Abstract

INTRODUCTION

Childhood behavioral disorders are increasingly prevalent and result in substantial costs to families and society, with impacts on the educational system, quality of life and often on productivity into adulthood.¹ ADHD is one of the most common neurodevelopmental disorders of childhood, affecting 8-12% of children worldwide², yet the etiology is not well understood.^{3, 4} Increasing evidence supports associations between metals and ADHD-related behaviors, including prenatal and postnatal lead exposures.^5-7

The developmental neurotoxicity of mercury is well-established, demonstrated by mass poisoning episodes in Japan^{8, 9} and Iraq.¹⁰ Central nervous system effects of mercury have been shown in animal models¹¹, including changes in rodent dopaminergic function¹², providing a biologic basis for effects on ADHD.¹³ Epidemiologic studies of lower-dose mercury exposure are inconsistent¹⁴, with some studies showing associations between mercury and ADHD-related behaviors^{15, 16} and others reporting null associations.^17-20

Non-occupational methylmercury exposure results primarily from fish consumption, which led the US Environmental Protection Agency and Food and Drug Administration to issue a joint federal advisory recommending that pregnant women limit their total fish intake to no more than two 6-ounce servings/week.²¹ Fish is also a source of nutrients, such as omega-3 fatty acids, which have been shown to benefit brain development^22-25, potentially confounding mercury-related risk estimates.²⁶

We investigated the association of peripartum maternal hair mercury and prenatal fish intake with ADHD-related behaviors at 8 years of age in a prospective birth cohort.

METHODS

RESULTS

For the 604 singleton births with an 8-year exam, 421 (70%) and 515 (85%) had prenatal mercury and fish consumption data, respectively. Summary statistics for mercury, fish consumption and outcome measures are presented in Table 1. As shown in Table 2, participants with maternal mercury levels (n=421) were similar to all participants with 8-year follow-up data (n=604), and were diverse with respect to sociodemographic indicators, including education (39% of mothers and 67% of fathers had no college education), household income (18% earned <$20,000/year), marital status (39% of mothers were unmarried) and race (26% of children are non-white). Child’s age at the 8-year exam ranged from 7-10 years. Table 2 also shows higher mercury levels among mothers who were older, married, had higher household income, did not smoke during pregnancy or use illicit drugs the year before birth, consumed more fish during pregnancy and had children of white race. Mercury-education associations were U-shaped, with higher levels among parents with the lowest and highest educational status. Mercury was also positively correlated with HOME score, prenatal omega-3 and fish servings/week, and cord serum PCBs, and inversely correlated with maternal depression symptoms.

Mercury and ADHD

Several ADHD-related endpoints had non-linear associations with hair mercury levels. Figure 1, which shows the covariate-adjusted association between prenatal hair mercury and log-transformed CRS-T DSM-IV total t-score from a penalized spline⁴⁰, demonstrates an apparent threshold for exposure-response at approximately 1 μg/g. For outcomes with this threshold exposure-response pattern, we used piecewise linear regression, which produces separate mercury-behavior associations at mercury levels <1 μg/g (n=355) and ≥1 μg/g (n=66).

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Figure 1

Penalized spline of the adjusted association of perinatal maternal hair mercury with log-transformed DSM-IV Total t-score (centered on 0) from the CRS-T for 8-year old children born in New Bedford, 1993-1998.

Unadjusted and adjusted associations between prenatal hair mercury and ADHD-related behaviors are reported in Table 3. Mercury and CRS-T associations were consistent for continuous and dichotomized CRS-T scores; we present RRs for the dichotomized CRS-T in Table 3 for ease of interpretation. We detected an apparent threshold at mercury levels of 1 μg/g for the CRS-T and piecewise regression suggested a slightly protective association between mercury and inattentive, impulsive/hyperactive and combined behaviors with increasing mercury levels up to 1 μg/g, and an increase in risk for these behaviors with increasing mercury levels ≥1 μg/g, particularly for impulsivity/hyperactivity (adjusted RR for an interquartile range (IQR) increase in mercury=1.7; 95% CI: 1.2, 2.4). Higher hair mercury was also associated with higher risk for errors of commission (RR=1.1; 95% CI: 1.0, 1.2) and lower scores on the WISC subscales, particularly processing speed (β=-1.5; 95% CI: -2.9, -0.1).

Table 3

Unadjusted and adjusted associations between hair Hg and ADHD-like behaviors, for 8-year-old children born in New Bedford, 1993-1998.

