DOI 10.1515/jpm-2013-0349 J. Perinat. Med. 2014; 42(6): 725–729
Review article Tom Daniel Solan and Stephen W. Lindow*
Mercury exposure in pregnancy: a review Abstract: Mercury exposure in pregnancy has been asso ciated with both pregnancy complications and devel opmental problems in infants. Apart from industrial accidents and contaminated food, mercury exposure is likely to arise from predatory fish consumption, environ mental contamination and dental amalgam restorations placed before or during pregnancy. It would be prudent to recommend that pregnant women avoid these potential problems and minimize any risk. The available literature indicates a linear relationship with mercury levels and IQ deficit, and therefore a safe limit of mercury cannot be calculated. Keywords: Mercury; pregnancy; pregnancy outcome. *Corresponding author: Stephen W. Lindow, Hull York Medical School, Women and Children’s Hospital, Hull Royal Infirmary Anlaby Road Hull, HU3 2JZ, UK, Tel.: +44 1482 607830, Fax: +44 1482 382781, E-mail: [email protected] Tom Daniel Solan: Hull York Medical School, Loxley Building, University of Hull, Cottingham Road, Hull, HU6 7RX, UK
Overview The toxicity to humans from mercury ingestion has been observed for hundreds of years. The phrase “mad as a hatter” comes from the neurological effects suffered by hat makers who were chronically exposed to mercury. Over time, several incidents involving mercury exposure have occurred, which have resulted in significant effects on the human population. In the 1900s, reports of acro dynia (pink disease) [32] in children were thought to be linked to the use of teething powders and ointments con taining mercurous chloride, and in the 1950s, industrial releases of mercury in Japan resulted in significant neu rotoxicity to the infants exposed in utero. More recently, concern has increased surrounding the pervasive nature of mercury in the environment and its effect on fetal development reported at low levels of exposure. More over, there is controversy in the literature regarding the true toxic effects of mercury exposure during pregnancy
and the perinatal period. This review aims to provide an up-to-date overview of the available evidence surround ing these issues.
Chemistry Mercury is a naturally occurring element found in water, air and soil. It exists in three main forms: elemental, inor ganic (e.g., mercuric chloride) and organic (e.g., methyl mercury) (http://www.who.int/phe/news/Mercury-flyer. pdf; accessed 20 December 13). It is released into the environment from volcanic activity, weathering of rocks and as a result of human activity [34]. Human activity such as coal-fired power stations, cement production and industrial processes accounts for 30% of mercury release [26]. Once in the environment, liquid mercury vaporizes and stays in the atmosphere for up to 1 year, where it can be deposited globally. It settles in lakes, rivers and bays, where it is transformed by aquatic microorganisms into methylmercury [34]. Methylmercury exists in most sea species and bioaccumulates in the aquatic food chain, reaching highest concentrations in large predatory fish.
Exposure Elemental and inorganic mercury Exposure to elemental mercury can occur in a number of ways including volcanic explosions, combustion pro cesses, gold mining, dental amalgam restorations and han dling of sphygmomanometers and fluorescent lights [30]. The major route of exposure is via inhalation of mercury vapor, but mercury can also be absorbed cutaneously [8]. Adverse effects of mercury exposure have been observed in dental workers, miners and industrial workers, among others. A major concern in developing countries is that uncontrolled working conditions in small-scale mining activities can lead to extremely high levels of mercury vapor exposure. It is estimated that these activities release
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726 Solan and Lindow, Mercury exposure in pregnancy: a review up to 1000 tons of mercury into the environment where up to 15 million people work [24]. The use of dental amalgam is a potential significant source of exposure as it can contain up to 50% elemen tal mercury (http://www.who.int/phe/news/Mercuryflyer.pdf) [2]. This issue is controversial, and the advice from the British Dental Association [36] is “to avoid where clinically reasonable, the placement or removal of amalgam fillings during pregnancy”. Despite this advice, there is no available evidence of links between the use of dental amalgam and birth defects or still births. Dental amalgam restorations lead to inhalation of mercury vapor, which is oxidized to its inorganic form, Hg2+, and appears in the blood. Mercury concentrations in the blood have shown to positively correlate with the number and surface area of amalgam restorations and are significantly higher when compared to those without dental amalgam [1, 17]. Animal research has shown that mercury from dental amalgam restorations is able to cross the placenta in sheep and accumulate in fetal tissues to achieve a steady state with advancing gesta tion [31]. Placental transfer in human subjects is more difficult to study, but there is evidence of transfer from maternal and fetal hair studies [17].
