Beyond
the simple question of dose, other factors suggest that humans
are likely to be less sensitive to phthalates than test animals
are, even if exposures were at comparable levels. Human exposure
pathways, metabolic processes, exposure frequency and duration
are almost always different than those of experimental animals
shown to suffer damage in toxicological testing.
Finally,
the question of benefits is relevant in any holistic assessment
of the risk-altering impacts of proposed regulations. The number
of Americans currently receiving benefits from the use of phthalate
softened vinyl is substantial: In 1996, 31.5 million outpatient
surgeries and 40.3 million inpatient surgeries were performed.
If phthalate-softened PVC products are used in only half of
all surgeries (a very conservative estimate), nearly one-third
of the population derives a health benefit from them in any
given year.
Whole
blood stored in a PVC bag remains viable for 42 days, compared
to only 21 days for other containers. According to America's
Blood Centers, more than 23 million blood components are made
from about 14 million whole blood donations (stored in PVC bags)
yearly.
WHAT
ARE PHTHALATES, AND WHY DO WE NEED A PLAIN-ENGLISH GUIDE?
Increasingly,
issues of public and environmental health involve complex scientific
issues that neither the public nor policymakers have the time
or energy to study in depth. Advocacy groups publish materials
promoting one side of a policy issue or the other, but generally
present only the scientific evidence that supports their policy
proposal. Rarely do issue-advocacy groups attempt to paint a
balanced picture with suitable detail to allow for meaningful
policy consideration or discussion. Scientific review bodies
and blue-ribbon commissions strive for more balanced portrayal
of scientific evidence (and often do so very well), but they
rarely translate that information into language that the interested
lay reader or policymaker can understand. The growing debate
over regulation of vinyl plasticizers, or phthalates is one
such issue.
Phthalates
render what would otherwise be rigid plastic into flexible vinyl.
Linking together individual molecules of vinyl chloride produces
solid polyvinyl chloride (PVC) plastic. Without the addition
of other chemicals, called plasticizers, PVC is a hard, relatively
inflexible plastic. If plasticizers are added before the final
product is made, a wide variety of softer plastics can be produced
from the vinyl chloride stock.
The
most commonly used vinyl plasticizers are diethylhexyl phthalate
(DEHP) and diisononyl phthalate (DINP). DEHP is most commonly
used in manufacturing vinyl medical devices, while DINP is most
commonly used in manufacturing vinyl children’s products,
construction materials, and other consumer products.
Several
advocacy groups have suggested that exposure to phthalates in
consumer products and medical devices poses a health risk, particularly
to children. Greenpeace, for example, suggests that phthalates
are suspected as human cancer-causing agents, could damage liver
and kidneys, might damage the development of reproductive organs,
and might interfere with development by acting as a mimic of
the sex hormone estrogen. A study commissioned by Health Care
Without Harm concluded that humans are exposed to substantial
levels of DEHP through medical devices. Citing various animal
studies, the authors conclude: "Inadequate evidence exists
to conclude that the toxic mechanisms found in laboratory animals
do not occur in humans."
Other
groups have disputed some or all of these claims, including:
1) the U.S. Consumer Product Safety Commission (CPSC); 2) an
expert panel chaired by former U.S. Surgeon General C. Everett
Koop and convened by the American Council on Science and Health
(ACSH); 3) the United Nations International Agency for Research
on Cancer (IARC), and 4) the authors of a comprehensive review
of phthalate toxicology published in the authoritative Critical
Reviews in Toxicology. In the latter study, Wolfgang Huber and
his associates conclude that "an actual threat to humans
by DEHP seems rather unlikely." The CPSC staff found that
the estimated human exposure was below the acceptable daily
intake or level of concern. The CPSC concluded that "few,
if any, children are at risk from liver or other organ toxicity
from the release of DINP from these [teethers, rattles and toys
made from PVC] products." They stopped short of giving
DINP a clean bill of health, however, suggesting additional
study of the cancer-causing potential of DINP.
The
ACSH report by C. Everett Koop, Juberg et al., takes a broader
view of the question of risk, pointing out that even if phthalates
pose some risk to human health, such risks need to be assessed
alongside of the health benefits that phthalates provide. Such
benefits, according to the ACSH report include higher quality
medical devices available to more people at less cost than alternatives,
and the preservative effect that phthalates exert on the supply
of blood in the United States. The ACSH report concludes that
"DEHP in medical devices is not harmful to even highly
exposed people. . . ," and suggests that DEHP "imparts
a variety of important physical characteristics that are critical
to the functioning of medical devices, and eliminating DEHP
in these products could cause harm to some individuals."
