Study of selenium intake and disposition in various matrices based on mathematical algorithms derived from pooled biomonitoring data.

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 (R(2)=0.884), plasma concentrations (R(2)=0.863) and urinary excretion rates (R(2)=0.958). Blood and plasma concentrations were also strongly related (R(2)=0.874), as were whole blood concentrations and urinary excretion rates (R(2)=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.

A novel toxicokinetic modeling of cypermethrin and permethrin and their metabolites in humans for dose reconstruction from biomarker data.

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.

Systematic analysis of the relationship between standardized biological levels of polychlorinated biphenyls and thyroid function in pregnant women and newborns.

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 (µg PCBMPEQ kg(-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<1000 µg PCBMPEQ kg(-1) lipids) appears low according to this systematical analysis.

Systematic analysis of the relationship between standardized prenatal exposure to polychlorinated biphenyls and mental and motor development during follow-up of nine children cohorts.

Impact of prenatal exposure to polychlorinated biphenyls (PCBs) on mental and motor development has been investigated in various children cohorts, but findings show temporal inconsistencies. Because a direct comparison of results obtained from different cohorts remains difficult, temporal relationship between biological PCB concentrations and long-term developmental effects is still not clearly established. The objective of this research was to use a procedure previously developed to standardize PCB biological concentration data across cohorts in order to perform a systematic analysis of temporal associations between prenatal PCB exposure and mental and motor development from neonatal period (or a young age) until school age. Prenatal exposure data from nine cohorts were standardized in terms of total PCBs per kg of lipids in maternal plasma. Systematic analysis of the "standardized biological concentration-development" relationship during follow-up of each cohort was then conducted through the application of Hill criteria. This led to retain six of the studied cohorts in the final analysis. A biological level of prenatal PCB exposure below which risk of mental or motor development should be negligible was established in the order of 1000µg/kg of lipids in maternal plasma.

Relationship between prenatal exposure to polychlorinated biphenyls and birth weight: a systematic analysis of published epidemiological studies through a standardization of biomonitoring data.

Impact of prenatal PCB exposure on birth weight was investigated in various children cohorts and findings of published studies show inconsistencies. Because a direct comparison of results obtained from different studies remains difficult, the "biological concentration-birth weight" relationship is not clearly established. The objective of this research was to perform a systematic analysis of published epidemiological data to reassess relationship between prenatal PCB exposure and low birth weight, using toxicokinetic considerations and a novel standardization procedure of biological concentration data across studies. A systematic analysis of 20 epidemiological studies published up to 2011 on this topic was conducted. This was achieved through a standardization of reported exposure data in terms of total PCBs per kg of lipids in maternal plasma. Systematic analysis of the "standardized biological concentration-birth weight" relationship across studies was then conducted through the application of Hill criteria. Combining results of all 20 reviewed studies did not allow to establish an association between prenatal exposure to PCBs at the described levels and abnormal birth weight (<2500g). Our approach provides a framework for the use of published data to establish "PCB biological concentration-response" relationships.

Comparison of a toxicokinetic and a questionnaire-based approach to assess methylmercury intake in exposed individuals.

Methylmercury (MeHg) is a neurotoxic contaminant and one of the main sources of exposure in humans is seafood consumption. It is thus of interest to assess precisely MeHg exposure. The objective of this study was to estimate MeHg daily intake in exposed individuals using two different approaches, a food questionnaire and toxicokinetic modeling, and compare the complementary and use of each method. For this purpose, a group of 23 fishermen from northern Quebec provided blood and hair samples and answered a standard food questionnaire focusing on seafood consumption. A published and validated toxicokinetic model was then used to reconstruct MeHg daily intakes from mercury (Hg) measurements in biological samples. These intakes were compared to those estimated using a standard food questionnaire on seafood consumption. Daily intakes of MeHg from seafood (mean/median (range)) estimated from hair concentrations with the toxicokinetic-based approach were 6.1/5.2 (0.0-19) µg/day. These intake values were on average six times lower than those estimated using a food questionnaire, that is, 49/32 (7.2-163) µg/day. No correlation was found between the toxicokinetic-based and the questionnaire estimates of MeHg daily intakes. Most of the MeHg intakes estimated with the food questionnaire (21/23) exceeded the US EPA RfD of 0.1 µg/kg bw/day, whereas only a small proportion (6/23) of modeled estimates exceeded the RfD. This study shows that human health risk estimates strongly depend on the chosen approach.

