In this study designed to distinguish among absent, reversible, persistent, and progressive associations of cumulative lead dose on six cognitive domains over time, we found that higher tibia lead levels were associated with a progressive decline in eye-hand coordination (EHC), that was statistically significant in the full cohort and in African-Americans. Similar to the previous results from the cross-sectional analysis of first visit data,4
persistent associations of higher tibia lead concentrations with worse cognitive function were consistently found in all domains. These weakened after increasing control for SES and race/ethnicity. However, the increased power of the three visits of data allowed us to complete a stratified analysis. In whites, even after full adjustment, persistent effects were substantiated in EHC, executive functioning, and verbal memory and learning. These robust and consistent findings are the strongest evidence to date concerning cumulative lead dose and cognitive function in adults. They support and augment evidence from the only prior longitudinal study of cumulative lead dose and cognitive function in adults,11,14,15,18
but in a sample that is considerably more diverse in its sex and racial/ethnic composition.
Although the strongest findings on persistence were observed in whites, we believe it mistaken to conclude that there are not more general implications of the findings. As discussed in our prior cross-sectional publications in this population,4,43
there are many possible reasons why associations might attenuate after adjustment for race/ethnicity and SES even if cumulative lead dose contributes to cognitive decline in all subjects (e.g., unmeasured effect modification, reciprocal effects43
). Detailed additional discussion is beyond the present scope, but other explanations for our failure to substantiate an association of lead among African-Americans, if an underlying association exists, include the “weathering” hypothesis,44
survivor bias and out selection,46,47
and difficulty in “unchaining” the effect of a single health insult in the presence of multiple health insults.49-51
We believe these considerations leave well open that cumulative lead dose may contribute to decrements in cognitive function in adults regardless of race/ethnicity.
Data from multiple visits provides longitudinal evidence. Longitudinal data more strongly support causal inferences than cross-sectional data by establishing temporality and allowing comparisons treating individuals as their own controls. The strongest inferences possible in our study were tied to progressive effects, which involve within-person changes in cognitive outcomes over time. These were observed only in isolated instances, perhaps due to the relatively short duration of follow-up. The primary benefit of longitudinal data for analyses of persistent effect is to increase precision in characterizing cognitive functioning and, where persistence is observed, demonstrate stability over time in the relations of lead dose and cognitive test scores.
There were several strengths of this study. It is the largest study of bone lead and cognitive decline to date; it randomly selected study subjects to be representative of its sampling frame; it is diverse by sex, race/ethnicity, and SES; it rigorously measured SES; it rigorously assessed cognition in multiple domains; it measured a large number of covariates; it is longitudinal with reasonably successful follow-up; and it employed theoretically driven, state-ofthe-art longitudinal analyses. The main limitation was loss of subjects from the studied cohort due to initial refusal to participate, uncompleted or negative tibia lead measurements and dropout during the study. Loss of data by all of these mechanisms impacted power and precision for analyses and has the potential to bias findings. Because recruitment achieved designed targets, and loss to follow-up was at the rate anticipated in initial study design, we do not consider power loss related to sample size a primary concern.
Biases are not as easily dismissed, as data loss was systematically related to both demographic factors and tibia lead. It is possible that refusal or dropout could have related to cognitive status independently of measured characteristics. We consider the most likely scenario of informative data loss to be a higher likelihood of dropout among of individuals with impaired cognition, both theoretically and because mean cognitive performance improved over rounds in most domains. We believe such a mechanism would have tended to mask progressive or persistent effects due to loss of individuals with impaired cognition, rather than create spurious ones. By this standard, the persistence findings are particularly compelling. Then, it must be noted that the primary analytic plan was to not stratify, and that we made multiple comparisons by domains and by strata. Among 18 fully-adjusted joint tests of persistence (6 domains by total, white and African-American samples), 1.8 positive findings are anticipated (at alpha level = 0.10); by comparison, our three positive findings is suggestive but not overwhelmingly conclusive of a signal. We consider weight to be added in that all three findings were in a single cohort (whites) and were strengthened upon eliminating spline terms not supported by the data.
We believe it critical that public health researchers continue to characterize the cognitive effects of cumulative lead dose and, if present, evaluate possible interventions to prevent or mitigate them. Our study subjects were born between 1930 and 1950. Lead use in gasoline increased dramatically during the subsequent decades of 1950 to 1970 in the U.S., peaking in 1969.2
We estimate that this use distributed, on average, approximately 800,000 μg of lead per person into the environment each year during these decades. Although general population surveillance studies were not performed until the late 1970s, data within single cities suggest that mean blood lead levels in 1965 were as high as 25 μg/dL in the general population.2
By the time NHANES II measured blood lead levels in the general population in the late 1970s, use of lead in gasoline had declined considerably, but mean blood lead levels still exceeded 15 μg/dL across virtually all age and sex groups in the U.S. With growing numbers of older Americans achieving increasing life expectancies, population aging will soon collide with the peak lead dosing experienced by this cohort. It is therefore critical to characterize the late life consequences of early-, mid-, and late-life lead exposures. Our study contributes to this developing understanding.
In conclusion, this study provides the strongest evidence to date that cumulative lead dose is associated with adverse effects on cognitive function that are at least persistent in nature, decades after the majority of lifetime dose was achieved. While there may be a signal of progressive effect in one cognitive domain, the relatively short follow-up duration and the relatively low average age of study subjects makes conclusions about the existence of a progressive effect uncertain at this time. The data suggest that a proportion of what has been termed “normal cognitive aging” may in fact be due to lifetime exposure to neurotoxicants such as lead. As persons with the highest cumulative lead doses age, the role of lead dose on cognitive aging could not only become more apparent but have important public health consequences which we are only beginning to understand.