Industrial Toxins and Levels of Risk - Wall Street Journal

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Levels of Risk

Common Industrial Chemicals

In Tiny Doses Raise Health Issue

Advanced Tests Often Detect

Subtle Biological Effects;

Are Standards Too Lax?

Getting in Way of Hormones

By PETER WALDMAN

Staff Reporter of THE WALL STREET JOURNAL

July 25, 2005; Page A1

For years, scientists have struggled to explain rising rates of some

cancers and childhood brain disorders. Something about modern living

has driven a steady rise of certain maladies, from breast and

prostate cancer to autism and learning disabilities.

One suspect now is drawing intense scrutiny: the prevalence in the

environment of certain industrial chemicals at extremely low levels.

A growing body of animal research suggests to some scientists that

even minute traces of some chemicals, always assumed to be

biologically insignificant, can affect such processes as gene

activation and the brain development of newborns.

FIRST IN A SERIES

An especially striking finding: It appears that some substances may

have effects at the very lowest exposures that are absent at higher

levels.

Some scientists, many of them in industry, dismiss such concerns.

But the new science of low-dose exposure is challenging centuries of

accepted wisdom about toxic substances and rattling the foundation

of environmental law.

Modern pollution restrictions aim to limit exposures to levels past

studies have found safe. For example, it's known mercury can cause

learning problems in children if it's above 58 parts per billion in

the bloodstream. Dividing 58 by 10 to provide a margin of safety,

U.S. regulators advise that children and young women not accumulate

more than 5.8 parts per billion of mercury, by limiting consumption

of certain fish such as tuna.

But what if it turned out some common substances have essentially no

safe exposure levels at all? That was ultimately what the U.S.

Environmental Protection Agency concluded about lead after studying

its effects on children for decades. Indications some other

chemicals may have no safe limits have led regulators in Europe and

Japan to bar the use of certain compounds in toys and in objects

used to serve food. In the U.S., federal scientists are devising new

tests that could be used to screen thousands of common chemicals to

make sure they're safe at extremely low exposures.

Using advanced lab techniques, scientists have found that with some

chemicals, traces as minute as mere parts per trillion have

biological effects. That's one-millionth of the smallest traces even

measurable three decades ago, when many of today's environmental

laws were written. With some of these chemicals, such trace levels

exist in the blood and urine of the general population.

Some chemical traces appear to have greater effects in combination

than singly, another challenge to traditional toxicology, which

tests things individually.

EXPOSURE MILESTONES

• See an illustration of research findings on the effects of

bisphenol A contrasted with EPA guidelines.

The human body is complex, and effects seen in tests on small

laboratory animals and in human cells don't necessarily mean health

risks to people. " The question is what do we do about these low

levels once we know they're there, " says Steve Hentges of the

American Plastics Council, a trade association.

For their part, companies and industry groups have attacked low-dose

research as alarmist and are challenging the findings with

scientific studies of their own. Some industry studies have

contradicted the low-dose findings of university and government

labs. One reason, says Rochelle Tyl, a toxicologist who does rodent

studies on contract for industry groups, is that academics seek " to

find out if a chemical has an intrinsic capacity to do harm, " while

industry scientists try to measure actual dangers to people.

The result is that low-dose research has sparked a number of heated

scientific and regulatory controversies:

• Tiny doses of bisphenol A, which is used in polycarbonate plastic

baby bottles and in resins that line food cans, have been found to

alter brain structure, neurochemistry, behavior, reproduction and

immune response in animals. Makers and users of the chemical

maintain, citing a Harvard review of 19 studies, that the chemical

is harmless to humans at such levels. (See illustration)

• Minute levels of phthalates, which are used in toys, building

materials, drug capsules, cosmetics and perfumes, have been

statistically linked to sperm damage in men and genital changes,

asthma and allergies in children. The U.S. Centers for Disease

Control and Prevention has detected comparable levels in Americans'

urine. Manufacturers say there is no reliable evidence that

phthalates cause any health problems.

• A chemical used in munitions, called perchlorate, is known to

inhibit production of thyroid hormone, which children need for brain

development. The chemical has been detected in drinking-water

supplies in 35 states, as well as in fruits, vegetables and breast

milk. The EPA has spent years mulling what is a safe level in

drinking water. The Defense Department and weapons makers maintain

it is harmless at much higher doses than those that Americans ingest.

• The weed killer atrazine has been linked to sexual malformations

in frogs that were exposed to water containing just 1/30th as much

atrazine as the EPA regards as safe in human drinking water. The

herbicide's main manufacturer, Syngenta AG, says other studies prove

atrazine is safe. The EPA favors more study.