	Mercury Categories	Unadjusted		Adjusted *		Adjusted* + fish consumption†
Outcome Measure		N	β or RR (95% CI)	N	β or RR (95% CI)	N	β or RR (95% CI)
Conners Rating Scale – Teachers (CRS-T) dichotomized at 86th percentile
DSM-IV Inattentive (RR)	< 1 μg/g‡	412	0.7 (0.5, 0.9)	362	0.8 (0.5, 1.1)	362	0.8 (0.6, 1.2)
	1+ μg/g‡		1.3 (1.0, 1.6)		1.4 (1.0, 1.8)		1.3 (1.0, 1.7)
DSM-IV Impuls/Hyper (RR)	< 1 μg/g‡	412	0.6 (0.4, 0.8)	362	0.8 (0.5, 1.2)	362	0.8 (0.5, 1.3)
	1+ μg/g‡		1.6 (1.3, 2.0)		1.7 (1.2, 2.4)		1.6 (1.1, 2.4)
DSM-IV Total (RR)	< 1 μg/g‡	412	0.6 (0.4, 0.8)	362	0.7 (0.5, 1.0)	362	0.7 (0.5, 1.1)
	1+ μg/g‡		1.5 (1.2, 1.8)		1.6 (1.2, 2.1)		1.5 (1.1, 2.0)
NES2 Continuous Performance Test (CPT)
Mean Reaction Time (β)	< 1 μg/g‡	417	-8.6 (-20.4, 3.2)	359	-9.6 (-22.9, 3.8)	359	-11.9 (-25.7, 1.8)
	1+ μg/g‡		6.5 (-2.8, 15.7)		2.5 (-9.5, 14.5)		3.6 (-8.5, 15.7)
Reaction Time Variability (β)	< 1 μg/g‡	417	-3.9 (-9.3, 1.5)	359	-3.1 (-8.7, 2.4)	359	-3.0 (-8.8, 2.7)
	1+ μg/g‡		3.5 (-0.7, 7.8)		4.7 (-0.3, 9.7)		4.6 (-0.4, 9.7)
Errors of Omission (RR)	continuous	417	1.0 (0.9, 1.1)	359	1.0 (0.9, 1.2)	359	1.0 (0.9, 1.2)
Errors of Commission (RR)	continuous	417	1.0 (1.0, 1.1)	359	1.1 (1.0, 1.2)	359	1.1 (1.0, 1.2)
Wechsler Intelligence Scale for Children – Third Edition (WISC-III)
Processing speed (β)	continuous	421	-0.5 (-1.7, 0.7)	362	-1.5 (-2.9, -0.1)	362	-1.6 (-3.0, -0.2)
Freedom from Distractibility (β)	continuous	421	-0.5 (-1.5, 0.5)	362	-0.9 (-2.2, 0.3)	362	-1.0 (-2.2, 0.3)

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Abbreviations: RR=risk/rate ratio for an interquartile range increase (75%ile-25%ile=0.48 μg/g) in Hg; β=change in outcome score for an interquartile range increase in Hg; CI=confidence interval.

^*Adjusted for child’s age (continuous), sex and race (white vs. non-white), maternal age (continuous), education (<12 years vs. 12+ years), marital status (married vs. unmarried), IQ (continuous), depression symptoms (continuous), prenatal smoking (yes/no and average # cigarettes per day), prenatal alcohol consumption (yes/no and average grams per day) and illicit drug use (ever vs. never during year before birth), paternal education (<12 years vs. 12+ years), household income (<$20,000 per year vs. $20,000+ per year) and HOME score (continuous).

^†Total fish consumption:(>2 servings/week vs. ≤2 servings/week).

^‡Modeled using piecewise linear regression, producing separate slopes at <1 μg/g and 1+ μg/g hair mercury.

Adjusting for total fish consumption (Table 3) and omega 3 intake (data not shown) did not consistently change associations between mercury and ADHD-related endpoints. PCBs, though moderately correlated with mercury (r=0.42), neither confounded nor modified mercury-ADHD associations (data not shown). Finally, adjusting for two-year Pb levels and excluding children who were treated with ADHD medications (n=26) did not change associations between mercury and endpoints (data not shown).

DISCUSSION

In this population-based prospective cohort study, prenatal hair mercury levels were consistently associated with ADHD-related behaviors, including inattention and hyperactivity/impulsivity. We also found that higher prenatal fish consumption was protective with respect to these behaviors. Results are supported by data from a well-characterized birth cohort with prospectively measured exposure and covariate data, including important confounders.

Hair is a well-established biomarker of methylmercury and maternal hair mercury levels correlate well with fetal brain and blood mercury.⁴¹ Median hair mercury levels for this cohort were higher (0.45 μg/g) than levels reported among women of childbearing age during 1999-2000 in the National Health and Nutrition Examination Survey (NHANES) (geometric mean=0.12 μg/g), though comparable to levels in NHANES participants that were frequent fish consumers (geometric mean=0.38 μg/g).⁴²