Organic mercury The most common form of organic mercury is methylmer cury. High levels of methylmercury can accumulate in the muscle of long-living predatory fish that have survived in contaminated waters. The major source of methylmercury in humans is via ingestion of contaminated fish, shellfish and marine mammals [8]. This is most notable in popu lations who rely heavily on fish consumption [19, 25, 38]. Industrial and mining activities have resulted in environ mental hotspots where fish in local waters become heavily contaminated from the excessive levels of methylmercury. Fish containing high levels of methylmercury include shark, swordfish, mackerel and large tuna (http://www. fda.gov/food/resourcesforyou/consumers/ucm110591. htm; accessed 20 December 13). Another significant source of methylmercury exposure may be from electric generation [29].
Metabolism Mercury is not needed in any physiological or biolochemi cal process in humans. Elemental mercury can be inhaled, where around 75–85% absorption occurs. Approximately
10% of ingested inorganic mercury is absorbed. Expo sure to skin can have serious adverse effects. It is elimi nated via the renal system, and toxicity may occur to the kidneys, gastrointestinal tract and central nervous system (CNS) [8]. Organic mercury is efficiently absorbed (95% of ingested methylmercury) from the gastrointestinal tract and extensively distributed throughout the body. Other exposure routes include parenteral, transplacental and via breast milk. Degradation is slow with a half-life of 45–70 days, therefore allowing significant accumulation to occur. Elimination is via the fecal route [8].
Fetal, neonatal and infant consequences Mercury is usually analyzed in blood and hair but is found in many organs.
Scalp hair Scalp hair analysis provides an indication of long-term exposure to mercury. It is possible to use this biopsy material to evaluate the fetal mercury status by coupled cold vapor atomic absorption and inductively coupled plasma mass spectrometry [15]. A UK study reported sig nificantly higher levels of mercury in maternal and fetal hair samples following dental amalgam restorations when compared to women with no dental amalgam [17]. Similar results have also been observed in China [7]. Furthermore, maternal hair mercury levels have been found to correlate with fetal brain levels when studied at autopsy [6]. Maternal hair concentrations of methylmercury posi tively correlate with dietary intake. Indeed, the concentra tion of methylmercury found at varying distances from the root can provide further information; timing, peak and magnitude of exposure can be determined [23].
Blood Mercury levels in the blood can reflect current and recent exposure of both elemental and organic mercury [8]. Blood levels are lower than hair levels, and it may be dif ficult to detect low exposure states. The WHO verified that the “concentration of mercury in hair is approximately 250 times the concentration in blood”. However, this relation ship has shown to vary between populations [18].
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Solan and Lindow, Mercury exposure in pregnancy: a review 727
Cord blood Umbilical cord mercury levels reflect in the in utero exposure of methylmercury during pregnancy. Cordblood mercury concentrations correlate well with fetal brain levels in the final trimester of pregnancy, but levels associated with maternal dietary intake are less sensitive [23]. A study by Mahaffey et al. [18], who investigated the relationship between cord-blood and maternal blood mercury levels, revealed a ratio of 1.7:1 μg/L to exist for the total mercury in cord blood to the total mercury in maternal blood. Thus it would appear that mercury is positively transferred across the placental barrier; however, hair samples indicate a higher concentration in maternal hair [17].
