Lead exposure is confirmed by measurement of a venous blood lead concentration (see section 5). An elevated blood lead concentration may be due to a single acute exposure or to continuing exposure. Termination of lead exposure is an overarching principle of this guideline, as, without this action, lead will continue to exert toxic effects in target organs, with both short-term and long-term negative health effects (see section 4.4). Some examples of measures to identify and terminate exposure are described in section 8. For some cases of lead ingestion, it may be appropriate to use GI decontamination to stop further absorption, as discussed in section 7.1. Nutritional supplementation with calcium and iron may mitigate some of the effects of exposure, as described in section 7.2. When blood lead concentrations are high and/or the patient is showing significant features of lead toxicity, chelation therapy to facilitate lead excretion may improve health outcomes, as described in section 7.3.
A systematic evidence review was not considered necessary to determine the threshold blood lead concentration at which interventions should be initiated to manage lead exposure and poisoning because reviews have already been issued by international and national bodies, including WHO (15,16,17,34,93,103). These document the adverse health impacts of lead particularly at exposure levels of 5 g/dL and below, which is summarized in sections 4.4 and 4.5. The factors taken into account in this decision are described in an evidence-to-decision table available online (Web Annex).
Poison centres offer advice on the management and treatment of lead poisoning. Credit: WHO / Blink Media -Amanda Mustard

# Recommendations for all age groups
1 / In all cases of suspected or confirmed lead exposure, the patient or carer should be given information about sources of lead exposure, methods for reducing exposure and the importance of good nutrition, in particular adequate dietary intakes of iron and calcium.

# Good practice statement
Providing health and preventive information to lead-exposed patients or their carer in the case of children is in line with WHO recommendations on the importance of health literacy in promoting good health (144) and is, therefore, considered to be good practice. Specific recommendations for improving calcium and iron intake are given in section 7.2.
WHO provides a range of information and advocacy materials on lead that can be adapted for local use (145).
2 / For an individual with a blood lead concentration  5 g/dL, the source(s) of lead exposure should be identified and appropriate action taken to reduce and terminate exposure.
Strong recommendation, high-certainty evidence of the toxicity of low-level exposure to lead
There is consistent evidence from human observational studies and experimental animal data that exposure to lead even at low levels is associated with deleterious health effects (15,16,17,34,93,103). As described in sections 4.4 and 4.5, a blood lead concentration below which there are no negative effects on health has not been identified; blood lead concentrations as low as 5 g/dL and 10 g/dL are associated with a range of effects, including impaired neurocognitive and behavioural development in children and cardiovascular disease in adults (Fig. 2). The health impacts of lead exposure in childhood may persist into adolescence and adulthood (119)(120)(121)(122); therefore, terminating exposure is particularly important for this age group. The lack of a threshold blood lead concentration for toxicity implies that action should be taken if any lead is measured in blood. This is not necessarily practicable, however, because reliable measurement of very low blood lead concentrations requires advanced analytical equipment and a high level of technical skill (142), which are not available in all countries.
In high-income countries with effective regulatory control of sources of lead exposure, blood lead concentrations have been decreasing steadily over the past 10-20 years and are now very low in most people. Typically, the health authorities in those countries define excessive exposure to lead in relation to the reference value for the population as a whole. This is usually the blood lead concentration that characterizes that of the top 2.5% or 5% of the population, i.e. the 97.5th or 95th percentile, respectively. In France, for example, 5 g/dL is the 98th percentile value for children < 7 years (146). Germany has adopted reference values of 3.5 g/dL for children aged 3-14 years, 7 g/dL for women and 9 g/dL for men (147) In view of the above and the extensively reviewed toxicological data and practical considerations, the guideline development group decided that a blood lead concentration of 5 g/dL was a pragmatic value at which to initiate clinical interventions.

# Values, equity, feasibility and acceptability of a 5 g/dL threshold value
The anticipated outcome of this recommendation is a reduced likelihood of lead-related health, social and economic impacts. This would be expected to be valued by the person concerned, the carer in the case of a child and by society as a whole.
Health equity considerations include the disproportionate burden of lead exposure in economically deprived and disadvantaged populations, particularly in low-and middle-income countries (151)(152)(153)(154). The United Nations Children's Fund has estimated that about one in three children globally has a blood lead concentration > 5 g/dL (151). In some settings, working with lead is an important livelihood, and options for stopping exposure may be limited. This is particularly true when individuals and communities lack the influence or power to improve their work or environmental conditions. When effective action is taken, however, a blood lead concentration > 5 g/dL could improve health outcomes by reducing the short-and long-term adverse health and social impacts of lead exposure.
Blood lead concentrations  5 g/dL can be measured without highly sophisticated laboratory instrumentation (142). For screening purposes, a capillary blood sample can be analysed in a point-ofcare analyser, which is relatively low-cost and simple to operate (142).
The feasibility of terminating lead exposure depends on the type of intervention required. This could be relatively simple, such as stopping sale of lead paints or more complicated and costly, such as remediation of contaminated land. Where the source of exposure is related to economic activities, such as lead recycling or mining, the feasibility and acceptability of terminating lead exposure will depend on whether working methods can be changed to reduce exposure or on the availability of alternative sources of income. This is a particular challenge in lowincome communities engaged in small-scale artisanal industries (155). At low blood lead concentrations, the toxic effects are largely subclinical. Therefore, in the absence of understanding of the potential long-term impacts of exposure, governments may be less motivated to take action.

# Considerations for implementation
Health-care providers, in particular family doctors, community health nurses, paediatricians, obstetricians and midwives, should be trained in identifying the risk factors for lead exposure and the prevention, diagnosis and management of lead poisoning.
Identification and confirmation of exposure require access to analytical equipment and laboratory services for measuring blood lead concentrations. WHO guidance is available on the selection of analytical methods and for establishing a laboratory service for this purpose (142). As discussed in section 5, the venous blood lead concentration is the definitive biomarker of exposure and risk on which management decisions are routinely based; however, for screening purposes, use of capillary samples is acceptable.
When lead exposure is suspected but the blood lead concentration is < 5 g/dL, a follow-up measurement may be carried out after 6-12 months to rule out a continuing source of lead exposure.
Lead poisoning and gold processing in Zamfara state, Nigeria, Ap. Credit: Olga Victorie/MSF 07 /

# Recommendations for specific treatment interventions
This section provides WHO recommendations on specific aspects of the clinical management of patients with lead poisoning and descriptions of the type and strength of the evidence for each. The recommendations are for:
- GI decontamination after ingestion of lead;
- nutritional interventions in children and pregnant and lactating women; and
- chelation therapy in children, adolescents, adults and pregnant women.
The single most important action in the management of any lead exposure is to take measures to stop the exposure as quickly as possible. This alone will itself result in a reduction in the blood lead concentration and clinical improvement.
- 1 Gastrointestinal decontamination after ingestion of a lead foreign body or other lead-containing material
The aim of GI decontamination is to remove lead objects or lead compounds from the GI tract and reduce or prevent absorption, thereby reducing the risk and severity of lead poisoning. The available methods for GI decontamination in the management of poisoning have been reviewed by the American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists. The methods are administration of activated charcoal (156), induced emesis (157), gastric lavage (158), administration of cathartics (159) and WBI (160). Not all of these methods are, however, applicable to the clinical management of lead ingestion, as discussed below.
In addition, objects or materials can be removed from the gut by endoscopic or surgical procedures.
A number of factors bear on the efficacy of any of these methods, including the interval between ingestion and attempted decontamination, the quantity of toxic substance ingested, the physicochemical properties of the substance (e.g. whether it can bind to activated charcoal, its solubility) and the potential adverse effects of the decontamination technique in the context of the substance ingested (e.g. the risks of inserting a lavage tube if a corrosive substance has been swallowed).
Lead poisoning is most often associated with chronic ingestion of small amounts, e.g. in young children who ingest lead-contaminated dust through hand-to-mouth behaviour or some individuals with pica who eat large quantities of lead compounds, e.g. paint flakes, over time.
In such cases, there may be significant amounts of lead in the gut, which is often visible on an abdominal X-ray (161). Lead poisoning can also occur after acute ingestion of a lead object, e.g. a curtain weight or a fishing weight or sinker, which remains in the acidic environment of the stomach or in the intestines for days or weeks and from which lead is slowly absorbed (68,69). More rarely, lead poisoning can result from intentional or unintentional acute ingestion of a toxic amount of a lead compound.
Evidence was sought for the impact of GI decontamination on the following outcomes:
Critical outcomes - blood lead concentration;
- neurological (cognitive, neurobehavioural and neuromotor) effects of lead poisoning measured in standardized, validated tests;
- mortality; and
- symptoms and signs of lead poisoning, e.g. abdominal colic and encephalopathy.

# Important outcomes
- lead foreign bodies seen in vomitus, lavage fluid, stools or effluent; and
- adverse events of GI decontamination.
The search found only case reports and small case series describing GI decontamination following lead ingestion. There were no randomized or other controlled studies. In many studies, multiple methods of GI decontamination were used. The type and quantity of ingested material varied considerably. The most commonly reported outcome was removal of the material from the GI tract with a few studies reporting on adverse events (8). Patients with elevated blood lead concentrations were usually given chelation, which confounded any interpretation of the impact of GI decontamination on clinical outcomes. The evidence could not be evaluated with the GRADE approach; rather the level of the evidence was categorized according to a scheme adapted from the Oxford Centre for Evidence-based Medicine Levels of Evidence Working Group (2009) (157).
As there were no randomized controlled studies, the certainty of evidence for all outcomes was categorized as very low. Tables summarizing the interventions and outcomes are provided in a supplementary online document (Web Annex). The basis for the recommendations below is described in the evidence-to-decision table provided online (Web Annex). No specific studies were identified that examined issues of values, equity, feasibility or acceptability with regard to GI decontamination following lead ingestion, however, some observations are made in section 7.1.3. Considerations for the implementation of these recommendations are given in section 7.1.4.
The recommendations below suggest use of medical imaging in certain circumstances to confirm the presence of and locate and monitor the movement of lead in the GI tract. The most commonly used technique is abdominal X-ray. WHO guidance is available on the factors to be considered in deciding on radiological imaging (162).
X-Ray image of pica in child's gastrointestinal tract.
Credit: Courtesy of Paul Dargan.

