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1.  Ethics issues experienced in HBM within Portuguese health surveillance and research projects 
Environmental Health  2008;7(Suppl 1):S5.
Background
In keeping with the fundamental practice of transparency in the discussion and resolution of ethics conflicts raised by research, a summary of ethics issues raised during Portuguese biomonitoring in health surveillance and research is presented and, where applicable, their resolution is described.
Methods
Projects underway aim to promote the surveillance of public health related to the presence of solid waste incinerators or to study associations between human exposure to environmental factors and adverse health effects. The methodological approach involves biomonitoring of heavy metals, dioxins and/or other persistent organic pollutants in tissues including blood, human milk and both scalp and pubic hair in groups such as the general population, children, pregnant women or women attempting pregnancy. As such, the projects entail the recruitment of individuals representing different demographic and health conditions, the collection of body tissues and personal data, and the processing of the data and results.
Results
The issue of autonomy is raised during the recruitment of participants and during the collection of samples and data. This right is protected by the requirement for prior written, informed consent from the participant or, in the case of children, from their guardian. Recruitment has been successful, among eligible participants, in spite of incentives rarely being offered. The exception has been in obtaining guardians' consent for children's participation, particularly for blood sampling. In an attempt to mitigate the harm-benefit ratio, current research efforts include alternative less invasive biomarkers.
Surveys are currently being conducted under contract as independent biomonitoring actions and as such, must be explicitly disclosed as a potential conflict of interests. Communication of results to participants is in general only practised when a health issue is present and corrective action possible. Concerning human milk a careful approach is taken, considering breast-feeding's proven benefits.
Conclusion
No national legislation currently accounts for the surveillance component of biomonitoring as distinct from research. Ethics issues arising within the domain of research are resolved according to available regulations. For issues encountered during surveillance, the same principles are used as guidance, completed by the authors' best judgement and relevant ethics committees' findings.
doi:10.1186/1476-069X-7-S1-S5
PMCID: PMC2423454  PMID: 18541071
2.  A Unique Patient Population? Health-Related Quality of Life in Adolescent Athletes Versus General, Healthy Adolescent Individuals 
Journal of Athletic Training  2013;48(2):233-241.
Context:
Normative scores for patient-rated outcome (PRO) instruments are important for providing patient-centered, whole-person care and making informed clinical decisions. Although normative values for the Pediatric Quality of Life Generic Core Scale (PedsQL) have been established in the general, healthy adolescent population, whether adolescent athletes demonstrate similar values is unclear.
Objective:
To compare PedsQL scores between adolescent athletes and general, healthy adolescent individuals.
Design:
Cross-sectional study.
Setting:
Secondary schools.
Patients or Other Participants:
A convenience sample of 2659 interscholastic athletes (males = 2059, females = 600, age = 15.7 ± 1.1 years) represented the athlete group (ATH), and a previously published normative dataset represented the general, healthy adolescent group (GEN).
Intervention(s):
All participants completed the PedsQL during 1 testing session.
Main Outcome Measure(s):
The PedsQL consists of 2 summary scores (total, psychosocial) and 4 subscale scores (physical, emotional, social, school), with higher scores indicating better health-related quality of life (HRQOL). Groups were stratified by age (14, 15, or 16 years old). Independent-samples t tests were conducted to compare between-groups and sex differences.
Results:
The ATH group scored higher than the GEN group across all ages for total and psychosocial summary scores and for emotional and social functioning subscale scores (P ≤ .005). For physical functioning, scores of the 15-year-old ATH were higher than for their GEN counterparts (P = .001). Both 14- and 15-year-old ATH scored higher than their GEN counterparts for the school functioning subscale (P ≤ .013), but differences between 16-year olds were not significant (P = .228). Male adolescent athletes reported higher scores than female adolescent athletes across all scores (P ≤ .001) except for social functioning (P = .229).
Conclusions:
Adolescent athletes reported better HRQOL than GEN, particularly in emotional functioning. These findings further support the notion that ATH constitutes a unique population that requires its own set of normative values for self-reported, patient-rated outcome instruments.
doi:10.4085/1062-6050-48.2.12
PMCID: PMC3600926  PMID: 23672388
patient outcome assessment; patient-centered care; physical activity
3.  A Role of ath5 in Inducing neuroD and the Photoreceptor Pathway 
Photoreceptors in the vertebrate retina are light-sensitive neurons, and their degeneration results in irreversible visual loss. Understanding how photoreceptor fate is determined is a prerequisite for developing photoreceptor replacement therapies. Previous studies identified two basic helix-loop-helix genes, neurogenin2 (ngn2) and neuroD, participating in a genetic pathway leading to photoreceptor genesis. Here we present experimental data suggesting that ath5, which is known for its critical role in retinal ganglion cell development, may also lead to photoreceptor production. In the developing retina, ath5 expression was detected in two zones of cells, and coexpression with neuroD was observed in the zone adjacent to young photoreceptor cells accumulating on the retinal pigment epithelial side. Retroviral-driven misexpression of ath5 in retinal cells increased the population of photoreceptor cells, as well as ganglion cells, in a developmental stage-dependent manner that is consistent with ath5 being involved in the development of multiple types of retinal neurons. Ectopic ath5 expression in cultures of non-neural retinal pigment epithelial cells elicited transdifferentiation into cells that expressed photoreceptor-specific genes and displayed photoreceptor-like morphologies. Gene expression analysis showed that ngn2 did not induce ath5, and ath5 did not induce ngn2, but both induced neuroD and RaxL. These data suggest a pathway of “ath5 → neuroD → photoreceptor genes” separate from yet convergent with the ngn2 pathway.
doi:10.1523/JNEUROSCI.2266-04.2004
PMCID: PMC1986841  PMID: 15306648
gene; transcription; differentiation; regeneration; photoreceptor; retina
4.  Quantitative Trait Loci Affecting Atherosclerosis at the Aortic Root Identified in an Intercross between DBA2J and 129S6 Apolipoprotein E-Null Mice 
PLoS ONE  2014;9(2):e88274.
