Estimating potential cardiovascular health benefits of improved population level control of LDL cholesterol through a twice-yearly siRNA-based approach: A simulation study of a health-system level intervention.

BACKGROUND AND AIMS: Inclisiran, an siRNA therapy, consistently reduces low-density lipoprotein cholesterol (LDL-C) with twice-yearly dosing. Potential cardiovascular benefits of implementing inclisiran at a population level, added to statins, were evaluated through simulation. METHODS: For each participant in the ORION-10 and ORION-11 trials comparing inclisiran with placebo, baseline 10-year cardiovascular risk was estimated using the SMART equation. The time-adjusted LDL-C difference from baseline observed 90-540 days after baseline was assumed to persist and used to estimate potential reduction in 10-year cardiovascular risk. Impact on 500,000 ORION-like individuals was simulated with Monte-Carlo. RESULTS: Mean baseline LDL-C and predicted 10-year major vascular risk among patients randomized to inclisiran (n = 1288) versus placebo (n = 1264) were 2.66 mmol/L versus 2.60 mmol/L and 24.9% versus 24.6%, respectively. Placebo-corrected time-adjusted absolute reduction in LDL-C with inclisiran was -1.32 mmol/L (95% CI -1.37 to -1.26; p < 0.001), which predicted a 10-year cardiovascular risk of 18.1% with inclisiran versus 24.7% with placebo (absolute difference [95% CI], -6.99% [-7.33 to -6.66]; p < 0.001) NNT 15. Extrapolating to 500,000 inclisiran-treated individuals, the model predicted large population shifts towards lower quintiles of risk with fewer remaining in high-risk categories; 3350 to 471 (≥80% risk), 11,793 to 3332 (60-<80% risk), 52,142 to 22,665 (40-<60% risk), 197,752 to 141,014 (20-<40% risk), and more moving into the lowest risk category (<20%) from 234,963 to 332,518. CONCLUSIONS: Meaningful gains in population health might be achieved over 10 years by implementing at-scale approaches capable of providing substantial and sustained reductions in LDL-C beyond those achievable with statins.

Translational Population-Pharmacodynamic Modeling of a Novel Long-Acting siRNA Therapy, Inclisiran, for the Treatment of Hypercholesterolemia.

Inclisiran is a novel N-acetylgalactosamine (GalNAc) conjugated small-interfering ribonucleic acid (siRNA) therapy designed to specifically target proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA in the liver for the treatment of hypercholesterolemia. Inclisiran's GalNAc attachment results in a rapid uptake into the liver, and thus a short plasma half-life, but long duration of effects on PCSK9 inhibition and low-density lipoprotein cholesterol (LDL-C) lowering. The effects on PCSK9 inhibition and consequent LDL-C reduction are sustained for more than 6 months following a single subcutaneous (s.c.) dose, despite inclisiran being detectable in the plasma only for up to 48 hours. A kinetic-pharmacodynamic (K-PD) model was developed to characterize inclisiran's dose-related LDL-C lowering effects and to evaluate the impact of intrinsic and extrinsic factors on LDL-C lowering. To accommodate the long duration of action, the K-PD model incorporated an effect compartment which represents the liver. Inclisiran concentration in the liver leads to decreased production of the PCSK9 protein and allow recycling of more LDL-C receptors on the hepatocyte cell surface, which results in a reduction of circulating LDL-C. The analysis of covariates identified PCSK9 and LDL-C baseline levels as important factors for the effects of LDL-C lowering. Observations and modeling and simulation results demonstrated that PCSK9 and LDL-C reductions are achieved rapidly after dosing and sustained when patients are treated with a 300 mg s.c. dose once every 6 months.

Population Pharmacokinetics of Heptanoate in Healthy Subjects and Patients With Long-Chain Fatty Acid Oxidation Disorders Treated With Triheptanoin.

Triheptanoin is an odd-carbon, medium-chain triglyceride consisting of three fatty acids with seven carbons each on a glycerol backbone, indicated for the treatment of adult and pediatric patients with long-chain fatty acid oxidation disorders (LC-FAOD). A total of 562 plasma concentrations of heptanoate, the most abundant and pharmacologically active metabolite of triheptanoin, from 13 healthy adult subjects and 30 adult and pediatric subjects with LC-FAOD were included in the population pharmacokinetic (PK) analyses. Multiple peaks of heptanoate observed in several subjects were characterized by dual first-order absorption with a lag time in the second absorption compartment. The disposition of heptanoate in human plasma was adequately described by one-compartmental distribution with a linear elimination. The apparent clearance (CL/F) and apparent volume of distribution were allometrically scaled with body weight to describe PK data across a wide range of age groups in subjects with LC-FAOD. The typical CL/F in adult subjects with LC-FAOD was ≈19% lower than that in healthy subjects. Model-estimated elimination half-life for LC-FAOD patients was ∼1.7 hours, supporting a recommended dosing frequency of ≥4 times per day. Covariate analyses indicate that age, race, and sex did not lead to clinically meaningful changes in the exposure of heptanoate.

