Lead (Pb) exposure continues to plague vulnerable communities with exposure to children causing a litany of health disorders throughout life.(1–7) Previous work in children has focused on the cognitive impacts, but it is likely these early life exposures have lifetime impacts on many major organ systems, as studies have shown cardiovascular disease and neurodegenerative impacts later in life.(5,7,8) To combat some of these major health impacts, many hospitals implement clinical treatments for children impacted by high levels of Pb exposure to reduce biological burden. In China, the standard of care in Pb-poisoned children (defined as blood Pb >25ug/dL) involves inpatient chelation using ethylenediaminetetraacetic acid (EDTA) administered intravenously. Chelation has been shown previously to successfully remove Pb from blood, but can have negative impacts on growth with potentially little benefit for cognition.(9–11) The point at which chelation is used as a standard of care varies among treatment facilities, with some widely cited references in the US recommending treatment if blood Pb levels exceed 45 ug/dL and other hospitals not recommending chelation at any level.(12,13) However, previous studies investigating chelation only identified non-significant effects on cognition at blood lead levels less than 45 μg/dL, with only one study considering the impact of the treatment on total body stores of Pb.(14,15)

It is well-known that Pb in the body is stored primarily in bone, with up to 90% of total Pb stores in adults residing in bone with studies showing that even for young children more than 60% of total body Pb is in bone.(16,17) Blood Pb has a half-residence time of about 30 days and thus is typically only reflective of acute exposures within a few months of collection; however, this can depend on the amount of lead in bone that is resorbed into blood over time.(18) Resorption of bone lead to blood lead can result in sustained blood lead levels for years.(18,19) The storage of Pb in bone can be measured using x-ray fluorescence (XRF) and is reflective of cumulative exposures on the order of years to decades.(16,18,20) However, Pb in bone can be remobilized over time and represents a continuing threat to the individual as Pb is resorbed from bone into blood to potentially impact cognitive health, cardiovascular health, and numerous other organ systems impacted by Pb.(21–23) In the major clinical trials of chelation on Pb-poisoned children, the effects were only evaluated using blood measurements; thus, they are missing a critically important aspect of Pb exposure via the total body stores in bone.(10,11,13,24) Chelation, while actively reducing blood Pb levels, would be dependent on bone stores of Pb, which would be released over time after the decrease of Pb in blood. Measuring bone Pb in studies of Pb poisoning is critical to understand the potential for ongoing endogenous release of Pb impacting health. The reduction of bone Pb stores would thus lead to a potential reduction in lifelong exposure from endogenous release of Pb. However, it remains unclear how bone Pb is impacted by chelation treatments. One previous study measured the changes of bone Pb in a pediatric population – noting that the bone Pb did decrease over time.(14) Importantly, this study was not able to clarify if this change could be related to chelation or if this was due to natural decay of bone stores in children.(14) Another case study identified changes in bone Pb associated with treatment, but again did not compare this data to predicted decay from known release of Pb from bone.(25) Understanding the effects of chelation of Pb in bone is important, and with little definitive literature on this critical aspect of chelation therapy, it is difficult to assess the potential effect of chelation on total body Pb stores.

In our study, we evaluated the impact of chelation on bone Pb measured via XRF of Pb-poisoned children in China in comparison to known bone turnover parameters. Thus, we are able to fill a critical gap in evidence relating chelation more directly to decreases in bone Pb. Using repeated measures of blood and bone Pb, we are uniquely able to determine the impact of chelation on bone Pb in comparison with natural bone turnover in a pediatric population.

This study demonstrates the positive effects of chelation in removing Pb from bone and, in-turn, reducing the long-term storage of Pb in the body. Alongside a multi-participant case study by Batuman et al. (25) and a study by Markowitz et al.(14) this study bolsters the evidence and found a significant reduction in total body burden stores of Pb as a result of chelation treatments. Although the study by Markowitz et al. did not show a significant reduction after adjustment for initial levels over the 7 week period, which is different from our study. Our results add vital information to the debate surrounding the efficacy of chelation treatment following elevated blood Pb levels.

Notably, this difference was shown to be much greater than could be attributed to bone turnover alone. Our calculation and comparison conservatively assumes a value of 60% uptake of Pb back into bone (K₁₂ in Figure 2), as other studies have reported ~60% for infants and an increase with age that peaks at ~90% in adulthood.(18,35,38) If uptake is in fact greater than 60%, resulting differences would be greater than what we found in our analysis. Further, we assumed that the children were completely removed from external Pb exposures. However, if exposures continued, the observed differences would move towards a null association. Thus, based on known bone turnover markers, our results indicate that chelation therapy is significantly effective in reducing bone Pb stores as well as blood Pb in highly exposed children. The bones of children may be more amenable to chelation of lead than the bones of adults because children’s bones are more porous than adults - the Haversian canals occupy a larger space in the bones of children, and therefore afford more surface area for chelation to occur. However, a previous case study did show a dramatic reduction in bone lead with chelation treatments in an adult.(25) Finally, the reduction in bone lead was greater with more EDTA treatments – even with a non-significant difference in total time elapsed.