With so much still unknown, regulators are proceeding on different

tracks in different countries. Japan's government designates about

70 chemicals as potential " endocrine disruptors " -- substances that

may, at tiny doses, interfere with hormonal signals that regulate

human organ development, metabolism and other functions. Japan has

just completed a $135 million research push on endocrine disruptors,

including setting up a national research center. The Japanese

government also has banned certain phthalates in food handlers'

gloves and containers, after detecting them in food. One

manufacturer, Fujitsu Ltd., has pledged to phase out its use of most

suspected endocrine disruptors over coming years.

The European Union has banned some kinds of phthalates in cosmetics

and toys, and it is considering a ban on nearly all phthalates in

household goods and medical devices. The EU also is planning to

require new safety tests for thousands of industrial chemicals, many

of which already exist in people's bodies at trace levels. Industry,

which would have to bear the cost of proving countless current

products safe, is fighting the measures, calling them a massive

unnecessary burden.

In the U.S., there are divisions within the government. The White

House plays down the issue, saying the low-dose hypothesis is

unproved. But many federal scientists and regulators at the EPA and

Health and Human Services Department are forging ahead with new

methods for assessing possible low-dose dangers. Legislatures in two

states, California and New York, are considering bills that would

ban use of certain phthalates in toys, child-care products and

cosmetics, while a California bill would restrict bisphenol A.

Earliest Concerns

One of the early scientists to focus on possible low-dose risks was

biologist Theo Colborn of the World Wildlife Fund. Studying the

decline of certain birds, mammals and fish in the upper Midwest, Dr.

Colborn spotted some patterns: Species that struggled to survive in

the industrialized Great Lakes thrived in inland areas that were

less polluted. And some offspring in more-polluted regions had

gender abnormalities, such as feminized sex organs in males. She

theorized that trace amounts of chemicals in the environment were

disrupting hormones.

Dr. Colborn and colleagues popularized low-dose concerns in a series

of conferences, articles and a best-selling 1996 book called " Our

Stolen Future. " That year the EPA asked an outside advisory panel to

consider ways of screening industrial chemicals for hormonal

effects, a process still incomplete.

In 2000, a separate EPA-organized panel, after reviewing 49 studies,

said some hormonally active chemicals affect animals at doses as low

as the " background levels " to which the general human population is

subject. The panel said the health implications weren't clear but

urged the EPA to revisit its regulatory procedures to make sure such

chemicals are tested in animals at appropriately small doses.

The EPA hesitated. It responded in 2002 that " until there is an

improved scientific understanding of the low-dose hypothesis, EPA

believes that it would be premature to require routine testing of

substances for low-dose effects. "

The Bush administration's regulatory czar, Graham --

administrator of the Office of Information and Regulatory Affairs at

the White House Office of Management and Budget -- later publicly

dismissed as unproven the idea that the hormonal system could be

disrupted by multiple low-dose exposures to industrial chemicals.

For the past two years, the administration has proposed funding cuts

for EPA research on suspected endocrine disrupters, but Congress has

kept the funding roughly level at about $10 million a year.

Since the review panel met in 2000, scientists have published more

than 100 peer-reviewed articles reporting further low-dose effects

in living animals and in human cells. These findings are generating

some early insights in the thorny process of translating laboratory

data into conclusions about human health.

Less Is More

One of the most provocative is that some hormonally active chemicals

seem to have more effects at extremely low exposures than at higher

ones. This challenges an axiom of toxicology stated by the Swiss

chemist Paracelsus nearly 500 years ago: The dose makes the poison.

Toxicologists traditionally derive risk by exposing rodents to

chemicals to find the lowest dose that leads to tumors, birth

defects or other readily observable effects. Regulators then divide

the highest " no-observable-effect " dose by an " uncertainty factor " --

anywhere from 10 to 1,000 -- to set a maximum human exposure they

can be confident is safe.

But now researchers have found chemicals that have hormonal effects

on lab animals and on human cells in much tinier amounts than their

standard no-observable-effect levels. And with some of these

chemicals, as the tiny doses given to animals are increased, the

effects recede. Then, at much higher levels, broad systemic impacts

appear, such as reduced body weight.

An example is bisphenol A, or BPA, the ingredient in polycarbonate

baby bottles and food-can linings. It evidently is widespread in the

environment. In the U.S., the CDC has found traces of it in 95% of

urine samples tested. In Japan, researchers have detected BPA in

fetal amniotic fluid and the umbilical cords of newborns.

