This article was downloaded by: [University of Waterloo] On: 14 October 2014, At: 11:48 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Journal of Toxicology and Environmental Health, Part B: Critical Reviews Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uteb20
Biomonitoring of Human Fetal Exposure to Environmental Chemicals in Early Pregnancy Gerard M. Cooke
ab
a
Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Sir Frederick G. Banting Research Centre, Tunney’s Pasture, Ottawa, Ontario, Canada b
Departments of Cellular and Molecular Medicine and Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada Published online: 14 May 2014.
To cite this article: Gerard M. Cooke (2014) Biomonitoring of Human Fetal Exposure to Environmental Chemicals in Early Pregnancy, Journal of Toxicology and Environmental Health, Part B: Critical Reviews, 17:4, 205-224, DOI: 10.1080/10937404.2014.898167 To link to this article: http://dx.doi.org/10.1080/10937404.2014.898167
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Journal of Toxicology and Environmental Health, Part B, 17:205–224, 2014 Copyright © 2014 Crown copyright ISSN: 1093-7404 print / 1521-6950 online DOI: 10.1080/10937404.2014.898167
BIOMONITORING OF HUMAN FETAL EXPOSURE TO ENVIRONMENTAL CHEMICALS IN EARLY PREGNANCY Gerard M. Cooke
Downloaded by [University of Waterloo] at 11:48 14 October 2014
Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Sir Frederick G. Banting Research Centre, Tunney’s Pasture, Ottawa, Ontario, Canada, and Departments of Cellular and Molecular Medicine and Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada The first trimester of human fetal life, a period of extremely rapid development of physiological systems, represents the most rapid growth phase in human life. Interference in the establishment of organ systems may result in abnormal development that may be manifest immediately or programmed for later abnormal function. Exposure to environmental chemicals may be affecting development at these early stages, and yet there is limited knowledge of the quantities and identities of the chemicals to which the fetus is exposed during early pregnancy. Clearly, opportunities for assessing fetal chemical exposure directly are extremely limited. Hence, this review describes indirect means of assessing fetal exposure in early pregnancy to chemicals that are considered disrupters of development. Consideration is given to such matrices as maternal hair, fingernails, urine, saliva, sweat, breast milk, amniotic fluid and blood, and fetal matrices such as cord blood, cord tissue, meconium, placenta, and fetal liver. More than 150 articles that presented data from chemical analysis of human maternal and fetal tissues and fluids were reviewed. Priority was given to articles where chemical analysis was conducted in more than one matrix. Where correlations between maternal and fetal matrices were determined, these articles were included and are highlighted, as these may provide the basis for future investigations of early fetal exposure. The determination of fetal chemical exposure, at the time of rapid human growth and development, will greatly assist regulatory agencies in risk assessments and establishment of advisories for risk management concerning environmental chemicals.
Human fetal development represents an extremely rapid phase of organogenesis and growth (for a timeline of human fetal development, the reader is referred to Moore, 1989; Langman, 1981; and http://embryology. med.unsw.edu.au, a website from Dr. Mark Hill of the University of New South Wales, Sydney, Australia). Within a few weeks of fertilization, several key systems have begun their development. By the end of the first month of gestation, neurodevelopment has commenced, the heart starts beating, and the pituitary begins differentiating. After 6 wk, the fetal adrenal cortex is formed and at 8 wk the
testis is capable of secreting testosterone and is responsive to human chorionic gonadotropin (hCG). At 10 wk, growth hormone and adrenocorticotrophic hormone (ACTH) are detectable in the pituitary; at wk 12 it is possible to distinguish between male and female genitalia, and at 14 wk, the ovary contains visible primary follicles. Later development in utero shows that at 20 wk pituitary growth hormone is being actively secreted, and at 30 wk testicular descent occurs. Of all the systems that make up human fetal physiology, these systems are highlighted because they have been implicated as targets for disruption by environmental
Address correspondence to Gerard M. Cooke, PhD, Toxicology Research Division, Sir Frederick G. Banting Research Centre, 2202D Tunney’s Pasture, Ottawa, ON, K1A 0L2, Canada. E-mail: [email protected] 205
Downloaded by [University of Waterloo] at 11:48 14 October 2014
