Nitrate, Nitrite, Nitrosatable Drugs, and Congenital Malformations

C H A P T E R

6 Nitrate, Nitrite, Nitrosatable Drugs, and Congenital Malformations Jean D. Brender, PhD, RN, FACE Texas A&M Health Science Center, College Station, Texas, USA

INTRODUCTION

MATERNAL EXPOSURES TO NITRATE, NITRITE, AND N-NITROSO COMPOUNDS

Congenital malformations remain the greatest contributor to infant mortality in the United States [1] and other developed countries [2]. In 2010, 5107 US children under 1 year of age died from birth defects, accounting for 20.8% of infant deaths [3]. During the same year, approximately 394,000 discharges of newborns from short-stay hospitals were attributed to congenital malformations [4]. About 3% of births in the United States have major structural or genetic birth defects [5]; yet, causes are unknown for an estimated 65 to 75% of these defects [6]. Numerous epidemiologic studies have explored the potential risk factors of birth defects, including prenatal use of medications, patterns of maternal dietary intake, and maternal exposures to environmental contaminants. This chapter will focus on the potential separate and combined effects of nitrosatable drugs, dietary intake of nitrate and nitrite, and exposure to nitrate in drinking water on the risk of congenital malformations. N-nitroso compounds are known to cause congenital malformations in animal models [7,8], and these compounds can be formed in the human stomach after ingestion of nitrosatable compounds in conjunction with nitrate or nitrite [9,10]. In this chapter, the following will be discussed: (1) sources of exposure to nitrate, nitrite, and N-nitroso compounds; (2) the characteristics of nitrosatable drugs and their potential role in birth defects; (3) the role that endogenous formation of N-nitroso compounds might have in the risk of birth defects; and (4) the experimental and epidemiologic evidence regarding vitamin C as an inhibitor of the formation of endogenous N-nitroso compounds.

Various dietary components contribute to exogenous exposure to nitrate, nitrite, and N-nitroso compounds, although drinking water sources may also be a major contributor of daily nitrate intake if levels are high in the water supplies [11,12]. Estimates of daily nitrate intake from the dietary sources range from 31 mg in Norway to 245 mg in Italy [13], with vegetables contributing the largest proportion of daily intake [14,15]. In a study using control mothers from the National Birth Defects Prevention Study (NBDPS), one of the largest population-based, case-control studies conducted on the etiology of birth defects, Griesenbeck et al. [16] observed a median intake of 40.5 mg/day of nitrate from dietary sources. In this study population, vegetables contributed an estimated 50 to 75% of daily intake of nitrate from the diet, depending on the mother’s race/ethnicity. In an earlier report, the National Academy of Sciences (NAS) [17] concluded that 87% of dietary nitrate was from vegetables. Nitrate content varies considerably in vegetables with asparagus, broccoli, carrots, peppers, and tomatoes containing less than 50 mg/100 g, to celery, lettuce, radishes, and spinach containing more than 250 mg/100 g nitrate (fresh weight) [18,19]. Nitrate is the most widespread chemical contaminant in aquifers around the world [20]. Generally, water nitrate contributes only a small percentage of total daily nitrate intake unless levels approach or exceed the allowable maximum contaminant level (MCL) [17]. The U.S. Environmental Protection Agency (EPA) has set the MCL for nitrate in public water supplies at 10 mg/L nitratenitrogen (45 mg/L total nitrate) primarily to protect

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62 6.  Nitrate, Nitrite, Nitrosatable Drugs, and Congenital Malformations against methemoglobinemia in infants (“blue-baby syndrome”) [21]. Agricultural populations, who often obtain their drinking water from private wells, are more likely to be exposed to elevated levels of nitrate in drinking water than urban populations with an estimated 22% of domestic wells in US agricultural areas exceeding 10 mg/L nitrate-nitrogen [22]. Cured meats and baked goods and cereals contribute most of the dietary nitrite intake with drinking water being a negligible source [17]. However, the endogenous conversion of nitrate to nitrite is also a significant source of exposure to nitrite; an estimated 5% of ingested nitrate in food and water are converted to nitrite in the saliva [23]. Once ingested and absorbed, approximately 25% of nitrate is secreted in saliva [24], where about 20% is converted to nitrite by bacteria in the mouth [25]. The National Academy of Sciences estimated that 47% of dietary nitrite was from meat, with cured meat providing most of this contribution (39%), 34% from baked goods and cereals, 16% from vegetables, and 3% from other sources [17]. In contrast, relative contributions of nitrite in the NBDPS participants’ diets included 61% from meat, 12% from grain products, 11% from vegetables, and 16% from other foods [16]. Humans are exposed to N-nitroso compounds from exogenous sources and through endogenous formation. Exogenous sources include cured meats and smoked fish [12], beer [26], tobacco products and tobacco smoke [27,28], cosmetics [29,30], and occupational exposures in rubber or rocket fuel factories and leather tanneries [17]. Endogenous formation of nitrosamines contributes 40 to 75% of exposure to these compounds in humans [31], and the formation depends on precursors such as nitrate, nitrite, and secondary/tertiary amines and amides. After several decades of research on nitrosation and N-nitroso compounds, Lijinsky concluded that “any circumstance in which a nitrosating agent and a nitrosatable amino compound come in contact is a potential source of ­N-nitroso compounds” [32]. Extensive experimental evidence indicates that N-­ nitroso compounds can be formed in vivo via the reaction of nitrosatable amines or amides and nitrosating agents, such as nitrite, in an acidic environment as found in the stomach [33]. Endogenous formation of these compounds can also occur through cell-mediated nitrosation with stimulated macrophages [34] and with some bacterial strains of Alcaligenes, Bacillus, Escherichia, Klebsiella, Neisseria, Proteus, and Pseudomonas that are capable of catalyzing the nitrosation of secondary amines [31]. A ­variety of drugs contribute nitrosatable amines or amides in the endogenous formation of N-nitroso compounds. In experiments with simulated gastric conditions, the combination of drugs containing secondary or tertiary amines or amides with nitrite have yielded a range of N-nitroso compounds depending on the chemical

s­tructure of the drug [10,35,36]. These drugs will be ­discussed in more detail in the next section of this chapter. Other significant sources of nitrosatable amino compounds include certain foods and beverages (fish, pork, cereals, spices, coffee, tea, beer, wine), cosmetics, tobacco products, and agricultural chemicals [17].

