Environmental Medicine

Toxic Effects of the Easily AvoidablePhthalates and ParabensWalter J. Crinnion, ND

WalterCrinnion, N D -1982graduateofBastyrUniversity; practice since1982 with a special focus ontreating chronic diseasescaused by environmentaltoxic burden; conductspost-graduate seminars inenvironmental medicine;professor and chair of theEnvironmental MedicineProgram, Southwest Collegeof Naturopathic Medicine,Tempe, AZ; contributingeditor. Alternative MedicineReviewEmail: w.crinnion@scnm.edu

AbstractSome environmental toxins like DDT and other chlorinatedcompounds accumulate in the body because of theirfat-soluble nature. Other compounds do not stay long in thebody, but still cause toxic effects during the time they arepresent. For serious health problems to arise, exposure tothese rapidly-clearing compounds must occur on a daily basis.Two such classes of compounds are the phthalate plasticizersand parabens, both of which are used in many personal careproducts, some medications, and even foods and foodpreservation. The phthalates are commonly found in foodsand household dust. Even though they have relatively shorthalf-lives in humans, phthalates have been associated with anumber ofserious health problems, including infertility,testicular dysgenesis, obesity, asthma, and allergies, as well asleiomyomas and breast cancer. Parabens, which can bedermally absorbed, are present in many cosmetic products,including antiperspirants. Their estrogenicity and tissuepresence are a cause for concern regarding breast cancer.Fortunately, these compounds are relatively easy to avoid andsuch steps can result in dramatic reductions of urinary levels ofthese compounds.('Mem/Wei//?ei/2010;15(3):190-196)

PhthalatesWith over 18 billion pounds of phthalates used

each year, they represent one of the world's highproduction chemical families. Phthalates, innumerous consumer items, provide flexibility andresilience to plastic products. Di-ethylhexylphthalate (DEHP) is the most commonly usedplasticizer forpolyvinyl chloride (PVC); theproduction volume of DEHP alone in 1999 wasestimated to be two million tons. Phthalates arefound in adhesives, automotive plastics, detergents,flooring, raincoats, personal care products (cosmet-ics, shampoos, fragrances, etc.), plastic bags,garden hoses, building materials, householdfurnishings, pharmaceuticals, nutritional

supplements, children's toys, food packaging,cleaning material, insecticides, and other commoncompounds. Phthalates are also used to manufac-ture the 500 million pairs of disposable medicalexamination and sterile surgical vinyl gloves thatare produced every year. Typically, the moreflexible the plastic, the higher the amount ofphthalates in the product. Because phthalates arenot chemically bound to the plastics to which theyare added, they can easily be released into theenvironment. This includes leaching and releaseinto air, dust, and food. Since phthalates arerapidly excreted from the body, their presence inthe urine indicates current exposure.

The CDC 4th National Report lists urinary levels(mcg/g creatinine) of several common phthalates(Table 1).^

A study of 100 pregnant women in theNetherlands examined urinary levels of a numberof phthalate metabolites.^ Table 2 illustrates someof their findings, presented in the same order asTable 1 from the CDC 4th Report.

Types and Sources of PhthalatesA comparison of the two studies shows that

multiple phthalate metabolites are present in twodifferent human populations. Note that the levelsof these metabolites vary between U.S. andRotterdam women. Expectant mothers from theNetherlands have much higher levels of mono-isobutyl phthalate (MiBP) and mono-n-butylphthalate (MnBP). MiBP is the metabolite ofdi-isobutyl phthalate (DIBP) and MnBP is themetabolite of di-n-butyl phthalate (DNBP), and aremost commonly used in PVC plastics, latexproducts, cosmetics, personal care products,cellulose plastics, and as solvents for some dyes.Mono-ethyl phthalate (MEP), the metabolite foundin the highest levels in both studies, is the

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Table 1. Urinary Levels of Several Common Phthalates (mcg/g creatinine)

