Chemical regulation and kids: In search of a better fit.

Regulationx t is human nature to want to protect our children from harm. Toys, car seats, sports equipment-all are designed with a child's safety in mind. Those same children, however, have been often overlooked in two critical research areas: the effects of exposure to chemicals and guidelines for prescription medications. Environmental exposure standards have usually been set according to research on adults, and prescription medications are primarily designed for grown-ups as well. This has led to a shortage of concrete information on how children's developing bodies respond to potential hazards in their environment and to the; drugs they may take. "The single most important point I would liketo make is that children are not little adults," said E. RamonaTovt ddirector of

Spheres of Influence * Chemical Requlation and Kids~I n Search of a Better Fit the Office of Children's Health Protection of the U.S. Environmental Protection Agency (EPA), before a congressilonal subcommittee in May. In order to learn more about children's health needs with respect to their environments, she added, "we [the EPA] support and encourage extensive, coordinated research to establish the scientific basis for our risk assessments and regulatory decision making." From the womb to the schoolyard, children may be exposed to a wide array of environmental health contaminants, including chemicals, lead, pesticides, fertilizers, ozone, and asbestos. Their young metabolisms affect how they may absorb, metabolize, ,-excr,ete, and res o psychotropic drugs, anesthesia, and medica-!ipF9 Protctio AS such as asthma, epilepsy, severe pain, gastroin-Fm them s, and allergic reactions. Because children are often Environmental Health Perspectives * VOLUME 108 1 NUMBER 6 1 June 2000~1 ---~~~.
Spheres of Influence * Chemical Regulation and Kids overlooked in clinical trials, many are pi scribed such drugs off-label, meaning thi receive treatments that were not design for that particular use or age grou Although the practice is not illegal, litt is known about the efficacy and safety drugs used in this way. "At one time, it wasn't considered eth cal to study children in clinical tria because children can't really give inform( consent. They can't really understand tl risks and benefits of participating in trial," says Dianne Murphy, associa director for pediatrics at the Center f Drug Evaluation and Research of the U. Food and Drug Administration (FDA). There were also technical problems, she says, one of which was the relatively large volume of blood samples frequently needed for trials, which were difficult to obtain from children because of the discomfort such tests can cause. For these and other reasons, children have seldom been enrolled in either chemical research studies or pharmaceutical drug development trials.

Filling the Data Gap
Per pound of weight, children drink more water, eat more food, and breathe more air than adults, potentially placing them at greater risk for adverse effects from environmental exposures, says William Farland, dire tor of the EPA National Center f, Environmental Assessment. "We al know that they have windows of vulner bility," he says, meaning that there a periods in a child's earliest development which any damage that may occur c; have lifelong effects.
In April 1998, Vice President Al Ge called for the EPA "to review and repc on what new testing may be needed assess the special impact industrial chen cals may have on children." In Augu 1999, the EPA announced its plans develop a Voluntary Children's Chemic Evaluation Program, which would evalua chemicals with children's health concerr Once appropriate chemicals are identifi as having potential negative effects on ch dren, chemical producers will be asked voluntarily conduct any tests that mig confirm such suspicions. what kids are actually exposed lives. It will be very hard to get ndle on why they get diseases if know what they interact with." ern has been growing about the lence of pesticides and other micals that children are exposed o in a variety of ways, at home, via their toys, and in the schoolyard. Chemicals used near schools to control everything from bumblebees to mold include pesticides such as organophosphates, chlorpyrifos, and synthetic pyrethroids. Certain children's toys are manufactured with chemical plasticizers called phthalates that have been linked to adverse health effects such as liver and kidney damage and testicular problems. And many, if not most, of these hemicals are used with little ierstanding of their potential Dn children's health. tionally data have come from on animals in which the results ctrapolated to humans. Although pesticide registrations require ntal toxicity studies and generaoduction studies that are used to xtential pre-and postnatal toxicolating from animal bioassays is ect method. For example, says dman, an adjunct professor in rtment of Health Policy and nt at the Johns Hopkins School ne and Public Health in ,Maryland, "Prenatal and perihie times when cells are rapidly d differentiating. We know that dhood cancers are of primitive . If you wait to test, you miss ere immune and metabolic sysmmature. Moreover, if genetic occur, they can become perma-*esult in increased cancer risk in euticals data on children has challenged aceutical industry as well. In the VOLUME 108 1 NUMBER 6 1 June 2000 * Environmental Health Perspectives z001, A 270 Spheres of Influence * Chemical Regulation and Kids late 1970s, the American Academy of Pediatrics called for companies to perform clinical trials for children so that medications would feature labels that described dosing, usage, contraindications, and other warnings related specifically to children. The academy argued that it would be more ethical to include children in clinical trials than to continue uncontrolled experimenting on them by giving them off-label drugs. Without proper guidelines, pediatricians are forced to estimate dosing regimens.
"In general, two-thirds to three-quarters of the prescriptions pediatricians write for patients are off-label," says Murphy. "But you can't tell them that they can't prescribe off-label because you would cut off care to kids who need treatment. We don't want to deny access to children who need these therapies." In 1994, the FDA published a rule requiring pharmaceutical companies to submit any available information on their products' potential use by children so that the labels could be updated. The response was disappointing, according to Murphy. Few companies had ever run clinical trials on r children around the United States. "Controlled clinical studies to evaluate the efficacy and safety of psychotropic medications for preschoolers are rare," they report. "Because children's responses to medications are not necessarily similar to those of adults, systematic and careful outcome research specifically needs to be done for them." The report continues, "[T]he possibility of adverse effects on the developing brain cannot be ruled out. Active surveillance mechanisms for ascertaining subtle changes that the developing personality may undergo as a result of a psychotropic drug's impact on brain neurotransmitters should be developed." In March, the Clinton administration initiated a campaign to address the issue of the increase in the use of such medications by very young children. ization Act in 1997, which brain cannot be ruled oL allowed pharmaceutical companies to obtain six more months of market exclusivity for a product if they would conduct pediatric drug trials. We've had a -JAMA, 23 February 2000 tremendous response to that." One of the higher-profile medications used off-label today is Ritalin, a stimulant effort, the FDA plans to develop new pedi designed to treat attention disorders. atric drug labeling information for psy Ritalin has been tested and approved for chotropic drugs used in young childrer use in children six years old and above. Ir drugs in pediatric wards throughout Europe. In response to concern about the lack of information on the actual effects of such medications, the European Union (EU) is developing guidance on the clinical ,, * * * investigation of medicinal products in children that encourages pharmaceutical companies to test new prodping ucts in children when clinically appropriate. The EU also approved an emergency ban on certain plastic baby toys in December 1999. The EU feared that the phthalates used to soften the toys could harm babies by leaching out when infants teethe or suck on them.
It is clear that children in the United States and abroad are increasingly finding themselves in an environmental health research and drug development category of their own. Widespread pesticide use in the schoolyard, for example, and the growing use of psychotropic drugs in very young populations provide just a few compelling reasons for increasing the focus on testing chemicals for their impact on children's health. But the questions remain of who should do the testing and how it should be carried out.

Rebecca Clay
A 271 Environmental Health Perspectives * VOLUME 1081 NUMBER 61 June 2000