- Email: [email protected]
Plasticizer incident and its health effects in Taiwan
Kaohsiung Journal of Medical Sciences (2012) 28, S17eS21
Available online at www.sciencedirect.com
journal homepage: http://www.kjms-online.com
REVIEW ARTICLE
Plasticizer incident and its health effects in Taiwan* Jih-Heng Li a, Ying-Chin Ko b,c,* a
School of Pharmacy and Ph.D. Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan b Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan c Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Taiwan Received 2 February 2012; accepted 15 March 2012 Available online 7 July 2012
KEYWORDS Cloudy agent; Food safety; Health effect; Phthalate; Plasticizer
Abstract The May 23, 2011, plasticizer incident was one of the most serious food safety issues that ever occurred in Taiwan. Most, if not all, plasticizer-contaminated food items were due to malicious replacement of palm oil with phthalate plasticizer(s) in the cloudy-agent formulas by two upstream manufacturers. The incumbent agencies in Taiwan took necessary actions to minimize the harm caused by the incident and to ease the panic of the general public. In this paper, the incident was briefly reviewed and the situations of phthalate exposure in general public and pregnant women were assessed. Subsequently, the associations between phthalates exposure and the adverse health effects, such as shortened anogenital distance in baby boys, premature thelarche in young girls, endometriosis, adenomyosis, and leiomyoma in women, and decreased semen quality in men, were discussed. Food safety issue has become a worldwide concern and early detection of potential new toxicants in the foods is indispensable. Therefore, it is imperative to establish an international network for early warning or sentinel on food safety. Copyright ª 2012, Elsevier Taiwan LLC. All rights reserved.
Introduction
* This article is based on a paper presented at the Summit & 40th anniversary of National Center for Toxicological Research, Food and Drug Administration, U.S.A. on August 11, 2011. * Corresponding author. Center of Excellence for Environmental Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung City 80708, Taiwan. E-mail address: [email protected] (Y.-C. Ko).
On May 23, 2011, all major news media in Taiwan reported the explosive news on the incident of plasticizercontaminated food on the market. One of the major newspapers even described the incident in its headline as “the biggest plasticizer-contaminated food episode in human history [1].” The contaminated food items, including beverages (juice, sport drinks and tea), fruit jams/jelly, and dietary supplements, were taken off the
1607-551X/$36 Copyright ª 2012, Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.kjms.2012.05.005
S18 shelves by the mandate of the Department of Health [2]. With the widespread reports on the undesirable effects of plasticizer intake without providing complete information of exposure time and period (dose and dose rate), the general public was very nervous about the possible aftermaths of carcinogenesis and sex organ malformation in babies or young children. Such an incident has resulted in tremendous social costs. Therefore, we review this incident in hopes that some lessons can be learned from this scandalous experience.
J.-H. Li, Y.-C. Ko The affected food items were so profound that even Taiwan President Ma Ying-Jeou admitted in an interview that the plasticizer incident was a severe blow to public health and Taiwan’s international image. He also urged people not to panic over the incident. However, fear and panic spread among the general public as plasticizertainted food items were reported one after another. Pregnant women and parents with younger children were especially nervous for fear that their babies or kids might have been affected by the plasticizers and developed sex organ malformation.
Prologue to the incident Actions of the Taiwan government Although the explosive news was reported on May 23, 2011, the incident was initially detected 2 months earlier from a batch of probiotics raw material by a laboratory chemist at Taiwan’s Food and Drug Administration (TFDA). The discovery of a high concentration (600 ppm) of di-(2ethylhexyl) phthalate (DEHP) from the probiotics raw material soon led the TFDA in cooperation with local health bureaus and prosecutor’s office to track down the first upstream manufacturer of illicit “cloudy agents,” Yu-Shen Chemical Company in Chung-Ho District, New Taipei City [2]. A few days later, a second upstream manufacturer, PinHan Perfumery Company of Tu-Cheng District in New Taipei CIty, was also identified for illicitly replacing palm oil with DEHP and diisononyl phthalate (DiNP) in the so called “cloudy agents.”
Plasticizers as cloudy agents Plasticizers are added to plastics to increase their flexibility, durability, and pliability. Phthalates, which are the most widely used plasticizers in polyvinyl chloride (PVC) plastics, can be found in toys, food packages, paints, pharmaceuticals, medical devices, catheters, blood transfusion devices, personal-care products, cosmetics, and PVC flooring [3,4]. Addition of “cloudy agents” in foods had been a common practice for food processing in Taiwan. These cloudy agents were generally a variety of formulas served as emulsifiers to stabilize the emulsion-type foods. The plasticizers, such as phthalates, were adulterated in the cloudy agents for reasons of lower costs and longer preservation time [5].
Spread of panic After thorough investigation, it was found that Yu-Shen and Pin-Han were the two major providers of cloudy agents in Taiwan. These two companies manufactured cloudy agents and dispatched to eight distributors, which in turn distributed to 186 providers of food ingredients (for fruit flavoring powder, yogurt flavoring powder, and concentrated jam) and 229 end-product providers (for sports drinks, fruit juice, tablet, or a powder form of dietary supplements). As a result, a majority of food items were contaminated with plasticizers. These contaminated food products could be found in most of the super markets, pharmacies, beverage chain stores, restaurants, betel quid venders, night markets, and bakeries [6].
Under the pressure from the public and mandate from the Executive Yuan, the Department of Health expedited their actions to tackle with the plasticizer issue. As of July 20, 2011, 49,652 companies and stores were inspected by TFDA and 29,337 food items were pulled off the shelves [7]. Among these items, 1527.8 tons were confiscated and destroyed. After the nationwide inspection, 1291 food products were sampled for laboratory tests on plasticizer contamination, but no further violation was detected. To ease the agony of the public, the Department of Health also offered free health consultations in 119 hospitals in which 4133 people sought help from May 28 through July 19, 2011 [8]. Because the tainted foods may had been exported to other countries, the TFDA also notified the incident to 22 countries/regions, including Argentina, Australia, Brazil, Brunei, Canada, China, Costa Rica, Egypt, Germany, Hong Kong, Indonesia, Japan, Macao, Malaysia, Marshall Islands, New Zealand, the Philippines, Singapore, South Africa, Vietnam, United Kingdom, and the United States [8].
