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Cadmium (Cd), lead (Pb) and mercury (Hg) are known nephrotoxicants that have been associated with the risk of developing type-2 diabetes (T2D). The aim of this pilot study was to explore relations between biomarkers of Cd, Pb and Hg exposure, early urinary biomarkers of renal dysfunction (kidney-injured molecule-1 (KIM-1), N-acetylglucosaminidase and retinol-binding protein (RBP)) and plasma biomarkers deemed predictive of the risk of developing T2D (adiponectin, leptin, branched-chain and aromatic amino acids), among 70 participants (age range: (46-87 yrs)) from the Canadian Longitudinal Study on Aging (CLSA) with normal glycemic control (glycated haemoglobin ≤ 6.5%) in all but four of them. Significant (p 0.05) Spearman correlation coefficients were obtained between: plasma adiponectin and RBP (r = 0.42), urinary Cd (r = 0.32), blood Cd (r = 0.36); KIM-1 and CdU (r = 0.33) as well as HgU (r = 0.37); RBP and isoleucine (r = -0.28), leucine (r = -0.33), tyrosine (r = -0.3) and valine (r = -0.44); CdU and isoleucine and valine (r = -0.27 for both). Multiple linear regression analyses showed that some T2D-related biomarkers are confounders of associations between RBP and Hg or Cd biomarkers. Path analyses support a mediating effect of adiponectin on the relation between urinary Cd and RBP. Concluding, this pilot study originally investigated a comprehensive set of biomarkers on complex interactions between toxic metal exposure, renal function and T2D in a group of aging Canadians. Its findings warrant further investigation of longitudinal data in a greater number of participants.

Pesticide residues in food is a public health concern. This study aimed to evaluate health risk and benefit associated with chronic consumption of fruits and vegetables (F&V) containing residual pesticides in the province of Quebec, Canada. Based on a representative sample of Quebecers (n=4727, aged 1–79) enrolled in the Canadian nutrition survey, population's mean chronic dietary exposure through consumption of F&V was evaluated for 169 different pesticide active ingredients (PAI), including 135 for which toxicological reference values (TRV) were available in the literature. Total lifetime cancer risk was estimated to be 3.3×10−4 considering the 28 substances for which an oral slope factor was also available. Non-cancer risk quotients greater than 1 were obtained at the 95th percentile of children's exposure for 10 of the 135 PAIs, and considering the most severe pesticide-specific TRV. Dithiocarbamates and imazalil are the authorized PAI that contribute the most to cancer and non cancer risk; they are therefore identified as “priority” PAI. For each estimated case of cancer triggered by PAI exposure, at least 88 cases were deemed prevented by the consumed F&V, based on the population's etiological fraction of the cancer risk that F&V prevent. Concluding, chronic health risks investigated are low and health benefits of F&V consumption by far outweigh the PAI-related risk. However, risk estimates are not negligeable and uncertainties remain. Thus, reducing PAI exposure through F&V consumption with a particular focus on “priority” PAI mentionned above, while maintaining an abundant and varied F&V diet, is desirable. Keywords: Fruits, Risk assessment, Pesticide, Prioritization, Risk/benefits balance, Vegetables

Drinking water intake of arsenic (As) from private wells may represent a significant exposure pathway and induce oxidative DNA damage. We measured total As concentrations in hair and nails, and concentrations of the different species of As and its metabolites as well as 8-OHdG in urine of 110 non-smoking adults living in a rural region of the Province of Quebec, Canada. Significant differences in exposure biomarker levels were observed between individuals consuming drinking water with As levels of≤1.0,1.0 -≤10 and10 μg/l. Multivariate linear regression analysis also showed a significant relationship between estimated daily drinking water intakes of As and biomarker levels. Conversely, 8-OHdG levels were not significantly related to daily drinking water intakes of As or to hair, nail or urinary exposure biomarker levels, according to multivariate linear regression analysis. Even at the relatively low levels of As found in well water of our participants, water consumption significantly increases their body load of As, as confirmed by multiple matrix measurements, which reflected exposure over different time frames. However, this increased internal As dose was not associated with higher oxidative damage to DNA as reflected by urinary 8-OHdG levels.

