Chapter 23 Metal Toxicity
Assessment of Exposure and Retention
The incidence of high-level exposure to toxic metals and acute “poisoning” is rare and is most commonly associated with occupational exposure. Associated symptoms are well defined and accepted. A plethora of published research has clearly defined many of the precise biochemical mechanisms by which specific metals elicit a vast array of adverse effects that can culminate in neurotoxicity, nephrotoxicity, cardiovascular and pulmonary disease, cancer, teratogenicity, and dysregulation of immune function. Despite knowledge of the effects of metals on the most basic biochemical processes that affect human health, the concept that “subthreshold” levels of metals in the body can negatively affect health and daily functioning is not generally accepted by the dominant medical community. However, with respect to lead, mercury, and cadmium, a consultant to the National Institute of Environmental Health Sciences stated that the margin between the levels of exposure for people in industrialized nations and the levels of exposure that are currently recognized as producing the lowest adverse effect levels is small.1,2
The methods for assessing metal toxicity established as standards for medical practice are best suited for detection of acute metal poisoning or recent or ongoing exposure, but do not provide an accurate estimate of the actual levels of metals that have accumulated in the body. The purpose of this chapter is to provide an overview of the various laboratory tests for the assessment of (1) exposure to toxic metals and (2) the net retention of toxic metals. It is beyond the scope of this chapter to discuss the sources and symptoms associated with long-term exposure to the most commonly encountered metals. Thorough reviews of these topics have been published elsewhere.3–7
The most commonly encountered toxic metals (mercury, lead, cadmium, and arsenic) are natural constituents of the earth’s crust, but their increasing abundance in air, water, and surface soil results primarily from industrial demand and energy production (pollution). Consequently, the environment today has become contaminated to the point that we are all, regardless of occupation, at higher risk for at least long-term, low-level exposure to toxic metals. However, consistent with the basic principles of toxicology, confirmation of exposure is by no means valid documentation of clinically significant retention and toxicity. For a given individual, toxicity is exhibited when the level of retention exceeds physiologic tolerance, and net retention (body burden) is determined by the relative rates of toxic metal assimilation and excretion.
Two important concepts that have been largely overlooked with respect to metal toxicity may explain the discrepancies of opinion expressed by practitioners of traditional medicine and preventive medicine. The first is the potential for the combined effects of multiple toxic metals, which can have not only additive, but also synergistic, adverse physiologic effects.8,9
This concept should be further extended to include consideration of the potential combined effects of toxic chemicals and toxic metals, the total toxic load. The broad heading of toxic chemical entities includes not only naturally occurring and synthetic exogenous compounds but also noxious endogenous compounds derived from a severely dysbiotic or poorly functioning gastrointestinal (GI) system. The second is the remarkable individual variability in susceptibility or tolerance to toxic metals. Established precedence for the phenomena has been provided by such observations as the rapid contact allergic response that is elicited by mercury in a small percentage of a population.10 Individual variability in susceptibility is determined in part by genetic polymorphisms, nutritional status, and the total toxic load.7,9
No single perfect test is available for the diagnosis of chronic metal toxicity; any test result must be interpreted in conjunction with a thorough review of a patient’s physical findings, exposure history, and symptoms. However, the symptoms associated with a chronic toxic metal retention appear to be diverse and rather nondescript, and they may not be fully expressed until later in life. Clear examples of such latency of symptom expression have been provided for lead and hypertension11 and cardiovascular mortality.12 Therefore, to address the needs of clinicians who focus on preventive medicine as opposed to crisis management, the following review of laboratory tests emphasizes testing that has greater sensitivity with respect to detection of the bioaccumulation of the most commonly encountered toxic metals. Emphasis has been placed on the distinction between testing that is most appropriate for assessment of exposure versus net retention.