Epilogue To reinforce source control of plasticizers, the Taiwan Environmental Protection Agency (TEPA) rescheduled some items of plasticizers from Class 4 to Class 1 (non-biodegradable or bioaccumulative) and Class 2 (carcinogenic, teratogenic or mutagenic) poisons on July 20, 2011. According to the Toxic Substances Control Act, the use of class one to three poisons should be approved by the TEPA and their flows are subject to the monitoring and inspection of TEPA. On August 8, 2011, the TFDA announced that all the plasticizer-contaminated food items had been cleared from the market [9]. In order to prevent contamination of plasticizer from reoccurring, the TFDA vowed to protect the general public with more inspection and constant risk assessment on food safety. Meanwhile, in consultation with the food nutrition experts, the TFDA enacted an interim tolerable daily intake (TDI) for five commonly used plasticizers, i.e., di-(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), di-isononyl phthalate (DiNP), butyl benzyl phthalate (BBP), and di-isodecyl phthalate (DIDP) [9,10]. The interim TDI is shown in Table 1.
Plasticizer incident in Taiwan Table 1 Taiwan.
DEHP DBP BBP DiNP DIDP
S19
Interim TDI (mg/kgBW/day) of five plasticizers in Reference dose (EPA, USA)
TDI (EFSA, EU)
TDI (TFDA)
0.02 0.1 0.2
0.05 0.01 0.5 0.15
0.05 0.01 0.5 0.15 0.15
0.4
BBP Z butyl benzyl phthalate; DBP Z dibutyl phthalate; DEHP Z di-(2-ethylhexyl)phthalate; DIDP Z di-isodecyl phthalate; DiNP Z di-isononyl phthalate; EFSA Z European Food Safety Authority; TDI Z tolerable daily intake; TFDA Z Taiwan’s Food and Drug Administration.
Assessment of phthalates exposure in Taiwan There has been concern for the ubiquitous presence of phthalates in the environment. Phthalates can leach into our environment and food chain because they are not covalently bound to plastics [11,12]. According to the studies that are stated below, exposure to phthalates may have been a long-term phenomenon in Taiwan.
Exposure assessment in general population Microwaving food with a cover of polyvinyl chloride (PVC) film is a common cooking practice in Taiwan. In order to assess the migration level of phthalate from PVC films to food, Chen and colleagues [13] conducted a simulation study by microwaving PVC film-covered food for 3 minutes. It was then calculated that 1705.6 mg (or 92.2% of TDI for a 60-kg person) of DEHP would be ingested from a 400-g meal. In the same study, more than 90% of urine samples collected from 60 office workers were detectable for phthalate metabolites, including monomethyl phthalate (MMP), monobutyl phthalate (MBP), and monoethylhexyl phthalate (MEHP) [13]. The median value of estimated DEHP intake was 33.9 (0.1e309.6) mg/kg BW/day, which was about three times the value observed in a German study [14]. It was also found that 37% or 85% of the daily DEHP intake of the study subjects exceeded the TDI (37 mg/kg BW/day) of the European Union Scientific Committee for Toxicity, Ecotoxicity and the Environment, or the reference dose (200 mg/kg BW/day) of the U.S. Environmental Protection Agency (EPA), respectively [14]. Because the study was initiated in 2004, the results also imply that the general population in Taiwan may have already had high body burden of plasticizers long before the 2011 plasticizer incident.
Exposure assessment in pregnant women In another study, serum and urine samples of 76 Taiwanese pregnant women at second trimester were collected and analyzed for the association between phthalate exposure and thyroid hormones [15]. It was found that high median levels of metabolites of phthalate, including monobutyl
phthalate (MBP, 81.8 ng/ml), monoethyl phthalate (MEP, 27.7 ng/ml), and mono ethylhexyl phthalate (MEHP, 20.6 ng/ml) were present in the urine of subjects. The results also revealed significant mild negative correlations between thyroxine (T4) and urinary MBP and between free T4 and urinary MBP. In addition, direct skin contact and inhalation of evaporated di-ethyl phthalate (DEP) from cosmetic products may also be a risk factor of plasticizer exposure because a subject who had worked as a cosmetologist for over 10 years had the highest urinary MEP level (5466 ppb) [15].
Health effects of phthalates Phthalates are known environmental hormones or endocrine disruptors [16e20]. Because of their estrogenic and antiandrogenic effects, phthalates have been shown to prolong menstrual cycles and increase the proportion of premature menopause in animal models [21,22]. Some phthalates-associated adverse health effects in humans have also been observed. These adverse effects, especially those conducted in Taiwan, are discussed as follows.
Effects of phthalate exposure to fetus and young children Prenatal phthalate exposure can impair testicular function and decrease ano-genital distance (AGD) among male infants [23]. In a birth cohort of 300 newborns conducted in central Taiwan, the testosterone levels of subjects decreased with increasing phthalate exposures at the ages of 0, 2, and 5 years [24]. In addition, their prenatal exposure to phthalates was associated with decreased pre-school activities inventory (PSAI) scores at the age of 5 years and their feminine role was associated with prenatal exposure to BBP and DiNP metabolites [24]. Another study further confirmed that higher concentrations of dibutyl phthalate metabolites, mono-nbutyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP) and their sum, were associated with a decreased (less masculine) composite score in boys. A decreased masculine score was also associated with higher concentrations of two DEHP metabolites, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and the sum of these DEHP metabolites plus MEHP [25]. These findings suggest that some phthalates may alter androgen-responsive brain development in humans.
Major effects of phthalates on females In Taiwan, it has been found that girls with premature thelarche had significantly higher levels of MMP (96.5 134.0 ng/ml) than the normal controls (26.4 30.0 ng/ml). The results suggest phthalates may be one of the contributing factors for early puberty in Taiwanese girls [26]. Recently the association of phthalate exposures with endometriosis (EN), adenomyosis (AD), and leiomyoma (LEI) was studied on 28 Taiwanese female patients with confirmed pathologic EN, AD, and LEI. It was found that patients with LEI had significantly higher levels of total urinary MEHP than the controls, whereas patients
S20 with EN had an increased level of urinary MBP [27]. Furthermore, participants whose urinary levels of total MEHP were high and carried the glutathione S-transferase (GST) M1 null genotype showed a significantly increased risk for AD and LEI after adjustment for age, compared with those of low urinary levels of total MEHP with GSTM1 wildtype [27]. These results imply that a pregnant woman with a high exposure and defective metabolism of phthalates would be vulnerable to AD and LEI.
