# Aggregate Exposures to Phthalates in Humans

July 2002ACKNOWLEDGMENTS

Contributors Joseph DiGangi, PhD, USA, Ted Schettler MD, MPH, USA Madeleine Cobbing, UK Mark Rossi, MA, USA

Reviewers

HCWH thanks the following individuals for reviewing an earlier draft of this report. Their comments and suggestions were invaluable and substantially improved the manuscript. We are grateful for their contribution. Their review, however, does not constitute endorsement of the report or its conclusions. Two additional reviewers chose to remain anonymous.

Earl Gray PhD Michael McCally MD, PhD

The contributing authors would also like to thank Cecilia DeLoach, Tracey Easthope, Per Rosander, Jamie Harvie and Charlotte Brody for their editing and proofreading of this report.

Health Care Without Harm 1755 S St. NW, Suite 6B • Washington, DC 20009 • www.noharm.org • 202-234-0091Aggregate Exposures to Phthalates in Humans iii 

# Contents

Acknowledgements......................................................................................ii

Executive Summary.....................................................................................1

Abbreviations..............................................................................................4

Preface......................................................................................................5

Introduction................................................................................................6

Phthalates in Consumer Products.................................................................9

Phthalate Toxicity ......................................................................................14

Exposures Resulting from Medical Procedures .............................................17

Aggregate Exposures in the General Population............................................20

A Legacy of Inadequate Responses ............................................................28

Safer Alternatives......................................................................................31

Conclusions .............................................................................................33

Appendix I. MEHP Exposures in the Hospital................................................36

Appendix II. Phthalate Toxicity ....................................................................39

References...............................................................................................43Aggregate Exposures to Phthalates in Humans 1 

# Executive Summary

Phthalates are a family of chemicals that are produced in the millions of tons annually worldwide,and are a principal component of many diverse products that consumers come into contact with athome, at work, and in hospitals. They include products made of flexible polyvinyl chloride plastic(PVC), cosmetics and other personal care goods, pesticides, building materials, lubricants, adhesives, and film, among other items. Phthalates are released into the environment by manufacturers and escape from consumer products in which they are used.Worldwide ecosystem contamination and direct contact with phthalate-containing products result in virtually ubiquitous human exposures.

Health effects that may be caused by exposure tophthalates differ among the various individual compounds and depend on the timing and the size of thedose. Young, developing organisms are more vulnerable to exposure to phthalates than adults. In particular, the developing male reproductive tract appears to be the most sensitive endpoint, although effects on the liver, kidneys, lungs, and blood clotting are also of concern. In animal tests considered relevant to humans, several of the phthalates, including di-(2- ethylhexyl) phthalate (DEHP), di-butyl phthalate (DBP), benzyl butyl phthalate (BBP), and perhaps di-isononyl phthalate (DINP), interfere with male reproductive tract development and are toxic to cells in the testes responsible for assuring normal sperm and hormone production.

Human exposure to DEHP from PVC medical devices used in patient care has been known for some time. Expert panels of the US National Toxicology Program (NTP) and Health Canada, as well as the US Food and Drug Administration(FDA), however, have recently reviewed the toxicology of DEHP and considered exposures to patients that may result from the use of DEHP-containing equipment. Each review concluded that some patients are likely to be exposed to potentially unsafe amounts of DEHP while receiving medical care. Testing by the US Centers for Disease Control and Prevention (CDC) recently showed that phthalateexposures are virtually ubiquitous in the general population. Women of reproductive age experience some ofthe highest exposure levels to phthalates that can interfere with normal male reproductive tract development.

In this report, we summarize what is known about human exposures to phthalates and consider the potential health impacts of exposure to real-world mixtures of these chemicals. Using a relative potencyapproach, based on what is known about mechanisms of action and available experimental data, it becomes clear that, for a large number of women ofreproductive age, their aggregate exposure to phthalates is sufficient to significantly increase the risk of abnormal development in male fetuses and babyboys. Women of reproductive age who require medical care may be exposed to additional phthalates, largely DEHP, in the medical setting, that, dependingon the procedure, can add significantly to their existing levels.

According to sample data from the CDC, an estimated 5% of women of reproductive age from the general population are contaminated with 75% or more of the level of just one of the phthalates, DBP, that maybegin to impair normal reproductive tract development in their baby boys. Many of these women are also regularly exposed to significant amounts of BBP and DEHP, so that their aggregate exposures pose even greater risks. When any of these women requires medical care that exposes them to additional DEHP from PVC medical devices, even more is added.Where are these phthalates coming from in the general population? No one knows for certain, but perhaps the high exposures to DBP in women of reproductive age provide a clue, at least for that phthalate. DBP is used in a variety of cosmetic and personal care products. Recent testing identified DBP in some hair spray, fragrances, and deodorants. Many nail polishes also have large quantities of DBP. Unfortunately, labeling requirements are sufficiently lax so that it is extraordinarily difficult to identifyphthalate-containing products and to begin to narrow down the search for the sources of widespread general population exposures.

Chemical policy in the US is severely “Balkanized” 161 and requires major revisions. For example, the Foodand Drug Administration is responsible for food contaminants (including phthalates), drug ingredients (including phthalates), medical devices (including phthalate-containing PVC products), and cosmetics (including phthalates). Unfortunately, each of these activities is a responsibility of a different divisionwithin FDA, each of which carries out its work in isolation from the others. As a consequence, when themedical device division considers the safety of exposure to DEHP, they consider only medical devices and not the real world of population-wide exposures to multiple phthalates from multiple sources. And, whenthe cosmetics division considers phthalates in personal care products, not only do they limit their concerns to products in their domain, but they must prove thelikelihood of harm with no requirement that manufacturers will supply safety data.

When the Consumer Products Safety Commission (CPSC) considers the safety of phthalates in, for example, children’s toys, they consider only the phthalate that may leach out of the toy when a child chews on it, and not the other phthalates that the same child may be exposed to from contaminated food, contaminated air, or medical care.

And when the Environmental Protection Agency (EPA) considers whether or not to allow phthalatesin a pesticide formulation, they examine those proposals one at a time, failing to consider aggregate exposures to multiple phthalates from multiple

sources. As a result, phthalates permeate the environment and contaminate large populations of people throughout the world. Phthalates are in the blood of pregnant women at levels of concern, particularlywhen the contaminants are considered in the aggregate. Phthalates cross the placenta and also contaminate breast milk. Relevant animal tests show that phthalates interfere with normal fetal and infant development.

Manufacturers of phthalates continue to producelarge amounts and sell them to product manufacturers who use them in thousands of products. Manufacturers consistently argue that there is noevidence that anyone has been harmed by phthalates. As we note, however, and as confirmed by the NTP panel and FDA, no study has ever examined the impacts of phthalate exposure on the developing male reproductive tract in people. Not one.

Lack of evidence can hardly be used as evidence of safety when no one has ever looked. The increasingincidence of hypospadias, undescended testes, testicular cancer, and declining sperm counts in the US and many other parts of the world suggests that a closer look at many reproductive tract toxicants and endocrine disruptors is urgently needed in people. With respect to phthalates, however, evidence from relevant animal studies and from limited studies of non-reproductive tract impacts in hospitalized patients is sufficient to require phasing out the use of many of the phthalates. As the Health Canada panel concluded, “the status quo is not an acceptable option.”

Regulatory agencies charged with protecting medical patients, public health, and the environment mustsubstantially revise procedures and protocols to consider the potential impacts of phthalate exposures inthe aggregate, rather than as single chemical exposures. In Europe, vigorous debate is underway regarding the phase-out of the general use of many phthalates in consumer products. Alternatives to phthalates that perform well are currently on the market for nearly every use.

Phthalates also serve as a case-study that demonstrates the failure of current chemical policy in the US. Regulatory authority is spread among agenciesthat compete with one another rather than cooperate. Lines of communication are limited and infrequently used. No one agency is authorized to look at the “big picture”.

Health Care Without Harm 2Public health and the environment can only be truly protected when safer materials are substituted far upstream in the manufacturing process. Humans have demonstrated the capacity to contaminate every nook and cranny of every ecosystem and every developing fetus with synthetic chemicals that can impair normal development. Now we need to demonstrate that we can change.

First, we need to recognize that a major overhaul of current regulatory policy is long overdue. Under the current framework, government approval simply does not provide adequate real-world protection from chemical exposures. The FDA, the EPA, the CPSC, and other government agencies, with necessaryauthorization, must begin to transform their makebelieve regulatory framework into a new, sciencebased system that properly considers the reality of aggregate exposures to toxic chemicals and that requires meaningful pre-market testing of commercial chemicals. Second, consumers mustinsist on the right to know about chemicals in commercial products and must have unhindered access to toxicity and exposure data. Third, manufacturers can and must shift to cleaner production practicesand materials that produce cleaner, sustainable products more suited to the contemporary world and the one we will leave to future generations.

Aggregate Exposures to Phthalates in Humans 3

# Abbreviations

μg Microgram ATBC O-acetyl tributyl citrate BEP Butyl A-ethylhexyl phthalate BBP Butyl benzyl phthalate CABG Coronary artery bypass graft
CDC US Centers for Disease Control and Prevention CPB Cardiopulmonary bypass CPSC US Consumer Product Safety Commission DBGP Di-butylglycol phthalate DBP Di-(n-butyl) phthalate DCHP Dicyclohexyl phthalate DEHA Di-(2-ethylhexyl) adipate DEHP Di-(2-ethylhexyl) phthalate DEHPA Di-(2-ethylhexyl) phosphate DEP Diethyl phthalate DHP Dihexyl phthalate DHP Di-n-hexyl phthalate DIBE Di-isobutylhexahydro phthalate DIBP Di-isobutyl phthalate DIDP Di-isodecyl phthalate DIHP Di-isoheptyl phthalate DINP Di-isononyl phthalate DIOP Di-isooctyl phthalate DMP Di-methyl phthalate DOP Di-n-octyl phthalate DPHP Di-(2-propylheptyl) phthalate DPOP Diphenyl 2-ethylhexyl phosphate DPP Di-n-pentyl phthalate DTDP Di-tridecyl phthalate ECMO Extracorporeal membrane oxygenation FDA US Food and Drug Administration KEMI Swedish National Chemicals Inspectorate Kg Kilogram
L Liter L11 Di-L-undecyl phthalate L7-11 Di-L-heptyl, undecyl phthalate L7-9 Di-L-heptyl, nonyl phthalate L9 Di-L-nonyl phthalate L9-11 Di-L-nonyl, undecyl phthalate MBP Mono-n-butyl phthalate MEHP Mono-(ethylhexyl) phthalate MPP Monopentyl phthalate NTP US National Toxicology Program PVC Polyvinyl chloride plastic RPF Relative potency factor TETM Tri-2-ethylhexyl trimellitate
TI Tolerable intake TPN Total parenteral nutrition UDP Undecyl dodecyl phthalate US EPA US Environmental Protection Agency

Health Care Without Harm 4Aggregate Exposures to Phthalates in Humans 5 

# Preface

Health Care Without Harm (HCWH), the campaign for environmentally responsible health care, works to help reduce the public health and environmentalimpacts of activities associated with medical institutions, without compromising the quality of care. To a large extent, the materials used in medical facilities influence those impacts. Metals, solvents, plastics, pharmaceuticals, radioactive materials, and other toxic compounds can pose threats to public healthand the environment, as well as to patients and hospital workers, if they are not carefully chosen and manufactured, used, and disposed of properly.

Polyvinyl chloride (PVC) is one of the predominant plastics used in medical care. Initially, HCWH was concerned with the public health and environmental impacts of the manufacture and disposal of PVC medical products. These concerns centered primarily on the generation of dioxins, furans, and other toxic organochlorine compounds during the manufacture and incineration of PVC. PVC also requires additives to impart certain qualities like stability and flexibility. Medical products made of PVC are usually softened with a plasticizer from the family of chemicals knownas phthalates. Under certain circumstances, a considerable amount of the phthalate most commonly used in these devices, di-(2-ethylhexyl) phthalate (DEHP), can leach out of medical devices causing direct patient exposures. A closer look at DEHP leaching led to additional concerns about patient safety. Consequently, HCWH petitioned the US Food and Drug Administration (FDA) to examinethe safety of DEHP-containing products more closely. The results of the FDA safety assessment, as wellas those of other government-sponsored expert panels are discussed in this report. HCWH became even more concerned about phthalates when the US Centers for Disease Control andPrevention (CDC) published data about general population exposures. Not only are medical devices only one of a number of sources of phthalate exposures, but the levels of phthalate exposure in the general population are high enough to raise serious questionsabout their safe use in hundreds of consumer products to which we are regularly exposed. Many people from the general population are contaminated with a significant body burden of phthalates. Some kinds of medical care add more. As these exposures add up, it becomes clear that aggregate phthalate exposures, from multiple sources, raise a significant public health concern.

Where are human exposures to phthalates comingfrom? We have only partial answers. The search cannot be confined to only one business sector, since phthalates are so widely used in so many products. Inaddition to medical devices, HCWH looked at information about phthalates in food, air, cosmetics, children’s toys, and many other consumer products tohelp identify other exposure sources. This investigation leads to serious concerns about the adequacy ofcurrent regulatory policies and manufacturing practices for protecting public health and the environment. It is a cautionary tale about the risks associated with divided responsibilities and failure to connect the dots.People and wildlife are regularly exposed to industrial chemicals through food, water, air, or from direct contact with a variety of consumer products. Many of these chemicals are toxic at some dose and under certain conditions of exposure. Attempts to estimate the risks from contact with industrial chemicals rely heavily on understanding their toxicity and the nature of exposures. The route of exposure, whether through ingestion, inhalation, absorption throughthe skin, or intravenous administration, can significantly influence a chemical’s toxicity. The magnitude of exposure is also important, but the timing, duration, and pattern of exposure are also critical factors that determine toxic impacts. We know, for example, that low-level exposures to industrial chemicals that have no discernable effects on adultscan have profound and lifelong impacts if the exposure occurs during developmental windows of vulnerability, as, for example, during fetal life, infancy, or childhood.

