Detoxifying This Modern-Day Threat to Health
By Chris D. Meletis, ND
Phthalates are a group of chemical plasticizers found in many personal care and consumer products. The ability of these chemicals to leach, migrate, or off gas from these products is of concern given that numerous studies associate this exposure to a number of diseases, a concept we will discuss in more depth later in this article. Widespread exposure to phthalates occurs through ingestion, inhalation, contact through the skin, and parenteral exposure from medical devices containing phthalates. Low-molecular-weight phthalates, such as diethyl phthalate (DEP), di-n-butyl phthalate (DnBP), and di-iso-butyl phthalate (DiBP) are used primarily in personal care products such as body lotions, cosmetics, shampoos, perfumes/colognes and deodorants and as varnishes and coatings, including coatings used for time release in some orally administered medications.1,2
Phthalates are also used as solvents and plasticizers for cellulose acetate, a substance used in some coating materials, in frame material for eyeglasses, and as a synthetic fiber in the manufacture of cigarette filters and playing cards. High-molecular-weight phthalates such as di(2-ethylhexyl) phthalate (DEHP) and di-isononyl phthalate (DiNP) are used primarily as plasticizers in the manufacture of flexible vinyl, which, in turn, is used in consumer products, flooring and wall coverings, food contact applications, and medical devices.3,4 Phthalates can also be found in waterproof clothing such as raincoats, artificial leather, car parts, garden hoses, and furniture.5,6 Young children have an increased risk of exposure, due to the tendency of these chemicals to accumulate in household dust and the fact that children are more likely to stick their fingers in their mouths.7
The multitude of sources for exposure means that most people have been exposed. Urinary concentrations of phthalate biomarkers have been detected in 75% to 90% or more of individuals in the U.S., Europe, and Canada.8,9 Lifestyle choices can impact concentrations of phthalates. Studies have found that dining out is associated with higher phthalate levels compared to eating at home. One study found that compared to people who eat more grocery store food, individuals who eat a lot of food from restaurants, fast food places, and cafeterias have 35% higher phthalate levels.10 In another study, phthalate levels were as much as 40% higher in people who ate the most fast food, burgers, fries and other foods compared to individuals who only occasionally ate those types of meals.11
The fact that so many people are encountering phthalates from so many different sources is of particular concern, given these chemicals’ toxic nature and their association with a concerning number of diseases. Furthermore, phthalate exposure is associated with lower levels of vitamin D, indicating these chemicals have a widespread effect on health.12
Phthalates, Metabolic Syndrome, and Obesity
Phthalate exposure has been associated with insulin resistance and obesity in both human and animal studies. There is concern that increased exposure to these chemicals may be responsible for the elevated incidence of insulin resistance and obesity observed in modern children. Trasnade and colleagues found that in adolescents, higher levels of Di-2-ethylhexylphthalate (DEHP) were associated with increased scores on the homeostatic model assessment of insulin resistance (HOMA-IR).13 This correlation remained even after controlling for the endocrine-disrupting chemical bisphenol A. The association also seemed to be exclusively related to the high-molecular weight phthalate as no significant correlation was found between HOMA-IR and insulin resistance and lower molecular-weight phthalate metabolites commonly found in cosmetics and other personal care products. In a study published the same year, Trasnade and associates found that higher levels of DEHP were associated with higher systolic blood pressure in children and adolescents.14 Furthermore, in a study of Chinese school children, exposure to mono (2-ethylhexyl) phthalate (MEHP) and monoethyl-phthalate (MEP) was associated with increased body mass index or waist circumference.15
In adults, epidemiological studies have noted a pronounced association between obesity, insulin resistance and exposure to one or more phthalates.16,17 Gender and age differences are often observed in these studies. Buser and coworkers found a significant correlation with low molecular weight phthalate metabolites and an increased risk for obesity in male children and adolescents.18 High molecular weight phthalate metabolites and DEHP metabolites were associated with a higher occurrence of obesity in all adults.18 There was a significant correlation between DEHP, high molecular weight phthalate metabolites and the risk of obesity in males 60 years and older.18
The mechanism by which phthalates impact glucose metabolism and contribute to obesity involves their interaction with human peroxisome proliferator activated receptors (PPAR) alpha and gamma. Phthalates’ ability to bind to these receptors may activate target genes associated with obesity and insulin resistance, thus leading to elevations in glucose concentrations.19
