Hong Kong College of Paediatricians Position Paper on Exposure to Lead and Mercury in Children and Chelation Therapy
Summary As there is relatively little controversy about the need for treatment of acute and chronic lead and mercury poisoning in children, this review focuses on low level exposure to these two metals and the use of chelation therapy. For lead, although low level exposure may affect children's intellectual development, reduction in the blood lead level does not necessarily correlate with improvement in cognition. Although chelating agents can reduce blood lead levels, this can also be achieved more safely with environmental interventions. With regard to mercury, major concerns relate to its presence in fish and vaccines, and the hypothesis that it can cause autism. Apart from a few fish high in mercury content identified by the US Food and Drug Administration, common dietary fish in Hong Kong are generally safe. The World Health Organization has recently reaffirmed the safety of thimerosal in vaccines and there is no evidence that autism is related to mercury toxicity. Although newer and safer chelating agents can remove organic mercury from the body, they cannot reverse the damage to the central nervous system. The use of hair analysis for the screening of lead or mercury toxicity is controversial and is not recommended for routine clinical practice. The use of challenge test as a guide to the necessity for therapy is unreliable and not without danger. Non-conventional or alternative treatments should be used only in formal research protocols to evaluate their effectiveness. Currently, reduction of environmental pollution and balanced nutrition are considered to be the best strategies to prevent exposure to lead and mercury.
Exposure to Lead and Chelation Therapy
Children can be exposed to lead from many sources including lead in the air from combustion of leaded petrol, licking lead-based paint on furniture and toys, chewing crayons and ingesting contaminated soil particles, especially in children exhibiting pica. Certain populations may be at particular risk e.g. children from fishermen's families in Hong Kong as reported by Yu and Yeung.1 Over past decades there has been considerable effort to reduce environmental lead exposure with the introduction of legislation related to lead-free petrol and children's products.
Measurement of Lead Exposure
The Centers for Disease Control and Prevention (CDC)2 defined in 1991 a blood lead level (BLL) >= 10 mcg/dL as an indictor for concern. Lead exposure can be assessed by a number of laboratory means.3 The standard procedure for determining BLLs is the use of venous blood samples collected properly and analyzed in laboratories with quality assurance programmes. Capillary blood samples from finger prick can be contaminated with environmental lead, and require confirmation with a venous sample when levels are above 10 mcg/dL. The use of hair analysis for assessing lead exposure is not recommended by CDC.4 The American Academy of Pediatrics (AAP)5 has stated that the calcium disodium ethylenediaminetetra-acetic acid (EDTA) mobilisation (challenge) test is difficult and expensive to perform. The test has the potential to increase lead toxicity when EDTA is used alone, which has made the test "obsolete".
Lead Level and Development
Although even low levels of lead exposure may affect children's intellectual development, the threshold at which harmful effects from lead exposure occur is not clearly established. A systemic review by Pocock et al6 in 1994 found that doubling the body lead burden (from 10 to 20 mcg/dL blood lead) was associated with a mean deficit in full scale IQ of around 1-2 IQ points. Other explanations for this deficit were also possible e.g. children with a lower IQ might adopt behaviours that could make them more prone to lead uptake. Locally, Chow and Tse7 reported on the health status of Chinese new immigrant children and found that although 20.7% of the children had BLLs above 0.47 mmol/L (10 mcg/dL), no child had a BLL above 0.96 mmol/L (19 mcg/dL). Some of these children had symptoms, including learning difficulties, that could have been related to lead exposure but these symptoms bear no relationship with BLL.
Chelation Therapy and Lead Levels
O'Connor and Rich8 in a double-blind placebo-controlled trial found that reduction of elevated BLL could be achieved with environmental remediation as well as chelation therapy with 2,3 dimercaptosuccinic acid (DMSA). However changes in cognitive test results and changes in BLLs with chelation therapy did not always correlate. An earlier observational study in 1993 by Ruff et al9 reported an improvement of cognitive test scores for children with BLLs between 25 to 55 mcg/dL after chelation with EDTA (with iron therapy when indicated). Tong et al10 followed a group of children from birth to 11-13 years who lived in the vicinity of a large lead smelter. From 2 years to 11-13 years, there was a fall in the mean BLL but the improvement in cognitive scores did not correlate with the degree of change in BLLs. From 7 years to 11-13 years, cognition was slightly better among children whose BLL declined most but did not reach statistical significance.
In 2001, Rogan et al11 reported for the Treatment of Lead-exposed Children Trial Group the results of a randomised, placebo-controlled, double blind trial on the effect of succimer (DMSA) in over 700 children with BLLs of 20 to 44 mcg/dL. Although DMSA therapy lowered BLLs, it did not improve scores on tests of cognition, behaviour, or neuropsychological function in the children at the 36 months follow-up. In 2002, Liu et al12 did another analysis of the results from the above group using change in BLL as the independent variable. By 6 months after randomisation, BLLs had fallen by similar amounts in both chelated and placebo groups despite the immediate drops in the chelated group. At the 36 months follow-up, cognitive test scores increased with a fall in BLL in the placebo group only.