Population Pharmacokinetics and Pharmacodynamics of Burosumab in Adult and Pediatric Patients With X-linked Hypophosphatemia.

Burosumab is a fully human monoclonal antibody against fibroblast growth factor 23, which has been approved to treat X-linked hypophosphatemia (XLH) in adult and pediatric patients. The present work describes the pharmacokinetics (PK) of burosumab and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between burosumab and serum phosphorus in adult and pediatric patients with XLH. A total of 2844 measurable serum concentrations of burosumab and 6047 measurable serum concentrations of phosphorus in 277 subjects from 9 clinical studies were included in the population PK and PK-PD modeling. The serum concentration of burosumab following a subcutaneous administration was well described by a population PK model comprising a first-order absorption, 1-compartmental distribution, and a linear elimination. The relationship between serum burosumab and serum phosphorus was adequately described by a sigmoid maximal efficacy model. Body weight was the only covariate associated with PK and PK-PD parameters. No other intrinsic factors affected PK or PK-PD relationship in adult and pediatric patients with XLH. Further simulations helped to guide the dosing regimen of burosumab in adult and pediatric patients with XLH including age groups with no clinical data.

Population Pharmacokinetic-Pharmacodynamic Model of Serum Transthyretin Following Patisiran Administration.

Hereditary transthyretin-mediated amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by mutated transthyretin (TTR) protein. Patisiran is a small interfering RNA (siRNA) formulated in a lipid nanoparticle that inhibits hepatic TTR protein synthesis by RNA interference. We have developed an indirect-response pharmacokinetic-pharmacodynamic model relating plasma siRNA (ALN-18328) levels to serum TTR reduction across five clinical studies. A sigmoidal function described this relationship, with estimated Hill coefficient of 0.548, and half maximal inhibitory concentration (IC50), IC80, and IC90 values of 9.45, 118.5, and 520.5 ng/mL, respectively. Following patisiran 0.3 mg/kg every 3 weeks (q3w), steady-state plasma ALN-18328 exposures were between IC80 and IC90, yielding average serum TTR reductions of 80%-90% from baseline. Covariate analysis indicated similar TTR reduction across evaluated intrinsic and extrinsic factors, obviating the need for dose adjustment. Modeling results support the recommended patisiran dosing schedule of 0.3 mg/kg q3w, with a maximum dose of 30 mg for patients weighing ≥100 kg.

Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants.

Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo-controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients (<2 years of age) who were undergoing surgery or had experienced a traumatic injury and were expected to need pain management for at least 24 hours were enrolled. Subjects were randomly assigned to receive intravenous acetaminophen low dose, intravenous acetaminophen high dose, or placebo. A population PK model of intravenous acetaminophen was updated by combining 581 samples from the current study of 158 neonate and infant subjects with results from a previously developed model. The individual predicted-versus-observed concentrations plots showed that the structural PK model fit the blood and plasma acetaminophen concentration-versus-time profiles in the active and placebo groups. Terminal elimination half-life was prolonged in neonates and younger infants and in intermediate and older infants similar to values in adults. When compared with placebo, total rescue opioid consumption was similar and significantly fewer intravenous acetaminophen patients prematurely discontinued because of treatment-emergent adverse events (P < .01). For intravenous acetaminophen, neonates receiving 12.5 mg/kg every 6 hours had PK profiles similar to younger, intermediate, and older infants, adolescents, and adults weighing <50 kg receiving 15 mg/kg every 6 hours and adults ≥ 50 kg receiving 1000 mg every 6 hours.

A randomized, double-blind, placebo-controlled, pharmacokinetic and pharmacodynamic study of a fixed-dose combination of phentermine/topiramate in adolescents with obesity.