Disposition kinetics of selenium in healthy volunteers following therapeutic shampoo treatment.

This study was aimed at documenting the kinetic time courses of selenium (Se) in accessible biological matrices of volunteers following controlled applications of therapeutic shampoo containing Se, to better elucidate the mechanisms by which shampoo-Se accumulates in hair and hence estimate the contribution of this source to total Se body burden. Ten healthy volunteers were exposed to Se-shampoo three times a week over a month. Blood, hair and toenail concentrations along with daily urinary excretions were repeatedly measured over an 18-month period following the onset of application. Over the entire study period, blood concentrations of Se (range: 127-233µg/l) and daily urinary excretions (range: 11.9-150µg/d) remained within baseline range of the general population. Conversely, during shampoo application, mean Se concentrations in hair reached transitional levels of 89µg/g while, following cessation of treatment, a mono-exponential decrease was observed with a mean half-life of 4.5 weeks. Two of the volunteers also exhibited an increase in toenail concentrations of Se during the study period. Results show that Se-shampoo does not contribute significantly to total Se body burden, as assessed from blood and urine levels. Differences observed between blood and urine time courses as compared to hair profiles and the presence of Se on hair grown before treatment indicates an adsorption on hair; however, the gradual decrease in Se concentrations in successive centimeters of hair grown following the application period suggests a concomitant absorption from the scalp during treatment with subsequent excretion in hair.

Determination of carboxyhaemoglobin in humans following low-level exposures to carbon monoxide.

This study proposes to estimate carboxyhaemoglobin (COHb) levels in the blood of men and women of various ages exposed to common concentrations of carbon monoxide (CO) using a model with only one free parameter while integrating alveoli-blood and blood-tissue CO exchanges. The model retained is essentially that of Coburn et al. (1965) with two important additions: an alveoli compartment for the dynamics of CO exchanges between alveoli and blood, and a compartment for the significant amounts of CO bound to heme proteins in extravascular spaces. The model was validated by comparing its simulations with various published data sets for the COHb time profiles of volunteers exposed to known CO concentrations. Once the model was validated, it was used to simulate various situations of interest for their impact on public health. This approach yields reliable estimations of the time profiles of COHb levels resulting from different levels of CO exposure over various periods of time and under various conditions (resting, exercise, working, and smoking). The non-linear kinetics of CO, observed experimentally, were correctly reproduced by simulations with the model. Simulations were also carried out iteratively to determine the exposure times and CO concentrations in ambient air needed to reach the maximum levels of COHb recommended by Health Canada, the U.S. Environmental Protection Agency (EPA), and the World Health Organisation (WHO) for each age group of the general population. The lowest CO concentrations leading to maximum COHb levels of 1.5, 2, and 2.5% were determined.

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.

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

BACKGROUND: Assessment 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. METHODS: Using 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. RESULTS: Estimation 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. CONCLUSION: The unit chosen to express biomonitoring data may influence the validity of estimated individual absorbed dose as well as the outcome of between population comparisons.

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.

Assessment of absorbed doses of carbaryl and associated health risks in a group of horticultural greenhouse workers.

