Environmental Research 202 (2021) 111723

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Environmental Research
journal homepage: www.elsevier.com/locate/envres

Urban green spaces and childhood leukemia incidence: A population-based

case-control study in Madrid.
C. Ojeda Sánchez a, *, J. Segú-Tell b, c, D. Gomez-Barroso b, c, E. Pardo Romaguera d, J.
A. Ortega-García e, f, R. Ramis b, c, f
a
Albacete University Hospital, Albacete, Spain
b
National Epidemiology Centre, Carlos III Health Institute, Madrid, Spain
c
Centre for Biomedical Research in Epidemiology & Public Health (CIBER Epidemiología y Salud Pública - CIBERESP), Spain
d
Spanish Registry of Childhood Tumours (RETI-SEHOP), University of Valencia, Valencia, Spain
e
Pediatric Environmental Health Speciality Unit, Department of Paediatrics, Environment and Human Health (EH2) Lab., Institute of Biomedical Research, IMIB-
Arrixaca, Clinical University Hospital Virgen de la Arrixaca, Murcia, Spain
f
European and Latin American Environment, Survival and Childhood Cancer Network (ENSUCHICA), Spain

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Childhood leukemia is the most common childhood cancer. To date, few risk factors related to
Childhood cancer predisposition have been identified; therefore, new hypotheses should be considered.
Urban green spaces Objective: To explore the possible relationship of residential proximity to urban green spaces on childhood
Environmental factors
leukemia.
Greenness
Spatial epidemiology
Methods: We conducted a population-based case control study in the metropolitan area of Madrid from 2000 to
2015. It included 383 incident cases and 1935 controls, individually matched by birth year, sex and area of
residence. Using the geographical coordinates of the participants’ home residences, we built a proxy for exposure
with four distances (250 m, 500 m, 750 m and 1 km) to urban parks (UPs) and urban wooded areas (UWAs). We
employed logistic regression models to determinate the effect of them on childhood leukemia adjusting for
environmental and socio-demographic covariates.
Results: we found a reduction in childhood leukemia incidence at a distance of 250 m from UPs (OR = 0.78; 95%
CI = 0.62–0.98), as well as a reduction of the incidence in the Q3 and Q4 quintiles for exposure to UWAs, in the
250 m and 500 m buffers respectively (Q3 (250 m): OR = 0.69; 95%CI = 0.48–1.00; and, Q4 (500 m): OR = 0.69;
95%CI = 0.48–0.99).
Conclusions: Our results suggest a possible association between lower incidence of childhood leukemia and
proximity to different forms of urban green space. This study is a first approach to the possible urban green space
effects on childhood leukemia so is necessary to continue studying this spaces taking into account more indi­
vidual data and other environmental risk factors.

1. Introduction et al., 2010). Acute leukemia (AL) accounts for more than 95% of all
childhood leukemia cases, including acute lymphoblastic leukaemias
Leukemia remains the most common type of childhood cancer (<15 (ALL) (80%) and acute myeloblastic leukaemias (AML) (15%) (Sant
years old), and represents 30% of all childhood cancers (Peris-Bonet et al., 2010).

Abbreviations: UGS, urban green spaces; UP, urban park; UWA, urban wooden area; AL, acute leukemia; ALL, acute lymphoblastic leukaemias; AML, acute
myeloblastic leukaemias; CML, chronic myeloblastic leukaemias; RF, risk factor; mM, metropolitan area of Madrid; RETI-SEHOP, Spanish Register of Childhood
Tumours; INE, Spanish Statistical Office; SIOSE, Spanish Land Use Information System; IGN, National Geographic Institute; DGUR, degree of urbanization; EEA,
European Environment Agency; PM2.5, particular matter with a diameter of less than 2.5 μm; NVDI, Normalized Difference Vegetation Index; EOSDIS, Earth
Observing System Data and Information System; SES, socio-economic status; SD, standard deviation; IQR, interquartile range; Q, quintile; B, buffer; OR, odds ratio;
CI, confidence interval.
* Corresponding author. Albacete University Hospital, Servicio de Medicina Preventiva y Salud Pública, Calle Hermanos Falco 37, CIP: 02006, Albacete, Spain.
E-mail addresses: casert.93@gmail.com, cojedas@sescam.jccm.es (C. Ojeda Sánchez).