AIMS: To assess the pharmacokinetic (PK) and pharmacodynamic characteristics of VI-0521, a fixed-dose combination of immediate-release phentermine (PHEN) and extended-release topiramate (TPM) in adolescents aged 12 to 17 years with obesity, and to report weight loss and adverse events using this drug combination. MATERIALS AND METHODS: This was a multicentre, randomized, double-blind, parallel-design, placebo-controlled study in adolescents with obesity. A total of 42 adolescents were randomly assigned in a 1:1:1 ratio to placebo, or to a mid-dose (PHEN/TPM 7.5 mg/46 mg), or a top-dose (PHEN/TPM 15 mg/92 mg) of VI-0521. A total of 26 adolescents were included in the PK analysis (14 from the mid-dose group and 12 from the top-dose group). RESULTS: On day 56, arithmetic means of terminal elimination half-life, apparent clearance (CL/F) and apparent central volume of distribution (Vc/F) were consistent across dose levels for both PHEN and TPM. Arithmetic means of CL/F and Vc/F for PHEN and TPM administered as a combination in adolescents with obesity were within 10% to 30% of those previously assessed in adults with obesity enrolled in phase II and III studies. A higher proportion of adolescents in both the mid- and top-dose groups (13.3% and 50.0%, respectively) compared with placebo (0.0%) reached ≥5% weight loss at day 56. The least squares (LS) mean change in systolic blood pressure from baseline to day 56 was -5.2 mmHg for the placebo group, -2.5 mmHg for the mid-dose group, and - 5.5 mmHg for the top-dose group. The LS mean change in diastolic blood pressure from baseline to day 56 was -2.4 mmHg for the placebo group, +3.8 mmHg for the mid-dose group, and + 2.0 mmHg for the top-dose group. Participants in the top-dose group had increases in heart rate from baseline of 4.1 bpm, while participants in the mid-dose group experienced a mean decrease in heart rate of 4.5 bpm at day 56. Both PHEN/TPM dose combinations were safe and well tolerated. CONCLUSIONS: Treatment of adolescents with obesity using a fixed-dose combination of PHEN/TPM for 8 weeks resulted in exposure to PHEN and TPM that was comparable to that observed in adults, statistically significant weight loss, and a tolerable safety profile. These data indicate that both mid- and top-dose levels are appropriate for longer-term safety and efficacy studies in adolescents.

Population pharmacokinetics of bevacizumab in cancer patients with external validation.

BACKGROUND: Bevacizumab is approved for various cancers. This analysis aimed to comprehensively evaluate bevacizumab pharmacokinetics and the influence of patient variables on bevacizumab pharmacokinetics. METHODS: Rich and sparse bevacizumab serum concentrations were collected from Phase I through IV studies in early and metastatic cancers. Bevacizumab was given intravenously as single agent or in combination with chemotherapy for single- and multiple-dose schedules. RESULTS: Model-building used 8943 bevacizumab concentrations from 1792 patients with colon/colorectal, non-small cell lung, kidney, pancreatic, breast, prostate and brain cancer. Bevacizumab doses ranged from 1 to 20 mg/kg given once every 1, 2 or 3 weeks. A two-compartment model best described the data. The population estimates of clearance (CL), central volume of distribution (V1) and half-life for a typical 70-kg patient were 9.01 mL/h, 2.88 L and 19.6 days. CL and V1 increased with body weight and were higher in males than females by 14 and 18 %, respectively. CL decreased with increasing albumin and decreasing alkaline phosphatase. The final model was externally validated using 1670 concentrations from 146 Japanese patients that were not used for model-building. Mean prediction errors were -2.1, 3.1 and 1.0 % for concentrations, CL and V1, respectively, confirming adequate predictive performance. CONCLUSIONS: A robust bevacizumab pharmacokinetic model was developed and externally validated, which may be used to simulate bevacizumab exposure to optimize dosing strategies. Asian and non-Asian patients exhibited similar bevacizumab pharmacokinetics. Given the similarity in pharmacokinetics among monoclonal antibodies, this may inform pharmacokinetic studies in different ethnic groups for other therapeutic antibodies.

