Are Blood Lead Levels in the United States Still Declining? The US National Health Nutrition and Examination Survey (NHANES) 1999-2016 CURRENT STATUS:

Background: Lead is toxic without a safe limit. The current upper reference blood lead level (BLL), 5 μg/dL, came from the 97.5th percentile in children aged 1-5 years in NHANES 2007-2010. Objectives: We studied the latest trend in BLL in US NHANES and estimated the proportion of children with BLL ≥5 μg/dL, which would inform the setting of an upper reference level. Methods: We analyzed 68877 participants (aged 1 to 85 years) with BLL measurements in NHANES 1999-2016 using SPSS complex sample module v25.0. Results: In NHANES 2011-2012, 2013-2014, and 2015-2016, the mean and 95% confidence intervals (CIs) of BLLs (μg/dL) were 0.97 (0.96, 0.99), 0.86 (0.85, 0.87), and 0.82 (0.81, 0.83), respectively (P <0.0001). The estimated proportion (95% CI) of children aged 1-5 years with elevated BLL (EBLL) in 2011-2012, 2013-2014, and 2015-2016 were 2.0% (1.3, 3.0), 0.5% (0.4, 0.7), and 1.3% (0.8, 2.3), respectively (P=0.267). In 2015-2016, the proportion of children with EBLL was similar in high- and low-income groups ( P = 0.9979). The estimated 97.5th percentile of BLL in children was 3.71 μg/dL in NHANES 2015-2016. Conclusions: BLL continued to decline in the overall US population. The disparity in BLL in children from higher and lower income families has decreased. Our findings support a reduction in the reference BLL, continual monitoring of population BLL and continual efforts to reduce environmental exposure to lead.


Introduction
Lead is a well-documented environmental toxin. Environmental lead exposure is mainly from water pipe, soil, paint, and gasoline. Several mechanisms of lead poisoning have been proposed, including enzyme inhibition, oxidative stress, inflammation and epigenetic modifications [1,2]. In adults, lead can affect multiple organ systems. A recent systemic review and meta-analysis has shown that lead exposure is associated with increased risk of cardiovascular disease, coronary heart disease, and stroke [3]. Even at low blood lead levels (BLLs), blood pressure and other cardiovascular outcomes are linked to lead exposure [4,5]. Lead in blood is also related to renal dysfunction [6][7][8] and has an additive effect with hypertension [9]. Lead toxicity in children is particularly worrying as they suffer from more serious consequences. In children, high BLLs is a risk factor for cognitive deficits [10][11][12][13] and attention-deficit hyperactivity disorder [14,15]; and chelation therapy seems to be unable to correct the damage [16]. For this reason, efforts have been focusing on reducing environmental exposure to lead through monitoring and regulation.
In 2012, the US Centers for Disease Control and Prevention (CDC) set, as the upper reference BLL, the 97.5th percentile of BLLs in children aged 1 to 5 years in the National Health Nutrition and Examination Survey (NHANES) 2007-2010 [17]. This reference limit of 5 μg/dL has been adopted by the US and many other places to identify children with elevated BLLs. However, a recent US population-based cohort study suggests that even among individuals with BLLs lower than 5 μg/dL, an increase of BLL from 1.0 μg/dL to 5.0 μg/dL was associated with 38% increase in all-cause mortality, almost two-fold increase in cardiovascular disease mortality, and more than 150% increase in mortality related to ischemic heart disease [18]. This finding has provided another important piece of evidence to support the notion that there is no safe limit of BLL and there is no room for complacency [19].
However, 132 (79%) schools and 95 (13%) childcare providers in Vermont had elevated tap water lead level 20 . The testing of this water lead level is conducted in accordance to Act 66 which requires all Vermont schools, supervisory unions, independent schools and childcare providers to measure water lead level 21 . The government provided the resources to replace the affected water pipes and taps. All affected water taps are not allowed to use 20

Statistical Analysis
The model we used accounted for the stratification and clustering of the complex sampling design of NHANES. Sample weights were used to adjust for biases arising from oversampling, differential probability of selection, non-response, and post-stratification. BLLs were natural logarithmtransformed to correct for the skewness in the data. Estimates were adjusted for age, gender, and ethnicity.
The estimated proportions of pregnant women and children 1-5 years old with elevated BLL (EBLL) (defined as ≥5 μg/dL), and other categorical variables were presented as percentages with 95% confidence intervals (CIs). BLLs were expressed as geometric means and 95% CIs. Results were analyzed by socio-demographic subgroups, e.g. age, gender, ethnicity, poverty income ratio (PIR).

