Pharmacology_Katzung

Pharmacology_Katzung. In humans, 2,4-D in large doses can cause coma and generalized muscle hypotonia. Rarely, muscle weakness and marked hypotonia may persist for several weeks. In laboratory animals, signs of liver and kidney dysfunction have also been reported with chlorphenoxy herbicides. Several epidemiologic studies performed by the U.S. National Cancer Institute confirmed the causal link between 2,4-D and non-Hodgkin’s lymphoma. Evidence for a causal link to soft tissue sarcoma, however, is considered equivocal.


Pharmacology_Katzung

Pharmacology_Katzung. The dichlorophenoxy and related herbicides have been found to contain and to generate dimethylnitrosamine (N-nitrosodimethylamine; NDMA), a potent human carcinogen, during environmental transformation as well as non-chlorine water disinfection. Studies by Environment Canada and others have questioned the use of this compound because of water contamination. Studies of related nitrosamine-forming herbicidal compounds have raised questions about the suitability of these compounds for general weed control. Because of the extremely high economic value of herbicides to the agricultural community, however, long-term decisions on their use have been delayed.


Pharmacology_Katzung

Pharmacology_Katzung. Glyphosate (N-[phosphonomethyl] glycine, Figure 56–1), the principle ingredient in Roundup, is now the most widely used herbicide in the world. It functions as a contact herbicide and is absorbed through the leaves and roots of plants. It is generally formulated with surfactant to enhance its intended effect on noxious plants. Because it is nonselective, it may damage important crops and desirable ornamental plants even when used as directed. Therefore, genetically modified plants such as soybean, corn, and cotton that are glyphosate-resistant have been developed and patented. They are widely grown throughout the world. Almost all soybean crops and many corn crops grown today are of the glyphosate-resistant type. These genetically modified (GMO) crops are grown from patented seeds and have great economic value to growers, contributing to the food supply in a meaningful way. However, in some jurisdictions their use is highly controversial. While there is no evidence that the modified


Pharmacology_Katzung

Pharmacology_Katzung. great economic value to growers, contributing to the food supply in a meaningful way. However, in some jurisdictions their use is highly controversial. While there is no evidence that the modified crops are toxic or dangerous to humans or animals, the long-term agricultural impact of widespread use of glyphosate herbicides on resistant crops remains to be determined. Additionally, the impact of effective weed elimination on the food supply and habitat of critical insect species, eg, bees, and some migrating birds has been a source of increasing concern.


Pharmacology_Katzung

Pharmacology_Katzung. Because of the widespread availability and use of this herbicide, glyphosate-surfactant poisonings are common. Many of the observed ingestions and reports of poisoning are from developing countries, where suicide by pesticide is common. Many injuries are minor, but some serious and lethal poisonings have been reported. Glyphosate is a significant eye and skin irritant. When ingested it can cause mild to moderate esophageal erosion. It also causes aspiration pneumonia and renal failure. There have been some reports of teratogenic outcomes in workers who handle and apply glyphosate, but the epidemiologic evidence is not clear. There is a growing literature on management of acute glyphosate poisoning. Treatment is symptomatic and no specific protocol is indicated. Hemodialysis has been used with success in cases of renal failure.


Pharmacology_Katzung

Pharmacology_Katzung. Although glyphosate seems to have little persistence and lower toxicity than other herbicides, the commercial formulations often contain surfactants and other active compounds that complicate the toxicity of the product. Some of the toxic effects are related to the surfactant material. Paraquat is the most important agent of this class (Figure 56–1). Its mechanism of action is said to be similar in plants and animals and involves single-electron reduction of the herbicide to free radical species. Ingestion (accidental or suicidal) is among the most serious and potentially lethal pesticide poisonings. Many serious exposures take place in developing countries where limited treatment resources are available. Paraquat accumulates slowly in the lung by an active process and causes lung edema, alveolitis, and progressive fibrosis. It probably inhibits superoxide dismutase, resulting in intracellular free-radical oxygen toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. In humans, the first signs and symptoms after oral exposure are hematemesis and bloody stools. Within a few days, however, delayed toxicity occurs, with respiratory distress and the development of congestive hemorrhagic pulmonary edema accompanied by widespread cellular proliferation. During the acute period, oxygen should be used cautiously to combat dyspnea or cyanosis, because it may aggravate the pulmonary lesions. Hepatic, renal, or myocardial involvement may develop. The interval between ingestion and death may be several weeks.


Pharmacology_Katzung

Pharmacology_Katzung. Because of the delayed pulmonary toxicity, prompt immobilization of the paraquat to prevent absorption is important. Adsorbents (eg, activated charcoal, Fuller’s earth) are routinely given to bind the paraquat and minimize its absorption. Gastric lavage is not recommended as it may promote aspiration from the stomach into the lungs. Once the paraquat is absorbed, treatment is successful in less than 50% of cases. Monitoring of plasma and urine paraquat concentrations is useful for prognostic assessment. Computed tomography scanning has also been used to follow the pulmonary lesions as they develop and to help with prognosis. The pulmonary proliferative phase begins 1–2 weeks after paraquat ingestion. Although a few reports indicate some success with dialysis, hemodialysis and hemoperfusion rarely change the clinical course. Many approaches have been used to slow or stop the progressive pulmonary fibrosis. Immunosuppression using corticosteroids and cyclophosphamide is widely


Pharmacology_Katzung

Pharmacology_Katzung. rarely change the clinical course. Many approaches have been used to slow or stop the progressive pulmonary fibrosis. Immunosuppression using corticosteroids and cyclophosphamide is widely practiced, but evidence for efficacy is weak. Antioxidants such as acetylcysteine and salicylate might be beneficial through free radical-scavenging, anti-inflammatory, and nuclear factor kappa-B inhibitory actions. However, there are no published human trials. The case fatality rate is high in all centers despite large variations in treatment. Patients require prolonged observation and treatment for respiratory and renal insufficiency if they survive the acute stage of poisoning.


Pharmacology_Katzung

Pharmacology_Katzung. Highly halogenated biphenyl compounds, which have desirable properties for insulation, fire retardancy, and many other uses, were manufactured in large quantities during the mid-20th century. The quantities produced and the almost universal dispersion of the materials in which they were incorporated have produced an enormous environmental problem. Both chlorinated and brominated biphenyls are environmentally dangerous and significantly toxic, and are now banned from use.


Pharmacology_Katzung

Pharmacology_Katzung. The polychlorinated biphenyls (PCBs, coplanar biphenyls) were used as dielectric and heat transfer fluids, lubricating oils, plasticizers, wax extenders, and flame retardants. Their industrial use and manufacture in the USA were terminated by 1977. The chlorinated products used commercially were actually mixtures of PCB isomers and homologs containing 12–68% chlorine. These chemicals are very stable, highly lipophilic, poorly metabolized, and very resistant to environmental degradation; thus they bioaccumulate in food chains.


Pharmacology_Katzung

Pharmacology_Katzung. Food is the major source of PCB residues in humans. Accumulation of PCB in fish species led Canada and the USA to restrict commercial fishing and to limit consumption of fish from the Great Lakes of North America (see Box: Bioaccumulation & Biomagnification, earlier). In addition, large industrial site contamination, illegal dumping, migration from hazardous waste sites and other large-scale sources, and widespread use of PCBs in electrical transformers has led to multiple localized areas of contamination and human exposure. Leakage of transformer dielectric fluids in neighborhoods and backyards has caused significant numbers of serious but highly localized PCB exposure events.


Pharmacology_Katzung

Pharmacology_Katzung. There are numerous reports of large population exposures to PCBs. A serious exposure to PCBs—lasting several months— occurred in Japan in 1968 as a result of cooking oil contamination with PCB-containing transfer medium (Yusho disease). A similar outbreak called Yucheng disease occurred at about the same time in Taiwan. Effects on the fetus and on the development of the offspring of poisoned women were reported. It is now known that the contaminated cooking oil contained not only PCBs but also polychlorinated dibenzofurans (PCDFs) and polychlorinated quaterphenyls (PCQs). It is likely that the effects initially attributed to the PCBs were actually caused by a mixture of contaminants. Workers occupationally exposed to PCBs develop dermatologic problems that include chloracne, folliculitis, erythema, dryness, rash, hyperkeratosis, and hyperpigmentation. Some hepatic abnormalities have been found in PCB poisoning, and plasma triglycerides are elevated.


Pharmacology_Katzung

Pharmacology_Katzung. Information about the effects of PCBs on reproduction and development is accumulating. The halogenated pesticides are potent endocrine disrupters and there is widespread concern about the persistent estrogenic effect of these chemicals. Adverse reproductive impacts of PCBs have been found in many animal studies. Direct teratogenic effects in humans have yet to be established: studies in workers and in the general population exposed to moderate or to very high levels of PCBs have not been conclusive. Some adverse behavioral effects in infants have been reported. An association between prenatal exposure to PCBs and deficits in childhood intellectual function was described for children born to mothers who had eaten large quantities of contaminated fish. Epidemiologic studies have established increases in various cancers including melanoma, breast, pancreatic, and thyroid cancers. These findings and animal studies provided a sufficient basis for the IARC to classify some co-planar PCBs as


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Pharmacology_Katzung. increases in various cancers including melanoma, breast, pancreatic, and thyroid cancers. These findings and animal studies provided a sufficient basis for the IARC to classify some co-planar PCBs as class 1, carcinogenic to humans, in volume 100 of the IARC monographs.


Pharmacology_Katzung

Pharmacology_Katzung. Introduction to Toxicology: Occupational & Environmental 1015 A comprehensive EPA fact sheet on PCBs may be found at https:// www.epa.gov/pcbs. The polybrominated biphenyls (PBBs) and their ethers (PBDEs) share many of the toxic and environmentally damag ing persistent qualities of PCBs. They were introduced as fire retardants in the 1950s and have been used in massive quantities since that time. The biphenyls are no longer produced and may no longer be used, but the biphenyl ethers remain in use as fire retardants in plastics for bedding and in automobile upholstery. PBB fire retardant contamination has been extensive in the Great Lakes region, resulting in large exposure to the population. PBBs are considered IARC class 2a: probable human carcino gens. PBDEs are not classified. An EPA technical fact sheet on PBB and PBDEs may be found at http://www2.epa.gov/fedfac/ polybrominated-biphenyls-pbbs.