Apolipoprotein E-null mice on a DBA/2J genetic background (DBA-apoE) are highly susceptible to atherosclerosis in the aortic root area compared with those on a 129S6 background (129-apoE). To explore atherosclerosis-responsible genetic regions, we performed a quantitative trait locus (QTL) analysis using 172 male and 137 female F2 derived from an intercross between DBA-apoE and 129-apoE mice. A genome-wide scan identified two significant QTL for the size of lesions at the root: one is Ath44 on Chromosome (Chr) 1 at 158 Mb, and the other Ath45 on Chr 2 at 162 Mb. Ath44 co-localizes with but appears to be independent of a previously reported QTL, Ath1, while Ath45 is a novel QTL. DBA alleles of both Ath44 and Ath45 confer atherosclerosis-susceptibility. In addition, a QTL on Chr 14 at 73 Mb was found significant only in males, and 129 allele conferring susceptibility. Further analysis detected female-specific interactions between a second QTL on Chr 1 at 73 Mb and a QTL on Chr 3 at 21 Mb, and between Chr 7 at 84 Mb and Chr 12 at 77 Mb. These loci for the root atherosclerosis were independent of QTLs for plasma total cholesterol and QTLs for triglycerides, but a QTL for HDL (Chr 1 at 126 Mb) overlapped with the Ath44. Notably, haplotype analysis among 129S6, DBA/2J and C57BL/6 genomes and their gene expression data narrowed the candidate regions for Ath44 and Ath45 to less than 5 Mb intervals where multiple genome wide associations with cardiovascular phenotypes have also been reported in humans. SNPs in or near Fmo3, Sele and Selp for Ath44, and Lbp and Pkig for Ath45 were suggested for further investigation as potential candidates underlying the atherosclerosis susceptibility.
doi:10.1371/journal.pone.0088274
PMCID: PMC3930552  PMID: 24586312
5.  Participant experiences in a breastmilk biomonitoring study: A qualitative assessment 
Background
Biomonitoring studies can provide information about individual and population-wide exposure. However they must be designed in a way that protects the rights and welfare of participants. This descriptive qualitative study was conducted as a follow-up to a breastmilk biomonitoring study. The primary objectives were to assess participants' experiences in the study, including the report-back of individual body burden results, and to determine if participation in the study negatively affected breastfeeding rates or duration.
Methods
Participants of the Greater Boston PBDE Breastmilk Biomonitoring Study were contacted and asked about their experiences in the study: the impact of study recruitment materials on attitudes towards breastfeeding; if participants had wanted individual biomonitoring results; if the protocol by which individual results were distributed met participants' needs; and the impact of individual results on attitudes towards breastfeeding.
Results
No participants reported reducing the duration of breastfeeding because of the biomonitoring study, but some responses suggested that breastmilk biomonitoring studies have the potential to raise anxieties about breastfeeding. Almost all participants wished to obtain individual results. Although several reported some concern about individual body burden, none reported reducing the duration of breastfeeding because of biomonitoring results. The study literature and report-back method were found to mitigate potential negative impacts.
Conclusion
Biomonitoring study design, including clear communication about the benefits of breastfeeding and the manner in which individual results are distributed, can prevent negative impacts of biomonitoring on breastfeeding. Adoption of more specific standards for biomonitoring studies and continued study of risk communication issues related to biomonitoring will help protect participants from harm.
doi:10.1186/1476-069X-8-4
PMCID: PMC2649062  PMID: 19226469
6.  Correlation of G/A -22018 single-nucleotide polymorphism with lactase activity and its usefulness in improving the diagnosis of adult-type hypolactasia among North Indian children 
Genes & Nutrition  2012;8(1):145-151.
Adult-type hypolactasia (AtH or lactase non-persistence) is the physiological decline in lactase activity that manifests in majority of the world’s population after weaning. Recently, various single-nucleotide polymorphisms (SNPs) upstream of lactase gene (LCT) have been suggested to be associated with AtH or the lactase persistent trait in different human populations. C/T -13910 SNP was found be completely associated with AtH in Finnish population, and G/A -22018 SNP was found to be strongly, but not completely, associated with AtH. The aim of this study was to correlate G/A -22018 SNP with intestinal lactase activity in North Indian children. These children were also genotyped for C/T -13910 SNP. We also examined the differences in milk consumption and milk-related clinical symptoms in children with different genotypes of G/A -22018 and C/T -13910 SNPs. Intestinal biopsies were obtained from 231 children aged 2–16 years undergoing routine endoscopy for various abdominal complaints. The biopsies were assayed for lactase, sucrase, and maltase activities and genotyped for G/A -22018 and C/T -13910 SNPs using restriction fragment length polymorphism and DNA sequencing analysis. There was a significant correlation between lactase activity and different genotypes of G/A -22018 SNP. Children with G/G -22018 genotype had low lactase activity. With a reference value of <10 U/g protein (lactase activity) to be indicative of AtH, the sensitivity and specificity of genetic test based on G/A -22018 SNP was 94.4 and 94.1 %, respectively. Furthermore, the consumption of milk was lower in children with G/G -22018 genotype. Flatulence was the only symptom significantly more frequent among the children with G/G -22018 genotype compared to those with G/A and A/A -22018 genotypes. However, most of the children with G/G -22018 genotype seem to tolerate small amounts of milk without any significant difference in gastrointestinal symptoms from those with G/A and A/A -22018 genotypes.
doi:10.1007/s12263-012-0305-7
PMCID: PMC3535002  PMID: 22763774
Adult-type hypolactasia; G/A -22018 SNP; Milk intake; Indian children
7.  Thiamine Status in Humans and Content of Phosphorylated Thiamine Derivatives in Biopsies and Cultured Cells 
PLoS ONE  2010;5(10):e13616.
