[Show abstract][Hide abstract] ABSTRACT: Benzo[a]pyrene (BaP) is a human carcinogen, but there are no validated biomarkers of exposure and the relationship of carcinogenesis with early biological alterations is not fully documented. This study aimed at better documenting the toxicokinetics of diolBaP and hydroxyBaP metabolites as potential biomarkers of exposure to BaP in relation to DNA adduct formation and gene expression. Rats were intravenously (iv) injected with 40 μmol/kg BaP. BaP and several metabolites were measured in blood, tissues, and excreta collected at frequent intervals over 72 h posttreatment. BaP diol epoxide (BaPDE)-DNA adduct formation and gene expression were assessed in lungs. 3-HydroxyBaP (3-OHBaP) and 4,5-diolBaP were the most abundant measured metabolites, and differences in time courses were apparent between the two metabolites. Over the 0-72 h period, mean proportions of BaP dose recovered in urine as 3-OHBaP and 4,5-diolBaP (±SD) were 0.017 ± 0.003% and 0.1 ± 0.03%. Corresponding values in feces were 1.5 ± 0.5% and 0.42 ± 0.052%. BaPDE-DNA adducts were significantly increased in lungs and a correlation was observed with urinary 3-OHBaP and 4,5-diolBaP. Analysis of gene expression showed a modulation of expression of metabolic genes (Cyp1a1, Cyp1b1, Nqo1, Ahr) and oxidative stress and repair genes (Nrf2, Rad51). However, BaPDE adducts formation did not exhibit any significant correlation with expression of genes, except a negative correlation with Rad51 expression. Similarly, there was no significant correlation between urinary excretion of OHBaP and diolBaP and expression of genes, except for urinary 7-OHBaP excretion, which was negatively correlated with Rad51 expression. Results indicate that concomitant measurements of diolBaP and OHBaP may serve to better assess the extent of exposure as compared to single metabolite measurements, given kinetic differences between metabolites. Further, although some urinary metabolites were correlated with BaPDE adducts, links with gene expression need to be further investigated.
Journal of Toxicology and Environmental Health Part A 06/2015; 78(12):725-46. DOI:10.1080/15287394.2015.1028119 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The effects of benzo[a]pyrene (BaP) administration on biomarkers of exposure and early effects were studied in male Sprague-Dawley rats intravenously injected with doses of 0.4, 4, 10, or 40 μmol BaP/kg . Blood, tissues, and excreta were collected 8 and 24 h posttreatment. BaP and several of its metabolites were simultaneously measured in blood, tissues and excreta by ultra-high-performance liquid chromatography (UHPLC)/fluorescence. DNA adducts of BaP diol epoxide (BaPDE) in lungs were quantified using an ultrasensitive immunoassay with chemiluminescence detection. Expression of selected genes in lungs of treated rats (lung RNA) compared to control rats was also assessed by quantitative real-time polymerase chain reaction. There was a dose-dependent increase in blood, tissue, and excreted levels of BaP metabolites. At 8 and 24 h postinjection, BaP and hydroxyBaP were found in higher concentrations in blood and tissues compared to other analytes. However, diolBaP were excreted in greater amounts in urine and apparently more rapidly than hydroxyBaP. Mean percentages (± SD) of injected dose excreted in urine as 4,5-diolBaP during the 0-8 h and 0-24 h period posttreatment were 0.16 ± 0.027% and 0.14 ± 0.083%, respectively. Corresponding values for 3-OHBaP were 0.0045 ± 0.0009% and 0.026 ± 0.014%. BaP-diones were not detectable in blood, tissues, and excreta; 7,8-diolBaP and BaPtetrol were found to be minor metabolites. There was also a dose-dependent increase in DNA adduct formation in lung. Analysis of gene expression further showed a modulation of Cyp1a1, Cyp1b1, Nqo1, Nrf2, Fos, and Ahr expression at 10- and 40-μmol/kg doses, but not at the lower doses. This study provided a better assessment of the influence of absorbed BaP doses on biological levels of diolBaP and OHBaP exposure biomarkers and association of the latter with early biological alterations, such as DNA adducts and gene expression.