Chemicals, or their metabolic byproducts with long half-lives, may build up to toxic concentrations in the environment and in people and wildlife. Even those chemicals that do not persist for long periods of time may pose a problem if they are so widely used that we are repeatedly and continuously exposed to them. This report is about such a class of chemicals. They are the phthalates—a family of chemicals thatare produced in the millions of tons annually worldwide and used in hundreds of consumer and industrial products. Phthalates are ubiquitous environmental contaminants and are nearly always found at some concentration in virtually all people and wildlife.

This report discusses three parallel lines of research. First, we review the toxicity of members of the phthalate family, with an emphasis on health effects relevant to people. Second, we describe relatively recent data concerning general population exposures to phthalates and consider the sources of those exposures. We discuss those exposures in light of the current understanding of the toxicity of phthalates, and focus our concerns on exposures to women of reproductive age, developing children, and young medical patients. Finally, using studies that shed light on the mechanisms by which phthalates exerttheir toxicity, particularly with respect to reproduction and development, we conclude that phthalate exposures should be considered in the aggregate when estimating the potential harm that may result from human exposures. Unfortunately, product manufacturers and regulatory agencies responsible for protecting public health and the environment each fail to consider total exposures to this family ofchemicals. As a result, a substantial number of people are at risk of harm.

A combination of limited human data and a wealth of animal studies show that phthalates can impairreproduction and development, alter liver and kidney function, damage the heart and lungs, and affect blood clotting. Studies that have focused on cancer as a phthalate-related health concern show that phthalates cause liver cancer in rodents, but many investigators have concluded that the cancer seen in animal tests is not relevant to people because of species differences in response.

Early studies looked largely at impacts in adults, where phthalates seemed to have relatively low acute toxicity. It also seemed that, in adult animals, fairly large doses were necessary to cause impacts on the testes, ovaries, and liver. Scientific reports then showed, however, that some medical patients exposed to DEHP, a phthalate that leaches from PVC, or polyvinyl chloride plastic medical devices, receive doses that are similar to those causing health effects in laboratory animals.

Reports in the scientific literature over the past 10- 15 years have raised additional concerns. Developingorganisms are uniquely vulnerable to phthalate exposures, and, in particular, the developing male reproductive tract appears to be the most sensitive organ system. Abnormal development of the testes, penis,

Health Care Without Harm 6 

# Introductionand other components of the male reproductive tract occurs at levels of exposure that are hundreds or thousands of times lower than those necessary to cause damage in adults. Several expert panels, including those assembled by the US Food and Drug Administration (FDA), the National Toxicology Program’s Center for the Evaluation of Risks to Human Reproduction (NTP), and Health Canada (HC) have recently independently concluded that those animal studies are relevant for predicting health impacts in people.

The second line of research addresses human exposures to phthalates. One of the phthalates, di-(2-ethylhexyl) phthalate (DEHP) is added to polyvinyl chloride (PVC) plastic to soften and make flexible this inherently rigid material. DEHP-containing PVC is used for many purposes, and one application is in avariety of medical products. Under certain circumstances, depending on the product and the purpose for which it is used, DEHP leaches out of these devices causing direct patient exposures. The FDA, NTP, and HC have each determined that the level of exposure can, in some instances, rise to a level ofserious concern, particularly in vulnerable individuals, such as fetuses and infants, and even in adults who are repeatedly exposed.

Beyond health care institutions, however, the CDCstudied phthalate exposures in the general population. The results were surprising. Virtually all peoplestudied had some level of various phthalate by-products in their urine, indicating widespread exposures. But some people had far higher concentrations than others. When the investigators looked more closely at highly exposed subgroups, they found that womenof reproductive age were among them. This is a particularly troubling finding, in light of the particular vulnerability of the fetus to phthalate toxicity.

A third line of research has examined the mechanisms of phthalate toxicity and considered the cumulative or aggregate impacts of members of the phthalate family in experimental animals. Studiesshow that some industrial chemicals act as antiandrogens, interfering with male development in atleast two ways. They can decrease testosterone synthesis in the fetal testes or they can block the androgen receptor through which testosterone initiates its control over male development. In either case, testosterone-dependent gene activation is reduced.Several phthalates interfere with testosterone synthesis in the developing organism, including DEHP, BBP, DBP, and perhaps DINP. 6 63 107 109 It follows that exposures to these phthalates should be considered in the aggregate for the purposes of estimating risks from exposure. Moreover, exposure to these phthalates should be considered in the aggregate with exposures to other chemicals that are also anti-androgenic through androgen receptor blockade or interference with testosterone synthesis.

The problem is that regulatory agencies generally donot estimate risks from chemical exposure by considering aggregate exposures. They assess safety as if we are exposed to single chemicals, despite real world evidence of multiple exposures to multiple chemicalsfrom multiple sources. There are two notable exceptions. The EPA has been directed by Congressionallegislation to consider cumulative exposures to pesticides used on food when the chemicals act through a common mechanism of action. The other is in the pharmaceutical division of the FDA where there is some recognition that biologically active drugs often interact with each other and may have additiveeffects. Physicians, nurses, and pharmacists are routinely expected to consider drug interactions and cumulative impacts when prescribing, administering,or providing medications. Most patients also understand this concern and have learned to ask about it when new medications are considered.

In the medical products division of the FDA, however, their 2001 Safety Assessment of DEHP Released from PVC Medical Devices compares an estimated safe exposure level (tolerable intake) to individual kinds of therapy. They acknowledge that patients are exposed to DEHP from multiple medical sources, but focus their safety analysis on single sources. The FDA safety assessment also concentrates entirely on sources of phthalate exposure in the medical care setting and fails to consider exposures to phthalates in individuals from the general population who also happen to require medical care. Data from the CDC show that pregnant women come to the hospital already significantly contaminated with phthalates, and medical exposures add more. And, when theFDA assesses the safety of phthalates used in cosmetics, they typically consider only exposures to one kind of phthalate from individual cosmetic products. No regulatory agency is adding up all the exposures to all of the phthalates from all of the sources and assessing the safety of that real world mixture. Yet, many people in the general population are currently exposed to various phthalates at levels of concern.

In this report we outline an approach that attempts to address the reality of multiple sources of phthalate

Aggregate Exposures to Phthalates in Humans 7exposures. We know far less than we ought to about the consequences of exposure to real world complex mixtures of industrial chemicals. For the phthalates, however, available exposure and toxicity data make it clear that the world in which people and wildlife live is not the make-believe world of the FDA, the EPA, and the Consumer Product Safety Commission.People are exposed to phthalates at levels of significant concern. As we will see, however, people arenot being protected by product manufacturers or regulatory agencies, and are hard-pressed to find ways to protect themselves.

Health Care Without Harm 8Aggregate Exposures to Phthalates in Humans 9 

# Phthalates in Consumer Products

Phthalates are a principal component of flexible PVC products, cosmetics, pesticides, building maintenance products, lubricants, and personal care goods that surround consumers at home, work, and in hospitals.PVC without additives is inherently a rigid and brittle material, requiring large amounts of plasticizers to make flexible products. In fact, approximately 90% of global plasticizer production is destined for use in polyvinyl chloride plastic (PVC). 14 The remaining10% is used in adhesives, caulks, skin creams, detergents, electrical capacitors, hairsprays, inks, solvents,lubricating oils, lotions, nail polish, paints, fragrances, and pharmaceuticals. 23 74 120 In personal care products, phthalates provide flexibility, impart an oily “moisturizing” film, and help dissolve and fix other cosmetic ingredients. 15 The film forming and flexibility properties imparted by phthalates are also useful in paints, inks, fillers, adhesives and caulks and insulating properties in electrical cabling and capacitors. 25



## Phthalate structure The oily, plasticizing properties of phthalates come from their chemical structures. Phthalates represent a broad chemical family containing a benzene ring,two carbonyl groups, and two alcohol groups to generate a diester structure. Common branched phthalates such as DEHP, DBP, BBP, and DINP feature branched-chain alcohol moieties of 6 to 13 carbons. The linear phthalates contain linear alcohol groups and include short chain phthalates such as DEP and DMP, and other phthalates with chain lengths of seven to 11 carbons that are use to impart increased flexibility at low temperatures. 48 The benzene ringbased structure of phthalates helps reduce their viscosity but also makes them harder to degrade. 68 Phthalates move freely through the PVC polymer to impart flexibility and other characteristics. 144 Since they are not covalently bound to the polymer, they are fairly easily released to air, water, saliva, blood, IV solutions, nutritional formulas, and other extracting materials. 46 86 110 153 Since phthalates tend to be fat soluble, they leach more readily into lipid-containing solutions. Depending on the circumstances of use, 2% - 50% of the phthalate content can emerge from products over their service life. 86



## Phthalates in personal care and other consumer products Many personal care products, building materials, clothing, toys, adhesives, inks, pesticides, films, food wraps, food containers, and other consumer itemscontain phthalates. Phthalate concentrations in personal care products can approach and sometimes exceed 200 gm/kg (20%). 5 Other consumer products can contain levels of phthalates ranging from 60 - 800 gm/kg (6-80%). 36 86 116 141 Four of the principal phthalates used in commerce are BBP, DBP, DEHP, and DINP. Butyl benzyl phthalate (BBP) is added tocosmetic products, flooring, paints, coatings, adhesives, and printing inks. 45 113 Di-n-butyl phthalate (DBP) is used in cosmetics, toys, flooring, adhesives, wallpaper, furniture, raincoats, plastic cling wrap, and shower curtains. 1 4 Di-(2-ethylhexyl) phthalate (DEHP) is the principal phthalate used in a varietyof products including medical devices, cabling, flooring, and auto parts and interiors. 86 Di-isononyl phthalate (DINP) is widely used in children’s toys, flooring, fabrics, gloves, tarps, garden hoses, shoes,autos, paper packaging materials used for food contact, and sealing gaskets for food containers. 24 114 See Table 1 for examples of phthalates in commerce.A recent study by the Danish EPA tested PVC shower curtains, flooring, gloves, carpet tiles, wallpaper, and bags and found at least one type of phthalate in all products at levels that varied from 24 - 630 gm/kg. 30 Combined levels of DIDP-DINP were found at 88 gm/kg in shower curtains, 110 gm/kg in bags, 260 gm/kg in wallpaper, 290 gm/kg in carpet tiles, 310 gm/kg in flooring, and 600 gm/kg in gloves. A recent Greenpeace study found phthalates at levelsup to 390 gm/kg in a variety of PVC consumer products made for children including diaper pants (DINP), diaper-changing mats (DINP), rain coversfor strollers (DEHP), drinking straws (DINP), cribrail teethers (DINP), and hats (DEHP). 67 

## Phthalates in PVC medical products PVC medical products also contain phthalates. Levels of DEHP, the most commonly used, range from 200-800 gm/kg (20-80%). 36 116 PVC products that release DEHP in the clinical setting include IV storage bags, ventilator tubing, IV infusion sets,endotracheal tubes, IV infusion catheters, nasogastric tubes, blood storage bags, enteral and parenteralnutrition storage bags and tubing, blood administration sets, urinary catheters, exam gloves, suction catheters, chest tubes, nasal cannula tubing,hemodialysis tubing, syringes, extracorporeal membrane oxygenation (ECMO), and cardiopulmonary bypass (CPB) tubing. 153

Health Care Without Harm 10 

### Table 1. Types of products containing phthalates

Product Type Examples Phthalates

Automotive PVC auto floor mats DEHP Auto sheeting L11 PVC underbody DINP PVC upholstery DEHP

Beauty Aftershaves DEP Deodorants DBP, DEP Skin Creams DEP Hair preparations BBP, DMP, DBP, DEP Nail polishes DBP Fragrances DEHP, BBP, DBP, DEP Powders DEP

Building -Home Adhesives BBP, DHP, DIOP, DIDP PVC carpet covers DEHP Caulks /grouting unspecified Paint unspecified PVC drawer liners DEHP, DINP PVC flooring BBP, DEHP, DBP PVC furniture covers DEHP PVC garden hoses DIBP PVC gaskets BBP, DEHP, DINP, L7-9, L7-11 PVC inflatable furniture DEHP PVC inflatable pools DEHP PVC insulation DEHP PVC mattress pads DEHP PVC roofing film DEHP PVC shades DEHP, DINP PVC shower curtains DEHP, DBP PVC tarps DEHP PVC tubing BBP, DEHP, DINP, L7-11 PVC wall coverings L7-9, DINP, DEHP, DBP PVC water beds DEHP PVC-coated fabrics L7-9 PVC-covered cables DEHP, DIDP, L11, L7-11

## Lack of consumer notificationThis widespread use of phthalates in consumer products is largely invisible to the public because mostproducts do not require labels to identify their presence. PVC building products, PVC toys, PVC auto parts, PVC clothing, PVC baby products and other common PVC consumer products do not require labeling that reveals their phthalate content or even identifies the plastic as PVC. The US Food and DrugAdministration (FDA) requires some labeling of cosmetic ingredients, but the law does not require listingof phthalates or other ingredients considered fragrance components nor does the law require labeling of products sold to professional salons. 152

Aggregate Exposures to Phthalates in Humans 11 

### Table 1. Types of products containing phthalates (continued)

Product Type Examples Phthalates

Consumer PVC aprons DEHP PVC backpacks DEHP PVC balls DEHP PVC bibs DEHP PVC changing pads DEHP PVC clothing DEHP, DINP PVC crib rail teether DINP PVC diaper pants DEHP PVC luggage DEHP, DBP PVC notebook covers DEHP PVC packaging DEHP PVC purses DEHP PVC shoes DIBP, DEHP, DINP PVC stroller covers DEHP PVC tablecloths DEHP PVC toys DEHP, DINP PVC umbrellas DEHP PVC weight covers DEHP

Food Packaging PVC squeeze bottles unspecified PVC packaging unspecified PVC straws DINP, DEHP PVC tubing unspecified Cling Wrap unspecified

Industrial/Agriculture Electric capacitors DEHP Fillers unspecified Pesticides DEHP Printing ink BBP, DBP PVC conveyer belts DINP, L7-11 Vacuum pump oil DEHP

Medical PVC blood bags DEHP PVC catheters DEHP PVC colostomy bags DEHP PVC dentures DBP PVC enteral feeding bags DEHP PVC gloves DEHP PVC IV bags DEHP PVC mattress covers DEHP PVC oxygen tents DEHP PVC pillow case covers DEHP PVC syringes DEHP PVC tubing DEHP PVC urine bags DEHP

Pharmaceutical Coating ingredient DBP Stabilizer DBP

Sources: 4 5 24 49 74 86 98 114 127 144 See the Health Care Without Harm website for updates to this table: http://www.noharm.orgAccording to a voluntary reporting system used by the FDA, DEP-containing products include 42 colognes, 7 powders, 8 aftershaves and 8 skin

creams. 151 The Agency also lists DMP in 11 hair preparations and DBP in 120 nail basecoats, polishes and enamels and 27 other manicuring preparations. Since this is a voluntary system and manufacturershave no obligation to report, a comprehensive analysis of the use of phthalates in personal care products is not publicly available.

