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. Author manuscript; available in PMC: 2017 Jan 23.
Published in final edited form as: Cancer Causes Control. 2015 Jul 2;26(9):1257–1270. doi: 10.1007/s10552-015-0618-0

Home paint exposures and risk of childhood acute lymphoblastic leukemia: Findings from the Childhood Leukemia International Consortium

Helen D Bailey 1, Catherine Metayer 2, Elizabeth Milne 3, Eleni Petridou 4, Claire Infante-Rivard 5, Logan G Spector 6, Jacqueline Clavel 7, John D Dockerty 8, Luoping Zhang 2, Bruce K Armstrong 9,10, Jérémie Rudant 7, Lin Fritschi 11, Alicia Amigou 7, Emmanouel Hatzipantelis 12, Alice Y Kang 2, Eftychia Stiakaki 13, Joachim Schüz 1
PMCID: PMC5257283  NIHMSID: NIHMS825681  PMID: 26134047

Abstract

Purpose

It has been suggested that home paint exposure increases the risk of childhood acute lymphoblastic leukemia (ALL).

Methods

We obtained individual level data from eight case-control studies participating in the Childhood Leukemia International Consortium. All studies had home paint exposure data (sometimes including lacquers and varnishes) for the pregnancy period with additional data for the 1–3 month period before conception in five, the year before conception in two, and the period after birth in four studies respectively. Cytogenetic subtype data were available for some studies. Data were harmonized to a compatible format. Pooled analyses of individual data were undertaken using unconditional logistic regression.

Results

Based on 3,002 cases and 3,836 controls, the pooled odds ratio (OR) for home paint exposure in the 1–3 months before conception and risk of ALL was 1.54 (95% confidence interval (CI) 1.28, 1.85), while based on 1160 cases and 1641 controls for exposure in the year before conception it was 1.00 (95% CI 0.86, 1.17). For exposure during pregnancy, using 4,382 cases and 5,747 controls, the pooled OR was 1.14 (95% CI 1.04, 1.25) and for exposure after birth, the OR was 1.22 (95% CI 1.07, 1.39), based on data from 1,962 cases and 2,973 controls. The risk was greater for certain cytogenetic subtypes and if someone other than the parents did the painting.

Conclusions

Home paint exposure shortly before conception, during pregnancy and/or after birth appeared to increase the risk of childhood ALL. It may be prudent to limit exposure during these periods.

Keywords: paint, acute lymphoblastic leukemia, childhood, pooled analysis

Introduction

Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, occurs mainly in children under five years of age, suggesting a role for parental exposures before birth or the child’s exposure in early childhood. Exposure to house paints has been suggested to be one potentially hazardous exposure in this period (1). ALL is a relatively rare disease in developed countries, with an annual incidence rate of 30–50 per million; hence individual studies rarely have sufficient statistical power to detect an effect, especially when investigating potential risk factors by sub-types that may have differing etiologies. To overcome this problem, we pooled data from studies participating in the Childhood Leukemia International Consortium (CLIC), a multi-national collaboration of case-control studies of childhood leukemia (2). The focus of these analyses was to investigate home paint exposure in relation to ALL. We have previously published findings of pooled analyses investigating parental occupational exposure to paints and the risk of childhood ALL using data from CLIC studies and found no association with paternal occupational exposure around conception, but had insufficient statistical power to investigate maternal occupational exposure during pregnancy (3).

Home paint exposure has been identified as a potential risk factor for ALL in previous studies (47), two of which are part of the current pooled analyses (6,4). There is also some evidence of a trend of increasing risk with more rooms painted (6,7) or with painting done by someone other than the parents (6,4), such as a professional painter. In addition, the level of risk may vary by cytogenetic subtype, such as ALL with the ETV6-Runx-1 t12;21 translocation (6,4), the most common subtype of childhood ALL, which may be of prenatal origin (8). A working group of the of the International Agency for Cancer (IARC) Monograph Program on the evaluation of carcinogenic risks to humans concluded in 2010 that there was ‘limited evidence that paint exposure is related to childhood leukemia’, based mainly on reports of maternal exposure (1). Paint, which is a coating, is a generic name for a diverse range of products which in some studies has been broadened to include other coating products such as lacquers and varnishes. All of these contain a large number of individual chemical compounds such as solvents, resins, binders, extenders and pigments, and some of these individual compounds have been classified as human carcinogens or probable or possible human carcinogens such as ethyl acrylate, titanium dioxide and other pigments (1). In the home, paint exposure can occur by actively using paint or spending time in an environment where paint has recently been used.

The aim of these analyses was to investigate whether home paint exposure in the time leading up to conception, during pregnancy or after the child’s birth increased the risk of childhood ALL. We also investigated whether the relationship varied by immunophenotype or cytogenetic subtype of ALL.

Methods

We included data from eight CLIC studies conducted in North America, Europe and Australasia over a 30 year period that had relevant data (Table 1), three of which have previously published findings in relation to home paint exposure (9,6,4). Original data were requested from each study including demographics, disease subtypes, covariates, variables used for control selection or matching factors and any data related to home paint exposure. A summary of study design and participant details, including inclusion criteria, has already been published (2). All studies recruited children under the age of 15 years and were approved by the relevant institutional or regional ethics committees.

Table 1.

Selected characteristics and definitions of home paint exposure in the studies in the CLIC pooled analyses of home paint exposure and the risk of ALL in the offspring

Country, Study
(years of case accrual)
Reference
(if
previously
published)
Cases Controls Time period Definition of exposure Prevalence
amongst
Controls