When performed properly, hair elemental analysis can serve as a qualitative screening test for exposure to toxic metals, but it is not a reliable method for the diagnosis of metal toxicity. Hair is an excretory tissue that can provide a chronologic record of bioavailable trace elements in the body, and the hair content of mercury, arsenic, lead, and thallium has been used as evidence for the cause of death.13 Once metals are incorporated into growing hair, there is no back exchange into the body; therefore, the concentration of metals in hair is usually far greater than that in blood or urine. The length of the hair specimen analyzed dictates the duration of time during which exposure occurred, and segmental analysis of hair can be used forensically to estimate the chronologic course of exposure. A study of the lead and mercury content of hair from a long-deceased president of the United States was performed at the Armed Forces Institute of Pathology in Washington, DC, exemplifying the potential utility of hair analysis for exposure to toxic metals.14 Detection of toxic metals in hair actually predates that in blood and urine.15
A growing number of peer-reviewed publications support the value of elemental analysis of hair specimens for the detection of exposure to toxic metals. For example, elevations of arsenic in both hair and urine confirmed arsenic exposure from a pesticide in an individual with peripheral neuropathy and macrocytosis.16 Hair levels of lead, manganese, cadmium, and other toxic metals have been correlated with psychological conditions and deviant or violent behaviors.17 Lead, cadmium, and mercury levels in children’s hair have been correlated with childhood intelligence. Hair analysis has been used to identify historical as opposed to current exposure to lead.18 School children with relatively high levels of lead in their hair had slower reaction times and less flexibility in changing their focus of attention than children with relatively low concentrations of lead in hair.19
The Agency for Toxic Substances and Disease Registry (ATSDR), the U.S. Environmental Protection Agency, and the National Academy of Sciences recognize the scientific validity of hair mercury levels as an indicator of maternal and fetal exposure to methylmercury. In a cognitive performance study of children in the Faroe Islands, there were detectable effects on brain function in the children whose mothers had elevated levels of hair mercury.20 History of fish consumption and mercury in hair samples are considered the best indicators of human exposure to methylmercury.21 Fish consumption among Scandinavian22 and Tyrrhenian men,23 Amazonian children,24 and people from the Minamata Bay area24 was positively correlated with hair and blood mercury levels. Note that hair elemental analysis definitely provides useful information about exposure to methylmercury (fish consumption); however, it is not nearly as useful for disclosing information about exposure to inorganic mercury as derived from dental amalgams.24 The concentration of methylmercury in hair is about 300 times higher than that in blood.25 In sharp contrast, about 75% of total hair arsenic is present in the inorganic form.26
Although an increasing number of peer-reviewed reports support the clinical utility of elemental analysis of hair for the assessment of exposure to specific toxic metals, some considerations prevent its acceptance by governmental agencies in the United States. In June 2001, the ATSDR convened a panel of scientists with some expertise in hair analysis or risk assessment to explore “the state of the science of hair analysis.”27 Overall, the discussion was objective and focused on the existing scientific data. A summary statement from the meeting concluded, “In general, hair analysis results can provide limited qualitative insights into environmental exposures and rarely can answer questions about potential health effects.”28 Primary concerns raised by the group pertained to uncertainties about the quantitative relationship among the actual “internal dose,” the rate of incorporation into hair, and the current lack of well-established data to enable one to predict potential health effects for a given concentration of a specific metal in hair. Over interpretation of the results of elemental analysis of hair is a serious concern shared by science-based laboratories and astute clinicians as well as the ATSDR. It should be kept in mind that the ATSDR has been interested in the use of hair analysis as an initial screening tool for inexpensive exposure biomonitoring of groups of people who are exposed to toxins at suspected sites of contamination. The goal of the ATSDR to be able to use hair elemental analysis as confirmation of toxicity is quite different from the use of the procedure in preventive or comprehensive medicine simply to provide an initial indication of exposure.
The consensus report by the ATSDR is consistent with the aforementioned statement that hair analysis can provide some qualitative information about exposure to toxic metals but does not provide a basis for diagnosis of metal toxicity. As such, hair analysis may be helpful to clinicians as a step toward identifying potential health problems that may be associated with toxic metal exposures before significant symptoms are expressed. Further testing should be performed before treatment options are considered. The clinician should be wary of laboratories that perform hair analysis as a vehicle to sell nutritional supplements and should be aware of interlaboratory variation.29 Clinicians are recommended to use only laboratories that can validate their certification or accreditation and incorporate state-of-the-art methodologies for washing, digesting, and analyzing hair specimens.30 Appropriate quality control characteristics and the validation of the establishment of reference ranges, accuracy, precision, and reliability of state-of-the-art hair analysis have been described.31–33