On DINP, the ACSH report is somewhat more ambivalent, concluding
that "much of the evidence [for DINP’s harmfulness]
has little relevance to humans, and that DINP in toys is not
harmful for children in the normal use of these toys."
The panel recommends detailed studies of DINP use in mouthing
toys or substances that children might normally mouth or chew
on.
Most
recently, the United Nation’s International Agency for
Research on Cancer (IARC) downgraded the classification of DEHP
from a "possible" human carcinogen to "Cannot
be classified as to its carcinogenicity in humans."
As
can be seen from the approach taken in expressing the risks,
the groups discussed above view the question of risk in very
different lights, which shapes which information they feel should
be considered in determining risk. Greenpeace, Health Care Without
Harm and similar advocacy organizations invoke a regulatory
approach often called the precautionary principle, which presumes
that chemicals are likely to cause harm and must be proven innocent.
Information suggesting a risk is considered meaningful, but
exculpatory data is rarely given equal weight. One potential
risk of this approach is the potential for regulatory overload,
where all chemicals are to be regulated by default, and only
permitted for specific uses after demonstrations of harmlessness.
Greenpeace,
Health Care Without Harm, and similar advocacy organizations
invoke a regulatory approach often called the precautionary
principle, which presumes that chemicals are likely to cause
harm and must be proven innocent.
Most
U.S. regulatory agencies eschew this approach, and use an approach
similar to the authors of the CPSC study, employing a standard
scientific risk-assessment approach (though still one focused
only on risk and not on benefit). In such a framework, a chemical
might warrant regulatory control if evidence supports the contention
that the chemical is capable of causing harm to human beings
at a relevant level of exposure. Further, most regulatory agencies
(and others favouring "conservatism" in risk assessment)
hold that a chemical which proves harmful in animal testing
is suspected of potential human harm unless exposure levels
are 100 times lower for even the most highly exposed humans.
In the case of phthalates, human exposures for highly exposed
individuals receiving medical treatment do not always meet this
conservative test of safety.
Finally,
analysts such as those authoring the ACSH report take an agency-like
approach to evaluating risk, but may not hold with as high a
degree of conservatism. Further, they tend to invoke a more
holistic view of risk, suggesting that meaningful risk assessments
must consider benefits and potential tradeoffs as well as risks.
But
how is the lay public to choose between the various perspectives
and policy proposals? Making sound policy judgements about issues
like phthalates, climate change, pesticide exposures, the ozone
hole, and so on requires more than just cursory understanding
of the subject.
As
the late policy analyst Aaron Wildavsky demonstrated, formulating
policy without a solid understanding of both the certain and
uncertain elements of a potential risk wastes resources, invites
unintended consequences, and generally makes for policy that
does more harm than good.
This
guide is designed to help policymakers, the media, and the interested
public gain a deeper understanding of the certainties and uncertainties
in our scientific understanding of the risk posed by vinyl plasticizers,
so that they can decide which perspective they feel is most
applicable and useful in the formation of public policy.
INTERPRETING
ANIMAL TEST RESULTS
DEHP
and DINP have been tested on a variety of animals, including
rats, mice, rabbits, monkeys (macaque, marmosets, and rhesus),
dogs, and cats. Studies of phthalate’s cancer-causing
potential were first conducted in the 1950s when long-term exposure
tests were conducted using rats and dogs. The animals were fed
DEHP doses of up to 0.025 percent of their total body weight
for several years. The study found no evidence of increased
tumour growth.
The
current concern that phthalates might be able to cause cancer
stems, in part, from a 1982 study by the National Toxicology
Program. Looking at dose rates nearly four times higher than
the early studies (up to 0.09 percent of body weight), the NTP
study found that some rats and mice developed liver tumours
when exposed to high doses of DEHP over the majority of their
normal life span. Subsequent studies have added substantially
to our understanding of phthalate toxicity.
Before
reviewing the findings of such studies, however, some discussion
of the relevancy and applicability of animal test results to
evaluating health risks to human beings is in order. Gathering
animal-test data is only the beginning of a meaningful process
of assessing risk—many other factors have to be considered,
reflective of the many differences between human beings and
other animals.
A.
Exposure Pathways Often Differ
The
exposure pathway is an important element in understanding the
potential toxicity or cancer-causing activity of a chemical.
In animal studies, different exposure pathways can be used to
illuminate different potential risks and to account for different
biochemical conditions that the chemical might encounter as
it passes through the body. To examine the impacts on the digestive
system, for example, the chemical might be administered by passing
a tube directly into the esophagus or stomach. If one is only
concerned with the impacts of the chemical when directly injected
into the blood stream, the test dose might be injected intravenously.