Compound

Mono benzyl phttialate

Mono isobutyl phthalate

Mono ethyl phthalate

Mono-2-ethylhexyl phthalate

Mono-(2-ethyl-5-hydroxyhexyl) phthalate

Mono-(2-ethyl-5-carboxypentyl) phthalate

Mono methyl phthalate

Mono {3-carboxypropyl) phthalate

Geometricmean

12.9

3.57

181

50thpercentile

12.6

3.57

153

2.20

20.4

32.6

<LOD

2.74

1.89

17.7

27.0

1.53

2.60

75thpercentile

24.6

6.21

452

4.31

35.8

54.6

3.45

4.39

90thpercentile

46.0

10.9

1,110

10.8

93.5

139

7.95

7.70

95thpercentile

70.0

2,040

25.4

182

251

13.5

10.7

LOD=level of detection

Keywords: phthalate,paraben, toxic, toxkity, toxin,plasticizer, environment,environmental

metabolite of di-ethyl phthalate (DEP), which isprimarily found in cosmetics and personal careproducts. Thus, it appears that the majority ofphthalate metaholites in the urine of both popula-tions came from personal care products andcosmetics. A report from the EnvironmentalWorking Group and Healthcare Without Harmrevealed that DEP and di-hutyl phthalate (DBP)were the two phthalates most prevalent in cosmet-ics.^ DEP was found in 71 percent of all cosmeticstested, including deodorant, hair mousse, hair

spray, and hand and body lotions; it was found in100 percent of all fragrances and 86 percent of allhair gels. The fragrances carried the highestconcentrations (in parts per million [ppm]) of DEP,with five products having 20,000-28,000 ppm ofthis plasticizer. DBP was also found in 67 percentof all nail polishes tested.

Mono-ethylhexyl phthalate (MEHP) is one of themetabolites of DEHP (previously known asdi-n-octyl phthalate [DOP]), which is considered tohe the most toxic phthalate.^ MEHP was among the

Table 2. Urinary Levels of Phthalate Metabolites in Pregnant Women

Phthalate

Mono-benzyl phthalate

Mono-isobutyl phthalate

Mo^po-p^u^|Tf|.i|j^?; *Mono-ethyl phthalate

Mono-ethylhexyl phthalate

Mono-(2-ethyl-5-hyd roxyhexyl)phthalate

Detectionfrequency

100%

100%

ioo%97%

96%

100%

Geometricmean

8.9

41.3

112

6.9

14.3

50thpercentile

7.5

42.1

42.7' , '

117

6.9

14

75thpercentile

16.8

72.8

8Í6'/ ' • -

425

17.3

30

95thpercentile

95.8

249

197 i ' '1150

82.8

86.2

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Environmental Medicine

lowest of the phthalate metabolites found inindividuals in both studies, accounts for less than10 percent of all DEHP metabolites, and has theshortest half-life. The major metabolites of DEHPare secondary oxidized metabolites with a half-lifeup to 24 hours and were only measured in the CDCstudy. These include mono-(2-ethyl-5-hydroxy-hexyl) phthalate representing about 24 percent ofDEHP, mono-(2-ethyl-5-oxyhexyl) phthalateaccounting for about 15 percent of total DEHP, andmono-(2-ethyl-5-carboxypentyl) phthalateaccounting for 18.5 percent of DEHP. While thesecomprise the majority of DEHP metabolites, theymay also account for the majority of its toxicity,especially regarding developmental damage.^ Theprimary environmental source of DEHP and DBP isthe diet, rather than cosmetics or personal careproducts.^

DEHP leaches into foods from wrappings usedfor food storage and from PVC gloves worn by foodhandlers.' In a study of Korean and Japanesebeverages, DEHP and di-methyl phthalate (DMP)were the two phthalates most frequently found andin highest concentrations.^ The highest levels ofthese compounds were found in the beer, wine, and

