metal toxicity

Evaluation and Treatment
of Chronic Metal Toxicity
Dr. Chris Spooner B. Sc. ND
Sunday, 6 May, 12
Exposure
Absorption
Excretion:
Chronic Retention:
(Absorption – Excretion) = Retention
Retention Over Time = Chronic Retention = Total Body Burden
Sunday, 6 May, 12
Exposure
Absorption
Excretion:
Chronic Retention:
(Absorption – Excretion) = Retention
Retention Over Time = Chronic Retention = Total Body Burden
Sunday, 6 May, 12
Chronic Metal Retention
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D.W. Quig, PhD
D.W. Quig, PhD
• “Low-level exposures associated with long-term effects not
previously recognized” (NIEHS)
8=04(,M'!"#$%'9"#"(-4('
• Knowledge of
adverse effects based primarily on independent
•" “Low-level
exposures associated with long-term
studies
of single toxicants
and
dy
effects not previously recognized” (NIEHS)!
• Metals
can elicitofindependent,
additive
or synergistic toxic
•" Knowledge
adverse effects
based primarily
effects on
(CDC)
independent studies of single toxicants!
•" Metals can elicit independent, additive or
synergistic toxic effects (CDC)!
• MRLs for exposures have not considered that humans
•" MRLs for exposures have not considered that
bioaccumulate
metals (CDC)
humans bioaccumulate metals (CDC)!
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D.W. Quig, PhD
Sunday, 6 May, 12
D.W. Quig, PhD
Distribution Endpoint Model
EXPOSURE
Storage
Biotransformation
Toxicant
ABSORPTION
Metabolite
TOXICOKINETIC
Interaction
With Cells
TOXICODYNAMIC
Sunday, 6 May, 12
(A.D.M.E.)
Excretion
Cartoon by Nick D Kim
Sunday, 6 May, 12
Metal Complexing
Agent Affinity
• Different agents have (higher or lower) affinities for various metal ions
DMPS – high affinity for free and bound Mercury
DMSA – high affinity for Mercury and free Lead EDTA – good affinity for Cd & Pb bound in bone stores
Sunday, 6 May, 12
Relative Affinities of Chelating Agents for Metals
Metal
1st Choice
2nd Choice
Inorganic Hg
DMPS
DMSA
Organic Hg
DMPS/DMSA
Pb
DMSA/EDTA
As
DMPS
Cd
EDTA
DMPS
Sb
DMPS/DMSA
EDTA
Sn
DMPS/DMSA
EDTA
Tl
Prussian Blue
DMSA
Al
EDTA
Ni
EDTA
W
DMPS/DMSA
DMPS
DMPS
-­‐ Kemper in Aposhian, Toxicol (1990) 97, 23-­‐38 Sunday, 6 May, 12
Other routes of administration of chelating agents:
• EDTA, DMPS and DMSA, have been administered p.r. via suppository
• DMPS/DMSA suppositories
– e.g. ASD
• DMPS, and less commonly EDTA, have been used t.d.
Sunday, 6 May, 12
• meso-­‐2,3-­‐Dimercaptosuccinic acid
• Synonyms: Succimer; Chemet
Because of the two neighboring SH groups, it has
a high affinity for many heavy metals that have an
affinity for sulfur and forms stable complexes
with them.
Sunday, 6 May, 12
• meso-­‐2,3-­‐Dimercaptosuccinic acid
• Synonyms: Succimer; Chemet
Because of the two neighboring SH groups, it has
a high affinity for many heavy metals that have an
affinity for sulfur and forms stable complexes
with them.
Sunday, 6 May, 12
DMSA
• Indications: FDA approved for the treatment of lead poisoning in pediatric patients with blood lead levels above 45 μg/dL (2.17 μmol/L)*
• Contraindications: Chemet should not be administered to patient with a history of allergy to the drug
• Warnings: Mild neutropenia has been reported in some patients receiving DMSA
• Check CBC with differential prior to starting treatment
*U.S Department of Health and Human Services. Succimer approved for severe lead poisoning. FDA Medical Bulletin 1991; 21:5
Sunday, 6 May, 12
DMSA
•
Precautions: Ensure adequate hydration during treatment
•
Transient mild elevations of serum transaminases have been observed in <10% of patients.
•
Check LFT prior to starting treatment
•
Drug Interactions: None
•
Pregnancy: Category C
•
Nursing mothers: If treatment is necessary, mothers should be discouraged from nursing
•
Pediatric Use: Safety in patients <1 yr has not been established
Sunday, 6 May, 12
Adverse Reactions
(oral / i.v.):
•
•
•
•
Sunday, 6 May, 12
Rare; transient
Perhaps some upper-GI upset with oral
agents (DMSA; less so with DMPS)
Often relieved with small amount of food
Occasional “warm” / “itchy” sensation or
redness around i.v. infusion site with EDTA
or DMPS
DMSA
• Adverse Reactions:
• GI side effects—nausea, vomiting, diarrhea, metallic taste in mouth <10%. Most common: gas/bloating (Peppermint/ginger tea and peppermint tablets often can alleviate GI side effects)
• Skin—mucocutaneous eruption, pruritus, uriticarial rash, erythematous rash
• Neutropenia
• Metabolic—elevated transaminases (ALT, AST),
Alkaline Phosphatase, Cholesterol <10%
Sunday, 6 May, 12
DMSA
• Adverse Reactions:
Sunday, 6 May, 12
DMSA
• Adverse Reactions:
Clinical Toxicology (2009) 47, 617-631
Sunday, 6 May, 12
Adverse Reactions to
oral agents:
•
Can screen for potential adverse rxns with a small “test
dose” – 50 to 100 mg p.o. 2-3 days before the larger
provocative challenge dose
Assess and treat dysbiosis:
Sunday, 6 May, 12
•
If dysbiosis present, may exacerbate symptoms (SH
groups may enhance proliferation of some bacteria /
yeast)
•
Imperative to assess for and treat any dysbiosis before
initiating a treatment protocol with oral DMPS or DMSA
Evaluating Toxic Metal
Burden
Sunday, 6 May, 12
Current Medicinal Chemistry, 2005, 12, 2771-2794
2771
Chelators as Antidotes of Metal Toxicity: Therapeutic and Experimental
Aspects
13
Occupational and Environmental Medicine 1995;52:13-19
Maja Blanusa
˘ * , Veda M. Varnai, Martina Piasek and Krista Kostial
Mineral Metabolism Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2,
P.O. Box 291, HR-10001 Zagreb, Republic of Croatia
Abstract: The effects of chelating drugs used clinically as antidotes to metal toxicity are reviewed. Human
exposure to a number of metals such as lead, cadmium, mercury, manganese, aluminum, iron, copper, thallium,
arsenic, chromium, nickel and platinum may lead to toxic effects, which are different for each metal. Similarly
the pharmacokinetic data, clinical use and adverse effects of most of the chelating drugs used in human metal
poisoning are also different for each chelating drug. The chelating drugs with worldwide application are
dimercaprol (BAL), succimer (meso-DMSA), unithiol (DMPS), D-penicillamine (DPA), N-acetyl-Dpenicillamine (NAPA), calcium disodium ethylenediaminetetraacetate (CaNa2 EDTA), calcium trisodium or zinc
trisodium diethylenetriaminepentaacetate (CaNa3 DTPA, ZnNa3 DTPA), deferoxamine (DFO), deferiprone (L1),
triethylenetetraamine (trientine), N-acetylcysteine (NAC), and Prussian blue (PB). Several new synthetic
homologues and experimental chelating agents have been designed and tested in vivo for their metal binding
effects. These include three groups of synthetic chelators, namely the polyaminopolycarboxylic acids (EDTA
and DTPA), the derivatives of BAL (DMPS, DMSA and mono- and dialkylesters of DMSA) and the
carbodithioates. Many factors have been shown to affect the efficacy of the chelation treatment in metal
poisoning. Within this context it has been shown in experiments using young and adult animals that metal
toxicity and chelation effects could be influenced by age. These findings may have a bearing in the design of
new therapeutic chelation protocols for metal toxicity.