Labeling requirements on medical products vary considerably, and the agency does not require manufacturers to note the presence of PVC or phthalates specifically. Some products warn against the use of DEHP-containing IV bags to administer certain drugs that can accelerate DEHP leaching. 76 77 The FDA is currently drafting a risk management strategyas a follow up to their September, 2001 safety assessment of DEHP in PVC medical devices. That strategy may include labeling recommendations.



## Phthalates in the environment The manufacture, use, and disposal of PVC and other phthalate-containing products have resulted in extensive environmental releases of phthalates. Consequently, phthalates are now one of the most abundant industrial pollutants in the environment,and are widely present in air, water, soils, and sediments. 29 140

Available data underestimate the release of phthalates from manufacturing facilities since companiesare not required to report releases of many commonly produced chemicals. In the US, for example, companies are not currently required to report releases ofDINP, DEP, or BBP, despite their high production volume. However, large US industries are required to report environmental releases of DBP and DEHP to the US EPA as part of the Toxic Release Inventory when annual releases exceed 25,000 pounds or when the facility otherwise uses in excess of 10,000 pounds. 32 In 1999, the top 100 US companies reported total DBP releases of more than 390,000 pounds. The same year, the top US 100 companies emitting DEHP reported nearly 1.2 million pounds of releases. In Germany, total DEHP emissions during processing were estimated at over 1.5 million pounds per year in 1998 and the overall annual environmental releasesof DEHP in Germany are estimated to be considerably in excess of 3.3 million pounds. These reports, however, do not include phthalates released to the environment from the use or disposal of finished consumer products.

Phthalates such as DEHP have been measured in virtually all fresh water and marine environments andin lake sediments, storm water runoff, sewage treatment plants, and sewage sludge. DEHP, DBP, and DEP were found at levels exceeding 700 μg/kg in sediments from Lake Mead, a national park in the US. 13 DEHP is in ocean sediments at sewage outfall points (25 mg/kg) and all the sediments in rivers near sewage outflows in New Jersey, USA. 3 DEHP is also the most prominent toxic organic chemical in sewage sludge. 57 DEHP levels in sludge have been measured at 55 – 300 mg/kg. More than five billion pounds of sludge are spread onto US land each year. 3

Buried PVC products in landfills release phthalates into landfill leachates. 31 DEHP levels in these liquids have been measured at 34-7,900 μg/kg. 3 In the US, DEHP, DEP, and DBP have been found in 18%, 44%, and 30% respectively, of the hazardous waste sites designated as national priorities for clean-up (Superfund sites.) 3 4 5 In Sweden, Italy, Germany and the UK, various phthalates and their metabolites have also been detected in landfill leachates. Phthalate concentrations for phthalic acid, DEP, and DMP were 18,900 μg/kg, 540 μg/kg, and 300 μg/kg respectively. 9

DEHP has been measured in indoor air at concentrations ranging from 8 ng/cm3 to 3 mg/cm3

. 99 156 A Health Canada Expert Panel evaluation of the risks associated with DEHP exposures concluded that inhalation exposure to DEHP is second only to ingestion of DEHP-contaminated food. 35 Presumably DEHP air contamination is the result of its being released from PVC in the indoor environment.

Even remote areas contain phthalates. DEHP has been found in the Antarctic pack ice, the Antarctic sub-surface snow at depths up to three meters, and in deep-sea jellyfish from more than 3000 feet below the surface of the Atlantic Ocean. 3 100

Health Care Without Harm 12

## Phthalates in people Given the multiple uses of phthalates in hundreds of consumer products and worldwide environmentalcontamination with phthalates, it comes as no surprise that people and wildlife are virtually universally exposed to phthalates. The general population is exposed to phthalates through food, water, air, and the use of phthalate-containing consumer products that may be eaten, inhaled, or applied directly to theskin and absorbed. Whatever the sources, most people are regularly exposed to phthalates so that some combination of these chemicals or their byproducts can be detected in the blood or urine of virtually everyone in the general population.

Unlike some chemicals, like dioxin, lead, or mercury, that tend to persist and build up in various tissues, phthalates are generally not persistent, though undersome circumstances, phthalates do tend to accumulate in certain organs. 80 But because exposures are so frequent and common, some level or body burden of the phthalate family of chemicals can regularly bedetected. The potential health impacts of these universal exposures are discussed in the following sections of this report with special attention paid to groups of people who are disproportionately exposed.

Aggregate Exposures to Phthalates in Humans 13Health Care Without Harm 14 

# Phthalate Toxicity

Phthalates display a variety of toxic effects in animal studies following chronic exposure or even after short-term exposures in particularly vulnerable organisms. These effects include damage to the liver, kidney, heart, and lungs as well as adverse effects on reproduction, development, and blood clotting. The effects of human exposures to phthalates have notbeen well studied. Long latency periods between relevant exposures and health impacts, unquantified exposures, and subtle effects that are difficult todetect complicate and limit the few existing epidemiological studies of phthalate impacts in humans. But these limitations do not fully explain why the impacts of phthalates on humans have not been thoroughly investigated.

The testicular toxicity of DEHP in experimental animals, for example, was described in 1972, but no onehas investigated its effect on human male reproductive capacity. 10 116 Even the consequences of potentially high exposures to DEHP from, for example,total parenteral nutrition or hemodialysis of breastfeeding mothers have not been the subject of scientific review. Although most toxicity data come from studies in laboratory animals, human correlates to some effects seen in animal studies have also beendescribed. This body of data collectively has generated concern in the medical and public health communities as well as government regulatory agencies. 

## Reproductive and developmental effects In general, the monoester metabolite of the parent phthalate compound is thought to be responsible for adverse reproductive and developmental effects of phthalates. In animal testing, impacts include decreased fertility in females, fetal defects, reduced survival of offspring, birth defects, altered hormone levels, and uterine damage. Phthalates that display one or more of these effects include BBP 39 40 41 44 64 109 121
, DBP 40 92 131, DEP 52 92, DHP 92, DIDP 75 155, DINP 64 114 150
, MBP 38 130, MDP 43, and MEHP 97 129

.In males, phthalates cause prostate damage, femalelike areolas/nipples, and reproductive malformationsin infants, including altered hormone levels, testicular atrophy, reduced sperm production and motility, undescended testes, hypospadias, Sertoli cell damage, and Leydig cell tumors. Phthalates that display one or more of these effects include BBP 2 64 109 121 134
, DBP 42 54 56 106 108 157, DEHP 8 12 56 64 65 94 124, DEP 19 82 92
, DHP 92, DINP 64 114 150, DPP 55, MEHP 71, MBP 71, and MPP 71

. Some of the effects caused by DEHP in malesinclude altered zinc concentrations, testicular atrophy and infertility. 153 The FDA notes that these same symptoms are seen in male hemodialysis patients. In fact, the Agency called the similarity between the testicular damage observed in animals and malehemodialysis patients “strikingly similar” and concluded that the effects seen in rodents “may have a clinical correlate in humans.” 153

Several other government agencies have concluded that the reproductive effects caused by DEHP are relevant to humans. The US NTP’s Center for the Evaluation of Risks to Human Reproduction (CERHR) Expert Panel concluded in its review of DEHP toxicity that the “rodent data are assumed relevant to predicting that DEHP has the potential to produce adverse reproductive system effects inhumans.” 116 In 2001, the Swedish National Chemicals Inspectorate concluded in its review ofDEHP for the EU that, “The effects on testis, fertility, and development, observed in different animal species and at relatively low levels, are considered to be relevant to humans.” 86 Finally, in 2002, Health Canada’s Expert Advisory Panel on DEHP in Medical Devices concluded that, “the mechanism bywhich developmental and testicular toxicity in particular occur in rodents appears relevant to humans.” 69



## Altered liver and kidney function
Phthalates such as DBP, DEHP, and DINP cause a variety of alterations in kidney function in animalsincluding renal cysts, reduction in creatinine clearance, and transitional cell carcinoma. 20 27 158

Phthalates also increase liver weight, affect liver function, and alter liver enzymes in rodents. These effects have been observed after exposure to DBP, DEHP, DMP, DEP, DINP, and DIDP. 4 17 52 87 133 150 Some, but not all, of the liver changes seen in rodents are thought by many researchers not to be relevant to humans (see below). However, certain effects due tophthalate exposure have been observed in both primates and humans. In a small study of monkeys, for example, DEHP caused adverse effects in the liver after leaching from PVC blood bags during blood transfusions. 79 In contrast, transfusions given to two monkeys from polyethylene containers without DEHP did not cause liver damage. Human patients undergoing hemodialysis are also exposed to large doses of DEHP from PVC tubing. Changes in liver enzymes similar to those observed in animal studies are also seen in these patients. 153 In the US alone,approximately 250,000 people require dialysis treatment. 111

Other human liver effects that have been reported to occur following DEHP exposure include cholestasis, in which bile excretion is impaired. One prospectivestudy found cholestasis in infants undergoing extracorporeal membrane oxygenation (ECMO). 135 These infants received large doses of DEHP, which leached from PVC tubing. Another study failed to find ECMO-related cholestasis when exposure to DEHP was lower. 83 Cholestasis and other liver abnormalities are also observed in neonatal infants receiving total parenteral nutrition. 59 The cause(s) of these liver abnormalities are not fully understood, and thepotential role of DEHP has never been fully investigated. The high lipid content of the nutrition solution facilitates phthalate leaching from DEHP-containing products, and these patients likely receive even larger DEHP doses than dialysis patients. 96 Arecent Health Canada Expert Advisory Panel recommended that “total parenteral nutrition solutions beadministered to newborns and infants only via products which do not contain DEHP.” 69

DEHP and DINP cause liver carcinoma and adenomas in rodents. 20 89 105 These tumors are linked to the proliferation of small cellular organelles known as peroxisomes. In humans, peroxisome proliferation inthe liver after exposure to phthalates and other peroxisome proliferators is generally not found to an appreciable degree. Therefore, one possibility is that phthalates do not have the potential to cause livercancer in humans. However, phthalates cause peroxisome proliferation by interacting with a nuclearsteroid hormone receptor that governs gene expression. This receptor is also found in humans but at 1-10% of the amount observed in rodents. 86 Sincethe difference between the human and rodent receptor is quantitative, the potential for human responsemay vary with the receptor content in different individuals. In fact, a 10-fold difference in receptor transcription has been observed in different individuals. 146 These observations led a researcher in the field to conclude that, “the potential human carcinogenicity of these chemicals cannot be summarily ignored.” 154



## Heart, lung, and hematologic effects Phthalates can also adversely impact the heart and blood pressure, though many animal studies have used fairly high exposure levels. One study, however,using intravenous injection of MEHP in rats, reported a slowing of the heart rate beginning at a totaldose of 57 mg/kg and a drop in blood pressure beginning at 157 mg/kg. 126 Patients undergoing coronary artery bypass grafting can be exposed to 2.2-80 mg MEHP/operation and patients undergoing heart transplants 0.5-2.5 mg/operation. 11 Neonates undergoing exchange transfusion can be exposed to MEHP at levels up to 0.68 mg/kg. 138 Little is known about species differences in susceptibility to cardiac effects of phthalates.

The effects of phthalates on the lung are not well known. DIDP increases the width of alveolar septaand causes inflammatory reactions in animal studies. 60 In humans, lung disorders similar to hyaline

Aggregate Exposures to Phthalates in Humans 15membrane disease occurred in several pre-term infants ventilated with PVC tubing containing DEHP. 128 The symptoms diminished when the PVCtubing was replaced with ethylene vinyl acetate tubing that does not contain plasticizers. A 1999 study found that phthalates such as DEHP and BBP migrate from PVC flooring to house dust. 117 The authors reported a higher frequency of children with bronchial obstruction, characteristic of asthma attacks, in homes with PVC flooring. 78 They proposed that the structural similarity between phthalates and prostaglandins might provide a mechanistic explanation for the observed association.

