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Chapter 6

Trends of Dioxin, PCB, and Other Persistent Organohalogen Compound Concentrations in Human Breast Milk from 1972 to 2008 in Osaka, Japan Yoshimasa Konishi* and Kensaku Kakimoto Osaka Prefectural Institute of Public Health, Nakamichi 1-3-69, Higashinari-ku, Osaka 537-0025, Japan *E-mail: [email protected]

Persistent organic pollutants (POPs) are accumulated in the environment, exerting their toxicities not only on humans but also on wildlife. The levels of organochlorine compounds in the breast milk of lactating women living in the Osaka Prefecture, Japan have been annually monitored since 1972. Following the highest concentration found at the start of the measurements, the amounts of polychlorinated biphenyls (PCBs) and organochlorine pesticides, such as dichloro-diphenyl-trichloroethanes (DDTs) (dichloro-diphenyldichloroethylene (DDE) and DDT), β-hexachlorocyclohexane (β-HCH), and hexachlorobenzene (HCB) declined to about 1.4–6.4% of their peak levels in the mid-1970s and continued to decrease to low-level equilibrium states. This decline was greatly variable, depending on the compound in question. In the case of chlordanes (trans-nonachlor, cis-nonachlor, and oxychlordane), termite insecticides monitored from 1986, more than 20 years have passed since their use was prohibited in Japan. Nevertheless, they continue to be found in breast milk, although at a low level. Dioxins (polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like PCBs (DL-PCBs)) possess typical characteristics of organochlorine compounds, are difficult to © 2016 American Chemical Society Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


decompose, and are readily soluble in fat. We monitored the dioxin content of breast milk from 1973 to 2008, finding that their levels constantly decreased during this period. This was probably due to the greatly decreased amount of dioxins from agricultural chemicals and the curtailed use of PCBs. To reduce dioxin emissions from combustion and industrial processes, the Ministry of the Environment has enforced a “Dioxins special-measures law” in 1999, which successfully reduced the emission of dioxins by over 90% by 2003, compared to that of 1997. However, the levels of combustion-origin dioxins in breast milk showed a small decline rate. The PCB contamination of the Japanese population is estimated to be largely caused by seafood intake, but the proportions of PCB congeners in fish commodities are different from those in breast milk. The absorption, metabolism, and therefore, the accumulation of PCBs in the human body differed greatly for various congeners. The time course of hexabromocyclododecane (HBCD) concentrations in breast milk samples appeared to be related to the technical HBCD annual demand levels in Japan. In recent years, the level of HBCDs in breast milk remained roughly constant, attributed to the recent flat trend of HBCD consumption in Japan. The time point of total HBCD concentration rise appeared to be later than that of the total polybrominated diphenyl ether concentration rise in breast milk samples collected in Osaka, Japan.

Introduction Numerous organohalogen compounds were produced as a result of chemical industry development and high economic growth, offering great benefits and convenience to humans. However, these compounds are chemically very stable and thus non-degradable in natural environments (1, 2). Twelve compounds (aldrin, dieldrin, endrin, DDTs, heptachlor, chlordane, HCB, mirex, toxaphene, PCBs, PCDDs and PCDFs) were specified as POPs in the “Stockholm Convention on Persistent Organic Pollutants” (3). POPs travel over long distances and contaminate the entire atmosphere and oceans (4, 5), easily accumulating in the living body and exhibiting detrimental effects (6), being difficult to decompose and readily soluble in fat. POPs emitted into the environment stay there for a long time, entering the food cycle and accumulating in humans and animals. Human breast milk is not only the perfect infant nutrition, but is also helpful for phylaxis; breast-feeding is also very important for the psychological development of the infant (7). However, breast milk secretion is the major excretion route of lipid-soluble contaminants such as PCBs, β-HCH, and DDTs (8). An infant consuming breast milk for only 3–6 months can take in 30–50% of mother body contaminants that have been accumulating from food and other 128 Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


sources for 20–30 years (9). Thus, although breast milk should be an important infant nutrition source, it may also exhibit adverse effects on infant health. PCBs became infamous after the Kanemi rice oil disease incident “Yusho” in 1968 (10, 11), which occurred following an accident causing PCB contamination of food oil in Kitakyusyu, Japan (12–14). In particular, this incident raised concern about the effects of PCB contamination on infant health in Japan. In Osaka, the environmental contamination by PCBs was recognized in 1972, and “The Osaka Prefecture Breast Feeding Promotion Project Review Board” was established, supported by the Ministry of Health, Labour and Welfare. Reports were published on the basis of cooperation and long-term monitoring, with investigations of maternal blood and breast milk performed to characterize the effects of PCBs and organochlorine pesticides on infant health (15–20). Dioxins were recognized as a serious social problem in Japan after the 1980s. These compounds, generated during the incineration of industrial waste and production of organochlorine compounds, are deadly poisons (21). Dioxins are difficult to decompose and are highly soluble in fat, which are typical features of organochlorine compounds. When emitted into the environment, these species remain there for a long time, entering the food cycle and being accumulated and concentrated by humans and animals. During breast-feeding periods, the accumulated dioxins shift to the suckling through breast milk. The influence of dioxins on humans via this route caused concern. The Ministry of Health, Labour and Welfare initiated a nation-wide investigation of dioxins in breast milk after the 1980s, when air contamination by dioxins generated during waste incineration was recognized as a social problem. “The Osaka Prefecture Breast Feeding Promotion Project Review Board” utilized frozen breast milk samples that were accumulated by us. PCBs are accumulated in the environment, exerting their toxicities not only on humans but also on wildlife. PCB analysis in 1972 was performed using a packed-column gas chromatograph with an electron capture detector (GC-ECD) to determine total PCB concentrations (17). Since PCBs feature 209 congeners, the analytical data obtained by this method does not meet the requirement of PCB congener risk assessment, requiring a detailed analysis. HBCDs were widely used as flame retardants, being a replacement for polybrominated diphenyl ethers (PBDEs) in consumer products, and are now classified as POPs. HBCDs are lipophilic and accumulate in the fatty tissue of wild animals and humans. Infant exposure to HBCDs via breastfeeding may potentially cause neurodevelopmental disorders and thyroid hormone production disruption (22). Therefore, monitoring the levels of these new POPs in breast milk is also important. The contents of this chapter are as follows: 1) 2) 3) 4)