Fetal consequences Many factors determine the severity of adverse health effects caused by mercury. These include the type of mercury concerned, the dose, the developmental stage of the individual fetus exposed, the duration of exposure and the route of exposure [34]. All forms of mercury can lead to maternal and fetal toxicity, as it is distributed to many tissues and ultimately poses risk to multiple systems. The main forms of toxicity include neurotoxicity, nephrotox icity, teratogenicity, cardiovascular disease and possible carcinogenicity [8]. Mercury in maternal blood is able to cross the pla centa and enter the fetal circulation. Despite mercury being relatively abundant environmentally, the main risk to infants is exposure from contaminated fish in the maternal diet [33]. Trans-placental transfer of mercury offers the greatest risk to the fetus. The most recent evaluation of the ratio between cord-blood and maternal-blood mercury concen trations indicates that, on average, the concentration of mercury is 70% higher in the cord blood than in the mater nal blood [18]. This study suggests that levels of total blood mercury ≥ 3.5 μg/kg could increase the risk of adverse effects on the fetal nervous system. Further support of these detrimental effects comes from Kuntz et al. [16] who demonstrated a positive correlation between maternal and cord blood levels of mercury and the rate of stillbirths and birth defects. Similarly, a meta-analysis from China [11] reported that occupational exposure to mercury could cause menstrual dysfunction and adverse reproductive outcomes including pregnancy-induced hypertension, stillbirth, low birth weight and birth defects. However, a
contrary view is expressed by Brodsky et al. [3] who did not find any increased rates of miscarriage or birth defects in occupationally exposed dental assistants when com pared to the wives of dental surgeons. Evidence of significant harm comes from acute highlevel exposure. Two major incidents are known to have occurred whereby high levels of mercury exposure in pregnant women have resulted in significant neurologi cal findings in their offspring. Firstly, in Minamata Bay, Japan, between 1932 and 1968, a large-scale factory began discharging chemical waste high in methylmercury into the bay. Fish bioconcentrated the methylmercury, and maternal consumption resulted in elevated blood levels of the toxicant. Mothers remained unaffected by the poison ing, but their children were born with severe disabilities including microcephaly, cerebral palsy, severe mental retardation, seizure disorders, blindness, deafness and other malformations [35, 37]. Secondly, in Iraq, children were exposed in utero following maternal consumption of methylmercury-treated seed grain, which was made into bread. Significant delays in developmental milestones were later reported and found to correlate strongly with mercury levels in maternal hair [20, 27].
Developmental neurotoxicity The fetal nervous system is much more sensitive to the effects of methylmercury than that of an adult. The in utero exposure can cause irreversible damage to the CNS [8]. Toxicodynamic studies have shown methylmercury to impede nerve cell division and migration by binding to microtubules that are critical for the normal neuronal development. Methylmercury has also been shown to bind to and distort vital structures such as DNA and RNA [5]. Three cohort studies carried out in the Faroe Islands, New Zealand and the Republic of Seychelles have inves tigated prenatal methylmercury exposure from contami nated fish. Each of these studies measured maternal hair mercury concentrations, which were 4.3, 8.3 and 5.8 μg/g, respectively [23, 33]. The Faroe Islands study demon strated both neuropsychological and neurophysiological dysfunctions including deficits in language, attention and memory, as well as delayed brainstem evoked potentials and decreased autonomic heart rate variability, which were all thought to be associated with the in utero expo sure to methylmercury [13, 21]. Similarly, the New Zealand study reported significant fetal neurotoxicity associated with maternal consumption of seafood. However, the Seychelles Island study did not report any significant risks of neurodevelopmental damage due to prenatal
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728 Solan and Lindow, Mercury exposure in pregnancy: a review methylmercury exposure [12, 22]. The levels found in the three studies are higher than the levels in pregnant women in the UK by a factor of 8- to 40-fold approximately. The relationship between prenatal methylmercury exposure and IQ deficits in children has also been reported [2, 4, 9]. Each of these studies found a positive correla tion between maternal hair mercury concentrations and reduction in infant IQ. The most recent meta-analysis by Axelrad et al. [2] in 2007 incorporated information from all three of the cohort studies and reported a linear relation ship between 1 μg/g increase in maternal hair mercury concentration and 0.18 decrease in IQ.
Infant consequences Studies have also suggested that the cardiovascular system may be at risk. A study of the Faroese cohort reported sig nificant increases in systolic and diastolic blood pressures at age 7 years when cord-blood levels of methylmercury were elevated [28]. However, at 14 years, there was no association between cord-blood levels and raised blood pressure. Furthermore, heart rate variability has shown to decrease as methylmercury exposure increases. This was found to be consistent at both 7- and 14-year follow-ups. However, the impact of this on future disease remains uncertain [14]. Children who inhale mercury vapor or have skin contact with elemental or inorganic mercury can develop a toxic reaction known as acrodynia. Acrodynia is char acterized by irritability, polyneuritis and a pink discol oration of the hands and feet. Although this is a rare idiosyncratic reaction, it can be very distressing for the
infant (http://www.t3db.org/toxins/T3D0349?; accessed 20 December 13).