Provocative chelation with DMSA and EDTA:
evidence for differential access to lead storage
sites
Byung-Kook Lee, Brian S Schwartz, Walter Stewart, Kyu-Dong Ahn
Abstract
Objectives-To validate a provocative
chelation test with 2,3-dimercaptosuccinic acid (DMSA) by direct comparison
with the standard ethylene diamine
tetraacetic acid (EDTA) test in the same
subjects; and to compare and contrast
the predictors of lead excretion after
DMSA with those after EDTA. A metal
chelating agent given orally, DMSA may
mobilise and enhance the excretion of
lead from the storage sites in the body
that are most directly relevant to the
health effects of lead. A provocative
chelation test with DMSA could thus
have wide potential application in clinical
Keywords: Chelating agents, BAL derivatives, carbodithioates, deferiprone, deferoxamine, D-penicillamine,
care and epidemiological studies.
polyaminopolycarboxylic acids, metals, metal toxicity.
Methods-34 male lead workers in the
Republic of Korea were given a single
oral dose of 10 mglkg DMSA, urine was
1. INTRODUCTION
of the most important information on common metal
collected over the next eight to 24 hours,
and urine volume and urinary lead conpoisonings and possibilities for their chelating treatment,
centration determined at 0, 2, 4, 6, 8, and
A chelating agent is a molecule that forms a complex
both by clinical and experimental agents, are listed in Table
24 hours. Either two weeks before or two
with a metal ion. The chelating agent molecule has electrons
1.
The
effects
of
chelating
agents
presently
applied
in
human
the dose of DMSA 17 of these
weeks after
A
comparison
of
different
lead
biomarkers
in
their
associations
with
leadavailable to form a bond with a positively charged transition
clinical practice and the metal binding effects of newly
workers also received 1 g intravenous
EDTA followed by an eight hour urine
symptoms
metal ion. Chelators can be attached to the metal ion by related
two
synthesized
chelators are described in separate sections.
collection with fractionation at 0, 2, 4, 6,
or more bonds forming a ring, which is called the chelate
Three groups of chelators are described, namely the
and 8 hours.
Institute of Industrial
ring [1]. The main goal of chelation treatment is to
polyaminopolycarboxylic
acids, suchA1
as ethylenediaminetelead concentration
Results-Urinary
A1, K. -D. Ahn A1, S.
A1, Y. -B. Kim A1
A2
Medicine,
B.
-K.
Lee
-S.
Lee
,
G.
-S.
Lee
,
B.
S.
Schwartz
peaked at two hours after DMSA and four
transform the toxic metal complex with biological ligands
traacetic acid (EDTA) and diethylenetriaminepentaacetic acid
Soonchunhyang
hours after EDTA. Lead excretion after
University, Chunan,
into a new, non-toxic complex between the metal ion A1
and
(DTPA);
the derivatives
of Soonchunhyang
dimercaprol (British-Antiof Korea
Republic
DMSA
was less than after EDTA, and
Institute
of
Industrial
Medicine,
University,
23-20
Bongmyung-Dong,
Chonan,
B-K
Lee
chelator, which can be excreted from the organism. To fulfill
Lewisite, BAL), such as 2,3-dimercaptopropane-1-sulfonic
cumulative excretion after DMSA
K-D Ahn
Choongnam
Republic of Korea acid (DMSA), and
plateaued at six to eight hours. The two
this purpose chelating agents must possess several
acid 330-100,
(DMPS), 2,3-dimercaptosuccinic
Department of
hour and four hour cumulative lead
Environmental Health
A2 Department
characteristics. The profile of a successful chelating drug
mono- and
dialkylesters
of
DMSA;
and
the
carbodithioates.
of Environmental Health Sciences, Division of Occupational
and Environmental
of
excretions after DMSA were highly corSciences, Division
includes high affinity for the toxic metal(s) but low affinity
Occupational Health
Not only are newer agents being sought, but also
related
with the eight hour total (r = 0-76
Lee
B-K
Johns
Hopkins University School of Hygiene and Public Health,
Baltimore, USA
and 0.95). In multiple linear regression
for essential metals, minimal toxicity, lipid solubility, Health,
and,
combinations of new or already known chelators are tested
B S Schwartz
analyses, blood lead was found to be an
W Stewart
preferably, good absorbability from the gastrointestinal tract.
for possible synergistic action. Age-related differences in
Abstract:
important predictor of EDTA-chelatable
Department of
These conditions, however, are not easy to fulfill. For
efficacy of chelation therapy are also included, since the
Epidemiology, Johns
lead, whereas urinary aminolevulinic
Hopkins School of
example, the advantage of lipid soluble substances is Abstract
that
acid
(ALAU)
binding
of toxic
in thewhether
very young
is an important acid (DMSA)
Tometals
evaluate
dimercaptosuccinic
-chelatable
lead,
an was associated with DMSAObjectives:
Public
Hygiene and
chelatable lead. Notably, lead excretion
Health
they easily cross the cell membrane and bind metals within
topic presently under investigation.