Chronic exposure to inorganic arsenic leads to an increased risk of cancer. A biological measurement was conducted in 153 private well owners and their families consuming water contaminated by inorganic arsenic at concentrations that straddle 10 μg/L. The relationship between the external dose indicators (concentration of inorganic arsenic in wells and daily well water inorganic arsenic intake) and the internal doses (urinary arsenic--sum of As(III), DMA, and MMA, adjusted for creatinine--and total arsenic in toenails) was evaluated using multiple linear regressions, controlling for age, gender, dietary sources of arsenic, and number of cigarettes smoked. It showed that urinary arsenic was associated with concentration of inorganic arsenic in wells (p.001) and daily well water inorganic arsenic intake (p.001) in adults, and with daily well water inorganic arsenic intake (p = .017) and rice consumption (p = .022) in children (n = 43). The authors' study reinforces the drinking-water quality guidelines for inorganic arsenic.

A longitudinal biomonitoring study was conducted to assess exposure to polycyclic aromatic hydrocarbons (PAH) in non-occupationally exposed nonsmoking adults living in the vicinity of an aluminum plant. Metabolites of several PAH (pyrene, naphthalene, chrysene, fluoranthene, benz[a]anthracene) were measured in the urine of the participants, including 1-hydroxypyrene (1-OHP) as a validated biomarker and pyrene diones as novel biomarkers. In total, 73 individuals living about 1 km away from the plant (taken as the exposed group) were compared repeatedly with 71 individuals living at least 11 km from the smelter (used as the control group). Complete first morning voids were collected twice, at a 2-wk interval, in the fall of 2005 and twice weekly for 2 consecutive weeks in the spring of 2006. Urinary biomarker concentrations were then measured by an ultra-performance liquid chromatography (UPLC) method with time-of-flight mass spectrometry detection (MS-TOF) (UPLC-MS-TOF). For most sampling days, individuals living near the plant showed significantly higher excretion values of both 1-OHP and pyrene diones (mean ratio up to 2- and 2.4-fold, respectively) than individuals living further from the plant. In the group living near the plant, geometric mean concentrations of 1-OHP varied from 0.047 to 0.058 micromol/mol creatinine, depending on the sampling day, as compared to 0.025 to 0.04 micromol/mol creatinine in the reference group. Corresponding mean values for pyrene diones were 0.017-0.056 micromol/mol creatinine and 0.014-0.039 micromol/mol creatinine, respectively. Urinary 1- and 2-naphthols were also measured as a reference and showed no significant differences between the two groups for most sampling days; metabolite concentrations of the other monitored PAH (chrysene, fluoranthene, benz[a]anthracene) were mostly below the analytical limit of detection of 0.005 to 0.01 microg/L, depending on the metabolite, with a detection rate varying from 0 to at most 21%. Individuals living near the aluminum plant thus appeared to be repeatedly exposed to higher pyrene levels than the control group, on the basis of both 1-OHP and pyrene dione excretions. However, 1-OHP concentrations observed in this first group were similar to those of other reference populations of nonsmokers studied in the past. Uptake of the other PAH associated with plant emissions was too small to significantly increase the excretion of their metabolites.

In Canada, Methylcyclopentadienyl manganese tricarbonyl (MMT) replaced tetraethyl lead in gasoline as an antiknock agent from 1976 until 2003. The combustion of MMT leads to increased manganese (Mn) concentrations in the atmosphere, and represents one of the main sources of human exposure to Mn. The nervous system is the major target of the toxicity of Mn and Mn compounds. The purpose of this study was to investigate exposure-response relationships for neuropathology and tremor, and the associated electromyogram (EMG), following subchronic inhalation exposure of rats to a mixture of Mn phosphate/sulfate particles. Rats were exposed 6 h per day, 5 days per week for 13 consecutive weeks at 30, 300 or 3000 microg m(-3) Mn phosphate/sulfate mixture and compared with controls. Half of the rats had EMG electrodes implanted in the gastrocnemius muscle of the hind limb to assess tremor at the end of Mn exposure. Two days after the end of Mn exposure, rats were killed by exsanguination and Mn concentrations in the brain (caudate putamen, globus pallidus and frontal cortex) were determined by neutron activation analysis while neuropathology was assessed by counting neuronal cells in 2.5 mm x 2.5 mm grid areas. Increased Mn concentrations were observed in all brain sections at the highest level of exposure. The neuronal cell loss was significantly different in the globus pallidus and the caudate putamen at the highest level of exposure (3000 microg m(-3)). No sign of tremor was observed among the rats. In conclusion, exposure to a high level of Mn phosphate/sulfate mixture brought on neuropathological changes in a specific area of the brain; however, no sign of tremor was observed.

