Estimation of toluene exposure in air from BMA (S-benzylmercapturic acid) urinary measures using a reverse dosimetry approach based on physiologically pharmacokinetic modeling.

This study aimed to use a reverse dosimetry PBPK modeling approach to estimate toluene atmospheric exposure from urinary measurements of S-benzylmercapturic acid (BMA) in a small group of individuals and to evaluate the uncertainty associated to urinary spot-sampling compared to 24-h collected urine samples. Each exposure assessment technique was developed namely to estimate toluene air exposure from BMA measurements in 24-h urine samples (24-h-BMA) and from distributions of daily urinary BMA spot measurements (DUBSM). Model physiological parameters were described based upon age, weight, size and sex. Monte Carlo simulations with the PBPK model allowed converting DUBSM distribution (and 24-h-BMA) into toluene air levels. For the approach relying on DUBSM distribution, the ratio between the 95% probability of predicted toluene concentration and its 50% probability in each individual varied between 1.2 and 1.4, while that based on 24-h-BMA varied between 1.0 and 1.1. This suggests more variability in estimated exposure from spot measurements. Thus, estimating toluene exposure based on DUBSM distribution generated about 20% more uncertainty. Toluene levels estimated (0.0078-0.0138 ppm) are well below Health Canada's maximum chronic air guidelines. PBPK modeling and reverse dosimetry may be combined to interpret urinary metabolites data of VOCs and assess related uncertainties.

An assessment of the impact of multi-route co-exposures on human variability in toxicokinetics: A case study with binary and quaternary mixtures of volatile drinking water contaminants.

This study aimed to assess the impact of multi-route co-exposures to chemicals on interindividual variability in toxicokinetics. Probabilistic physiologically based pharmacokinetic multi-route interaction models were developed for adults and four younger subpopulations. Drinking water-mediated multi-route exposures were simulated for benzene alone or in co-exposure with toluene, ethylbenzene and m-xylene, for trichloroethylene or vinyl chloride (VC), alone and in mixture. These simulations were performed for "low" and "high" exposure scenarios, involving respectively the US EPA's short-term drinking water health advisories, and 10 times these advisory values. Distributions of relevant internal dose metrics for benzene, trichloroethylene and VC were obtained using Monte Carlo simulations. Intergroup variability indexes (VI) were computed for the "low" (VIL ) and "high" (VIH ) exposure scenarios, as the ratio between the 95th percentile in each subpopulation over the median in adults. Thus, for benzene, parent compound's area under the curve-based VIL for single exposures vs. co-exposures correspondingly varied between 1.7 (teenagers) and 2.8 (infants) vs. 1.9 and 3.1 respectively. VIH varied between 2.5 and 3.5 vs. 2.9 and 4.1. Inversely, VIL and VIH for the amount of benzene metabolized via CYP2E1 pathway decreased in co-exposure compared to single exposure. For VC and trichloroethylene, similar results were obtained for the "high" exposure, but "low" co-exposures did not impact the toxicokinetics of individual substances. In conclusion, multi-route co-exposures can have an impact on the toxicokinetics of individual substances, but to an extent, that does not seem to challenge the default values attributed to the factors deemed at reflecting interindividual or child/adult differences in toxicokinetics.

Reverse dosimetry modeling of toluene exposure concentrations based on biomonitoring levels from the Canadian health measures survey.