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chemicals. Cognitive deficits in children have been associated with exposure in utero to polychlorinated biphenyls (PCB) (Grandjean et al., 2001), PCB and organochlorine (OC) pesticides (Sagiv et al., 2010), manganese (Hsieh et al., 2011); lactational exposure to PCB, polychlorinated dibenzodioxins (PCDD), and polychlorinated dibenzofurans (PCDF) (Huisman et al., 1995); and maternal seafood consumption during pregnancy (with the implication being that methylmercury [MeHg] and possibly other contaminants in the diet may be responsible, Hibbeln et al., 2007). Recently, prenatal bisphenol A (BPA) exposure was linked to aberrations in neurobehavior in postnatal life (Braun et al., 2011; Sathyanarayana et al., 2011). Genitourinary problems and cryptorchidism in males have been associated with flame retardant exposure in utero (Main et al., 2007; Small et al., 2009). Exposure to phthalates in utero has been implicated in producing low birth weight (Zhang et al., 2009), and exposures to the chemical ethyl benzene, trichloroacetic acid, or dichloroacetic acid in utero are associated with an increased risk of the occurrence of congenital heart disease (McCarver et al., 2011). These examples are presented only for the purpose of raising the point that human fetal exposure to environmental chemicals may produce deleterious consequences. However, this review does not consider the arguments of “cause and effect” of environmental chemicals but rather discusses the ways to assess human fetal chemical exposure during early pregnancy. The importance of such early determination of fetal exposure was underlined recently when the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine stated that “Intervention as early as possible during the preconception period is advised to alert patients regarding avoidance of toxic exposure and to ensure beneficial environmental exposure” (ACOG/ASRM, 2013, p. 932). Thus, doctors are being advised not just to alert patients early in pregnancy of the dangers of chemical exposure, because “By the first prenatal care visit, exposure to toxic environmental agents and disruptions of
G. M. COOKE
organogenesis may have already occurred,” but in fact, to advise patients of the dangers of chemical exposure even before they become pregnant in order to avoid possible adverse outcomes (p. 932). Most correlations made between chemical exposure and adverse outcomes are based on the analysis of samples obtained at the time of birth, which may be months after the chemical insult that programmed the observed abnormality. Added to this is the possibility that the pharmacokinetics and tissue distribution of a chemical may be quite different at different stages of fetal development (Makri et al., 2004), and thus, fetal samples obtained at term may not represent the true picture of exposure at critical times during organogenesis. Consequently, there is a need for analytical chemistry data for earlier times in pregnancy to estimate fetal exposure at the time of organogenesis to provide models to estimate exposure as has been done for BPA in the pregnant rat (Shin et al., 2002). Clearly, such data cannot be obtained directly from the fetus, except from elective terminations or miscarriages. Alternative matrices were reviewed in the recent past (Barr et al., 2007; Esteban and Castano, 2009; Arbuckle, 2010; Schoeters et al., 2011; Ünüvar and Büyükgebiz, 2012), and feasibility with respect to the methodologies needed, ethical considerations, and practical difficulties associated with obtaining samples from the pregnant women have been examined. This review considers the alternative matrices, the available data for environmental contaminants in these matrices, and correlations between them for chemical loading. Emphasis is placed on ways to estimate fetal exposure at earlier stages of pregnancy and discusses some of the research needs to validate them. The structure of the review considers (a) contaminant data obtained from fetuses in early pregnancy (mostly second trimester), (b) contaminant data from perinatal maternal and fetal matrices, and (c) contaminant data obtained from less invasive or noninvasive methods. The discussion is limited to environmental chemicals because the general human population is exposed to
ASSESSING THE HUMAN FETUS FOR CHEMICAL EXPOSURE
these through food, water, and air and where there is little choice in being exposed. While there is a wealth of data on using noninvasive matrices in the detection of recreational drugs, prescription drugs, nicotine/cotinine, and alcohol, there is an element of choice in exposure to these chemicals, and therefore these are not considered in this review.
ESTIMATION OF FETAL CHEMICAL EXPOSURE IN EARLY PREGNANCY Downloaded by [University of Waterloo] at 11:48 14 October 2014
Placenta and Fetal Liver Placenta and fetal tissues from early pregnancy have not been investigated extensively for chemical contaminants, yet these tissues represent the most reliable estimates of exposure. Mathematical models of human fetal exposure extrapolated from animal studies (Clarke et al., 1993) still need the support of data from estimates from fetal tissues. In most cases, placental estimates have used term placenta, although a few studies employed tissues from earlier stages of pregnancy. Singh et al. (2008) measured polyaromatic hydrocarbons (PAH) in preterm (
Journal of Toxicology and Environmental Health, Part B: Critical Reviews Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uteb20
Biomonitoring of Human Fetal Exposure to Environmental Chemicals in Early Pregnancy Gerard M. Cooke
ab
a
Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Sir Frederick G. Banting Research Centre, Tunney’s Pasture, Ottawa, Ontario, Canada b
Departments of Cellular and Molecular Medicine and Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada Published online: 14 May 2014.