Background
Thiamine (vitamin B1) is an essential molecule for all life forms because thiamine diphosphate (ThDP) is an indispensable cofactor for oxidative energy metabolism. The less abundant thiamine monophosphate (ThMP), thiamine triphosphate (ThTP) and adenosine thiamine triphosphate (AThTP), present in many organisms, may have still unidentified physiological functions. Diseases linked to thiamine deficiency (polyneuritis, Wernicke-Korsakoff syndrome) remain frequent among alcohol abusers and other risk populations. This is the first comprehensive study on the distribution of thiamine derivatives in human biopsies, body fluids and cell lines.
Methodology and Principal Findings
Thiamine derivatives were determined by HPLC. In human tissues, the total thiamine content is lower than in other animal species. ThDP is the major thiamine compound and tissue levels decrease at high age. In semen, ThDP content correlates with the concentration of spermatozoa but not with their motility. The proportion of ThTP is higher in humans than in rodents, probably because of a lower 25-kDa ThTPase activity. The expression and activity of this enzyme seems to correlate with the degree of cell differentiation. ThTP was present in nearly all brain and muscle samples and in ∼60% of other tissue samples, in particular fetal tissue and cultured cells. A low ([ThTP]+[ThMP])/([Thiamine]+[ThMP]) ratio was found in cardiovascular tissues of patients with cardiac insufficiency. AThTP was detected only sporadically in adult tissues but was found more consistently in fetal tissues and cell lines.
Conclusions and Significance
The high sensitivity of humans to thiamine deficiency is probably linked to low circulating thiamine concentrations and low ThDP tissue contents. ThTP levels are relatively high in many human tissues, as a result of low expression of the 25-kDa ThTPase. Another novel finding is the presence of ThTP and AThTP in poorly differentiated fast-growing cells, suggesting a hitherto unsuspected link between these compounds and cell division or differentiation.
doi:10.1371/journal.pone.0013616
PMCID: PMC2963613  PMID: 21049048
8.  Structure of Avian Thymic Hormone, a High-affinity Avian β-parvalbumin, in the Ca2+-free and Ca2+-bound States 
Journal of molecular biology  2010;397(4):991-1002.
Originally isolated on the basis of its capacity to stimulate T-cell maturation and proliferation, avian thymic hormone (ATH) is nevertheless a parvalbumin, one of two β-lineage isoforms expressed in birds. We recently learned that addition of Ca2+-free ATH to a solution of 8-anilinonaphthalene-1-sulfonate (ANS) markedly increases ANS emission. This behavior, not observed in the presence of Ca2+, suggests that apolar surface area buried in the Ca2+-bound state becomes solvent-accessible upon Ca2+ removal. In order to elucidate the conformational alterations that accompany Ca2+ binding, we have obtained the solution structure of the Ca2+-free protein using NMR spectroscopy and compared it to the Ca2+-loaded protein, solved by x-ray crystallography. Although the metal ion-binding (CD-EF) domains are largely coincident in the superimposed structures, a major difference is observed in the AB domains. The tight association of helix B with the E and F helices in the Ca2+-bound state is lost upon removal of Ca2+, producing a deep hydrophobic cavity. The B helix also undergoes substantial rotation, exposing the side-chains of F24, Y26, F29, and F30 to solvent. Presumably, the increase in ANS emission observed in the presence of unliganded ATH reflects the interaction of these hydrophobic residues with the fluorescent probe. The increased solvent exposure of apolar surface area in the Ca2+-free protein is consistent with previously collected scanning calorimetry data, which indicated an unusually low change in heat capacity upon thermal denaturation. The Ca2+-free structure also provides added insight into the magnitude of ligation-linked conformational alteration compatible with a high-affinity metal ion-binding signature. The exposure of substantial apolar surface area suggests the intriguing possibility that ATH could function as a reverse Ca2+ sensor.
doi:10.1016/j.jmb.2010.02.014
PMCID: PMC3091166  PMID: 20156445
calcium-binding protein; EF-hand protein; parvalbumin; NMR structure; crystal structure
9.  Human biomonitoring data interpretation and ethics; obstacles or surmountable challenges? 
Environmental Health  2008;7(Suppl 1):S13.
The use of human samples to assess environmental exposure and uptake of chemicals is more than an analytical exercise and requires consideration of the utility and interpretation of data as well as due consideration of ethical issues. These aspects are inextricably linked.
In 2004 the EC expressed its commitment to the development of a harmonised approach to human biomonitoring (HBM) by including an action in the EU Environment and Health Strategy to develop a Human Biomonitoring Pilot Study. This further underlined the need for interpretation strategies as well as guidance on ethical issues. A workshop held in December 2006 brought together stakeholders from academia, policy makers as well as non-governmental organisations and chemical industry associations to a two day workshop built a mutual understanding of the issues in an open and frank discussion forum. This paper describes the discussion and recommendations from the workshop.
The workshop developed key recommendations for a Pan-European HBM Study:
1. A strategy for the interpretation of human biomonitoring data should be developed.
2. The pilot study should include the development of a strategy to integrate health data and environmental monitoring with human biomonitoring data at national and international levels.
3. Communication strategies should be developed when designing the study and evolve as the study continues.
4. Early communication with stakeholders is essential to achieve maximum efficacy of policy developments and facilitate subsequent monitoring.
5. Member states will have to apply individually for project approval from their National Research Ethics Committees.
6. The study population needs to have sufficient information on the way data will be gathered, interpreted and disseminated and how samples will be stored and used in the future (if biobanking) before they can give informed consent.
