Methylmercury in the breast milk of Japanese mothers and lactational exposure of their infants

Chemosphere 126 (2015) 67–72

Contents lists available at ScienceDirect

Chemosphere journal homepage: www.elsevier.com/locate/chemosphere

Methylmercury in the breast milk of Japanese mothers and lactational exposure of their infants Miyuki Iwai-Shimada a,b,⇑, Hiroshi Satoh a,1, Kunihiko Nakai c, Nozomi Tatsuta c, Katsuyuki Murata d, Hirokatsu Akagi e a

Environmental Health Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan Research Fellow of the Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo, Japan Department of Development and Environmental Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan d Environmental Health Sciences, Akita University Graduate School of Medicine, Akita, Japan e International Mercury Laboratory Inc., Minamata, Kumamoto, Japan b c

h i g h l i g h t s  Exposure of infants to methylmercury (MeHg) via milk has not been well examined.  One half or more of total mercury in milk was comprised of MeHg in Japanese.  Milk MeHg was associated with the internal accumulation of MeHg and milk lipid.

a r t i c l e

i n f o

Article history: Received 8 September 2014 Received in revised form 15 December 2014 Accepted 26 December 2014 Available online 25 February 2015 Handling Editor: Andreas Sjodin Keywords: Mercury Methylmercury Inorganic mercury Milk Lactational exposure

a b s t r a c t The human fetus is known to be exposed to methylmercury (MeHg), but little is known about the risk of infant exposure via breast milk. To evaluate the lactational exposure to MeHg via breast milk in Japanese infants, the levels of total mercury (THg) and MeHg were determined in breast milk and maternal blood using samples from a birth cohort study at the Tohoku Study of Child Development. Maternal blood and breast milk were collected one day postpartum and one month after delivery, respectively. The median THg (and MeHg) concentrations in maternal RBCs, plasma and breast milk were 17.8 ng g 1 (17.8 ng g 1), 1.51 ng g 1 (1.33 ng g 1) and 0.81 ng g 1 (0.45 ng g 1), respectively (n = 27). The median percentage of MeHg in THg was 54% in breast milk. Breast milk contained substantial amounts of MeHg, which was strongly associated with the internal accumulation of MeHg and the lipid content of the milk (r = 0.684). The range of lipid contents in milk varied widely from 0.50 to 6.60 g/100 g of milk, with a median of 3.60 g/100 g. The median (range) weekly average intake of MeHg via breast milk was estimated to be 0.63 lg kg 1 (0.08–1.68 lg kg 1) BW/week. Because the MeHg and lipid contents in milk substantially fluctuate, an investigation of the variations of MeHg and lipid content in breast milk may be required for a more precise risk assessment. Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction Abbreviations: THg, total mercury; MeHg, methylmercury; IHg, inorganic mercury; Me/T, percentage of MeHg in THg; BW, body weight; PCB, polychlorinated biphenyls; TSCD, Tohoku Study of Child Development; FFQ, food frequency questionnaire; CVAAS, cold vapor atomic absorption spectrometry; GC-ECD, gas chromatography with electron capture detection; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; PUFAs, polyunsaturated fatty acids; BMI, body mass index; TWI, tolerable weekly intake; RfD, reference dose. ⇑ Corresponding author. Present address: Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramakiazaaoba, Aoba-ku, Sendai, Miyagi 9808578, Japan. Tel.: +81 22 795 6871; fax: +81 22 795 6872. E-mail address: [email protected] (M. Iwai-Shimada). 1 Present address: Professor Emeritus, Tohoku University, Sendai, Miyagi, Japan. http://dx.doi.org/10.1016/j.chemosphere.2014.12.086 0045-6535/Ó 2015 Elsevier Ltd. All rights reserved.

The human fetus is known to be exposed to for methylmercury (MeHg) (IPCS, 1990), but little is known about the risk of infant exposure via breast milk. Breastfeeding has many benefits, and breast milk is the best source of nutrition for infants (Gartner et al., 2005) and is an important factor in the initiation, development and/or composition of the neonatal gut microflora (Caicedo et al., 2005). However, breast milk may also be a source of environmental contaminants, such as polychlorinated biphenyls (PCBs), methylmercury (MeHg) and lead (Anderson and Wolff, 2000;

