ENDOCRINE DISRUPTORS

Environmental Toxins in Drinking Water: Phthalates

Part 1 of 4. Phthalates as Endocrine Disruptors in the Environment

Reproductive, Endocrine, Immune, Genotoxic, and Nephrotoxic Damages in Wildlife

In recent years, the safety of phthalates as potentially powerful endocrine disruptors has been hotly debated worldwide by scientists, government regulators, and consumer advocates. Phthalates are found in our drinking water, air, and food all over the world. Phthalates are a major environmental pollutant and a cause for concern because they are found in most people's blood, tissue, breast milk, and urine. The European Union banned phthalates in soft PVC toys and childcare products in 1999 through its Commission Decision 1999/815/EC. In 2004, the EU banned phthalates in cosmetics and other beauty products. No such bans are in effect in the United States and elsewhere outside European Union. The U.S. Food and Drug Administration (FDA) stated that there is no clear evidence of harm from phthalates in cosmetics and other products.

Researchers estimated that more than 75% of the U.S. population is exposed to phthalates. Starting as early as the 1950s, scientists have published research findings in peer-reviewed academic and science journals on human and animal exposure to phthalates and their wide variety of health problems, as follows:

• Infertility especially among men)
• Cancers (e.g., liver, breast, prostate, testicular, colon)
• Autoimmune diseases (e.g., lupus)
• Fertility problems (e.g., low sperm count, poor mobility of sperm, DNA damage in sperm, lower testosterone level, and ovarian dysfunction)
• Obesity, resistance to insulin, and diabetes in men
• Smaller testes and smaller genitals on average among male babies exposed to phthalates in mothers' wombs Asthma
• "Feminization" of male fish, frogs, and other amphibians living in phthalates-contaminated rivers in the wild

What Are Phthalates and Where Are They Found?

Phthalates are a class of synthetic chemical compounds used widely as softeners in many plastic products (or commonly called as "plasticizers" in plastics) and other consumer products, as follows:

• All polyvinyl chloride plastics (PVCs), including PVC plastic bags and PVC pipes
• Pharmaceutical products and medical devices (e.g., tubes, PVC blood bags, dialysis equipment, disposable medical examination and sterile surgical vinyl gloves)
• Cosmetics, perfumes, and other beauty products (e.g., face cream, nail polish)
• Personal care products (e.g., lotion, shampoo, soaps)
• Children's soft-squeeze plastic toys
• Baby's pacifiers, infants' teething rings
• Common household products (e.g., shower curtains, raincoats)
• Industrial lubricants
• Building products (e.g., carpet backing, putty, caulk)
• Solvents in glues and other adhesives, paints, and wood finishes
• As the inert ingredient in pesticides and insect repellents
• Food packaging
• Sex toys (specifically the so-called jelly rubber toys)

Specifically, phthalates are used as softeners and plasticizers of plastics, as solubulizers (for other ingredients to dissolve in), denaturants (to make products taste bitter), as holders of colors and prolongers of scents in beauty and personal care products, and as solvents in glues and paints.

Photographs: PVC (#3) plastic contains phthalates, which soften plastics to make them flexible. Babies' pacifiers and rubber-duck toys also contain phthalates, which make them soft and squeezable.

How Much Phthalates Are Produced?

Exact amount of phthalates produced each year varies from source to source. One figure cited was that worldwide in 1999, the phthalates volume manufactured was about 10 billion pounds (valued at U.S.$5 billion), with an average annual growth rate of 2% to 3% according to one estimate. Another figure has researchers estimated that more than 18 billion pounds are used each year. Still others estimated that as of 2004, manufacturers produce about 363,000 metric tons (800 million pounds or 400,000 short tons) of phthalates annually according to another estimate. They were first produced during the 1920s, and have been produced in large quantities since the 1950s, when PVC was introduced commercially. In Australia, industry uses approximately 12,000 tons of phthalates each year to plasticize PVC products. In Sweden, approximately 5,000 to 6,000 tons of phthalates—including di(2-ethylhexyl) phthalate (DEHP)—are used annually. Even in 1969, more than 800 million pounds were produced annually (according to the U.S. Tariff Commission, 1971).

