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\begin{document}

\title{ROLE OF PARENTAL SMOKING AND ENVIRONMENTAL TOBACCO SMOKE EXPOSURE IN
CHILDHOOD CANCER: A STUDY USING HAIR COTININE ANALYSIS AND
QUESTIONNAIRES}



\author[1]{Adil Guzel}%
\author[1]{Nurdan Tacyildiz}%
\author[2]{Filiz Bakar Ates}%
\author[3]{Derya Ozyoruk}%
\author[2]{Aybuke Celik}%
\author[1]{Handan Dincaslan}%
\author[1]{Emel Cabi Unal}%
\affil[1]{Ankara Universitesi Tip Fakultesi}%
\affil[2]{Ankara Universitesi Eczacilik Fakultesi}%
\affil[3]{Ankara Sehir Hastanesi Cocuk Hastanesi}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
\textbf{OBJECTIVES} In the etiology of childhood cancers, many genetic
and environmental factors play a role. One of these factors is cigarette
smoking and the main source of tobacco smoke exposure of children is
parental smoking. However, establishing a causal relationship between
parental smoking and childhood cancers has proven challenging due to
difficulties in accurately detecting tobacco smoke exposure
\textbf{METHODS} To address this issue, we used hair cotinine analysis
and a questionnaire to get information about tobacco smoke exposures of
pediatric cancer patients and healthy children. 104 pediatric cancer
patients and 99 healthy children participated in our study. Parental
smoking behaviours (pre-conceptional, during pregnancy and current
smoking) and environmental tobacco smoke (ETS) exposures of children are
compared. \textbf{RESULTS} We have found no differences between two
groups by means of maternal smoking behaviours. However, the rates of
paternal pre-conceptional smoking and smoking during pregnancy were
significantly low in cancer patients (p\textless{}0,05). These data
suggests that social desirability bias among fathers of cancer patients
may have contributed to this discrepancy. According to questionnaire
cancer patients had significantly lower ETS exposures than healthy
children (p\textless{}0,05). However, ETS exposure assessment through
cotinine analysis demonstrated that cancer patients had higher exposure
to ETS compared to healthy children (p\textless{}0.001).
\textbf{CONCLUSION} Our findings provide evidence supporting the
potential role of smoking as a risk factor for childhood cancers. This
study also revealed that questionnaires could cause biases. We suggest
that cotinine analysis along with validated questionnaires can be used
to prevent biases in studies of tobacco smoke in the etiology of
childhood cancers.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Childhood cancer has become a significant public health issue, with an
overall increase in incidence rates by 1\% every year in the past three
decades \textsuperscript{1}. Life style changes and exposure to various
environmental factors are thought to contribute this trend besides
better cancer diagnosis. One of these environmental factors is cigarette
smoke, which contains approximately 7000 chemical compounds, 72 of them
are carcinogenic \textsuperscript{2}. Main source of cigarette smoke
exposure of children is parental smoking.Various chemicals related to
cigarette use have been detected in fetal blood, placenta, human breast
milk and tissue samples of infants including urine, blood and
hair\textsuperscript{3}. However, numerous studies have encountered
challenges in establishing a clear correlation between tobacco smoke
exposure and the incidence of childhood cancers. The application of
questionnaires, which are the most used method may potentially introduce
bias in studies. Cotinine is the main metabolite of nicotine which is
the most abundant organic compound of cigarette and is a reliable
biomarker of tobacco smoke exposure. Hair cotinine has longer half-time
than the other body samples and hair cotinine analysis is an efficient
way to detect chronic exposure. In this study, we used both
questionnaire and hair cotinine analysis to detect the extent of
environmental tobacco smoke (ETS) exposure among cancer patients and
establish the relationship between ETS and childhood cancer.

\textbf{METHODS}

\textbf{Study Design}

This study was conducted in two hospitals in Turkey, namely Ankara
University Faculty of Medicine Children's Hospital and Ankara City
Hospital, Bilkent between 2018 and 2020. The study comprised 104
pediatric cancer patients and 99 healthy children, all of whom were
below the age of 18.

