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Yankai Xia Editor

Early-life
Environmental
Exposure and
Disease
Facts and Perspectives
Early-life Environmental Exposure and Disease
Yankai Xia
Editor

Early-life Environmental
Exposure and Disease
Facts and Perspectives
Editor
Yankai Xia
School of Public Health
Nanjing Medical University
Nanjing, Jiangsu, China

ISBN 978-981-15-3796-7 ISBN 978-981-15-3797-4 (eBook)

https://doi.org/10.1007/978-981-15-3797-4

© Springer Nature Singapore Pte Ltd. 2020

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I dedicate this book to Professor Xinru Wang,
for his great contributions in the field of
environment and health.
Preface

Man and nature have always coexisted in harmony. Nature produces resources
necessary for humankind’s survival and development. In the long history of the
Earth, various substances in the environment have cultivated living organisms
ranging from prokaryotes to humans, who have constantly taken advantage of
nature’s great capacity for self-regulation to modify the environment to suit their
needs. Regrettably, the rapid development of human activities has broken this
balance, leading to resource shortages and severe environmental contamination,
among other irreversible damages. Environmental pollutants spread and circulate
in nature and eventually enter the human body, potentially causing changes in
hormones, proteins, metabolites, and so on, ultimately resulting in various adverse
health effects. Particularly, it should be noted that people are particularly vulnerable
to these environmental risks in early life and pollutant exposure during this crucial
period could result in intergenerational effects.
Nowadays, as life expectancy has risen to an unprecedented level, more attention
has been paid to environmental chemical exposure, which is ubiquitous yet largely
invisible. Environmental exposures include all the chemicals and compounds with
which we come into contact. Evidence suggests that the elementary composition of
the human body is identical with that of the Earth’s crust, mainly as a result of the
exchange of substances through metabolism, evidencing the intimate connection that
the human body has with its surroundings. Toxins discharged as a result of industrial
production or daily living activities enter the human body directly through polluted
air, water, and soil or indirectly through food intake, due to the biomagnification
properties of plants and animals.
Environmental chemical pollutants can enter the human body via inhalation,
ingestion, or dermal contact, with inhalation being the most rapid route of uptake.
Inhalation is the major route of polluted air and tobacco smoke exposure, which
consists mostly of particulate matter (PM), heavy metals like lead and cadmium,
polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs), and
carbonyls. Ingestion exposure mainly occurs via consumption of contaminated food
and drink or via the intentional or inadvertent non-dietary ingestion of soil, dust, or
chemical residues on surfaces or objects containing complex chemical contaminants,
vii
viii Preface

which include pesticides, polybrominated diphenyl ethers (PBDEs), phenols,

perfluorinated alkyl substances (PFAS), and heavy metals like lead and mercury.
Especially for young children, ingestion exposure through hand-to-mouth or object-
to-mouth activity must not be overlooked. Dermal exposure can result from skin
contact with contaminated environmental media, including water, sediment, outdoor
soil or dust, surfaces, and personal care products containing triclosan, oxybenzone,
parabens, and heavy metals like lead and cadmium.
Humans encounter hundreds or even thousands of different environmental pol-
lutants daily. Many substances appear almost harmless, others may be potentially
harmful but are uneasily absorbed by the human body, and others may be incredibly
harmful, even in very small quantities. Generally, environmental chemicals such as
those listed in the above paragraph have the following characteristics. First, they
affect a wide area and a large population. Second, there is a long term of exposure
between the pollutant and the affected humans. Third, the environmental chemicals
are commonly transformed and metabolized in nature and in humans. Fourth, a
variety of substances can act on the human body at the same time, resulting in a joint
effect. Fifth, humans are affected by environmental chemicals to a greater degree due
to biomagnification. Considering the level and variety of contaminants in all envi-
ronmental media, the chronic exposure that people face eventually leads to a high
risk of adverse health effects.
Comprehensive assessment of exposure is particularly important. In addition to
substances necessary for human survival, many known and potential toxins can be
detected in blood, urine, hair, fingernails, and other tissues, acting as biomarkers of
exposure. Different poisons can damage different systems of the human body, with
special attention being paid to the nervous system, immune system, and reproductive
system, as well as childhood growth and development. For example, the accumula-
tion of lead in the body may cause syndromes affecting the nervous system, digestive
system, and circulatory system, such as sensory and motor disorders, lead colic, and
anemia. Due to the individual and combined effects of various toxins, the human
body can experience damage at the system, organ, tissue, and cellular levels.
While such damage can occur in both males and females of all ages, women
during pregnancy and lactation periods, infants and children are more sensitive to
toxins, such that the same dosage of exposure may lead to more severe outcomes.
For instance, studies indicate that prenatal exposure to organophosphate pesticides
may not only cause health damage to the mother’s neural system but also result in
preterm birth and attention deficit hyperactivity disorder (ADHD) in the offspring.
Given the potential for health damage to two or more generations, more studies
ought to focus on the effects of toxins at these special stages, with further discussion
on appropriate production limits to be enforced for the sake of prevention.
The issue of early-life environmental exposure and resulting diseases is one of the
hottest topics in life sciences. Exposure to adverse environmental conditions during
early life, a period critical for tissue organogenesis and functional development, can
Preface ix