# Recommendations for all age groups
1 / Take measures to remove solid lead objects, such as a bullets, lead pellets, jewellery, fishing or curtain weights, that are known to be in the stomach.
Strong recommendation, very low-certainty evidence.
The available evidence consisted of 13 case reports and was categorized as of very low certainty (8, Web Annex). Endoscopic procedures were the most commonly reported intervention (Web Annex); they were partially or fully successful in removing foreign bodies in nine cases and ineffective in two. One of the cases in which it was ineffective subsequently underwent surgery, and surgery alone was used in two cases. WBI was used in two cases, in combination with other methods of GI decontamination (Web Annex).
In four case reports of lead objects in the stomach, GI decontamination was not used (Web Annex). Three cases were fatal, as the presence of lead was either discovered when poisoning was at an advanced stage or post mortem.
In the fourth case, the object was seen in the antrum of the stomach shortly after ingestion and had moved into the large intestine by day 5. The risk of severe lead poisoning is high when a lead object remains in the stomach as the acidic environment increases dissolution of lead, which is then absorbed. The longer the object remains in the stomach, the more likely it is that toxicity will occur. There is, however, insufficient evidence to establish how long a lead object can be left in the stomach without harming the patient, in view of many variables, including the nature of the object (size, number and surface area) and patient characteristics (e.g. age, clinical status). When multiple small objects, such as pellets, have been ingested, the blood lead concentration can rise rapidly (163).
In spite of the very low certainty evidence, the guideline development group considered that the balance of harms and benefits favoured removal of a lead object to prevent potentially severe or fatal lead poisoning and advised a strong recommendation. Removal is particularly important if the blood lead concentration is increasing, there are features of lead toxicity, or the position of the object has been monitored and it has not moved for some time. Suggested methods are oesophagogastroduodenoscopy or surgery or, if these are not available, WBI. The decision on the approach to be used should be made for each case, usually in discussion with other specialist teams such as of endoscopists and surgeons.
The use of emesis or gastric lavage was considered unlikely to be effective owing to the weight, size and shape of most lead foreign bodies; moreover, emesis carries the risk that the object will cause choking. Metallic lead is not bound by activated charcoal (164).
2 / Consider whole bowel irrigation for removing solid lead objects, such as a bullets, lead pellets, jewellery, fishing or curtain weights that are known to have passed through the stomach.
Remarks: If WBI fails, i.e. the object or objects are not removed, and there is evidence of lead absorption, e.g. an increasing blood lead concentration or features of lead toxicity, consider endoscopic or surgical removal.
Conditional recommendation, very low-certainty evidence.
The only evidence identified was from 18 case reports and is categorized as very low certainty. The cases involved ingestion of lead pellets, bullets or fishing weights in numbers ranging from one to several thousand (8, Web Annex). In 12 cases, a combination of WBI and/ or a cathartic and/or endoscopy and/or surgery was used.
The duration of WBI varied from 6 h to 3 days. In four of five cases in which only a cathartic was used, expulsion of lead was reported over periods of 4-20 days. In six cases in which no GI decontamination was used, the lead objects cleared from the GI tract in 7-17 days (Web Annex). The diversity of the cases made it difficult to draw conclusions about the relative effectiveness of WBI, cathartics and allowing spontaneous elimination in preventing lead toxicity.
In view of the very low-certainty evidence, a conditional recommendation was made for WBI, on the grounds this method is that generally accepted for removing bulky or poorly soluble toxic materials from the GI tract (160).
The guideline development group took note of the evidence-informed joint position statement of the American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists, which concluded that there was no evidence for the effectiveness of cathartics in the management of poisoning and advised against use of more than one dose of cathartic (159). On the basis of the limited available evidence and clinical experience, the guideline development group considered it unlikely that one dose of cathartics would remove a solid object from the gut.
Some solid objects pass through the GI tract of their own accord, and a decision to use WBI should be taken case by case. When WBI cannot be conducted or is unsuccessful and there is evidence of increasing toxicity, more invasive methods such as endoscopy or surgery may be considered.

# / Consider surgical removal of solid lead objects, such as bullets or lead pellets, that are known to be in the appendix if the patient shows clinical signs of appendicitis or an increasing blood lead concentration.
Remarks: If the patient is clinically well, surgical removal is not necessary but the blood lead concentration should be measured periodically to check for lead absorption. Treatment options should be reviewed if the patient becomes symptomatic or if the blood lead concentration starts rising.
Conditional recommendation, very low-certainty evidence.
The evidence for this intervention is based on case reports and small case series on a total of 87 patients (8, Web Annex). Six patients showed lead toxicity and 13 developed appendicitis, including one with lead toxicity. Appendectomy was performed on 31 patients, including all those with lead toxicity, and the remainder were monitored. Only three patients were given chelation therapy. These cases suggested that the presence of lead in the appendix does not necessarily result in harmful effects.
In view of the very low-certainty evidence, a conditional recommendation was made. For a patient with no evidence of appendicitis or clinical or biochemical evidence of lead absorption, the guideline development group suggested monthly assessment for the first 3 months, followed by less frequent monitoring thereafter, provided the patient remains clinically well. It is recognized that some patients and physicians may prefer to remove the lead, even if it is not affecting health, as a preventive measure.

# / Consider whole bowel irrigation for removing liquid or solid lead-containing substances, such as paint chips, lead-containing complementary or alternative medicines or ceramic glaze, when the material is known to be dispersed in the gut.
Conditional recommendation, very low-certainty evidence.
Twenty case reports were identified, most of which involved ingestion of ceramic glaze or lead paint chips, shown on abdominal X-ray to be dispersed through the GI tract (8, Web Annex). In nine cases, several methods of GI decontamination were used, including gastric lavage, activated charcoal, WBI and cathartics. WBI was used alone in six cases, gastric lavage in four cases and cathartics in one case. WBI cleared the GI tract of ceramic glaze in all three cases in which it was used and lead paint chips in three of five cases. GI decontamination did not necessarily prevent an increase in blood lead concentrations.
Lead compounds are toxic, and absorption occurs mainly in the duodenum (93). The guideline development group considered that, when lead-containing materials are visible in the GI tract, GI decontamination is justified to reduce absorption and, potentially, the severity of poisoning. While the certainty of evidence for any method is very low, WBI is preferred over other methods as a means of clearing the whole of the GI tract. In view of the very low-certainty evidence, a conditional recommendation was made.

# Values, equity, feasibility and acceptability of GI decontamination
Patients and children's carers would be expected to value the possibility of reducing the risk of potentially severe toxic effects through GI decontamination.
The identified evidence was from high-income countries, and it was recognized that the availability of equipment and trained staff to carry out more invasive procedures such as paediatric oesophagogastroduodenoscopy or surgery would depend on the setting. A patient might have to be transferred to a tertiary-care hospital. Polyethylene glycol-electrolyte solution, used for WBI, may be more readily available in lower resource settings as it has other medical uses, such as bowel cleansing before surgery or colonoscopy. This preparation is not, however, on the WHO Model List of Essential Medicines (165). Health equity would be improved if the necessary resources were available to provide appropriate GI decontamination interventions for ingestion of lead and other harmful or toxic agents.
Feasibility and acceptability would be influenced by the availability of resources for these interventions and the associated costs. Some patients, particularly young children, may find WBI difficult to tolerate, as it involves administration of a fairly large volume of polyethylene glycol-electrolyte solution, usually through a nasogastric tube. Home-administered WBI was used in a case of ingestion of lead foreign bodies, although no details were provided of the regimen used (166). No description of such use was found for lead compounds; however, as lead absorption is likely to be rapid, treatment at home may not be appropriate.

# Implementation considerations for GI decontamination
The review of GI decontamination covered ingestion of various types and quantities of lead-containing material. Thus, the most appropriate method of GI decontamination differs from case to case. Factors to be taken into account include the size, nature and quantity of the lead object(s) or lead-containing material ingested, the time that the material has been in the stomach or other parts of the GI tract, evidence of lead absorption, the clinical condition of the patient and the availability of resources for the intervention.
GI decontamination is often considered in the management of poisoning. It is therefore important that medical personnel be trained in the appropriate use of GI decontamination methods. Medical personnel should also be trained in the diagnosis and management of lead poisoning. The management of lead poisoning requires access to laboratory services for measuring blood lead concentrations. WHO guidance is available on the selection of analytical methods and establishing a laboratory service for this purpose (142).
Endoscopic procedures are standard practice for removing foreign bodies when there is a risk of harm to the patient (167). National and international professional societies have developed evidence-based or evidence-informed clinical guidelines on the use of these procedures in children (168,169) and adults (170). Oesophagogastroduodenoscopy is particularly applicable for large objects that will not easily pass the pylorus, and its use may obviate surgery.
General skills in the administration of abdominal surgery (including laparoscopy) should be available in secondary and tertiary medical services. WHO guidance is available on appendectomy (171).
WBI should be conducted only with an iso-osmotic polyethylene glycol-electrolyte solution, in order to avoid electrolyte or fluid imbalance in the patient during administration. A procedure for administering WBI is provided in Appendix 3 of the joint position statement of the American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists (160).
The patient's clinical status and blood lead concentration should be monitored and additional interventions taken accordingly (see sections 7.2-7.3).
After GI decontamination, it is, of course, essential to ensure that the patient is not further exposed by taking appropriate preventive measures, for example removing lead paint and lead objects from the home or ensuring that they are kept out of sight and out of reach of children.