Guidelines The WHO has addressed the safety issues and provided recommendations: “The provisional tolerable weekly intake (PTWI) of methylmercury is 1.6 μg/kg body weight based on assessment of results from various epidemiologi cal studies involving fish-eating populations and develop mental neurotoxicity”. The FDA has advised that pregnant females, nursing mothers and young children avoid the consumption of shark, swordfish, king mackerel and tile fish owing to elevated levels of methylmercury [10].
Conclusions Mercury exposure in pregnancy has been associated with both pregnancy complications and developmental prob lems in infants. Apart from industrial accidents and con taminated food, mercury exposure is likely to arise from predatory fish consumption, environmental contamina tion and dental amalgam restorations placed before or during pregnancy. It would be prudent to recommend that pregnant women avoid these potential problems and minimize any risk. The available literature indicates a linear relation ship with mercury levels and IQ deficit, and therefore a safe limit of mercury cannot be calculated. Received December 24, 2013. Accepted March 6, 2014. Previously published online April 3, 2014.
References [1] Abraham J, Svare C, Frank C. The effect of dental amalgam restorations on blood mercury levels. J Dent Res. 1984; 63:71–3. [2] Axelrad DA, Bellinger DC, Ryan LM, Woodruff TJ. Dose–response relationship of prenatal mercury exposure and IQ: an integrative analysis of epidemiologic data. Environ Health Perspect. 2007;115:609–15. [3] Brodsky J, Cohen E, Whitcher C, Brown B, Wu M. Occupational exposure to mercury in dentistry and pregnancy outcome. J Am Dent Assoc. 1985;111:779–80. [4] Budtz-Jorgensen E, Debes F, Weihe P, Grandjean P. Adverse mercury effects in 7 year-old children as expressed as loss in “IQ.” Odense: University of Southern Denmark; 2004. [5] Casarett and Doull. Toxicology. The basic science of poisons, 8th ed, McGraw Hill Education: New York; 2013.
[6] Cernichiari E, Brewer R, Myers GJ, Marsh DO, Lapham LW, Cox C, et al. Monitoring methylmercury during pregnancy: maternal hair predicts fetal brain exposure. Neurotoxicology 1994;16:705–10. [7] Chai Z, Feng W, Qian Q, Guan M. Correlation of mercury with selenium in human hair at a typical mercury-polluted area in China. Biol Trace Elem Res. 1998;63:95–104. [8] Clarkson TW, Magos L. The toxicology of mercury and its chemical compounds. Crit Rev Toxicol. 2006; 36:609–62. [9] Cohen JT, Bellinger DC, Connor WE, Shaywitz BA. A quantitative analysis of prenatal intake of n-3 polyunsaturated fatty acids and cognitive development. Am J Prev Med. 2005b;29:366–74. [10] FDA. What you need to know about mercury in fish and shellfish. Silver Spring, MD: FDA; 2004.
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Solan and Lindow, Mercury exposure in pregnancy: a review 729 [11] Fok TF, Lam HS, Ng PC, Yip AS, Sin NC, Chan IH, et al. Fetal methylmercury exposure as measured by cord blood mercury concentrations in a mother–infant cohort in Hong Kong. Environ Int. 2007;33:84–92. [12] Grandjean P, Landrigan PJ. Developmental neurotoxicity of industrial chemicals. Lancet 2006;368:2167–78. [13] Grandjean P, Weihe P, White RF, Debes F, Araki S, Yokoyama K, et al. Cognitive deficit in 7 year old children with prenatal exposure to methylmercury. Neurotoxicol Teratol. 1997; 19:417–28. [14] Grandjean P, Murata K, Budtz-Jorgensen E, Weihe P. Cardiac autonomic activity in methylmercury neurotoxicity: 14-year follow-up of a Faroese birth cohort. J Pediatr. 2004;144:169–76. [15] Knight R, Haswell SJ, Lindow SW, Batty J. Determination of mercury in hair by coupled CVAA-ICP-MS. J Anal At Spectrom. 1999;14:127–9. [16] Kuntz WD, Pitkin R, Bostrom A, Hughes M. Maternal and cord blood background mercury levels: a longitudinal surveillance. Am J Obstet Gynecol. 1982;143:440–3. [17] Lindow SW, Knight R, Batty J, Haswell SJ. Maternal and neonatal hair mercury concentrations: the effect of dental amalgam. Br J Obstet Gynecol. 2003;110:287–91. [18] Mahaffey KR, Clickner RP, Bodurow CC. Blood organic mercury and dietary mercury intake: National Health and Nutrition Examination Survey, 1999 and 2000. Environ Health Perspect. 2004;112:562. [19] Mahaffey KR, Clickner RP, Jeffries RA. Methylmercury and omega-3 fatty acids: co-occurrence of dietary sources with emphasis on fish and shellfish. Environ Res. 2008;107:20–9. [20] Marsh DO, Myers GJ, Clarkson TW, Amin-Zaki L, Tikriti S, Majeed MA. Fetal methylmercury poisoning: clinical and toxicological data on 29 cases. Ann Neurol. 1980;7:348–53. [21] Murata K, Weihe P, Araki S, Budtz-Jørgensen E, Grandjean P. Evoked potentials in Faroese children prenatally exposed to methylmercury. Neurotoxicol Teratol. 1999;21:471–2. [22] Myers GJ, Davidson PW, Cox C, Shamlaye CF, Palumbo D, Cernichiari E, et al. Prenatal methylmercury exposure from ocean fish consumption in the Seychelles child development study. Lancet 2003;361:1686–92. [23] NRC. Toxicological effects of methylmercury. Washington, DC: National Academy Press; 2000. [24] Pacyna EG, Pacyna J, Sundseth K, Munthe J, Kindbom K, Wilson S, et al. Global emission of mercury to the atmosphere from anthropogenic sources in 2005 and projections to 2020. Atmos Environ. 2010;44:2487–99.
[25] Phelps RW, Clarkson TW, Kershaw TG, Wheatley B. Interrelationships of blood and hair mercury concentrations in a North American population exposed to methylmercury. Arch Environ Health. 1980;35:161–8. [26] Pirrone N, Cinnirella S, Feng X, Finkelman R, Friedli H, Leaner J, et al. Global mercury emissions to the atmosphere from anthropogenic and natural sources. Atmos Chem Phys. 2010;10:5951–64. [27] Satoh H. Occupational and environmental toxicology of mercury and its compounds. Ind Health. 2000;38:153–64. [28] Sørensen N, Murata K, Budtz-Jorgensen E, Weihe P, Grandjean P. Prenatal methylmercury exposure as a cardiovascular risk factor at seven years of age. Epidemiology 1999;10:370–5. [29] Trasande L, Landrigan PJ, Schechter C. Public health and economic consequences of methyl mercury toxicity to the developing brain. Environ Health Perspect. 2005;113:590. [30] United Nations Environment Programme. Global Mercury Assessment. Chemicals, Geneva, Switzerland: United Nations; 2002. [31] Vimy MJ, Takahashi Y, Lorscheider FL. Maternal-fetal distribution of mercury (203Hg) released from dental amalgam fillings. Am J Physiol. 1990;258:R939–45. [32] Warkany J, Hubbard DM. Acrodynia and mercury. J Pediatr. 1953;42:365–86. [33] WHO. Safety evaluation of certain food additives and contaminants. Geneva, Switzerland: WHO; 2004. [34] WHO. Mercury and health. Fact sheet. Geneva, Switzerland: WHO; September 2013. [35] WHO. Mercury: training for healthcare providers. Children’s health and the environment. Geneva, Switzerland: WHO; 2008. [36] Wild J, Metters J. Dental amalgam. London: Department of Health Child Dental Officer; 1998. [37] Yorifuji T, Tsuda T, Takao S, Harada M. Long-term exposure to methylmercury and neurologic signs in Minamata and neighboring communities. Epidemiology 2008;19:3–9. [38] Zhang Y, Nakai S, Masunaga S. An exposure assessment of methyl mercury via fish consumption for the Japanese population. Risk Analysis. 2009;29:1281–91.
The authors stated that there are no conflicts of interest regarding the publication of this article.