B S Schwartz symptoms
after than
DMSA
estimate of current bioavailable lead stores, is a better predictor of lead-related
arewas greatly increased if
the cell. Unfortunately, such chelators are usually more toxic
W Stewart
EDTA was given first. An earlier dose of
The
chemical
structures
of
some
clinically
used
and
Department of
other
than those which are not lipid soluble. Thus, it is
a commonly used lead biomarkers.
EDTA also modified the relation between
Medicine, Johns
experimental chelators are presented in Figs. 1 and 2.
ALAU and DMSA-chelatable lead in that
challenging task to find optimal conditions for binding
Hopkins School of
Conclusions: DMSA-chelatable lead was found to be the best predictor
ofBaltimore,
lead-related
workers who received EDTA before
Medicine,
specific toxic metal with minimal risk of adverse effects.
MD, USA
DMSA showed a much steeper doseB S Schwartz
symptoms,
particularly
of both AND
total HEALTH
symptomEFFECTS
scores and neuromuscular
symptoms, than
were relation
the
2. METAL
EXPOSURE
between these two
response
Exposure and toxicity of several metals and metalloids
measures.
to:
Correspondence
other other lead biomarkers.
such as lead, cadmium, mercury, manganese, aluminum,
Conclusions-The predictors of lead
Dr Byung-Kook Lee,
Metals can disturb organ functions and cause disease
Institute of Industrial
excretion after DMSA and EDTA are difiron, copper, thallium, arsenic, chromium, nickel and
Medicine, Soonchunhyang
through excess, deficiency, or imbalance in the body. A
ferent and an earlier dose of EDTA may
University, 23-20
platinum, are of major concern to human health. A summary
Bongmyung-Dong, Chunan,
numberArchives
of metal ions
regulate a vast array
physiological
increase lead excretion after a subseInternational
of Occupational
andofEnvironmental
Health
Choongnam 330-100,
quent dose of DMSA. The results suggest
Republic of Korea.
mechanisms that are essential for organ functioning and
Publisher:
Springer-Verlag Heidelberg ISSN: 0340-0131 (Paper) 1432-1246
(Online)
that two hour or four hour cumulative
1994
Accepted I September
development. However, under conditions of metal overload,
*Address correspondence to this author at the Mineral Metabolism DOI:
Unit,
Institute for Medical Research and Occupational Health, P.O. Box 291,
HR-10001 Zagreb, Republic of Croatia; E-mail: [email protected]
0929-8673/05 $50.00+.00
Sunday, 6 May, 12
10.1007/s004200000132
Volumecan
73,beNumber
toxic side effects can occur.Issue:
Metal overload
caused by5Date: June 2000 Pages: 298 - 304
© 2005 Bentham Science Publishers Ltd.
lead excretion after DMSA may provide
an estimate of lead in storage sites that
are most directly relevant to the health
effects of lead.
(Occup Environ Med 1995;52:13-19)
Keywords: chelating agents; dimercaptosuccinic acid;
lead
Human exposure to lead is ubiquitous and its
absorption can be assessed by different measures thought to reflect several definable lead
storage compartments.'-3 Blood lead and zinc
protoporphyrin (ZPP) are the two most common measures used to identify people at risk
of excess exposure or ill health caused by lead.
A limitation of both of these measures is that
they are poor predictors of such ill health, do
not necessarily reflect recent exposure, and
are generally thought to be inadequate measures of cumulative lead absorption.4 Blood
lead concentrations are influenced by recent
exposure, bioavailable internal stores, and differences between individuals in lead toxicokinetics.5 The interpretation of ZPP, an early
biological intermediary in the haematopoietic
system, is complicated by differences between
people in the kinetics of lead, the kinetics of
the multiple steps in the haem synthetic pathway, and the kinetics of red blood cells.5
The limitations of blood lead and ZPP have
led to the development of other biological
measures of lead absorption. As 90-95% of
the total body burden of lead resides in bone,'
in at least two definable compartments-a relatively inert cortical bone storage pool and a
more bioavailable pool in trabecular bone-x
ray fluorescence has emerged as a technique
for measurement of bone lead.7-'0 Although
x ray fluorescence of cortical bone lead
probably best estimates cumulative lead
absorption, few studies have validated this as
a predictor of health effects. It can be hypothesised that because much of the bone lead
compartment is biologically inert, with lead
deep in cortical bone, x ray fluorescent measurements of cortical bone lead may be less
relevant to long term changes in health than
biological measures that estimate the bioavailable lead pool. Such measures may include
x ray fluorescence of trabecular bone lead and
chelatable lead.
Provocative chelation with 1 g of intravenous calcium disodium ethylene diamine
tetraacetic acid (EDTA) followed by a six to
24 hour urine collection for measurement of
Articles
Diagnostic Chelation Challenge with DMSA: A Biomarker of Long-Term
Mercury Exposure?