The FDA cites numerous studies that indicate that DEHP stimulates complement activation and platelet aggregation and that these effects are significantly reduced when non-PVC/non-DEHP alternatives are used. 153 According to the FDA, complement activation appears to be involved in the inflammatory response observed in cardiopulmonary bypasspatients. Platelet aggregation can lead to the formation of small blood clots that are thought to cause neurological complications in cardiopulmonary bypass patients and infarcts of the brain, lung, andkidney in patients that receive extracorporeal membrane oxygenation. 53



## Potential role of isomeric mixtures in phthalate toxicity Phthalate toxicity can be further complicated by the presence of large numbers of isomers or chemical variants. In a study of DINP, the US Consumer Product Safety Commission (CPSC) noted that DINP is a mixture of up to 100 isomers and that only five have been even minimally studied. 149 One type of DINP was carcinogenic, but the CPSC claimed that it was never commercialized. However, the agency didwarn that, “It is conceivable that one or more existing types of DINP for which data are unavailable could also be more toxic and/or carcinogenic.” 149

Health Care Without Harm 16Aggregate Exposures to Phthalates in Humans 17 

# Exposures Resulting from Medical Procedures

The deposition of DEHP in human tissues resulting from the use of DEHP-containing PVC medical products has been documented for thirty years. In 1972, DEHP released from PVC blood-bags was detected in the lungs, liver, spleen, and abdominal fat. 80 In the mid-1970s, investigators found significant levels of DEHP in the heart and gastrointestinal tract of neonatal infants treated with PVC umbilical catheters. 72 Higher levels of DEHP were correlated with more extensive transfusion, catheter use, and death. In 1976, DEHP was found in human serum following hemodialysis. 62 93 In 1985, DEHP and its more toxic metabolite, MEHP, were found in hemodialysis patients. 123 Both the parent compound and its metabolite were also found in newborn infants who had received exchange transfusions. 137 138Sjoberg et al., (1985) measured post-exchange transfusion levels of MEHP in plasma of newborn infants at 2.4-15.1 μg/mL. In 1989, DEHP was also found in the blood, liver, heart, and testes of neonatal infants undergoing extracorporeal membrane oxygenation. 132 Ventilation with PVC tubing also deposits DEHP in the lungs. 128 In the 1990s, further evidence accumulated of DEHP deposition due to exchange transfusions and dialysis and its high exposure potentialfrom infusion lines used in total parenteral nutrition. 50 96 122



## FDA Safety Assessment of DEHP
In 2001, the FDA released its Safety Assessment of DEHP Released from PVC Medical Devices. 153 The Agency estimated DEHP exposures from a variety of medical procedures and compared the results to their calculated tolerable intake for DEHP. Table 2 shows that a variety of medical procedures result in DEHP exposures close to the tolerable intake established by the Agency. These procedures include IV infusionwith drugs requiring pharmaceutical vehicles for solubilization, adult total parenteral nutrition, adult coronary artery bypass graft (CABG) replacement transfusion, neonatal replacement transfusion, adult orthotopic heart transplant, and adult hemodialysis. In addition, the FDA estimates indicate that several procedures exceed the Agency’s tolerable intake of DEHP. These include total parenteral nutrition with lipids in neonates, transfusions to trauma patientsand ECMO in adults, neonatal exchange transfusions, adult coronary artery bypass graft, adult and neonatal artificial heart transplant, and adult and neonatal enteral nutrition.

The FDA concluded that DEHP exposures may not be safe for patients receiving medical treatments that exceed the tolerable intake as shown in Table 2. TheAgency also expressed concern over the risk to children and cited three main findings: 1) Children receive a greater DEHP dose than adults from some procedures; 2) Metabolic differences may cause children to absorb more DEHP, create more of its toxic metabolite, MEHP, and excrete less MEHP; and 3) Children may be more sensitive to the toxic effects of DEHP than adults.

The FDA safety assessment of DEHP is consistent with the conclusions of the National Toxicology Program’s Center for the Evaluation of Risks to Human Reproduction. In 2000, the NTP Expert Panel concluded in its review of DEHP that:

“The available reproductive and developmental toxicity data and the limited but suggestive humanexposure data indicate that exposures of intensivelytreated infants/children can approach toxic doses in rodents, which causes the Panel serious concernthat exposure may adversely affect male reproductive tract development.” 116Health Care Without Harm 18 

### Table 2. Estimated DEHP doses from PVC medical products for various medical procedures calculated by the US FDA compared to tolerable intakes (mg/kg/day)

Procedure DEHP Dose Tolerable Intake Ratio Tolerable Intake/Dose*

IV infusion

Crystalloid solutions 0.005 0.6 120 Drugs requiring solubilization 0.15 0.6 4

TPN

Adult; added lipid 0.13 0.6 5 Neonatal; added lipid 2.5 0.6 0.2

Transfusion

Adult; trauma patient 8.5 0.6 0.1 Adult; ECMO 3.0 0.6 0.2 Adult; CABG replacement 0.28 0.6 2 Neonate; exchange 22.6 0.6 0.02 Neonate; replacement 0.3 0.6 2

Cardiopulmonary bypass

Adult; CABG 1.0 0.6 0.6 Adult; orthotopic heart transplant 0.3 0.6 2 Adult; artificial heart transplant 2.4 0.6 0.3

ECMO

Neonate 14 0.6 0.04

Dialysis

Adult hemodialysis 0.36 0.6 2 Adult peritoneal dialysis <0.01 0.6 >60

Enteral nutrition

Adult 0.14 0.04 0.3 Neonate 0.14 0.04 0.3

Data source: 153 Abbreviations: IV: intravenous; TPN: total parenteral nutrition; ECMO: extracorporeal membrane oxygenation; CABG: coronary artery bypass graft

. See the Health Care Without Harm website for updates to this table: http://www.noharm.org *a ratio of <1 means that the dose exceeds the tolerable intakeAggregate Exposures to Phthalates in Humans 19 

# Limits of the FDA Safety Assessment

The FDA failed to consider two significant issues when comparing the tolerable intake for DEHP to exposures from various medical procedures: 1) Although the agency mentioned the problem of aggregate exposures to DEHP from multiple medical sources, they did not take this reality into account when listing medical procedures that might result in exposures in excess of the tolerable intake. 2) When calculating the tolerable intake for DEHP, the FDA attempted to factor in exposures to other phthalates in the hospital setting. But,they failed to consider exposures to all phthalates in the general population that result in a pre-existing body burden in patients entering the health care system.



## Aggregate exposures in the hospital DEHP is not the only phthalate to which patients are exposed in the hospital. The FDA cites studiesthat identified DBP, DEP, DMP, or BEP in PVC medical devices including nasogastric tubing, microfilters, butterfly catheters, denture base material, infusion tubing, infusion bags, and intestinal tubing. Levels of these additional phthalates varied from 1% to 20% in the medical products. 153

The FDA derived a tolerable intake for DEHP, which included a safety factor of 3 that is intended toaccount for both “increased sensitivity to DEHPinduced testicular effects during pre- and post-natal exposure and the possibility that humans can be exposed to phthalates other than DEHP and MEHP that exert their effect via a similar mechanism of action.” Based on relevant animal studies, an increased sensitivity to DEHP-induced testicular effects in very young developing organisms seems clear. Whether or not a safety factor of 3 is sufficientprotection for that population is a matter of conjecture. Beyond that, however, the Agency limited their consideration of concurrent exposures to multiple phthalates to those resulting only from medicalcare. If one considers concurrent exposure to multiple phthalates from multiple sources, including those that result in a body burden of phthalates before a patient enters a medical facility, a different picture emerges. A safety factor of 3, intended to account for both increased prenatal/postnatal sensitivity and multiple phthalate exposures from all sources, appears to be inadequate.

In addition, the FDA notes that, in some instances, DEHP metabolizes to its toxic metabolite MEHP prior to the initiation of medical therapies. This transformation is facilitated by lipases present in stored blood and plasma, but can also occur by hydrolysis in stored IV solutions. The FDA cites studies that measured MEHP in hospital patientsundergoing coronary bypass, hemodialysis, and peritoneal dialysis. The Agency also acknowledged that nursing infants could receive significant doses of MEHP in breast milk from mothers undergoing hemodialysis. The FDA performed some calculations to estimate the impact of MEHP that are described further in Appendix I. However, in the end, theAgency focused only on DEHP when listing procedures that might result in exposures exceeding the tolerable intake.

In conclusion, although the FDA acknowledges that individual patients can be exposed to DEHP frommultiple sources in the medical setting and to multiple phthalates from medical devices, they fail to integrate that information into the real world in which patients live—a world where people are exposed to multiple phthalates from non-medical and medical sources at levels that, for many prospective patients, are close to or exceed FDA’s tolerable intake.Health Care Without Harm 20

# Aggregate Exposures in the General Population

Human exposure to phthalates in the general population has been recognized for over 30 years, but the levels of contemporary exposures were demonstrated in a study recently conducted by the US Centers for Disease Control and Prevention (CDC). The resultssuggest that some of the highest exposures to phthalates occur in women of childbearing age, a population that is most vulnerable to phthalates’ ability to damage the developing child. Previous attempts tomeasure phthalates in human tissue have been complicated by their ubiquitous presence that contaminates samples and prevents accurate measurement. A new analytical method developed by the CDCpermitted estimates of phthalate exposure by determining levels of their monoester metabolites in urine.



## The CDC study
In 1999, investigators from the CDC measured thelevels of various chemicals in blood and urine samples from 1,029 people, six years or older, as part of the National Health and Nutrition Examination Survey (NHANES). 23 Among the chemicals of interest were seven common phthalates. Investigatorsmeasured metabolites of these phthalate parent compounds in urine samples of the participants. Thestudy revealed evidence of population-wide exposures to multiple phthalates with DEP, DBP, and BBP present at the highest levels. Breakdown metabolites of DEHP, DOP, and DINP were also observed. Surprisingly, the concentrations of DEP, DBP, and BBP metabolites exceeded those of DEHP and DINP, even though DEHP and DINP are produced in larger volumes and are more widely used. This may reflect lower exposures, storage in fat or other tissues, or metabolism and excretion by a different pathway. 15

The results of this study suggest that we know far less than we should about the sources of human exposure to these industrial chemicals produced in high volume and used for so many different purposes. Perhaps the extensive use of both DEP and DBP in cosmetic products, including perfumes, nail polishes, lotions, deodorants, and hairsprays, which result in skin absorption or inhalation, explains the CDC findings. Or perhaps other combinations of consumer products are also responsible. We don’t know.

A closer review of an important subsetCDC scientists examined a subset of the initial population more closely. This sub-group consisted of 289participants who were 20 – 60 years old. Fifty-six percent were females and the group included Caucasians(39%), African-Americans (30%), and MexicanAmericans (23%). The study measured breakdown metabolites of DEP, DEHP, DBP, DCHP, BBP, DOP, and DINP in random urine samples. 15 Phthalate exposures were higher and more common than in the larger study population. More than 75% of the participants excreted metabolites of DEHP, DEP, BBP, and DBP. An analysis of demographic factors revealed the study’s most disturbing finding. The highest levels of the DBP monoester (MBP) were found in women of childbearing age. In fact, six of the eight highest MBP levels for the entire 289-member group were found in women of reproductive age.

Given what is known about the pharmacokinetics of these chemicals, scientists from the CDC and the National Institute of Environmental Health Sciences (NIEHS) back-calculated to estimate the oral intake of individual phthalates that would be expected to result in the observed urinary residues. 90 The calculations were applied to the 289-person sub-group and a steady-state intake and clearance was assumed. The 289 participants were further divided into two demographic groups: 1) women of reproductive age between 20 and 40 years old (n=97) and 2) the rest of the adult sample (n=192).

The authors considered their estimates to be withinan order of magnitude of the true value due to limited understanding of absorption, transformation, and excretion and its high variability.

## Exceeding previous intake estimatesEstimates of exposure to phthalates in the two demographic groups, based on actual measurements of urinary metabolic residues, exceeded previous daily intake estimates, which had been based largely on contaminated food intake, for almost all of the phthalates. Table 3 shows exposure estimates for the two groups. In this sample, women of reproductive age are exposed to BBP, DBP, and DEP at levels that are 2 – 45 times higher than previous daily intake estimates. The rest of the adult group shows BBP, DBP, and DEP exposures that are 1.7 – 30 times higher than previous daily intake measurements for adults. In the 95th percentile and above, women of reproductive age are exposed to significantly higher levels of DBP than the population at large (32 vs. 6.5 μg/kg/day). That is, in this study, the upper 5% of the population of women of reproductive age are estimated to have oral-equivalent intakes of DBP of 32 μg DBP/kg/day or higher while the upper 5% ofthe rest of the population is estimated to have oralequivalent intakes of 6.5 μg DBP/kg/day or higher.



## Demographic differences in phthalate exposuresUsing the NHANES data, CDC and NIEHS scientists also examined other demographic differences in phthalate exposures. 91 They determined that individuals with a high school education or less had higher levels of DBP than those with an education beyond high school. Lower income and lower educationallevel was associated with higher levels of BBP exposure. DEHP exposures were higher in males, in urban populations, and in lower income individuals.

CDC scientists also examined exposure to phthalates in children using the same methods as prior studies with adults. 18 The study group contained 14 boys and 5 girls between 12 and 18 months old. The children live in an agricultural area of California, USA. Metabolites of BBP, DBP, and DEP were detected in all 19 children. Six children also contained the breakdown product of DEHP. Median exposure levels in these children were approximately the same as adult exposures for DBP and BBP, and somewhat lower for DEP. For MEHP, the median values wereapproximately the same, though the number of children was small.

