s
UvA-DARE (Digital Academic Repository)
Later childhood effects of perinatal exposure to background levels of dioxins in
the Netherlands
ten Tusscher, G.W.
Publication date 2002
Link to publication
Citation for published version (APA):
ten Tusscher, G. W. (2002). Later childhood effects of perinatal exposure to background levels of dioxins in the Netherlands.
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22
DECREASEDD LUNG
FUNCTIONN ASSOCIATED
WITHH PERINATAL
EXPOSUREE TO DUTCH
BACKGROUNDD LEVELS OF
DIOXINS S
tenn Tusscher GW, Weerdt J de, Roos CM, Griffioen RW, De Jongh FH, Westraa M, Slikke JW van der, Oosting J, Olie K, Koppe JG. Decreased lungg function associated with perinatal exposure to Dutch background levelss of dioxins. Acta Paediatr 2001; 90: 1292-1298. Stockholm. ISSN 0803-5253. .
Abstract t
Perinatall exposure to Dutch background dioxin levels is rather high. Studiess of calamities have shown that dioxins negatively influence the respiratoryy system. It was hypothesized that perinatal exposure to backgroundd dioxin levels leads to lung suboptimality, probably through developmentall interference. This study aimed to assess lung function in relationn to perinatal dioxin exposure. Spirometry was performed in 41 healthyy children (aged 7-12 y, mean 8.2 y) with known perinatal dioxin exposure.. The ratio of forced expiratory volume in 1 s to forced vital capacityy (FEVi/FVC ratio) was determined. A complete medical history wass taken. The prenatal exposure ranged from 8.74 to 88.8 (mean 34.6) ngg TEQ dioxin kg fat-1, measured in breast milk. The postnatal exposure rangedd from 4.34 to 384.51 (mean 75.4) ng TEQ dioxin. Twelve children hadd to be excluded. A significant decrease in lung function in relation to bothh prenatal (p=0.045) and postnatal (p=0.0002) dioxin exposure was seenn in the 29 non-excluded children. A clinical association between chestt congestion and perinatal dioxin exposure was seen.
Conclusion:: Perinatal background dioxin exposure may be inversely associatedd with the FEVi/FVC ratio.
Introduction n
Polychlorinatedd dioxins and furans (henceforth jointly referred to as dioxins)) belong to the most toxic group of substances known, and have beenn associated with malignancy, congenital malformations, immuno-suppressionn and respiratory disorders (1-5). Dioxins are formed as waste productss of combustion processes and municipal incinerators are amongstt the primary sources of these compounds in The Netherlands. Heatingg of polychlorinated biphenyls (PCBs) is a notable source of polychlorinatedd dibenzofiirans. Dioxins, being poorly degradable in nature,, persist in the environment, entering the human food chain via fish oilss and animal fats (6). These polychlorinated aromatic compounds are highlyy lipophilic and in humans are primarily stored in adipose tissues. Theirr lipophilicity allows them to readily pass the placenta, whereupon
theyy are stored in foetal adipose tissues, especially triglycerides (7;8). In 19866 relatively high dioxin concentrations in the breast milk of Dutch motherss were reported, followed by similar findings in other industrializedd countries (9; 10). Thus, unborn children and breastfed childrenn are exposed to relatively high "background" dioxin levels.
Perinatall exposure to dioxins and related compounds may have consequencess spanning many years. Moreover, in both animals and humans,, the respiratory system is a target of dioxin toxicity (11). Consequently,, it was hypothesized that perinatal exposure to background levelss of dioxins in The Netherlands would have a negative influence on lungg function, probably as a result of developmental interference. In an ongoingg study of the development of children with known perinatal exposuree to dioxins, the lung function of the study participants was assessedd using spirometry and a detailed medical history.
Thee medical ethics committees of De Heel Zaans Medical Centre (Zaandam,, The Netherlands) and the Academic Medical Centre (Amsterdam,, The Netherlands) permitted the study.