Major effects of phthalates on males The semen samples of 45 male workers, employed in two PVC pellet plants in Taiwan, were collected and assessed for sperm concentration, motility, morphology, and chromatin DNA integrity. The results demonstrated an association between DEHP concentration in ambient air and the adverse effects in sperm motility and chromatin DNA integrity [28]. In addition to decreased semen quality and sperm concentration, testicular dysgenesis syndrome, male reproductive tract abnormalities and testicular cancer have also been suggested to be associated with phthalate exposures [29].
Phthalate-related asthma A correlation between phthalate exposures and asthma has been observed by epidemiologic approaches [30e32]. One plausible mechanism is that exposure to phthalate esters can trigger the bronchial epithelium to produce inflammatory cytokines interleukin-8 (IL-8) and regulated upon activation, Normal T cell Expressed and presumably Secreted (RANTES), which, in turn, contributes to airway remodeling by increasing the migration and proliferation of human bronchial smooth muscle cells [33]. In the same study, bioactive components of ginger (Zingiber officinale), including [6]-shogaol, [6]-gingerol, [8]-gingerol, and [10]gingerol, were found capable of suppressing phthalate ester-mediated airway remodeling in human bronchial epithelial cell culture systems [33].
Characterization of the plasticizer incident From the above description, we may find the plasticizer incident unique in at least two aspects if we compare it with the previous major food safety issues. First, by contrast to the causing agents in the previous major food safety issues that could be detected only after an incident occurred, DEHP was identified before the plasticizer incident broke out. For instance, when the rice-bran oil incident [polychlorinated biphenyls (PCBs) poisoning or Yu-Cheng] broke out on May 21, 1979, the causing agent was totally unknown to the government officials and experts [34]. Identification of PCB contamination by instrumental analysis was performed only on limited information of rice-bran oil used from a common source: a local rice-bran oil company in Changhua County. Such a difference can be attributed, at least in part, to the rapid development of analytical instruments and methods whose sensitivity can now detect tiny amounts of unknown toxicants that could not be detected decades ago. Second, as summarized in this paper, some adverse effects have been
J.-H. Li, Y.-C. Ko associated with phthalate exposures. However, the exact cause-effect relationship and health risks in humans due to phthalate exposures are yet to be validated. Unlike previous food safety incidents that could be easily identified from the affected victims by their pathologic symptoms, the plasticizer incident had no apparent patients and seemed victimless. But, on the other hand, we may have been victimized because phthalates can be detected for a long time in most, if not all, people in Taiwan [13,15,24]. Thus, for toxicants with chronic or delayed adverse effects, their toxicological profiles, especially toxicokinetics and TDI for long-term repetitive exposures, should be thoroughly examined. Furthermore, phthalates, similar to PCBs, are a mixture of compounds and their toxicity in sum total should be weighted for their differential toxic effects. Therefore, the toxic equivalent (TEQ) should also be established according to their specific toxic equivalency factor (TEF).
Conclusion and future direction In the 2011 plasticizer incident, many food companies/ stores were severely affected. It has been estimated that approximately $350 million (10 billion NT dollars) were at the expenses of food industry in Taiwan [35]. The confidence of general public on the food safety remains to be restored. Although it is understandable that risk perceptions are different among the lay general public and experts due to the unawareness and naivete ´ of the general public to a specific toxicant, the responsible agency, TFDA, should elaborate on a more delicate plan of risk communications so that unnecessary panic of the public can be eliminated or minimized [36,37]. Exposure to phthalates can cause a variety of health effects, notably reproductive and developmental toxicities. It may also result in allergic diseases or pose a carcinogenic threat. Therefore, pregnant women/fetus and children are the most vulnerable population. While it is the responsibility of the TFDA and related agencies to monitor more closely on the food safety issues, it also reveals that an adulterated food product, as witnessed in the plasticizer incident, may not be easily detected through the routine official examinations. Although exposure to phthalates has been related to several human diseases, further research on safety assessment and management is needed. Meanwhile, regulatory actions such as establishment of official criteria of TDI for phthalate (and other plasticizers) and food market surveillance should be prioritized. While an epidemiologic study may manifest an association between phthalate exposures and a specific human disease, it takes time to demonstrate such a link. To facilitate the process, approaches with toxicogenomic studies on phthalates for inferred human diseases, as shown by a toxicogenomic study that the top three categories of phthalate toxicity could be cardiotoxicity, hepatotoxicity, and nephrotoxicity [38], may be of help from the viewpoint of preventive medicine. On the other hand, food safety issue has become a worldwide concern and early detection of potential new toxicants in the foods is indispensable. Therefore, it is imperative to establish an international network for early warning or sentinel on food safety.
Plasticizer incident in Taiwan
Acknowledgment The authors would like to thank the Department of Health, Executive Yuan, ROC, for providing the information that is posted on the website (http://www.fda.gov.tw/news.aspx? newssn, as shown in the references).
