PART 14 Poisoning, Drug Overdose, and Envenomation 458 Heavy Metal Poisoning Howard Hu Toxic metals (hereafter referred to simply as “metals”) pose a significant threat to health through low-level as well as high level environmental and occupational exposures. One indication of their importance relative to other potential hazards is their ranking by the U. Agency for Toxic Substances and Disease Registry, which maintains an updated list of all hazards present in toxic waste sites according to their prevalence and the severity of their toxicity. The first, second, third, and seventh hazards on the list are heavy metals: arsenic, lead, mercury, and cadmium, respectively (http://www.
Specific information pertaining to each of these four metals, including sources and metabolism, toxic effects produced, diagnosis, and the appropriate treatment for poisoning, is summarized in Table 458-1. TABLE 458-1 Heavy Metals Metals are inhaled primarily as dusts and fumes (the latter defined as tiny particles generated by combustion). Metal poisoning can also result from exposure to vapors (e., mercury vapor in creating dental amalgams). When metals are ingested in contaminated food or drink or by hand-to-mouth activity (implicated especially in children), their gastrointestinal absorption varies greatly with the specific chemical form of the metal and the nutritional status of the host.
Once a metal is absorbed, blood is the main medium for its transport, with the precise kinetics dependent on diffusibility, protein binding, rates of biotransformation, availability of intracellular ligands, and other factors., bone, liver, and kidney) sequester metals in relatively high concentrations for years. Most metals are excreted through renal clearance and gastrointestinal excretion; some proportion is also excreted through salivation, perspiration, exhalation, lactation, skin exfoliation, and loss of hair and nails. The intrinsic stability of metals facilitates tracing and measurement in biologic material, although the clinical significance of the levels measured is not always clear. Some metals, such as copper and selenium, are essential to normal metabolic function as trace elements (Chap.
333) but are toxic at high levels of exposure. Others, such as lead and mercury, are xenobiotic and theoretically are capable of exerting toxic effects at any level of exposure. Indeed, much research is currently focused on the contribution of low-level xenobiotic metal exposure to chronic diseases and to subtle changes in health that may have significant public health consequences. Genetic factors, such as polymorphisms that encode for variant enzymes with altered properties in terms of metal binding, transport, and effects, also may modify the impact of metals on health and thereby account, at least in part, for individual susceptibility to metal effects.
The most important component of treatment for metal toxicity is the termination of exposure. Chelating agents are used to bind metals into stable cyclic compounds with relatively low toxicity and to enhance their excretion. The principal chelating agents are dimercaprol (British anti-Lewisite [BAL]), ethylenediamine tetraacetic acid (EDTA), succimer (dimercaptosuccinic acid [DMSA]), and penicillamine; their specific use depends on the metal involved and the clinical circumstances. Activated charcoal does not bind metals and thus is of limited usefulness in cases of acute metal ingestion.
In addition to the information provided in Table 458-1, several other aspects of exposure, toxicity, or management are worthy of discussion with respect to the four most hazardous toxicants (arsenic, cadmium, lead, and mercury). Arsenic, even at moderate levels of exposure, has been clearly linked with increased risks for cancer of the skin, bladder, renal pelvis, ureter, kidney, liver, and lung. These risks appear to be modified by smoking, folate and selenium status, genetic traits (such as ability to methylate arsenic), and other factors. Recent studies in community-based populations have generated strong evidence that arsenic exposure is also a risk factor for increased risk of hypertension, coronary heart disease and stroke, lung function impairment, acute respiratory tract infections, respiratory symptoms, hinhanhykhoa.com and nonmalignant lung disease mortality.
The association with cardiovascular disease may hold at levels of exposure in drinking water that are below the World Health Organization (WHO) provisional guideline value of 10 μg/L. Evidence has also continued to build indicating that low-level arsenic is a likely cause of neurodevelopmental delays in children and likely contributes to the development of diabetes. Serious cadmium poisoning from the contamination of food and water by mining effluents in Japan contributed to the 1946 outbreak of “itai-itai” (“ouch-ouch”) disease, so named because of cadmium- induced bone toxicity that led to painful bone fractures. Modest exposures from environmental contamination have been associated in some studies with a lower bone density, a higher incidence of fractures, and a faster decline in height in both men and women, effects that may be related to cadmium’s calciuric and other toxic effects on the kidney.
Cadmium burdens have also been associated with an increased risk of long-term kidney graft failure, and there is evidence for synergy between the adverse impacts of cadmium and lead on kidney function. Environmental exposures have also been linked to lower lung function (even after adjusting for smoking cigarettes, which contain cadmium) as well as increased risk of cardiovascular disease and mortality, stroke, and heart failure. Cadmium triggers pulmonary inflammation, and a recent population- based study of U. adults found that higher cadmium burdens are associated with higher mortality from influenza or pneumonia.
The International Agency for Research on Cancer has classified cadmium as a known carcinogen, with evidence indicating it contributes to elevated risks of prostate, lung, breast, and endometrial cancer. Overall, this growing body of research indicates that cadmium exposure is contributing significantly to morbidity and mortality rates in the general population. Advances in our understanding of lead toxicity have recently benefited by the development of K x-ray fluorescence (KXRF) instruments for making safe in vivo measurements of lead levels in bone, which, in turn, reflect cumulative exposure over many years, as opposed to blood lead levels, which mostly reflect recent exposure. Higher levels of cumulative lead exposure are now known to be a risk factor for chronic disease, even though blood lead levels have continued to decline in the general population over the past few decades following the removal of lead from gasoline, plumbing, solder in food cans, and other consumer products, with mean levels in the U.
population now hovering in the 1–2 μg/dL range. For example, higher bone lead levels measured by KXRF have been linked to increased risk of hypertension and accelerated declines in cognition in both men and women living in urban communities. These relationships, in conjunction with other epidemiologic and toxicologic studies, persuaded a federal expert panel to conclude they were causal. Prospective studies have also demonstrated that higher bone lead levels, as well as blood lead levels as low as 1–7 μg/dL, are a major risk factor for increased cardiovascular morbidity and mortality rates in both community-based and occupational- exposed populations.
Lead exposure at community levels has also been associated with increased risks of hearing loss, Parkinson’s disease, and amyotrophic lateral sclerosis. With respect to pregnancy-associated risks, high maternal bone lead levels were found to predict lower birth weight, head circumference, birth length, and neurodevelopmental performance in offspring by age 2 years. Offspring have also been shown to have higher blood pressures at age 7–14 years, an age range at which higher blood pressures are known to predict an elevated risk of developing hypertension. In a randomized trial, calcium supplementation (1200 mg daily) was found to significantly reduce the mobilization of lead from maternal bone into blood during pregnancy.
The toxicity of low-level organic mercury exposure (as manifested by neurobehavioral performance) is of increasing concern based on studies of the offspring of mothers who ingested mercury- contaminated fish. With respect to whether the consumption of fish by women during pregnancy is good or bad for offspring neurodevelopment, balancing the trade-offs of the beneficial effects of the omega-3-fatty acids (FAs) in fish versus the adverse effects of mercury contamination in fish has led to some confusion and inconsistency in public health recommendations. Overall, it would appear that it would be best for pregnant women to either limit fish consumption to those species known to be low in mercury contamination but high in omega-3-FAs (such as sardines or mackerel) or to avoid fish and obtain omega-3-FAs through supplements or other dietary sources. Accumulated evidence has not supported the contention that ethyl mercury, used as a preservative in multiuse vaccines administered in early childhood, has played a significant role in causing neurodevelopmental problems such as autism.
With regard to adults, there is conflicting evidence as to whether mercury exposure is associated with increased risk of hypertension and cardiovascular disease. There is also some evidence that mercury exposure in the general population is associated with the development of diabetes, perturbations in markers of autoimmunity, and depression. At this point, conclusions cannot be drawn and the clinical significance of these findings remains unclear. Heavy metals pose risks to health that are especially burdensome in selected parts of the world.
For example, arsenic exposure from natural contamination of shallow tube wells inserted for drinking water is a major environmental problem for millions of residents in parts of Bangladesh and Western India. Contamination was formerly considered only a problem with deep wells; however, the geology of this region allows most residents only a few alternatives for potable drinking water. Arsenic contamination of drinking water is also a major problem in China, Argentina, Chile, Mexico, and some regions of the United States (Maine, New Hampshire, Massachusetts). The global campaign to phase out leaded gasoline has had continued success, with only a few countries still remaining (Algeria, Iraq, Yemen, Myanmar, North Korea, and Afghanistan).
However, significant population exposures to lead remain, particularly in the United States with respect to older housing that contains lead paint or that receives drinking water through lead pipes, and there are indications that exposures are beginning to increase again in many low- and middle-income countries due to industrial pollution, electronic waste, and a variety of contaminated consumer products. Populations living in the Arctic have been shown to have particularly high exposures to mercury due to long-range transport patterns that concentrate mercury in the polar regions, as well as the traditional dependence of Arctic peoples on the consumption of fish and other wildlife that bioconcentrate methylmercury. A few additional metals deserve brief mention but are not covered in Table 458-1 because of the relative rarity of their being clinically encountered or the uncertainty regarding their potential toxicities. Aluminum contributes to the encephalopathy in patients with severe renal disease, who are undergoing dialysis (Chap.
High levels of aluminum are found in the neurofibrillary tangles in the cerebral cortex and hippocampus of patients with Alzheimer’s disease, as well as in the drinking water and soil of areas with an unusually high incidence of Alzheimer’s. The experimental and epidemiologic evidence for the aluminum–Alzheimer’s disease link remains relatively weak, however, and it cannot be concluded that aluminum is a causal agent or a contributing factor in neurodegenerative disease. Hexavalent chromium is corrosive and sensitizing. Workers in the chromate and chrome pigment production industries have consistently had a greater risk of lung cancer.
The introduction of cobalt chloride as a fortifier in beer led to outbreaks of fatal cardiomyopathy among heavy consumers., of miners, dry-battery manufacturers, and arc welders) to manganese (Mn) can cause a parkinsonian syndrome within 1–2 years, including gait disorders; postural instability; a masked, expressionless face; tremor; and psychiatric symptoms. With the introduction of methylcyclopentadienyl manganese tricarbonyl (MMT) as a gasoline additive, there is concern for the toxic potential of environmental manganese exposure. Some epidemiologic studies have found an association between the prevalence of parkinsonian disorders and estimated manganese exposures emitted by local ferroalloy industries; others have found evidence suggesting that manganese may interfere with early childhood neurodevelopment in ways similar to that of lead. Manganese toxicity is clearly associated with dopaminergic dysfunction, and its toxicity is likely influenced by age, gender, ethnicity, genetics, and preexisting medical conditions.
Nickel exposure induces an allergic response, and inhalation of nickel compounds with low aqueous solubility (e.