Gaétan Carrier

Concentration-dependent TCDD elimination kinetics in humans: Toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort

Serial measurements of serum lipid 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations in 36 adults from Seveso, Italy, and three patients from Vienna, Austria, with initial serum lipid TCDD concentrations ranging from 130 to 144,000 ppt, were modeled using a modified version of a previously published toxicokinetic model for the distribution and elimination of dioxins. The original model structure accounted for a concentration-dependent increase in overall elimination rate for TCDD due to nonlinear distribution of TCDD to the liver (secondary to induction of the binding protein CYP1A2), from which elimination takes place via a first-order process. The original model structure was modified to include elimination due to lipid partitioning of TCDD from circulation into the large intestine, based on published human data. We optimized the fit of the modified model to the data by varying the hepatic elimination rate parameter for each of the 39 people. The model fits indicate that there is significant interindividual variability of TCDD elimination efficiency in humans and also demonstrate faster elimination in men compared to women, and in younger vs. older persons. The data and model results indicate that, for males, the mean apparent half-life for TCDD (as reflected in changes in predicted serum lipid TCDD level) ranges from less than 3 years at serum lipid levels above 10,000 ppt to over 10 years at serum lipid levels below 50 ppt. Application of the model to serum sampling data from the cohort of US herbicide-manufacturing workers assembled by the National Institute of Occupational Safety and Health (NIOSH) indicates that previous estimates of peak serum lipid TCDD concentrations in dioxin-exposed manufacturing workers, based on first-order back-extrapolations with half-lives of 7–9 years, may have underestimated the maximum concentrations in these workers and other occupational cohorts by several-fold to an order of magnitude or more. Such dose estimates, based on a single sampling point decades after last exposure, are highly variable and dependent on a variety of assumptions and factors that cannot be fully determined, including interindividual variations in elimination efficiency. Dose estimates for these cohorts should be re-evaluated in light of the demonstration of concentration-dependent elimination kinetics for TCDD, and the large degree of uncertainty in back-calculated dose estimates should be explicitly incorporated in quantitative estimates of TCDDs carcinogenic potency based on such data.

Biological monitoring of exposure to pyrethrins and pyrethroids in a metropolitan population of the Province of Quebec, Canada.

Pyrethroid and pyrethrins are neurotoxic insecticides widely used to control agricultural and domestic insect pests. The general population is potentially chronically exposed through food consumption, but the actual exposure is poorly documented in Canada. This study aimed at obtaining an indication of the absorption of those insecticides in residents of Montreal Island, the largest metropolitan area of the Province of Quebec, Canada. We randomly recruited 120 adults and 120 children aged 18-64 and 6-12 years old, of which 81 adults and 89 children completed the study. The absorption of pyrethroids and pyrethrins was assessed through measurements of six urinary metabolites: chrysanthemum dicarboxylic acid (CDCA), cis- and trans-2,2-(dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acids (cDCCA and tDCCA), cis-2,2-(dibromovinyl)-2,2-dimethylcyclopropane carboxylic acid (DBCA), 3-phenoxybenzoic acid (PBA) and 4-fluoro-3-phenoxybenzoic acid (FPBA). Metabolites were determined in 12-h urine collections for children and 2-consecutive 12-h collections for adults, and were analyzed by gas-chromatography/mass spectrometry. In both adults and children, the relative distribution of the various metabolites was as follows: tDCCA>PBA>cDCCA>CDCA>DBCA>FPBA. In adults, median (95th percentiles) cumulative amounts of these metabolites were 12.0 (231.1), 8.2 (177.9), 5.0 (110.1), 0.3 (8.2), 0.1 (4.7) and 0.1 (0.5)pmol/kg bw, respectively, in nighttime 12-h urine collections. Corresponding values in children were 12.6 (207.7), 10.2 (73.2), 5.1 (59.6), 2.1 (14.2), 0.1 (4.9) and 0.1 (0.8)pmol/kg bw. The main metabolites observed are indicative of exposure mainly to permethrin and cypermethrin and amounts absorbed are in the same range in adults and children. The distribution levels of the main metabolites in our sample also appeared similar to those reported in the US population.

