Toxicity of Phthalates in animals and Humans: 
The Koop et al review and other viewpoints. 
(www.turnertoys.com   ©1999 18th Century Industries, Inc.)

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There has been some mass media coverage of a report produced by C. Everett Koop and a group medical and toxicologic specialists.  Dr. Koop is a former U.S. Surgeon General, lends his name and prestige to the popular health site www.koop.com,  and has a connection personally to the American Council on Science & Health, which is a private non-profit group based in New York City, funded by foundation and corporate donations.  We will refer to this review as the Koop Report. The report reviewed studies, primarily experimental and mostly with rodents, some with lower primates, on the health effects of DEHP & DINP.  [See "references" section for download information.]
They concluded:

"DEHP. DEHP, as used in medical devices, is not harmful to humans even under chronic or higher-than-average conditions of exposure. DEHP confers considerable benefits to certain medical devices and procedures, and its elimination without a suitable substitute could pose a significant health risk to some individuals.

"DINP. Although results of animal toxicity tests in DINP suggest the need for thorough evaluation, the Panel concludes that much of this evidence has little relevance for humans and that DINP in toys is not harmful for children in the normal use of these toys."

There is presently little disagreement about the finding that significant amounts of phthalates, coming mostly from the many vinyl objects in our daily life, but also from water-based paints, cosmetics, rubbing alcohol, and other sources, end up in our bloodstreams, digestive systems, body fat, and organs such as liver, lung, and heart.  There continues to be legitimate disagreement over how much harm these substances are doing to people, whether children or adults.  A  number of medical studies have demonstrated the probability that adult humans, and to a greater extent children, especially newborns or preterm infants, display symptoms of toxicity  due to accumulation of DEHP.  DEHP is present in vinyl medical tubing, blood bags, and other devices, and migrate to blood or the lungs during intravenous feeding, transfusions, dialysis, IV-dispensed medications, artifical ventilation with air tubes, and so on.  We have cited a few such studies in our References section.  There is little epidemiologic data for humans regarding effects of DEHP exposure, even though desirability of this data is unquestioned, and could be available by, for example, following dialysis patients or hemopheliacs for health effects due to DEHP.  Obviously, there are no controlled studies in humans.  There have been many controlled animal sudies on the effects of DEHP, primarily in rodents, also in monkeys.  The argument, which is central to the discussion on this page, is over the relevance of the findings of damage  in lower animals exposed experimentally to phthalates, especially lab rats and mice, to human beings.

DINP, used as a plasticizer for toys, has been less extensively studied.  Estimates of exposure of children to DINP released from PVC teethers (Dutch National Institute of Health: see references on this site) assumed mouthing by a teething child of 12 minutes per day, and thus reached the conclusion that daily dosage was far below hazardous levels.  This also assumes that DINP does not accumulate in body tissue (as DEHP is known to do), and that extrapolations from animal data to human infants are valid.  The studies on DINP cited in the Koop et al review were done primarily with rodents, and involved relatively short term exposures.  We have not actually read any of those studies.  Because of this, and because of the comparative scarcity of data on DINP compared to DINP, we will discuss the Koop report in terms of DEHP toxicity.  This topic has been examined very thoroughly and expertly by the Lowell Center for Sustainable Production, at University of Massachussetts at Lowell.  In fact (we hate to admit it), it is one of the best efforts we have seen at presenting technical information in language accessible to the lay public. We are providing a download link for this file and for the Koop Report below on this page.  We will refer to this review on this page as the Lowell Report.

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The Koop Report appears to rely for its conclusions on the safety of DEHP on two findings:
1. An assumption that human exposure is primarily intravenous rather than oral.  The DEHP exposure for humans reviewed in the Koop Report mostly occurs in patients undergoing dialysis, transfusion, and intravenous feeding.  Intravenous exposure results in lower production of mono ethylhexyl phthalate (MEHP) than does exposure through digestion.  MEHP is considered the actively toxic agent in phthalate exposure.
2. There are certain species differences between rodents and humans in their response to DEHP.

