Elmer M. Cranton, M.D.
ABSTRACT: Trace and toxic element
testing is important in the practice of chelation therapy. No single
clinical test for adequacy or toxicity of metallic elements exists that does
not also have serious weaknesses. Each element has its own unique
distribution in body fluids, tissues and organs. Elemental blood
concentrations fluctuate widely throughout the day while levels in solid
tissues vary more slowly. Factors that alter elemental concentrations in
body fluids and tissues include diet, nutritional supplements, atmospheric
and environmental contamination, industrial exposure, and physical exertion.
Concentrations in fluids and tissues in different parts of the body
accumulate and fluctuate in unique and different ways for each element.
Acute exposures have different effects than gradual accumulation over longer
periods of time. Extremely low levels of trace elements in biological
specimens can make contamination of test specimens a serious source of
error—beginning with initial collection, during transport and storage, and
during laboratory handling and measurement. Extremely low concentrations can
make accurate laboratory testing difficult and expensive. Provocative urine
testing and chelation of mercury is covered in detail because of a recent
upsurge in interest for that particular toxic element.
Each type of testing for adequacy or
toxicity of metallic elements has its own unique strengths, weaknesses, and
potential sources of error, which also differ for each element tested.
Medical, dietary, and occupational histories (combined with careful physical
examination) are helpful, but not always adequate to make a reliable
The most accurate assessment for trace
and toxic elements would require multiple measurements of a variety of
specimens--including whole blood, erythrocytes, leukocytes, serum, plasma,
urine, hair, nails, muscle, liver, and other tissues. High cost and
impracticalities of specimen collection place limits on what can be done in
a clinical setting. Provocative urine testing following a chelator seems a
When testing urine for metallic elements,
it has been customary to compensate for intraday dilutional fluctuations by
collecting 24-hour, timed specimens. A serious limitation of 24-hour urine
collection is lack of patient compliance. Accurate collection of 24-hour
specimens has proven unreliable in an ambulatory setting.(1) Specimens
become contaminated by skin, feces, vaginal secretions, menstrual blood,
perspiration, and fingers in transfer containers. Some urine may be lost
during defecation, and voidings are missed entirely. Errors from
contamination are compounded by collection of multiple voidings over a
24-hour period. Female patients have difficulty voiding into narrow-neck
containers, and transfer from wide-mouth cups adds to the risk of
contamination. Even with careful and detailed instructions prior to
collection, followed by questioning of patients when specimens are returned,
it is not possible to consistently obtain accurate 24-hour collections.(1)
A six-hour urine collection obtained in the doctor’s office under
supervision is much more likely to be accurate.
By measuring elements in micrograms or
nanograms per gram of urinary creatinine, clinically meaningful data can be
obtained without the need to collect 24-hour urine specimens.(2) By
collecting a six-hour timed urine specimen under supervision, a provocative
chelation test can thus be accurately performed. When testing urine for
nutritional trace elements and minerals, it is necessary to avoid intake of
nutritional supplements containing those elements for at least 36 hours
prior to urine collection. Otherwise test results will reflect recent intake
and not tissue levels.
Testing urine is less expensive and more
convenient than testing blood. Whole blood, erythrocytes, plasma, and serum
are all too viscous to nebulize in the test instrument without first
digesting with acid, which dilutes those specimens before measurement,
reducing sensitivity and accuracy at the very low levels of some trace and
toxic elements. Like blood and serum, hair and other biopsy specimens must
also be digested in acid prior to testing. Because addition of acid dilutes
the elements being measured, sensitivity of hair testing may be less than
that for urine. Urine is not viscous and can be tested directly without
digestion or dilution. An urine concentrations can be greatly increased by
Using multi-channel test instruments,
accurate measurements can be made of a wide spectrum of low-level elements
in urine with a single pass through the instrument. This multi-element
procedure results in a relatively low cost per element. Because of the need
for digestion and dilution, measurements of equal sensitivity for the very
lowest-level elements in blood may require individual tests for each element
using more sophisticated and more expensive instruments. The cost for each
element might then equal or exceed the cost to measure a spectrum of 20 or
more elements in urine.
Minerals and trace elements in systemic
circulation are continuously filtered through renal glomeruli into the
urine. Absorption and excretion by renal tubules maintains equilibrium
between blood and urine. Metallic elements in blood maintain equilibrium
with body cells and tissues. Trace elements and minerals in urine thus
reflect concentrations of those elements throughout the body.
Regardless of whether blood, urine, hair,
saliva or another type of tissue biopsy is used, certain principles must be
considered relative to the test protocol and interpretation. Mercury
testing is described in detail below as just one example of the principles,
pitfalls and precautions of trace element testing.
MERCURY TESTING IS OFTEN PERFORMED
People frequently contact me with
questions about mercury test results performed elsewhere after being told
that their mercury level is high. Often they have been told that they
require a course of mercury chelation therapy, based on those test results.
Upon reviewing the laboratory reports, I frequently find that urine was
tested immediately after administering DMPS or a similar chelating agent.