Pharmacology_Katzung

Pharmacology_Katzung. PBB and PBDEs may be found at http://www2.epa.gov/fedfac/ polybrominated-biphenyls-pbbs. The polychlorinated dibenzo-p-dioxins (PCDDs), or dioxins, are a group of halogenated congeners of which tetra chlorodibenzodioxin (TCDD) has been the most carefully stud ied. There is a large group of dioxin-like compounds, including biphenyls. While PCBs were used commercially, PCDDs and


Pharmacology_Katzung

Pharmacology_Katzung. PCDFs are unwanted byproducts that appear in the environ ment and in manufactured products as contaminants because of improperly controlled combustion processes. They are also produced when unexpected heating to temperatures over 600°C occurs as in lightning strikes or electrical fires in PCB-containing transformers. Like PCBs, these chemicals are very stable and highly lipophilic. They are poorly metabolized and very resistant to environmental degradation. Several significant environmen industrial sites have occurred. Recent publications have demon strated an elevated incidence of subsequent chronic diseases (eg, diabetes, metabolic syndrome, and obesity) in exposed persons. Laboratory studies of the blood concentrations of TCDD and its metabolites have provided insight into the persistence and metabolism of the contaminants.


Pharmacology_Katzung

Pharmacology_Katzung. Laboratory studies of the blood concentrations of TCDD and its metabolites have provided insight into the persistence and metabolism of the contaminants. In laboratory animals, TCDD has produced a variety of toxic effects. Wasting syndrome (severe weight loss accompanied by reduction of muscle mass and adipose tissue), thymic atrophy, epidermal changes, hepatotoxicity, immunotoxicity, effects on reproduction and development, teratogenicity, and carcinogenic ity have been produced. The effects observed in workers involved in the manufacture of 2,4,5-T (and therefore presumably exposed to TCDD) consisted of contact dermatitis and chloracne. In severely TCDD-intoxicated patients, discrete chloracne may be the only manifestation. The presence of TCDD in 2,4,5-T, commercially known as


Pharmacology_Katzung

Pharmacology_Katzung. The presence of TCDD in 2,4,5-T, commercially known as Silvex, was believed to be responsible for other human toxicities associated with the herbicide. There is epidemiologic evidence for an association between occupational exposure to the phenoxy herbicides and an excess incidence of non-Hodgkin’s lymphoma. The TCDD contaminant in these herbicides seems to play a role in a number of cancers such as soft tissue sarcomas, lung cancer, Hodgkin’s lymphomas, and others. TCDD is considered an IARC class 1, known human carcinogen. Other halogenated compounds of this type are not currently classifiable as to carcinogenicity; they are listed as IARC class 3.


Pharmacology_Katzung

Pharmacology_Katzung. Fluorinated hydrocarbon chemicals have been of commercial interest since the mid-20th century. Their uses have included coolant materials in air conditioning systems; artificial oxygen-carrying substances in experimental clinical studies; and heat-, stain-, and stick-resistant coatings for cookware, fabrics, and other materials. The fluorocarbons were produced in very large quantities and have become widespread in the environment. When it later became apparent that migration of lower molecular weight fluorocarbons to the troposphere had a deleterious effect on the protective ozone layer, they were banned from use. The higher molecular weight, more highly fluorinated compounds, now called perfluorinated substances (eg, Teflon), have remained in broad use. Like the heavily chlorinated and brominated hydrocarbons, their commercial usefulness has been complicated by a recognition of adverse environmental and suspected human toxic impacts that resemble some of the adverse qualities of the


Pharmacology_Katzung

Pharmacology_Katzung. hydrocarbons, their commercial usefulness has been complicated by a recognition of adverse environmental and suspected human toxic impacts that resemble some of the adverse qualities of the other halogenated hydrocarbons. A useful reference is the Centers for Disease Control and Prevention (CDC) fact sheet on PFCs. It is found at https://www.cdc.gov/biomonitoring/pdf/ PFCs_FactSheet.pdf.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Human toxicology—Concerns about the toxicology of PFCs have centered on their estrogenic properties and accumulation and persistence in humans. Human exposure to perfluoro compounds takes place through ingestion and inhalation. Since these compounds enter the food chain and water sources and are persistent, ingestion of contaminated food and water products is a major source of human accumulation. The human half-life of PFOA is estimated to be about 3 years. As a persistent chemical and an endocrine disrupter, it is likely that it has some long-term adverse impact on reproductive function, cellular proliferation, and other cellular homeostatic mechanisms. Several PFCs (but not perfluoro compounds derived from PFOA) have been found to act as proliferators of breast cancer cells. However, a large epidemiologic study recently demonstrated a statistically significant association between high and very high serum PFOA levels in workers and kidney cancer, and possibly prostate cancer,


Pharmacology_Katzung

Pharmacology_Katzung. a large epidemiologic study recently demonstrated a statistically significant association between high and very high serum PFOA levels in workers and kidney cancer, and possibly prostate cancer, ovarian cancer, and non-Hodgkin’s lymphoma. There also may be modest associations with cholesterol elevation and uric acid abnormalities. Finally, an acute pulmonary disorder, polymer fume fever, is caused by the pyrolysis of PFOA. Like metal fume fever, seen in welders as a result of cadmium vaporization, polymer fume fever has an acute onset several hours after exposure to the vaporized PFOA and may cause severe respiratory distress. The onset of constitutional symptoms, malaise, chills and fever, and respiratory distress is characteristic of fume fevers. While polymer fume fever is usually mild and self-limited, noncardiogenic pulmonary edema has occurred. Whenever PFOA is heated above 350–400°C, toxic fumes capable of causing polymer fume fever are emitted. Overheated household cookware or


Pharmacology_Katzung

Pharmacology_Katzung. and self-limited, noncardiogenic pulmonary edema has occurred. Whenever PFOA is heated above 350–400°C, toxic fumes capable of causing polymer fume fever are emitted. Overheated household cookware or burning of coated fabrics present this risk.


Pharmacology_Katzung

Pharmacology_Katzung. Other human effects are not clearly defined, although animal studies have shown toxic effects on immune, liver, and endocrine function, and some increase in tumors and neonatal deaths. A useful American Cancer Society fact sheet on the subject may be found at https://www.cancer.org/cancer/cancer-causes/teflon-andperfluorooctanoic-acid-pfoa.html. 2. Environmental toxicology—Perfluoro compounds are persistent environmental chemicals having a broad environmental impact. PFOA and related compounds are now found widely in water, soil, and many terrestrial and avian species. Aquatic organisms have accumulated significant loads of PFCs. An extensive risk assessment of the perfluoro chemicals has been carried out by Environment Canada, and guidelines have been developed for the management of PFOA and related compounds. These may be found at http://www.ec.gc.ca/ese-ees/default. asp?lang=En&n=451C95ED-1.


Pharmacology_Katzung

Pharmacology_Katzung. As described above, the potential hazardous effects of some chemicals in the environment are receiving considerable attention because of their estrogen-like or antiandrogenic properties. Compounds that affect thyroid function are also of concern. Since 1998, the process of prioritization, screening, and testing of chemicals for such actions has been undergoing worldwide development. These chemicals mimic, enhance, or inhibit a hormonal action. They include a number of plant constituents (phytoestrogens) and some mycoestrogens as well as industrial chemicals, persistent organochlorine agents (eg, DDT), PCBs, and brominated flame retardants. Concerns exist because of their increasing contamination of the environment, the appearance of bioaccumulation, and their potential for toxicity. In vitro assays alone are unreliable for regulatory purposes, and animal studies are considered indispensable. Modified endocrine responses in reptiles and marine invertebrates have been observed. In


Pharmacology_Katzung

Pharmacology_Katzung. In vitro assays alone are unreliable for regulatory purposes, and animal studies are considered indispensable. Modified endocrine responses in reptiles and marine invertebrates have been observed. In humans, however, a causal relation between exposure to a specific environmental agent and an adverse health effect due to endocrine modulation has not been fully established. Epidemiologic studies of populations exposed to higher concentrations of endocrine-disrupting environmental chemicals are underway. There are indications that breast and other reproductive cancers are increased in these patients. Prudence dictates that exposure to environmental chemicals that disrupt endocrine function should be reduced.


Pharmacology_Katzung

Pharmacology_Katzung. Asbestos in many of its forms has been widely used in industry for over 100 years. All forms of asbestos have been shown to cause progressive fibrotic lung disease (asbestosis), lung cancer, and mesothelioma. Every form of asbestos, including chrysotile asbestos, causes an increase in lung cancer and mesothelioma. Lung cancer occurs in people exposed at fiber concentrations well below concentrations that produce asbestosis. Very large-scale studies of insulation workers have shown that cigarette smoking and exposure to radon daughters increase the incidence of asbestos-caused lung cancer in a synergistic fashion. Asbestos exposure and smoking is a very hazardous combination.


Pharmacology_Katzung

Pharmacology_Katzung. All forms of asbestos cause mesothelioma of the pleura or peritoneum at very low doses. Other cancers (colon, laryngeal, stomach, and perhaps even lymphoma) are increased in asbestos-exposed patients. The mechanism for asbestos-caused cancer is not yet delineated. Arguments that chrysotile asbestos does not cause mesothelioma are contradicted by many epidemiologic studies of worker populations. Recognition that all forms of asbestos are dangerous and carcinogenic has led many countries to ban all uses of asbestos. Countries such as Canada, Zimbabwe, Russia, Brazil, and others that still produce asbestos argue that asbestos can be used safely with careful workplace environmental controls. However, studies of industrial practice make the “safe use” of asbestos highly improbable. Recent attempts to limit international trade in asbestos have been thwarted by heavy pressure from the asbestos industry and the producing countries. Information on countries that currently ban asbestos and the


Pharmacology_Katzung

Pharmacology_Katzung. to limit international trade in asbestos have been thwarted by heavy pressure from the asbestos industry and the producing countries. Information on countries that currently ban asbestos and the International Ban Asbestos movement may be found at http://ibasecretariat.org/ alpha_ban_list.php.


Pharmacology_Katzung

Pharmacology_Katzung. Occupational and environmental poisoning with metals, metalloids, and metal compounds is a major health problem. Toxic metal exposure occurs in many industries, in the home, and elsewhere in the nonoccupational environment. The classic metal poisons (arsenic, lead, and mercury) continue to be widely used. (Treatment of their toxicities is discussed in Chapter 57.) Occupational exposure and poisoning due to beryllium, cadmium, manganese, and uranium are relatively new occupational problems. In 2016, cobalt and cobalt-releasing compounds were listed by the National Institute of Environmental Health Sciences as “reasonably anticipated to be” human carcinogens.


Pharmacology_Katzung

Pharmacology_Katzung. Beryllium (Be) is a light alkaline metal that confers special properties on the alloys and ceramics in which it is incorporated. Beryllium-copper alloys find use as components of computers, in the encasement of the first stage of nuclear weapons, in devices that require hardening such as missile ceramic nose cones, and in heat shield tiles used in space vehicles. Because of the use of beryllium in dental appliances, dentists and dental appliance makers are often exposed to beryllium dust in toxic concentrations and may develop beryllium disease.