NITROSATABLE DRUGS AND BIRTH DEFECTS Some drugs are capable of reacting with nitrite in an acidic environment, such as in the stomach, to form Nnitroso compounds [37]. These drugs include secondary amines, tertiary amines, and amides. Early epidemiologic studies of maternal exposure to nitrosatable drugs and birth defects in offspring focused on these drugs as a single group [38–42], but more recent studies have examined the separate associations of amides and secondary or tertiary amines [43,44]. Prenatal exposure to these drugs in relation to childhood cancer has also been investigated [45–48]. Estimates of prevalence of nitrosatable drug exposure during pregnancy have varied across these studies. Olshan and Faustman [42] published one of the first studies on nitrosatable drug use during pregnancy in which they identified a total of 13 drug components deemed to have nitrosation potential. Among 51,228 pregnancies followed between 1959 and 1965 as part of the U.S. National Collaborative Perinatal Project, 3.5% of mothers used nitrosatable drugs during the first four months of pregnancy and 11.8% took these drugs anytime during pregnancy. In a population-based casecontrol study of childhood brain cancer that included study participants in eight U.S. states, an estimated 5% of control mothers took nitrosatable drugs anytime during pregnancy; medications taken included 24 different nitrosatable components [46]. Three subsequent case-control studies of the relation between prenatal nitrosatable drug exposure and childhood cancer used a broader classification scheme for nitrosatable drugs. Classification with respect to nitrosatability was based on published experimental data or chemical structure [45,47,48]. Prevalence of any nitrosatable drug use among control mothers anytime during pregnancy ranged from 14.9 to 18.4%, but prevalence of use during the first trimester was not reported. Two of these studies also reported prevalence of nitrosatable intake by molecular structure including 7.5–9% for secondary amines, 10–13% for tertiary amines, and 2.5–3% for amides [45,48]. Using data from the NBDPS for births occurring from 1997 to 2005, Brender et al. [49] studied the prevalence and patterns of nitrosatable drug use among study controlmothers who were representative of the base populations in their respective states of residence. In this project, the

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Nitrosatable drugs and birth defects

investigators classified drugs reported taken according to their nitrosatability using the following procedures. First, all orally administered prescription and nonprescription medications reported by control participants and the active drug components in each were identified, including orally inhaled medications (e.g., albuterol, epinephrine) that might be swallowed. The resulting group of active ingredients was cross-referenced against previously compiled lists of nitrosatable medicinal compounds [37,48] and categorized based on the presence of amine (secondary and tertiary) and amide functional groups in their chemical structure. Finally, each component was categorized by its primary indication or therapeutic use (e.g., analgesic, anti-infective) and pharmacologic class (e.g., opioid, macrolide). In this study population, approximately 24% of the control mothers took any nitrosatable drug during the first trimester, including 12.4, 12.2, and 7.6% who took secondary amines, tertiary amines, and amides, respectively [49]. Table 6.1 shows the 10 most commonly taken nitrosatable drugs by the NBDPS control mothers. Five tertiary amines (promethiazine, dextromethorphan, diphenydramine, chlorpheniramine, doxylamine, and caffeine [also classified as an amide]), three secondary amines (pseudoephedrine, albuterol, and fluoxetine), and two amides (amoxicillin and caffeine [also a tertiary amine]) were included on this list. These drugs represented a wide variety of therapeutic indications, including asthma, antidepressant, anti-infective, anti-emetic, antihistamine, cough suppressant, decongestant, and stimulant medications. It is noteworthy that four of the five most commonly taken drugs classified as nitrosatable tertiary amines are also available over the counter. The number of identified nitrosatable drugs in this study was much higher than

other studies on the relation between prenatal nitrosatable drug exposure and birth defects with 24 secondary amine components, 51 tertiary amine components, and 22 amide components detected [49]. Between 1989 and 2014, seven epidemiologic studies were published on the relation between maternal exposure to nitrosatable drugs and birth defects in offspring. Table 6.2 summarizes the characteristics and major findings of each of these studies. Olshan and Faustman [42] studied the association between ingestion of nitrosatable drugs during the first four months and anytime during pregnancy and adverse reproductive outcomes including congenital malformations; low birth weight; 5-min Apgar score; fetal, neonatal, and infant death; neurological abnormalities at the end of seven years; and childhood tumors among offspring of women in the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke. Relative to women not taking these drugs, women who took nitrosatable drugs during the first four months of pregnancy were more likely to have infants with eye (relative risk [RR] 2.71, 95% CI 1.43, 5.15), musculoskeletal (RR 1.33, 95% CI 1.05, 1.70), or gastrointestinal abnormalities (RR 1.68, 95% CI 1.19, 2.35); ­hydrocephaly (RR 1.99, 95% CI 0.47, 8.49); spina bifida (RR 4.58, 95% CI 0.66, 31.62); or children who subsequently developed tumors (RR 2.29, 95% CI 0.99, 5.26). Because of the small number of women exposed and the relatively rare occurrence of specific malformations, some of the data did not yield stable risk estimates for individual defects, and the 95% confidence intervals (CI) for several of the risk estimates included 1.0. Gardner et al. [40] studied the effect of prenatal drug exposures on the risk for craniosynostosis in offspring

TABLE 6.1 Ten Most Commonly Used Nitrosatable Drug Components During the First Trimester of Pregnancy, NBDPS Control Women, 1997–2005 Rank

Nitrosatable drug component

Type of molecular structure

Number

%*

1

Pseudoephedrine

Secondary amine

515

7.7

2

Amoxicillin

Amide

271

4.0

3

Promethiazine

Tertiary amine

207

3.1

4

Albuterol

Secondary amine

178

2.7

5

Dextromethorphan

Tertiary amine

139

2.1

6

Diphenydramine

Tertiary amine

115

1.7

7

Chlorpheniramine

Tertiary amine

104

1.6

8

Doxylamine

Tertiary amine

82

1.2

9

Caffeine

Amide/tertiary amine

64

1.0

10

Fluoxetine

Secondary amine

53

0.8

* Complete information available for 6678 women for any secondary amines, 6708 women for any tertiary amines, and 6701 women for any amides. Adapted from Ref. [49].