68

M. Iwai-Shimada et al. / Chemosphere 126 (2015) 67–72

Dórea, 2004). Infants nourished with breast milk for a long period might be at increased risk for mercury exposure (Grandjean et al., 1994). Populations that consume fish and fish products are exposed to naturally occurring MeHg. Recently, certain studies described MeHg concentrations in breast milk from fish-eating populations in Europe (Valent et al., 2011; Miklavcˇicˇ et al., 2011, 2013), and inconsistent results regarding the correlation between MeHg in breast milk and fish consumption were obtained. Inorganic mercury (IHg) is excreted into breast milk (Sundberg et al., 1999; Vahter et al., 2000). Correlations between the total mercury (THg) levels in milk and plasma (primarily consisting of IHg) (Skerfving, 1988) and between the IHg levels in milk and whole blood (Oskarsson et al., 1996) have been reported. THg in breast milk is correlated with the number of amalgam fillings but not with fish consumption (Oskarsson et al., 1996). However, IHg is poorly absorbed in the gastrointestinal tract at a level averaging less than 10% (IPCS, 1991), whereas intestinal absorption of MeHg is nearly complete. Thus, MeHg in breast milk may have toxicological significance in infants nursed with breast milk. Because fish and fish products are staple foods of the Japanese people, in the present study, we determined the THg and MeHg concentrations in breast milk of lactating Japanese women. We assumed that certain nutritional factors, such as lipids and proteins, in breast milk might contribute to the mercury concentrations in the milk. For the MeHg analysis of breast milk, the analytical method conventionally used to analyze biological samples, such as blood and tissues, was applied with slight modifications in the pretreatment processes. Because breast milk contains various nutrients, such as casein, lactose and lipids, it is easily carbonized. Moreover, the emulsion formed during pretreatment gives low MeHg concentrations and inaccurate measurements with a large distribution. Finally, we attempted to estimate MeHg intake via breast milk to evaluate the transfer of MeHg from the breast milk to the infants.

2. Materials and methods 2.1. Study design, subjects and sampling We have been conducting a birth cohort study called the Tohoku Study of Child Development (TSCD). The study protocol of the TSCD has been described elsewhere (Nakai et al., 2004). The medical ethics committee of the Tohoku University Graduate School of Medicine approved the study protocol. The research was conducted in two areas, an urban area and a coastal area (Suzuki et al., 2010; Tatsuta et al., 2012). In this study, the samples from the coastal area were used. We enrolled 884 pregnant women who gave their written informed consent to participate in this study, and 749 mother–child pairs were registered according to the eligibility criteria. However, because MeHg analysis requires a long pretreatment process and is laborious, only 27 subjects were selected for determination of MeHg in breast milk. To ensure that the MeHg exposure of the subjects was representative of the full range of the registered mother–child pairs, we randomly selected five to six subjects from each of the five categories of maternal hair THg using statistical software. All of the subjects had complete data sets, sufficient volumes (>20 mL) of breast milk, and hair without permanent waving or straightening (Ohba et al., 2008). Information on demographics and dental fillings was obtained through an interview and questionnaire. Information on the delivery conditions and neonatal characteristics was obtained from hospital medical records. Fish intake during pregnancy was estimated from a food frequency questionnaire (FFQ) administered four days after delivery (Yaginuma-Sakurai et al., 2009).

