Defining Metal Intoxication
Blood is a part of the human circulatory system. It transports oxygen, nutrients, and toxins to and from the cells and organs. The nutrients and toxins taken in will either "feed" body cells, be stored, or be excreted through the urinary or digestive tract, through breathing and sweat. While circulating in the bloodstream, toxins can be measured and monitored, hence the term Human Biomonitoring.

Human monitoring of occupational exposures started in the 1890s through a variety of blood lead monitoring programs. Population-based biomonitoring is more recent and has been implemented at various levels within the United States (both federally and among states) and internationally. In the US, the recent advent of the National Health and Nutrition Examination Survey (NHANES) resulted in population-based biomonitoring studies of lead and cadmium in clinical specimens. The combined effort, nationally and internationally, improved our understanding of how widespread some chemical exposures are in the general population.¹

New technology allows the detection of minute amounts of potentially toxic metals. Never before in the history of medicine have we had the analytical accuracy to correlate such traces of toxins with early onset of disease. Modern analytic chemistry allows physicians to take early action.

Through early diagnosis, we can utilize chelation therapy or metal detoxification treatments not only for the treatment of acute metal intoxication, but also for preventive and curative measures. Diagnostic abilities improve treatment potential. Specific monitoring of low dose intoxication allows early removal of harmful toxins from the body to prevent disease. Early intervention enables us to remove the potential cause(s) of an existing disease.

First Diagnose, Then Treat
To treat metal intoxication, we must first define the degree of toxicity. An acute intoxication at the workplace demands another, more aggressive treatment than a chronic case of metal intoxication. While a low-level metal exposure can be one cause of chronic diseases and disease patterns, it is important that we first identify the type of metal toxicity (lead, mercury, etc.) and the severity thereof. From that information, we can safely select a) the appropriate chelating agent and b) the route of delivery and the frequency of treatment.

Diagnosing Acute Metal Intoxication
Medically, a patient is considered acutely exposed, or toxic, when his blood levels exceed the Biological Tolerance Value, also referred to as the BAT level. The BAT value is defined as the maximum permissible quantity of a chemical substance or its metabolites, or the maximum permissible deviation from the norm of biological parameters induced by these substances in exposed humans. The BAT value is established on the basis of currently available scientific data that indicate that these concentrations generally do not affect the health of the employee in any significant adverse way, even when they are attained regularly under workplace conditions. BAT values are established on the assumption that persons are exposed at work for at most eight hours daily and 40 hours weekly. BAT values established on this basis may also be applied without the use of correction factors to other patterns of working hours. Interestingly, BAT values are lower for the German than the US population. A cynic might say that either Germans are more sensitive than US citizens, or that US BAT values protect employers more than employees.

BAT values are conceived as ceiling values for healthy individuals. They are generally established for blood and/or urine and take into account the effects of the substances and an appropriate safety margin, being based on occupational medical and toxicological criteria for the prevention of adverse effects on health.

Whole blood, serum, and urine samples are used as assay materials. Hair samples are not suitable assay materials for occupational medical testing, because hair growth is slow and thus the immediate exposure cannot be verified. Under workplace conditions, the employee's immediate intoxication is of concern, not the chronic or long-term exposure. Therefore, in occupational medicine, the diagnosis concerns itself with immediate intoxication.

Occupational medical treatment is aimed at reducing the toxicity level to below the BAT level. The most common "treatment" of acute workplace intoxication is the removal of the patient from the workplace. Chelation is considered in serious conditions only, and reported cases are rare. Instead, the patient is monitored via blood or urine analysis, and as soon as levels fall below the accepted BAT range (usually within a day or two after exposure), "treatment" is considered successful. The patient is brought back to the workplace. In serious cases of intoxication, the patient is voluntarily removed from the workplace for one week or longer. In debilitating accidents, a patient is placed into early retirement, and treatment is palliative.

Comparison of Reference Ranges for the Unexposed and Those Exposed at the Workplace
It is apparent from the data below that, for most metals, a definite ceiling range does not exist. Different countries and regulatory agencies provide differing ranges, and these differences are usually due to the use of various analytical techniques or population models. For the general population, even for physicians, comparing reference ranges is cumbersome, because units may be given in mmol/L or µg/dl, instead of the more common µg/L.

The Toxicity of (Some) Blood Metals

Arsenic (Blood): Blood arsenic levels are not considered diagnostically useful, and the total arsenic concentration may be markedly increased after dietary consumption of seafood. Urine samples are more valid for the diagnosis of arsenic intoxication, but these too are influenced and often rise dramatically after a seafood meal. Hence, when taking a blood specimen for blood metal testing, the patient should be instructed not to eat seafood for at least one day prior to sample-taking and refrain from smoking for as long as possible. Cigarette smoke does contain arsenic, beryllium, nickel, cadmium, lead, and other potentially harmful metals. Hair and nail levels are useful only for diagnosing a past exposure.