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64 6.  Nitrate, Nitrite, Nitrosatable Drugs, and Congenital Malformations TABLE 6.2 Epidemiologic Studies of Prenatal Nitrosatable Drug Exposure and Birth Defects in Offspring Study design regional description

Years of outcome ascertainment

Brender, 2004, USA [38]

Population-based case-control study 14 Texas counties bordering Mexico

1995–2000

All medications reported taken three months before and after conception classified with respect to nitrosatability based on literature

NTDs

Adjusted OR for NTDs in relation to any nitrosatable drug exposure during the periconceptional period: 2.7 (95% CI 1.4, 5.3)

Brender, 2011, USA [43]

Population-based case-control study NBDPS in 10 states

1997–2005

All medications reported taken one month before and after conception classified with respect to nitrosatability based on literature and further classified by molecular structure

NTDs, grouped and specific ­phenotypes

OR for any neural tube defect with any nitrosatable drug exposure: 1.31 (95% CI 1.12, 1.55) and stronger association noted for tertiary amines (OR 1.60, 95% CI 1.31, 1.95). Strongest association noted between anencephaly and tertiary amine drug exposure (OR 1.96, 95% CI 1.40, 2.73)

Brender, 2012, USA [44]

Population-based case-control study NBDPS in 10 states

1997–2005

All medications reported taken the first trimester classified with respect to nitrosatability based on literature and further classified by molecular structure

Limb deficiencies, oral clefts, and congenital heart malformations

Limb deficiencies significantly associated with prenatal exposure to secondary amines Selected congenital heart defects associated with secondary and tertiary amine and amide drugs

Croen, 2001, USA [39]

Population-based case-control study California

1989–1991

Drugs taken in early pregnancy classified according to potential for nitrosatability based on method of Olshan and Faustman [42]

NTDs

OR of NTDs in relation to any nitrosatable drug exposure during periconceptional period: 1.2 (95% CI 0.77, 1.8)

Gardner, 1998, USA [40]

Population-based case-control study Colorado

1986–1989

Used Olshan and Faustman [42] list of 13 nitrosatable drugs; study participants reported taking three of these drugs

Craniosynostosis

OR of 1.87 (95% CI 1.08, 3.24) for sagittal/ lambdoid suture synostosis with prenatal exposure to nitrosatable drugs chlorpheniramine, chlordiazepoxide, and nitrofurantoin

Kallen, 2005, Sweden and France [41]

Two case-control studies; all deliveries in Sweden and Central-East France

1995–2002 (Sweden); 1980–2002 (France)

Examined exposure to the three nitrosatable drugs identified by Gardner et al. [40] (chlorpheniramine, chlordiazepoxide, and nitrofurantoin)

Craniostenosis

With Swedish data, risk ratio of 3.4 (95% CI 1.10, 7.94) in conjunction with three nitrosatable drugs; no such exposure occurred in French study population

Olshan, 1989, USA [42]

Prospective cohort study National Collaborative Perinatal Project in which women were recruited in 12 study centers

1959–1965

Examined exposure to 13 nitrosatable drugs identified in the literature

Any congenital malformations

RRs increased for several birth defects with exposure to drugs within first four months of pregnancy, including spina bifida and eye, musculoskeletal, and gastrointestinal defects

First author, year, country

Exposure description

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Birth defects included

Summary of findings



Nitrate in drinking water and birth defects

i­ncluding exposures to nitrosatable drugs. Women who took any nitrosatable drug (limited to three, including chlorpheniramine, chlordiazepoxide, and nitrofurantoin), as classified by Olshan and Faustman [42], were more likely to give birth to infants with sagittal/lambdoid suture synostosis (odds ratio [OR] 1.87, 95% CI 1.08, 3.24) than women who did not report taking these drugs. However, when the investigators examined all potentially nitrosatable drugs taken by the women, no association was seen between the larger group of compounds and any type of craniosynostosis. In a study of Swedish women and their offspring, Kallen and Robert-Gnansia [41] also noted an association (OR 3.4, 95% CI 1.1, 7.9) between craniostenosis and maternal exposure to the three nitrosatable drugs that Gardner et al. identified in their study. In a study published in 2001, Croen et al. [39] used the Olshan and Faustman list to classify women’s exposure to nitrosatable drugs in a study of neural tube defects (NTDs). No association (OR 1.2, 95% CI 0.77, 1.8) was found between periconceptional exposure with these drugs and NTDs in the offspring of California women giving birth during 1989–1991. On the other hand, Brender et al. [38] found a significant positive association between the reported use of drugs with potential for nitrosation and NTDs in offspring among Mexican-American women who resided in one of the 14 Texas counties bordering Mexico (OR 2.7, 95% CI 1.4, 5.3). None of these studies examined nitrosatable drugs by their molecular structures (e.g., secondary or tertiary amines, amides) in relation to birth defects, and most focused on the list of 13 nitrosatable drugs that Olshan and Faustman compiled from drugs reported taken by US women who gave birth during 1959–1965, over 45 years ago. Using more recent data from the NBDPS that included women giving birth during 1997 through 2005, Brender et al. [43,44] examined the relation between nitrosatable drug use in early pregnancy and selected birth defects in offspring. As described earlier, nitrosatable drugs were classified with respect to their molecular structure as well as for therapeutic indications and pharmacologic class. For NTDs, the investigators defined the exposure window of interest for nitrosatable drugs as one month prior to one month postconception. Women with NTD-affected pregnancies were more likely (19.5%) than control-mothers of babies with no major birth defects (16.9%) to report taking drugs classified as nitrosatable during this period (adjusted OR 1.31, 95% CI 1.12, 1.55) [43]. All ORs in this study were adjusted for maternal race/ethnicity, educational level, and folic acid supplementation around the time of conception. Furthermore, stronger associations were observed for tertiary amine drugs for NTDs overall (adjusted OR 1.60, 95% CI 1.31, 1.95), and specifically for anencephaly (adjusted OR 1.96, 95% CI 1.40, 2.73) and spina bifida (adjusted OR 1.48, 95% CI 1.15, 1.91).