7. The participants must be given the option of anonymity. This has an impact on follow-up.
8. The pilot study should develop guidelines and best practice for Ethics for pan European studies.
In conclusion all participants felt there that there has to be stakeholder involvement in any planned pan-European Human Biomonitoring Study and the format of the workshop was appropriate for such dialogue.
doi:10.1186/1476-069X-7-S1-S13
PMCID: PMC2423450  PMID: 18541067
10.  Is there a future for biomonitoring of elemental air pollution? A review focused on a larger-scaled health-related (epidemiological) context 
The present paper focuses on biomonitoring of elemental atmospheric pollution, which is reviewed in terms of larger-scaled biomonitoring surveys in an epidemiological context. Based on the literature information, today’s availability of solar-powered small air filter samplers and fibrous ion exchange materials is regarded as adequate or an even better alternative for biomonitor transplant materials used in small-scaled set-ups, but biomonitors remain valuable in larger-scaled set-ups and in unforeseen releases and accidental situations. In the latter case, in-situ biomonitoring is seen as the only option for a retrospective study: biomoniors are there before one even knows that they are needed. For biomonitoring, nuclear analytical techniques are discussed as key techniques, especially because of the necessary multi-element assessments in both source recognition and single-element interpretation. To live up to the demands in an epidemiological context, larger-scaled in-situ biomonitoring asks for large numbers of samples, and consequently, for large total sample masses, this all to ensure representation of both local situations and survey area characteristics. Possibly, this point should direct studies into new “easy-to-sample” biomonitor organisms, of which high masses and numbers may be obtained in field work, rather than continue with biomonitors such as lichens. This also means that both sample handling and processing are of key importance in these studies. To avoid problems in comparability of analytical general procedures in milling, homogenization and digestion of samples of large masses, the paper proposes to involve only few but high-quality laboratories in the total element assessment routines. In this respect, facilities that can handle large sample masses in the assessment of element concentrations are to be preferred. This all highlights the involvement of large-sample-volume nuclear facilities, which, however, should be upgraded and automated in their operation to ensure the necessary sample throughput in larger-scaled biomonitoring.
doi:10.1007/s10967-010-0637-y
PMCID: PMC4514461
Biomonitoring; Element air pollution; Epidemiology; Health; Large sample analysis; Nuclear analytical techniques; Survey methods; C83; I10; Q51; Q53
11.  Evaluation of Biomonitoring Data from the CDC National Exposure Report in a Risk Assessment Context: Perspectives across Chemicals 
Environmental Health Perspectives  2012;121(3):287-294.
Background: Biomonitoring data reported in the National Report on Human Exposure to Environmental Chemicals [NER; Centers for Disease Control and Prevention (2012)] provide information on the presence and concentrations of > 400 chemicals in human blood and urine. Biomonitoring Equivalents (BEs) and other risk assessment–based values now allow interpretation of these biomonitoring data in a public health risk context.
Objectives: We compared the measured biomarker concentrations in the NER with BEs and similar risk assessment values to provide an across-chemical risk assessment perspective on the measured levels for approximately 130 analytes in the NER.
Methods: We identified available risk assessment–based biomarker screening values, including BEs and Human Biomonitoring-I (HBM-I) values from the German Human Biomonitoring Commission. Geometric mean and 95th percentile population biomarker concentrations from the NER were compared to the available screening values to generate chemical-specific hazard quotients (HQs) or cancer risk estimates.
Conclusions: Most analytes in the NER show HQ values of < 1; however, some (including acrylamide, dioxin-like chemicals, benzene, xylene, several metals, di-2(ethylhexyl)phthalate, and some legacy organochlorine pesticides) approach or exceed HQ values of 1 or cancer risks of > 1 × 10–4 at the geometric mean or 95th percentile, suggesting exposure levels may exceed published human health benchmarks. This analysis provides for the first time a means for examining population biomonitoring data for multiple environmental chemicals in the context of the risk assessments for those chemicals. The results of these comparisons can be used to focus more detailed chemical-specific examination of the data and inform priorities for chemical risk management and research.
doi:10.1289/ehp.1205740
PMCID: PMC3621178  PMID: 23232556
biomonitoring; Biomonitoring Equivalents; blood; cancer risk; CDC National Exposure Report; hazard quotient; NHANES; risk assessment; urine
12.  Comparing United States and Canadian population exposures from National Biomonitoring Surveys: Bisphenol A intake as a case study 
The Centers for Disease Control and Prevention provides biomonitoring data in the United States as part of the National Health and Nutrition Examination Survey (NHANES). Recently, Statistics Canada initiated a similar survey — the Canadian Health Measures Survey (CHMS). Comparison of US and Canadian biomonitoring data can generate hypotheses regarding human exposures from environmental media and consumer products. To ensure that such comparisons are scientifically meaningful, it is essential to first evaluate aspects of the surveys' methods that can impact comparability of data. We examined CHMS and NHANES methodologies, using bisphenol A (BPA) as a case study, to evaluate whether survey differences exist that would hinder our ability to compare chemical concentrations between countries. We explored methods associated with participant selection, urine sampling, and analytical methods. BPA intakes were also estimated to address body weight differences between countries. Differences in survey methods were identified but are unlikely to have substantial impacts on inter-survey comparisons of BPA intakes. BPA intakes for both countries are below health-based guidance values set by the US, Canada and the European Food Safety Authority. We recommend that before comparing biomonitoring data between surveys, a thorough review of methodologic aspects that might impact biomonitoring results be conducted.
doi:10.1038/jes.2012.1
PMCID: PMC3331622  PMID: 22333730
NHANES; CHMS; bisphenol A; intake; biomonitoring; methodological comparison
13.  Mercury Exposure in Young Children Living in New York City 
Journal of Urban Health   2007;85(1):39-51.