"nutritive drink" samples. According to data fromthe National Health and Nutrition ExaminationSurvey (NHANES), poultry and eggs were thegreatest sources of DEHP, and tomatoes andpotatoes were the highest sources of DEP; fruitscontained DMP and fish contained DIBP

theophylline.^" In a German study, the other mainsource of phthalate exposure for individuals washouse dust, with the two highest phthalates in dustbeing DEHP and DINP (but DEP and DBP were alsopresent).•'•'^

Adverse Health EffectsThe greatest concern about phthalates, known to

have anti-androgenic activity, is regarding repro-duction and human development. Various animalstudies have demonstrated phthalates can reducesperm counts, cause histological changes in thetestes, and reduce male fertility. There are alsoconcerns about phthalates causing fetal mortality,low birth weights, and fetal malformations."*

Although phthalates have not been shown tocause low birth weight in human studies,^^ theywere associated with preterm deliveries.^^ In adultmales, a combination of either MBP or mono-benzyl phthalate (MBzP) (metabolites of di-butylphthalate and di-benzyl phthalate, respectively)and PCBs was positively associated with reducedsperm motility. "* The researchers noted that PCBswere able to inhibit the activity of glucuronyltransferase, thereby reducing the effective clear-ance of phthalates from the body. With thesefindings it appears that prolonging the exposure toeither mono-butyl or mono-benzyl phthalate canlead to reduced sperm motility. Significantly, theparticipants in this study were all male partners ofinfertile couples who were seeking fertility help.

Table 3. Comparison of Phthalate Metabolite Levels in NHANES and in Cases of Male Infertility in the Häuser Study ^

1 Metabolite

Geometricmean(ng/mL)

Frequencyof detection

50thpercentile

Häuser NHANES

75thpercentile

Häuser NHANES

95thpercentile

Häuser NHANES

Medications are another source of phthalateexposure. In a large study that utilized NHANESdata, very high levels of mono-butyl phthalate(MBP) were found in persons taking mesalamine(approximately 100 times higher than non-mesala-mine users), didanosine, omeprazole, and

Another study of men presenting at fertility clinicsrevealed a strongly significant association betweenDNA-damaged sperm and urinary levels of eithermono-ethyl phthalate or the oxidative metabolitesof DEHP (mono-[2-ethyl-5-hydroxyhexyl] phthal-ate [MEHHP] and mono-[2-ethyl-5-oxyhexyl]

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phthalate [MEOHP]). ^ Interestingly, the levels ofMEP in this group of infertile males were strikinglysimilar to those found in NHANES (Table 3), whilethe levels of MEHHP and MEOHP were muchhigher. This increased level of DEHP metabolitesmay reflect either a greater exposure or a metabolicdefect. The sperm DNA damage was significantlycorrelated to all three metabolites individually, notjust cumulatively. Thus, the presence of any ofthem at levels commonly found in the U.S. popula-tion can damage sperm.

Phthalates appear to cause more damage to malereproduction when the exposure occurs duringmale fetal development. Exposure to environmen-tal endocrine disruptors during germ cell develop-ment appears to be the most opportune time fordamage to occur. In an animal study, prenatalexposure to phthalates resulted in the maleoffspring developing testicular dysgenesis syn-drome as a result of Leydig cell dysfunction.-" ^ Invitro experimentation with human fetal testesrevealed that MEHP, the least toxic of the metabo-lites of DEHP, caused increased apoptosis of germcells." Because the researchers only used MEHP, itcannot be determined whether the more toxicmetabolites of DEHP or other phthalate metabo-lites would have had similar or more powerfuleffects.