Maternal blood was collected one day postpartum by venipuncture into a tube containing heparin. Maternal hair and breast milk were collected two days and one month after delivery, respectively. RBC, plasma and breast milk samples were stored at 80 °C until the analyses. 2.2. Analytical methods 2.2.1. Determination of THg The THg levels in maternal hair, maternal RBCs, plasma and breast milk were measured using cold vapor atomic absorption spectrometry (CVAAS, HG-201, Sanso Seisakusho Co. Ltd., Tokyo, Japan). The analytical method of CVAAS has been fully described elsewhere (Ministry of the Environment, 2004). 2.2.2. Determination of MeHg The MeHg levels in the blood samples were measured using gas chromatography with electron capture detection (GC-ECD) (Akagi et al., 2000; Ministry of the Environment, 2004). To accurately analyze the MeHg in breast milk, the method was modified from the referenced procedure (see Supplemental material, Fig. S1). To avoid carbonization, the length of the heating period was shortened based on trial results. The formation of an emulsion during pretreatment was minimized by washing the organic layer with 1N NaOH twice without adding Na2SO4 to the aqueous layer. 2.3. Analytical quality control Sample analysis was performed in triplicate and was repeated when the coefficient of variation (CV) of the triplicate analyses was more than 5%. Accuracy was ensured using a certified reference material (DOLT-3: dogfish liver, NRC, Canada) for quality control. The average of the duplicate THg (or MeHg) determinations was 3.288 lg g 1 (1.454 lg g 1), and the certified value was 3.37 ± 0.14 lg g 1 (1.59 ± 0.12 lg g 1). We also used another certified reference material (TORT-2: Lobster hepatopancreas, NRC, Canada), for which the average of the duplicate THg (MeHg) determinations was 0.269 lg g 1 (0.146 lg g 1) and the recommended value was 0.27 ± 0.06 lg g 1 (0.152 ± 0.013 lg g 1). We confirmed the analytical precision using the standard addition method. Reproducibility was tested by repeated measurements of a pooled sample of breast milk, resulting in a value of 1.136 ± 0.004 ng g 1 (n = 6; CV = 0.39%). 2.4. Other assays The protein concentrations of the breast milk samples were determined according to the Bradford Coomassie blue dye-binding method (Bio-Rad, Richmond, CA). The lipid content in the breast milk was determined according to the Röse-Gottlieb method and was performed at the Japan Food Research Laboratories (Tokyo, Japan). To evaluate fish consumption, we transferred the analyses of maternal plasma levels of EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) to SRL, Inc. (Tokyo, Japan). 2.5. Data analysis The concentration of IHg was calculated as the difference between THg and MeHg. Milk IHg was logarithmically transformed because of the apparently skewed distribution. These data were analyzed using the Pearson product-moment correlation coefficient (r). Multiple regression analysis was used to investigate factors affecting the mercury levels in breast milk. The independent variables were RBCs and plasma Hg (as indicators of internal mercury accumulation), milk protein, milk lipid, and BMI before pregnancy (Model 1). Then, unrelated variables were excluded from the

69

M. Iwai-Shimada et al. / Chemosphere 126 (2015) 67–72

independent variables (Model 2). THg in hair, RBCs and plasma and MeHg in RBCs and plasma were significantly correlated with each other (r = 0.7–0.9). These Hg levels, as well as the fish intake by FFQ and maternal EPA + DHA were also significantly correlated with each other (r = 0.380–0.553). Therefore, we selected one of these variables for the multiple regression analyses to avoid multicollinearity. A value of P < 0.05 was considered statistically significant. The software package JMP9.0.1 (SAS Institute Inc., Cary, NC, USA) was used to analyze the data. 2.5.1. Exposure estimation We estimated the lactational exposure to MeHg in one-monthold infants, assuming a body weight of 4.0 kg (median birth weight + 30 g d 1  30 d) and an average daily milk consumption of 800 mL (EFSA, 2012). 3. Results The characteristics of the 27 subjects are summarized in Table 1. The median THg concentration in maternal hair was 3.43 lg g 1 (range, 0.96  9.41 lg g 1). Table 2 shows the sample correlation coefficients between the milk Hg level and related parameters. Milk THg was significantly correlated with milk MeHg (r = 0.820) and milk IHg (r = 0.783). Milk MeHg was significantly correlated with the RBC MeHg level and milk lipid content (Fig. 1). No significant correlation was observed between THg (or MeHg) in breast milk and indicators of fish intake (annual fish intake and EPA + DHA in maternal plasma). However, when the THg (or MeHg) level in breast milk was adjusted for the lipid content, the correlation became statistically significant. Fig. 2 shows the significant correlation between the lipid-adjusted MeHg concentration in breast milk and EPA + DHA in maternal plasma.

Table 2 Pearson product-moment correlation coefficients (r) between breast milk Hg and other parameters. Breast milk (n = 27) RBCs THg RBCs MeHg Plasma THg Plasma MeHg Plasma IHg Milk proteinb Milk lipid Maternal BMI before pregnancy Fish intake during pregnancy EPA+DHA in maternal plasma

THg

IHga

MeHg **

0.674 0.680** 0.591** 0.589** 0.197 0.086 0.498** 0.367+ 0.299 0.170

**

0.551 0.563** 0.369+ 0.396* 0.049 0.031 0.684** 0.090 0.141 0.151

0.524** 0.538** 0.580** 0.540** 0.354+ 0.099 0.124 0.467* 0.411* 0.228

Maternal blood and breast milk were collected one day postpartum and one month after delivery, respectively. + P < 0.1. * P < 0.05. ** P < 0.01. a Logarithmically transformed. b n = 25.