CDC has a set of recommendations for action for various BLLs (Table 1).4 Chelation therapy is only recommended when BLL is >= 45 mcg/dL. The AAP3 has slightly different recommendations in that if BLL is >25 mcg/dL, chelation could be considered after consultation with clinicians experienced in lead toxicity.
Chelation therapy is not without side effects. AAP reviewed the various chelating agents that have been used.5 As much as 50% of patients experience side effects from dimercaprol (BAL in Oil) which has to be given intramuscularly. Significant haemolysis was reported in patients with glucose-6-phosphate dehydrogenase deficiency. EDTA has to be given parenterally and if used alone in the treatment of patients at risk for encephalopathy, there is a danger of lead redistribution from soft tissues to the central nervous system. In this situation, pre-treatment with BAL has been recommended. Slower infusion rates in patients without the risk of encephalopathy may be safer but loss of zinc could result in zinc deficiency. Careful monitoring of renal and hepatic functions is needed. DMSA can be given orally and only minimally increases the excretion of iron, zinc and calcium. Side effects include mild gastrointestinal upset, malaise, hypersensitivity reactions, transient elevation of liver enzymes and reversible neutropaenia. Adverse effects in the longer term are not yet known.
The current situation was summarised by AAP5 as "Given the lack of data regarding an improvement in outcome associated with any chelation therapy and the lack of sufficient data on safety to exclude rare but potentially severe side effects, therapy for lower-level exposures should include only environmental and nutritional intervention". If chelation therapy for low-level lead exposure (BLL of 25 to 44 mcg/dL) is considered, it should be undertaken as part of a research protocol.
Exposure to Mercury and Chelation Therapy
Children can be exposed to elemental, inorganic and organic mercury. An example of elemental mercury exposure is ingestion of mercury from a broken thermometer. This is generally not a problem to the child as the ingested mercury passes out unchanged.13 If the mercury is spilt onto the floor, it is important not to clean up the mercury using a vacuum cleaner as vapourised mercury is rapidly absorbed by the respiratory tract causing acute toxicity. Inorganic mercury in teething powders used to cause acrodynia or 'pink disease' but such teething powders are no longer used. Mercurochrome, once a common household antiseptic, could give rise to extremely high blood mercury levels and acute poisoning after ingestion of 20 ml of 2% of the compound.14 The major organic mercury compounds of current concern are methyl and ethylmercury.
Mercury in Fish
Methylmercury is found in sea sediments and accumulates in predatory fish along the food chain. It was also used as a fungicide. Infants were brain-damaged when mothers ate heavily contaminated fish from industrial release of mercury into Minamata Bay in Japan in the 1950's and bread made from contaminated grain in Iraq in the early 1970's.
A prospective study in the Faroe Islands in the Norwegian Sea15 found infants of mothers who ate small amounts of cod but had episodic feasts of pilot whale meat with a mean content of methylmercury of 1.9 ppm developed subtle neuropsychological dysfunction. Another prospective study in the Seychelles in the Indian Ocean16,17 did not find similar adverse effects in infants followed up to 9 years whose mothers frequently ate fish with relatively low methylmercury content of a mean of <0.3 ppm. However the mean mercury level in mothers' hair in the Seycelles study (6.8 ppm, range: 0.5-27 ppm) was higher than that in the Faroe Islands (4.3 ppm, range: 0.2-39.1 ppm).
Although the exposure patterns to methylmercury in the mothers of the two studies were different, the US Environmental Protection Agency (EPA) has recommended a limit of mercury exposure of 0.1 mcg/kg/d as a precaution using the results of the Faroe Islands study.18 The FDA19 advises pregnant women, and women of childbearing age who may become pregnant, not to eat certain fish with high methylmercury content (>1 ppm) such as shark, swordfish, king mackerel or tilefish. This advice has also been extended to breast-feeding mothers and young children. Up to 12 ounces a week of other fish can be eaten with smaller portions for children. These recommendations also emphasise the benefit of fish in a balanced diet.
A Hong Kong study on environmental mercury exposure in children by Ip et al20 has found that more frequent fish consumption is correlated with a higher blood and hair mercury level. However another study of 29 common dietary fish in Hong Kong, whose mercury content was assessed, has shown that none exceeded the Hong Kong legal limit of 0.5 ppm21 (Fok TF, personal communication). In June 2003, the Joint Food and Agriculture Organization of the United Nations and World Health Organization Expert Committee on Food Additives (JECFA) revised the provisional tolerable weekly intake (PTWI) for methylmercury from 3.3 mcg to 1.6 mcg per kg body weight per week in order to sufficiently protect the foetus from exposure to methylmercury through contaminated food eaten by the pregnant mother.22 As approximately 70% of total mercury in fish is methylmercury, for Hong Kong, around 0.3 kg of mackerel to 5.3 kg of white pomfret could be safely consumed per week (Fok TF personal communication).
