Intrinsic Elimination Half-life Research Articles

Historical human exposure to perfluoroalkyl acids in the United States and Australia reconstructed from biomonitoring data using population-based pharmacokinetic modelling

Perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS) and perfluorohexanesulfonic acid (PFHxS) are found in the blood of humans and wildlife worldwide. Since the beginning of the 21st century, a downward trend in the human body burden, especially for PFOS and PFOA, has been observed while there is no clear temporal trend in wildlife. The inconsistency between the concentration decline in human serum and in wildlife could be indicative of a historical exposure pathway for humans linked to consumer products that has been reduced or eliminated. In this study, we reconstruct the past human exposure trends in two different regions, USA and Australia, by inferring the historical intake from cross-sectional biomonitoring data of PFOS, PFOA and PFHxS using a population-based pharmacokinetic model. For PFOS in the USA, the reconstructed daily intake peaked at 4.5ng/kg-bw/day between 1988 and 1999 while in Australia it peaked at 4.0ng/kg-bw/day between 1984 and 1996. For PFOA in the USA and Australia, the peak reconstructed daily intake was 1.1ng/kg-bw/day in 1995 and 3.6ng/kg-bw/day in 1992, respectively, and started to decline in 2000 and 1995, respectively. The model could not be satisfactorily fitted to the biomonitoring data for PFHxS within reasonable boundaries for its intrinsic elimination half-life, and thus reconstructing intakes of PFHxS was not possible. Our results indicate that humans experienced similar exposure levels and trends to PFOS and PFOA in the USA and Australia. Our findings support the hypothesis that near-field consumer product exposure pathways were likely dominant prior to the phase-out in industrialized countries. The intrinsic elimination half-life, which represents elimination processes that are common for all humans, and elimination processes unique to women (i.e., menstruation, cord-blood transfer and breastfeeding) were also investigated. The intrinsic elimination half-lives for PFOS and PFOA derived from model fitting for men were 3.8 and 2.4years, respectively, for the USA, and 4.9 and 2years respectively for Australia. Our results show that menstruation is a depuration pathway for PFOA for women, similarly but to a lesser extent compared to previous reports for PFOS. However menstruation, cord-blood transfer and breastfeeding together do not fully explain the apparently more rapid elimination of PFOA and PFOS by women compared to men; the intrinsic elimination half-lives in women were up to 13% lower for PFOS and up to 12% lower for PFOA compared to the corresponding half-lives in men.

Contribution of Direct and Indirect Exposure to Human Serum Concentrations of Perfluorooctanoic Acid in an Occupationally Exposed Group of Ski Waxers.

The contribution of direct (i.e., uptake of perfluorooctanoic acid (PFOA) itself) and indirect (i.e., uptake of 8:2 fluorotelomer alcohol (FTOH) and metabolism to PFOA) exposure to PFOA serum concentrations was investigated using a dynamic one-compartment pharmacokinetic (PK) model. The PK model was applied to six occupationally exposed ski waxers for whom direct and indirect exposures via inhalation were characterized using multiple measurements with personal air sampling devices. The model was able to predict the diverging individual temporal trends of PFOA in serum with correlation coefficients of 0.82-0.94. For the four technicians with high initial concentrations of PFOA in serum (250-1050 ng/mL), the ongoing occupational exposure (both direct and indirect) was of minor importance and net depuration of PFOA was observed throughout the ski season. An estimated average intrinsic elimination half-life of 2.4 years (1.8-3.1 years accounting for variation between technicians and model uncertainty) was derived for these technicians. The remaining two technicians, who had much lower initial serum concentrations (10-17 ng/mL), were strongly influenced by exposure during the ski season with indirect exposure contributing to 45% of PFOA serum concentrations. On the basis of these model simulations, an average metabolism yield of 0.003 (molar concentration basis; uncertainty range of 0.0006-0.01) was derived for transformation of 8:2 FTOH to PFOA. An uncertainty analysis was performed, and it was determined that the input parameters quantifying the intake of PFOA were mainly responsible for the uncertainty of the metabolism yield and the initial concentration of PFOA in serum was mainly contributing to the uncertainty of estimated serum half-lives.

