Our Stolen Future _Phthalates
Theo Colburn
Disclaimer: This research stated below is for information only. Novena does not take credit for this research or the content with in these articles.
What are phthalates? How are they used?
Phthalates are a class of widely used industrial compounds known technically as dialkyl or alkyl aryl esters of 1,2-benzenedicarboxylic acid. There are many phthalates with many uses, and just as many toxicological properties.
Phthalates crept into widespread use over the last several decades because of their many beneficial chemical properties. Now they are ubiquitous, not just in the products in which they are intentionally used, but also as contaminants in just about anything. About a billion pounds per year are produced worldwide.
Intentional uses of phthalates include softeners of plastics, oily substances in perfumes, additives to hairsprays, lubricants and wood finishers. That new car smell, which becomes especially pungent after the car has been sitting in the sun for a few hours, is partly the pungent odor of phthalates volatilizing from a hot plastic dashboard. In the evening's cool they then condense out of the inside air of the car to form an oily coating on the inside of the windshield.
What are the health concerns?
Much of the existing literature on phthalates' toxicological properties focuses on the old approach to toxicology: high level exposure for cancer endpoints, and occupational exposure leading to adult infertility. In the past several years, however, particularly led by Earl Gray's laboratory at the US Environmental Protection Agency, attention has turned to low-dose toxicity of phthalates during crucial windows of fetal development. As these studies have advanced, they have fundamentally changed our perception of potential health risks of phthalates.
According to Hauser et al. (2006): "Phthalates are a class of multifunctional chemicals used in a variety of consumer and personal care products. Highmolecular- weight phthalates (eg, di-2-ethylhexyl phthalate --DEHP-- and butylbenzyl phthalate --BBzP--) are primarily used as plasticizers in the manufacture of flexible vinyl, which is used in consumer products, flooring and wall coverings, food contact applications, and medical devices. Manufacturers use low-molecular-weight phthalates (eg, diethyl phthalate --DEP-- and dibutyl phthalate --DBP-) in personal care products (eg, perfumes, lotions, cosmetics), as solvents and plasticizers for cellulose acetate, and in making lacquers, varnishes, and coatings, including those used to provide timed release in some pharmaceuticals."
While high doses of phthalates do constitute risks in the sense of traditional toxicology, these low doses change the stakes dramatically. Gray's work reveals that male reproductive development is acutely sensitive to some phthalates. For example, the phthalates dibutyl phthalate (DBP) and diethylhexyl phthalate (DEHP) produced dramatic changes in male sexual characteristics when exposure took place in utero, at levels far beneath those of previous toxicological concern. These changes included increases in the rates of hypospadias and other indications of demasculinization.
Enough questions about phthalates have been raised during the last few years for the National Toxicology Program, under the auspices of its recently established "Center for the Evaluation of Risks to Human Reproduction" (CERHR), to convene a panel of independent experts in 1999 to review scientific evidence addressing developmental threats of phthalates. The panel issued a draft report in August 2000. Its conclusions are severely restricted by the fact that few of studies necessary to address fetal impacts of phthalates have been done. For a least one of the phthalates they addressed, DEHP, the panel had serious concern about health impacts. Not surprisingly, given the state of research the report's conclusions are tentative, establishing plausible but uncertain risk. One of the key points is DEHP's impact on developing Sertoli cells, cells in the male reproductive tract that are central to sperm formation. Damaged Sertoli cells during development lead to sperm maladies in adulthood, including low sperm count. DEHP does not cause Sertoli damage directly; damage instead is caused by a metabolite of DEHP, monoethylhexyl phthalate (MEHP).
In summer 2006, two papers upped the ante considerably on possible low-level effects of phthalates. The ranges at which Gray et al. have conducted their experiments are close to the range of common human exposure, but still somewhat above. These new papers reveal biological impacts in animals well within the range of common human exposure, and show show non-monotonic action of DEHP at environmentally-relevant levels. One examined impacts on the activity of the enzyme aromatase, which is essential for masculinizing male brains. The second experimented with DEHP's ability to exacerbate allergic reactions to an allergen, providing a possible clue as to why allergy rates have gone up so much in the developed world. Non-monotonic dose response curves are important because they invalidate current approaches to developing health standards.