Source Partici
pation1
N Source Participatio
n1
N
Australia, Aus-ALL
(2003–2007)
Bailey et
al 2011
Reference 6
Hospitals (nationwide) 75% 388 RDD 64% of
agreed
controls
870 In year before conception Any painting inside the home or the mother or father did
any outdoor painting
52.7
During pregnancy Any painting inside the home or the mother did any
outdoor painting
31.0
After birth until reference date2 Any painting inside the home 49.8
Canada, Quebec
(1980–2000)4
Infante-
Rivard C
et al 2005
Reference 9
Hospitals (province
wide)
93% 790 Health Insurance file
population-based registry
(province-wide)
86% 790 In year before conception Any house painting 57.8
During pregnancy Any house painting 53.7
After birth until reference date2 Any house painting 77.9
France, ADELE
(1993–1999)
Hospitals 95% 240 Hospitals (same as cases) 99% 288 During pregnancy Domestic maternal exposure to paints 12.2
Greece, NARECHEM
(1993–94)
Nationwide hospital
cancer registry
100% 140 Hospital 96% 300 In the month before conception Mother exposed to paints or varnish in the residence 0.7
During pregnancy Mother exposed to paints or varnish in the residence 14.7
Greece, NARECHEM
(1996–97)
Nationwide hospital
cancer registry
83% 86 Hospital 96% 99 In the month before conception Mother or father exposed to paints or varnish in the
residence
5.1
During pregnancy Mother exposed to paints or varnish in the residence 14.1
New Zealand, NZCCS
(1990–1993)
Registry (nationwide) 92% 97 Birth registry
(nationwide)
69% 303 In three months before conception Mother exposed to paints, lacquers, paint removers,
turpentine products or thinners (home, work or other)
5.9
During pregnancy Mother exposed to paints, lacquers, paint removers,
turpentine products or thinners (home, work or other)
11.6
After birth until reference date2 Child ever exposed to paints, lacquers, paint removers,
turpentine products or thinners
11.2
US, COG-E15
(1989–1993)
Children’s Cancer
Group clinical trials
87% 1914 RDD 70% 1987 In the month before conception Mother or father had any contact with paints, stains,
lacquers in the home
6.0
During pregnancy Mother had any contact with paints, stains, lacquers in the
home
30.3
US, NCCLS
(1995–2008)5
Scelo 2009
Reference 2
Hospitals 86% 840 Birth registry (state wide) 68% 1226 In the three months before conception Any paints, stains or lacquers use in the home 8.4
During pregnancy Any paints, stains, or lacquer use in the home 19.3
After birth until the child’ 3rd birthday Any paints, stains, or lacquer use in the home 42.4
1

Participation fractions are based on information available from published studies or obtained directly from study personnel. Definition of the participation fraction may vary across studies.

2

Date of diagnosis for cases and the date of recruitment or questionnaire return for controls.

RDD: random digit dialing

Exposure assessment

We included in the analyses any CLIC study that had a measure of home paint exposure in any of three time periods: before the child’s conception, during the pregnancy and after the child’s birth. The measures of home paint exposure in each included study are summarized in Table 1. All studies had exposure data for the pregnancy period. Seven studies had exposure data for a period before conception: three had data for exposure in the month before conception (Greece: NARECHEM 1993–1994 and 1996–97; COG-E15); two for the three months before conception (NCCLS and New Zealand) and two for the year before conception (Australia, Canada). Given these differences, we analyzed exposure 1–3 months before conception separately from exposure in the year before conception. Four studies had data for exposure after birth: Australia, Canada and New Zealand, had data for exposure after the child’s birth until the reference date, which was the date of diagnosis for the cases and the date of recruitment or questionnaire return for the controls, while the NCCLS had data for exposure until the child’s third birthday.

Exposure was defined as ‘paint’ in one study (France), ‘paint or varnish’ in two, (Greece: NARECHEM 1993–1994 and 1996–97), ‘paints, stains or lacquers’ in two studies (NCCLS and COG-E15), paints, lacquers, paint removers, turpentine products or thinners in another (New Zealand) and ‘house painting’ in two studies (Australia and Canada) (Table 1).

Exposure was considered relevant in either parent before conception, the mother during pregnancy and the child after birth. For the studies with information on household paint use in a specified time period (Australia, Canada and NCCLS), we assumed everyone living in the house was exposed. For the other studies, we used the relevant person(s)’s exposure data. The New Zealand study had defined exposure based on maternal exposure in the home or workplace, but as we had previously found that maternal occupational exposure to paints was rare in the other CLIC studies, we used this as a proxy for home exposure (3). We also conducted subgroup analyses in subsets of studies for: the main types of paint used (‘not oil-based’ or ‘oil-based’) (Australia, Canada and France); and the trimester of exposure during pregnancy (Australia, Canada and NCCLS); and the person who had done the painting (categorized as ‘mother’, ‘father’, ‘someone other than the parents’) (Australia, Canada and NCCLS). This final group of analyses were only conducted in time periods where the exposure from the parents actively using paint could be more important than spending time in an environment where paint had been used, that is, before conception for both parents and during pregnancy for the mother.

Immunophenotype and cytogenetic classification of ALL

Information about lineage (B cell and T cell) was available for all studies. In addition, for B cell ALL cases, data for low hyperdiploidy (47–50 chromosomes) and high hyperdiploidy (51 or more chromosomes) which had been determined using conventional banding karyotypes or fluorescence in situ hybridization screening (FISH) were available for three studies (Australia, France, and NCCLS). For two studies (Australia and NCCLS) data were available for ETV6-Runx-1 gene fusion (cryptic t(12;21) translocations) in B cell ALL cases, determined by FISH or molecular detection of fusion transcripts and for 11q23/MLL rearrangement including either conventional cytogenetic identifying chromosome translocation involving the 11q23 region or MLL gene rearrangement by RT-PCR (AF4/MLL) or FISH-MLL break apart. Less common cytogenetic types were not included in our pooled analyses. The number of metaphases was not available in all studies, meaning that the karyotypes with no structural or numerical changes could not be considered normal karyotypes.

All studies routinely extracted existing data from medical records at the time of the diagnosis for all cases. In addition, NCCLS had performed specific analyses at a central laboratory from samples taken at the time of enrollment in the study. Before pooling the cytogenetic data, JC and experts in molecular biology (LZ, MPO) checked the consistency of CLIC data by conducting sex- and age-frequency analyses. In particular, there was no substantial heterogeneity between studies for the B cell cytogenetic abnormalities of interest (low hyperdiploidy, high hyperdiploidy, presence of ETV6-Runx1) or the presence of 11q23/MLL rearrangement, despite the assumed variations in methods across studies and time periods, and the prevalence of these cytogenetic abnormalities matched known distributions from clinical series.

Statistical analyses

Two distinct analytic approaches were taken. Firstly, study specific odds ratios (ORs) of exposure to paints around the home and risk of ALL were estimated and included in meta-analyses so we could explore heterogeneity between studies. Secondly, individual data were pooled in a single dataset and the pooled ORs estimated. As the findings using both methods were similar, the Methods and Results of the meta-analytical approach are presented as Supporting Material.