https://doi.org/10.1016/j.envres.2021.111723
Received 31 March 2021; Received in revised form 13 July 2021; Accepted 15 July 2021
Available online 19 July 2021
0013-9351/© 2021 Elsevier Inc. All rights reserved.
C. Ojeda Sánchez et al.
The peak age of emergence varies, with ages 2–5 for ALL, while AML
is more frequent in children younger than age one. The worldwide age-
adjusted incidence of this disease is 3.3 cases per 100,000 children. In
Spain, AL has an age-adjusted incidence in both sexes is 4.8 cases per
100,000 in children and 2.9 cases per 100,000 in adolescents. This is
slightly higher in children (1.2 and 1.6 respectively) (PardoRomaguera
et al., 2018).
The etiology of childhood leukemia remains unknown. Only a few
causes have been established so far. According to the US National Cancer
Institute, risk factors (RFs) with conclusive evidence for AL include
exposure to ionizing radiation in utero, postnatal therapeutic radiation,
and genetic conditions, such as Down syndrome (Belson et al., 2007). Its
etiology is a topic that is garnering interest due to the distinct incidence
patterns by sex, age, and geography that suggest a potential role of the
environment in it. So much so that during last decades several studies
have explored other potential RFs such as exposure to magnetic fields
(Ahlbom et al., 2000), radon exposure (Tong et al., 2012) or atmospheric
pollution, especially close to high-density traffic (Tamayo-Uria et al.,
2018). Moreover, there are some studies that have focused on associa­
tions related to the parental habits and occupational exposures (Metayer
et al., 2014; Perez-Saldivar et al., 2008). However, all of this studies are
inconclusive and they could not establish the possible pathological
mechanism.
At the same time, the possible urban green spaces (UGS) effects
studies have grown considerably. UGS definition is not well established,
it depends on particular environmental-health pathways under consid­
eration. Different researches usually include public parks and gardens
but other structured and unstructured vegetation places can be consid­
ered too (Urban, 2016). There is increasing evidence that these spaces
can improve health and well-being of urban residents. In fact, cities like
Vancouver or London have given special importance to these places in
their urban development plans (The Greenest City, 2020 Ac, 2015;
Laybourn-Langton and Quilter-Pinner, 2016).
A variety of biopsychosocial pathways have been proposed to
explain the health benefits of greenspaces. These can be organized into
three domains related to general functions of greenspaces which is
suggested that they may act together (Markevych et al., 2017; Dzham­
bov et al., 2020). As examples, these spaces have been associated with a
mortality (Gascon et al., 2016; Kihal-Talantikite et al., 2013), and
obesity reduction, increasing physical activity (Lachowycz and Jones,
2011; Björk et al., 2008; Manandhar et al., 2019). They have also
improved mental health (van den Berg et al., 2015; McCormick, 2017).
In infant population, a positive association between the presence of and
access to greenspaces close to pregnant women and birth weights and a
diminishing preterm birth risk have been observed (Dzhambov et al.,
2014; Grazuleviciene et al., 2015). In addition, related to surrounding
environmental effects, UGS can reduce suspended pollutants like PM10
(Kroeger et al., 2018) and carbon dioxide by the so-called “carbon
sequestration” (Paoletti et al., 2011; Nowak and Crane, 2002). They also
help reduce noise pollution (Klingberg et al., 2017), which has been
associated with health problems (Tobías et al., 2015; Gupta et al., 2018).
However, not all studies found beneficial association between these
spaces and health outcomes. Some examples of these adverse effects are
the allergenic pollen diffusion, which could increase allergic disease
incidence (Cariñanos and Casares-Porcel, 2011), or being habitats for
disease vector, leading to grow up the rate of infections (Zhao et al.,
2020).
Backing to AL, although there are studies that have obtained positive
results from the associations between these spaces and some types of
cancer (O’Callaghan-Gordo et al., 2018; Demoury et al., 2017), there are
not evidence about childhood cancer. This article tries to explore the
possible link of residential proximity to UGS on childhood AL.
2
Environmental Research 202 (2021) 111723
2. Methods
2.1. Study design
We designed a case and control population study of childhood leu­
kemia in metropolitan area of Madrid (mM) (Spain), covering the period
2000–2015 (Fig. 1).
For the study we used data from children aged 0 to 14 with diagnoses
of leukemia between 2000 and 2015. Incidence cases were registered by
the Spanish Registry of Childhood Tumours (RETI-SEHOP). RETI-
SEHOP collects information from cases of childhood cancer from hos­
pital’s paediatric oncology units over all Spain. The average coverage of
this database is 99.8% in Madrid (PardoRomaguera et al., 2018). Con­
trols were extracted from the Birth Registry of the Spanish Statistical
Office (Instituto Nacional de Estadistica, INE) using random sampling
and were individually matched to cases by year of birth, sex and mu­
nicipality of residence, in a 6:1 ratio. This selected ratio could solve the
possible georeferenced errors of the chosen controls. This study was
approved by the Carlos III Health Institute Committee for Ethical
Research.
We geocoded the home addresses of the cases at the moment of
diagnosis which were included in the RETI-SEHOP database. We suc­
cessfully geocoded all cases addresses. For the controls we geocoded the
mother’s home address listed on the birth certificate (included in the
Birth Registry of the INE). These controls’ addresses have a 30-m
random error to preserve participant’s anonymity. We excluded con­