Biomonitoring might provide useful estimates of population exposure to environmental chemicals. However, data uncertainties stemming from interindividual variability are common in large population biomonitoring surveys. Physiologically based pharmacokinetic (PBPK) models might be used to account for age- and gender-related variability in internal dose. The objective of this study was to reconstruct air concentrations consistent with blood toluene measures reported in the third Canadian Health Measures Survey using reverse dosimetry PBPK modeling techniques. Population distributions of model's physiological parameters were described based upon age, weight, and size for four subpopulations (12-19, 20-39, 40-59, and 60-79 years old). Monte Carlo simulations applied to PBPK modeling allowed converting the distributions of venous blood measures of toluene obtained from CHMS into related air levels. Based upon blood levels observed at the 50th, 90th and 95th percentiles, corresponding air toluene concentrations were estimated for teenagers aged 12-19 years as being, respectively, 0.009, 0.04 and 0.06 ppm. Similarly, values were computed for adults aged 20-39 years (0.007, 0.036, and 0.06 ppm), 40-59 years (0.007, 0.036 and 0.06 ppm) and 60-79 years (0.006, 0.022 and 0.04 ppm). These estimations are well below Health Canada's maximum recommended chronic air guidelines for toluene. In conclusion, PBPK modeling and reverse dosimetry may be combined to help interpret biomonitoring data for chemical exposure in large population surveys and estimate the associated toxicological health risk.

Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance.

The application of chemical-specific toxicokinetic or toxicodynamic data to address interspecies differences and human variability in the quantification of hazard has potential to reduce uncertainty and better characterize variability compared with the use of traditional default or categorically-based uncertainty factors. The present review summarizes the state-of-the-science since the introduction of the World Health Organization/International Programme on Chemical Safety (WHO/IPCS) guidance on chemical-specific adjustment factors (CSAF) in 2005 and the availability of recent applicable guidance including the WHO/IPCS guidance on physiologically-based pharmacokinetic (PBPK) modeling in 2010 as well as the U.S. EPA guidance on data-derived extrapolation factors in 2014. A summary of lessons learned from an analysis of more than 100 case studies from global regulators or published literature illustrates the utility and evolution of CSAF in regulatory decisions. Challenges in CSAF development related to the adequacy of, or confidence in, the supporting data, including verification or validation of PBPK models. The analysis also identified issues related to adequacy of CSAF documentation, such as inconsistent terminology and often limited and/or inconsistent reporting, of both supporting data and/or risk assessment context. Based on this analysis, recommendations for standardized terminology, documentation and relevant interdisciplinary research and engagement are included to facilitate the continuing evolution of CSAF development and guidance.

Pesticide exposures and chronic kidney disease of unknown etiology: an epidemiologic review.

The main causes of chronic kidney disease (CKD) globally are diabetes and hypertension but epidemics of chronic kidney disease of unknown etiology (CKDu) occur in Central America, Sri Lanka, India and beyond. Althoug also being observed in women, CKDu concentrates among men in agricultural sectors. Therefore, suspicions fell initially on pesticide exposure, but currently chronic heat stress and dehydration are considered key etiologic factors. Responding to persistent community and scientific concerns about the role of pesticides, we performed a systematic review of epidemiologic studies that addressed associations between any indicator of pesticide exposure and any outcome measure of CKD. Of the 21 analytical studies we identified, seven were categorized as with low, ten with medium and four with relatively high explanation value. Thirteen (62%) studies reported one or more positive associations, but four had a low explanation value and three presented equivocal results. The main limitations of both positive and negative studies were unspecific and unquantified exposure measurement ('pesticides'), the cross-sectional nature of most studies, confounding and selection bias. The four studies with stronger designs and better exposure assessment (from Sri Lanka, India and USA) all showed exposure-responses or clear associations, but for different pesticides in each study, and three of these studies were conducted in areas without CKDu epidemics. No study investigated interactions between pesticides and other concommittant exposures in agricultural occupations, in particular heat stress and dehydration. In conclusion, existing studies provide scarce evidence for an association between pesticides and regional CKDu epidemics but, given the poor pesticide exposure assessment in the majority, a role of nephrotoxic agrochemicals cannot be conclusively discarded. Future research should procure assessment of lifetime exposures to relevant specific pesticides and enough power to look into interactions with other major risk factors, in particular heat stress.

Assessing human variability in kinetics for exposures to multiple environmental chemicals: a physiologically based pharmacokinetic modeling case study with dichloromethane, benzene, toluene, ethylbenzene, and m-xylene.

