Update on Lead Poisoning: Implications for Blood Pressure and Intervention Strategies

Lead (Pb) poisoning can be evaluated at 3 levels: fundamental biochemical effects, subclinical organ dysfunction, and clinical disease. The presence of Pb in a child’s blood sample is an indicator that exposure and absorption have occurred. Blood Pb level (BLL) is a measure of potential toxicity because it is correlated with several health outcomes in groups of children. However, there are limitations to interpreting individual results.

What is measured is not plasma Pb, the immediate and most dangerous component of blood Pb, which can leave the blood compartment and enter cells. Rather, due to historical limitations of the laboratory, the overwhelming (≈98%) Pb content of red blood cells is measured . Therefore, BLL is a 2-step surrogate measure of Pb removed from the tissue cell, the site of greatest toxicity.

Furthermore, the residence time (similar to the half-life, a term that is strictly defined as the time it takes for the radioactivity of an isotope to decrease by 50%) of Pb atoms in blood is very different from that in the organs where it is produced. accumulates

If Pb atoms are injected into the blood, half disappear after approximately 3 weeks. In contrast, those that reach and enter brain cells remain for 1 to 2 years.

Most of the Pb accumulated in the body through prolonged exposure is found in the skeleton, where it can remain for years or decades.

Finding Pb in a single blood sample, assuming it accurately reflects the amount of Pb in the child’s blood at that time and is not due to sample contamination or other laboratory problems, does not define the duration of Pb exposure. , the accumulation of Pb or the degree of toxicity. Indicates past or current exposure. However, because there are many studies correlating BLLs in populations with health outcomes, it remains the gold standard for assessing risk of harm.

New laboratory methods, such as inductively coupled plasma mass spectrometry, that are increasingly available allow the measurement of nanogram per deciliter quantities of Pb in plasma.

These newer methods may allow us to finally define a threshold for the risk of Pb toxicity using this measure. At present, a “safe” BLL has not been determined, i.e. any BLL greater than 0 µg/dL (> 0 µmol/L) may be associated with toxicity in susceptible individuals.

Children ingest Pb. Pb rarely enters a child’s body through inhalation and pulmonary absorption. With few exceptions, Pb compounds do not significantly penetrate the skin topically to appreciably alter BLLs. Pb crosses the placenta; BLLs in pregnant women and fetuses are highly correlated.

When Pb-containing particles, such as paint chips or dust derived from such chips, are swallowed, only a small amount is digested enough to cause the release of Pb ions into a liquid phase. This prevents the death that could occur from eating a single chip of 1930s and 1940s premium paint the size of a child’s fingernail. That chip could contain 500,000 µg of Pb.

However, only a few micrograms will be released to be available for absorption. Although Pb atoms have an atomic weight of about 207 and calcium (Ca) has an atomic weight of about 40, the Pb atom is packed much more densely, producing a smaller radius. It can slip through Ca channels to enter cells.

Inside cells, Pb is distributed throughout the cytoplasm and nucleus. Pb binds to proteins through competition with Ca, zinc, and other metals at ionic binding sites, as well as accessible sulfhydryl, amine, phosphate, and carboxyl groups. It induces conformational changes, thus altering function. For example, calmodulin is a critical protein that normally binds Ca, which activates the protein, making it capable of multiple downstream actions.

Pb decreases these functions. The production pathways of the molecule can be affected by Pb at multiple enzymatic levels. The best description is Pb deficiency of the heme pathway. Heme is not only a part of hemoglobin, but is also an essential component of cytochrome p450 enzymes involved in steroidogenesis, vitamin D metabolism, detoxification, and fatty acid metabolism. The cytochrome p450 enzyme pathway is so crucial that it is ubiquitously distributed in almost every cell in the body. Three of the 8 enzymes in the pathway are susceptible to Pb inhibition.

The second enzyme, d-aminolevulinic acid dehydratase (ALAD), is one of the main Pb chelators in erythrocytes and is very sensitive to Pb. BLLs of at least 10 µg/dL (≥ 0.48 µmol/L) sufficiently inhibit the function of this enzyme to raise the concentration of its substrate, d-aminolevulinic acid. Congenital deficiency of ALAD results in one of the porphyria syndromes, indicating that excess substrate of this enzyme may be toxic.