Surveillance of organochlorine pesticides and PCBs Trends of dioxin and furan concentrations in breast milk PCB congeners and chiral analysis Trends of brominated flame retardant concentrations 129

Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Materials and Methods Human breast milk specimens were collected from women living in the Osaka Prefecture. To minimize maternal factors, the specimens were obtained from women who were primiparous from one to three months postpartum. PCB analysis of ca. 60 samples employed Kanechlor 500 (chlorine content of ca. 54.6%W/W) as a standard, with the total amount of PCBs measured by GC-ECD using a column packed with 2% dimethyl silicone gum (OV-1). The calculation method was based on the total height of seven major peaks with retention times greater than that of p,p′-DDE, as recommended by one of the official PCB quantitation methods. The levels of other POPs were measured every year, from 1972 to 2008, using gas chromatography/low-resolution mass spectrometry (GC/LRMS), with the exception of dioxins, PCB congeners, and chiral analysis (19). DDT concentration was defined as the sum of p,p′-DDT and p,p′-DDE levels, and sand chlordane levels were defined as the sum of trans-nonachlor, cis-nonachlor, and oxychlordane amounts. Separately, the milk specimens were collected between 1973 and 2008 and stored frozen at –20 °C. Breast milk fat samples prepared from the preserved milk specimens dated 1973 to 2008 were used for the determination of dioxins, PBDEs, PCB congeners, and chiral compounds. Equivalent amounts of milk fat were mixed per sampling year from 13 to 39 samples. The milk fat samples of 25 to 29 years old women were used. Dioxin, PBDE, PCB congener, and chiral analyses of PCB were conducted using gas chromatography/high-resolution mass spectrometry (GC/HRMS) with a capillary column for selected ion monitoring (SIM) (20, 23–25). Dioxin toxic equivalency quantities (TEQs) were calculated based on toxic equivalency factors (TEFs) according to the World Health Organization (WHO) in 2005 (26). HBCDs were analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS) in electrospray ionization mode (27). Breast milk samples were obtained with the donors’ informed consent from the Health Prevention Section of the Osaka Prefectural Health Division.

Results and Discussion Organochlorine Pesticides and PCBs Organochlorine compounds have been banned in Japan since the first half of the 1970s, and their contribution to environmental contamination has been decreasing year by year (19, 28). The main source of organochlorine compounds in the human body is food intake. Since seafood makes up about 80% of the food supply, e.g., various kinds of fish and shellfish, especially in Japan, contamination originating from drinking water and atmospheric sources is insignificant, except for special cases such as short-term exposure due to pesticide spraying (29, 30). PCBs are stable in acids and alkalis and do not easily decompose at high temperatures. These compounds were used in Japan mainly as insulating materials in condensers and other equipment, with large amounts said to remain. PCBs are accumulated in the environment, exerting their toxicities not only on humans 130 Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