References [1] Editorial Team, The biggest plasticizer-contaminated food episode in human history, Column A1, Apple Daily, May 28, 2011. [2] Taiwan’s Food and Drug Administration report, May 23, 2011. http://www.fda.gov.tw/news.aspx?newssnZ7618&key_ yearZ2011&keywordZ&classifysnZ4 [accessed 27.06.12]. [3] Wormuth M, Scheringer M, Vollenweider M, Hungerbuhler K. What are the sources of exposure to eight frequently used phthalic acid esters in Europeans? Risk Anal 2006;26:803e24. [4] Ticker JA, Schettler T, Guidotti T, McCally M, Rossi M. Health risks posed by use of di-ethylhexyl phthalate (DEHP) in PVC medical devices: a critical review. Am J Ind Med 2001;39: 100e11. [5] Taiwan’s Food and Drug Administration report, May 28, 2011. http://www.fda.gov.tw/news.aspx?newssnZ7641&key_ yearZ2011&keywordZ&classifysnZ4 [accessed 26.06.12]. [6] Taiwan’s Food and Drug Administration report, May 28, 2011. http://www.fda.gov.tw/news.aspx?newssnZ7642&key_ yearZ2011&keywordZ&classifysnZ4 [accessed 26.06.12]. [7] Report of the 24th multi-ministerial committee on food safety, July 20, 2011. http://www.fda.gov.tw/news.aspx? newssnZ7863&key_yearZ2011&keywordZ&classifysnZ4 [accessed 27.06.12]. [8] Report of the 19th multi-ministerial committee on food safety, June 24, 2011. http://www.fda.gov.tw/news.aspx? newssnZ7791&key_yearZ2011&keywordZ&classifysnZ4 [accessed 27.06.12]. [9] Taiwan’s Food and Drug Administration report, August 8, 2011. http://www.fda.gov.tw/news.aspx?newssnZ7898&classifysn Z4 [accessed 27.06.12]. [10] Taiwan’s Food and Drug Administration Gazette, July 14, 2011. http://jensen.happywin.com.tw/new_detail.php?nidZ65 [accessed 27.06.12]. [11] Heudorf U, Mersch-Sundermann V, Angerer JG. Phthalates: toxicology and exposure. Int J Hyg Environ Health 2007;210: 623e34. [12] Silva MJ, Barr DB, Reidy JA, Malek NA, Hodge CC, Caudill SP, et al. Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999-2000. Environ. Health Perspect 2004;112:331e8. [13] Chen ML, Chen JS, Tang CL, Mao IF. The internal exposure of Taiwanese to phthalate e an evidence of intensive use of plastic materials. Environ Int 2008;34:79e85. [14] Koch HM, Drexler H, Angerer JR. An estimation of the daily intake of di(2-ethylhexyl)phthalate (DEHP) and other phthalates in the general population. Int J Hyg Environ Health 2003; 206:77e83. [15] Huang PC, Kuo PL, Guo YL, Liao PC, Lee CC. Associations between urinary phthalate monoesters and thyroid hormones in pregnant women. Human Rep 2007;22:2715e22. [16] Siddiqui A, Srivastava SP. Effect of di(2-ethylhexyl) phthalate administration on rat sperm count and on sperm metabolic enzymes. Bull Environ Contam Toxicol 1992;48:115e9. [17] Fredricsson B, Mu ¨ller L, Pousette A, Westerholm R. Human sperm motility is affected by plasticizers and diesel particle extracts. Pharmacol Toxicol 1993;72:128e33.
S21 [18] Imajima T, Shono T, Zakaria O, Suita S. Prenatal phthalate causes cryptorchidism postnatally by inducing transabdominal ascent of the testis in fetal rats. J Pediatr Surg 1997;32:18e21. [19] Poon R, Lecavaliert P, Mueller R, Valli V, Procter B, Chu I. Subchronic oral toxicity of di-n-octyl phthalate and di(2-ethylhexyl) phthalate in the rat. Food Chem Toxicol 1997;35:225e39. [20] Arcadi R, Costa C, Imperatore C. Oral toxicity of DEHP during pregnacy and suckling in the Long-Evans rat. Food Chem Toxicol 1998;36:963e74. [21] Ma M, Kondo T, Ban S, Umemura T, Kurahashi N, Takeda M, et al. Exposure of prepubertal female rats to inhaled di(2ethylhexyl)phthalate affects the onset of puberty and postpubertal reproductive functions. Toxicol Sci 2006;93:164e71. [22] Moore NP. The oestrogenic potential of the phthalate esters. Reprod Toxicol 2000;14:183e92. [23] Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect 2005;113:1056e61. [24] Wang S, Su B, Ku H, Chen J, Huang H, Guo Y, et al. Prenatal phthalate exposure and gender role behavior in preschool children from central Taiwan. Epidemiology 2008;19:s277. [25] Swan SH, Liu F, Hines M, Kruse RL, Wang C, Redmon JB, et al. Prenatal phthalate exposure and reduced masculine play in boys. Int J Androl 2010;33:259e69. [26] Chou YY, Huang PC, Lee CC, Wu MH, Lin SJ. Phthalate exposure in girls during early puberty. J Pediatr Endocrinol Metab 2009;22:69e77. [27] Huang PC, Tsai EM, Li WF, Liao PC, Chung MC, Wang YH, et al. Association between phthalate exposure and glutathione Stransferase M1 polymorphism in adenomyosis, leiomyoma and endometriosis. Human Reproduction 2010;25:986e94. [28] Huang LP, Lee CC, Hsu PC, Shih TS. The association between semen quality in workers and the concentration of di(2ethylhexyl) phthalate in polyvinyl chloride pellet plant air. Fertil Steril 2011;96:90e4. [29] Fisher JS. Environmental anti-androgens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome. Reproduction 2004;127:305e15. [30] Jaakkola JJ, Parise H, Kislitsin V, Lebedeva NI, Spengler JD. Asthma, wheezing, and allergies in Russian schoolchildren in relation to new surface materials in the home. Am J Public Health 2004;94:560e2. [31] Wang TN, Lin MC, Wu CC, Leung SY, Huang MS, Chang HY, et al. Risks of exposure to occupational asthmogens in atopic and nonatopic asthma: a case-control study in Taiwan. Am J Respir Crit Care Med 2010;182:1369e76. [32] Bornehag CG, Nanberg E. Phthalate exposure and asthma in children. Int J Androl 2010;33:333e45. [33] Kuo PL, Hsu YL, Huang MS, Tsai MJ, Ko YC. Ginger suppresses phthalate ester-induced airway remodeling. J Agr Food Chem 2011;59:3429e38. [34] Hsu ST, Ma CI, Hsu SH, Wu SS, Hsu NHM, Yeh CC, et al. Discovery and Epidemiology of PCB Poisoning in Taiwan: A Four-Year Followup. Environ Health Perspect 1985;59:5e10. [35] Workshop on Plasticizer incident-related regulations and practices. Taipei Biotechnology Service and Commercial Association, Taipei, June 25, 2011. [36] Cope S, Frewer LJ, Houghton J, Rowe G, Fischer ARH, de Jonge J. Consumer perceptions of best practice in food risk communication and management: implications for risk analysis policy. Food Policy 2010;35:349e57. [37] van Kleef E, Frewer LJ, Chryssochoidis GM, Houghton JR, Korzen-Bohr S, Krystallis T, et al. Perceptions of food risk management among key stakeholders: results from a crossEuropean study. Appetite 2006;47:46e63. [38] Singh S, Li SSL. Phthalates: toxicogenomics and inferred human diseases. Genomics 2011;97:148e57.