Table 3 presents the results of the multiple regression analyses. The milk THg level was significantly correlated with the RBC THg level, the milk lipid content and BMI before pregnancy. Similarly, milk MeHg was significantly correlated to the RBC MeHg level and the milk lipid content. The milk IHg level was significantly correlated with the plasma THg level. The relationship between milk IHg and BMI before pregnancy was nearly significant. The contribution ratios (R2) of the multiple regression analyses when 4 independent variables were used were 70.7% for milk THg, 72.6% for milk MeHg and 45.6% for milk IHg, as shown in Model 1 of Table 3. When omitting one variable (i.e., each Hg in blood) from Model 1, the R2 values were 47.7% for milk THg, 60.4% for milk MeHg and 28.4% for milk IHg (data not shown). Therefore, the contributions

Table 1 Characteristics of the study subjects and concentrations of mercury and nutritional factors in maternal blood and breast milk. Median (mean)

Range

32 (31) 157 (157) 53.0 (54.3) 20.9 (21.9) 26.0 (27.9)

22–38 150–168 41.0–82.0 17.1–33.7 2.1–65.3

49.6 (49.0) 3138 (3177)

45.0–52.4 2678–3858

THg (ng g 1) MeHg (ng g 1) IHg (ng g 1)a Me/T (%)

17.8 17.8 0.19 99

3.69–40.6 3.63–40.6 0–2.92 81–100

Maternal plasma

THg (ng g 1) MeHg (ng g 1) IHg (ng g 1)a Me/T (%) EPA + DHA (lg mL 1) n 3 PUFAs (lg mL 1) n 6 PUFAs (lg mL 1) Total FAs (lg mL 1)

1.51 1.33 0.22 85 256 318 1396 4148

0.35–3.90 0.35–3.71 0.01–0.63 50–99 119–417 151–489 960–2051 2909–6481

Breast milk

THg (ng g 1) MeHg (ng g 1) IHg (ng g 1)a Me/T (%) Lipid (g/100 g) Protein (mg mL

0.81 0.45 0.38 54 3.60 7.81

0.14–1.87 0.06–1.20 0.04–1.24 17–87 0.50–6.60 3.94–11.3

Characteristic (n = 27) Maternal age (years) Maternal height (cm) Maternal weight before pregnancy (kg) BMI before pregnancy (kg m 2) Fish intake during pregnancy (kg year 1) Birth order (first child, %) Birth height (cm) Birth weight (g) Concentrations of Hg and nutritional factors Maternal RBCs

%

33.3

1 b

)

Maternal blood and breast milk were collected one day postpartum and one month after delivery, respectively. a IHg: THg – MeHg. b n = 25.

70

M. Iwai-Shimada et al. / Chemosphere 126 (2015) 67–72

Fig. 2. The relationship between lipid-adjusted MeHg in breast milk and EPA + DHA (lg mL 1) in maternal plasma. Maternal blood and breast milk were collected one day postpartum and one month after delivery, respectively.

Fig. 1. The relationships between MeHg in breast milk and MeHg in maternal RBCs (A) and milk lipid (B). Maternal blood and breast milk were collected one day postpartum and one month after delivery, respectively.

of each Hg in blood to the milk THg, MeHg, and IHg levels were estimated to be 23%, 12.3% and 17.2%, respectively. The lactational exposure to mercury in each infant was calculated. The median (range) estimated weekly intakes (average milk consumption) of THg, MeHg and IHg were 1.13 (0.20–2.62), 0.63 (0.08–1.68) and 0.53 (0.06–1.74) lg kg 1 body weight (BW)/week, respectively.

4. Discussion In this study, we found that MeHg constituted a substantial portion of the mercury in breast milk. MeHg in milk was analyzed using a slightly modified version of the method authorized by the Ministry of the Environment of Japan, which has been conventionally applied to biological samples, such as blood and tissues. Using this method, the carbonization and emulsion formation during pretreatment, caused by the characteristic constitution of the breast milk, were minimized. The accuracy and reproducibility were proven satisfactory using certified reference materials and pooled samples. Furthermore, an advantage of our method is that the basic method has been applied to biological samples. To our knowledge, there are only three recent reports in which THg and MeHg were measured in breast milk. The analytical method was based on a procedure originally applied to inorganic materials, such as soil and water (Horvat et al., 1993a,b), in which MeHg was ethylated and absorbed onto carbon materials. Then, after separation of the mercury species on a gas chromatography column, it was pyrolyzed into Hg0 for detection. The mean concentrations of THg (n = 492), MeHg (n = 182) and Me/T (n = 182) in Italy were 0.33 ng g 1, 0.17 ng g 1 and 58%, respectively (Valent et al., 2013), and those for MeHg (n = 11) and Me/T in Slovenia were 0.68 ng g 1 and 38%, respectively, in

