Everyday substances that may cause birth defects
by Judy Bolyard Purdy
Would-be parents worldwide share the same hope: to have normal, healthy babies.
But women may be exposed to things during - or even before - pregnancy that can put their unborn babies at risk.
Which substances are toxic, and how much exposure is too much?
To help determine safe dosage levels and develop better risk assessments, Smith studies a variety of everyday substances that may induce birth defects. The toxicologist's research spans chemicals in household and industrial products, such as paints and varnishes; heavy metals that contaminate the environment, like mercury and lead; and even the bacterium Listeria monocytogenes, which occasionally slips into processed foods, such as hot dogs and soft cheeses.
For example, Thalidomide, a prescription for morning sickness, may have caused as many as 8,000 -10,000 birth defects and miscarriages worldwide from 1956 to 1962. Culprits also include other medications like retinoic acid found in the acne prescription Accutane, viruses like those that cause German measles and cat scratch fever, and environmental contaminants like chemical solvents.
"Increasingly, working women who get pregnant are staying on the job, and in some cases that could pose a potential hazard to the unborn child," Smith said.
But exposure doesn't necessarily spell birth defect. It depends on several factors, including the amount and duration of exposure and the fetus' stage of development.
"I am trying to develop methods to better predict risk because this may help us prevent birth defects," said Smith, who has garnered research funding from the U.S. Air Force, the Food and Drug Administration and the National Institute for Occupational Safety and Health.
Her studies already are painting a clearer picture of how toxic substances might interfere with early human growth and development, particularly the early stages of cartilage development, which sets the stage for normal bone formation in arms and legs.
Building a Better Model
The nine months from fertilized egg to fully developed infant are marked by rapid cell growth, differentiation and development that unfolds in an exquisitely timed and precisely ordered sequence of events. The wrong environmental factor at a particular developmental stage can derail the delicate process, altering the growth of whatever tissues - bone, muscle or organ - happen to be developing at the time.
Smith is among only a handful of scientists in the country to do research on cartilage and limb development and how they are affected by chemicals.
"Cartilage is a fairly good indicator of limb development and it's easy to manipulate in culture," she said.
Most of the other labs use cell cultures from embryonic rodents or other mammals, but Smith uses embryonic tissue from fertilized chicken eggs. A reliable, effective chick embryo model could offer a faster, less expensive toxicity test, she said.
In separate experiments published in American Society for Testing and Materials and the journal In Vitro Toxicology, Smith and former graduate student Amita Kanti showed that "chick cells compare favorably with rodent cells. Essentially, the same processes and results occur in both," Smith said.
To further test the reliability of chick embryo cells as a screen for birth defects, Smith now is conducting chick cell experiments with retinoic acid, a vitamin A derivative found in some prescription acne medications.
"Retinoic acid has been used to study birth defects for many years, and we know a lot about the birth defects it causes in humans and other mammals," she said.
Smith's lab is developing dose response information based on retinoic acid to devise a model for how chemicals can move from the mother into the fetus. Her team collects data on length and timing of exposure on early wing development from fertilized, incubated chicken eggs. The cells are grown in culture in a manner similar to the way human throat cells are cultured to diagnose strep throat.
"We want to see if we can use the tissue culture system to pinpoint the way retinoic acid works in cell cultures and compare it to how it works in whole animals," she said. This process enables scientists to study a broad range of biological-environmental interaction using tissue cultures instead of whole animals.
Toxic Chemicals and Metals
Smith and graduate student Emily Hanson have just completed a U.S. Air Force-funded study of two chemical solvents to see if they have toxic effects on embryonic development of chicken wing cells. Both chemicals - ethylene glycol monomethyl ether (EG) and diethylene glycol monomethyl ether (DEG) - are readily absorbed through the skin. They also are common ingredients in many household and commercial products: paints and dyes, varnishes and lacquers, gasoline and antifreeze.