but also on wildlife. The cumulative worldwide PCB production in the 1972 was estimated at ca. 1.2 million tons, with about 60,000 tons produced in Japan. The presence of PCBs in breast milk has been reported in studies conducted in many parts of the world, including Sweden (31), Canada (32, 33), Finland (34), and Poland (35). In these nations, PCB concentrations in breast milk were maximal in the 1970s and 1980s, similarly to Japanese findings. DDTs are insecticides widely used after World War II to exterminate fleas and other pests (36), their main component being p,p′-DDT. p,p′-DDE is a metabolite of p,p′-DDT and exhibits high chronic toxicity and persistence, similarly to DDTs. DDTs in breast milk of Japanese women were almost completely represented by p,p′-DDE. The worldwide cumulative DDT output was reported to be about three million tons in the 1970s (37), with about 30,000 tons produced in Japan (38). The presence of p,p′-DDT and p,p′-DDE in breast milk at levels higher than the Food and Agriculture Organization/World Health Organization (FAO/WHO) recommended levels has been reported in Mexico (39), Swaziland (40), and Iran (41). DDTs were used as low-cost pesticides for the extinction of malaria in tropical and subtropical countries (42), where the levels of DDT contaminants in breast milk are considerably higher than in Japan (43–45). HCHs are effective insecticides for noxious paddy field insects and were abundantly used in Southeast Asia, where rice cultivation is popular. The chronic toxicities of HCH isomers, α, β, γ, and δ-HCH, increase in the following order: δ < γ < α < β. β-HCH exhibits particularly easy accumulation and is difficult to degrade in animal tissue (46). Most of HCHs in the breast milk of Japanese women corresponded to β-HCH. No data is available on the cumulative worldwide production of HCHs, but it is thought to exceed a million tons, with the share of Japan estimated as ~ 400,000 tons. In developing countries, such as India, it is abundantly used up to the present day and continues to contaminate the surrounding regions or marine areas. Due to the popularity of rice cultivation in Japan, the corresponding breast milk HCH concentrations are higher than those in foreign countries, with the exception of Southeast Asia (39, 41, 43). The levels of PCBs, DDTs, and β-HCH in breast milk were found to decrease year after year from 1972 to the 1990s, subsequently mostly reaching an equilibrium state. However, this decline greatly depended on the individual compounds. Taking the maximal breast milk levels of the 1970s as 100%, the concentration of β-HCH decreased to about 1.4% (6.8 μg/g fat in 1974 and 0.097 μg/g fat in 2006), that of DDTs to about 4.5% (4.0 μg/g fat in 1976 and 0.18 μg/g fat in 2004), and that of PCBs to about 6.4% (1.5 μg/g fat in 1974 and 0.097 μg/g fat in 2006). The year-by-year reduction of pesticide levels in breast milk (Figure 1) indicated their different half-lifes in the environment, with the persistency of PCBs being especially high. The present intakes of these chemicals are below the acceptable daily intake (ADI), assuming an infant milk fat intake of 4.5 g/kg of body weight per day. The average 2008 intakes are estimated as 3.6, 26, and 17% of the ADI for β-HCH, DDTs, and PCBs, respectively (19, 20).

131 Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 1. Time courses of β-HCH, DDTs and PCBs levels in breast milk on a fat basis from 1972 to 2008: β-HCH (●), DDTs (○), and PCBs (▲).

HCB is an impurity generated during the production of the pentachlorophenol (PCP) herbicide, and is produced by the combustion of chlorine-containing compounds. Despite never having been registered as a pesticide in Japan, HCB was detected in breast milk, recently drawing attention as a pigment impurity (47). Pigments are thought to be responsible for increased HCB levels in breast milk, attracting increased attention (Figure 2).

Figure 2. Time courses of CHLs and HCB levels in breast milk on a fat basis from 1980 to 2008: CHLs (●) and HCB (○). 132 Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


In Japan, chlordanes are insecticides sprayed in the house and used for tree pest control (48), with their use showing a rapid increase in the 1980s. The Environment Agency of Japan published the results of a national environmental pollution survey in 1986, announcing that seafood contamination was mainly found in West Japan. Chlordanes were designated as a specified chemical substance by the Ministry of Health, Labour and Welfare and the Ministry of Economy, Trade and Industry of Japan, since they meet the three conditions of persistence, bioaccumulation, and chronic toxicity. In September 1986, chlordanes were designated as a Class I specified chemical substance in Japan by the “Law Concerning the Examination and Regulation of Chemical Substances” (49). As a result, the use of chlordanes became controlled, and the import of products containing chlordanes and termite pest control agents, such as insecticides, was also forbidden. In Japan, chlordane contamination can arise from both the open-system environment and seafood intake. Chlordanes were mainly applied under the house floor for termite pest control, resulting in direct contamination (closed system) of breast milk (50). In an earlier study, we clearly demonstrated that chlordane contamination in humans was mainly caused by the corresponding aerosol vaporized indoors during termite pest control, as opposed to the intake with sea food (50). Another contamination source is generated when vaporized chlordane particles are adsorbed on rice stored in a treated house (20). Therefore, human exposure to chlordane features three intake pathways: 1) fish, 2) air, 3) polluted rice. Consequently, chlordane levels in breast milk gradually increased due to the respiration of polluted air and consumption of contaminated rice over a period of 4–10 years. Ten years after the termite treatment of a house, the accumulation of chlordane in body fat decreases. The metabolism and excretion of chlordane are thought to be faster than the reduction of chlordane air pollution (20). Our findings suggest a need to investigate the state of organochlorine compounds in the environment and their effects on wildlife and human health. In addition, further detailed studies on the impact of breast milk on infant health should be performed. Maximum and minimum daily POP intake values for infants via breast milk from 1972 to 2008, as well as ADI values (assuming the infant intake of milk fat to be 4.5 g/kg of body weight per day) are listed in Table 1.


