Goodman and Gilman Manual of Pharmacology and Therapeutics

Section IX
Special Systems Pharmacology

chapter 67
Environmental Toxicology: Carcinogens and Heavy Metals

Myriad authoritative textbooks are available in the area of environmental toxicology. This chapter does not attempt a thorough coverage; rather, it sets forth a few basic principles, briefly discusses carcinogens and chemoprevention, and then focuses on the pharmacotherapy of heavy metal intoxication.

ASSESSMENT AND MANAGEMENT OF ENVIRONMENTAL RISK

When assessing the risks of environmental exposures to xenobiotics, one must consider population exposures to low-dose toxicants over long periods of time. Thus, one must give careful attention to the low end of the dose-response curve, using experiments based on chronic exposures. Unlike drugs, which are given to treat a specific disease and should have benefits that outweigh the risks, environmental toxicants usually are only harmful. In addition, exposures to environmental toxicants usually are involuntary, there is uncertainty about the severity of their effects, and people are much less willing to accept their associated risks.

Epidemiology and toxicology are 2 approaches used to predict the toxic effects of environmental exposures. Epidemiologists monitor health effects in humans and use statistics to associate those effects with exposure to an environmental stress, such as a toxicant. Toxicologists perform laboratory studies to try to understand the potential toxic mechanisms of a chemical to predict whether it is likely to be toxic to humans. Information from both approaches is integrated into environmental risk assessment. Risk assessment is used to develop laws and regulations to limit exposures to environmental toxicants to a level that is considered safe.

EPIDEMIOLOGICAL APPROACHES TO RISK ASSESSMENT

Assessing human exposures over long periods of time and drawing conclusions about the health effects of a single toxicant present great challenges. Epidemiologists usefully rely on biomarkers in assessing risk. There are 3 types of biomarkers:

• Biomarkers of exposure usually are measurements of toxicants or their metabolites in blood, urine, or hair. Blood and urine concentrations measure recent exposures, while hair levels measure exposure over a period of months. An example of an unusual exposure biomarker is X-ray fluorescent measurement of bone lead levels, which estimates lifetime exposure to lead.

• Biomarkers of toxicity are used to measure toxic effects at a subclinical level and include measurement of liver enzymes in the serum, changes in the quantity or contents of urine, and performance on specialized exams for neurological or cognitive function.

• Biomarkers of susceptibility are used to predict which individuals are likely to develop toxicity in response to a given chemical. Examples include single nucleotide polymorphisms in genes for metabolizing enzymes involved in the activation or detoxification of a toxicant. Some biomarkers simultaneously provide information on exposure, toxicity, and susceptibility. For example, the measurement in the urine of N7-guanine adducts from aflatoxin B1 provides evidence of both exposure and a toxic effect (in this case, DNA damage). Such biomarkers are valuable because they can support a proposed mechanism of toxicity.

Several types of epidemiological studies are used to assess risks, each with its own set of strengths and weaknesses. Ecological studies correlate frequencies of exposures and health outcomes between different geographical regions. These studies can detect rare outcomes but are prone to confounding variables, including population migration. Cross-sectional studies examine the prevalence of exposures and outcomes at a single point in time. Such studies determine an association but do not provide a temporal relationship and are not effective for establishing causality. Case-control studies start with a group of individuals affected by a disease, which then is matched to another group of unaffected individuals for known confounding variables. Questionnaires often are used to evaluate past exposures. This method also is good for examining rare outcomes because the endpoint is known. However, case-control studies rely on assessments of past exposures that often are unreliable and can be subject to bias.Prospective cohort studies measure exposures in a large group of people and follow that group for a long time to measure health outcomes. These studies are good at establishing causality, but they are extremely expensive, particularly when measuring very rare outcomes, because a large study population is required to observe sufficient disease to obtain statistical significance. One of the key types of human studies used in drug development is the randomized clinical trial (see Chapter 1). Such studies cannot be used to directly measure the effects of environmental toxicants (for obvious ethical reasons) but can be used to examine the effectiveness of an interventional strategy for reducing both exposure to toxicants and disease.

TOXICOLOGICAL APPROACHES TO RISK ASSESSMENT

Toxicologists use model systems, including experimental animals, to examine the toxicity of chemicals and predict their effect on humans. The significance of these model systems to human health is not always established. Toxicologists also test chemicals at the high end of the dose-response curve in order to see enough occurrences of an outcome to obtain statistical significance. As a result, there often is uncertainty about the effects of very low doses of chemicals. To determine the applicability of model studies, toxicologists study the mechanisms involved in the toxic effects of chemicals.

To predict the toxic effects of environmental chemicals, toxicologists perform subchronic (3 months of treatment for rodents) and chronic studies (2 years for rodents) in at least 2 different animal models. Subchronic experiments provide a model for occupational exposures, while chronic experiments are used to predict effects from lifetime exposures to chemicals in food or the environment. Doses are chosen with the goal of having 1 concentration that does not have a significant effect, 1 concentration that results in statistically significant toxicity at the low end of the dose-response curve, and 1 or more concentrations that will have moderate-to-high levels of toxicity. A theoretical dose-response curve for an animal study is shown in Figure 67–1. An animal study provides 2 numbers that estimate the risk from a chemical. The no observed adverse effect level (NOAEL) is the highest dose used that does not result in a statistically significant increase in negative health outcomes. The lowest observed adverse effect level (LOAEL) is the lowest dose that results in a significant increase in toxicity. The NOAEL is divided by 10 for each source of uncertainty to determine a reference dose (RfD), which is commonly used as a starting point for determining regulations on human exposures to chemicals. The modifiers used to determine the RfD are based on the uncertainties between the experimental and human exposure. The most common modifiers used are for interspecies variability (human to animal) and interindividual variability (human to human), in which case RfD = NOAEL/100. When a NOAEL is unavailable, a LOAEL may be used, in which case another 10-fold uncertainty factor is used. The use of factors of 10 in the denominator for determination of RfD is an application of the “precautionary principle,” which attempts to limit human exposure by assuming a worst-case scenario for each unknown variable. Animal studies typically are designed to obtain statistical significance with a 10% increase in an outcome. As a result, there is considerable uncertainty about what occurs below that level, as demonstrated in Figure 67–1. Toxicologists often assume that there is a threshold dose (T), below which there is no toxicity. However, many carcinogens and other toxicants with specific molecular targets (e.g., lead) do not exhibit a threshold. Ideally, mechanistic studies should be done to predict which dose-response curve is most likely to fit a given chemical.

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Figure 67–1 LOAEL and NOAEL. The theoretical dose-response curve from an animal study demonstrates the no observed adverse effect level (NOAEL) and the lowest observed adverse effect level(LOAEL). Below the NOAEL level, there is considerable uncertainty as to the shape of the response curve. It could continue linearly to reach a threshold dose (T) where there would be no harmful effects from the toxicant, or it could have a number of different possible inflection points. Each of these curves would reflect very different effects on human populations. *, statistically significant; BW, body weight.

Toxicologists perform a variety of mechanistic studies to understand how a chemical might cause toxicity. Computer modeling using a compound’s 3-dimensional structure to determine quantitative structure-activity relationships (QSARs) is commonly performed on both drugs and environmental chemicals. QSAR approaches can determine which chemicals are likely to exhibit toxicities or bind to specific molecular targets. Cell-based approaches in prokaryotes and eukaryotes are used to determine whether a compound damages DNA or causes cytotoxicity. DNA damage and the resulting mutagenesis often are determined with the Ames test. The Ames test uses Salmonella typhimurium strains with specific mutations in the gene needed to synthesize histidine. These strains are treated with chemicals in the presence or absence of a metabolic activating system, usually the supernatant fraction from homogenized rat liver. If a compound is a mutagen in the Ames test, it reverts the mutation in the histidine operon and allows the bacteria to form colonies on plates with limited histidine. Gene chip microarrays assess gene expression in cells or tissues from animals treated with a toxicant and provide a very useful tool to identify the molecular targets and pathways altered by toxicant exposures. The susceptibility of knockout mice to a toxicant can help to determine whether the knocked-out genes are involved in the metabolic activation and detoxification of a given toxicant.

CARCINOGENS AND CHEMOPREVENTION

CARCINOGENESIS

The International Agency for Research on Cancer (IARC) classifies compounds into groups based on risk assessments using human, animal, and mechanism data. Chemicals in group 1 are known human carcinogens; group 2A includes chemicals that probably are carcinogenic in humans; group 2B chemicals possibly are carcinogenic in humans; group 3 chemicalslack data to suggest a role in carcinogenesis; and group 4 are those with data indicating they are unlikely to be carcinogens. Table 67–1 presents information of some Group 1 carcinogens.

