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Toxic effects of the easily avoidable phthalates and parabens
Alternative Medicine Review. 15.3 (Sept. 2010): p190+.
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Abstract

Some environmental toxins like DDT and other chlorinated compounds accumulate in the body because of their fat-soluble nature. Other compounds do not stay long in the body, but still cause toxic effects during the time they are present. For serious health problems to arise, exposure to these rapidly-clearing compounds must occur on a daily basis. Two such classes of compounds are the phthalate plasticizers and parabens, both of which are used in many personal care products, some medications, and even foods and food preservation. The phthalates are commonly found in foods and household dust. Even though they have relatively short half-lives in humans, phthalates have been associated with a number of serious health problems, including infertility, testicular dysgenesis, obesity, asthma, and allergies, as well as leiomyomas and breast cancer. Parabens, which can be dermally absorbed, are present in many cosmetic products, including antiperspirants. Their estrogenicity and tissue presence are a cause for concern regarding breast cancer. Fortunately, these compounds are relatively easy to avoid and such steps can result in dramatic reductions of urinary levels of these compounds.

(Altern Med Rev 2010;15 (3):190-196)

Phthalates

With over 18 billion pounds of phthalates used each year, they represent one of the world's high production chemical families. Phthalates, in numerous consumer items, provide flexibility and resilience to plastic products. Di-ethylhexyl phthalate (DEHP) is the most commonly used plasticizer for polyvinyl chloride (PVC); the production volume of DEHP alone in 1999 was estimated to be two million tons. Phthalates are found in adhesives, automotive plastics, detergents, flooring, raincoats, personal care products (cosmetics, shampoos, fragrances, etc.), plastic bags, garden hoses, building materials, household furnishings, pharmaceuticals, nutritional supplements, children's toys, food packaging, cleaning material, insecticides, and other common compounds. Phthalates are also used to manufacture the 500 million pairs of disposable medical examination and sterile surgical vinyl gloves that are produced every year. Typically, the more flexible the plastic, the higher the amount of phthalates in the product. Because phthalates are not chemically bound to the plastics to which they are added, they can easily be released into the environment. This includes leaching and release into air, dust, and food. Since phthalates are rapidly excreted from the body, their presence in the urine indicates current exposure.

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

A study of 100 pregnant women in the Netherlands examined urinary levels of a number of phthalate metabolites. (2) Table 2 illustrates some of their findings, presented in the same order as Table 1 from the CDC 4th Report.

Types and Sources of Phthalates

A comparison of the two studies shows that multiple phthalate metabolites are present in two different human populations. Note that the levels of these metabolites vary between U.S. and Rotterdam women. Expectant mothers from the Netherlands have much higher levels of monoisobutyl phthalate (MiBP) and mono-n-butyl phthalate (MnBP). MiBP is the metabolite of di-isobutyl phthalate (DIBP) and MnBP is the metabolite of di-n-butyl phthalate (DNBP), and are most commonly used in PVC plastics, latex products, cosmetics, personal care products, cellulose plastics, and as solvents for some dyes. Mono-ethyl phthalate (MEP), the metabolite found in the highest levels in both studies, is the metabolite of di-ethyl phthalate (DEP), which is primarily found in cosmetics and personal care products. Thus, it appears that the majority of phthalate metabolites in the urine of both populations came from personal care products and cosmetics. A report from the Environmental Working Group and Healthcare Without Harm revealed that DEP and di-butyl phthalate (DBP) were the two phthalates most prevalent in cosmetics. (3) DEP was found in 71 percent of all cosmetics tested, including deodorant, hair mousse, hair spray, and hand and body lotions; it was found in 100 percent of all fragrances and 86 percent of all hair gels. The fragrances carried the highest concentrations (in parts per million [ppm]) of DEP, with five products having 20,000-28,000 ppm of this plasticizer. DBP was also found in 67 percent of all nail polishes tested.