Discussion
Our results show a persistent decline in BLLs in the US from 1999-2000 to 2015-2016 irrespective of age, gender, ethnicity, and poverty-income ratio. The decline is consistent with a number of previous population-based studies [22][23][24][25][26][27][28], including our previous study [29]. This has once again demonstrated the effectiveness of public health efforts to abate environmental exposure to lead in the US. Nevertheless, the rate of decline has been diminishing in recent years, which may indicate that there are other environmental lead sources yet to be identified and controlled.
Despite the substantial decline in BLLs, disparities between different income and ethnic groups remain. From our analysis, we found in NHANES 2015-2016, for the first time, that there was no longer a disparity between high-and low-income families in the proportion of children aged 1 to 5 years with EBLLs. This is a very encouraging finding. Lead affects neurocognitive development in children and BLL may partly lead to a poverty trap in which children from poor families will remain poor when they grow up. The elimination of income disparity in EBLLs is likely to be a result of targeted screening in high-risk children. Until 2014, black children (below age of 18) were twice as likely to live in poverty as white children [30]. Black children in poverty are also more likely to live in substandard housing and hence, at a higher risk of exposure to lead paint at home and lead pollutants from nearby factories [31,32]. The racial and income disparity has been historically important in blood lead monitoring. In 1982, Mahaffey and colleagues first reported higher BLLs in young children who were black and from low-income families in a national estimate (NHANES II, 1976-1980 [33]. Since then, the observation was confirmed in numerous studies and the disparities persisted over the past four decades [22-4, 27, 33-36]. In 2013-2014, the mean BLLs in black children was still 36% higher than in white children [29]. Children at the age of 1-5 years that were non-Hispanic black, from a low-income family and living in housing built before 1950 were in the highest risk groups for lead poisoning [24,34,35]. The black-white disparity in higher BLLs has been found to be independent of income level, housing quality and environmental conditions [38]. Targeted prevention strategies have been implemented such as increased screening on these high-risk groups and identification of high-risk environment [17]. the percentage of non-Hispanic black children with EBLL is still higher compared to other ethnicities, and so more efforts to reduce the environmental exposure to lead, particularly by removing lead paint and lead plumbing in houses, are necessary.
The proportion of EBLL among children aged 1-5 years in NHANES 2015-2016 increased numerically, albeit insignificantly. This should be interpreted with caution. 30.9% of these participants had missing blood lead measurements. The sample size was 790 and only 12 children had EBLL. Caldwell et al. [39] reported an estimated 35% of lot screening failures due to lead contamination, which could In conclusion, our latest analysis of BLL in US NHANES showed that BLL continued to decline overall in the US population. The disparity in BLL in children in high and low-income households has diminished. Black children still have higher BLLs than white children. In young children aged 1 to 5 years in the 2015-2016 survey, BLL did not decline and appeared to increase. Our data suggest that monitoring the trend in BLL in the population is as necessary as ever and that efforts to reduce environmental exposure to lead must not be relaxed.

Ethical Approval and Consent to participate
All participants gave informed consent before participation and ethics approval of the study was granted by the Research Ethics Review Board at the National Center for Health Statistics of the Centers for Disease Control and Prevention, USA.

Availability of supporting data
Data used in this study can be downloaded from: https://wwwn.cdc.gov/nchs/nhanes/Default.aspx

Competing interests
BMYC reports personal fees from Amgen, Pfizer and Roche, outside the submitted work.
The remaining authors declare no potential conflicts of interest.

Funding
No specific funding was received for this work.
wrote the first draft of the manuscript. All authors contributed to the interpretation of results. The corresponding author had full access to the data and had final responsibility for the decision to submit for publication. All authors read and approved the final manuscript.