samples from mothers with hair THg concentrations > 1.0 lg g 1 (Miklavcˇicˇ et al., 2011). The third study analyzed mercury in breast milk from Italian, Croatian, Slovenian and Greek women with hair THg levels >1.0 lg g 1 (Miklavcˇicˇ et al., 2013). The median values for Me/T were 60% in Italians (n = 224), 56% in Croatians (n = 26), 47% in Slovenians (n = 7), and 7% in Greeks (n = 21). Although the methods of analysis for MeHg were different, the Me/T levels were comparable to our data, except for the value for Greek women. Despite the low average of Me/T in Greek women, the individual values ranged from 2% to 96%. Note that the breast milk from Greek women was collected at three to eight months after delivery, whereas that from the others was collected at one month after delivery. In an Iraqi MeHg poisoning disaster, it was reported that the percentage of IHg in THg in breast milk was 39%, corresponding to a Me/T value of 61% (Bakir et al., 1973). The median levels of THg in breast milk in the above populations were 0.2 ng g 1 in Italians (n = 605), Croatians (n = 125), and Slovenians (n = 284), and 0.6 ng g 1 in Greeks (n = 44) (Miklavcˇicˇ et al., 2013). Our mean value of 0.8 ng g 1 was higher than the median values from these European countries. In other studies in which THg in breast milk was analyzed, the mean THg concentrations were 0.53 ng mL 1 (n = 100) in Spain (GarciaEsquinas et al., 2011) and 0.94 ng g 1 (n = 158) in the Slovak Republic (Ursinyova and Masanova, 2005). The median THg concentrations were 0.29 ng mL 1 in colostrum and 0.14 ng mL 1 in mature milk (n = 20) in Sweden (Björnberg et al., 2005). The median IHg concentration in milk was 0.2 ng mL 1 (n = 21) in Austrians, but no MeHg was detected in the milk (Gundacker et al., 2010). Only a limited number of studies have reported concentrations of mercury in human milk (THg: Björnberg et al., 2005; Ursinyova and Masanova 2005; Garcia-Esquinas et al., 2011; Miklavcˇicˇ et al., 2011, 2013, MeHg: Miklavcˇicˇ et al., 2011, 2013; Valent et al., 2013 and IHg: Gundacker et al., 2010). The mean or median THg levels were between 0.2 and 0.9 ng g 1 (or mL), depending on the region in which the subjects resided and, presumably, the level of fish consumption. Previous studies investigated the correlations of MeHg and THg in breast milk with fish consumption, with certain studies observing statistically significant, but weak, correlations (MeHg: Valent et al., 2011, THg: Miklavcˇicˇ et al., 2011, 2013) and other studies observing no significant correlation (THg: Abballe et al., 2008; Valent et al., 2013). In our study, no correlation between annual fish consumption estimated using the FFQ (or maternal EPA + DHA) and MeHg (or THg) in milk was observed. The octanol–water partition coefficient (log Kow) of MeHg is 1.7–2.5; thus, MeHg has a lipid affinity instead of being

71

M. Iwai-Shimada et al. / Chemosphere 126 (2015) 67–72 Table 3 Relations of breast milk Hg to mercury parameters and confounders: results of multiple regression analysis. Breast milk (n = 27)

THg Model 1

Multiple correlation coefficient (R) Standardized b coefficient RBCs THg RBCs MeHg Plasma THg Milk lipid Milk proteina Maternal BMI

