We report an association between urinary DMAP metabolite concentrations -- indicators of exposure to dimethyl-containing OP pesticides -- and increased odds of ADHD in children 8 to 15 years. There was a 55 to 72% increase in the odds of ADHD for a 10-fold increase in DMAP concentration, depending on criteria used for case identification. This association was not explained by sex, age, poverty-income ratio, race/ethnicity, fasting duration, or creatinine concentration. Whether DAP metabolite concentrations are more strongly associated with a specific subtype of ADHD is uncertain due to the small numbers of cases, though the association was stronger for the predominantly hyperactive-impulsive subtype. This study should be generalizable to the U.S. population since the NHANES sample is nationally representative, unlike previous studies in groups with higher exposure levels.11–15
Adding to the importance of these findings, OPs are among the most widely used pesticides and the concentrations of DAP metabolites did not decrease from 2000 to 2003–2004 in children.
The most important limitation of the present study is the assessment of OP exposure by measurement of DAP metabolites in only one spot urine sample. Given that long-term exposure to OPs would likely be necessary to produce neurochemical changes causing ADHD-like behaviors, serial measurements of urinary metabolites of OPs over a longer time period would provide a better assessment of average exposure, but NHANES does not include longitudinal follow-up. For OPs coming from the diet, the measure of OP metabolites in a single urine sample may reflect average exposure levels reasonably well, to the extent that diet is consistent. Given that OPs are eliminated from the body after 3–6 days,28
the detection of DAPs in the urine of most children indicates continuing exposure. An additional consideration is that urinary DAP levels might reflect not only exposure to OPs, but also direct exposure to DAPs present in the environment resulting from degradation of OPs by hydrolysis or photolysis. Significant amounts of DAPs have been found on several fruits and vegetables.29
In any case, misclassification of exposure based on measurements of urinary DAPs should be non-differential, and would bias effect estimates towards the null.
Given the cross-sectional nature of our analysis, we cannot rule out that children with ADHD engage in behaviors that expose them to higher levels of OPs. However, if this was the case, we would have expected to see higher levels of urinary DEAP metabolites as well, which was not the case. Another limitation is measurement error in that the concentration for the individual DMAP metabolites was below the analytical limit of detection for a large proportion of children. This problem, however, does not apply to the analysis showing that children with levels higher than the median of detectable dimethylthiophosphate concentrations were twice as likely to be diagnosed with ADHD as those with non-detectable concentrations.
The present study uses a larger sample size than previous investigations on neurodevelopmental effects of OP exposure, as well as a DSM-IV based diagnostic outcome. Comparisons are difficult across studies because of differences in exposure levels, timing of exposure, choice of outcomes assessed, and age at assessment. Higher concentrations of blood chlorpyrifos during pregnancy were found to be associated with poorer mental and motor development at 3 years,11
and higher postnatal exposure to OPs have been associated with difficulties with memory, attention, motor tasks, behavioral problems,14
and reaction time.13
Prenatal exposure to OPs was also associated with poorer mental development at 2 years of age, and, as in our study, the association was with DMAP rather than DEAP metabolites.12
The stronger association with DMAP metabolites could be explained by higher exposure to OPs metabolized into DMAP metabolites, or it could indicate greater toxicity of these OPs.
Several biological mechanisms could underlie an association between OP pesticides and ADHD. A primary action of OPs, particularly with respect to acute poisoning, is inhibition of acetylcholinesterase,30
and disruptions in cholinergic signaling are thought to occur in ADHD.31
At doses lower than those needed to inhibit acetylcholinesterase, certain OPs affect different neurochemical targets, including growth factors, several neurotransmitter systems, and second messenger systems,.32, 33
Exposure to some of these OP compounds have been shown to cause hyperactivity and cognitive deficits in animal studies.34, 35
Developmental exposure to OPs could have persistent effects on multiple neural systems that may underlie ADHD behaviors, such as inattention and cognitive deficits, similar to effects of developmental nicotine exposure.36, 37