lead to lifelong negative health effects. The Developmental Origins of Health and
Disease (DOHaD) theory posits that exposure to various substances during early life
is an important potential contributor to long-term disease. From this theory, it can be
inferred that the increased incidence of chronic noncommunicable diseases, such as
allergic diseases, neurobehavioral developmental disorders, and metabolic disorders,
can be attributed in part to harmful environmental exposure.
Adverse environmental conditions before conception, in utero, and during
infancy can lead to negative health effects during the subsequent lifetime of the
exposed individuals. Concerning the central topic of early-life environmental expo-
sure and disease, our book is divided into five parts, starting with an overview of
environmental exposure measurement and evaluation, followed by a review of the
effects of various exposures like tobacco smoke, pesticides, metals, and stress on
offspring’s health. Next is a discussion of the developmental origins of various
childhood diseases that affect growth, neural development, and reproductive health,
as well as allergic diseases, highlighting the importance of longitudinal studies that
measure exposure at potentially sensitive time points during childhood. The book
then provides up-to-date evidence of early-life environmental exposure’s
intergenerational/transgenerational effects, especially through genetic and epigenetic
pathways, underlining a crucial point in the book’s discussion of pollutants’
far-reaching potential for harm (Fig. 1).

Fig. 1 The structure diagram of this book

x Preface

The book provides readers a thorough understanding of the predominating

perspectives of epidemiologic, clinical, and basic science studies in the burgeoning
area of early-life environmental exposure and diseases. Importantly, the book also
includes a comprehensive discussion of possible preventive measures. Unlike in any
other book, we synthesize the existing knowledge of environmental exposure’s
impact on children’s health in early life, systematically expounding different sources
of environmental exposure and their impact on childhood development and disease
and adding new discoveries and insights into their intergenerational/
transgenerational effects.
With great pleasure, we extend our sincere thanks to all our well-qualified and
internationally renowned contributors from various countries for providing the
important, authoritative, and scientific information and technology to make this
book a reality. Our contributors have enriched the book with cutting-edge knowl-
edge and informative illustrations, tables, and figures. We are extremely thankful to
Springer Nature for completing the review process expeditiously for publication.
Finally, we express heartfelt thanks to our family members and friends for all the
support they have provided in the preparation of this book.
In short, we hope for harmony between man and nature!

Nanjing, China Yankai Xia

Cover Page

Ministry of Education and Shanghai Key Laboratory of Children’s Environmental

Health, Institute of Early Life Health, Xinhua Hospital, Shanghai Jiao Tong Uni-
versity School of Medicine. [email protected]
It has been over 30 years since Dr. David Barker, an epidemiologist in U.K.,
published his milestone paper on a simple observation of the inverse association
between birthweight and the risk of death due to coronary heart disease later in life.
The theory of “fetal programming” or “Developmental Origin of Health and Disease
(DOHaD)” has been confirmed both in human epidemiologic investigations and
animal studies, and is now widely accepted. It has also become clear that the critical
window of fetal programming and developmental elasticity is in early life, com-
monly defined as from conception to 2 years of age (approximately 1,000 days).
Insults from external and internal sources on embryo, fetus and infant may leave a
permanent mark with important health implications in future life. The underlying
biological mechanisms are not totally clear but epigenetic changes caused by the
insults have been proposed. In this emerging area, environmental exposure to
pollutants and psychosocial factors during pregnancy and infancy are the prominent
examples of such insults that have drawn keen interest worldwide.
The editor of this book, Professor Yankai Xia, Dean of School of Public Health,
the Nanjing Medical University, China, led a team of esteemed international experts
in the field of early-life environmental health, and produced this informative and
timely book. It covers comprehensive yet closely related topics, ranging from
common environmental exposures to health outcomes in children and adults. What
makes this book more valuable and refreshing is that it addresses some practical
issues such as cautions on contamination and other potential pitfalls in biosample
collection, and includes topics such as paternal environmental exposure, impact of e-
cigarettes, transgenerational effects, and molecular mechanisms.
The contents of this book are well organized, systematic and easy to read. The
gathered evidence is up-to-date. This book is truly an objective review of rich

xi
xii Cover Page

scientific evidence, making it a “must-have” by researchers and graduate students in

this field. Clinicians engaging in maternal and child health who often encounter
patients with suspected environmental exposures may also find it a useful reference.
More importantly, as two-thirds of the early-life window is at postpartum, this
precious time may offer an opportunity to initiate clinical interventions for fetal
reprogramming and avoid health consequences later in life. Furthermore, the evi-
dence collected by this book may serve as a scientific basis for policy-makers to set
up environment and health policies that could have wide and long-term impacts on
human health.