Participants in the case group were diagnosed with malignancy based on
the International Classification of Childhood Cancer, Third Edition
(ICCC-3) and had sufficient hair samples for analysis. Patients with
relapsed cancer were excluded from the study. Controls were selected
from volunteers who visited general pediatrics outpatient clinics had no
history of malignancy and matched in age and gender with the case group.
Although it was initially planned to exclude any controls diagnosed with
malignancy during the study, no such cases were observed. All
participants provided informed consent before participating in the
study.

ETS exposure was evaluated using both questionnaire and hair cotinine
enzyme-linked immunosorbent assay (ELISA) methods. The questionnaire was
utilized to collect information on, parental smoking habits
(pre-conceptional, during pregnancy and current smoking status), ETS
exposures experienced by children, cancer risk factors (living place;
birth weight; gestation week; parental age at birth; family malignancy
history; congenital anomalies; chronic illnesses; ionized radiation
exposure; use of category C, D, X drugs in pregnancy; infectious agents)
as well as socio-demographic characteristics such as age, gender, number
of siblings, and the education level of parents.

To perform hair cotinine analysis, hair samples were collected from the
occipital region of scalp with a stainless-steel scissors. Each hair
samples were at least two centimeters in lenght, 90 miligrams, and
concisted of approximately 90-100 strands of hair\textbackslash{}sout.
All samples were stored at room temparute in ziplock bags in a dark
place until they were processed in the laboratory.

\textbf{Hair Cotinine Extraction}

Hair samples weighing 30 mg from both case and control groups washed
with distilled water, and extracted with 2 ml of hair extraction buffer
(Immunalysis, USA) for 30 minutes using an ultrasonic water bath at 23
\selectlanguage{ngerman}°C. Following the extraction process, 200 \selectlanguage{greek}µ\selectlanguage{english}l of neutralization buffer
(Immunalysis, USA) were added to finalize the extraction procedure,
followed by initiation of the ELISA process\textbackslash{}sout.

\textbf{Measurement of Cotinine Levels}

The ELISA (Bioassay Technology, China) application standards were
prepared according to the manufacturer's instructions. Briefly, 50 \selectlanguage{greek}μ\selectlanguage{english}l of
the standards were added to the standard wells, 40 \selectlanguage{greek}μ\selectlanguage{english}l of samples were
added to the sample wells, and 10 \selectlanguage{greek}μ\selectlanguage{english}l of anti-cotinine antibody was added
to the sample wells. Afterward, streptavidin-HRP is added to both
standard and sample wells, and the plate was incubated at 37 \selectlanguage{ngerman}°C for 60
minutes. The plate was washed 5 times and 50 \selectlanguage{greek}µ\selectlanguage{english}l of substrate A and B
were added to each well and incubated in the dark for 10 min. The
reaction was stopped by adding 50 \selectlanguage{greek}µ\selectlanguage{english}l stop solution to each well and the
absorbance was determined by spectrophotometer at 450 nm.

\textbf{Statistical Analysis:}

In the study by Gunay et al., it was reported that the rate of smoking
exposure among pediatric patients who visited the general outpatient
clinic was approximately 55\% \textsuperscript{4}. Assuming that this
rate can be 75\% in pediatric patients with cancer, it has been
calculated a total of 196 participants , 98 in each group, to be
included in the control and patient groups with 80\% power and 0.05
error level, using G Power 3.1.9.2 package program.

The descriptive statistics were used to report the mean, standard
deviation, median, minimum, and maximum values for the continuous data,
number and percentage values for discrete data. The Shapiro-Wilk test
was used to check for the normal distribution. T-test was used for
comparing continuous data between case and control groups for normally
distributed data, while Mann-Whitney U test was used for non-normally
distributed data. Chi-square and Fisher's exact tests were used for
group comparisons (cross tables) of nominal variables. IBM SPSS
Statistics 20 program was used and p \textless{} 0.05 was accepted as
statistical significance limit.

\textbf{RESULTS}

This study, involved an evaluation of 104 cases and 99 controls with a
median age of 6.05 years for the case group and 6.06 years for the
control group. Out of the case group, 45.2\% (n=47) were female, and
54.8\% (n=57) were male; while the control group comprised 51.5\% (n=51)
female and 48.5\% (n=48) male. Details of socio-demographic features and
cancer-related risk factors are presented in Table 1 and Table 2,
respectively. Cancer patients are classified according to ICCC-3
classification system and their distribution is shown in Table 3.