Pooled analyses

Unconditional logistic regression (SAS version 9.2, SAS Institute Inc, Cary, NC, USA) was used to estimate pooled ORs and 95% CIs for paint exposures around the home for the following four time periods: in the 1–3 months before conception, in the year before conception, during pregnancy and between the child’s birth and reference date. All models included the child’s age, sex, year of birth (grouped into four approximately equal time periods) and ethnicity (Caucasian, European or White versus the rest) and a variable denoting the study of origin. The following variables were considered a priori to be potential confounders and were tested to determine whether they met the empirical definition of confounding; that is, were independently associated with both the exposure and outcome: birth order; birth weight (where available); mother’s age and highest education of either parent (secondary education not completed, completed secondary education, and tertiary education); and study-specific matching variables (by allocating all the other studies the same dummy value for each variable). Of these, only highest education of either parent was retained. Subgroup analyses were undertaken for immunophenotypes. We stratified analyses by child’s sex, age at diagnosis (0–1 years, 2–4 years, 5–9 years and 10 or more years) and year of birth (before 1996 or later) as there were changes to the maximum levels of volatile organic compounds (VOCs) allowed in paints in the mid 1990’s (10,11), and tests for interaction were performed. The analyses for exposures after birth were first run using all studies with data for any time period after birth and then rerun, restricting them to the three studies with exposures up until the reference date. Where there were two or more studies with at least 30 cases with compatible data, sub group analyses were also done by trimester of pregnancy, the person who had done the painting, the type of paint used and the cytogenetic subtype.

To assess whether risk varied between ‘before’ and ‘during’ pregnancy, logistic regression models were also repeated using a four level exposure variable: (1) no exposure before or during pregnancy, (2) exposure only before pregnancy, (3) exposure only during pregnancy and (4) exposure during both these time periods. In addition, the OR for exposure in the 1–3 months before or during pregnancy was calculated to allow comparison with previous studies (7,12).

As children with Down syndrome have higher rates of ALL than other children, analyses were repeated excluding these children. Analyses were also repeated adjusting for paternal occupational paint exposure around conception and maternal occupational paint exposure during pregnancy and using combined home and/or occupational paint exposure variables.

Results

Data were available for up to 4,495 cases and 5,863 controls, depending on the analyses. The demographic characteristics of the pooled sample are shown in Table 2 and those for individual studies in Supplementary Table 2. Cases and controls were generally similar, but control parents were more likely to have had a tertiary education than case parents (51.0% vs 45.6%). As expected, case children were more likely to have Down Syndrome than control children. Data for exposure during pregnancy were available for all studies and over 97% of cases and controls, while exposure data for other time periods were available for subsets of studies.

Table 2.

Demographic and other characteristics of participants in the CLIC pooled analyses of home paint exposure and the risk of ALL in the offspring (8 studies)

Case (n= 4495) Control (n = 5863)
n %1 n %1

Type of ALL
  B cell lineage 3416 76.0
  T cell lineage 435 9.7
  Other 630 14.0
  Missing 14 0.3
Sex
  Boy 2513 55.9 3248 55.4
  Girl 1982 44.1 2615 44.6
Age (years)2
  0–1 485 10.8 738 12.6
  2–4 2096 46.6 2505 42.7
  5–9 1319 29.3 1772 30.2
  10–14 595 13.2 848 14.4
Year of birth
  <1985 1116 24.8 1276 21.7
  1985–1988 1258 28.0 1429 24.4
  1989–1995 1233 27.4 1594 27.2
  1996–2007 888 19.8 1564 26.7
Child’s reference year3
  1980–1987 280 6.2 280 4.8
  1988–1993 2295 51.0 2541 43.3
  1994–2000 961 21.4 1333 22.7
  2001–2008 959 21.3 1709 29.1
Birth order
  1st 1954 43.5 2540 43.3
  2nd 1571 34.9 2002 34.1
  3rd or more 951 21.2 1295 22.1
  Missing 19 0.4 26 0.4
Mother’s age at child’s birth
  <25 years 1364 30.3 1584 27.0
  25–34 years 2633 58.6 3558 60.7
  >34 years 495 11.0 720 12.3
  Missing 3 0.1 1 0.0
Child has Down Syndrome
  Yes 41 0.9 4 0.1
  No 4452 99.0 5858 99.9
  Missing 2 0.0 1 0.0
Highest level of education of either parent
  Did not finish secondary education 551 12.3 636 10.8
  Completed secondary education 1895 42.2 2234 38.1
  Tertiary education 2048 45.6 2989 51.0
  Missing 1 0.0 4 0.1
Ethnicity
  White/Caucasian/European 3432 76.4 4645 79.2
  Other 1040 23.1 1180 20.1
  Indeterminate 17 0.4 37 0.6
  Missing 6 0.1 1 0.0
1

All percentages have been rounded to one decimal place and thus the totals may range from 99.9%–100.1%

2

Age groups are based on the child’s age at the censoring date. For case, this was the date at diagnosis and for controls, it was the date that the study investigators nominated (either the date of recruitment or the date of the questionnaire return).

3

Reference years are based on the censoring date. For case, this was the date at diagnosis and for controls, it was the date that the study investigators nominated (either the date of recruitment or the date of the questionnaire return)

Pooled analyses of individual data

The pooled OR for home paint exposure in the 1–3 months before conception using data from five studies was 1.54 (95% CI 1.28, 1.85) (Table 3). In the analyses of immunophenotype, the increased risk was seen in B cell and not T cell ALL (ORs 1.52, 95% CI 1.25, 1.86, and 1.01 95% CI 0.60, 1.67 respectively) (Woolf's test for heterogeneity p value 0.24). There was little difference when the analyses were stratified by child’s sex, age at diagnosis, or year of birth (Table 3).

Table 3.