134


Table 1. Daily infant intake of organic chlorine compounds with breast milk Compound

5a

PCBs HCH

c

12.5

DDTs

5a

HCB

−

CHLs a

ADI (µg/kg/day)

0.5

Daily Intake from Breast Milk e (ng/kg/day)

Daily Intake/ADI ratio (%)

d

22,300−2.25

446 ― 0.045

13,500 (′74)−0.36 (′06)

60,600−1.62

485−0.013

15,000 (′76)−1.14 (′06)

67,700−5.13

1,350−0.103

148 (′81)−0.25 (′04,′05)

666−1.13

−

2,020′−1.71

403−0.342

Concentration of Breast Milk Max-Min (ng/g-fat) 166 (′74)′−0.50 (′06)

a

b

448 (′98)′−0.38 (′06) b

ADI established by the Ministry of Health, Labour and Welfare, Japan (1972). ADI established by FAO/WHO (1992) (no reference value in Japan). β-HCH was adopted. d Figures in parentheses represent the fiscal year. e The fat intake of an infant was calculated as 4.5 g/kg of body weight per day.


c


Dioxin and Furan Level Trends in Breast Milk Dioxins were first synthesized in 1872, and their toxicity seldom attracted attention until the occurrence of numerous infant abnormalities at delivery due to the teratogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxins (TCDD) impurities in the 2,4,5-trichlorophenoxyacetic acid (2,4,5-T, defoliant) that the U.S.A. used in the Vietnam War (51). Moreover, American soldiers returning from Vietnam initiated lawsuits related to health issues (52). Another infamous incident was that of Love Canal and the abandonment of industrial waste. In the U.S.A., the increased concern about dioxins and other environmental pollutants led to the establishment of the “Superfund Act” (53). In Europe, an explosion accident occurred at a 2,4,5-tetrachlorophenol factory in Seveso, Italy, in July 1976 (54). Over 1810 ha of soil were polluted with large quantities of dioxins (2 kg as TCDD), and about 37,000 people were exposed to 2,3,7,8-TCDD. Poisoning (chloracne) of local residents occurred frequently. Incidences of digestive organ and lymph blood vessel cancer in residents of the designated contamination area (where refraining from pregnancy was advised) increased over 15 years after the accident (55). All 12 children born in a neighboring area between 1977 and 1984 were girls, with no boys born at all. The effects of dioxins on the reproduction system were strongly suspected. In Europe, such incidents raised concern regarding the problem of environmental contamination by dioxins. In Japan, Wakimoto et al. (Ehime University) detected 2,3,7,8-TCDD in the fly ash and residual materials of a city garbage incineration area in 1985 (56). In response, the Ministry of Health and Welfare (the present Ministry of Health, Labor and Welfare) conducted a “Research on the mechanism of dioxin generation by waste processing” over a five-year period from 1985. “Guidelines for preventing dioxin generation” were announced in December 1990. The Environment Agency (the present Ministry of the Environment) started monitoring sediments and various living organisms from 1985. In 1999, the Ministry of the Environment enacted the “Dioxin special-measures method” and began working toward reducing contaminant levels. The main sources of dioxin exposure can be classified as follows.

1. Impurities in PCB Products Small quantities of PCDFs are present in PCB products as impurities and are reported to have caused the Kanemi-yusho incident. Dioxin-like PCBs (DL-PCBs) are also present in PCB products, with their individual contents being greatly variable. Although the content of 3,3′,4,4′-tetrachlorinated biphenyl (TeCB) is the highest in all PCB products, that of 3,3′,4,4′,5,5-hexachlorinated biphenyl (HxCB) is very small (57). Among the PCB products, 3,3′,4,4′-TeCB is considered to be present at high levels in the environment. Starting from the mid-1970, there has been a rapid decrease in 3,3′,4,4′-TeCB and some PCDF levels in breast milk, partly due to a decrease of dioxin levels related to PCB products (58). 135 Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


2. Agricultural Chemicals Pentachlorophenol (PCP), with five chlorine atoms and one hydroxyl group attached to the benzene ring, is an agricultural chemical used abundantly from the 1960s as a weed killer and as a disinfectant in paddy fields in the 1970s. Chlornitrofen (CNP), with two benzene rings on both sides of an oxygen atom, was used from the 1960s as a weed killer in paddy fields. The chemical structure of these agricultural chemicals resembles that of dioxins. In the case of PCP, joining two molecules together would result in octachlorodibenzo-p-dioxin (OCDD). The PCP manufacturing process is thought to have generated a large amount of dioxins as impurities, causing very high OCDD and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxins dioxin (HpCDD) concentrations in breast milk in the 1970s. The high concentration of chlorinated dioxins in breast milk decreased sharply with a decrease in the amount of PCP used. After the 1980s, the manufacture of these agricultural chemicals was curtailed. The TEFs of OCDD and HpCDDs are low, having little influence on TEQs (59, 60) (Figure 3).

Figure 3. Time courses of HpCDD and OCDD in breast milk: OCDD (●) and 1,2,3,4,6,7,8-HpCDD (○).

3. Chlorine Processing Dioxins, mainly 2,3,7,8-tetrachlorodibenzofuran (TCDF), are produced during paper pulp bleaching, with areas in the vicinity of paper pulp factories possibly contaminated. For example, high concentrations of 2,3,7,8-TCDF were detected in areas near a paper pulp factory (61) when Masunaga investigated dioxin levels in the material at the bottom of different parts of the Tokyo Bay (62, 63). 136 Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


4. Combustion Dioxins are produced by the combustion of garbage and industrial waste (64), with their precursors generated by combustion of chlorine-containing compounds, mainly pentachlorodibenzo-p-dioxins (PeCDDs) (de novo composition). Large amounts of dioxins are generated at incineration temperatures of less than 300 °C (65). Small-scale and old incinerators easily generate dioxins. Large amounts are also generated during the incineration of industrial waste. To reduce the generation of dioxins, the incineration facilities need to be improved, e.g., by raising the incineration temperature. Unacceptable levels of PeCDD and hexachlorodibenzop-dioxin (HxCDD) contaminants were detected in breast milk over the past 27 years (Figure 4). Recently, the levels of dioxins unintentionally generated by human activities due to incomplete combustion of chlorine-containing compounds have been increasing. These dioxins, generated from industrial and residential waste, are deadly poisons.