Journal of Toxicology and Environmental Health Part A 02/2015; 78(3):166-84. DOI:10.1080/15287394.2014.954072 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Biomonitoring is increasingly used to assess exposure to selenium (Se) in the population. However, there is little harmonization among protocols used in the different studies (varying biological matrices, differences in expression of results (concentrations versus amounts, units)). This makes inter-comparison of biomonitoring results across studies difficult. From a public health risk perspective, it also becomes challenging to estimate baseline levels in biological matrices for populations exposed by various sources. The aim of this study was thus to perform a systematic analysis of the relationship between Se intakes and biological concentrations based on published data. Inclusion and exclusion criteria were used and led to select 75 published biomonitoring data in humans from an extended review of Se biomonitoring studies. This represents 8 628 individuals who provided biological samples aiming at documenting Se exposure and/or Se concentrations in two or more biological matrices. Mathematical algorithms that relate Se intakes to biological concentrations and establish matrix-to-matrix associations were derived from these pooled biomonitoring data. Logarithmic regressions showed good correlations between Se intakes and whole blood concentrations (R2 = 0.884), plasma concentrations (R2 = 0.863) and urinary excretion rates (R2 = 0.958). Blood and plasma concentrations were also strongly related (R2 = 0.874), as were whole blood concentrations and urinary excretion rates (R2 = 0.953). The interpretation of the log-regression coefficients allowed illustrating Se physiology. Se concentrations in plasma tend to plateau when daily intake exceed 150 μg/d, whereas Se in urine increases rapidly above this threshold. The application of the algorithms to other independent data sets in order to reconstruct past Se intakes confirmed that interpretation of results on the basis of Se in integuments may be misleading if external contamination is not avoided. This approach based on pooled data covered a wide range of exposure and the large number of data integrated increased the level of confidence of results.
International Journal of Hygiene and Environmental Health 09/2014; 217(7). DOI:10.1016/j.ijheh.2014.04.005 · 3.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Biomathematical modeling has become an important tool to assess xenobiotic exposure in humans. In the present study, we have used a human physiologically-based pharmacokinetic (PBPK) model and an simple compartmental toxicokinetic model of benzo(a)pyrene (BaP) kinetics and its 3-hydroxybenzo(a)pyrene (3-OHBaP) metabolite to reproduce the time-course of this biomarker of exposure in the urine of industrially exposed workers and in turn predict the most plausible exposure scenarios. The models were constructed from in vivo experimental data in rats and then extrapolated from animals to humans after assessing and adjusting the most sensitive model parameters as well as species specific physiological parameters. Repeated urinary voids from workers exposed to polycyclic aromatic hydrocarbons (PAHs) have been collected over the course of a typical workweek and during subsequent days off work; urinary concentrations of 3-OHBaP were then determined. Based on the information obtained for each worker (BaP air concentration, daily shift hours, tasks, protective equipment), the time courses of 3-OHBaP in the urine of the different workers have been simulated using the PBPK and toxicokinetic models, considering the various possible exposure routes, oral, dermal and inhalation. Both models were equally able to closely reproduce the observed time course of 3-OHBaP in the urine of workers and predicted similar exposure scenarios. Simulations of various scenarios suggest that the workers under study were exposed mainly by the dermal route. Comparison of measured air concentration levels of BaP with simulated values needed to obtain a good approximation of observed time course further pointed out that inhalation was not the main route of exposure for most of the studied workers. Both kinetic models appear as a useful tool to interpret biomonitoring data of PAH exposure on the basis of 3-OHBaP levels.
PLoS ONE 07/2014; 9(7):e102570. DOI:10.1371/journal.pone.0102570 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim: Diabetes rising prevalence is of great concern in Africa because of its socio-economic impacts in a context of limited access to health care. The inappropriate use of pesticides may add to the burden of diabetes in Africa. The present study was carried out in a cotton producing area of Benin in order to assess the relationship between the highest prevalence of diabetes observed in the country and organochlorine pesticide (OCP) exposure.
Methods: A case-control study was conducted in 2011. A sample of 106 subjects with diabetes and 106 non-diabetic controls were paired by age, gender, ethnicity and residential area. Personal and socioeconomic information, along with anthropometric measurements were collected. Blood samples were assayed for total lipids and 14 OCPs by gas-chromatography coupled with mass-spectrometry. Data were recorded for the four detectable OCPs: p,p’-dichlorodiphenyldichloroethylene (p,p’-DDE), p,p’-dichlorodiphenyltrichloroethane (p,p’-DDT), β -hexachlorocyclohexane (β-HCH), and trans-nonachlor.
