Phthalates and medical treatment
The most common interaction between phthalates and humans involves plastics and plasticized products. The use of phthalates in medical devices (most commonly DEHP) has been known to cause toxicity. Medical devices include intravenous tubing, endotracheal tubes, catheters, fluid and blood product bags. DEHP does not bond chemically to PVC and hence can leach into the environment or into products that come into contact with it. Blood being transfused can accumulate high concentrations of DEHP.7 DEHP is the only phthalate approved for medical devices in the USA.
Neonatal Intensive Care Units (NICUs) provide critically ill infants with a high level of exposure to DEHP. Within the NICU, infants are exposed to DEHP through equipment (ventilators, incubators, plastic tubing), construction materials (vinyl flooring, paints), soaps, lotions, powders used on the infants as well as the cosmetic and personal care products used by staff and visitors. Research by Mallow and colleagues8 suggests that preterm infants may be exposed to DEHP levels that are 4,000 to 160,000 times higher than levels currently deemed safe. They concluded that the exposure to DEHP could have both short- and long-term effects on the health of these patients and “might contribute to common early and chronic complications of prematurity”.
Medications too are a source of exposure to all individuals, regardless of age. Medications are now designed to provide a specific dosage at a specific site. Oral medications have enteric coatings that permit active ingredients to be released only in the area of the small intestine or colon. These coatings generally contain plasticizers and phthalates including diethyl phthalate (DEP) and DBP.9 Timed-release nutritional supplements may also be coated with phthalates. Kelley and colleagues checked prescription, over-the-counter medications and dietary supplements for the use of phthalates as excipients and found that many contained DBP or DEP in oral products.10 They noted that a complete listing of the type and amount of inactive ingredients for many of these products was not available because the information was considered proprietary. Hence exposure to phthalates in prescribed and over-the-counter medications and in dietary supplements cannot be quantified.
In 2008, the FDA banned the used of DnBP, BBzP and DeHP in any amount over 0.1% in child care articles, including toys. Interim restrictions have been placed on DnOP, DiNP and DiDP in children’s toys. Other phthlate content has not been legislated. In the last decade, exposure from the use of DnBP, BbzP and DEHP as measured in urinary concentrations of their metabolites, has declined by about 20% to 50% while that of DiNP and DiBP has increased significantly by >100% as they are used as a substitute for DEHP.11 The Environmental Protection Agency expressed concern about the use of DiNP in 2012. In 2014 California added DiNP to the list of possible carcinogens.
Effects of prenatal exposure to phthalates
Phthalates have been found in air, water, dust and sediments. Concern about phthalates has increased with research. In murine studies phthalates such as DEHP and DBP are known to be reproductive toxins.12 They cause damage to the liver, kidneys, lungs and developing testes.13, 14
DEHP and DBP are environmental contaminants. Health concerns have mainly focussed on their role in the development of cancer and reproductive defects but research has shown that mono (2- ethyl- hexyl) phthalate (MEHP) limits proliferation and causes apoptosis in developing bone marrow B cells.14 Monoethyl phthalate (MEP) affects DNA in human sperm at environmental levels.15
A Center for Disease Control population study tested for the presence of seven phthalates and found all of them present in the people tested. The study also found that exposure to DBP in women of child-bearing age was up to twenty times greater than that of the average individual. This level of exposure was above the federal safety standard.16
Phthalates appear to target the endocrine system and mimic the hormone estrogen. They have been linked to adverse reproductive system outcomes such as reduced semen quality and altered male genital development.4Some phthalates have earned the nickname of ‘gender-benders’ because they cause the feminization of baby boys. A study involving 134 male babies from two to 35 months of age measured residual levels of phthalates in the mothers’ urine during pregnancy and after birth. It showed that the phthalates monoethyl phthalate (MEP), mono-n-butyl phthalate (MBP), monobenzyl phthalate (MBzP), and monoisobutyl phthalate (MiBP) affected both testicular development and the anogenital distance (AGD). AGD, used as a measure of feminisation, may be reduced through exposure to phthalates. Smaller penises and testes that do not descend properly into the scrotum were also associated with high residual levels of phthalates.17 A recent Swedish study showed that prenatal exposure during the first trimester to phthalates, and to DEP, DBP, DEHP, BBAP and DiNP particularly, was related to male genital birth defects, particularly a shorter AGD in male children at the age of 21 months and to an impaired reproductive function (reduced fertility, lower serum testosterone levels) in adult men. The link was strongest and most significant between DiNP and shorter AGD.18
Phthalate exposure during pregnancy may be related to negative birth outcomes. Ferguson and colleagues found an association between such exposure and increased oxidative stress biomarkers in pregnant women.19 Theirs was a nested case-controlled study of preterm birth wherein nine urinary phthalate metabolites were measured to determine the degree of exposure. When compared with DEHP, increased oxidative stress was related to MBzP, MBP, MiBP. An earlier study by the same researchers found that exposure to some phthalates significantly increased the risk for pre-term birth.20
Prenatal exposure and behaviour
Researches21 found that prenatal exposure adversely affects the child’s mental, motor and behavioural development in the early years. The phthalates involved included DEHP, DiBP, DiNP and BbzP. There was a direct correlation between the levels of exposure and the increased odds of these problems in preschoolers – motor delay indicating future problems with coordination, significant decrease in mental development, anxiety, depression, withdrawn behaviour and emotionally reactive behaviour. While the effects differed by gender, they remained statistically significant.