Available online at www.sciencedirect.com
journal homepage: http://www.kjms-online.com
REVIEW ARTICLE
Plasticizer incident and its health effects in Taiwan* Jih-Heng Li a, Ying-Chin Ko b,c,* a
School of Pharmacy and Ph.D. Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan b Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan c Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Taiwan Received 2 February 2012; accepted 15 March 2012 Available online 7 July 2012
KEYWORDS Cloudy agent; Food safety; Health effect; Phthalate; Plasticizer
Abstract The May 23, 2011, plasticizer incident was one of the most serious food safety issues that ever occurred in Taiwan. Most, if not all, plasticizer-contaminated food items were due to malicious replacement of palm oil with phthalate plasticizer(s) in the cloudy-agent formulas by two upstream manufacturers. The incumbent agencies in Taiwan took necessary actions to minimize the harm caused by the incident and to ease the panic of the general public. In this paper, the incident was briefly reviewed and the situations of phthalate exposure in general public and pregnant women were assessed. Subsequently, the associations between phthalates exposure and the adverse health effects, such as shortened anogenital distance in baby boys, premature thelarche in young girls, endometriosis, adenomyosis, and leiomyoma in women, and decreased semen quality in men, were discussed. Food safety issue has become a worldwide concern and early detection of potential new toxicants in the foods is indispensable. Therefore, it is imperative to establish an international network for early warning or sentinel on food safety. Copyright ª 2012, Elsevier Taiwan LLC. All rights reserved.
Introduction
* This article is based on a paper presented at the Summit & 40th anniversary of National Center for Toxicological Research, Food and Drug Administration, U.S.A. on August 11, 2011. * Corresponding author. Center of Excellence for Environmental Medicine, Kaohsiung Medical University, 100 Shih-Chuan 1st Road, Kaohsiung City 80708, Taiwan. E-mail address: [email protected] (Y.-C. Ko).
On May 23, 2011, all major news media in Taiwan reported the explosive news on the incident of plasticizercontaminated food on the market. One of the major newspapers even described the incident in its headline as “the biggest plasticizer-contaminated food episode in human history [1].” The contaminated food items, including beverages (juice, sport drinks and tea), fruit jams/jelly, and dietary supplements, were taken off the
1607-551X/$36 Copyright ª 2012, Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.kjms.2012.05.005
S18 shelves by the mandate of the Department of Health [2]. With the widespread reports on the undesirable effects of plasticizer intake without providing complete information of exposure time and period (dose and dose rate), the general public was very nervous about the possible aftermaths of carcinogenesis and sex organ malformation in babies or young children. Such an incident has resulted in tremendous social costs. Therefore, we review this incident in hopes that some lessons can be learned from this scandalous experience.
J.-H. Li, Y.-C. Ko The affected food items were so profound that even Taiwan President Ma Ying-Jeou admitted in an interview that the plasticizer incident was a severe blow to public health and Taiwan’s international image. He also urged people not to panic over the incident. However, fear and panic spread among the general public as plasticizertainted food items were reported one after another. Pregnant women and parents with younger children were especially nervous for fear that their babies or kids might have been affected by the plasticizers and developed sex organ malformation.
Prologue to the incident Actions of the Taiwan government Although the explosive news was reported on May 23, 2011, the incident was initially detected 2 months earlier from a batch of probiotics raw material by a laboratory chemist at Taiwan’s Food and Drug Administration (TFDA). The discovery of a high concentration (600 ppm) of di-(2ethylhexyl) phthalate (DEHP) from the probiotics raw material soon led the TFDA in cooperation with local health bureaus and prosecutor’s office to track down the first upstream manufacturer of illicit “cloudy agents,” Yu-Shen Chemical Company in Chung-Ho District, New Taipei City [2]. A few days later, a second upstream manufacturer, PinHan Perfumery Company of Tu-Cheng District in New Taipei CIty, was also identified for illicitly replacing palm oil with DEHP and diisononyl phthalate (DiNP) in the so called “cloudy agents.”
Plasticizers as cloudy agents Plasticizers are added to plastics to increase their flexibility, durability, and pliability. Phthalates, which are the most widely used plasticizers in polyvinyl chloride (PVC) plastics, can be found in toys, food packages, paints, pharmaceuticals, medical devices, catheters, blood transfusion devices, personal-care products, cosmetics, and PVC flooring [3,4]. Addition of “cloudy agents” in foods had been a common practice for food processing in Taiwan. These cloudy agents were generally a variety of formulas served as emulsifiers to stabilize the emulsion-type foods. The plasticizers, such as phthalates, were adulterated in the cloudy agents for reasons of lower costs and longer preservation time [5].
Spread of panic After thorough investigation, it was found that Yu-Shen and Pin-Han were the two major providers of cloudy agents in Taiwan. These two companies manufactured cloudy agents and dispatched to eight distributors, which in turn distributed to 186 providers of food ingredients (for fruit flavoring powder, yogurt flavoring powder, and concentrated jam) and 229 end-product providers (for sports drinks, fruit juice, tablet, or a powder form of dietary supplements). As a result, a majority of food items were contaminated with plasticizers. These contaminated food products could be found in most of the super markets, pharmacies, beverage chain stores, restaurants, betel quid venders, night markets, and bakeries [6].
Under the pressure from the public and mandate from the Executive Yuan, the Department of Health expedited their actions to tackle with the plasticizer issue. As of July 20, 2011, 49,652 companies and stores were inspected by TFDA and 29,337 food items were pulled off the shelves [7]. Among these items, 1527.8 tons were confiscated and destroyed. After the nationwide inspection, 1291 food products were sampled for laboratory tests on plasticizer contamination, but no further violation was detected. To ease the agony of the public, the Department of Health also offered free health consultations in 119 hospitals in which 4133 people sought help from May 28 through July 19, 2011 [8]. Because the tainted foods may had been exported to other countries, the TFDA also notified the incident to 22 countries/regions, including Argentina, Australia, Brazil, Brunei, Canada, China, Costa Rica, Egypt, Germany, Hong Kong, Indonesia, Japan, Macao, Malaysia, Marshall Islands, New Zealand, the Philippines, Singapore, South Africa, Vietnam, United Kingdom, and the United States [8].