0.841

IHgb

MeHg a

**

0.563**

0.365* 0.014 0.246+

Model 2 0.839

**

Model 1 0.852

a

**

Model 2 0.839

**

Model 1a

Model 2a

*

0.655**

0.519* 0.089 0.156 0.247

0.482**

0.675

0.580**

0.430** 0.272*

0.413**

0.490**

0.625** 0.149 0.026

0.627**

0.330+

+

P < 0.1. P < 0.05. ** P < 0.01. a n = 25. b Logarithmically transformed. *

water-soluble. However, this log Kow is moderate relative to organochlorine substances (e.g., DDT compounds >5.5) (Environment Canada, 2002). In mouse milk, 40% of MeHg is associated with the fat fraction separated by ultracentrifugation (Sundberg et al., 1999). MeHg is bound to thiol-containing molecules, such as proteins, and does not distribute into fatty tissues (Clarkson, 1997). Due to the biochemistry of MeHg, it may be associated with the fat globule membrane protein instead of being distributed within the milk fat globule (Sundberg et al., 1999). A portion of the MeHg transfer could depend on the internal accumulation of MeHg, and another portion may be associated with lipid transfer into the milk. Therefore, an obvious relationship was indicated between the lipid-adjusted milk MeHg level and maternal EPA + DHA, serving as a fish intake indicator (Fig. 2). The comparison of IHg in plasma and breast milk between subgroups with and without dental fillings did not show significant differences (data not shown). Dental amalgam fillings have been considered a potential source of exposure to metallic mercury for American and European populations (IPCS, 1991; ATSDR, 1999), but few Japanese people have these fillings (Takahashi and Yoshida, 2002). We estimated the weekly intakes of THg, IHg and MeHg via breast milk consumption. The tolerable weekly intake (TWI) for breastfed infants is not established. Compared with the TWI (2 lg kg 1 BW as Hg) of the Food Safety Commission of Japan (FSCJ, 2005), the provisional tolerable weekly intake (PTWI for MeHg, 1.6 lg kg 1 BW as Hg) of the Joint FAO/WHO Expert Committee on Food Additives (JECFA, 2003) and the TWI (for MeHg, 1.3 lg kg 1 BW as Hg) of the European Food Safety Authority (EFSA, 2012), only one case exceeded the PTWI of the JECFA and two cases exceeded that of the EFSA. The United States Environmental Protection Agency (US EPA, 2001) recommends a reference dose (RfD) for MeHg of 0.1 lg kg 1 BW per day. The estimated values of lactational exposure exceeded the RfD by 44% (12/ 27). Because the breast milk intakes of infants and the lipid contents most likely fluctuate over time (Lammikeefe et al., 1990) and the MeHg content of breast milk greatly differs, an investigation of the variations of MeHg and lipid contents in breast milk might be required for a more precise risk assessment.

5. Conclusions Breast milk contains a substantial amount of MeHg, although the concentration and Me/T (%) greatly differ among individual samples. MeHg is strongly associated with the internal accumulation of MeHg and the lipid content of the breast milk. This result suggests that MeHg is transferred into the breast milk with fat

globules. Estimation of lactational exposure revealed that breastfed Japanese infants were exposed to a level of MeHg below the TWI of the FSCJ via average milk consumption. Acknowledgments We would like to thank all of the families for their participation in the cohort study. We would also like to acknowledge all of the staff members at the Environmental Health Sciences, Tohoku University Graduate School of Medicine, for their time and assistance with organizing the data collection for the cohort study. We thank Dr. Naoyuki Kurokawa for statistical advice. This research was funded by the Japan Ministry of the Environment. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.chemosphere. 2014.12.086. References Abballe, A., Ballard, T.J., Dellatte, E., Di Domenico, A., Ferri, F., Fulgenzi, A.R., Grisanti, G., Iacovella, N., Ingelido, A.M., Malisch, R., Miniero, R., Porpora, M.G., Risica, S., Ziemacki, G., De Felip, E., 2008. Persistent environmental contaminants in human milk: concentrations and time trends in Italy. Chemosphere 73, S220– S227. Akagi, H., Castillo, E.S., Corles-Maramba, N., Francisco-Rivera, A.T., Timbang, T.D., 2000. Health assessment for mercury exposure among schoolchildren residing near a gold processing and refining plant in Apokon, Tagum, Davao del Norte, Philippines. Sci. Total Environ. 259, 31–43. Anderson, H.A., Wolff, M.S., 2000. Environmental contaminants in human milk. J. Expo. Anal. Environ. Epidemiol. 10, 755–760. ATSDR (Agency for Toxic Substances and Disease Registry), 1999. Toxicological Profile for Mercury. US Department of Health and Human Services, Atlanta, GA. . Bakir, F., Damluji, S.F., Aminzaki, L., Murtadha, M., Khalidi, A., Alrawi, N.Y., Tikriti, S., Dhahir, H.I., Clarkson, T.W., Smith, J.C., Doherty, R.A., 1973. Methylmercury poisoning in Iraq – an interuniversity report. Science 181, 230–241. Björnberg, K.A., Vahter, M., Berglund, B., Niklasson, B., Blennow, M., SandborghEnglund, G., 2005. Transport of methylmercury and inorganic mercury to the fetus and breast-fed infant. Environ. Health Perspect. 113, 1381–1385. Caicedo, R.A., Schanler, R.J., Li, N., Neu, J., 2005. The developing intestinal ecosystem: implications for the neonate. Pediatri. Res. 58, 625–628. Clarkson, T.W., 1997. The toxicology of mercury. Crit. Rev. Clin. Lab. Sci. 34, 369– 403. Dórea, J.G., 2004. Mercury and lead during breast-feeding. Br. J. Nutr. 92, 21–40. EFSA, 2012. Scientific opinion on the risk for public health related to the presence of mercury and methylmercury in food. European Food Safety Authority (EFSA) 10, 2985. . Environment Canada, 2002. Canadian Tissue Residue Guidelines for the Protection of Consumers of Aquatic Life: Methylmercury. Scientific Supporting Document. Ecosystem Health: Science-based Solutions Report No. 1–4. National Guidelines and Standards Office, Environmental Quality Branch, Environment Canada, Ottawa.

