamin E deficiency led to functional neurological and ophthalmic changes in a small number of patients but only one developed areflexia. Finally, genotype-phenotype correlation is not obvious in our cohort with CRD; even if, the Canadian subjects with the allele 409G>A had a more severe degree (P<0.001) of hypocholesterolemia than the other patients, many clinical data are inconsistent with a hypothetical genotype-phenotype correlation. This study provides new insights on the phenotypic expression of CRD over time and emphasizes the need to screen the lipid profile of infants with chronic diarrhea and failure to thrive.

Hepatocyte transplantation in the Long Evans Cinnamon rat model of Wilson's disease.

Wilson's disease (WD), caused by a mutation in the P-type copper transporting ATPase (Atp7b) gene, results in excessive accumulation of copper in the liver. Long Evans Cinnamon rats (LEC) bear a mutation in the atp7b gene and share clinical characteristics of human WD. To explore hepatocyte transplantation (HT) as therapy for metabolic liver diseases, 8-week-old LEC rats (n = 12) were transplanted by intrasplenic injection of hepatocytes from donor Long Evans (LE) rats. Immunosuppression was maintained with intraperitoneal tacrolimus. The success of HT was monitored at 24 weeks of life. Serum aminotransferases and bilirubin peaked at 14-21 weeks in both HT rats and nontransplanted controls, but at 24 weeks, survival was 97% in LEC-HT versus 63% in controls. All transplanted rats showed restored biliary copper excretion and reduced liver iron concentration associated with increased ceruloplasmin oxidase activity. Liver tissue expressed atp7b mRNA (11.9 +/- 13.6%) indicative of engraftment of normal cells in 7 of 12 HT rats, associated with a reduced liver copper concentration compared to untreated LEC rats. Periportal islets of normal appearing hepatocytes, recognized by atp7b antibody, were observed in transplanted livers while lobular host cells showed persistent pleomorphic changes and inflammatory infiltrates. In conclusion, transplantation of normal hepatocytes prevented fulminant hepatitis, reduces chronic inflammation, and improved 6-month survival in LEC rats. Engraftment of transplanted cells, which express atp7b mRNA, repopulated the recipient liver with normal functional capacity.

Rapidly progressive aortic aneurysmal dilation in a child with systemic lupus erythematosus: too early too severe.

About 10-20% of systemic lupus erythematosus cases occur in children, often with more severe features at onset and more active disease over time compared with adults. Cardiovascular complications are common in this population but thoracic aortic aneurysms rarely occur. Although the pathophysiology of this complication remains unclear, vasculitis seems to play an important role, leading to degeneration and fibrosis of the media and formation of the aneurysm. We report the case of a 9-year-old systemic lupus erythematosus patient with important renal involvement, who underwent aortic replacement surgery for the treatment of an aortic aneurysm. This case highlights the importance of monitoring the thoracic aorta in children with systemic lupus erythematosus and the need for the development of appropriate early management strategies for this serious complication.

Undifferentiated gonadal tissue, Y chromosome instability, and tumors in XY gonadal dysgenesis.

Patients with XY gonadal dysgenesis are at increased risk of developing gonadal tumors. The etiology of several cases of XY gonadal dysgenesis remains unknown, but X/XY gonadal mosaicism has been hypothesized to play a role. At the histologic level, the presence of persistent primitive sex cords containing immature germ cells in dysgenetic gonads (an entity called undifferentiated gonadal tissue, or UGT) was recently described, and these immature germ cells are thought to be at risk of neoplastic transformation. To further investigate both these aspects, we retrospectively studied the gonads from 30 patients with pure (22) and mixed (8) gonadal dysgenesis. Cytogenetic analyses performed on 35 gonads revealed that structurally abnormal Y chromosomes were lost in a majority of cells from the gonads, explaining the gonadal dysgenesis of patients bearing a rearranged Y chromosome. On the other hand, normal Y chromosomes were less often lost in gonads of patients with gonadal dysgenesis. At the histologic level, 43 of the 51 gonads presented areas characteristic of a streak; 13 of these streak gonads also presented areas of UGT. Structures resembling sex cords but without germ cells were found in many of the streaks not containing UGT, suggesting that UGT was initially present. Of the 13 gonads containing both UGT and a streak, 9 developed a tumor. The proximity of UGT with the tumors as well as the immunostaining patterns (PLAP+, OCT3/4+, and CD117/KIT+) suggests that germ cells found in UGT are a risk factor for gonadal tumors.

Coexistence of a choriocarcinoma and a gonadoblastoma in the gonad of a 46,XY female: a single nucleotide polymorphism array analysis.

Females with 46,XY complete gonadal dysgenesis are at significant risk of developing germ cell tumors, mostly gonadoblastomas. We present here the case of 2 half-sisters, sharing the same father, diagnosed with 46,XY complete gonadal dysgenesis. The 1st sister developed a gonadoblastoma and an invasive dysgerminoma, whereas the 2nd sister developed a gonadoblastoma and an invasive choriocarcinoma within the same gonad. No SRY mutation, chromosome abnormalities, or mosaicism were detected in blood. Single nucleotide polymorphism (SNP) profiling of the choriocarcinoma revealed a complex hyperdiploid pattern with gains of 1 to 4 copies of material from several autosomes, as well as the loss of the Y chromosome and a homozygous SNP profile without copy number change for the X chromosome. Our results are in agreement with the recurrent chromosome gains and losses previously published in germ cell tumors, and the coexistence of both tumors within the same gonad suggests that choriocarcinomas may derive from gonadoblastomas.

Abnormal intracellular lipid processing contributes to fat malabsorption in cystic fibrosis patients.

A common feature of cystic fibrosis (CF) is the functional derangement of the exocrine pancreas, which affects output of pancreatic lipase. This condition results in severe dietary malabsorption due to the poor hydrolysis of triacylglycerol (TG) in the lumen of the small intestine. Despite the benefits of pancreatic enzyme supplements, patients with CF present with persistent intestinal fat malabsorption. The aim of the present investigation was to determine whether defects in the intracellular phase of lipid transport occur in this pathophysiology in addition to the known disturbed digestive processes. Our hypothesis was tested by incubating intestinal biopsies from six CF and six healthy subjects with radiolabeled lipid and protein precursors. Lipid esterification and secretion were markedly decreased by 22-31% and 38-42%, respectively, in CF samples, as noted by the low incorporation of [(14)C]palmitic acid into TGs, phospholipids, and cholesteryl esters in patients' duodenal explants and culture media compared with controls (100%). Accordingly, the output of TG-rich lipoproteins was substantially reduced (P < 0.05), and a similar trend was observed for high-density lipoproteins. Because intestinal lipoprotein assembly/secretion shows an absolute requirement for apolipoprotein (apo) B-48, radioactive labeling experiments were performed; these experiments demonstrated a significantly (P < 0.05) diminished synthesis of apoB-48 (40%) and apoA-I (30%). Given the critical role of microsomal triglyceride transfer protein in the formation of apoB-containing lipoproteins, its activity was determined and not found to be altered in CF intestinal tissue. Together, these results suggest that CF malabsorption may also be caused by defects in mucosal mechanisms leading to abnormal lipoprotein delivery into the blood circulation.