Impact of Exposure to Environmental Pollutants on Birth Outcomes in an Israeli Cohort
Impact of Exposure to Environmental Pollutants on Birth Outcomes in an Israeli Cohort
Objectives and hypothesis The scale and diversity of chemicals in worldwide use today is
 vast. Many of these chemicals are released into the environment where they are found in air,
 water, soil, house dust, and in the food supply, resulting in exposure to humans.
 Characterizing the extent of exposure and the effects of exposure in vulnerable populations,
 such as pregnant women and children, is of the utmost importance as the chemical structure of
 many of these compounds resembles hormones such as estrogen, testosterone and thyroid
 hormone, affect neurodevelopment and other health effects. Here, we focus on few classes of
 compounds: heavy metals, volatile organic compounds (VOCs), brominated flame retardants
 (PBDEs) and phthalates. We will characterize the extent of exposure to pregnant women and
 their infants in Israel, where biomonitoring studies in the general population are scarce. We
 will also examine selected outcomes in pregnant women and their offspring in relation to
 these compounds, and to establish a biorepository for further studies.

 Specific Aims:

 1. To assess Heavy metals, VOCs, PBDEs and phthalates body burdens through measurement of
 these chemicals in maternal and paternal serum and urine, cord blood, breastmilk and
 neonatal meconium among several representative sub-populations.

 2. To examine associations between exposure to heavy metals, VOCs, PBDEs and phthalates and
 (a) pregnancy complications, (b) anthropometrics at birth (i.e. birth weight adjusted
 for gestational age, ponderal index, head circumference adjusted for gestational age),
 and (c) cryptorchidism incidence, (d) maternal and infant thyroid function.

 3. To establish a bio repository of these media for future studies and to establish follow
 up methods for this cohort to later assess development and growth in the infants,
 toddlers and children.

 Patients and Methods:

 Patients will be recruited from three delivery rooms in Israel: "Assaf Harofeh Medical
 Center" , "Lis (Sorasky) Medical Center" and "Rambam Medical Center", all together with
 around 21,000 births annually, representing all sub-populations in Israel. 500
 mother-father-infant trios (for a total of 4500) will be recruited.

 When arriving to the delivery room, after signing the informed consent, blood and urine will
 be withdrawn from the mothers and fathers for Heavy metals, VOCs, PBDEs and phthalates
 levels. At the same time thyroid function tests will also be taken from the mothers. After
 delivery, cord blood will be taken, as well as meconium from the neonate. Hair, nails and
 Breastmilk will also be collected. From the mothers The samples will be analyzed for heavy
 metals, VOCs, PBDEs and phthalates. During their stay at the hospital, mothers and fathers
 will fill out a standardized questionnaire regarding life style factors, background
 information, and exposure opportunities. Detailed information on family history, previous and
 present pregnancy, method of delivery, perinatal complications, and pregnancy outcome will be
 recorded from the medical files.

 Expected contribution to environmental health in Israel:

 This will be the first data on sub-populations exposure to Heavy metals, VOCs, PBDEs and
 phthalates in Israel. Neonatal meconium levels will provide important information on
 magnitude of exposure during the last months of pregnancy, and, thus, will provide insights
 into the bioaccumulative nature of these Heavy metals, VOCs, PBDEs and phthalates during
 early stages of human development, important data for future risk assessments. Our
 comprehensive approach will provide detailed information on the status of each subject. Such
 novel knowledge would also lead to the development of preventive and counseling strategies
 for men and women with high BFR and phthalates exposure in order to minimize the risks of
 adverse outcomes. Knowledge transfer strategies are essential in order that the general
 public, health professionals, scientists and policy/law regulators have the appropriate
 knowledge on which to base their understandings and recommendations for the future. In this
 way, the knowledge that is generated will facilitate the development of prevention strategies
 to minimize health risks of Israel population.
Objectives and hypothesis The scale and diversity of chemicals in worldwide use today is
 vast, ranging from pharmaceuticals and food products, to plastics, gasoline, and
 semiconductor chips. Many of these chemicals are released into the environment where they are
 found in air, water, soil, in house dust, and in the food supply, resulting in exposure to
 humans. Characterizing the extent of exposure and the effects of exposure in vulnerable
 populations, such as pregnant women and children, is of the utmost importance as the chemical
 structure of many of these compounds resemble hormones such as estrogen, testosterone and
 thyroid hormone , affect neurodevelopment and other health effects. Here, we focus on few
 classes of compounds: heavy metals, volatile organic compounds (VOCs), brominated flame
 retardants (PBDEs) and phthalates., and will characterize the extent of exposure to pregnant
 women and their infants in Israel, where biomonitoring studies in the general population are
 scarce. We also propose to examine selected outcomes in pregnant women and their offspring in
 relation to these compounds, and to establish a biorepository for further studies.