The objective of this study was to compare the magnitude of interindividual variability in internal dose for inhalation exposure to single versus multiple chemicals. Physiologically based pharmacokinetic models for adults (AD), neonates (NEO), toddlers (TODD), and pregnant women (PW) were used to simulate inhalation exposure to "low" (RfC-like) or "high" (AEGL-like) air concentrations of benzene (Bz) or dichloromethane (DCM), along with various levels of toluene alone or toluene with ethylbenzene and xylene. Monte Carlo simulations were performed and distributions of relevant internal dose metrics of either Bz or DCM were computed. Area under the blood concentration of parent compound versus time curve (AUC)-based variability in AD, TODD, and PW rose for Bz when concomitant "low" exposure to mixtures of increasing complexities occurred (coefficient of variation (CV) = 16-24%, vs. 12-15% for Bz alone), but remained unchanged considering DCM. Conversely, AUC-based CV in NEO fell (15 to 5% for Bz; 12 to 6% for DCM). Comparable trends were observed considering production of metabolites (AMET), except for NEO's CYP2E1-mediated metabolites of Bz, where an increased CV was observed (20 to 71%). For "high" exposure scenarios, Cmax-based variability of Bz and DCM remained unchanged in AD and PW, but decreased in NEO (CV= 11-16% to 2-6%) and TODD (CV= 12-13% to 7-9%). Conversely, AMET-based variability for both substrates rose in every subpopulation. This study analyzed for the first time the impact of multiple exposures on interindividual variability in toxicokinetics. Evidence indicates that this impact depends upon chemical concentrations and biochemical properties, as well as the subpopulation and internal dose metrics considered.

BTEX air concentrations and self-reported common health problems in gasoline sellers from Cotonou, Benin.

To examine the relation between BTEX exposure levels and common self-reported health problems in 140 gasoline sellers in Cotonou, Benin, a questionnaire documenting their socioeconomic status and their health problems was used, whereas 18 of them went through semi-directed qualitative individual interviews and 17 had air samples taken on their workplace for BTEX analysis. Median concentrations for BTEX were significantly lower on official (range of medians: 54-207 µg/m³, n = 9) vs unofficial (148-1449 µg/m³, n = 8) gasoline-selling sites (p < 0.05). Self-reported health problems were less frequently reported in sellers from unofficial vs official selling sites (p < 0.05), because, as suggested by the semi-directed interviews, of their fear of losing their important, but illegal, source of income. Concluding, this study has combined quantitative and qualitative methodological approaches to account for the complex socioeconomic and environmental conditions of the investigated sellers, leading to their, in some cases, preoccupying BTEX exposure.

Characterization of the human kinetic adjustment factor for the health risk assessment of environmental contaminants.

A default uncertainty factor of 3.16 (√10) is applied to account for interindividual variability in toxicokinetics when performing non-cancer risk assessments. Using relevant human data for specific chemicals, as WHO/IPCS suggests, it is possible to evaluate, and replace when appropriate, this default factor by quantifying chemical-specific adjustment factors for interindividual variability in toxicokinetics (also referred to as the human kinetic adjustment factor, HKAF). The HKAF has been determined based on the distributions of pharmacokinetic parameters (e.g., half-life, area under the curve, maximum blood concentration) in relevant populations. This article focuses on the current state of knowledge of the use of physiologically based algorithms and models in characterizing the HKAF for environmental contaminants. The recent modeling efforts on the computation of HKAF as a function of the characteristics of the population, chemical and its mode of action (dose metrics), as well as exposure scenario of relevance to the assessment are reviewed here. The results of these studies, taken together, suggest the HKAF varies as a function of the sensitive subpopulation and dose metrics of interest, exposure conditions considered (route, duration, and intensity), metabolic pathways involved and theoretical model underlying its computation. The HKAF seldom exceeded the default value of 3.16, except in very young children (i.e., <≈ 3 months) and when the parent compound is the toxic moiety. Overall, from a public health perspective, the current state of knowledge generally suggest that the default uncertainty factor is sufficient to account for human variability in non-cancer risk assessments of environmental contaminants.

Assessing the impact of child/adult differences in hepatic first-pass effect on the human kinetic adjustment factor for ingested toxicants.