Pharmacology_Katzung

Pharmacology_Katzung. Beryllium is highly toxic by inhalation and is classified by the IARC as a class 1, known human carcinogen. Inhalation of beryllium particles produces both acute beryllium disease and chronic disease characterized by progressive pulmonary fibrosis. Skin disease also develops in workers exposed to beryllium. The pulmonary disease is called chronic beryllium disease (CBD) and is a chronic granulomatous pulmonary fibrosis. In the 5–15% of the population that is immunologically sensitive to beryllium, CBD is the result of activation of an autoimmune attack on the skin and lungs. The disease is progressive and may lead to severe disability,


Pharmacology_Katzung

Pharmacology_Katzung. Introduction to Toxicology: Occupational & Environmental 1017 cancer, and death. Although some treatment approaches to CBD show promise, the prognosis is poor in most cases. The current permissible exposure levels for beryllium of 0.01 mcg/m3 averaged over a 30-day period or 2 mcg/m3 over an 8-hour period are insufficiently protective to prevent CBD. Both NIOSH and the ACGIH have recommended that the 8-hour PEL and TLV be reduced to 0.05 mcg/m3. These recommendations have not yet been implemented. Current OSHA information on beryllium appears at https://www.osha.gov/SLTC/beryllium/index.html. Environmental beryllium exposure is not generally thought to be a hazard to human health except in the vicinity of industrial sites where air, water, and soil pollution have occurred. Cadmium (Cd) is a transition metal widely used in industry.


Pharmacology_Katzung

Pharmacology_Katzung. Cadmium (Cd) is a transition metal widely used in industry. Workers are exposed to cadmium in the manufacture of nickel cadmium batteries, pigments, low-melting-point eutectic materi als; in solder; in television phosphors; and in plating operations. It is also used extensively in semiconductors and in plastics as a sta bilizer. Cadmium smelting is often done from residual dust from lead smelting operations, and cadmium smelter workers often face both lead and cadmium toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Cadmium is toxic by inhalation and by ingestion. When met als that have been plated with cadmium or welded with cadmium- containing materials are vaporized by the heat of torches or cutting implements, the fine dust and fumes released produce an acute respiratory disorder called cadmium fume fever. This disor der, common in welders, is usually characterized by shaking chills, cough, fever, and malaise. Although it may produce pneumonia, it is usually transient. However, chronic exposure to cadmium dust produces a far more serious progressive pulmonary fibrosis. Cad mium also causes severe kidney damage, including renal failure if exposure continues. Cadmium is a human carcinogen and is listed as a class 1, known human carcinogen by the IARC. The current OSHA PEL for cadmium is 5 mcg/m3 but is insufficiently protective of worker health. The OSHA cadmium standard may be found at https://www.osha.gov/pls/oshaweb/ owadisp.show_document?p_table=STANDARDS&p_id=10036.


Pharmacology_Katzung

Pharmacology_Katzung. Nanomaterials are defined as any material, natural or manufac tured, that has at least one dimension that lies between 1 and 100 nanometers (nm) in size. The Stanford University Health and Safety Department gives a more precise definition at https://ehs. stanford.edu/topic/hazardous-materials/nanomaterials. Nanomaterials have been of increasing commercial interest and are now used for an extraordinary range of purposes. In the phar maceutical manufacturing industry, nanoparticles are being tested and used to deliver cancer chemotherapeutic and other drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Currently produced nanomaterials include gold, silver, cadmium, germanium, ceramic, and aluminum oxide nanowires; carbon, silicon, and germanium nanotubes; zinc oxide nanocrystals; gold nanowafers; and copper oxide nanocubes. The increasing use of nanomaterials has led to release of these nanoscale substances into the workplace and the general environment. Because nanomaterials behave in unique patterns of chemical and physical reactivity, their toxicology is often novel and there is insufficient information on the likely human or environmental impact of dispersal of these manufactured products in the environment. The University of North Carolina laboratory safety and health manual outlines the problems of working with nanomaterials in the laboratory and their safe use at http://ehs.unc.edu/manuals/laboratory/chapter-18/. 1.


Pharmacology_Katzung

Pharmacology_Katzung. Human toxicology—Inhalation, oral ingestion, dermal absorption, and parenteral administration of nanomaterials have been the sources of human exposure. Because of the unique physicochemical properties of nanomaterials, their toxicity may be similar to or very different from the larger, bulk materials encountered in traditional toxicology studies. The nature of the exposure will impact the likelihood that nanomaterials will reach target organs or cells. Nanomaterials can cross cellular membranes, penetrate nuclear material and genetic information, and may impact cellular response at a nanoscale. Silica nanoparticles have been demonstrated to produce kidney toxicity in humans, and zinc oxide nanoparticles are toxic to human liver cells. Multiwalled carbon nanotubes have been found to be cytotoxic in human lung cells. Titanium dioxide nanoparticles that are widely used in sunscreens, other cosmetics, pharmaceuticals, and many other products have been noted to be toxic in the lungs and


Pharmacology_Katzung

Pharmacology_Katzung. in human lung cells. Titanium dioxide nanoparticles that are widely used in sunscreens, other cosmetics, pharmaceuticals, and many other products have been noted to be toxic in the lungs and elsewhere.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Environmental toxicology—Nanomaterials can enter the environment at all stages of their industrial life cycle, including manufacturing, delivery, use, and disposal. When nanomaterials are placed into waste streams they may enter water systems, or be carried by wind or soils, and enter the food chain. An EPA fact sheet on nanomaterials in the environment is available at https://www .epa.gov/sites/production/files/2014-03/documents/ffrrofactsheet_ emergingcontaminant_nanomaterials_jan2014_final.pdf. The increasing production of nanomaterials and their multiple uses has led to environmental contamination. Many species, including bacteria, small mammals, and fish and other aquatic organisms have been studied in laboratory assessments of nanomaterial toxicity. The ecotoxicology of nanomaterials remains an area of deep concern and ongoing research. Anonymous: Acute illnesses associated with insecticides used to control bed bug— seven states, 2003-2010. MMWR 2011;60:1269.


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Pharmacology_Katzung. Anonymous: Acute illnesses associated with insecticides used to control bed bug— seven states, 2003-2010. MMWR 2011;60:1269. Brandt A et al: The neonicotinoids thiacloprid, imidacloprid, and clothianidin affect the immunocompetence of honey bees (Apis mellifera L.). J Insect Physiol 2016;86:40. Bräuner EV et al: A prospective study of organochlorines in adipose tissue and risk of non-Hodgkin lymphoma. Environ Health Perspect 2012;120:105. Buckley A et al: Hyperbaric oxygen for carbon monoxide poisoning: A systematic review and critical analysis of the evidence. Toxicol Rev 2005;24:75. Carlsen HK et al: Ozone is associated with cardiopulmonary and stroke emergency hospital visits in Reykjavík, Iceland 2003–2009. Environ Health 2013;12:28. Cattani D et al: Mechanisms underlying the neurotoxicity induced by glyphosatebased herbicide in immature rat hippocampus. Involvement of glutamate excitotoxicity. Toxicology 2014;320C:34.


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Pharmacology_Katzung. Cattani D et al: Mechanisms underlying the neurotoxicity induced by glyphosatebased herbicide in immature rat hippocampus. Involvement of glutamate excitotoxicity. Toxicology 2014;320C:34. Cha YS et al: Pyrethroid poisoning: Features and predictors of atypical presentations. Emerg Med J 2014;31:899. Cummings KJ et al: A reconsideration of acute beryllium disease. Environ Health Perspect 2009;117:1250. Dockery DW et al: Effect of air pollution control on mortality and hospital admissions in Ireland. Res Rep Health Eff Inst 2013;176:3. Fanelli V et al: Acute respiratory distress syndrome: New definition, current and future therapeutic options. J Thorac Dis 2013;5:326. Fucic A et al: Environmental exposure to xenoestrogens and oestrogen related cancers: Reproductive system, breast, lung, kidney, pancreas, and brain. Environ Health 2012;11(Suppl 1):S8. Gawarammana IB, Buckley NA: Medical management of paraquat ingestion. Br J Clin Pharmacol 2011;72:745.


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Pharmacology_Katzung. Gawarammana IB, Buckley NA: Medical management of paraquat ingestion. Br J Clin Pharmacol 2011;72:745. Geusau A et al: Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: Clinical and laboratory effects. Environ Health Perspect 2001;109:865. Gosselin RE, Smith RP, Hodge HC: Clinical Toxicology of Commercial Products, 5th ed. Williams & Wilkins, 1984. Goyal P, Mishra D, Kumar A: Vehicular emission inventory of criteria pollutants in Delhi. Springerplus 2013;2:216. Haley RW et al: Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicol Appl Pharmacol 1999;157:227. Hamm JI, Chen CY, Birnbaum LS: A mixture of dioxin, furans, and non-ortho PCBs based upon consensus toxic equivalency factors produces dioxin-like reproductive effects. Toxicol Sci 2003;74:182.


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Pharmacology_Katzung. Hamm JI, Chen CY, Birnbaum LS: A mixture of dioxin, furans, and non-ortho PCBs based upon consensus toxic equivalency factors produces dioxin-like reproductive effects. Toxicol Sci 2003;74:182. Hatch GE et al: Biomarkers of dose and effect of inhaled ozone in resting versus exercising human subjects: Comparison with resting rats. Biomark Insights 2013;8:53. Heinrich J et al: Long-term exposure to NO2 and PM10 and all-cause and cause-specific mortality in a prospective cohort of women. Occup Environ Med 2013;70:179. Jacobson JL, Jacobson SW: Association of prenatal exposure to an environmental contaminant with intellectual function in childhood. J Toxicol Clin Toxicol 2002;40:467. Järvholm B, Reuterwall C: A comparison of occupational and non-occupational exposure to diesel exhausts and its consequences for studying health effects. Occup Environ Med 2012;69:851. Kao JW, Nanagas KA: Carbon monoxide poisoning. Emerg Med Clin North Am 2004;22:985.


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Pharmacology_Katzung. Kao JW, Nanagas KA: Carbon monoxide poisoning. Emerg Med Clin North Am 2004;22:985. Kelleher P, Pacheco K, Newman LS: Inorganic dust pneumonias: The metal-related parenchymal disorders. Environ Health Perspect 2000;108(Suppl 4):685. Lorenzoni PJ et al: An electrophysiological study of the intermediate syndrome of organophosphate poisoning. J Clin Neurosci 2010;17:1217. Lotti M, Moretto A: Organophosphate-induced delayed polyneuropathy. Toxicol Rev 2005;24:37. Mann A, Early GL: Acute respiratory distress syndrome. Mo Med 2012;109:371. Maras M et al: Estrogen-like properties of fluorotelemer alcohols as revealed by mcg-7 breast cancer cell proliferation. Environ Health Perspect 2006;114:100. Mrema EJ et al: Persistent organochlorinated pesticides and mechanisms of their toxicity. Toxicology 2013;307:74. Nowack B et al: Analysis of the occupational, consumer and environmental exposure to engineered nanomaterials used in 10 technology sectors. Nanotoxicology 2013;7:1152.