A recent study of 46 African-American women 35- 49 years old from the Washington DC area reported levels of urinary metabolites of several phthalates and compared them to results from the CDC NHANES study. The median level of MEHP (the metabolite of DEHP) in the African-American women was more than twice as high as adults in the

Aggregate Exposures to Phthalates in Humans 21 

### Table 3. Estimated phthalate exposures in the 95th percentile

group of women of reproductive age and general population compared to previous estimates of daily intake. (μg/kg/day) 90

Phthalate Women of reproductive age Rest of group Daily Intake Estimate (95th percentile) (95th percentile) (μg/kg/day)

All phthalates 1-11 UK

DEP 90 130 4.0 US

DBP 32 6.5 1.9 Canada

BBP 4.5 3.4 2.0 Canada

DCHP 0.24 0.25

DEHP 3.8 3.5 3.8 - 30 US 5.8 Canada 12 EU

DOP 0.65 1.0 <3.0 US

DINP 3.7 1.4 <3.0 US

References for daily intake estimates for adults: all phthalates: UK103, EU (multiple pathway) 86, DEP: 5, BBP: 46, DBP: 22 , DEHP: US 3, DEHP: Canada 21, DINP: 114 and DOP: 115

.NHANES study (6.4 vs. 2.8 μg/gm creatinine), and about twice as high for MBP (the metabolite of DBP; 43.4 vs. 22 μg/gm creatinine). 73 MEP levels were approximately the same.



## Individual adult exposures and regulatory limits The CDC calculations of phthalate exposures demonstrate surprisingly high levels of phthalates in the bodies of women during their childbearing years. However, the regulatory systems in the US andEuropean Union view each phthalate exposure individually instead of collectively. Table 4 compares the exposure for each phthalate to its regulatory limit. The data show that none of the phthalate exposuresexceeds exposure limits. In fact, phthalate manufacturers use this data to conclude that exposures to phthalates are negligible. 33 

## Assessing aggregate exposures to multiple phthalates: a relative potency approach Actual human exposures to chemicals do not occursingly, but in aggregate, complex mixtures. In addition, many phthalates display similar toxic effects as
a group. 64 These realities require a new approach to assessing phthalate exposures and impacts that result from exposure to multiple phthalates in mixtures from multiple sources in order to protect public health.

In 1996, the Food Quality Protection Act directedthe US EPA to consider aggregate exposures to pesticides for chemicals that exert their toxicity through a common mechanism of action. Since then, the FDA and the Swedish National Chemicals Inspectorate (KEMI), have also acknowledged the importance of considering aggregate phthalate exposures. 85 153

Estimating the relative potency of individual chemicals and adding them in order to estimate the total potencyof a mixture is one way to evaluate the impacts associated with aggregate exposures. Two pieces of information are useful for justifying this approach. First, it is helpful to know something about mechanisms of action. A relative potency approach is justified when chemicals exert their toxicity, at least in part, through a common mechanism of action or a final common pathway. Second, a common endpoint or related set of endpoints adds to the evidence that chemicals may have at least additive effects in an organism.

Health Care Without Harm 22 

### Table 4. Estimated exposures in women of reproductive age compared to regulatory limits for phthalates. (μg/kg/day)

Phthalate CSTEE US EPA Women of Reproductive Age Tolerable intake Reference Dose (95th percentile)

DEP 800 90

DBP 100 100 32

BBP 850 200 4.5

DCP 0.24

DEHP 50 22 3.8

DOP 370 0.65

DINP 150 3.7

Abbreviations: CSTEE: EU Scientific Committee on Toxicity, Ecotoxicity and the Environment; EPA: Environmental Protection Agency. Exposure data from the CDC. 90 CSTEE Tolerable Intake values46 from EPA Reference Doses available at http://www.epa.gov/iris/index.html. See the Health Care Without Harm website for updates to this table: http://www.noharm.orgFor the phthalates BBP, DEHP, DBP, and perhaps forDINP, this approach is supported by the general consensus that these phthalates act, at least in part,through a common mechanism when they independently cause harmful effects on the developing male reproductive system, which appears to be their most sensitive endpoint. DEHP, BBP, and DBP each reduce testosterone synthesis in the developing male organism. 6 63 107 109 It should also be noted that antiandrogens that act by blocking the androgen receptor will also likely have a cumulative impact with chemicals that interfere with testosterone synthesis. Each mechanism will reduce the effective level of activated androgen receptors at the level of the gene—the final common pathway of toxicity.

For phthalates, the potency of each component in a mixture can be expressed relative to DEHP, the most well characterized member of the phthalate family. Each individual phthalate can then be converted to a “DEHP-equivalent” for the purpose of estimating the total potency of a mixture of different phthalates. This approach is similar to using “toxic equivalencyfactors” for estimating the toxicity of complex mixtures of other chemicals, like, for example, dioxins, that also act through a common mechanism ofaction. The DEHP-equivalent potency of the mixture can then be calculated by adding the DEHPequivalency of each individual phthalate. Thisapproach requires data that directly compares endpoint-specific toxicity of various individual phthalates with DEHP. These calculations assume that the combined effect of a mixture is additive, though it is certainly possible for a combination to be more toxic than the sum of its individual parts.



## Relative potency calculationsWe applied the relative potency approach to phthalates shown to cause reproductive and developmental toxicity in males. Few data are available that compare these toxic effects from exposures to various phthalates in the same experiment. However, two well-controlled studies did compare other phthalates with DEHP for this endpoint in vivo. 64 65 To determine the relative potency, the ability of each phthalate to cause a certain effect was compared withDEHP. For example, two litters of rats exposed prenatally and through lactation to equal amounts of DEHP or BBP showed different results. For DEHP,87% of the infant males displayed female-like areolas/nipples after exposure, but for BBP 70% of the males displayed this defect. 64 This suggests that BBP is roughly 80% as effective as DEHP at causing this effect, and therefore, could be assigned a relative potency value of 0.8.

Another recent rodent study compared the impacts of gestational exposures to DEHP, DBP, or DEHP + DBP on the developing male reproductive tract. Pregnant rats were given DEHP (100 mg/kg/day), DBP (100 mg/kg/day), DEHP + DBP (each at 100 mg/kg/day) on gestational days 12-21 by gavage. DBP and DEHP + DBP caused similar reductions in anogenital distance in male offspring when comparedto controls, but DEHP at that dose caused no reduction in anogenital distance. The doses chosen, therefore, were too low to detect potential additivity, since DEHP alone at that dose had no effect. With respect to male areolae/nipple retention, an additiveresponse from DEHP + DBP was observed at postnatal day 13, though it did not achieve statistical significance, perhaps as a result of the dose and the small number of animals in each dose group. 163

Relative potencies of several phthalatesTable 5 shows the potencies of four phthalates relative to DEHP. The relative potency of BBP varied from 1.0 to 0.8 for effects including development of female-like areolas/nipples, reduced pup weight, shortened anogenital distance, malformed males, andreduced testis weights. DBP showed greater variability in its effects compared to DEHP. Hypospadias was the only effect in which DEHP was much more potent. Estimating the relative potencies for DBP is complicated by the fact that DBP was used at lower doses than DEHP. We ignore this dosing difference, however, for the purposes of estimating their relative potency, and still note that DBP is similar to DEHP in potency for shortened anogenital distance. For other effects, potency ranged from 0.5 – 0.6 that of DEHP. DINP showed much less potency than DEHP in producing malformed males, but about 0.3 the potency for generating female-like areolas/nipples. DEP did not produce either malformed males or male infants with female-like areolas/nipples in these experiments. In other studies, DEP increased testes weights, altered Leydig cell structure, and decreased sperm concentration. 19 82 92 However, these studies did not directly compare DEP to DEHP.

To calculate exposure in a mixture of phthalates, arelative potency value must be selected for a phthaAggregate Exposures to Phthalates in Humans 23late. However, Table 5 shows a variety of relative potencies for each phthalate. Since a higher relativepotency value means a higher total estimated effective exposure, the highest relative potencies were selected for each phthalate for the purposes of the calculations in this paper. This conservative rationale yields relative potencies for BBP, DBP, DINP, and DEP of 1.0, 0.9, 0.3, and 0 respectively.

Relative potency factors determined for BBP, DBP,DINP and DEP were applied to the phthalate exposures calculated by the CDC for women of reproductive age and other adults. A sample calculation isshown in Table 6. The exposure level of each phthalate is multiplied by the relative potency to yield the DEHP-equivalent dose. Unfortunately, relative potency factors could not be calculated for DCP and DOP, two phthalates that were measured in the CDC study, because of lack of experimental data.

Total phthalate exposures are likely to be higher than estimates derived from this list since several common phthalates are not included. These high-production chemicals include DHP, DIDP, and DOP as well as a host of new linear chain phthalates.

Health Care Without Harm 24 

### Table 5. Estimated potencies of phthalates relative to DEHP: Reproductive and developmental toxicity in males.

Effect Phthalate Dose Percent of animals Relative (mg/kg) or size of impact Potency Study

Male infants with DEHP 750 87 1.0 64 female-like areolas/nipples BBP 750 70 0.8 DINP 750 22 0.3 DEP 750 0 0

Reduced pup weight at birth DEHP 750 15 1.0 BBP 750 18 1.0

Malformed males DEHP 750 82 1.0 BBP 750 84 1.0 DINP 750 7.7 0.1 DEP 750 0 0

Reduced testis weights DEHP 750 35 1.0 BBP 750 35 1.0

Shortened anogenital distance DEHP 750 30 1.0 BBP 750 30 1.0

DEHP 750 2.45 1.0 65 DBP 500 2.79 1.1

Percent areolas DEHP 750 88 1.0 At birth in male infants DBP 500 55 0.6

Hypospadias DEHP 750 67 1.0 DBP 500 6.2 0.1

Testicular and epididymal DEHP 750 90 1.0 atrophy or agenesis DBP 500 46 0.5

All phthalates dosed orally. Note that no corrections were made to the effects in experiments where different doses of DEHP andDBP were used. See the Health Care Without Harm website for updates to this table: http://www.noharm.org

## Exceeding tolerable intakes DEHP-equivalent exposures from the CDC datawere calculated and compared to some current tolerable intakes. Clearly, in this sample population, DBP is the individual phthalate with the highest estimated exposure and the one that tends to drive aggregate exposures, expressed as DEHP-equivalents, most sharply toward the tolerable intake. As seen in Table 7, 5% of women of reproductive age from the generalpopulation in the CDC study show evidence of exposure to just DBP, expressed as DEHP-equivalency, that is 75% of the FDA’s oral tolerable intake. This is without any consideration of exposure to additional phthalates with toxic impacts that are additive to those of DBP. If, for example, one of these womenwere to be exposed to DEHP from a medical procedure, 25% or less of FDA’s calculated tolerableintake would be necessary before her aggregate exposure would exceed safe levels. Women from the general population who happen to be in the top 5% of exposure for DEHP, BBP, and DBP will exceed the tolerable intake without any additional exposure from medical care. Total maximum exposure to just DBP, BBP, and DEHP, based on these estimates, would be on the order of 130 μg/kg/day. Assuming that DBP, BBP, and DEHP are roughly equivalent inpotency for impacts on male reproductive development, that daily exposure to these three phthalates would exceed the DEHP tolerable intake by 3 fold.

One study describes the co-variability of exposure to several of these phthalates, or the extent to whichexposures to one correlates with exposures to another. 91 In the NHANES sample population, DBP exposure was highly correlated with BBP exposure and BBP exposure was moderately correlated with DEHP. This suggests that there may be common exposure sources for some phthalates, and that women with high DBP levels are also likely to have higher levels of BBP.

Aggregate Exposures to Phthalates in Humans 25 

### Table 6. Using relative potency values to calculate the DEHP-equivalent dose individual phthalates in women of reproductive age in the CDC study

Phthalate Women of reproductive age Relative potency DEHP-equivalent 95th percentile/max potency (μg/kg/day) (μg/kg/day)

DEP 90 (95%) 0 0 170 (max)

DBP 32 0.9 29 113

BBP 4.5 1.0 4.5 7.8

DCP 0.24 0.45

DEHP 3.8 1.0 3.8 10

DOP 0.65 1.5

DINP 3.7 0.3 0.9 7.8

Exposure data from the CDC. 90 Relative potency values calculated above. The DEHP-equivalent dose is the product of the exposure and the relative potency. The total DEHP-equivalent dose is the sum of the individual doses.

## Limits of the relative potency approach The aggregate exposure calculations shown above highlight some of the limitations of the relativepotency approach. For example, the lack of comparison data for DEP in Table 6 resulted in a relative potency factor of 0 even though the compound shows reproductive effects in other studies. 19 82 92 The lack of comparison data limits the utility of this approach when a large number of phthalates are at issue because it may underestimate total potency of a mixture. In addition, a low relative potency for oneendpoint may be unrelated to a relative potency calculated for a different endpoint. Although it wouldbe useful to use No-Observable-Adverse-EffectLevels (NOAEL) for comparison purposes, those dose estimations have not been determined for manyof these impacts on the developing male reproductive system, and the calculations were based on single-dose studies. Finally, value judgments are used toassign an actual relative potency number to a chemical that will be used to determine equivalent doses. The wide variation in relative potencies observed in Table 5 can demonstrate close to a one-to-one equivalence or a one-to-ten equivalence for the same phthalate.

A significant exposure problemThe relative potency calculations suggest that aggregate exposures to phthalates in the general population are, in many cases, near to, or above regulatory levels for the developing male reproductive toxicityendpoint. Assuming that the population sample studied by the CDC is representative of the total US population, census data reveal the public health implications of the data.

If the CDC sample is representative of the general US population, approximately 2 million women of reproductive age would be exposed to just DBP on a daily basis at levels, expressed as DEHP-equivalents, that are 75% or more of the tolerable intake for DEHP. DEHP, BBP, DINP, and other phthalates addto this number. An unknown number of these 2 million women who happen to be pregnant run the risk of being exposed to unsafe levels of DEHP, if theyrequire medical care provided from DEHP-containing medical devices, even if the DEHP exposures are well below the FDA’s tolerable intake. These women will not have been free of phthalates before medical care is provided. On the contrary, as we have seen,baseline exposures in the general population are significant and set the stage for potentially unsafe levels of exposure to phthalates from any number of

sources.
These exposure estimates are disturbing even if only in utero male developmental toxicity is considered. The wider spectrum of health effects caused by phthalates adds additional concern to the widespread exposures in the general population.