 BTEX (Benzene, Toluene, Ethylbenzene, Xylene):

 Volatile organic compounds (VOCs) are compounds with low boiling points; VOC exposures
 originate from numerous natural and anthropogenic sources such as cleaning products, paints,
 solvents, personal care products, automotive exhaust, and tobacco smoke. Exposure to certain
 VOCs may increase the risk for birth defects, neurocognitive impairment, asthma, and cancer.
 The known VOC metabolites are acrolein, acrylamide, acrylonitrile, benzene, 1-bromopropane,
 1,3-butadiene, carbon disulfide, crotonaldehyde, cyanide, N,N-dimethylformamide,
 ethylbenzene, ethylene oxide, propylene oxide, styrene, tetrachloroethylene, toluene,
 trichloroethylene, vinyl chloride, and xylene exposures. Benzene, toluene, ethylbenzene and
 xylene isomers (BTEX), aromatic hydrocarbons, are part of VOC metabolites that play a major
 role in industries and air pollution 1.

 Prena¬tal exposure to air pollution (contains BTEX) might be associated with adverse
 pregnancy outcomes, including intrauterine growth restriction (IUGR), low birth weight (LBW),
 preterm birth (PTB), and intrauter¬ine mortality. Exposure to BTEX chemicals has been
 associated with negative impacts on sperm quantity and quality. Benzene and toluene exposure
 have been associated with abnormal menstrual cycle. Direct adverse effects of BTEX chemicals
 have been observed on ovarian cell apoptosis, proliferation, and hormone release in animal
 ovarian cells. Exposures to benzene and toluene, commonly used and produced by unconventional
 oil and gas (UOG) operations, have been associated with increased risks for miscarriage 2.

 Xylene is an environmental pollutant. It is also used in dyes, paints, polishes, medical
 technology and different industries as a solvent. Human life is surrounded by a wide range of
 VOCs, including xylene causing harmful health effects xylene exposure occurs through breath,
 eye, oral, and dermal route. Xylene is mainly metabolized in the liver via oxidation of
 methyl groups, followed by conjugation with glycine to yield hippuric acid, which is excreted
 through urine. High amount and dose of xylene may harm the liver. Prolonged exposure to
 xylene may cause a multiorgan damages such as: toxicity to nervous, reproductive, immune,
 hepatic and respiratory systems. Furthermore, xylene reduces reproductive hormones in women
 and cause male infertility. Studies have reported the subsequent effects in experimental
 animals: deformities in fetus skeletal, increased interruption in bone formation, redness and
 blood in fetus organs, and reduced fetus weight3.

 Benzene is known as one of the predominant air pollutants in the environment. Chronic
 exposure to benzene is known to cause oxidative stress, DNA damage, aplastic anemia and
 increased risk of acute myelogenous leukemia in humans. The mechanism is through crucial
 toxic metabolism, reactive metabolites and probably epigenetic changes. Common exposures to
 benzene are tobacco smoke, automobile service stations, exhaust from motor vehicles, and
 industrial emissions. Chromosomal abnormalities in sperm have also been reported with benzene
 exposure4 [4],

 Ethylbenzene originates from tobacco smoke, burning fossil fuels, industries using
 ethylbenzene, carpet glues, varnishes and paints. The hazards of ethylbenzene include acute
 toxicity, mutagenicity, systemic toxicity, developmental and reproductive toxicity,
 immunotoxicity, metabolism and pharmacokinetics, carcinogenicity, neurotoxicity, and
 developmental neurotoxicity. At doses that produced maternal effects (> 1000 ppm) in animals,
 ethylbenzene was fetotoxic causing decreased fetal body weight (bwt) and increased skeletal
 variations5.

