8/17 中西醫聯合討論會 Nephro Fellow 1 潘恆之

Heavy metal poisoning associated with the use of

traditional Chinese medicines

Sources of toxic chemicals in herbal products : A. Contamination – 1. Environmental conditions 2. The conditions under which they are air-dried 3. The storage and transport conditions 4. The manufacturing processes

B. Deliberate inclusion as an ingredient – 1. For therapeutic purpose. 2. to increase the weight of the product prior to sale.

~ Lead Encephalopathy Due to Traditional Medicines – Current Drug Safty 2008 January; 3(1):54-59

~ Some aspects of toxic contaminants in herbal medicines – chemosphere 52 (2003) 1361-1371

~ Toxicology 181-182 (2002) 571-576

California offiical study analysed 251 Chinese medicine: 24/251 products contained lead. 36/251 products contained arsenic. 35/251 products contained mercury; at least 83/251 (32 %) contained heavy metals, and 23 had more than one adulterant.

Koh and Woo analysed 2080 traditional Chinese medicine in Singapore: 42/2080 medicines contained metals – 28/2080 products contained mercury, 8/2080 products contained lead, 6/2080 products contained arsenic. 1/2080 product contained both mercury and lead and another contained both mercury and arsenic.

~ Adulterants in Asian Patent Medcines – NEJM Vol 339, No.12, Sep 17, 1998

~ Toxic heavy metals and undeclared drugs in Asian herbal medicines – TRENDS in Pharmacological Sciences Vol.23 No.3 March 2002

Melchart et al. analysed all 317 Chinese herbs in German . Heavy metal content was detected in 3.5%.~ Toxic heavy metals and undeclared drugs in Asian herbal medicines –

TRENDS in Pharmacological Sciences Vol.23 No.3 March 2002

~ Heavy metals in traditional Chinese medicines: A systematic review –

Clinical Pharmacology and Therapeutics, Vol 70, No. 6, Dec 2001

~ Heavy metals in traditional Chinese medicines: A systematic review –

Clinical Pharmacology and Therapeutics, Vol 70, No. 6, Dec 2001

~ Heavy metals in traditional Chinese medicines: A systematic review –

Clinical Pharmacology and Therapeutics, Vol 70, No. 6, Dec 2001

~ Heavy metals in traditional Chinese medicines: A systematic review –

Clinical Pharmacology and Therapeutics, Vol 70, No. 6, Dec 2001

~ Heavy metals in traditional Chinese medicines: A systematic review –

Clinical Pharmacology and Therapeutics, Vol 70, No. 6, Dec 2001

~ Heavy metals in traditional Chinese medicines: A systematic review –

Clinical Pharmacology and Therapeutics, Vol 70, No. 6, Dec 2001

What are the toxic ingredient in the traditional Chinese medicine?

Up to 10-15% of Asian patent medicines contained lead, mercury or arsenic. Such as Lithargyrum ( 密陀僧 – lead), Cinnabaris ( 硃砂— mercury sulfide), for sedative purposes. Sulphur ( 硫磺 ), Realgar ( 雄黃— arsenic) , Calomela( 輕粉— mercury chloride), ‘hydrargyri oxydum rubrum’ (mercury oxide) and Chalcanthitum ( 膽礬 ) for systemic infection, ulcer and insomnia.

What are the toxic ingredient in the traditional Chinese medicine?

~ Hong Kong Med J Vol 8 No 4 August 2002 ~ Toxic heavy metals and undeclared drugs in Asian herbal medicines – TRENDS in Pharmacological Sciences Vol.23 No.3 March 2002

Ba Bow Sen ( 八寶散 ) – contain more than 1000 ppm lead => lead encephalopathy

Po Ying Tan ( 保嬰丹 ) – mean lead content of 7.5 mg/pc

Bao ning dan ( 保寧丹 ), Cordyceps ( 冬蟲夏草 ), Hai ge fen ( 海蜇粉 ), Ji jue di huang wan ( 杞菊地黃丸 )~ Childhood lead poisoning in China– The Science of the Total

Environment 181 (1996)101-109

~ Lead Encephalopathy Due to Traditional Medicines – Current Drug Safty 2008 January; 3(1):54-59

~ The Science of the Total Environment 182 (1996) 193-195

~ Three patient with lead posioning following use of a Chinese herbal pill -- HKMJ Vol 8 No 1 February 2002

~ Medical Hypotheses 72 (2009) 285-287~ Current Drug Safety 2008 January;3(1):54-59

Chinease herbal medicine and Lead posioning

Lonicera japonica Thunberg’s dry flos ( 金銀花 ) and Radix Morinda officinalis How’s ( 巴戟天 ). ~ Some aspects of toxic contaminants in herbal medicines – chemosphere 52 (2003) 1361-1371

Chinease herbal medicine and Arsenic posioning

~ Heavy metals in traditional Chinese medicines: A systematic review –

Clinical Pharmacology and Therapeutics, Vol 70, No. 6, Dec 2001

~ Heavy metals in traditional Chinese medicines: A systematic review –

Clinical Pharmacology and Therapeutics, Vol 70, No. 6, Dec 2001

Heavy metal poisoning complications

~ Heavy metals in traditional Chinese medicines: A systematic review –

Clinical Pharmacology and Therapeutics, Vol 70, No. 6, Dec 2001

Lead exposure produces chronic interstitial nephritis, progressive tubular atrophy, overexpression of angiotensin II, oxidative stress, salt retention, hypervolemia and hypertension

more rapid progression of renal failure in CKD patientArsenic affects the renal capillaries, tubules,

and glomeruli, causing tubular necrosis

Mercury causes damage to the renal proximal tubule and hemebiosynthetic pathways .