According to the Table 4, the smoking status of parents was assessed,
revealing no significant difference between the case and control groups
in terms of pre-conceptional, during pregnancy and current smoking
behaviors of the mothers based on questionnaire responses. However, it
was observed that in the case group 68.1\% (n=64) of the fathers had a
history of regular smoking, while in the control group, 81.8\% (n=81) of
the fathers stated the same (p\textless{}0.05). Furthermore, smoking
rates of fathers during the pre-conceptional period and throughout the
mother's pregnancy with the case (61.7\%) were found significantly lower
compared to the control group (75.8\%) (p\textless{}0.05).

In the event of the mother, father, another household member (such as a
brother, grandparent, etc.) or any another individual (such as a
teacher, bus driver, friend, etc.) being a regular smoker, exposure to
ETS was considered to be present. According to the questionnaire, the
ETS exposure rate of the case group (n=66, 68.8\%) was found to be
significantly lower than the ETS exposure rate of the control group
(n=83, 83.8\%) (p\textless{}0.05), as presented in Table 5.

The mean hair cotinine levels for children in the case group were
0.224\selectlanguage{ngerman}±0.088 ng/mg, while the mean hair cotinine levels of the control
group were 0.136±0.048 ng/mg. The hair cotinine levels in the case group
were significantly higher than the control group. The cut-off value for
cotinine for ETS exposure were accepted as 0.2 ng/mg\textsuperscript{5}.
According to the results of cotinine analysis, the ETS exposure rate in
children with cancer was 59.4\% (n=60) while it was only 14.1\% (n=14)
in the control group. The analysis showed that ETS exposure was found to
be significantly higher in children with cancer according to cotinine
levels (p\textless{}0.001) (Table 6)