Epilogue To reinforce source control of plasticizers, the Taiwan Environmental Protection Agency (TEPA) rescheduled some items of plasticizers from Class 4 to Class 1 (non-biodegradable or bioaccumulative) and Class 2 (carcinogenic, teratogenic or mutagenic) poisons on July 20, 2011. According to the Toxic Substances Control Act, the use of class one to three poisons should be approved by the TEPA and their flows are subject to the monitoring and inspection of TEPA. On August 8, 2011, the TFDA announced that all the plasticizer-contaminated food items had been cleared from the market [9]. In order to prevent contamination of plasticizer from reoccurring, the TFDA vowed to protect the general public with more inspection and constant risk assessment on food safety. Meanwhile, in consultation with the food nutrition experts, the TFDA enacted an interim tolerable daily intake (TDI) for five commonly used plasticizers, i.e., di-(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), di-isononyl phthalate (DiNP), butyl benzyl phthalate (BBP), and di-isodecyl phthalate (DIDP) [9,10]. The interim TDI is shown in Table 1.
Plasticizer incident in Taiwan Table 1 Taiwan.
DEHP DBP BBP DiNP DIDP
S19
Interim TDI (mg/kgBW/day) of five plasticizers in Reference dose (EPA, USA)
TDI (EFSA, EU)
TDI (TFDA)
0.02 0.1 0.2
0.05 0.01 0.5 0.15
0.05 0.01 0.5 0.15 0.15
0.4
BBP Z butyl benzyl phthalate; DBP Z dibutyl phthalate; DEHP Z di-(2-ethylhexyl)phthalate; DIDP Z di-isodecyl phthalate; DiNP Z di-isononyl phthalate; EFSA Z European Food Safety Authority; TDI Z tolerable daily intake; TFDA Z Taiwan’s Food and Drug Administration.
Assessment of phthalates exposure in Taiwan There has been concern for the ubiquitous presence of phthalates in the environment. Phthalates can leach into our environment and food chain because they are not covalently bound to plastics [11,12]. According to the studies that are stated below, exposure to phthalates may have been a long-term phenomenon in Taiwan.
Exposure assessment in general population Microwaving food with a cover of polyvinyl chloride (PVC) film is a common cooking practice in Taiwan. In order to assess the migration level of phthalate from PVC films to food, Chen and colleagues [13] conducted a simulation study by microwaving PVC film-covered food for 3 minutes. It was then calculated that 1705.6 mg (or 92.2% of TDI for a 60-kg person) of DEHP would be ingested from a 400-g meal. In the same study, more than 90% of urine samples collected from 60 office workers were detectable for phthalate metabolites, including monomethyl phthalate (MMP), monobutyl phthalate (MBP), and monoethylhexyl phthalate (MEHP) [13]. The median value of estimated DEHP intake was 33.9 (0.1e309.6) mg/kg BW/day, which was about three times the value observed in a German study [14]. It was also found that 37% or 85% of the daily DEHP intake of the study subjects exceeded the TDI (37 mg/kg BW/day) of the European Union Scientific Committee for Toxicity, Ecotoxicity and the Environment, or the reference dose (200 mg/kg BW/day) of the U.S. Environmental Protection Agency (EPA), respectively [14]. Because the study was initiated in 2004, the results also imply that the general population in Taiwan may have already had high body burden of plasticizers long before the 2011 plasticizer incident.
Exposure assessment in pregnant women In another study, serum and urine samples of 76 Taiwanese pregnant women at second trimester were collected and analyzed for the association between phthalate exposure and thyroid hormones [15]. It was found that high median levels of metabolites of phthalate, including monobutyl
phthalate (MBP, 81.8 ng/ml), monoethyl phthalate (MEP, 27.7 ng/ml), and mono ethylhexyl phthalate (MEHP, 20.6 ng/ml) were present in the urine of subjects. The results also revealed significant mild negative correlations between thyroxine (T4) and urinary MBP and between free T4 and urinary MBP. In addition, direct skin contact and inhalation of evaporated di-ethyl phthalate (DEP) from cosmetic products may also be a risk factor of plasticizer exposure because a subject who had worked as a cosmetologist for over 10 years had the highest urinary MEP level (5466 ppb) [15].
Health effects of phthalates Phthalates are known environmental hormones or endocrine disruptors [16e20]. Because of their estrogenic and antiandrogenic effects, phthalates have been shown to prolong menstrual cycles and increase the proportion of premature menopause in animal models [21,22]. Some phthalates-associated adverse health effects in humans have also been observed. These adverse effects, especially those conducted in Taiwan, are discussed as follows.
Effects of phthalate exposure to fetus and young children Prenatal phthalate exposure can impair testicular function and decrease ano-genital distance (AGD) among male infants [23]. In a birth cohort of 300 newborns conducted in central Taiwan, the testosterone levels of subjects decreased with increasing phthalate exposures at the ages of 0, 2, and 5 years [24]. In addition, their prenatal exposure to phthalates was associated with decreased pre-school activities inventory (PSAI) scores at the age of 5 years and their feminine role was associated with prenatal exposure to BBP and DiNP metabolites [24]. Another study further confirmed that higher concentrations of dibutyl phthalate metabolites, mono-nbutyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP) and their sum, were associated with a decreased (less masculine) composite score in boys. A decreased masculine score was also associated with higher concentrations of two DEHP metabolites, mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and the sum of these DEHP metabolites plus MEHP [25]. These findings suggest that some phthalates may alter androgen-responsive brain development in humans.
Major effects of phthalates on females In Taiwan, it has been found that girls with premature thelarche had significantly higher levels of MMP (96.5 134.0 ng/ml) than the normal controls (26.4 30.0 ng/ml). The results suggest phthalates may be one of the contributing factors for early puberty in Taiwanese girls [26]. Recently the association of phthalate exposures with endometriosis (EN), adenomyosis (AD), and leiomyoma (LEI) was studied on 28 Taiwanese female patients with confirmed pathologic EN, AD, and LEI. It was found that patients with LEI had significantly higher levels of total urinary MEHP than the controls, whereas patients
S20 with EN had an increased level of urinary MBP [27]. Furthermore, participants whose urinary levels of total MEHP were high and carried the glutathione S-transferase (GST) M1 null genotype showed a significantly increased risk for AD and LEI after adjustment for age, compared with those of low urinary levels of total MEHP with GSTM1 wildtype [27]. These results imply that a pregnant woman with a high exposure and defective metabolism of phthalates would be vulnerable to AD and LEI.