The toxicokinetics of pyrene and its metabolites in rats

Five experiments were conducted in male Sprague-Dawley rats regarding the kinetic of urinary excretion of 1-hydroxypyrene (1-OHP) following i.v., oral and dermal exposure to 0.5-50 micromol/kg pyrene either as a single substance or as mixture of various polycyclic aromatic hydrocarbons (PAH). Frequent urine collections over 48 h after exposure and a tissue versus time distribution experiment using [14C]pyrene allowed to define the kinetic profile of both pyrene and 1-OHP. For all exposure routes, there is a linear relationship over two orders of magnitude between the dose of pyrene and the urinary excretion of 1-OHP. Differences in biliary/urinary 1-OHP excretion ratio in canulated rats (3) versus faecal/urinary 1-OHP excretion ratio in non-canulated rats (0.6) indicate major enterohepatic recirculation of the metabolite. Half-lives of both pyrene and 1-OHP in all measured tissues were all comprised between 3.1 and 5.4 h, and 5.2-6.7 h, respectively, so that no long term accumulation would be predicted from these values for any tissue. Binary and ternary mixtures involving naphthalene and benzo(a)pyrene in addition to pyrene has no influence on the urinary excretion profile of 1-OHP. All these observations led to the proposal of a dynamic compartment model of pyrene and metabolite flows indicating that following rapid initial distribution to fatty tissues, pyrene is rapidly biotransformed into various metabolites and undergoes major enterohepatic recycling. Part of the initially formed and part of the recirculated 1-OHP eventually undergoes urinary excretion such that close to 60% of pyrene is eliminated as metabolites in urine by 24 h after injection while 20% is excreted in the faeces over the same period.

Reconstruction of methylmercury intakes in indigenous populations from biomarker data

Significant amounts of methylmercury (MeHg) can bioaccumulate in fish and sea mammals. To monitor MeHg exposure in individuals, organic and inorganic mercury are often measured in blood samples or in hair strands, the latter being by far the best integrator of past exposure. With knowledge of the MeHg kinetics in humans, the levels of both biomarkers can be related to MeHg body burden and intakes. In the present study, we use the toxicokinetic model of Carrier et al. (2001) describing the distribution and excretion of MeHg in humans, to reconstruct the history of MeHg intakes of indigenous women of the Inuvik region in Canada starting from total mercury concentrations in hair segments. From these reconstructed MeHg intakes, the corresponding simulated mercury blood concentrations are found to be good predictors of the concentrations actually measured in blood samples. An important conclusion of this study is that, for almost all subjects, the reconstructed history of their MeHg intakes provides much lower intake values than intakes estimated from questionnaires on food consumption and estimated MeHg levels in these foods; the mean value of the reconstructed MeHg intakes is 0.03 μg/kg/day compared with the mean value of 0.20 μg/kg/day obtained from questionnaires. The model was also used to back-calculate the MeHg intakes from concentrations in hair strands collected from aboriginals of the Amazon region in Brazil, a population significantly more exposed than the population of the Inuvik region.

Concentrations versus amounts of biomarkers in urine: a comparison of approaches to assess pyrethroid exposure.

BackgroundAssessment of human exposure to non-persistent pesticides such as pyrethroids is often based on urinary biomarker measurements. Urinary metabolite levels of these pesticides are usually reported in volume-weighted concentrations or creatinine-adjusted concentrations measured in spot urine samples. It is known that these units are subject to intra- and inter-individual variations. This research aimed at studying the impact of these variations on the assessment of pyrethroid absorbed doses at individual and population levels.MethodsUsing data obtained from various adult and infantile populations, the intra and inter-individual variability in the urinary flow rate and creatinine excretion rate was first estimated. Individual absorbed doses were then calculated using volume-weighted or creatinine-adjusted concentrations according to published approaches and compared to those estimated from the amounts of biomarkers excreted in 15- or 24-h urine collections, the latter serving as a benchmark unit. The effect of the units of measurements (volume-weighted or creatinine adjusted concentrations or 24-h amounts) on results of the comparison of pyrethroid biomarker levels between two populations was also evaluated.ResultsEstimation of daily absorbed doses of permethrin from volume-weighted or creatinine-adjusted concentrations of biomarkers was found to potentially lead to substantial under or overestimation when compared to doses reconstructed directly from amounts excreted in urine during a given period of time (-70 to +573% and -83 to +167%, respectively). It was also shown that the variability in creatinine excretion rate and urinary flow rate may introduce a bias in the case of between population comparisons.ConclusionThe unit chosen to express biomonitoring data may influence the validity of estimated individual absorbed dose as well as the outcome of between population comparisons.