Residential exposure to vapor from current or previous cultural use of mercury could harm children living in rental (apartment) homes. That concern prompted the following agencies to conduct a study to assess pediatric mercury exposure in New York City communities by measuring urine mercury levels: New York City Department of Health and Mental Hygiene’s (NYCDOHMH) Bureau of Environmental Surveillance and Policy, New York State Department of Health/Center for Environmental Health (NYSDOHCEH), Wadsworth Center’s Biomonitoring Program/Trace Elements Laboratory (WC-TEL), and Centers for Disease Control and Prevention (CDC). A previous study indicated that people could obtain mercury for ritualistic use from botanicas located in Brooklyn, Manhattan, and the Bronx. Working closely with local community partners, we concentrated our recruiting efforts through health clinics located in potentially affected neighborhoods. We developed posters to advertise the study, conducted active outreach through local partners, and, as compensation for participation in the study, we offered a food gift certificate redeemable at a local grocer. We collected 460 urine specimens and analyzed them for total mercury. Overall, geometric mean urine total mercury was 0.31 μg mercury/l urine. One sample was 24 μg mercury/l urine, which exceeded the (20 μg mercury/l urine) NYSDOH Heavy Metal Registry reporting threshold for urine mercury exposure. Geometric mean urine mercury levels were uniformly low and did not differ by neighborhood or with any clinical significance by children’s ethnicity. Few parents reported the presence of mercury at home, in a charm, or other item (e.g., skin-lightening creams and soaps), and we found no association between these potential sources of exposure and a child’s urinary mercury levels. All pediatric mercury levels measured in this study were well below a level considered to be of medical concern. This study found neither self-reported nor measured evidence of significant mercury use or exposure among participating children. Because some participants were aware of the possibility that they could acquire and use mercury for cultural or ritualistic purposes, community education about the health hazards of mercury should continue.
doi:10.1007/s11524-007-9230-2
PMCID: PMC2430136  PMID: 17957474
Mercury; Urine; Children; Botanicas; Azogue (Spanish word for mercury)
14.  A Comparison of the Human Buccal Cell Assay and the Pollen Abortion Assay in Assessing Genotoxicity in an Urban-Rural Gradient  
Air pollution is exacerbated near heavy traffic roads in cities. Air pollution concentration and composition vary by region and depend on urban-rural gradients. The aim of this study was to evaluate the distribution of air pollution in areas of varying population densities and to compare plant biomonitoring with an established biomarker of human exposure to traffic-related air pollution in children. The areas of study were selected near a major street in 3 different regions. Areas A, B and C represent high, intermediate and low population densities, respectively. Micronucleus assay, an established biomarker of human exposure, was performed in children from these areas. For a plant biomonitoring assay, the pollen abortion assay was performed on Bauhinia variegata in these areas. NO2 and O3 concentrations were determined by passive sampling. We report here that the pollen abortion frequency in Bauhinia variegata is correlated with NO2 concentration (P = 0.004) and is strongly associated with vehicular flow and population density in the studied areas. Micronuclei frequency in buccal cells of children was higher in the regions with more degree of urbanization (P < 0.001) following the same pattern of O3 concentrations (P = 0.030). In conclusion, our results demonstrate that high concentrations of air pollutants in Porto Alegre are related to both human and plant genotoxicity. Areas with different concentration of pollutants demonstrated to have an urbanization gradient dependent pattern which also reflected on genotoxic damage among these areas.
doi:10.3390/ijerph110908825
PMCID: PMC4198993  PMID: 25166920
micronucleus; air pollution; biomonitoring; bioindicator; passive sampling; genotoxicity; ozone; nitrogen dioxide
15.  Oxidative stress and DNA repair and detoxification gene expression in adolescents exposed to heavy metals living in the Milazzo-Valle del Mela area (Sicily, Italy) 
Redox Biology  2014;2:686-693.
Background
The area of Milazzo-Valle del Mela (Sicily, Italy) is considered at high risk of environmental crisis by regional authorities.
Objective
To measure oxidative-stress, DNA repair and detoxification genes in school children living near the industrial area and in age-matched controls.
Methods
The parent study was a biomonitoring investigation evaluating heavy metal urine levels in 226 children aged 12–14 years, living in the high risk area, and in 29 age-matched controls living 45 km far from the industrial site. In the present study 67 exposed adolescents and 29 controls were included. Samples were analyzed for urinary 8-hydroxydeoxyguanosine (8OHdG) levels, and gene expression of OGG1 (DNA repair gene), NQO1, ST13, and MT1A (detoxifying genes).
Results
Urinary cadmium was higher (p = 0.0004) in exposed [geometric mean, 0.46 µg/L; 25th–75th percentile: 0.3–0.56] than in control adolescents [geometric mean, 0.26 µg/L; 25th–75th percentile: 0.2–0.3]. Chromium was also significantly elevated in exposed [geometric mean, 1.52 µg/L; 25th–75th percentile: 1.19–1.93] compared with controls [geometric mean, 1.25 µg/L; 25th–75th percentile: 1.05–1.48; p = 0.02]. Urinary 8-OHdG concentration was greater in exposed than in controls (71.49 vs 61.87 µg/L, p = 0.02), and it was correlated with cadmium levels (r = 0.46, p < 0.0001), and with the combined exposure index (r = 0.43, p < 0.0001). Moreover, cadmium levels showed a robust correlation with OGG1 and MT1A gene expression levels (r = 0.44, p < 0.0001; r = 0.39, p < 0.0001, respectively). Finally, OGG1 and MT1A were over-expressed in adolescents from Milazzo-Valle del Mela area compared with controls (p = 0.0004; p < 0.0001, respectively).
Conclusions
Continuous exposure at relatively low concentrations of heavy metals is associated with increased oxidative DNA damage and impaired expression of DNA repair and detoxification genes in adolescents.
doi:10.1016/j.redox.2014.05.003
PMCID: PMC4052524  PMID: 24936443
16.  The Use of Biomonitoring Data in Exposure and Human Health Risk Assessments 
Environmental Health Perspectives  2006;114(11):1755-1762.