The central nervous system is an important target for manganese (Mn) intoxication in humans; it may cause neurological symptoms similar to Parkinson's disease. Manganese compounds emitted from the tailpipe of vehicles using methylcyclopentadienyl manganese tricarbonyl (MMT) are primarily Mn phosphate, Mn sulfate, and Mn phosphate/sulfate mixture. The purpose of this study is to compare the patterns of Mn distribution in various brain regions (olfactory bulb, frontal parietal cortex, globus pallidus, striatum and cerebellum) and other tissues (lung, liver, kidney, testis) and the neurobehavioral damage following inhalation exposure of rats to three Mn species. Rats (n=15 rats per Mn species) were exposed 6 h per day, 5 days per week for 13 consecutive weeks to metallic Mn, Mn phosphate or Mn phosphate/sulfate mixture at about 3000 microgm(-3) and compared to controls. At the end of the exposure period, spontaneous motor activity was measured for 36 h using a computerized autotrack system. Mn in tissues was determined by instrumental neutron activation analysis (INAA). The Mn concentrations in the brain were significantly higher in rats exposed to Mn phosphate and Mn phosphate/sulfate mixture than in control rats or rats exposed to metallic Mn. Exposure to Mn phosphate/sulfate mixture caused a decrease in the total ambulatory count related to locomotor activity. Our results confirm that Mn species and solubility have an influence on the brain distribution of Mn in rats.

Methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese (Mn) compound added to unleaded gasoline in Canada. The primary combustion products of MMT are Mn phosphate, Mn sulfate, and a Mn phosphate/Mn sulfate mixture. Concerns have been raised that the combustion products of MMT containing Mn could be neurotoxic, even at low levels of exposure. The objective of this study is to investigate exposure-response relationships for bioaccumulation and locomotor effects following subchronic inhalation exposure to a mixture of manganese phosphates/sulfate mixture. A control group and three groups of 30 male Sprague-Dawley rats were exposed in inhalation chambers for a period of 13 weeks, 5 days per week, 6 h a day. Exposure concentrations were 3000, 300, and 30 microg/m(3). At the end of the exposure period, locomotor activity and resting time tests were conducted for 36 h using a computerized autotrack system. Rats were then euthanized by exsanguination and Mn concentrations in different tissues (liver, lung, testis, and kidney) and blood and brain (caudate putamen, globus pallidus, olfactory bulb, frontal cortex, and cerebellum) were determined by neutron activation analysis. Increased manganese concentrations were observed in blood, kidney, lung, testis, and in all brain sections in the highest exposure group. Mn in the lung and in the olfactory bulb were dose dependent. Our data indicate that the olfactory bulb accumulated more Mn than other brain regions following inhalation exposure. Locomotor activity was increased at 3000 microg/m(3), but no difference was observed in resting time among the exposed groups. At the end of the experiment, rats exposed to 300 and 3000 microg/m(3) exhibited significantly decreased body weight in comparison with the control group. Biochemical profiles also revealed some significant differences in certain parameters, specifically alkaline phospatase, urea, and chlorate.