In May 2005: For the first time, researchers have identified an association between pregnant women’s exposure to phthalates and adverse effects on genital development in their male children. The pattern of genital changes seen in these baby boys is consistent with the "phthalate syndrome" previously observed in rodents prenatally exposed to phthalates. It is also suggestive of "testicular dysgenesis syndrome," a human health condition proposed to be linked to exposure to endocrine-disrupting compounds. The adverse effects are seen at phthalate levels below those found in one-quarter of women in the United States, based on a nation-wide survey by the Centers for Disease Control. More...
In August 2000, Puerto Rican scientists reported on an association between exposure to DEHP and premature breast development in young girls, possibly linking phthalates to trends in puberty.
In September 2000, the US Centers for Disease Control released the first substantial assessment of phthalate exposure in the American public. Their study analyzed urine metabolite residues of seven phthalates. Levels were high for several of the compounds studied, particularly the metabolite of DBP. Of greatest concern was the discovery that in their sample, an disproportionate number of women of child-bearing age bore high levels of this metabolite. Given Gray's data on fetal vulnerability, this is precisely the population that should minimize exposure to this anti-androgen.
In winter/spring 2002-2003, three studies linked phthalate exposure to reductions in semen quality. All were of men exposed to background, environmental levels of phthalates, not higher occupational levels. One showed DNA damage in sperm. Two others (one from the US, the other from India) found reductions in sperm quality in men with slightly elevated phthalate levels. Phthalate levels associated with the damage were well within the range experienced by many Americans.
The debate about regulation and public health protection
Over the past several years, debate has grown in the regulatory world about what to do about phthalates. Industry argues that years of phthalate use without visible harm prove product safety. Critics counter that animal studies establish plausible risk but that the relevant human epidemiological studies focused specifically on the impacts of fetal exposure simply haven't been done. They point, moreover, to the fact that human health endpoints consistent with phthalate damage are found in animal experiments. They also point out that certain exposures, particularly those associated with children chewing on soft polyvinyl chloride toys and patients receiving intravenous medication through polyvinyl chloride equipment may lead to very high exposures. [The CDC report, above, adds to that list of high exposure concern: the fetuses of pregnant women using cosmetics containing phthalates.]
European regulators kicked off this debate when they began to explore the possibility of bans on toys intended for infants that contained DEHP. This set in motion fierce industry lobbying from the United States to head off the ban, an effort that not only proved unsuccessful ultimately in Europe, but one that was matched in the US by a call by the Consumer Products Safety Commission for a voluntary phase-out by US manufacturers, not only from pacifiers and toys but also from certain medical devices. Several large US toy manufacturers, including Disney and Mattel, made public commitments supporting the phase-out.
The debate heated up further in the US when an industry PR firm that masquerades as a public health organization, the American Council on Science and Health, put together a panel to review the safety of phthalates. Headed by retired Surgeon General C. Everett Koop, the panel ultimately issued a flawed report that concluded phthalates were safe. Their report failed to consider several key recent publications and misrepresented another, citing the latter as stating that no kidney damage was caused when in fact the research did not assess kidney damage. They committed an even more basic error, moreover, by accepting the absence of data as proof of safety. Absence of data proves only ignorance. A devastating critique of this report was published by Health Care Without Harm (a PDF file; long download on slow modems).
The American Academy of Pediatrics entered the debate in June 2003, issuing a report in Pediatrics that recommends research on phthalates effects on the fetus and infants. Their review of the literature found that no studies had directly addressed this issue, yet animal research clearly documents harm and data from the US Centers for Disease Control shows widespread
This mouthful of a title, below, may deflect casual readers from very important results. Don't let it.