A previous study identifying changes in bone Pb in children after chelation found a similar change in bone Pb on average.(14) In this previous study, bone Pb was measured similarly, but results were given as total net counts from the XRF measurement. Using the average value for the bone net counts of 191.4 in treated individuals and the average change of this value as 44.9, there is a 23% observed difference in bone lead after chelation. In our study, using the average values for children before treatment and the average difference, we observe at 27% difference in bone Pb. These values are similar and although the previous study used a higher blood lead Pb cut-off of 45 ug/dL, we saw similar, if not greater, differences in bone Pb for children with a blood lead cut-off of 25 ug/dL. This may indicate that chelation has a consistent impact across differing exposure levels. However, we are not able to compare important differences, as the study used different dosing and follow-up procedures in comparison to our study.

Importantly, we were unable to track the potential implications for changes in these children associated with zinc, copper, or iron. These bioessential metals would be additionally impacted by chelation treatments. In a previous clinical trial, children who were treated using succimer, a different chelating agent, were shorter on average.(13) It is unclear how repeated EDTA chelation treatments in our study may additionally impact the nutritional status of these children.

This study did have limitations that should be acknowledged when considering the results. The study relied on modeled data for control results rather than actual measurements of children not undergoing chelation therapy. This study was limited to young children with an average age of 4.1 ± 2.9 years, so the generalizability to other ages is lacking. As identified in our previous study, biokinetic markers vary significantly by age, and this will likely mean any biokinetic changes as a result of chelation would similarly depend on age. This study was also completed on children with blood Pb levels >25 μg/dL. The reduction may not have been so drastic had initial exposure levels been lower. Therefore, the beneficial effects of chelation may also be less. From Figure 4, children generally had decreases in bone lead on an individual basis, which would support the idea that further ingestion of lead was reduced or eliminated in these individual cases. However, from Figure 5 three children had increases in blood lead level, which may be from short-term exposure. Further studies would help to reduce these observed limitations and identify the key components in further reducing long-term bone Pb stores as a result of chelation therapy. Furthermore, it would be incredibly beneficial in future studies to identify biochemical markers of Pb toxicity such as protoporphyrin levels or aminolaevulinic acid dehydratase, markers of bone turnover, measurements of urine Pb, and other bioessential elemental changes.

The previous standard of care for chelation was identified based on literature that did not show the complete positive impact of chelation therapy on Pb storage in the body. With our results demonstrating a reduction of bone Pb after chelation therapy, there may be significantly increased advantages to treatment, while the risks remain the same. More research is needed to identify 1) whether there are potential benefits of removal of Pb from bone and 2) if so, at which point treatment should be ceased. These parameters will depend heavily on each individual case. Endogenous exposure from bone stores of Pb are identified as a significant source of exposure for years after the initial lead poisoning event.(21–23,36) A reduction in bone Pb would mean a significant reduction in endogenous exposure, which could reduce circulating Pb levels years after the initial exposure. This could potentially have a significant positive result on chronic health outcomes related to Pb exposure, as the release of bone stores as endogenous exposure is related to health outcomes.(21,22) More study is needed to identify how long-term health is impacted after chelation treatments due to a potential decrease in endogenous stores. On the other hand, chelating children with blood Pb levels in the 20–44 ug/dL range failed to result in demonstrable improvements in measures of intelligence in a multi-center NIH-funded randomized trial in the USA.(39) Moreover, the children who received succimer (a lead chelating agent) had significantly lower increases in height, a phenomenon that may reflect chelation’s collateral effect of increasing the excretion of nutrients involved in growth.(40) However, succimer did seem to improve motor function for children who had treatment.(41) Finally, succimer did not seem to improve brain function in the treated children and was shown to be potentially harmful. Although succimer, the chelating agent used in the trial, is an oral agent, it otherwise has similar pharmacologic properties to EDTA.

In conclusion, our study suggests that chelating children with various degrees of lead poisoning with EDTA, a treatment that is practiced in China and elsewhere, seems to reduce bone stores of Pb. Whether this ultimately results in improvements to health outcomes remains an important topic for research.