Exposure Reconstruction for the TCDD-Exposed NIOSH Cohort Using a Concentration- and Age-Dependent Model of Elimination

Recent studies demonstrating a concentration dependence of elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suggest that previous estimates of exposure for occupationally exposed cohorts may have underestimated actual exposure, resulting in a potential overestimate of the carcinogenic potency of TCDD in humans based on the mortality data for these cohorts. Using a database on U.S. chemical manufacturing workers potentially exposed to TCDD compiled by the National Institute for Occupational Safety and Health (NIOSH), we evaluated the impact of using a concentration- and age-dependent elimination model (CADM) (Aylward et al., 2005) on estimates of serum lipid area under the curve (AUC) for the NIOSH cohort. These data were used previously by Steenland et al. (2001) in combination with a first-order elimination model with an 8.7-year half-life to estimate cumulative serum lipid concentration (equivalent to AUC) for these workers for use in cancer dose-response assessment. Serum lipid TCDD measurements taken in 1988 for a subset of the cohort were combined with the NIOSH job exposure matrix and work histories to estimate dose rates per unit of exposure score. We evaluated the effect of choices in regression model (regression on untransformed vs. ln-transformed data and inclusion of a nonzero regression intercept) as well as the impact of choices of elimination models and parameters on estimated AUCs for the cohort. Central estimates for dose rate parameters derived from the serum-sampled subcohort were applied with the elimination models to time-specific exposure scores for the entire cohort to generate AUC estimates for all cohort members. Use of the CADM resulted in improved model fits to the serum sampling data compared to the first-order models. Dose rates varied by a factor of 50 among different combinations of elimination model, parameter sets, and regression models. Use of a CADM results in increases of up to five-fold in AUC estimates for the more highly exposed members of the cohort compared to estimates obtained using the first-order model with 8.7-year half-life. This degree of variation in the AUC estimates for this cohort would affect substantially the cancer potency estimates derived from the mortality data from this cohort. Such variability and uncertainty in the reconstructed serum lipid AUC estimates for this cohort, depending on elimination model, parameter set, and regression model, have not been described previously and are critical components in evaluating the dose-response data from the occupationally exposed populations.

Health risk assessment for inuit newborns exposed to dioxin-like compounds through breast feeding

Inuit people living in the Arctic receive an unusually high dose of dioxin-like compounds through their traditional diet, which comprises large amounts of fatty tissues from various sea mammal species. During breast feeding, the mother transfers part of their body burden to its newborn. We estimated the impact of breast feeding on the body burden of Inuit from birth to age 75 years. Simulations performed with a toxicokinetic model revealed that breast feeding strongly influences body burden during childhood but not after age 20 years. Liver and adipose tissue concentrations expected in Inuit are well below those which induced severe adverse health effects in laboratory animals, e.g. cancer and reproduction. However, these concentrations approach levels generating subtle effects on reproductive systems.

Assessment of exposure to pyrethroids and pyrethrins in a rural population of the Montérégie area, Quebec, Canada.

