External Exposure Data Research Articles

Physiologically based pharmacokinetic (PBPK) modeling of BDE-209 following oral exposure in Chinese population.

The wide usage of decabromodiphenyl ether (BDE-209) as additive brominated flame retardant has caused its widespread occurrence in the environment and high exposure risk in humans. Estimating its internal exposure dose and reconstruction of external exposure dose using physiologically based pharmacokinetic (PBPK) modelling approach is a key step in the risk assessment of BDE-209. However, the PBPK model for BDE-209 is currently unavailable. This study has established two oral permeability-limited PBPK models of BDE-209 without enterohepatic recirculation (EHR) (model 1) and with EHR (model 2) for Chinese population. Using the in vitro experiments, the average binding of BDE-209 to human plasma protein (99.64%±2.97%) was obtained. Moreover, blood sample analysis and systematic literature review were performed to obtain internal and external exposure data of BDE-209 used for model calibration and validation. The predictions of both models were within 2-fold of the observed, and a longer half-life of serum BDE-209 was observed in model 2 than model 1. Based on the models, a human biomonitoring guidance value (HBM-GV) of 93.61μg/g lw was derived for BDE-209, and there is no health risk found for Chinese population currently. This study provides new quantitative assessment tools for health risk assessment of BDE-209.

Co-exposure and health risks of parabens, bisphenols, triclosan, phthalate metabolites and hydroxyl polycyclic aromatic hydrocarbons based on simultaneous detection in urine samples from guangzhou, south China.

Polycyclic aromatic hydrocarbons (PAHs) and certain ingredients in personal care products, such as parabens, bisphenols, triclosan and phthalate metabolites, have become ubiquitous in the world. Concerns of human exposure to these pollutants have increased during recent years because of various adverse health effects of these chemicals. Multiple compounds including parabens, bisphenols, triclosan, phthalate metabolites (mPAEs) and hydroxyl PAHs (OH-PAHs) in urine samples from Guangzhou were determined simultaneously to identify the human exposure pathways without external exposure data combined with data analysis, and the toxicants posed the highest risk to human health were screened in the present study. The detection frequencies for the chemicals exceeded 90%. Among the contaminants, mPAEs showed the highest concentrations, followed by OH-PAHs, with triclosan present at the lowest concentrations. Mono-n-butyl phthalate, methylparaben, bisphenol A, and hydroxynaphthalene represented the most abundant mPAE, parabens, bisphenol, and OH-PAH compounds, respectively. The present PAHs are mainly exposed to human through inhalation, while the chemicals added to personal care products are mainly exposed to human through oral intake and dermal contact. The urine samples from suburban subjects showed significantly higher OH-PAH levels than the urine samples from urban subjects, and females had lower OH-PAH levels than males. Urinary concentrations of the analyzed contaminants were significantly correlated with age, body mass index, residence time, as well as the frequencies of alcohol consumption and swimming. Risk assessments based on Monte Carlo simulation indicated that approximately 30% of the subjects suffered non-carcinogenic risks from mPAEs and OH-PAHs, with mPAEs accounting for 89% of the total risk.

GPS-coupled contaminant monitors on free-ranging Chernobyl wolves challenge a fundamental assumption in exposure assessments

Measurements of external contaminant exposures on individual wildlife are rare because of difficulties in using contaminant monitors on free-ranging animals. Most wildlife contaminant exposure data are therefore simulated with computer models. Rarely are empirical exposure data available to verify model simulations, or to test fundamental assumptions inherent in exposure assessments. We used GPS-coupled contaminant monitors to quantify external exposures to individual wolves (Canis lupus) living within the Belarus portion of Chernobyl's 30-km exclusion zone. The study provided data on animal location and contaminant exposure every 35 min for 6 months, resulting in ~6600 individual locations and 137Cs external exposure readings per wolf, representing the most robust external exposure data published to date on free ranging animals. The data provided information on variation in external exposure for each animal over time, as well as variation in external exposure among the eight wolves across the landscape of Chernobyl. The exposure data were then used to test a fundamental assumption in screening-level risk assessments, espoused in guidance documents of the U.S. Environmental Protection Agency and U.S. Department of Energy, — Mean contaminant concentrations conservatively estimate individual external exposures. We tested this assumption by comparing our empirical data to a series of simulations using the ERICA modeling tool. We found that modeled simulations of mean external exposure (10.5 mGy y−1), based on various measures of central tendency, under-predicted mean exposures measured on five of the eight wolves wearing GPS-contaminant monitors (i.e., 12.3, 26.3, 28.0, 28.8 and 35.7 mGy y−1). If under-prediction of exposure occurs for some animals, then arguably the use of averaged contaminant concentrations to predict external exposure is not as conservative as proposed by current risk assessment guidance. Thus, a risk assessor's interpretation of simulated exposures in a screening-level risk analysis might be misguided if contaminant concentrations are based on measures of central tendency. We offer three suggestions for risk assessors to consider in order to reduce the probability of underestimating exposure in a screening-level risk assessment.

