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Re: "Biomedical Treatment - Parents' Group "
hi mimi
have problem pm u so attaching the paper here. maybe a bit out of date as written in 2004.
Hong Kong College of Paediatricians
Position paper
on Exposure to lead and mercury in children and chelation therapy
Working Group Members:
Dr Patricia Ip
Dr Paul Ko
Dr Catherine Lam
Prof Tony Nelson
Prof Virginia Wong
Advisors:
Prof Thomas Chan Yan Keung
Prof C R Kumana
Acknowledgement: Dr Albert Martin Li for assistance in literature search
Endorsed by the Council of the Hong Kong College of Paediatricians 16th March 2004
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) mobilization (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 randomized, 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 randomization, 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 summarized 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.
Table 1
Summary of Recommendations for Children with Confirmed (Venous) Elevated Blood Lead Levels4
Blood Lead Level (mcg/dL)
10-14 15-19 20-44 45-69 >70
Lead education
-Dietary
-Environmental
Follow-up blood lead
monitoring
Lead education
-Dietary
-Environmental
Follow-up blood lead
monitoring
Proceed according to
actions for 20-44
mcg/dL if:
-a follow-up BLL
is in this range at
least 3 months
after initial
venous test
or
-BLLs increase
Lead education
-Dietary
-Environmental
Follow-up blood lead
monitoring
Complete history and
physical exam
Lab work:
-Hemoglobin or
hematocrit
-Iron status
Environmental
investigation
Lead hazard
reduction
Neurodevelopmental
monitoring
Abdominal X-ray (if
particulate lead
ingestion is
suspected) with
bowel
decontamination if
indicated
Lead education
-Dietary
-Environmental
Follow-up blood lead
monitoring
Complete history and
physical exam
Complete
neurological exam
Lab work:
-Hemoglobin or
hematocrit
-iron status
-FEP or ZPP
Environmental
investigation
Lead hazard
reduction
Neurodevelopmental
monitoring
Abdominal X-ray
with bowel
decontamination if
indicated
Chelation therapy
Hospitalize and
commence chelation
therapy
Proceed according to
actions for 45-69
mcg/dL
The following actions are NOT recommended at any blood lead level:
-Searching for gingival lead lines
-Testing of neurophysiologic function
-Evaluation of renal function
(except during chelation with EDTA)
-Testing of hair, teeth, or fingernails for lead
-Radiographic imaging of long bones
-X-ray fluorescence of long bones
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 emphasize the
benefit of fish in a balanced diet.
A Hong Kong study on environmental mercury exposure in children by Ip P 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 methyl mercury 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 metabolized 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 emphasized 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.
References:
1. Yu ECL, Yeung CY. Lead poisoning in fishermen's children. HK J of Paediatr 1990;7:62-3.
2. Centers for Disease Control and Prevention. Preventing lead poisoning in young children:
a statement by the Centers for Disease Control, October 1991. Atlanta, GA: US Dept of
Health and Human Services; 1991.
3. American Academy of Pediatrics, Committee on Environmental Health. Screening for
elevated blood lead levels. Pediatrics 1998;101:1072-8.
4. Centers for Disease Control and Prevention. Managing elevated blood lead levels among
young children: recommendation from the Advisory Committee on Childhood Lead
Poisoning Prevention, March 2002. Atlanta, GA: US Dept of Health and Human Services,
Public Health Service; 2002.
5. American Academy of Pediatrics, Committee on Drugs. Treatment guidelines for lead
exposure in children. Pediatrics 1995;96:155-60.
6. Pocock SJ, Smith M, Baghurst P. Environmental lead and children’s intelligence: a
systematic review of the epidemiological evidence. Br Med J 1994;309:1189-97.
7. Chow CB, Tse K. Report-survey on the childhealth status of Chinese new immigrants. HK
J Paediatr (new series) 2000;5:15-24.
8. O'Connor ME, Rich D. Children with moderately elevated lead levels: is chelation with
DMSA helpful? Clin Pediatr 1999;38:325-31.
9. Ruff HA, Bijur PE, Markowitz M, Ma YC, Rosen JF. Declining blood levels and cognitive
changes in moderately lead-poisoned children. JAMA 1993;269:1641-6.
10. Tong S, Baghurst PA, Sawyer MG, Burns J, McMichael AJ. Declining blood lead levels
and changes in cognitive function during childhood. JAMA 1998;280:1915-9.
11. Rogan WJ, Dietrich KN, Ware JH, et al. The effect of chelation therapy with succimer
on neuropsychological development in children exposed to lead. N Engl J Med
2001;344:1421-6.