Population pharmacokinetic and pharmacodynamic analyses from a 4-month intradose escalation and its subsequent 12-month dose titration studies for a human monoclonal anti-FGF23 antibody (KRN23) in adults with X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is an inherited metabolic bone disease with abnormally elevated serum FGF23 resulting in low renal maximum threshold for phosphate reabsorption, low serum phosphate (Pi) and 1,25-dihydroxyvitamin D levels with subsequent development of short stature and skeletal deformities. KRN23 is a novel human anti-FGF23 antibody for the treatment of XLH. The pharmacokinetics (PK) and pharmacodynamics (PD) models of KRN23 were assessed following subcutaneous dosing every 28 days over an initial 4-month dose escalation (0.05-0.6 mg/kg) and a subsequent 12-month titration period (0.1-1.0 mg/kg) in XLH adults. The PK of KRN23 was described by a 1-compartmental model with first-order absorption and elimination at doses ≥0.1 mg/kg. The elimination half-life was 17.8 days. Covariates did not affect KRN23 PK. Mean peak serum Pi was attained 7-10 days after dosing and progressively increased following each of the initial 4 doses with comparable peak values attained following the sixth through tenth doses with a slight decrease thereafter. A PK-PD model with a maximum effect (Emax ) and a time-varying effective concentration to reach 50% of Emax (EC50,t ) described data adequately. Typical Emax was 1.5 mg/dL. Typical EC50,t was 1780 ng/mL and 5999 ng/mL after first and last dose, respectively.

Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation.

AIM: The aim of the present study was to evaluate the pharmacokinetics of bevacizumab and various dosing strategies for this agent in paediatric patients. METHODS: Data were collected from 232 paediatric patients (1971 concentrations) in five studies, with a wide range of age (0.5-21 years), body weight (BWT; 5.9-125 kg), and regimens (5-15 mg kg(-1) biweekly or triweekly). Data from 152 patients (1427 concentrations) and 80 patients (544 concentrations) were used for model building and external validation, respectively. Steady-state exposure was simulated under BWT-based, body surface area (BSA)-based, ideal body weight (IBW)-based, and tier-based doses. NONMEM and R were used for analyses. RESULTS: Typical estimates of clearance, central volume of distribution (V1), and median half-life were 9.04 ml h(-1) , 2851 ml, and 19.6 days, respectively. Clearance decreased with increasing albumin. Clearance and V1 increased with BWT and were higher in male patients. Clearance and V1 were lower in children with primary central nervous system (CNS) tumours than in children with sarcomas, resulting in 49% higher trough (C min) and 29% higher peak (Cmax) concentrations. BWT-adjusted clearance and V1 remained unchanged across ages. Paediatric C min was similar to adult C min under all dosing strategies. Paediatric Cmax exceeded adult Cmax under tier-based doses. CONCLUSIONS: BWT-adjusted pharmacokinetic parameter estimates in paediatric patients were similar to those in adults, and similar across ages. Bevacizumab exposure was higher in children with primary CNS tumours than in children with sarcomas. BSA-based, IBW-based, and tier-based doses offered no substantial advantage over the BWT-based dose currently used in adults for bevacizumab. Given the similarity in pharmacokinetics among many monoclonal antibodies, this may help to develop practical paediatric dosing guidelines for other therapeutic antibodies.

Population pharmacokinetic modeling of motesanib and its active metabolite, M4, in cancer patients.

Motesanib is a small molecule and potent multikinase inhibitor with antiangiogenic and antitumor activity. Population pharmacokinetic (POPPK) modeling of motesanib and M4, an active metabolite, was performed to assess sources of variability in cancer patients. The analysis included data collected from 451 patients from 8 clinical trials with oral doses of motesanib ranging from 25 to 175 mg, either once daily or twice daily. The POPPK analyses were performed using nonlinear mixed-effect models with a sequential approach. Covariate effects of demographics and other baseline characteristics were assessed with stepwise covariate modeling. A 2-compartment model with food effect on absorption parameters fitted the PK data of motesanib well. The effects albumin and sex on apparent clearance (CL/F) of motesanib were statistically significant. The albumin effect was more important but remained below a 25% difference. A 1-compartment model fitted PK data of M4 well. Effects of race (Asian vs non-Asian) and dosing frequency were identified as statistically significant covariates on the CL/F of M4. The maximum effect of albumin would result in less than 25% change in motesanib CL/F and as such would not warrant any dosing adjustment. However, faster elimination of M4 in Asian patients requires further investigation.

Population pharmacokinetic analysis of dutogliptin, a selective dipeptidyl peptidase-4 inhibitor.