Phthalates substitutes are available but they cost about 50% more, or even double in the case of one phthalate. More than 90% of the plasticizer volume produced annually goes into PVC. Without phthalates, PVC is brittle and hard and has little commercial application or value.

Ever since its popular use in the 1920s and 1930s, phthalates have leached into drinking water, food, and air. Phthalates are found all over the world, from the most populated urban areas to the most remote corners of the earth. Phthalates leach easily from products because in general they are not chemically bound to the product matrix and may thus migrate readily (Högberg et al., 2008).

Chemistry of Phthalates: What Are Phthalates?

Phthalate plasticizers are colorless liquids (similar in viscosity and appearance to vegetable oil) with a faint odor, and they are insoluble in water. They are, however, miscible in mineral oil, hexane, and most organic solvents, which makes them readily soluble in bodily fluids, such as saliva and plasma. The most widely used phthalates are di-2-ethyl hexyl phthalate (DEHP), diisodecyl phthalate (DIDP), and diisononyl phthalate (DINP). DEHP is the dominant plasticizer used in PVC, due to its low cost. Benzylbutylphthalate (BBzP) is used in the manufacture of foamed PVC, which is mostly used as a flooring material. Phthalates with small R and R' groups are used as solvents in perfumes and pesticides. Of the ester plasticizers, standard phthalate esters comprise more than 85% of the tonnage produced annually. Phthalates command the market because of their low cost and availability.

The basic structure of "phthalate" is the benzene ring consisting of six carbons and six hydrogen atoms (the left-most part of the structure) bonded with two esters (which are the two carbon atoms double-bonded to two oxygen atoms on one side and single-bonded to two other oxygen atoms on another side). When one compares the structures of the phthalates, one sees the similarity, as in Bis(2-ethylhexyl)phthalate and diisodecyl phthalate above.

A list ofphthalates commonly used in consumer and industrial products worldwide

Typically because phthalates are not chemically bound to the product matrix, they migrate out of the product easily and cause extensive exposure among humans and animals that come into contact with them (Högberg et al., 2008).

Phthalates in the Environment

Effects on Fish, Frogs, and Other Amphibians in the Wild: Reproductive, Endocrine, Immune, Genotoxic, and Nephrotoxic Damages.

Phthalates and their metabolites are excreted from human urine and wastewater (such as water that washes off cosmetics, facial cream, lotion, shampoo). Phthalate-containing wastewater reaches the environment via treated sewage discharged into streams, rivers, lakes, oceans, and other bodies of water. Phthalates also reach the natural environment via pesticides, industrial lubricants, and phthalate-containing garbage humans throw away. Because everything humans use eventually get disposed of into the environment, it is inevitable that phthalates are found in the environment.

Humans and wildlife are exposed to phthalates and other environmental pollutants which can interfere with endocrine-signaling pathways in the body. For about four decades (since the 1970s), hundreds of scientists conducting research all over the world have found that phthalates and other environmental pollutants (such as pesticides, synthetic industrial lubricants and solvents) can disrupt the endocrine functioning of wildlife species, thus causing permanent alterations in the structure and function of the endocrine system.

Since phthalates are extensively used as plasticizers decades ago, researchers have found them in the rivers and lakes. In an article published in January 1973, a MIT researcher has found that the phthalate concentration increases as one moves upstream: "Phthalates are added to the river from one or more sources which are located above river mile. As this contaminated water flows downstream, more water is added from runoff and other sources, thus diluting the phthalates. In addition, biological activity in this slowly flowing river [Charles River] also tends to reduce the phthalate concentration as the water moves downstream. The two samples taken at river mile 1 but at two different depths differ significantly. This is certainly due to the severe vertical stratification exhibited by the river at this location (Hites, 1973).

Although phthalates' concentrations may decrease due to dilution by river water, even the low concentrations of phthalates affect a wide variety of wildlife in the rivers (e.g., fish, frogs and tadpoles, and other amphibians). Numerous scientific studies focusing on how phthalates affect aquatic animals have been conducted by researchers since the 1970s; we present only a few studies here.