For the most commonly encountered toxic metals, the current standard for diagnosis of metal toxicity is abnormally high concentrations in whole blood or urine. However, blood analysis for toxic metals is a better indicator of exposure than toxicity in most cases. Distribution of metals, such as lead, in the body has been long recognized as initially dependent on the rate of delivery via the blood to various tissues and organs.34 Subsequent redistribution then depends on the relative affinities of tissues for the metals and toxicodynamics, which can vary markedly among individuals. Tissue affinities for metals are determined in large part by the high relative intracellular concentrations of reduced glutathione and metallothionein.35 Further, blood levels can fluctuate considerably with intermittent exposure and assimilation. Thus, as stated by the ATSDR/Centers for Disease Control, the concentration of lead in blood reflects mainly the exposure history of the previous few months and does not necessarily reflect the larger burden and much slower elimination kinetics of lead in bone.9
Examining kinetic models of metal metabolism shows that the blood metal compartment has the shortest biological half-life. Metals leave the blood by excretion (urine, bile, and sweat) and transfer to tissues. The retention by tissues, such as bone, kidneys, and brain, accounts for the much longer biological half-lives of most toxic metals in the body. This simple concept has been obviated in studies presented in the Physician’s Desk Reference.36 Adult and pediatric patients who were diagnosed with lead toxicity on the basis of elevated blood lead values exhibited marked reductions in blood lead levels after chelation therapy with succimer. However, 2 weeks after cessation of chelation, blood lead levels rebounded between 60% to 85% of pretreatment levels (the rebound effect was associated to some degree with all pharmacologic chelators). The relationship between blood lead levels and the quantity of lead excreted in urine after calcium ethylenediaminetetraacetic acid (Ca-EDT) or succimer chelation was nonlinear, in that arithmetic increases in blood lead were associated with exponential increases in lead excretion.1,37
Under extreme conditions of massive accumulation of metals (long-term occupational exposure), the equilibrium between tissue stores and blood can result in blood metal levels that are at or above the established threshold values for the diagnosis of metal toxicity but still do not indicate the extent of total body retention. The current gold standard of blood lead measurement for assessment of lead toxicity in children is disturbing: no minimum response levels have been established for lead because a threshold has yet to be defined for the most sensitive effect of lead neurotoxicity.38
Interestingly, fractionization of blood into the plasma versus red blood cell compartments can provide valuable information to the clinician about the primary sources of exposure to mercury. Approximately 95% of methylmercury, most commonly derived from contaminated fish, is associated with red blood cells,39,40 whereas about 90% of inorganic mercury (amalgams, occupational exposure) is found in the plasma compartment bound to albumin, cysteine, and nonspecific proteins.40 Because the first step in successful detoxification is to remove the source of exposure, documentation of the primary source of exposure to mercury can be instrumental for efficient detoxification. Blood arsenic levels, albeit with a very short half-life (approximately 6 hours), reflect exposure to inorganic arsenic and methylated metabolites of arsenic, but not dietary arsenic (shellfish), which is rapidly excreted in the urine.41,42
The analysis of whole blood, plasma, and red blood cells can provide valuable information about exposure to specific forms of some metals without the need for expensive determination of subspeciation.
In general, and despite the current standards for medical care, urinalysis for toxic metals does not provide a scientifically valid basis for diagnosis of metal toxicity. However, in some cases it provides an indication of recent or ongoing exposure to certain metals.
Such is not the case for lead, because urinary lead is generally not a useful biomarker to estimate low-level exposure to lead. However, elevated urinary lead–chelate complexes resulting from the Ca-EDTA mobilization test provide a good means to assess increased lead retention.9
A different scenario exists for organic arsenic as well as inorganic and organic mercury. The most commonly accepted biomarker for exposure to inorganic mercury is the urinary level of inorganic mercury.43 However, the World Health Organization (WHO) standard for occupational exposure is very high (50 mcg/g creatinine).44 This high standard has been challenged because neurologic impairment has been reported for occupationally exposed subjects45,46 whose urinary mercury levels were well below the WHO standard. Evidence that urinary mercury levels are indicative of exposure to implanted mercury amalgams has also been published.47 In a study of 1127 Vietnam-era veterans reported by the National Institute of Dental Research, a highly statistically significant correlation was detected between the level of amalgam exposure and urinary mercury levels, although mean urinary mercury levels were only about 2 mcg/g creatinine. Several other studies have reported an association between amalgam exposure and urinary mercury levels.48–51 Elevations of urinary arsenic have been detected in workers during periods of occupational exposure, including copper smelting, spraying of insecticides or herbicides, and application of wood treatments.52
Arsenic can be markedly and transiently elevated in individuals within 48 hours after consumption of shellfish that contain high levels of relatively nontoxic species of organic arsenic.53 Urinary mercury is frequently elevated in people who consume high levels of fish.22,54 Therefore, analysis of an unprovoked urine specimen is highly recommended to avoid alarmism and confounding the interpretation of the results of a urinary metals provocation test, and patients should be instructed to abstain from the consumption of fish and shellfish for about a week before a chelation challenge is performed. Elevated urinary values of arsenic and mercury associated with the specific dietary and occupational conditions reflect recent or ongoing high-level exposure, but are not necessarily reflective of the body burden of the specific metals. Although blood metal levels reflect transient transport in the body, urinary levels qualitatively reflect excretion of an unknown fraction of the total body pools of assimilated metals.