Of interest, patients who receive chelation therapy for Pb poisoning that results in a reduction in BLLs have immediate recovery in ALAD function. Polymorphisms in the ALAD gene result in the production of proteins with different Pb-binding affinities; these may differentiate populations at risk of Pb toxicity, that is, while the enzymatic function of the protein may decrease, it acts to sequester Pb, thus preventing toxicity elsewhere. The last enzyme of the heme pathway is ferrochelatase. This enzyme promotes the binding of iron (Fe) to protoporphyrin.

Pb levels greater than 20 µg/dL (> 0.97 µmol/L) are associated with altered enzyme function, resulting in increased protoporphyrin levels and eventually reduced heme production. . In children with higher BLLs, serial measurements of erythrocyte protoporphyrin levels are a useful indicator not only of the effects of Pb but of the success of interventions to reduce the Pb load of a child’s body.

Protoporphyrin levels fall slowly after Pb ingestion is prevented. In summary, the cellular effects of Pb result not only in a reduction in the production of essential products but also in increases in concentrations of unmetabolized substrate that may be toxic in their own right.

When enough biochemical alterations accumulate in an organ, a subclinical disease occurs. The organ that appears to be most sensitive to Pb is the brain , and it is the effects on the brain that have largely driven public health efforts to eliminate childhood exposure to Pb over the past 40 or more years.

Tests of cognitive and behavioral function indicate inverse relationships with BLLs across the age spectrum; It is not limited to children. In fact, studies of maternal plasma Pb concentrations or BLLs during pregnancy, including the first trimester, find inverse correlations with offspring cognitive scores even 2 years after birth.

Estimates of the association between BLLs and IQ-type scores derived from multiple studies of children indicate a loss of approximately 0.5 IQ points for every 1 µg/dL (0.05 µmol/L) of increase in BLL, although the association may not be linear.

In a composite analysis of 7 longitudinal studies of more than 1,300 children, BLLs of 2 to 10 µg/dL (0.10-0.48 µmol/L) were associated with a 4-point drop in IQ versus an additional drop of 2 points for BLLs of 10 to 20 µg/dL (0.48 to 0.97 µmol/L), indicating a curvilinear relationship.

Other organs are also affected subclinically. Pb inhibits erythropoiesis, in part through reduced erythropoietin production. At high Pb concentrations, red blood cell survival is shortened. Renal failure eventually results in gouty nephropathy with a decreased glomerular filtration rate and development of Fanconi syndrome.

Spermatogenesis is abnormal, with a reduced number of sperm and fewer motile sperm. It seems that no organ is free from the effects of Pb. Epidemiological studies relate BLLs of 0 to 40 µg/dL (0 to 1.93 µmol/L) inversely with height in children, although it is not a sufficient decrease in height to give rise to endocrinological referrals for short stature. .

Similar studies indicate reductions in hearing ability at all frequencies, that is, more volume is needed for sounds to be heard as BLLs increase. Blood pressure increases as BLLs increase, initially without symptoms associated with elevated blood pressure.

Encephalopathy, seizures, and death are rarely reported with BLLs less than 100 µg/dL (<4.83 µmol/L) in children. However, fetal exposure to Pb increases the risk of death at much lower levels.

In a study conducted in Mexico City, Mexico, in a cohort of women enrolled in the first trimester of pregnancy, the risk of fetal loss doubled in women with initial BLLs of 5 to 10 µg/dL (0.24 to 0 .48 µmol/L) compared to a group with BLLs less than 5 µg/dL (<0.24 µmol/L) and was doubled again in the group with BLLs of 10 to 15 µg/dL (0.48–0 .72 µmol/L).

A recent analysis of adults aged 20 years and older who had BLLs measured and then tracked over the next 19 years found that the risk of death from cardiovascular causes increased by 70% as BLLs ranged between 1 and 6.7 µg. /dL (0.05-0.32 µmol/L) (10th and 90th percentiles). Similar studies on the risk of mortality with low levels of BLLs in children have not been reported.