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Pharmacology_Katzung. Nowack B et al: Analysis of the occupational, consumer and environmental exposure to engineered nanomaterials used in 10 technology sectors. Nanotoxicology 2013;7:1152. Rappaport SM et al: Human benzene metabolism following occupational and environmental exposures. Chem Biol Interact 2010;184:189. Raub JA et al: Carbon monoxide poisoning—a public health perspective. Toxicology 2000;145:1. Ray DE, Fry JR: A reassessment of the neurotoxicity of pyrethroid insecticides. Pharmacol Ther 2006;111:174. Rusyn I et al: Trichloroethylene: Mechanistic, epidemiologic and other supporting evidence of carcinogenic hazard. Pharmacol Ther 2014;141:55. Sadasivaiah S, Tozan Y, Breman JG: Dichlorodiphenyltrichloroethane (DDT) for indoor residual spraying in Africa: How can it be used for malaria control? Am J Trop Med Hyg 2007;77(6 Suppl):249. Sharifi S et al: Toxicity of nanomaterials. Chem Soc Rev 2012;41:2323.


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Pharmacology_Katzung. Sharifi S et al: Toxicity of nanomaterials. Chem Soc Rev 2012;41:2323. Shusterman DJ: Polymer fume fever and other fluorocarbon pyrolysis-related syndromes. Occup Med 1993;8:519. Soderlund DM et al: Mechanisms of pyrethroid neurotoxicity: Implications for cumulative risk assessment. Toxicology 2002;171:3. St Hilaire S et al: Estrogen receptor positive breast cancers and their association with environmental factors. Int J Health Geogr 2011;10:10. Storm JE, Rozman KK, Doull J: Occupational exposure limits for 30 organophosphate pesticides based on inhibition of red blood cell acetylcholinesterase. Toxicology 2000;150:1. Trabert B et al: Maternal pregnancy levels of trans-nonachlor and oxychlordane and prevalence of cryptorchidism and hypospadias in boys. Environ Health Perspect 2012;120:478. Vieira VM, et al: Perfluorooctanoic acid exposure and cancer outcomes in a contaminated community: A geographic analysis. Environ Health Perspect 2013;121:318.


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Pharmacology_Katzung. Vieira VM, et al: Perfluorooctanoic acid exposure and cancer outcomes in a contaminated community: A geographic analysis. Environ Health Perspect 2013;121:318. Introduction to Toxicology: Occupational & Environmental 1019 Warheit DB: How to measure hazards/risks following exposures to nanoscale or pigment-grade titanium dioxide particles. Toxicol Lett 2013; 220:193. Warner M et al: Diabetes, metabolic syndrome, and obesity in relation to serum dioxin concentrations: The Seveso women’s health study. Environ Health Perspect 2013;121:906. Wigfield YY, McLenaghan CC: Levels of N-nitrosodimethylamine in nitrogen fertilizers/herbicide mixtures containing 2,4-D present as dimethylamine salt. Bull Environ Contam Toxicol 1990;45:847.


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Pharmacology_Katzung. The child presents with classic signs (and history) of carbon monoxide (CO) exposure. Pulse oximetry is unreliable in CO poisoning, although newer instruments may distinguish between carboxyhemoglobin (CO-Hgb) and oxyhemoglo-bin. Institute the ABCDs of poisoning (see Chapter 58). Immediate high-flow oxygen is mandatory and should be administered via a tight-fitting face mask or endotracheal catheter. A blood sample for blood gases and carboxyhemo-globin content should be obtained. If the CO-Hgb is greater than 50%, hyperbaric oxygen treatment (if available) may be considered. The electrocardiogram should be continuously monitored for arrhythmias. Anticonvulsant drugs may be required if seizures occur. Neurologic damage due to CO exposure may be subtle and long-lasting; the child should be followed for years if necessary. The fetus is particularly sus-ceptible to hypoxia, and if the mother is pregnant, her blood gases and CO-Hgb should be measured. If the latter is high, hyperbaric


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Pharmacology_Katzung. be followed for years if necessary. The fetus is particularly sus-ceptible to hypoxia, and if the mother is pregnant, her blood gases and CO-Hgb should be measured. If the latter is high, hyperbaric oxygen therapy should be considered.


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Pharmacology_Katzung. Michael J. Kosnett, MD, MPH Following Sunday morning services, 27 people attended a church social where coffee, baked goods, and sandwiches were served. Within 15–60 minutes, 13 people developed vomiting and abdominal discomfort, accompanied over the next several hours by nonbloody diarrhea. Within 12 hours, seven of these individuals were hospitalized with ongoing gastrointestinal symptoms, hypotension, and anion gap metabolic acidosis. Fluid resuscitation and pressors were accompanied by adequate urine output. What diagnoses should be considered? What tests should be conducted, and what therapy should be considered?


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Pharmacology_Katzung. Some metals such as iron are essential for life, whereas others such as lead are present in all organisms but serve no useful biologic purpose. Some of the oldest diseases of humans can be traced to heavy metal poisoning associated with metal mining, refining, and use. Even with the present recognition of the hazards of heavy metals, the incidence of intoxication remains significant, and the need for preventive strategies and effective therapy remains high. Toxic heavy metals interfere with the function of essential cations, cause enzyme inhibition, generate oxidative stress, alter gene expression, and perturb cell signaling. As a result, multisystem signs and symptoms are a hallmark of heavy metal intoxication. When intoxication occurs, chelator molecules (from chela “claw”), or their in vivo biotransformation products, may be used to bind the metal and facilitate its excretion from the body. Chelator drugs are discussed in the second part of this chapter.


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Pharmacology_Katzung. Lead poisoning is one of the oldest occupational and environmental diseases in the world. Despite its recognized hazards, lead continues to have widespread commercial application, including production of storage batteries (nearly 90% of US consumption), ammunition, metal alloys, solder, glass, plastics, pigments, and ceramics. Corrosion of lead plumbing in older buildings or supply lines may increase the lead concentration of tap water. Environmental lead exposure, ubiquitous by virtue of the anthropogenic distribution of lead to air, water, and food, has declined considerably in the last three decades as a result of the elimination of lead as an additive in gasoline, as well as diminished contact with lead-based paint and other lead-containing consumer products, such as lead solder in cans used as food containers. Legislation in the United States in 2011 further reduced the maximum permissible lead content of children’s products to 100 ppm. Lead continues to be used in some


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Pharmacology_Katzung. in cans used as food containers. Legislation in the United States in 2011 further reduced the maximum permissible lead content of children’s products to 100 ppm. Lead continues to be used in some formulations of aviation gasoline for piston-engine aircraft. The presence of lead in certain folk medicines (eg, the Mexican remedies azarcon and greta, and certain Ayurvedic preparations) and in cosmetics (eg, kohl utilized around the eyes in certain African and Asian communities) has contributed to lead exposure to children and adults. Although public health measures, together with improved workplace conditions, have decreased the incidence of serious overt lead poisoning, there remains considerable concern over the effects of low-level lead exposure. Extensive evidence indicates that low levels of lead exposure may have subtle subclinical adverse effects on neurocognitive function in children and may contribute to hypertension and cardiovascular disease in adults. Lead serves no useful


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Pharmacology_Katzung. of lead exposure may have subtle subclinical adverse effects on neurocognitive function in children and may contribute to hypertension and cardiovascular disease in adults. Lead serves no useful purpose in the human body. In key target organs such as the developing central nervous system, no level of lead exposure has been shown to be without deleterious effects.


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Pharmacology_Katzung. Inorganic lead is slowly but consistently absorbed via the respiratory and gastrointestinal tracts. It is poorly absorbed through the skin. Absorption of lead dust via the respiratory tract is the most common cause of industrial poisoning. The intestinal tract is the primary route of entry in nonindustrial exposure (Table 57–1). Absorption via the gastrointestinal tract varies with the nature of the lead compound, but in general, adults absorb about 10–15% of the ingested amount, whereas young children absorb up to 50%. Low dietary calcium, iron deficiency, and ingestion on an empty stomach all have been associated with increased lead absorption.


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Pharmacology_Katzung. Once absorbed from the respiratory or gastrointestinal tract, lead enters the bloodstream, where approximately 99% is bound to erythrocytes and 1% is present in the plasma. Lead is subsequently distributed to soft tissues such as the bone marrow, brain, kidney, liver, muscle, and gonads; then to the subperiosteal surface of bone; and later to bone matrix. Lead also crosses the placenta and poses a potential hazard to the fetus. The kinetics of lead clearance from the body follows a multicompartment model, composed predominantly of the blood and soft tissues, with a half-life of 1–2 months; and the skeleton, with a half-life of years to decades. Approximately 70% of the lead that is eliminated appears in the urine, with lesser amounts excreted through the bile, skin, hair, nails, sweat, and breast milk. The fraction not undergoing prompt excretion, approximately half of the absorbed lead, may be incorporated into the skeleton, the repository of more than 90% of the body lead burden in


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Pharmacology_Katzung. breast milk. The fraction not undergoing prompt excretion, approximately half of the absorbed lead, may be incorporated into the skeleton, the repository of more than 90% of the body lead burden in most adults. In patients with high bone lead burdens, slow release from the skeleton may elevate blood lead concentrations for years after exposure ceases, and pathologic high bone turnover states such as hyperthyroidism or prolonged immobilization may result in frank lead intoxication. Migration of retained lead bullet fragments into a joint space or adjacent to bone has been associated with the development of lead poisoning signs and symptoms years or decades after an initial gunshot injury.


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Pharmacology_Katzung. Lead exerts multisystemic toxic effects that are mediated by multiple modes of action, including inhibition of enzymatic function; interference with the action of essential cations, particularly calcium, iron, and zinc; generation of oxidative stress; changes in gene expression; alterations in cell signaling; and disruption of the integrity of membranes in cells and intracellular organelles. TABLE 57–1 Toxicology of selected arsenic, lead, and mercury compounds. A. Nervous System


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Pharmacology_Katzung. TABLE 57–1 Toxicology of selected arsenic, lead, and mercury compounds. A. Nervous System The developing central nervous system of the fetus and young child is the most sensitive target organ for lead’s toxic effect. Epidemiologic studies suggest that blood lead concentrations <5 mcg/dL may result in subclinical deficits in neurocognitive function in lead-exposed young children, with no demonstrable threshold or “no effect” level. The dose response between low blood lead concentrations and cognitive function in young children is nonlinear, such that the decrement in intelligence associated with an increase in blood lead from <1–10 mcg/dL (6.2 IQ points) exceeds that associated with a change from 10 to 30 mcg/dL (3.0 IQ points).