Pooled OR (95% CI) for the association between home paint exposure and the risk of ALL in the offspring: Overall and by subgroups

Within 1–3 months before conception (5 studies1 unless
otherwise indicated)
Within the year before conception (2 studies2) During pregnancy
(all 8 studies, unless otherwise indicated)
After birth (4 studies3)

Total N
Case/Controls
% exposed OR4,5 (95% CI) Total N
Case/Controls
%
exposed
OR4,5 (95% CI) Total N
Case/Controls
%
exposed
OR4,5 (95% CI) Total N
Case/Controls
% exposed OR4,5 (95% CI)

Any paint exposure 3002/3836 9.0/6.3 1.54 (1.28, 1.85) 1160/1641 52.6/52.8 1.00 (0.86, 1.17) 4382/5747 32.1/28.5 1.14 (1.04, 1.25) 1962/2973 59.5/50.8 1.22 (1.07, 1.39)
Immunophenotype
  B-lineage cases 2141/3836 8.9/6.3 1.52 (1.25, 1.86) 1012/1641 52.6/52.8 1.01 (0.86, 1.19) 3331/5747 33.1/28.5 1.19 (1.08, 1.31) 1732/2973 58.8/50.8 1.20 (1.05, 1.38)
  T-lineage cases 285/3836 6.7/6.3 1.01 (0.60, 1.67) 111/1641 49.5/52.8 0.87 (0.59, 1.30) 423/5747 27.2/28.5 0.96 (0.75,1.21) 184/2973 62.5/50.8 1.26 (0.89, 1.78)
Age at diagnosis
  0–1 years 325/519 8.6/5.8 1.63 (0.94, 2.85) 125/155 42.4/57.4 0.52 (0.32, 0.62) 472/725 37.7/30.6 1.29 (0.99,1.68) 159/242 50.3/36.8 1.53 (0.93, 2.52)
  2–4 years 1355/1579 9.3/6.3 1.64 (1.24, 2.17) 578/793 52.8/50.9 1.10 (0.88, 1.37) 2040/2447 33.9/31.1 1.15 (1.01, 1.32) 963/1361 59.7/53.3 1.15 (0.96, 1.39)
  5–9 years 876/1123 9.0/5.8 1.62 (1.15,2.30) 350/523 56.0/53.3 1.12 (0.84, 1.49) 1295/1747 30.3/26.4 1.13 (0.96, 1.34) 605/946 63.8/53.1 1.29 (1.00, 1.65)
  10 or more years 446/615 8.1/7.5 1.12 (0.70, 1.80) 107/170 52.3/55.9 0.83 (0.50, 1.39) 575/828 24.9/22.9 1.08 (0.82, 1.41) 235/424 54.4/46.0 1.26 (0.85, 1.86)
Interaction p value = 0.34 Interaction p value = 0.28 Interaction p value = 0.48 Interaction p value =
0.50
Sex
  Girls 1349/1723 9.6/6.2 1.71(1.30, 2.25) 503/735 52.5/53.7 0.97 (0.76, 1.22) 1942/2577 34.6/30.5 1.18 (1.03, 1.35) 853/1314 59.6/50.7 1.20 (0.99, 1.46)
  Boys 1653/2113 8.4/6.3 1.40 (1.09,1.81) 657/906 52.7/52.1 1.04 (0.84, 1.27) 2440/3170 30.1/26.6 1.12 (0.99, 1.27) 1109/1659 59.5/50.9 1.23 (1.04, 1.46)
Interaction p value = 0.32 Interaction p value = 0.84 Interaction p value = 0.67 Interaction p value =
0.98
Child’s birth year
  Before 1996 2526/3111 8.6/6.2 1.47 (1.20, 1.80) 798/886 50.9/52.0 0.99 (0.82,1. 21) 3534/4230 29.1/32.8 1.13 (1.02, 1.25) 1198/1637 65.3/54.3 1.24 (1.03, 1.49)
  1996 or later 476/725 10.7/6.5 1.86 (1.22, 2.84) 362/755 55.1/54.0 1.03 (0.80, 1.34) 848/1517 26.6/29.1 1.19 (0.98, 1.46) 764/1336 50.5/46.6 1.20 (1.00, 1.45)
Interaction p value = 0.32 Interaction p value = 0.82 Interaction p value = 0.53 Interaction p value =
0.78
Who used the paint? Data not shown as only 1 study had data
  Mother used paint 896/1210 38.6/36.0 1.02 (0.85, 1.23) 1559/23436 21.7/18.9 1.13 (0.95, 1.33)
  Father used paint 1032/1506 46.7/48.6 0.96 (0.81, 1.13)
  Someone other than parents used paint 608/832 9.5/7.0 1.53 (1.03, 2.26) 1305/19856 6.4/4.3 1.66 (1.21, 2.28) 928/14556 23.3/18.0 1.46 (1.18, 1.80)
Type of paint used Data not shown as only 1 study had data
  Use of water-based paints 1146/1617 29.8/34.3 0.87 (0.72, 1.04) 1387/19037 26.0/25.7 0.96 (0.80, 1.15) 1157/16322 41.7/39.7 1.01 (0.83, 1.23)
  Use of oil-based paints (+/− water-based) 1146/1617 22.3/17.8 1.27 (1.03, 1.57) 1387/19037 14.1/11.1 1.22 (0.98, 1.53) 1157/16322 27.5/22.9 1.17 (0.94, 1.45)
1

France (ADELE), Greece (NARECHEM 1993–1994 & 1996–1997), New Zealand, US (COG-E15), US, NCCLS.

2

Australia (Aus-ALL), Canada.

3

Australia (Aus-ALL), Canada, New Zealand, US, NCCLS.

4

The reference group was those with no paint exposure in that time period.

5

Adjusted forage, sex, birth year group, study, ethnicity and highest level of education of either parent

6

Australia (Aus-ALL), Canada, US, NCCLS only.

7

Australia (Aus-ALL), Canada, France (ADELE) only.

Using data from two studies, the pooled OR for home paint exposure in the year before conception and the risk of ALL was 1.00 (95% CI 0.86, 1.17) (Table 3). There was little difference in the OR when the analyses were done by immunophenotype or when stratified by child’s sex, or year of birth (Table 3). The OR was lower for those diagnosed before the age of 2 years, but this was based on small numbers.

The pooled OR for home paint exposure during pregnancy using eight studies analyses was 1.14 (95% CI 1.04, 1.25) overall and was higher for B cell than T cell ALL (ORs 1.19, 95% CI 1.08, 1.31, and 0.96, 95% CI 0.75, 1.21 respectively) (Woolf's test for heterogeneity p value 0.02) (Table 3). There was little difference when the analyses were stratified by child’s sex, age or year of birth (Table 3) or by trimester of pregnancy (~3000 case and ~ 4000 controls from three studies, results not shown).