Howard Frumkin,1 Claudine C. Manning,2 Phillip L. Williams,3 Amanda Sanders,1 B. Brooks Taylor,4
Marsha Pierce,4 Lisa Elon,2 and Vicki S. Hertzberg 2
1 Departm ent
of Environ m ental and Occupational Health, 2 Departm ent of Biostatistics, Rollins School of Public Health, E m ory U niversity,
Atlanta, G eorgia, U S A; 3 Departm ent of Environ m ental Health Science, U niversity of G eorgia, Athens, G eorgia, U S A; 4 Coastal Health
District, G eorgia Division of Public Health, Brunswick, G eorgia, U S A
bioaccumulation. It is excreted with a half-life
of 1–2 months (17,32–35). This suggests that
Scandchallenge
J Work Environ Health 1992;18 :113-9
the primary use of DMSA chelation
for mercury would occur in the first weeks
after exposure. However, a long terminal
elimination phase has been described (36),
with mercury retention in nervous system,
Chelated lead and bone lead
kidneys, and other soft tissues. Consequently,
there could also be a role for DMSA chelation
by Inge
Tell, MD,1 Lillian J Somervaille, PhD,3 Ulf Nilsson, BSC,2 Inger Bensryd, RN,1
challenge some time after mercury
exposure,
Andrejs and
Schutz, PhD,1 David R Chettle, PhD,3 Malcolm C Scott, PhD,3
especially if exposure had been prolonged
Staffan
Skerfving,
MD1
intense. Support for this notion comes from
animal evidence (37) that DMSA draws merTELL I, SOMERVAILLE LJ , NILSSON U, BENSRYD I, SCHUTZ A, CHETTLE DR , SCOTT MC,
cury with special avidity from the kidneys—
SKERFVING S. Chelated lead and bone lead. Scand J Work En viron Health 1992;18:113-9. In this
an important mercury storage site known
to a close correlation [correlation coefficient (r) = 0.86, P < 0.001) was found between the blood lead
study
have a relatively slow turnover (38). Indeed,
level of 20 lead workers and their urinary excretion of lead for 24 h after intravenous infusion with
I g of the chelating agent calcium disodium edetate, In addition , there were significant associations beDMSA chelation challenge has been used
tween lead levels in different bones (tibia /calcaneus: r=0.93, P<O.OOI; tibia /phalanx: r =0.67,
clinically on a limited basis following mercury
P < 0.002; calcaneu s/phalanx: r = 0.80, P < 0.001), as measur ed by in vivo X-ra y fluorescence. Chelation
exposure (15,26,39). A related agent used
in
produced no significant chang e in the lead level in either tibia or calcaneu s. There was a significant correEurope, 2,3-dimercaptopropane-1-sulfonic
lation between chelated lead and bone lead (eg, for calcaneu s, r=0.62) in currently expo sed workers .
acid (DMPS), has been used in a similar
Ho wever, there was no significant relation ship when a retired worker and an inactive worker were included (r = 0.14). It was concluded that chelatable lead mainly reflects the blood and soft-tissue lead pool,
manner (40,41).
which is only partly dependent upon the skeletal lead content that comprises the biggest sha re of the total
Assessment of biological exposure is a key
DMSA is used primarily in the treatment
At present the interpretation of DMSA
bod y burden.
challenge in evaluating metal toxicity, for
of metal toxicity, rather than in diagnosis.
challenge tests for mercury is difficult
Key terms: blood, calcaneus, calcium disodium edetate, finger bone, occup ation al, pha lanx, skeleton,
both clinicians
and epidemiologists.
Blood 1986;
The43:636-641
most common therapeutic use has been
because we lack reliable data on the normal
British Journal
of Industrial Medicine
tibia, urine, X-ray fluor escence.
and urine measurements traditionally have
in treating lead toxicity (9–11), but DMSA
range of mercury excretion in unexposed
been used, but these have several shortcomhas also been used to treat a variety of other
people following DMSA, the expected range
ings, such as failure to reflect true body burmetal overexposures ( 12–1 4 ). Besides its
of elevations following mercury exposure,
den, failure to correlate with biological
treatment role, DMSA offers considerable
the correlation between DMSALead
response
is anand
ubiquitous metal that is still widely used
X-ray fluorescence. Lead levels in the mainly cortical
effects, high interperson variability following
diagnostic potential as a chelation challenge
other measures of mercury exposure,
and
theOnce inside the body , it can be incorpophalanx were first measured in occupationally exindustrially.
similar exposures, and relatively rapid clearagent. First, it is convenient: DMSA is an
clinical significance of elevations.
Such
posed workers with the use of the gamma-ray source
rated
intodata
the skeleton, where the turnover is slow comance (1). X-ray fluorescence is being used
oral agent, whereas EDTA must be adminiswould be necessary to validatepared
the DMSA
with that in the blood and soft tissues. One meth- 57cobalt to fluore sce the K-shell X rays of lead (61increasingly to assess exposure to lead but not
tered parenterally. Second, DMSA has an
chelation challenge response as
An alternative method, developed more recently, is to
odaofpractical,
assessing lead exposure is to use chelation techexposure
Environmental Health Perspectives
to other metals (2–5).
excellent safety profile. Third, DMSA has
informative biomarker of mercury
exposure.
use the gamma rays of l09 cadmium
niques.
Thus a chelating agent such as penicillamine
57-62, 1991 the
Vol. 91,topp.fluoresce
Because chelating agents bind metals
been shown to mobilize a range of metals
In this paper we report a study
of
DMSA
(PCA) can be administe red orally (1), or the inK-shelliead X rays, the initial measurement being on
and promote
their urinary
excretion,
theoeffectively in both animals and humans.
chelation challenge testing among
workers
H AONO,
K MURATA
S ARAKI,
travenous
administration of calcium disodium edetate
the cortical midshaft of the tibia (7). Since the latter
retically they can be used in challenge tests
Fourth, DMSA acts quickly. The blood conwith long-term, high-level exposure
to mer- can be used (2). Increased levels of ex- technique is self-normalizing to bone mineral and is
(CaNazEDTA)
From
the
Department
of
Public
Health
and
Hygiene,
Medical
of
Oita,
Hazama-machi,
879-56,
College
Oita
to assess metal levels. The rationale for
centration of DMSA peaks in 3 hr, and the
cury in a chloralkali plant and among
a comindependent of geometry and overlying tissue depth,
creted urinary lead are then used as an indicator of
Japanchelation challenge is straightfordiagnostic
half-life is 3.2 hr (15). DMSA-induced excreparison population of unexposed
workers.
an excess body burden (3). In addition, chelation has it is applicable to any superficial bone site and has been
ward: If a person has an elevated body burtion of both lead ( 16 ) and mercury ( 17 )
been used therapeutically in cases of lead poisoning,
extended to the measurement of lead levels in the
Methods
den of a metal, then administration of a
peaks within 2 hr. In the clinical setting,
especially
among
children
(4),
for
whom
it
is
assumed
trabecular
calcaneus, or heel bone (8), and in the skull
ABSTRACT
To investigate
the effects of
calcium
disodium
ethylenediamine
Study sub(CaEDTA)
jects. This study was that
conducted as
chelating
agent should
cause a short-term
chelation
challenge
would
therefore requiretetra-acetate
chelation
causes
an
overall
reduction
of
the
lead
frontal
bone.
In addition, tibia lead levels have also
on in
thethe
concentrations
andhours.
indicators
ofstudy
sevenof the health effects of
urinary
excretion,
and plasma
exposure part
of a larger
increase
urinary
excretionerythrocyte,
of that
urinary
collection
only over several
body burden. However, the relative input s from the been measured by fluorescence of the lower energy
to
heavy
metals,
CaEDTA
was
administered
by
intravenous
infusion
to
20
workers
exposed
lead,
metal. The most commonly used chelation
For these reasons, DMSA chelation challenge
body compartments, such as soft tissue and bone, to
L-shell X rays (9), which, because of the short attenufrom 22 to
zinc,test
andhascopper.