72

M. Iwai-Shimada et al. / Chemosphere 126 (2015) 67–72

FSCJ, 2005. Food safety risk assessment related to methylmercury in seafood. Food Safety Commission of Japan (FSCJ). . Garcia-Esquinas, E., Perez-Gomez, B., Fernandez, M.A., Perez-Meixeira, A.M., Gil, E., de Paz, C., Iriso, A., Sanz, J.C., Astray, J., Cisneros, M., de Santos, A., Asensio, A., Garcia-Sagredo, J.M., Garcia, J.F., Vioque, J., Pollan, M., Lopez-Abente, G., Gonzalez, M.J., Martinez, M., Bohigas, P.A., Pastor, R., Aragones, N., 2011. Mercury, lead and cadmium in human milk in relation to diet, lifestyle habits and sociodemographic variables in Madrid (Spain). Chemosphere 85, 268–276. Gartner, L.M., Morton, J., Lawrence, R.A., Naylor, A.J., O’Hare, D., Schanler, R.J., Eidelman, A.I., 2005. Breastfeeding and the use of human milk. Pediatrics 115, 496–506. Grandjean, P., Jørgensen, P.J., Weihe, P., 1994. Human milk as a source of methylmercury exposure in infants. Environ. Health Perspect. 102, 74–77. Gundacker, C., Frohlich, S., Graf-Rohrmeister, K., Eibenberger, B., Jessenig, V., Gicic, D., Prinz, S., Wittmann, K.J., Zeisler, H., Vallant, B., Pollak, A., Husslein, P., 2010. Perinatal lead and mercury exposure in Austria. Sci. Total Environ. 408, 5744– 5749. Horvat, M., Bloom, N., Liang, L., 1993a. Comparison of distillation with other current isolation methods for the determination of methylmercury compounds in low level environmental samples: Part 1. Sediments. Anal. Chim. Acta 281, 135–152. Horvat, M., Bloom, N., Liang, L., 1993b. Comparison of distillation with other current isolation methods for the determination of methylmercury compounds in low level environmental samples: Part 2. Water. Anal. Chim. Acta 281, 153–168. IPCS (International Programme on Chemical Safety), 1990. Methylmercury (Environmental Health Criteria 101). World Health Organisation, Geneva. IPCS (International Programme on Chemical Safety), 1991. Inorganic Mercury (Environmental Health Criteria 118). World Health Organisation, Geneva. JECFA, 2003. Summary Report of the Sixty-first JECFA Meeting. Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives (JECFA). . Lammikeefe, C.J., Ferris, A.M., Jensen, R.G., 1990. Changes in human milk at 0600, 1000, 1400, 1800, and 2200h. J. Pediatr. Gastroenterol. Nutr. 11, 83–88. Miklavcˇicˇ, A., Cuderman, P., Mazej, D., Tratnik, J.S., Krsnik, M., Planinsek, P., Osredkar, J., Horvat, M., 2011. Biomarkers of low-level mercury exposure through fish consumption in pregnant and lactating Slovenian women. Environ. Res. 111, 1201–1207. Miklavcˇicˇ, A., Casetta, A., Tratnik, J.S., Mazej, D., Krsnik, M., Mariuz, M., Sofianou, K., Spiric, Z., Barbone, F., Horvat, M., 2013. Mercury, arsenic and selenium exposure levels in relation to fish consumption in the Mediterranean area. Environ. Res. 120, 7–17. Ministry of the Environment, Japan, 2004. Mercury analysis manual. . Nakai, K., Suzuki, K., Oka, T., Murata, K., Sakamoto, M., Okamura, K., Hosokawa, T., Sakai, T., Nakamura, T., Saito, Y., Kurokawa, N., Kameo, S., Satoh, H., 2004. The Tohoku Study of Child Development: a cohort study of effects of perinatal exposures to methylmercury and environmentally persistent organic pollutants on neurobehavioral development in Japanese children. Tohoku J. Exp. Med. 202, 227–237.