The objective of this study was to evaluate the impact of interindividual differences in hepatic first-pass effect (FPE) on the magnitude of the human kinetic adjustment factor (HKAF) for ingested toxicants. This factor aims at replacing a default value of 3.2 used in non-cancer risk assessment. Coupled with Monte Carlo simulations, steady-state equations that account for FPE were used to obtain distributions of arterial blood concentrations (CAss) and rates of metabolism in adults, neonates, infants and toddlers continuously exposed to an oral dose of 1 µg/kg/d of theoretical CYP2E1 and CYP1A2 substrates. For such substrates exhibiting a range of blood:air partition coefficients (Pb: 1-10,000) and hepatic extraction ratios in an average adult (E(ad): 0.01-0.99), HKAFs were computed as the ratio of the 95th percentile of dose metrics for each subpopulation over the 50th percentile value in adults. The reduced hepatic enzyme content in neonates as compared to adults resulted in correspondingly diminished FPE. Consequently, HKAFs greater than 3.2 could be observed, based on CAss only, in the following cases: for some CYP2E1 substrates with E(ad) ≤ 0.3, in neonates (max.: 6.3); and for some CYP1A2 substrates with E(ad) ≤ 0.1 and 0.7, in, respectively, neonates and infants (max.: 28.3). Overall, this study pointed out the importance of accounting for child/adult differences in FPE when determining the HKAF for oral exposure.

Determination of a guidance value for the communication of individual-level biomonitoring data for urinary arsenic.

BACKGROUND: Available guidance values to interpret individual-level biomonitoring data (ILBD) for the sum of urinary inorganic-related arsenic species (SUIAS) are generally based on population statistical descriptors and not on a predetermined exposure level that should not be exceeded. The objective of this study was thus to propose a range of SUIAS concentrations, reflecting an exposure corresponding to WHO's provisional guideline value (PGV) for arsenic in drinking water (10 µg/L), within which an exposure-based biomonitoring guidance value can be identified. METHOD A comprehensive literature review was carried out in order to identify studies that were relevant to the determination of a guidance value. Drinking water arsenic exposure and urinary biomonitoring concentrations obtained from selected studies were used to conduct a structural equation modeling meta-analysis, from which regression coefficients were obtained to derive an interpretative guidance range. RESULTS Individuals exposed to the arsenic background level comparable to North American and European countries and to a water source contaminated at the WHO's PGV, would have, on average, urinary SUIAS between 9 and 20 µg/L, with the most probable value being 15 µg/L. To address the associated uncertainty, the final guidance value selection within this range may be based on a targeted sensitivity and specificity towards detecting overexposed individuals. Indeed, spans of sensitivity of 60-82%, and of specificity of 58-85%, were estimated for the proposed range based on drinking water exposure raw data from the literature. CONCLUSION The range of guidance values obtained appears suitable for interpreting and communicating ILBD in any population biomonitoring studies in which background exposure is comparable to the North American and European context. Before selecting a single value within the proposed range, it will be important for Public Health officials to assess the possible consequences of this selection on the management and communication of the biomonitoring results.

Biological monitoring of exposure to rare earth elements and selected metals in the Inuit population of Nunavik, Canada.