Another study22 of a multiethnic group by Miodovnik and colleagues found that prenatal exposure to phthalates was associated with behavioural problems such as aggression, conduct and attention-related problems in the children.
Prenatal exposure and IQ
There are no regulations pertaining to phthalate exposure during pregnancy. Factor-Litvak and colleagues assessed 328 women with low socioeconomic levels and their children in New York City. They compared the IQ scores of children of mothers exposed to DnBP and DiBP. Children whose mothers were exposed during pregnancy to the highest 25% concentration had lower IQ scores than children of mothers exposed to the lowest 25% concentration. The difference was between 6 and 8 points in IQ scores and was particular noticeable with perceptual reasoning, processing speed and working memory.23 The researchers strongly recommended that pregnant women avoid or limit exposure to phthalates by * not using a microwave to heat food in plastic containers * not using scented products, particularly air fresheners and scented dryer sheets * avoiding use of recyclable plastics
The same findings applied to both single and multi-family dwellings. The more rooms with PVC flooring, the higher the levels of BBzP and DEHP. Some of the physical characteristics26 of the homes and the level of different phthalates is shown in Figure 3.
|Phthalate levels related to features of homes|
|House or room feature||DEHP||BBzP||DnBP|
|Multi-family home (compared to a single family)||⬆||⬆||⬆|
|Bedroom with PVC flooring||⬆||⬆|
|PVC flooring in other rooms||⬆||⬆|
|High ventilation rate in bedroom||⬆|
|Concrete slab foundation (instead of basement)||⬆|
|Water leakage in past three years||⬆||⬆|
- Houlihan J, Brody C, Schwan B. 2002. Not Too Pretty: Phthalates, Beauty Products, and the FDA. Washington, DC:Environmental Working Group. Available: http://www.safecosmetics.org/downloads/NotTooPretty_report.pdf Retrieved Dec 30, 2014
- Liang Y1, Xu Y. Emission of phthalates and phthalate alternatives from vinyl flooring and crib mattress covers: the influence of temperature. Environ Sci Technol. 2014 Dec 16;48(24):14228-37. doi: 10.1021/es504801x. Epub 2014 Dec 5.
- www.atsdr.cdc.gov/phs/phs.asp?id=857&tid=167/ Accessed Dec 30, 2014
- Dodson RE, Nishioka M et al. Endocrine disruptors and asthma-associated chemicals in consumer products. Environ Health Perspect. 2012; 120(7):935-43. DOI:10.1289/ehp.1104052
- www.inchem.org/documents/ehc/ehc/ehc189.htm#SubSectionNumber:3.2.2 Retrieved Dec 30, 2014
- www.atsdr.cdc.gov/substances/toxsubstance.asp?toxid=65 Accessed Dec 30, 2014
- Center for the Evaluation of Risks to Human Reproduction. NTP-CERHR Expert Panel Report on Di-2-ethylhexyl phthalate. Science International, Alexandria. 2000
- Mallow EB, Fox MA. Phthalates and critically ill neonates: device-related exposures and non-endocrine toxic risks. Journal of Perinatology, 2014; DOI: 10.1038/jp.2014.157
- Hauser R, Duty S, Godfrey-Bailey L, Calafat AM. Medications as a source of human exposure to phthalates. Environ Health Perspect. 2004 May;112(6):751-3.