To cite this article: Gerard M. Cooke (2014) Biomonitoring of Human Fetal Exposure to Environmental Chemicals in Early Pregnancy, Journal of Toxicology and Environmental Health, Part B: Critical Reviews, 17:4, 205-224, DOI: 10.1080/10937404.2014.898167 To link to this article: http://dx.doi.org/10.1080/10937404.2014.898167
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Journal of Toxicology and Environmental Health, Part B, 17:205–224, 2014 Copyright © 2014 Crown copyright ISSN: 1093-7404 print / 1521-6950 online DOI: 10.1080/10937404.2014.898167
BIOMONITORING OF HUMAN FETAL EXPOSURE TO ENVIRONMENTAL CHEMICALS IN EARLY PREGNANCY Gerard M. Cooke
Downloaded by [University of Waterloo] at 11:48 14 October 2014
Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Sir Frederick G. Banting Research Centre, Tunney’s Pasture, Ottawa, Ontario, Canada, and Departments of Cellular and Molecular Medicine and Obstetrics and Gynecology, University of Ottawa, Ottawa, Ontario, Canada The first trimester of human fetal life, a period of extremely rapid development of physiological systems, represents the most rapid growth phase in human life. Interference in the establishment of organ systems may result in abnormal development that may be manifest immediately or programmed for later abnormal function. Exposure to environmental chemicals may be affecting development at these early stages, and yet there is limited knowledge of the quantities and identities of the chemicals to which the fetus is exposed during early pregnancy. Clearly, opportunities for assessing fetal chemical exposure directly are extremely limited. Hence, this review describes indirect means of assessing fetal exposure in early pregnancy to chemicals that are considered disrupters of development. Consideration is given to such matrices as maternal hair, fingernails, urine, saliva, sweat, breast milk, amniotic fluid and blood, and fetal matrices such as cord blood, cord tissue, meconium, placenta, and fetal liver. More than 150 articles that presented data from chemical analysis of human maternal and fetal tissues and fluids were reviewed. Priority was given to articles where chemical analysis was conducted in more than one matrix. Where correlations between maternal and fetal matrices were determined, these articles were included and are highlighted, as these may provide the basis for future investigations of early fetal exposure. The determination of fetal chemical exposure, at the time of rapid human growth and development, will greatly assist regulatory agencies in risk assessments and establishment of advisories for risk management concerning environmental chemicals.
Human fetal development represents an extremely rapid phase of organogenesis and growth (for a timeline of human fetal development, the reader is referred to Moore, 1989; Langman, 1981; and http://embryology. med.unsw.edu.au, a website from Dr. Mark Hill of the University of New South Wales, Sydney, Australia). Within a few weeks of fertilization, several key systems have begun their development. By the end of the first month of gestation, neurodevelopment has commenced, the heart starts beating, and the pituitary begins differentiating. After 6 wk, the fetal adrenal cortex is formed and at 8 wk the
testis is capable of secreting testosterone and is responsive to human chorionic gonadotropin (hCG). At 10 wk, growth hormone and adrenocorticotrophic hormone (ACTH) are detectable in the pituitary; at wk 12 it is possible to distinguish between male and female genitalia, and at 14 wk, the ovary contains visible primary follicles. Later development in utero shows that at 20 wk pituitary growth hormone is being actively secreted, and at 30 wk testicular descent occurs. Of all the systems that make up human fetal physiology, these systems are highlighted because they have been implicated as targets for disruption by environmental
Address correspondence to Gerard M. Cooke, PhD, Toxicology Research Division, Sir Frederick G. Banting Research Centre, 2202D Tunney’s Pasture, Ottawa, ON, K1A 0L2, Canada. E-mail: [email protected] 205
Downloaded by [University of Waterloo] at 11:48 14 October 2014
206