Biomonitoring uses analytic methods that permit the accurate measurement of low levels of environmental chemicals in human tissues. However, depending on the intended use, biomonitoring, like all exposure tools, may not be a stand-alone exposure assessment tool for some of its environmental public health uses. Although biomonitoring data demonstrate that many environmental chemicals are absorbed in human tissues, uncertainty exists regarding if and at what concentrations many of these chemicals cause adverse health outcomes. Moreover, without exposure pathway information, it is difficult to relate biomonitoring results to sources and routes of exposure and develop effective health risk management strategies. In September 2004, the Health and Environmental Sciences Institute, U.S. Environmental Protection Agency, Centers for Disease Control and Prevention, Agency for Toxic Substances and Disease Registry, and International Council of Chemical Associations co-sponsored the International Biomonitoring Workshop, which explored the processes and information needed for placing biomonitoring data into perspective for risk assessment purposes, with special emphasis on integrating biomarker measurements of exposure, internal dose, and potential health outcome. Scientists from international governments, academia, and industry recommended criteria for applying biomonitoring data for various uses. Six case studies, which are part of this mini-monograph, were examined: inorganic arsenic, methyl eugenol, organophosphorus pesticides, perfluorooctanesulfonate, phthalates, and polybrominated diphenyl ethers. Based on the workshop and follow-up discussions, this overview article summarizes lessons learned, identifies data gaps, outlines research needs, and offers guidance for designing and conducting biomonitoring studies, as well as interpreting biomonitoring data in the context of risk assessment and risk management.
doi:10.1289/ehp.9056
PMCID: PMC1665402  PMID: 17107864
arsenic; biomarkers; biomonitoring; exposure; methyl eugenol; organophosphorus; PBDE; PFOS; phthalates; risk assessment
17.  Cross-sectional Biomonitoring of Metals in Adult Populations in Post-war Eastern Croatia: Differences Between Areas of Moderate and Heavy Combat 
Croatian Medical Journal  2010;51(5):451-460.
Aim
To determine differences in metal and metalloid exposure between residents of areas in eastern Croatia exposed to heavy fighting during the war in Croatia and residents of areas exposed to moderate fighting.
Methods
Concentrations of aluminum (Al), arsenic (As), barium (Ba), cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), nickel (Ni), lead (Pb), uranium (U), vanadium (V), and zinc (Zn), reported to be associated with military operations, were determined in hair, serum, and urine samples using inductively-coupled plasma mass spectroscopy. A total of 127 and 46 participants from areas of heavy and moderate fighting, respectively, were included.
Results
Compared with participants from areas exposed to moderate fighting, participants from areas exposed to heavy fighting had significantly higher serum concentrations of Al (87.61 vs 42.75 μg/L, P = 0.007), As (5.05 ± 1.79 vs 4.16 ± 1.55 μg/L, P = 0.003), Ba (7.12 vs 6.01 μg/L, P = 0.044), and V (17.98 vs 16.84 μg/L, P = 0.008); significantly higher urine concentrations of As (43.90 vs 11.51 μg/L, P < 0.001) and Cd (0.67 vs 0.50 μg/L, P = 0.031); and significantly higher hair concentrations of Al (12.61 vs 7.33 μg/L, P < 0.001), As (0.32 vs 0.05 μg/L, P < 0.001), Cd (0.03 vs 0.02 μg/L, P = 0.002), Fe (22.58 vs 12.68 μg/L, P = 0.001), Pb (1.04 vs 0.69 μg/L, P = 0.006), and V (0.07 vs 0.03 μg/L, P < 0.001).
Conclusion
Differences between populations from eastern Croatian areas exposed to heavy and populations exposed to moderate fighting point to the need for extensive monitoring of metal and metalloid exposure, emphasizing the role of biomonitoring through ecologic and preventive activities.
doi:10.3325/cmj.2010.51.451
PMCID: PMC2969140  PMID: 20960595
18.  Increased atherosclerosis in streptozotocin-induced diabetic mice. 
Journal of Clinical Investigation  1996;97(7):1767-1773.
Premature and extensive atheroscleroses involving renal, peripheral, and cardiovascular sites remain major complications of diabetes mellitus. Controversy exists as to the contribution of hyperglycemia versus elevated local or systemic concentrations of insulin to atherosclerosis risk. In this report, we developed the first murine model susceptible to both atherosclerosis and diabetes to determine which diabetogenic factors contribute to vascular disease. C57BL/6 and BALB/c mice were treated with multiple low-dose streptozotocin (STZ) or control citrate buffer and fed rodent chow or an atherogenic-promoting (Ath) diet for 12-20 wk. STZ treatment resulted in sustained hyperglycemia (250-420 mg/dl) and a modest reduction in plasma insulin levels for both strains regardless of diet. Citrate-treated C57BL/6 mice fed the Ath diet showed extensive oil red O-staining fatty streak aortic sinus lesions (20,537+/-2,957 micron2), the size of which did not differ for Ath-fed mice treated with STZ (16,836+/-2,136 micron2). In contrast, hyperglycemic BALB/c mice fed the Ath diet showed a 17-fold increase in atherosclerotic lesion area (7,922+/-2,096 micron2) as compared with citrate-treated mice fed the Ath diet (467+/-318 micron2). Correlations between lesion size and plasma glucose levels were significant for BALB/c (r = 0.741, P < 0.009), but not C57BL/6 (r = 0.314, P<0.3) mice. Lesion size correlated significantly with plasma cholesterol for C57BL/6 (r = 0.612, P<0.03) but not BALB/c (r = 0.630, P<0.1) mice. Immunohistochemistry showed that aortic sinus lesions from both strains contained macrophages, but smooth muscle cells were clearly present in lesions of BALB/c mice. In summary, we present the first small animal model showing accelerated atherosclerosis in response to hyperglycemia. Fatty streaks resembled those of human type II lesions in that both macrophages and smooth muscle cells were evident. In addition, our results support the concept that hyperglycemia as opposed to hyperinsulinemia contributes heavily to risk of atherosclerosis.
PMCID: PMC507242  PMID: 8601643
19.  Urinary Creatinine Concentrations in the U.S. Population: Implications for Urinary Biologic Monitoring Measurements 
Environmental Health Perspectives  2004;113(2):192-200.