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Pharmacology_Katzung. Adults are less sensitive to the central nervous system (CNS) effects of lead, but long-term exposure to blood lead concentrations in the range of 10–30 mcg/dL may be associated with subclinical effects on neurocognitive function. At blood lead concentrations higher than 30 mcg/dL, behavioral and neurocognitive signs or symptoms may gradually emerge, including irritability, fatigue, decreased libido, anorexia, sleep disturbance, impaired visual-motor coordination, and slowed reaction time. Headache, arthralgias, and myalgias are also common complaints. Tremor occurs but is less common. Lead encephalopathy, usually occurring at blood lead concentrations higher than 100 mcg/dL, is typically accompanied by increased intracranial pressure and may cause ataxia, stupor, coma, convulsions, and death. Recent epidemiological studies suggest that lead may accentuate an age-related decline in cognitive function in older adults. In experimental animals, developmental lead exposure, possibly


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Pharmacology_Katzung. and death. Recent epidemiological studies suggest that lead may accentuate an age-related decline in cognitive function in older adults. In experimental animals, developmental lead exposure, possibly acting through epigenetic mechanisms, has been associated with increased expression of beta-amyloid, increased phosphorylated tau protein, oxidative DNA damage, and Alzheimer’s-type pathology in the aging brain. There is wide interindividual variation in the magnitude of lead exposure required to cause overt lead-related signs and symptoms.


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Pharmacology_Katzung. Overt peripheral neuropathy may appear after chronic high-dose lead exposure, usually following months to years of blood lead concentrations higher than 100 mcg/dL. Predominantly motor in character, the neuropathy may present clinically with painless weakness of the extensors, particularly in the upper extremity, resulting in classic wrist-drop. Preclinical signs of lead-induced peripheral nerve dysfunction may be detectable by electrodiagnostic testing. B. Blood


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Pharmacology_Katzung. Lead can induce an anemia that may be either normocytic or microcytic and hypochromic. Lead interferes with heme synthesis by blocking the incorporation of iron into protoporphyrin IX and by inhibiting the function of enzymes in the heme synthesis pathway, including aminolevulinic acid dehydratase and ferrochelatase. Within 2–8 weeks after an elevation in blood lead concentration (generally to 30–50 mcg/dL or greater), increases in heme precursors, notably free erythrocyte protoporphyrin or its zinc chelate, zinc protoporphyrin, may be detectable in whole blood. Lead also contributes to anemia by increasing erythrocyte membrane fragility and decreasing red cell survival time. Frank hemolysis may occur with high exposure. Basophilic stippling on the peripheral blood smear, thought to be a consequence of lead inhibition of the enzyme 3′,5′-pyrimidine nucleotidase, is sometimes a suggestive—albeit insensitive and nonspecific—diagnostic clue to the presence of lead intoxication.


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Pharmacology_Katzung. C. Kidneys Chronic high-dose lead exposure, usually associated with months to years of blood lead concentrations >80 mcg/dL, may result in renal interstitial fibrosis and nephrosclerosis. Lead nephropathy may have a latency period of years. Lead may alter uric acid excretion by the kidney, resulting in recurrent bouts of gouty arthritis (“saturnine gout”). Acute high-dose lead exposure sometimes produces transient azotemia, possibly as a consequence of intrarenal vasoconstriction. Studies conducted in general population samples have documented an association between blood lead concentration and measures of renal function, including serum creatinine and creatinine clearance. The presence of other risk factors for renal insufficiency, including hypertension and diabetes, may increase susceptibility to lead-induced renal dysfunction. D. Reproductive Organs


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Pharmacology_Katzung. D. Reproductive Organs High-dose lead exposure is a recognized risk factor for stillbirth or spontaneous abortion. Epidemiologic studies of the impact of low-level lead exposure on reproductive outcome such as low birth weight, preterm delivery, or spontaneous abortion have yielded mixed results. However, a well-designed nested case-control study detected an odds ratio for spontaneous abortion of 1.8 (95% CI 1.1–3.1) for every 5 mcg/dL increase in maternal blood lead across an approximate range of 5–20 mcg/dL. Recent studies have linked prenatal exposure to low levels of lead (eg, maternal blood lead concentrations of 5–15 mcg/dL) to decrements in physical and cognitive development assessed during the neonatal period and early childhood. In males, blood lead concentrations higher than 40 mcg/dL have been associated with diminished or aberrant sperm production. E. Gastrointestinal Tract


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Pharmacology_Katzung. E. Gastrointestinal Tract Moderate lead poisoning may cause loss of appetite, constipation, and, less commonly, diarrhea. At high dosage, intermittent bouts of severe colicky abdominal pain (“lead colic”) may occur. The mechanism of lead colic is unclear but is believed to involve spasmodic contraction of the smooth muscles of the intestinal wall, mediated by alteration in synaptic transmission at the smooth muscle-neuromuscular junction. In heavily exposed individuals with poor dental hygiene, the reaction of circulating lead with sulfur ions released by microbial action may produce dark deposits of lead sulfide at the gingival margin (“gingival lead lines”). Although frequently mentioned as a diagnostic clue in the past, in recent times this has been a relatively rare sign of lead exposure. F. Cardiovascular System


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Pharmacology_Katzung. Epidemiologic, experimental, and in vitro mechanistic data indicate that lead exposure elevates blood pressure in experimental animals and in susceptible humans. The pressor effect of lead may be mediated by an interaction with calcium-mediated contraction of vascular smooth muscle, as well as generation of oxidative stress and an associated interference in nitric oxide signaling pathways. In populations with environmental or occupational lead exposure, blood lead concentration is linked with increases in systolic and diastolic blood pressure. Studies of middle-aged and elderly men and women have identified relatively low levels of lead exposure sustained by the general population to be an independent risk factor for hypertension. Lead exposure has also been associated with prolongation of the QTc interval on the electrocardiogram. Epidemiologic studies have linked chronic environmental lead exposure associated with population blood lead concentrations in the range of 10–25 mcg/dL to


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Pharmacology_Katzung. the QTc interval on the electrocardiogram. Epidemiologic studies have linked chronic environmental lead exposure associated with population blood lead concentrations in the range of 10–25 mcg/dL to a significantly increased risk of cardiovascular mortality. This is of considerable public health concern because these concentrations were prevalent in the USA prior to the 1980s. Although general population blood lead concentrations have since fallen considerably (see below), exposure associated with blood lead in this range persists in occupational settings worldwide.


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Pharmacology_Katzung. Major Forms of Lead Intoxication A. Inorganic Lead Poisoning (Table 57–1) 1. Acute—Acute inorganic lead poisoning is uncommon today. It usually results from industrial inhalation of large quantities of lead oxide fumes or, in small children, from ingestion of a large oral dose of lead in the form of lead-based paint chips; small objects, eg, toys coated or fabricated from lead; or contaminated food or drink. The onset of severe symptoms usually requires several days or weeks of recurrent exposure and manifests as signs and symptoms of encephalopathy or colic. Evidence of hemolytic anemia (or anemia with basophilic stippling if exposure has been subacute) and elevated hepatic aminotransferases may be present.


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Pharmacology_Katzung. The diagnosis of acute inorganic lead poisoning may be difficult, and depending on the presenting symptoms, the condition has sometimes been mistaken for appendicitis, peptic ulcer, biliary colic, pancreatitis, or infectious meningitis. Subacute presentation, featuring headache, fatigue, intermittent abdominal cramps, myalgias, and arthralgias, has often been mistaken for a flu-like viral illness. When there has been recent ingestion of lead-containing paint chips, glazes, pellets, or weights, radiopacities may be visible on abdominal radiographs. 2.


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Pharmacology_Katzung. 2. Chronic—The patient with symptomatic chronic lead intoxication typically presents with multisystemic findings, including complaints of anorexia, fatigue, and malaise; neurologic complaints, including headache, difficulty in concentrating, and irritability or depressed mood; weakness, arthralgias, or myalgias; and gastrointestinal symptoms. Lead poisoning should be strongly suspected in any patient presenting with headache, abdominal pain, and anemia; and less commonly with motor neuropathy, gout, and renal insufficiency. Chronic lead intoxication should be considered in any child with neurocognitive deficits, growth retardation, or developmental delay. It is important to recognize that adverse effects of lead that are of considerable public health significance, such as subclinical decrements in neurodevelopment in children and hypertension in adults, are usually nonspecific and may not come to medical attention.


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Pharmacology_Katzung. The diagnosis of lead intoxication is best confirmed by measuring lead in whole blood. Although this test reflects lead currently circulating in blood and soft tissues and is not a reliable marker of either recent or cumulative lead exposure, most patients with lead-related disease have blood lead concentrations higher than the normal range. Average background blood lead concentrations in North America and Europe have declined by 90% in recent decades, and the geometric mean blood lead concentration in the United States in 2011–2012 was estimated to be 0.973 mcg/dL. Though predominantly a research tool, the concentration of lead in bone assessed by noninvasive K X-ray fluorescence measurement of lead has been correlated with long-term cumulative lead exposure, and its relationship to numerous lead-related disorders is the subject of ongoing investigation. Measurement of lead excretion in the urine after a single dose of a chelating agent (sometimes called a “chelation challenge test”)


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Pharmacology_Katzung. lead-related disorders is the subject of ongoing investigation. Measurement of lead excretion in the urine after a single dose of a chelating agent (sometimes called a “chelation challenge test”) primarily reflects the lead content of soft tissues and may not be a reliable marker of long-term lead exposure, remote past exposure, or skeletal lead burden. Accordingly, this test is rarely indicated in clinical practice. Because of the lag time associated with lead-induced elevations in circulating heme precursors, the finding of a blood lead concentration of 30 mcg/dL or more with no concurrent increase in zinc protoporphyrin suggests that the lead exposure was of recent onset.