Table 67–1

Examples of Important Carcinogensa

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The transformation of a normal cell to a malignancy is a multi-stage process, and exogenous chemicals can act at 1 or more of these stages (Figure 67–2). A classic model of chemical carcinogenesis is tumor initiation followed by tumor promotion. A tumor initiator causes gene mutations that increase the ability of cells to proliferate and avoid apoptosis. A tumor promoter does not directly modify genes but changes signaling pathways and/or the extracellular environment to cause initiated cells to proliferate. Although this model is an oversimplification, it demonstrates the types of changes that must occur to transit a normal cell into tumorigenesis.

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Figure 67–2 Carcinogenesis: initiation and promotion. There are many steps that occur between the exposure to a genotoxic carcinogen and the development of cancer. Processes in red lead to the development of cancer, while those in green reduce the risk. Non-genotoxic carcinogens act by enhancing steps leading to cancer and/or inhibiting protective processes. A chemopreventive agent acts by inhibiting steps leading to cancer or by increasing protective processes.

Chemical carcinogens cause cancer through genotoxic and non-genotoxic mechanisms (Figure 67–2). Genotoxic carcinogens induce tumor formation through damage to DNA. Typically, genotoxic carcinogens undergo metabolism in a target tissue to a reactive intermediate. This reactive intermediate can directly damage DNA via covalent reaction to form a DNA adduct. Alternatively, it can indirectly damage DNA through the formation of reactive oxygen species (ROS), which can oxidize DNA or form lipid peroxidation products that react with DNA. If DNA damage from a genotoxic carcinogen is not repaired prior to DNA replication, a mutation can result. If this mutation is in a key tumor suppressor gene or proto-oncogene, it provides advantages in proliferation or survival. Alternatively, if the mutation is in a DNA repair gene, the mutation increases the probability that other mutations will occur. Genotoxic carcinogens are tumor initiators.

Benzo[a]pyrene, a key carcinogen in tobacco smoke, is an example of a genotoxic carcinogen that forms both direct DNA adducts and ROS. Benzo[a]pyrene is oxidized by CYPs to a 7,8-dihydrodiol, which represents a proximate carcinogen (a more carcinogenic metabolite). This metabolite can either undergo a second oxidation step by a CYP to form a diol epoxide, which readily reacts with DNA, or it can undergo oxidation by aldo-keto reductases to form a catechol, which will redox cycle to form ROS.

Non-genotoxic carcinogens increase the incidence of cancer without damaging DNA. Many non-genotoxic carcinogens bind to receptors that stimulate proliferation or other tumor-promoting effects, such as tissue invasion or angiogenesis. For example, phorbol esters mimic diacylglycerol and activate PKC isoforms. This in turn stimulates MAP kinase pathways, leading to proliferation, invasiveness, and angiogenesis (see Chapter 3). In most normal cells, prolonged activation of this pathway stimulates apoptosis, but cells with defective apoptotic mechanisms due to preceding mutation(s) are resistant to this effect. Estrogenic carcinogens activate estrogen receptor-α (ERα) and stimulate proliferation and invasiveness of estrogen responsive cells. Chronic inflammation is another mechanism of non-genotoxic carcinogenesis. Inflammatory cytokines stimulate PKC signaling, leading to proliferation, invasiveness, and angiogenesis. Irritants such as asbestos are examples of carcinogens that work through inflammation. Chronic exposure to hepatotoxic chemicals (or chronic liver diseases) also causes non-genotoxic carcinogenesis by stimulating compensatory proliferation to repair the liver damage. This damage and repair process increases the likelihood of DNA damage becoming a mutation, causes chronic inflammation, and selects for cells that proliferate faster or are less sensitive to apoptosis.

Tumor initiation also may occur through non-genotoxic mechanisms. For example, some heavy metals do not directly react with DNA but interfere with proteins involved in DNA synthesis and repair, increasing the likelihood that an error will be made during replication. Non-genotoxic carcinogens also can cause heritable changes to gene expression by altering the methylation state of cytosines in 5’-CpG-3 islands of gene promoters, thus acting as tumor initiators. Methylation can silence tumor suppressor genes, while demethylation of protooncogenes can increase their expression.

CHEMOPREVENTION

Drugs that interfere with the carcinogenic process to prevent cancer before it is diagnosed are termed chemopreventive agents. Chemoprevention strategies often are based on epidemiological studies of nutrition, where there are many examples of clear protective effects of plant-based foods and drinks on the incidence of various types of cancer. A number of compounds for the prevention of cancer are in clinical trials (Table 67–2). There currently are no drugs approved for chemoprevention of environmental carcinogenesis, but there are approved drugs to prevent carcinogenesis due to endogenous estrogen (tamoxifen and raloxifene) and viruses (hepatitis B and human papillomavirus vaccines).

Table 67–2

Chemopreventive Agents Being Studied in Humans

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Chemopreventive agents interfere with the processes of initiation and promotion (see Figure 67–2). One mechanism of anti-initiation is prevention of carcinogen activation. Isothiocyanates and similar compounds inhibit CYPs involved in activating many carcinogens and also upregulate genes controlled by the antioxidant response element (ARE); the ARE-responsive group includes γ-glutamylcysteine synthase light chain (the gene responsible for the rate-determining step in GSH synthesis) and quinone reductase (NQO1). Increased expression of ARE-regulated genes is predicted to increase the detoxification of proximate carcinogens. Isothiocyanates also stimulate apoptosis of p53-deficient cells via the formation of cytotoxic DNA adducts. Compounds that act as antioxidants may provide protection because many carcinogens work through the generation of ROS. Some compounds simultaneously prevent carcinogen activation and act as antioxidants. For example, flavonoids and other polyphenols found in a wide variety of plants are potent antioxidants that inhibit CYPs and induce expression of ARE-regulated genes. Chlorophyll and other compounds can protect against carcinogens by binding to or reacting with carcinogens or their metabolites and prevent them from reaching their molecular target.

Inflammation is a potential target for chemoprevention through interference with promotion. The COX-2 inhibitor celecoxib has demonstrated efficacy at reducing the risk of colorectal cancer. However, this benefit was offset by an increased risk of death due to cardiovascular events, forcing the early termination of the trial. Studies examining long-term treatment with aspirin for cardiovascular benefits found that aspirin also reduces the incidence of colorectal adenomas. Natural compounds, such as α-tocopherol, also can exert chemoprevention by reducing inflammation.

One successful approach to chemoprevention is modification of nuclear receptor signaling. Promising preliminary data suggested that retinoids might be beneficial for preventing lung and other cancers. The selective ER modulators tamoxifen and raloxifene reduce the incidence of breast cancer in high-risk women and are approved for chemoprevention in these patients.

AFLATOXIN B1. Promising agents are being developed as chemopreventants of hepatocarcinogenesis mediated by aflatoxin B1. Aflatoxins are produced by Aspergillus flavus, a fungus that is a common contaminant of foods, especially corn, peanuts, cottonseed, and tree nuts. A. flavus is abundant in regions with hot and wet climates.

ADME. Aflatoxin B1 is readily absorbed from the GI tract and initially distributed to the liver, where it undergoes extensive first-pass metabolism. Aflatoxin B1 is metabolized by CYPs, including 1A2 and 3A4, to yield either an 8,9-epoxide or products hydroxylated at the 9 position (aflatoxin M1) or 3 position (aflatoxin Q1Figure 67–3). The hydroxylation products are less susceptible to epoxidation and are therefore detoxification products. The 8,9-epoxide is highly reactive toward DNA and is the reactive intermediate responsible for aflatoxin carcinogenesis. The 8,9-epoxide is short lived and undergoes detoxification via nonenzymatic hydrolysis or conjugation with GSH. Aflatoxin M1 enters the circulation and is excreted in urine and milk. Hydroxylated aflatoxin metabolites also can undergo several additional phase 1 and phase 2 metabolic pathways prior to excretion in urine or bile.

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Figure 67–3 Metabolism and actions of aflatoxin B1. Following ingestion and absorption of food containing A. flavus, aflatoxin B1 undergoes activation by CYPs to its 8,9-epoxide, which can be detoxified by glutathione S-transferases (GSTs) or by spontaneous hydration. Alternatively, it can react with cellular macromolecules such as DNA and protein, leading to toxicity and cancer. Oltipraz, green tea polyphenols (GTPs), and isothiocyanates (ITCs) decrease aflatoxin carcinogenesis by inhibiting the CYPs involved aflatoxin activation and increasing the synthesis of GSH for GSTs involved in detoxification.

Toxicity. Aflatoxin B1 primarily targets the liver, although it also is toxic to the GI tract and hematological system. High-dose exposures result in acute necrosis of the liver, leading to jaundice and, in many cases, death. Acute toxicity from aflatoxin is relatively rare in humans and requires consumption of milligram quantities of aflatoxin per day for multiple weeks. Chronic exposure to aflatoxins results in cirrhosis of the liver and immunosuppression.

Carcinogenicity. Based on increased incidence of hepatocellular carcinoma in humans exposed to aflatoxin and supporting animal data, IARC has classified aflatoxin B1 and several other natural aflatoxins as known human carcinogens (group 1). Aflatoxin exposure and hepatitis B virus work synergistically to cause hepatocellular carcinoma. Separately, aflatoxin or hepatitis B exposure increases the risk of hepatocellular carcinoma 3.4- or 7.3-fold, respectively; those exposed to both have a 59-fold increased risk of cancer compared to unexposed individuals. Aflatoxin primarily forms DNA adducts at deoxyguanosine residues, reacting at either the N1 or N7 position. The N7-guanine adduct mispairs with adenine, leading to G → T transversions. Human aflatoxin exposure is associated with hepatocellular carcinomas bearing an AGG to AGT mutation in codon 249 of the p53 tumor suppressor gene, resulting in the replacement of an arginine with cysteine.

The interaction between aflatoxin and hepatitis B that is responsible for the increased incidence of hepatocellular carcinoma is not well understood. Hepatitis B influences the metabolism of aflatoxin B1 by upregulating CYPs, including 3A4, and decreasing glutathione S-transferase activity. In addition, hepatocellular proliferation to repair damage done by hepatitis B infection increases the likelihood that aflatoxin-induced DNA adducts will cause mutations. The hepatotoxic and tumor-promoting effects of hepatitis B also could provide a more favorable environment for the proliferation and invasion of initiated cells.

Chemoprevention of Aflatoxin-Induced Hepatocellular Carcinoma. Inhibiting CYP activity or increasing glutathione conjugation will reduce the intracellular concentration of the 8,9-epoxide and thus prevent DNA adduct formation. One drug that has been tested as a modifier of aflatoxin metabolism is oltipraz. Oltipraz, an anti-schistosomal drug, potently inhibits CYPs and induces genes regulated by the ARE. Oltipraz increases the excretion of aflatoxin N-acetylcysteine, indicating enhanced glutathione conjugation of the epoxide. At 500 mg/wk, oltipraz reduced the levels of aflatoxin M1, consistent with inhibition of CYP activity.

Green tea polyphenols also have been used to modify aflatoxin metabolism in exposed human populations. Individuals receiving a daily dose of 500 or 1000 mg (equivalent to 1 or 2 L of green tea) demonstrated a small decline in the formation of aflatoxin–albumin adducts and a large increase in the excretion of aflatoxin N-acetylcysteine, consistent with a protective effect.

Another approach used for the chemoprevention of aflatoxin hepatocarcinogenesis is the use of “interceptor molecules.” Chlorophyllin, an over-the-counter mixture of water-soluble chlorophyll salts, binds tightly to aflatoxin in the GI tract, forming a complex that is not absorbed. In vitro, chlorophyllin inhibits CYP activity and acts as an antioxidant. In a phase 2 trial, administration of 100 mg of chlorophyllin with each meal reduced aflatoxin–N7-guanine adduct levels in the urine by >50%. Because of the strong interaction between hepatitis B and aflatoxin in carcinogenesis, the hepatitis B vaccine will reduce the sensitivity of people to the induction of cancer by aflatoxin. Primary prevention of aflatoxin exposure through hand or fluorescent sorting of crops to remove those with fungal contamination can also reduce human exposure. A more cost-effective primary prevention approach is to improve food storage to limit the spread of A. flavus, which requires a warm and humid environment.

METALS

Arsenic, lead, and mercury are the top 3 substances of concern due to their toxicity and likelihood of human exposure as listed under the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA, also known as Superfund).

Many of the toxic metals in the environment also are carcinogens (Table 67–3). In addition, several essential metals also are toxic under conditions of overdose. Copper and especially iron are associated with toxicities, primarily targeting the liver through generation of ROS.

Table 67–3

Toxic Metals with Frequent Environmental or Occupational Exposurea

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Not listed in Table 67–3 is the metal gold, which has its own uses and toxicities. Among heavy metals, perhaps only gold is addictive: gold has been used for centuries for relief of the itching palm, and many cannot get enough of its influence.

LEAD. Chronic exposure of populations to even very low levels of lead (Pb) has major deleterious effects that are only now beginning to be understood.

Exposure. Until late in the 20th century, the potential for exposure to Pb was high. In the U.S., paint containing Pb for use in and around households was banned in 1978, while the use of tetraethyl lead in gasoline was eliminated in 1996. Despite these bans, past use of lead carbonate and lead oxide in paint and tetraethyl lead in gasoline remain the primary sources of Pb exposure. Pb is not degradable and remains throughout the environment in dust, soil, and the paint of older homes. Young children often are exposed to lead by nibbling sweet-tasting paint chips or eating dust and soil in and around older homes. Renovation or demolition of older buildings may cause substantial Pb exposure. Removal of Pb from gasoline caused Pb levels in air pollution to drop by >90% between 1982 and 2002. Acidic foods and beverages dissolve Pb when stored in containers with Pb in their glaze or lead-soldered cans. Pb exposure also has been traced to other sources such as lead toys, non-Western folk medicines, cosmetics, retained bullets, artists’ paint pigments, ashes and fumes from painted wood, jewelers’ wastes, home battery manufacture, and lead type. The CDC recommends screening of children at 6 months of age and the use of aggressive Pb abatement for children with blood Pb levels >10 μg/dL.

Chemistry and Mode of Action. Divalent lead is the primary environmental form; inorganic tetravalent Pb compounds are not naturally found. Organo-Pb complexes primarily occur with tetravalent Pb and include the gasoline additive tetraethyl lead. Pb toxicity results from molecular mimicry of other divalent metals, principally zinc and calcium. Because of its size and electron affinity, Pb alters protein structure and can inappropriately activate or inhibit protein function.

Absorption, Distribution, and Excretion. Pb exposure occurs through ingestion or inhalation. Children absorb a much higher percentage of ingested Pb (~40% on average) than adults (<20%). Absorption of ingested Pb is drastically increased by fasting. Dietary calcium or iron deficiencies increase Pb absorption, suggesting that Pb is absorbed through divalent metal transporters. The absorption of inhaled Pb generally is much more efficient (~90%). Tetraethyl Pb is readily absorbed through the skin; transdermal absorption is not a route of exposure for inorganic Pb.

About 99% of Pb in the bloodstream binds to hemoglobin. Pb initially distributes in the soft tissues, particularly in the tubular epithelium of the kidney and the liver. Over time, Pb is redistributed and deposited in bone, teeth, and hair. About 95% of the adult body burden of Pb is found in bone. Growing bones will accumulate higher levels of Pb and can form lead lines visible by radiography. Bone Pb is very slowly reabsorbed into the bloodstream. Small quantities of Pb accumulate in the brain. Pb readily crosses the placenta. Pb is excreted primarily in the urine. The concentration of Pb in urine is directly proportional to its concentration in plasma. Pb is excreted in milk and sweat and deposited in hair and nails. The serum t1/2 of Pb is 1-2 months, with a steady state achieved in ~6 months. Pb accumulates in bone, where its t1/2 is estimated at 20-30 years.

Health Effects. The nervous, hematological, cardiovascular, and renal systems are the most sensitive.

Neurotoxic Effects. The biggest concerns with low-level Pb exposure are cognitive delays and behavior changes in children. Pb interferes with the pruning of synapses, neuronal migration, and the interactions between neurons and glial cells. Together, these alterations in brain development result in decreased IQ, poor performance on exams, and behavioral problems such as distractibility, impulsivity, short attention span, and inability to follow even simple sequences of instructions. Because different areas of the brain mature at different times, the neurobehavioral changes vary between children, depending on the timing of the Pb exposure. Children with very high Pb levels (>70 μg/dL) are at risk for encephalopathy. Symptoms of lead-induced encephalopathy include lethargy, vomiting, irritability, anorexia, and vertigo, which can progress to ataxia, delirium, and eventually coma and death. Mortality rates for lead-induced encephalopathy are ~25%, and most survivors develop long-term sequelae such as seizures and severe cognitive deficits.