For those with exposure data for the 1–3 months before as well as during pregnancy, the ORs for the four-level exposure variable (exposure only before pregnancy, exposure only during pregnancy and exposure during both these time period, with no exposure before or during pregnancy as the reference group) were as follows; Only before pregnancy: 1.53, 95% CI 1.16, 2.03; only during pregnancy: OR 1.15, 95% CI 1.02, 1.30; and in both time periods: 1.61, 95% CI 1.26, 2.06 (Results not otherwise shown). The OR for exposure either in the 1–3 months before conception or during pregnancy was OR 1.25, 95% CI 1.12, 1.39 (Results not otherwise shown). For those with exposure data for the year before as well as during pregnancy, however, the ORs were all similar (Only before pregnancy: 0.96, 95% CI 0.78, 1.19; only during pregnancy: OR 1.05, 95% CI 0.82, 1.35; and in both time periods: 1.07, 95% CI 0.87, 1.30) (Results not otherwise shown).

Using data from four studies, the pooled OR for exposure to paint around the home after birth was 1.22 (95% CI 1.07, 1.39) (Table 3). When the analyses were restricted to the three studies that included exposures up until the reference date, the OR was 1.12 (95% CI 0.94, 1.33) (Results not otherwise shown). There was little difference when the analyses were stratified by immunophenotype, child’s sex, or year of birth (Table 3). The ORs for those diagnosed before the age of 2 years appeared to be higher than for other age groups (OR 1.53, 95% CI 0.93, 2.52, age group interaction p value 0.50), but there were fewer children in this age group.

The ORs for either parent using paint in the year before pregnancy, or the mother using it during pregnancy were not elevated, while those for someone other than the parents doing the painting were elevated for all time periods (Table 3). The ORs for using oil-based paints were generally higher than for other paint types in both the year before pregnancy and during pregnancy, but were similar for painting after birth (Table 3).

There were sufficient studies and cases to do analyses by cytogenetic subtypes for paint exposure during pregnancy and after birth. For exposures during pregnancy, risk varied by cytogenetic subtype (Table 4); the ORs was highest among those with any 11q23/MLL rearrangement: 3.30 (95% CI 1.71, 6.35). Most cases with any 11q23/MLL rearrangement were aged two years or under (66.6%). The proportion of control mothers who reported paint exposure during pregnancy was inversely associated with the child’s age, which suggested that parents of young children recalled more exposures than the parents of older children. Therefore, we restricted these analyses to subjects aged two years or younger. The resulting OR, based on 26 cases, was 2.60 (95% 1.05, 6.43) (results not otherwise shown). Elevated ORs were also found in B cell cases with the presence of ETV6-Runx1 and low hyperdiploidy (Table 4). The NCCLS contributed between 48–70% of cases for the cytogenetic subtype analyses. When the analyses were repeated excluding this study, the results were less precise, with an OR of 2.46 (0.99, 6.10) for any 11q23/MLL rearrangement and the other ORs were generally in the same direction and magnitude as when it was included (data not shown). For exposures after birth, only two studies had cytogenetic data and the NCCLS contributed 67–78% of the data. The ORs for B cell cases with low hyperdiploidy and those with the t(12;21) translocation were both elevated (Table 4). Excluding the NCCLS data, the OR among B cell cases with low hyperdiploidy was 1.57 (95% CI 0.71, 3.48) while the OR for B cell cases with the t(12;21) translocation was similar to that for all B cell cases from that study. There were insufficient cases to investigate 11q23/MLL rearrangements.

Table 4.

Pooled OR (95% CI) for the association between exposures to paint around the home during pregnancy and the risk of ALL in the offspring by cytogenetic subtype

During pregnancy After birth

No of studies Total N
Case/Controls
% exposed OR1,2, (95% CI) No of studies Total N
Case/Controls
% exposed OR1,2, (95% CI)
B cell ALL low hyperdiploidy 33 147/2301 27.2/22.9 1.48 (0.99, 2.20) 24 120/1881 59.2/45.8 1.94 (1.32, 2.86)
B cell ALL high hyperdiploidy 33 338/2301 21.0/22.9 1.05 (0.78, 1.40) 24 288/1881 47.9/45.8 1.21 (0.94, 1.57)
B cell ALL ETV6-Runx1 t(12;21) 24 193/2030 31.6/24.3 1.51 (1.08, 2.11) 24 183/1881 57.4/45.8 1.60 (1.16, 2.21)
Any MLL rearrangement 24 39/2030 48.7/24.3 3.30 (1.71, 6.35) 24 25/1881 36.0/45.8 Insufficient data
1

The reference group was those with no paint exposure in that time period.

2

Adjusted forage, sex, birth year group, study, ethnicity and highest level of education of either parent

3

Australia (Aus-ALL), France (ADELE), US (NCCLS)

4

Australia (Aus-ALL), US (NCCLS)

When the analyses for all time periods were repeated excluding children with Down syndrome (41 cases and four controls for the during pregnancy analyses and less for other time periods), there was little change in the results and there was also little difference when the analyses were adjusted for parents’ occupational paint exposure or when the home and occupational exposure was combined into a single variable (data not shown).

Discussion

These pooled analyses add to the existing evidence that paint exposure around the home may be related to childhood ALL in certain circumstances. Using data from five studies, we found that paint exposure in the few months leading up to conception could be associated with an increased risk of ALL, and that this risk may be restricted to B cell ALL. By contrast, no association was found using data from the two studies with exposure data for the year before conception. Using data from eight studies, there was some evidence of association between paint exposure during pregnancy and an increased risk of B cell ALL, and among a subset of these studies, of certain cytogenetic subtypes (any 11q23/MLL rearrangement or ETV6-Runx-1 (t(12;21) translocations). Using data from four studies, there was evidence of a weak association between exposure after birth and ALL, which was more evident with certain cytogenetic subtypes and possibly in younger children. In addition, using data from a subset of studies, using any oil-based paints seemed to increase the risk of ALL before, during and after birth as did having someone other than the parents (likely to be a professional painter) paint the home. This last finding may reflect a higher dose or intensity of exposure, but we did not have the data to investigate this further. On the other hand, the risk associated with parents actively using the paint in relevant time periods appeared to be similar to any exposure in that time period.