Subjects,, materials and methods
Eightt years after Pluim's Zaandam study (12), his study participants were againn contacted, as was the group from his first study (up to 12 y ago) (13;14).. The perinatal dioxin exposure is known for all these study participants.. The children were born to healthy, well-nourished Caucasiann women, aged between 23 and 38 y (mean 29.2 y), who intendedd to breastfeed for a minimum of 2 mo. The mothers were recruitedd by their obstetrician or midwife. Out of the original cohort of 61 subjects,, those born prematurely, born out of suboptimal pregnancies, or whoo were twins, were not included in this follow-up study (9 children). Twoo children had emigrated with their families, five children chose not too participate in the follow-up study and five children were untraceable. Thee prenatal and postnatal dioxin exposures of the excluded subjects weree varied and in no way did their exclusion introduce an unfair populationn bias. The elder sister of a participant requested to take part in thee study and was included in the cohort for this reason. Her
breastfeedingg period was known and she was assigned the same prenatal dioxinn exposure (25.4 ng kg fat-1) as her younger sister (in reality her prenatall exposure would have been higher than that of her younger sister).. Therefore, a total of 41 children took part in the current study. Thee parents or guardians of the children had knowledge of the exposures andd test results of the previous studies, but did not hint at or disclose the resultss to the investigators, who were blinded to these outcomes.
Thee study was performed with 41 children, aged 7-12 y (mean SD 8.2 1.64 y), consenting to spirometry, in whom the perinatal dioxin exposuree was known. The children underwent spirometry on one of three Saturdayy afternoons in spring 1998, at De Heel Zaans Medical Centre, Zaandam.. The dioxin toxic equivalency and cumulative toxic equivalencyy values in the breast milk of their mothers, as determined by Pluim,, were used as such in this follow-up study. In brief, the concentrationn of dioxins, using the I-Teq method, in the mother's breast milk,, shortly (3-4 wk) after having given birth, was taken as the prenatal dioxinn exposure level of the child (TEQDiox). The postnatal cumulative dioxinn exposure (TEQCum) was calculated as TEQDiox multiplied by thee amount of breast milk ingested during the breastfeeding period of the child.. A 2.5% fat concentration in the milk, 700 g daily milk intake duringg the exclusively breastfeeding period and 350 g daily intake during thee transition period to formula feed were assumed (12). Dutch formula feedd is dioxin free. The mothers kept a diary during the breastfeeding periodd for data validation. The mean of the breastfeeding period was 3 ^ moo (range 16 d to 2.5 y). With the exception of the outlier, where a correctionn was applied, no correction was made for a possible lowering off dioxin levels in breast milk due to lactation. The lactation period was relativelyy short. The prenatal exposure ranged from 8.74 to 88.8 (mean 34.6)) ng TEQ dioxin kg fat"1. The postnatal exposure ranged from 4.34 to 384.511 (mean 75.4) ng TEQ dioxin. These exposures are indicative of the backgroundd exposures in The Netherlands, and similar studies in other partss of the country have found similar background concentrations (15;; 16). Subsequent (childhood) dioxin exposures are far less than during thee foetal and breastfeeding period, and it can safely be assumed that all thee subjects had similar childhood exposures, as they all had similar diets. .
Spirometry Spirometry
Ann optimal flow-volume curve was measured by means of spirometry, in childrenn not using respiratory medication. The height of the study participantss was measured immediately before the spirometry, by one nurse,, using the same measuring instrument for all the subjects. The heightt of the children ranged from 1.17 to 1.60 m. Thereafter, the participantss were taken to a room where they were instructed to sit upright.. Their noses blocked by means of a nose clip, they were instructedd to inspire maximally, followed by a maximally forced and completee expiration. The inspiration and expiration were registered on a Sensormedicss Spirolab® spirometer using Spida 3.0® software and Knudsonn reference values. The forced expiratory volume in 1 s (FEVi) andd forced vital capacity (FVC) were thus expressed as a percentage of thee expected value, according to height, as determined by Knudson (17). Thee spirometry was repeated until three measurements within 5% of each otherr were obtained.
AA full respiratory history was taken from the parent(s) of the children, in orderr to control for confounders and to substantiate the lung function statuss determined by spirometry.
Thee spirometry was conducted by one respiratory technician, with experiencee in paediatric spirometry. The best of three technically acceptablee spirometry attempts was taken as the true measure of lung function,, in accordance with the European Respiratory Society (ERS) reproducibilityy criteria for correctly performed spirometry (18). The judgingg of the reliability of the measurements was performed under the
criticall scrutiny of both an adult (CMR) and a paediatric (RWG) pulmonologist.. Bronchodilators were not used and arterial saturations weree not measured.