# Nutritional interventions in children and in pregnant and lactating women exposed to lead 7.2.1 Introduction
Evidence from studies in experimental animals and humans indicates that nutritional factors, including intake of minerals and vitamins, alter susceptibility to lead (15,34,172). Possible mechanisms include modification of lead absorption, deposition in tissues and release from body stores and modification of the toxic effects of lead, for example through interaction with lead bound to cellular enzymes (34,173,174). The interactions of lead with dietary factors such as calcium, iron and zinc are complex.
Lead is thought to compete with calcium and iron for absorption from the gut, and low-calcium diets and iron deficiency have both been associated with higher blood lead concentrations (34,(175)(176)(177)(178)(179)(180)(181). Low calcium intake is associated with increased deposition of lead in soft tissues and bone (173). During pregnancy, lead can be remobilized from bone stores as calcium is taken to form the fetal skeleton (93,100,182). High calcium intake during pregnancy can reduce maternal skeletal-bone turnover (183,184) and may therefore protect against an increased blood lead concentration. In the case of iron, there may be synergistic or additive effects between iron deficiency and lead toxicity, in particular with regard to anaemia and impaired cognitive functions (174,185,186). Low dietary intake of zinc is also associated with higher blood lead concentrations in young children; however, the mechanism has not been determined (34).
With regard to vitamin intake, vitamin D may have a protective effect, as it increases intestinal absorption of calcium and phosphate and is important for maintaining adequate serum concentrations for bone mineralization (187). Studies in experimental animals suggest that some antioxidant vitamins, such as vitamin C, have a protective effect against lead toxicity (188). A cross-sectional study in the USA of data from the Third National Health and Nutrition Examination Survey found an association between high serum levels of ascorbic acid and decreased prevalence of elevated blood lead levels (189).
Supplementation with minerals and/or vitamins may protect against or mitigate the toxic effects of lead. This may be particularly the case in economically deprived populations who are doubly burdened by nutritional deficiencies and high lead exposure (173).
The systematic review considered the following outcomes:

# Critical outcomes
- blood lead concentration;
- cord blood lead concentration;
- neurological (cognitive, neurobehavioural and neuromotor) outcomes in children measured in standardized, validated tests;
- mortality in neonates and severely poisoned children and women;
- symptoms and signs of lead poisoning; and
- pregnancy outcomes, namely live birth and survival to one year, birth weight and neurological status of the neonate.

# Important outcomes
- lead concentration in breast milk,
- mobilization of lead from bone (in women) and
- adverse effects of nutritional supplementation.
Good nutrition is important in protecting and mitigating against the toxic effects of lead. Credit: WHO
The systematic evidence review addressed the groups most vulnerable to lead toxicity, namely neonates, children, adolescents (< 19 years) and pregnant and lactating women. It was initially planned to include only studies in which participants had blood lead concentrations  5 g/dL; however, very few relevant studies were found, and it was decided to include studies in which participants had lower blood lead concentrations, although this resulted in some indirectness of the evidence.
A small number of RCT were identified of calcium supplementation for children and pregnant and lactating women and of iron and zinc supplementation for children.
The outcomes reported after calcium intake were lead concentrations in blood, breast milk and bone; the outcomes reported after iron and zinc supplementation were blood lead concentrations and cognitive and behavioural outcomes. The studies with zinc provided moderate-certainty evidence of no benefit, and no recommendation was made. Small, individual studies, most including fewer than 100 subjects, were identified for combinations of calcium with vitamin A, C or D, but the evidence they provided was insufficient to make a recommendation. No studies that met the inclusion criteria were found for other vitamins or minerals.
The available studies were conducted with patients who had relatively low blood lead concentrations, and they did not address the question of whether such interventions would be of benefit to patients with significant (blood lead concentration > 45 g/dL) or severe (blood lead concentration > 70 g/dL) lead poisoning.
The study populations included subjects judged to be deficient in the nutrient under study and subjects judged to have adequate nutrition. Overall, the certainty of the evidence was moderate to very low (9). GRADE summary-of-findings tables and evidence-to-decision tables are provided in supplementary online material (Web Annex).
No specific studies were identified that examined issues of values, equity, feasibility or acceptability with regard to nutritional supplementation after lead ingestion; however, some observations are made in sections 7.
The level of calcium supplementation should be sufficient to ensure that the total calcium intake meets the national age-appropriate recommended nutrient intake value.

# Strong recommendation, very low-certainty evidence
Evidence was provided by four RCTs, two of which were placebo-controlled. The studies were small, and the populations differed in age, blood lead concentration, calcium intake and calcium dose and were therefore not pooled (9, Web Annex). In the largest study (400 subjects, variable regular intake of calcium), the mean blood lead concentration in the intervention group was 5 g/dL lower (95% CI, -6.42 ; -3.58 g/dL) than that of the control group after 3 months of supplementation with 500 mg calcium, with a smaller effect in the group given 250 mg calcium (190). A treatment effect was still seen after multivariate regression analysis with control for nutritional status and dietary calcium intake. Two smaller studies (total number of subjects, 116) showed reductions in blood lead concentration (191,192), but a study in children (n = 88) judged to have adequate calcium intake, who were given supplements to reach a daily intake of 1800 mg, showed no treatment effect (193). Adverse events were evaluated in three studies, and none were seen (191)(192)(193). The certainty of evidence provided by these studies was rated as very low because of risk of bias and imprecision.
The guideline development group noted the reduction in blood lead concentration associated with calcium administration in some studies and the lack of adverse events. It also noted that, in children whose daily calcium intake is below recommended values, increasing calcium intake has other health benefits, such as maintaining bone health (194). For these reasons, a strong recommendation was considered appropriate for children who have inadequate calcium intake, in spite of very low-certainty evidence. The group emphasized that this intervention is only one component of the general management of lead exposure, the most important being removal or control of lead sources.
Vitamin D is important for calcium absorption and homeostasis; therefore, it is also necessary to maintain an adequate vitamin D intake (195). Additional information on implementation is provided in section 7.2.6.

# / For a child ( 10 years) with a blood lead concentration of  5 g/dL who has, or is likely to have, iron-deficiency, administration of iron supplementation is recommended.
Remarks: The dose should be in line with WHO guidelines (196,197) or standard clinical practice.
Strong recommendation, very low-certainty evidence.
Evidence for this intervention was from one small RCT (n=135) in children who were iron-deficient (serum ferritin, < 15 g/L) and two larger RCTs in children, the majority of whom were not iron deficient (9, Web Annex). In the iron-deficient children, after 16 weeks' administration of either 15 mg of elemental iron in a daily fortified meal or an identical unfortified meal, the median blood lead concentration was 2.1 g/dL lower in the iron-fortified group (95% CI not calculable).
Significantly fewer children in the iron group had a blood lead concentration  10 g/dL, with a risk ratio of 0.52 (95% CI, -0.23 to 0.51) (P < 0.001) (198). This study provided very low-certainty evidence of a treatment effect.
In the two RCTs in mostly iron-sufficient children, who were given 9.75 mg or 8 mg of elemental iron, the difference in the reduction in blood lead concentrations was extremely small (199,200). The mean difference in the decrease in blood lead concentrations between the treated and placebo groups was 0.14 g/dL (95% CI, -0.23 ; 0.51) in the larger study (n=304) (199) and 0.5 g/dL (95% CI not calculable) in the other (n=227) (200). Related studies of cognitive and behavioural outcomes found no difference between intervention and placebo groups (200)(201)(202).
These studies provided moderate-certainty evidence of no treatment effect.
In spite of the very low-certainty evidence for iron-deficient children, the guideline development group made a strong recommendation, for the following reasons: i) both iron deficiency and lead exposure are associated with anaemia and impaired cognitive development in children and there may be an additive or synergistic effect; ii) an existing WHO guideline recommends correction of iron deficiency in children to prevent anaemia (196); and iii) iron deficiency is associated with increased lead absorption in the GI tract and may increase the risk of pica, which may include lead ingestion (20,203). Additional information on implementation is provided in section 7.2.6.
For children who were not iron-deficient, there was moderate-certainty evidence of no treatment effect, and the guideline development group did not make a recommendation.

# Values, equity, feasibility and acceptability of calcium and iron supplementation in children
A reduction in blood lead concentration and the other health benefits of calcium and iron supplementation would be regarded as desirable outcomes and would be expected to be valued by children's carers.
Health equity considerations include the fact that children in economically deprived and disadvantaged populations bear the greatest burden of lead exposure, particularly in low-and middle-income countries (151).
Nutritional deficiencies, including of calcium (194) and iron (197), are also prevalent in these populations, and addressing these deficiencies has important benefits independent of the termination of lead exposure. These interventions would therefore be expected to be acceptable to children's carers. Providing calcium or iron supplements could, however, cause harm if this was used as a substitute for reduction and removal from exposure to lead.
With regard to feasibility, while oral calcium preparations are not on the WHO Model List of Essential Medicines for Children (204), calcium supplements suitable for children are available at a range of prices (205). Iron supplements can cause constipation and abdominal discomfort, and these effects might reduce treatment adherence. The supplements are on the WHO Model List of Essential Medicines for Children for the treatment of iron-deficiency anaemia (204).

# Recommendations for pregnant and lactating women
1 / For a pregnant woman with a blood lead concentration of  5 g/dL who has, or is likely to have, inadequate calcium intake, administration of calcium supplementation is recommended.
Remarks: The dosage should be sufficient to raise the total calcium intake to the national guideline for calcium in pregnant women or to the WHO/FAO-recommended nutrient intake value (1.2 g) (204). This should be given as soon as the pregnancy is recognized, for the duration of the pregnancy.

# Strong recommendation, moderate-certainty evidence Rationale
The systematic review identified only one study that provided moderate-certainty evidence of an effect on blood lead concentration (9,Web Annex). This was a placebo-controlled RCT in 670 pregnant women given a daily supplement of 1.2 g of calcium carbonate (480 mg elemental calcium) for the duration of pregnancy. The women had a mean daily calcium intake before the study of 900 mg. The calcium supplement was associated with an 11% lower (95% CI, -17.8% to -3.7%) blood lead concentration, with a larger effect in women who adhered better to treatment (206). The study population had a geometric mean blood lead concentration  5 g/g bone mineral, suggesting that calcium supplementation may reduce mobilization of lead from bone.
In formulating this recommendation, the guideline development group took account of the following factors.
During pregnancy, the physiological demand of the mother for calcium is increased for formation of the fetal skeleton, and some of this demand is met by increased bone resorption. In lead-exposed mothers, this process releases lead from bone stores into blood, exposing both the mother and the fetus (100). Lead exposure is associated with adverse pregnancy outcomes, including increased risk of hypertension (16,93,136), reduced fetal growth (16,136) and preterm birth (16,34). The study provided moderate-certainty evidence that administration of a low dose of calcium is associated with a reduction in blood lead concentration, possibly by reducing mobilization of lead from bone. No evidence was identified for other prioritized outcomes, such as live births.
In pregnant women in general, an adequate calcium intake is important to protect against the risk of hypertensive disorders, including pre-eclampsia, and related problems such as preterm birth and neonatal death. There is low certainty evidence from a systematic review for pregnant women in general that high-dose calcium supplementation (> 1 g/day) may reduce the risk of pre-eclampsia and preterm birth, particularly for women with low-calcium diets (207). This review also found limited evidence that low-dose calcium supplementation may be associated with reductions in pre-eclampsia, hypertension and admission to neonatal high care.
The guideline development group took account of the moderate-certainty evidence of a benefit in reducing the blood lead concentration and potential wider benefits on pregnancy outcomes of providing calcium supplementation for women with low calcium intake and considered that a strong recommendation was justified. As the optimum dose of calcium is not established, the recommendation is for a dose sufficient to meet nationally established guideline intake values or the WHO/FAO recommended intake (195). Calcium supplementation should be started as soon as pregnancy is recognized and should continue throughout pregnancy. Additional information on implementation is provided in section 7.2.6.
2 / Initiation or continuation of calcium supplementation is suggested for lactating women who have a blood lead concentration of  5 g/dL. This should be for the duration of lactation.