chemicals. Cognitive deficits in children have been associated with exposure in utero to polychlorinated biphenyls (PCB) (Grandjean et al., 2001), PCB and organochlorine (OC) pesticides (Sagiv et al., 2010), manganese (Hsieh et al., 2011); lactational exposure to PCB, polychlorinated dibenzodioxins (PCDD), and polychlorinated dibenzofurans (PCDF) (Huisman et al., 1995); and maternal seafood consumption during pregnancy (with the implication being that methylmercury [MeHg] and possibly other contaminants in the diet may be responsible, Hibbeln et al., 2007). Recently, prenatal bisphenol A (BPA) exposure was linked to aberrations in neurobehavior in postnatal life (Braun et al., 2011; Sathyanarayana et al., 2011). Genitourinary problems and cryptorchidism in males have been associated with flame retardant exposure in utero (Main et al., 2007; Small et al., 2009). Exposure to phthalates in utero has been implicated in producing low birth weight (Zhang et al., 2009), and exposures to the chemical ethyl benzene, trichloroacetic acid, or dichloroacetic acid in utero are associated with an increased risk of the occurrence of congenital heart disease (McCarver et al., 2011). These examples are presented only for the purpose of raising the point that human fetal exposure to environmental chemicals may produce deleterious consequences. However, this review does not consider the arguments of “cause and effect” of environmental chemicals but rather discusses the ways to assess human fetal chemical exposure during early pregnancy. The importance of such early determination of fetal exposure was underlined recently when the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine stated that “Intervention as early as possible during the preconception period is advised to alert patients regarding avoidance of toxic exposure and to ensure beneficial environmental exposure” (ACOG/ASRM, 2013, p. 932). Thus, doctors are being advised not just to alert patients early in pregnancy of the dangers of chemical exposure, because “By the first prenatal care visit, exposure to toxic environmental agents and disruptions of
G. M. COOKE
organogenesis may have already occurred,” but in fact, to advise patients of the dangers of chemical exposure even before they become pregnant in order to avoid possible adverse outcomes (p. 932). Most correlations made between chemical exposure and adverse outcomes are based on the analysis of samples obtained at the time of birth, which may be months after the chemical insult that programmed the observed abnormality. Added to this is the possibility that the pharmacokinetics and tissue distribution of a chemical may be quite different at different stages of fetal development (Makri et al., 2004), and thus, fetal samples obtained at term may not represent the true picture of exposure at critical times during organogenesis. Consequently, there is a need for analytical chemistry data for earlier times in pregnancy to estimate fetal exposure at the time of organogenesis to provide models to estimate exposure as has been done for BPA in the pregnant rat (Shin et al., 2002). Clearly, such data cannot be obtained directly from the fetus, except from elective terminations or miscarriages. Alternative matrices were reviewed in the recent past (Barr et al., 2007; Esteban and Castano, 2009; Arbuckle, 2010; Schoeters et al., 2011; Ünüvar and Büyükgebiz, 2012), and feasibility with respect to the methodologies needed, ethical considerations, and practical difficulties associated with obtaining samples from the pregnant women have been examined. This review considers the alternative matrices, the available data for environmental contaminants in these matrices, and correlations between them for chemical loading. Emphasis is placed on ways to estimate fetal exposure at earlier stages of pregnancy and discusses some of the research needs to validate them. The structure of the review considers (a) contaminant data obtained from fetuses in early pregnancy (mostly second trimester), (b) contaminant data from perinatal maternal and fetal matrices, and (c) contaminant data obtained from less invasive or noninvasive methods. The discussion is limited to environmental chemicals because the general human population is exposed to
ASSESSING THE HUMAN FETUS FOR CHEMICAL EXPOSURE
these through food, water, and air and where there is little choice in being exposed. While there is a wealth of data on using noninvasive matrices in the detection of recreational drugs, prescription drugs, nicotine/cotinine, and alcohol, there is an element of choice in exposure to these chemicals, and therefore these are not considered in this review.
ESTIMATION OF FETAL CHEMICAL EXPOSURE IN EARLY PREGNANCY Downloaded by [University of Waterloo] at 11:48 14 October 2014
Placenta and Fetal Liver Placenta and fetal tissues from early pregnancy have not been investigated extensively for chemical contaminants, yet these tissues represent the most reliable estimates of exposure. Mathematical models of human fetal exposure extrapolated from animal studies (Clarke et al., 1993) still need the support of data from estimates from fetal tissues. In most cases, placental estimates have used term placenta, although a few studies employed tissues from earlier stages of pregnancy. Singh et al. (2008) measured polyaromatic hydrocarbons (PAH) in preterm (