Apart from the studies included in the pooled analyses which have previously publishing their findings(6,4), there are only three other published reports (12,7,5), that have investigated whether home paint exposure is associated with ALL. All were conducted in the US, and one included the subpopulation of ALL cases with Down syndrome (12), and thus its findings may have limited generalisability. While the study of Down Syndrome children found no association between exposure to paints, stains and lacquers in the month before or during pregnancy (12), Freedman et al (7) reported an OR of 1.2 (95% CI 0.9, 1.5) for exposure to home painting in the year before birth, which is similar to our OR for the 1–3 months before or during pregnancy (1.2, 95% CI 1.1, 1.4). The third previous non-CLIC study, based on 123 cases, investigated parental use of paints or lacquers during pregnancy or while the mother was breastfeeding and reported an increased risk with maternal paint use, but no association if the father or either parent used paint (5). The other potential source of paint exposure during pregnancy is maternal occupational paint exposure, but using a pooled sample of more than 8,000 cases from 12 CLIC studies, we had too few exposed mothers to draw any conclusions about maternal occupational exposure during pregnancy (3).

Only two studies other than the studies included in these pooled analyses have reported findings in relation to paint exposure after birth (12,7). While the study restricted to children with Down Syndrome (12) found no association, the other (7), like ours found a weak association. In addition, they found that the risk was elevated with higher doses or frequency of exposure.

To the best of our knowledge, two of the studies in the current pooled analyses are the only previous reports by immunophenotype (6) or cytogenetic subtypes, (6,4). Using this pooled sample, we found that the risk with paint exposure before birth was higher for B cell ALL than for T cell ALL, while ORs for exposure after birth were similar for both immunophenotypes; this could provide some insight into their different etiologies. It is plausible that prenatal exposures are more important for B cell ALL, which occurs in younger children. Not surprisingly, our pooled findings for exposure during pregnancy and after birth in relation to the most common cytogenetic subtype seen in childhood ALL, the ETV6-Runx-1 t(12;21) translocation, are similar to the previously published data (6,4) as these were the two studies in these analyses, and findings in both were in the same direction. However, with the larger sample size, our estimates are more precise. This translocation is thought to occur in utero as it has been detected in newborn blood samples (8), but a second postnatal event may be necessary to initiate disease (13). It is plausible that exposure to paints could be either the primary hit initiating DNA damage, or the subsequent event. The increased risk seen with exposure during pregnancy and 11q23/MLL rearrangement is novel. 11q23/MLL rearrangement is predominantly seen in infant ALL and are thought to originate in utero during fetal hematopoiesis (14). Unlike other types of ALL, infant ALL is hypothesized to require only a single exposure in utero to trigger the disease (15). Among the two studies with 11q23/MLL rearrangement data, 66.7% of the cases were aged under two years, but they made up only about ~13% of total cases in this age group from these studies. This may explain that while the OR (1.29, 95% CI 0.99,1.68) for children under two years was higher than for other age groups, it was not of the same magnitude as we found for 11q23/MLL rearrangement.

Our finding of an increased risk with painting close to the time of conception (in both the analyses of the individual time period and when combined with pregnancy) could support the hypothesis that environmental exposure results in paternal germ cell damage prior to fertilization. However, this is not supported by our previous finding that paternal occupational exposure to paints around conception was not associated with ALL risk (3) and one would assume that the frequency and level of exposure to paint chemicals would be much higher in occupational paint exposure than in home exposure. Perhaps the explanation for this is that the period when the painting was done may not reflect the true ‘critical time of exposure’. For example, there is evidence that VOCs released by paints remain elevated in a home for at least a month after the painting occurred and that the levels were also high in rooms other than those painted (16). Therefore, levels of chemical residues could still be raised in the early weeks of pregnancy following painting done just before conception (or similarly levels could be raised after birth because of painting done in late pregnancy). Maternal exposure in early pregnancy could be critical, as hematopoiesis in the liver and bone marrow commences after the first month of fetal life, whereas in the extra-embryonic yolk sac it commences earlier (17).

Paints contain many individual compounds, some of which are thought to be carcinogenic (1). In addition, other potentially harmful agents can be associated with paint use, such as those used in preparation of surfaces or in the cleaning up process. About 75% of modern paints are water-based, while the remainder are oil-based and contain solvents such as toluene and xylene (18). Oil-based paints release VOCs into the atmosphere as do some water-based paints, albeit at lower levels (18). However, the composition of paints used over the relevant time periods for the studies would have changed, at least partly because of changing government legislation which continues to reduce VOC levels (19,11). Using a subset of studies, we found that the OR associated with the use of any oil-based appeared to be higher than for only water-based paints, which suggests that compounds found in higher concentrations in oil-based paints could be implicated, but our findings are based on small numbers. However, if historically there was a risk with these paints, this risk may disappear with changing paint compositions and reducing VOC levels.

The major strength of this current investigation was the large sample size, especially for exposures during pregnancy to which all eight studies contributed data. While three of the studies (NCCLS (4), Australia, (6) and Canada (9)) included in the pooled analyses have previously published their findings in relation to paint exposure in the home, the other five studies had not. In addition, for these pooled analyses, we were able to include 50% more NCCLS cases than were available for the previous report. The access to the original data allowed us to harmonize exposure data and other information such as immunophenotype. However, because the studies had collected data for different time periods before conception or after birth, or did not have these data at all, the different combinations of studies made it hard to judge whether changes to the OR reflected true differences by time period or were related to which studies were included, which is especially a concern for the two windows before pregnancy (1–3 months versus one year). Similarly, the interpretation of the analyses by cytogenetic subtypes is complicated as not all studies with data had information for all subtypes, thus changing the denominator. The pooled studies also included cases diagnosed over a fifteen year time period (1993– 2008) so the availability and classification of the cytogenetic abnormalities of interest varied between studies. Therefore, we only included the classical subtypes the most routinely done in order to account at best for a part of the B-cell ALL cytogenetic heterogeneity while limiting the risk of inducing misclassifications due to insufficient data. Despite this, the analyses by cytogenetic subtypes lacked statistical power because of the limited number of cases.