Figure 4. Time courses of PeCDD and HpCDD in breast milk: 1,2,3,7,8-PeCDD (○), 1,2,3,6,7,8-HxCDD (●), and 1,2,3,7,8,9-HxCDD (▲). The dioxin levels in breast milk have been decreasing in advanced nations (66–70). In Japan, investigations of dioxin levels in breast milk have continued (19, 71, 72). In June 1999, the Ministry of the Environment and the Ministry of Health, Labor and Welfare enacted a special-measures law related to dioxins (28). Monitoring of exhaust gases from incinerators, as well as dioxin levels in atmosphere, soil, and rivers should be performed periodically (73). The Ministry of the Environment also conducted investigations of animals (74), with this information available on the Internet. Our work has shown a rapid decrease in the levels of DL-PCBs and highly chlorinated PeCDDs with low TEFs in breast milk over the past three decades. The concentrations of PeCDDs and HxCDDs with high TEFs decreased to minimal values (Figure 5). Although dioxins of combustion origin have been a matter of public concern, their effects on breast milk have not been evident. However, it 137 Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


seems that the effect of the abovementioned law has gradually become visible after 2001. To further reduce environmental contamination by dioxins, the present monitoring surveillance must continue (28). The evaluation of dioxin toxicity (TEQs) revealed that their harmful effects on reproduction, as well as their toxicity, endocrine disruption, immunity toxicity, and carcinogenicity were based on the interaction with the Aryl hydrocarbon receptor (AhR) (75). Findings from various animal examinations led the WHO to announcing 86 ng/kg as a body burden for the calculation of TDI (the amount of one-day ingestion per weight of 1 kg that does not lead to a detrimental influence over a lifetime), with an uncertainty coefficient of ten. In May 1998, the WHO set the TDI reduction from 1–4 pg/kg/day to less than 1 pg/kg/day as an ultimate target (76). In Japan, the Environment Agency and the Ministry of Health and Welfare, based on their own research, adopted the WHO guidelines. In June 1999 (77), the maximum acceptable TDI was set at 4 pg TEQs/kg/day, including DL-PCBs, with the aim of decreasing this value to less than 1 pg/kg/day.

Figure 5. Time courses of non-ortho PCB in breast milk: PCB#77 (●), PCB#81 (○), PCB#126 (▲), and PCB#169 (4). At present, the dioxin concentration in the breast milk of a primiparous female in labor is about 26.5 pg TEQ/g-fat on average. If a nursing infant takes in an average of 4.5 g fat per 1 kg of body weight with breast milk as the only source of nutrition, the amount of dioxin ingestion amounts to 120 pg/kg/day. As the milk formula products also contain small quantities of dioxins, about 60 pg/kg/ day of them will be taken in by the infant even if half of the nutrition source is from the above products. This amount of ingestion is 15 times larger than the target value and exceeds the uncertainty coefficient of ten (78), raising the question of why no adverse effects have been reported. Possible explanations include the following. Since TDI is computed based on the quantity which people take in during their entire life, it cannot serve as an index for a short period such as breastfeeding. TDI values differ between humans and experimental animals, such as rats (79). Comparisons of infants nursed on formula milk and breast milk may not 138 Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


be reliable, and data for the fetus are difficult to obtain (80). Factors such as air pollution and lifestyles, including eating habits, may also have significant effects. It is difficult to sample musing infants of about 20 years ago, when the dioxin contamination of breast milk was more pronounced, with those being raised today, when there is little obvious dioxin contamination. Better test methods are needed for detecting dioxin effects and establishing more accurate TDI values. Non-ortho PCB concentrations in breast milk were 697 pg/g fat in 1973, but decreased to about 1/12, or 56 pg/g fat, in 2004. The levels of 3,3′,4,4′-TeCB (#77) decreased sharply from 277 pg/g fat in 1973 to 6.8 pg/g fat (2.5%) in 1999. The reduction of the 3,3′,4,4′,5-pentachlorinated biphenyl (PeCB) (#126) level was 12%. The smallest reduction was not observed for 3,3′,4,4′,5,5′-HxCB (#169) from 1973 to 2004 (Figure 5). These results suggest different sources of DL-PCB contaminants in breast milk. PCB#153 (di-ortho PCB), detected in the highest concentration, reduces the T4 (thyroxin) level in serum. Thus, the possibility of a thyroid hormone action of PCB#153 has been suggested (81). Thus, not only dioxins, such as DL-PCBs, but also other non-DL-PCBs should be considered when evaluating the effects of PCBs on humans. Dioxin exposure experiments on animals during the lactation period support their effect on the thyroid hormone system and the increase of IgE antibody levels after TCDD exposure (82). Thus, dioxin exposure during the lactation period may lead to the development of atopic symptoms. The increased consumption of meat has led to problems such as obesity. In the past, the Japanese have consumed more n-3 unsaturated fatty acids with fish and shellfish (83). However, these food sources tend to be more contaminated by POPs such as PCBs and dioxins, as compared to other ones. To lower health risks, we need to reduce the environmental contamination and exposure of animals and plants. DL-PCB contaminants in breast milk showed a decline tendency, similarly to PCBs (Figure 6) (84–87). Thus, the long-term monitoring of environment and food, including breast milk, is important.