Biologic monitoring (i.e., biomonitoring) is used to assess human exposures to environmental and workplace chemicals. Urinary biomonitoring data typically are adjusted to a constant creatinine concentration to correct for variable dilutions among spot samples. Traditionally, this approach has been used in population groups without much diversity. The inclusion of multiple demographic groups in studies using biomonitoring for exposure assessment has increased the variability in the urinary creatinine levels in these study populations. Our objectives were to document the normal range of urinary creatinine concentrations among various demographic groups, evaluate the impact that variations in creatinine concentrations can have on classifying exposure status of individuals in epidemiologic studies, and recommend an approach using multiple regression to adjust for variations in creatinine in multivariate analyses. We performed a weighted multivariate analysis of urinary creatinine concentrations in 22,245 participants of the Third National Health and Nutrition Examination Survey (1988–1994) and established reference ranges (10th–90th percentiles) for each demographic and age category. Significant predictors of urinary creatinine concentration included age group, sex, race/ethnicity, body mass index, and fat-free mass. Time of day that urine samples were collected made a small but statistically significant difference in creatinine concentrations. For an individual, the creatinine-adjusted concentration of an analyte should be compared with a “reference” range derived from persons in a similar demographic group (e.g., children with children, adults with adults). For multiple regression analysis of population groups, we recommend that the analyte concentration (unadjusted for creatinine) should be included in the analysis with urinary creatinine added as a separate independent variable. This approach allows the urinary analyte concentration to be appropriately adjusted for urinary creatinine and the statistical significance of other variables in the model to be independent of effects of creatinine concentration.
doi:10.1289/ehp.7337
PMCID: PMC1277864  PMID: 15687057
biomonitoring; creatinine; creatinine adjustment; urine
20.  Urinary, Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A 
Environmental Health Perspectives  2010;118(8):1055-1070.
Background
Bisphenol A (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Thus, there are concerns that the amount of BPA to which humans are exposed may cause adverse health effects. Importantly, results from a large number of biomonitoring studies are at odds with the results from two toxicokinetic studies.
Objective
We examined several possibilities for why biomonitoring and toxicokinetic studies could come to seemingly conflicting conclusions.
Data sources
We examined > 80 published human biomonitoring studies that measured BPA concentrations in human tissues, urine, blood, and other fluids, along with two toxicokinetic studies of human BPA metabolism.
Data extraction and synthesis
The > 80 biomonitoring studies examined included measurements in thousands of individuals from several different countries, and these studies overwhelmingly detected BPA in individual adults, adolescents, and children. Unconjugated BPA was routinely detected in blood (in the nanograms per milliliter range), and conjugated BPA was routinely detected in the vast majority of urine samples (also in the nanograms per milliliter range). In stark contrast, toxicokinetic studies proposed that humans are not internally exposed to BPA. Some regulatory agencies have relied solely on these toxicokinetic models in their risk assessments.
Conclusions
Available data from biomonitoring studies clearly indicate that the general population is exposed to BPA and is at risk from internal exposure to unconjugated BPA. The two toxicokinetic studies that suggested human BPA exposure is negligible have significant deficiencies, are directly contradicted by hypothesis-driven studies, and are therefore not reliable for risk assessment purposes.
doi:10.1289/ehp.0901716
PMCID: PMC2920080  PMID: 20338858
endocrine disruptor; human exposure; PBPK/PBTK model; pregnancy; risk assessment; toxicokinetics
21.  Toxic metal levels in children residing in a smelting craft village in Vietnam: a pilot biomonitoring study 
BMC Public Health  2014;14:114.
Background
In Vietnam, environmental pollution caused by small-scale domestic smelting of automobile batteries into lead ingot is a growing concern. The village of Nghia Lo is a smelting craft village located roughly 25 km southeast of Hanoi in the Red River Delta. Despite the concern of toxic metal exposure in the village, biomonitoring among susceptible populations, such as children, has not been previously conducted. The aim of this study was to determine the body burden of toxic metals in children residing in a smelting craft village.
Methods
Twenty children from Nghia Lo, Vietnam, ages 18 months to four years were selected for capillary whole blood and toenail biomonitoring. Whole blood lead levels (BLLs) were measured using a portable lead analyzer, and toenail levels of arsenic, cadmium, chromium, lead, manganese, and mercury were analyzed with inductively coupled plasma-mass spectrometry.
Results
The findings show that all of the 20 children had detectable BLLs, and every child had levels that exceeded the Centers for Disease Control and Prevention guideline level of 5 μg/dL. Eighty percent of tested subjects had BLLs higher than 10 μg/dL. Five children (25%) had BLLs greater than 45 μg/dL, the level of recommended medical intervention. In addition to blood lead, all of the children had detectable levels of arsenic, cadmium, chromium, lead, manganese, and mercury in toenail samples. Notably, average toenail lead, manganese, and mercury levels were 157 μg/g, 7.41 μg/g, and 2.63 μg/g respectively, well above levels previously reported in children. Significant Spearman’s rank correlations showed that there were relationships between blood and toenail lead levels (r = 0.65, p < 0.05), toenail levels of lead and cadmium (r = 0.66, p < 0.05), and toenail levels of manganese and chromium (r = 0.72, p < 0.001). Linear regression showed that reducing the distance to the nearest active smelter by half was associated with a 116% increase in BLL (p < 0.05).
Conclusions
The results suggest that children in battery recycling and smelting craft villages in Vietnam are co-exposed to toxic metals. There is an urgent need for mitigation to control metal exposure related to domestic smelting.
doi:10.1186/1471-2458-14-114
PMCID: PMC3922956  PMID: 24495283
22.  A New Spin on Research Translation: The Boston Consensus Conference on Human Biomonitoring 
Environmental Health Perspectives  2008;117(4):495-499.
Background
Translating research to make it more understandable and effective (research translation) has been declared a priority in environmental health but does not always include communication to the public or residents of communities affected by environmental hazards. Their unique perspectives are also commonly missing from discussions about science and technology policy. The consensus conference process, developed in Denmark, offers a way to address this gap.