When
interpreting animal test results, it is also important to consider
whether humans are likely to be exposed to comparable levels
of a chemical through the same pathway that was tested in the
animals studied. The length of exposure also matters, since
short-term impacts are not necessarily related to long-term
effects, and vice verse. Finally, the age of the animal during
testing matters. As Huber, et al. point out, studies of testicular
toxicity in rats, for example, were carried out on immature
rats, which, because they are in a rapid growth phase, are more
susceptible to testicular damage than an adult rat might be.
One can see why it would be problematic to assume that the risk
of testicular damage in a human exposed to a single dose of
DEHP as an adult is comparable to the risk faced by an immature
rat exposed to chronic, high doses of DEHP during development.
B.
Different Levels of Absorption
Simply
assuming that an ingested dose of chemical given to a mouse
or rat is equivalent to the same dose given to a human could
also lead to misunderstanding risk because different animals
process chemicals differently. In rats, for example, 20 percent
of the DEHP put into the digestive tract was found to have passed
right out, even at low doses where saturation could not be a
factor. In marmoset monkeys, absorption was even lower, with
barely half of the DEHP administered absorbed through the intestine.
The human digestive system may absorb even less than marmosets.
Though detailed studies of the excretion of DEHP in humans feces
have not been done, the percentage of administered DEHP and
breakdown products passed out through the kidneys accounted
for only 11 and 31 percent of the original dose. This result
suggests that the remainder (70 to 90 percent) was never taken
into the bloodstream at all. As mentioned above, when painted
on the skin of a rat, 86 percent of the chemical stayed on the
skin and was not absorbed, even after seven days, and tests
suggest that human skin is even less permeable.
When
interpreting animal test results, it is also important to consider
whether humans are likely to be exposed to comparable levels
of a chemical through the same pathway that was tested in the
animals studied.
C.
Different Metabolic Processing
Different
animals breakdown different chemicals differently. In the case
of phthalates, while it is clear that the metabolic pathway
in rats and mice requires more steps than in primates or humans,
it is unclear exactly how that alters the exposure of possibly
sensitive tissues to DEHP, or the main breakdown product, mono(2-ethylhexyl)phthalate,
or MEHP. It is also unknown whether DEHP is the chemical uniquely
responsible for causing the negative symptoms seen in animal
studies, or whether a breakdown product, such as MEHP, is responsible.
This could be important since in primates and humans, for example,
MEHP is formed at much lower levels within the digestive system
than is the case in rats and mice. It also relates back to the
pathway of exposure, in that humans receiving an exposure to
phthalates through, say, a feeding tube would subject the DEHP
to different metabolic processing than they would to DEHP injected
during, say, a dialysis procedure.
D. Different Cancer-causation Mechanisms
Besides
the direct observation of tumour growth, there are other methods
of testing a chemical for cancer-causing potential. One physiological
process that scientists monitor to gauge the cancer-causing
potential of a chemical is called "peroxisome proliferation."
In peroxisome proliferation studies, scientists look for evidence
that certain cell bodies called peroxisomes have developed at
abnormally high levels in liver cells or other suspected sites
of cancer formation. But the peroxisome proliferation ability
of different chemicals differs among different animal species,
and it is uncertain whether peroxisome proliferation is truly
an indicator of cancer-causing potential. The Syrian hamster,
for example, is four times less likely to display peroxisome
proliferation when given the same dose of a known peroxisome
proliferator as a rat or mouse. Dogs and rhesus monkeys are
even less likely to experience peroxisome proliferation when
given chemicals known to cause peroxisome proliferation in rats
and mice. Huber, et al. point out that: "The greater sensitivity
of the rat to peroxisome proliferators such as DEHP suggests
that human risk calculations based exclusively on rat data and
dose might lead to an overestimation of the actual threat."
Huber, et al. also observe that: "These results emphasize
that substances stronger than DEHP by several orders of magnitude
at very high doses, far above those found in risk groups of
DEHP exposure, are required to induce the phenomenon of peroxisome
proliferation in primates, probably including humans."
Most recently, the United Nation’s International Agency
for Research on Cancer changed the classification of DEHP from
a "possible" human carcinogen to "Cannot be classified
as to its carcinogenicity in humans."
Most
recently, the United Nation’s International Agency for
Research on Cancer changed the classification of DEHP from a
"possible" human carcinogen to "Cannot be classified
as to its carcinogenicity in humans."
E.
The Dose Makes the Poison
The
magnitude of the final absorbed dose is critical. The first
law of toxicology is that "the dose makes the poison."
With the exception of extracorporeal oxygenation, a life-saving
procedure used on infants, human exposures to phthalates are
generally orders of magnitude lower than the doses shown to
cause even minor illness in experimental animal subjects.