\textbf{TABLE 1} Socio-demographic Factors and Cancer Related Risk
Factors\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Variables}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Cases}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Control}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{p}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Age(year)} Mean\selectlanguage{ngerman}±sd Median (min- max)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7.58\selectlanguage{ngerman}±5.89 6.05(0.04-17.79)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7.09\selectlanguage{ngerman}±4.95 6.06(0.08-17.38)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.911\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Gender, n(\%)} Female Male\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
47(45.2) 57(54.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
51(51.5) 48(48.5)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.368\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Birth Weight(gr)} Mean\selectlanguage{ngerman}±sd Median (min- max)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3294.23 \selectlanguage{ngerman}±542.94 3300(2100-4500)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3245.28\selectlanguage{ngerman}±503.51 3200(2170-4500)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.516\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Birth Weight for Gestational Age, n (\%)} SGA AGA LGA\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (4.1) 85 (87.6) 8 (8.2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (4.1) 85 (87.6) 8 (8.2))\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.000\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Gestaional Week, n (\%)} Preterm Term\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
17 (17) 83 (83)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
9 (9.1) 86 (86.9)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.129\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Mother Age at Bi}r\textbf{th} Mean\selectlanguage{ngerman}±sd Median (min- max)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
27.10\selectlanguage{ngerman}±4.88 26 (18-42)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
26.41\selectlanguage{ngerman}±5.05 26 (17-40)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.330\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Father Age at Birth} Mean\selectlanguage{ngerman}±sd Median (min- max)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
31.37\selectlanguage{ngerman}±6.10 30 (23-64)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
30,71\selectlanguage{ngerman}±5.34 30 (17-53)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.424\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{TABLE 2} Socio-demographic Factors and Cancer Related Risk
Factors\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Variables}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Cases} \textbf{n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Control} \textbf{n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
p\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Residency} Urban Rural\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
87 (87) 13 (13)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
98 (99) 1 (1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Intrauterine Radiation Exposure} Absent Pressent\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
94 (98.9) 1 (1.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
96 (99) 1 (1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.621\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Intrauterine Drug(C,D,X) Exposure} Absent Present\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
95 (99) 1 (1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
99 (100) 0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.492\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Chronic Disease} Absent Present\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
83 (88.3) 11 (11.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
82 (82.8) 17 (17.2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.281\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{CT Scan History} Absent Present\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
90 (94.7) 5 (5.3)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
87 (87.9) 12 (12.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.091\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Congenital Anomaly} Absent Present\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
93 (96.9) 3 (3.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
96 (97) 3 (3.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.00\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Infection History with Oncogenic Viruses} Absent Present\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
94 (96.9) 3 (3.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
99 (100) 0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.119\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Having Elder Sibling} Absent Present\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
40 (40.4) 59 (59.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
62 (63.3) 36 (36.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Familial} \textbf{Malignancy History} Absent Present\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
49 (49) 51 (51)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
63 (63.6) 36 (36.4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.037}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Relative Having Malignancy} First Degree Relative Second Degree
Relative Third Degree and Beyond\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
5 (9.8) 24 (47.1) 22 (43.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0 (0) 23 (63.9) 13 (36.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.087\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{TABLE 3} Distribution of Cancer Patients According to ICCC-3
Classification\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
ICCC-3 Classification & Case(n) & \%\tabularnewline
\midrule
\endhead
Leukemias, myeloproliferative diseases, and myelodysplastic diseases & 9
& 8.7\tabularnewline
Lymphoid leukemias & 8 & 7.7\tabularnewline
Other leukemias & 1 & 1\tabularnewline
Lymphomas and reticuloendothelial neoplasms & 29 & 27.9\tabularnewline
Hodgkin lymphomas & 14 & 13.5\tabularnewline
Non-Hodgkin lymphomas & 10 & 9.6\tabularnewline
Langerhans cells histiocytosis & 5 & 4.8\tabularnewline
CNS and miscellaneous intracranial and intraspinal neoplasms & 10 &
9.6\tabularnewline
Ependymomas and choroid plexus tumor & 1 & 1\tabularnewline
Astrocytomas & 2 & 1.9\tabularnewline
Intracranial and intraspinal embryonal tumors & 3 & 2.9\tabularnewline
Other gliomas & 4 & 3.8\tabularnewline
Neuroblastoma and other peripheral nervous cell tumors & 9 &
8.7\tabularnewline
Neuroblastoma & 9 & 8.7\tabularnewline
Retinoblastoma & 7 & 6.7\tabularnewline
Renal Tumors & 3 & 2.9\tabularnewline
Nephroblastoma & 2 & 1.9\tabularnewline
Renal Carcinomas & 1 & 1\tabularnewline
Hepatic tumors & 3 & 2.9\tabularnewline
Hepatoblastoma & 3 & 2.9\tabularnewline
Malignant bone tumors & 17 & 16.3\tabularnewline
Osteosarcomas & 9 & 8.7\tabularnewline
Ewing sarcomas & 8 & 7.6\tabularnewline
Soft tissue and other extraosseous sarcomas & 11 & 10.6\tabularnewline
Rhabdomyosarcomas & 7 & 6.7\tabularnewline
Fibrosarcomas & 2 & 1.9\tabularnewline
Other soft tissue sarcomas & 2 & 1.9\tabularnewline
Germ cell tumors, trophoblastic tumors, and neoplasms of gonads & 5 &
4.8\tabularnewline
Malignant extracranial and extragonadal germ cell tumors & 3 &
2.9\tabularnewline
Malignant gonadal germ cell tumors & 2 & 1.9\tabularnewline
Other malignant epithelial neoplasms and malignant melanomas & 1 &
1\tabularnewline
& 104 & 100\tabularnewline
\bottomrule
\end{longtable}