A study of mother-infant pairs showed a clearassociation between maternal levels of urinaryphthalate metabolites (MEP, MBP, MBzP, MEHP)and reduced ano-genital distances in their off-spring.^^ The ano-genital distance was measured inthis study because it is a sensitive marker for inutero anti-androgen exposure. An association wasalso found between phthalate metabolite levels inmaternal breast milk and sex hormone levels andratios in male offspring.^^ MEP and MBP werepositively associated with levels of sex-hormonebinding globulin, while MEP was negativelycorrelated with free testosterone. Maternalphthalate exposure has also been positivelyassociated with hypospadias in their offspring,which also reflects anti-androgenic effects duringfetal sexual development.^" Young girls withexposure to phthalates appear to have problemswith premature sexual development, especiallythelarche (premature breast development). •• •

Fetal exposure to maternal phthalate burden hasalso been associated with behavior and mentalability. Urine phthalate metabolites were tested inpregnant women in New York City during theirthird trimester and their offspring were first

assessed within five days of birth^^ and againbetween ages four and nine years.^'' Within daysafter birth, children whose mothers had higherlevels of phthalates exhibited more problems withalertness and orientation. Unfortunately, whenthey were tested again between the ages of fourand nine, the neurological problems had persistedand even increased. Children with higher exposureto phthalates in utero had more problems withaggression, conduct, attention, and depression.They also exhibited poorer executive functioningand emotion control.

Other chronic health problems have also recentlybeen associated with ongoing phthalate exposures.It was mentioned earlier that house dust is one ofthe sources of phthalate exposure. In a Swedishstudy, high levels of butylbenzyl phthalate (BBzP)in house dust were associated with higher rates ofrhinitis and eczema, while dust-borne DEHP wasassociated with increased rates of asthma." Alongwith asthma, other chronic health problems thatare considered worldwide epidemics are obesityand type 2 diabetes, which are now being associ-ated with phthalate exposure.^^ In a study utilizingNHANES data, urinary levels of MBzP, MEP, andthe oxidative metabolites MEHHP and MEOHPwere all associated with increased waist circumfer-ence in men. ^ The metabolites MBP, MBzP, andMEP were also associated with insulin resistance. Adifferent study showed a positive associationbetween MBzP at any level and body mass index(BMI).28

In women, MEP levels were positively correlatedwith both BMI and waist circumference. Womenwith higher levels of urinary MEHP also had higherrates of uterine leiomyomas, while those withhigher levels of MBP had more endometriosis.'^' Inaddition, women with elevated MEHP and aglutathione transferase Mu 1 null genotype hadodds ratios of 10.4 for adenomyosis and 5.9 forleiomyomas. Urinary MEP levels were also posi-tively associated with increased rates of breastcancer.^° Women with the highest levels of MEPwere 2.2 times more likely to develop breast cancerthan those with the lowest levels. Eor premeno-pausal women the odds ratio was even higher at4.13. The mean MEP levels (mcg/g creatinine) were169.6 for cases and 106.8 for controls, which areapproximately the same as NHANES normalranges. Thus, just as was found with infertility inmales, the levels of phthalates that can lead tocancer were similar to the levels found in most U.S.residents.

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Avoidance MeasuresA dietary intervention study confirmed the role

of foods as a major source of phthalate exposure. Agroup of 25 individuals participated in a five-daystay at a Buddhist temple in Korea and ate thevegetarian diet that was normally served to theresident monks.^^ Metabolites of four phthalateswere found in all of the participants before theirstay. Although all the metabolites dropped dra-matically by the end of the stay, they did notdisappear completely, as one might expect becauseof their short half-lives, indicating that not allsources of exposure (such as personal care productsand medications) were eliminated by changing tovegetarianism. While this study does not state howthe foods were purchased or prepared, an easy wayto avoid phthalates in foods is to purchase foodsthat are not wrapped in plastic. In the book SlowDeath by Rubber Duck,^^ the author conducted anexperiment where he avoided all personal careproducts with phthalates for two days and thentested baseline phthalate levels, followed by twodays of using classic personal care products andretesting. The levels of MEP went from 64 (aftertwo days of avoidance) to 1,410 mg/mL afteranother two days of exposure. These two studiesshow that making dietary and lifestyle changes caneither increase or decrease daily exposure tophthalates, and that proper avoidance may alterthe risk of developing diseases associated withdaily phthalate exposure.