In Nunavik (Northern Quebec, Canada), some mining projects are envisioned, that could increase the contamination of the environment by various chemicals, including rare earth elements (REEs), and implicitly Inuit population exposure. The objective of this study was to determine the baseline biological exposure of the population to these elements, before the potential mining development occurs. In the framework of the 2017 Qanuilirpitaa? Inuit health survey, urine samples were obtained from a representative sample of the adult Nunavik population, which were used to constitute 30 pooled samples according to age, sex and Nunavik subregions. Pooled samples were analyzed using sensitive and accurate methods involving ICP-MS platforms to quantify urinary concentrations of 17 REEs and 7 elements of interest in Nunavik (arsenic, antimony, chromium, cobalt, nickel, thallium and uranium). REEs were mostly not detected in pooled samples from this population. Detectable concentrations were found in some samples for cerium (range: 0.5-0.7 nmol/L; 27% > method detection limit (MDL) and lanthanum (range: 0.2-0.4 nmol/L; 33% > MDL). As for the other elements of interest, antimony, arsenic, cobalt and thallium were detected in 100% of the samples, whereas chromium and nickel were detected in 83% and 80% of the samples, respectively. Concentrations of arsenic (geometric mean (GM) = 0.5 µmol/L) and cobalt (GM = 5.2 nmol/L) were greater than in the general Canadian population; the opposite was observed for nickel (GM = 8.9 nmol/L). Arsenic concentrations increased significantly with age, whereas the opposite trend was observed for nickel and thallium. In this first biomonitoring study focusing on REEs and carried out in a representative sample of the Nunavik population, we found no evidence of significant exposure from pooled samples analysis. These results could eventually be used as baseline values in future studies aiming to assess temporal trends of exposure to REEs.

Assessing the impact of the duration and intensity of inhalation exposure on the magnitude of the variability of internal dose metrics in children and adults.

The objective of this study was to assess the impact of the exposure duration and intensity on the human kinetic adjustment factor (HKAF). A physiologically based pharmacokinetic model was used to compute target dose metrics (i.e. maximum blood concentration (C(max)) and amount metabolized/L liver/24 h (Amet)) in adults, neonates (0-30 days), toddlers (1-3 years), and pregnant women following inhalation exposure to benzene, styrene, 1,1,1-trichloroethane and 1,4-dioxane. Exposure scenarios simulated involved various concentrations based on the chemical's reference concentration (low) and six of U.S. EPA's Acute Exposure Guideline Levels (AEGLs) (high), for durations of 10 min, 60 min, 8 h, and 24 h, as well as at steady-state. Distributions for body weight (BW), height (H), and hepatic CYP2E1 content were obtained from the literature or from P3M software, whereas blood flows and tissue volumes were calculated from BW and H. The HKAF was computed based on distributions of dose metrics obtained by Monte Carlo simulations [95th percentile in each subpopulation/median in adults]. At low levels of exposure, ranges of C(max)-based HKAF were 1-6.8 depending on the chemical, with 1,4-dioxane exhibiting the greatest values. At high levels of exposure, this range was 1.1-5.2, with styrene exhibiting the greatest value. Neonates were always the most sensitive subpopulation based on C(max), and pregnant women were most sensitive based on Amet in the majority of the cases (1.3-2.1). These results have shown that the chemical-specific HKAF varies as a function of exposure duration and intensity of inhalation exposures, and sometimes exceeds the default value used in risk assessments.

A probabilistic toxicokinetic modeling approach to the assessment of the impact of daily variations of lead concentrations in tap water from schools and daycares on blood lead levels in children.

The aim of this study was to assess the impact of exposure to tap water lead concentration ([Pb]TW) occurring in schools or daycares on blood lead level (BLL) of attending children. Given the potentially wide variations in space and time of ([Pb]TW) documented in the literature, a simple probabilistic toxicokinetic (STK) model that allows the simulation of the time-varying evolution of BLL in response to these variations was developed. Thus, basic toxicokinetic equations were assembled to simulate BLL in a typical infant, toddler and pupil. The STK model's steady-state BLL predictions showed good correspondence when validated against Integrated Exposure and Uptake BioKinetic model predictions for comparable [Pb]TW values. Exposures to three distributions of [Pb]TW in specific sets of Canadian schools and daycares documented in the scientific literature were simulated probabilistically with Monte Carlo simulations. For the highest distribution of [Pb]TW simulated (median, 90th percentile = 24, 412 µg/L), average annual BLL (median, 97.5th percentile) varies between 1.5 and 6.4 µg/dL in infant and 1.1 and 3 µg/dL in pupils. Toddler's results were midway between those from the infants and pupils. Under this exposure scenario, the infant may present BLL > 5 µg/dL for a significant number of days over the course of the academic year (median; 97.5th: 17; 227 days). However, peak exposure may remain unnoticed if rare and drowned out by the background BLL. In conclusion, even if they may be sparse, peak exposure episodes to [Pb]TW in schools and daycares may suffice to increased BLL in attending individuals. This finding emphasizes the need for further characterization of [Pb]TW in schools and daycares in order to identify potentially problematic institutions and therefore avoid undesirable exposures for the children attending them.