Recommendations for Evaluating Temporal Trends of Persistent Organic Pollutants in Breast Milk.

Background:Biomonitoring data of persistent organic pollutants (POPs) in breast milk are increasingly collected and available for quantitative analysis of levels and time trends. A common approach is to apply log-linear regression to calculate doubling and halving times of the POP concentrations based on the temporal trend observed in breast milk. However, there are different, sometimes conflicting interpretations of these doubling and halving times.Objectives:We provide a mechanistic understanding of doubling and halving times where possible. Five recommendations are proposed for dealing with POP concentration trends in breast milk during three distinct periods (pre-ban, transition, post-ban period).Discussion:Using temporal trends of BDE-47 and PCB-153 in breast milk data, we show which information can be gained from the time-trend data. To this end, we analyzed time trends of hypothetical POPs for different periods with time-variant exposure and different intrinsic elimination half-lives, using a dynamic population-based pharmacokinetic model. Different pieces of information can be extracted from time-trend data from different periods. The analysis of trends of short-lived POPs is rather straightforward and facilitates extraction of the intrinsic elimination half-lives from the breast milk data. However, trends of slowly eliminated POPs only provide indications for the exposure time trend.Conclusions:Time-trend data of rapidly eliminated POPs provide information on exposure time trends and elimination half-lives. Temporal trends of slowly eliminated POPs are more complicated to interpret, and the extraction of exposure time trends and elimination half-lives require data sets covering several decades.Citation:Gyalpo T, Scheringer M, Hungerbühler K. 2016. Recommendations for evaluating temporal trends of persistent organic pollutants in breast milk. Environ Health Perspect 124:881–885; http://dx.doi.org/10.1289/ehp.1510219

Phlebotomy treatment for elimination of perfluoroalkyl acids in a highly exposed family: a retrospective case-series.

BackgroundPerfluoroalkyl acids (PFAAs) are a family of commonly used synthetic chemicals that have become widespread environmental contaminants. In human serum, perfluorohexane sulfonate (PFHxS), perflurooctane sulfonate (PFOS), and perfluorooctanoate (PFOA) are most frequently detected, in part owing to their long elimination half-lives of between 3.8 yrs (PFOA) and 8.5 yrs (PFHxS). These PFAAs also cross the placenta and have been associated with developmental toxicity, and some are considered likely human carcinogens. Interventions to eliminate PFAAs in highly contaminated individuals would reduce future health risks, but minimal research has been conducted on methods to facilitate accelerated human clearance of these persistent substances.MethodsSix patients with elevated serum concentrations from a single family were treated by intermittent phlebotomy over a 4–5 year period at intervals similar to, or less frequent than what is done for routine blood donation at Canadian Blood Services. The apparent elimination half-life (HLapp) for PFHxS, PFOS, and PFOA in this treated population was calculated in each patient and compared to the intrinsic elimination half-lives (HLin) from a literature reference population of untreated fluorochemical manufacturing plant retirees (n = 26, age >55 yrs).ResultsFor all three PFAAs monitored during phlebotomy, HLapp in each of the family members (except the mother, who had a low rate of venesection) was significantly shorter than the geometric mean HL measured in the reference population, and in some cases were even shorter compared to the fastest eliminator in the reference population.ConclusionThis study suggests significantly accelerated PFAA clearance with regular phlebotomy treatment, but the small sample size and the lack of controls in this clinical intervention precludes drawing firm conclusions. Given the minimal risks of intermittent phlebotomy, this may be an effective and safe clinical intervention to diminish the body burden of PFAAs in highly exposed people.