Jun Jim Zhang

[email protected]
Acknowledgments

This book was supported by NSFC-NIH Biomedical collaborative research program

(No. 81961128022) and the Priority Academic Program for the Development of
Jiangsu Higher Education Institutions (Public Health and Preventive Medicine)

xiii
Contents

Environmental Exposure Measurements and Evaluations . . . . . . . . . . . 1

Yankai Xia, Xu Wang, and Minjian Chen
Early-life Tobacco Smoke/Nicotine Exposure and Offspring Health . . . . 23
Katherine M. Kuniyoshi, Bo Hang, and Virender K. Rehan
Prenatal Pesticide Exposure and Child Health . . . . . . . . . . . . . . . . . . . . 51
Monica K. Silver and John D. Meeker
Prenatal Metal Exposure and Child Health . . . . . . . . . . . . . . . . . . . . . . 67
Binafsha Manzoor Syed
Prenatal Stress and Offspring Health Outcomes . . . . . . . . . . . . . . . . . . . 89
Guizhen Du and Di Wu
The Unique Vulnerabilities of Children to Environmental Hazards . . . . 103
Karen English, Colleen Lau, and Paul Jagals
Early-Life Environmental Influences on Growth . . . . . . . . . . . . . . . . . . 113
Eva Cecilie Bonefeld-Jorgensen and Manhai Long
Early-Life Environmental Toxic Influences on Neural Development . . . . 141
Gro D. Villanger, Johan Øvrevik, Heidi Aase, and Oddvar Myhre
Early-Life Environmental Influences on Allergic Diseases . . . . . . . . . . . 161
Yu Ait Bamai, Chihiro Miyashita, Atsuko Araki, and Reiko Kishi
Early-Life Social and Economic Adversities on Health . . . . . . . . . . . . . . 181
Omar Ben Forge Risk, Hein Tun, Logan Manikam, and Monica
Lakhanpaul
Endocrine-Disrupting Chemical Exposure and Later-Onset Diseases . . . 195
Di Wu and Guizhen Du
Paternal-Specific Exposure and Child Health . . . . . . . . . . . . . . . . . . . . . 207
Hong Qian, Wei Wu, Francis Manyori Bigambo, and Chuncheng Lu
xv
xvi Contents

Molecular Mechanism of Early-Life Chemical Exposure-Induced

Harmful Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Hua Wang and De-Xiang Xu
Transgenerational Epigenetic Inheritance of Developmental Origins
of Health and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Wei Wu, Peihao Wu, Qiuqin Tang, and Chuncheng Lu
Environmental Exposure Measurements
and Evaluations

Yankai Xia, Xu Wang, and Minjian Chen

1 Introduction

Environmental exposure is defined as the exposure of individuals to environmental

factors in a specific period. The environmental factors include biological, chemical,
physical, and sociopsychological factors [1].
Exposure assessment is a quantitative process for the measurement and following
evaluation of exposure burden. Exposure assessment is an important part of environ-
mental health risk assessment [2], and we need to identify the potential exposure
population. Therefore, the understanding of environmental exposure measurements
and evaluations is important for the assessment and prediction of the health risk caused
by environmental factors in early life. Among the environmental factors, the studies on
the assessment of chemical factor exposure in early life were widely reported.
This chapter focused on the topic of chemical exposure assessment. The chemical
exposure assessment includes internal and external exposure assessment [3], and the
future of a more comprehensive environmental exposure assessment was
discussed, and the outline of the chapter is shown in Fig. 1.

2 Internal Exposure Assessment

Internal exposure assessment is to recruit a certain number of representative

populations after exposure, collect and analyze the biomarkers in the human bio-
materials, and estimate the exposure of environmental pollutants in biomaterials
through the concentration of biomarkers [4].

Y. Xia · X. Wang · M. Chen (*)

School of Public Health, Nanjing Medical University, Nanjing, China
e-mail: [email protected]

© Springer Nature Singapore Pte Ltd. 2020 1

Y. Xia (ed.), Early-life Environmental Exposure and Disease,
https://doi.org/10.1007/978-981-15-3797-4_1
2 Y. Xia et al.

Fig. 1 Outline of the chapter

2.1 Biomarkers

Biomarkers might be specific to chemicals, so that the content of biomarkers is

related to the degree of chemical exposure. For the biomarker of exposure, the
process of chemical absorption, distribution, metabolism, and excretion (ADME)
must be understood. This is important for choosing the appropriate biomaterials [5].

2.2 Biomaterials

In the selection of biomaterials, the ADME process of chemicals should be studied

[6]. After the chemicals are absorbed into the blood, they are distributed to the whole
body, so the blood is an important biomaterial for the detection of chemical
exposures. The body’s storage depot includes plasma proteins, the liver, the kidney,
adipose tissue, and bone. Therefore, adipose tissue is also commonly used as a
biomaterial for the detection of chemical exposures. One of the main ways of
excretion is the kidney, so urine is also a main biomaterial. Chemicals can also be
excreted through hair and nails, so these two are also major biomaterials. It should be
noted that the placenta and umbilical cord (blood) are the main media of chemical
Environmental Exposure Measurements and Evaluations 3