# Conditional recommendation, low-to very-low certainty evidence Rationale
Only one RCT was identified, which provided low-certainty evidence of an impact on blood lead concentrations; a further, linked study provided very-low certainty evidence of an effect on breastmilk lead concentrations (9, Web Annex). In the RCT, 617 lactating women were given 1.2 g of elemental calcium or placebo for 6 months (208). The women had mean blood lead concentrations of about 9 g/dL. The group that received supplement showed a small decrease in blood lead concentrations, and the effect was greater in women who had > 50% adherence and had higher patella lead concentrations (> 5 g/g bone mineral), in whom the mean blood lead concentration was 1.16 g/dL lower (95% CI, -2.08 to -0.23) than in the placebo group. In the linked study of lead in breastmilk, there was no significant difference in lead concentrations at different times between women given calcium and those given placebo; however, the rate of decrease was 5-10% higher in the calcium group during lactation (209). In addition, very low-certainty evidence suggested that calcium supplementation was associated with reduced release of lead from bone in breastfeeding women (208). The evidence of a benefit of calcium supplementation was very limited, although there was a suggestion of greater benefit in women with higher past exposure to lead and significant bone lead stores.
No evidence was identified for other prioritized outcomes.
Bone resorption continues during lactation, and blood lead concentrations have been shown to rise during this period (100). In addition, a small amount of lead is secreted from blood into breastmilk (101). There is uncertainty about the role of dietary calcium in preventing bone resorption during lactation and the WHO/FAO guidance on mineral requirements in lactating women does not make a recommendation for calcium intake (195).
The interaction between lead and calcium is complex, however, and, as there could be a more general benefit for the women's health, the guideline development group advised a conditional recommendation to give calcium supplementation to lactating women.
Additional information on implementation is provided in section 7.2.6.

# Values, equity, feasibility and acceptability of calcium supplementation in pregnant and lactating women
No studies were found that specifically addressed these issues in lead-exposed women; however, some evidence was available for pregnant women in general. A qualitative systematic review of women's expectations of antenatal care found that women in high-, middle-and low-resource settings valued a positive pregnancy experience, including effective clinical practices such as nutritional supplements and relevant, timely information on diet and nutrition (210).
Health equity considerations include the fact that the greatest health burden of lead exposure is in economically deprived and disadvantaged populations, particularly in low-and middle-income countries. Women in these countries who are poor, least educated, and live in rural areas have less coverage with health interventions and worse health outcomes than more advantaged women (211). They are also more likely to have inadequate calcium intake (211). Provision of calcium supplements, particularly if part of a programme of antenatal and postnatal support, could improve health equity, provided the interventions was not used as a substitute for environmental remediation of lead hazards.
With regard to feasibility, calcium preparations are on the WHO Model List of Essential Medicines (165) and on 64% of national essential medicines lists (212). While calcium tablets tend to be large and may be unpalatable to some women, in the above RCTs over 80% of subjects had > 50% adherence in taking the supplement (205, 208).

# Implementation considerations for supplementation with calcium and iron
Health-care providers, particularly family doctors, community health nurses, paediatricians, obstetricians and midwives, should be trained in identifying the risk factors for lead exposure and the prevention, diagnosis and management of lead poisoning. Management of lead poisoning requires access to laboratory services for measuring blood lead concentrations. WHO guidance is available on selecting analytical methods and establishing a laboratory service for this purpose (142).
In all cases, nutrition counselling should be given to promote diet diversity and food combinations that improve calcium and iron absorption. This should be combined with counselling on sources of lead exposure and methods for reducing exposure. For pregnant women this information can be provided during routine antenatal care visits (213).
Calcium and iron may compete for absorption; therefore, if supplementation with both nutrients is required, they should be taken at different times of the day (187).
Calcium intake can be assessed by taking a dietary history and comparing intake against national recommended values (195). As the optimal dose for mitigating the effect of lead exposure is unknown, the guideline development group decided to refer to recommended daily intake values. It is recognized that calcium requirements may be different in different dietary cultures; therefore, national guidelines should be used when possible (195). When determining a dosage for a pregnant or lactating woman, health-care providers should consider the woman's calcium intake from other sources, such as medications (e.g. antacids) (211).
While the evidence supported use of calcium supplements, calcium intake can also be improved by increasing the amount of calcium-rich foods in the diet, use of fortified foods or traditional supplements such as dried fish. As calcium supplements may be manufactured from natural sources such as animal bone, they may be contaminated with lead, and care should be taken in sourcing products (214,215).
Vitamin D is important for calcium absorption and homeostasis; therefore, it is also necessary to maintain an adequate vitamin D intake. In the case of pregnant women, WHO does not recommend routine vitamin D supplementation, and women should be advised that sunlight is the most important source of vitamin D (216).
If vitamin D deficiency is suspected, vitamin D supplements may be given at the current recommended nutrient intake of 200 IU (5 g) per day (216).
In children, it is suggested that dietary calcium intake be re-assessed after 3 months. If it is still inadequate and the blood lead concentration remains elevated, consideration should be given to a further period of supplementation. If necessary, the source of lead exposure should be investigated further.
In pregnant women, calcium should be given for the duration of pregnancy and consideration given to extending supplementation into lactation.
Iron deficiency can be determined by estimating the serum ferritin concentration and a marker of inflammation (e.g. C-reactive protein or a1-acid glycoprotein) (217).
If serum ferritin cannot be measured, evaluation of anaemia is a non-specific marker of iron deficiency.
Note that anaemia may also be a feature of lead toxicity.
The optimal dose and duration of iron supplementation for mitigating the effects of lead exposure are unknown; therefore, reference should be made to WHO guidance for treating iron deficiency (196,197), which recommends a minimum treatment duration of 3 months, after which the iron status should be re-assessed to evaluate continuation (197). In malaria-endemic areas, iron supplementation may be harmful to children who do not have regular access to malaria surveillance and treatment services (196). Children with malaria may, however, be more susceptible to the neurotoxic effects of lead when they are exposed to high levels (111). These two considerations should be taken into account when deciding on iron supplementation.
Inclusion of vitamin C will improve iron absorption from the diet and from iron supplements (195).

# Chelation therapy in individuals exposed to lead 7.3.1 Introduction
Chelating agents are pharmaceuticals that, by physicochemical means, bind to lead and other trace elements and facilitate their excretion from the body (218). The aim of chelation therapy is to facilitate renal excretion, thereby decreasing the lead body burden and, potentially, resolving toxic effects and improving clinical outcomes by decreasing the availability of lead for binding at its sites of action. Four chelating agents were reviewed: dimercaprol, penicillamine, sodium calcium edetate and succimer (10)(11)(12)(13). In evaluating the efficacy of chelation therapy, the following critical and important outcomes were considered:

# Critical outcomes
- blood lead concentration;
- neurological (cognitive, neurobehavioural and neuromotor) effects of lead poisoning measured in standardized, validated tests;
- symptoms and signs of lead poisoning, e.g. abdominal colic and encephalopathy; and
- long-term health outcomes that may be affected by lead exposure, such as cardiovascular and renal effects.

# Important outcomes
- urinary excretion of lead,
- mobilization of lead from bone and - adverse events associated with chelation therapy.
In view of the importance of preventing the harmful effects of lead in children without overt lead poisoning, studies in children with blood lead concentrations < 45 g/dL were analysed separately for the outcomes for which data were available.
The evidence review found very few randomized or non-randomized controlled studies, and most of the data found were from retrospective or prospective case series. The latter studies did not include control for the confounding effect of removal from lead exposure, which is an essential aspect of management. This made it difficult to differentiate the impacts of chelation and of removal from exposure on the studied outcomes. The certainty of the evidence for most outcomes was therefore very low.
The only blinded, randomized, placebo-controlled trial of chelation was the treatment of lead-exposed children (TLC) Trial, conducted with children with blood lead concentrations < 45 g/dL treated with succimer.
GRADE summary of findings tables for chelation in children, adolescents and non-pregnant adults and evidence-to-decision tables are provided in supplementary material online (Web Annex).
The evidence identified for chelation therapy in pregnancy is described in section 7.3.7.