MedicalMedical history
AA complete medical history was taken of each child as well as a brief historyy of the families of the children. A history of coughing spells, dyspnoea,, asthma, bronchitis, pneumonia, otitis, chickenpox, measles and atopyy was noted.
Thee respiratory history of each subject was taken from both the accompanyingg parent (mostly mother) and the child. Questions asked included: :
1.. Has the subject coughed for minimally 3 consecutive months during thee last 2 y?
2.. Has the subject produced phlegm for minimally 3 consecutive months duringg the last 2 y?
3.. Is the subject dyspnoeic when walking at normal pace over flat terrain? ?
4.. Does the subject regularly have a wheeze? 5.. Does the subject experience chest congestion?
6.. Does the subject use medication for the respiratory system? 7.. Does the subject have allergies and/or atopy?
Statistics Statistics
Statisticall analysis was performed using SPSS 6.0® and expressed as a linearr regression, a two-sided test. In this manner a dose-response curve wass produced. Multiple regression and p-values were calculated. P-valuess less than 0.05 were considered statistically significant. A best-fit linee was applied to the scatter diagrams. Smoking was considered a confounder,, as smoking may influence lung function. Maternal smoking wass also considered a confounder, as various studies have indicated that maternall smoking may have a negative effect on the lung function of the children.. Paternal smoking was not considered a confounder because theree seems to be no documented link between the lung function of childrenn and smoking fathers. Children using respiratory system influencingg medication, e.g. corticosteroids and salbutamol, were excludedd from analysis because of the obvious confounding influence of thee medications and to approximate the exclusion of asthmatics. Other
potentialpotential confounders, e.g. atopy, were assessed by means of the respiratoryy history taken. The respiratory history questions were
answeredd with a "yes" or "no". This was further elaborated on when indicated.. The dichotomous outcome was analysed by means of logistic regression. .
Results s
Sixx children were excluded from analysis: one child coughed during spirometry,, producing an abnormal curve, one child did not exhibit a maximall inspiration, and four children stopped too early with expiration (AVV > 0.25 ml during the last 0.5 s). Six children reported using respiratoryy medication at the time of testing and were also excluded from analysis.. The perinatal dioxin exposures of the excluded children varied andd their exclusion did not introduce an unfair population bias.
Thee 29 remaining children (Table 1) produced an FEX^/FVC ratio of 0.900 0.06 (mean SD), ranging from 0.71 to 0.99.
Smoking Smoking
Upp to the time of testing (and up to follow-up more than 1 y later), none off the children had smoked. Four of the subjects' mothers smoked during pregnancyy and at the time of testing. Of these four, two of the children hadd relatively low perinatal dioxin exposure and two had relatively averagee perinatal exposure (prenatal: 13.75, 19.72, 33.01, 38.02 ng kg fat1;; postnatal: 13.69, 30.77, 45.46, 86.13 ng, respectively). In this study maternall smoking had no statistical influence on the results and there was noo need to correct for smoking mothers in the statistics. The children of thee smoking mothers had perinatal dioxin exposures in the lower half of thee group and this may be explained by the fact that smoking in general decreasess the dioxin concentration in breast milk (19). This is probably byy enzyme induction causing an increased metabolic rate.
PrenatalPrenatal exposure
Linearr regression of the FEVi/FVC ratio versus prenatal dioxin exposure (TEQDiox)) revealed a significant (p=0.045) decrease in lung function withh increasing exposure (Fig. 1). Age and gender showed no effect in thee outcomes.
Noo relation between prenatal dioxin exposure and airway diseases such ass otitis and bronchitis was found.
u u
> >Ê Ê
> >w w
E E
o o
H H 03 3FEV1/FVCC vs Prenatal Exposure
I.OOi i .90--.80 0 .70 0 ( ( A A AA A A AA A ~"—-~^^ A A ~ ~ - ~ ~ ^^ A A A AA ^ \ i i A ^ ~ ~ — ^ ^ ^^ A AA , ^ ^ ^ AA ^ ~ ~ — ^ ^ _ ^ A A A AA ^ ^ - - ^ ^ ~~~~ - ^ ^ A A A A A A A A A )) 20 40 60 80 100
Dioxinn toxic equivalency (ng TEQ/kg fat)
Fig.. 1. Ratio of forced expiratory volume in 1 s to forced vital capacity (FEV,/FVC ratio)) versus prenatal dioxin exposure. A line of best fit has been applied.