OBJECTIVE: This study was undertaken to estimate the absorbed doses of carbaryl and the associated health risks in a group of horticultural greenhouse workers in the Province of Quebec, Canada, using a toxicokinetic modeling approach. METHODS: A mathematical model was developed to relate the absorbed dose of carbaryl, the evolution of its body burden and that of its metabolites and the urinary excretion rate of biomarkers. The free parameters of this model were determined using published time course data in volunteers exposed to carbaryl under controlled conditions. The model was used to determine cumulative urinary amounts of 1-naphthol that would be excreted by a typical worker exposed to a pre-established no-observed-adverse-effect level (NOAEL) dose; this biomarker amount was then taken as a biological reference value below which the risks of health effects were considered negligible. As a measure of the applicability of this approach to practical situations, the model was used to estimate the dose of carbaryl absorbed by each greenhouse worker, starting from his/her cumulative urinary excretion time courses of 1-naphthol over a 24-h period following the onset of a work exposure. Their cumulative 1-naphthol levels were then compared to the biological reference value obtained from the model and the NOAEL dose. RESULTS: Following the onset of a work exposure to carbaryl, a clear increase in the urinary excretion rate of 1-naphthol was observed in most workers. The reconstructed absorbed doses were found to vary between 3.3 and 143 nmol/kg of body weight (bw) depending on the working conditions. Simulations of the observed cumulative urinary excretion time course of each worker also showed that exposure appeared to occur mainly (a) through inhalation for the applicators and individuals without direct contact with treated plants and (b) through the dermal route for individuals manipulating treated plants. Although the workers under study clearly appeared to have been exposed to carbaryl in the greenhouses, 24-h cumulative 1-naphthol levels ranged from 4.8 to 65.1% of the proposed biological reference value of 32 nmol/kg bw in 24-h urine collections following the onset of a work exposure. CONCLUSION: This suggests that the workers under study probably did not incur a serious health risk under the normal exposure conditions prevailing during the study period.

Evaluation of the health impact of lowering the formaldehyde occupational exposure limit for Quebec workers.

This study aimed at assessing the impact on irritating effects of lowering the current occupational exposure limit (OEL) for formaldehyde in occupational settings in the Province of Quebec, Canada, from a 2 ppm ceiling value to 1, 0.75 or 0.3 ppm. This was achieved through (i) a re-assessment of the exposure-response relationship based on a pooled analysis of published controlled human studies on the incidence of the most sensitive effects related to acute formaldehyde exposure (irritation of the eyes, nose and throat) and (ii) application of this relationship to the data on current exposure to formaldehyde in industrial sectors of Quebec. Results show that the exposure-irritating effect relationship compiled by concentration ranges and by degree of severity was best described by quadratic regression. Considering the current distribution of formaldehyde exposure among the 143,491 Quebec workers concerned, eye irritation, the most sensitive effect, could affect 526 workers (0.367%) at a moderate degree and 50 workers (0.035%) at a severe degree. By reducing the OEL to 1, 0.75 and 0.3 ppm, the proportion of these effects estimated to be avoided would be 442/526 (84%), 526/526 (100%) and 526/526 (100%), respectively. Results for nose and throat irritation follow the same trend. The greatest gain would thus be obtained by respecting the current OEL; the additional gain was estimated to be negligible below 0.75 ppm. The level of 0.75 ppm can be considered as a safe level that allows protecting virtually all workers.

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.

Biological monitoring of exposure to organophosphorus insecticides in a group of horticultural greenhouse workers.