Results: Serum levels of all four detected OCPs were consistently higher in diabetic subjects than in non-diabetic controls. The odds ratio of diabetes was nearly three-fold higher when comparing the third tertile of p,p’-DDE and p,p’-DDT and β-HCH levels with the first tertile, without adjustment for potential confounders. The association remained significant for p,p’-DDT (OR = 2.59; 95% CI: 1.17-5.42) and p,p’-DDE (OR = 2.11; 95% CI: 1.01-4.54) after adjusting for a family history of diabetes, abdominal obesity, and wealth index or education.
Conclusion: Our data showed that exposure to p,p’-DDT and p,p’-DDE was associated with an increased risk of diabetes. These findings have major public health implications.
[Show abstract][Hide abstract] ABSTRACT: The Borgou region of northern Benin is a major cotton producing area and consistently uses higher amounts of pesticides than other areas of the country. Organochlorine pesticides (OCPs), poorly handled, have been widely used and are still illegally present. We therefore hypothesized that serum OCP levels would be high in Borgou. As part of a case-control study on diabetes status and pesticide exposure, we measured the distribution of serum concentrations of 14 OCPs by gas chromatography with mass spectrometry. A sample of 118 diabetic subjects was selected using a four-stage cluster sampling with 54.2% of men and 45.8% of women; 43% lived in urban areas, 14.4% were obese and 39.8% had high economic status. The four detected OCPs were p,p'-DDT, p,p'-DDE, β-HCH and trans-nonachlor with respective geometric means (geometric standard deviation) of 497.1 (4.5), 20.6 (7.9), 2.9 (3.4), and 2.0 (2.3) ng/g of total serum lipids. OCP levels were significantly higher in obese, wealthier and more educated subjects and in those living in urban areas as compared to the other groups, particularly for p,p'-DDE, p,p'-DDT and β-HCH. Levels of DDT and DDE were higher than reported in other countries where DDT is no longer permitted. The low DDT/DDE ratio of 0.05 suggests past human exposure through food contamination. There is thus a need to reinforce governmental regulations for a more responsible use of pesticides in the country, in order to reduce health risks associated with persistent organic pollutants.
Environment international 04/2014; 69C:1-8. DOI:10.1016/j.envint.2014.04.002 · 5.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To assess exposure to pyrethroids in the general population, one of most widely used method nowadays consists of measuring urinary metabolites. Unfortunately, interpretation of data is limited by the unspecified relation between dose and levels in biological tissues and excreta. The objective of this study was to develop a common multi-compartment toxicokinetic model to predict the time courses of two mainly used pyrethroid pesticides, permethrin and cypermethrin, and their metabolites (cis-DCCA, trans-DCCA and 3-PBA) in the human body and in accessible biological matrices following different exposure scenarios. Toxicokinetics was described mathematically by systems of differential equations to yield the time courses of these pyrethroids and their metabolites in the different compartments. Unknown transfer rate values between compartments were determined from best fits to available human data on the urinary excretion time courses of metabolites following an oral and dermal exposure to cypermethrin in volunteers. Since values for these coefficients have not yet been determined, a mathematical routine was programmed in MathCad to establish the possible range of values on the basis of physiological and mathematical considerations. The best combination of parameter values was then selected using a statistic measure (reliability factor) along with a statistically acceptable range of values for each parameter. With this approach, simulations provided a close approximation to published time course data. This model allows to predict urinary time courses of trans-DCCA, cis-DCCA and 3-PBA, whatever the exposure route. It can also serve to reconstruct absorbed doses of permethrin or cypermethrin in the population using measured biomarker data.
PLoS ONE 02/2014; 9(2):e88517. DOI:10.1371/journal.pone.0088517 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Borgou region of northern Benin is a major cotton producing area and consistently uses higher amounts of pesticides than other areas of the country. Organochlorine pesticides (OCPs), poorly handled, have been widely used and are still illegally present. We therefore hypothesized that serum OCP levels would be high in Borgou. As part of a case–control study on diabetes status and pesticide exposure, we measured the distribution of serum concentrations of 14 OCPs by gas chromatography with mass spectrometry. A sample of 118 diabetic subjects was selected using a four-stage cluster sampling with 54.2% of men and 45.8% of women; 43% lived in urban areas, 14.4% were obese and 39.8% had high economic status. The four detected OCPs were p,p′-DDT, p,p′-DDE, β-HCH and trans-nonachlor with respective geometric means (geometric standard deviation) of 497.1 (4.5), 20.6 (7.9), 2.9 (3.4), and 2.0 (2.3) ng/g of total serum lipids. OCP levels were significantly higher in obese, wealthier and more educated subjects and in those living in urban areas as compared to the other groups, particularly for p,p′-DDE, p,p′-DDT and β-HCH. Levels of DDT and DDE were higher than reported in other countries where DDT is no longer permitted. The low DDT/DDE ratio of 0.05 suggests past human exposure through food contamination. There is thus a need to reinforce governmental regulations for a more responsible use of pesticides in the country, in order to reduce health risks associated with persistent organic pollutants.