Phthalates, Infertility, and Pre- and Postnatal Health
Animal and human studies indicate these chemicals are linked to fertility issues and concerns during pregnancy. For example, a study of 256 women determined that increased urinary levels of DEHP metabolites were associated with reduced oocyte yield and lower rates of clinical pregnancy and live birth following assisted reproductive technologies.1 Furthermore, additional human studies have indicated that some phthalates can reduce sperm quality,20 while animal studies have shown that some phthalates are anti-androgenic and impair the development of the male fetus and lead to male infertility after gestational exposure to high doses.21 Another potential effect is that during pregnancy, phthalate exposure may increase the risk of gestational diabetes.8
Phthalate exposure to the fetus during pregnancy may have both immediate and long-term effects. In an animal study, prenatal exposure to male rodents resulted in cryptorchidism, hypospadias, and reduced testicular volume and testosterone levels.22 Some human studies have also established a correlation between prenatal phthalate exposure and lower free serum testosterone in infant boys and shorter anogenital distance (the distance from the anus to the genitals), an indicator of male feminization.22
Attention Deficit Hyperactivity Disorder
Research indicates there is a relationship between exposure to phthalates and attention deficit hyperactivity disorder (ADHD). A study of 261 Korean children ages 8 to 11 years found that higher levels of urinary phthalate metabolites significantly correlated with ADHD.23 Researchers evaluating data from the National Health and Nutrition Examination Survey (NHANES, 2001-2004) also found a strong connection between phthalates and attention deficit disorder (ADD) and learning disability (LD) in 1,493 U.S. children.24 Furthermore, in a study of 460 Korean mother-infant pairs, Kim and associates found that prenatal exposure to phthalates resulted in reduced Mental and Psychomotor Developmental Indices in infants, especially in 6-month-old males.25
Phthalates, especially when they’re inhaled, may act as allergens, leading to alterations in immunity and increased inflammation. Studies of children in Europe have established a clear link between phthalate exposure and asthma.6 Phthalates may also react with other toxic chemicals such as bisphenol-A to increase the risk of asthma. Prenatal exposure to higher than median levels of monobenzyl phthalate may increase the susceptibility to developing asthma in children exposed to BPA during their early years.26
Phthalates have a number of detrimental effects on the thyroid. DEHP decreases plasma free thyroxine (FT4), thyroxine (T4) and thyrotropin releasing hormone (TRH) levels.27,28,29 DEHP also causes histopathologic changes such as a decreased thyroid follicular cavity diameter and oxidative stress in the thyroid.27,28,29 DEHP is able to alter biosynthesis, biotransformation, biotransport, and metabolism of thyroid hormones.27,28,29
Phthalates and Cardiovascular Health
Phthalates may impact various aspects of the cardiovascular system. A number of studies have found that exposure to this class of chemicals is associated with hypertension. A review of the medical literature determined that epidemiological data indicated a possible relationship between phthalate exposure and hypertension in adults.30 Researchers have also established a correlation between urine levels of monoethyl-phthalate (MEP) and serum triglyceride levels, visceral adiposity, lipid accumulation product, and triglyceride to high-density lipoprotein (HDL) ratio among obese human subjects.31 In normal weight subjects, urine phthalate concentrations were negatively associated with HDL serum levels.32 Phthalates have also been shown to impair heart rate variability and increase
cardiovascular reactivity in mice.32
Phthalates have been implicated in a number of different cancers. A study of 710 women diagnosed with primary breast cancer observed an association between urinary concentrations of several phthalate metabolites and breast cancer as well as subsequent survival.33 A meta-analysis found that MECPP levels positively correlated with breast cancer risk, while DEHP metabolites were associated with elevated risk of breast cancer and uterine leiomyoma.34 Furthermore, an in vitro study indicated phthalates encourage resistance to colon cancer drugs.35
Detoxification of Phthalates
It is difficult to remove phthalates from the body simply by avoiding sources of exposure. One study found that subjects put on a low-phthalate diet to minimize exposure actually had higher levels of phthalates during the study.36 There was an unexpected rise in urinary DEHP metabolite concentrations from a median of 283.7 nmol/g at baseline to 7027.5 nmol/g in subjects eating the low-phthalate diet. When the study authors tested the foods for phthalate levels, DEHP levels were 21,400 ng/g in ground coriander and 673 ng/g in milk.