Health Care Without Harm 26 

### Table 7. Calculated daily intake of individual phthalates from the CDC study referenced to DEHP and compared to regulatory levels for DEHP. (μg/kg/day) for the most highly exposed women of reproductive age in the general population

Group Total DEHP- EPA FDA TDI Health Canada CSTEE Women of reproductive equivalent dose Reference Dose Oral TDI TDI age-top 5% (DEHP) (DEHP) (DEHP) (DEHP)

DBP 29 or higher 22 40 44 50

BBP 4.5 or higher 22 40 44 50

DEHP 3.8 or higher 22 40 44 50

DINP 0.9 or higher 22 40 44 50

Abbreviations: TDI: tolerable daily intake; EPA: US Environmental Protection Agency; FDA: US Food and Drug Administration; CSTEE: Science Committee of Toxicity, Ecotoxicity and the Environment for the European Union. The mixture contained DEHP, DBP, BBP, DINP, andDEP. Note that the table only reflects a DEHP-equivalent dose for the male reproductive toxicity endpoint. DCP and DOP could not be included d ue to the lack of comparative experimental data. See the Health Care Without Harm website for updates to this table: http://www.noharm.orgAggregate Exposures to Phthalates in Humans 27 

### Table 8. US Census 2000 data and National Center for Health Statistics calculations of samples in the CDC study

To Calculate Category Number

Women in upper 95th percentile Adults 20-44 104,004,252

Women 20-44 52,938,164

Women 20-44 95th percentile 2,646,908

Children born to women in upper 95th percentile Births to women 20 to 40 in 2001 3,579,886

Births to women in 95th percentile or above 178,994

Male births to women in 95th percentile or above 89,497

US Census 2000 data from http://www.census.gov. Birth data from the National Vital Statistics Report at http://www.cdc.gov/nchs/. Note that the CDC sample of reproductive age women was between 20 and 40, not 44 as provided in Census data. An approximate estimate of this category would be 2 million for reproductive age women.Health Care Without Harm 28

# A Legacy of Inadequate Responses

Phthalates have become ubiquitous environmental and human contaminants. The concern over their potential impacts on human health expressed by the FDA, NTP, Health Canada, and the EU ScientificCommittees and the CDC’s documentation of aggregate exposures in humans reinforces the need to seriously examine and learn from the legacy of industry and government policies surrounding their use.



## Inadequate industry solutionsThe chemical industry has dealt with regulatory pressures on phthalates by proposing voluntary agreements and switching to alternative plasticizers. In 1986, DEHP in chew toys came under scrutiny in theUS. Toy makers responded by entering into a voluntary agreement with the US Consumer Product Safety Commission to substitute DINP for DEHP. 7In 1998, toy makers assured the public and US regulators that the voluntary agreement had successfully removed DEHP from children’s toys in 1986. However, toys containing DEHP were found the same year at national chain stores in the US. 37 145 Currently, the $70 billion European PVC industry is actively lobbying the European Commission for a voluntary approach to regulating PVC in the EU. 125

Voluntary agreements fail to ensure safety because compliance is optional and usually unsupervised by the industry, regulators, or outside groups. When industry voluntarily proposes to solve one phthalateproblem by switching to another phthalate or plasticizer, the substitution decision can be weighted toward solutions that are easier for the industryrather than safer for consumers. Changing to different plasticizers is relatively easy for manufacturers since alternative phthalates or other plasticizers of PVC can often be produced in the same facilities.Since voluntary agreements allow companies to market consumer products with substitute plasticizers, leaching and exposure problems remain with new concerns about the safety of the substitutes. Plasticizer leaching problems can be avoided by switching to materials that are inherently flexible, requiring no plasticizers to impart flexibility.

Recent controversies surrounding PVC and phthalates in toys and medical products have led to the substitution of alternative plasticizers. The chemical industry estimates that there are approximately 50- 100 plasticizers in commercial use. 47 Common nonphthalate plasticizers in flexible PVC includeadipates (e.g., DEHA), citrates (e.g., ATBC), phosphates (e.g., DEHPA), and trimellitates (e.g.,TETM). Most are poorly characterized toxicologically, but a summary of some known properties from a Danish EPA report is shown in Table 9. 28 Non-phthalate plasticizers can also leach from PVC causing exposures, though the degree of leaching may vary from that of phthalates. 26 In addition, alternative plasticizers may share some of the liver, reproductive, and developmental toxicity features of phthalates. The No-Observable-Adverse-Effect-Levels (NOAEL) for reproductive toxicity of these common alternative plasticizers varies from 28 – 100 mg/kg/day compared with a 3.7 – 2,800 mg/kg/day for DEHP. 28 153



## Inadequate government solutions Government approaches to phthalate regulation have not protected consumers and hospital patients from aggregate phthalate exposures. A patchwork ofgovernmental policies and regulations usually considers only individual chemicals and individual products. No regulatory agency is adding up the multiple phthalate exposures from multiple sources in order to draw safety conclusions.

Regulatory authority is dispersed both among governmental agencies and within agencies and is separatedby product category, such as consumer products, pesticides, medical devices, pharmaceuticals, food, and cosmetics. This separation creates formidable barriersto regulatory control of aggregate exposures to toxicchemicals of all sorts from multiple sources. A phthalate prohibited or limited for one use can be presentin high concentrations in another product. For example, the allowable concentration of DEHP is limited in food containers but not in medical devices. In light of the multiple applications of phthalates in a wide variety of products, focusing on only one product or class of products is unlikely to have a substantive impact on total population-wide exposures.

Regulatory authority is also limited. For example, the Federal Food, Drug, and Cosmetics Act (FDCA) authorizes the FDA to regulate food, drugs, medical devices, and cosmetics. The Agency can deny the marketing of cosmetics that contain “a poisonous or deleterious substance which may render it injurious to health.” 51 However, with the exception of coloradditives, which must be shown to be safe, the burden of proof is on the FDA to demonstrate violations of this provision. The FDA does not review the safety of cosmeticproducts or cosmetic ingredients before they are marketed. It cannot require manufacturers to do safety testing of products before they are marketed and has no reporting requirements. The FDA maintains avoluntary data collection program. Cosmetic companies that wish to participate forward data to the agency. If the FDA wishes to remove a cosmetic product from the market, it must first prove that the product may be injurious to users, improperly labeled, or otherwise violates the law.

In addition to the FDCA, the Fair Packaging andLabeling Act requires labeling of ingredients on cosmetic products offered for sale, but not those used inprofessional salons or given away. Unfortunately, fragrances that are claimed to be protected by trade secret provisions in the law do not have to identify ingredients on the label.

Aggregate Exposures to Phthalates in Humans 29 

### Table 9. Properties of some alternative plasticizers

Source: 28 Abbreviations: NOAEL: No-Observable-Adverse-Effect-Level; LOAEL: Lowest-Observable-Adverse-Effect-Level. See the Health Care Without Harm website for updates to this table: http://www.noharm.org Plasticizer

DEHA

ATBC

DEHPA

TETM Properties

Easily migrates

Water soluble Expected to be bioaccumulative

Water soluble

Heat resistant Easily migrates Expected to be bioaccumulative Current/Potential PVC Use

Cling wrap, medical products, packaging

Toys, medical products, packaging

Medical products, cabling, flooring, wall coverings, packaging

Medical products, packaging, cables, floor and wall coverings Effects

Negative effects on liver, kidney, spleen, and fetus Liver adenomas and carcinomas Skeletal and ureter defects Toxic to crustaceans NOAEL: fetal toxicity 28 mg/kg/day

Decreased blood pressure and respiration Central nervous system toxicity Decreased body weights in male offspring NOAEL: reproductive toxicity 100 mg/kg/day

Increased liver weights Causes weakness, irritability, headache, second-degree skin burns, and eye irritation in humans Harmful to algae, crustaceans, fish NOAEL: insufficient data

Skin and eye irritation Increased liver and spleen weights LOAEL: liver and spleen 42 mg/kg/dayIn 1976, the FDCA was amended to allow the agency to regulate the testing, marketing, and use of medicaldevices. New medical products proposed for the market must undergo pre-market testing, but the use of medical devices already on the market in 1976 and considered safe at that time was allowed to continue.New devices made of substantially the same formulations were also readily allowed entry to the market. As a consequence, phthalate-containing medical products have been on the market for over 30 years, and manufacturers claim a record of safety. What they fail to acknowledge, however, is that no one has ever studied the impacts of phthalate exposure from their products on the reproductive development of young boys. Reports of clotting disorders andcholestasis that may be attributable to DEHP exposure from medical devices are infrequently publicized or addressed. Indeed, if a medical practitioner wished to identify products containing phthalates, in most cases it would be impossible since the FDA does not require identifying labeling and manufacturers are often reluctant to disclose product formulations.

Sometimes, phthalate-containing PVC products areregulated according to the age of potential consumers. Recently, the EU banned the use of certain phthalates in PVC toys designed for the mouths of children under three. This approach is unlikely to protect children since children of all ages routinely handle products designated for older children or adults.

Despite the reality of aggregate exposures, phthalates have been regulated individually. What may appearto be a “tolerable” level of exposure to a single compound can actually contribute to an unsafe aggregateexposure. In addition, the tolerable daily intake levels are ordinarily determined by assessing the toxicityof a single compound. Presumed “safe” levels virtually never take into account other similar compounds that have additive toxic effects and to which people are regularly exposed. 

## European regulatory action Phthalates have been identified as a priority for action in Europe. In 1998, the Oslo and Paris Commission (OSPAR) listed DBP and DEHP among substances for priority action. The 13 countries named as Contracting Parties agreed to make “...every endeavor to move towards the target ofcessation of discharges, emissions and losses of hazardous substances by the year 2020. We emphasize the importance of the precautionary principle in this work.” 101 143 That same year, Sweden passed an Environmental Bill that states “all uses of phthalates and other plasticizers with harmful or potentially harmful effects should be phased out on a voluntary basis.” 142 The phase-out of DEHP is prioritized and further measures including prohibition are to be introduced if the voluntary phase-out fails. In 1999, a PVC Strategy in Denmark included an Action Planfor reducing and phasing out phthalates in soft plastics. 102 The Plan prioritizes large uses and emissions of phthalates and includes bans, taxes, levies, subsidies, public-sector green purchasing, and eco-labeling. In 2001, the Swedish National Chemicals Inspectorate (KEMI) recommended to the Swedish Government that, “The Swedish PVC industry should continue its work to phase out DEHP and should broaden that work so as also to include DBP and BBP, insofar as these phthalates are used.” 85 KEMI also recommended the “rapid phase-out of DEHP and other fertilityimpairing phthalates in feed tubes for premature babies.” 85

Health Care Without Harm 30Aggregate Exposures to Phthalates in Humans 31 

# Alternatives to Phthalates

The reality of aggregate phthalate exposures calls for fundamental changes in chemical manufacture, use,and regulatory policies. These high production volume chemicals permeate the market in large numbers of products and contaminate people, wildlife, and ecosystems throughout the world. Speaking of DEHP-containing PVC medical devices, the Health Canada Expert Advisory Panel concluded that “The level of concern, even though the concerns are based entirely on data derived from animal research, is nevertheless too high to recognize status quo as an option.” 69



## Material substitution Since PVC accounts for 90% of global phthalate use, converting to PVC-free materials would substantially reduce global contamination with phthalates. Alternative, inherently pliable plastics can substitute for nearly every flexible PVC product on the market today. 160 However, even if all phthalate use in PVCwere eliminated, the residual use of non-PVC phthalate-containing products with which people come into contact would likely contribute to continuedhuman exposure. For these end uses, including cosmetics, inks, adhesives, paints, and food packaging,phthalate-free alternatives can also readily be substituted.

Plastics that compete with PVC include polyolefins (polyethylene and polypropylene), ethylene vinyl acetate (EVA), polyurethane, and silicone. These plastics compete with PVC “on the cost/performance requirements” of particular applications. 81 A subclass of polyolefins, called metallocene polyolefins, isespecially competitive with PVC. Metallocene polyolefins are inherently flexible and can be tailored to specific applications. They compete with PVC in flexible medical products, packaging film, wire and cable insulation, transportation, flooring, and geomembranes.” 81 

## Implementing alternatives A wide variety of companies and institutions have initiated PVC phase-out policies for all or part of their product lines. Concerns over PVC includephthalates, metal stabilizers (lead, cadmium, organotins), toxicants used during manufacturing (vinyl chloride, ethylene dichloride), toxicants generated during manufacture and disposal (dioxins, furans), performance, and its poor recyclability (less than 1 percent annually in the US). 162 Table 10 shows numerous examples from the auto industry, building and construction uses, cabling, packaging, toys, and medical products. Industry giants moving away from PVC include prominent global corporations based in Japan, the EU, and the US.



## Identifying alternatives Alternatives to PVC products in health care and construction can be found in four online databases:

Database on Non-PVC Products for Health Care Institutions Aarhus County, Denmark http://cold.aaa.dk/pvc/english/index.htm The database provides health care professionals witha comprehensive, easily searched, and readily available tool for identifying PVC-free products. Released online in January 2002 in English, the database includes hundreds of PVC-free products in sevencategories: cleaning articles, empty packaging, hospital supplies, hospital supplies packaging, kitchen articles, kitchen articles packaging, and office supplies.Sustainable Hospitals Project, Lowell Center for Sustainable Production Massachusetts, USA www.sustainablehospitals.org The website includes lists of alternative products for: bedding covers, catheters, enteral feeding products, gloves, intravenous (IV) solutions, office products, and other products.