The resulting test, however, is then reported incorrectly on a form using
reference ranges derived from urine collected without a prior provocative
chelation--without using DMPS or any other chelator. If that is done, the
result is always much higher than references ranges on the report form and
an attempt at interpretation is not possible. That type of incorrect
reporting sometimes frightens patients into believing they are poisoned and
need mercury chelation, when in fact no interpretation can be made without
proper reference ranges.
Every person has mercury and other toxic
elements in their body. That was true since time began, long before
present-day environmental and technological pollution. If DMPS (dimercapto
propane sulfonic acid), DMSA (dimercapto succinic acid) or any other
chelator of mercury is administered before urine collection, mercury
excretion will increase greatly for everyone, even for people with
relatively low and nontoxic levels of mercury. The question to answer is
whether or not the amount of mercury measured is enough to cause symptoms of
ill health. Is it a toxic level? Or is it below a non-toxic and
well-tolerated threshold. The only way to know that is to use accurate
reference ranges for interpretation and comparison. Physicians and patients
are advised to contact the laboratory and insure that the reference ranges
on the report form are correct for the provocative method used to collect
the urine, as described below.
Following a single dose of the mercury
chelators DMPS or DMSA (but not EDTA), urine mercury will increase
enormously in healthy subjects without toxicity, up to 4,000 percent even if
the person tested has relatively low and nontoxic amounts of mercury in the
body. If a mercury chelator is given before collection, test results should
therefore be interpreted using reference ranges derived in that same
laboratory, using the same instruments, from a large number of people, and
following the same protocol of provocative chelation for urine collection.
Mercury chelators will always cause a great increase of mercury in the
urine, regardless of the amount in the body. The safe, nontoxic threshold
will always be much higher after a chelator. If proper procedure is
followed, a large majority of healthy Americans tested will be in the
nontoxic range. The way mercury testing has been reported by many
laboratories, provoked urine measurements are printed on forms intended for
urine collected without a chelator, and every patient mistakenly reads very
high, regardless of the amount in the body.
It is true that there is no "good" level
for mercury. It is a toxin. It is also true that every toxin has a safe
level below which it is well tolerated. But if tens of millions of people
can live in good health and without toxic symptoms, at a tolerably low level
of mercury, it is highly misleading to tell patients they have mercury
toxicity and need to undergo a course of mercury chelation when they are at
or below that same level.
To correctly interpret a laboratory test
report and to know if a patient really has a mercury problem, it is
necessary to compare results with mercury levels measured by that same
laboratory in urines from a large population of typical Americans, most of
whom have no symptoms of toxicity. Reference ranges must be derived using
the same method of provocative testing and specimen collection. Laboratories
should also print the means and standard deviations on the report forms,
computed from test results of a large series (200 consecutive healthy test
subjects or more) using the same collection protocol. At the mean level,
approximately 50-percent of all people tested will be higher. At the mean
plus one standard deviation (SD), approximately 16-percent will be higher.
At mean plus two SD, 2½-percent
will be higher. At mean plus three SD, less than 1-percent will be higher.
Reference ranges reported by clinical
laboratories are customarily set to fall between the 2.5th
percentile and the 97.5th percentile (mean +/- 2 SD). That is the
method recommended by the International Federation of Clinical Chemistry (IFCC).(3)
For toxic elements with no known nutritional value, such as lead, the
reference range might better be established below 95th percentile
(approximately the mean plus 1.8 SD).
Those percentiles will vary somewhat if
the distribution of values is skewed, but this method allows a reasonable
approximation. Clinicians are
often not aware that ranges printed on laboratory forms are rarely
represented as “normal” by the lab. It is properly left to the doctor to
interpret what is normal and what is abnormal. Laboratory reports generally
have reference ranges based the mean +/- 2 SD, derived a large number of
similar tests at that same laboratory.
It is not justified to diagnose metal
toxicity at levels lower than those found in the majority of the population
with no symptoms of toxicity. In my practice the cut-off point for toxicity
is set at 1.8 SD above the mean for most toxic metals (approximately the 95th
percentile), and sometimes lower for mercury, depending on clinical
findings. In the absence of scientific evidence to indicate otherwise, that
is the accepted scientific procedure laboratories follow when establishing
reference ranges printed on report forms. If that level does not cause
symptoms in two hundred million Americans who are below the 95th
percentile, then that same level is not likely to be causing symptoms in the
person being tested.
Hair analysis can also be used a
screening test, but hair is subject to external contamination. If hair
analysis is used, results are best confirmed by provocative urine testing
before a course of therapy is undertaken. The sensitivity of measurements
of hair elements is generally lower because of the need to first dilute and
digest specimens in solution. On the other hand, the concentration of
elements in hair is usually higher.
It is not advisable to make a diagnosis
using hair analysis alone. If the laboratory report on hair is accurate
(not always the case), and if hair mercury is less than 1.5 to 1.8 standard
deviations above the mean for that laboratory, then it is unlikely that
mercury is a significant cause of symptoms. If hair mercury is greater than
1.5 standard deviations above the mean, a confirmatory DMSA provocative
urine test will determine the extent to which mercury toxicity might be a
problem and will rule out hair contamination. In my experience, reference
ranges listed on laboratory report forms are sometimes quite arbitrary. I
recommended using means and standard deviations, as described above.