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Pharmacology_Katzung. B. Organolead Poisoning Poisoning from organolead compounds is now very rare, in large part because of the worldwide phase-out of tetraethyl and tetra-methyl lead as antiknock additives in gasoline. However, organolead compounds such as lead stearate or lead naphthenate are still used in certain commercial processes. Because of their volatility or lipid solubility, organolead compounds tend to be well absorbed through either the respiratory tract or the skin. Organolead compounds predominantly target the CNS, producing dose-dependent effects that may include neurocognitive deficits, insomnia, delirium, hallucinations, tremor, convulsions, and death. A. Inorganic Lead Poisoning


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Pharmacology_Katzung. A. Inorganic Lead Poisoning Treatment of inorganic lead poisoning involves immediate termination of exposure, supportive care, and the judicious use of chelation therapy. (Chelation is discussed later in this chapter.) Lead encephalopathy is a medical emergency that requires intensive supportive care. Cerebral edema may improve with corticosteroids and mannitol or hypertonic saline, and anticonvulsants may be required to treat seizures. Radiopacities on abdominal radiographs may suggest the presence of retained lead objects requiring gastrointestinal decontamination. Adequate urine flow should be maintained, but overhydration should be avoided. Intravenous edetate calcium disodium (CaNa2EDTA) is administered at a dosage of 1000–1500 mg/m2/d (approximately 30–50 mg/kg/d) by continuous infusion for up to 5 days. Some clinicians advocate


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Pharmacology_Katzung. Production of lead began 6000 years ago, and lead poisoning is one of the oldest known occupational illnesses. Worldwide, lead production has doubled over the past two decades in part because of the growing demand for lead acid storage batteries. Efforts to prevent lead poisoning from multiple industrial, commercial, and environmental sources remain an active focus of public health in the USA.


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Pharmacology_Katzung. that chelation treatment for lead encephalopathy be initiated with an intramuscular injection of dimercaprol, followed in 4 hours by concurrent administration of dimercaprol and EDTA. Parenteral chelation is limited to 5 or fewer days, at which time oral treatment with another chelator, succimer (DMSA), may be instituted. In symptomatic lead intoxication without encephalopathy, treatment may sometimes be initiated with succimer. The end point for chelation is usually resolution of symptoms or return of the blood lead concentration to the premorbid range. In patients with chronic exposure, cessation of chelation may be followed by an upward rebound in blood lead concentration as the lead re-equilibrates from bone lead stores.


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Pharmacology_Katzung. Although most clinicians support chelation for symptomatic patients with elevated blood lead concentrations, the decision to chelate asymptomatic subjects is more controversial. Since 1991, the Centers for Disease Control and Prevention (CDC) has recommended chelation for all children with blood lead concentrations of 45 mcg/dL or greater. However, a randomized, double-blind, placebo-controlled clinical trial of succimer in children with blood lead concentrations between 25 and 44 mcg/dL found no benefit on neurocognitive function or long-term blood lead reduction. Prophylactic use of chelating agents in the workplace should never be a substitute for reduction or prevention of excessive exposure.


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Pharmacology_Katzung. Management of elevated blood lead levels in children and adults should include a conscientious effort to identify and reduce all potential sources of future lead exposure. Many local, state, or national governmental agencies maintain lead poisoning prevention programs that can assist in case management. Blood lead screening of family members or coworkers of a lead poisoning patient is often indicated to assess the scope of the exposure. In 2012, the CDC adopted a new policy that defined as elevated any childhood blood lead concentrations at or exceeding a reference value corresponding to the 97.5th percentile of quadrennial reports of the National Health and Nutrition Examination Survey (NHANES). The blood lead reference value established in 2012 was 5 mcg/dL, and it is projected to decline in the future. Because there is no blood lead concentration known to be devoid of deleterious effects, the finding of a blood lead concentration exceeding the reference value (ie, elevated in


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Pharmacology_Katzung. decline in the future. Because there is no blood lead concentration known to be devoid of deleterious effects, the finding of a blood lead concentration exceeding the reference value (ie, elevated in relation to the general population) should prompt clinical and environmental investigation (https://www.cdc.gov/nceh/lead/acclpp/final_document_030712.pdf ). Although the US Occupational Safety and Health Administration (OSHA) lead regulations introduced in the late 1970s mandate that workers be removed from lead exposure for blood lead levels higher than 50–60 mcg/dL, an expert panel in 2007 recommended that removal be initiated for a single blood lead level >30 mcg/dL or when two successive blood lead levels measured over a 4-week interval are 20 mcg/dL or greater (https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC1849937/pdf/ehp0115-000463.pdf ). The longer-term goal should be for workers to maintain blood lead levels <10 mcg/dL, and for pregnant women to avoid occupational or avocational


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Pharmacology_Katzung. articles/PMC1849937/pdf/ehp0115-000463.pdf ). The longer-term goal should be for workers to maintain blood lead levels <10 mcg/dL, and for pregnant women to avoid occupational or avocational exposure that would result in blood lead levels higher than 5 mcg/dL. Environmental Protection Agency (EPA) regulations effective since 2010 require that contractors who perform renovation, repair, and painting projects that disturb lead-based paint in pre-1978 residences and child-occupied facilities must be certified and must follow specific work practices to prevent lead contamination (see Box: Prevention of Lead Poisoning: An Ongoing Effort).


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Pharmacology_Katzung. B. Organic Lead Poisoning Initial treatment consists of decontaminating the skin and preventing further exposure. Treatment of seizures requires appropriate use of anticonvulsants. Empiric chelation may be attempted if high blood lead concentrations are present.


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Pharmacology_Katzung. Arsenic is a naturally occurring element in the earth’s crust with a long history of use as a constituent of commercial and industrial products, as a component in pharmaceuticals, and as an agent of deliberate poisoning. Recent commercial applications of arsenic include its use in the manufacture of semiconductors, wood preservatives for industrial applications (eg, marine timbers or utility poles), nonferrous alloys, glass, and the turf herbicide monosodium methane arsonate (MSMA). The use of phenyl-arsenic compounds as feed additives for poultry and swine was terminated in the United States in 2015. In some regions of the world, groundwater may contain high levels of arsenic that has leached from natural mineral deposits. Arsenic in drinking water in the Ganges delta of India and Bangladesh is now recognized as one of the world’s most pressing environmental health problems. Environmental risk assessments have suggested that arsenic migrating from coal combustion wastes (eg, coal


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Pharmacology_Katzung. is now recognized as one of the world’s most pressing environmental health problems. Environmental risk assessments have suggested that arsenic migrating from coal combustion wastes (eg, coal ash) deposited in unlined landfills may contaminate underlying groundwater. Arsine, an arsenous hydride (AsH3) gas with potent hemolytic effects, is manufactured predominantly for use in the semiconductor industry but may also be generated accidentally when arsenic-containing ores or scrap gallium arsenide semiconductors come in contact with acidic solutions.


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Pharmacology_Katzung. It is of historical interest that Fowler’s solution, which contains 1% potassium arsenite, was widely used as a medicine for many conditions from the eighteenth century through the mid-twentieth century. Organic arsenicals were the first pharmaceutical antimicrobials * and were widely used for the first half of the twentieth century until supplanted by sulfonamides and other more effective and less toxic agents. Other organoarsenicals, most notably lewisite (dichloro[2-chlorovinyl]arsine), were developed in the early 20th century as chemical warfare agents. Arsenic trioxide was reintroduced into the United States Pharmacopeia in 2000 as an orphan drug for the treatment of relapsed acute promyelocytic leukemia and is finding expanded use in experimental cancer treatment protocols. Melarsoprol, another trivalent arsenical, is used in the treatment of advanced African trypanosomiasis (see Chapter 52).


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Pharmacology_Katzung. Soluble arsenic compounds are well absorbed through the respiratory and gastrointestinal tracts (Table 57–1). Percutaneous absorption is limited but may be clinically significant after heavy exposure to concentrated arsenic reagents. Most of the absorbed inorganic arsenic undergoes methylation, mainly in the liver, to monomethylarsonic acid and dimethylarsinic acid, which are excreted, along with residual inorganic arsenic, in the urine. When chronic daily absorption is <1000 mcg of soluble inorganic arsenic, approximately two thirds of the absorbed dose is excreted in the urine within 2–3 days. After massive ingestions, the elimination half-life is prolonged. Inhalation of arsenic compounds of low solubility may result in prolonged retention in the lung and may not be reflected by urinary arsenic excretion. Arsenic binds to sulfhydryl groups present in keratinized tissue, and following cessation of exposure, hair, nails, and skin may contain elevated levels after urine values have


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Pharmacology_Katzung. arsenic excretion. Arsenic binds to sulfhydryl groups present in keratinized tissue, and following cessation of exposure, hair, nails, and skin may contain elevated levels after urine values have returned to normal. However, arsenic in hair and nails as a result of external deposition may be indistinguishable from that incorporated after internal absorption.


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Pharmacology_Katzung. Arsenic compounds are thought to exert their toxic effects by several modes of action. Interference with enzyme function may result from sulfhydryl group binding by trivalent arsenic or by * Paul Ehrlich’s “magic bullet” for syphilis (arsphenamine, Salvarsan) was an arsenical.


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Pharmacology_Katzung. substitution for phosphate. Inorganic arsenic or its metabolites may induce oxidative stress, alter gene expression, and interfere with cell signal transduction. Although on a molar basis, inorganic trivalent arsenic (As3+, arsenite) is generally two to ten times more acutely toxic than inorganic pentavalent arsenic (As5+, arsenate), in vivo interconversion is known to occur, and the full spectrum of arsenic toxicity has occurred after sufficient exposure to either form. Recent studies suggest that the trivalent form of the methylated metabolites (eg, monomethylarsonous acid [MMAIII]) may be more toxic than the inorganic parent compounds. Reduced efficiency in the methylation of MMA to dimethylarsonous acid (DMA), resulting in an elevated percentage of MMA in the urine, has been associated with an increased risk of chronic adverse effects. Arsenic methylation requires S-adenosylmethionine, a universal methyl donor in the body, and arsenic-associated perturbations in one-carbon


Pharmacology_Katzung

Pharmacology_Katzung. with an increased risk of chronic adverse effects. Arsenic methylation requires S-adenosylmethionine, a universal methyl donor in the body, and arsenic-associated perturbations in one-carbon metabolism may underlie some arsenic-induced epigenetic effects such as altered gene expression.