The workers'
blood could
lead concentrations
ranged
(mean 38 4g/dl
challenge
been EDTA
administrabe a convenient,
safe approach
to 59 ig/dl
Address correspondence to H. Frumkin,
Department
the
measured
chelated
lead
output
in
urine
have
not
ation
length of L-shell X rays, samples the lead in the
8
Theexposure
24 hour urinary
metals
afterburden
CaEDTA
administration
(mobilisation
tion (1following
lead
( 6,7 ), excretion
assessingofthe
biological
of various
of Environmental
and Occupationalbeen
Health,
Rollins
established
.
outer few millimeters of the bone only.
11 times forSchool
yield)
wasAnti-Lewisite
on average and
13 times
excretion
for lead, challenge
times
for
zinc,of3-8
although
British
penicil-the background
metals. Indeed,
DMSA chelation
Public Health, Emory University, 1518
Because over 900/0 of the body burden of lead is in
Lead levels in cortical bone , as measured by X-ray
lamine
have also 3*4
been
usedfor
( 8cadmium,
). More 1 has
I 1 times
been for
usedcopper,
in several
(16,18,19
)
Clifton Road,
Atlanta, GA 30322 USA. Telephone:
andstudies
for chromium;
no significant
manganese,
times
3 times
the
skeleton
(5),
a
more
direct
measure
of
this
burden
fluorescence,
have been shown to be a good index of
(404)
727-3697.
Fax
(404)
727-8744.
E-mail:
recently,
attention
focused
on dimer- The and
in clinical settings
burden.
increase
was has
found
for mercury.
mobilisation
was significantly correlated
yield toofassess
lead lead
(MPb)
in vivo is the assessment of skeletal content from
cumulative
past
exposure, both in finger bone (10)
[email protected]
captosuccinic
acid
(DMSA),
or
succimer,
a
Another
metal
that
might
be
assessed
in
with whole blood and erythrocyte concentrations and the urinary excretion of lead
but not with its
This study was funded by grant 1measurement
RO1 ES08346 s of the lead levels of various bone sites,
and
in
tibia
(11).
However, the relationship between
chelating
agentconcentration;
approved by thesimilarly,
U.S. Foodthe mobilisation
this way is mercury.
mobilizes
plasma
yield ofDMSA
cadmium
was mersignificantly
from correlated
the Nationalwith
Institute of Environmental
either
by
biopsy
or
by
the
noninvasive
technique
of
chelatable
lead
and
bone lead levels remains unclear .
and Drug
Administration
(U.S. FDA)In
in addition,
cury effectively
in significantly
both animals (20–25
) and withHealth
With the development of L X-ray fluorescence (LXRF) to measure cortical bone lead directly, safely,
its erythrocyte
concentration.
MPb was
correlated
intra-erythrocytic
Sciences.
reLXRF as a possible
to a) evaluate
wasrecent
undertaken
rapidly, and noninvasively, the present study In
reports,
associations
were found
between
1991 enzyme
for the treatment
of
pediatric
lead
in
humans
(
8,17,26–31
).
However,
unlike
Received
7 July 2000;
excretion.
The accepted 28 September
5-aminolaevulinic acid dehydratase activity and urinary coproporphyrin
placement for the CaNa2EDTA test; b) quantify lead in tibial cortical bones of mildly to moderately
CaNazEDT
A-chelated
lead
and
tibia
lead
levels
of
chilin
tibial
cortical
bones
lead-toxic
lead-toxic children before treatment; and c) quantify lead
toxicity.
lead,
undergoes
relatively
relation between the mobilisation yield
of mercury
heavy metals
and their
bodylittle
burden 2000.
(and toxic signs) is
was
research
of chelationby
The (12)
clinical
design
to two coursespredicted
therapy.
dren sequentially
following
I Department of Occupational
and Environmen
talone
Medicine,
K-shell
(13)X-ray
fluoresL-shell
and
a longitudinal assessment of 59 untreated lead-toxic children. At enrollment, if the blood
based upon
discussed in the light of these findings.
University Hospital, Lund,
Sweden.
2 35 glg/dL,
(EP)in
concentration
protoporphyrin
lead (PbB) was 25 to 55 jg/dL and the erythrocyte
cence.
However,
a similarwas
study,
PCA -chelatable
2 Department of Radiation
Ph ysics,
Lund University,
Malmo
lead was carried out. One day later, each child underwent a
of tibial bone
LXRF
measurement
lead
was
not
related
to
the
lead
levels
Environmental Health Perspectives • V OLU ME 109 | NU MBER 2 | February 2001
167
General Hospital, Malmo
, Sweden.
provocative test. If this test was positive, lead-toxic children were admitted to thepredicted by
CaNa2EDTA
months bone
after , while there
testsX-ray
were repeated
6 weeks and
for 5 days
of CaNa2EDTA ,therapy.
hospital
K-shell
fluorescence
for6finger
3 Department of Ph ysics,
University
of Birmingham
Bir- These
enrollment. Abatement of lead paint hazards was achieved in most apartments by the time of initial
mingham , United Kingdom
.
was an association with biopsy specimens from the verhospital discharge.
It has recently been shown that plasma lead (PPb) different from that of lead; the PZn concentration fell
The LXRF instrument consists of a low energy X-ray generator with a silver anode, a lithium-doped
tebra
Moreover,
there were
associations
between
Sunday, 6 May,
12
and a(14).
multichannel
Partially
polarX-ray analyzer.
silicon detector, a polarizer of incident photons,
concentration
and urinary lead excretion are rapidly, followed by a gradual rise in the EZn concenChelation challenge testing has been used to assess the body burden of various metals. The bestknown example is EDTA challenge in lead-exposed individuals. This study assessed diagnostic
chelation challenge with dimercaptosuccinic acid (DMSA) as a measure of mercury body burden
among mercury-exposed workers. Former employees at a chloralkali plant, for whom detailed
exposure histories were available (n = 119), and unexposed controls (n = 101) completed 24-hr
urine collections before and after the administration of two doses of DMSA, 10 mg/kg. The urinary response to DMSA was measured as both the absolute change and the relative change in
mercury excretion. The average 24-hr mercury excretion was 4.3 µg/24 hr before chelation, and
7.8 µg/24 hr after chelation. There was no association between past occupational mercury exposure and the urinary excretion of mercury either before or after DMSA administration. There was
also no association between urinary mercury excretion and the number of dental amalgam surfaces, in contrast to recent published results. We believe the most likely reason that DMSA chelation challenge failed to reflect past mercury exposure was the elapsed time (several years) since the
exposure had ended. These results provide normative values for urinary mercury excretion both
before and after DMSA challenge, and suggest that DMSA chelation challenge is not useful as a
biomarker of past mercury exposure. Key words: biomarkers, chelation, chloralkali, DMSA, environmental diseases, mercury, neurotoxicity, occupational diseases, renal toxicity, succimer.