\textbf{TABLE 4} Mothers and Fathers Smoking Status According to
Questionnaire\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Variables}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Case} \textbf{(n=75) (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Control} \textbf{(n=38) (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
p\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Mother Smoking Status} Not Smoking Smoking Only Smoke
Exposure\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
53 (55.8) 27 (28.4) 15 (15.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
55 (55.6) 31 (31.3) 13 (13.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.830\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Mother Smoking Amount (Piece of cigarette a day)} 1-9 pieces [?]10
pieces\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
18 (66.7) 9 (33.3\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
17 (54.8) 14 (45.2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.358\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Mother Pre-conceptional Smoking} Absent Present\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
66 (69.5 39 (30.5)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
65 (65.7) 34 (34.3)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.570\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Mother Smoking Status in Pregnancy} Not Smoking Smoking Only
Smoke Exposure\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
64 (67.4) 12 (12.6) 19 (20)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
54 (54.5) 20 (20.2) 25 (25.3)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.167\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Mother Smoking Amount in Pregnancy} 1-9 pieces [?]10 pieces\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
8 (66.7) 4 (33.3)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
13 (65) 7 (35)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.000\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Mother Having Been Regular Smoker at Anytime} No Yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
61 (64.2) 34 (35.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
62 (62.6) 37 (37.4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.819\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Father Smoking Status} Not Smoking Smoking Only Smoke
Exposure\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
32 (34) 53(56.4) 9(9.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
24 (24.2) 66 (66.7) 9(9.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.296\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Father Smoking Amount} 1-9 cigarettes [?]10 cigarettes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
12 (22.6) 41 (77.4)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
17 (25.8 49 (74.2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.694\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Father Pre-conceptional Smoking} Absent Present\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
36 (38.3) 58 (61.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
24 (24.2) 75 (75.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.035}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Father Smoking Status in Pregnancy} Absent Present\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
36 (38.3) 58 (61.7)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
24 (24.2) 75 (75.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.035}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Father Having Been Regular Smoker at Anytime} No Yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
30 (31.9) 64 (68.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
18 (18.2) 81 (81.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.027}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{TABLE 5} Patients Smoking Status and ETS Exposure According to
Questionnaire\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{TABLE 5} Patients Smoking Status and ETS Exposure According to
Questionnaire \textbf{TABLE 5} Patients Smoking Status and ETS Exposure
According to Questionnaire \textbf{TABLE 5} Patients Smoking Status and
ETS Exposure According to Questionnaire \textbf{TABLE 5} Patients
Smoking Status and ETS Exposure According to Questionnaire
\textbf{Variables} \textbf{Case} \textbf{Control} p \textbf{Smoking
Status of Patient, n (\%)} Not Smoking Smoking 100 (96,2) 4 (3.6) 97
(98) 2 (2) 0.683 \textbf{ETS Exposure, n (\%)} Absent Present 30 (31.2)
66 (68.8) 16 (85.9) 83 (14.1) \textbf{0.013} & & &\tabularnewline
\bottomrule
\end{longtable}

\&

\textbf{TABLE 5} Patients Smoking Status and ETS Exposure According to
Questionnaire\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Variables}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Case}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Control}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Smoking Status of Patient, n (\%)} Not Smoking Smoking\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
100 (96,2) 4 (3.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
97 (98) 2 (2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.683\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{ETS Exposure, n (\%)} Absent Present\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
30 (31.2) 66 (68.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
16 (85.9) 83 (14.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.013}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\&

\textbf{TABLE 5} Patients Smoking Status and ETS Exposure According to
Questionnaire\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Variables}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Case}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Control}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Smoking Status of Patient, n (\%)} Not Smoking Smoking\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
100 (96,2) 4 (3.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
97 (98) 2 (2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.683\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{ETS Exposure, n (\%)} Absent Present\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
30 (31.2) 66 (68.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
16 (85.9) 83 (14.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.013}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\&

\textbf{TABLE 5} Patients Smoking Status and ETS Exposure According to
Questionnaire\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Variables}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Case}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{Control}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
p\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Smoking Status of Patient, n (\%)} Not Smoking Smoking\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
100 (96,2) 4 (3.6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
97 (98) 2 (2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.683\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{ETS Exposure, n (\%)} Absent Present\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
30 (31.2) 66 (68.8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
16 (85.9) 83 (14.1)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.013}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Variables}

\&

\&

\& p

\& 0.224\selectlanguage{ngerman}±0.0880.25(0.05-0.42) \& 0.136±0.0480.13(-0.02-0.25)
\&\textbf{0.001}



\textbf{4. DISCUSSION}

Childhood cancers are a multifactorial group of disease that have both
genetic and environmental causes. Many studies on the causes of
childhood cancers have limitations due to the rare occurrence of these
cancers, reliance on retrospective evaluation based on parental
statements, which can lead to biases in recalling and reporting, and
inability to design appropriate studies due to the presence of multiple
factors in the cancer mechanism \textsuperscript{6,7}. For this reason,
there are studies in the literature containing many different results on
risk factors that may play a role in the etiology of childhood
cancers\textsuperscript{6-10}. Therefore, we aimed to account for as
many confounding factors as possible in order to evaluate the effect of
ETS exposure on childhood cancers in details.