At levels above 100 µg/dL (> 4.83 µmol/L) the risk of death increases in children. In the United States, there has not been a death attributed to such BLLs in more than 10 years. However, in other parts of the world, lead poisoning remains a cause of death.

Around 2010 and again in 2015, in the northeastern and central agrarian regions of Nigeria, public health workers found that more than 400 young children had died as a result of lead exposure that came from gold mining efforts.

Behavioral problems have been linked to BLLs of 20 µg/dL or more (≥ 0.97 µmol/L) in school-aged children, including attention deficits and disruptive and aggressive disorders. Pb exposure levels have been highly correlated with violent criminal behavior, after correcting for approximately a 20-year span, that is, greater Pb exposure in early childhood was associated with a higher crime rate than It happens 20 years later.

Epidemiological studies also relate BLLs to the number of dental cavities, indicating the need for careful attention to teeth during the evaluation and treatment of Pb poisoning.

Gastrointestinal discomfort consists of abdominal pain, constipation, and loss of appetite. Although constant abdominal pain (cramping) is associated with BLLs of 50 µg/dL or greater (≥ 2.42 µmol/L), intermittent recurrent gastrointestinal symptoms were found to be twice as common in young children with BLLs greater than 20 µg/dL (> 0.97 µmol/L) compared to those with BLLs less than 20 µg/dL (<0.97 µmol/L): 40% vs 20% in 1 unpublished study

Largely because Pb-containing paint was highly promoted and used in the United States, especially during the first half of the 20th century, the legacy of Pb poisoning continues to this day.

Ingestion of paint with Pb or its derived dust is the main source of Pb poisoning in children.

While several countries banned the use of Pb-based paints in the early 20th century, the United States did not establish national limits until 1978, when a minus 0.07% limit on allowable Pb content went into effect.

The Consumer Product Safety Commission (CSPC) revised that limit to 0.009% in 2009. State and local governments set limits long before the federal government. New York State limited the amount of Pb allowed in paint in 1970, and Baltimore, Maryland, banned paint with Pb in 1951.

The laws applied to Pb paint were intended for domestic use; apparently no such limit was imposed on schools. For example, the New York City Department of Education continued Pb paint applications until 1985. This was discovered in 2019 when a journalist visiting her son’s first grade class found chips of paint on the floor next to to the rug he sat on. Looking up she saw a crack under the window sill. She had the paint chips tested and discovered they were full of lead. She continued to collect samples of chips and dust from 4 other schools built before 1985, finding that all samples contained Pb.

The published story prompted the Department of Education to conduct an evaluation of New York City classrooms housing children ages 3 to 6 in schools built before 1985: 20% (1,800 classrooms) were found to have hazardous safety conditions. painting with Pb. Reduction efforts were carried out during the following summer vacation. Were the children hurt in those classrooms. No systematic testing of blood Pb or comparison of cognitive values ​​was performed to answer that question. Pb paint in schools is a potential major source of exposure.

Because this versatile metal has hundreds of other commercial uses, Pb can come from many sources. Older sources include the gasoline additive tetraethyl lead. Unlike other Pb compounds, tetraethyl Pb can penetrate the skin. Unfortunately, with Pb tetraethyl Pb, as the hydrocarbons in the gasoline burned, the Pb was expelled into the air. The use of Pb tetraethyl Pb was widely disseminated, causing contamination of surfaces, including soil, especially in urban areas.

The use of Pb tetraethyl was phased out beginning in the 1970s in the United States after having been widely used since its introduction in the 1920s. Food and beverage cans were sealed with Pb solder until the 1980s. , which contaminated foods and drinks, particularly those that were acidic. Today, the CSCP and the Food and Drug Administration (FDA) periodically report new items with unacceptably high levels of Pb that result in product recalls.

Product recalls may include contaminated foods (especially spices), ceramics, kitchen utensils, traditional medicines, jewelry, cosmetics, toys, crayons, wire coatings, pipes, furniture, and more. Most of these products are imported.