PostnatalPostnatal exposure
Linearr regression of the FEVi/FVC ratio versus postnatal dioxin exposuree (TEQCum) revealed a significant (p=0.0002) tendency towards aa lower ratio with increasing exposure (Fig. 2). One subject tended to be ann outlier in the postnatal group, because of a high postnatal exposure. Re-analysiss of the statistics with this subject excluded resulted in the decreasingg FEVi/FVC retaining its significance with p=0.031. Age and genderr showed no effect in the outcomes.
Noo relation between postnatal dioxin exposure and airway diseases such ass otitis and bronchitis was found.
FEVl/FVCC vs Postnatal Exposure
1.001 1 .90 0FEVl/FV
C C
b o o O O O O11 .70
( ( A A AAA A AA A AA A \ l ii A AA i S v A ^ ^^ A AA ^ \ ^ ^ AA A ^ \ A ^ " ^ \ ^^ A AA ^ ^ ^ ^ AA ^ ^ ^ ^ AA ^ ^ ~ - ^ ^ A A JJ 100 200 300 400Cumulativee toxic equivalency (ng)
Fig.. 2. Ratio of forced expiratory volume in 1 s to forced vital capacity (FEVi/FVC ratio)) versus postnatal dioxin exposure. A line of best fit has been applied.
RespiratoryRespiratory history
Theree was a significant increase in the reporting of chest congestion (n=4)) with increasing prenatal dioxin exposure (p=0.016), and a borderlinee increase (p=0.074) with increasing postnatal dioxin exposure. Theree was no evident relation between perinatal dioxin exposure and atopy.. No cases of infectious bronchiolitis were reported. No correction waswas made for air pollution, but this was arguably unnecessary: nearly all off the children grew up in the same environment (the Zaanstreek), an areaa not known as being air polluted.
Sub--j e c t t 1 1 5 5 6 6 7 7 8 8 9 9 10 0 15 5 16 6 22 2 26 6 28 8 29 9 31 1 32 2 34 4 35 5 39 9 40 0 43 3 46 6 48 8 52 2 53 3 54 4 56 6 57 7 64 4 65 5 TEQDiox x (prenatal) ) 25.40 0 33.10 0 67.30 0 43.78 8 80.48 8 67.07 7 88.80 0 49.66 6 59.84 4 30.80 0 16.56 6 37.30 0 38.49 9 13.75 5 31.10 0 38.02 2 33.01 1 26.79 9 43.42 2 29.21 1 27.96 6 20.63 3 19.72 2 30.34 4 21.07 7 15.09 9 46.62 2 56.10 0 25.40 0 TEQCum m (postnatal) ) 111.13 3 86.63 3 212.00 0 384.51 1 140.80 0 107.30 0 279.70 0 173.80 0 157.08 8 44.46 6 10.55 5 21.93 3 109.69 9 30.77 7 59.49 9 86.13 3 45.46 6 39.62 2 45.93 3 8.11 1 64.15 5 46.96 6 13.69 9 38.06 6 45.97 7 40.07 7 68.71 1 58.91 1 120.02 2 FEVj j 2.13 3 1.72 2 2.50 0 2.19 9 2.32 2 2.29 9 2.24 4 2.34 4 1.79 9 1.56 6 1.57 7 1.94 4 1.68 8 1.53 3 1.37 7 2.03 3 1.51 1 1.57 7 1.56 6 1.51 1 1.42 2 1.81 1 1.33 3 1.65 5 1.40 0 1.56 6 1.73 3 1.57 7 2.81 1 %% Predic-tedd FEV, 115 5 95 5 101 1 92 2 89 9 93 3 102 2 115 5 85 5 94 4 109 9 84 4 96 6 105 5 103 3 116 6 121 1 118 8 116 6 112 2 88 8 107 7 113 3 114 4 109 9 116 6 103 3 98 8 128 8 FEV,/ / FVC C 0.87 7 0.91 1 0.88 8 0.71 1 0.90 0 0.81 1 0.85 5 0.87 7 0.93 3 0.91 1 0.91 1 0.87 7 0.78 8 0.92 2 0.91 1 0.94 4 0.88 8 0.96 6 0.99 9 0.96 6 0.89 9 0.93 3 0.96 6 0.93 3 0.95 5 0.94 4 0.80 0 0.91 1 0.95 5 Gender r F F F F F F M M F F M M M M M M M M F F F F M M M M F F M M F F F F M M F F F F M M M M F F F F F F F F M M F F F F Maternall smoking duringg pregnancy No o No o No o No o No o No o No o No o No o No o No o No o No o Yes s No o Yes s Yes s No o No o No o No o No o Yes s No o No o No o No o No o No o
Tablee 1. Subjects' dioxin and spirometry data. TEQDiox: dioxin exposure level; TEQCum:: cumulative dioxin exposure; FEV]: forced expiratory volume in 1 s; FVC: forcedd vital capacity; F: female; M: male.