Ohba, T., Kurokawa, N., Nakai, K., Shimada, M., Suzuki, K., Sugawara, N., Kameo, S., Satoh, C., Satoh, H., 2008. Permanent waving does not change mercury concentration in the proximal segment of hair close to scalp. Tohoku J. Exp. Med. 214, 69–78. Oskarsson, A., Schutz, A., Skerfving, S., Hallen, I.P., Lagerkvist, B.J., 1996. Total and inorganic mercury in breast milk and blood in relation to fish consumption and amalgam fillings in lactating women. Arch. Environ. Health 51, 234–241. Skerfving, S., 1988. Mercury in women exposed to methylmercury through fish consumption, and in their newborn babies and breast milk. Bull. Environ. Contam. Toxicol. 41, 475–482. Sundberg, J., Ersson, B., Lonnerdal, B., Oskarsson, A., 1999. Protein binding of mercury in milk and plasma from mice and man — a comparison between methylmercury and inorganic mercury. Toxicology 137, 169–184. Suzuki, K., Nakai, K., Sugawara, T., Nakamura, T., Ohba, T., Shimada, M., Hosokawa, T., Okamura, K., Sakai, T., Kurokawa, N., Murata, K., Satoh, C., Satoh, H., 2010. Neurobehavioral effects of prenatal exposure to methylmercury and PCBs, and seafood intake: neonatal behavioral assessment scale results of Tohoku study of child development. Environ. Res. 110, 699–704. Takahashi, Y., Yoshida, M., 2002. Effects of mercury vapor released from dental amalgam on health and environment. St Marianna Med. J. 30, 1–10 (in Japanese with English Abstract). Tatsuta, N., Nakai, K., Murata, K., Suzuki, K., Iwai-Shimada, M., Yaginuma-Sakurai, K., Kurokawa, N., Nakamura, T., Hosokawa, T., Satoh, H., 2012. Prenatal exposures to environmental chemicals and birth order as risk factors for child behavior problems. Environ. Res. 114, 47–52. Ursinyova, M., Masanova, V., 2005. Cadmium, lead and mercury in human milk from Slovakia. Food Addit. Contam. 22, 579–589. US EPA, 2001. Water quality criterion for the protection of human health: Methylmercury, Final (EPA-823-R-01-001). Environmental Protection Agency (US EPA). . Vahter, M., Akesson, A., Lind, B., Bjors, U., Schutz, A., Berglund, M., 2000. Longitudinal study of methylmercury and inorganic mercury in blood and urine of pregnant and lactating women, as well as in umbilical cord blood. Environ. Res. 84, 186–194. Valent, F., Pisa, F., Mariuz, M., Horvat, M., Gibicar, D., Fajon, V., Mazej, D., Daris, F., Barbone, F., 2011. Fetal and perinatal exposure to mercury and selenium: baseline evaluation of a cohort of children in Friuli Venezia Giulia, Italy. Epidemiol. Prev. 35, 33–42. Valent, F., Mariuz, M., Bin, M., Little, D., Mazej, D., Tognin, V., Tratnik, J., McAfee, A.J., Mulhern, M.S., Parpinel, M., Carrozzi, M., Horvat, M., Tamburlini, G., Barbone, F., 2013. Associations of prenatal mercury exposure from maternal fish consumption and polyunsaturated fatty acids with child neurodevelopment: a prospective cohort study in Italy. J. Epidemiol. 23, 360–370. Yaginuma-Sakurai, K., Shimada, M., Ohba, T., Nakai, K., Suzuki, K., Kurokawa, N., Kameo, S., Satoh, H., 2009. Assessment of exposure to methylmercury in pregnant Japanese women by food frequency questionnaire. Public Health Nutr. 12, 2352–2358.