transfer between mother and infant, and they are important biomaterials for chemical
detection in early life.
Blood
After the chemicals are absorbed into the blood, they are distributed and metabo-
lized, and the chemicals may also be released into the blood from the storage depot,
so the blood is important for chemical internal exposure detection. Blood samples
are easy to be obtained and can be divided into serum and plasma. Plasma samples
are anticoagulated. Serum samples often encounter the problem of hemolysis, but the
use of anticoagulants in plasma samples may cause the risk of pollution in the
detection of some chemicals [7]. Therefore, for plasma samples, the blank samples
should be tested to estimate the experiment contamination. Many unstable chemicals
in blood may be oxidized, polymerized, or degraded after collection. And we need to
ensure the reproducibility of the experiment and prevent the obvious dynamic
changes of chemicals in blood after collection. Thus, standardized procedure should
be conducted during and after blood sample collection. Attention should also be paid
to fasting status, blood collection time and method, anticoagulant usage, blood
collection volume, sample storage condition, hemolysis, etc. For example, if
chemicals have a short half-life in the human body and are abundant in the food,
the fasting status may have an obvious impact on these chemicals’ levels in the
blood [8].
Dry blood spots on paper are the standard clinical sample types for neonatal
screening programs around the world [9]. The sample is collected by puncturing the
infant’s heel with the vent tube and dropping each drop of blood onto the standard
paper, so that each blood spot in the collected blood sample contains about 50 μ l of
blood. This kind of sample is easy to be obtained because of its clinical use, and can
be used in exposure science [10]. However, the sample of this method has been dried
with the risk of loss of some chemicals, and the chemicals on the paper can be
contaminated by some chemicals. And the concentration of analyte in the center and
periphery of the spot is often different.
Urine
Urine reflects the excretion of chemicals exposed to humans. Therefore, to select
biomarkers in urine, we need to fully understand the ADME process of chemicals.
Generally, morning urine is the commonly used sample [11]. Due to the large
content of polar chemicals in urine, the specific polar chemical is the common
detection target. The adequate separation of polar chemicals should be considered
when using a chromatography-based method to avoid the detection interference/
matrix effects. The advantages of urine samples are noninvasive, easy to be obtained,
and large volume. Therefore, it is suitable for infant sample collection. Diapers are
also used for urine collection [12], but attention should be paid to chemical loss and
contamination. Urine samples are affected by the drinking and sweating of the
subjects, and there is a phenomenon of urine concentration and dilution. Generally,
urine creatinine and specific gravity are used for concentration detection
correction [13].
4 Y. Xia et al.

Placenta
The placenta is a special endocrine organ during pregnancy. It is the place of
chemical and metabolic waste exchange between mother and fetus [14]. The pla-
centa is easy to be obtained in childbirth. It should be noted that the placenta has a
barrier function [15], so it is necessary to distinguish its maternal side and fetal side.
The blood supply of the mother penetrates from the maternal side of the placenta to
the fetal side. There may be inhomogeneity in the concentration of chemicals on the
maternal and fetal sides of the placenta [16]. Therefore, the analysis of the concen-
tration of chemicals should not be randomly selected in any part of the placenta;
otherwise, it may produce inaccurate estimation.
Umbilical Cord (Blood)
The umbilical cord is the only channel connecting the mother and the fetus. Its
collection is simple and noninvasive. The determination of the chemicals in the
umbilical cord or cord blood can provide a direct evaluation for the chemical
exposure of the fetus in the mother [17]. Compared with the determination of the
maternal blood, it can more directly link to the exposure of the fetus [18]. Notably,
some researchers have pointed out that the umbilical cord is the best sample to
evaluate the fetal exposure status of persistent organic pollutants (POPs) [19]. The
umbilical cord (blood) has been used to determine trace metals (such as mercury and
cadmium), polychlorinated biphenyls (PCBs), and organochlorine pesticides for
early life exposure [20].
Breast Milk
Breastfeeding has always been considered as the safest and best way for healthy
mothers to feed their babies. However, due to environmental pollution, it cannot be
ignored that breast milk is also a way of excretion of chemicals, reflecting the
internal exposure of the mother and indirectly revealing the exposure of the baby
[21]. The pollutants that have been reported to be detected in human milk include
pesticides, herbicides, drugs, industrial chemicals, toxic metals, and radionuclides.
Among them, fat-soluble pollutants are the most important [22]. Breast milk con-
tains milk fat. In addition, due to the concentration of milk tube, the concentration of
pollutants in milk sometimes is several times higher than that in the blood of
lactating mothers.
Saliva
Saliva has an excretory function, so it can reflect the internal exposure of chemicals
[23]. Saliva sample collection is simple and noninvasive. Especially for the detection
of chemicals in children, the collection of saliva has a higher acceptance. Attention
should be paid to the standardization of methods when collecting saliva samples.
Food and drink residues in the mouth can cause experiment contamination, which
can be avoided by collecting saliva without eating for a period of at least 2–3 h
[24]. In addition, the volume of saliva is small, so the error caused by evaporation
should be avoided.
Hair
Hair sampling is simple and painless, which is easy to be stored. In addition, hair
chemicals may reflect the dynamic changes of human chemical exposure in a certain
Environmental Exposure Measurements and Evaluations 5

period of time [25], so it has been used as an ideal biomaterial. Hair is mainly used
for the detection of trace elements and drugs, such as arsenic and mercury [26]. The
disadvantage of hair is that it is easy to be polluted by the environment, such as the
substances passed by hand, the chemicals used in hair routine, and the deposition of
atmospheric particles or aerosols in the environment. The use of washing to remove
contamination may introduce new contamination [27]. Therefore, when using hair
for internal exposure detection, we should fully consider the possible contamination
of target chemicals.
Nails
Nail is a way of excretion of chemicals. The advantage is that nails are easy to be
collected and stored. When the population is recruited, the sampling of children’s
nails can be simple, rapid, and easily accepted. The growth of foot nails can
accurately record the metabolism of trace elements (such as arsenic, lead, cadmium,
copper, and zinc) during this period [28]. Some studies have pointed out that nails
can reflect chemical intake 6–12 months ago [28]. In addition, nails can also reflect
drug exposure [29].
Teeth
Because deciduous teeth fall off naturally, they can be called noninvasive biomate-
rials, and they are easy to be stored. Another advantage of teeth is that they can
record the exposure of chemicals for a long time (from birth to falling off)
[30]. Teeth are mainly used to reflect the exposure of elements, such as calcium,
lead, fluorine, and manganese [31, 32].