Much
of the concern over phthalates stems from the level of "conservatism"
that different analysts or regulators believe is the most valid
metric of safety. Most regulatory agencies in the U.S. hold
that a chemical exposure is potentially dangerous unless it
is 100 times lower than the level at which experimental animals
show no observed adverse effects. Others hold that such conservatism
is inherently arbitrary.
Even
in the liver, the body organ most susceptible to chemical impacts,
and even for highly exposed people, the DEHP dose rate is at
least eight fold below the "no effect" threshold for
liver enlargement or other signals of possible cancer-causation.
And the dose rate is over 16 times less than the Low Observed
Effect Level seen to actually produce liver tumours or other
cancer indicators (peroxisome proliferation) in animal tests.
For more moderately exposed people, exposures are thousands
of times lower than the Low Observed Effect Levels seen to produce
liver tumours or other possible cancer indicators.
With
the exception of extracorporeal oxygenation, a life-saving procedure
used on infants, human exposures to phthalates are generally
orders of magnitude lower than the doses shown to cause even
minor illness in experimental animal subjects.
EXPOSURE
DEHP
is a very minor skin or eye irritant when administered topically,
though when injected directly into the skin the evidence for
irritation is contradictory. For humans in occupational settings,
inhalation of mixed phthalate levels at concentrations 1 and
60 milligrams of phthalate per cubic meter of air were observed
to cause irritation to the nose and pharynx. After long exposure
to such an air concentration (two years), there is some evidence
that phthalates cause problems with the neuromuscular system,
mostly in the legs. However, the only studies suggesting this
effect had methodological problems that cast doubt on the validity
of that finding.
DEHP
has tested negative for the ability to cause genetic destruction
or alteration in a number of test systems based on microbes,
mammalian cells, or mammalian cell components. Finally, DEHP
does not seem to trigger allergic responses in humans.
BENEFITS:
THE OTHER SIDE OF RISK
In
the case of medical devices, people are receiving exposures
to DEHP as a by-product of beneficial medical treatment. If
one is concerned about the risk posed by DEHP exposure, a holistic
view of risk would also have to consider the alternatives, and
the prospect for trading one risk (the risk of DEHP exposure)
for another (such as the risk of using an inferior medical device).
As the ACSH study points out, PVC medical products convey many
benefits that alternative products do not. Phthalate-softened
plastics offer benefits such as clarity, strength, flexibility,
kink resistance, compatibility with intravenous solutions, and
cost-effectiveness. Koop, Juberg et al., also point out that
DEHP has a very important preservative effect on stored blood,
reportedly doubling the shelf-life of whole blood and increasing
the stability of red blood cells both when stored and when being
transfused into patients. Another benefit of PVC intravenous
bags is their self-collapsing nature, which eliminates the need
to feed air into the bag in order to get the liquid out. This
reduces the need for air sterilization equipment that is not
only costly but can allow an additional chance of infection
during drug or blood administration.
The
number of Americans currently receiving such benefits is substantial:
In 1996, 31.5 million outpatient surgeries and 40.3 inpatient
surgeries were performed. If phthalate-softened PVC products
are used in only half of all surgeries, nearly one-third of
the population derives a health benefit from them in any given
year.
Whole
blood stored in a PVC bag remains viable for 42 days, compared
to only 21 days for other containers. According to America's
Blood Centers, more than 23 million blood components are made
from about 14 million whole blood donations (stored in PVC bags)
yearly. And that blood supply is fully utilized. Table 12 gives
some examples of blood product use.
In
addition to blood, surgical procedures frequently require the
administration of saline and medicinal solutions via intravenous
delivery, which is both safer and more cost-effective when administered
via PVC bags as compared to alternatives.
Another
use of vinyl where transparency and kink-resistance is important
is in the use of tubing used for long-term chronic oxygen therapy.
For the nearly 800,000 Americans tethered to oxygen tanks or
outlets in their homes, flexible PVC tubing provides a considerable
benefit in terms of lifestyle improvement.
SUMMARY
People
are increasingly concerned about the safety of their food, water,
consumer, and medical products. Groups such as Greenpeace and
Health Care Without Harm have suggested that phthalates, chemicals
used to soften normally-rigid polyvinyl chloride plastics, pose
a threat to human health via exposures through medical and consumer
products, and should be banned.
Yet
as several research groups have shown, few humans, if any, are
exposed—even on a short-term basis—to a dose of
phthalates shown to cause even minor harm in animal tests when
administered over a lifetime. Indeed, with the exception of
short-term, life-saving medical procedures, safety margins for
typical human exposure to phthalates are well over 1000, while
phthalates provide benefits which some have suggested outweigh
the incremental risk posed by exposure to them. With few exceptions,
human exposures stemming from medical procedures are well below
those shown to cause harm in animal tests:
