[Pharmwaste] Toxic Cocktail
dldebiasi at deq.virginia.gov
Mon Sep 10 10:55:24 EDT 2007
This is interesting, and shows yet again that we need to look at
chemical toxins in more ways than just as an individual chemical.
New Scientist (pg. 44), September 1, 2007
By Bijal Trivedi
Today, and every day, you can expect to be exposed to some 75,000
artificial chemicals. All day long you will be breathing them in,
absorbing them through your skin and swallowing them in your food.
Throughout the night they will seep out of carpets, pillows and
curtains, and drift into your lungs. Living in this chemical soup is an
inescapable side effect of 21st-century living. The question is: is it
doing us any harm?
There are good reasons to think that it might be. Not because of the
action of any one chemical but because of the way the effects of
different components combine once they are inside the body. As evidence
stacks up that this "cocktail effect" is real, regulators around the
world are rethinking the way we measure the effects of synthetic
mixtures on health.
Environmentalists have long warned of this danger, but until recently
there was no solid evidence to confirm their fears -- nor any to allay
them. Most toxicity testing has been done on a chemical-by-chemical
basis, often by exposing rats to a range of concentrations to find the
maximum dose that causes no harm. It's a long way from gauging the
effects of the complex mixtures we experience in everyday life, and that
could be a dangerous omission.
"When you get a prescription the doctor will ask what else you are
taking, because they are concerned about drug interactions, which
everyone knows can be quite devastating," says Shanna Swan, director of
the Center for Reproductive Epidemiology at the University of Rochester
in New York. This also happens with chemicals like pesticides and
endocrine disrupters, she adds. "You have to consider their
interactions, and we are just starting to do that."
To assess the risk posed by such mixtures, a small number of scientists
in Europe and the US are now testing chemical brews on yeast, fish and
rats. The effects could be additive, or they might be synergistic --
that is, greater than the sum of the parts. They could even cancel each
other out. Finding out is important, because we don't have enough data
on many compounds to anticipate how they will interact when mixed. Other
researchers are probing for associations between disease in humans and
past exposure to groups of chemicals.
Andreas Kortenkamp, an environmental toxicologist at the School of
Pharmacy, University of London, and his colleagues developed an interest
in these mixture effects after they noticed a rise in endocrine
disorders, suggesting that the body's hormonal systems may have been
disrupted. In men there were increases in congenital malformations like
hypospadia -- in which the urethra is on the wrong side of the penis --
and cryptorchidism, a condition in which the testes fail to descend into
the scrotum. There was also a rise in testicular cancer and lower sperm
counts. In women there were more breast cancers and polycystic ovaries.
These increases posed a conundrum for the researchers. When they
examined people who had these disorders, and their mothers, they found
they had only very low levels of the chemicals that are known to cause
the disorders; in the lab, only much higher concentrations of these
individual compounds have be found to produce the same effects. This led
Kortenkamp to suspect that mixtures were the missing link. He wondered
if the effects of different chemicals, acting through the same
biochemical pathway, could add up.
Kortenkamp's group focused on groups of chemicals called xenoestrogens,
compounds that disrupt the activity of the hormone oestrogen and induce
the development of female sexual characteristics. High levels of
xenoestrogens in the environment have been shown to feminise male fish,
and have even driven one species in an isolated experimental lake in
Canada almost to extinction.
In 2002 Kortenkamp and his colleagues tested a mix of eight
xenoestrogens on yeast. These included chemicals used as plasticisers,
sunscreen ingredients and others found in cooling and insulating fluids.
In the mixture, each was below the level that toxicologists call the
"no-observed-effect concentration" -- the level that should be safe.
Sure enough, the combination triggered unusual effects in the yeast.
Kortenkamp and his colleagues dubbed the mixture effect "something from
nothing" (see Diagram).
Kortenkamp and his colleagues found that if the doses of all eight
chemicals were simply added together, after adjusting for the varying
potencies, this new cumulative dose could be used to predict the effect
-- a principle called "dose addition". "This result was to be expected,
but it had never been shown with endocrine disrupters until our work,"
says Kortenkamp. Intuitively this makes sense, he says: "Every mixture
component contributes to the effect, no matter how small."
Since then the effect has been shown with other species, too. Kortenkamp
and his colleagues now report that mixtures of xenoestrogens feminised
males to varying degrees even though the individual components should
have been harmless. In July this year the team showed that a blend of
anti-androgens -- chemicals that block the effect of male sex hormones
-- can work in the same way. They exposed pregnant rats to two common
fungicides, vinclozolin and procymidone, and the prostate cancer drug
flutamide, and then screened the male offspring for reproductive
deformities. At higher doses, each of these three chemicals wreaks havoc
with sex hormones, and they all do it via the same mechanism: they
disrupt male development by blocking androgen receptors and so prevent
natural hormones from binding. The researchers found that even when the
chemicals were used in doses that had no effect when given individually
to pregnant rats, a mixture of them disrupted the sexual development of
Earl Gray, an ecotoxicologist at the reproductive toxicology division of
the US Environmental Protection Agency's Health and Environmental
Effects Research Laboratory (HEERL) in Research Triangle, North
Carolina, and his team also tried exposing pregnant rats to vinclozolin
and procymidone. When they exposed the animals to the compounds
individually, they too saw no effect. But when they combined the two,
half of the males were born with hypospadia. Gray calls this phenomenon
"the new math -- zero plus zero equals something".
Gray then tried the same experiment with phthalates -- the ubiquitous
compounds that are used to soften plastics and thicken lotions, and are
found in everything from shampoo to vinyl flooring and flexible medical
tubing. They also disrupt male development, in this case by stopping the
fetus from making testosterone. The mix of two phthalates that Gray used
caused many of the same effects on male rat fetuses as a mixture of
vinclozolin and procymidone.
It makes sense that chemicals targeting the same pathway would have an
additive effect. But what about mixtures of chemicals that work via
different mechanisms? Surely the individual doses of such chemicals
would not be additive in the same way.
"The mixture of different chemicals shouldn't have had any effect. But
it did"In 2004, Gray and his team put this to the test by mixing
procymidone with a phthalate at levels that, on their own, would produce
no effect. Because the chemicals work via different routes, he expected
that the combination wouldn't have any effect either. But they did. Then
the team mixed seven compounds -- with four independent routes of action
-- each at a level that did not produce an effect. "We expected nothing
to happen, but when we give all [the compounds] together, all the
animals are malformed," Gray says. "We disrupted the androgen receptor
signalling pathway by several different mechanisms. It seems the tissue
can't tell the difference and is responding in an additive fashion."
All of this is throwing up problems for regulatory agencies around the
world. Governments generally don't take into account the additive
effects of different chemicals, with the exception of dioxins -- which
accumulate to dangerous levels and disrupt hormones in the body -- and
some pesticides. For the most part, risk assessments are done one
chemical at a time.
Even then, regulation is no simple issue. First you need to know a
chemical's potency, identify which tissues it harms and determine
whether a certain population might be exposed to other chemicals that
might damage the same tissue. Add in the cocktail effect and it gets
harder still. "It is a pretty difficult regulatory scenario," admits
Gray. "At this point the science is easier than implementing the
Mixed up inside
For one thing, with many mixtures it's almost impossible to work out how
much we're getting. The endocrine disrupter diethyl phthalate, for
example, easily escapes from plastics and is in so many different
products -- from toothbrushes to toys, and packaging to cosmetics and
drugs -- that it would be difficult to work out the aggregate exposure
from all sources, says Gray. This also makes it tricky to investigate
possible links between chemical mixtures and disease. "Everyone has
exposure to chemicals, even people living in the Arctic," says John
Sumpter, an ecotoxicologist at Brunel University in London. "We can't go
to a group with a mixture of nasty chemicals and then go to another who
have had no exposure and compare their rate of breast cancer risk or
sperm count. We are doing a scientific experiment by letting these
chemicals accumulate in our bodies, blood and wildlife."
That's why some researchers are suggesting new ways to gauge the effects
of chemical mixtures on the body. For example, rather than trying to
identify levels of individual xenoestrogens in a patient's blood, it may
be more efficient to take a serum sample and determine the "oestrogenic
burden" being imposed on their body from a variety of different sources
by testing the sample on oestrogen-sensitive cells in the lab. "It might
work well as a screening tool to identify people with potential
problems," says Linda Birnbaum, director of the experimental toxicology
division at HEERL. Then, for example, you could make cocktails of foods,
water and other products from the person's life to try to identify the
source of the chemicals.
Nicolas Olea, a doctor and oncologist at the University of Granada,
Spain, is already trying this kind of approach. He is exploring whether
exposure to chemicals with oestrogenic activity leads to genital
malformations like cryptorchidism and hypospadia in men, and breast
cancer in women. He and his colleagues took samples from various tissues
and measured the ability of the environmental contaminants in them to
trigger the proliferation of lab-cultured oestrogen-sensitive cells.
Because it is difficult to predict from a compound's structure whether
it might have oestrogenic effects, a cell-based assay like this is a
cheap way to screen potentially harmful chemicals. They found that the
higher this "total effective xenoestrogen burden" the greater the chance
the contaminants could disrupt oestrogen-dependent processes.