trols whose georeferenced coordinates were out of the municipalities
selected. From the initial sample we were able to get valid coordinates
for 84% of the controls. As we had all the entries from the Birth Registry,
we used a matching strategy to find cases with the same address at the
time of birth (birth certificate) and diagnosis (included in the RETI-
SEHOP register) to perform a sensitivity analysis to evaluate the po­
tential for misclassification due to residential mobility.
2.2. Urban green space selection
The UGS were selected from the Spanish Land Use Information
System (SIOSE) database. This information is available in the media
resources section of the Spanish National Geographic Institute (IGN)
(Centro Nacional de Inform, 2020).
SIOSE database divides the terrain into areas (polygons) classifying
them in different aggregation levels. There is a first level which de­
scribes the land for its type use, and a second level which describe the
land composition using percentages. This database counts with 56 first
level types and 40 s level types. The minimum mapping unit for urban
areas is 1ha.
For this study we selected the levels and sublevels that were related
directly with UGS: urban park (UP) and urban wooden area (UWA). UP
belongs to the first level and UWA belongs to the second level, conse­
quently all UPs contain an UWA percentage in their descriptions.
Accordingly, we built two categories: one to discriminate if the children
are near a UPs and another to know the proportion of UWA they have
around them.
We used the cartographic databases from 2005 to 2011. The dataset
from 2005 was used for the participants born between 2000 and 2007,
and the 2011 dataset for those born between 2008 and 2015.
2.3. Measurement of the exposure to UGS
2.3.1. Measurement of the exposure to UP
We selected the areas described as UP from the SIOSE database.
Then, we constructed buffers for distances of 250 m, 500 m, 750 m and
1 km from the participants’ home residences. Finally, we produced a
dichotomous variable according to the presence or absence of UP in a
given buffer – for both the cases and controls. In this way, two values
were obtained for this variable: 0 = absence of UP in a given buffer and
C. Ojeda Sánchez et al.
Fig. 1. Map of the Madrid’s community. The towns included in the study are highlighted and listed.
1 = presence of UP in a given buffer.
2.3.2. Measurement of the exposure to UWA
We selected all areas that contain in their description UWA and we
categorized them based on the UWA proportion they have (Table 1).
Then, using the geographical coordinates of the cases and controls,
we established the same buffer distances as for UP exposure (250 m, 500
m, 750 m and 1 km). Finally, we intersected both UWA areas and buffers
of each subject, and we calculated the weighted average for each case
and control for each of the four exposure buffers applying the formula:
∑ UWA LAND SURFACE
( × UWA LAND CATEGORY) = WEIGHTED ​ AVERAGE
TOTAL BUFFER SURFACE
For the purpose of avoid the linear effect assumption we categorized
the exposure followed these steps. First, using only the controls in each
area, we calculated the quintiles for each buffer exposure. Second, we
categorized both cases and controls into the corresponding quintile. In
this way, each continuous UWA exposure variable was defined as a
categorical with 5 levels in each of the exposure buffers: Q1 = reference
group (lowest exposure to UWA), Q2 = group belonging to the second
Table 1
Categorization of urban wooded areas (UWAs).
Category UWA content Observations
0 0%
1 <30%
2 15%–60% Mixed land
3 30%–60%
4 >60%
a
Category 2 represent the spaces with different types of land that content
UWA in a wide range of proportion.
Environmental Research 202 (2021) 111723
quintile, Q3 = group belonging to the third quintile, Q4 = group
belonging to the fourth quintile and Q5 = group belonging to the fifth
quintile (greatest exposure to UWA).
2.4. Residence based information
After geocoding all studied subjects, we assigned indicators of degree
of urbanization, socio-economic status (SES), activity rate, levels of air
pollution and surrounding greenness to each one of them.
We assigned indicators of urbanization using data from the European
data set on degree of urbanization (DGUR) (Eurostat, 2011). DGUR
classifies municipalities into thinly, intermediate and densely populated
areas. This classification is based on a criterion of geographical conti­
guity in combination with a minimum population threshold based on
km2 population grid square cells of 1. Due to the mM characteristics, we
classified the DGUR in two categories: densely populated areas (i.e.
cities) and less than densely populated areas (i.e. suburbs).
SES is an important factor related to childhood cancer (Kehm et al.,
2018). Although we did not have individual data about SES, we took the
data at census-tract level from the 2001 Census of the INE. SES combines
information regarding the occupation, activity and professional situa­
tion of the heads of families in each census tract ranging from 0.46
(worst) to 1.57 (best) (Instituto Nacional de Est). In addition, we
included activity rate as confounding variable. It’s defined as the quo­
tient between adult people working and population older or equal than
16 years old at the census tract. (Tamayo-Uria et al., 2018).
a Applying available data from the European Environment Agency
(EEA), we could assign levels of particular matter with a diameter of less
than 2.5 μm (PM2.5) around each child’s home. EEA has European
interpolated air quality maps since 2006. This maps are derived pri­
marily from database stations monitoring data across all the continent.
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C. Ojeda Sánchez et al. Environmental Research 202 (2021) 111723