Briefly, these statements neglect certain findings which may be found in studies cited and discussed in the Lowell Report, and in one case, on this website (Ganning, 1984 - see "references") 

1. When DEHP enters the human body, the compound is metabolized into various substances that are more readily excreted. Unfortunately, the most important of these metabolites, mono-ethylhexyl phthalate  (MEHP) is thought to be responsible for much of DEHPís toxicity. The enzymes that break down DEHP into MEHP are found mainly in the intestines but also occur in the liver, kidney, lungs, pancreas, and plasma. Because conversion of DEHP to MEHP occurs primarily in the intestinal tract, exposures to DEHP by ingestion may be more hazardous than by intravenous exposure, which largely bypasses the intestinal tract. However, MEHP has been measured in stored adult human serum as well as in the blood sera of neonates undergoing exchange transfusions and adults undergoing hemodialysis. MEHP is not the only metabolite of DEHP and many of the known secondary metabolites have not been studied for their toxicity. The initial metabolism of DEHP is qualitatively similar among mammalian species, so that animal studies are likely to be useful in understanding the consequences of human exposure. The ability to metabolize DEHP is age-related and may also depend on underlying health status in ways that are not well-understood.
It is generally accepted that the toxicity of DEHP via one route of exposure should be considered relevant to exposure by other routes, in the absence of evidence to the contrary. [Lowell Report, p.3]

2. The Koop Report seems to be based largely on the finding that primates, especially humans, are resistant to a class of substances called peroxisome proliferators.  Peroxisomes are normal components of cells, including liver cells, which break down fatty acids and help synthesize cholesterol.  When exposed to substances like DEHP, they multiply abnormally and are thought to become  promoters of liver cancer.  This effect is seen clearly in rodents, but its relevance to humans is disputed.
The studies cited by Koop  generally involve DEHP administration of relatively short duration.  Ganning et al (1984) (see references below) demonstrates that peroxisome proliferation can occur in human dialysis patients after a year of regular treatment, using PVC equipment containing DEHP.  Also, rodents strains who are bred for non-response to Peroxisome Proliferators still do show toxic responses to DEHP, notably testicular damage in newborn & very young animals, including ones exposed in utero by administration of DEHP to the mother. 
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We conclude this update for the time being with the following quote from the Lowell Report:

"There is a general lack of adequate human toxicity or epidemiologic studies to determine whether DEHP exposure is associated with adverse outcomes in humans, despite the compoundís high volume production, documented human exposure, and  documented adverse effects in animals. The lack of epidemiologic studies is at least partly explained by: (1) the difficulty in following high risk groups, such as premature infants, because of long latent periods between exposures and possible effects; (2) the impacts of DEHP exposure may be subtle (such as a partial loss in sperm production); (3) the considerable variability in human exposure levels and the difficulty in measuring human exposure adequately; and (4) the ubiquity of phthalate exposure in the environment, which means that humans are exposed to DEHP through many different routes, making it difficult to distinguish exposed and unexposed groups."  (p. 5) 
[A thought occurs here - Ganning et al, p.547 (1984, cited) mention briefly that subject rats exposed to DEHP showed changes in liver synthesis of Cholesterol:
"Total blood is unchanged in rats treated with DEHP; however, redistribution occurs involving a decrease of high density lipoprotein and an increased amount of low density lipoprotein.  If a similar situation occurs in humans, these moderate changes could have an unfavorable effect on the circulatory system".  
They cite for this information Bell F.P., Patt C.S, Gillies P.J.  Effect of phthalate esters on serum cholesterol and lipid biosynthesis in liver, testes, and epididymal fat in the rat and rabbit. Lipids 1978; 13:673-678. Instead of looking for an epidemic of liver disease after several decades of exposure to phthalates, ought we instead to be looking at the prevalence of circulatory diseases - heart attack and stroke - and asking if there are other factors besides diet, exercise, and genetics?] 

Our conclusions:
Despite the assertions of the Koop Report, the issue is far from settled.  In view of the clear weight of evidence of the toxicity of phthalates in mammals, and at least a healthy disagreement among academic and medical researchers regarding the relevance of controlled animal studies to humans, the prudent course would seem obvious:  avoid unnecessary exposure to sources of DEHP and DINP.  As discussed in detail on the "plasticizers" page on this website, in our modern industrial society we ingest phthalates from many sources very difficult to avoid: we inhale it in our homes and cars, we eat it in fat-containing packaged foods such as cheese and meats, we are exposed during medical procedures.  Why give toys containing the substance to young children, who may be especially at risk?  This is just simple common sense. 