Pesticide use remains a preoccupation of the population and public health authorities given its possible impact on health. Pyrethroids can be listed among the widely used pesticides. The general population is potentially chronically exposed to pyrethroids mainly through food intake, but acute or sporadic exposures can also occur by other routes. Although pyrethroids are considered among the least toxic pesticides, their neurotoxic properties can affect humans, but current exposure levels in the population of Quebec are not known. The study thus aimed at assessing pyrethroid exposure in a rural, agricultural population during summer through measurements of urinary biomarkers. A total of 163 volunteers, 49 children and 114 adults, living in the Montérégie area of Quebec, participated in the study, which took place from June to August 2006, the period of intensive application of pesticides. Participants were asked to collect all their micturitions from 6 p.m. until the next morning, including first morning void, and to fill out a questionnaire to document factors that could potentially contribute to exposure. A gas-chromatography mass-spectrometry method was used to quantify six urinary metabolites resulting from pyrethroid biotransformation: cis- and trans-2,2-(dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (cDCCA and tDCCA), 3-phenoxybenzoic acid (PBA), chrysanthemum dicarboxylic acid (CDCA), cis-2,2-(dibromovinyl)-2,2-dimethylcyclopropane carboxylic acid (DBCA) and 4-fluoro-3-phenoxybenzoic acid (FPBA). Distributions of amounts of the six metabolites excreted per unit of body weight, during a standardized 12-hr period, followed the same decreasing pattern in adults and in children: tDCCA > PBA > cDCCA > CDCA > DBCA > FPBA. No statistically significant difference was observed between the two groups, but amounts of metabolites varied greatly among individuals, suggesting important interindividual variations in the absorbed doses of these compounds. No consistent associations were observed between the excretion of correlated metabolites and the various factors documented by questionnaire (personal factors, life habits, sources of exposure). Comparison of the current data with those observed in an urban population of the same province during the summer of 2005 suggests a greater summertime exposure to some pyrethroids in the rural population.

TCDD exposure-response analysis and risk assessment

We examined the relation between cancer mortality and time-dependent cumulative exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) estimated from a concentration- and age-dependent kinetic model of elimination, and we estimated incremental cancer risks at age 75. Data from the National Institute for Occupational Safety and Health study of 3,538 workers with occupational exposure to TCDD were analyzed using standardized mortality ratios and Cox regression procedures. Analyses adjusted for potential confounding by age, year of birth, and race and considered exposure lag periods of 0, 10, or 15 years. Other potential confounders including smoking and other occupational exposures were evaluated indirectly. To explore the influence of extreme values of cumulative TCDD ppt-years, we restricted the analysis to observations with exposure below the 95th percentile or used logarithmic (ln) transformed exposure values. We applied penalized smoothing splines to examine variation in the exposure-response relation across the exposure range. TCDD was not statistically significantly associated with cancer mortality using the full data set, regardless of the lag period. When we restricted the analysis to observations with exposure below the 95th percentile, TCDD was associated positively with cancer mortality, particularly when a 15-year lag was applied (untransformed exposure data: regression coefficient , standard error (s.e.) = 1.4 x 10(-6), p < 0.05; ln-transformed exposure data: , s.e. = 2.9 x 10(-2), p < 0.05). The estimated incremental lifetime risk of mortality at age 75 from all cancers was about 6 to more than 10 times lower than previous estimates derived from this cohort using exposure models that did not consider the age and concentration dependence of TCDD elimination.

Estimation of annual Mn emissions from MMT source in the Canadian environment and the Mn pollution index in each province

Methylcyclopentadienyl manganese tricarbonyl (MMT), is an organic derivative of Mn used as an anti-knock agent in Canadian unleaded gasoline since 1976. This study aims to estimate Mn emissions from MMT source in the Canadian environment as well as the Mn pollution index per capita in each of the Canadian provinces. In concomitance, lead emissions will also be addressed. The quantities of Mn and Pb used in gasoline were calculated from data on annual gasoline sales in Canada supplied by Statistics Canada. Obviously, the Pb emission profile shows a substantial decrease with an annual average of -28% until 1991, when MMT totally replaced Pb in Canadian gasoline. The case of Mn is quite different. Since emission rates of Mn at the tailpipe vary between 6 and 45%, the quantities released into the atmosphere were calculated for each of these rates, as well as for 100 and 25% emission rate scenarios. For 1981 and 1999, the quantities of Mn used in gasoline were estimated at 101122 and 344880 kg, respectively. Based on the realistic 25% emission rate scenario and a concentration of 0.009 g/l of Mn in gasoline, Mn emissions from car exhausts were estimated to 25280 and 86220 kg, respectively. The mean annual increase in emission rate between 1981 and 1999 is 7.34%. The atmospheric Mn pollution index seems to be stable over time, and it varies from 0.0024 kg/capita to 0.0041 kg/capita in 1999. In the context of a notable decrease in Mn emissions from industrial sources, these results suggest that the combustion of MMT used in gasoline may be an important factor contributing to maintaining stable atmospheric Mn concentrations instead of a significant decrease due to reduced industrial emissions.