Probabilistic human health risk assessment for quarterly exposure to high chloroform concentrations in drinking-water distribution network of the Province of Quebec, Canada.

Because quarterly concentrations of total trihalomethanes (THM) exceeding the 80 µg/L guideline are often tolerated by the public health authorities of the Province of Quebec (Canada), this study examined whether quarterly episodes of high concentrations of THM may pose a risk to the health of its population. Using Monte Carlo simulations, a probabilistic risk assessment was performed for infants (0-<6 mo), toddlers (6 mo-<5 yr) and adults (≥20 yr). Multiroute exposure including ingestion of drinking water as well as inhalation and dermal exposure while showering or bathing was considered. The resulting absorbed doses were compared to short-term reference values for chloroform, used as surrogate for THM, by calculating risk quotients (RQ). On the basis of THM concentrations values in Quebec's drinking water distribution systems during the months of July to October and exceeding the guideline value (>80 µg/L), the 95th percentile value of RQ were 0.65, 0.46, and 0.24 for infants, toddlers, and adults, respectively. Back-calculation allowed determining that a chloroform concentration of 330 µg/L would result in RQ ≤ 1 for 99% of infants, the subgroup considered the most susceptible among the general population. Overall, this study showed that episodes of high THM concentration encountered in Quebec drinking-water distribution network need not be considered as an immediate health concern for the general population. However, these results should not be interpreted as an authorization to exceed the 80 µg/L standard but rather as a risk management tool for public health authorities.

Regional variations in human chemical exposures in Canada: A case study using biomonitoring data from the Canadian Health Measures Survey for the provinces of Quebec and Ontario.

The Canadian Health Measures Survey (CHMS), an ongoing national health survey conducted in two-year cycles, collects extensive biomonitoring data that is used to assess the exposure of Canadians to environmental chemicals of concern. Combining data from multiple cycles of the CHMS allows for the calculation of robust regional estimates of chemical concentrations in blood and urine. The objective of this work was to compare biomarkers of exposure to several environmental chemicals for the provinces of Quebec and Ontario, two major CHMS regions, as well as the entire CHMS (representing Canada) minus Quebec (CMQ), and the entire CHMS minus Ontario (CMO), and to interpret differences between regions. Geometric means and 95th percentiles of blood and/or urinary concentrations of 45 environmental chemicals or their metabolites for Ontario, Quebec, CMQ, and CMO were calculated by combining the two most recent cycles of data available for a chemical (cycles 1 and 2, or cycles 2 and 3) from the first three cycles of the CHMS (2007-2013). Weighted one-way ANOVA was used to test the differences between regional estimates. After applying a Bonferonni-Holm adjustment for multiple comparisons, the following measures were significantly higher in Quebec as compared to Ontario and CMQ: blood lead, urinary lead and the urinary polyaromatic hydrocarbon (PAH) metabolites, 9-hydroxyfluorene, 1-hydroxyphenanthrene, 2- hydroxyphenanthrene and 3-hydroxyphenanthrene. In Quebec compared to CMQ only, urinary 2-hydroxfluorene, 3-hydroxyfluorene, 2-hydroxynaphthalene, and 4-hydroxyphenanthrene were higher. The concentration of urinary fluoride was significantly higher in Ontario as compared to Quebec and CMO. Blood manganese and urinary fluoride were significantly lower in Quebec compared to CMQ, and blood and urinary selenium were significantly lower in Ontario compared to CMO. Regional differences in tobacco use, age of dwellings and drinking water fluoridation are among the possible contributing factors to some of the observed differences. In conclusion, this is the first study where biomonitoring data from multiple cycles of CHMS were combined in order to generate robust estimates for subsets of the Canadian population. Such assessments can contribute to a regional-level prioritization of control measures to reduce the exposure of Canadians to chemicals in their environment.