Objectives
The Boston Consensus Conference on Human Biomonitoring, held in Boston, Massachusetts, in the fall of 2006, was designed to educate and elicit input from 15 Boston-area residents on the scientifically complex topic of human biomonitoring for environmental chemicals. This lay panel considered the many ethical, legal, and scientific issues surrounding biomonitoring and prepared a report expressing their views.
Discussion
The lay panel’s findings provide a distinct and important voice on the expanding use of biomonitoring. In some cases, such as a call for opt-in reporting of biomonitoring results to study participants, they mirror recommendations raised elsewhere. Other conclusions have not been heard previously, including the recommendation that an individual’s results should be statutorily exempted from the medical record unless permission is granted, and the opportunity to use biomonitoring data to stimulate green chemistry.
Conclusion
The consensus conference model addresses both aspects of a broader conception of research translation: engaging the public in scientific questions, and bringing their unique perspectives to bear on public health research, practice, and policy. In this specific application, a lay panel’s recommendations on biomonitoring surveillance, communication, and ethics have practical implications for the conduct of biomonitoring studies and surveillance programs.
doi:10.1289/ehp.0800037
PMCID: PMC2679590  PMID: 19440485
biomonitoring; consensus conference; environmental health surveillance; participatory democracy; research translation
23.  Applicability of non-invasively collected matrices for human biomonitoring 
With its inclusion under Action 3 in the Environment and Health Action Plan 2004–2010 of the European Commission, human biomonitoring is currently receiving an increasing amount of attention from the scientific community as a tool to better quantify human exposure to, and health effects of, environmental stressors. Despite the policy support, however, there are still several issues that restrict the routine application of human biomonitoring data in environmental health impact assessment. One of the main issues is the obvious need to routinely collect human samples for large-scale surveys. Particularly the collection of invasive samples from susceptible populations may suffer from ethical and practical limitations. Children, pregnant women, elderly, or chronically-ill people are among those that would benefit the most from non-invasive, repeated or routine sampling. Therefore, the use of non-invasively collected matrices for human biomonitoring should be promoted as an ethically appropriate, cost-efficient and toxicologically relevant alternative for many biomarkers that are currently determined in invasively collected matrices. This review illustrates that several non-invasively collected matrices are widely used that can be an valuable addition to, or alternative for, invasively collected matrices such as peripheral blood sampling. Moreover, a well-informed choice of matrix can provide an added value for human biomonitoring, as different non-invasively collected matrices can offer opportunities to study additional aspects of exposure to and effects from environmental contaminants, such as repeated sampling, historical overview of exposure, mother-child transfer of substances, or monitoring of substances with short biological half-lives.
doi:10.1186/1476-069X-8-8
PMCID: PMC2660315  PMID: 19272133
24.  What Additional Factors Beyond State-of-the-Art Analytical Methods Are Needed for Optimal Generation and Interpretation of Biomonitoring Data? 
Environmental Health Perspectives  2009;117(10):1481-1485.
Background
The routine use of biomonitoring (i.e., measurement of environmental chemicals, their metabolites, or specific reaction products in human biological specimens) to assess internal exposure (i.e., body burden) has gained importance in exposure assessment.
Objectives
Selection and validation of biomarkers of exposure are critical factors in interpreting biomonitoring data. Moreover, the strong relation between quality of the analytical methods used for biomonitoring and quality of the resulting data is well understood. However, the relevance of collecting, storing, processing, and transporting the samples to the laboratory to the overall biomonitoring process has received limited attention, especially for organic chemicals.
Discussion
We present examples to illustrate potential sources of unintended contamination of the biological specimen during collection or processing procedures. The examples also highlight the importance of ensuring that the biological specimen analyzed both represents the sample collected for biomonitoring purposes and reflects the exposure of interest.
Conclusions
Besides using high-quality analytical methods and good laboratory practices for biomonitoring, evaluation of the collection and handling of biological samples should be emphasized, because these procedures can affect the samples integrity and representativeness. Biomonitoring programs would be strengthened with the inclusion of field blanks.
doi:10.1289/ehp.0901108
PMCID: PMC2790499  PMID: 20019895
BPA; contamination; DEHP; extraction efficiency; field blank; phthalates
25.  Recruitment methods in Alzheimer's disease research: general practice versus population based screening by mail 
Background
In Alzheimer's disease (AD) research patients are usually recruited from clinical practice, memory clinics or nursing homes. Lack of standardised inclusion and diagnostic criteria is a major concern in current AD studies. The aim of the study was to explore whether patient characteristics differ between study samples recruited from general practice and from a population based screening by mail within the same geographic areas in rural Northern Norway.
Methods
An interventional study in nine municipalities with 70000 inhabitants was designed. Patients were recruited from general practice or by population based screening of cognitive function by mail. We sent a questionnaire to 11807 individuals ≥ 65 years of age of whom 3767 responded. Among these, 438 individuals whose answers raised a suspicion of cognitive impairment were invited to an extended cognitive and clinical examination. Descriptive statistics, chi-square, independent sample t-test and analyses of covariance adjusted for possible confounders were used.
Results
The final study samples included 100 patients recruited by screening and 87 from general practice. Screening through mail recruited younger and more self-reliant male patients with a higher MMSE sum score, whereas older women with more severe cognitive impairment were recruited from general practice. Adjustment for age did not alter the statistically significant differences of cognitive function, self-reliance and gender distribution between patients recruited by screening and from general practice.
Conclusions
Different recruitment procedures of individuals with cognitive impairment provided study samples with different demographic characteristics. Initial cognitive screening by mail, preceding extended cognitive testing and clinical examination may be a suitable recruitment strategy in studies of early stage AD.
Clinical Registration
ClinicalTrial.gov Identifier: NCT00443014
doi:10.1186/1471-2288-10-35
PMCID: PMC2880123  PMID: 20429946

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