It is rarely advisable to make any type
of final diagnosis or to begin a lengthy course of therapy based on a single
laboratory test. Laboratory error is not uncommon.. For example, it is not
acceptable to begin life-long treatment for diabetes with only one blood
sugar reading, or to treat gout after a single uric acid measurement.
Accurate mercury testing is very
difficult and not all laboratories have proper quality control. In the
past, I have submitted multiple samples of the same specimens to several
different licensed laboratories to compare results. The reports varied
widely. I have also submitted homogeneous portions of the same specimen to
the same laboratory at different times, again with widely different
results. Some of that type of error will be cancelled out, if the
laboratory is consistent and if the means and standard deviations for that
laboratory are used to interpret results as described above. Reputable
laboratories will usually refund charges for duplicate test specimens
submitted only to check their accuracy and reproducibility. It helps the
laboratory and adds to their internal quality control.
I do not recommend blindly accepting
reference ranges listed on laboratory report for toxic elements. I have
personally computed the means and SD for each metal using a large number of
test results from my own patients, using the method described below. With
the computed means and SDs. I have established my own reference ranges. I do
this because laboratories often do not provide me with that kind of data and
ranges on the forms often seem so arbitrary.
Provocative Test for Mercury
To test for mercury and a spectrum of
toxic elements I administer a single 500-mg dose of DMSA by mouth on an
empty stomach with a glass of water, preferably in the morning before
breakfast. All urine is then carefully collected for six hours, while under
supervision in my office. Care is taken not to contaminate the urine or the
container. Using this method, a wide range of toxic metals (mercury, lead,
arsenic, cadmium, nickel, and others) are be measured relative to urine
creatinine. I no longer use 24-hour urines, as explained earlier, because
they are subject to much greater collection errors.(1) Urine is more
concentrated with fasting and has higher concentrations of trace metals.
Concentrated urine facilitates testing and improves accuracy for metals with
the lowest levels. Creatinine is excreted in urine at a relatively constant
rate throughout the day. On average, 1.2 grams of creatinine is excreted
daily—varying with weight and decreasing with age. If urine is more dilute,
creatinine is more dilute. By measuring mercury and other metals relative to
urine creatinine, a partial correction is made for variations in dilution.
All chelation, including DMSA, should be stopped at least four weeks before
initial or follow-up provocative urine testing to allow equilibration
throughout in the body. I periodically update reference ranges I personally
use in my practice for this test protocol and post them on the website
TREATMENT OF MERCURY TOXICITY
In my opinion, intravenous DMPS is
obsolete and no longer has a place in medicine. I have heard from many
people who received DMPS elsewhere and were sicker by it—one was permanently
disabled. Even if DMPS is used, it can effectively be given by mouth
without intravenous infusions. EDTA is a very weak chelator of mercury and
is not an effective treatment for mercury toxicity. For mercury removal, I
recommend DMSA, by mouth as a the safest, most effective, and least
expensive treatment for mercury removal.(4)
The form of mercury with greatest
toxicity is methyl mercury and related compounds. Those have a high
affinity for the brain and nervous system. DMSA crosses the blood-brain
barrier and removes mercury from the brain and spinal cord. DMPS is much
less effective in that regard. DMPS is also three times more toxic than DMSA,
based on LD-50. Animal studies show DMSA to be approximately three times
more effective than DMPS in removing mercury from the brain.(4) DMSA has the
great advantage that it is taken by mouth in capsule form. As reported at
the fifth Nordic Symposium on Trace Elements in Human Health and Disease,
Norway, in 1994, "DMSA may now be considered as the treatment of first
choice in cases of acute or subacute lead poisoning and in mercury
poisoning. All experimental and clinical experiences show a low toxicity
for this drug. Some chemically sensitive patients react adversely to any
type of medicine, but DMSA is so safe that the FDA approves its use in small
It has been mistakenly said that EDTA and
DMSA can cause mercury to enter the brain. That is false. Those chelators
bind tightly and inertly to metals and remove them from the body in urine
and feces. According to some studies, much more is removed in feces than in
The general principles applied above to
mercury can also be applied to testing and interpretation of other metals,
with appropriate modifications.
Cockcroft DW, Gault MH. Prediction of
creatinine clearance from serum creatinine. Nephron.
2. Skerfving S.
Toxicology of inorganic lead. In: Prasad
AS, ed.: Essential and Toxic Elements in Human Health and Disease.
New York, Alan R Liss Inc; 1987:619.
Expert Panel on Theory of Reference
Values. Part 5, Statistical treatment of collected reference values,
determination of reference limits. J Clin Chem Clin Biochem.
Aaseth J, Jacobsen D, Andersen O, Wickstrom E. Treatment of mercury and lead
poisonings with dimercaptosuccinic acid (DMSA) and sodium
dimercaptopropanesulfonate (DMPS). Analyst 1995 Mar;120:853ff.
(Presented at the fifth Nordic Symposium on Trace Elements in Human Health
and Disease, Loen, Norway, June 19-20, 1994).