Major effects of phthalates on males The semen samples of 45 male workers, employed in two PVC pellet plants in Taiwan, were collected and assessed for sperm concentration, motility, morphology, and chromatin DNA integrity. The results demonstrated an association between DEHP concentration in ambient air and the adverse effects in sperm motility and chromatin DNA integrity [28]. In addition to decreased semen quality and sperm concentration, testicular dysgenesis syndrome, male reproductive tract abnormalities and testicular cancer have also been suggested to be associated with phthalate exposures [29].
Phthalate-related asthma A correlation between phthalate exposures and asthma has been observed by epidemiologic approaches [30e32]. One plausible mechanism is that exposure to phthalate esters can trigger the bronchial epithelium to produce inflammatory cytokines interleukin-8 (IL-8) and regulated upon activation, Normal T cell Expressed and presumably Secreted (RANTES), which, in turn, contributes to airway remodeling by increasing the migration and proliferation of human bronchial smooth muscle cells [33]. In the same study, bioactive components of ginger (Zingiber officinale), including [6]-shogaol, [6]-gingerol, [8]-gingerol, and [10]gingerol, were found capable of suppressing phthalate ester-mediated airway remodeling in human bronchial epithelial cell culture systems [33].
Characterization of the plasticizer incident From the above description, we may find the plasticizer incident unique in at least two aspects if we compare it with the previous major food safety issues. First, by contrast to the causing agents in the previous major food safety issues that could be detected only after an incident occurred, DEHP was identified before the plasticizer incident broke out. For instance, when the rice-bran oil incident [polychlorinated biphenyls (PCBs) poisoning or Yu-Cheng] broke out on May 21, 1979, the causing agent was totally unknown to the government officials and experts [34]. Identification of PCB contamination by instrumental analysis was performed only on limited information of rice-bran oil used from a common source: a local rice-bran oil company in Changhua County. Such a difference can be attributed, at least in part, to the rapid development of analytical instruments and methods whose sensitivity can now detect tiny amounts of unknown toxicants that could not be detected decades ago. Second, as summarized in this paper, some adverse effects have been
J.-H. Li, Y.-C. Ko associated with phthalate exposures. However, the exact cause-effect relationship and health risks in humans due to phthalate exposures are yet to be validated. Unlike previous food safety incidents that could be easily identified from the affected victims by their pathologic symptoms, the plasticizer incident had no apparent patients and seemed victimless. But, on the other hand, we may have been victimized because phthalates can be detected for a long time in most, if not all, people in Taiwan [13,15,24]. Thus, for toxicants with chronic or delayed adverse effects, their toxicological profiles, especially toxicokinetics and TDI for long-term repetitive exposures, should be thoroughly examined. Furthermore, phthalates, similar to PCBs, are a mixture of compounds and their toxicity in sum total should be weighted for their differential toxic effects. Therefore, the toxic equivalent (TEQ) should also be established according to their specific toxic equivalency factor (TEF).
Conclusion and future direction In the 2011 plasticizer incident, many food companies/ stores were severely affected. It has been estimated that approximately $350 million (10 billion NT dollars) were at the expenses of food industry in Taiwan [35]. The confidence of general public on the food safety remains to be restored. Although it is understandable that risk perceptions are different among the lay general public and experts due to the unawareness and naivete ´ of the general public to a specific toxicant, the responsible agency, TFDA, should elaborate on a more delicate plan of risk communications so that unnecessary panic of the public can be eliminated or minimized [36,37]. Exposure to phthalates can cause a variety of health effects, notably reproductive and developmental toxicities. It may also result in allergic diseases or pose a carcinogenic threat. Therefore, pregnant women/fetus and children are the most vulnerable population. While it is the responsibility of the TFDA and related agencies to monitor more closely on the food safety issues, it also reveals that an adulterated food product, as witnessed in the plasticizer incident, may not be easily detected through the routine official examinations. Although exposure to phthalates has been related to several human diseases, further research on safety assessment and management is needed. Meanwhile, regulatory actions such as establishment of official criteria of TDI for phthalate (and other plasticizers) and food market surveillance should be prioritized. While an epidemiologic study may manifest an association between phthalate exposures and a specific human disease, it takes time to demonstrate such a link. To facilitate the process, approaches with toxicogenomic studies on phthalates for inferred human diseases, as shown by a toxicogenomic study that the top three categories of phthalate toxicity could be cardiotoxicity, hepatotoxicity, and nephrotoxicity [38], may be of help from the viewpoint of preventive medicine. On the other hand, food safety issue has become a worldwide concern and early detection of potential new toxicants in the foods is indispensable. Therefore, it is imperative to establish an international network for early warning or sentinel on food safety.
Plasticizer incident in Taiwan
Acknowledgment The authors would like to thank the Department of Health, Executive Yuan, ROC, for providing the information that is posted on the website (http://www.fda.gov.tw/news.aspx? newssn, as shown in the references).