Figure 6. Time courses of dioxin TEQs in breast milk (25 to 29 year-old primiparous mothers): PCDDs (●), PCDFs (▲), and DL-PCBs (○). 139 Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


PCB Congeners and Chiral Analysis PCB analysis has been performed since 1972, using a packed-column gas chromatograph equipped with an electron capture detector to determine total PCB concentrations (17). However, as many as 209 congeners of PCBs exist, depending on the number and substitution sites of chlorine atoms. Therefore, the analytical data obtained by this method does not meet the risk assessment requirement for PCB congeners, with individual congener-based PCB analysis required for this assessment. Toxicities, such as endocrine disruption, differ among congeners, making it necessary to analyze them individually using GC/HRMS (20). Among the 154 PCB congeners analyzed, 51 of them, ranging from TeCBs to heptachlorinated biphenyls (HpCBs), were detected in the milk fat samples collected in 1973. However, only 48 PCB congeners were detected in samples from 2000 (20). Twelve types of major PCB congeners were detected in breast milk. In terms of the composition ratio, the congeners ranked from high to low as follows: #138, #153, #118, #74, #66, #99, #180, #105, #187, #60, #170, and #52. The total concentration of all PCB congeners in breast milk steadily decreased, but its change over time differed greatly among individual species. TeCBs decreased to about 5.1% of their highest levels in 2000 (0.18 µg/g fat in 1973, 0.009 in 2000), while PeCB concentrations declined to about 12% of their highest levels (0.21 µg/g fat in 1973, 0.024 in 2000). HxCB levels dropped to about 23% of their maximum (0.31 µg/g fat in 1974, 0.071 in 1998), and HpCBs showed a decrease to about 34% (0.006 µg/g fat in 1978, 0.039 in 2000). These findings suggest that the half-lives of congeners in the body are longer for the ones with a higher degree of chlorination (28). PCB congener concentrations decreased starting from the 1970s (when the levels of breast milk contamination were highest): congener #138 decreased to about 21% of the concentration in the 1970s (119 ng/g fat in 1974, 25 in 1998), #153 to about 26% (126 ng/g fat in 1974, 32 in 1998), #118 to about 11.6% (84.8 ng/g fat in 1973, 9.9 in 2000), #74 to about 6.3% (81.9 ng/g fat in 1973, 5.2 in 1998), #66 to about 2.3% (45.5 ng/g fat in 1973, 1.1 in 1998), #99 to about 16% (45 ng/g fat in 1975, 7.0 in 1998), #180 to about 34.0% (38 ng/g fat in 1975, 13 in 2000), #105 to about 8.3% (24 ng/g fat in 1978, 2.6 in 2000), #187 to about 36% (24 ng/g fat in 1978, and 8.4 in 1997), #60 to about 2.5% (20 ng/g fat in 1973, 0.48 in 2000) , #170 to about 27% (25 ng/g fat in 1978, 6.6 in 2000), and #52 to about 1.2% (16 ng/g fat in 1973, 0.20 in 1998). With #153 as a reference (as it had the highest congener composition ratio of concentrations in breast milk), the HpCB and HxCB composition ratios exhibited almost no changes between 1973 and 2000, while those of PeCB and TeCB congeners decreased. In particular, the composition ratio of TeCBs declined markedly (Figure 7). PCB contamination of the Japanese is largely caused by the seafood intake, but the distribution of PCB congeners differed greatly between fish and breast milk. The absorption or metabolism of each congener in the human body may greatly differ, resulting in different internal body concentrations among the PCB congeners. The chromatogram pattern of PCBs in breast milk was similar to the pattern of Kanechlor-500 (KC-500). Therefore, KC-500 was used as the standard for PCBs in 70’s, when their monitoring in breast milk was started (20). 140 Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 7. PCB congener composition in breast milk fat mixtures in 1973 and 2000. A nearly parallel correlation has been established between the packed-column GC-ECD pattern method (the analytical method used in the past) using KC-500 as the standard and the analytical values for each congener (total from TeCBs to HpCBs) obtained by GC/HRMS, although the former method gave values 1.2 to 2.5 times higher than those obtained by the latter method for each congener. This disparity was shown to decrease yearly. This marked difference between the PCB congener compositions of breast milk and KC-500 is puzzling. These findings suggest that the half-lives of PCBs in breast milk are longer than those reported previously (19), and that the PCBs are highly persistent in the body (Figure 8). In Japan, Kanechlor-300 (KC-300) is mainly used for PCBs. As for KC-300, many PCB congeners with low chlorine substitution exist, with the GC chromatograph pattern of the packed-column analysis being quite different from that of breast milk. The pattern method was used previously due to the non-availability of microanalysis equipment similar to that used today. However, the PCB concentrations determined by GC/HRMS microanalysis in actual breast milk were different from the packed-column method values. Naturally, the half-life was also different, being actually longer than that determined by the pattern method (20).