Photos: A deformed frog with five legs (left) and a chytrid-infected (fungus-infected) dead frog floating in the water (right). (Photos courtesy of Wikipedia).

Freshwater Fish Became "Feminized" and Developed Impaired Kidneys

A team of British scientists from the University of Exeter, University of Plymouth, and Brunel University found that when freshwater fish (belonging to species Rutilus rutilus) were exposed for 300 days to treated sewage effluent containing phthalates and other endocrine disruptors, the fish experienced the following reproductive, endocrine, immune, genotoxic, and nephrotoxic effects (Liney et al., 2006):

• Feminization of male fish (with histologically altered gonads)
• "Statistically significant" changes in kidney development (tubule diameter)
• Modulated immune function (with differential cell count, total number of thrombocytes)
• Genotoxic damage (as indicated by micronucleus induction and single-strand breaks in gill and blood cells)

Male Tadpoles Developed Ovaries When Exposed to Dibutyl Phthalates

Japanese scientists from Hiroshima University and Hiroshima Prefectural Women's University studied the effects of dibutyl phthalate (DBP) on male Japanese wrinkled frog (Rana rugosa). This particular phthalate, DBP, is one of the phthalate esters widely used as a plasticizer of polyvinyl chloride resins.

The scientists discovered that "DBP is an environmentally dangerous hormone that disrupts the pathways of testicular differentiation in genetically male animals" (Ohtani et al., 2000). In exposing male tadpoles to tiny amounts of DBP, after 0.1, 1, and 10 µM DBP treatment, 0%, 7%, and 17% of tadpoles, respectively, had developed partial or complete ovarian structure when they should be developing complete testes.

In other words, these male tadpoles developed female reproductive structures (ovaries) when they should be growing male structures (testes). Why does this result occur among male tadpoles? Scientists explained that chemical compounds that mimic estrogenic activity must be directly examined for their estrogenic or antiandrogenic action on living animal species. Therefore, these scientists concluded that DBP is a dangerous chemical and is an environmental endocrine disruptor.

Fewer Eggs and Fewer Surviving Fry in Fish Exposed to Phthalates

Abnormal Calcium Metabolism in Phthalate-Exposed Zebra Fish and Salmon

In as early as 1973, American government scientists working with the U.S. Department of Interior's Bureau of Sport Fisheries and Wildlife have found that fishes exposed to phthalates have fewer eggs and fewer surviving fry. Scientists exposed di-2-ethylhexyl phthalate to zebra fish (Brachydanio rerio) and guppies (Poecilia reticulatus) discovered that fish exposed to phthalates produced fewer eggs per spawn than controlled, non-exposed fish (Mayer Jr. and Sanders, 1973). The researchers also found that fry survival was "significantly reduced (P < 0.05) by phthalate exposure," with an 8 percent incidence of abortions observed among the guppy fry. Water fleas (Daphnia magna) exposed to di-2-ethylhexyl phthalate also suffered "significantly reduced" reproduction.

Additionally, these U.S. government scientists also found that coho salmon (Oncorhynchus kisutch) injected with 3 milligrams of di-2-ethylhexyl phthalate/kg of fish demonstrated increased serum calcium. They noted that "All of the dying [zebra fish] fry exposed to di-2-ethylhexyl phthalate died in tetany; however, tetany did not occur in dying controls." Tetany is an abnormal condition characterized by tetanic spasms of voluntary muscles; tetany is the state of continuous contraction of a muscle, especially caused by a series of rapidly repeated stimuli. What does this finding mean? It means that the tetany observed in zebra fish and the increased serum calcium in coho salmon are indications that di-2-ethylhexyl phthalate "may alter normal calcium metabolism in fish" (Mayer Jr. and Sanders, 1973).