There is uncertainty concerning the effect of low-level mercury on neurodevelopment.¹⁴ Two seminal studies of prenatal mercury exposure report inconsistent results with respect to behavioral outcomes. For 1,022 children born in the Faroe Islands during 1986-1987 with high mercury levels (geometric mean=22.9 μg/l in cord blood, 4.27 μg/g in maternal hair), higher cord blood mercury was associated with more errors of omission and longer mean reaction time on the NES2 CPT at 7 and 14 years of age.^{15, 43} In contrast, a study of 779 children born in the Seychelles Islands during 1989-1990 with high mercury levels (mean=6.8 μg/g in maternal hair) reported null associations with neurodevelopmental outcomes, including measures from the Child Behavior Checklist, the Conners’ CPT, and improved scores on the impulsivity/hyperactivity index of the CRS-T.^{17, 19, 20} Mixed results have also been reported in other studies of mercury and behavior.^{16, 18, 44}

One explanation for inconsistency is that nutrients in fish that promote neurodevelopment, such as omega-3 fatty acids, may offset the neurotoxicant effects of mercury exposure²⁶; this is supported by previous studies that report enhanced deleterious associations between mercury and neuropsychological endpoints after adjusting for fish consumption (benefits of fish consumption were also stronger after adjusting for mercury)^{25, 45}, and by a second study in the Seychelles Islands that reported deleterious mercury effects on neurodevelopment only after adjusting for omega-3 and omega-6 fatty acids measured in prenatal maternal blood.^{46, 47} Adjusting for fish consumption (or omega-3 intake) did not change mercury-behavior associations in the current study. Measurement error in collecting self-reported dietary intake of fish and related nutrients may have resulted in residual confounding by these factors. In addition, the degree of confounding by fish consumption is likely a function of the fish species (and their respective nutrient content) consumed by the study population. Fish consumption was associated with better behavioral scores for most of our study outcomes, however, and for the CRS-T outcomes in particular. Notably these associations were protective for fish consumption during pregnancy >2 servings/week, which is higher than the FDA-EPA federal advisory limit.²¹ Adjusting for mercury enhanced the protective association for fish consumption with WISC-III outcomes. Previous studies report associations between greater childhood omega-3 fatty acid intake and reduced risk of ADHD, though mostly in the context of alleviating clinical ADHD symptoms.⁴⁸ To our knowledge this is the first study to report a protective association of prenatal fish consumption with offspring ADHD-related behavior.

We previously reported associations of PCBs with ADHD-related behaviors in this cohort.^{27, 28} Though PCBs were moderately correlated with mercury, adjusting for PCBs did not change mercury-ADHD associations. We did not find an interaction between PCBs and mercury on ADHD-related behavior, in contrast to two previous studies of cognitive and behavioral outcomes. ^{49, 50}

For the CRS-T outcomes and CPT reaction time threshold associations between mercury and ADHD-related behavior were detected at approximately 1 μg/g. This is consistent with a study of hair mercury and neurodevelopment that also found a threshold for adverse effects between 0.5 and 1 μg/g.⁵¹ In addition, the U.S. EPA reference dose for mercury (0.1 μg/kg/day)³¹ is equivalent to 1.2 μg/g in hair⁵², which is roughly the level for the threshold we report in this study. We detected slightly protective associations of mercury with ADHD-related behavior at mercury levels <1 μg/g. Because fish is the main source of mercury, this may reflect the beneficial effect of fish consumption, which may have been inadequately adjusted due to measurement error. At higher mercury levels (≥1 μg/g) these nutritional benefits may have been outweighed by neurotoxicity from mercury exposure.

We detected sex differences for mercury and some ADHD-related behaviors, with associations found primarily among boys. Previous studies have reported stronger mercury-related associations among boys vs. girls.^{15, 19, 53} Though the mechanism underlying sex differences in exposure-related neurotoxicity is unknown, a growing literature shows differences in the impact of endocrine disrupting chemicals (including mercury) on neurodevelopment among males and females⁵⁴, such as Bisphenol A⁵⁵ and phthalates.⁵⁶

We did not assess clinical ADHD diagnosis in this study. Though common, clinically diagnosed ADHD is too rare to study in moderate-sized prospective population-based samples. Measuring behavior on a continuum in this study has several advantages, including: 1) minimization of bias due to outcome misclassification, where categorization is often made at an arbitrary cutoff point that may change over time, 2) detection of early or milder manifestations of a disorder that a clinical diagnosis could miss, and 3) enhancement of power to detect an effect of exposure.⁵⁷ A limitation of using the CPT and WISC-III outcomes as markers for inattentive and hyperactive/impulsive behaviors is that these outcomes may also reflect other skills that could compromise or enhance resulting scores for these neuropsychological tests.

CONCLUSION

In summary, our results suggest that prenatal mercury exposure is associated with higher risk for ADHD-related behaviors, and fish consumption during pregnancy is associated with lower risk for these behaviors. While a single estimate combining these beneficial vs. detrimental effects vis-à-vis fish intake is not possible with our data, these findings are consistent with a growing literature showing risk of mercury and benefits of maternal consumption of fish on fetal brain development and are important for informing dietary recommendations for pregnant women.

Acknowledgments

References