Mono-ethylhexyl phthalate (MEHP) is one of the metabolites of DEHP (previously known as di-n-octyl phthalate [DOP]), which is considered to be the most toxic phthalate. (4) MEHP was among the lowest of the phthalate metabolites found in individuals in both studies, accounts for less than 10 percent of all DEHP metabolites, and has the shortest half-life. The major metabolites of DEHP are secondary oxidized metabolites with a half-life up to 24 hours and were only measured in the CDC study. These include mono-(2-ethyl-5-hydroxyhexyl) phthalate representing about 24 percent of DEHP, mono-(2-ethyl-5-oxyhexyl) phthalate accounting for about 15 percent of total DEHP, and mono- (2-ethyl-5-carboxypentyl) phthalate accounting for 18.5 percent of DEHP. While these comprise the majority of DEHP metabolites, they may also account for the majority of its toxicity, especially regarding developmental damage. (5) The primary environmental source of DEHP and DBP is the diet, rather than cosmetics or personal care products. (6)

DEHP leaches into foods from wrappings used for food storage and from PVC gloves worn by food handlers. (7) In a study of Korean and Japanese beverages, DEHP and all-methyl phthalate (DMP) were the two phthalates most frequently found and in highest concentrations. (8) The highest levels of these compounds were found in the beer, wine, and "nutritive drink" samples. According to data from the National Health and Nutrition Examination Survey (NHANES), poultry and eggs were the greatest sources of DEHP, (9) and tomatoes and potatoes were the highest sources of DEP; fruits contained DMP and fish contained DIBP.

Medications are another source of phthalate exposure. In a large study that utilized NHANES data, very high levels of mono-butyl phthalate (MBP) were found in persons taking mesalamine (approximately 100 times higher than non-mesalamine users), didanosine, omeprazole, and theophylline. (10) In a German study, the other main source of phthalate exposure for individuals was house dust, with the two highest phthalates in dust being DEHP and DINP (but DEP and DBP were also present). (11)

Adverse Health Effects

The greatest concern about phthalates, known to have anti-androgenic activity, is regarding reproduction and human development. Various animal studies have demonstrated phthalates can reduce sperm counts, cause histological changes in the testes, and reduce male fertility. There are also concerns about phthalates causing fetal mortality, low birth weights, and fetal malformations. (4)

Although phthalates have not been shown to cause low birth weight in human studies, (12) they were associated with preterm deliveries. (13) In adult males, a combination of either MBP or monobenzyl phthalate (MBzP) (metabolites of di-butyl phthalate and di-benzyl phthalate, respectively) and PCBs was positively associated with reduced sperm motility. (14) The researchers noted that PCBs were able to inhibit the activity of glucuronyl transferase, thereby reducing the effective clearance of phthalates from the body. With these findings it appears that prolonging the exposure to either mono-butyl or mono-benzyl phthalate can lead to reduced sperm motility. Significantly, the participants in this study were all male partners of infertile couples who were seeking fertility help. Another study of men presenting at fertility clinics revealed a strongly significant association between DNA-damaged sperm and urinary levels of either mono-ethyl phthalate or the oxidative metabolites of DEHP (mono-[2-ethyl-5-hydroxyhexyl] phthalate [MEHHP] and mono-[2-ethyl-5-oxyhexyl] phthalate [MEOHP]). (15) Interestingly, the levels of MEP in this group of infertile males were strikingly similar to those found in NHANES (Table 3), while the levels of MEHHP and MEOHP were much higher. This increased level of DEHP metabolites may reflect either a greater exposure or a metabolic defect. The sperm DNA damage was significantly correlated to all three metabolites individually, not just cumulatively. Thus, the presence of any of them at levels commonly found in the U.S. population can damage sperm.

Phthalates appear to cause more damage to male reproduction when the exposure occurs during male fetal development. Exposure to environmental endocrine disruptors during germ cell development appears to be the most opportune time for damage to occur. In an animal study, prenatal exposure to phthalates resulted in the male offspring developing testicular dysgenesis syndrome as a result of Leydig cell dysfunction. (16) In vitro experimentation with human fetal testes revealed that MEHP, the least toxic of the metabolites of DEHP, caused increased apoptosis of germ cells. (17) Because the researchers only used MEHP, it cannot be determined whether the more toxic metabolites of DEHP or other phthalate metabolites would have had similar or more powerful effects.