Others are cautiously optimistic about Olea's approach. "The concept is
correct, I cannot comment on how well the cell effect tracks a cancer
effect," says James Pirkle, deputy director of the US Centers for
Disease Control's Environmental Health Laboratory in Atlanta, Georgia.
Shanna Swan is doing something similar. In a study published in 2005 she
showed that boys whose mothers had had higher levels of five phthalates
while their babies were in the womb had a shorter distance between the
anus and genitals -- a marker of feminising activity. They also had
higher rates of cryptorchidism compared to sons of mothers with lower
phthalate levels. Swan devised a cumulative score to reflect exposure
levels to all five phthalates and found that score was "very predictive
of ano-genital distance".
The method is still expensive, and a regular "phthalate scan" isn't on
the cards just yet. A potentially less costly approach, says Pirkle, is
regular biomonitoring of subsets of the population to measure the levels
of dangerous chemicals in blood and urine, and link particular chemicals
to specific health effects. Every two years since 2001, the US Centers
for Disease Control has published data on the US population's exposure
to a range of potentially harmful chemicals. In 2005 the agency released
data for 148 chemicals; next year it plans to release a report covering
275. While that number falls far short of the number of new chemicals
entering the fray each year, Pirkle says that technology is making it
ever easier to monitor new substances. The reports do not consider
specific mixtures but include exposure data for each individual chemical
to make it easier to calculate the likely effects of mixtures.
The European Union, meanwhile, is taking steps to control the number of
chemicals being released in the first place. On 1 June its REACH
(registration, evaluation, authorisation and restriction of chemical
substances) regulations became law. The aim is to cut health risks
associated with everyday chemicals by forcing chemical manufacturers and
importers to register their compounds and provide safety information to
the new European Chemicals Agency, based in Helsinki, Finland. This
information must be provided before the chemicals are sold. The new law
shifts the burden of responsibility for the health effects of chemicals
from government to industry and is also intended to encourage the use of
less harmful alternatives for the more toxic chemicals.
Not everyone is so worried about the cocktail effect. Some researchers
even find it reassuring -- or at least not as bad as it could be. Kevin
Crofton, a neurotoxicologist at the EPA, explored how a mixture of 18
polyhalogenated aromatic hydrocarbons found in electrical equipment,
flame retardants and paints could disrupt thyroid hormone levels in
rats. At the lowest doses of the mixture the effect on the levels of the
thyroid T4 hormone was what you would expect from the principle of dose
addition; at the highest doses the effect was twice that. "Some people
would call that synergy," says Crofton, "but it is not a very big
synergistic effect. It was a twofold difference."
He adds: "These results are quite reassuring because EPA's default to
calculate the cumulative risk of mixtures is dose addition." Only
recently, however, have scientists like Crofton been able to prove that
this default is correct. "If it had been a 20-fold difference I would
have said, 'Boy, the agency needs to look into how it is doing things.'"
Kortenkamp says that regulatory bodies seem to be starting to
acknowledge that chemical-by-chemical risk assessment provides a false
sense of security. In November last year around 100 scientists and EU
policy-makers at the "Weybridge +10" workshop held in Helsinki concluded
that mixture effects must be considered during risk assessment and
regulation. The European Commission plans to spend more on probing the
effects of environmental chemicals on human health.
For now, though, chemicals are an inescapable part of life. And while
high-profile campaigns by pressure groups like WWF seek to alert us to
what they see as the dangers of artificial chemicals, some toxicologists
warn that they may be overstating the case. "I think you need to be
careful about hyping the risk," says Crofton, referring to stories in
which individuals have been screened for several hundred chemicals.
"When you say I have 145 chemicals in my body, that in itself does not
translate into a hazard. You have to know something about the dose, the
hazard and how all these chemicals can add up." Olea, however, suggest
that it is sensible to be cautious. "If you don't know it is good,
assume it is bad," he says.
Like it or not, the chemicals are with us. "People can't keep phthalates
[or other chemicals] out of their air, water or food," says Swan. "Most
people don't have the information or money to do these things." A more
productive approach might be to tell people how to limit exposure to
harmful substances and request better labelling from manufacturers. "We
need to put a lot of money into figuring out what these things do in
real-world scenarios and take regulatory action," she says. "Just like
we limited cigarette smoke exposure, we'll have to limit other
Bijal Trivedi is a freelance science writer based in Washington DC
Copyright Reed Business Information Ltd.
Deborah L. DeBiasi
Email: dldebiasi at deq.virginia.gov
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