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Associations between medications and pregnancy outcomes might be due to a confounding effect from the condition that is being treated; for example, women with diabetes are more likely to be treated with antidiabetic medications and diabetes is associated with some types of birth defects. This type of confounding is known as confounding by indication and might be considered potentially present if drugs associated with the pregnancy outcome represented relatively few indications. However, in the nitrosatable drug and NTD study with NBDPS participants, NTDs were associated with drugs classified as tertiary amines across a broad range of indications, such as analgesic opioids, antidiabetic drugs, anti-emetic phenothiazines, anti-epileptics, antihistamines, anti-infective macrolides, cough medications, gastrointestinal histamine 2 blockers, and stimulants [43]. Brender et al. [44] also examined prenatal nitrosatable drug exposure and limb deficiencies, oral clefts, and congenital heart defects in offspring. In this study, the critical exposure window was defined as the first trimester of pregnancy. The following associations were noted between prenatal nitrosatable drug exposure and birth defects: amides with cleft palate (OR [adjusted for study center, maternal age, race/ethnicity, education, folic acid supplementation, and smoking] 1.27, 95% CI 1.00, 1.62); secondary amines with longitudinal and transverse limb deficiencies (ORs respectively 1.46 [95% CI 1.04, 2.04] and 1.42 [95% CI 1.07, 1.90] that were adjusted for study center, maternal age, race/ethnicity, education, and multivitamin supplementation); tertiary amines with hypoplastic left heart syndrome (OR 1.50, 95% CI 1.10, 2.04) and single ventricle (OR 1.61, 95% CI 1.06, 2.45 [all ORs for congenital heart defects were adjusted for study center, maternal race/ethnicity, education, smoking, and multivitamin use]); secondary amines with atrioventricular septal defects (OR 1.97, 95% CI 1.19, 3.26); and amides with hypoplastic left heart syndrome (OR 1.49, 95% CI 1.02, 2.17), single ventricle (OR 1.84, 95% CI 1.15, 2.95), and septal defects (OR 1.24, 95% CI 1.04, 1.49). Within the secondary and tertiary amine categories, a wide range of drugs with different indications were associated with the various birth defects, although the only nitrosatable amides associated with these defects to any appreciable degree were sulfonamide anti-infectives.

NITRATE IN DRINKING WATER AND BIRTH DEFECTS Findings from several epidemiologic studies suggest an effect of prenatal exposure to nitrates in drinking water on the risk of congenital malformations in offspring (Table 6.3). Scragg et al. [50] noted that women who lived in Mount Gambier, South Australia, were more likely than women residing in other areas to give birth to stillborns

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66 6.  Nitrate, Nitrite, Nitrosatable Drugs, and Congenital Malformations TABLE 6.3 Nitrate in Maternal Drinking Water Sources and Birth Defects in Offspring First author, year, country

Study design regional description

Years of outcome ascertainment

Arbuckle, 1988 Canada [53]

Population-based, case-control study New Brunswick

1973–1983

Collected and analyzed a water sample at maternal residence at time of index birth (as nitrate)

Congenital malformations of CNS

OR of 2.3 (95% CI 0.73, 7.3) for CNS malformations with exposure to nitrate 26 mg/L relative to baseline of 0.1 mg/L

Aschengrau, 1993 USA [54]

Hospital case-control study Massachusetts

1977–1980

Matched maternal residence during pregnancy or outcome to results of tap water sample taken in respective city as part of routine analysis

Congenital malformations combined

Overall, congenital anomalies were not associated with ­detectable levels of water nitrate (0.2–4.5 mg/L)

Brender, 2004 USA [38]

Population-based, case-control study Texas counties along Texas–Mexico border

1995–2000

Usual periconceptional drinking-water source tested for nitrates (as nitrate)

NTDs

OR of 1.9 (95% CI 0.8, 4.6) for NTDs if water nitrates ≥ 3.52 mg/L. Increased water nitrate associated with spina bifida (OR 7.8) but not with ­anencephaly (OR 1.0). Drinking water nitrate modified association between nitrosatable drug exposure and NTDs

Brender, 2013 USA [55]

Population-based, case-control study Iowa and Texas

1997–2005

Linked maternal addresses to public water utilities; estimated nitrate intake from bottled water with bottled water survey and testing; modeled and predicted nitrate levels in private drinking water wells (Texas only)

NTDs, oral clefts, limb deficiencies, and congenital heart defects

With the lowest tertile of nitrate intake as the referent group, mothers of babies with spina bifida were 2.0 times more likely (95% CI: 1.3, 3.2) to ­ingest ≥ 5 mg nitrate daily from drinking water than controls; during 1 month preconception through the first trimester, mothers of limb deficiency, cleft palate, and cleft lip cases were, respectively, 1.8 (95% CI: 1.1, 3.1), 1.9 (95% CI: 1.2, 3.1), and 1.8 (95% CI: 1.1, 3.1) times more likely than control mothers to ingest ≥ 5.42 mg of nitrate daily from drinking water

Cedergren, 2002 Sweden [56]

Population-based, retrospective cohort study Infants born in Ostergotland County

1982–1996

Linked address at ­periconception or early pregnancy to water supplies

Any congenital heart defect

Weak positive association (OR 1.2, 95% CI 0.97, 1.4) between water nitrate ≥ 2 mg/L and heart malformations

Croen, 2001 USA [39]

Population-based, case-control study California live births, stillbirths, and terminations

1989–1991

Periconceptional addresses linked to water utilities and nitrate databases (as nitrate)

NTDs

Exposure to water nitrates >45 mg/L associated with ­anencephaly (OR 4.0, 95% CI 1.0, 15.4) but not with spina bifida. Increased risk of ­anencephaly with water nitrate levels below U.S. EPA MCL among groundwater drinkers only (5–15 mg/L: OR 2.1, 16–35 mg/L: OR 2.3, and 36-67 mg/L: OR 6.9)

Exposure description*

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Birth defects included

Summary of findings



67

Nitrate in drinking water and birth defects

TABLE 6.3 Nitrate in Maternal Drinking Water Sources and Birth Defects in Offspring (cont.) Study design regional description

Years of outcome ascertainment

Ericson, 1988 Sweden [57]

Population-based, case-control study All deliveries in Sweden

1976–1977

Earliest known maternal address linked to water nitrate results

NTDs

Average drinking water nitrate similar between NTD cases and comparison infants

Holtby, 2014 Canada [58]

Population-based, case-control study Deliveries in Kings County, Nova Scotia

1988–2006

Addresses at delivery linked to public water systems and a sample of rural wells selected for routine monitoring

Congenital malformations combined

Adjusted ORs of 1.65 and 1.66, respectively, for nitratenitrogen levels in drinking water 1–5.56 mg/L and >5.56 mg/L nitrate-nitrogen relative to < 1 mg/L; for births 1998–2006, ORs 2.44 (95% CI 1.05, 5.66) and 2.25 (0.92, 5.52) for same levels respectively

Scragg, 1982 Dorsch, 1984 Australia [50,51]

Population-based, case-control study Mount Gambier region South Australia

1951–1979

Address at delivery linked to sources of water and data on nitrates

Congenital malformations combined and malformations by system

Elevated ORs for any congenital malformation (2.8, 95% CI 1.6, 5.1), defects of CNS (3.5, 95% CI 1.1, 14.6), musculoskeletal system (2.9, 95% CI 1.2, 8.0) if primarily drank groundwater. Elevated ORs for congenital malformations associated with nitrate levels ≥ 5 mg/L relative to nitrate levels < 5 mg/L

Zierler, 1988 USA [59]

Population-based, case-control study All live born deliveries in Massachusetts

1980–1983

Address at the date of conception matched to water nitrate samples of respective water utilities that were drawn on the date closest to the conception date

Congenital heart disease

No association noted between water nitrates higher than minimum detection limit and congenital heart disease

First author, year, country

Exposure description*

Birth defects included

Summary of findings

* Nitrate units are specified as reported in publications. Some articles did not specify type of nitrate. Adapted (and updated) from Ref. [52].

and liveborns with congenital malformations. Examination of the source of drinking water revealed that women who drank groundwater from the Mount Gambier region were 2.8 times more likely (95% CI 1.6, 5.1) to give birth to offspring with congenital malformations than women who drank rainwater; central nervous system (CNS) defects showed the greatest groundwater-related increase (OR 3.5, 95% CI 1.1, 14.6). The groundwater in this area was found to have higher levels of nitrates (∼15 mg/L as nitrate) than rainwater (< 2 mg/L). A positive association was also noted between prenatal groundwater consumption and defects of the musculoskeletal system (OR 2.9), NTDs (OR 3.5), and oral clefts (OR 4.0) [51]. Relative to women who drank water with less than 5 mg/L nitrate, women who consumed water with estimated nitrate levels of 5 to 15 mg/L were 2.6 times more likely to have offspring with malformations, and women who consumed water with nitrates greater than 15 mg/L were 4.1 times more likely to have offspring with malformations. The

investigators used the maternal address of residence at the time of hospital admission of the index birth to assign nitrate exposure to the source of drinking water instead of addresses during the periconceptional period. Using the address at delivery likely introduced some misclassification of exposure because a proportion of women may have moved during their pregnancies. A study of water nitrates and CNS defects conducted by Arbuckle et al. [53] among women in New Brunswick, Canada, also used addresses at birth rather than those during the periconceptional period. However, the investigators obtained water samples from 77% of the residences rather than relying on public water supply data. Therefore, they were able to examine the relation between private well water and CNS defects as well as that from water from public water supplies. Results indicated that relative to 0.1 mg/L, women who drank water from private wells at 26 mg/L or more were 2.3 times (95% CI 0.73, 7.29) more likely to give birth to

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68 6.  Nitrate, Nitrite, Nitrosatable Drugs, and Congenital Malformations ­ abies with CNS defects, while a negative association b was found between water nitrates in spring or public water and these defects. In another study conducted in Canada in the area of Kings County, Nova Scotia, Holtby et al. [58] noted a nonsignificant positive association between nitrate-nitrogen levels in drinking water greater than 1 mg/L (> 4.43 mg/L as nitrate) and all congenital malformations combined in offspring. However, when they stratified the analyses by the periods of pre- and postfortification of grain products with folic acid, higher nitrate in drinking water (> 1 mg/L) was significantly associated with congenital malformations in offspring after fortification (OR for 1–5.56 mg/L 2.44 [95% CI 1.05, 5.66] and OR for greater than 5.56 mg/L 2.25 [95% CI 0.92, 5.52]). In a study of community drinking water and late adverse pregnancy outcomes, Aschengrau et al. [54] found no increased risk of congenital malformations among women who drank groundwater (relative to women who drank surface water) or whose drinking water supplies had measurable levels of nitrate greater than 0.1 mg/L (relative to women whose water supplies had 0.1 mg/L or less of nitrate). The highest measured nitrate in the public drinking water supplies was reported as 4.5 mg/L, considerably lower than that found in the Australian and Canadian studies. Several studies have been published that focused on the relation between prenatal exposure to nitrate in drinking water and congenital heart defects. In a retrospective cohort study conducted in Sweden, Cedergren et al. [56] found a weakly positive association between maternal prenatal consumption of water nitrates 2.0 mg/L or greater and congenital cardiac defects in offspring (OR 1.18, 95% CI 0.97, 1.44). On the other hand, Zierler et al. [59] noted no association between nitrate levels higher than the minimum detection limit in public water supplies and congenital heart defects in offspring (OR 1.08, 95% CI 0.72, 1.62) in a case-control study conducted in Massachusetts. Four published studies have reported on the relation between drinking water nitrates and NTDs. Among women giving birth in Sweden, the average water nitrate did not differ appreciably between women who gave birth to offspring with NTDs (average nitrate: 4.9 mg/L) and control women (5.1 mg/L) [57]. In a study conducted among California residents, Croen et al. [39] estimated drinking water nitrates through linkage of residential addresses during the periconceptional period to water supply companies and accompanying nitrate test results during the most relevant period during periconception. Women whose public water supplies had nitrates above 45 mg/L relative to 45 mg/L or less were four times more likely (95% CI 1.0, 15.4) to have offspring with anencephaly; no association was seen between water nitrate above the MCL and spina bifida in

offspring. Furthermore, increased risks for anencephalic offspring were observed with nitrate levels below the MCL for groundwater drinkers. Relative to women who consumed water with nitrate levels less than 5 mg/L, a dose-response was noted between increasing water nitrate and risk for anencephaly (5–15 mg/L: OR 2.1; 16– 35 mg/L: OR 2.3; and 36–67 mg/L: OR 6.9). In a study conducted among Mexican-American women, drinking water nitrate was measured in the usual periconceptional drinking water source if available and accessible [38]. Women whose drinking water nitrates measured 3.5 mg/L or greater (median level of control women’s drinking water sources) were 1.9 times more likely (CI 0.8–4.6) to have an NTD-affected pregnancy relative to women with drinking water nitrates below 3.5 mg/L. Using data from Iowa and Texas participants in the NBDPS, Brender et al. [55] examined the daily intake of nitrate from drinking water and selected birth defects in the offspring, including NTDs, oral clefts, limb deficiencies, and congenital heart malformations. In this study, the investigators estimated daily intake of nitrate from all sources of drinking water reported by the participants, including public water utilities, bottled water, and private wells (Texas only and estimated through modeling of groundwater flow and nitrate transport). Daily intake of nitrate from drinking water (milligrams per day) was calculated for two time periods: for analyses involving NTDs, the period of one month prior to one month postconception and for the other defects, the period of one month prior to conception through the first trimester. Daily intake was based on the reported sources of drinking water with respective nitrate concentrations and quantity reported consumed at home and at work, use of water filters and type, reported consumption of tea and coffee, and any reported changes in water consumption or source of water during the specified exposure periods. With the lowest tertile of nitrate (less than 0.91 mg/day) around conception serving as the referent group (tertiles based on the control-women’s distribution), mothers of spina bifida cases were two times more likely (95% CI 1.3, 3.2) to ingest 5 mg or more per day of nitrate from drinking water than control mothers. During the period of one month prior to conception through the first trimester, mothers of limb deficiency, cleft palate, and cleft lip cases were, respectively, 1.8 (95% CI 1.1, 3.1), 1.9 (95% CI 1.2, 3.1), and 1.8 (95% CI 1.1, 3.1) times more likely than control mothers to ingest 5.42 mg or more of nitrate daily than control mothers (vs. less than 1 mg/day). In summary, a number of published studies indicate that a higher intake of nitrate from drinking water sources during pregnancy may be associated with birth defects in offspring, especially NTDs. One of the issues in drinking water studies is the potential presence of other contaminants. While some of these studies also examined other water contaminants, none examined

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Joint exposures of nitrosatable drugs and nitrate/nitrite and birth defects

exposures to mixtures of contaminants. In a study that evaluated chemical mixtures in U.S. groundwater including 383 public wells distributed across 35 states, nitrate was found to occur with other contaminants in drinking water, especially in conjunction with ­pesticides, arsenic and other trace metals, and water disinfection by-products [60].

DIETARY INTAKE OF NITRATES, NITRITES, AND NITROSAMINES IN FOODS AND BIRTH DEFECTS While nitrate intake from drinking water sources has been associated with birth defects, the estimated higher dietary intake of nitrate has not been observed to be ­associated with selected birth defects, including NTDs, oral clefts, or limb deficiencies. Studies conducted to date have estimated dietary nitrate, nitrite, and nitrosamine intake based on responses to food frequency questionnaires and the published literature of nitrate, nitrite, and nitrosamine content of the various foods included on these questionnaires [38,39,61]. Such an approach is subject to potential measurement error, although it is likely that misclassification of intake is nondifferential with respect to case-control status. Using the 100-item Block food frequency questionnaire [62], Croen et al. [39] estimated daily intake of nitrate, nitrite, and N-nitroso compounds from the diets in 538 case-mothers with NTD-affected pregnancies and 539 control-mothers of nonmalformed babies. With estimated intake divided into quartiles, no positive associations were noted between estimated higher intake of any of these compounds and NTDs in offspring. All point estimates for the ORs were at or below 1.0 for the second, third, and fourth quartiles of intake relative to the lowest quartiles of intake. In the Texas Neural Tube Defect Project, 184 casewomen and 225 control-women were questioned about their food intake during the period three months prior through three months postconception with a 98-item food frequency questionnaire that was specifically designed for the Mexican-American population living in Texas counties bordering Mexico [38]. Nitrite and total nitrite (5% nitrate intake + nitrite intake) were estimated and categorized into tertiles based on the controlwomen’s distributions. With the lowest tertiles of intake as the referent categories, the ORs for the upper tertiles of nitrite intake were 0.8 and 0.9 and for total nitrite, 0.9 and 0.8. Using data from the NBDPS, Huber et al. [61] examined maternal dietary intake of nitrates, nitrites, and nitrosamines in a sample of 6544 mothers of cases with NTDs, oral clefts, or limb deficiencies and 6807 control mothers. Daily consumption of nitrate, nitrite, and n ­ itrosamines

69

was estimated from a 58-item food frequency questionnaire based on the Willett Food Frequency Questionnaire [63,64]. Overall, NTDs, oral clefts, and limb deficiencies were not significantly associated with estimated dietary intake of these compounds. A few positive associations were noted, including daily intake of nitrite from animal sources and cleft lip with or without cleft palate (adjusted OR and CI for fourth quartile compared with the lowest quartile of intake: 1.24, 95% CI 1.05, 1.48), animal nitrite with cleft lip only (fourth quartile OR 1.32, 95% CI 1.01, 1.72), and total nitrite intake and intercalary limb deficiencies (fourth quartile OR 4.70, 95% CI 1.23, 17.93). In contrast to previous studies, the investigators also estimated the potential impact of measurement error ­using the Simulation Extrapolation (SIMEX) algorithm [65] and hypothetically varying the amount of measurement error included in the model from no error to a multiplicative factor of 1.6 in increments of 0.10. The investigators did not find any evidence based on these ­simulations that even the highest levels of measurement error made any substantial differences in the results.

JOINT EXPOSURES OF NITROSATABLE DRUGS AND NITRATE/NITRITE AND BIRTH DEFECTS Previous publications of studies on the relation ­ etween birth defects in offspring and prenatal expob sure to drinking water nitrate and nitrosatable drugs have hypothesized that observed positive associations might be due to the endogenous formation of N-nitroso compounds and their subsequent teratogenic effects [39,42,51]. Results from animal studies, however, have indicated that nitrite and some nitrosatable compounds were teratogenic only in combination with one another, and no excess incidence in malformations were noted when each was administered separately [66]. Recent published studies in humans also suggest that a higher intake of nitrate and nitrite increases positive associations between prenatal exposure to nitrosatable drugs and several types of congenital malformations in offspring, including NTDs, cleft lip alone, cleft palate alone, conotruncal heart defects, single ventricle, and atrioventricular septal defects [38,43,44,55]. Table 6.4 summarizes the characteristics and major findings of these studies. In each of the studies, reported medications during the periconceptional period and/or the first trimester were classified with respect to their nitrosatability based on the available literature, and dietary intake of nitrite and total nitrite were divided into low, moderate, and high intake based on the control-women’s distributions. One study also included daily intake from drinking water in the estimates of total nitrite [55]. Stronger associations between nitrosatable drug exposure and NTDs among

A.  Overview on Fertility

70 6.  Nitrate, Nitrite, Nitrosatable Drugs, and Congenital Malformations TABLE 6.4 Epidemiologic Studies of the Interaction Effects of Prenatal Nitrosatable Drug Exposure with Nitrite Intake in Relation to Birth Defects in Offspring First author, year, country

Study design regional description

Birth defects included

Description of exposure assessment including how interaction assessed

Summary of findings

Brender, 2004, USA [38]

Population-based case-control study 14 Texas counties bordering Mexico

NTDs

Nitrosatable drug use during the periconceptional period stratified by tertiles of dietary nitrite and total nitrite intake based on the controlwomen’s distributions of intake

Positive associations between prenatal exposure to nitrosatable drug use and NTDs observed only in offspring of women whose intake of nitrite/total nitrite were in the second or third tertiles. Case-women within the highest tertile of total nitrite intake were 7.5 times more likely than control-women to report use of drugs classified as nitrosatable (95% CI 1.8, 45.4)

Brender, 2011, USA [43]

Population-based case-control study NBDPS in 10 states

NTDs, grouped and specific phenotypes

Nitrosatable drug use (any type, secondary amines, tertiary amines) during the period ± 1 month of conception stratified by tertiles of dietary nitrite and total nitrite based on control-women’s distributions of intake; additive and multiplicative interaction assessed

Trends of stronger positive associations between secondary and tertiary amine drug exposures and NTDs among women with higher nitrite and total nitrite intake observed for both anencephaly and spina bifida in offspring. Strongest associations and trend noted between tertiary amines and anencephaly stratified by total nitrite intake: ORs associated with tertiary amines from the lowest tertile to the highest tertile of total nitrite intake were 1.16 (95% CI 0.59, 2.29); 2.19 (95% CI 1.25, 3.86); and 2.51 (95% CI 1.45, 4.37)

Brender, 2012, USA [44]

Population-based case-control study NBDPS in 10 states

Limb deficiencies, oral clefts congenital heart malformations

Nitrosatable drug use (any type, secondary amines, tertiary amines, amides) during the first trimester stratified by tertiles of dietary nitrite and total nitrite based on controlwomen’s distributions of intake; additive and multiplicative interaction assessed

Positive associations between tertiary amines and cleft lip alone and between amides and cleft palate alone noted only among women with the highest tertile of total nitrite intake (ORs of 1.46 [95% CI 0.93, 2.27] and 1.57 [95% CI 1.01, 2.54], respectively) and significant additive interaction was present for both sets of associations; significant additive and multiplicative interaction present between the combination of higher total nitrite intake with tertiary amine and amide drug exposures in relation to conotruncal heart defects; association between amide exposure and single ventricle heart defects strongest in offspring of women in the highest tertile of total nitrite exposure (OR 3.30, 95% CI 1.59, 6.84); strongest association between secondary amine drug exposure and atrioventricular septal defects noted in offspring of women with highest intake of total nitrite (OR 3.30, 95% CI 1.44, 7.58)

Brender, 2013, USA [55]

Population-based, case-control study Iowa and Texas

NTDs, limb deficiencies, oral clefts congenital heart malformations

Nitrosatable drug use (any type) stratified by nitrate intake from drinking water and total nitrite based on controlwomen’s distributions of intake; total nitrite included contributions of nitrate from food and water and nitrite from food

Associations between nitrosatable drug use and selected birth defects in offspring were not stronger among women with higher daily intake of nitrate from drinking water. A pattern of stronger associations between nitrosatable drug exposure and some birth defects were noted for women in the upper two tertiles of total nitrite intake that included contributions from drinking water nitrate; this pattern was noted for the associations between nitrosatable drug exposure and NTDs, cleft lip alone, cleft palate alone, limb deficiencies, atrioventricular septal defects, and single ventricle. Associations between prenatal nitrosatable drug exposure and birth defects in the upper two tertiles of total nitrite intake were particularly strong for cleft palate alone (OR 2.51, 95% CI 1.24, 5.06); atrioventricular septal defect (OR 5.10, 95% CI 1.40, 18.6), and single ventricle (OR 3.25, 95% CI 1.13, 9.31)

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Vitamin C, prenatal nitrosatable drug use, and birth defects in offspring

women with higher nitrite intake were observed in the Texas Neural Tube Defect Study and the NBDPS populations. The NBDPS had sufficient sample size to examine these effects by the molecular structure of the nitrosatable drugs, and associations between secondary and tertiary amines with anencephaly and spina bifida were strengthened in the presence of estimated higher intake of dietary nitrite. The strongest trend was noted between tertiary amines and anencephaly stratified by total nitrite intake; ORs associated with tertiary amines from the lowest tertile to the highest tertile of total nitrite intake were 1.16 (95% CI 0.59, 2.29), 2.19 (95% CI 1.25, 3.86), and 2.51 (95% CI 1.45, 4.37). In contrast to the positive associations noted between nitrosatable drug use and birth defects with higher maternal intake of total dietary nitrite, stronger associations between nitrosatable drug exposure and birth defects were not observed with higher daily intake of nitrate from drinking water sources among Iowa and Texas NBDPS participants [55]. On the other hand, stronger associations were noted between these types of drugs and selected birth defects in offspring of this study population in the upper two tertiles of total nitrite intake that included contributions of nitrate from dietary and drinking water sources and dietary nitrite. Associations between nitrosatable drugs and birth defects in the upper two tertiles of total nitrite intake were particularly strong for cleft palate alone (OR 2.51, 95% CI 1.24, 5.06), atrioventricular septal defect (OR 5.10, 95% CI 1.40, 18.6), and single ventricle (OR 3.25, 95% CI 1.13, 9.31). The lack of synergy between nitrosatable drug use and higher intake of nitrate from drinking water in relation to birth defects might be explained by the relatively low contribution of drinking water nitrate intake to daily nitrate intake. In the Iowa and Texas study populations, median contribution of nitrate per day from drinking water was approximately 6%. The World Health Organization recently concluded that the contribution of drinking water to daily nitrate intake is usually less than 14% [67]. As discussed earlier, drinking water sources of nitrate contribute a small percentage of total daily nitrate intake unless levels in the water supply approach or exceed the allowable MCL as set by the U.S. Environmental Protection Agency.

VITAMIN C, PRENATAL NITROSATABLE DRUG USE, AND BIRTH DEFECTS IN OFFSPRING A number of compounds, including vitamin C, vitamin E (nonesterified forms), and polyphenols (antioxidants found in a variety of foods and beverages) [68], have been noted to inhibit in vivo nitrosation when administered with a nitrosatable compound [31,69]. Vitamin C is the most well-studied with respect to its role as a nitrosation

71

inhibitor, so this chapter will focus on the impact of this vitamin. Vitamin C (ascorbic acid) has been shown to inhibit the formation of N-nitroso compounds through a rapid reduction of nitrous acid to nitric oxide and the production of dehydroascorbic acid [70]. Several experiments in human volunteers have demonstrated the inhibition of nitrosation when vitamin C was given in sufficient doses concomitantly with nitrate and nitrosatable precursors, including proline (a nitrosatable compound) [71] and a fish meal rich in amines [72]. Based on their experimental research in humans with nitrate and proline in conjunction with vitamin C, Mirvish et al. [71] concluded that 120 mg of ascorbic acid taken with each meal would significantly reduce endogenous nitrosamine formation when nitrate and nitrosatable compounds were ingested together. Helser et al. [73] noted a significant inhibition of endogenous formation of N-nitroso compounds when ascorbic acid was given up to 5 h before a nitrosatable compound, although the investigators observed the greatest reduction of nitrosation with concurrent administration of ascorbic acid with proline. Some evidence from epidemiologic studies supports the potential beneficial effects of vitamin C in weakening associations between prenatal exposures to nitrosatable compounds and precursors and birth defects in offspring [39,43,74]. Croen et al. [39] noted lower ORs for the association between higher water nitrate in groundwater and anencephaly among women who consumed at least 103 mg/day of vitamin C (ORs associated with higher water nitrate ranged from 1.8 to 5.3) than among women who consumed less than 103 mg/day of this vitamin (ORs ranged from 4.0 to 18.0). With respect to nitrosatable drug exposure, Brender et al. [43] observed diminished associations between prenatal exposure to drugs classified as tertiary amines and anencephaly in offspring (OR 1.52) of women in the NBDPS population who reported taking a daily supplement with vitamin C around the time of conception compared with women who took a supplement less than daily (OR 2.77) or not at all during this period (OR 2.11). While this pattern with supplementation was not noted in conjunction with nitrosatable drugs and spina bifida, a higher dietary intake of vitamin C (≥85 mg/day) lessened the association between tertiary amines and spina bifida (OR 1.15) compared with that (OR 1.81) for offspring of women with a lower dietary intake of vitamin C. Shinde et al. [74] also noted lower ORs for selected limb deficiency, oral cleft, and heart defects in relation to nitrosatable drugs if women reported daily supplementation and/or higher dietary vitamin C intake. This pattern was particularly pronounced for longitudinal limb deficiencies in conjunction with tertiary amines (dietary intake of vitamin C ≥85 mg per day/daily supplementation versus dietary intake <85 mg/day/no supplementation: ORs,

A.  Overview on Fertility

72 6.  Nitrate, Nitrite, Nitrosatable Drugs, and Congenital Malformations respectively 0.68 and 1.90), transverse limb deficiencies in conjunction with secondary amines (ORs, respectively 1.23 and 4.16), amides with cleft lip with cleft palate (ORs, respectively 1.08 and 2.46), atrial septal defect (not otherwise specified) with tertiary amines (ORs, respectively 1.65 and 2.44), and atrial septal defect with amides (ORs, respectively 0.79 and 4.43). None of these studies had information on specific doses of vitamin C in supplements or the timing of supplementation in relation to exposures to nitrosatable precursors.

CONCLUSIONS, CLINICAL IMPLICATIONS, AND SUGGESTIONS FOR FURTHER RESEARCH The findings of several epidemiologic studies indicate that nitrosatable drugs may function as potential teratogens in humans, particularly in the presence of higher dietary intake of nitrate and nitrite. The finding that a high proportion of the nitrosatable drugs taken by the NBDPS population were preparations that were available without a prescription underscores the importance of cautioning women in their childbearing years, especially those who are pregnant, to check with their healthcare providers before taking OTC preparations. On the other hand, higher estimated dietary intakes of nitrate, nitrite, and nitrosamines have not been associated with birth defects in several US populations, unless coupled with nitrosatable compounds such as certain drugs. Although studies in the past have attributed associations between higher levels of nitrate in drinking water and birth defects to the endogenous formation of N-nitroso compounds, the levels of nitrate associated with these defects were relatively low, suggesting that concomitant pollutants or other factors associated with these sources of water might be responsible for the associations. Since some of the highest nitrate levels in drinking water have been detected in private wells, women of childbearing age who obtain their drinking water from these types of wells should consider having their drinking water tested for nitrate and other routinely monitored contaminants that are tested in public water systems. Alternately, they might consider switching to purified bottle water if pregnant or trying to conceive. While more research is indicated on the potential beneficial effects of vitamin C in preventing birth defects associated with nitrosatable drugs, the results of the few epidemiologic studies that examined the impact of vitamin C on nitrosatable drugs and birth defects appear promising. Based on results from experimental studies, fruits or vegetables (or their juices) that contain vitamin C might need to be consumed shortly before or concomitantly with drugs that are nitrosatable. Further

research is indicated on the timing of supplementation and ingestion of foods high in vitamin C in relation to exposure to nitrosatable compounds and pregnancy outcomes.

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