A study of mother-infant pairs showed a clear association between maternal levels of urinary phthalate metabolites (MEg MBP, MBzP, MEHP) and reduced ano-genital distances in their offspring. (18) The ano-genital distance was measured in this study because it is a sensitive marker for in utero anti-androgen exposure. An association was also found between phthalate metabolite levels in maternal breast milk and sex hormone levels and ratios in male offspring. (19) MEP and MBP were positively associated with levels of sex-hormone binding globulin, while MEP was negatively correlated with free testosterone. Maternal phthalate exposure has also been positively associated with hypospadias in their offspring, which also reflects anti-androgenic effects during fetal sexual development. (20) Young girls with exposure to phthalates appear to have problems with premature sexual development, especially thelarche (premature breast development). (21,22)

Fetal exposure to maternal phthalate burden has also been associated with behavior and mental ability. Urine phthalate metabolites were tested in pregnant women in New York City during their third trimester and their offspring were first assessed within five days of birth (23) and again between ages four and nine years. (24) Within days after birth, children whose mothers had higher levels of phthalates exhibited more problems with alertness and orientation. Unfortunately, when they were tested again between the ages of four and nine, the neurological problems had persisted and even increased. Children with higher exposure to phthalates in utero had more problems with aggression, conduct, attention, and depression. They also exhibited poorer executive functioning and emotion control.

Other chronic health problems have also recently been associated with ongoing phthalate exposures. It was mentioned earlier that house dust is one of the sources of phthalate exposure. In a Swedish study, high levels of butylbenzyl phthalate (BBzP) in house dust were associated with higher rates of rhinitis and eczema, while dust-borne DEHP was associated with increased rates of asthma. (25) Along with asthma, other chronic health problems that are considered worldwide epidemics are obesity and type 2 diabetes, which are now being associated with phthalate exposure. (26) In a study utilizing NHANES data, urinary levels of MBzP, MEP, and the oxidative metabolites MEHHP and MEOHP were all associated with increased waist circumference in men. (27) The metabolites MBP, MBzP, and MEP were also associated with insulin resistance. A different study showed a positive association between MBzP at any level and body mass index (BMI). (28)

In women, MEP levels were positively correlated with both BMI and waist circumference. Women with higher levels of urinary MEHP also had higher rates of uterine leiomyomas, while those with higher levels of MBP had more endometriosis. (29) In addition, women with elevated MEHP and a glutathione transferase Mu I null genotype had odds ratios of 10.4 for adenomyosis and 5.9 for leiomyomas. Urinary MEP levels were also positively associated with increased rates of breast cancer. (30) Women with the highest levels of MEP were 2.2 times more likely to develop breast cancer than those with the lowest levels. For premenopausal women the odds ratio was even higher at 4.13. The mean MEP levels (mcg/g creatinine) were 169.6 for cases and 106.8 for controls, which are approximately the same as NHANES normal ranges. Thus, just as was found with infertility in males, the levels of phthalates that can lead to cancer were similar to the levels found in most U.S. residents.

Avoidance Measures

A dietary intervention study confirmed the role of foods as a major source of phthalate exposure. A group of 25 individuals participated in a five-day stay at a Buddhist temple in Korea and ate the vegetarian diet that was normally served to the resident monks. (31) Metabolites of four phthalates were found in all of the participants before their stay. Although all the metabolites dropped dramatically by the end of the stay, they did not disappear completely, as one might expect because of their short half-lives, indicating that not all sources of exposure (such as personal care products and medications) were eliminated by changing to vegetarianism. While this study does not state how the foods were purchased or prepared, an easy way to avoid phthalates in foods is to purchase foods that are not wrapped in plastic. In the book Slow Death by Rubber Duck, (32) the author conducted an experiment where he avoided all personal care products with phthalates for two days and then tested baseline phthalate levels, followed by two days of using classic personal care products and retesting. The levels of MEP went from 64 (after two days of avoidance) to 1,410 mg/mL after another two days of exposure. These two studies show that making dietary and lifestyle changes can either increase or decrease daily exposure to phthalates, and that proper avoidance may alter the risk of developing diseases associated with daily phthalate exposure.