Pb in water re-emerged as a concern in 2014 due to contamination of the Flint, Michigan water supply when the source was switched. The new water supply had corroded old Pb pipes, releasing Pb into the drinking water. Like paint, Pb pipes were widely promoted for use in water utilities: for water mains in water treatment plants, leader pipes connecting water mains on streets, and pipes inside buildings and homes. .

The pipe connections used Pb solder. Brass taps contained between 8% and 25% Pb. If the water is acidic, it may leach Pb from these fixtures. Generally, stagnant water (from taps that are not used for hours) can have higher amounts of Pb if the sources of Pb are within the property, that is, not from the network under the streets.

Pb from water can usually be removed by running water for 1 to 5 minutes before use. Although BLLs may increase in the children examined who lived in Flint homes with water containing Pb, serious poisoning did not appear to have occurred.

The discovery raised enough concern that water testing was conducted in many other places in the U.S. For the first time, New York state mandated that all public schools in the state test their tap water.

New York City found that nearly 90% of its public schools had at least 1 faucet producing water with Pb above the Environmental Protection Agency’s (EPA) 15 µg/L (15ppb) limit for domestic water. . Please note that this standard is aimed at water supply companies and is not health-based. Currently, the American Academy of Pediatrics recommends no more than 1 ppb of Pb in drinking water. The APA is in the process of reviewing its Pb standards, although dropping to 1 ppb is highly unlikely.

For more than 50 years, the Centers for Disease Control and Prevention (CDC) has been conducting surveys, the NHANES, to determine the general health of the US population. The NHANES II was the first to include measurements of BLLs in the more than 20,000 participants from 1 to 70 years old.

From these data, the CDC determined the ages at which BLLs are highest and derived blood Pb detection concepts to evaluate the groups of children at highest risk. Peaks of BLLs were observed at ages 2 to 3 years. The original risk factors that were identified were being poor, living in older housing (especially in cities), and being of a minority race/ethnicity.

Recognizing that environmental exposure combined with non-nutritive hand-mouth activity is the combination that results in the majority of Pb poisonings, screening guidelines were developed that indicated the need to screen 1- and 2-year-old children: 1 year of age to identify those already ingesting Pb to intervene and prevent further ingestion and again at 2 years because the ability to walk and climb could increase access to new Pb-containing locations in the child’s environment during the period in which remains developmentally normal, non-nutritive hand-to-mouth activity. Other risk factors were later identified, including being an immigrant from a poor country.

Because ingestion is the main route of entry, pica behavior at any age is a risk factor. Careful examination of the relationship between BLLs and age shows that, although there is a sharp decline in average BLLs after age 3, the drop is only about one-third of the peak level. So, for example, if the peak BLL in children aged 2 to 3 years averaged 12 µg/dL (0.58 µmol/L), then the level at 4 to 19 years was approximately 7 to 8 µg/dL (0.58 µmol/L). .34 to 0.39 µmol/L).

In other words, the risk of Pb poisoning did not decrease to zero in the older participants in this cohort. This could reflect bone accumulation of Pb that occurred at younger ages with slow and steady release into the bloodstream or new ingestions occurring in a smaller portion of the cohort or at lower amounts of Pb ingestion.

Given that hand-to-mouth activity does not end at age 3 years but only declines in prevalence, it could be that persistent ingestion of Pb dust from contaminated hands is sufficient to account for the occurrence of measurable BLLs in older children. . Although epidemiological data are lacking to determine the prevalence of non-food-related hand-to-mouth activity in general populations, smaller studies are informative.

A study of 343 medical students in Poland found that 20% bit their nails at the time of assessment; an additional 27% had previously been nail biters.

Since the 1970s, the average BLL has decreased by more than 90%. With that reduction, the severity of Pb poisoning in the United States has also improved dramatically, with the near elimination of Pb-related infant mortality. Unfortunately, Pb continues to cause deaths in other parts of the world.