- Kelley KE, Hernandez-Diaz S et al. Identification of phthalates in medications and dietary supplement formulations in the United States and Canada. Environ Health Perspect. 2012; 120(3):379-84. doi: 10.1289/ehp.1103998
- Zota AR, Calafat AM, Woodruff TJ. Temporal trends in phthalate exposures: findings from the National Health and Nutrition Examination Survey, 2001–2010. Environ Health Perspect. 2014; DOI: 10.1289/ehp.1306681
- Kang JS, Morimura K, Toda C, Wanibuchi H, Wei M, Kojima N, Fukushima S. Testicular toxicity of DEHP, but not DEHA, is elevated under conditions of thioacetamide-induced liver damage. Reprod Toxicol. 2005 Nov 19; Abstract.
- Kavlock R, Boekelheide K, et al. NTP Center for the Evaluation of Risks to Human Reproduction: Phthalates - expert panel report on the reproductive and developmental toxicity of butyl benzyl phthalate. Reprod Toxicol. 2002;16:453–487.
- Schlezinger JJ, Howard GJ, Hurst CH, et al. Environmental and endogenous peroxisome proliferator-activated receptor gamma agonists induce bone marrow B cell growth arrest and apoptosis: interactions between mono(2-ethylhexyl)phthalate, 9-cis-retinoic acid, and 15-deoxy-Delta12, 14-prostaglandin J2. J Immunol. 2004 ;173(5): 3165-77
- Duty SM, Singh NP, Silva MJ et al. The relationship between environmental exposures to phthalates and DNA damage in human sperm using the neutral comet assay. Environ Health Perspect 2003; 111: 1164-1169 Abstract.
- Blount BC, Silva MJ, Caudill SP, et al. Levels of seven urinary phthalate metabolites in a human reference population. Environ Health Perspect. 2000 Oct;108(10):979-82.
- Swan SH, Main KM, et al. Decrease in anogenital distance among male Infants with prenatal phthalate exposure. Environ Health Perspect 2005; 113: 1056-1061 Abstract.
- Bornehag CG, Carlstedt F, et al. Prenatal phthalate exposures and anogenital distance in Swedish boys. Environ Health Perspect. , 2014; DOI: 10.1289/ehp.1408163
- Ferguson KK, McElrath TF, Chen YH et al. Urinary phthalate metabolites and biomarkers of oxidative stress in pregnant women: a repeated measures analysis. Environ Health Perspect. November 2014 DOI: 10.1289/ehp.1307996
- Ferguson KK, McElrath TF, Meeker JD. Environmental phthalate exposure and preterm birth. JAMA Pediatrics, 2013; DOI: 10.1001/jamapediatrics.2013.3699
- Whyatt RM, Liu X, Rauh VA et al. Maternal prenatal urinary phthalate metabolite concentrations and child mental, psychomotor and behavioral development at age three years. Environ Health Perspect. 2011; DOI: 10.1289/ehp.1103705
- Miodovnik A1, Engel SM, Zhu C et al. Endocrine disruptors and childhood social impairment. Neurotoxicology. 2011 Mar;32(2):261-7. doi: 10.1016/j.neuro.2010.12.009.
- Factor-Litvak P, Insel B, Calafat AM et al. Persistent associations between maternal prenatal exposure to phthalates on child IQ at age 7 years. PLoS ONE, 2014; 9 (12): e114003 DOI: 10.1371/journal.pone.0114003
- Adibi JJ, Perera FP, Jedrychowski W et al. Prenatal exposures to phthalates among women in New York City and Krakow, Poland. Environ Health Perspect. 2003; 111(14): 1719–1722.
- Bornehag CG, Sundell J, Weschler CJ et al. The association between asthma and allergic symptoms in children and phthalates in house dust: a nested case–control study. Environ Health Perspect. 2004; 112(14): 1393–1397.
- Bornehag CG, Lundgren B, Weschler CJ et al. Phthalates in indoor dust and their association with building characteristics. Environ Health Perspect. 2005;113(10): 1399-404