Greenpeace PVC Alternatives Database: Building the Future http://www.greenpeaceusa.org/toxics/vinylhouse.htm

or http://www.greenpeace.org/%7Etoxics/pvcdatabase/The database includes alternatives to PVC in construction, for both flexible and rigid PVC applications. Flexible products covered include flooring, wall coverings, and electrical equipment. Healthy Building Network http://www.healthybuilding.net See PVC section on webpage

Health Care Without Harm 32 

### Table 10. Examples of companies and institutions with PVC phase-out policies

Type Companies

Auto Nissan (Japan), General Motors (USA), Mercedes Benz (Germany), Toyota (Japan), Opel (Germany), Honda (Japan), Ford (UK), Daimler Benz (Germany)

Building / Construction Construction Res. Centre (UK), Reserve Centre (UK), Tate Gallery (UK), Krohnengen School (Norway), Society of Danish Engineers (Denmark), Nike (Netherlands), JM (Sweden), Svenska (Sweden), Anglian Water Services (UK), Eco AB (Sweden), Borastapeter (Sweden)

Cabling Matsushita Electric (Japan), North German Television (Germany), Bilbao Metro System (Spain), US Navy (USA), P&O Cruises (UK), Deutsche Bahn (Germany), London Underground (UK), Eurotunnel (UK), Sumitomo (Japan), German Telekom (Germany), Nippon Telegraph (Japan), Ricoh (Japan)

Home / Consumer Sony (Japan), Kinnarps (Sweden), Toppan Printing Co. (Japan), AEG Electronics (Germany), Vorwerk (Germany), Electrolux (Sweden), OBI (Germany), Ikea (Sweden), Bene (Austria), EWE Kuechen (Austria), Hennes & Mauritz (Denmark), Nike (USA)

Medical Braun-Melsungen (Germany), Fresenius (Germany), Terumo (Japan), Kaiser Permanente (USA), Baxter Healthcare (USA), Catholic Healthcare West (USA), SMZ Ost Hospital (Austria), Universal Health Services (USA), Tenet Healthcare Corp (USA)

Packaging The Body Shop (UK), Migros (Switzerland), Tengelmann (Germany), Nestle (Spain, France), Evian (France), Sony (EU), Wella (Germany), Neals Yard (UK), SPAR (Austria), BILLA (Austria), ADEG (Austria), LoeWA (Austria), MEINL (Austria), Matas (Denmark), Ica (Sweden), Konsum (Sweden), Waitrose (UK), Perrier (Spain), Fonvella (Spain), Bayer (Germany), Helene Curtis (USA), Den-Mat (USA), Evian (EU), Spa (Belgium), Greenseal (USA), Carlsberg Italia (Italy), VegiWash (USA), Federated Group (USA), Eagle Family Foods (USA), Proctor & Gamble (Japan), Victoria's Secret (USA), Shiseido (Japan), Henry Thayer (USA), Ito-Yokado (Japan), Simple Green (USA), Educa Sallent (Spain), IRMA (Denmark), am/pm (Japan), Lawson (Japan), Seven-Eleven (Japan), Mycal (Japan), Seiyu (Japan), Jusco (Japan), Consumers Co-operative (Japan), Daiei (Japan), Kao (Japan), Lion (Japan), Dean Foods (USA), Cargill (Brazil)

Toys APRICA Kassai (Japan), McDonalds (EU, Australia), Young Epoch (Japan), Pilot Ink (Japan), Tomy (Japan), First Years (USA), Early Start (USA), LEGO (Denmark), Playmobil (Germany), Chicco (Italy), Ravensburger (Netherlands), BRIO (Sweden), Bandai (Japan), Ambitoys (Netherlands), Artbaby (Argentina), Babelito (Argentia), Grazioli (Italy), Kiko International (Spain), Little Tikes (USA), Novatex (Germany), Continua (Germany), Fashy (Germany), Mapa (Germany), Sassy Products (USA), Mattel (USA), A-One (Japan), Ampa Hispania (Spain), Tiny Love (USA), People Co. (Japan), Juguetes y Herrajes Joal (Spain), Toho (Japan), Tolico (Denmark), Giochi Preziosi (Italy), Lamaze (USA), Play by Play (Spain)

Sources: 66 70Aggregate Exposures to Phthalates in Humans 33 

# Conclusions

Phthalate use:Phthalates are produced in the millions of tons annually worldwide and used in a wide variety of consumer and industrial products. These chemicals readily escape into the environment and contaminate the world’s ecosystems. Environmental contaminationand direct contact with phthalate-containing products results in virtually ubiquitous human exposures.



## Phthalate toxicity: Health effects that may result from exposure to thephthalates differ among the various individual compounds and depend on the timing and the size ofthe dose. Young, developing organisms are inherently more vulnerable to exposure to some phthalates. In particular, the developing male reproductive tract appears to be the most sensitive endpoint, althougheffects on the liver, kidneys, lungs, and blood clotting are also of concern. In animal tests considered relevant to humans, several of the phthalates,including DEHP, DBP, BBP, and perhaps DINP, interfere with male reproductive tract development andare toxic to cells in the testes responsible for assuring normal sperm and hormone production. DEP appears to have little impact on reproductive tract development but in test tube experiments alters the microscopic appearance of cells responsible for testosterone production.



## Human exposure: Human exposure to DEHP from PVC medical devices used in patient care has been known for some time. Expert panels of the US National Toxicology Program and Health Canada, as well as the Food and Drug Administration, have recentlyreviewed the toxicity of DEHP and considered exposures to patients that may result from the use ofDEHP-containing equipment. Each review has independently concluded that some patients are likely to be exposed to potentially unsafe amounts of DEHP while receiving medical care.

The CDC has discovered that phthalate exposures are virtually ubiquitous in the general population and that women of reproductive age experience some of the highest exposure levels to phthalates that interfere with normal male reproductive tract development.



## Public health implications: In this report, we have attempted to summarize what is known about human exposures to phthalates and to consider the potential health impacts of exposure to real-world mixtures of these chemicals. Using a relative potency approach, based on what is knownabout mechanisms of action and available experimental data, it becomes clear that a large number ofwomen of reproductive age are sufficiently contaminated with phthalates to the point of significantly increasing the risk of abnormal development in male fetuses and baby boys. Women of reproductive agewho require medical care may be exposed to additional phthalates, largely DEHP, in the medical setting, that will add significantly to their existing exposure acquired from the non-medical world inwhich we all live. Using CDC sample data, an estimated 5% of women of reproductive age from the general population are contaminated with 75% or more of the amount of just DBP that may begin to impair normal reproductive tract development. Manyof these women will also be regularly exposed to significant amounts of BBP and DEHP, so that their aggregate exposures will pose even greater risks. When any of these women requires medical care that exposes them to additional DEHP from PVC medical devices, even more is added.

Where are these phthalates coming from in the general population? No one knows for certain, but perhaps the high exposures to DBP in women of reproductive age provide a clue, at least for thatphthalate. DBP is used in a variety of cosmetic and personal care products. Recent testing identifies DBP in some hair spray, perfume, and deodorants. 159 Many nail polishes also have large quantities of DBP. Unfortunately, labeling requirements are sufficiently lax that cosmetic ingredients considered part of the fragrance need not be identified on the label. For many consumer products, however, virtually nolabeling requirements exist. Moreover, a large number of synonyms used for various phthalates complicate a label search. As a result, it is extraordinarily difficult to identify phthalate-containing productsand to begin to narrow down the sources of widespread general population exposures.



## “Balkanization” of chemical policy: Chemical policy in the US is severely “Balkanized” 161 and requires major revisions. For example, the Foodand Drug Administration is responsible for food contaminants (including phthalates), drug ingredients (including phthalates), medical devices (including phthalate-containing PVC products), and cosmetics (including phthalates). Unfortunately, each of these activities is a responsibility of a different division within FDA, each of which carries out its work inisolation from the others. Moreover, the enabling legislation that authorizes the Agency to monitor these various products differs considerably among food,drugs, medical devices, and cosmetics. As a consequence, when the medical device division considers the safety of exposure to DEHP, they consider onlymedical devices and not the real world of population-wide exposures to multiple phthalates from multiple sources. And, when the cosmetics division considers phthalates in personal care products, not only do they limit their concerns to products in their domain, but they must prove the likelihood of harm with no requirement that manufacturers will supply safety data.

When the Consumer Products Safety Commission considers the safety of phthalates in, for example, children’s toys, they consider only the phthalate that may leach out of the toy when a child chews on it, and not the other phthalates that that same childmay be exposed to from contaminated food, contaminated air, or medical care. And when the Environmental Protection Agency considers whether or not to allow phthalates in a pesticide formulation, they examine those proposals one at a time, failing to consider aggregate exposures to multiple phthalates from multiple sources.

As a result, phthalates permeate the environment and contaminate large populations of people throughout the world. Phthalates are in the blood of pregnant women at levels of concern, particularlywhen the contaminants are considered in the aggregate. Phthalates cross the placenta and contaminatebreast milk. Relevant animal tests show that phthalates interfere with normal fetal development. The length of the period of susceptibility to relatively low levels of phthalate exposure in humans is not known. But, animal tests suggest that, with respect to male reproductive tract development, boys may remain vulnerable to phthalate exposure beyond fetal life until early puberty, since testes undergo rapid change at several stages, including later childhood. 69



## What is needed: Manufacturers of phthalates continue to producelarge amounts and sell them to product manufacturers who use them in thousands of products. Manufacturers have consistently argued that there isno evidence that anyone has been harmed by phthalates. However, as we have noted, and as confirmed by the NTP Expert Panel and FDA, no study has ever examined the impacts of phthalate exposure on the developing male reproductive tract in people. Not one.

But lack of evidence can hardly be used as evidenceof safety when no one has ever looked. The increasing incidence of hypospadias, undescended testes, and testicular cancer, and declining sperm counts in the US and many other parts of the world suggeststhat a closer look at many reproductive tract toxicants and endocrine disruptors is urgently needed in people. 16 With respect to phthalates, however, evidence from relevant animal studies and from limitedstudies of non-reproductive tract impacts in hospitalized patients is sufficient to require phasing out the use of many of the phthalates. As the Health Canada panel concluded, “the status quo is not an acceptable option.”

Health Care Without Harm 34Regulatory agencies charged with protecting medical patients, public health, and the environment must substantially revise procedures and protocolsto consider the potential impacts of phthalate exposures cumulatively, rather than as single chemical
exposures.
Finally, phthalates serve as a case study that demonstrates the failure of current chemical policy in the US. Regulatory authority is spread among agenciesthat compete with one another rather than cooperate. Lines of communication are limited and infrequently used. No one agency is authorized to look atthe “big picture”, which can have tragic consequences. In Europe, vigorous debate is underway regarding the phase-out of the general use of many phthalates in consumer products. Public health and the environment can only be truly protected when safer materials are substituted far upstream in the manufacturing process. Humans have demonstrated the capacity to contaminate every nook and cranny of every ecosystem and every developing fetus withsynthetic chemicals that can impair normal development. Now we need to demonstrate that we can change. First, we need to recognize that a major overhaul of current regulatory policy is long overdue. Under the current framework, government approval simply does not provide adequate real-world protection from chemical exposures. The FDA, the EPA, the CPSC, and other government agencies, with necessaryauthorization, must begin to transform their makebelieve regulatory framework into a new, sciencebased system that properly considers the reality of aggregate exposures to toxic chemicals and thatrequires meaningful pre-market testing of commercial chemicals. Second, consumers must insist on theright to know about what chemicals are in commercial products and must have unhindered access to toxicity and exposure data. Third, manufacturers can and must shift to cleaner production practices that produce cleaner, sustainable products more suited to the contemporary world and the one that we will leave to future generations.

Aggregate Exposures to Phthalates in Humans 35Health Care Without Harm 36

# Appendix I. MEHP Exposures through Medical Procedures

In its safety assessment of DEHP, the FDA noted that patients are also exposed to MEHP, the highly toxic monoester metabolite of DEHP. MEHP is formed in medical products as DEHP degrades over time resulting in patient exposure to both phthalates. MEHP is formed by the action of lipases in stored blood and plasma and by hydrolysis in IV fluids. The FDA cited studies that measured MEHP in hospital patients undergoing coronary bypass, hemodialysis, and peritoneal dialysis. In addition, the Agencyacknowledged that nursing infants could receive significant doses of MEHP in breast milk from mothers undergoing hemodialysis. To estimate the amount of MEHP exposure, the FDA needed to calculate the relative potency of MEHP so that its level could be expressed in terms of DEHP concentration.



## Relative potency of MEHP The FDA used testicular toxicity to develop a relative potency calculation for DEHP and MEHP exposures from medical products. 153 First, the Agency examined the relative potency of MEHP and DEHP to cause testicular toxicity. Second, the FDA compared theabilities of the two compounds to cause maternal toxicity as a comparison. Finally, a relative potency factor of 10 was assigned to MEHP after considering the differences in experimental results. This means thatthe FDA considers MEHP to be 10-fold more effective in causing testicular toxicity than DEHP.



## FDA conclusions The FDA calculated the equivalent dose of DEHPfor MEHP exposure from a variety of medical procedures and then added it to the DEHP dose to yield an aggregate dose of DEHP and MEHP. The Agencyfound that procedures that did not exceed the tolerable intake when considering only DEHP still did not exceed it when considering both DEHP and MEHP. However, the data shows that considering MEHP had a large impact on the dose. Table 11 shows that infusion of crystalloid solutions is far below the tolerable intake when only DEHP is considered. However, when both DEHP and MEHPare considered, the biologically relevant dose increases by 30-fold and draws much closer to the tolerable intake. In addition, several procedures that were less than the tolerable intake when only considering DEHP exposure, became close to the limit when MEHP was considered. These procedures include replacement transfusions in neonates and orthotopic heart transplants.