Encephalopathy in adults requires blood Pb levels >100 μg/dL. The symptoms are similar to those observed with children. Pb induces degeneration of motor neurons, usually without affecting sensory neurons. Studies in older adults have shown associations between Pb exposure and decreased performance on cognitive function tests. The neurodevelopmental effects of Pb primarily result from inhibition of Ca2+ transporters and channels and altered activities of Ca2+ responsive proteins, including PKC and calmodulin. These actions limit the normal activation of neurons caused by Ca2+ release and cause inappropriate production and/or release of neurotransmitters. At high concentrations, lead causes disruption of membranes, including the blood-brain barrier, increasing their permeability to ions. This effect is likely responsible for encephalopathy.

Cardiovascular and Renal Effects. Elevated blood pressure is a lasting effect of lead exposure. Lead exposure also is associated with an increased risk of death due to cardiovascular and cerebrovascular disease. In the kidney, even low-level Pb exposure (blood levels <10 μg/dL) depresses glomerular filtration. Higher levels (>30 μg/dL) cause proteinuria and impaired transport, while very high levels (>50 μg/dL) cause permanent physical damage, including proximal tubular nephropathy and glomerulosclerosis. The cardiovascular effects of Pb are thought to involve the production of ROS through an unknown mechanism. Pb also forms inclusion bodies with various proteins, including metallothionein, in the kidney. The formation of these bodies essentially chelates the Pb and appears to be protective.

Hematological Effects. Chronic Pb intoxication is associated with hypochromic microcytic anemia, which is observed more frequently in children and is morphologically similar to Fe-deficient anemia. The anemia is thought to result from both decreased erythrocyte life span and inhibition of several enzymes involved in heme synthesis, which is observed at very low lead levels (see Figures 67–4 and 67–5). Pb also causes both immunosuppression and increased inflammation, primarily through changes in helper T-cell and macrophage signaling.

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Figure 67–4 Actions of lead on heme biosynthesis.

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Figure 67–5 Blood levels of lead and manifestations of in children and adults. δ-ALA, δ-aminolevulinate.

GI Effects. Pb affects the smooth muscle of the gut, producing intestinal symptoms that are an early sign of high-level exposure to the metal. The abdominal syndrome often begins with a persistent metallic taste, mild anorexia, muscle discomfort, malaise, headache, and constipation (or occasionally, diarrhea). As intoxication advances, symptoms worsen and include intestinal spasms and pain (lead cholic). Intravenous calcium gluconate can relieve this pain.

Carcinogenesis. IARC recently upgraded Pb to “probably carcinogenic in humans” (group 2A). Epidemiological studies have shown associations between lead exposure and cancers of the lung, brain, kidney, and stomach. Rodents exposed to Pb develop kidney tumors, and some rats develop gliomas. Pb is not mutagenic but increases clastogenic events. Pb carcinogenesis may result from inhibition of DNA binding zinc-finger proteins, including those involved in DNA repair and synthesis. Pb is a good example of a non-genotoxic carcinogen.

Treatment. The most important response to Pb poisoning is removal of the source of exposure. Supportive measures should be undertaken to relieve symptoms. Chelation therapy is warranted for children and adults with high blood Pb levels (>45 μg/dL and >70 μg/dL, respectively) and/or acute symptoms of Pb poisoning. Although chelation therapy is effective at lowering blood Pb levels and relieving immediate symptoms, it does not reduce the chronic effects of Pb beyond the benefit of abatement alone.

MERCURY. Mercury (Hg) has been used industrially since ancient Greece due to its capacity to amalgamate with other metals. Mercury also was used as a therapeutic drug for several centuries. Its use for the treatment of syphilis inspired Paracelsus’s observation that “the dose makes the poison,” one of the central concepts of toxicology, and also gave rise to the cautionary expression, “A night with Venus, a year with Mercury.” The phrase “mad as a hatter” originated from the exposure of hatters to metallic Hg vapor during production of felt for hats using mercury nitrate.

Exposure. Hg vapor is released naturally into the environment through volcanic activity and off-gassing from soils. Hg also enters the atmosphere through human activities such as combustion of fossil fuels. Once in the air, metallic mercury is photo-oxidized to inorganic mercury, which can then be deposited in aquatic environments in rain. Microorganisms can then conjugate inorganic mercury to form methyl mercury. Methyl mercury concentrates in lipids and will bioaccumulate up the food chain so that concentrations in aquatic organisms at the top of the food chain, such as swordfish or sharks, are quite high (Figure 67–6).

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Figure 67–6 Mobilization of mercury in the environment. Metallic mercury (Hg0) is vaporized from the Earth’s surface both naturally and through human activities such as burning coal. In the atmosphere, Hg0 is oxidized to form divalent inorganic mercury (Hg2+), which falls to the surface in rain. Aquatic bacteria can methylate Hg2+ to form methyl mercury (MeHg+). MeHg+ in plankton is consumed by fish. Because of its lipophilicity, MeHg+ bioaccumulates up the food chain.

The primary source of exposure to metallic Hg in the general population is vaporization of Hg in dental amalgam. There also is limited exposure through broken thermometers and other Hg-containing devices. Human exposure to organic Hg primarily is through the consumption of fish. Workers are exposed to metallic and inorganic mercury, most commonly though exposure to vapors. The highest risk for exposure is in the chloralkali industry (i.e., bleach) and in other chemical processes in which Hg is used as a catalyst. Hg is a component of many devices, including alkaline batteries, fluorescent bulbs, thermometers, and scientific equipment, and exposure occurs during the production of these devices. Dentists also are exposed to Hg from amalgam. Hg can be used to extract gold during mining. Mercuric salts are used as pigments in paints.

Thimerosal is an antimicrobial agent used as a preservative in some vaccines. Its use is controversial because it releases ethyl mercury, which is chemically similar to methyl mercury. Some have argued that thimerosal might contribute to autism; however, studies have not found an association between thimerosal use in vaccines and negative health outcomes. Nonetheless, with the exception of some influenza (flu) vaccines, thimerosal is no longer used as a preservative in routinely recommended childhood vaccines.

Chemistry and Mode of Action. There are 3 general forms of Hg of concern to human health. Metallic, or elemental, mercury (Hg0) is the liquid metal found in thermometers and dental amalgam; it is quite volatile, and exposure is often to the vapor. Inorganic mercury can be either monovalent (mercurous, Hg1+) or divalent (mercuric, Hg2+) and forms a variety of salts. Organic mercury compounds consist of divalent mercury complexed with 1 or occasionally 2 alkyl groups. The organic mercury compound of most concern is methyl mercury (MeHg+), which is formed environmentally from inorganic Hg by aquatic microorganisms. Both Hg2+ and MeHg+ readily form covalent bonds with sulfur, an interaction that accounts for most of the biological effects of mercury. At very low concentrations, Hg reacts with sulfhydryl residues on proteins and disrupts their functions. There also may be an autoimmune component to Hg toxicity.

ADME. Hg0 vapor is readily absorbed through the lungs (~70-80%), but GI absorption of elemental (liquid) Hg is negligible. Absorbed Hg0 distributes throughout the body and crosses membranes such as the blood-brain barrier and the placenta via diffusion. Hg0 is oxidized by catalase in the erythrocytes and other cells to form Hg2+. Some Hg0 is eliminated in exhaled air. After a few hours, distribution and elimination of Hg0 resemble the properties of Hg2+. Hg0 vapor also is oxidized to Hg2+ and retained in the brain.

GI absorption of Hg salts averages ~10-15% but varies with the individual patient and the particular salt. Hg1+ will form Hg0 or Hg2+ in the presence of sulfhydryl groups. Hg2+ primarily is excreted in the urine and feces; a small amount also can be reduced to Hg0 and exhaled. With acute exposure, the fecal pathway predominates, but following chronic exposure, urinary excretion becomes more important. All forms of Hg also are excreted in sweat and breast milk and deposited in hair and nails. The t1/2 for inorganic Hg is ~1-2 months. Orally ingested MeHg+ is almost completely absorbed from the GI tract. MeHg+ readily crosses the blood-brain barrier and the placenta and distributes fairly evenly to the tissues, although concentrations are highest in the kidneys. MeHg+ can be demethylated to form inorganic Hg2+. The liver and kidney exhibit the highest rates of demethylation, but this also occurs in the brain. MeHg+ is excreted in the urine and feces, with the fecal pathway dominating. The t1/2 for MeHg+ is 2 months. Complexes between MeHg+ and cysteine resemble methionine and can be recognized by transporters for that amino acid and taken across membranes.

Health Effects

Metallic Mercury. Inhalation of high levels of Hg vapor over a short duration is acutely toxic to the lung. Respiratory symptoms start with cough and tightness in the chest and can progress to interstitial pneumonitis and severely compromised respiratory function. Other initial symptoms include weakness, chills, metallic taste, nausea, vomiting, diarrhea, and dyspnea. Acute exposure to high doses of Hg also is toxic to the CNS (Figure 67–7).

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Figure 67–7 Concentrations of mercury in air and urine are associated with specific toxic effects.

Toxicity to the nervous system is the primary concern with chronic exposure to Hg vapor. Symptoms include tremors (particularly of the hands), emotional lability (irritability, shyness, loss of confidence, and nervousness), insomnia, memory loss, muscular atrophy, weakness, paresthesia, and cognitive deficits. These symptoms intensify and become irreversible, with increases in duration and concentration of exposure. Other common symptoms of chronic Hg exposure include tachycardia, labile pulse, severe salivation, gingivitis, and kidney damage.

Inorganic Salts of Mercury. Ingestion of Hg2+ salts is intensely irritating to the GI tract, leading to vomiting, diarrhea, and abdominal pain. Acute exposure to Hg2+ salts (typically in suicide attempts) leads to renal tubular necrosis, resulting in decreased urine output and often acute renal failure. Chronic exposures also target the kidney.

Organic Mercury. The CNS is the primary target of methyl mercury toxicity. Symptoms of methyl mercury exposure include visual disturbances, ataxia, paresthesia, fatigue, hearing loss, slurring of speech, cognitive deficits, muscle tremor, movement disorders, and, following severe exposure, paralysis and death. Children exposed in utero can develop severe symptoms, including mental retardation and neuromuscular deficits, even in the absence of symptoms in the mother.

Treatment. With exposure to metallic Hg, termination of exposure is critical and respiratory support may be required. Emesis may be used within 30-60 min of exposure to inorganic Hg, provided the patient is awake and alert and there is no corrosive injury. Maintenance of electrolyte balance and fluids is important for patients exposed to inorganic Hg. Chelation therapy is beneficial in patients with acute inorganic or metallic Hg exposure. There are limited treatment options for methyl mercury. Chelation therapy does not provide clinical benefits, and several chelators potentiate the toxic effects of methyl mercury. Nonabsorbed thiol resins may be beneficial by preventing reabsorption of methyl mercury from the GI tract.

Because of the conflicting effects of mercury and ω-3 fatty acids, there is considerable controversy regarding the restriction of fish intake in women of reproductive age and children. The EPA recommends limiting fish intake to 12 oz (2 meals) per week. Many experts feel this recommendation is too conservative, and the FDA is considering revising their recommendation to state that the benefits of fish consumption outweigh the risks. The recommendation that women consume fish that is lower in Hg content (i.e., canned light tuna, salmon, pollock, catfish) and avoid top predators, such as swordfish, shark, and tilefish, is not controversial.

ARSENIC. Arsenic (As) is a metalloid that is common in rocks and soil. The use of arsenic in drugs has been mostly phased out, but arsenic trioxide (ATO) is still used as an effective chemotherapy agent for acute promyelocytic leukemia (see Chapter 61).

Exposure. The primary source of exposure to As is through drinking water. Levels of As in drinking water average 2 μg/L (ppb) in the U.S. but can be >50 μg/L (5 times the EPA standard) in private well water, particularly in California, Nevada, and Arizona. Drinking water from other parts of the world sometimes is contaminated with much higher levels of As (sometimes several hundred μg/L), and widespread poisonings have resulted (see Figure 67–8 in the 12th edition of the parent text). Arsenic can enter the environment through the use of arsenic-containing pesticides, mining, and burning of coal. Food, particularly seafood, often is contaminated with As. The average daily human intake of As is 10 μg/day, almost exclusively from food and water.

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Figure 67–8 Metabolism of arsenic. AS3MT, arsenite methyltransferase; DMAV, dimethylarsinic acid; GSH, reduced glutathione; GSSG, oxidized glutathione; MMAIII, monomethylarsonous acid; MMAV, monomethylarsonic acid; SAH, S-adenosyl-L-homocysteine; SAM, S-adenosyl-L-methionine.

Before 2003, >90% of As used in the U.S. was as a preservative in pressure-treated wood, but the lumber industry has voluntarily replaced As with other preservatives. As-treated wood is thought to be safe unless burned. The major source of occupational exposure to As is in the production and use of organic arsenicals as herbicides and insecticides. Exposure to metallic As, arsine, arsenic trioxide, and gallium arsenide also occurs in high-tech industries, such as the manufacture of computer chips and semiconductors.

Chemistry and Mode of Action. Arsenic exists in its elemental form and trivalent (arsenites/arsenious acid) and pentavalent (arsenates/As acid) states. Arsine is a gaseous hydride of trivalent As that exhibits toxicities that are distinct from other forms. The toxicity of a given arsenical is related to the rate of its clearance from the body and its ability to concentrate in tissues. In general, toxicity increases in the sequence: organic arsenicals < As5+ < As3+ < arsine gas (AsH3). Like mercury, trivalent arsenic compounds form covalent bonds with sulfhydryl groups. The pyruvate dehydrogenase system is particularly sensitive to inhibition by trivalent arsenicals because the 2 sulfhydryl groups of lipoic acid react with As to form a 6-membered ring. Inorganic arsenate (pentavalent) inhibits the electron transport chain. It is thought that arsenate competitively substitutes for phosphate during the formation of ATP, forming an unstable arsenate ester that is rapidly hydrolyzed.

ADME. Poorly water-soluble forms such as arsenic sulfide, lead arsenate, and arsenic trioxide are not well absorbed. Water-soluble As compounds are readily absorbed from both inhalation and ingestion. GI absorption of As dissolved in drinking water is >90%. At low doses, As is fairly evenly distributed throughout the tissues of the body. Nails and hair, due to their high sulfhydryl content, exhibit high concentrations of As. After an acute high dose (i.e., fatal poisoning), As is preferentially deposited in the liver and, to a lesser extent, kidney, with elevated levels also observed in the muscle, heart, spleen, pancreas, lungs, and cerebellum. Arsenic readily crosses the placenta and blood-brain barrier.

Arsenic undergoes biotransformation in humans and animals (see Figure 67–8). Trivalent compounds can be oxidized to pentavalent compounds, but there is no evidence for demethylation of methylated arsenicals. Humans excrete much higher levels of monomethyl-As (MMA) compounds than most other animals. The trivalent methylated arsenicals are more toxic than inorganic arsenite, due to an increased affinity for sulfhydryl groups; formation of MMAIII now is considered a bioactivation pathway. Elimination of arsenicals by humans primarily is in the urine, although some is also excreted in feces, sweat, hair, nails, skin, and exhaled air. Compared to most other toxic metals, arsenic is excreted quickly (t1/21-3 days). In humans, ingested inorganic As in urine is a mixture of 10-30% inorganic arsenicals, 10-20% monomethylated forms, and 60-80% dimethylated forms.

Health Effects. With the exception of arsine gas, the various forms of inorganic As exhibit similar toxic effects. Inorganic As exhibits a broad range of toxicities and has been associated with effects on every organ system tested. Acute exposure to large doses of As (>70-180 mg) often is fatal. Death immediately following arsenic poisoning typically is the result of its effects on the heart and GI tract. Death sometimes occurs later as a result of As’s combined effect on multiple organs.

Cardiovascular System. Acute and chronic As exposure cause myocardial depolarization, cardiac arrhythmias, and ischemic heart disease; these are known side effects of As trioxide for the treatment of leukemia. Chronic exposure to As causes peripheral vascular disease, the most dramatic example of which is “blackfoot disease,” a condition characterized by cyanosis of the extremities, particularly the feet, progressing to gangrene. Arsenic dilates capillaries and increases their permeability, causing edema, an effect likely responsible for peripheral vascular disease following chronic exposure.

Skin. Dermal symptoms often are diagnostic of As exposure. Arsenic induces hyperkeratinization of the skin (including formation of multiple corns or warts), particularly of the palms of the hands and the soles of the feet. It also causes areas of hyperpigmentation interspersed with spots of hypopigmentation. These symptoms can be observed in individuals exposed to drinking water with As concentrations of at least 100 μg/L and are typical in those chronically exposed to much higher levels. Hyperpigmentation can be observed after 6 months of exposure; hyperkeratinization takes years. Children are more likely to develop these effects than adults.