# Overview of recommendations for chelation therapy
The recommendations for chelation therapy are differentiated according to threshold blood lead concentrations, age, sex, and severity of lead poisoning. The management of pregnant women is described in section 7.3.7. Chelation therapy is not usually indicated for individuals with blood lead concentrations < 45 g/dL, and this is discussed in the recommendations below.
Further information on the use of chelation, including criteria for hospital admission and selection of chelating agents, is given in section 7.3.9.
As described in section 4.3, absorbed lead is distributed to blood, soft tissues and bone. In chronic poisoning, bone stores of lead are significant, and the lead may remain there for many years. Only some of the lead in bone is directly mobilizable by chelating agents. After chelation therapy, a rebound increase in the blood lead concentration may be seen as lead stored in soft tissues and bone is released and the concentration in blood re-equilibrates. It is therefore important to re-check the blood lead concentration after allowing a period for re-equilibration, to determine whether further chelation is necessary.
The following principles apply:
- As in all cases of lead exposure, action should be taken to identify the source of lead and stop ongoing exposure, as this will, in itself, reduce the blood lead concentration and improve clinical features of toxicity.
- In applying these recommendations to individual patients, room must be left for clinical judgement according to potential vulnerability to lead toxicity, the circumstances, the nature and chronicity of exposure, clinical features, the blood lead concentration or trends in concentrations and location of treatment. Some allowance may also be required for possible inaccuracy in measurements of blood lead concentrations.
- If possible, chelation should be administered by, or in consultation with, a clinical toxicologist or other medical practitioner experienced in the management of lead poisoning.
- The blood lead concentration should be re-checked 2-4 weeks after the end of chelation, with the shorter interval for higher initial blood lead concentrations. This is necessary to determine whether there is continuing lead exposure and/or whether chelation has been effective in reducing the blood lead concentration. Follow-up treatment depends on the blood lead concentration, as specified in this guideline.
The evidence for these recommendations was derived from a suite of studies from the TLC trial that specifically addressed the effect of chelation in children with blood lead concentrations < 45 g/dL, and small quasi-randomized studies, small case series and studies with historical controls involving children with higher blood lead concentrations (10-13, Web Annex).
The TLC trial was a randomized, double-blinded, placebo-controlled study of succimer involving 780 children aged  3 years. Both treatment and placebo groups were removed from lead exposure. A suite of studies investigated short-term and long-term outcomes (219)(220)(221)(222)(223)(224). The trial provided moderate-certainty evidence of an initially faster decrease in blood lead concentration in the first 6 months that did not persist to 12 months. There was low-to moderate-certainty evidence of no benefit for other critical or important outcomes, such as cognitive, behavioural and neuromuscular development. A statistically significant association between a fall in blood lead concentration and increased cognitive scores was seen only in the placebo group, in whom there was an increase of four points per 10 g/dL fall in the blood lead concentration (223). Chelation with succimer was associated with slightly reduced growth at age 7 years (224). Overall, the guideline development group considered that the balance of risks and benefits in children with blood lead concentrations < 45 g/dL favours not giving chelation therapy, as removal from lead exposure is considered to be adequate.
No equivalent studies were found for use of other chelating agents in treating children with blood lead concentrations < 45 g/dL; however, the guideline development group considered it unlikely that other agents would provide different results in terms of benefits, and chelating agents with significant adverse event profiles may be more harmful (see Box 1 in section 8.4).

# Blood lead  45 g/dL
For children with a blood lead concentration  45 g/dL, there were no studies equivalent to the TLC trial for individual chelating agents or chelating agent combinations, and the evidence for all outcomes was of very low certainty (10-13, Web Annex). Lack of a control group in most of the studies meant that the results were confounded by the effect of removal from lead exposure. Rapid decreases in blood lead concentrations to values ranging from 39% to 79% of the baseline value and increased urinary excretion of lead were reported. In the few studies that reported symptoms and signs of lead poisoning, resolution or improvement was noted. In cases of severe neurotoxicity, some children were left with sequalae such as mental retardation and convulsive disorders, although there were fewer than among controls who had not been chelated (225)(226)(227).
Despite the limited availability of chelating agents in many low-and middle-income countries, the guideline development group decided that a strong recommendation for chelation therapy in children with blood lead concentrations  45 g/dL was justified, whether or not the child had clinical features of lead poisoning. This is because children are particularly vulnerable to the neurotoxicity of lead, with possible long-term neurological, cognitive and behavioural impairment (see section 4.4). Active elimination of lead from the body could confer an additional benefit to that of removal from lead exposure.

# Blood lead 40-44 g/dL
The guideline development group made a conditional recommendation for oral chelation in children with borderline but persistently elevated blood lead concentrations. This reflected concern about the accuracy of blood lead measurement, which depends on the method used, the equipment and whether the laboratory has adequate quality control. This is particularly likely to be a consideration in low-and middle-income countries where laboratories are often poorly resourced, but it may also be an issue in high-resource settings. In the USA, for example, the federal requirement for acceptable analytical performance in the measurement of blood lead concentrations is an accuracy of  4 g/dL, although many laboratories have better accuracy (228). In addition, the blood lead concentration provides only a partial guide to the risk of toxicity, and there is some variation in the health impacts of lead at specific concentrations. Thus, chelation is suggested for children with a blood lead concentration of 40-44 g/dL, persistently elevated blood lead concentrations after removal from exposure, symptoms and signs of lead poisoning or doubt about the accuracy of the blood lead measurement.
A decision to chelate should be made case by case, ideally guided by discussions with a clinical toxicologist or other medical practitioner experienced in the management of lead poisoning. An oral chelating agent is suggested, as it is less invasive than parenteral treatment and the child is unlikely to require hospital admission.

# Blood lead  70 g/dL
Young children with very high blood lead concentrations ( 70 g/dL) are more likely than adults to develop severe neurological toxicity, including lead encephalopathy, and they can quickly deteriorate, particularly if there is continuing lead exposure (115). It is considered good clinical practice to closely monitor such children, including through regular neurological assessment, to detect any signs of deterioration. Depending on the circumstances, this may be done as an in-or an outpatient, as discussed in section 7.3.9.
Any sign of lead encephalopathy in children can be lifethreatening and is associated with permanent neurological damage such as mental retardation and seizure disorder (115). For this reason, although the evidence was of very low certainty, the guideline development group advised a strong recommendation for hospitalization and parenteral chelation therapy (see section 7.3.9 on selection of chelating agents).
The evidence on the use of chelation in adolescents and adults was largely from uncontrolled case series (10)(11)(12)(13)Web Annex). Most adult cases involved occupational exposure in men. Older age groups are less vulnerable to developing serious neurological toxicity than children, and chelation is usually given for high blood lead concentrations.
The guideline development group considered that a special case could be made for chelation therapy in girls and women of child-bearing age with a blood lead concentration in the range 45-70 g/dL, even if there are no clinical features of lead poisoning. The rationale is that enhancing the elimination of lead could reduce the amount of lead available for deposition in bone and, for individuals with chronic exposure, might also release some lead from bone into the chelatable pool for elimination. This could be a protective measure for the future when the girl or woman becomes pregnant, when lead is released into blood from bone stores, thereby exposing the fetus and re-exposing the mother. As a clinically well patient does not require hospital admission, an oral chelating agent is preferred (see selection of chelating agents in section 7.3.9). It was also recognized that not all girls or women would wish to have chelation therapy if they were asymptomatic of lead poisoning. The recommendation was therefore conditional. The use of chelation should be decided after a discussion between the physician and the patient about potential benefits and harms.
For chelation in pregnancy see section 7.3.7.
The evidence for this group of patients was from small case series, usually with no control group. The patients had a range of blood lead concentrations, and specific ranges and outcomes could not be distinguished (10)(11)(12)(13)Web Annex). There were very few cases in adolescents, and most of the adult exposures were occupational. Chelation therapy was associated with a variable but rapid reduction in blood lead concentrations to values ranging from 9% to 95% of the pre-treatment value and an increase in urinary excretion of lead. Some studies noted considerable inter-individual and intra-individual differences in urinary excretion during chelation. Most symptoms and signs of lead poisoning improved within 1.5-14 days, although some neurological features, such as weakness, took longer. No evidence was found on the effect of chelation therapy on the longer-term impacts of lead exposure, such as increased risks of cardiovascular and renal disease.
For patients without symptoms or signs of lead poisoning, the balance of benefits and harms of chelation therapy with removal from lead exposure alone is unclear.
The guideline development group considered that emphasis should be placed on removal from exposure rather than chelation therapy. The blood lead concentration and clinical status of the patient should, however, be re-evaluated after 2-4 weeks to ensure that exposure has terminated. They made a conditional recommendation, as some physicians and patients might prefer chelation therapy to be given.
When patients have mild-moderate clinical features of lead poisoning, the benefits of chelation therapy as compared with removal from exposure were also unclear.
As chelation therapy is associated with rapid improvement in symptoms, some patients might prefer to be treated.
A conditional recommendation for chelation therapy was made, as, ultimately, a decision on chelation depends on the specific case. Information on selection of chelating agents is provided in section 7.3.9.
For chelation in pregnancy see section 7.3.7.
Recommendations for non-pregnant adolescents (11-18 years) and adults ( 19 years) with blood lead concentrations of > 70-100 g/dL 1 / An adolescent or adult with a blood lead concentration > 70-100 g/dL should be closely monitored for signs of clinical deterioration, regardless of whether chelation therapy is given.

# Good practice statement
Some patients with blood lead concentrations > 70-100 g/dL can deteriorate suddenly, without necessarily showing prodromal symptoms and signs. It is considered good clinical practice to closely monitor the clinical status and blood lead concentrations of these patients on an in-or out-patient basis (see section 7.3.9). Patients who are deteriorating, or in whom there is no or a slow decrease in blood lead concentration despite removal from exposure, should be reassessed for chelation therapy if this has not been given.
3 / For a non-pregnant adolescent or adult with a blood lead concentration > 70-100 g/dL and with significant neurological features of lead toxicity (e.g. irritability, drowsiness, ataxia, convulsions, coma) or lead encephalopathy, urgent parenteral chelation therapy is recommended.
Strong recommendation, very low-certainty evidence.
The evidence for this group of patients was from small case series, usually without control groups, and was therefore of very low certainty (10)(11)(12)(13)Web Annex).
The patients had a range of blood lead concentrations, the highest being 710 g/dL, and it was not possible to distinguish specific ranges and outcomes. As described above, chelation therapy was associated with a rapid decrease in the blood lead concentration, increased urinary excretion and improvements in symptoms and signs of lead poisoning. Lead encephalopathy is unusual in adults, and only three cases were identified, all of whom improved after chelation.

# No significant neurological features
For patients who are clinically well or show only mild-moderate features of lead toxicity but no significant neurological features in spite of high blood lead concentrations, the guideline development group recognized that not all physicians would give chelation.
Depending on the circumstances of exposure and the severity of poisoning, some physicians would wait to see whether removal from exposure alone resulted in improvement. For this reason, a conditional recommendation was made for chelation therapy.