Studying BPA in rats in 1988, the EPA concluded the lowest exposure

with an " observed adverse effect " was 50 milligrams a day per

kilogram of body weight (one kilogram = 2.2 pounds). Dividing 50 by

an uncertainty factor of 1,000, the agency set a daily safe limit

for humans of 0.05 milligrams of BPA per kilogram of body weight.

Since then, however, academic scientists in several countries have

done more than 90 studies that have found BPA effects on animals and

human cell cultures from exposures well below this level.

The EPA used a relatively crude measure of the chemical's effects:

changes in rodents' body weights. The new studies looked at subtler,

hormone-related effects. Some studies found changes in rodents'

reproductive organs and brains at doses as low as 0.002 milligram

per kilogram of body weight per day. That is just one-25,000th the

dose that the EPA said was the lowest exposure having an observable

adverse effect.

Disrupting Hormones

Seeking to explain this pattern, scientists cite the endocrine

system's exquisite sensitivity. Animals and humans secrete

infinitesimal amounts of various hormones, such as estrogen, that

trigger responses when they occupy special receptors on the cells of

various organs. BPA is among numerous chemicals that can mimic

estrogen by occupying cells' estrogen receptors. When they do this

at critical phases of development, the chemicals can trigger

unnatural biological responses, such as brain and reproductive

abnormalities.

At higher doses, however, BPA and other endocrine disruptors --

instead of triggering the unnatural responses -- appear to overwhelm

the receptors. That explains, scientists say, why some chemicals

seem to have more potent hormonal effects at very low doses than at

higher ones.

Mr. Hentges of the American Plastics Council says studies show BPA

is harmless at the tiny levels to which humans are exposed. In 2001

the plastics council agreed to pay Harvard's Center for Risk

Analysis, part of the Harvard School of Public Health, $600,000 to

review BPA studies. The 10 panelists found " no consistent

affirmative evidence of low-dose BPA effects " on the basis of 19

studies that were selected by April 2002 for review.

However, many more BPA studies kept coming out, and when the center

published its report last fall, three of the 10 panelists declined

to be listed as authors. " There are other papers published after

the 'cut-off' date that the panel did not review that may have

altered their conclusions, " says one of the three, of

the National Institute of Environmental Health Sciences. A fourth,

Claude of Quintiles Transnational Corp., a pharmaceutical

consulting firm, signed but made the same point in a journal

commentary criticizing the report and calling for a new EPA risk

assessment. The Harvard risk center's executive director,

Gray, acknowledges that a " torrent of new papers on BPA " may have

made it impossible for the panel to review everything by its

deadline.

The plastics council's Mr. Hentges says his group reviews all

studies on BPA and believes none have changed the basic conclusion

of the Harvard report. " We continue to believe that the weight of

evidence indicates BPA poses no risk to human health, " he says.

Chemicals in Combination

Environmental chemicals don't exist in isolation. People are exposed

to many different ones in trace amounts. So scientists at the

University of London checked a mixture. They tested the hormonal

strength of a blend of 11 common chemicals that can mimic estrogen.

Alone, each was very weak. But when scientists mixed low doses of

all 11 in a solution with natural estrogen -- thus simulating the

chemical cocktail that's inside the human body today -- they found

the hormonal strength of natural estrogen was doubled. Such an

effect inside the body could disrupt hormonal action.

" In isolation, the contribution of individual [estrogen-like

chemicals] at the concentrations found in wildlife and human tissues

will always be small, " wrote the scientists, led by s

Kortenkamp, who directs research on endocrine disruptors for the EU.

But because such compounds are so widespread in the environment, the

researchers concluded, the cumulative effect on the human endocrine

system is " likely to be very large. "

To test chemicals, toxicologists traditionally dose animals with a

single substance and then dissect them. But this method can't spot

the subtle effects associated with today's multiple exposures to low-

dose chemicals, says Bucher, of the National Institute of

Environmental Health Sciences.

Now he and his boss, Portier, are revamping the federal

government's National Toxicology Program, which sets standards for

how chemicals are tested. Over about seven years, they hope to

develop a series of lab tests that will ultimately screen some

100,000 industrial compounds, individually and in mixtures, for

biochemical " markers " such as effects on specific genes.

The chemicals then will be ranked by mechanism of action and

suspected toxicity, and assigned priorities for further study. " It's

taken us 25 years and $2 billion to study 900 chemicals, " Dr.

Portier says. " If this works, we can study 15,000 in a year. "

Write to Waldman at peter.waldman@...