Each grid of the map covers an area of 100 km2 (Interpolated air quality, Table 2
2021). For our study we get PM2.5 levels of mM for all possible studied Characteristics of childhood leukemia – cases, sensitivity group (cases with the
years (i.e. from 2006 to 2015) and subsequently, we estimated the PM2.5 same address at birth and at diagnosis) and controls of the study.
level mean to each child. Characteristics Cases (n = Cases = P valuea Controls (n
Finally, we assigned the surrounding greenness estimating the 383) address (n = = 1935)
amount of photosyntethically-active greenness in each previous con­ 55)

structed buffers. We used the Normalized Difference Vegetation Index Sex

(NDVI). NDVI is an indicator of vegetative density based on land surface Boy 14 29 (52,7%) 1076
(55.9%) (55.6%)
reflectance of visible (red) and near-infrared parts of spectrum. It ranges #
Girl 169 26 (47.3%) 0.49 859 (44.4%)
between − 1 and 1 with higher numbers indicating more vegetative (44.1%)
density (Yengoh et al., 2014). We looked for cloud-free Landsat TM Age at diagnosis, 4.2 (3.1) 2.7 (1.8) <0.001* x
images for SIOSE database used (2005 and 2011) with the possible mean (SD)
highest NDVI value (i.e. spring). These images were taken from the Activity Rate, mean 80 (5.2) 79.9 (4) 0.813* 80.4 (4.8)
(SD)
NASA’s Earth Observing System Data and Information System website SES, mean (SD) 1.10 1.08 0.350* 1.13 (0.14)
(EOSDIS) (Earth Observing System Da, 2021). (0.14)
Histologic type
2.5. Statistical analysis ALL 302 45 (81.8%) x
(78.9%)
AML 58 7 (12.7%) x
To estimate the odds ratios (ORs) and 95% confidence intervals (95% (15.1%)
CIs) associated with exposure to UPs and UWAs we fitted mixed multiple CML 9 (2.4%) 1 (1.8%) x
unconditional logistic regression models, including sex, birth year, SES, Other specific 10 (2.6%) 1 (1.8%) x
activity rate, DGUR, PM2,5 levels and surrounding greenness. For UPs we leukaemias
Non-specific 4 (1%) 1 (1.8%) 0.954# x
fitted an initial unadjusted model that included only the green space leukaemias
effect and a final model with all covariates. For UWAs exposure we fitted DGUR
adjusted models by all covariates. These all regression models were Densely populated 364 (95%) 55 (100%) 1858 (96%)
estimated for overall childhood leukemia, ALL subtype and sensitivity Less than densely 19 (5%) 0 0.088# 77 (4%)
populated
group.
PM2,5 levels at 9.26 9.32 (0.76) 0.52* 9.14 (0.76)
The statistical programs R® version 1.1.463, STATA® version 15, residence, mean (0.69)
Microsoft Excel 2016® and the geographic information system QGIS® (SD)
version 3.4.4 were used across the various stages of the study. Surrounding greenness (NDVI), median (IQR)
in 250 buffer − 0.02 − 0.01 (0.10) 0.003¥ − 0.02 (0.08)
(0.08)
3. Results in 500 buffer − 0.02 0.02 (0.10) <0.001 ¥
− 0.02 (0.08)
(0.07)
The descriptive analysis included 383 cases and 1935 controls. in 750 buffer − 0.02 0.03 (0.10) <0.001 ¥
− 0.01 (0.07)
Table 2 shows the characteristics of the children in the study. Despite (0.07)
in 1000 buffer − 0.02 0.04 (0.09) <0.001¥ − 0.01 (0.07)
having eliminated the initially selected controls who were not resident
(0.06)
in the mM, the distribution of cases and controls after the selection UP within 250 m buffer
process was very even. Yes 180 (47%) 23 (41.8%) 1038
Regarding the distribution by histological subtypes, the largest (53.6%)
#
contingent were ALL cases (the main histological subtype of childhood No 203 (53%) 32 (58.2%) 0.471 897 (46.4%)
UP within 500 m buffer
leukemia). There were 302 cases (78.9%). The ALL proportion was Yes 303 43 (78.2%) 1569
slightly higher in boys than in girls. As for other histological subtypes (79.1%) (82.5%)
worth highlighting, AML does not quite account for a fifth of cases. No 80 12 (21.8%) 0.874# 339 (17.5%)
Finally, it is necessary to mention that those classified in the RETI- (20.9%)
UP within 750 m buffer
SEHOP database as “other specific leukaemias” relate to myelodys­
Yes 350 50 (90.9%) 1813
plastic syndrome cases like juvenile myelomonocytic leukaemias and (91.4%) (93.7%)
refractory anaemias with excess blasts were a minimum part of the total No 33 (8.6%) 5 (9.1%) 0.907# 122 (6.3%)
of cases selected. UP within 1000 m buffer
We were able to identify 55 cases with exactly the same address at Yes 371 54 (98.2%) 1874
(96.9%) (96.9%)
birth and diagnosis, the 14.4% of the cases. For the remaining 85.6% we No 12 (3.1%) 1 (1.8%) 0.591 #
61 (3.1%)
did not find the same address. Compare to the main group of cases, the
age at diagnosis of the sensitivity group was earlier (p-value <0.001) Abbreviations: SD - standard deviation, IQR – interquartile range, ALL - acute
lymphoblastic leukaemias, AML - acute myeloblastic leukaemias, CML – chronic
and they had higher surrounding greenness values for all the constructed
myeloblastic leukaemias, DGUR – degree of urbanization, NDVI – Normalized
exposure buffers (p-value <0.005). The rest of these identified cases
Difference Vegetation Index, UP – urban park.
characteristics were fairly similar to the whole cases as it can be seen in a
P value from main group of cases compare to sensitivity group. # Chi-square
Table 2. test for categorical variables, ¥ Kruskal-Wallis test, * Student’s t-test.
Table 3 shows the ORs for total leukemia, ALL subtype and identified
cases with same residences and exposure to UPs. Estimations from these
1000 m). Table 4 presents the resulting ORs and 95%ICs. Each OR es­
models show an increasing trend: as the distance to UPs grows, the ORs
timates the odds of exposure between the cases compared to control for
seems to rise. Fig. 2 shows it. Looking at individual results, the lowest
the quintile Q of UWA at buffer distance B and children in the reference
ORs and statistically significant, were that associated to residence at <
group (children with the lowest exposure to UWA). This was performed
250 m of the UPs for the full group of cases (OR = 0.78; 95%CI =
for childhood leukemia in general as well as for ALL subtype.
0.62–0.98) and the result associated to the same distance to UPs for the
We can see that as the UWA buffer is reduced, a reduction of the ORs
sensitivity group (OR = 0.52; 95%CI = 0.30–0.94).
appears in each quintile as compared with the reference quintile (Q1).
We fitted a total of 16 adjusted models by group of cases to estimate
Specifically, as it is shown in Table 4, the exposure ORs for the cases
the ORs for UWA exposure at the distinct distances (250, 500, 750 and

