20 May 2003 17:00 GMT

by Vicki Brower

A growing body of evidence suggests that early exposure to toxic chemicals in the environment increases risk of subsequent neurological disease, and that children are at particularly high risk for exposure. Yet only relatively few of these chemicals have been tested in animal or human studies.

When such chemicals are tested in humans or animals, they are not tested in multiple exposures and in combination with other chemicals, which confounds true risk assessment, according to experts who met at this month's New York Academy of Medicine meeting. The meeting, "Early Environmental Origins of Neurodegenerative Disease in Later Life" was organized by the Mount Sinai Center for Children's Health and the Environment, the International Longevity Center, and others, with support from the US Environmental Protection Agency and the National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health (NIH).

That children are particularly vulnerable to environmental toxins was only recognized in the US in 1993, when the National Research Council published a report on pesticides in the diets of infants and children, notes Philip Landrigan, professor and chair of the department of community and preventive medicine, and director of the Center for Children's Health and the Environment at Mount Sinai School of Medicine in New York City. Landrigan was instrumental in developing both the report and a 1996 federal pesticide law, which mandates that standards for safe consumption limits for children be set for all pesticides in use. Of about 3,000 currently used, important chemicals, minimal toxicity data are available only on about half. "While we are doing a decent job testing new chemicals that come to market, testing ones that are already on the market is lagging," said Landrigan.

"Much of the current risk assessment being done is based on faulty premises - it reflects the single exposure of an individual at one particular age, and to one chemical," said Landrigan. But this does not reflect the realities of multiple exposures over a lifetime that recent research indicates are often synergistic and cumulatively damaging.

To help broaden the picture of what impact pre- and post-natal exposures to chemicals have in the development of neurodegenerative diseases is the National Children's Study, sponsored by the NIH and initiated two years ago. Still in planning and in need of funding, it is slated to begin field studies in 2005, and will study 100,000 children from before birth through age 21.

Researchers will examine the impact of environmental factors - both positive and negative contributing factors - in child development and health, says Bernard Weiss, professor of environmental medicine at the University of Rochester School of Medicine and Dentistry in New York. Many are comparing it to the Framingham Heart Study, the multi-decade, ongoing study of cardiovascular health of tens of thousands of men and women, with. the hope that it will help fill in current gaps of knowledge about the development of neurodegenerative diseases, which are expected to skyrocket in the next decades.

While not all parts of the brain lose cells with aging, some that do are the same ones that lose cells in Parkinson's disease (PD), said Weiss. "Simple calculations demonstrate that even a minute acceleration of this natural process by environmental exposures can market shift the age distribution of PD toward younger ages." While such a shift might be difficult to detect epidemiologically, the economic consequences would be great, he adds. Methyl mercury poisoning of fetuses in Minimata, Japan in the 1960s from chemical dumping illustrates how in utero toxin exposures may not discernibly affect mothers, but can have deadly effects on offspring.

To better study effects of exposures, more prospective studies need to be conducted, preferably covering subjects from "conception to death," said Ezra Susser, professor and chair, department of epidemiology, at New York City's Columbia University Mailman School of Public Health. The relation of fetal exposures to brain disorders has improved recently, with the utilization of archived prenatal biological specimens from large birth cohorts established in the 1950s and which have been followed into adulthood.

"As they grow, a window is opening up for the first time," said Susser. These cohorts are providing data for midlife brain disorders, and as patients age, they will provide the basis for similar studies of late life brain disorders, Susser said. He discussed new findings from a birth cohort in Oakland, California where specific prenatal exposures have been measured in archived maternal sera and related to schizophrenia risk. Risk factors of infection, nutrition, hormones, and chemical exposures correlated with the disease, and a second study from Boston found patients with the disease had twice the lead exposure as controls.

"Exposures to environmental contaminants may serve, not as root causes, but simply as factors that hasten the progression of nervous system changes associated with aging," said Weiss. While not all the same parts of the brain lose cells with aging, some of the brain structures that do are also the structures that lose cells in PD, Weiss adds.

"Simple calculations demonstrate that even a minute acceleration of this natural process by environmental exposures can markedly shift the age distribution of PD patients toward younger ages," he said. "Such a shift would be difficult to discern epidemiologically, but its economic consequences would be considerable."

Family studies have shown that only a very small percentage of PD and Alzheimer's disease (AD) can be ascribed to genetic causes. Researchers believe that neurodegenerative diseases such as PD, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) are multigenic, complex disorders that are about 25-30% of genetic origin and 70% behavioral or environmental.

Deborah Cory-Slechta, chair of the department of environmental medicine at the University of Rochester, has found that the herbicide paraquat (PQ) and fungicide maneb (MB) kills cells in the brain's nigrostriatal region alone, but, when combined, potentiate these effects, producing a PD phenotype in adult mice that could be further exacerbated by aging and genetic background.

In new research, she examined developmental (postnatal) exposure to see if it could permanently damage the dopaminergic (DA) system and enhance vulnerability to pesticide challenges later in life. She treated mice with saline, PQ, MB or PQ and MB. As adults, the mice were rechallenged twice a week for three weeks. Postnatal exposures only to each pesticide resulted in losses of dopamine and diminished numbers of nigral DA neurons, which were exacerbated by combined exposure to PQ and MB that was progressive over time. Cory-Slechta saw similar but more severe changes in mice developmentally exposed and then rechallenged with pesticides as adults: losses of DA neurons reached 67%. She then looked at gestational exposure to MB, and rechallenged adults with MB or PQ, which resulted in the most significant PD phenotype - a loss of motor function.

"Silent, early toxicities were unmasked with later challenges," she said. Early studies of the damage of lead exposure to children's IQ and behavior are strong evidence for the need to fund studies like this on the impact of environmental exposures in children in order to prevent future damage, concluded Landrigan.