 Exposure to toluene is from, industrial paints and paint thinner, tobacco smoke, and fossil
 fuels6. Toluene has intoxicating and rewarding effects in the brain. Acute exposure to
 inhalants has dose dependent, reversible effects like depressed central nervous system (CNS).
 High concentrations can cause sedation and anesthesia, while higher concentration can result
 in coma or death by respiratory depression. At delivery, toluene-exposed infants were
 characteristically premature and/or delayed in growth as. Additionally, as the children grow,
 a number of developmental delays and impairments become evident (e.g., language impairments,
 growth retardation, hyperactivity, cerebellar dysfunction)7.

 Trichloroethylene (TCE) and perchloroethylene (PCE) are part of the VOCs and the air
 pollution. It is known that the risk of epilepsy and certain types of cancer such as cervical
 cancer may be increased among adults who were exposed to PCE-contaminated drinking water.
 Exposure during gestation and early childhood and exposure to a major metabolite of TCE, TCAA
 (trichloroacetic acid)administered in drinking water, resulted in increased numbers of
 implantation and resorption sites, and selective cardiac teratogenicity8,9.

 Heavy metal elements:

 Metal intake can be via air, water and food. Air pollution exposure includes inhalation or
 ingestion of ultrafine particulate matter, also called nanoparticles. Epidemiological studies
 have consistently found an association between small increases in urban particulates and
 health effects, including increased morbidity and mortality in people with respiratory and
 cardiac disease. All metals in excess can cause disease. Long term exposure to metal is a
 cause of increased metal accumulation in a variety of body tissue. Some metals are more toxic
 than others10.

 The prevalent elements that found in soil in Haifa bay:

 -  Nickel (Ni) - Nickel sensitivities are the most common harmful health effect in humans.
 People working in nickel refineries or nickel-processing plants are more affected with
 chronic bronchitis, asthma and reduced lung function then the general population.

 -  Lead (Pb) - neurological ailments and learning impairments can inactive enzymes, thus
 affecting red blood cell production, amino acid function and number of biochemical
 systems in the body. Lead exposure is associated with an increased risk of miscarriage
 and stillbirth potentially due to placental rupture.

 -  Chromium (Cr) - is found in all phases of the environment including air, water, and
 soil, and its many chemical forms are pollutants with serious implication to the
 environment and human health. Hexavalent chromium (Cr6) occurs in the environment from
 the erosion of natural chromium deposits, but is also a product of industrial processes.
 There are demonstrated instances of Cr6 being released into the environment by leakage,
 poor storage, or inadequate industrial waste disposal practices.

 -  Mercury (Hg) - affects central nervous function. A source of it is an exposure to
 breathing air from spills, incinerators and industries burning mercury containing fuels.
 Mercury, at high levels, may damage the brain, kidneys, and the developing fetus.
 Short-term exposure to high levels of metallic mercury vapors may cause lung damage,
 nausea, vomiting, diarrhea, increases in blood pressure or heart rate, skin rashes, and
 eye irritation11.

 -  Cadmium- elevated cadmium exposure during pregnancy may be inversely associated with
 children's cognitive function measured at pre-school age. Exposure to cadmium has been
 shown to result in miscarriage and stillbirths in exposed mothers, potentially through
 decreased levels of antioxidants or enhanced lipid peroxidation resulting in oxidative
 stress12.

 -  Mangenase (Mn) - is used in steel production to improve hardness, stiffness, and
 strength. It may be used as an additive in gasoline to improve the octane rating of the
 gas. Exposure to high level of manganese in air can cause lung irritation and
 reproductive effects.13 The central nervous system is a common target organ for many
 environmental metals. The adverse effects of heavy metal exposure in the prenatal and
 early childhood periods are of increasing concern in terms of high exposure on a body
 weight basis, immature metabolic pathways, delicate developmental processes, and life
 course effects. Prenatal exposure to lead and mercury has been related to congenital
 anomalies and impaired neurodevelopment. Metals may interact to cause synergistic or
 antagonistic effects on neurodevelopment that are different from the main effects of
 exposure to each metal alone. Metals exposure during prenatal and childhood may affect
 the neurodevelopment/cognitive and behavior14.