4
C. Ojeda Sánchez et al. Environmental Research 202 (2021) 111723

Table 3 4. Discussion
Results of the UPs analysis for overall childhood leukemia, ALL subtype and
identified cases with same address at birth and diagnosis. Adjusted models for In this study we investigated the possible association between UGS
sex, birth year, SES, activity rate, DGUR, PM2,5 levels and surrounding and childhood leukemia in the mM, taking into account different kind of
greenness. green spaces and exposure distances. Our study reveals possible rela­
Childhood leukemia tionship between themselves. In particular, our findings showed a
Distance to UPs Unadjusted OR (95% CI) Adjusted OR (95% CI) reduced OR for cases resident in the proximity of UPs compared to
controls, particularly at 250 m distance of the child’s place residence.
250 m 0.77 (0.62–0.95) 0.78 (0.62–0.98)
500 m 0.80 (0.61–1.06) 0.83 (0.62–1.11) Moreover, we found lower ORs for cases resident at specific exposures
750 m 0.71 (0.48–1.07) 0.70 (0.46–1.08) distances and with greater concentrations of UWAs compared to con­
1000 m 1 (0.54–1.89) 1.12 (0.56–2.24) trols. Although we do have some significant results, in our knowledge,
ALL subtype this study is the first time that this relationship is explored hence we
should be cautious with its interpretation. In addition, we cannot
Distance to UPs Unadjusted OR (95% CI) Adjusted OR (95% CI)
compare our results with those of other studies.
250 m 0.80 (0.63–1.02) 0.81 (0.62–1.04)
We used a national land-use database to select the UGS types and to
500 m 0.86 (0.63–1.17) 0.87 (0.63–1.18)
750 m 0.78 (0.50–1.23) 0.81 (0.50–1.31)
create buffers distances as exposure metrics to explore their possible
1000 m 1.20 (0.56–2.53) 1.32 (0.60–2.93) effects on childhood leukemia incidence. This methodology is one of the
most important ways in which studies into the possible effects of green
Cases with the same address at birth and diagnosis (55 cases)
spaces on health can be differentiated from others.
Distance to UPs Unadjusted OR (95% CI) Adjusted OR (95% CI)
The majority of green spaces studies have based their analyses on
250 m 0.62 (0.36–1.07) 0.52 (0.30–0.94) NDVI. Despite of his broad use for green spaces studies, NDVI values are
500 m 0.76 (0.40–1.46) 0.63 (0.32–1.27) limited by the spatial and temporal availability of the satellite images
750 m 0.67 (0.26–1.72) 0.43 (0.16–1.18)
1000 m 1.76 (0.24–12.91) 0.99 (0.13–7.82)
used in their calculation. Due to its low temporal resolution captured by
the Landsat images, some studies try to use only the most favourable
a. OR and 95% CI for each distance buffer taking as reference subjects without acquisitions to extract NDVI or calculate an annual average (Demoury
UPs in each buffer.; Abbreviations: UPs – Urban parks, OR – odds ratio, CI –
et al., 2017; James et al., 2016). Moreover, as a vegetation index, it does
confidence interval, ALL - acute lymphoblastic leukaemias, SES – socioeconomic
not differ between structured and unstructured vegetation so private
status, DGUR – degree of urbanization.
greenspaces can be aggregated to NDVI value and overestimate it.
against controls for those groups is 0.69 for Q3 (95%CI = 0.48–1.00) at Although these limitations, we decided to introduce NDVI as a greenness
250 m and 0.69 for Q4 (95%CI = 0.48–0.99) at 500 m. The adjusted measurement covariate in the analysis in order to have a better esti­
models for the ALL subtype produced practically the same results as for mator for the effect of UGS.
the overall analysis of childhood leukemia (Table 4). Comparing to the Instead of using it for the UGS selection, we choose SIOSE because it
main group, results for the sensitivity group showed a similar trend for had some advantages respect NDVI and other land cover databases.
UPs but not for UWAs exposure, in which we observed an OR of 0.33 for SIOSE database presents land descriptions via land cover or combina­
Q5 (95%CI = 0.12–0.95) at 250 m. (Tables 3 and 4). tions of them, with their different percentages of occupation and attri­
Finally, we analyzed the possible effect of SES at census tract level on butes. It offers this without loss of information, with a minimum
the risk of childhood leukemia. There was a protective effect from this mapping unit of 0.5 ha for blue spaces to 2 ha for crops and forests. In
index irrespectively of the UWA exposure buffer established, for which contrast, European database CORINE has a bigger minimum mapping
the OR was close to 0.25. unit (Markevych et al., 2017). It was necessary to try to evaluate the UGS

Fig. 2. Overall childhood leukemia exposure to UPs: Graphical representation of adjusted models for sex, birth year, SES, activity rate, DGUR, PM2,5 levels and
surrounding greenness. Orange line represents OR exposure to UPs for each buffer distance comparing to the reference group (0 = absence of UP). Blue dashed lines
represent their lower and upper 95%CI. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

5
C. Ojeda Sánchez et al. Environmental Research 202 (2021) 111723

Table 4
Results of the UWAs analysis for overall childhood leukemia, ALL subtype and identified cases with same address at birth and diagnosis. Adjusted models for sex, birth
year, SES, activity rate, DGUR, PM2,5 levels and surrounding greenness.
Buffer_Quintile Childhood leukemia ALL subtype Cases with the same address at birth and diagnosis (55 cases)
a a
Cases Controls OR (95% CI) Cases OR (95% CI) Cases OR (95% CI) a

