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30 September 2016 - Psychiatric Times - Understanding the Link Between Lead Toxicity and ADHD

Joel T Nigg PhD

Lead’s effects on childhood IQ, ADHD, and conduct problems as well as physical health have been of concern for decades. We now know a great deal about how lead affects the brain, including disruption of signaling in the prefrontal cortex and striatum.

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Several neurotoxic chemicals can disrupt brain development, which contributes to neurodevelopmental and psychiatric disorders—including ADHD. Lead is among the most studied neurotoxicants relevant to mental disorders. Because lead is stable and inert, the total amount on earth never changes. Over the past 6000 years, people have mined about 300 million tons of lead; some 150 million tons are still dispersed in the environment in one form or another.

Exposure routes

Most exposure in children in the US (about 70%) occurs through lead paint in older houses, schools, and other buildings; or in surrounding soil and dust, which has accumulated and bound lead over the decades from airborne pollution. Other sources of exposure include water (leaching from lead in pipes, as in the recent Flint water crisis); and lead in imported toys, jewelry, candles, canned foods, candy wrappers, cosmetics, and poorly regulated dietary supplements. For those who live near airports, air pollution is a further source—airplane gasoline is still leaded. Pica is an obvious potential contributor when present in the child or mother.
 
Lead’s effects on childhood IQ, ADHD, and conduct problems as well as physical health have been of concern for decades. We now know a great deal about how lead affects the brain, including disruption of signaling in the prefrontal cortex and striatum.
 
History
During the evolutionary period, from one million years ago until 10,000 years ago, humans may have had a typical blood lead level of about 0.01 to 0.02 µg/dL, based on limited fossil data. This may be the best estimate of a “normal” level of lead for humans. Lead is fatal to children at 100 to 150 µg/dL—or 10,000 times the “normal” level. During the 19th and 20th century, the levels among American children spiked to around 30 to 50 µg/dL on average, with thousands of children killed and many others sickened and permanently injured by lead poisoning. This was the direct result of unrestrained commercial and industrial use of lead in gasoline, house paint, and other products.
 
Lead’s poisonous properties were already known in antiquity. However, harm to children in modern times as a result of routine exposure to commercial products was first documented in the 1890s. By the 1920s lead’s harmful effect on child development was medically established, and several nations had begun to restrict or phase out lead paint. In parallel with subsequent industry activity related to health and societal threats from cigarettes, asbestos, aerosols and ozone, and climate change, industry groups and politicians in the US resisted restrictions on lead use in paint and other consumer products—ignoring or distorting the science—for much of the 20th century.

Lead use was finally restricted in the US in the 1970s and phased out of gasoline and paint by 1986, which reduced the average lead level among children to about 1.0 µg/dL by the 2000s. This improved level, however, is still about 100 times the “normal” background level if the prehistoric fossil studies are close to accurate. At this level, acute toxicity is not observed. Instead, there are subtle effects on IQ and attention caused by alterations in neurodevelopment.

Crucially for clinical reflection, this average still masks wide variation. Low income and racial and ethnic minority children can have levels much higher than average. Children in nations that do not regulate lead have exposure and blood lead levels higher than in the US as well.

Association with ADHD

The correlational association of lead with conduct problems, IQ, and ADHD is well established. Goodlad and colleagues4 concluded from their comprehensive meta-analysis that the association of lead with symptoms of inattention was r = .03 to .25 with a point estimate of r = .16. This effect holds even at low, previously safe levels. While this is a small statistical effect, small effects have large public health consequences when exposures are widespread. The effect on ADHD and IQ results in part from lead’s disruption of executive functions.
 
While many studies in the literature and the meta-analysis by Goodlad and colleagues assayed lead levels that were higher than are now common among the US population, several studies using varying methodology from 2005 to 2015 confirmed that blood lead level was associated with ADHD even at levels in the 0.5 to 3.0 µg/dL range, after control for many covariates. If there exists a “safe” level of lead for children, it is below the detection limit of the best mass spectroscopy instruments.
 
Causality
 
Lead’s association with violent crime is well established, and its possible causality in that regard has provoked interest because of the association of reduced lead exposure with reduced next-generation violent crime in recent decades. However, ADHD incidence has not declined during the same period, perhaps because other chemicals have taken up the slack.
Yet, animal studies using random assignment show that lead causes altered gene expression, brain development, attention, and hyperactivity in rodents, which strongly suggests that the association of lead with lowered IQ and with inattention and hyperactivity in humans is also causal. Still, human behavior is complex. Humans live in uncontrolled environments, so a vast array of possible “unmeasured confounds” could explain a correlation of lead level with ADHD and are impossible to fully rule out in even the best-controlled correlational study.
 