 If more risk factors such as genetic, ethnic and environmental exposure coincide, disease
 development is more likely to progress. Exposure to heavy metals during pregnancy is
 associated with increased risks of miscarriage and/or stillbirths.

 Heavy metals may be routinely mobilized during hydraulic fracturing operations and have been
 shown to contaminate surface and ground water in some cases (e.g., lead), they are also
 inadvertent contaminants in fracturing fluids.

 Brominated Flame Retardants Brominated Flame Retardants (BFRs) constitute a group of chemical
 substances that are used worldwide to reduce fire-related injury and property damage. They
 are found in polymers (polystyrene foams, high impact polystyrene, epoxy resins) that are
 incorporated into a wide variety of consumer products (textiles, foam furniture, insulating
 foams, electrical equipment, kitchen appliances, televisions and computers). In 2000, it was
 estimated that >200,000 metric tons of BFRs were produced annually. There are currently five
 major BFRs: three commercial mixtures of polybrominated diphenyl ethers (penta-, octa- and
 deca-BDEs), hexabromocyclododecane (HBCD) and tetrabromobisphenol A (TBBPA) routinely present
 in a broad variety of consumer goods. Because BFRs leach out of manufactured products and
 these products are dumped in the environment, we are exposed to BFRs from a wide variety of
 sources.

 The concentration of BFRs in the environment, has increased dramatically over the past two
 decades while, thanks to international regulatory policies, that of other known toxicants
 (DDT, lead, PCBs) has declined.

 Exposure through contaminated food, particularly meat and dairy products, is believed to be
 the major contributor to BFR exposure in humans.

 There are reports that newborns and young infants have higher serum concentrations than older
 children and adults, since it is generally believed that infants are more vulnerable to
 toxicological insults. Scientists in the USA have reported that the median levels of BDEs in
 human breast milk increased almost 10-fold from the 90's to the early 2000's. The in-utero
 period is a critical period for exposure; however, there is a scarcity of information with
 respect to BFR exposure during the earliest stages of human development. A study monitoring
 tetra- to octa-BDE levels in early to mid-gestation human fetal liver and placenta from
 1998-2006, demonstrated not only that these toxicants cross the placenta from as early as
 nine weeks fetal age but also that the 2006 fetal tissue levels are >5-fold higher than they
 were nine years previously. Thus, fetal BFR exposure is also on the rise.

 Although the BFR burden in humans is increasing and exposures occur from an early stage in
 development, the consequences are relatively unexplored. Three clinical studies have been
 published to date on the potential effects of in-utero BFR exposure and fetal outcome.
 Elevated levels of BFRs in breast milk correlated significantly with lower newborn birth
 weight, birth length, head size, chest circumference and body mass index. Significant
 associations between maternal serum BFR levels at 35 weeks gestation and the levels of
 several sex hormones (testosterone, estradiol, LH, SHBG) in 3 month old female and male
 offspring were reported. In addition, Main and colleagues have found significantly higher BFR
 levels in the breast milk of mothers whose newborn sons had cryptorchidism. If left
 untreated, cryptorchidism can lead to serious reproduction-related problems: low sperm counts
 and infertility as well as a 2- to 8-fold increase in the risk of testicular cancer. These
 data suggest that BFRs are impacting early stages of human development and that at least one
 outcome is abnormal reproductive systems. This is a serious issue: not only is an
 individual's health potentially affected but so is that of future generations.

 Phthalates Phthalates are a class of high production volume chemicals used in a wide variety
 of consumer products. They are commonly used as plasticizers to increase flexibility and
 durability. They are also used to hold fragrances, and as propellants. Global production of
 phthalates has increased dramatically since World War II and is currently estimated to exceed
 3.5 million metric tons/year. DEHP constitutes roughly 50% of the market share, but uses of
 DBP and BBzP are also large (> 100,000 metric tons/year each). The widespread use has
 resulted in ubiquitous contamination, including of the indoor environment, with exposures
 higher in industrialized than in developing nations. Table 1 below shows sources of exposure
 of the phthalate diesters that will be evaluated in the proposed study.