Exposure to selected organophosphorus insecticides (OPs), malathion, diazinon and acephate, was evaluated in a group of horticultural greenhouse workers. This was achieved through measurements of the cumulative urinary excretion time courses of specific and non-specific biomarkers over a 24 h period following the onset of work exposure. For malathion, the absorbed daily doses were estimated from the 24 h cumulative urinary amounts of the specific mono- and di-carboxylic acid metabolites (the sum of MCA and DCA) through the use of a kinetic model. The observed 24 h urinary levels were also compared with a biological reference value (BRV) of 57 nmol kg(-1) of body weight established in a previous work on the basis of a human no-observed-effect level exposure dose. Excretion values were found to be 2.5% or less of the BRV, suggesting a negligible health risk. Both median and 95th percentile concentrations of DCA (n = 57 samples) were, however, slightly higher than the baseline values determined by the Centers for Disease Control and Prevention (CDC) in the US civilian population (MCA was not analyzed by the CDC). The cumulative urinary excretion time course of the methyl phosphoric (MP) derivatives, which are metabolites of malathion but also of several other OPs, was also determined. Though relatively low, the MP levels were from 3 to 31 times higher than would be expected on the basis of the malathion specific MCA and DCA excretions, indicating that MP excretions stem from sources other than malathion exposure. Accordingly, only the time courses of MCA and DCA excretion rate (nmol h(-1)) were compatible with the time of work exposure. Urinary biomarkers of exposure to diazinon and acephate were also measured. Urinary concentrations were essentially below or equal to the analytical limit of detection of 1 microg l(-1) for 2-isopropyl-4-methyl-6-hydroxypyrimidine (n = 54) and of 0.8 microg l(-1) for acephate and methamidophos (n = 59): values within the baseline range of the US civilian population, like the observed phosphoric metabolite concentrations. The workers under study thus appeared to be only slightly more exposed to malathion than the general population. However, their overall exposure to OPs, as measured by non-specific phosphoric metabolites, was similar to that of the general population, whose exposure occurs mainly through the ingestion of contaminated food. These results question the relevance of measuring non-specific phosphoric metabolites when attempting to assess low-dose occupational exposure to a specific OP.

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 microg/kg/day compared with the mean value of 0.20 microg/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.

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.

Determination of biological reference values for chlorpyrifos metabolites in human urine using a toxicokinetic approach.

Urinary biomarkers of chlorpyrifos (CPF) exposure are often measured in field studies, although biological reference values (BRVs) are not yet available to assess health risks. This study aimed at proposing BRVs for CPF metabolites in workers' urine based on a toxicokinetic approach. As a first step, a toxicokinetic model was developed, using published human kinetic data, to link the absorbed dose of CPF under a variety of exposure routes and temporal scenarios to the urinary excretion of its major metabolites, 3,5,6-trichloro-2-pyridinol (3,5,6-TCP) and alkyl phosphates (AP). The model was then used to propose BRVs for CPF metabolites in urine below which workers should not experience adverse health effects. This was achieved by linking (1) a literature-reported, repeated CPF no-observed-effect level (NOEL) daily exposure dose for the inhibition of red-blood-cell acetylcholinesterase activity to a corresponding absorbed daily dose, and (2) this absorbed daily dose to the urinary excretion of CPF metabolites. Model simulations under a variety of exposure scenarios showed that the safest BRVs are obtained from a dermal exposure scenario with the slowest absorption rate compatible with available literature data rather than from respiratory or oral exposure scenarios. Also, model simulations showed that, for a given total absorbed dose, absorption over 8 hours results in smaller 3,5,6-TCP and AP urinary excretion rates than those obtained from the same dose absorbed over shorter durations. From these considerations, BRVs were derived by simulating an 8-hour dermal CPF exposure such that the total absorbed daily dose corresponds to the absorbed NOEL. The reference values are proposed in the form of total amounts of 3,5,6-TCP and AP metabolites excreted in urine over chosen time periods (24 and 48 hours).

Worker exposures to triclopyr: risk assessment through measurements in urine samples.

In the province of Quebec (Canada), the phytocide Garlon 4, whose active ingredient is triclopyr, is often used to prevent trees from reaching electrical conductors. The object of this paper is to assess the potential health risks in workers coming into contact with Garlon 4. Ten workers collected their urine during the 22 h following the beginning of a work shift. Measured urinary amounts of triclopyr varied between 1 and 13 mg. The absorbed daily doses were estimated from the amounts of triclopyr in urine through the use of a kinetic model that links the rates of triclopyr elimination to absorbed doses. These estimated doses were compared with the no-observed-effect level (NOEL) observed in rats: 5 mg per kg of body weight. The upper-bound estimations of the worker's daily absorbed doses were found to be 13.3% or less of the rat NOEL.

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 TCDD's carcinogenic potency based on such data.