[Show abstract][Hide abstract] ABSTRACT: 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 and>10 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.Journal of Exposure Science and Environmental Epidemiology advance online publication, 6 November 2013; doi:10.1038/jes.2013.80.
Journal of Exposure Science and Environmental Epidemiology 11/2013; 24(2). DOI:10.1038/jes.2013.80 · 3.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The impact polychlorinated biphenyl (PCB) exposure on thyroid status in pregnant women and newborns was investigated in various epidemiological studies, but findings show inconsistencies, and differences in biological indicators of exposure between studies limits comparison of results. The aim of this research was to use a procedure previously developed to standardize PCB biological concentration data between published studies to perform a systematic analysis of associations between PCB exposure and thyroid hormones (THs) (total and free T3 and T4) or thyroid stimulating hormone (TSH) in pregnant women and newborns. Biological concentrations from nineteen studies were expressed in total PCB equivalent per kg of lipids in maternal plasma (μgPCBMPEQkg(-1) lipids). Systematic analysis of the "standardized biological concentration-thyroid parameters" relationship was conducted through the application of methodological criteria in both pregnant women and newborns. Standardization of PCB levels and application of methodological criteria led to assign higher confidence to ten of the reviewed studies. Among the retained studies in pregnant women, only one reported a significant association between PCBs and total T3 levels, but no association were observed when circulating TSH and free T4 levels were used to assess thyroid function. Regarding the association between prenatal PCB exposure and thyroid status in newborns, a lack of significant association was consistently obtained in the retained studies assigned an overall high confidence. The weight of evidence of a significant impact of PCB exposure on TSH and TH levels at the described biological levels in pregnant women and newborns (mean<1000μgPCBMPEQkg(-1) lipids) appears low according to this systematical analysis.
[Show abstract][Hide abstract] ABSTRACT: 3-Hydroxybenzo(a)pyrene (3-OHBaP) in urine has been proposed as a biomarker of occupational exposure to polycyclic aromatic hydrocarbons. However, to reconstruct exposure doses in workers from biomarker measurements, a thorough knowledge of the kinetics of the benzo(a)pyrene (BaP) and 3-OHBaP given different routes of exposure is needed. A rat physiologically-based pharmacokinetic model of BaP and 3-OHBaP was built. Organs (tissues) represented as compartments were based on in vivo experimental data in rats. Tissue: blood partition coefficients, permeability coefficients, metabolism rates, excretion parameters, and absorption fractions and rates for different routes-of-entry were obtained directly from published in vivo time courses of BaP and 3-OHBaP in blood, various tissues and excreta of rats. The latter parameter values were best-fitted by least square procedures and Monte Carlo simulations. Sensitivity analyses were then carried out to ensure the stability of the model and the key parameters driving the overall modeled kinetics. This modeling pointed out critical determinants of the kinetics: (1) hepatic metabolism of BaP and 3-OHBaP elimination rate as the most sensitive parameters; (2) the strong partition of BaP in lungs compared to other tissues, followed by adipose tissues and liver; (3) the strong partition of 3-OHBaP in kidneys; (4) diffusion-limited tissue transfers of BaP in lungs and 3-OHBaP in lungs, adipose tissues and kidneys; (5) significant entero-hepatic recycling of 3-OHBaP. Very good fits to various sets of experimental data in rats from four different routes-of-entry (intravenous, oral, dermal and inhalation) were obtained with the model.
Journal of Pharmacokinetics and Biopharmaceutics 10/2013; 40(6). DOI:10.1007/s10928-013-9338-9 · 1.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 m(3) /day (26.7) compared to those of data in m(3) /kg-day (12.2) and m(3) /m(2) -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 m(3) /day) and 99th percentile (55.55 m(3) /day) values were found in obese class 2 adults. They inhale on average 8.21 m(3) more air per day than normal-weight adults.