Synergistic Effect of Prenatal Tobacco and Early Lead Exposure on ADHD

Pauline Anderson

November 26, 2009

November 26, 2009 — Children who were exposed to prenatal tobacco smoke and have high blood lead levels are more than 8 times more likely to have attention-deficit/hyperactivity disorder (ADHD) than youngsters with neither of these exposures, according to a new study.

The study results suggest that the combined effect of prenatal tobacco and childhood lead exposure is more than just the sum of the 2 separate exposures; rather, there is a synergistic effect that is even greater than what would be expected if the individual exposure risks were multiplied.

The authors estimate that more than one third of ADHD cases can be explained by the combination of these 2 exposures.

The study should be a wake-up call for women planning to become pregnant, said the study's lead author, Tanya Froehlich, MD, MS, from the Department of Pediatrics at Cincinnati Children's Hospital Medical Center in Ohio. They should not only quit smoking but plan to reduce as much as possible their child's exposure to lead, she said.

The study was published online November 23 in Pediatrics.

Wake-Up Call

For the study, Dr. Froehlich and colleagues used the National Health and Nutrition Examination Survey, a multistage, nationally representative survey of the US population in 2001 to 2004. The sample included 2588 children aged 8 to 15 years.

Using caregiver responses to the National Institute for Mental Health Diagnostic Interview Schedule for Children, researchers determined that 8.7% of the sample met gold standard diagnostic criteria for ADHD, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). This is equivalent to 2.4 million American children.

To assess prenatal exposure to tobacco smoke, researchers asked caregivers whether the child's biological mother smoked at any time while pregnant. Children who were exposed to tobacco prenatally were more than twice as likely to meet ADHD criteria compared with children who were not exposed (adjusted odds ratio [AOR], 2.4; 95% confidence interval [CI], 1.5 – 3.7).

To ascertain current blood lead concentrations, researchers used graphite furnace atomic absorption spectrophotometry. They categorized these levels into tertiles of low, medium, and high exposure (high exposure was 1.3 μg/dL or more). Compared with children in the lowest tertile, those in the highest tertile were at significantly higher risk for ADHD (AOR, 2.3; 95% CI, 1.5 – 3.8).

"We're showing this effect of lead even at very low exposures," commented Dr. Froehlich, adding that this level is significantly below the limit of 10 μg/dL currently designated by the Centers for Disease Control and Prevention.

When these 2 exposures were added together, the risk for ADHD shot up dramatically. Those who were exposed prenatally to tobacco and who were in the highest tertile of lead exposure had a greater than 8-fold increased likelihood of ADHD (AOR, 8.1; 95% CI, 3.5 – 18.7).

Dr. Froehlich explained that both prenatal tobacco and childhood lead exposure perturb the brain dopamine pathway, which is known to be disrupted in ADHD. Animal studies have shown that nicotine exposure in utero causes decreased brain dopamine metabolism. Experiments that involved adding lead to brain cell cultures found decreased dopamine neuron length, as well as decreased dopamine uptake by brain cells.

Cracks in Foundation

In describing this synergistic effect, Dr. Froehlich explained that tobacco and lead exposure effectively provide a "double hit" to the brain dopamine system. She likened the 2 exposures to cracks in the foundation of a building. "If you have a building that has 1 crack in the foundation, it may be somewhat weakened, but things may dramatically destabilize if you add another crack in the same area."

If you have a building that has 1 crack in the foundation, it may be somewhat weakened, but things may dramatically destabilize if you add another crack in the same area.

The authors estimated that 38.2% of ADHD cases among 8- to 15-year-old children might be attributable to prenatal tobacco exposure, lead concentrations of more than 1.3 μg/dL, or both. This corresponds to 900,000 cases of the estimated 2.4 million cases of ADHD in this age group nationwide.

These exposures are very real: A 2004 population-based study found that about 15% of women in the United States smoked during pregnancy. As for lead, an estimated 1.8% of US children had blood lead levels above 10 μg/dL in 1999 to 2002, and almost 14% had levels of 5 to 9 μg/dL.

Even though lead was removed from paint manufactured in the United States in 1978, it is still found in the paint of older houses, in old pipes, in some children's toys manufactured in other countries, and in some ceramic serving dishes, Dr. Froehlich told Medscape Psychiatry. "Lead was also in gasoline for quite some time," he added. "As a result of having been in so many products, lead is in the soil in many areas, so kids can absorb or ingest it after playing in the soil."

The authors estimate that the number of ADHD cases would be reduced by 25% if exposure to lead were reduced. Similarly, a reduction to prenatal tobacco exposure could result in 21.7% fewer cases of ADHD.

Enforce Laws

To reduce the risk that their baby will develop ADHD, women who are planning a pregnancy or who have the potential to become pregnant should quit smoking. As for reducing exposure to ADHD-related toxicants later on, society as a whole could do more to "enforce laws making landlords clean up the lead that's in the housing stock that they rent to people," said Dr. Froehlich.

Where there are lead pipes, families should let the water run for a bit before taking a drink from the tap. Kids should be especially vigilant about hand washing after playing outside in soil, or in areas in the home where there may be lead dust from old paint or old window sills or casings. Parents should also be aware that children who are deficient in iron and calcium tend to absorb more lead.

One of the limitations of the study is that it cannot actually prove that these exposures cause ADHD, the authors note. The study cannot rule out, for example, that genetic factors or confounding factors such as prenatal alcohol exposure, may explain the relationship between these exposures and ADHD. In addition, the study's assessment of prenatal tobacco exposure was based on caregiver reports that did not take into account dose response or timing effects.

When asked for a comment on these findings, Glenn J. Kashurba, MD, a child and adolescent psychiatrist in Somerset, Pennsylvania, said the study is important because it shows that prenatal tobacco and lead exposure are independent risk factors for ADHD and that combined exposure is even more dangerous.

"Any study that calls attention to the significant negative consequences of tobacco, lead, and other prenatal toxins can decrease the risk of problems for children and families in the future," he told Medscape Psychiatry.

The authors have disclosed no relevant financial relationships.

Pediatrics. Published online November 23, 2009.


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