# Significant neurological features
For patients who show significant neurological features of lead toxicity, in particular encephalopathy, very low-certainty evidence suggested that chelation could improve survival. Despite the limited availability of chelating agents in many low-and middle-income countries, the guideline development group decided that a strong recommendation for chelation therapy was justified, as lead encephalopathy is a life-threatening condition.
For chelation in pregnancy see section 7.3.7. Information on selection of chelating agents is provided in section 7.3.9.

# Values, equity, feasibility and acceptability for chelation in children and non-pregnant adolescents and adults
It was considered that carers of lead-poisoned children and adolescents and lead-exposed adults would value resolution of toxic effects and improved survival. Evidence from economic modelling in a high-income country indicated that parents would be willing to pay for chelation to reduce a child's lead body burden; however, the applicability of the modelling to other settings is unknown (229).
Health equity considerations include the greater prevalence of lead exposure in economically deprived and disadvantaged populations (151) and in settings where regulatory control of lead exposure, e.g. from environmental sources, is weak. Impaired neurocognitive development can have high personal and societal costs in terms of lost earnings, lost tax revenue and increased risk of antisocial behaviour (121,230). While there is a consistent association between chelation therapy and enhanced elimination of lead, evidence is lacking for prevention of the long-term cognitive and behavioural impacts of lead; therefore, the impact on health equity is unclear. Provision of chelation therapy to these groups could cause harm if the therapy is given as a substitute for measures to terminate lead exposure, such as identifying and removal from source of exposure.
The four chelating agents are on the WHO model lists of essential medicines (169,204); however, the availability of chelating agents in countries varies. An analysis in 2019 of 137 national essential medicines lists provided to WHO showed that penicillamine was listed in 70 (51%), dimercaprol in 59 (43%), sodium calcium edetate in 41 (30%) and succimer in only 8 (6%). All four chelating agents were listed in only four countries (212). This finding bears on the feasibility of the recommendations.
Factors that might influence the acceptability of chelation therapy include the duration of treatment and whether it is given on an in-or out-patient basis, as these factors have impacts on cost and convenience.
In the case of mild-to-moderate poisoning, when hospital admission is not necessarily required for clinical reasons, children's carers and patients might prefer oral to parenteral therapy because it is less painful and can be given at home. Ensuring adherence to treatment for prolonged courses of chelation may be difficult, particularly if it requires repeated stays in or visits to medical facilities.

# Recommendations for chelation in pregnancy
Exposure to lead during pregnancy is known to have negative effects on both the mother and the fetus. These include an increased risk of hypertension and possibly pre-eclampsia and reduced fetal growth, lower birth weight, preterm birth and spontaneous abortion. The risks are greater with higher blood lead concentrations (16,34,136). During pregnancy, calcium is mobilized from bone to form the fetal skeleton, which also releases stored lead, thereby re-exposing the mother and exposing the fetus (100).
The only evidence identified was from case reports, which were compiled in a narrative review (14,Web Annex). Some of the cases were poorly documented, and the main outcomes reported were the maternal and newborn blood lead concentrations. It was not possible to draw conclusions about the impact of chelation on other outcomes such as reversal of toxic effects in the fetus. For pregnant women, the certainty of the evidence was very low.
In the recommendations below, a distinction is made between pregnant women who have lead encephalopathy, for whom there is a strong case for chelation regardless of trimester, and women who are not encephalopathic, in whom the trimester of pregnancy influences treatment decisions. Considerations for selecting a chelating agent are provided in section 7.3.9.
In all cases, regardless of the blood lead concentration, it is important to identify and remove the source(s) of exposure and to monitor the blood lead concentration.
In addition to occupational and environmental sources, important sources of lead exposure of some pregnant women are pica (i.e. ingestion of soil, clay or other lead-containing materials) and use of traditional medicines and tonics (136). After treatment, the mother should be returned to an environment from which sources of lead exposure have been removed.
Ideally, chelation should be administered by, or in consultation with, medical practitioners experienced in the management of lead poisoning and the management of high-risk pregnancy.
Note that the mother's blood lead concentration can vary during pregnancy, with a decrease due to haemodilution in the second trimester and an increase in the third trimester and post-partum (93).
1 / For a pregnant woman with lead encephalopathy, regardless of trimester, urgent chelation therapy is recommended. The preferred chelating agent depends on the stage of the pregnancy and available data on safety of use in pregnancy.
Strong recommendation, very low-certainty evidence.
The only evidence for use of chelation in pregnant women was from case reports, most of which concerned women in the third trimester of pregnancy; only two cases (in non-encephalopathic women) were found of chelation during the first trimester (14,Web Annex). The only evidence on use of chelation therapy in pregnant women with lead encephalopathy was from one case report of a woman in the third trimester with chronic lead exposure (231). Lead encephalopathy is a life-threatening condition, and the survival of both mother and fetus may be at risk. There is very low-certainty evidence in other patients with lead encephalopathy that chelation therapy is associated with improved survival. The guideline development group decided that the balance of potential benefits and harms favoured giving chelation therapy, and they advised a strong recommendation.
A decision on which agent to use depends on the circumstances (e.g. trimester of pregnancy, availability of the chelating agent), adverse effects of the chelating agent, including the risk of fetal harm in the first trimester, the setting (e.g. availability of treatment facilities) and clinical judgement (e.g. which chelating agent(s) can most safely and effectively be administered). In the first trimester, precedence should be given to the patient's preference if she can express it.
2 / For a pregnant woman with a blood lead concentration  45 g/dL, with or without clinical features of lead poisoning, but without lead encephalopathy:
(i) in the first trimester: the guideline development group could not make a recommendation because of uncertainties in the balance of risks and benefits (see Rationale):
(ii) in the second or third trimester: chelation therapy is recommended.
Strong recommendation, very low-certainty evidence.
The only evidence identified was from case reports of the treatment of women, most of whom were in the third trimester of pregnancy (14,Web Annex). Some of the cases were poorly documented, and the main outcomes reported were maternal and newborn blood lead concentrations; no evidence was identified for other outcomes such as reversal of toxic effects in the fetus. The only data on use of chelation during the first trimester were from two cases involving succimer that were known to a member of the guideline development group (14, Web Annex).

# First trimester
For pregnant women who do not have life-threatening lead encephalopathy and in the absence of data for an evaluation of the harms and benefits of chelation, the guideline development group could not make a specific recommendation and concluded that each case should be considered individually. A decision about chelation should be taken in consultation with the pregnant woman. Factors that should be considered include the severity of poisoning and the availability of specific chelating agents, as the risk of adverse effects in the fetus varies. According to the US Food and Drug Administration (232), the safest agent for use in the first trimester of pregnancy is sodium calcium edetate (category B: experimental animal studies do not demonstrate a risk to the fetus, and there are no adequate studies in pregnant women). The use of penicillamine should be avoided in the first trimester.

# Second and third trimesters
For second and third trimester pregnancies, case reports provide very low-certainty evidence that chelation is associated with a reduction in the maternal blood lead concentration and does not appear to harm the fetus (14, Web Annex). Data are lacking on whether chelation improves fetal or neonatal outcomes. In spite of the lack of evidence and the limited availability of chelating agents in many low and middle-income countries, the guideline development group decided to advise a strong recommendation for chelation. This was because the fetus is particularly susceptible to the toxic effects of lead and there is a known risk of adverse pregnancy outcomes associated with lead poisoning. It was considered that the more rapid reduction in the maternal blood lead concentration associated with chelation therapy would be likely to benefit both the mother and the baby.
The threshold blood lead concentration at which chelation should be given could not be derived from the available evidence. The guideline development group decided to use the same threshold as for children (45 g/dL) in view of the vulnerability of the fetus. The blood lead concentration should be monitored regularly and further chelation given if the blood lead concentration exceeds 45 g/dL.
Antenatal care in Jamaica. Credit: WHO / Aphaluck Bhatiasevi

# Values, equity, feasibility and acceptability for chelation in pregnant women
The intended outcomes of chelation therapy in a pregnant woman are survival of the mother and the fetus, in the case of lead encephalopathy, and more generally, improvement in clinical features of lead poisoning and reduction of lead exposure of the fetus. Most cases of lead poisoning in pregnancy are a consequence of unintended exposure, such as use of a traditional medicine containing lead, pica or environmental contamination. The guideline development group considered that the intended outcomes would be valued by most women.
Health equity considerations include the fact that economically deprived and disadvantaged populations have the greatest lead exposure (149), particularly in low-and middle-income countries. Women in these countries who are poor, least educated and live in rural areas may have less health intervention coverage and worse health outcomes than more advantaged women (211). Improvements in symptoms and signs and in survival from severe lead poisoning contribute to health equity. There is, however, lack of evidence for improved pregnancy outcomes and for prevention of the cognitive and behavioural impacts of lead exposure that can adversely affect an individual's economic productivity and social status later in life. Provision of chelation therapy could worsen health outcomes if it was given as a substitute for measures to terminate lead exposure.
As described in section 7.3.6, the availability of chelating agents in low-and middle-income countries is limited, penicillamine being the most commonly available (212). This agent is contraindicated in first-trimester pregnancy because of its teratogenicity. The availability of chelating agents bears on the feasibility of the recommendations.
Factors that might influence the acceptability of chelation therapy include the availability of a suitable chelating agent, e.g. an alternative to penicillamine for a woman in the first trimester, and the duration of treatment and whether it is given on an in-or out-patient basis, as these factors affect cost and convenience.

# Implementation considerations for chelation therapy
Health-care providers, in particular family doctors, community health nurses, paediatricians, obstetricians and midwives, should be trained in identifying the risk factors for lead exposure and in the prevention, diagnosis and management of lead poisoning. Management of lead poisoning requires access to laboratory services for measuring blood lead concentrations. WHO guidance is available on the selection of analytical methods for measuring blood lead concentrations and on establishing a laboratory service for this purpose (142). As discussed in section 5, the venous blood lead concentration is the definitive biomarker of exposure and risk on which management decisions are routinely based.
Removal from, or termination of, exposure is an essential first step in the management of lead poisoning.