Lead (Blood): Lead in the human body can be measured in blood, urine, bones, teeth, or hair. By measuring an individual's blood lead level (BLL), we can detect lead poisoning in adults or children. When blood lead is high, an increase in erythrocyte protoporphyrin (EP) follows.²

• The standard elevated blood lead level (BLL) for adults' set by the Centers for Disease Control (CDC) is 25 micrograms per deciliter (25 µg/dl) of whole blood. This level recognizes that every adult has accumulated some lead contamination.
• The level for a child is lower; currently it is 10 micrograms per deciliter (10 µg/dl) of blood.²

The CDC states that a blood lead level above 10 µg/dL is a cause for concern. It also states that lead can impair development even at BLLs below 10 µg/DL.³ The German Environmental Agency's BLLs are lower than those set by US agencies. (See Table 1.)

In Australia, the acceptable level of lead in blood was lowered from 25 µg/dL to 10 µg/dL in 1992. In 1993, the National Health and Medical Research Council (NH&MRC) set a national target for 1998 for all Australian to have a BLL less than 15 µg/dL (except where they worked with lead), and strategies were put in place whereby 90% of pre-school children would have BLLs below 15 µg/dL. In 1996, the National Blood Lead Survey (the Donovan Survey) found 7.7% of children aged one to four were above 10 µg/dL, and 1.7% were above 15 µg/dL.⁴

Biomonitoring Ranges for a Normal, i.e., Non-Exposed, Population; Levels Above the Given Range Indicate Need for Action:

• CDC recommends that all children be screened for lead poisoning yearly. This is especially important for children between six months and six years of age.
• Children with an erythrocyte protoporphyrin level (EP) of 35 micrograms per deciliter (=350µg/l) should be tested for a blood lead level.
• Children with a BLL of 20 micrograms per deciliter (=200µg/L) or higher should be screened by their doctor for lead poisoning.
• Medical treatment is necessary if the BLL is higher than 45 micrograms per decilitre (=450 µg/l).

Levels of Acute Exposure as Utilized in Occupational Medicine

The OSHA Safety and Health Achievement Recognition Program (SHARP) collect and maintain a registry of blood lead levels by occupation and industry. Table 1 shows elevated blood lead levels measured in Washington State construction workers. Blood results are reported in micrograms per deciliter (µg/dl), and the data shows that exposure is common. Companies that do not test their workers are not represented, and sadly, enough many exposed workers do not have their blood tested.² (Note: 1mcg/dl = 10mcg/L)

Table 1: Blood Levels in Washington State Construction Workers (100KB .pdf)

Treatment Options
All forms of EDTA (NaEDTA, NaMgEDTA, CaEDTA) have a high lead-binding capacity. CaEDTA has been approved by the FDA to chelate lead, and the proper infusion rate is 1gr/hr. If infused too quickly, EDTA is nephrotoxic. Although CaEDTA bolus injections are becoming increasingly popular, it is dangerous to administer EDTA at such a fast rate. The International Board of Clinical Metal Toxicology (IBCMT) strongly advises against it.⁷

Cadmium (Blood): According to the Agency for Toxic Substances and Disease Registry (ATSDR), elevated blood cadmium levels confirm acute exposure, (Jarup 2002; ATSDR 1999) but do not correlate with body burden or clinical outcome.⁵ According to the ATSDR, a blood test alone is not sufficient validation for treatment, possibly because blood cadmium levels are easily influenced through smoking or smoke exposure.

The 95% confidence limit for blood cadmium levels in the United States for healthy nonexposed, nonsmokers is 0.4 micrograms per liter (µg/L) (CDC 2005). ATSDR recognizes that occupationally exposed persons may have higher blood levels than the general population. OSHA (www.osha.gov) considers a whole blood level of 5µg/l or higher hazardous.⁵

German agencies have set stricter standards:
Non-smoking children 6-12 years <0.5µg/L
Non-smoking adults, 18-69 years <1.0µg/L

Treatment Options
All forms of EDTA (NaEDTA, NaMgEDTA, CaEDTA) bind cadmium. A recent statistical evaluation by Micro Trace Minerals Laboratory of post chelation urine tests (Table 2) indicates that EDTA seems to be the best option available at this time.