Discussion n
Respiratoryy problems have been reported amongst victims of dioxin disasterss (11;20;21). To the authors' knowledge, this is the first study to showw that background levels of dioxins (in The Netherlands), during the perinatall period, may result in lung function suboptimality later in childhood.. However, the study group was small and, in the light of the
Maternall cigarette smoking during pregnancy also seems to affect airway development,, as measured immediately after birth (22). This supports the hypothesiss that background environmental factors may influence airway development.. Smoking and dioxin exposure during pregnancy have partlyy comparable effects on metabolism, as is also demonstrated by the effectss on orofacial clefts (4;23).
Spirometry Spirometry
Spirometryy was considered the most suitable method of testing the hypothesis.. Spirometry is a widely used and reliable method of testing lungg function in a non-invasive manner. The ratio of air expired in one secondd (FEVi) to the total forced expiratory capacity (FVC) is a sensitive quantificationn of lung function. The FEVi and FVC were assessed accordingg to the Knudson predictive value for the individual, based on heightt (17). Clinical studies and experience have shown that it is possible too achieve reliable lung function test results in children from about 7 y of agee (24). The curves and values produced in this study were evaluated by bothh an adult and a paediatric pulmonologist. Curves not meeting the ERSS criteria were excluded, which meant the exclusion of six individuals. .
Thee spirometry results revealed a significant decline in the FEVi/FVC ratioo in relation to increasing prenatal and postnatal dioxin exposure. Postnatall exposure is dependent on both the prenatal exposure and the lengthh of breastfeeding. A subject with a relatively low prenatal exposure mayy exhibit a relatively high postnatal exposure, as a result of a long breastfeedingg period. This was seen in the one outlier, whose prenatal exposuree was well below the mean, but whose long breastfeeding period resultedd in a high postnatal exposure. When excluding him from analysis, statisticall significance remained. It therefore seems that (background) perinatall dioxin exposure of the children resulted in lung suboptimality thatt was visible more than 7 y after birth. This decreased lung function mayy be related to a developmental effect of dioxins.
Yusho Yusho
Thee 1968 leakage of PCBs, dioxins and furans into rice oil in Japan, the "Yushoo accident", resulted in a large population being exposed to high
concentrationss of polychlorinated biphenyls and furans. Follow-up of the exposedd population has revealed various toxic effects. Frequent respiratoryy infections were attributed to immunotoxicity. Around 40% of thee exposed individuals suffered from chronic bronchitis, with PCBs beingg detected in the lung and sputum of the victims and with furans beingg detected in the Clara cells of the lung. The respiratory symptoms improvedd gradually during the 10 y after the accident but changed little thereafter.. The FEVi/FVC ratio was described as "almost normal" (20). Inn contrast to the present study, the Yusho study was not a perinatal study,, and hence accounted for a toxic, not for a developmental, effect.
Yucheng Yucheng
AA similar PCB poisoning of rice oil occurred in Taiwan ("Yucheng") in 1978,, with results similar to Yusho (21). Respiratory system developmentall problems were observed. Mortality was high, with 25% of thee highly exposed babies dying within 4 y after birth as a result of respiratoryy disorders. Respiratory distress and pneumonia during the first 66 mo of life were common (25).