Human exposure pathways to organophosphate flame retardants: Associations between human biomonitoring and external exposure

Organophosphate flame retardants (PFRs) have largely replaced the market of polybrominated diphenyl ethers (PBDEs). Concerns about PFR contamination and its impact on human health have consequently increased. A comprehensive investigation on the human exposure pathways to PFRs is to be endeavoured. This study investigated the occurrence of PFR metabolites in human urine, serum and hair, correlating them with external exposure data that was presented in our previous studies. Participants from Oslo (n = 61) provided a set of samples, including dust, air, handwipes, food, urine, serum and hair. Associations between PFR metabolites analyzed in the biological samples and the PFRs in environmental samples were explored. Different sampling strategies for dosimeters (e.g. floor/surface dust, personal/stationary air) were also compared to understand which is better for predicting human exposure to PFRs. Seven out of the eleven target PFR metabolites, including diphenyl phosphate (DPHP) and bis(1-chloro-2-propyl)-1-hydroxy-2-propyl phosphate (BCIPHIPP), were frequently detected (DF > 30%) in urine. DPHP was the most frequently detected metabolite in both serum and hair. Several PFR metabolites had higher levels in morning urine than in afternoon urine. Floor dust appeared to be a better proxy for estimating PFR internal exposure than surface dust, air, and handwipes. Some PFRs in handwipes and air were also correlated with their metabolites in urine and hair. Age, beverage consumption and food consumption were negatively associated with DPHP levels in urine. Discrepancies observed between the external and internal exposure for some PFRs call for further investigation on PFR bioaccessibility and clearance.

Assessment of phthalates/phthalate alternatives in children's toys and childcare articles: Review of the report including conclusions and recommendation of the Chronic Hazard Advisory Panel of the Consumer Product Safety Commission.

The Consumer Product Safety Commission (CPSC) convened a Chronic Hazard Advisory Panel (CHAP) on Phthalates found in children's toys, and childcare products, and in products used by women of childbearing age. The CHAP conducted a risk assessment on phthalates and phthalate substitutes, and made recommendations to either ban, impose an interim ban, or allow the continued use of phthalates and phthalate substitutes in the above products. After a review of the literature, the evaluation included toxic end points of primary concern, biomonitoring results, extant exposure reconstruction, and epidemiological results. The health end points chosen were associated with the rat phthalate syndrome, which is characterized by malformations of the epididymis, vas deferens, seminal vesicles, prostate, external genitalia (hypospadias), and by cryptorchidism (undescended testes), retention of nipples/areolae, and demasculinization (~incomplete masculinization) of the perineum, resulting in reduced anogenital distance. Risk assessment demonstrated that some phthalates should be permanently banned, removed from the banned list, or remain interim banned. Biomonitoring and toxicology data provided the strongest basis for a mixture risk assessment. In contrast, external exposure data were the weakest and need to be upgraded for epidemiological studies and risk assessments. Such studies would focus on routes and sources. The review presents recommendations and uncertainties.

Interpreting biomarker data from the COPHES/DEMOCOPHES twin projects: Using external exposure data to understand biomarker differences among countries

In 2011 and 2012, the COPHES/DEMOCOPHES twin projects performed the first ever harmonized human biomonitoring survey in 17 European countries. In more than 1800 mother–child pairs, individual lifestyle data were collected and cadmium, cotinine and certain phthalate metabolites were measured in urine. Total mercury was determined in hair samples. While the main goal of the COPHES/DEMOCOPHES twin projects was to develop and test harmonized protocols and procedures, the goal of the current paper is to investigate whether the observed differences in biomarker values among the countries implementing DEMOCOPHES can be interpreted using information from external databases on environmental quality and lifestyle.In general, 13 countries having implemented DEMOCOPHES provided high-quality data from external sources that were relevant for interpretation purposes. However, some data were not available for reporting or were not in line with predefined specifications. Therefore, only part of the external information could be included in the statistical analyses. Nonetheless, there was a highly significant correlation between national levels of fish consumption and mercury in hair, the strength of antismoking legislation was significantly related to urinary cotinine levels, and we were able to show indications that also urinary cadmium levels were associated with environmental quality and food quality. These results again show the potential of biomonitoring data to provide added value for (the evaluation of) evidence-informed policy making.