Figure 8. Trends in the arithmetic mean of PCB congener concentration in breast milk on a fat basis (25 to 29 year-old primiparous mothers): TeCBs (●), PeCBs (○), HxCBs (▲), and HpCBs (4). 141 Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Dioxins with chemical structures similar to PCBs are known to be highly persistent. We previously reported the changes of dioxin concentration in breast milk from 1973 to 1996 (23). This study included a detailed analysis of DL-PCBs, which are a type of dioxins, showing that the concentration of #77, which belongs to the TeCB class, decreased to 2.4% of earlier concentrations (277 pg/g fat in 1973, 7 pg/g fat in 1999), whereas #169, an HxCB class member, showed no significant decrease (35 pg/g fat in 1973, 34 pg/g fat in 1999) (28). A possible rationalization of this finding is that these concentrations are related not only to contamination due to PCB products, but also to the one caused by the incineration of chlorinated products. These PCBs pollute the environment and accumulate in the human body (88, 89), with their impacts on humans differing greatly depending on the congener in question (90). In particular, DL-PCBs, having a flat structure, are similar to dioxins (91). In 1998, the WHO determined the TDI of dioxins for humans as 1–4 pg/kg/day, and established dioxin TEFs for four types of non-ortho and eight types of mono-ortho PCBs (92). The TEFs of DL-PCBs (0.0001–0.1) are relatively small, but since PCBs tend to concentrate in the body, their TEQs in breast milk and blood may be comparable to those of PCDDs and PCDFs. There have also been reports of toxicity based on hormone effects and neurotoxicity related to PCBs, for which no TEFs have been reported (91). The TEFs of PCBs differ greatly with the type of accumulating congener (93). Due to these reasons, it is important to measure the concentration of each PCB congener that accumulates in the body. The enantiomers of chiral pesticides are often metabolized at different rates (94). Enantiomer fractions (EFs) of chiral compounds have been used to explain the mechanisms of enantiomer enrichment in environmental pollution (95). Nineteen PCB congeners chlorine-substituted in the 3- or 4- ortho-position have enantiomers (96). In general, the physical properties of chiral molecules, such as density, melting point, boiling point, refractive index, and thermal conductivity are identical. However, the physiological behaviors of enantiomers are thought to be quite different in vivo, since functional biomolecules like metabolic enzymes precisely distinguish between their three-dimensional structures (94). The enantiometric PCBs are also thought to behave similarly to other chiral molecules, which is closely related to their physiological effects, such as stability in the body and toxicity strength (97). To precisely estimate the risk to human health posed by POPs in breast milk and food, it is necessary to analyze the enantiomers separately and to caluculate EFs, which indicate the deviation from the racemic composition (industrial material). Recently, several enantioselective analyses of PCB congeners have been reported (98, 99). However, there are no reports on the time-dependent EF change for enantiometric PCBs in human food or biological samples. The EFs were calculated as follows (100), with numbers closer to EF = 0.5 indicating a composition nearer to the racemic form of the PCB contaminant.



The concentrations of each PCB#183 (2,2′,3,4,4′,5′,6-HpCB) enantiomer were plotted as a scatter graph starting at 1973 and fitted by an exponential approximation. The apparent half-lifes of each enantiomer were calculated using the parameters of exponential approximation as follows, where a is the concentration of year 1973 and b is the parameter of the fitted curve.

We analyzed enantiomeric PCB#183 in breast milk and fish samples prepared by a market basket study for around 30 years and confirmed the time trends of EFs while considering the relationship between food intake and human metabolism of chiral PCBs. The time trend of PCB#183 intake from fish, the largest source of human exposure to PCBs, shows that this intake was drastically decreased by the first half of the 1990s. In the case of breast milk, the concentration of PCB#183 decreased by half by the first half of the 1990s, similarly to the fish sample. The EFs of fish were close to racemic values (EF = 0.5) for 30 years. On the other hand, the EFs in breast milk were elevated year by year, as compared to fish samples, despite the decreasing concentration with time (Figure 9). This fact indicated that (–)-PCB#183 is metabolized more rapidly than (+)-PCB-183 in the human body. We also calculated the half-life of each enantiomer. First, the data plotted in the scatter chart were exponentially approximated, yielding a total PCB#183 half-life of 13.1 years. The half-life of (–)-PCB#183 was 11.6 years, while that of (+)-PCB #183 was 14.4 years (Figure 10). Due to the lack of information on the physiological effect of PCB#183 on the human body, detailed studies of the metabolic fate of each enantiomer and the toxicity of (+)-PCB-183 are required (25, 101)

Figure 9. Trends of PCB#183 EFs in breast milk and fish samples.