3 External Exposure Assessment

External exposure assessment measures the content of chemicals in the media (such
as atmosphere, soil, water, personal care products, food, etc.) and calculates the level
of individual exposure by combining the information of exposure source, route, and
time [33]. External exposure assessment method is widely used in the science of
exposure assessment, especially for large-sample-size human population study
because of its easy collection and calculation [34]. The disadvantage of the external
exposure method is that it ignores the bioavailability of chemicals in the human body
[35]. In addition, if the external exposure information collection is not comprehen-
sive, it may also cause incomplete evaluation [35]. These may lead to some deviation
in the evaluation. The materials of external exposure analysis including air, water,
and soil are disscussed.
Air
Air samples mainly reflect the chemicals entering the human body through the
respiratory tract, and some chemicals can also enter the human body through the
air due to swallowing into the digestive tract. The existing forms of air pollutants
include gas, vapor, and aerosol. In general, direct collection method and enrichment
6 Y. Xia et al.

collection method can be used to collect air samples [36]. The direct collection
method is suitable for the situation of high concentration of chemicals in the
atmosphere. Generally, syringes, plastic bags, collection tubes, and vacuum bottles
can be used to collect samples. The collection time is generally short, reflecting the
situation of pollutants in the air in a short time. Therefore, it is necessary to increase
the number of samples to achieve longer coverage or to use in the case of a stable
pollution state. Enrichment collection method is a method of preconcentration of
chemicals during collection by using liquid and solid absorbent. It is applicable to
the situation of low concentration of chemicals [36]. The sampling time is generally
long, which can represent the average concentration of the sampling time period and
reflect the real situation of air pollution. Personal and area sampling can be used for
air sample collection. Personal exposure assessment is more accurate, which can
directly reflect individual exposure level [37]. Area sampling can reflect the expo-
sure of a certain region. According to the spatial distance between the individual and
each sampling point and other pollution-related information, individual exposure
burden can be evaluated by calculation, which is suitable for epidemiological
research of a large sample size.
Water
Pollutants in the water mainly enter the human body through the digestive tract, and
can also volatilize into the air and enter the human body through the respiratory tract.
The contact between human skin and polluted water can also make some chemicals
enter the human body. Water sampling can be divided into natural water body,
industrial wastewater, domestic sewage, and water supply pipe network sampling
[38]. The setting of water sampling sites should be representative. The sampling
should consider the frequency and time, consider the changes in the wet and dry
periods, and consider the pollution information. For the detection of different
chemical categories, different water collection and storage containers should be
selected. For example, if the substance to be tested is a trace metal or glass
component, glass bottle cannot be used. On the contrary, if plastic-related chemicals
are to be assessed, plastic containers should be avoided. The amount of sampling
should be enough to meet the needs of analysis. If the concentration of the tested
chemical is very low and it needs to be preconcentrated [39], the sampling amount
should be increased. In addition, attention should be paid to the storage method.
According to the characteristics of the target chemical, freezing or cold storage
should be considered or preservatives should be added [40].
Soil
The chemicals in the soil mainly enter the human body through air, water, and the
food chain [41]. Therefore, the detection of soil chemical content can be used as an
external exposure evaluation, reflecting the potential exposure route and burden in
the human body. Soil can be used for the detection of organic and inorganic
exposure. First of all, it should be noted that the containers in the experiment may
cause contamination. For example, plastic containers can cause phthalate contami-
nation. Volatile organic compound (VOC) detection may be contaminated by other
organic solvents used in the analytical process. For heavy metal analysis, tree
Environmental Exposure Measurements and Evaluations 7

branches and other non-soil debris should be removed from soil samples before
drying. The digestion method is used to make the metal in soil measurable. For the
organic chemicals, the proper pretreatment method should be selected according to
the physicochemical characters. For VOCs, the pretreatment may cause loss and
contamination. The headspace injection method can be used for substances with low
water solubility. For substances with high water solubility, vacuum distillation can
be used [42]. For semi-volatile organic compounds, Soxhlet extraction and purifi-
cation can be used to concentrate the target chemicals and remove the interferences.

4 Analytical Instruments for Environmental Exposure

4.1 Gas Chromatography

Gas chromatography (GC) is a chromatographic separation method using gas as a

mobile phase. The vaporized chemicals are carried into the chromatographic column
by carrier gas [43]. The stationary phase in the column has different molecular forces
with the chemicals in the sample, so the chemicals can be separated. The retention
time and chromatogram of each chemical can be recorded by the subsequent
detection system. According to the retention time and order, the chemicals can be
qualitatively analyzed; according to the peak height and area size, the compounds
can be quantitatively analyzed. It can be used in combination with a flame ionization
detector (FID), mass spectrometer (MS), etc. Generally, GC can be used for organic
chemicals with heat stability and a boiling point of no more than 500  C, such as
volatile organic compounds, organic chlorine, organic phosphorus, polycyclic aro-
matic hydrocarbons, phthalates, etc. Nonvolatile liquid and solid substances can be
analyzed by pyrolysis and gasification.

