Claude Emond

Apparent Half-Lives of Dioxins, Furans, and Polychlorinated Biphenyls as a Function of Age, Body Fat, Smoking Status, and Breast-Feeding

Objective In this study we reviewed the half-life data in the literature for the 29 dioxin, furan, and polychlorinated biphenyl congeners named in the World Health Organization toxic equivalency factor scheme, with the aim of providing a reference value for the half-life of each congener in the human body and a method of half-life estimation that accounts for an individual’s personal characteristics. Data sources and extraction We compared data from > 30 studies containing congener-specific elimination rates. Half-life data were extracted and compiled into a summary table. We then created a subset of these data based on defined exclusionary criteria. Data synthesis We defined values for each congener that approximate the half-life in an infant and in an adult. A linear interpolation of these values was used to examine the relationship between half-life and age, percent body fat, and absolute body fat. We developed predictive equations based on these relationships and adjustments for individual characteristics. Conclusions The half-life of dioxins in the body can be predicted using a linear relationship with age adjusted for body fat, smoking, and breast-feeding. Data suggest an alternative method based on a linear relationship between half-life and total body fat, but this approach requires further testing and validation with individual measurements.

Non-monotonic dose-response relationships and endocrine disruptors: a qualitative method of assessment

Experimental studies investigating the effects of endocrine disruptors frequently identify potential unconventional dose-response relationships called non-monotonic dose-response (NMDR) relationships. Standardized approaches for investigating NMDR relationships in a risk assessment context are missing. The aim of this work was to develop criteria for assessing the strength of NMDR relationships. A literature search was conducted to identify published studies that report NMDR relationships with endocrine disruptors. Fifty-one experimental studies that investigated various effects associated with endocrine disruption elicited by many substances were selected. Scoring criteria were applied by adaptation of an approach previously used for identification of hormesis-type dose-response relationships. Out of the 148 NMDR relationships analyzed, 82 were categorized with this method as having a “moderate” to “high” level of plausibility for various effects. Numerous modes of action described in the literature can explain such phenomena. NMDR can arise from numerous molecular mechanisms such as opposing effects induced by multiple receptors differing by their affinity, receptor desensitization, negative feedback with increasing dose, or dose-dependent metabolism modulation. A stepwise decision tree was developed as a tool to standardize the analysis of NMDR relationships observed in the literature with the final aim to use these results in a Risk Assessment purpose. This decision tree was finally applied to studies focused on the effects of bisphenol A.

Use of a Physiologically Based Pharmacokinetic Model for Rats to Study the Influence of Body Fat Mass and Induction of CYP1A2 on the Pharmacokinetics of TCDD

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly lipophilic chemical that distributes into adipose tissue, especially at low doses. However, at high doses TCDD sequesters in liver because it induces cytochrome P450 1A2 (CYP1A2) that binds TCDD. A physiologically based pharmacokinetic (PBPK) model was developed that included an inducible elimination rate of TCDD in the Sprague-Dawley rat. Objectives of this work were to characterize the influence of induction of CYP1A2 and adipose tissue mass fraction on the terminal elimination half-life (t1/2) of TCDD using this PBPK model. When the model assumes a fixed elimination of TCDD, t1/2 increases with dose, due to hepatic sequestration. Because experimental data indicate that the t1/2 of TCDD decreases with dose, the model was modified to include an inducible elimination rate. The PBPK model was then used to compare the t1/2 after an increase of adipose tissue mass fraction from 6.9 to 70%. The model suggests that at low exposures, increasing adipose tissue mass increases the terminal t1/2. However, at higher exposures, as CYP1A2 is induced, the relationship between adipose tissue mass and t1/2 reaches a plateau. This demonstrates that an inducible elimination rate is needed in a PBPK model in order to describe the pharmacokinetics of TCDD. At low exposures these models are more sensitive to parameters related to partitioning into adipose tissue.

Comparison of the use of a physiologically based pharmacokinetic model and a classical pharmacokinetic model for dioxin exposure assessments.

In epidemiologic studies, exposure assessments of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) assume a fixed elimination rate. Recent data suggest a dose-dependent elimination rate for TCDD. A physiologically based pharmacokinetic (PBPK) model, which uses a body-burden–dependent elimination rate, was developed previously in rodents to describe the pharmacokinetics of TCDD and has been extrapolated to human exposure for this study. Optimizations were performed using data from a random selection of veterans from the Ranch Hand cohort and data from a human volunteer who was exposed to TCDD. Assessment of this PBPK model used additional data from the Ranch Hand cohort and a clinical report of two women exposed to TCDD. This PBPK model suggests that previous exposure assessments may have significantly underestimated peak blood concentrations, resulting in potential exposure misclassifications. Application of a PBPK model that incorporates an inducible elimination of TCDD may improve the exposure assessments in epidemiologic studies of TCDD.