# Location of treatment
Lead-poisoned patients can be managed as out-or in-patients. Admission to a treatment centre is advised in the following situations:
- The patient shows significant neurological features of toxicity, e.g. irritability, drowsiness, ataxia, convulsions, coma, or lead encephalopathy.
- Parenteral chelation therapy is required.
- The patient is particularly vulnerable because of co-morbidities such as malaria.
- It is not otherwise possible to remove the patient from lead exposure, e.g. if their home environment is heavily contaminated and alternative accommodation is not available.
- It would otherwise be difficult to monitor the patient and the effectiveness of management measures, e.g. because of logistical issues.
- There are doubts about the ability of the patient to adhere to treatment.  (204). Inclusion on the Model Lists indicates that the four agents have been evaluated for their public health relevance, safety, efficacy and comparative cost-effectiveness. In spite of listing, however, the availability of chelating agents in many low-and middle-income countries is limited (212).

# Selection of chelating agents

# Non-pregnant patients
The evidence for individual chelating agents and chelating agent combinations was of very low certainty, and there were no good-quality studies in which chelating agents or chelating agent combinations were compared. In addition, there were very limited data on use of penicillamine in patients with severe poisoning; most published data were for patients with mild-moderate poisoning.
For patients with severe lead poisoning, in particular lead encephalopathy, very low-certainty evidence suggested that chelation with succimer, sodium calcium edetate or dimercaprol, alone or in combination, could improve survival as compared with no chelation. It has been standard practice in some settings to treat lead encephalopathy with dimercaprol before giving sodium calcium edetate, because it was suggested that the latter increases distribution of lead to the brain (218).
The systematic evidence reviews did not find adequate evidence to determine whether this combination was more effective than alternative regimens, and the evidence for a distribution effect is considered to be weak (104).
The guideline development group therefore decided that use of sodium calcium edetate alone or in combination with dimercaprol or succimer was acceptable for patients with lead encephalopathy. Case reports from the 1950s described use of dimercaprol alone in severe poisoning; however, such use is considered less optimal then use of other agents.
Parenteral administration of chelation therapy is safer in encephalopathic patients who have an unprotected airway. A patient with adequate airway protection could, however, be given an oral chelating agent, provided there was no concern about impaired GI absorption. Some limited evidence from a large case series in a low-resource setting suggests that succimer can safely be used alone in children with severe lead poisoning, including those with encephalopathy (4).
The guideline development group recognized that the availability and costs of chelating agents vary by country and that this bears on the choice of chelating agent for treating individual patients. Other factors that influence the choice of chelating agent include whether parenteral rather than oral therapy is preferable and a preference for out-patient rather than in-patient treatment.
On the basis of the available, though very limited, evidence and practical considerations, the guideline development group made the following suggestions for the use of chelating agents.
- For mild to moderate poisoning: succimer or penicillamine
- For severe poisoning: sodium calcium edetate alone or in combination with succimer (if an oral medicine can be administered safely) or with dimercaprol.
When treatment is provided to an outpatient and there is concern about adherence to treatment, consideration could be given to directly observed treatment (4).

# Pregnant patients
In pregnant women in the first trimester, the potential for fetal harm caused by lead must be balanced against potential harm caused by the chelating agent. Data on the safety of chelation in pregnancy are very limited. Most data concern penicillamine, which has other indications and is therefore more widely used than other agents. The evidence review of chelation in pregnancy provided many reports of congenital malformations associated with penicillamine therapy for chronic conditions, although none for lead poisoning (14). The US Food and Drug Administration has categorized the risk of fetal harm as follows: sodium calcium edetate is in category B (experimental animal studies do not demonstrate a risk to the fetus, and there are no adequate studies in pregnant women); succimer and dimercaprol are in category C (experimental animal data suggest a fetal risk); and penicillamine is in category D (known fetal risk) (232).
In the second and third trimesters, teratogenicity is no longer a concern. On the basis of the available, though very limited, evidence and practical considerations, the guideline development group suggests that chelating agents can be used on the same basis as in non-pregnant patients, described above.

# Other remarks applicable to all groups
While the decision to give chelation usually depends on measurement of the blood lead concentration, there may be circumstances, such as in an outbreak, in which there is strong evidence of widespread exposure to lead. In such circumstances, the guideline development group considered that it would be justified to initiate treatment in a patient of any age with encephalopathy while awaiting confirmation of the blood lead concentration.
The end-point of chelation therapy is not clear cut but should include resolution of clinical features of lead poisoning and a reduction in the blood lead concentration that is maintained on reassessment. Some patients with chronic lead poisoning and a significant store of lead in bone and soft tissues may require multiple courses of chelation therapy. Furthermore, there may be continuing exposure to lead in spite of efforts to terminate it, for example, when remediation has been incomplete. In one mass lead poisoning incident caused by environmental contamination, some children had five or more courses of chelation without achieving a blood lead concentration  45 g/dL and has not fallen significantly from the baseline blood lead concentration, further investigation is strongly advised to determine whether measures to terminate exposure have been effective or whether there is a previously unrecognized source of exposure. Expert advice on further management should also be sought.

# Integration and implementation
-f the recommendations in the management of lead poisoning Sections 6 and 7 provide recommendations for specific aspects of the management of lead exposure. These should be integrated into an overall management plan for cases of lead poisoning. As a general principle, decisions about the management of lead poisoning should be made on the basis of the clinical condition of the patient, the circumstances of exposure, the blood lead concentration and trends in concentration and the best interests of the patient according to the resources available for treatment.
Once lead exposure has been confirmed by measurement of an elevated blood lead concentration (section 6.2), the steps in the management of exposure are:
- taking a history to identify the source(s) of exposure;
- evaluating the severity of exposure in clinical examination and investigations;
- reducing and terminating exposure, including improving nutrition;
- GI decontamination if indicated
- chelation therapy if indicated;
- other supportive measures if required; and
- follow-up to determine whether further management measures are necessary.
Children's playground equipment can be a source of exposure to lead paint. Credit: WHO / Sergey Volkov It is also important to take a dietary history to determine whether the patient has adequate nutrient intake, particularly of iron and calcium, as deficiency in these minerals is associated with increased absorption of lead and exacerbation of toxic effects (34,(172)(173)(174).

# Reduction and termination of exposure, including improving nutrition
Means for terminating exposure depend on the source.
In the case of lead ingestion, this may require GI decontamination (see section 7.1). In environmental exposure, identification of the source is important and may require the involvement of local public health or environmental health services. Measures to reduce and terminate exposure may include rehousing, remediation of contaminated soil or removal of lead paint, as well as longer-term measures such as implementation of environmental lead emission controls.
Occupational exposures may require temporary removal from work with lead. This should be followed by investigation of the cause(s) of exposure and implementation of the appropriate corrective measures. The regulatory limits for blood lead concentrations from occupational exposure vary around the world, some countries setting relatively high values. A review of national regulations showed that the concentration at which a worker should be removed from exposure ranged from 20 to 70 g/dL for men and 10 to 70 g/dL for women (234). The values are under review in some countries.
In the European Union, for example, a limit of 15 g/dL for men and avoidance or minimization of exposure for women of childbearing age have been recommended for adoption (235,236). There are no WHO guideline values for this purpose.
The patient or carer should be given information about the harmful health effects of lead, about sources of exposure and how exposure can be reduced or avoided, including the importance of good nutrition, in particular adequate intake of iron and calcium and of vitamins C and D, as these facilitate absorption of iron and calcium, respectively (195). If necessary nutritional supplementation should be given (see section 7.2).

# Chelation therapy
Issues in the choice of chelating agent for treatment are discussed in section 7.3.9. Table 2 provides a summary of information on chelating agents used for lead exposure.
The systematic evidence reviews of chelating agents found that a variety of dosing regimens were used; however, the data were inadequate to compare the safety and efficacy of different regimens (10)(11)(12)(13)(14). The dose regimens listed in Table 2 are taken from WHO formularies, pharmaceutical reference books and summaries of product characteristics provided by manufacturers. Information on adverse effects is taken from the same sources and from the systematic evidence reviews in which this was reported.
Seams of lead ore in Uganda. Credit: WHO / Christopher Black

# Dimercaprol (Intramuscular injection)
Dimercaprol (British Anti-Lewisite, BAL, dimercaptopropanol) is administered by deep intramuscular injection (218). It is usually formulated in a lipid solvent such as arachis or vegetable oil.
A typical regimen is 2.5-3 mg/kg body weight intramuscularly every 4 h for 2 days, 3 mg/kg intramuscularly two to four times on the third day, then 3 mg/kg intramuscularly once or twice daily for 10 days or until recovery (237).

# Adverse events
These include: rise in blood pressure, tachycardia, nausea and vomiting, which increase in severity with increasing doses, headache, a burning sensation in the lips, mouth and throat, a feeling of throat and chest constriction, conjunctivitis, lachrymation, blepharospasm, sweating, salivation, rhinorrhoea, tingling of the hands, abdominal pain, muscle pain and spasm, pain at the site of injection and occasional appearance of painful sterile abscesses (238)(239)(240). Fever may occur in children after the second or third injection and persist until treatment is stopped (239). Many of the adverse events are dose-related (10,240). Transient elevations of liver enzymes may occur with higher doses (10). In patients with glucose-6-phosphate-dehydrogenase deficiency, haemolysis may occur (239,241,242). Exacerbation of lead toxicity has been reported (9).

# Safety in pregnancy
Category C: Experimental animal data suggest a fetal risk (231).

# Penicillamine (Oral)
Penicillamine is a sulfhydryl amino acid product of the hydrolysis of penicillin, but it has no antibiotic properties. The pharmaceutical form is D-penicillamine, as L-penicillamine and the racemic mixture are toxic (243). Penicillamine is given orally.
Typical regimens are:
Adult: 1-2 g by mouth daily in divided doses before food (236) Child (all ages): 7.5 mg/kg body weight three or four times daily (196) 15-20 mg/kg body weight per day in two or three doses (244).
Some sources suggest starting at the lower dose initially, then increasing gradually, to reduce adverse effects (245).