Pharmacology_Katzung

Pharmacology_Katzung. Arsine gas is oxidized in vivo and exerts a potent hemolytic effect associated with alteration of ion flux across the erythrocyte membrane; it also disrupts cellular respiration in other tissues. Arsenic is a recognized human carcinogen and has been associated with cancer of the lung, skin, and bladder. Marine organisms may contain large amounts of a well-absorbed trimethylated organoarsenic, arsenobetaine, as well as a variety of arsenosugars and arsenolipids. Arsenobetaine exerts no known toxic effects when ingested by mammals and is excreted in the urine unchanged; arsenosugars are partially metabolized to dimethylarsinic acid. Thioarsenite compounds that occur as minor metabolites of inorganic arsenic and methylated arsenic compounds in vivo may contribute to toxicity. Major Forms of Arsenic Intoxication A. Acute Inorganic Arsenic Poisoning


Pharmacology_Katzung

Pharmacology_Katzung. Within minutes to hours after exposure to high doses (tens to hundreds of milligrams) of soluble inorganic arsenic compounds, many systems are affected. Initial gastrointestinal signs and symptoms include nausea, vomiting, diarrhea, and abdominal pain. Diffuse capillary leak, combined with gastrointestinal fluid loss, may result in hypotension, shock, and death. Cardiopulmonary toxicity, including congestive cardiomyopathy, cardiogenic or noncardiogenic pulmonary edema, and ventricular arrhythmias (particularly in association with QTc prolongation on the electrocardiogram) may occur promptly or after a delay of several days. Pancytopenia usually develops within 1 week, and basophilic stippling of erythrocytes may be present soon after. Central nervous system effects, including delirium, encephalopathy, and coma, may occur within the first few days of intoxication. An ascending sensorimotor peripheral neuropathy may begin to develop after a delay of 2–6 weeks. This neuropathy may


Pharmacology_Katzung

Pharmacology_Katzung. encephalopathy, and coma, may occur within the first few days of intoxication. An ascending sensorimotor peripheral neuropathy may begin to develop after a delay of 2–6 weeks. This neuropathy may ultimately involve the proximal musculature and result in neuromuscular respiratory failure. Months after an acute poisoning, transverse white striae (Aldrich-Mees lines) may be visible in the nails.


Pharmacology_Katzung

Pharmacology_Katzung. Acute inorganic arsenic poisoning should be considered in an individual presenting with abrupt onset of gastroenteritis in combination with hypotension and metabolic acidosis. Suspicion should be further heightened when these initial findings are followed by cardiac dysfunction, pancytopenia, and peripheral neuropathy. The diagnosis may be confirmed by demonstration of elevated amounts of inorganic arsenic and its metabolites in the urine (typically in the range of several thousand micrograms in the first 2–3 days after acute symptomatic poisoning). Arsenic disappears rapidly from the blood, and except in anuric patients, blood arsenic levels should not be used for diagnostic purposes. Treatment is based on appropriate gut decontamination, intensive supportive care, and prompt chelation with unithiol, 3–5 mg/kg intravenously every 4–6 hours, or dimercaprol, 3–5 mg/kg intramuscularly every 4–6 hours. In animal studies, the efficacy of chelation has been highest when it is administered


Pharmacology_Katzung

Pharmacology_Katzung. unithiol, 3–5 mg/kg intravenously every 4–6 hours, or dimercaprol, 3–5 mg/kg intramuscularly every 4–6 hours. In animal studies, the efficacy of chelation has been highest when it is administered within minutes to hours after arsenic exposure; therefore, if diagnostic suspicion is high, treatment should not be withheld for the several days to weeks often required to obtain laboratory confirmation.


Pharmacology_Katzung

Pharmacology_Katzung. Succimer has also been effective in animal models and has a higher therapeutic index than dimercaprol. However, because it is available in the United States only for oral administration, its use may not be advisable in the initial treatment of acute arsenic poisoning, when severe gastroenteritis and splanchnic edema may limit absorption by this route. B. Chronic Inorganic Arsenic Poisoning


Pharmacology_Katzung

Pharmacology_Katzung. Chronic inorganic arsenic poisoning also results in multisystemic signs and symptoms. Overt noncarcinogenic effects may be evident after chronic absorption of more than 0.01 mg/kg/d (~500–1000 mcg/d in adults). The time to appearance of symptoms varies with dose and interindividual tolerance. Constitutional symptoms of fatigue, weight loss, and weakness may be present, along with anemia, nonspecific gastrointestinal complaints, and a sensorimotor peripheral neuropathy, particularly featuring a stocking glove pattern of dysesthesia. Skin changes—among the most characteristic effects—typically develop after years of exposure and include a “raindrop” pattern of hyperpigmentation, and hyperkeratoses involving the hands and feet (Figure 57–1). Peripheral vascular disease and noncirrhotic portal hypertension may also occur. Epidemiologic studies suggest a possible link to hypertension, cardiovascular disease mortality, diabetes, chronic nonmalignant respiratory disease, and adverse


Pharmacology_Katzung

Pharmacology_Katzung. portal hypertension may also occur. Epidemiologic studies suggest a possible link to hypertension, cardiovascular disease mortality, diabetes, chronic nonmalignant respiratory disease, and adverse reproductive outcomes. Cancer of the lung, skin, bladder, and possibly other sites, including the kidney and liver, may appear years after exposure to doses of arsenic that are not high enough to elicit other acute or chronic effects. Some studies suggest that tobacco smoking may interact synergistically with arsenic in increasing the risk of certain adverse health outcomes.


Pharmacology_Katzung

Pharmacology_Katzung. Administration of arsenite in cancer chemotherapy regimens, often at a daily dose of 10–20 mg for weeks to a few months, has been associated with prolongation of the QT interval on the electrocardiogram and occasionally has resulted in malignant ventricular arrhythmias such as torsades de pointes.


Pharmacology_Katzung

Pharmacology_Katzung. The diagnosis of chronic arsenic poisoning involves integration of the clinical findings with confirmation of exposure. The urine concentration of the sum of inorganic arsenic and its primary metabolites MMA and DMA is <20 mcg/L in the general population. High urine levels associated with overt adverse effects may return to normal within days to weeks after exposure ceases. Because it may contain large amounts of nontoxic organoarsenic such as arsenobetaine, or arsenosugars that are metabolized to DMA, all seafood should be avoided for at least 3 days before submission of a urine sample for diagnostic purposes. The arsenic content of hair and nails (normally <1 ppm) may sometimes reveal past elevated exposure, but results should be interpreted cautiously in view of the potential for external contamination. Segmental analysis of hair or nails using sensitive methods such as neutron activation analysis or synchrotron radiation sources may sometimes have forensic value for investigation


Pharmacology_Katzung

Pharmacology_Katzung. contamination. Segmental analysis of hair or nails using sensitive methods such as neutron activation analysis or synchrotron radiation sources may sometimes have forensic value for investigation of the temporal pattern of arsenic poisoning.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 57–1 Dermatologic lesions associated with chronic ingestion of arsenic in drinking water. (Photo courtesy of Dipankar Chakraborti, PhD.) Management of chronic arsenic poisoning consists primarily of termination of exposure and nonspecific supportive care. Although empiric short-term oral chelation with unithiol or succimer for symptomatic individuals with elevated urine arsenic concentrations may be considered, it has no proven benefit beyond removal from exposure alone. Preliminary studies suggest that dietary supplementation of folate—thought to be a cofactor in arsenic methylation—might be of value in arsenic-exposed individuals, particularly men, who are also deficient in folate. C. Arsine Gas Poisoning


Pharmacology_Katzung

Pharmacology_Katzung. Arsine gas poisoning produces a distinctive pattern of intoxication dominated by profound hemolytic effects. After a latent period that may range from 2 to 24 hours postinhalation (depending on the magnitude of exposure), massive intravascular hemolysis may occur. Initial symptoms may include malaise, headache, dyspnea, weakness, nausea, vomiting, abdominal pain, jaundice, and hemoglobinuria. Oliguric renal failure, a consequence of hemoglobin deposition in the renal tubules, often appears within 1–3 days. In massive exposures, lethal effects on cellular respiration may occur before renal failure develops. Urinary arsenic levels are elevated but are seldom available to confirm the diagnosis during the critical period of illness. Intensive supportive care—including exchange transfusion, vigorous hydration, and, in the case of acute renal failure, hemodialysis—is the mainstay of therapy. Currently available chelating agents have not been demonstrated to be of clinical value in arsine


Pharmacology_Katzung

Pharmacology_Katzung. vigorous hydration, and, in the case of acute renal failure, hemodialysis—is the mainstay of therapy. Currently available chelating agents have not been demonstrated to be of clinical value in arsine poisoning.


Pharmacology_Katzung

Pharmacology_Katzung. Metallic mercury as “quicksilver”—the only metal that is liquid under ordinary conditions—has attracted scholarly and scientific interest from antiquity. The mining of mercury was early recognized as being hazardous to health. As industrial use of mercury became common during the last 200 years, new forms of toxicity were recognized that were found to be associated with various transformations of the metal. In the early 1950s, a mysterious epidemic of birth defects and neurologic disease occurred in the Japanese fishing village of Minamata. The causative agent was determined to be methylmercury in contaminated seafood, traced to industrial discharges into the bay from a nearby factory. In addition to elemental mercury and alkylmercury (including methylmercury), other key mercurials include inorganic mercury salts and aryl mercury compounds, each of which exerts a relatively unique pattern of clinical toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Mercury is mined predominantly as HgS in cinnabar ore and is then converted commercially to a variety of chemical forms. Key industrial and commercial applications of mercury are found in the electrolytic production of chlorine and caustic soda; the manufacture of electrical equipment, thermometers, and other instruments; fluorescent lamps; and dental amalgam. The widespread use of elemental mercury in artisanal gold production is a growing problem in many developing countries. Mercury use in pharmaceuticals and in biocides has declined substantially in recent years, but occasional use in antiseptics, folk medicines, and cosmetic skin-lightening creams is still encountered. Thimerosal, an organomercurial preservative that is metabolized in part to ethylmercury, has been removed from almost all the vaccines in which it was formerly present. Environmental releases of mercury from the burning of fossil fuels, which contributes to the bioaccumulation of methylmercury in fish, remains a


Pharmacology_Katzung

Pharmacology_Katzung. all the vaccines in which it was formerly present. Environmental releases of mercury from the burning of fossil fuels, which contributes to the bioaccumulation of methylmercury in fish, remains a concern in some regions of the world. Low-level exposure to mercury released from dental amalgam fillings occurs, but systemic toxicity from this source has not been established.