Parabens

Methyl-, ethyl-, propyl-, butyl-, and benzyl parabens, all esters of p-hydroxybenzoic acid, are widely used as antimicrobial preservatives in cosmetics, pharmaceuticals, food, and beverages. Because of their low cost and low toxicity, they are used commonly throughout the world. Once in the bloodstream they can be conjugated in the liver with glycine, sulfate, or glucuronate for excretion in the urine. But, they are also lipophilic and can be absorbed through the skin and are found intact in tissue. In fact, these compounds have been found in breast cancer tissue in levels ranging from 20 ng/g tissue to 100 ng/g tissue. (33) Urinary levels of the parabens (ng/mL) from 100 U.S. residents are provided in Table 4. (34)

Parabens have weak estrogenic activity and have been shown to induce the growth of MCF-7 human breast cancer cells in vitro, (35) leading some researchers to suggest their potential as initiators or promoters of breast cancer. Part of the concern stems from the fact that an increasing number of breast cancers are occurring in the upper outer quadrant of the breast, where paraben-containing antiperspirant application occurs. (36) Others debate that the estrogenic effect is too weak to cause problems. (37) The current consensus is that parabens' effect on health, including cancer risk, is due to much more than estrogen mimicry.

An alternative mechanism by which parabens can indirectly affect estrogen levels is via inhibition of sulfotransferase activity inside the cytosol of human skin cells. By blocking sulfotransferases, the estrogen levels can remain higher than normal. (38) If this same action occurs in breast tissue, then these compounds may indeed be linked to increased rates of breast cancer.

Methyl- and propyl parabens, the two most commonly found, are also potent inhibitors of mitochondrial function. (39,40) This action alone would make them unwanted xenobiotics, especially for anyone with mitochondrial dysfunction-related health problems. This effect on mitochondrial function has been proposed as a mechanism for their possible role in male infertility. (41)

Conclusion

Phthalates are ubiquitous in foods, home dust, medications, and personal care products. Unless glucuronidation is inhibited, they are rapidly excreted by the body, making reductions in daily exposure readily apparent. Unfortunately, when exposed in utero, these compounds cause lasting health effects. In children of both genders phthalate exposure leads to increased rates of inattention and mood disorders as well as cognitive problems. In males exposure can cause reduced Leydig cell function, lower testosterone, hypospadias, and infertility. In young girls phthalates have been associated with premature sexual development, especially with early breast development. In adults phthalates are associated with increased weight, insulin resistance, asthma and allergies, uterine fibroids, and breast cancer.

The effects of phthalates are surprising and shocking considering they are supposedly safe and do not bioaccumulate. Testing for urinary phthalate metabolite levels provides a quick and easy means 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 careful selection of personal care products (by using only those stating that they are phthalate- and paraben-free) can dramatically reduce one's daily exposure to these compounds. It is quite possible that such steps could help reduce the risk of asthma, allergies, diabetes, and breast cancer. Avoidance of phthalates may also dramatically improve the life-experience of unborn children by preventing neurological, reproductive, and endocrine disorders.

Paraben exposure comes mainly from the use of personal care products containing these compounds. While their exact health effects are currently unknown, they do possess some estrogenic activity, can adversely affect the breakdown of endogenous estrogens, and cause mitochondrial dysfunction. These compounds can be easily measured in the urine; testing can evaluate what exposures are occurring and monitor the effectiveness of avoidance procedures.

References

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Walter Crinnion, ND 1982 graduate of Bastyr University; practice since 1982 with a special focus on treating chronic diseases caused by environmental toxic burden; conducts post-graduate seminars in environmental medicine; professor and chair of the Environmental Medicine Program, Southwest College of Naturopathic Medicine, Tempe, AZ; contributing editor, Alternative Medicine Review Emaih w.crinnion@scnm.edu

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

                                           Geometric   50th
Compound                                   mean        percentile

Mono benzyl phthalate                      12.9        12.6
Mono isobutyl phthalate                    3.57        3.57
Mono n-butyl phthalate                     19.8        19.3
Mono ethyl phthalate                       181         153
Mono-2-ethylhexyl phthalate                2.20        1.89
Mono-(2-ethyl -5-hydroxyhexyl) phthalate   20.4        17.7
Mono-(2-ethyl-5-oxyhexyl) phthalate        13.6        12.1
Mono-(2-ethyl-5-carboxypentyl) phthalate   32.6        27.0
Mono methyl phthalate                      <LOD        1.53
Mono (3-carboxypropyl) phthalate           2.74        2.60