References [1] Editorial Team, The biggest plasticizer-contaminated food episode in human history, Column A1, Apple Daily, May 28, 2011. [2] Taiwan’s Food and Drug Administration report, May 23, 2011. http://www.fda.gov.tw/news.aspx?newssnZ7618&key_ yearZ2011&keywordZ&classifysnZ4 [accessed 27.06.12]. [3] Wormuth M, Scheringer M, Vollenweider M, Hungerbuhler K. What are the sources of exposure to eight frequently used phthalic acid esters in Europeans? Risk Anal 2006;26:803e24. [4] Ticker JA, Schettler T, Guidotti T, McCally M, Rossi M. Health risks posed by use of di-ethylhexyl phthalate (DEHP) in PVC medical devices: a critical review. Am J Ind Med 2001;39: 100e11. [5] Taiwan’s Food and Drug Administration report, May 28, 2011. http://www.fda.gov.tw/news.aspx?newssnZ7641&key_ yearZ2011&keywordZ&classifysnZ4 [accessed 26.06.12]. [6] Taiwan’s Food and Drug Administration report, May 28, 2011. http://www.fda.gov.tw/news.aspx?newssnZ7642&key_ yearZ2011&keywordZ&classifysnZ4 [accessed 26.06.12]. [7] Report of the 24th multi-ministerial committee on food safety, July 20, 2011. http://www.fda.gov.tw/news.aspx? newssnZ7863&key_yearZ2011&keywordZ&classifysnZ4 [accessed 27.06.12]. [8] Report of the 19th multi-ministerial committee on food safety, June 24, 2011. http://www.fda.gov.tw/news.aspx? newssnZ7791&key_yearZ2011&keywordZ&classifysnZ4 [accessed 27.06.12]. [9] Taiwan’s Food and Drug Administration report, August 8, 2011. http://www.fda.gov.tw/news.aspx?newssnZ7898&classifysn Z4 [accessed 27.06.12]. [10] Taiwan’s Food and Drug Administration Gazette, July 14, 2011. http://jensen.happywin.com.tw/new_detail.php?nidZ65 [accessed 27.06.12]. [11] Heudorf U, Mersch-Sundermann V, Angerer JG. Phthalates: toxicology and exposure. Int J Hyg Environ Health 2007;210: 623e34. [12] Silva MJ, Barr DB, Reidy JA, Malek NA, Hodge CC, Caudill SP, et al. Urinary levels of seven phthalate metabolites in the U.S. population from the National Health and Nutrition Examination Survey (NHANES) 1999-2000. Environ. Health Perspect 2004;112:331e8. [13] Chen ML, Chen JS, Tang CL, Mao IF. The internal exposure of Taiwanese to phthalate e an evidence of intensive use of plastic materials. Environ Int 2008;34:79e85. [14] Koch HM, Drexler H, Angerer JR. An estimation of the daily intake of di(2-ethylhexyl)phthalate (DEHP) and other phthalates in the general population. Int J Hyg Environ Health 2003; 206:77e83. [15] Huang PC, Kuo PL, Guo YL, Liao PC, Lee CC. Associations between urinary phthalate monoesters and thyroid hormones in pregnant women. Human Rep 2007;22:2715e22. [16] Siddiqui A, Srivastava SP. Effect of di(2-ethylhexyl) phthalate administration on rat sperm count and on sperm metabolic enzymes. Bull Environ Contam Toxicol 1992;48:115e9. [17] Fredricsson B, Mu ¨ller L, Pousette A, Westerholm R. Human sperm motility is affected by plasticizers and diesel particle extracts. Pharmacol Toxicol 1993;72:128e33.
S21 [18] Imajima T, Shono T, Zakaria O, Suita S. Prenatal phthalate causes cryptorchidism postnatally by inducing transabdominal ascent of the testis in fetal rats. J Pediatr Surg 1997;32:18e21. [19] Poon R, Lecavaliert P, Mueller R, Valli V, Procter B, Chu I. Subchronic oral toxicity of di-n-octyl phthalate and di(2-ethylhexyl) phthalate in the rat. Food Chem Toxicol 1997;35:225e39. [20] Arcadi R, Costa C, Imperatore C. Oral toxicity of DEHP during pregnacy and suckling in the Long-Evans rat. Food Chem Toxicol 1998;36:963e74. [21] Ma M, Kondo T, Ban S, Umemura T, Kurahashi N, Takeda M, et al. Exposure of prepubertal female rats to inhaled di(2ethylhexyl)phthalate affects the onset of puberty and postpubertal reproductive functions. Toxicol Sci 2006;93:164e71. [22] Moore NP. The oestrogenic potential of the phthalate esters. Reprod Toxicol 2000;14:183e92. [23] Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect 2005;113:1056e61. [24] Wang S, Su B, Ku H, Chen J, Huang H, Guo Y, et al. Prenatal phthalate exposure and gender role behavior in preschool children from central Taiwan. Epidemiology 2008;19:s277. [25] Swan SH, Liu F, Hines M, Kruse RL, Wang C, Redmon JB, et al. Prenatal phthalate exposure and reduced masculine play in boys. Int J Androl 2010;33:259e69. [26] Chou YY, Huang PC, Lee CC, Wu MH, Lin SJ. Phthalate exposure in girls during early puberty. J Pediatr Endocrinol Metab 2009;22:69e77. [27] Huang PC, Tsai EM, Li WF, Liao PC, Chung MC, Wang YH, et al. Association between phthalate exposure and glutathione Stransferase M1 polymorphism in adenomyosis, leiomyoma and endometriosis. Human Reproduction 2010;25:986e94. [28] Huang LP, Lee CC, Hsu PC, Shih TS. The association between semen quality in workers and the concentration of di(2ethylhexyl) phthalate in polyvinyl chloride pellet plant air. Fertil Steril 2011;96:90e4. [29] Fisher JS. Environmental anti-androgens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome. Reproduction 2004;127:305e15. [30] Jaakkola JJ, Parise H, Kislitsin V, Lebedeva NI, Spengler JD. Asthma, wheezing, and allergies in Russian schoolchildren in relation to new surface materials in the home. Am J Public Health 2004;94:560e2. [31] Wang TN, Lin MC, Wu CC, Leung SY, Huang MS, Chang HY, et al. Risks of exposure to occupational asthmogens in atopic and nonatopic asthma: a case-control study in Taiwan. Am J Respir Crit Care Med 2010;182:1369e76. [32] Bornehag CG, Nanberg E. Phthalate exposure and asthma in children. Int J Androl 2010;33:333e45. [33] Kuo PL, Hsu YL, Huang MS, Tsai MJ, Ko YC. Ginger suppresses phthalate ester-induced airway remodeling. J Agr Food Chem 2011;59:3429e38. [34] Hsu ST, Ma CI, Hsu SH, Wu SS, Hsu NHM, Yeh CC, et al. Discovery and Epidemiology of PCB Poisoning in Taiwan: A Four-Year Followup. Environ Health Perspect 1985;59:5e10. [35] Workshop on Plasticizer incident-related regulations and practices. Taipei Biotechnology Service and Commercial Association, Taipei, June 25, 2011. [36] Cope S, Frewer LJ, Houghton J, Rowe G, Fischer ARH, de Jonge J. Consumer perceptions of best practice in food risk communication and management: implications for risk analysis policy. Food Policy 2010;35:349e57. [37] van Kleef E, Frewer LJ, Chryssochoidis GM, Houghton JR, Korzen-Bohr S, Krystallis T, et al. Perceptions of food risk management among key stakeholders: results from a crossEuropean study. Appetite 2006;47:46e63. [38] Singh S, Li SSL. Phthalates: toxicogenomics and inferred human diseases. Genomics 2011;97:148e57.