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Review article Tom Daniel Solan and Stephen W. Lindow*
Mercury exposure in pregnancy: a review Abstract: Mercury exposure in pregnancy has been asso ciated with both pregnancy complications and devel opmental problems in infants. Apart from industrial accidents and contaminated food, mercury exposure is likely to arise from predatory fish consumption, environ mental contamination and dental amalgam restorations placed before or during pregnancy. It would be prudent to recommend that pregnant women avoid these potential problems and minimize any risk. The available literature indicates a linear relationship with mercury levels and IQ deficit, and therefore a safe limit of mercury cannot be calculated. Keywords: Mercury; pregnancy; pregnancy outcome. *Corresponding author: Stephen W. Lindow, Hull York Medical School, Women and Children’s Hospital, Hull Royal Infirmary Anlaby Road Hull, HU3 2JZ, UK, Tel.: +44 1482 607830, Fax: +44 1482 382781, E-mail: [email protected] Tom Daniel Solan: Hull York Medical School, Loxley Building, University of Hull, Cottingham Road, Hull, HU6 7RX, UK
Overview The toxicity to humans from mercury ingestion has been observed for hundreds of years. The phrase “mad as a hatter” comes from the neurological effects suffered by hat makers who were chronically exposed to mercury. Over time, several incidents involving mercury exposure have occurred, which have resulted in significant effects on the human population. In the 1900s, reports of acro dynia (pink disease) [32] in children were thought to be linked to the use of teething powders and ointments con taining mercurous chloride, and in the 1950s, industrial releases of mercury in Japan resulted in significant neu rotoxicity to the infants exposed in utero. More recently, concern has increased surrounding the pervasive nature of mercury in the environment and its effect on fetal development reported at low levels of exposure. More over, there is controversy in the literature regarding the true toxic effects of mercury exposure during pregnancy
and the perinatal period. This review aims to provide an up-to-date overview of the available evidence surround ing these issues.
Chemistry Mercury is a naturally occurring element found in water, air and soil. It exists in three main forms: elemental, inor ganic (e.g., mercuric chloride) and organic (e.g., methyl mercury) (http://www.who.int/phe/news/Mercury-flyer. pdf; accessed 20 December 13). It is released into the environment from volcanic activity, weathering of rocks and as a result of human activity [34]. Human activity such as coal-fired power stations, cement production and industrial processes accounts for 30% of mercury release [26]. Once in the environment, liquid mercury vaporizes and stays in the atmosphere for up to 1 year, where it can be deposited globally. It settles in lakes, rivers and bays, where it is transformed by aquatic microorganisms into methylmercury [34]. Methylmercury exists in most sea species and bioaccumulates in the aquatic food chain, reaching highest concentrations in large predatory fish.
Exposure Elemental and inorganic mercury Exposure to elemental mercury can occur in a number of ways including volcanic explosions, combustion pro cesses, gold mining, dental amalgam restorations and han dling of sphygmomanometers and fluorescent lights [30]. The major route of exposure is via inhalation of mercury vapor, but mercury can also be absorbed cutaneously [8]. Adverse effects of mercury exposure have been observed in dental workers, miners and industrial workers, among others. A major concern in developing countries is that uncontrolled working conditions in small-scale mining activities can lead to extremely high levels of mercury vapor exposure. It is estimated that these activities release
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726 Solan and Lindow, Mercury exposure in pregnancy: a review up to 1000 tons of mercury into the environment where up to 15 million people work [24]. The use of dental amalgam is a potential significant source of exposure as it can contain up to 50% elemen tal mercury (http://www.who.int/phe/news/Mercuryflyer.pdf) [2]. This issue is controversial, and the advice from the British Dental Association [36] is “to avoid where clinically reasonable, the placement or removal of amalgam fillings during pregnancy”. Despite this advice, there is no available evidence of links between the use of dental amalgam and birth defects or still births. Dental amalgam restorations lead to inhalation of mercury vapor, which is oxidized to its inorganic form, Hg2+, and appears in the blood. Mercury concentrations in the blood have shown to positively correlate with the number and surface area of amalgam restorations and are significantly higher when compared to those without dental amalgam [1, 17]. Animal research has shown that mercury from dental amalgam restorations is able to cross the placenta in sheep and accumulate in fetal tissues to achieve a steady state with advancing gesta tion [31]. Placental transfer in human subjects is more difficult to study, but there is evidence of transfer from maternal and fetal hair studies [17].
Organic mercury The most common form of organic mercury is methylmer cury. High levels of methylmercury can accumulate in the muscle of long-living predatory fish that have survived in contaminated waters. The major source of methylmercury in humans is via ingestion of contaminated fish, shellfish and marine mammals [8]. This is most notable in popu lations who rely heavily on fish consumption [19, 25, 38]. Industrial and mining activities have resulted in environ mental hotspots where fish in local waters become heavily contaminated from the excessive levels of methylmercury. Fish containing high levels of methylmercury include shark, swordfish, mackerel and large tuna (http://www. fda.gov/food/resourcesforyou/consumers/ucm110591. htm; accessed 20 December 13). Another significant source of methylmercury exposure may be from electric generation [29].