"They are used by the U.S. Air Force and its workers, and many of the
women in the Air Force are of child-bearing age, so the Air Force had a general
interest in learning more about the chemicals," Smith said.
The study, which will be submitted to the Journal of Toxicology and Environmental Health, showed that both EG and DEG had toxic effects on cell growth in general, an effect that was observable within the first 24 hours at the highest concentration tested.
"We are finding that there are not many compounds that directly affect cartilage development and bone formation," Smith said. "For most compounds it takes an extremely high concentration of chemicals to cause any effects, and then they are usually toxic to the cells in general rather than to the specific process of cartilage development."
Pathogens, Pregnancy and Public Health
At certain, but as yet unknown levels, Listeria can cause diarrhea in healthy adults. But in people who have suppressed or compromised immune systems and in developing fetuses, it can be fatal.
"We will develop a mathematical model to predict the amounts of Listeria that would affect an unborn child if the pregnant mother was unintentionally exposed to contaminated food," Smith said.
Among the goals of the research team is to determine at what concentration the Listeria bacterium becomes a threat to public health.
"This study will help determine if there is an acceptable low-dose threshold level that does not jeopardize human health," she said. "We know Listeria can have adverse outcomes, and we want to find out how much it takes to cause these adverse outcomes.
"Some of us are much more susceptible than others," she said. "What we really want to know for regulation purposes is what dose would cause 10 percent of the population to get sick? What dose would affect 5 percent or 1 percent? We would really like to protect everyone."
A recall of Listeria-contaminated hotdogs and other meats last fall touched 22 states. Sixteen people died, four women had spontaneous abortions and another 100 or so people got sick, Smith said.
"Approximately one-third of women exposed to high doses of Listeria during pregnancy have stillbirths or spontaneous abortions," she said. "Listeria crosses the placenta and colonizes in the fetus - in the liver, spleen, skin - when the woman is in the second or third trimester."
Listeria, which can grow well in moist areas of food processing plants, has been found in soft cheeses, milk and cole slaw. Ordinarily, it thrives in places such as the soil and water drains.
Their findings will help federal agencies that regulate the food industry monitor food-borne bacteria in processed, ready-to-eat food and set realistic standards for maximum acceptable tolerance - the greatest amount of something that you can be exposed to without concern.
Currently, the FDA and U.S. Department of Agriculture have a zero tolerance of Listeria monocytogenes and certain other bacteria in processed, ready-to-eat foods. That means a food recall any time a manufacturer finds any level of Listeria in ready-to-eat foods.
"But low levels of some pathogenic bacteria may be harmless," said Michael Doyle, head of the UGA Food Science and Technology Department and a recognized authority worldwide on E. coli 0157.
"We know that low levels of some bacteria are safe, but what we don't know is the threshold at which these levels become a health threat.
"Risk analysis is an emerging field that is considered to be the future approach for regulating the safety of food," said Doyle, who also directs the College of Agricultural and Environmental Sciences Center for Food Safety and Quality Enhancement.
Food-related illness in the United States now affects an estimated 6 million to more than 30 million people a year and has an economic price tag of several billion dollars, Smith said.
"More people probably die every year from food-borne infections than they do from chemicals, but we spend lots of money on chemicals and risk assessment," said Smith, who used to work in the private sector assessing toxic environmental contaminants.
Smith, Doyle and four other UGA researchers already have compared six dose-response models for food-borne pathogens to determine which models are most appropriate for a wide range of disease-causing bacteria, including Salmonella typhi, which causes typhoid fever.
"We wanted to find out how those models would predict very low infectious doses where only 5 to 10 percent of people would get sick," Smith said.
Their findings, which will be published in the Journal of Risk Analysis later this year, point out the similarities and differences among the various models.
Ultimately, Smith's wide-ranging risk assessment studies will give scientists and policymakers new tools to reduce the public health threat, including to unborn babies, of exposure to bacteria and chemicals.