4.2 Liquid Chromatography

Liquid chromatography (LC) is a chromatographic separation method using liquid as

a mobile phase. The chemicals are brought into the column by the liquid mobile
phase, and the stationary phase in the column has different forces to the chemicals in
the sample, so the chemicals can be separated. Similar to GC, LC can also provide
information of the retention time and order, peak height, and area size of each
chemical to the detector for qualitative and quantitative analysis. It can also be
used in combination with mass spectrometry, etc. Modern LC consists of a high-
pressure pump, injection system, temperature control system, chromatographic
column, detector, signal recording system, etc. Compared with the classical liquid
chromatography, it has the characteristics of high efficiency, rapidity, and
sensitivity [44].
8 Y. Xia et al.

4.3 Capillary Electrophoresis

The capillary electrophoresis (CE) instrument uses the elastic quartz capillary as the
separation channel and the high-voltage direct current electric field as the driving
force to separate the components according to the difference of the mobility and
distribution behavior of the chemicals in the sample. CE is particularly suitable for
the separation of polar chemicals [45].

4.4 Ultraviolet–Visible Spectroscopy

Ultraviolet–visible (UV-Vis) spectrophotometer is a kind of analytical instrument

which uses the radiation absorption of the UV-Vis spectral region (190–400 nm) of
chemical substances [46]. It is mainly composed of a light source, monochromator,
absorption cell, detector, and signal processor. The absorption spectrum of the
chemical has characteristics related to its structure, so the UV-Vis spectrophotometer
has a certain qualitative ability. When it is used for quantitative analysis, the
absorbance of a certain concentration of sample solution is measured at the maxi-
mum absorption wavelength and compared with that of a certain concentration of
reference solution to calculate the concentration of sample solution. It can be used
for the determination of transition metal ions and highly conjugated organic
compounds [47].

4.5 Fluorescence Spectroscopy

Fluorescence analysis is a method that can be used for qualitative or quantitative

analysis, because some chemical substances are in excited state after being irradiated
by ultraviolet (UV) light, and the fluorescence of excited state molecules can reflect
the characteristics of the substance [48]. The advantage of fluorescence analysis is
that there is a molecular excitation process, which greatly improves the sensitivity of
fluorescence spectrum-based detection. Ultralow-concentration organic chemicals
with UV excitation characteristics can be detected by fluorescence analysis [49].

4.6 Atomic Absorption Spectroscopy

Atomic absorption spectroscopy (AAS), also known as atomic spectrophotometry, is

an analysis method for chemical element detection based on the absorption of optical
radiation (light) by free atoms in the gaseous state. The limits of detection (LODs)
can be reached to the 10 9 g/ml level by flame AAS (FAAS) and 10 13 g/ml by
Environmental Exposure Measurements and Evaluations 9

graphite furnace AAS (GFAAS). More than 70 kinds of inorganic elements can be
detected by AAS [50].

4.7 Atomic Fluorescence Spectroscopy

Atomic fluorescence spectroscopy (AFS) is a method of element quantitative anal-

ysis by measuring the fluorescence emission intensity from atoms in the gaseous
state that have been excited to higher energy levels by absorption of electromagnetic
radiation. Atomic fluorescence photometer is suitable for the detection of inorganic
elements [51]. Compared with the atomic absorption spectrometer, the atomic
fluorescence photometer has a significantly improved sensitivity due to lower
interferences [52].

4.8 Mass Spectrometry

Mass spectrometer (MS) has the structure of ion source, mass analyzer, and ion
detector. The ion source is to ionize the chemical molecules under high vacuum. The
ionized molecules will be further changed into many kinds of fragment ions and
neutral particles with smaller mass due to receiving too much energy. The mass
analyzer is a device to separate the ions of different masses into it at the same time
according to the mass-to-charge ratio m/z. The separated ions enter the ion detector
which collects and amplifies the ion signals, and then the computer draws a mass
spectrogram. Mass spectrometer is divided into high resolution, medium resolution,
and low resolution mass spectrometer. It can be connected with LC, GC, and CE
[53]. It is widely used in the detection of organic and inorganic substances [54].

4.9 Nuclear Magnetic Resonance Spectroscopy

Nuclear magnetic resonance (NMR) spectrometer is one of the most powerful tools
for the qualitative analysis of the composition and structure of substances [55], and
sometimes it can also be used for quantitative analysis. NMR is mainly used for
organic chemical analysis, and compared with a mass spectrometer, it has a nonde-
structive advantage for chemical analysis, but the detection sensitivity is often lower
than that of a mass spectrometer [56].
10 Y. Xia et al.

4.10 Direct-Reading Instruments

Direct-reading gas detector, using the sensor principle, can quantitatively analyze a
variety of toxic and harmful gases by replacing the corresponding sensor module.
The precision of the instrument depends on the sensor. The result is directly
readable, and the sensor does not need to be calibrated every time. The instrument
can be used in field investigation [57]. In addition, there are also direct-reading water
detectors. Attention should be paid to the differences between the detection principle
of direct-reading detectors and that of the standard methods, so as to clarify the
potential problems that need to be paid attention to when interpreting the detection
results by direct-reading detectors [57, 58].