Cadmium causes proximal tubular injury

Renal complications of heavy metal poisoing

~ A Review of Dietary Supplement-Induced Renal Dysfunction – CJASN 2:757-765 2007

~Blood Lead Levels in the US go Down, but Higher Levels Are Still Associated with a Higher Burden of CKD – JASN 17:317-322,2006

Brief Review of Lead Poisoning

Lead is a xenobiotic metal, normal blood lead levels do not exist. Ideally, blood lead levels < 10 μg/dL.

Adult lead poisoning – blood lead level ≥40 μg/dL. Symptoms usually begins with levels > 50-60 μg/dL

Gastrointestinal absorption 15 % of ingested lead. In blood, 99 % lead is bound to the erythrocyte, 1% lead is distributed in blood, bone, and soft tissues. Lead also can crosses the blood-brain barrier, the placenta and into breast milk.

Half-life : in blood -- several weeks in soft tissues -- several months in bone -- 5–15 years. Excretion : primarily by kidney

~ Lead Encephalopathy Due to Traditional Medicines – Current Drug Safety 2008 January; 3(1):54-59

Acute exposure: abdominal pain, constipation, joint pains, muscle aches, headache, anorexia, decreased libido, difficulty concentrating and deficits in short-term memory, anemia, Fanconi-type syndrome

Chronic exposure: myalgias, fatigue, irritability, insomnia, anorexia, impaired short-term memory, difficulty concentrating, hypertension, neuropsychiatric defects, reproductive defects, nephropathy, cataract, carcinogenic effect, mortality.

Clinical manifestations

~ Lead Encephalopathy Due to Traditional Medicines – Current Drug Safty 2008 January; 3(1):54-59

Summary of lowest lead levels for key lead-induced health effects in

adults

Basophilic stippling

Lead line

~ Herbal Medicine-Associated Lead Intoxication – Internal Medicine Vol 36, No.1 ( Jan 1997)

~ Neural tube defects and herbal medicines contaiing lead: A possible relationship – Medical Hypotheses 72 (2009) 285-287

~ Neural tube defects and herbal medicines contaiing lead: A possible relationship – Medical Hypotheses 72 (2009) 285-287

History –Ooccupational/environmental/medication

Laboratory testing : a. Blood lead level b. Free erythocyte protoporphyrin (FEP) or zinc protoporphyrin (ZPP) both measure the effect of lead on hemoglobin synthesis c. Others –CBC, blood smear morphology, BUN, serum creatinine and urinalysis

Diagnostic evaluation

Other tests: a. X-ray fluorescence b. Neurobehavioral testing c. Nerve conduction velocity testing

Diagnostic evaluation

Reducing lead exposureChelation therapy: a. DMSA b. Ca-EDTA c. Asorbic acid (?)

Management

Research in progress

The potential role of oxidative stress injury associated with lead poisoning suggests to mitigate lead-induced toxicity

The aim of the study was to evaluate the protective effect of Smilax glabra against lead toxicity in rats.

Histological changes of liver tissues

Histological changes of kidney tissues

Calcium lactate, zinc sulfate, ferrous sulfate, ascorbic acid and calcium-rich milk and natural antioxidants (extract of Chinese wolfberry, extract of Hangzhou white chrysanthemum and antioxidant extract of bamboo leaves) have promising capacity of reducing BLL in lead-exposed mice.

Randomized controlled trials have found that calcium supplementation reduced lead levels in pregnant and lactating women.

Other research .…

Reduction of blood lead levels in lead-exposed mice by dietary supplements and natural antioxidants -- J Sci Food Agric.2011 Feb;91(3):485-91. doi: 10.1002/jsfa.4210. Epub 2010 Oct 28.

Other opinions

Heavy metals can indeed have therapeutic effects:

1. Salvarsan, an arsenical, was the most effective treatment against syphilis until penicillin was introduced in the 1940s 2. Potassium arsenite, an arsenic compound, was the first chemotherapy introduced to treat leukemia in 1865 and used until the 1950s. 3. Arsenic trioxide was found to treat treat acute promyelocytic leukemia (APL)in the 1970s 4. Arsenic compounds are now being tested against various cancers

Some traditional Chinese drugs are especially rich in Zn, Fe, Se, Cu, Cr, and Mn. Appropriate use of these CM materials might be valuable in the prevention and treatment of heavy metal poisoning and maintenance of healthy conditions.

Garlic and Cilantro (Coriandrum sativum) also reduced lead deposition in rats, mice, and sheep

herbs should be tested in humans to see whether an oral chelating effect is demonstrated.

Conclusions

~ Lead Encephalopathy Due to Traditional Medicines – Current Drug Safty 2008 January; 3(1):54-59

In many cases, TCM intake had been prolonged until a diagnosis of intoxication was made.

It Would be important that health care professionals be aware of the possibility of heavy metal contamination, recognize clinical symptoms, and inform their patients accordingly to prevent the occurrence of heavy metal poisoning.

When handling a suspicous herbal posioning: 1. What is the herb involved? 2. What condition was the herb used for? 3. What is the active ingredient? 4. What is its mechanism of action? 5. Are the symptoms and signs consistent with the description in the literature ? 6. What are the toxicokinetics of the active ingredient ? 7. What is the associated pathology? 8. What is the most effective treatment of the victim ?