12. Liu X, Dietrich KN, Radcliffe J, Ragan NB, Rhoads GG, Rogan WJ. Do children with
falling blood lead levels have improved cognition? Pediatrics 2002;110:787-91.
13. Clarkson TW, Magos L, Myers GJ. The toxicology of mercury - current exposures and
clinical manifestations. N Engl J Med 2003;349:1731-7.
14. Magarey JA. Absorption of mercurochrome. Lancet 1993;342.1424.
15. Grandjean P, Weihe P, White RF, et al. Cognitive deficit in 7-year-old children with
prenatal exposure to methylmercury. Neurotoxicol Teratol 1997;19:417-28.
16. Davidson PW, Myers GJ, Cox C, et al. Effects of prenatal and postnatal methylmercury
exposure from fish consumption on neurodevelopment: outcomes at 66 months of age in
the Seychelles Child Development Study. JAMA 1998;280:701-7.
17. Myers GJ, Davidson PW, Cox C, et al. Prenatal methylmercury exposure from ocean
fish consumption in the Seychelles child development study. Lancet 2003;361:1686-92.
18. US Environmental Protection Agency. Mercury Study Report to Congress. Washington,
DC: US Environmental Protection Agency; 1997.
19. Center for Food Safety and Applied Nutrition, US Food and Drug Administration. An
important message for pregnant women and women of childbearing age who may become
pregnant about the risks of mercury in fish. Available at:
http://vm.cfsan.fda.gov/~dms/admehg.html Accessed 21 February 2004.
20. Ip P, Wong V, Ho M, Lee J, Wong W. Environmental mercury exposure in children -
south China experience. Pediatric International. 2004 in press.
21. Food and Environmental Hygiene Department, HKSAR. Risk of mercury in fish. Risk in
brief 2003;13. Available at:
http://www.fehd.gov.hk/safefood/report/mercury_fish/report.html Accessed 21 February
2004.
22. Joint Food and Agriculture Organization/WHO Expert Committee on Food Additives.
Toxicological recommendations and information on specifications. June 2003. Available at:
http://www.who.int/mediacentre/notes/2003/np20/en/ Accessed 21 February 2004.
23. Ball LK, Ball R, Pratt RD. An assessment of thimerosal use in childhood vaccines.
Pediatrics 2001;107:1147-54.
24. World health Organization, the Global Advisory Committee on Vaccine Safety.
Statement on thiomersal. August 2003. Available at:
http://www.who.int/vaccine_safety/topics/thiomersal/statement200308/en/index.html
Accessed 21 February, 2004.
25. Bernard S, Enayati A, Redwood L, Roger H, Binstock T. Autism: a novel form of
mercury poisoning. Med Hypotheses. 2001;56:462-71.
26. Nelson KB, Bauman, ML. Thimerosal and autism? Pediatrics 2003;111:674-9.
27. Madsen KM, Lauritsen MB, Pedersen CB, et al. Thimerosal and the occurrence of
autism: negative ecological evidence from Danish population-based data. Pediatrics
2003;112:604-6.
28. Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Association between
thimerosal-containing vaccine and autism. JAMA 2003;290:1763-6.
29. Ip P, Wong V, Ho M, Lee J, Wong W. Mercury exposure in children with autistic
spectrum disorder: a case-control study. J Child Neuro. 2004 in press.
30. American Academy of Pediatrics, Committee on Children with Disabilities. Technical
report: The pediatrician's role in the diagnosis and management of autistic spectrum
disorder in children. Pediatrics 2001;107(5). URL:
http://pediatrics.aappublications.org/cgi/content/full/107/5/e85.
31. Chiang WK. Mercury. In: Ford MD, Delaney KA, Ling LJ, Erickson T, editors. Clinical
Toxicology. Philadelphia: WB Saunders Company, 2001:737-43.
32. Sweetman SC. Martindale. Great Britain: The Pharmaceutical Press, 2002.
33. Goldman LR, Shannon MW, the Committee on Environmental Health, American
Academy of Pediatrics. Technical report: mercury in the environment: implications for
pediatricians. Pediatrics 2001;108:197-205.
34. Esteban E, Rubin C, Jones RL, Noonan G. Arch Environ Health 1999;54:436-40.
35. Barrett S. Commercial hair analysis. Science or scam? JAMA 1985;254:1041-5.
36. Seidel S, Kreutzer R, Smith D, McNeel S, Gilliss D. Assessment of commercial
laboratories performing hair mineral analysis. JAMA 2001;285:67-72.
37. Drasch G, Roider G. Assessment of hair mineral analysis commercially offered in
Germany. J Trace Elem Med Biol 2002;16:27-31. |
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