Metabolism Mercury is not needed in any physiological or biolochemi cal process in humans. Elemental mercury can be inhaled, where around 75–85% absorption occurs. Approximately
10% of ingested inorganic mercury is absorbed. Expo sure to skin can have serious adverse effects. It is elimi nated via the renal system, and toxicity may occur to the kidneys, gastrointestinal tract and central nervous system (CNS) [8]. Organic mercury is efficiently absorbed (95% of ingested methylmercury) from the gastrointestinal tract and extensively distributed throughout the body. Other exposure routes include parenteral, transplacental and via breast milk. Degradation is slow with a half-life of 45–70 days, therefore allowing significant accumulation to occur. Elimination is via the fecal route [8].
Fetal, neonatal and infant consequences Mercury is usually analyzed in blood and hair but is found in many organs.
Scalp hair Scalp hair analysis provides an indication of long-term exposure to mercury. It is possible to use this biopsy material to evaluate the fetal mercury status by coupled cold vapor atomic absorption and inductively coupled plasma mass spectrometry [15]. A UK study reported sig nificantly higher levels of mercury in maternal and fetal hair samples following dental amalgam restorations when compared to women with no dental amalgam [17]. Similar results have also been observed in China [7]. Furthermore, maternal hair mercury levels have been found to correlate with fetal brain levels when studied at autopsy [6]. Maternal hair concentrations of methylmercury posi tively correlate with dietary intake. Indeed, the concentra tion of methylmercury found at varying distances from the root can provide further information; timing, peak and magnitude of exposure can be determined [23].
Blood Mercury levels in the blood can reflect current and recent exposure of both elemental and organic mercury [8]. Blood levels are lower than hair levels, and it may be dif ficult to detect low exposure states. The WHO verified that the “concentration of mercury in hair is approximately 250 times the concentration in blood”. However, this relation ship has shown to vary between populations [18].
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Solan and Lindow, Mercury exposure in pregnancy: a review 727
Cord blood Umbilical cord mercury levels reflect in the in utero exposure of methylmercury during pregnancy. Cordblood mercury concentrations correlate well with fetal brain levels in the final trimester of pregnancy, but levels associated with maternal dietary intake are less sensitive [23]. A study by Mahaffey et al. [18], who investigated the relationship between cord-blood and maternal blood mercury levels, revealed a ratio of 1.7:1 μg/L to exist for the total mercury in cord blood to the total mercury in maternal blood. Thus it would appear that mercury is positively transferred across the placental barrier; however, hair samples indicate a higher concentration in maternal hair [17].
Fetal consequences Many factors determine the severity of adverse health effects caused by mercury. These include the type of mercury concerned, the dose, the developmental stage of the individual fetus exposed, the duration of exposure and the route of exposure [34]. All forms of mercury can lead to maternal and fetal toxicity, as it is distributed to many tissues and ultimately poses risk to multiple systems. The main forms of toxicity include neurotoxicity, nephrotox icity, teratogenicity, cardiovascular disease and possible carcinogenicity [8]. Mercury in maternal blood is able to cross the pla centa and enter the fetal circulation. Despite mercury being relatively abundant environmentally, the main risk to infants is exposure from contaminated fish in the maternal diet [33]. Trans-placental transfer of mercury offers the greatest risk to the fetus. The most recent evaluation of the ratio between cord-blood and maternal-blood mercury concen trations indicates that, on average, the concentration of mercury is 70% higher in the cord blood than in the mater nal blood [18]. This study suggests that levels of total blood mercury ≥ 3.5 μg/kg could increase the risk of adverse effects on the fetal nervous system. Further support of these detrimental effects comes from Kuntz et al. [16] who demonstrated a positive correlation between maternal and cord blood levels of mercury and the rate of stillbirths and birth defects. Similarly, a meta-analysis from China [11] reported that occupational exposure to mercury could cause menstrual dysfunction and adverse reproductive outcomes including pregnancy-induced hypertension, stillbirth, low birth weight and birth defects. However, a
contrary view is expressed by Brodsky et al. [3] who did not find any increased rates of miscarriage or birth defects in occupationally exposed dental assistants when com pared to the wives of dental surgeons. Evidence of significant harm comes from acute highlevel exposure. Two major incidents are known to have occurred whereby high levels of mercury exposure in pregnant women have resulted in significant neurologi cal findings in their offspring. Firstly, in Minamata Bay, Japan, between 1932 and 1968, a large-scale factory began discharging chemical waste high in methylmercury into the bay. Fish bioconcentrated the methylmercury, and maternal consumption resulted in elevated blood levels of the toxicant. Mothers remained unaffected by the poison ing, but their children were born with severe disabilities including microcephaly, cerebral palsy, severe mental retardation, seizure disorders, blindness, deafness and other malformations [35, 37]. Secondly, in Iraq, children were exposed in utero following maternal consumption of methylmercury-treated seed grain, which was made into bread. Significant delays in developmental milestones were later reported and found to correlate strongly with mercury levels in maternal hair [20, 27].
