Toxic Traces:
New Questions About Old Chemicals

by Peter Waldman
Wall Street Journal. (Eastern edition).
New York, N.Y.: Jul 25, 2005. pg. A.1
(See also 7/22/05 WSJ article by Waldman
"Presence of Harmful Chemicals In Humans Is Broad, Common")

[First in a Series]

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.

An especially striking finding: It appears that some substances may

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


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


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.

-- 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.

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


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, John 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.

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. 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


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, Paul Foster of the National

Institute of Environmental Health Sciences. A fourth, Claude Hughes 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, George 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.

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 Andreas 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


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 John Bucher, of the National Institute of Environmental

Health Sciences.

Now he and his boss, Christopher 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."


Exposure Milestones

Scientists have found effects on rodents from steadily smaller

exposures to

some chemicals, such as Bisphenol A, used in food-can linings and

polycarbonate plastic.

Daily dose in milligrams per kilogram of body weight

-- 1988 (EPA's predicted safe dose for humans): 0.05 mg

-- 1997 (Linked to enlarged prostate in male mice): 0.002 mg

-- 1999 (Linked to early puberty in female mice): 0.0024 mg

-- 2003 (Linked to altered sperm in male rats): 0.0002 mg

Source: Scientific articles


In the Laboratory

Studies have linked some common chemicals with toxic effects, though not

necessarily at levels to which humans are exposed:

CHEMICAL: Bisphenol A (BPA)

WHAT IT'S IN: Polycarbonate plastic bottles and food-can linings

WHAT IT'S LINKED TO: Altered brain, behavior and sex organs in rats

CHEMICAL: Dibutyl Phthalate (DBP)

WHAT IT'S IN: Cosmetics, shampoos, pills, nail polish, plastic toys

WHAT IT'S LINKED TO: Gene and hormone changes in rodents; genital

abnormalities in human infants

CHEMICAL: Diethylhexyl Phthalate (DEHP)

WHAT IT'S IN: Polyvinyl chloride building products, food packaging,


medical tubing

WHAT IT'S LINKED TO: Birth defects in mice; pre-term birth in human

infants; early puberty in girls

CHEMICAL: Perchlorate

WHAT IT'S IN: Drinking water in 35 states, fruits, vegetables, breast


WHAT IT'S LINKED TO: Brain and behavior changes in rats; thyroid

effects in


Sources: Scientific articles; U.S. Environmental Protection Agency