U.S. children diagnosed with behavior and psychiatric problems increasingly receive more than one medication despite very little proof that many of the drugs are safe or effective for kids, suggests a research review out Monday.

“We don't know how these drugs may interact with each other, and we don't even have safety studies in children for many of the drugs on their own,” says child psychiatrist Joseph Penn of Brown University Medical School and Bradley Hospital in Providence, R.I.

He and co-author Henrietta Leonard searched the Pub Med database, covering published scientific research, for all studies on children's psychiatric “polypharmacy” use between 1994 and 2004. Their report is in the journal Psychiatry 2005.

They found only six studies. Updates over time showed soaring use of multiple medicines with kids.

For example, a survey of primary care doctors giving children stimulants, commonly prescribed for attention deficit/hyperactivity disorder (ADHD), found multiple psychiatric medicines prescribed in about 5% of office visits during 1993-94. That surged to 25% of visits in 1997-98. Another study on privately insured kids found that 3% given psychiatric drugs got more than one in 1987. It was up to 23% in 1996.

Doctors are using more medications for several reasons, says Penn:

•Drug companies are marketing their products more aggressively to consumers and doctors. “Many parents come in and want that ‘quick fix.' ”

•One drug often causes side effects; since more medications than ever are available, kids get another drug to deal with these side effects. For example, stimulants may cause insomnia, which leads to prescribing sleeping pills.

•Insurers often are more willing to pay for pills than for therapy.

“Doctors are doing this polypharmacy stuff all the time with kids,” says Penn, “but when you look for the research, there is none.”

A newer class of medicines called “atypical antipsychotics” are increasingly combined with other drugs, he says. They're used for kids with bipolar disorder (manic-depression) or severe temper problems. These drugs — Abilify, Seroquel and Risperdal — are approved for adult psychosis, “and we just don't know if they're safe for kids,” Penn says.

However, there is “lots of shared anecdotal experience between doctors saying it's OK to use more than one drug with children and adolescents,” says Lawrence Diller, a Walnut Creek, Calif., behavioral pediatrician.

And “sometimes you have to have different treatments to stabilize a child,” adds Boris Birmaher, a University of Pittsburgh psychiatrist who specializes in childhood bipolar disorder. “We wish one medication would take away their symptoms, but it doesn't always happen.”

Many kids with ADHD have other problems, such as depression, and they may need multiple medicines, he says.

There's not much profit incentive for drug companies to do research on multiple psychiatric medicines with kids, so more studies are unlikely, Diller believes. “Every doctor weighs the degree of symptoms against possible side effects of drugs. But in the absence of science, we're all guessers.”

Like the glint of a knife in the dark, a laboratory accident in 1998 helped scientists realize that some chemicals commonly used to make life more convenient can be health hazards.

Since what they still call “the disaster” in geneticist Pat Hunt's lab, more scientists have come to suspect that, even in tiny amounts, some of the chemicals that keep our food fresh, our hair stylish, our floors shiny and our fabrics stain-free might be confusing our hormone systems and derailing fetal development.

Hunt says she's not the only researcher who has come to study these chemicals — called endocrine disruptors — because she got “smacked in the face” by an unexpected result. “Almost everybody in this field was drafted into this, but we feel we can't leave this area, because if this stuff is dangerous, then we need to know a whole lot more about it.”

Here's what happened seven years ago at Hunt's lab at Case Western Reserve University in Cleveland:

While researching why women miscarry because of chromosomal abnormalities in the fetus, Hunt found that the eggs of the mice she was studying were inexplicably developing serious chromosomal problems.

It took months for Hunt to realize that the problem was caused by a temporary employee's error. “He had two bottles of detergent, one for the floor and one for the cages, and he picked up the wrong one.”

The harsh alkaline floor detergent caused the plastic in the cages to begin to disintegrate, which leached a chemical called bisphenol A into the animals' food and water. Suddenly, 40% of the eggs had chromosomal abnormalities.

The question this posed for scientists: If plastic can do this to mice, what dangers do people face?

You can't see them. There's no way to tell from a product label whether they've been used. And they don't appear in every variation of the same kind of product. Scientists are not always sure how they are transmitted from product to person.

These man-made chemicals are endocrine mimics. By sheer chance, their molecules are perfectly shaped to form keys that open the hormonal locks that control the proper development and function of our bodies.

They may do little harm to adults, but evidence mounts that they can wreak havoc in the development of fetuses and children:

•Ana Soto, a professor of cell biology at Tufts University School of Medicine in Boston, found that exposure to bisphenol A, a common ingredient in plastics such as reusable water bottles and the housing of laptop computers and in resins that line some food cans and dental sealants, can change the course of fetal development. Fetal mice developed tissue associated with higher rates of breast cancer later in life. Soto's findings were presented in San Diego this summer at the yearly meeting of the Endocrine Society, the largest professional organization of endocrinologists.

•Exposure to phthalates (pronounced THAL-ates) comes from direct contact with products that contain them, such as vinyl flooring, detergents, automotive plastics, soap, shampoo, deodorants, fragrances, hair spray, nail polish, plastic bags, food packaging, garden hoses, inflatable toys, blood-storage bags and intravenous medical tubing, according to the Centers for Disease Control and Prevention.

Research published in the journal Environmental Health Perspectives by epidemiologist Shanna Swan at the University of Rochester in New York found an association between higher phthalate levels in pregnant women and changes in the genitals in their infant sons that suggest lower concentrations of male hormones and can lead to incomplete testicular descent.