Table 2: Cadmium-Binding and Urine Excretion After Various Chelation Treatments
Source Micro Trace Minerals, Germany/Boulder, Colorado

Mercury (blood): Blood levels are used as markers to determine the severity of a mercury exposure. For standard blood mercury test, mercury is measured as total mercury (inorganic and organic). Except for methylmercury exposures, blood is considered useful if samples are taken within a few days of exposure. This is because most forms of mercury in the blood decrease by one-half every three days if exposure has been stopped. Thus, mercury levels in the blood provide more useful information after recent exposures than after long-term exposures.⁶

Human Biomonitoring Range:
Normal (unexposed population): < 5.8 µg/L (US Environmental Protection Agency)
Normal (unexposed population): < 8 µg/L (University of Iowa, USA)
Normal (unexposed population): < 2 µg/L (Environmental Protection Agency, Germany)

Levels of Acute Exposure as Utilized in Occupational Medicine:
BEI (Biological Exposure Index): 15 µg/L (total inorganic, end of shift, end of work week)
BAT (Biological Tolerance Value): 50µg/L (organic and inorganic)
BAT (Biological Tolerance Value):100µg/L (organic)

Treatment Options
When a blood test no longer reflects a mercury exposure, a DMPS challenge test may be performed to confirm or rule out mercury intoxication. DMSA can also be used to provoke mercury binding and excretion, though the binding ability of intravenously administered DMPS is much stronger.

Note: many physicians assume that oral DMPS has the same binding capacity as IV DMPS. The fact is, the mercury-binding ability of oral DMSA and oral DMPS is similar, and both of these oral chelators have a lower mercury binding capability than IV DMPS.

Blood Sampling Specifics
Collection Medium: Metal free royal blue EDTA tube
Please note that Heparin or regular EDTA tubes are no longer used for metal testing due to contamination.
Minimum: 3 mL whole blood
Analysis: Must be AA hydrid method or ICP-MS with collision or cell reaction technique. All other ICP-MS instruments are too much affected by interferences and are unable to have the needed sensitivity to detect low levels. False highs may be a problem.
Analytical Time: Two days to one week

Diagnosing Chronic (Over)Exposure
Biomonitoring ranges apply for a population considered "nonexposed." Ironically and sadly, the long-term exposed are often chronically ill people with sad histories of "unknown cause." Medically, they are considered "unexposed" until the diagnosis indicates a blood or urine value above the biomonitoring range. Table 3 shows human biomonitoring ranges as set by the German Environmental Agency. These ranges apply to people not working in industries that may lead to occupational exposure. People with past exposures, or those exposed to low levels on a daily basis, may or may not show blood levels above these ranges. Most importantly, unremarkable results do not rule out chronic exposure.

Table 3: Biomonitoring Ranges Last Updated by German Environmental Agency 2005 (528KB .pdf)

When we suspect past or chronic exposure, but blood tests are negative, we consider a "challenge test," also referred to a "provocation test." By introducing a chelating substance into the bloodstream, we force metal binding and excretion. Results are often astonishing. Depending on how much of a metal has been stored in the body, urine excretion levels may rise well above the expected range. In most cases, patients respond favorably, if not unexpectedly. Symptoms, even unrelated ones, may disappear. Every doctor practicing chelation therapy has such case histories.

Case History:
Beate, a 45-year-old biologist, works in our laboratory. She is extremely disciplined and efficient, but rheumatoid arthritis (with a high positive RA factor) has proven to be a challenge since her early twenties. She had been on cortisone, but stopped after experiencing strong side effects. During her frequent rheumatic attacks, strong pain medication was her only alternative. Beate has suffered from asthma since childhood and also suffers from Hashimoto disease. She currently takes thyroxin, 175 mcg daily. During history taking, it became apparent that the Hashimoto appeared after the removal of her many amalgam fillings, which her dentist took out "all at once and without any precautions." At that time, she experienced multiple food sensitivities and an allergy to penicillin. Migraine became another problem.

Mercury overexposure seemed a reasonable diagnosis. Hair mercury levels were at 1.89mg/kg (=ppm), far exceeding the upper range of 0.6 ppm. Medical analysis showed a normal renal function and blood pressure. We first tested her reaction to DMSA by giving her 500 mg under close supervision. Her urine mercury excretion level was a modest 3.37 mcg/g creatinine. Other than feeling weak and light-headed, she noticed no side effects. The next day, she felt amazingly well. Joint swelling and pain was noticeably decreased.

We supported her nutritionally before the next "challenge test" two weeks later. Again, she felt weak and light-headed, urine results showed a slight increase in urine mercury at 5.36µg/g crea, and again, the day after, she was without pain and felt energetic. We have continued this treatment cycle, and so far, results have been amazing. After three months of biweekly treatment, DMSA was increased to 1000 mg and urine mercury excretion rose to a significant 36.2µg/g crea. She continued to be symptom-free. A repeat RA factor turned out to be normal. Two weeks later, she experienced a monosodium glutamate (MSG) reaction after eating at an Italian restaurant. A severe migraine was followed by another rheumatic attack.