Due to the difficulty in avoiding exposure, detoxification is critical to ensure these toxins are removed from the body. Selenium supplementation can ameliorate the negative effects of phthalates on the thyroid. In a study of rodents exposed to phthalates, selenomethionine (SeMet) elevated plasma free T4 that had been decreased by DEHP.37 Selenium also reduced other negative effects of phthalates on thyroid hormones and improved DEHP-induced histopathologic alterations.37 The effects of DEHP on the thyroid as well as on spermatogenesis, decreased testosterone, leutinizing hormone (LH) and follicle stimulating hormone (FSH) levels, and sperm motility are significantly more pronounced in selenium-deficient rats.38,39 Selenium supplementation protected against these phthalate-induced reproductive effects.39 Additionally, selenium protected the kidneys of rats against the oxidative stress caused by DEHP.40
Folate is another nutrient that may be protective against the effects of phthalates. It was found to protect against hypospadias (a birth defect) in the infants of mothers exposed to phthalates through hair spray exposure at work.41 Likewise, vitamins C and E have been shown to be protective. These antioxidant vitamins when given to male rats exposed to DEHP eliminated the changes in testosterone and estradiol caused by phthalate exposure.42 These vitamins also significantly improved the reduced epididymal sperm head counts that occurred in the animals treated with DEHP and reduced levels of a marker of oxidative stress.42 Vitamins C and E also blocked DEHP-induced impairment in insulin signaling in adipose tissue and the development of glucose intolerance in rodents.43
Resveratrol and curcumin are two botanicals that can inhibit the toxic effects of phthalates. In male rodents, these phytonutrients resolved DEHP-induced testicular damage likely due to their antioxidant abilities and raising levels of Nrf2.44 Resveratrol has also been shown to reverse DBP-induced structural degeneration in the epididymis and deferens of rats.45 In vitro, curcumin was shown to inhibit adipogenesis stimulated by benzyl butyl phthalate (BBP), indicating it may suppress BBP-induced weight gain and inflammation.46
Supporting liver health is essential when eliminating toxins from the body. Curcumin is a hepatoprotective botanical that has been shown to inhibit damage to the liver caused by phthalates.47 Silymarin is another liver-supportive botanical. It was shown in a cell culture study to protect the liver against phthalate-induced damage.48 Cells treated with silymarin were hepatoprotective and had 79% cell viability while the DEHP-damaged control had only 46% cell viability.48
Phthalates are a toxic class of chemicals whose presence is ubiquitous in everyday life. These chemicals have been linked to multiple health concerns including infertility, gestational diabetes, ADHD, asthma, cardiovascular concerns, thyroid problems, and cancer. In our modern world, optimal health can only be achieved through the detoxification of phthalates. This can be accomplished with dietary supplements such as selenium, folate, vitamins C and E, resveratrol, curcumin, and silymarin.
1. Hauser R, Gaskins AJ, Souter I, et al. Urinary Phthalate Metabolite Concentrations and Reproductive Outcomes among Women Undergoing in Vitro Fertilization: Results from the EARTH Study. Environ Health Perspect. 2016 Jun;124(6):831-9.
2. Hauser R, Duty S, Godfrey-Bailey L, et al. Medications as a source of human exposure to phthalates. Environ Health Perspect. 2004 May;112(6):751-3.
3. Shea KM. Pediatric exposure and potential toxicity of phthalate plasticizers. Pediatrics. 2003 Jun;111(6 Pt 1):1467-74.
4. Hauser R, Calafat AM. Phthalates and human health. Occup Environ Med. 2005 Nov;62(11):806-18.
5. Crinnion WJ. Toxic effects of the easily avoidable phthalates and parabens. Altern Med Rev. 2010 Sep;15(3):190-6.
6. Benjamin S, Masai E, Kamimura N, et al. Phthalates impact human health: Epidemiological evidences and plausible mechanism of action. J Hazard Mater. 2017 Oct 15;340:360-83.
7. Centers for Disease Control and Prevention. https://www.cdc.gov/biomonitoring/Phthalates_FactSheet.html Accessed June 28, 2018.
8. James-Todd TM, Chiu YH, Messerlian C, et al. Trimester-specific phthalate concentrations and glucose levels among women from a fertility clinic. Environ Health. 2018 Jun 14;17(1):55.
9. Silva MJ, Barr DB, Reidy JA, 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 Mar;112(3):331-8.
10. Varshavsky JR, Morello-Frosch R, Woodruff TJ, et al. Dietary sources of cumulative phthalates exposure among the U.S. general population in NHANES 2005-2014. Environ Int. 2018 Jun;115:417-29.