Environ Health Perspect 109:167–171 (2001). [Online 25 January 2001]
http://ehpnet1.niehs.nih.gov/docs/2001/109p167-171frumkin/abstract.html
Mobilisation of heavy metals into the urine by
CaEDTA: relation to erythrocyte and plasma
concentrations and
indicators
yumol/l)).
Sequential Measurements of Bone Lead
Content by L X-Ray Fluorescence in
CaN a2EDTA-Treated Lead-Toxic Children
by John F. Rosen,* Morri E. Markowitz,* Polly E.
Bijur,* Sarah T. Jenks,* Lucian Wielopolski,t
John A. Kalef-Ezra,t and Daniel N. Slatkin§
Reprint request s to: Dr I Tell, Department of Occupational
at the
medial mid-tibial cortical bone. The LXRF spectrum,
Lab Test for Metal Toxicology
Metal Poisoning / Acute Toxicity"
•
•
Blood metal concentration
Urine Porphyrins
Exposure (very recent or ongoing)
•
•
Blood and unprovoked urine
Hair (longer temporal window)
Net Retention (estimation)
•
Pre- vs Post-Provocation
Metal –Induced Allergy / Autoimmunity
•
Sunday, 6 May, 12
MELISA® Test
Methods of Evaluating
Metal Burden
Sunday, 6 May, 12
•
Serum – good for acute exposures, keep in mind the
t1/2 in serum.
•
Urine – also good for acute exposures, when used
with chelating agent, will indicate relative levels of
tissue deposition
•
•
Hair - excellent for methyl mercury and lead
Fecal – good method for children
Non-provoked/Pre-Flush Urine Toxic Metal
 Identify current exposures to lead and mercury (whole blood is a better indicator)
 Currently the only means of identifying cadmium toxicity. (0.5-­‐2.0 μg/g creatinine indicated early renal damage in Swedish cohort, 2.5 μg/creatinine 4-­‐fold higher risk of tubular damage )
 24-­‐hr non-­‐provoked urinary test for arsenic toxicity (50μg/24 hours)
 Allows the clinician to identify what chelating agent is the most effective for the patient,
 if oral agents were employed, then possible absorption issues can be identified.
Sunday, 6 May, 12
DMSA
•
Dosage and Administration: (For assessing and treating a toxic heavy metal burden)
•
Ensure adequate hydration, normal kidney function, assessment of CBC, and bowel movements are regular (at least daily)
•
Serum and provoked heavy metal test prior to starting regimen
•
Sunday, 6 May, 12
Check serum metals and/or RBC minerals and/or unprovoked urine (first morning void or random spot urine)
DMSA Challenge
Protocol
• Rule out potential DMSA sensitivity
i.e. reactive to ALL sulfur-­‐containing compounds • No shellfish or seaweed for the week prior to testing
• No non-­‐essential meds or supplements for 48 hours
• Empty Bladder* and Empty Stomach -­‐-­‐> Use first morning urine for pre-­‐flush test
• Body weight DMSA (30 mg/kg up to 2250mg) • Collect all urine for 6 hours
Food can be consumed after 1 hour.
•
Sunday, 6 May, 12
Consider:
•
•
Pre-­‐treatment to alkalize urine and adequate nutritional status
Glycine (oral: 2000 mg the night before challenge test or 40 mg/kg) Test Interpretation
Sunday, 6 May, 12
No test can show the total
body burden of Heavy Metals
Provocation tests are
measurements of how much
is leaving not what is in the
body!!!
Sunday, 6 May, 12
Interpretation of
Provoked UTM Results
Sunday, 6 May, 12
•
•
Rarely a stand alone test.
•
Do consider results in context with amounts of all
metals excreted, physical exam, history of known
exposures and symptoms and, other biomarkers.
•
Cannot conclude “metal toxicity” based solely
upon higher than average net retention
Don’t interpret provocation results against
unprovoked reference values. (ACMT)!
Compare to the patient’s unprovoked results
Test Interpretation
• Were any of them above lab ranges?
• How many different heavy metals showed
up on the first pass? > 7 – “collectors”
• Did the patient experience any change in
their metal related symptoms?
Subsequent tests typically show increased
levels.
Sunday, 6 May, 12
DMSA vs. DMPS
Pb and Hg
Sunday, 6 May, 12
METAL
REF
RANGE
PRE
POST
DMSA
POST
DMPS
AS
<57
12
17
54
CD
<0.9
0.3
0.4
0.5
PB
<6
13
4.3
HG
<7.2
6.4
11
1
The Case for Pre &
Post Testing
• Helps Identify Current Exposure
• Helps determine the effectiveness of the
proposed chelating agent
• Assesses the level of absorption of the
chelating agent which, in turn, may help
identify sub-acute malabsorption
Sunday, 6 May, 12
Recognizing Current
Exposure
CDC National reports provide us with ‘normal’
ranges for US residents for the first time.
Levels above 75th percentile would typically
indicate current exposure.