The use of the additive methylcyclopentadienyl manganese tricarbonyl in unleaded gasoline has resulted in increased attention to the potential toxic effects of manganese (Mn). Hypothetically, people with chronic liver disease may be more sensitive to the adverse neurotoxic effects of Mn. In this work, bioaccumulation of Mn, as well as histopathology and neurobehavioral damage, in end-to-side portacaval anastomosis (PCA) rats exposed to Mn phosphate via inhalation was investigated. During the week before the PCA operation, 4 wk after the PCA operation, and at the end of exposure, the rats were subjected to a locomotor evaluation (day-night activities) using a computerized autotrack system. Then a group of 6 PCA rats (EXP) was exposed to 3050 microg m(-3) (Mn phosphate) for 8 h/day, 5 days/wk for 4 consecutive weeks and compared to a control group (CON), 7 PCA rats exposed to 0.03 microg m(-3). After exposure, the rats were euthanized and Mn content in tissues and organs was determined by neutron activation analysis. The manganese concentrations in blood (0.05 microg/g vs. 0.02 microg/g), lung (1.32 microg/g vs. 0.24 microg/g), cerebellum (0.85 microg/g vs. 0.64 microg/g), frontal cortex (0.87 microg/g vs. 0.61 microg/g), and globus pallidus (3.56 microg/g vs. 1.33 microg/g) were significantly higher in the exposed group compared to the control group (p.05). No difference was observed in liver, kidney, testes, and caudate putamen between the two groups. Neuronal cell loss was assessed by neuronal cell counts. The loss of cells in globus pallidus and caudate putamen as well as in frontal cortex was significantly higher (p.05) for the EXP group. Assessment of the locomotor activities did not reveal any significant difference. This study constitutes a first step toward our understanding of the potential adverse effects of Mn in sensitive populations.

The primary goal of this study is to determine the effects of Mn exposure via inhalation. The bioaccumulation of Mn in different organs and tissues, the alteration of biochemical parameters, and the locomotor activity were assessed. A group of 26 male Sprague-Dawley rats (E) were exposed to 3750 microg/m(3) of Mn dust for 6 h/day, 5 days/wk for 13 consecutive weeks and compared to a control group of 12 rats (C) exposed to 4 microg/m(3). After exposure, neurological evaluation was carried out for 36 h (a night-day-night cycle) using a computerized autotrack system. Rats were then sacrificed by exsanguination, and Mn content in organs and tissues was determined by neutron activation analysis. Mn concentrations in lung, putamen, and cerebellum were significantly higher in E than in C (0.30 vs. 0.17, 0.89 vs. 0.44, 0.63 vs. 0.48 ppm; p.01), as well as in the kidney, frontal cortex, and globus pallidus (1.15 vs. 0.96, 0.84 vs. 0.47, 1.28 vs. 0.55 ppm; p.05). Potassium concentration was significantly lower in E than in C (5.11 vs. 5.79 mmol/L; p.05), as was alkaline phosphatase (106.9 vs. 129.6 U/L; p.01). Locomotor activity indicated higher distance covered in the first 12-h period for E (45 383 vs. 36 098 cm; p.05) and lower resting time in the last 12-h period for E (36 326 vs. 37 393 s; p.05). This study is the first of several ongoing studies in our laboratory that address health concerns associated with inhalation exposure to different Mn species and to different levels of exposure.

Background & Aims: Manganese (Mn) deposition could be responsible for the T 1 -weighted magnetic resonance signal hyperintensities observed in cirrhotic patients. These experiments were designed to assess the regional specificity of the Mn increases as well as their relationship to portal-systemic shunting or hepatobiliary dysfunction. Methods: Mn concentrations were measured in (1) brain samples from basal ganglia structures (pallidum, putamen, caudate nucleus) and cerebral cortical structures (frontal, occipital cortex) obtained at autopsy from 12 cirrhotic patients who died in hepatic coma and from 12 matched controls; and from (2) brain samples (caudate/putamen, globus pallidus, frontal cortex) from groups (n = 8) of rats either with end-to-side portacaval anastomosis, with biliary cirrhosis, or with fulminant hepatic failure as well as from sham-operated and normal rats. Results: Mn content was significantly increased in frontal cortex (by 38%), occipital cortex (by 55%), pallidum (by 186%), putamen (by 66%), and caudate (by 54%) of cirrhotic patients compared with controls. Brain Mn content did not correlate with patient age, etiology of cirrhosis, or history of chronic hepatic encephalopathy. In cirrhotic and portacaval-shunted rats, Mn content was increased in pallidum (by 27% and 57%, respectively) and in caudate/putamen (by 57% and 67%, respectively) compared with control groups. Mn concentration in pallidum was significantly higher in portacaval-shunted rats than in cirrhotic rats. No significant changes in brain Mn concentrations were observed in rats with acute liver failure. Conclusions: These findings suggest that brain Mn deposition results both from portal-systemic shunting and from liver dysfunction. GASTROENTEROLOGY 1999;117:640-644