A weight of evidence approach for the assessment of the ototoxic potential of industrial chemicals

There is accumulating epidemiological evidence that exposure to some solvents, metals, asphyxiants and other substances in humans is associated with an increased risk of acquiring hearing loss. Furthermore, simultaneous and successive exposure to certain chemicals along with noise can increase the susceptibility to noise-induced hearing loss. There are no regulations that require hearing monitoring of workers who are employed at locations in which occupational exposure to potentially ototoxic chemicals occurs in the absence of noise exposure. This project was undertaken to develop a toxicological database allowing the identification of possible ototoxic substances present in the work environment alone or in combination with noise exposure. Critical toxicological data were compiled for chemical substances included in the Quebec occupational health regulation. The data were evaluated only for noise exposure levels that can be encountered in the workplace and for realistic exposure concentrations up to the short-term exposure limit or ceiling value (CV) or 5 times the 8-h time-weighted average occupational exposure limit (TWA OEL) for human data and up to 100 times the 8-h TWA OEL or CV for animal studies. In total, 224 studies (in 150 articles of which 44 evaluated the combined exposure to noise and a chemical) covering 29 substances were evaluated using a weight of evidence approach. For the majority of cases where potential ototoxicity was previously proposed, there is a paucity of toxicological data in the primary literature. Human and animal studies indicate that lead, styrene, toluene and trichloroethylene are ototoxic and ethyl benzene, n-hexane and p-xylene are possibly ototoxic at concentrations that are relevant to the occupational setting. Carbon monoxide appears to exacerbate noise-induced hearing dysfunction. Toluene interacts with noise to induce more severe hearing losses than the noise alone.

Chronic Exposure to Low Doses of Dioxin Promotes Liver Fibrosis Development in the C57BL/6J Diet-Induced Obesity Mouse Model

Background: Exposure to persistent organic pollutants (POPs) has been associated with the progression of chronic liver diseases, yet the contribution of POPs to the development of fibrosis in non-alcoholic fatty liver disease (NAFLD), a condition closely linked to obesity, remains poorly documented. Objectives: We investigated the effects of subchronic exposure to low doses of the POP 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor ligand, on NAFLD progression in diet-induced obese C57BL/6J mice. Methods: Male C57BL/6J mice were fed either a 10% low-fat (LFD) or a 45% high-fat (HFD) purified diet for 14 weeks and TCDD-exposed groups were injected once a week with 5 μg/kg TCDD or the vehicle for the last 6 weeks of the diet. Results: Liver histology and triglyceride levels showed that exposure of HFD fed mice to TCDD worsened hepatic steatosis, as compared to either HFD alone or LFD plus TCDD and the mRNA levels of key genes of hepatic lipid metabolism were strongly altered in co-treated mice. Further, increased liver collagen staining and serum transaminase levels showed that TCDD induced liver fibrosis in the HFD fed mice. TCDD in LFD fed mice increased the expression of several inflammation and fibrosis marker genes with no additional effect from a HFD. Conclusions: Exposure to TCDD amplifies the impairment of liver functions observed in mice fed an enriched fat diet as compared to a low fat diet. The results provide new evidence that environmental pollutants promote the development of liver fibrosis in obesity-related NAFLD in C57BL/6J mice. Citation: Duval C, Teixeira-Clerc F, Leblanc AF, Touch S, Emond C, Guerre-Millo M, Lotersztajn S, Barouki R, Aggerbeck M, Coumoul X. 2017. Chronic exposure to low doses of dioxin promotes liver fibrosis development in the C57BL/6J diet-induced obesity mouse model. Environ Health Perspect 125:428–436; http://dx.doi.org/10.1289/EHP316

Physiologically based modeling of the accumulation in plasma and tissue lipids of a mixture of PCB congeners in female Sprague-Dawley rats.