GI Tract. Acute or subacute exposure to high-dose As by ingestion causes GI symptoms ranging from mild cramping, diarrhea, and vomiting to GI hemorrhaging and death. GI symptoms are caused by increased capillary permeability, leading to fluid loss. At higher doses, fluid forms vesicles that can burst, leading to inflammation and necrosis of the submucosa and then rupture of the intestinal wall. GI symptoms are not observed with chronic exposure to lower levels of As.

Nervous System. The most common neurological effect of acute or subacute As exposure is peripheral neuropathy involving both sensory and motor neurons. This effect is characterized by the loss of sensation in the hands and feet, often followed by muscle weakness. Neuropathy occurs several days after exposure and can be reversible following cessation of exposure, although recovery usually is not complete. Arsenic exposure may cause intellectual deficits in children. Acute high-dose As exposure causes encephalopathy in rare cases, with symptoms that can include headache, lethargy, mental confusion, hallucination, seizures, and coma.

Other Non-Cancer Toxicities. Acute and chronic As exposures induce anemia and leukopenia, likely via direct cytotoxic effects on blood cells and suppression of erythropoiesis. Arsenic also may inhibit heme synthesis. and cause fatty infiltrations, central necrosis, and cirrhosis in the liver. Arsenic can cause severe kidney damage. Inhaled As is irritating to the lungs; ingested As may induce bronchitis progressing to bronchopneumonia in some individuals. Chronic exposure to As is associated with an increased risk of diabetes.

Carcinogenesis. In regions with very high As levels in drinking water, there are substantially higher rates of skin cancer, bladder cancer, and lung cancer. There also are associations between As exposure and other cancers, including liver, kidney, and prostate tumors. IARC classifies arsenic as “carcinogenic to humans (group 1).” Humans exposed to As in utero and in early childhood have an elevated risk of lung cancer.

Arsenic does not directly damage DNA; rather, As is thought to work through changes in gene expression, DNA methylation, inhibition of DNA repair, generation of oxidative stress, and/or altered signal transduction pathways. In humans, exposure to As potentiates lung tumorigenesis (5-fold increase) from tobacco smoke. Arsenic co-carcinogenesis may involve inhibition of proteins involved in nucleotide excision repair. Arsenic also has endocrine-disrupting activities on several nuclear steroid hormone receptors, enhancing hormone-dependent transcription at very low concentrations and inhibiting it at slightly higher levels.

Arsine Gas. Arsine gas is a rare cause of industrial poisonings. Arsine induces rapid and often fatal hemolysis, which probably results from arsine combining with hemoglobin and reacting with O2. A few hours after exposure, patients can develop headache, anorexia, vomiting, paresthesia, abdominal pain, chills, hemoglobinuria, bilirubinemia, and anuria. Jaundice appears after 24 h. Arsine induces renal toxicities that can progress to kidney failure. Fatality results in ~25% of cases of arsine exposure.

Treatment. Following acute exposure to As, stabilize the patient and prevent further absorption of the poison. Close monitoring of fluid levels is important because As can cause fatal hypovolemic shock. Chelation therapy is effective following short-term exposure to As but has very little or no benefit in chronically exposed individuals. Exchange transfusion to restore blood cells and remove As often is warranted following arsine gas exposure.

CADMIUM. Cadmium (Cd) is used in electroplating, galvanization, plastics, paint pigments, and Ni-Cd batteries.

Exposure. Exposure to Cd is through food (estimated average daily intake, μg/day) and tobacco (1 cigarette contains 1-2 μg of Cd). Workers in metal-processing industries can be exposed to high levels of Cd, particularly by inhalation.

Chemistry and Mode of Action. Cd exists as a Cd++ and does not undergo oxidation-reduction reactions. The mechanism of Cd toxicity is not fully understood. Like lead and other divalent metals, Cd can replace zinc in zinc-finger domains of proteins and disrupt them. Cd induces formation of ROS, resulting in lipid peroxidation and glutathione depletion, upregulates inflammatory cytokines, and may disrupt the beneficial effects of NO.

Absorption, Distribution, and Excretion. Cd is not well absorbed from the GI tract (1.5-5%) but is better absorbed via inhalation (~10%). Cd primarily distributes first to the liver and later the kidney, with those 2 organs accounting for 50% of the absorbed dose. Little Cd crosses the blood-brain barrier or the placenta. Cd primarily is excreted in the urine and exhibits a t1/2 of 10-30 years.

Toxicity. Acute Cd toxicity primarily is due to local irritation along the absorption route. Inhaled Cd causes respiratory tract irritation with severe, early pneumonitis accompanied by chest pains, nausea, dizziness, and diarrhea. Toxicity may progress to fatal pulmonary edema. Ingested Cd induces nausea, vomiting, salivation, diarrhea, and abdominal cramps; the vomitus and diarrhea often are bloody. Cd bound to metallothionein is transported to the kidney, where it can be released. The initial toxic effect of Cd on the kidney is increased excretion of small-molecular-weight proteins, especially β2microglobulin and retinol-binding protein. Cd also causes glomerular injury and decreased filtration. Chronic occupational exposure to Cd is associated with an increased risk of renal failure and death. Cd levels consistent with normal dietary exposure also can cause renal toxicity. Workers with long-term inhalation exposure to Cd exhibit decreased lung function. Symptoms initially include bronchitis and fibrosis of the lung, leading to emphysema. Chronic obstructive pulmonary disease increases mortality in Cd-exposed workers. When accompanied by vitamin D deficiency, Cd exposure increases the risks for fractures and osteoporosis, possibly due to interference with renal Ca2+ and phosphate regulation.

Carcinogenicity. Chronic occupational exposure to inhaled Cd increases the risk of developing lung cancer. Cd causes chromosomal aberrations in exposed workers and human cells. It also increases mutations and impairs DNA repair in human cells. Cd substitutes for zinc in DNA repair proteins and polymerases and may inhibit nucleotide excision repair, base excision repair, and the DNA polymerase responsible for repairing single-strand breaks. Cd also may alter cell signaling pathways and disrupts cellular controls of proliferation. Cd acts as a non-genotoxic carcinogen.

Treatment. Patients suffering from inhaled Cd may require respiratory support. Patients suffering from kidney failure due to Cd poisoning may require a transplant. Chelation therapy following Cd poisoning has no clinical benefits and may result in adverse effects.

CHROMIUM. Chromium (Cr) is an industrially important metal used in a number of alloys, particularly stainless steel (at least 11% chromium). Cr can be oxidized to multiple valence states, with the trivalent (CrIII) and hexavalent (CrVI) forms being the 2 of biological importance. Chromium exists almost exclusively as the trivalent form in nature, and CrIII is an essential metal involved in the regulation of glucose metabolism. CrVI is thought to be responsible for the toxic effects of Cr.

Exposure. Exposure to Cr in the general population primarily is through the ingestion of food, although there also is exposure from drinking water and air. Workers are exposed to Cr during chromate production, stainless steel production and welding, Cr plating, ferrochrome alloy and chrome pigment production, and in tanning industries. Exposure usually is to a mixture of CrIII and CrVI.

Chemistry and Mode of Action. Cr occurs in its metallic state or in any valence state between divalent and hexavalent. CrIII is the most stable and common form. CrVI is corrosive and is readily reduced to lower valence states. The primary reason for the different toxicological properties of CrIII and CrVI is thought to be differences in their absorption and distribution. CrVI resembles sulfate and phosphate and can be taken into the cell by anion transporters where it undergoes a series of reduction steps, ultimately forming CrIII, which causes most of the toxic effects. CrIII readily interacts covalently with DNA. CrVI also induces oxidative stress and hypersensitivity reactions.

ADME. Smaller particles are better deposited in the lungs. Absorption into the bloodstream of hexavalent and soluble forms is higher than the trivalent or insoluble forms, with the remainder often retained in the lungs. Approximately 50-85% of inhaled CrVI particles (<5 μm) are absorbed. Absorption of ingested Cr is <10%. CrVI crosses membranes by facilitated transport; CrIII crosses by diffusion. CrVI is distributed to all of the tissues and crosses the placenta. The highest levels are attained in the liver, kidney, and bone; CrVI also is retained in erythrocytes. Excretion primarily is through urine, with small amounts excreted in bile and breast milk and deposited in hair and nails. The t1/2 of ingested CrVI is ~40 h; the t1/2 of CrIII is ~10 h.