Seveso Seveso
Thee 1976 explosion at an Italian chemical plant in Seveso led to a pure dioxinn poisoning. Pesatori et al. found an excess mortality relative risk (RR)) of 3.7 for respiratory disease, mainly chronic obstructive pulmonary diseasess (COPD). The risk was highest during the first 5 y after the accident,, with a relative risk of 7.1. These mortality RRs were amongst thee group highest exposed to dioxin, with males being more susceptible thann females. However, no dose-response relationship was observed. Maless living in the neighbouring less contaminated zone had an RR of
1.0,, and those living in the least contaminated zone an RR of 1.1. The Sevesoo women displayed similarly inconsistent responses (11). The Sevesoo subjects were exposed to far higher concentrations than the backgroundd exposures of the subjects in the present study. However, it mustt be remembered that the Seveso study was again a toxic study and nott a perinatal study.
OccupationalOccupational exposure
Suskindd and Hertzberg found a deficit in respiratory function amongst factoryy workers exposed to 2,4,5-T, a herbicide. The spirometry data revealedd significantly increased odds for abnormal respiratory function valuess after adjustment for smoking (p=0.0099). In subgroups of never, formerr and present smokers, only the latter had a significant FEVi/FVC ratioo deficit for more exposed as opposed to less exposed individuals (p=0.0143)) (5). The 10 y mean age difference between Suskind's subject andd control groups might partly explain the results seen.
Inn contrast, Calvert et al. found no difference between workers and controlss in the risk for chronic bronchitis or COPD. Furthermore, no associationss between a history of dioxin exposure and FEVi, FVC or the FEVi/FVCC ratio were found (26). These studies addressed toxicity influences,, whereas the present study found a lung function deficit in relationn to perinatal exposure.
AnimalAnimal studies
Itt has long been known that the dioxin receptor (Ah receptor) is also presentt in lung tissue, especially in Clara cells, and that lung enzyme activityy can be altered by dioxins (27;28). In rat studies the Ah receptor hass been detected in bronchiolar, Clara and ciliated cells, but not in alveolarr epithelium. Localization of a functional Ah receptor in the same cellss where proliferative changes were induced by dioxin might indicate thatt the metaplastic changes of the alveolar-bronchiolar region, characterizedd by focal extrabronchiolar proliferation of cuboidal to columnarr mucociliary epithelium, are mediated via Ah receptors (29).
ClinicalClinical findings in Dutch toddlers
Inn their follow-up at the age of 42 mo, Weisglas-Kuperus et al. reported increasedd chest congestion, phlegm and coughing in relation to perinatal dioxinn exposure. The toddlers were too young for accurate spirometry (30). .
Summary Summary
Thee findings presented here indicate that perinatal exposure to backgroundd levels of dioxins (in The Netherlands) results in respiratory
deficit.. The deficit is mild to moderate. The pathophysiological process forr this deficit is not clear. Whether the answer lies in an increased incidencee of respiratory infections, morphological changes in lung tissue, alteredd surfactant production, altered Clara cell function, or a combinationn of these factors remains to be seen. Another Dutch study revealedd an increase in infections in relation to perinatal dioxin exposure (15).. The present study group is probably too small to assess this. Microscopicc investigations of lung biopsies are not possible, for ethical reasons,, in this group of "healthy" children. The association between a subjectivee feeling of chest congestion and perinatal dioxin exposure, althoughh in line with the spirometric findings, must be valued with caution,, owing to the limited number of positives (n = 4). A similar study withh a larger group might give more clarity on the association.
Thesee findings, found in "normal, healthy" Dutch children, bora after optimall pregnancies and birthweights, exposed perinatally to background dioxinn levels, are a cause for concern. However, the limited size of the cohortt means that a larger study is required to confirm these findings. Whatt would be seen if children with a less healthy start in life were studied?? Future follow-up of this cohort is warranted, specifically with respectt to lung function.
Too conclude, a decrease in the FEVj/FVC ratio in relation to an increasingg prenatal and postnatal dioxin exposure was found. The perinatall exposure is indicative of the background exposure in The Netherlands.. These findings suggest that prenatal and postnatal dioxin exposuree has a negative influence on lung development.
Acknowledgements s
Wee would like to express our gratitude to Mrs Margalith van Huiden-ten Brinkk for her invaluable organizational and secretarial help, Marcel Rouwenhorstt MD for his critical appraisal of the manuscript, Niesje Verheyy MD for her help with the study protocol, De Heel Zaans Medical Centree for graciously allowing this study to be performed under then-auspices,, and most of all to the children who participated in this study, andd their parents, for their time, effort and enthusiasm.
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