References to  reports cited on this page:
Ganning A.E., Brunk U., Dallner J. (1984)  Phthalate Esters and their Effect on the Liver.  Hepatology V4 No 3, Pp 541-547 [quoted on Main Phthalates Page]

The Koop Report (on Medscape - can be downloaded in print-friendly version.  You may need to go to home page - http://www.medscape.com - and register with username & password.  It's free, but will take a few minutes.  download is approx 150k) Cut and paste the following URL:
http://www.medscape.com/medscape/GeneralMedicine/journal/1999/
v01.n06/mgm0622.koop/mgm0622.koop-01.html

Lowell Center for Sustainable Development Report on Phthalates  Excellent overview.
http://www.uml.edu/centers/LCSP/newpdfs.htm
This is an interesting website for the environmentally concerned. They offer on this page a free download of Adobe Acrobat Reader, which you need to view paper. [Download is large] 

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More from the Lowell Report:

        DEHP produces a spectrum of toxic effects in laboratory animals (including rodents and primates) in multiple organ systems including the liver, reproductive tract (testes, ovaries, secondary sex organs), the kidneys, lungs, and heart. It is also toxic to the developing fetus. The studies documenting these effects range from large studies involving hundreds of animals, to smaller ones with few animals, as well as cell culture studies, and case reports in humans. While most of these effects have been observed in laboratory animals at high doses (the standard procedure by which experimental studies are made sufficiently powerful to detect small effects), in some cases these doses were close to those that might be experienced by individuals undergoing medical treatment. For some adverse effects, such as testicular toxicity, the developing organism (fetus and neonate) appears to be much more sensitive (greater toxicity and irreversibility of effect) than the adult. It is unclear whether a threshold (a level of exposure below which no adverse effect will occur) for adverse effects exists.  [table inserted here - download original report]

        DEHP belongs to a class of chemicals called "peroxisome proliferators." Peroxisomes are cell membrane organelles that contain enzymes responsible for oxidation of fatty acids, the biosynthesis of cholesterol, and other biochemical pathways. It is generally thought that peroxisome proliferation is associated with liver cancer in animals, although the causal mechanisms by which this happens are not currently known. Peroxisome proliferation occurs to a much lesser degree in humans than in rodents and for this reason some researchers have questioned the relevance of animal studies of DEHP to humans.

        There is still considerable uncertainty as to the exact mechanisms by which DEHP may cause various different adverse effects in diverse organs of laboratory animals. The mechanisms of toxicity are likely to be multiple and variable, depending on the health endpoint, the organ, and species studied. Recent studies in mice exposed to DEHP show fetal toxicity, teratogenicity, testicular lesions, and kidney cysts, though not liver lesions, in laboratory animals bred without the receptor necessary for mediating the enzymatic activity of peroxisomes (PPAR alpha, a receptor also present in humans). That is, mice that have been bred to lack one of the receptors necessary for the peroxisome development, in response to exposure to a peroxisome proliferator, still exhibit toxic effects of DEHP. These studies strongly support the conclusion that much of the non-hepatic toxicity of DEHP is at least partly independent of peroxisome proliferation.

        As regards toxic effects that are mediated exclusively through peroxisome proliferation, our under-standing of their relevance to humans turns on the extent of knowledge concerning the prevalence of this phenomenon in humans. There may, for example, be considerable inter-individual variability in the phenomenon of peroxisome proliferation from exposure to a chemical such as DEHP. As a result, it is prudent to assume that at least some fraction of the population may be as effective at peroxisome prolifera\tion as the laboratory animals in which most DEHP toxicity studies have been done. Moreover, it is still not clear that peroxisome proliferation is absolutely necessary for malignant transformation. It remains plausable that another mechanism, such as genotoxicity, may also contribute to cancer risks. For these reasons the carcinogenic activity of DEHP in animal experiments may well be relevant to humans. This same conclusion was recently reached by the California Office of Environmental Health Hazard Assessment  with regards to DEHP carcinogenicity. They stated, "at this point...OEHHA does not find this new body of evidence [on perixosome proliferation] points toward a determination that human exposure to any level of DEHP is without carcinogenic risk. Rather, the literature presents data that leave open the possibility of human sensitivity to DEHPís carcinogenic effects."

        There is a general lack of adequate human toxicity or epidemiologic studies to determine whether DEHP exposure is associated with adverse outcomes in humans, despite the compoundís high volume production, documented human exposure, and  documented adverse effects in animals. The lack of epidemiologic studies is at least partly explained by: (1) the difficulty in following high risk groups, such as premature infants, because of long latent periods between exposures and possible effects; (2) the impacts of DEHP exposure may be subtle (such as a partial loss in sperm production); (3) the considerable variability in human exposure levels and the difficulty in measuring human exposure adequately; and (4) the ubiquity of phthalate exposure in the environment, which means that humans are exposed to DEHP through many different routes, making it difficult to distinguish exposed and unexposed groups.
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