B.250_Q1 86 387 Reference 74 Reference 15 Reference

B.250_Q2 87 387 0.99 (0.71–1.39) 63 0.86 (0.60–1.23) 10 0.73 (0.32–1.70)
B.250_Q3 58 387 0.69 (0.48–1.00) 48 0.70 (0.48–1.04) 10 0.79 (0.35–1.79)
B.250_Q4 77 387 0.88 (0.61–1.26) 61 0.88 (0.60–1.27) 13 0.77 (0.34–1.75)
B.250_Q5 75 387 0.85 (0.56–1.28) 56 0.78 (0.50–1.21) 7 0.33 (0.12–0.95)
B.500_Q1 88 387 Reference 71 Reference 15 Reference
B.500_Q2 66 387 0.74 (0.52–1.06) 56 0.78 (0.54–1.14) 8 0.57 (0.23–1.41)
B.500_Q3 87 387 1.00 (0.72–1.41) 70 1.06 (0.74–1.51) 12 0.89 (0.40–1.99)
B.500_Q4 63 387 0.69 (0.48–0.99) 48 0.68 (0.46–1.01) 9 0.53 (0.22–1.28)
B.500_Q5 79 387 0.88 (0.59–1.30) 57 0.81 (0.53–1.24) 11 0.62 (0.26–1.51)
B.750_Q1 75 387 Reference 60 Reference 11 Reference
B.750_Q2 83 387 1.19 (0.84–1.71) 72 1.31 (0.90–1.91) 15 1.78 (0.78–4.07)
B.750_Q3 71 387 1.01 (0.70–1.45) 57 1.04 (0.70–1.55) 7 0.64 (0.24–1.70)
B.750_Q4 76 387 1.04 (0.73–1.51) 55 1.03 (0.70–1.53) 13 1.16 (0.50–2.68)
B.750_Q5 78 387 1.08 (0.73–1.60) 58 0.99 (0.64–1.51) 9 0.69 (0.26–1.79)
B.1000_Q1 76 387 Reference 64 Reference 13 Reference
B.1000_Q2 81 387 1.19 (0.83–1.70) 67 1.19 (0.82–1.74) 14 1.36 (0.61–3.04)
B.1000_Q3 79 387 1.10 (0.77–1.57) 61 1.05 (0.72–1.54) 7 0.57 (0.22–1.49)
B.1000_Q4 76 387 1.08 (0.75–1.56) 56 1.04 (0.71–1.53) 13 1.07 (0.48–2.42)
B.1000_Q5 71 387 0.94 (0.64–1.39) 54 0.85 (0.56–1.30) 8 0.47 (0.18–1.19)
a
OR and 95% CI for each quintile (Q) compare to the reference group (Q1 = lowest exposure to UWA), for the four buffers (B): 250, 500, 750 and 1000 m; Ab­
breviations: UWA – urban wooden area, OR – odds ratio, CI – confidence interval, ALL - acute lymphoblastic leukaemias, SES – socioeconomic status, DGUR – degree of
urbanization.

to which the participants were exposed as accurately as possible and we
had to take account the mM urban remodelling so two datasets were
used (2005 and 2011). Despite of that, we had to assume that the
characteristics identified did not vary across the studied period.
Regardless of the greenspace measure used, buffer size selection was
difficult to establish. A great variety of distances have been applied in
greenspaces studies, ranging from 30 m to 2 km (Dzhambov et al., 2014;
O’Callaghan-Gordo et al., 2018; Demoury et al., 2017; Browning and
Lee, 2017). As yet there is no available information of how to optimally
define minimum distances for green space exposure, we decided to apply
four progressive distances in 250 m steps according to the characteristics
of our study. In this way, it was possible to analyze the existence of any
variability in the effects related to the distance and quantity of the
greenspaces closed to the children residences. Even though it appears
that the ORs increase meanwhile the exposure distance decreases, we
can’t suggest any plausible mechanism for the association between UGS
and childhood leukemia. In fact, this trend has to be interpreted with
caution because we did not take into consideration the street network or
physical barriers such as railways or major roads.
Several mechanisms have been proposed to explain the association
between greenspaces and global health. Some studies have suggested
that greenspaces may reduce the risk of cancer in the population by
enabling healthy lifestyles and health behaviours or improving the im­
mune system (Kehm et al., 2018; Li et al., 2008). They also may help
reducing exposure levels to environmental factors suspected to have
negative health effects, and acting as mediators, such as noise or high
pollution (Markevych et al., 2017).