11. Eureka Alert. https://eurekalert.org/pub_releases/2018-03/gwu-doa032318.php Accessed June 28, 2018.
12. Johns LE, Ferguson KK, Meeker JD. Relationships Between Urinary Phthalate Metabolite and Bisphenol A Concentrations and Vitamin D Levels in U.S. Adults: National Health and Nutrition Examination Survey (NHANES), 2005-2010. J Clin Endocrinol Metab. 2016 Nov;101(11):4062-9.
13. Trasande L, Spanier AJ, Sathyanarayana S, et al. Urinary phthalates and increased insulin resistance in adolescents. Pediatrics. 2013 Sep;132(3):e646-55.
14. Trasande L, Sathyanarayana S, Spanier AJ, et al. Urinary phthalates are associated with higher blood pressure in childhood. J Pediatr. 2013 Sep;163(3):747-53.
15. Wang H, Zhou Y, Tang C, et al. Urinary phthalate metabolites are associated with body mass index and waist circumference in Chinese school children. PLoS One. 2013;8(2):e56800.
16. Stahlhut RW, van Wijngaarden E, Dye TD. Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males. Environ Health Perspect. 2007 Jun;115(6):876-82.
17. Hatch EE, Nelson JW, Qureshi MM, et al. Association of urinary phthalate metabolite concentrations with body mass index and waist circumference: a cross-sectional study of NHANES data, 1999-2002. Environ Health. 2008 Jun 3;7:27.
18. Buser MC, Murray HE, Scinicariello F. Age and sex differences in childhood and adulthood obesity association with phthalates: analyses of NHANES 2007-2010. Int J Hyg Environ Health. 2014 Jul;217(6):687-94.
19. Desvergne B, Feige JN, Casals-Casas C. PPAR-mediated activity of phthalates: A link to the obesity epidemic? Molecular and Cellular Endocrinology. 2009 May;304(1-2):43-8.
20. Hauser R, Meeker JD, Duty S, et al. Altered semen quality in relation to urinary concentrations of phthalate monoester and oxidative metabolites. Epidemiology. 2006 Nov;17(6):682-91.
21. Fisher JS. Environmental anti-androgens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome. Reproduction. 2004 Mar;127(3):305-15.
22. Hart RJ, Frederiksen H, Doherty DA, et al. The Possible Impact of Antenatal Exposure to Ubiquitous Phthalates Upon Male Reproductive Function at 20 Years of Age. Front Endocrinol (Lausanne). 2018 Jun 4;9:288.
23. Kim BN, Cho SC, Kim Y, et al. Phthalates exposure and attention-deficit/hyperactivity disorder in school-age children. Biol Psychiatry. 2009 Nov 15;66(10):958-63.
24. Chopra V, Harley K, Lahiff M, et al. Association between phthalates and attention deficit disorder and learning disability in U.S. children, 6-15 years. Environ Res. 2014 Jan;128:64-9.
25. Kim Y, Ha EH, Kim EJ, et al. Prenatal exposure to phthalates and infant development at 6 months: prospective Mothers and Children’s Environmental Health (MOCEH) study. Environ Health Perspect. 2011 Oct;119(10):1495-500.
26. Whyatt RM, Rundle AG, Perzanowski MS, et al. Prenatal phthalate and early childhood bisphenol A exposures increase asthma risk in inner-city children. J Allergy Clin Immunol. 2014 Nov;134(5):1195-7.
27. Ye H, Ha M, Yang M, et al. Di2-ethylhexyl phthalate disrupts thyroid hormone homeostasis through activating the Ras/Akt/TRHr pathway and inducing hepatic enzymes. Sci Rep. 2017 Jan 9;7:40153.
28. Zhang P, Guan X, Yang M, et al. Roles and potential mechanisms of selenium in countering thyrotoxicity of DEHP. Sci Total Environ. 2018 Apr 1;619-620:732-9.
29. Erkekoglu P, Giray BK, Kizilgun M, et al. Thyroidal effects of di-(2-ethylhexyl) phthalate in rats of different selenium status. J Environ Pathol Toxicol Oncol. 2012;31(2):143-53.
30. Lu X, Xu X, Lin Y, et al. Phthalate exposure as a risk factor for hypertension. Environ Sci Pollut Res Int. 2018 Jun 3. [Epub ahead of print.]
31. Milošević N, Milić N, Živanović Bosić D, et al. Potential influence of the phthalates on normal liver function and cardiometabolic risk in males. Environ Monit Assess. 2017 Dec 13;190(1):17.