4.11 Chromatography Tandem Mass Spectrometry

It mainly includes GC tandem MS and LC tandem MS [59]. The combination of

chromatography and MS occupies the primary position in the detection of organic
compounds. GC is suitable for the detection of volatile and heat-stable substances.
The derivatization method was used to expand the detection range of GC-MS
[60]. LC-MS has a wide range of organic compound detection using columns of
different retention characteristics [61]. Compared with LC-MS, GC-MS usually uses
standard 70 eV high-energy electrons to interact with atoms or molecules in the gas
phase to produce ions, which has high ionization efficiency and abundant fragments,
so there is a relatively complete database that can be used for the qualitative analysis
of chemicals for GC-MS [62].

4.12 Inductively Coupled Plasma Tandem Mass Spectrometry

Inductively coupled plasma tandem mass spectrometry (ICP-MS) is a mass spec-

trometry method that uses inductively coupled plasma to ionize samples. It atomizes
the sample and produces atoms and small polyatomic ions, which are then detected
by mass spectrometry. ICP-MS is more sensitive than GFAAS in the determination
of many trace and ultra trace elements. ICP-MS can measure almost all kinds of
samples, achieve simultaneous multielement determination at one time, and provide
the information of isotopes [63]. The combination of chromatography and ICP-MS,
in which ICP-MS is used as a detector, can determine the elements with different
chemical valences in samples [64]. These properties establish the primary position of
ICP-MS in trace element detection technology.
Environmental Exposure Measurements and Evaluations 11

4.13 Capillary Electrophoresis Tandem Mass Spectrometry

Similar to CG-MS and LC-MS, capillary electrophoresis tandem mass spectrometry

(CE-MS) combines the advantages of CE and MS, taking both the separation and
molecular mass information into account. Ions are usually formed by electrospray
[65]. It has a good detection performance for polar substances [45].

5 Analytical Methods for Environmental Exposure

Analytical methods for environmental exposure include the determination of

organic/inorganic chemicals in environmental and biological samples (Table 1)
[64–88].

5.1 Analytical Methods for Organic Chemicals

The stability, volatility, and other characteristics of chemicals should be considered

in the collection and storage of samples for the detection of organic chemicals, and it
should be noted that the containers used should not introduce new contamination.
For example, phthalate determination is easily contaminated by plastic
containers [91].
The sample preparation step for the measurement method of organic chemicals in
a biological and environmental matrix is to separate or preconcentrate the target
compounds from the matrix. For gas chromatography, because the detection sub-
stance sometimes does not have the characteristics for gas chromatography detec-
tion, it often needs derivative treatment [60]. For the pretreatment of liquid
chromatography, the particulates in the sample should be removed to prevent the
column from being blocked. At the same time, the proteins in the biological matrix
should be also removed to prevent the column from being blocked due to the
denaturation of proteins in the mobile phase. It should be noted that the more
complex the sample preparation steps are, the greater the experimental error will
be introduced [92].
The most common detection techniques for organic compounds include GC, LC,
and CE, which are usually connected with a mass spectrometer. In the detection
system, the specificity provided by a mass spectrometer is the strongest, while that
provided by an ultraviolet spectrophotometer commonly is the lowest. LOD of most
MS-based methods is in the range of pico- to nanogram per gram of matrix, which
usually meets the sensitivity requirements of detecting the level of chemicals in the
general population when the matrix is 1–10 g. The analysis deviation is usually
between 10% and 20%.
Table 1 Analytical methods for environmental chemical exposure assessment in early life
12

No. of
Instrument chemicals Volume/weight for
Exposure family Biomaterials (matrix) (methodology) measured No. of subjects analysis References
Organic chemical
Pesticides Meconium of infants GC-MS 8 200 0.5 g [66]
Urine of pregnant women GC–MS/MS 6 273 maternal urine samples and [67]
and their infants 107 neonatal urine samples
Urine of pregnant women GC-MS 6 413 [68]
Antibiotics Urine of pregnant women UPLC–Q/TOF 21 536 1.0 mL [69]
MS
Phthalates Urine of pregnant women HPLC-MS/ 18 642 [70]
MS
Urine of pregnant women UPLC-MS/ 7 1002 0.5 ml [71]
MS
Urine of pregnant women HPLC-MS 15 446 1 μl [72]
Phenols Urine of pregnant women HPLC-MS 11 446 [72]
Parabens Urine of pregnant women LC-MS/MS 4 439 [73]
Polybrominated Serum of pregnant women GC/MS 8 185 0.5 ml [74]
diphenyl ethers
Placenta, breast milk, fetal GC/MS 17 30 paired placenta, breast milk, [75]
cord blood, and neonatal fetal cord blood, and neonatal
urine samples urine samples
Perfluorinated Blood of pregnant women LC-MS/MS 2 50 2 ml [76]
alkyl acids and cord blood
Y. Xia et al.
 Serum of pregnant women LC-MS/MS 7 1533 [77]
Polycyclic aro- Placenta GC–FID 16 84 10 g [78]
matic
hydrocarbons
Urine of pregnant women UPLC-MS/ 1 627 1 ml [79]
MS
Cotinine Saliva of pregnant women LC-MS 1 147 maternal saliva samples and [80]
and their infants 120 infant saliva samples
Urine of infants GC-MS 1 265 maternal urine samples and [81]
93 infant urine samples
Volatile organic Urine of pregnant women UPLC-MS/ 28 488 [82]
compounds MS and
IC-ESI/MSMS
Urine of pregnant women UPLC-MS 3 29 5 ml [83]
Polychlorinated Serum of pregnant women GC-MS 7 281 [84]
biphenyls
Inorganic chemical
Environmental Exposure Measurements and Evaluations