Although the BLL is our gold standard for determining Pb exposure, ingestion, and risk of toxicity, there are caveats to the interpretation of BLLs in individual children. As noted earlier in this paper, BLL is a measure of whole blood because most Pb adheres to red blood cells and is not found in plasma; the residence time is much shorter in blood than in target tissues; The BLL does not define the duration of exposure or total accumulation of Pb, and the BLL is not a direct measure of the effects of Pb. There are concerns about the testing method.

Capillary blood, although convenient to obtain and useful for screening, is subject to contamination and therefore false positives; Squeezing forcefully to obtain the drop of blood can dilute the sample with extracellular fluid, giving a false negative. Positive screening with capillary blood should be confirmed immediately with a venous sample. Fingerstick false negatives are simply not identified.

For venous samples, CDC requires laboratories to have measurement error ranges of less than ± 4 µg/dL (± 0.19 µmol/L) or 10% to pass proficiency testing for certification. Furthermore, considering that cognitive scores are the primary health outcome measure of concern, they have yet to define a safe BLL, that is, a level below which no discernible effect on observed health can occur.

So how should we interpret the gold standard results? The following numbers represent BLLs that should activate certain clinical responses.

Studies have repeatedly shown that cognitive scores and BLLs are inversely related, with an apparent decline beginning when BLLs increase above 0 µg/dL (0 µmol/L).

The implication of this observation is that toxicity is associated with BLLs somewhere between 0 and 1 µg/dL (0 and 0.05 µmol/L). That effect threshold has not been determined because previous studies used laboratory methods that could not accurately measure submicrogram amounts of Pb in blood. In the absence of a defined toxicity BLL threshold, when should interventions begin?

The CDC’s Senior Advisory Committee has grappled with this question for decades. In 2012, its members chose to use an epidemiological basis to select the children most in need of care. Around 2010, an NHANES cohort that included BLLs data collected from children 1 to 6 years of age showed that the top 2.5% of the distribution had a BLL of 5 µg/dL or more (≥ 0.24 µmol /L).

Providing health care resources for the population in this tail of the BLLs distribution curve would mean that, in 2012, approximately 500,000 American children would be eligible for a nationwide medical and public health intervention.

Using an epidemiological approach to avoid the issue of determining a Pb effect threshold based on a measured BLL, meant that as future surveys provided new data, the level of intervention for the 2.5% of young children with the highest levels could easily be adjusted without deliberation. In 2016, a new NHANES cohort found that the 2.5% level had decreased to 3.5 µg/dL (0.17 µmol/L). However, the CDC has not adjusted its intervention level as of April 2021.

An interesting phenomenon occurred after the CDC declared 5 µg/dL (0.24 µmol/L) as the intervention level. Although based on a representative cohort of young American children in 2010, the number was extrapolated as the intervention threshold for children of all ages and was adopted by other countries around the world. Therefore, although it is already outdated based on the most recent data from 2016, it is still the value that drives clinical and public health efforts for people far beyond the database from which it was derived.

When is Pb poisoning a clinical disease? The main symptoms of abdominal pain, constipation, inability to concentrate, and disruptive behavior appear to be associated with BLLs greater than 20 µg/dL (> 0.97 µmol/L). These symptoms are certainly not specific for Pb and occur in children with lower levels. However, the frequency of this type of complaints appears to be higher in children with BLLs greater than 20 µg/dL (> 0.97 µmol/L).

Chelation treatment , the use of drugs to bind Pb, is indicated for children with levels greater than or equal to 45 µg/dL (≥ 2.17 µmol/L). Above this level, chelation markedly improves Pb excretion in most children.

The goal of chelation is to prevent further toxicity, at least of the removed Pb atoms, which would also ideally be associated with recovery.

Unfortunately, currently available medications are not very effective in removing Pb from children with BLLs less than 45 µg/dL (<2.17 µmol/L). However, chelation reduces BLL at any level. Performing chelation in children with BLLs less than 45 µg/dL (<2.17 µmol/L) may not only be ineffective in inducing Pb diuresis, but may also cause harm. This again highlights another limitation in the interpretation of the BLL.