                                           75th         90th
Compound                                   percentile   percentile

Mono benzyl phthalate                      24.6         46.0
Mono isobutyl phthalate                    6.21         10.9
Mono n-butyl phthalate                     33.9         59.0
Mono ethyl phthalate                       452          1,110
Mono-2-ethylhexyl phthalate                4.31         10.8
Mono-(2-ethyl -5-hydroxyhexyl) phthalate   35.8         93.5
Mono-(2-ethyl-5-oxyhexyl) phthalate        24.3         63.0
Mono-(2-ethyl-5-carboxypentyl) phthalate   54.6         139
Mono methyl phthalate                      3.45         7.95
Mono (3-carboxypropyl) phthalate           4.39         7.70

                                           95th
Compound                                   percentile

Mono benzyl phthalate                      70.0
Mono isobutyl phthalate
Mono n-butyl phthalate                     91.6
Mono ethyl phthalate                       2,040
Mono-2-ethylhexyl phthalate                25.4
Mono-(2-ethyl-5-hydroxyhexyl) phthalate    182
Mono-(2-ethyl-5-oxyhexyl) phthalate        118
Mono-(2-ethyl-5-carboxypentyl) phthalate   251
Mono methyl phthalate                      13.5
Mono (3-carboxypropyl) phthalate           10.7

LOD=level of detection

Table 2. Urinary Levels of Phthalate Metabolites in Pregnant Women

                                Detection   Geometric   50th
Phthalate                       frequency   mean        percentile

Mono-benzyl phthalate           100%        8.9         7.5
Mono-isobutyl phthalate         100%        41.3        42.1
Mono-n-butyl phthalate          100%        43.2        42.7
Mono-ethyl phthalate            97%         112         117
Mono-ethylhexyl phthalate       96%         6.9         6.9
Mono-(2-ethyl-5-hydroxyhexyl)   100%        14.3        14
phthalate

                                75th         95th
Phthalate                       percentile   percentile

Mono-benzyl phthalate           16.8         95.8
Mono-isobutyl phthalate         72.8         249
Mono-n-butyl phthalate          86.6         197
Mono-ethyl phthalate            425          1150
Mono-ethylhexyl phthalate       17.3         82.8
Mono-(2-ethyl-5-hydroxyhexyl)   30           86.2
phthalate

Table 3. Comparison of Phthalate Metabolite Levels in NHANES and in
Cases of Male Infertility in the Hauser Study (15)

                                              50th
             Geometric                     percentile
             mean        Frequency
Metabolite   (ng/mL)     of detection   Hauser   NHANES

MEP          171         100%           154      153
MEHHP        55.9        >95%           48.6     17.7
MEOHP        21.4        >95%           32       12.1

                  75th              95th
               percentile        percentile

Metabolite   Hauser   NHANES   Hauser   NHANES

MEP          513      452      2030     2040
MEHHP        111      35.8     601      182
MEOHP        71.3     24.3     444      118

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

          Percent     50th         75th         90th
Paraben   detection   percentile   percentile   percentile

Methyl    99          43.9         180          412
Ethyl     58          1.0          6.9          25.1
Propyl    96          9.1          49.2         144
Butyl     69          0.5          3.3          14.5
Benzyl    139         <LOD         10.2         10.4

          95th
Paraben   percentile

Methyl    680
Ethyl     47.5
Propyl    279
Butyl     29.5
Benzyl    10.5

LOD=level of detection
Source Citation   (MLA 8th Edition)
Crinnion, Walter J. "Toxic effects of the easily avoidable phthalates and parabens." Alternative Medicine Review, Sept. 2010, p. 190+. Academic OneFile, http%3A%2F%2Flink.galegroup.com%2Fapps%2Fdoc%2FA239916603%2FAONE%3Fu%3Docul_mcmaster%26sid%3DAONE%26xid%3D1ace54ec. Accessed 18 Mar. 2019.

Gale Document Number: GALE|A239916603