Figure 10. Time course of the concentration of PCB#183 enantiomers in breast milk: total PCB#183 (●), (+)-PCB#183 (▲), and (-)-PCB#183 (○). Trends for Brominated Flame Retardants HBCDs (Figure 11) are additive brominated flame retardants (BFRs) used in expanded and extruded polystyrene (EPS/XPS) insulation, high impact polystyrene (HIP) electronics, textiles, and polyvinyl chloride (PVC) cable sheathings. In Japan, HBCDs have been used as a replacement for PBDEs since the mid-1980s, with more than 2,000 metric tons of HBCDs annually used in industry since 2000. This figure increased to 2,400 tons in 2004 and to 2,577 tons in 2009, an amount that is nearly four times higher than the one in 1986 (The Chemical Daily Co., 1987–2006; Ministry of Economy, Trade and Industry of Japan) (Figure 12). HBCDs are lipophilic and have the potential for bioaccumulation (102), having been detected worldwide in various environmental matrices and aquatic/terrestrial animals. HBCDs were found in the breast milk of Norwegian women (103, 104), and stereoisomer-specific HBCD concentrations have been reported for the breast milk of women in North America (105). Human exposure to HBCDs takes place via multiple routes. For individuals not exposed to these compounds in their occupations, the major intake route is considered to be food and indoor air or dust (106, 107). Remberger et al. studied HBCD concentrations in foodstuffs and reported that the highest values were observed for fish (48 ng/g fat), followed by egg yolks (9.4 ng/g fat) and chicken (6.5 ng/g fat) (106). The European Union (EU) published a risk assessment report on HBCDs in 2008 (108), which described how these compounds disrupt the thyroid hormone systems, causing memory defects and significant changes in spontaneous behavior and learning. In the mid-2000’s, insufficient information on HBCD pollution in Japan was available, so contaminants were investigated via the determination of their concentration in food (27, 109, 110) and breast milk (111). For breast milk samples, we showed that the time course of HBCD concentrations appeared 144 Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


to be related to that of the technical HBCD demand (Figure 12). Akutsu et al. reported that PBDE was detected in breast milk samples collected in 1978, with concentrations continuously increasing until 1988 (112). The elevation time point for HBCD concentrations appeared later than that for PBDE concentrations (#28, #37, #75, #47, #66, #77, #100, #99, #85, #154, #153, #138, and #183) in breast milk collected in Japan (Figure 13). The concentration of HBCDs in samples obtained in 2000 or later was in the range of 1.0–4.0 ng/g fat, with these levels being approximately the same as those of PBDEs in breast milk (1.39 ng/g fat). Among the various HBCDs, α-HBCD was dominant. This compound was detected in all breast milk samples from Osaka, Japan, while γ-HBCD was detected in a number of samples, and β-HBCD was found in none of them.

Figure 11. Chemical structure of HBCDs.

Figure 12. Trend in the annual demand for HBCDs in Japan. 145 Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Figure 13. Time course of the HBCD (α, β, and γ stereoisomers) (▲) and PBDE (□) concentrations in the breast milk of Japanese women.

The estimated average HBCD intake level for breast-fed infants (aged 0 days to 3 months) was 7.5 ng/kg body weight per day, calculated based on breast milk samples collected from women aged 25–29 in 2007. This value was derived using a mathematical formula in the EU risk assessment report (108). For the market basket study samples, we detected HBCDs in fish group, with the estimated dietary intake of HBCDs being 6 ng/kg body weight per day (27). We also detected HBCDs in fish oil supplements (109) and estimated the daily intake of HBCDs according to the daily doses proposed by the product manufacturers. The maximum HBCD intake estimated for fish oil supplements in this study (200 ng/day) was higher than the reported median intake of HBCDs (141 ng/day) (107). The daily intake of HBCDs from fish by an average Japanese adult was tentatively calculated as 2.2 ng/kg body weight per day, which is much higher than the PBDE intake (115 pg/kg body weight per day) (110). Comparing these values to the reported estimated daily intake from fish, the HBCD intakes were comparatively higher than the reported value for Netherlands (0.12 ng/kg body weight per day) (113). Our data indicate that the frequent consumption of oil supplements or fish increases dietary exposure to HBCDs (109). The HBCD levels in both breast milk and food products were much lower than the no-observed-adverse-effect-level (NOAEL) of 10.2 μg/g body weight per day for HBCDs (114). The various reports revealed the bioaccumulation potential, toxicity, and persistent character of HBCDs, with enough circumstantial evidence to regard them as hazardous compounds. The industry began to slowly refrain from using HBCDs, with these compounds finally designated as a new persistent organic pollutant (Annex A) in the COP6 of the Stockholm Convention held in 2013 (115, 116). 146 Loganathan et al.; Persistent Organic Chemicals in the Environment: Status and Trends in the Pacific Basin Countries II ... ACS Symposium Series; American Chemical Society: Washington, DC, 2016.


Acknowledgments This research used frozen preserved milk fat to examine PCB contamination, and we wish to express our appreciation to the Maternal and Child Health Section of the Health Division, Health Prevention Section of the Osaka Prefecture for planning and implementing this study, and to the Environment and Public Health Bureau of Osaka City Office, the Sanitation Section of Sakai City, the Health Division of Higashi Osaka City, and all health centers in the Osaka Prefecture for the sample collection and delivery. We also gratefully acknowledge the contributions of all those who participated in the sample collection phase delivery. We also gratefully acknowledge and thank all study participants. We would like to thank Editage (www.editage.jp) for English language editing.

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