Toxicity. Acute exposure to very high doses of Cr causes death via damage to multiple organs, particularly the kidney. Chronic low-dose Cr exposure causes toxicity at the site of contact. Thus, workers exposed to inhaled Cr develop symptoms of lung and upper respiratory tract irritation, decreased pulmonary function, and pneumonia. Chronic exposure to Cr via ingestion causes symptoms of GI irritation (e.g., oral ulcer, diarrhea, abdominal pain, indigestion, and vomiting). CrVI is a dermal irritant and can cause ulceration or burns. Some individuals develop allergic dermatitis following dermal exposure to Cr. Cr-sensitized workers often also develop asthma.

Carcinogenicity. CrVI compounds are known human carcinogens (group 1). There is insufficient evidence for carcinogenesis from metallic and CrIII (group 3). Workers exposed to CrVI via inhalation have elevated incidence of and mortality from lung and nasal cancer. Environmental exposure to CrVI in drinking water increases the risk of developing stomach cancer. There are multiple potential mechanisms for CrVI carcinogenicity. Reduction of CrVI to CrIII within the cell occurs with concomitant oxidation of cellular molecules. CrIII forms a large number of covalent DNA adducts, primarily at the phosphate backbone. The DNA adducts are not very mutagenic and are repaired by nucleotide excision repair. It is thought that the high level of nucleotide excision repair activity following CrVI exposure contributes to carcinogenesis, either by preventing repair of mutagenic lesions formed by other carcinogens or through the formation of single-strand breaks due to incomplete repair. Cr also forms toxic cross-links between DNA and protein. Chronic inflammation due to Cr-induced irritation also may promote tumor formation.

Treatment. There are no standard protocols for treatment of acute Cr poisoning. One approach that has shown promise in rodents is the use of reductants such as ascorbate, glutathione, or N-acetylcysteine to reduce CrVI to CrIII after exposure but before absorption to limit bioavailability. These compounds and EDTA also increase urinary excretion of Cr after high-dose, particularly if given soon enough. Exchange transfusion to remove Cr from plasma and erythrocytes may be beneficial.

TREATMENT OF METAL EXPOSURE

The most important response to environmental or occupational exposures to metals is to eliminate the source of the exposure. It also is important to stabilize the patient and provide symptomatic treatment.

Treatment for acute metal intoxications often involves the use of chelators. A chelator is a compound that forms stable complexes with metals, typically as 5- or 6-membered rings. The ideal chelator would have the following properties: high solubility in water, resistance to biotransformation, ability to reach sites of metal storage, ability to form stable and nontoxic complexes with toxic metals, and ready excretion of the metal-chelator complex. A low affinity for the essential metals Ca and Zn also is desirable, because toxic metals often act through competition with these metals for protein binding. The structures of the most commonly used chelators are shown in Figure 67–9.

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Figure 67–9 Structures of chelators commonly used to treat acute metal intoxication. CaNa2EDTA, calcium disodium ethylenediamine tetraacetic acid; DMPS, sodium 2,3-dimercapto-propane sulfonate.

In cases of acute exposure to high doses of most metals, chelation therapy reduces toxicity. However, following chronic exposure, chelation therapy does not show clinical benefits beyond those of cessation of exposure alone and, in some cases, does more harm than good. Chelation therapy may increase the neurotoxic effects of heavy metals and is recommended only for acute poisonings.

ETHYLENEDIAMINETETRAACETIC ACID (EDTA). EDTA and its various salts are effective chelators of divalent and trivalent metals. Calcium disodium EDTA (CaNa2EDTA) is the preferred EDTA salt for metal poisoning, provided that the metal has a higher affinity for EDTA than Ca2+. CaNa2EDTA is effective for the treatment of acute lead poisoning, particularly in combination with dimercaprol, but is not an effective chelator of Hg or As in vivo.

Chemistry and Mechanism of Action. Accessible metal ions with a higher affinity for CaNa2EDTA than Ca2+ will be chelated, mobilized, and usually excreted. Because EDTA is charged at physiological pH, it does not significantly penetrate cells. CaNa2EDTA mobilizes several endogenous metallic cations, including those of Zn, Mn, and Fe. Additional supplementation with Zn following chelation therapy may be beneficial. The most common therapeutic use of CaNa2EDTA is for acute lead intoxication. CaNa2EDTA does not provide clinical benefits for the treatment of chronic lead poisoning.

CaNa2EDTA is available as edetate calcium disodium (calcium disodium versenate). Intramuscular administration of CaNa2EDTA results in good absorption, but pain occurs at the injection site; consequently, the chelator injection often is mixed with a local anesthetic or administered intravenously. For intravenous use, CaNa2EDTA is diluted in either 5% dextrose or 0.9% saline and is administered slowly by intravenous drip. A dilute solution is necessary to avoid thrombophlebitis. To minimize nephrotoxicity, adequate urine production should be established prior to and during treatment with CaNa2EDTA. However, in patients with lead encephalopathy and increased intracranial pressure, excess fluids must be avoided, and intramuscular administration of CaNa2EDTA is recommended.

ADME. Less than 5% of CaNa2EDTA is absorbed from the GI tract. After intravenous administration, CaNa2EDTA has a t1/2 of 20-60 min. In blood, CaNa2EDTA is found only in the plasma; it is excreted in the urine by glomerular filtration. Altering either the pH or the rate of urine flow has no effect on the rate of excretion. There is very little metabolic degradation of EDTA. The drug is distributed mainly in the extracellular fluids; very little gains access to the spinal fluid (5% of the plasma concentration).

Toxicity. Rapid intravenous administration of Na2EDTA causes hypocalcemic tetany. Slow infusion (<15 mg/min) elicits no symptoms of hypocalcemia in a normal individual because of the availability of extracirculatory stores of Ca2+. CaNa2EDTA can be administered intravenously with no untoward effects because the change in the concentration of Ca2+ in the plasma and total body is negligible. The principal toxic effect of CaNa2EDTA is on the kidney, most likely due to chelation of essential metals, particularly Zn, in proximal tubular cells. The early renal effects usually are reversible with cessation of treatment. Other side effects associated with CaNa2EDTA include malaise, fatigue, excessive thirst followed by chills and fever and subsequent myalgia, frontal headache, anorexia, occasional nausea and vomiting, and rarely, increased urinary frequency and urgency. CaNa2EDTA is teratogenic in laboratory animals; it should be used in pregnant women only under conditions in which the benefits clearly outweigh the risks. Other undesirable effects include sneezing, nasal congestion, and lacrimation; glycosuria; anemia; dermatitis with lesions similar to those of vitamin B6 deficiency; transitory lowering of systolic and diastolic blood pressures; prolonged prothrombin time; and T-wave inversion on the electrocardiogram.

DIMERCAPROL. Dimercaprol was developed during World War II as an antidote to lewisite, a vesicant arsenical war gas; hence its alternative name, British anti-Lewisite (BAL). Arsenicals form a stable and relatively nontoxic chelate ring with dimercaprol. Dimercaprol interacts with other heavy metals as well.

Chemistry and Mechanism of Action. The pharmacological actions of dimercaprol result from formation of chelation complexes between its sulfhydryl groups and metals. The sulfur–metal bond may be labile in the acidic tubular urine, which may increase the delivery of metal to renal tissue and increase toxicity. The dosage regimen should maintain a concentration of dimercaprol in plasma adequate to favor the continuous formation of the more stable 2:1 (BAL–metal) complex. However, because of pronounced and dose-related side effects, excessive plasma concentrations must be avoided. The concentration in plasma therefore must be maintained by repeated dosage until the metal is excreted. Dimercaprol is most beneficial when given very soon after exposure to the metal because it is more effective in preventing inhibition of sulfhydryl enzymes than in reactivating them. Dimercaprol limits toxicity from As, Au, and Hg, which form mercaptides with essential cellular sulfhydryl groups. It also is used in combination with CaNa2EDTA to treat Pb poisoning.

ADME and Therapeutic Use. Dimercaprol is given by deep intramuscular injection as a 100 mg/mL solution in peanut oil and should not be used in patients who are allergic to peanut products. Peak concentrations in blood are attained in 30-60 min. The t1/2 is short, and metabolic degradation and excretion essentially are complete within 4 h. Dimercaprol and its chelates are excreted in both urine and bile. Dimercaprol is contraindicated following chronic exposures to heavy metals because it does not prevent neurotoxic effects., and should not be used in patients with hepatic insufficiency, except when this condition is a result of As poisoning.