Determination of no-observed effect level (NOEL)-biomarker equivalents to interpret biomonitoring data for organophosphorus pesticides in children.

BACKGROUND: Environmental exposure to organophosphorus pesticides has been characterized in various populations, but interpretation of these data from a health risk perspective remains an issue. The current paper proposes biological reference values to help interpret biomonitoring data related to an exposure to organophosphorus pesticides in children for which measurements of alkylphosphate metabolites are available. METHODS: Published models describing the kinetics of malathion and chlorpyrifos in humans were used to determine no-observed effect level - biomarker equivalents for methylphosphates and ethylphosphates, respectively. These were expressed in the form of cumulative urinary amounts of alkylphosphates over specified time periods corresponding to an absorbed no-observed effect level dose (derived from a published human exposure dose) and assuming various plausible exposure scenarios. Cumulative amounts of methylphosphate and ethylphosphate metabolites measured in the urine of a group of Quebec children were then compared to the proposed biological reference values. RESULTS: From a published no-observed effect level dose for malathion and chlorpyrifos, the model predicts corresponding oral biological reference values for methylphosphate and ethylphosphate derivatives of 106 and 52 nmol/kg of body weight, respectively, in 12-h nighttime urine collections, and dermal biological reference values of 40 and 32 nmol/kg of body weight. Out of the 442 available urine samples, only one presented a methylphosphate excretion exceeding the biological reference value established on the basis of a dermal exposure scenario and none of the methylphosphate and ethylphosphate excretion values were above the obtained oral biological reference values, which reflect the main exposure route in children. CONCLUSION: This study is a first step towards the development of biological guidelines for organophophorus pesticides using a toxicokinetic modeling approach, which can be used to provide a health-based interpretation of biomonitoring data in the general population.

Biomarkers of cadmium, lead and mercury exposure in relation with early biomarkers of renal dysfunction and diabetes: Results from a pilot study among aging Canadians.

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.

WITHDRAWN: Corrigendum to "Biomarkers of cadmium, lead and mercury exposure in relation with early biomarkers of renal dysfunction and diabetes: Results from a pilot study among aging Canadian" [Toxicol. Lett. 312 (2019) 148-156].

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.toxlet.2019.05.020. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

A Physiologically-Based Pharmacokinetic Modeling Approach Using Biomonitoring Data in Order to Assess the Contribution of Drinking Water for the Achievement of an Optimal Fluoride Dose for Dental Health in Children.

Due to an optimal fluoride concentration in drinking water advised for caries prevention purposes, the population is now exposed to multiple sources of fluoride. The availability of population biomonitoring data currently allow us to evaluate the magnitude of this exposure. The objective of this work was, therefore, to use such data in order to estimate whether community water fluoridation still represents a significant contribution toward achieving a suggested daily optimal fluoride (external) intake of 0.05 mg/kg/day. Therefore, a physiologically-based pharmacokinetic model for fluoride published in the literature was used and adapted in Excel for a typical 4-year-old and 8-year-old child. Biomonitoring data from the Canadian Health Measures Survey among people living in provinces with very different drinking water fluoridation coverage (Quebec, 2.5%; Ontario, 70% of the population) were analyzed using this adapted model. Absorbed doses for the 4-year-old and 8-year-old children were, respectively, 0.03 mg/kg/day and 0.02 mg/kg/day in Quebec and of 0.06 mg/kg/day and 0.05 mg/kg/day in Ontario. These results show that community water fluoridation contributes to increased fluoride intake among children, which leads to reaching, and in some cases even exceeding, the suggested optimal absorbed dose of 0.04 mg/kg/day, which corresponds to the suggested optimal fluoride intake mentioned above. In conclusion, this study constitutes an incentive to further explore the multiple sources of fluoride intake and suggests that a new balance between them including drinking water should be examined in accordance with the age-related physiological differences that influence fluoride metabolism.