32. Jaimes R 3rd, Swiercz A, Sherman M, et al. Plastics band cardiovascular health: phthalates may disrupt heart rate variability and cardiovascular reactivity. Am J Physiol Heart Circ Physiol. 2017 Nov 1;313(5):H1044-53.
33. Parada H Jr, Gammon MD, Chen J, et al. Urinary Phthalate Metabolite Concentrations and Breast Cancer Incidence and Survival following Breast Cancer: The Long Island Breast Cancer Study Project. Environ Health Perspect. 2018 Apr 26;126(4):047013.
34. Fu Z, Zhao F, Chen K, et al. Association between urinary phthalate metabolites and risk of breast cancer and uterine leiomyoma. Reprod Toxicol. 2017 Dec;74:134-42.
35. Chen HP, Lee YK, Huang SY, et al. Phthalate exposure promotes chemotherapeutic drug resistance in colon cancer cells. Oncotarget. 2017 Dec 8;9(17):13167-80.
36. Sathyanarayana S, Alcedo G, Saelens BE, et al. Unexpected results in a randomized dietary trial to reduce phthalate and bisphenol A exposures. J Expo Sci Environ Epidemiol. 2013 Jul;23(4):378-84.
37. Zhang P, Guan X, Yang M, et al. Roles and potential mechanisms of selenium in countering thyrotoxicity of DEHP. Sci Total Environ. 2018 Apr 1;619-20:732-9.
38. Erkekoglu P, Giray BK, Kizilgun M, et al. Thyroidal effects of di-(2-ethylhexyl) phthalate in rats of different selenium status. J Environ Pathol Toxicol Oncol. 2012;31(2):143-53.
39. Erkekoglu P, Zeybek ND, Giray B, et al. Reproductive toxicity of di(2-ethylhexyl) phthalate in selenium-supplemented and selenium-deficient rats. Drug Chem Toxicol. 2011 Oct;34(4):379-89.
40. Erkekoglu P, Giray BK, Kizilgün M, et al. Di(2-ethylhexyl)phthalate-induced renal oxidative stress in rats and protective effect of selenium. Toxicol Mech Methods. 2012 Jul;22(6):415-23.
41. Ormond G, Nieuwenhuijsen MJ, Nelson P, et al. Endocrine disruptors in the workplace, hair spray, folate supplementation, and risk of hypospadias: case-control study. Environ Health Perspect. 2009 Feb;117(2):303-7.
42. Choi SM, Lim DS, Kim MK, et al. Inhibition of di(2-ethylhexyl) phthalate (DEHP)-induced endocrine disruption by co-treatment of vitamins C and E and their mechanism of action. J Toxicol Environ Health A. 2018 May 29:1-13. [Epub ahead of print.]
43. Rajesh P, Sathish S, Srinivasan C, et al. Phthalate is associated with insulin resistance in adipose tissue of male rat: role of antioxidant vitamins. J Cell Biochem. 2013 Mar;114(3):558-69.
44. Abd El-Fattah AA, Fahim AT, Sadik NAH, et al. Resveratrol and curcumin ameliorate di-(2-ethylhexyl) phthalate induced testicular injury in rats. Gen Comp Endocrinol. 2016 Jan 1;225:45-54.
45. Sahin E, IIgaz C, Erdoğan D, et al. Protective effects of resveratrol against di-n buthyl phthalate induced toxicity in ductus epididymis and ductus deferens in rats. Indian J Pharmacol. 2014 Jan-Feb;46(1):51-6.
46. Sakuma S, Sumida M, Endoh Y, et al. Curcumin inhibits adipogenesis induced by benzyl butyl phthalate in 3T3-L1 cells. Toxicol Appl Pharmacol. 2017 Aug 15;329:158-64.
47. Tsai CF, Hsieh TH, Lee JN, et al. Curcumin Suppresses Phthalate-Induced Metastasis and the Proportion of Cancer Stem Cell (CSC)-like Cells via the Inhibition of AhR/ERK/SK1 Signaling in Hepatocellular Carcinoma. J Agric Food Chem. 2015 Dec 9;63(48):10388-98.
48. Lo D, Wang YT, Wu MC. Hepatoprotective effect of silymarin on di(2-ethylhexyl)phthalate (DEHP) induced injury in liver FL83B cells. Environ Toxicol Pharmacol. 2014 Jul;38(1):112-8.