National Report on Human Exposure to Environmental Chemicals, Fourth Report http://www.cdc.gov/exposurereport/
Sunday, 6 May, 12
National Report on Human Exposure to Environmental
Chemicals, Fourth Report
Compound
Geometric Mean
50th percentile
75yh percentile
90th percentile
95th percentile
Antimony
NA
0.80
0.135
0.208
0.277
Arsenic (total)
8.24
7.04
14.1
30.4
50.4
Barium
1.48
1.41
2.68
4.92
7.10
Cadmium
0.210
0.208
0.412
0.678
0.940
Cobalt
0.314
0.290
0.255
0.455
1.02
Lead
0.632
0.622
0.979
1.65
2.35
Mercury
0.443
0.447
0.909
1.65
2.35
Thallium
0.154
0.153
0.214
0.286
0.350
Uranium
0.008
0.007
0.012
0.021
0.029
Sunday, 6 May, 12
Assessing Absorption
with Pre and Post
Provocation Testing
Sunday, 6 May, 12
29 f with amalgams and hx
of gluten sensitivity
Post DSMA
Pre DMSA Post DMSA 6 months
GF
METAL
REF
RANGE
CDC
90/95%
PB
<4.4
1.5/2
<dl
6.6
14
<7.2
1.65/
2.35
0.8
4.5
86
HG
+ anti-gliadin IgA of 26
Sunday, 6 May, 12
Testing Cases
Sunday, 6 May, 12
SJSK
• 55 yo wm
• Amyotrophic lateral sclerosis
• Hx. of making lead fishing weights
• DMSA flush UA done
• 30 mg/kg in one dose
• Empty bladder and stomach
Sunday, 6 May, 12
Sunday, 6 May, 12
Protocol
• DMSA – 30mg/kg in three divided daily doses of 10 mg/kg each.
• 5 days on and 9 days off
• Basic Detox Nutrients
• Vitamin C, Fiber, Whey
• Heavy metal support of the 9 days off
• Colonic irrigations weekly
Sunday, 6 May, 12
Sunday, 6 May, 12
Sunday, 6 May, 12
Protocol Change
• Day one: 2,000 mg CaNa2EDTA
• Day two – six: 30mg/kg DMSA
• 8 days off
• Continue colonics and other supplements
Sunday, 6 May, 12
Sunday, 6 May, 12
Metal
(ppm)
AL
1GB
4P
2ST
3LT
5TIP
471
1027
3731
60.3
96.1
AS
7.28
.829
99.9
1.53
<dl
CD
.487
.442
5.94
0.079
0.076
PB
8.71
7.54
56,185
10.49
1.12
HG
21.9
4.66
6,333
6.81
0.574
Ni
2.79
5.45
11.8
0.269
1.68
Th
0.01
0.017
0.017
<dl
<dl
SN
609
0.935
256.4
0.624
0.035
Sunday, 6 May, 12
What to Expect
•
•
DMSA flush gives a good representation of Hg and Pb.
•
EDTA will give the highest spill of Cd, Pb and will mobilized
Al. It will give a very poor spill of Hg
•
If GH is low you may get a deceptively low reading of Hg
DMPS gives a much higher dump of Hg and much lower
dump of Pb
•
Sunday, 6 May, 12
pre-treatment with NAC & MSM
When Results Go
Astray...
Consider:
•
•
•
Affinity of an agent for the metal in question – e.g. lab result showed
‘normal’ Arsenic but agent administered was EDTA
•
Dose of the challenge agent administered – e.g. lab result showed
‘normal’ Mercury but only administered DMPS 5 mg/kg p.o.
•
‘spill’ of Hg might have been higher if 10 mg/kg p.o. had been used
Length of collection period – e.g. lab result showed ‘normal’ Lead
but only collected urine for 2 hours post oral DMSA administration
•
Sunday, 6 May, 12
‘spill’ of As might have been higher if DMPS had been used
‘spill’ of Pb would have been higher if collection period had been 6
hours as recommended
Significance of Results
NB – Wide individual variation in tolerance
to toxic metals
Total toxic burden and TILT
Genetics
Nutritional status
Gut function
•
•
•
•
Sunday, 6 May, 12
•
Sunday, 6 May, 12
Take Home Message
for Testing
Provocation testing is valid when done correctly
and can serve as a component of diagnostic
judgement."
•
•
Assess status of liver & glomerular filtration.
•
Monitor efficacy of metal clearance:
Repeat provocations identically after 5-10
treatments!
Always do pre- and post provocation urinalysis
initially.
Treatment
Sunday, 6 May, 12
DMSA
•
Treatment
• Start treatment at no greater than 10 mg/kg every 8 hours for five days (for sensitive patients).*
• There are many different dosing regimens:
•
5-­‐10 mg/kg every 12 hours for 2 weeks on, then 2 weeks off
•
10 mg/kg every 8 hours for 3 days, then 11 days off
•
100 mg every night M-­‐F, skip weekends
•
500 mg 3x/day
•
30 mg/kg divided into three doses/day for 5 days on, then 9 days off •
10 mg/kg divided into two or three doses/day for 3 days, then 11 days off (extremely sensitive patients do better with a lower dose and with more days off)
•
Suppository • Provide mineral replacement during treatment
*J.Morrison (ACAM)
Sunday, 6 May, 12
DMSA
• Treatment
• Recheck CBC and kidney function and urine toxic metals periodically • If the patient is on a 30 mg/kg treatment protocol with 5 days on and 9 days off Recheck CBC and kidney function at 5th round and urine toxic metals at the 10th round
• Assess patient’s symptoms during course of treatment. • Symptom Survey
Sunday, 6 May, 12
DMSA
•
Treatment
• Journal of Advancement in Medicine (Vol 10—Number1—Spring 1997)
• 7 days of DMSA at dosages of 10 mg/kg every 8 hours followed by 14 days @ 10 mg/kg in 2 divided doses. No treatment administered for next 21 days. Repeat. (Theodore C. Rozema, MD, FAAFP)
• Chemistry profile after 10 days to check liver function and hemoglobin levels (DMSA can decrease hgb and increase liver enzymes)
• If a skin rash occurs -­‐ stop until gone, then lower dose. • For a patient having mercury amalgam removal: (Godrey and Campbell)
• Oral sodium ascorbate to bowel tolerance (4-­‐12 g in divided doses), seleno-­‐methionine (200 mcg/
day), and specifically prepared multi-­‐mineral tablets depending upon results of element analysis
• 500 mg DMSA once a week for 3 months if the pt had high initial Hg levels after DMPS urine Hg challenge. Challenge can be repeated 6 months or a yr laterto check on residual body levels of Hg.