Deformed Genitals and Adverse Spermatogenesis of African Clawed Frog

Scientists from Colorado State University have found that African clawed frogs (Xenopus laevis) exposed to very low concentrations of di-n-butyl phthalate (DBP) suffered numerous problems, as follows (Lee and Veeramachaneni, 2005):

• Between 4% and 6% of male frogs had only one testis (for those tadpoles that were exposed to very low concentrations DBP, at 0, 0.1, 0.5, 1.0, 5.0, or 10.0 ppm DBP, at the beginning of sexual differentiation).
• Between 2% and 4% of male frogs had retained oviducts (oviducts are tubes that allow for the passage of eggs from an ovary).
• For all DBP-treated male frogs, seminiferous tubule diameter and the average number of germ cell nests per tubule were lower. Also, the number of tubules with no germ cells was significantly higher (p < 0.05).
• The percent of secondary spermatogonial cell nests significantly decreased (p < 0.05) in 1.0, 5.0, and 10.0 ppm groups.
• Several lesions were observed in DBP-exposed frogs' testes (including denudation of germ cells, vacuolization of Sertoli cell cytoplasm, thickening of lamina propria of seminiferous tubules, and focal lymphocytic infiltration).
• Entire sections of testes containing almost exclusively mature spermatozoa were found in 1.0, 5.0, and 10.0 ppm DBP-exposed testes, indicating impairment of spermiation.
• Testicular hypoplasia (a condition of arrested development in which an organ or part remains below the normal size or in an immature state) and seminiferous tubular dysgenesis were observed in DBP-exposed frogs. Dysgenesis is defective development especially of the gonads.

The scientists concluded that "subchronic exposure to low concentrations of DBP impairs spermatogenesis" in African clawed frogs. Spermatogenesis is the process of male gamete formation including formation of a spermatocyte from a spermatogonium, meiotic division of the spermatocyte, and transformation of the four resulting spermatids into spermatozoa. These scientists also attributed DBP to the global decline of frogs and other amphibians, which have made headline news for more than a decade now.

Avoid Phthalates in Your Drinking Water and Food

For your health and your family's health, it is best to avoid all plastic containers—both for water and food—labeled #3 PVC and all containers containing phthalates. It is best to use glass or stainless-steel food and water bottles and containers when bottling your own filtered water at home. It is difficult to avoid phthalates in this world even if you want to, so do not voluntarily ingest more phthalates by using phthalate-containing water bottles and food containers!

Partial List of References: Scientific Literature

• Ronald A. Hites. 1973. "Phthalates in the Charles and the Merrimack Rivers," in Environmental Health Perspectives, January 1973, pages 17-21.
• Johan Högberg, Annika Hanberg, Marika Berglund, Staffan Skerfving, Mikael Remberger, Antonia M. Calafat, Agneta Falk Filipsson, Bo Jansson, Niklas Johansson, Malin Appelgren, and Helen Håkansson. 2008. "Phthalate diesters and their metabolites in human breast milk, blood or serum, and urine as biomarkers of exposure in vulnerable populations," in Environmental Health Perspectives, volume 116, number 3, March 2008, pages 334-339.
• Shannon K. Lee and D. N. Rao Veeramachaneni. 2005. "Subchronic exposure to low concentrations of di-n-butyl phthalate disrupts spermatogenesis in Xenopus laevis frogs," in Toxicological Sciences, volume 84, number 2, pages 394-407. (doi:10.1093/toxsci/kfi087)
• Katherine E. Liney, Josephine A. Hagger, Charles R. Tyler, Michael H. Depledge, Tamara S. Galloway, and Susan Jobling. 2006. "Health effects in fish of long-term exposure to effluents from wastewater treatment works," in Environmental Health Perspectives, volume 114, supplement 1, April 2006, pages 81-89.
• Foster L. Mayer Jr., and Herman 0. Sanders. 1973. "Toxicology of phthalic acid esters in aquatic organisms," in Environmental Health Perspectives, January 1973, pages 153-157.
• Hiromi Ohtani, Ikuo Miura, and Youko Ichikawa. 2000. "Effects of dibutyl phthalate as an environmental endocrine disruptor on gonadal sex differentiation of genetic males of the frog Rana rugosa," in Environmental Health Perspectives, volume 108, number 12, December 2000, pages 1189-1193.