Just as the definition of paint exposure varied across studies, so did the prevalence of exposure among the controls. The prevalence during pregnancy was 12–15% in the European studies with the definition of ‘paint’ or ‘paint or varnish’, 12% in the study using ‘paints, lacquers, paint removers, turpentine products or thinners’ (New Zealand), 19–30% in the two US studies using ‘paints, stains or lacquers’ and 31–54% in the two studies (Australia and Canada) with data on ‘house painting’. It would be expected that studies which used a broad definition would have the highest prevalence as paint exposure from other sources, such as hobbies would have been included, but this was not the case. These differences may reflect true variations by region or when the studies were conducted. Other published estimates of the prevalence of paint exposure during pregnancy range from 19% controls who participated in a case-control study of fetal death in California (20), 44% among controls in two of the previous case-control studies of paint and ALL in the US (7,12) and 45% in the Danish National Birth Cohort (21).

As our analyses used data derived from case-control studies, there is potential for recall bias. The individual studies attempted to minimize this by using standardized questionnaires. Nonetheless, this would not have removed the potential for case parents to think more deeply about past exposures and recall them more frequently (22). However, if this were the case, recall bias is unlikely to explain some of the findings, such as in relation to who did the painting (not the parents) or type of paint (only oil-based paint) or immunophenotype. Another explanation for some of our positive findings is chance.

In conclusion, these pooled analyses add to the existing evidence of a weak to modest association between painting in or around the home and the risk of childhood ALL, particularly B-cell ALL. We found that exposures close to conception, and, to a lesser extent those during pregnancy and in early childhood were associated with an increased risk in certain circumstances. The findings in relation to cytogenetic subtypes need to be replicated in a larger and more standardized sample. The existing evidence of cytogenetic and hematological changes in painters (1) adds weight to the plausibility of paint-induced DNA damage to the hematopoietic system at critical times of development being a precursor to childhood ALL. Until there is evidence to the contrary, we suggest that parents and those contemplating pregnancy limit paint use in the home in the year before birth and the child’s early years.

Supplementary Material

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Suppl Table 1
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Supporting Material

Acknowledgments

Funding

The work reported in this paper by Helen Bailey was undertaken mostly during the tenure of a Postdoctoral Fellowship from the International Agency for Research on Cancer (IARC), partially supported by the European Commission FP7 Marie Curie Actions, - People- Co-funding of regional, national and international programmes (COFUND), with additional support by the Environment and Radiation Section of IARC. The CLIC administration, annual meetings, and pooled analyses are partially supported by the National Cancer Institute, NCI, USA (grant R03CA132172), National Institute of Environmental Health Sciences, NIEHS, USA (grants P01 ES018172 and R13 ES021145-01), the Environmental Protection Agency, EPA, USEPA, USA (grant RD83451101), the Children with Cancer, CwC, UK (Award No. 2010/097) and Alex’s Lemonade Stand Foundation (grant 20140461).

Aus-ALL was supported by the Australian National Health and Medical Research Council (Grant ID 254539).

The Canadian study was funded by The National Cancer Institute of Canada; Grant numbers: #014113, #010735-CERN #RFA0405; The Medical Research Council of Canada; Grant number: MOP 37951; The Fonds de la recherche en santé du Québec; Grant number: #981141; The Bureau of Chronic Disease Epidemiology, Canada; Health and Welfare Canada; The Leukemia Research Fund of Canada; and the National Health and Research Development Program, Ottawa.

France: ADELE Grant sponsors: INSERM, the French Ministère de l’Environnement, the Association pour la Recherche contre le Cancer, the Fondation de France, the Fondation Jeanne Liot, the Fondation Weisbrem-Berenson, the Ligue Contre le Cancer du Val de Marne, the Ligue Nationale Contre le Cancer.

NARECHEM, is supported in part by the National and Kapodistrian University, Athens, Greece.

The New Zealand Childhood Cancer Study was funded by the Health Research Council of NZ, the NZ Lottery Grants Board, the Otago Medical School (Faculty Bequest Funds), the Cancer Society of NZ, the Otago Medical Research Foundation, and the A.B. de Lautour Charitable Trust.

The Northern California Childhood Leukemia Study (NCCLS) is supported by the National Institutes of Health (NIH), USA (grants P01 ES018172, R01 ES09137, and P42-ES04705), Environmental Protection Agency (USEPA), USA (grant RD83451101), and the CHILDREN with CANCER (CwC), UK (former Children with Leukaemia) for data collection. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, USEPA, or the CwC.

COG: The E15 cohort of the Children’s Oncology Group were funded by National Institutes of Health (NIH), USA (Grants R01CA049450 (E14) and R01CA048051 (E15)) and The Children’s Cancer Research Fund, Minneapolis, MN

We would like to thank Dr Maria S Pombo-de-Oliveira, Instituto Nacional de Câncer (INCA) who was one of experts in molecular biology who reviewed the consistency of CLIC cytogenetic data. We would like to thank our dear colleague and friend, Patricia Buffler, who passed away before the submission of this manuscript. She was a founding member and Chair of CLIC as well as the driving force behind the NCCLS. She provided unconditional support to finding the causes of childhood leukemia, and her scientific leadership and guiding forces within CLIC will be remembered.

The Aus-ALL consortium conducted the study and the Telethon Kids Institute (formerly Telethon Institute for Child Health Research; TICHR), University of Western Australia, was the coordinating centre. Bruce Armstrong (Sydney School of Public Health), Elizabeth Milne (TICHR), Frank van Bockxmeer (Royal Perth Hospital), Michelle Haber (Children’s Cancer Institute Australia), Rodney Scott (University of Newcastle), John Attia (University of Newcastle), Murray Norris (Children’s Cancer Institute Australia), Carol Bower (TICHR), Nicholas de Klerk (TICHR), Lin Fritschi (WA Institute for Medical Research, WAIMR), Ursula Kees (TICHR), Margaret Miller (Edith Cowan University), Judith Thompson (WA Cancer Registry) were the research investigators, and Helen Bailey (TICHR) was the project coordinator. The clinical Investigators were: Frank Alvaro (John Hunter Hospital, Newcastle); Catherine Cole (Princess Margaret Hospital for Children, Perth); Luciano Dalla Pozza (Children’s Hospital at Westmead, Sydney); John Daubenton (Royal Hobart Hospital, Hobart); Peter Downie (Monash Medical Centre, Melbourne); Liane Lockwood, (Royal Children’s Hospital, Brisbane); Maria Kirby (Women’s and Children’s Hospital, Adelaide); Glenn Marshall (Sydney Children’s Hospital, Sydney); Elizabeth Smibert (Royal Children’s Hospital, Melbourne); Ram Suppiah, (previously Mater Children’s Hospital, Brisbane).