With regard to exposure factors, childhood leukemia has been
related with environmental exposure factors such as industrial in­
stallations (García-Pérez et al., 2015), crops fields (on account of the
pesticides used in agriculture) (45,46), contamination from road traffic
(Filippini T et al., 2015), radon (Tong et al., 2012) or parents’ tobacco
consumption (Metayer et al., 2013). There are also individual factors of
personal nature like family history or parent’s lifestyles, that have been
shown to be related to the risk of developing childhood leukemia and
could act as confounders (Ahlbom et al., 2000; Tamayo-Uria et al., 2018;
Metayer et al., 2014; Whitehead et al., 2016). All of them are evidently
factors that can be in close proximity to the subjects and could have a
modifier role between UGS and childhood leukemia.
However, these possible modifier factors were not included in this
study. Although we selected the cities that conform the mM in order to
increase the study power, most of them didn’t have monitor data or their
registries didn’t cover all the studied context. To reduce this limitation,
we used interpolated air quality maps from the EEA. For mM area,
PM2,5 levels are available from 2006 so we decided to introduce them as
a covariate in the study. Conversely, NO2 levels are available from 2012
so we could not use them to estimate a possible exposure mean value to
all the studied period. Other individual factors and children interactions
with greenspaces, such as time or activities carried out in these spaces,
were not included due to the lack of individual data recorded in both
used databases.
Despite not having individualized information on the socio-
economic level of the children, we included ecological variables to
control for the potential effect of this important factor (Kehm et al.,
2018). For this, we used both SES and activity rate at census-tract level
in which each subject was registered. SES is a factor whose relationship
with childhood cancer or greenspaces has been studied and used as a
potential modifier (Tamayo-Uria et al., 2018; Kehm et al., 2018; Dad­
vand et al., 2012) while activity rate it’s not a common socio-economic
variable used. In our case, related to the SES, we found low ORs irre­
spectively of the UWA exposure buffer. Nevertheless, these data were
retrieved from the 2001 census, a year which was part of the study
period but not necessarily representative. These two issues – lack of
individualized socio-economic data, and the census tract data that are
from a single year – represent important limitations in our models.
We did not have information about address changes between birth
and diagnosis, so we could not rule out potential bias due to using the
address at diagnosis for cases and address at birth for control. According
to official data in Madrid’s community, more than a 20% of the children
change their residence to a different town in the same community
(Instituto de Estadística de la Comunidad de Madrid). To overcome this
limitation, we tried to identify cases with the same address in the two
instants. We compared both registries and we were able to identify only
55 cases with the exact same address at birth and at diagnosis. However,
we could not know if the remaining 328 of the cases moved between
birth and diagnosis or not due to differences in the recording between
the RETI-SEHOP and the Birth Registry. While UPs exposure results were
similar to the main group of cases, UWA exposure results were not.