Predicting Plasma Concentrations of Bisphenol A in Children Younger Than 2 Years of Age after Typical Feeding Schedules, using a Physiologically Based Toxicokinetic Model

BackgroundConcerns have recently been raised regarding the safety of potential human exposure to bisphenol A (BPA), an industrial chemical found in some polycarbonate plastics and epoxy resins. Of particular interest is the exposure of young children to BPA via food stored in BPA-containing packaging.ObjectivesIn this study we assessed the age dependence of the toxicokinetics of BPA and its glucuronidated metabolite, BPA-Glu, using a coupled BPA–BPA-Glu physiologically based toxicokinetic (PBTK) model.MethodsUsing information gathered from toxicokinetic studies in adults, we built a PBTK model. We then scaled the model to children < 2 years of age based on the age dependence of physiologic parameters relevant for absorption, distribution, metabolism, and excretion.ResultsWe estimated the average steady-state BPA plasma concentration in newborns to be 11 times greater than that in adults when given the same weight-normalized dose. Because of the rapid development of the glucuronidation process, this ratio dropped to 2 by 3 months of age. Simulation of typical feeding exposures, as estimated by regulatory authorities, showed a 5-fold greater steady-state BPA plasma concentration in 3- and 6-month-olds compared with adults, reflecting both a reduced capacity for BPA metabolism and a greater weight-normalized BPA exposure. Because of uncertainty in defining the hepatic BPA intrinsic clearance in adults, these values represent preliminary estimates.ConclusionsSimulations of the differential BPA dosimetry between adults and young children point to the need for more sensitive analytical methods for BPA to define, with greater certainty, the adult hepatic BPA intrinsic clearance, as well as a need for external exposure data in young children.

Neuropsychological effects of chronic low-dose exposure to polychlorinated biphenyls (PCBs): a cross-sectional study.

BackgroundExposure to indoor air of private or public buildings contaminated with polychlorinated biphenyls (PCBs) has raised health concerns in long-term users. This exploratory neuropsychological group study investigated the potential adverse effects of chronic low-dose exposure to specific air-borne low chlorinated PCBs on well-being and behavioral measures in adult humans.MethodsThirty employees exposed to indoor air contaminated with PCBs from elastic sealants in a school building were compared to 30 non-exposed controls matched for education and age, controlling for gender (age range 37–61 years). PCB exposure was verified by external exposure data and biological monitoring (PCB 28, 101, 138, 153, 180). Subjective complaints, learning and memory, executive function, and visual-spatial function was assessed by standardized neuropsychological testing. Since exposure status depended on the use of contaminated rooms, an objectively exposed subgroup (N = 16; PCB 28 = 0.20 μg/l; weighted exposure duration 17.9 ± 7 years) was identified and compared with 16 paired controls.ResultsBlood analyses indicated a moderate exposure effect size (d) relative to expected background exposure for total PCB (4.45 ± 2.44 μg/l; d = 0.4). A significant exposure effect was found for the low chlorinated PCBs 28 (0.28 ± 0.25 μg/l; d = 1.5) and 101 (0.07 ± 0.09 μg/l; d = 0.7). Although no neuropsychological effects exceeded the adjusted significance level, estimation statistics showed elevated effect sizes for several variables. The objectively exposed subgroup showed a trend towards increased subjective attentional and emotional complaints (tiredness and slowing of practical activities, emotional state) as well as attenuated attentional performance (response shifting and alertness in a cued reaction task).ConclusionChronic inhalation of low chlorinated PCBs that involved elevated blood levels was associated with a subtle attenuation of emotional well-being and attentional function. Extended research is needed to replicate the potential long-term low PCB effects in a larger sample.

Use of screening algorithms and computer systems to efficiently signal higher-than-expected combinations of drugs and events in the US FDA's spontaneous reports database.

Since 1998, the US Food and Drug Administration (FDA) has been exploring new automated and rapid Bayesian data mining techniques. These techniques have been used to systematically screen the FDA's huge MedWatch database of voluntary reports of adverse drug events for possible events of concern. The data mining method currently being used is the Multi-Item Gamma Poisson Shrinker (MGPS) program that replaced the Gamma Poisson Shrinker (GPS) program we originally used with the legacy database. The MGPS algorithm, the technical aspects of which are summarised in this paper, computes signal scores for pairs, and for higher-order (e.g. triplet, quadruplet) combinations of drugs and events that are significantly more frequent than their pair-wise associations would predict. MGPS generates consistent, redundant, and replicable signals while minimising random patterns. Signals are generated without using external exposure data, adverse event background information, or medical information on adverse drug reactions. The MGPS interface streamlines multiple input-output processes that previously had been manually integrated. The system, however, cannot distinguish between already-known associations and new associations, so the reviewers must filter these events. In addition to detecting possible serious single-drug adverse event problems, MGPS is currently being evaluated to detect possible synergistic interactions between drugs (drug interactions) and adverse events (syndromes), and to detect differences among subgroups defined by gender and by age, such as paediatrics and geriatrics. In the current data, only 3.4% of all 1.2 million drug-event pairs ever reported (with frequencies > or = 1) generate signals [lower 95% confidence interval limit of the adjusted ratios of the observed counts over expected (O/E) counts (denoted EB05) of > or = 2]. The total frequency count that contributed to signals comprised 23% (2.4 million) of the total number, 10.4 million of drug-event pairs reported, greatly facilitating a more focused follow-up and evaluation. The algorithm provides an objective, systematic view of the data alerting reviewers to critically important, new safety signals. The study of signals detected by current methods, signals stored in the Center for Drug Evaluation and Research's Monitoring Adverse Reports Tracking System, and the signals regarding cerivastatin, a cholesterol-lowering drug voluntarily withdrawn from the market in August 2001, exemplify the potential of data mining to improve early signal detection. The operating characteristics of data mining in detecting early safety signals, exemplified by studying a drug recently well characterised by large clinical trials confirms our experience that the signals generated by data mining have high enough specificity to deserve further investigation. The application of these tools may ultimately improve usage recommendations.