 Some recent studies, find prenatal exposure to phthalates to be associated with reductions in
 fetal growth, shorter pregnancy duration, perturbed thyroid function, and both cognitive and
 behavioral deficits in children. More data are clearly required to fully characterize the
 health effects in vulnerable populations of pregnant women and children.

 Specific Aims:

 1. To assess Heavy metals, VOCs, PBDEs and phthalates body burdens through measurement of
 these chemicals in maternal and paternal serum and urine, cord blood, breastmilk and
 neonatal meconium among several representative sub-populations.

 2. To examine associations between exposure to heavy metals, VOCs, PBDEs and phthalates and
 (a) pregnancy complications, (b) anthropometrics at birth (i.e. birth weight adjusted
 for gestational age, ponderal index, head circumference adjusted for gestational age),
 and (c) cryptorchidism incidence, (d) maternal and infant thyroid function.

 3. To establish a bio repository of these media for future studies and to establish follow
 up methods for this cohort to later assess development and growth in the infants,
 toddlers and children.

 Patients and Methods:

 Patients will be recruited from three delivery rooms in Israel: "Assaf Harofeh Medical
 Center" , "Lis (Sorasky) Medical Center" and "Rambam Medical Center", all together with
 around 21,000 births annually, representing all sub-populations in Israel. 500
 mother-father-infant trios (for a total of 4500) will be recruited.

 When arriving to the delivery room, after signing the informed consent, blood and urine will
 be withdrawn from the mothers and fathers for Heavy metals, VOCs, PBDEs and phthalates
 levels. At the same time thyroid function tests will also be taken from the mothers. After
 delivery, cord blood will be taken, as well as meconium from the neonate. Hair, nails and
 Breastmilk will also be collected. From the mothers The samples will be analyzed for heavy
 metals, VOCs, PBDEs and phthalates. During their stay at the hospital, mothers and fathers
 will fill out a standardized questionnaire regarding life style factors, background
 information, and exposure opportunities. Detailed information on family history, previous and
 present pregnancy, method of delivery, perinatal complications, and pregnancy outcome will be
 recorded from the medical files.

 Feasibility of the research:

 Delivery, maternal and neonatal departments in all medical centers have a large number of
 deliveries annually. The population admitted to these centers is representative of the
 population in Israel. Since blood work is part of the admission to the delivery room, and
 since the neonates will not have an invasive procedure (meconium), we expect many couples to
 participate in this innovative study. Our comprehensive approach, using a combination of a
 standardized questionnaire, maternal and paternal serum, cord blood, urine, breastmilk and
 meconium analysis of the chemicals, will provide a detailed definition of the body burden
 status of each subject. We have the means and the desire to facilitate knowledge exchange
 between basic and clinical scientists, between those who generate knowledge and those who use
 it in developing policies and regulations, as well as among scientists, health professionals
 and the general public.

 Expected contribution to environmental health in Israel:

 These will be the first data on sub-populations exposure to Heavy metals, VOCs, PBDEs and
 phthalatesin Israel. Neonatal meconium levels will provide important information on magnitude
 of exposure during the last months of pregnancy, and, thus, will provide insights into the
 bioaccumulative nature of these Heavy metals, VOCs, PBDEs and phthalatesduring early stages
 of human development, important data for future risk assessments. Our comprehensive approach
 will provide detailed information on the status of each subject. Such novel knowledge would
 also lead to the development of preventive and counseling strategies for men and women with
 high BFR and phthalate exposure in order to minimize the risks of adverse outcomes. Knowledge
 transfer strategies are essential in order that the general public, health professionals,
 scientists and policy/law regulators have the appropriate knowledge on which to base their
 understandings and recommendations for the future. In this way, the knowledge that is
 generated will facilitate the development of prevention strategies to minimize health risks
 of Israel population.
Inclusion Criteria:

 -  Israeli Arabs, Jews from Russia, Jews from Ethiopia, Jews with an Ashkenazic
 background and Jews with a Sephardic background

 Exclusion Criteria:

 -  refuse to take part in the study