# Adverse events
Most of the information on adverse events is for patients on long-term therapy for hepatolenticular degeneration (Wilson disease), cystinuria or rheumatoid arthritis. These may be less frequent with the shorter courses of therapy required for lead poisoning.
The most common adverse events are rash, anorexia, nausea, vomiting and taste disturbance (196). Uncommon events include fever, allergy, itching, urticaria, proteinuria and mouth ulcers. Rare events include haematuria, thrombocytopenia, leukopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia, nephrotic syndrome, lupus erythematosus, Goodpasture syndrome, hepatic dysfunction, pemphigus, dermatomyositis, myasthenia gravis, polymyositis and Stevens-Johnson syndrome (196,237). People with penicillin allergy may be at risk for cross-sensitivity, but this appears to be rare (245).
In the treatment of lead poisoning, the following adverse events have been reported: leukopenia, rashes, thrombocytopenia, eosinophilia, proteinuria and angioedema (11). These effects resolved on termination of treatment. Adverse events may be more likely at higher doses of penicillamine (11,245) Safety in pregnancy Category D: Known fetal risk (232)  (246).
A typical regimen is up to 40 mg/kg body weight twice daily intravenously or intramuscularly for up to 5 days. This can be repeated if necessary, after an interval of 48 h (237).

# Adverse events
Common adverse events include sneezing, nasal congestion, numbness, tingling, nausea, diarrhoea, abdominal cramps, fever, malaise, headache, myalgia, thirst and chills. Uncommon events include renal tubular necrosis, pain at the injection site, thrombophlebitis, lachrymation and transient hypotension. Rare events include mucocutaneous lesions (196). Nephrotoxicity appears to be dose dependent (247).
Prolonged administration of sodium calcium edetate at a high dose may produce transient bone marrow depression and skin and mucous membrane lesions (including cheilosis), but these usually resolve on discontinuation of the drug (248).
This drug may also cause increased excretion of trace elements such as zinc and copper (12,246).

# Safety in pregnancy
Category B: Studies in experimental animals do not indicate a risk to the fetus, and there are no adequate studies of pregnant women (232).

# Succimer (Oral)
Succimer (meso-2,3-dimercaptosuccinic acid, DMSA) is a water-soluble dithiol and is an analogue of dimercaprol. Succimer is usually administered orally (218).
A typical regimen is 10 mg/kg body weight or 350 mg/m2 orally every 8 h for 5 days, then every 12 h for an additional 14 days (245,248,249). The course of treatment may be repeated if necessary, usually after an interval of not less than 2 weeks, unless blood lead concentrations indicate that more prompt treatment is necessary (245). Other regimens have been used, e.g. prolonging the overall treatment course to 21 or 28 days (4,250).

# Adverse events
The most commonly reported adverse effects are GI disorders (nausea, vomiting, diarrhoea, loose stools), transient increases in serum transaminase activity, increased excretion of zinc or copper and skin eruptions, possibly affecting the mucosa (13,249,250). In a large case series, elevated alanine aminotransferase activity was seen in < 2.5% of children (4). Other reported effects include: flu-like symptoms, headache, drowsiness and dizziness (218,245) and mild-to-moderate neutropenia (245).
Hypersensitivity reactions with urticaria and angioedema have been reported rarely (245,250). Haemolytic anaemia was reported in a patient with glucose-6-phosphate dehydrogenase deficiency (251), but succimer has been used in other patients with this condition without incident (252)(253)(254). Most adverse effects are mild to moderate and resolve on termination of treatment (13,249).

# Safety in pregnancy
Category C: Data for experimental animals suggest a fetal risk (232).

# Supportive measures
Patients with severe lead poisoning may have seizures, raised intracranial pressure, cerebral oedema and coma. Supportive management for these conditions should be provided in accordance with the usual hospital management protocols. WHO guidance on the management of obtundation and seizures in limited-resource settings is available (255,256).
Whether or not chelation therapy has been given, it is important to re-evaluate the patient periodically, including the blood lead concentration, to determine the effectiveness of measures to terminate exposure and chelation and whether further action is necessary. If preventive measures are not successful, the blood lead concentration will continue to rise.
Chelation therapy removes lead from blood and soft tissues, but, if there are significant bone stores, remobilization occurs, and the blood lead concentration will rise again. The interval before re-evaluation of a patient depends on the severity of poisoning, the initial blood lead concentration (PbB) and whether the patient belongs to a vulnerable group. The following intervals were suggested by the guideline development group:
Children, adolescents and pregnant women:
- PbB > 30 g/dL: after 2-4 weeks
- PbB 5-29 g/dL: after 1-3 months
- PbB < 5 g/dL: after 6-12 months if there is continuing concern about possible lead exposure Other adults:
- PbB > 50 g/dL: after 2-4 weeks
- PbB 30-50 g/dL: after 1-3 months
- PbB 5-29 g/dL: after 3-6 months A shorter interval is suggested for severe poisoning, higher blood lead concentrations and for children, adolescents and pregnant women. As young children absorb proportionately more lead than adults, their blood lead concentrations may rise more rapidly (93). The fetal period and childhood are periods of particular susceptibility to the neurotoxic effects of lead. During pregnancy, physiological changes may result in an increase in blood lead concentrations and greater exposure of the fetus. The increased need for calcium for the developing fetal skeleton results in increased calcium absorption from the maternal GI tract and may also increase lead absorption.
In addition, stored lead may be released as maternal bone is resorbed (182).
As children who have been exposed to lead may suffer impaired neurocognitive and behavioural development, the guideline development group advised periodic assessment for signs of difficulty in meeting developmental goals, ideally until the end of secondary education. These children should be given whatever support is available locally.

# Research gaps
The systematic reviews of evidence identified very few good-quality studies of the effectiveness of any of the treatment interventions for lead exposure, and more evidence is needed for all the interventions. It is recognized, however, that conducting RCTs would, in most cases, be ethically and/or practically difficult. Observations are made below on the interventions considered in this guideline.

# Gastrointestinal decontamination
A number of variables influence the effectiveness of GI decontamination methods after ingestion of lead. These include the form of lead ingested (e.g. foreign body, liquid glaze, paint flakes), the interval after ingestion, the physical condition of the patient and the resources available at the treatment centre. Furthermore, the overall number of cases of lead ingestion for which GI decontamination could be considered is probably small. It would be difficult, therefore, to accumulate a sufficient number of comparable cases for a meaningful study.
For these reasons, it is likely that any evidence of the effectiveness of methods of GI decontamination will continue to be based on case reports or small case series. While this evidence is considered to be of very low certainty, case reports would be more useful if they were better documented and guidance is available (257). In particular, when practical, more details of the effect (success or failure) of each method used, for example by stool collection, more frequent blood lead concentration monitoring or serial abdominal X-rays, would be helpful, provided they can be justified as part of patient management. The use of several methods in the same patient or administration of chelating agents will, of course, complicate interpretation of changes in blood lead concentrations and clinical condition, but this is unavoidable. The information could also be used to evaluate whether chelation should be withheld until GI decontamination is complete, as some have proposed (116,258).

# Nutritional interventions
The available studies on nutritional interventions were conducted with patients who had relatively low blood lead concentrations, and they did not address the question of whether such interventions would be of benefit to patients with severe lead poisoning. In addition, there were no data on the value of combining nutritional supplementation with chelation therapy. This would be of interest, as chelating agents are known to also increase elimination of some trace elements.
More and better studies are needed to determine whether the efficacy of increasing iron or calcium intake in the diet differs from that of supplements, as well as the optimal dose and duration of supplementation. Studies are also needed on the impact of calcium supplementation on outcomes other than blood lead concentration, e.g. neurocognitive development. Studies should also be conducted on whether different age groups, e.g. young children, adolescents or adults, benefit more.

# Chelation therapy
While there is consistent evidence that chelation is associated with a reduction in the blood lead concentration and increased urinary excretion, there are still no data on longer-term outcomes, such as neurocognitive development, behaviour and cardiovascular disease, in patients with significant lead poisoning. Furthermore, the threshold blood lead concentration for chelation that is effective in improving outcomes in different age groups has not been established.
Oral chelating agents such as succimer can be given to outpatients, which offers economic and practical advantages when long courses of treatment are necessary. Directly observed treatment has been used in a low-resource setting (4), but more studies should be conducted of adherence to treatment in outpatient settings and the link to outcomes.
Very few reports were available of the use of chelating agents in patients with glucose-6-phosphate dehydrogenase deficiency, with mixed results. Therefore, the safety of these agents in this sub-group is not established.
No RCTs were found on use of chelation therapy in pregnancy, and it is difficult to see how such studies could be conducted, for ethical reasons. It is important, therefore, that cases in which chelation therapy is used in pregnancy be well documented and published in order to increase the body of knowledge about chelation in this patient group. Better national data are also needed on the prevalence of high blood lead concentrations in pregnant or lactating women.

# Considerations for implementation of the guideline
WHO recognizes lead as one of 10 key chemicals of public health concern and is actively working with partners and policy-makers to raise awareness about preventing and managing lead exposure (259).
To support implementation of this guideline, a derivative product will be developed that presents the recommendations in a format more easily used by clinicians and translated into many languages. A specific implementation plan will be developed with the WHO regional offices and partners, taking into account the challenges identified.
Two important challenges must be addressed in order to implement the guidelines. The first is the limited availability of good-quality laboratory services for the diagnosis of lead poisoning. WHO is advocating for greater availability of toxicology laboratories as a core capacity requirement under the International Health Regulations (2005) (260), and WHO's brief guide on methods for the analysis of lead in blood, published in 2020, is available in all six United Nations languages (142).
The second challenge is the limited availability of chelating agents in many low-and middle-income countries, as mentioned in section 7.3. The reviewed chelating agents are on the WHO model lists of essential medicines and of essential medicines for children (169,196). WHO will use the guidance to further advocate for greater availability of chelating agents as part of universal health coverage and to improve procurement of essential medicines through inter-country cooperation. The WHO Regional Office for South-East Asia has launched the Initiative for Coordinated Antidotes Procurement in the South-East Asia Region to help countries in the Region to procure antidotes for a range of common poisons including lead (261,262).
With regard to nutritional interventions, WHO is developing guidelines on single and multinutrient supplementation to improve the health of children and pregnant women. WHO is also working with FAO to update guidance on nutrient requirements for children.
WHO's initiative for strengthening and establishing poisons centres will be fully engaged in implementation of the guidelines, as these specialized centres are key target users (263).
Working with partners and as resources permit, training for medical practitioners will be organized in selected countries in the diagnosis and management of lead exposure, supplemented by online courses.
CONSIDERATIONS FOR IMPLEMENTATION OF THE GUIDELINE | 71

# Chelation therapy for a child with an elevated blood lead concentration