An estimate by two methods of thyroid absorbed doses due to BRAVO fallout in several Northern Marshall Islands.

Estimates of the thyroid absorbed doses due to fallout originating from the 1 March 1954 BRAVO thermonuclear test on Bikini Atoll have been made for several inhabited locations in the Northern Marshall Islands. Rongelap, Utirik, Rongerik and Ailinginae Atolls were also inhabited on 1 March 1954, where retrospective thyroid absorbed doses have previously been reconstructed. The current estimates are based primarily on external exposure data, which were recorded shortly after each nuclear test in the Castle Series, and secondarily on soil concentrations of 137Cs in samples collected in 1978 and 1988, along with aerial monitoring done in 1978. The external exposures and 137Cs soil concentrations were representative of the atmospheric transport and deposition patterns of the entire Castle Series tests and show that the BRAVO test was the major contributor to fallout exposure during the Castle series and other test series which were carried out in the Marshall Islands. These data have been used as surrogates for fission product radioiodines and telluriums in order to estimate the range of thyroid absorbed doses that may have occurred throughout the Marshall Islands. Dosimetry based on these two sets of estimates agreed within a factor of 4 at the locations where BRAVO was the dominant contributor to the total exposure and deposition. Both methods indicate that thyroid absorbed doses in the range of 1 Gy (100 rad) may have been incurred in some of the northern locations, whereas the doses at southern locations did not significantly exceed levels comparable to those from worldwide fallout. The results of these estimates indicate that a systematic medical survey for thyroid disease should be conducted, and that a more definitive dose reconstruction should be made for all the populated atolls and islands in the Northern Marshall Islands beyond Rongelap, Utirik, Rongerik and Ailinginae, which were significantly contaminated by BRAVO fallout.

Protracted exposure to fallout: the Rongelap and Utirik experience.

From June 1946 to August 1958, the U.S. Department of Defense and the U.S. Atomic Energy Commission (AEC) conducted nuclear weapons tests in the Northern Marshall Islands. On 1 March 1954, BRAVO, an above-ground test in the Castle series, produced high levels of radioactive material, some of which subsequently fell on Rongelap and Utirik Atolls due to an unexpected wind shift. On 3 March 1954, the inhabitants of these atolls were moved out of the affected area. They later returned to Utirik in June 1954 and to Rongelap in June 1957. Comprehensive environmental and personnel radiological monitoring programs were initiated in the mid 1950s by Brookhaven National Laboratory to ensure that body burdens of the exposed Marshallese subjects remained within AEC guidelines. Their body-burden histories and calculated activity ingestion rate patterns post-return are presented along with estimates of internal committed effective dose equivalents. External exposure data are also included. In addition, relationships between body burden or urine-activity concentration and declining continuous intake were developed. The implications of these studies are: (1) the dietary intake of 137Cs was a major component contributing to the committed effective dose equivalent for the years after the initial contamination of the atolls; (2) for persons whose diet included fish, 65Zn was a major component of committed effective dose equivalent during the first years post-return; (3) a decline in the daily activity ingestion rate greater than that resulting from radioactive decay of the source was estimated for 137Cs, 65Zn, 90Sr and 60Co; (4) the relative impact of each nuclide on the estimate of committed effective dose equivalent was dependent upon the time interval between initial contamination and rehabilitation; and (5) the internal committed effective dose equivalent exceeded the external dose equivalent by a factor of 1.1 at Utirik and 1.5 at Rongelap during the rehabitation period. Few reliable 239Pu measurements on human excreta were made. An analysis of the tentative data leads to the conclusion that a reliable estimate of committed effective dose equivalent requires further research.