Calculation of chemical elimination half-life from blood with an ongoing exposure source: The example of perfluorooctanoic acid (PFOA)

Determination of the chemical clearance rate from human blood is a critical component of toxicokinetic exposure assessment. Analysis of temporal biomonitoring data without consideration of ongoing exposure results in calculation of apparent elimination half-life values that are longer than the intrinsic value. The intrinsic elimination half-life is solely a function of the rate of elimination while the apparent elimination half-life reflects the processes of both elimination and ongoing exposure. Confusion between intrinsic and apparent half-life values can lead to misinterpretation of biomonitoring data and can result in exaggerated predictions in subsequent modeling efforts. This work provides a review of the first-order equations that have been developed to calculate intrinsic and apparent half-life values and the potential bias that can result from confusing these two values. Published human biomonitoring data for perfluorooctanoic acid (PFOA) are analyzed using these equations to provide examples of low, medium and high bias in determination of the intrinsic elimination half-life from plasma or serum, the components of blood typically analyzed for PFOA. An approach is also provided to estimate the extent of exposure reduction that is indicated by declining longitudinal or cross-sectional biomonitoring data. Based on the evaluation methodology presented in this work, the intrinsic elimination half-life of PFOA in humans is 2.4years, representing the average of independent estimates of 2.5years (95% CI, 2.4–2.7) and 2.3years (95% CI, 2.1–2.4). The declining concentration of PFOA in blood of the general USA adult population represents an estimated exposure reduction of 20–30% over the period 1999–2008.

Bounding uncertainties in intrinsic human elimination half-lives and intake of polybrominated diphenyl ethers in the North American population

We examine the balance between intake, intrinsic elimination half-lives and human body burdens measured in biomonitoring for polybrominated diphenyl ethers (PBDEs) in the North American population using the population-level pharmacokinetic model developed by Ritter et al. (2011). Empirical data are collected from two studies that made total intake estimates for the North American population for the years 2004 and 2005, and eight biomonitoring studies for the years 1992 to 2009. We assume intake of PBDEs increased exponentially to a peak in 2004, and has since exponentially declined. The model is fitted to the empirical PBDE intake and biomonitoring data on PBDE body burden using a least-square optimization method by adjusting the intake in 2004 and 2038, and the intrinsic elimination rate constants, which can be expressed as equivalent half-lives. We fit the model in two types of scenarios using different combinations of PBDE intake estimates and biomonitoring data. Our modeling results indicate that there is an inconsistency between the PBDE intake estimates and the biomonitoring data, and that the inconsistency is likely due to underestimation of population-level intake. More efforts are needed to better characterize intake rates and identify potentially-unrecognized exposure pathways. Additional age-stratified biomonitoring data, and time trends of PBDE intakes would better constrain the model and provide an improved estimation of the intrinsic elimination half-lives.

Intrinsic Human Elimination Half-Lives of Polychlorinated Biphenyls Derived from the Temporal Evolution of Cross-Sectional Biomonitoring Data from the United Kingdom

BackgroundMost empirical estimates of human elimination kinetics for persistent chemicals reflect apparent elimination half-lives that represent the aggregated effect of intrinsic elimination, ongoing exposure, and changes in body weight. However, estimates of intrinsic elimination at background levels are required for risk assessments for the general population.ObjectiveTo estimate intrinsic human elimination half-lives at background levels for nine polychlorinated biphenyl (PCB) congeners, we used a novel approach based on population data.MethodsWe used a population pharmacokinetic model to interpret two sets of congener-specific cross-sectional age–concentration biomonitoring data of PCB concentrations measured in lipid and blood samples that were collected from 229 individuals in 1990 and 2003. Our method is novel because it exploits information about changes in concentration in the human population along two dimensions: age and calendar time.ResultsOur approach extracted information about both elimination kinetics and exposure trends from biomonitoring data. The longest intrinsic human elimination half-lives estimated in this study are 15.5 years for PCB‐170, 14.4 years for PCB‐153, and 11.5 years for PCB‐180.ConclusionsOur results are further evidence that a maximum intrinsic elimination half-life for persistent chemicals such as PCBs exists and is approximately 10–15 years. A clear conceptual distinction between apparent and intrinsic half-lives is required to reduce the uncertainty in elimination half-lives of persistent chemicals. The method presented here estimates intrinsic elimination half-lives and the exposure trends of persistent pollutants using cross-sectional data available from a large and growing number of biomonitoring programs.