Developmental neurotoxicity The fetal nervous system is much more sensitive to the effects of methylmercury than that of an adult. The in utero exposure can cause irreversible damage to the CNS [8]. Toxicodynamic studies have shown methylmercury to impede nerve cell division and migration by binding to microtubules that are critical for the normal neuronal development. Methylmercury has also been shown to bind to and distort vital structures such as DNA and RNA [5]. Three cohort studies carried out in the Faroe Islands, New Zealand and the Republic of Seychelles have inves tigated prenatal methylmercury exposure from contami nated fish. Each of these studies measured maternal hair mercury concentrations, which were 4.3, 8.3 and 5.8 μg/g, respectively [23, 33]. The Faroe Islands study demon strated both neuropsychological and neurophysiological dysfunctions including deficits in language, attention and memory, as well as delayed brainstem evoked potentials and decreased autonomic heart rate variability, which were all thought to be associated with the in utero expo sure to methylmercury [13, 21]. Similarly, the New Zealand study reported significant fetal neurotoxicity associated with maternal consumption of seafood. However, the Seychelles Island study did not report any significant risks of neurodevelopmental damage due to prenatal
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728 Solan and Lindow, Mercury exposure in pregnancy: a review methylmercury exposure [12, 22]. The levels found in the three studies are higher than the levels in pregnant women in the UK by a factor of 8- to 40-fold approximately. The relationship between prenatal methylmercury exposure and IQ deficits in children has also been reported [2, 4, 9]. Each of these studies found a positive correla tion between maternal hair mercury concentrations and reduction in infant IQ. The most recent meta-analysis by Axelrad et al. [2] in 2007 incorporated information from all three of the cohort studies and reported a linear relation ship between 1 μg/g increase in maternal hair mercury concentration and 0.18 decrease in IQ.
Infant consequences Studies have also suggested that the cardiovascular system may be at risk. A study of the Faroese cohort reported sig nificant increases in systolic and diastolic blood pressures at age 7 years when cord-blood levels of methylmercury were elevated [28]. However, at 14 years, there was no association between cord-blood levels and raised blood pressure. Furthermore, heart rate variability has shown to decrease as methylmercury exposure increases. This was found to be consistent at both 7- and 14-year follow-ups. However, the impact of this on future disease remains uncertain [14]. Children who inhale mercury vapor or have skin contact with elemental or inorganic mercury can develop a toxic reaction known as acrodynia. Acrodynia is char acterized by irritability, polyneuritis and a pink discol oration of the hands and feet. Although this is a rare idiosyncratic reaction, it can be very distressing for the
infant (http://www.t3db.org/toxins/T3D0349?; accessed 20 December 13).
Guidelines The WHO has addressed the safety issues and provided recommendations: “The provisional tolerable weekly intake (PTWI) of methylmercury is 1.6 μg/kg body weight based on assessment of results from various epidemiologi cal studies involving fish-eating populations and develop mental neurotoxicity”. The FDA has advised that pregnant females, nursing mothers and young children avoid the consumption of shark, swordfish, king mackerel and tile fish owing to elevated levels of methylmercury [10].
Conclusions Mercury exposure in pregnancy has been associated with both pregnancy complications and developmental prob lems in infants. Apart from industrial accidents and con taminated food, mercury exposure is likely to arise from predatory fish consumption, environmental contamina tion and dental amalgam restorations placed before or during pregnancy. It would be prudent to recommend that pregnant women avoid these potential problems and minimize any risk. The available literature indicates a linear relation ship with mercury levels and IQ deficit, and therefore a safe limit of mercury cannot be calculated. Received December 24, 2013. Accepted March 6, 2014. Previously published online April 3, 2014.
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The authors stated that there are no conflicts of interest regarding the publication of this article.
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