On the basis of the molar ratio, the addition of a second chelating agent with a different toxicity profile allows for faster removal of a greater amount of Pb. In the United States, where chelating agents have been readily available, 2 medications are used for children with BLLs of 70 µg/dL or greater (≥ 3.38 µmol/L). However, chelation even with a single agent, such as succimer, markedly reduces Pb-associated mortality in children with BLLs greater than 100 µg/dL (> 4.83 µmol/L).

The risk of Pb encephalopathy and death increases at BLLs greater than 100 µg/dL (> 4.83 µmol/L), although there are rare reports of encephalopathy occurring at lower levels. These children require closer observation during chelation because their central nervous system condition may initially worsen. Additionally, kidney failure is more likely during treatment at such high levels.

There are 4 steps for the prevention and treatment of Pb poisoning. The first 3 steps apply to almost all PB exposure situations. Intervention can be divided into preventing Pb poisoning (primary prevention) or mitigating Pb poisoning (secondary prevention).

> Step 1: Eliminate environmental exposure

Primary prevention of Pb poisoning involves the elimination of all sources of environmental exposure. Past extensive use of Pb-containing paint remains the most common source of exposure for children in the United States, with millions of residences still containing such paints.

Removing Pb paint from areas where children spend time should be an effective and permanent way to decrease cases of Pb poisoning. It is also the most expensive; Few, if any, government agencies require this of home and building owners. A compromise is to allow Pb paint to remain on surfaces but ensure that those surfaces are covered and sealed, for example by new sheetrock, and that these covers and seals remain intact.

An exception to this strategy applies to Pb-painted friction surfaces, such as doors and windows, where friction between surfaces can release Pb dust. Pb paint removal must be performed on these surfaces to eliminate this hazard.

For the removal of old paint, the APA has developed a method that should be used for the reduction (removal) of Pb paint; These regulations collectively are known as the Renovation, Repair and Painting Rule. These regulations also include training and certification requirements for contractors.

Work practices are designed to prevent the spread of paint particles and Pb dust on the job site and beyond and to protect workers from inhalation of Pb dust. The APA sets standards for the allowable content of PB dust on surfaces; These standards are currently under review. The Occupational Safety and Health Administration sets standards for allowable amounts of Pb in the air.

The APA also has jurisdiction over the Pb content of drinking water.

Tap water containing more than 15 µg/L of lead requires further investigation to determine the source of water contamination. Replacing lead-containing fixtures or pipes may result in the permanent elimination of these lead sources; Using APA certified filters can act as an economical alternative if used correctly.

The CSPC has jurisdiction over the Pb content limit in children’s products, currently set at 100 ppm. The FDA limits the Pb allowed in foods, supplements and cosmetics. For example, the current limit on bottled water, as opposed to tap water, is 5 ppb; in candies, the maximum level is 0.1 ppm; and in juice, the limit is 50 ppb.

It is unlikely that any of these standards will be completely protective, as they are unlikely to prevent BLLs from exceeding the 5 µg/dL (0.24 µmol/L) level.

Secondary prevention begins when a child is already identified as Pb poisoned. Typically, the local health department is responsible for handling cases. Although the triggers for different levels of investigation vary between departments, intervention efforts generally include the provision of educational materials about Pb-containing products and how to avoid them, followed by monitoring subsequent BLLs.

For higher BLLs, with the definition of "higher" varying between state and local health departments, a health worker is sent to the home to investigate sources of exposure, often starting with the condition of painted surfaces.

X-ray fluorescence instrumentation allows rapid assessment of the presence of Pb on surfaces such as walls. Collecting dust samples from floors and window components adds additional information about potential sources and helps guide efforts to eliminate these sources. If sources of Pb paint are found in rental units, the landlord is notified with instructions to correct Pb hazards. Execution depends on the health resources department, the financial resources of the owners and the willingness to comply.

Because APA-certified contractors generally charge more, there is a temptation to use untrained workers. Such practice has led to marked Pb poisoning in children who remain living in the home while Pb mitigation work is being carried out. It is helpful when care providers warn families of the risk of unqualified parts.