• IV sodium ascorbate to 0.7 g/kg bw (25g/250 ml or 50 g/500 ml sterile water)
Sunday, 6 May, 12
DMSA
•
W. Crinnion’s Protocol:
• DMSA—30 mg/kg in 3 divided daily doses of 10 mg/kg each 5 days on & 9 days off or 2 days on & 5 days off for sensitive patients
•
If gas/bloating occurs: peppermint tablets or tea
•
Adverse reactions: Stop the DMSA. 3 capsules of activated charcoal or colon hydrotherapy
• Retest UTM in 10 weeks/rounds and re-­‐check CBC, liver, and kidney function
• Supplementation:
•
Basic Detox Nutrients
•
Vitamin C, Magnesium citrate, Fiber, Whey, Methionine (if pt has elevated cadmium)
•
Heavy Metal Support on the 9 days off
• Constitutional hydrotherapy weekly
• Colonic irrigation weekly (after hydrotherapy yields the best results)
• Magnesium sulfate/nutrient intravenous therapy, if needed Sunday, 6 May, 12
Chelating Agents/Supplements/Procedures
Notes
DMSA 100 mg
(Dose 30 mg/kg not to exceed 2200 mg)
Used for the challenge testing for initial investigation, Rounds 5, 10, 15, 20, 25
DMSA 250 mg
(Dose 30 mg/kg not to exceed 2200 mg or 2500 for a very large person)
Chelator, oral, usually for 5 days per two week schedule
DMPS IV injection
(Dose 5 mg/kg not to exceed 250 mg)
Chelator, intravenous once weekly or every other week
Calcium EDTA IV injection
(Dose 50 mg/kg not to exceed 3000 mg)
Chelator, intravenous once weekly or every other week
Hepatic Support formula LVDX, LIVER GI DETOX
Contains Phase 1 and Phase 2 support nutrients. ( NAC, Antioxidants, Cruciferous
vegetables etc).
Mineral replacement following chelation – trace metals, magnesium, Taurine. Spectra min, Mercury
Amalgam Detox, DMTX
Only used during days off from chelating agent
Fiber formulation containing psyllium Fibre –Plex, Ultra Detox Caps
To help bind metals excreted through the bowels, thus preventing their reabsorption
Hydrolysed Whey Protein 17 servings (2 tbsp daily)
To raise glutathione levels and aid in moving heavy metals out of the body
Cholagogue and cholerectic herbs (Night prior to a colonic)
To support the liver with detoxification. Will promote the production of bile and release
if taken the night prior to a colonic.
Vitamin C with Flavinoids 180 caps 6 caps daily
Important vitamin for proper adrenal support, an antioxidant. Helps reduce damage of
free radicals produced from toxicity. Increases fecal output of mercury
Magnesium Sulphate Injection 2 cc
Used when patient not feeling well after several rounds of DMSA. Used to replenish
(Usually administered 1 time per round chelation, following the 5 days of DMSA or other chelating agent) magnesium levels.
Colonic Irrigation (1-5 per week)
(Usually following the 5 days of DMSA or other chelating agent)
Constitutional Hydrotherapy (0 to 5 per week)
Sunday, 6 May, 12
Promotes release of bile in gallbladder and flush them out of the body, thus helps
eliminate metals that were mobilized by chelating agents. Recommendation between
1-5 per week depending on level of toxicity and reaction to chelation therapy. Reduces
symptoms of heavy metal cleansing. (Also used effectively for solvent toxicity)
Promotes detoxification. If applied immediately prior to colonic, will increase release of
bile from gall bladder. Recommendation between 0 and 2 per week depending on levels
of toxicity and reaction to chelation therapy. Increases mobilization of white blood cells.
Sunday, 6 May, 12
Sunday, 6 May, 12
Overview of DMSA & DMPS:
Use in Clinical Practice
Sunday, 6 May, 12
•
Identify sources of heavy metal exposure. Avoid fish/shellfish for about 1 week before challenge test.
•
Obtain baseline laboratory values—CBC & ensure adequate kidney function. Consider 24 hr urine creatinine clearance in geriatric patients.
•
Conduct a complete physical exam (and heavy metal symptom survey)
•
Be flexible with choice of chelating agents
•
Ensure good bowel health (at least one bowel movement/day and no GI dybiosis) •
Keep patients expectations for health improvement realistic and conservative
•
There is not always an association with a persons symptoms and their heavy metal test.
•
Decision to treat requires assessment of risk/benefit potential in view of known adverse side effects, patient’s symptoms, and laboratory assessment
Before you wake a tiger…
Sunday, 6 May, 12
…Make sure to open the doors and windows before you pinch the tail !
Sunday, 6 May, 12
Metabolism & EHC
Sunday, 6 May, 12
Facilitators of
Metal Mobilization
Sunday, 6 May, 12
• Oral L-Glycine
• Increases the post-provocative release of
metals into urine
Garrot P. Metabolism and possible health effects of aluminum. Environ Hlth
Perspect 65:363-411, 1986
• Dose – 80 mg/kg body wt BID in divided
doses 24 h and 12 h before provocative
testing
Sunday, 6 May, 12
Oral L-Glycine:
•
Markedly increases urinary spill of toxic metals when
used in conjunction with Ca-EDTA, DMSA and/or DMPS
•
Facilitates movement of toxic metals from intracellular
to extracellular compartment
•
Particularly useful with IV Ca-EDTA in the mobilization
of retained Al
•
May also be useful in mobilizing retained Pb, Hg and Sb
when used with DMSA and / or DMPS
- Quig DW. Assessment of Toxic Metal Body Burden: Amunition, Hot Topics and Food for Thought. Townsend Letter, Jun 2007
Sunday, 6 May, 12
Glutathione
•
•
The most abundant intracellular thiol
- Chouchane S, Snow, ET. In vitro effect of arsenical compounds on glutathionerelated enzymes. Chemical Research in Toxicology, 14(5): 517-22, 2001
Metal exposure depletes Glutathione levels
and thus may decrease hepatic detoxification
capacity
- Sheweita SA. Heavy metal-induced changes in the glutathione levels and
glutathione reductase/glutathione s-transferase activities in the liver of male mice.
International Journal of Toxicology, 17(4): 383-92, 1998
Sunday, 6 May, 12
Glutathione
supplementation:
•
Precursors (e.g. oral NAC) may raise
glutathione levels
- Schaller, Marie-Denise Oxidant-Antioxidant Balance in Granulocytes During
ARDS - Effect of N-Acetylcysteine, Chest, 109(1):163-166, Jan 1996
•
Sunday, 6 May, 12
Oral NAC dose 1200 to 2400 mg/day –
typically 500 mg tid
okanagan
naturalmedicine
Dr. Chris Spooner B.Sc. ND
Okanagan Natural Medicine
Vernon BC
250.275.1672
[email protected]
Sunday, 6 May, 12