Elements Urine of pregnant women ICP-MS 5 762 [85]

Amniotic fluid ICP-MS 22 65 [86]
Breast milk ICP-MS 7 35 of colostrum, 59 of transi- 0.2–0.3 g lyophilized [87]
tional milk, and 92 of mature breast milk sample
milk
Tooth of infants ICP-MS 3 156 [88]
Nail of pregnant women and ICP-MS 6 694 Approximately 1 cm in [89]
their infants depth and 1–2 cm in
diameter
Hair of infants ICP-MS 3 112 3g [90]
13
14 Y. Xia et al.

Other analytical methods that can be used for organic chemical determination also
include immunoassay and bioassay [93]. These techniques are usually used for
analysis by ultraviolet, fluorescence, or radioactivity detection. The sensitivity of
some of these methods is suitable for human sample detection. It should be noted
that, because these techniques do not use separation techniques, the problem about
specificity may be encountered.

5.2 Analytical Methods for Inorganic Chemicals

The containers used for the detection of inorganic chemicals should not introduce
new contamination into samples when samples are collected and stored. Sometimes,
glass containers may introduce metal contamination [94].
The sample preparation of inorganic chemicals is often simple. In some cases,
only dilution is needed for sample preparation [20]. However, we still need to pay
attention to the detection process to avoid the introduction of contamination. For
example, all the experimental equipment should be cleaned with acid.
The detection of inorganic elements mainly uses AAS or ICP-MS.

6 From Exposure Measurements to Evaluations: The Use

of Models

The goal of chemical measurement is to be used in the research and the assessment of
environmental exposure risk. Environmental exposure evaluation is one of the key
contents of risk assessment, which needs to be implemented by using specific
models and algorisms. The acquisition of exposure route, exposure frequency,
exposure dose, and other data in different exposure events is necessary for exposure
evaluation. Chemical measurement provides information of the internal and external
exposure of chemicals for exposure evaluation. The exposure of the human body to
chemicals can be divided into two forms: one is single exposure, i.e., a single kind of
pollutant enters the human body through a single way; the other is mixed exposure,
i.e., a variety of pollutants from multiple sources (diet, drinking water, and living
environment) enter the human body through multiple routes (skin, mouth, and
inhalation). The second one is more common. Through several links of exposure
event loop, individual loop, time loop, and uncertainty loop, the models including
data and the methods of demography, geostatistics, and biostatistics are used to
simulate exposure events and conduct exposure evaluations [95]. The first step of
exposure evaluation is to determine individual characteristic values, which are used
to determine parameters of exposure events. After determining the individual char-
acteristic values, exposure event loop should be established, which covers multi-
source and multi-route exposures. For multi-route exposure, the amount of exposure
Environmental Exposure Measurements and Evaluations 15

should be calculated based on the consideration of exposure route information. Some

routes may not occur in an exposure event, such as some chemicals only through
dietary intake, some only through air inhalation, and some only through skin contact.
When the calculation of the first individual’s multi-source and multi-route exposure
is completed, the exposure of the individual should be calculated with emphasis on
describing the variability of individual exposure to chemicals. The exposure evalu-
ation next describes the characteristics of exposure variability in different periods
and calculates uncertainty factors, including the selection of sampling points, anal-
ysis methods, calculation methods, the use of alternative data, etc. There are several
software that have been designed to conduct environmental exposure evaluation
including Crystal Ball, LifeLine, Calendex, etc. [96].

7 Future Perspective

People in early life are exposed to a variety of environmental factors. Therefore, the
future direction of environmental exposure assessment is from single exposure to
comprehensive exposure assessment.
In recent years, “exposome” has become a hot topic in the environmental research
area. Exposome is defined as the sum of human environmental exposure from early
life to death [97]. The combination of exposome and genome can greatly improve
our understanding of the cause of disease and various health outcomes.
The assessment of exposome includes a series of indicators of internal and
external exposure, which need to cover all stages of life. Exposome also includes
physical, biological, and sociopsychological factors, which need to be assessed by
various detection technologies and investigation methods [98]. Indeed, exposome
study remains challenging. In terms of chemical exposure assessment, the existing
high-throughput methods encounter the problems of huge differences in chemical
properties and concentrations in samples, which makes high-throughput methods
often compromise the detection performance of some chemicals in the sample
pretreatment and instrument analysis. Otherwise, the analysis can be conducted by
a highly optimized method for the detection of special chemicals. Because the
amount of information obtained from this kind of detection is relatively small, a
variety of methods and several rounds of analysis are required, increasing the
investment of time and cost for exposome analysis. And this kind of strategy is
not suitable for samples with small volume. Therefore, the realization of the assess-
ment of exposome depends on the development of high-throughput and high-
sensitivity detection technology and requires a high degree of technology integration
and teamwork. Fortunately, the concept of exposome has been introduced into
several birth cohort studies related to early life exposure, and exposome is now
moving from theory into practice [99]. These birth cohort studies are accumulating a
large volume of information about pregnancy exposure and following children’s
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