Dutogliptin is a selective dipeptidyl peptidase-4 inhibitor shown to be efficacious and safe in patients with type 2 diabetes mellitus (T2DM). Population pharmacokinetic (PK) analysis of dutogliptin was performed based on data collected in 561 healthy subjects and patients with T2DM enrolled in Phase I and II studies to assess sources of variability and support dosing rationale. The effect of extrinsic (formulations, fed/fasting conditions, potential drug-drug interaction with metformin) and intrinsic (baseline characteristics, markers of renal function, renal impairment category, and disease status) covariates was evaluated using non-linear mixed effect modeling. Plasma concentrations of dutogliptin were best fitted with a two-compartment model with a first-order rate constant of absorption (Ka) and a lag time. No differences were observed between healthy subjects and patients with T2DM. Apparent clearance (CL/F) and terminal elimination half-life of dutogliptin were 176 L/h and 12.2 hours, respectively. Typical CL/F values in patients with mild and moderate renal impairment were 121 and 79 L/h, respectively. No drug-drug interaction was observed with metformin. These results suggest that a reduction in dosing from 400 to 200 mg daily is warranted in T2DM patients with moderate renal impairment. No dose adjustments were deemed necessary for other evaluated patient characteristics and coadministration with metformin.

Pharmacokinetic and pharmacodynamic modeling to determine the dose of ST-246 to protect against smallpox in humans.

Although smallpox has been eradicated, the United States government considers it a "material threat" and has funded the discovery and development of potential therapeutic compounds. As reported here, the human efficacious dose for one of these compounds, ST-246, was determined using efficacy studies in nonhuman primates (NHPs), together with pharmacokinetic and pharmacodynamic analysis that predicted the appropriate dose and exposure levels to provide therapeutic benefit in humans. The efficacy analysis combined the data from studies conducted at three separate facilities that evaluated treatment following infection with a closely related virus, monkeypox virus (MPXV), in a total of 96 NHPs. The effect of infection on ST-246 pharmacokinetics in NHPs was applied to humans using population pharmacokinetic models. Exposure at the selected human dose of 600 mg is more than 4-fold higher than the lowest efficacious dose in NHPs and is predicted to provide protection to more than 95% of the population.

Differential Pharmacokinetics of Ganitumab in Patients With Metastatic Pancreatic Cancer Versus Other Advanced Solid Cancers.

Ganitumab is an investigational, fully human monoclonal antibody antagonist of the insulin-like growth factor-1 receptor (IGF1R) that has shown trends towards improved progression-free survival and overall survival in a phase 2 pancreatic cancer clinical trial. To characterize ganitumab pharmacokinetics (PK) and identify factors affecting PK, ganitumab serum concentration data from three clinical trials were analyzed. The PK of ganitumab as monotherapy and in combination with gemcitabine in patients with pancreatic or non-pancreatic cancer were assessed with a non-linear mixed-effect model. We found that ganitumab exhibited linear and time-invariant kinetics. A two-compartment model adequately described data over a dose range of 1-20 mg/kg with good predictive capability. Typical clearance and central volume of distribution values were 1.7- and 1.3-fold higher, respectively, in patients with pancreatic cancer than in patients with other advanced solid cancers, resulting in lower ganitumab exposure. Covariate analysis was used to evaluate effects of cancer type, gemcitabine coadministration, clinical study, demographics, and laboratory values on ganitumab PK. Pancreatic cancer type was the most significant covariate on clearance along with weight, albumin, and serum creatinine. Gemcitabine coadministration did not affect ganitumab clearance. Thus, disease state can significantly affect PK and should be considered when selecting the clinically effective dose.

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.

Population pharmacokinetics of teduglutide following repeated subcutaneous administrations in healthy participants and in patients with short bowel syndrome and Crohn's disease.

Teduglutide is a GLP-2 analog currently evaluated for the treatment of short bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The population pharmacokinetics (PK) of teduglutide were assessed following daily subcutaneous (SC) administrations of 2.5 to 80 mg doses in a total of 256 patients. A 1-compartment model with a site-specific rate constant of absorption in the abdomen, arm, and thigh was used to assess the PK of teduglutide. Apparent clearance (CL/F) of teduglutide in male participants was approximately 18% higher than that observed in female participants (12.4 vs 10.5 L/h, respectively). Body weight was detected as a significant covariate explaining the volume of distribution of teduglutide. The elimination half-life (t((1/2))) of teduglutide was also influenced by the body weight of participants. For a male patient weighing 50 and 90 kg, t((1/2)) of teduglutide was 0.897 and 2.99 hours, respectively. Renal and hepatic function of patients did not affect the PK of teduglutide. As a result, no dose adjustment was deemed necessary in patients with altered renal or liver function. The population PK model will help to support adequate drug labeling following SC administrations in patients and determine whether an individualized dosage is required.

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.

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.

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.