ParabensMethyl-, ethyl-, propyl-, butyl-, and benzyl

parabens, all esters of p-hydroxybenzoic acid, arewidely used as antimicrobial preservatives incosmetics, pharmaceuticals,food, and beverages. Becauseof their low cost and lowtoxicity, they are usedcommonly throughout theworld. Once in the blood-stream they can be conju-gated in the liver withglycine, sulfate, or glucuro-nate for excretion in theurine. But, they are alsolipophilic and can be

absorbed through the skin and are found intact intissue. In fact, these compounds have been foundin breast cancer tissue in levels ranging from 20ng/g tissue to 100 ng/g tissue.^^ Urinary levels ofthe parabens (ng/mL) from 100 U.S. residents areprovided in Table 4.'"

Parabens have weak estrogenic activity and havebeen shown to induce the growth of MCF-7 humanbreast cancer cells in vitro,^^ leading some research-ers to suggest their potential as initiators orpromoters of breast cancer. Part of the concernstems from the fact that an increasing number ofbreast cancers are occurring in the upper outerquadrant of the breast, where paraben-containingantiperspirant application occurs.'^ Others debatethat the estrogenic effect is too weak to causeproblems.^^ The current consensus is that parabens'effect on health, including cancer risk, is due tomuch more than estrogen mimicry.

An alternative mechanism by which parabenscan indirectly affect estrogen levels is via inhibitionof sulfotransferase activity inside the cytosol ofhuman skin cells. By blocking sulfotransferases,the estrogen levels can remain higher thannormal.^* If this same action occurs in breast tissue,then these compounds may indeed be linked toincreased rates of breast cancer.

Methyl- and propyl parabens, the two mostcommonly found, are also potent inhibitors ofmitochondrial function.^'•'"' This action alone wouldmake them unwanted xenobiotics, especially foranyone with mitochondrial dysfunction-relatedhealth problems. This effect on mitochondrialfunction has been proposed as a mechanism fortheir possible role in male infertility.''^

Table 4. Urinary Levels of Parabens (ng/mL) in 100 U.S. Residents

ParabenPercentdetection

Benzyl 39 <LODLOD=level of detection

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ConclusionPhthalates are ubiquitous in foods, home dust,

medications, and personal care products. Unlessglucuronidation is inhibited, they are rapidlyexcreted by the body, making reductions in dailyexposure readily apparent. Unfortunately, whenexposed in utero, these compounds cause lastinghealth effects. In children of both genders phthal-ate exposure leads to increased rates of inattentionand mood disorders as well as cognitive problems.In males exposure can cause reduced Leydig cellfunction, lower testosterone, hypospadias, andinfertility. In young girls phthalates have beenassociated with premature sexual development,especially with early breast development. In adultsphthalates are associated with increased weight,insulin resistance, asthma and allergies, uterinefibroids, and breast cancer.

The effects of phthalates are surprising andshocking considering they are supposedly safe anddo not bioaccumulate. Testing for urinary phthal-ate metabolite levels provides a quick and easymeans of identifying current exposure sources(that may not be as obvious as one would think).Avoidance of exposure through dietary changes,such as avoidance of foods packaged in plastic wrap,avoidance of fragrances and hair gels, and carefulselection of personal care products (by using onlythose stating that they are phthalate- and paraben-free) can dramatically reduce one's daily exposureto these compounds. It is quite possible that suchsteps could help reduce the risk of asthma, aller-gies, diabetes, and breast cancer. Avoidance ofphthalates may also dramatically improve thelife-experience of unborn children by preventingneurological, reproductive, and endocrinedisorders.

Paraben exposure comes mainly from the use ofpersonal care products containing these com-pounds. While their exact health effects arecurrently unknown, they do possess some estro-genic activity, can adversely affect the breakdownof endogenous estrogens, and cause mitochondrialdysfunction. These compounds can be easilymeasured in the urine; testing can evaluate whatexposures are occurring and monitor the effective-ness of avoidance procedures.

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