A determination that drinking water is contaminated should lead to a search for the source. Identifying and remediating the source can also be a costly endeavor, although the use of appropriate Pb filter devices at the tap can at least temporarily reduce the Pb content.

> Step 2: Elimination of non-nutritive hand or object-to-mouth behavior

Often, a single child in a household is the only member with Pb poisoning. Why don’t siblings and parents poison themselves too? One main reason is that being in a room with Pb is insufficient to cause poisoning.

Pb has to find a way into the body, which for children is usually due to non-nutritive hand or object-to-mouth behavior. Eliminating habitual non-nutritive oral behavior is easier to talk about than to do.

Developmental "aging" may be more effective. For older children with persistence of this behavior, numerous strategies have been used.

When behavior modification fails, residing in a Pb-safe but not Pb-free environment may not be sufficient to prevent further ingestion. Children are experts at making holes in walls, therefore accessing older layers of paint with higher amounts of Pb.

> Step 3: Promotion of adequate nutrition, especially for essential metals and their related vitamins

Pb taken on an empty stomach is more likely to be absorbed than when taken with food. Numerous studies have established that Pb competes with essential elements, especially Ca and Fe, for absorption.

Pb is more toxic and is more difficult to eliminate even with medications in children with deficiencies of essential metals, especially Fe.

Correcting such deficiencies is important. However, once corrected, continued prescription of Ca or Fe replacement doses does not appear to have any further substantial effects on BLLs.

At that point, the normal daily requirements seem to be sufficient. To absorb Ca, vitamin D is essential; To effectively absorb Fe from sources other than meat, vitamin C is useful.

> Step 4: Chelation Therapy

Treatment is guided by the BLL. Currently, there are 4 chelating agents available in the United States. The first, British anti-Lewisite (BAL), is no longer in use because it requires deep intramuscular injections every 4 hours, usually with 2 injections at a time, for 3 to 5 days.

BAL is toxic and its odor is nauseating. A second drug, penicillamine, is rarely used. The advantage of penicillamine is that it is taken orally. But penicillamine is a weak chelator, also with a high toxicity profile, and requires months of treatment.

Penicillamine also eliminates essential elements. The decision to use BAL or penicillamine for lead chelation should be made only in consultation with chelation experts. The third drug, calcium disodium (CaNa2) EDTA, can be administered intravenously or intramuscularly and has limited and reversible toxicity when administered correctly to control the rate of administration and prevent extravasation. This drug is always administered as Ca salt; administration of Na2EDTA will precipitate hypocalcemia. The most widely used drug, succimer, is also the newest drug.

Succimer is a congener of LAB and is administered orally. It has an excellent safety profile and, compared to most other agents, is less expensive. The amount of Pb removed over a 5-day period is comparable to CaNa2EDTA. Succimer has been available for clinical use in children since 1991. No new agents have been approved for Pb poisoning since that year. Both medications (succimer and CaNa2EDTA) are used together for children with BLLs greater than or equal to 70 µg/dL (≥ 3.38 µmol/L) to improve Pb excretion, with succimer replacing the previous use of BAL in this regimen .

Historically, a dose of BAL was given 4 hours before the start of CaNa2EDTA treatment because it seemed to better protect the brains of children severely poisoned with Pb. Similarly, succimer can be administered first as a “head start” in the current regimen.

Chelation does not remove all Pb from the body. Because there is residual Pb in the body after chelation, especially in the skeleton, BLLs recover over the following weeks or months. However, BLLs rarely reach the level of prechelation. If this occurs, re-ingestion should be strongly suspected. Currently used drugs do not eliminate substantial amounts of Pb in children with pretreatment BLL levels less than 45 µg/dL (<2.17 µmol/L). Because none of the chelators are specific for Pb, essential metals may be removed in greater quantities in children with low BLLs, a detrimental effect.

Zinc deficiency can affect growth and maturation; Fe deficiency contributes not only to anemia but also to cognitive impairment. Therefore, there is no effective and safe chelating agent for children with BLLs less than 45 µg/dL (<2.17 µmol/L).