Toxicity. Side effects occur in ~50% of subjects receiving 5 mg/kg intramuscularly. Dimercaprol causes an immediate rise in systolic and diastolic arterial pressures accompanied by tachycardia; these return to normal within 2 h. Dimercaprol also can cause anxiety, nausea and vomiting, headache, a burning sensation in the mouth and throat, a feeling of constriction in the throat and chest, conjunctivitis, blepharospasm, lacrimation, rhinorrhea, salivation, tingling of the hands, a burning sensation in the penis, sweating, abdominal pain, and the appearance of painful sterile abscesses at the injection site. The dimercaprol–metal complex breaks down easily in an acidic medium; production of alkaline urine protects the kidney during therapy. Children react similarly to adults, although ~30% also may experience a fever that disappears on drug withdrawal.

SUCCIMER. Succimer (2,3-dimercaptosuccinic acid [DMSA], CHEMET) is an orally effective chelator that is chemically similar to dimercaprol but contains 2 carboxylic acids that modify the spectrum of absorption, distribution, and chelation of the drug.

ADME. After absorption, succimer is biotransformed to a mixed disulfide with cysteine. Succimer lowers blood Pb levels and attenuates toxicity of Pb. The succimer–Pb chelate is eliminated in both urine and bile. The fraction eliminated in bile can undergo enterohepatic circulation. Succimer has several desirable features over other chelators. It is orally bioavailable, and because of its hydrophilic nature, it does not mobilize metals to the brain or enter cells. It also does not significantly chelate essential metals such as Zn, Cu, or Fe. Thus, succimer exhibits a better toxicity profile relative to other chelators. Succimer also is effective as a chelator of As, Cd, Hg, and other toxic metals.

Therapeutic Use. Succimer is approved for treatment of children with blood Pb levels >45 μg/dL. It also is used off label for the treatment of adults with Pb poisoning and As and Hg intoxication.

Toxicity. Succimer is much less toxic than dimercaprol. Commonly reported adverse effects are nausea, vomiting, diarrhea, and loss of appetite. Transient elevations in hepatic transaminases have been observed with succimer treatment. In a few patients, rashes necessitate discontinuation of therapy.

SODIUM 2, 3-DIMERCAPTOPROPANE SULFONATE (DMPS). DMPS is another dimercapto compound used for the chelation of heavy metals. DMPS is not approved by the FDA but is approved for use in Germany. DMPS is available from compounding pharmacies and is used by some doctors in the U.S.

Chemistry and Mode of Action. DMPS is a clinically effective chelator of Pb, As, and especially Hg. It is orally available and is rapidly excreted, primarily by the kidneys. It is negatively charged and exhibits distribution properties similar to those of succimer. DMPS is less toxic than dimercaprol but mobilizes Zn and Cu and thus is more toxic than succimer. There is evidence suggesting that DMPS might be effective for treatment of chronic heavy metal poisonings.

PENICILLAMINE; TRIENTINE. Penicillamine (CUPRIMINE, DEPEN) is an effective chelator of Cu, Hg, Zn, and Pb and promotes the excretion of these metals in the urine.

Penicillamine’s chelating properties led to its use in patients with Wilson disease (excess body burden of Cu due to diminished excretion) and heavy-metal intoxications. Penicillamine is a more toxic and less potent and selective chelator of heavy metals than other chelation drugs; thus, it is not a first-line treatment for acute intoxication with Pb, Hg, or As. Because it is inexpensive and orally bioavailable, it often is given at low doses following treatment with CaNa2EDTA and/or dimercaprol to ensure that the concentration of metal in the blood stays low following the patient’s release from the hospital.

ADME. Penicillamine is well absorbed (40-70%) from the GI tract. Food, antacids, and iron reduce its absorption. Peak plasma concentrations are obtained between 1 and 3 h. Penicillamine is relatively stable in vivo compared to its unmethylated parent compound cysteine. Hepatic biotransformation primarily is responsible for degradation of penicillamine, and very little drug is excreted unchanged. Metabolites are found in both urine and feces. N-Acetylpenicillamine is more effective than penicillamine in protecting against the toxic effects of Hg, presumably because it is more resistant to metabolism.

Therapeutic Use. Penicillamine is available for oral administration. For chelation therapy, the usual adult dose is 1-1.5 g/day in 4 divided doses, given on an empty stomach to avoid interference by metals in food. Penicillamine is used in Wilson disease, cystinuria, and rheumatoid arthritis (rarely). For the treatment of Wilson disease, 1-2 g/day usually is administered in 4 doses. The urinary excretion of Cu should be monitored to determine whether the dosage of penicillamine is adequate.

Toxicity. Penicillamine induces cutaneous lesions, including urticaria, macular or papular reactions, pemphigoid lesions, lupus erythematosus, dermatomyositis, adverse effects on collagen, dryness, and scaling. Cross-reactivity with penicillin may be responsible for some episodes of urticarial or maculopapular reactions with generalized edema, pruritus, and fever that occur in up to one-third of patients taking penicillamine. Hematological reactions include leukopenia, aplastic anemia, and agranulocytosis, which may be fatal. Renal toxicity is manifested as reversible proteinuria and hematuria, but it may progress to nephrotic syndrome with membranous glomerulopathy. Rare fatalities have been reported from Goodpasture syndrome. Although uncommon, severe dyspnea has been reported from penicillamine-induced bronchoalveolitis. Myasthenia gravis has been induced by long-term therapy. Penicillamine is a teratogen in animals, but for pregnant women with Wilson disease, the benefits outweigh the risks. Less serious side effects include nausea, vomiting, diarrhea, dyspepsia, anorexia, and a transient loss of taste for sweet and salt. Contraindications to therapy include pregnancy, renal insufficiency, or a previous history of penicillamine-induced agranulocytosis or aplastic anemia.

TRIENTINE. Penicillamine is the drug of choice for treatment of Wilson disease. Trientine (triethylenetetramine dihydrochloride, SYPRINE) is an acceptable alternative for patients who cannot tolerate penicillamine (see “Toxicity,” above). Trientine drug is effective orally. Maximal daily doses of 2 g for adults or 1.5 g for children are taken in 2 to 4 divided portions on an empty stomach. Trientine may cause iron deficiency; this can be overcome with short courses of Fe therapy, but iron and trientine should not be ingested within 2 h of each other.

DEFEROXAMINE; DEFERASIROX; DEFERIPRONE. Deferoxamine (deferoxamine mesylate, DESFERAL) has high affinity for ferric iron (Ka = 1031) and a very low affinity for calcium (Ka = 102). It removes Fe from hemosiderin and ferritin and, to a lesser extent, from transferrin. Iron in hemoglobin or cytochromes is not removed by deferoxamine.

ADME and Therapeutic Use. Deferoxamine is poorly absorbed after oral administration, and parenteral administration is required. For severe Fe toxicity (serum Fe levels >500 μg/dL), the intravenous route is preferred. The drug is administered at 10-15 mg/kg/h by constant infusion. Rapid boluses usually are associated with hypotension. Deferoxamine may be given intramuscularly in moderately toxic cases (serum Fe 350-500 μg/dL) at a dose of 50 mg/kg with a maximum dose of 1 g. Hypotension also can occur with this route. For chronic Fe intoxication (e.g., thalassemia), an intramuscular dose of 0.5-1.0 g/day is recommended. Continuous subcutaneous administration (1-2 g/day) is almost as effective as intravenous administration. Deferoxamine is not recommended in primary hemochromatosis; phlebotomy is the treatment of choice. Deferoxamine also has been used for the chelation of aluminum in dialysis patients. Deferoxamine is metabolized by plasma enzymes and excreted in the urine.

Toxicity. Deferoxamine causes a number of allergic reactions, including pruritus, wheals, rash, and anaphylaxis. Other adverse effects include dysuria, abdominal discomfort, diarrhea, fever, leg cramps, and tachycardia. Occasional cases of cataract formation have been reported. Deferoxamine may cause neurotoxicity during long-term, high-dose therapy; both visual and auditory changes have been described. A “pulmonary syndrome” has been associated with high-dose (10-25 mg/kg/h) deferoxamine therapy; tachypnea, hypoxemia, fever, and eosinophilia are prominent symptoms. Contraindications include renal insufficiency and anuria; during pregnancy, deferoxamine should be used only if clearly indicated.

DEFERASIROX. Deferasirox (EXJADE) is FDA-approved for treatment of chronic Fe overload in patients receiving therapeutic blood transfusions. It is administered orally.

DEFERIPRONE. Deferiprone (FERRIPROX) is an oral Fe chelator FDA-approved for treatment of Fe overload in patients with thalassemia receiving therapeutic blood transfusions.