6
C. Ojeda Sánchez et al.
Notwithstanding these results, it is necessary to explore in depth the
interactions between these identified cases, whose surrounding green­
ness values were higher than the main group (Table 1), and UGS. It’s
necessary to have more individual data to stablish a possible link.
The large control group (6 controls per case) provides a much more
realistic image of the spatial distribution of the at-risk population. The
controls were randomly selected from the Birth Registry without the
exclusion of the cases from the pool, what opened up the possibility of
having the same child case and as control. Furthermore, due to most of
the residences in mM are block of flats, it would not be rare that both
selected children (cases and controls), have the same coordinates.
Despite of this, the very low incidence rate of childhood leukemia makes
very unlikely it has occurred.
5. Conclusions
In conclusion, despite some limitations, our results could point out to
a possible link between the proximity to urban green spaces and child­
hood leukemia. Land-use databases and progressive exposure buffers
allowed us to study this relationship in detail. Nevertheless, this is a first
approach so it is important to continue to investigate this relation,
ideally by further controlling for potentially confounding variables via
more detailed information at an individual level. This should aid in
identifying a possible mechanism for this association.
Authors’ contributions
All the authors participated in the interpretation of the results and
contributed to the writing of the manuscript. O.S. designed the study,
analyzed the data and drafted the manuscript. S.T. designed the study
and critically revised the manuscript. G.B. contributed to interpret the
results and revise critically the manuscript. P.R. and O.J. revised criti­
cally the manuscript. R.P. contributed to design the study, analyze the
results and revise the manuscript. All authors have read and agreed to
the published version of the manuscript.
Funding
This study was funded by Carlos III Institute of Health, Spain (grant
numbers PI19ICIII_00025 and PI16ICIII_00009, and Spain’s Health
Research Fund (Fondo de Investigación Sanitaria - FIS grant number 12/
01416). The funders had no role in the design of the study; in the
collection, analyses, or interpretation of data; in the writing of the
manuscript, or in the decision to publish the results.
This study belongs to the project called “Factores ambientales y
socio-económicos e incidencia de cancer infantil en España. MEDEA 3 –
Cáncer infantil” which was approved by the Carlos III Health Institute
Committee for Ethical Research (Nº: CEI PI 72_2016-v2).
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgments
This study was funded by Carlos III Institute of Health, Spain (grant
numbers PI19ICIII_00025 and PI16ICIII_00009, and Spain’s Health
Research Fund (Fondo de Investigación Sanitaria - FIS grant number 12/
01416). The funders had no role in the design of the study; in the
collection, analyses, or interpretation of data; in the writing of the
manuscript, or in the decision to publish the results.
7
Environmental Research 202 (2021) 111723
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