The FDA decided not to account for aggregate exposures to DEHP and MEHP using the relative potencymethod. The Agency stated that “because of uncertainties associated with the relative potency of DEHP:MEHP and resulting estimates of DEHP equivalent dose, the TI/Dose ratios based on the dose of DEHP-equivalents received by patients will not be used to support regulatory decision making.” 153



## Limitations of the FDA approach In determining the relative potency of MEHP, the FDA made certain value judgments. The variationseen in potencies derived from studies with a testicular endpoint ranged from 2 to more than 1,000.Potencies derived using maternal effects in mice varied from 2 to 80. 153 The Agency chose a value of 10 using the testicular endpoint. The authors of this report illustrate the quantitative consequence of this decision in Table 12.

Table 12 shows that choosing a mid-range relative potency for MEHP of 80 instead of 10 significantly increases the DEHP-equivalent dose calculated for various medical procedures. In fact, using the higherrelative potency number increases the DEHP-equivalent dose of DEHP + MEHP by 2 – 8 fold. Theresult influences judgments about the safety of various procedures as shown below.The consequence of choosing a different relative potency for MEHP can be seen by comparing the aggregate dose of DEHP and MEHP released to patients during various medical procedures. Table 12 shows that a relative potency of 80 significantly changes the total exposure to patients.

When considering only DEHP exposure, infusion of IV crystalloid solutions has TI/DEHP ratio of 120 indicating that the DEHP dose is far below the TI. If MEHP is added to the dose consideration by using relative potency of 10, the ratio becomes 4.44. In contrast, when a relative potency of 80 is used, the ratio becomes 0.57. Under these conditions, infusion of crystalloid IV solutions would exceed the tolerable intake. In fact, all the procedures in Table 13 show a DEHP-equivalent dose that exceeds the tolerable intake if a relative potency of 80 is used instead of 10 to calculate the added impact of MEHP.

Aggregate Exposures to Phthalates in Humans 37 

### Table 11. Tolerable intake compared to DEHP and DEHP+MEHP

Procedure TI/DEHP TI/DEHP+MEHP

Infusion of IV crystalloid solutions 120 4.44

Adult transfusion /ECMO 0.2 0.03

Neonate exchange transfusion 0.03 0.02

Neonate replacement transfusion 2.0 1.75

CABG cardiopulmonary bypass 0.6 0.30

Orthotopic heart transplant 2.0 1.00

Artificial heart transplant 0.25 0.12

Data source: 153 Abbreviations: TI: tolerable intake. See the Health Care Without Harm website for updates to this table: http://www.noharm.org



### Table 12. DEHP equivalent doses for various medical procedures depending on MEHP relative potency value. Doses in mg/kg/day.

RPF = 10 RPF = 80 Procedure DEHP MEHP DEHP equivalent DEHP equivalent

Infusion of IV crystalloid solutions 0.005 0.013 0.14 1.0

Adult transfusion /ECMO 3.0 2.0 23 163

Neonate exchange transfusion 22.6 0.68 29 77

Neonate replacement transfusion 0.3 0.0043 0.34 0.64

CABG cardiopulmonary bypass 1.0 0.1 2.0 9.0

Orthotopic heartTransplant 0.3 0.03 0.6 2.7

Artificial heart transplant 2.4 0.26 5.0 23

Data source: 153 Abbreviations: RPF: relative potency factor. See the Health Care Without Harm website for updates to this table: http://www.noharm.org

## Exposures from medical procedures exceed tolerable intake The FDA Safety Assessment of DEHP Released from PVC Medical Devices reveals several procedures thatexpose patients to levels of DEHP close to the tolerable intake. When MEHP is also considered, theexposures provided even by common medical treatments such as IV infusions can draw close to or exceed the tolerable intake depending on the relative potency of MEHP used to calculate the aggregateexposure. This is in addition to the aggregate exposures to other phthalates calculated above.

Health Care Without Harm 38 

### Table 13. Tolerable intake compared to DEHP and DEHP+MEHP doses using different relative potency factors.

RPF = 10 RPF = 80 Procedure TI/DEHP TI/DEHP+MEHP TI/DEHP+MEHP

Infusion of IV crystalloid solutions 120 4.44 0.57

Adult transfusion /ECMO 0.2 0.03 0.00

Neonate exchange transfusion 0.03 0.02 0.01

Neonate replacement transfusion 2.0 1.75 0.93

CABG cardiopulmonary bypass 0.6 0.30 0.07

Orthotopic heart transplant 2.0 1.00 0.22

Artificial heart transplant 0.25 0.12 0.03

Data source: 153 Abbreviations: RPF: relative potency factor; TI: tolerable intake. See the Health Care Without Harm website for updates to this table: http://www.noharm.orgAggregate Exposures to Phthalates in Humans 39 

# Appendix II. Phthalate Toxicity

The toxicity of phthalates to mammals is shown in Table 14. Note that these effects are dose-dependent and that humans are not necessarily exposed to the levels that elicit these effects in animal studies. Impacts also depend on the route of exposure, species differences in metabolism, distribution, excretion, and tissue sensitivity. Critical windows of vulnerability during development significantly influence both the dose required to elicit an impact and the nature of the impact.



### Table 14. Toxicity of phthalates to various mammalian organ systems Part 1 of 4

Organ

Adrenal gland

Bone

Brain

Blood

Fetus/Embryo Phthalate

DEP

DHP

BBP

BBP

DEP

BBP

DBP

DIBP

DINP

BBP

DBP Species

Rat

Mouse

Rat

Cerebellar explants newborn rat

Rat

Rat

Human lymphocytes in vitro

Mouse

Human lymphocytes in vitro

Rat

Rat

Rat

Rat

Rat

Rat

Rat

Rat

Rat

Mouse Effect

Elevated organ weight

Decreased organ weight

Reduced bone marrow cellularity

Inhibit outgrowth of nerve fibers and glial cells in vitro

Increased weight

Myelomonocytic leukemia

DNA damage to lymphocytes

Anemia

DNA damage to lymphocytes

Mononuclear cell leukemia, reduced white blood cell counts
Decreased hemoglobin, decreased number of red blood cells

Increased post-implantation loss; deformed vertebral column and ribs, cleft palate, fused sternebrae

Reduced pup weight at birth
Reduced fetal weight, increased resorptions, increased skeletal defects
Embryo-fetal death, decreased fetal weight
Birth defects in the prosencephalon, the optic system, and the mandibular and maxillary processes
Transferred to placenta and embryo

Increased post-implantation loss; deformed vertebral column and ribs, cleft palate, fused sternebrae
Decreased fertility, fewer litters per pair, fewer pups per litter, fewer pups born alive Study

19

92

2

84

19

89

88

112

88

20

150

40

64

121

39

130

130

40

92Health Care Without Harm 40 

### Table 14. Toxicity of phthalates to various mammalian organ systems Part 2 of 4

Organ

Fetus/Embryo

Heart

Kidneys

Liver Phthalate

DEP

DHP

DIDP

DINP

MBP

MEHP

DEHP

DEP

MEHP

DBP

DEHP

DHP

DINP

DBP

DEHP

DEHP

DEP

DIDP Species

Mouse

Rat

Mouse

Rat

Rat

Rat

Rat

Rat

Rat

Rat

Rat

Rat granulosa cells

Isolated rat heart

Rat

Rat

Rat

Rat

Mouse

Rat

Rat

Rat

Rat

Rhesus monkey

Rat, Mouse

Rat

Rat liver microsomes

Rat

Rat

Rat Effect
Reduced pup size in offspring
Increased incidence of supernumerary ribs
Decreased fertility, decreased number of litters per pair, decreased number of live pups per litter, decreased number of pups born alive

Skeletal defects in the fetus
Reduced offspring survival in both generations

Reduced pregnancy weight gain
Skeletal and visceral birth defects, reduced offspring viability and weight gain
Birth defects in the prosencephalon, the optic system, and the mandibular and maxillary processes in vivo; growth retardation, dysmorphogenesis in vitro

Deformed vertebral column, deformed ribs, dilation of renal pelvis, cleft palate, fused sternebrae

Increased pre- and post-implantation loss, impaired uterine function
Maternal lethality, litter resorption, reduced fetal weight

Inhibition of estradiol production

Decrease in heart rate

Increase in heart weight

Decrease in heart rate and blood pressure

Causes renal cysts

Reduction in creatinine clearance; cystic changes

Decreased organ weight

Transitional cell carcinoma

Decreased transferrin levels, increased haemosiderin levels

Activate laurate hydroxylation in vitro

Inhibit mitochondrial respiration; peroxisome proliferation
Abnormalities in histology, reduction in liver function

Hepatocellular carcinoma

Hepatocellular adenoma

Activate laurate hydroxylation in vitro

Abnormal enzyme levels, elevated cholesterol and triglyceride levels.

Abnormal enzyme levels, reduced cytoplasmic basophilia, increased eosinophilia
Altered pathology, peroxisome proliferation Study

92

52

92

155

75

64

114

130

38

43

129

34

119

19

126

158

27

92

20

58

118

4

87

89

105

118

139

17

95Aggregate Exposures to Phthalates in Humans 41 

### Table 14. Toxicity of phthalates to various mammalian organ systems Part 3 of 4

Organ

Liver

Lungs

Mucosa

Ovaries

Pituitary

Prostate

Spleen

Developmental/ reproductive effects Phthalate

DINP

DMP

DEHP

DIDP

DBP

DIBP

DINP

BBP

MEHP

DEP

BBP

DEP

DBP

DEHP

DBP

BBP

BBP

DBP Species

Rat

Rat

Rat

Human pre-term infants

Rat

Human lymphocytes

Human lymphocytes

Rat

Rat

Rat granulosa cells

Rat

Rat

Mouse

Rat

Rat

Rat

Rat

Rat

Rat

Rat

Rat

Rat

Rat

Rat

Human sperm

Rat Effect

Carcinoma and adenoma
Spongiosis hepatitis
Increased organ weight in females

Respiratory distress, pathological changes similar to hyaline membrane disease
Increased width alveolar septa, inflammatory reactions, increased numbers macrophages and pneumocytes

DNA damage

DNA damage

Reduced organ weight

Reduced organ weight

Reduced estradiol production in vitro

Elevated organ weight

Atrophy of the prostate

Increased weight

Absent or partially developed ventral prostate

Anterior prostate agenesis

Increased hemoglobin, ferritin, and haemosiderin levels

Male infants with female-like areolas/nipples; shortened anogenital distance; reduced testis weights, reproductive malformations in males

Decreased testosterone, increased FSH
Reduced fetal testis weights, increased retarded testicular descent

Reduced sperm production, reduced testis weight
Atrophy of the testis, seminal vesicles; decreased testosterone, increased FSH and LH; immature sperm cells

Fetuses with undescended testes; decreased anogenital distance in male infants

Hypospadias; absent or partially developed epididymis, seminal vesicles, reduced weights of testis components; seminiferous tubule degeneration, interstitial cell hyperplasia and cell adenoma
Decreased mating, fertility, pregnancy

Decreased sperm mobility in vitro
Leydig cell adenomas in male offspring; fetal rats with decreased testosterone levels and increased Leydig cell numbers Study

20

150

52

128

60

88

88

114

109

97

19

2

92

108

104

58

64

109

121

134

2

42

108

157

56

54Health Care Without Harm 42 

### Table 14. Toxicity of phthalates to various mammalian organ systems Part 4 of 4

See the Health Care Without Harm website for updates to this table: http://www.noharm.org Organ

Developmental/ reproductive effects

Testes

Thymus

Thyroid

Uterus Phthalate

DBP

DEHP

DEP

DHP

DINP

DPP

MEHP

MBP

MPP

BBP

DEP

BBP

DBP

DINP Species

Human sperm

Rat

Rat

Rat

Rat

Rat

Human sperm

Rat

Mouse

Rat

Rat, Leydig cell culture

Mouse

Rat

Rat

Rat

Rat

Rat Sertoli cells

Rat Sertoli cells

Rat Sertoli cells

Rat

Rat

Rat

Rat

Mouse

Rat Effect

Decreased sperm density in university students with DBP in semen
Disorganization of seminiferous tubule structure in male offspring
Sertoli cell vacuolation; atrophy of seminiferous tubules; loss of spermatogenesis

Testicular, epididymal atrophy, and testicular agenesis; hemorrhagic testes; hypospadias in male offspring

Male infants with female-like areolas/nipples, shortened anogenital distance, reduced testis weights, reproductive malformations in males
Induction of Leydig cell tumors

Decreased sperm mobility in vitro
Sertoli cell/gonocyte detachment in vitro

Decreased sperm concentration

Increased testes weights

Alteration in Leydig cell structure

Decreased fertility, decreased percentage of mobile sperm, decreased sperm concentration; decreased weights of testis, epididymis, and seminal vesicles; atrophy of seminiferous tubules

Male infants with female-like areolas/nipples; reproductive malformations in male infants

Increased testes weights

Testicular hyperplasia, testicular tumors

Altered testicular enzymes, decreased progesterone binding

Inhibits FSH-stimulated cAMP accumulation in Sertoli cells in vitro; increases lactate secretion; decreases ATP levels in vitro

Inhibits FSH-stimulated cAMP accumulation in Sertoli cells in vitro;

Inhibits FSH-stimulated cAMP accumulation in Sertoli cells in vitro; increases lactate secretion

Thymus atrophy

Elevated organ weight

Decreased uterine decidual growth

Decreased uterine weight, decreased progesterone levels

Decreased weight
Endometrial hyperplasia and fibrous thickening; endometrial adenocarcinoma Study

106

8

124

65

64

12

56

94

92

19

82

92

64

114

150

55

7

71

71

2

19

44

41

92

150Aggregate Exposures to Phthalates in Humans 43 

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