In addition to improving Pb excretion, does chelation improve results? As noted above, the enzymatic activity of BLLs and ALAD is inversely related. Changes in BLLs are also inversely related to changes in ALAD activity, that is, if BLLs decrease after chelation and then ALAD activity increases. As BLLs recover, ALAD activity decreases.

On the other hand, erythrocyte protoporphyrin levels continue to fall after chelation even when BLLs rebound, indicating a more permanent effect. At very high BLLs (> 100 µg/dL [> 4.83 µmol/L]), chelation is associated with a marked reduction in mortality. There are no controlled studies showing cognitive improvement after chelation at lower levels.

In the previous paragraph, examples of biochemical reversibility were given. The heme pathway is in brain cells, so improvements in function are likely occurring there as well.

However, observational longitudinal studies have repeatedly shown that cognitive scores are inversely related to BLLs regardless of when those levels were determined; If BLLs at age 2 are associated with IQ scores at age 7, doesn’t that indicate permanent effects. Furthermore, studies of brain size and metabolic activity show differences in the parts of the brain involved in the control of memory/learning and behavior in young adults with Pb poisoning in early childhood.

However, 2 interventional studies that aimed to evaluate the effects of BLLs reduction and the effect on cognition scores offer hope that some of the deficits attributable to Pb are recoverable, at least in children.

The first study followed 154 previously untreated boys ages 1 to 7 for 6 months. BLLs at enrollment were 20 to 55 µg/dL (0.97 to 2.66 mmol/L). Interventions included efforts to reduce exposure, improve nutritional status, and encourage less nonnutritive behavior, and for approximately one-third of those enrolled, CaNa2EDTA chelation.

The drug was administered based on the result of the lead mobilization test, when a timed urinary Pb sample was taken after a single dose of the drug CaNa2EDTA was administered to demonstrate efficacy, or not, in inducing a urinary diuresis. Pb. This study found a significant inverse relationship in change scores on the BLLs and cognitive measures after controlling for confounding variables.

The magnitude of the change was approximately one-third of an IQ point per 1 µg change in BLLs. On average, BLLs decreased from 31 µg/dL (1.50 µmol/L) to 24 µg/dL (1.16 µmol/L) over the 6-month study period, and cognitive scores improved.

The second study was a multicenter, blinded, randomized, placebo-controlled trial to test the efficacy of succimer on cognitive and other outcomes. Seven hundred and eighty children approximately 2 years of age were treated with succimer or placebo up to 3 times in the first 6 months of the study and then followed until age 4 years when analyzes were performed.

Unlike the previous study, children in this study had lower pretreatment BLLs levels of 20 to 44 µg/dL (0.97 to 2.13 µmol/L), with a mean BLL of 26 µg/dL ( 1.26 µmol/L). BLLs were measured repeatedly and cognitive scores were obtained at the beginning and end of a 2-year period.

Although BLLs were lower at the end of 6 months in the succimer-treated group, the average BLLs of the 2 groups converged by 1 year. They remained statistically indistinguishable after 2 years of study. Similarly, the average cognitive scores in children who are now 4 years old were also indistinguishable.

The researchers concluded that succimer treatment of 2-year-old children in this BLL range was ineffective in improving cognitive outcomes or BLLs. The researchers then reanalyzed their data using a statistical approach from the previous intervention study. Instead of comparisons of 2 group means, they performed regression analyzes to look at the change in BLLs versus the change in cognitive scores.

As in the previous study, an inverse relationship was observed between change scores, that is, for any given change in BLLs over time, cognitive scores moved in the opposite direction (e.g., if the BLLs decreased, cognitive scores improved). Furthermore, they found that this relationship occurred only in the placebo group.

The magnitude of the relationship was also comparable: for every 1 µg/dL (0.05 µmol/L) change in BLLs, cognitive scores changed by 0.4 U. However, no relationship was observed between cognitive scores. change in the chelated group. One inference from this finding is that succimer was not only ineffective in improving scores on average, but was also potentially interfering with possible recovery in children whose BLLs were declining.