NARECHEM Greek Pediatric Hematology Oncology Clinicians: Margarita Baka MD, (Department of Pediatric Hematology –Oncology, “Pan.&Agl. Kyriakou” Children’s Hospital, Athens) Maria Moschovi MD, Sophia Polychronopoulou MD (Departments of Pediatric Hematology –Oncology, “A. Sophia” Children’s Hospital, Athens); Emmanuel Hatzipantelis MD, PhD (Pediatric Hematology Oncology Unit, 2nd Pediatric Department of Aristotle University, AHEPA General Hospital, Thessaloniki); Maria Kourti MD (Pediatric Oncology Department, Hippokration Hospital, Thessaloniki); Eftychia Stiakaki MD (Department of Pediatric Hematology-Oncology, University Hospital of Heraklion, Heraklion); Ioannis Matsoukis MD (Department of Hygiene, Epidemiology and Medical Statistics, Athens University Medical School, 11527 Athens); Nick Dessypris, MSc, PhD and Evanthia Bouka, MPH: Department of Hygiene, Epidemiology and Medical Statistics, Athens University Medical School, 11527 Athens, Greece.

The New Zealand Childhood Cancer Study was co-ordinated at the University of Otago, where the study team included JD Dockerty, GP Herbison (who helped prepare data for this pooled analysis), DCG Skegg and JM Elwood. The names of the interviewers, secretaries, research assistants, clinicians, pathologists and cancer registry staff who contributed are listed in earlier publications from the NZ study.

COG: The E15 cohort of the Children’s Oncology Group was identified by CCG (Children’s Cancer Group) principle and affiliate member institutions. Further information can be found on the web-site: http://www.curesearch.org/.

The NCCLS thanks the families for their participation and the clinical investigators at the following collaborating hospitals for help in recruiting patients: University of California Davis Medical Center (Dr. J. Ducore), University of California San Francisco (Drs. M. Loh and K. Matthay), Children's Hospital of Central California (Dr. V. Crouse), Lucile Packard Children's Hospital (Dr. G. Dahl), Children's Hospital Oakland (Dr. J. Feusner), Kaiser Permanente Roseville (former Sacramento; Drs. K. Jolly and V. Kiley), Kaiser Permanente Santa Clara (Drs. C. Russo, A. Wong, and D. Taggar), Kaiser Permanente San Francisco (Dr. K. Leung), and Kaiser Permanente Oakland (Drs. D. Kronish and S. Month). Finally, the NCCLS thanks the entire study staff and former University of California, Berkeley Survey Research Center for their effort and dedication.

The French authors would like to thank all of the Société Française de lutte contre les Cancers de l’Enfant et de l’Adolescent (SFCE) principal investigators: André Baruchel (Hôpital Saint-Louis/Hôpital Robert Debré, Paris), Claire Berger (Centre Hospitalier Universitaire, Saint-Etienne), Christophe Bergeron (Centre Léon Bérard, Lyon), Jean-Louis Bernard (Hôpital La Timone, Marseille), Yves Bertrand (Hôpital Debrousse, Lyon), Pierre Bordigoni (Centre Hospitalier Universitaire, Nancy), Patrick Boutard (Centre Hospitalier Régional Universitaire, Caen), Gérard Couillault (Hôpital d’Enfants, Dijon), Christophe Piguet (Centre Hospitalier Régional Universitaire, Limoges), Anne-Sophie Defachelles (Centre Oscar Lambret, Lille), François Demeocq (Hôpital Hôtel-Dieu, Clermont-Ferrand), Alain Fischer (Hôpital des Enfants Malades, Paris), Virginie Gandemer (Centre Hospitalier Universitaire – Hôpital Sud, Rennes), Dominique Valteau-Couanet (Institut Gustave Roussy, Villejuif), Jean-Pierre Lamagnere (Centre Gatien de Clocheville, Tours), Françoise Lapierre (Centre Hospitalier Universitaire Jean Bernard, Poitiers), Guy Leverger (Hôpital Armand-Trousseau, Paris), Patrick Lutz (Hôpital de Hautepierre, Strasbourg), Geneviève Margueritte (Hôpital Arnaud de Villeneuve, Montpellier), Françoise Mechinaud (Hôpital Mère et Enfants, Nantes), Gérard Michel (Hôpital La Timone, Marseille), Frédéric Millot (Centre Hospitalier Universitaire Jean Bernard, Poitiers), Martine Münzer (American Memorial Hospital, Reims), Brigitte Nelken (Hôpital Jeanne de Flandre, Lille), Hélène Pacquement (Institut Curie, Paris), Brigitte Pautard (Centre Hospitalier Universitaire, Amiens), Stéphane Ducassou (Hôpital Pellegrin Tripode, Bordeaux), Alain Pierre-Kahn (Hôpital Enfants Malades, Paris), Emmanuel Plouvier (Centre Hospitalier Régional, Besançon), Xavier Rialland (Centre Hospitalier Universitaire, Angers), Alain Robert (Hôpital des Enfants, Toulouse), Hervé Rubie (Hôpital des Enfants, Toulouse), Stéphanie Haouy (Hôpital Arnaud de Villeneuve, Montpellier), Christine Soler (Fondation Lenval, Nice), and Jean-Pierre Vannier (Hôpital Charles Nicolle, Rouen).

The Canada, Québec Study was conducted in the province over a twenty year period in all university-affiliated pediatric centers hospitals designated to diagnose and treat pediatric cancers, under the direction of Claire Infante-Rivard. Main support collaborators were Alexandre Cusson, Marcelle Petitclerc and Denyse Hamer. We thank all families for their generous participation.

Abbreviations

ALL

acute lymphoblastic leukemia

Aus-ALL

Australian Study of Causes of Acute Lymphoblastic Leukaemia in Children

CI

Confidence interval

CLIC

Childhood Leukemia International Consortium

COG

Childhood Oncology Group (Children’s Cancer Group)

NARECHEM

Nationwide Registration for Childhood Haemotological Malignancies

NCCLS

Northern California Childhood Leukemia Study (USA)

NZCCS

New Zealand Childhood Cancer Study.

OR

Odds ratio

RDD

random digit dialing

Footnotes

Authorship: All authors are principal investigators, co-investigators or designated collaborators of participating CLIC studies

The authors declare that they have no conflict of interest.

References

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Supporting Material

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