To get around this, genomic stratification can be used. This is a “natural experiment” in which nature’s random assignment of genes can be taken advantage of. We recently pursued this approach. In the case of lead, the hemochromatosis gene (HFE) modulates iron uptake in the gut via 2 common missense mutations. Consequently, HFE indirectly influences lead’s metabolic effects as a result of the complex physiological interplay of iron and lead in the body.
 
Therefore, it is a perfect candidate for a genomic stratification study to evaluate the likelihood that lead contributes causally to ADHD. Because the gene’s mutated form (occurring in 10% to 15% of the population) is randomly distributed by nature, explaining an influence of this gene on the lead-ADHD association is difficult to do if lead is not exerting a causal effect.
 
Study data supported the causal hypothesis. The association of lead with ADHD, even at levels less than 1.0 µg/dL, was reliably stronger or weaker depending on which HFE mutation a child had. This finding also illustrated that for some children, the association of lead with ADHD at levels around 1.0 µg/dL was very small (although still statistically significant). But for other children, depending on their genetic makeup, that association was substantial—much larger than in the overall population.
 
Lead may influence behavior and cognition by accelerating oxygenation-related cell death. Another interesting possibility is that lead’s effects are sustained epigenetically—that is, by means of chemical changes in brain DNA that create a stable change in gene expression. In 2014, Luo and colleagues explored that hypothesis.

Rats exposed to lead were, as usual, more hyperactive. They also, however, had altered histone modification in the hippocampus, and these changes statistically mediated the behavioral changes. The researchers went on to demonstrate that these histone changes were in fact correlated with changes in gene expression.

Clinical implications

Depending on exposure level, the potential clinical and medical effects of lead exposure are vast and even in asymptomatic children can include virtually every system in the body. A child may exhibit a range of motor, cognitive, or behavioral difficulties; may be anemic; and may have other medical problems.
 
The latest guidelines from the Advisory Committee on Childhood Lead Poisoning Prevention of the CDC were issued in 2012. The term “level of concern” was removed, and the reference value for clinical intervention was lowered from 10 µg/dL to 5 µg/dL. At the time the cutoff was in the 95th percentile in the US population, which implies that the standard level could be lowered again as population exposure levels decline.

Because clinical options for low-level lead exposure are limited and neurodevelopmental effects may be irreversible, the CDC’s primary focus is now on eliminating lead exposure entirely via attention to older homes with lead-based paint, rather than on screening of blood lead levels. Thus, universal screening has been abandoned and replaced by targeted screening of at-risk children (eg, Medicaid recipients, immigrants).

Therefore, when ADHD is present, a survey of possible lead exposure can be considered, especially if modifiable lead vectors exist for the family. Any lead test that passes a detectable level on routine screening (often at a sensitivity threshold of only about 3.0 µg/dL) warrants follow-up with a more sensitive test.

At levels greater than 45 µg/dL, chelation is appropriate. However, more typically, when the lead level is of concern—often at 3 to 20 µg/dL—you can still recommend the following:

• Remove possible exposure vectors one by one, usually starting with repair of paint exposures, and then re-test; lead levels should drop noticeably in the blood in a month or two if exposure has been stopped

• Conduct confirmatory follow-up testing using venipuncture (a skin prick blood test can be contaminated by lead on the skin); if lead levels have not declined, continue to remove possible sources of exposure

• Complete a nutritional assessment; iron, zinc, vitamin C, and calcium can partially protect against effects of low-level lead exposure; eating a smaller amount but more frequently to disrupt lead absorption may also help mitigate lead effects

• Manage stress (stress interacts with lead to worsen its effects)

• If there is a family history of hemochromatosis, rule out HFE+

• Consider testing of siblings

• Report levels higher than 5.0 µg/dL to local health officials (required by CDC regulations)

Conclusion

Reductions in current lead exposure may or may not reduce current symptoms, but they may prevent worsened outcomes in development subsequently. We still do not know what the minimum cumulative exposure is or whether exposure does permanent or irreversible damage at critical periods in development. However, postnatal exposure is at least as important as prenatal exposure.

Overall, while lead is neither a necessary nor a sufficient cause of ADHD, it appears to be one contributor, perhaps even at historically relatively low, currently typical exposure levels—and perhaps particularly in children who are susceptible because of genotype, poor diet, or prior/concurrent adversity. Clinicians are encouraged to take seriously parental concerns about possible lead exposure and to rule out environmental hazards and contributors when evaluating for ADHD, particularly in young children.