Jim Pirkle, deputy director for science at the CDC's Environmental Health Laboratory, says that while more research must be done to replicate Swan's findings, “The big concern of the phthalates is that they have anti-androgen activity. They get rid of things that are in the testosterone line, the things that make a man a man.”

•In a separate study, Harvard and CDC researchers found that boys in neonatal intensive care units had phthalate levels about 25 times higher than the general population. This is two years after the Food and Drug Administration warned hospitals that phthalate leaching out of plastics used in medical devices carries such a health risk to baby boys that those devices shouldn't be used on babies or on pregnant women carrying male fetuses.

•Perfluorooctanoic acid (PFOA) is a building block of chemicals used to make stain-, grease- and water-resistant coatings such as Teflon and Gore-Tex. An Environmental Protection Agency scientific advisory panel recently concluded PFOA is a likely carcinogen with liver, breast, pancreatic and testicular cancer of specific concern. The EPA has not yet adopted the finding and has not set acceptable limits.

• A study released last month by the U.S. Geological Survey and the City of Austin found that runoff from parking lot sealant, used to protect and beautify asphalt, is a source of polycyclic aromatic hydrocarbons known to be a likely carcinogen and a possible reproductive toxicant.

•Research published by Michael Skinner, director of the Center for Reproductive Biology at Washington State University, showed that exposure of rodents to an insecticide called methoxychlor and a fungicide called vinclozolin, both endocrine disruptors, caused changes in mice that affected not just the offspring exposed to the chemical in utero but all males born for at least four subsequent generations.

“If an environmental toxin can cause a transgenerational effect and affect your grandchild, this is a much more major hazard we need to consider in environmental toxins,” Skinner says.

Although these chemicals have been widely used since the 1960s, it has been only in the past five or so years that scientists have had tests sensitive enough to measure the extremely low doses present in the environment and our bodies. And they have found that phthalates and PFOA are ubiquitous.

In random sampling of participants in a national health survey, the CDC has found trace amounts of phthalates in all urine tested. In January, the Environmental Protection Agency reported that adults tested in three human biomonitoring studies had trace amounts of PFOA in their bloodstream.

“Certainly, we're concerned about what's happening to adults, but we're especially concerned about developmental exposure of the fetus and young child,” Retha Newbold, a developmental endocrinologist at the National Institute of Environmental Health Sciences, told the Endocrine Society.

“Protective mechanisms that are available to the adult, such as DNA repair, the immune system, detoxification enzymes, liver metabolism and the blood/brain barrier, are not fully functional in the fetus or newborn,” Newbold says. “Exposures to endocrine-disrupting chemicals during critical states of development may have permanent consequences, some of which may not be expressed or detected until later in life.”

But chemical producers say researchers aren't coming up with “smoking guns,” in the words of Sarah Brozena, assistant general counsel to the American Chemistry Council, an industry group. “The International Union of Pure and Applied Chemistry did this pretty comprehensive review and decided there was no evidence of humans being adversely impacted by environmental exposures to endocrine-active substances,” she says.

The past three years have seen significant advances in “epidemiological evidence and the development of animal models” to help understand how endocrine disruptors work, says Kenneth Korach, director of the Environmental Disease and Medicine Program at the National Institute of Environmental Health Sciences.

The means of exposure to endocrine disruptors can be difficult to determine. “It's not like smoking was,” says Swan, who did the phthalates research. “They're all around us, in food, in household dust and in products, but they're invisible.

“People don't know when they're exposed. Our old epidemiological tools — interviews, looking at medical records and questionnaires — are useless. We have to look at the body. But it's expensive and hard to get people to give blood.”

And if figuring out what a tiny amount of one chemical does is hard, researchers say they have almost no idea what happens when many chemicals interact. “Nobody's exposed to one thing,” Korach says. “The problem is we haven't done enough yet to look at combinations.”

Of course, each of these studies is only one small piece in a much larger puzzle that still must be filled out, says Earl Gray, a senior research biologist with EPA's endocrinology branch. “There are things that we know for sure,” he says. “It's obvious and has been for a long time that there are effects in wildlife due to endocrine-disrupting chemicals.”

In humans, the evidence isn't clear-cut: “A single study doesn't create a disaster; it's a hypothesis that needs to be replicated.”

Others wonder why compounds are turning up harmful in some studies, while “every test we've ever done in the past says they're inactive,” says James Lamb of scientific and engineering consulting firm Blasland, Bouck & Lee Inc.

“These things raise questions that need to be addressed by industry and government,” Lamb says. “I'd hate for people to come away feeling like they're in danger if they use these products.”

Environmental groups and researchers maintain that it's possible to have modern conveniences without all the health risks.

They note that the government has been able to eradicate other chemical dangers. “We've seen lead levels dramatically decline in kids, PCB (polychlorinated biphenyl) levels decline, all because of direct government intervention that gets these out of the environment,” says Jane Houlihan, a scientist with the Environmental Working Group.

The EPA says it's working on that.

The agency's Office of Pollution Prevention and Toxics has been exploring “green chemistry” options — a fundamental approach to pollution prevention on a molecular level — for 10 years now.

If the chemicals that make plastics soft are endocrine disruptors, chemists now have the ability to design them without that side effect. It just takes convincing industry that the result is going to be cheaper in the long run, says Mary Ellen Weber, director of the EPA's pollutions and toxics research group. “When you can replace a known toxic chemical with sugar or cornstarch or sunlight, you know you've got an environmentally preferable product.”