Mercury in Vaccines
The other organic salt of mercury causing concern is ethylmercury which is metabolised from thiomersal (known as thimerosal in the USA), a preservative in vaccines. Ethylmercury was thought to have similar toxic effects to methylmercury. Ball et al23 calculated that some infants may be exposed to cumulative levels of mercury during the first 6 months of life that exceeded EPA recommendation. This resulted in the removal of thimerosal from all the vaccines in the US as a precautionary measure. However further studies found that the half-life and toxicity levels of ethyl and methylmercury are different and the WHO has recently confirmed that it is safe to continue to use vaccines containing thiomersal.24
Mercury and Autism
Bernard et al25 in 2001 proposed that autism is a novel form of mercury poisoning. Nelson and Bauman26 reviewed the evidence for this hypothesis and concluded that mercury poisoning and autism have different clinical and neuropathological features. In Denmark, Madsen et al27 noted an increase in the incidence of autism despite the discontinuation of thimerosal-containing vaccines. Hviid et al28 also found in a Danish population-based cohort study that the risk of autism and other autistic spectrum disorder (ASD) did not differ significantly between children vaccinated with vaccines with or without thimerosal. A local study by Ip et al29 found no significant difference in the hair or blood mercury levels between autistic and normal children. The AAP30 in their technical report on the diagnosis and management of ASD in children affirmed the lack of any link between mercury exposure and ASD. The report also noted a lack of evidence to support chelation therapy to treat mercury toxicosis in order to improve developmental function and emphasised that chelating agents themselves can have toxic effects and precipitate allergic reactions.
Measurement of Mercury Exposure
Interpretation of mercury levels need to take into account the type and duration of exposure. Whole blood and urine assays can be used to detect elemental and inorganic mercury exposure. For organic mercury whole blood has to be used, as it is concentrated in the erythrocytes. The reference range from a local laboratory (Prince of Wales Hospital) is less than 10 mcg/L in blood and less than 10 mcg/day in urine. Either a 24-hour urine collection or a spot urine sample adjusted for creatine output should be used. However spot urine mercury alone is very misleading as large variations may occur in the same subject, depending on the hydration state. AAP does not recommend hair analysis for diagnosis of mercury exposure because of the ease of contamination. AAP also discourages the use of provocative chelation tests which have yet to be scientifically validated.30
Chelation Therapy for Mercury
Chelation regimens for mercury were developed for acute mercury poisoning. In theory, a patient can develop subacute or chronic methylmercury poisoning because of excessive intake of fish with a relatively high methylmercury content. In western societies in which all fish sold in the market are closely monitored, there has not been a single report of chronic exposure requiring treatment.
In general a blood mercury level greater than 35 mcg/L and urine concentration over 100 mcg/L requires treatment.31 As noted, 24-hour urine output or spot urine adjusted for creatine should be used. Dimercaprol and d-penicillamine have been used for chelation but are more toxic. In particular dimercaprol is not recommended for organic mercury toxicity because animal studies have shown an increase in mercury in the brain due to redistribution during treatment. DMSA and sodium dimercaptopropanesulfonate (DMPS) may be used to chelate inorganic, elemental and organic mercury and are safer than the older drugs. They are however not devoid of side effects.32 Adverse effects of DMSA include gastrointestinal upset, skin rashes, increased serum transaminases, flu-like symptoms, drowsiness and dizziness, and mild to moderate neutropaenia. DMSA should be used with caution in renal impairment and hepatic disease. DMPS can produce skin rashes and increase copper and zinc excretion. The major problem for organic mercury toxicity is that although chelators may remove methyl and ethylmercury from the body, they cannot reverse the damage done to the central nervous system.13 Hence when balancing the risks and benefits, there is no indication for the use of chelating agents for the treatment of low level exposure to mercury. The most effective and important therapeutic measure for managing excessive exposure to mercury is to identify and remove the source.
Mineral Analysis in Hair for Lead or Mercury
Methylmercury can be measured in hair specimens but usually in research settings with rigorous control of contamination.33 Esteban et al34 from CDC studied the use of hair lead concentration as a screening method for lead poisoning. The method was considered unacceptable with a sensitivity level of only 57% and with 18% of the children being classified as false negatives. Barret35 found in 1985 that commercial laboratories in the US gave highly unreliable results of hair analysis for a whole range of minerals and presented potentially frightening reports to clients with various recommendations for the use of food supplements. As laboratory methods may have improved since this time, Seidel et al36 performed a similar study which was reported in 2001. The study concluded that hair mineral analysis was still unreliable despite being undertaken by "Clinical Laboratory Improvement Act" certified laboratories. Certification of these laboratories was not specifically for hair analysis. The authors recommended that health care practitioners refrain from using such analyses to assess individual nutritional status or suspected environmental exposure. Drasch and Roider37 assessed hair mineral analysis commercially offered in Germany and came to the same conclusion. This is also the opinion of AAP.30 Hence the routine use of hair mineral analysis for the screening for lead and mercury toxicity is not recommended.
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