The distribution of acrylamide in food items frequently consumed by Canadian adolescents was determined along with estimates of their contribution to the overall dietary intake of acrylamide. A total of 196 non-smoking adolescents (10-17 years old) were recruited in Montreal Island population, Canada. Participants were invited to fill out a 2-day food diary and a food frequency questionnaire over the last month. 146 samples of foods most frequently consumed by participants were analyzed for acrylamide contents. The highest acrylamide contents were measured in deep-fried french fries and potato chips (mean ± SD: 1053 ± 657 and 524 ± 276 ng/g respectively). On the basis of the 2-day food diary, median total daily intake of acrylamide was estimated at 0.29 μg/kg bw/d, as compared to 0.17 μg/kg bw/d on the basis of the food frequency questionnaire. These values are similar to those reported in comparable populations. Deep-fried french fries consumption contributed the most to daily acrylamide intake (50%) followed by potato chips (10%), oven-baked french fries (8%) and breakfast cereals (8%). Margins of exposure based on genotoxic benchmark dose limits were estimated to be low (≈

Exposure to manganese in an industrial or clinical setting can lead to manganism, a neurological disorder with similarities to Parkinson's disease. Although the pathogenetic basis of this disorder is unclear, studies indicate this metal is highly accumulated in astrocytes, suggesting an involvement of these glial cells. To investigate this issue, we have used a recently characterized, sub-acute model of manganese neurotoxicity. Treatment of rats with manganese (II) chloride (50 mg/kg body weight, i.p.) once daily for 1 or 4 days led to increases in manganese levels of up to 232, 523, and 427% in the cerebral cortex, globus pallidus, and cerebellum, respectively, by instrumental neutron activation analysis. These changes were accompanied by development of pathological changes in glial morphology identified as Alzheimer type II astrocytosis in both cortical and sub-cortical structures. Co-treatment with either the antioxidant N-acetylcysteine or the manganese chelator 1,2-cyclohexylenedinitrilotetraacetic acid completely blocked this pathology, indicating the cellular transformation may be mediated by oxidative stress associated with the presence of this metal. These findings represent, to our knowledge, the first report of early induction of this pathological hallmark of manganese neurotoxicity, an event previously considered a consequence of chronic exposure to manganese in primates and in human cases of manganism. Our results also indicate that use of this rodent model may provide a novel opportunity to examine the nature and role of the Alzheimer type II astrocyte in the pathophysiology of this disorder as well as in other disease processes in which cerebral accumulation of manganese occurs.

Manganese neurotoxicity (MN) is a neurological disorder characterized by selective neuronal loss in the globus pallidus together with characteristic morphological changes known as Alzheimer type II astrocytosis. In order to understand the underlying mechanisms responsible for these processes, we studied early effects of this metal in a sub-acute rat model. Levels of manganese in the globus pallidus were increased by 81% after 1 day of treatment and elevated by 551% compared to controls after 4 days. In addition, manganese treatment led to a 60% increase in ptbr expression, and a 105% increase in levels of its product, the isoquinoline-carboxamide binding protein, a major constituent of the ‘peripheral-type’ benzodiazepine receptor (PTBR) that is localized to astrocytes, in this brain region after 4 days. These results indicate that PTBRs, and possibly neurosteroids, are an early response to manganese exposure and may play a major role in the pathophysiology of MN.