In our study, we observed that a positive family history of malignancy
was present in 51\% of the case group while 36.4\% of the control group
(p \textless{} 0.05). Among the cancer patients 9.1\% of individuals
with malignancy were first-degree relatives, whereas 90.8\% were
second-degree or more distant relatives. In contrast, all individuals
with malignancy in the control group were second degree or more
distantly related. Considering that environmental and hereditary factors
play a role in the etiology of cancer, it was an expected finding that
the rate of relatives with malignancy in cancer patients was
significantly higher.

Greaves and Kinlen suggested that early exposure to infection,
especially during and before infancy, reduces the risk of developing
leukemia \textsuperscript{8}. They stated that children who attend
kindergarten and have an older sibling are more likely to encounter such
infectious agents at an earlier and more frequently, and this will
reduce the risk of developing leukemia. Although there are both
supportive and contradictory findings regarding this claim. In our
study, revealed a significant disparity between the case and control
groups with regard to the proportion of children who had at least one
older sibling, it was significantly higher in case group(59.6\%; n=59)
than the children in the control group (36.7\%; n=36) (p \textless{}
0.05).

This finding does not support Greaves and Kinlen's hypothesis. Present
study showed that a significantly higher percentage of patients in the
case group (13\%) resided in rural areas compared to those in the
control group (1\%) (p \textless{} 0.05).This would be inconsistent with
Greaves and Kinlen's hypothesis of early exposure to infection, assuming
that rural residents may be infected more frequently and earlier;
however, an increased risk of insecticide and pesticide exposure or
exposure to other pathological infectious agents may explain the higher
rate of rural living in cancer patients. The fact that many infectious
agents are no longer present and undetectable at the time of diagnosis
makes it very difficult to evaluate the cancer-infection relationship.
For this reason, it may be useful to question indirect indicators such
as birth order, whether he went to a kindergarten, a history of
infection requiring hospitalization, and where he lived.

The fact that cigarettes contain many carcinogenic and toxic substances
and that these substances are detected in fetal blood, placenta, and
urine of exposed children lead us to consider smoking as a possible risk
factor in the etiology of childhood cancers \textsuperscript{2}. The
most important source of children's exposure to cigarette smoke is
parental smoking. For this reason, many studies on this subject focus on
smoking behaviors of parents \textsuperscript{1,2,6,11-14}. The fact
that smoking has been demonstrated to cause damage to almost every cell
and tissue by various mechanisms including DNA damage, epigenetic
changes, oxidative damage, inflammation among others, it is crucial to
evaluate the consequences of smoking from the prenatal stage. In our
study, pre-conceptional, during pregnancy and current smoking status of
the mother and father were examined in the case and control groups. In
the United Kingdom Childhood Cancer Study, the pre-conceptional period
was considered as the one-year period before the pregnancy of the index
case and was accepted as such in our study \textsuperscript{2}. For this
reason, parents were also asked whether they smoked regularly at any
time in their lives, and their smoking behaviors outside of these three
periods were also taken into account.

In a retrospective cohort study published by Kessous et al. in 2019, an
increased risk of benign neoplasm (hemangioma, thyroid cyst, etc.) was
found in the children of mothers who smoked during pregnancy; however,
no increased risk of malignant neoplasm was
detected\textsuperscript{14}. In a cohort study conducted in Canada
between 2006 and 2016, children whose mothers' used alcohol, drugs and
cigarettes during pregnancy were examined. Maternal smoking during
pregnancy was associated with the risk of AML and fibrosarcoma, and
weakly associated with neuroblastoma and renal tumors
\textsuperscript{11}. A Danish study found no association between
maternal smoking during pregnancy and an increased risk of childhood
cancer \textsuperscript{12}. We found no difference between the case and
control groups in terms of pre-conceptional, during pregnancy and
current smoking behaviors of the mother according to questionnaire (p
\textgreater{} 0,05).