The treatment cycle was temporarily stopped.

Choosing the Most Appropriate Chelator
Why did we, in Beate's case, not use IV DMPS, which is a stronger mercury chelator? We didn't do so for two reasons:

1. Beate is hypersensitive and afraid of experiencing reactions. A softer approach seemed warranted.
2. DMPS injectables were unavailable at the time. We could have used oral DMPS, but it has a similar binding as DMSA. We did not use oral DMPS, because it has a stronger affinity to bind zinc, and Beate's hair analysis showed borderline zinc levels. Unlike oral DMPS, DMSA does not bind zinc in any significant way.

Every chelating agent has a specific binding capacity to certain metals, and we can enhance the effectiveness of chelation therapy by paying attention to those chemical specificities. Similarly, we reduce the chelation benefit by ignoring "finer points."

Diagnostically, it is important to find out the type and severity of the existing metal intoxication. In addition, it is important to identify existing deficiencies and pay attention to borderline deficiencies. If we would use DMPS (or EDTA) on a borderline zinc-deficient patient, we could create an acute deficiency. Consequently, we must initiate a nutritional program before chelation is started to prevent potential problems. Zinc deficiency symptoms are not unknown among patients who have undergone chelation therapy and who have experienced side effects after DMPS or EDTA treatment. A proper supplementation schedule could have avoided the problems.

Before any chelation treatment is started, we must know renal function and order additional diagnostic tests, depending on the patient's health problems. A cardiac patient will require a different diagnostic schedule than a neurological patient. After we diagnostically defined the patient's general health status, we can select the appropriate and most effective chelating agent.

Are So-Called Unexposed Patients in Need of Chelation?
The term "unexposed" is used for people who do not work in a hazardous working environment and have not been exposed to environmental- or industry-related accidents. Unfortunately, chronic metal intoxication exists more than we are willing to admit. The following excerpt of the New York City Health Report of July 23, 2007 should be a warning. It indicates that one in four New Yorkers has elevated blood mercury levels, a clear sign of mercury overexposure.

Today's findings are the latest presented from New York City's Health and Nutrition Examination Survey (NYC-HANES), the first such survey ever conducted by a US city. It's possible that other cities have similarly high levels, or higher ones, but haven't yet documented them. Because mercury is a concern for the health of newborns, recommendations on mercury exposure are most important for pregnant and breastfeeding women.

• Among women 20-49 years old in New York City, the average blood mercury level is 2.64 µg/L (micrograms per liter), three times that of similarly-aged women nationally (0.83 µg/L).
• Approximately one-quarter of New York City women in this age group have a blood mercury level at or above 5 µg/L, the New York State reportable level.
• People who eat fish three or fewer times each week have, on average, levels of mercury below the reportable level, while average readings exceed the reportable level among those who eat fish four or more times.
• Higher-income New Yorkers have higher mercury levels; New Yorkers in the highest income bracket average 3.6 µg/L, compared to 2.4 µg/L among the lowest income group.
• Average blood mercury levels are considerably higher among New York City Asian women (4.1 µg/L); nearly half (45%) have blood mercury levels at or above the State reportable level.
• Among Asians, foreign-born Chinese women have particularly high levels compared to the rest of New York City. Two-thirds (66%) have mercury at or above the reportable level.
• Foreign-born Chinese New Yorkers eat an average of three fish meals per week, compared to about one among New Yorkers overall. About one-quarter of Chinese New Yorkers eat fish five or more times each week, compared to fewer than one in 15 overall.

Should we routinely check whole blood metals? Do one in four New Yorkers need chelation? The New York City Health Report speaks for itself. Is the mercury problem unique to New Yorkers? It would be naïve to believe that.

Notes
1. Committee on Human Biomonitoring for Environmental Toxicants, National Research Council; Human Biomonitoring for Environmental Chemicals (2006), Board on Environmental Studies and Toxicology (BEST)
2. Dept. of Ecology, State Washington. Available at: http://www.ecy.wa.gov/programs/hwtr/demodebris/pages2/lbloodtest.html
3. CDC Weekly. December 22, 2000;49(50):1133-7. Available at: www.cdc.gov/mmwr/preview/mmwrhtml/mm4950a3.htm
4. Australian Government. Dept. of Environment, Water, Heritage and the Arts. Available at: http://www.deh.gov.au/settlements/chemicals/index.html.
5. Agency for Toxic Substances and Disease Registry (ATSDR). 1999. Toxicological profile for Cadmium. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.
6. Agency for Toxic Substances and Disease Registry (ATSDR). 1999. Toxicological profile for Mercury. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.
7. Van der Schaar P. IBCMT Textbook of Clinical Metal Toxicology. 2008. Available at: www.ibcmt.com.