This study aimed to develop a physiologically based model for simulating the concentrations of polychlorinated biphenyls (PCBs) in tissue and plasma lipids of rats exposed to PCB mixtures. The model was based on the assumption that the neutral lipid fraction is the only critical determinant of the tissue distribution of PCBs, and that the solubility/retention in other tissue components is negligible. The volumes of the model compartments reflected the volumes of neutral lipids, whereas the flow rates corresponded to those of the neutral lipids in blood. Since the equilibrium ratio of PCB concentrations in neutral lipids of tissues and plasma equals 1, the present modeling approach does not require the use of tissue:blood partition coefficients. Metabolism rates were derived from the best visual fit of the model to the PCB concentrations in hepatic lipids determined on d 41 and 90 in rats exposed to a mixture containing 5, 50, or 500 μg PCBs (118, 138, 153, 170, 180 and 187) per kilogram body weight according to various protocols: (a) every-day dosing, (b) once-a-week dosing, (c) consecutive dosing for 13 d with no further treatment, and (d) 13 irregularly spaced doses. The resulting model consistently simulated the concentrations of PCBs in adipose tissue and plasma lipids of rats exposed according to the four described protocols. The physiologically based pharmacokinetic (PBPK) model developed in this study should be useful as a basis for interpretating blood or plasma lipid concentration data on PCBs collected during biomonitoring studies.

Temporal trends in serum concentrations of polychlorinated dioxins, furans, and PCBs among adult women living in Chapaevsk, Russia: a longitudinal study from 2000 to 2009

BackgroundThe present study assessed the temporal trend in serum concentrations of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls (PCBs) among residents of a Russian town where levels of these chemicals are elevated due to prior industrial activity.MethodsTwo serum samples were collected from eight adult women (in 2000 and 2009), and analyzed with gas chromatography-high-resolution mass spectrometry.ResultsThe average total toxic equivalency (TEQ) decreased by 30% (from 36 to 25 pg/g lipid), and the average sum of PCB congeners decreased by 19% (from 291 to 211 ng/g lipid). Total TEQs decreased for seven of the eight women, and the sum of PCBs decreased for six of eight women. During this nine year period, larger decreases in serum TEQs and PCBs were found in women with greater increases in body mass index.ConclusionsThis study provides suggestive evidence that average serum concentrations of dioxins, furans, and PCBs are decreasing over time among residents of this town.

Toward a general physiologically-based pharmacokinetic model for intravenously injected nanoparticles

To assess the potential toxicity of nanoparticles (NPs), information concerning their uptake and disposition (biokinetics) is essential. Experience with industrial chemicals and pharmaceutical drugs reveals that biokinetics can be described and predicted accurately by physiologically-based pharmacokinetic (PBPK) modeling. The nano PBPK models developed to date all concern a single type of NP. Our aim here was to extend a recent model for pegylated polyacrylamide NP in order to develop a more general PBPK model for nondegradable NPs injected intravenously into rats. The same model and physiological parameters were applied to pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs, whereas NP-specific parameters were chosen on the basis of the best fit to the experimental time-courses of NP accumulation in various tissues. Our model describes the biokinetic behavior of all four types of NPs adequately, despite extensive differences in this behavior as well as in their physicochemical properties. In addition, this simulation demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NP type included the blood:tissue coefficients of permeability and the rate constant for phagocytic uptake. Since only four types of NPs with several differences in characteristics (dose, size, charge, shape, and surface properties) were used, the relationship between these characteristics and the NP-dependent model parameters could not be elucidated and more experimental data are required in this context. In this connection, intravenous biodistribution studies with associated PBPK analyses would provide the most insight.

Dermal Exposure to Beryllium: A Pilot Case Study

The issue of dermal absorption of beryllium (Be) particles through intact healthy skin has not yet been demonstrated. The interest in Be dermal exposure as a potential pathway for toxic effects was emphasized in Quebec (Canada) when a recycling industry processing spent pot lining (SPL) related to the aluminum industry was recently requested by health authorities to conduct a Be particle size study and to provide a Tyvek coverall for full skin protection of workers. This study aimed to (1) calculate the dermal and inhalation exposures and (2) apply the results to the case study of a recycling SPL industry. Airborne dust was sampled in order to determine Be particles size. Exposure assessment via the skin and the respiratory routes was measured over a working day using standard calculations. The assessment of workers’ clothing protection was obtained by swiping the skin on the forearm and upper front leg before and after exposure. Respirable Be (0.044 μg) was 23% of the total Be (0.19 μg). Be particles with a median mass aerodynamic diameter (MMAD) of 0.93 and below totaled 0.0103 μg (5% of BeT). The daily dose for the respiratory route was calculated to be 0.022 μg/kg/d, while the daily doses for the dermal route varied between 0.027 × 10−7 μg/kg/d and 0.025 × 10−3 μg/kg/d. After exposure, no Be was found on the skin of workers wearing a cotton coverall protection. When using a polyester coverall, minor amounts of Be were found. These results showed that dermal daily dose exposure is negligible. However, note that the case study did not involve handling of contaminated items by the workers, which lead to significant dermal exposure if care is not taken. Although daily dermal exposure may be small, because of uncertainties, a precautionary principle should be applied in an active sense.