In our study, more than half of the fathers in the case and control
groups were smokers, and there was no significant difference between two
groups in this regard. All fathers who smoked during the
pre-conceptional period continued to smoke during pregnancy in both
groups. The rate of fathers who smoked in the pre-conceptional period
and during pregnancy in the control group (75.8\%) was significantly
higher than the cancer group (61.7\%) (p \textless{} 0.05). At the same
time, 81.8\% of the fathers in the control group stated that they used
to smoke regularly in any period of their lives, and this rate was
significantly higher than the cancer group (68.1\%) (p\textless{}0.05).
It would be wrong to interpret this situation as paternal smoking has a
protective effect on childhood cancers. As our objective measurement
findings show and we will talk about later, this may be a manifestation
of subjective methods such as surveys that can cause biases or a result
of our small sample size. Social desirability bias of cancer patients'
parents and socio-economic differences between two groups may also be a
reason.

Many methodological limitations make it difficult to establish a
relationship between childhood cancers and ETS exposure. Therefore, we
evaluated ETS exposure with the measurement of cotinine, which is an
objective marker. According to questionnaire data, the ETS exposure rate
of children with cancer (68.8\%) was found to be significantly lower
than the rate of children in the control group (83.8\%)
(p\textless{}0.05). Many studies define ETS exposure as 'cigarette
smoking in the child's environment' \textsuperscript{15}. The American
Academy of Pediatrics, on the other hand, defines a person's exposure to
second-hand and/or third-hand cigarettes as ''involuntary exposure to
tobacco smoke'' \textsuperscript{16}. As we mentioned before, the
children in the study were considered to have exposure to ETS in the
presence of at least one of the smoking conditions of their mother,
father, another individual in the house or another individual (friend,
etc.) whom they frequently encounter. However, the extent of exposure to
cigarette smoke depends on many factors such as the number of smokers,
the amount of cigarettes smoked, proximity to smokers, the size of the
environment and ventilation conditions, and the duration of
exposure\textsuperscript{17}. The fact that the definition of ETS
exposure does not cover these factors may be a reason for the higher ETS
exposure in the control group.

Cotinine is the primary metabolite of nicotine and is the most reliable
biomarker of tobacco smoke exposure according to Benowitz et
al\textsuperscript{17}. Cotinine levels can be measured from blood,
saliva, urine and hair. Plasma, saliva, and urine measurements cannot
detect long-term exposure due to their short half-lives, leading to
difficulties in sample storage. In contrast, hair cotinine analysis
allows for cross-sectional and long-term cumulative evaluation as
cotinine accumulates in the hair shaft as hair grows. While individual
differences such as age, gender and race may impact cotinine metabolism,
the meta-analysis of Florescu et al. aimed to determine the most
suitable hair cotinine threshold value for certain age groups and
pregnant women. The results of meta-analysis suggest that 0.2 ng/mg is
the most appropriate for distinguishing children exposed to ETS based on
its high sensitivity and specificity \textsuperscript{5}. The mean
cotinine value of the case group was found to be 0.224±0.088 ng/mg, and
the mean cotinine value of the control group was 0.136±0.048 ng/mg. Hair
cotinine levels were found to be significantly higher in children with
cancer (p\textless{}0.001). When the exposure to ETS was evaluated with
the hair cotinine analysis, 59.4\% of the children with cancer and
14.1\% of the children in the control group were found to be exposed to
cigarette smoke according to the threshold value. Cotinine analysis
shows that ETS exposure was significantly higher in cancer patients
(p\textless{}0.001). Our findings support the prediction that smoking
may be among the factors that cause childhood cancers.

In conclusion, in this study, which we evaluated the cigarette smoke
exposure of 104 children with cancer and 99 children without cancer
diagnosis, using a questionnaire and hair cotinine levels, supports the
idea that parental smoking may cause childhood cancer. As seen in this
study, the evaluation of cigarette smoke exposure by subjective methods
such as questionnaires can cause biases. Hair cotinine analysis is a
good test in the evaluation of cigarette smoke exposure, as it is an
easy to apply, non-invasive test and also shows cross-sectional and
long-term exposures. We believe that the use of hair cotinine analysis
together with valid and reliable questionnaires in studies aimed at
evaluating the effects of smoking on childhood cancers would prove
highly beneficial in preventing biases.

\textbf{Conflict of Interest}

The authors report no conflict of interest.

\textbf{Acknowledgments}

This work was suppported by a grant from Ankara University ( Project
No.20L0230008).

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11. Auger N, Goudie C, Low N, et al: Maternal use of illicit drugs,
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\selectlanguage{english}
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