Gray, LE, C Wolf, C Lambright, P Mann, M Price, RL Cooper and J Ostby. 1999. Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat. Toxicology and Industrial Health. 15:94-118.
Gray et al. establish definitively that endocrine disruption occurs through interaction with androgen receptor, that multiple compounds are antiandrogens, and that their interaction can produce a diversity of impacts on the developing male reproductive tract.
These results are important for several reasons.
* They reinforce the fact that endocrine disruption is not just about estrogens and estrogenicity.
* They demonstrate that systematic search though compounds in current use not yet identified as endocrine disruptors yields positive results... this search is just beginning, and the number revealed here suggests there will be many more.
* They show that the same compound can have multiple impacts on multiple components of the reproductive tract.
Among the results:
One of the endpoints Grey et al. measured was the percentage of male pups born with hypospadias (right). Males in the control group never had hypospadias.
Diethylhexyl phthalate (DEHP) proved to be highly toxic to the reproductive system of male offspring in transgenerational studies (in which the pregnant female was exposed and effects measured in her offspring). "DEHP induced high levels of testicular and epididymal abnormalities, including atrophy and agenesis. A striking effect of DEHP was noted in 8-day old pups. Several males from different litters displayed hemorrhagic testes that were visible by gross examination of the inguinal region. Obviously, the testis is a direct target of DEHP during perinatal life."
Treatment by procymidone demasculinized and feminized (two separate effects) the male rat offsprings in a manner nearly identical to that seen with vinclozolin. The effects included permanent nipples and hypospadias. Procymidone was more potent than p,p'-DDE, the parent compound of which (DDT) has been banned since 1976.
The collection of effects seen in offspring treated by PCB 169 is similar but more pronounced than exposures caused by TCDD (dioxin). Several aspects of this work indicate that PCB 169 is not functioning as an antiandrogen but instead is working through interaction with the Ah receptor, as does TCDD.
Hypospadias is a birth defect of the penis in which the position of the opening is shifted from its normal place on the head of the penis to somewhere along the shaft. The most extreme forms of hypospasias find the opening at the base, or even in the scrotum. Modest cases of this debilitating birth defect can be corrected through reconstructive surgery, but the most extreme cases sometimes cannot. The cause of hypospadias in humans has not been established, other than to observe that it must result from a developmental error in the womb that has prevented complete masculinization of the reproductive tract.
Experiments with laboratory animals reveal that hypospadias can be repeatedly and reliable produced by exposure to several endocrine disrupting chemicals, including DDE and vinclozilin, a commonly used fungicide.
The US Centers for Disease Control undertook a study of the rate of hypospadias in the US because of these animal studies. They had become concerned about endocrine disruption and decided that if it were a real problem, then there should be evidence in US health trends. They surveyed the animal studies looking for a reliable effect produced by endocrine disruption that, were it expressed in humans, would be readily and reliably detected. They were particularly interested in finding a health endpoint in which any changes in rate measured over time would not have been a result of differences in diagnosis or detection. This is a classic problem in longitudinal health studies. They selected hypospadias to study because it met these criteria.
The CDC's analysis of the changes in the frequency of hypospadias in the United States revealed a striking pattern: the rate has more than doubled since 1970. Indeed by 1993, hypospadias was detected in one out of every 125 boys born in the United States (graph, above).
Subsequent research has also revealed increases in hypospadias in several other countries, particularly Japan and Scandinavia. Data analyzed by Leonard Paulozzi of the US CDC indicates that the increase in hypospadias in some industrialized countries may have leveled off in the mid-1980s.
Research published in 2002 suggests but does not prove an ambiguous link to exposure to DDE in the womb. The study involved an analysis of umbilical cord blood kept frozen since it had been sampled during the period 1959-1965. More...
Note: the rate shown in the graph is per 10,000 births, i.e., of boys and girls. To estimate the rate per 10,000 boys, multiply any particular rate on the graph by 2.
exposure.
Added: 01/30/08© Novena 2008
Producto de Oregon USA Póliza Privada Términos y Condiciones