Pharmacology_Katzung

Pharmacology_Katzung. The United States banned the export of elemental mercury in 2013. Once fully implemented, the international Minamata Convention on Mercury, signed by 128 countries since 2013, will result in a worldwide phase-out by 2020 of mercury in numerous products including batteries, switches and relays, fluorescent lamps, pesticides, biocides and antiseptics, measuring instruments (eg, thermometers, sphygmomanometers), and manufacturing processes such as chloralkali production (by 2025)


Pharmacology_Katzung

Pharmacology_Katzung. The absorption of mercury varies considerably depending on the chemical form of the metal. Elemental mercury is quite volatile and can be absorbed from the lungs (Table 57–1). It is poorly absorbed from the intact gastrointestinal tract. Inhaled mercury is the primary source of occupational exposure. Organic short-chain alkylmercury compounds are volatile and potentially harmful by inhalation as well as by ingestion. Percutaneous absorption of metallic mercury and inorganic mercury can be of clinical concern following massive acute or long-term chronic exposure. Alkylmercury compounds appear to be well absorbed through the skin, and acute contact with a few drops of dimethylmercury has resulted in severe, delayed toxicity. After absorption, mercury is distributed to the tissues within a few hours, with the highest concentration occurring in the kidney. Inorganic mercury is excreted through the urine and feces. Excretion of inorganic mercury follows a multi-compartment model: most is


Pharmacology_Katzung

Pharmacology_Katzung. few hours, with the highest concentration occurring in the kidney. Inorganic mercury is excreted through the urine and feces. Excretion of inorganic mercury follows a multi-compartment model: most is excreted within weeks to months, but a fraction may be retained in the kidneys and brain for years. After inhalation of elemental mercury vapor, urinary mercury levels decline with a half-life of approximately 1–3 months. Urine mercury concentration is <3 mcg/L in most individuals without occupational exposure, and the median general population urine mercury concentration in the 2011–2012 NHANES was 0.324 mcg/L. Methylmercury, which has a blood and whole-body half-life of approximately 50 days, undergoes biliary excretion and enterohepatic circulation, with more than two thirds eventually excreted in the feces. The geometric mean total blood mercury concentration in the US population in the 2011–2012 NHANES was 0.703 mcg/L; the 95th percentile was 4.40 mcg/L (~90% present as


Pharmacology_Katzung

Pharmacology_Katzung. excreted in the feces. The geometric mean total blood mercury concentration in the US population in the 2011–2012 NHANES was 0.703 mcg/L; the 95th percentile was 4.40 mcg/L (~90% present as methylmercury). Mercury binds to sulfhydryl groups in keratinized tissue, and as with lead and arsenic, traces appear in the hair and nails. Mercury in hair has served as a valid biomarker of methylmercury exposure over an interval of weeks to months in epidemiologic studies.


Pharmacology_Katzung

Pharmacology_Katzung. Major Forms of Mercury Intoxication Mercury interacts with sulfhydryl groups in vivo, inhibiting enzymes and altering cell membranes. The pattern of clinical intoxication from mercury depends to a great extent on the chemical form of the metal and the route and severity of exposure. A. Acute Acute inhalation of elemental mercury vapors may cause chemical pneumonitis and noncardiogenic pulmonary edema. Acute gingivostomatitis may occur, and neurologic sequelae (see following text) may also ensue. Acute ingestion of inorganic mercury salts, such as mercuric chloride, can result in a corrosive, potentially life-threatening hemorrhagic gastroenteritis followed within hours to days by acute tubular necrosis and oliguric renal failure. B. Chronic


Pharmacology_Katzung

Pharmacology_Katzung. Chronic poisoning from inhalation of mercury vapor results in a classic triad of tremor, neuropsychiatric disturbance, and gingivostomatitis. The tremor usually begins as a fine intention tremor of the hands, but the face may also be involved, and progression to choreiform movements of the limbs may occur. Neuropsychiatric manifestations, including memory loss, fatigue, insomnia, and anorexia, are common. There may be an insidious change in mood to shyness, withdrawal, and depression along with explosive anger or blushing (a behavioral pattern referred to as erethism). Recent studies suggest that low-dose exposure may produce subclinical neurologic effects. Gingivostomatitis, sometimes accompanied by loosening of the teeth, may be reported after high-dose exposure. Evidence of peripheral nerve damage may be detected on electrodiagnostic testing, but overt peripheral neuropathy is rare. Acrodynia is an uncommon idiosyncratic reaction to subacute or chronic mercury exposure and occurs


Pharmacology_Katzung

Pharmacology_Katzung. nerve damage may be detected on electrodiagnostic testing, but overt peripheral neuropathy is rare. Acrodynia is an uncommon idiosyncratic reaction to subacute or chronic mercury exposure and occurs mainly in children. It is characterized by painful erythema of the extremities and may be associated with hypertension, diaphoresis, anorexia, insomnia, irritability or apathy, and a miliary rash. Chronic exposure to inorganic mercury salts, sometimes via topical application in cosmetic skin-lightening creams, has been associated with neurological symptoms and renal toxicity in case reports and case series.


Pharmacology_Katzung

Pharmacology_Katzung. Methylmercury intoxication affects mainly the CNS and results in paresthesias, ataxia, hearing impairment, dysarthria, and progressive constriction of the visual fields. Signs and symptoms of methylmercury intoxication may first appear several weeks or months after exposure begins. Methylmercury is a reproductive toxin. High-dose prenatal exposure to methylmercury may produce mental retardation and a cerebral palsy-like syndrome in the offspring. Low-level prenatal exposures to methylmercury have been associated with a risk of subclinical neurodevelopmental deficits.


Pharmacology_Katzung

Pharmacology_Katzung. A 2004 report by the Institute of Medicine’s Immunization Safety Review Committee concluded that available evidence favored rejection of a causal relation between thimerosal-containing vaccines and autism. In like manner, a recent retrospective cohort study conducted by the CDC did not support a causal association between early prenatal or postnatal exposure to mercury from thimerosal-containing vaccines and neuropsychological functioning later in childhood. Dimethylmercury is a rarely encountered but extremely neurotoxic form of organomercury that may be lethal in small quantities.


Pharmacology_Katzung

Pharmacology_Katzung. The diagnosis of mercury intoxication involves integration of the history and physical findings with confirmatory laboratory testing or other evidence of exposure. In the absence of occupational exposure, the urine mercury concentration is usually <5 mcg/L, and whole blood mercury is <5 mcg/L. In 1990, the Biological Exposure Index (BEI) Committee of the American Conference of Governmental Industrial Hygienists (ACGIH) recommended that workplace exposures should result in urinary mercury concentrations <35 mcg per gram of creatinine and end-of-work-week whole blood mercury concentrations <15 mcg/L. To minimize the risk of developmental neurotoxicity from methylmercury, the EPA and the US Food and Drug Administration (FDA) have advised A pregnant women, women who might become pregnant, nursing mothers, and young children to avoid consumption of fish with high mercury levels (eg, swordfish) and to limit consumption of albacore tuna to 6 ounces a week, but to otherwise consume 8–12


Pharmacology_Katzung

Pharmacology_Katzung. nursing mothers, and young children to avoid consumption of fish with high mercury levels (eg, swordfish) and to limit consumption of albacore tuna to 6 ounces a week, but to otherwise consume 8–12 ounces of fish per week (see http://www.fda.gov/Food/FoodborneIllnessContaminants/Metals/ucm393070.htm).


Pharmacology_Katzung

Pharmacology_Katzung. A. Acute Exposure In addition to intensive supportive care, prompt chelation with oral or intravenous unithiol, intramuscular dimercaprol, or oral succimer may be of value in diminishing nephrotoxicity after acute exposure to inorganic mercury salts. Vigorous hydration may help to maintain urine output, but if acute renal failure ensues, days to weeks of hemodialysis or hemodiafiltration in conjunction with chelation may be necessary. Because the efficacy of chelation declines with time since exposure, treatment should not be delayed until the onset of oliguria or other major systemic effects. B. Chronic Exposure


Pharmacology_Katzung

Pharmacology_Katzung. B. Chronic Exposure Unithiol and succimer increase urine mercury excretion following acute or chronic elemental mercury inhalation, but the impact of such treatment on clinical outcome is unknown. Dimercaprol has been shown to redistribute mercury to the central nervous system from other tissue sites, and since the brain is a key target organ, dimercaprol should not be used in treatment of exposure to elemental or organic mercury. Limited data suggest that succimer, unithiol, and N-acetyl-l-cysteine (NAC) may enhance body clear- ance of methylmercury.


Pharmacology_Katzung

Pharmacology_Katzung. Chelating agents are drugs used to prevent or reverse the toxic effects of a heavy metal on an enzyme or other cellular target, or to accelerate the elimination of the metal from the body. By forming a complex with the heavy metal, the chelating agent renders the metal unavailable for toxic interactions with functional groups of enzymes or other proteins, coenzymes, cellular nucleophiles, and membranes. Chelating agents contain one or more coordinating atoms, usually oxygen, sulfur, or nitrogen, which donate a pair of electrons to a cationic metal ion to form one or more coordinate-covalent bonds. Depending on the number of metal-ligand bonds, the complex may be referred to as mono-, bi-, or polydentate. Figure 57–2 depicts the hexadentate chelate formed by interaction of edetate (ethylenediaminetetraacetate) with a metal atom, such as lead.


Pharmacology_Katzung

Pharmacology_Katzung. In some cases, the metal-mobilizing effect of a therapeutic chelating agent may not only enhance that metal’s excretion—a desired effect—but may also redistribute some of the metal to other vital organs. This has been demonstrated for dimercaprol,


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 57–2 Salt and chelate formation with edetate (ethylenediaminetetraacetate, EDTA). A: In a solution of the disodium salt of EDTA, the sodium and hydrogen ions are chemically and biologically available. B: In solutions of calcium disodium edetate, calcium is bound by coordinate-covalent bonds with nitrogens as well as by the usual ionic bonds. C: In the lead–edetate chelate, lead is incorporated into five heterocyclic rings. (Adapted, with permission, from Meyers FH, Jawetz E, Goldfien A: Review of Medical Pharmacology, 7th ed. Originally published by Lange Medical Publications. McGraw-Hill, 1980. Copyright © The McGraw-Hill Companies, Inc.) which redistributes mercury and arsenic to the brain while also enhancing urinary mercury and arsenic excretion. Although several chelating agents have the capacity to mobilize cadmium, their tendency to redistribute cadmium to the kidney and increase nephrotoxicity has negated their therapeutic value in cadmium intoxication.


Pharmacology_Katzung

Pharmacology_Katzung. In addition to removing the target metal that is exerting toxic effects on the body, some chelating agents may enhance excretion of essential cations, such as zinc in the case of calcium EDTA and diethylenetriaminepentaacetic acid (DTPA), and zinc and copper in the case of succimer. No clinical significance of this effect has been demonstrated, although some animal data suggest the possibility of adverse developmental impact. If prolonged chelation during the prenatal period or early childhood period is necessary, judicious supplementation of the diet with zinc might be considered. The longer the half-life of a metal in a particular organ, the less effectively it will be removed by chelation. For example, in the case of lead chelation with calcium EDTA or succimer, or of plutonium chelation with DTPA, the metal is more effectively removed from soft tissues than from bone, where incorporation into bone matrix results in prolonged retention.


Pharmacology_Katzung

Pharmacology_Katzung. In most cases, the capacity of chelating agents to prevent or reduce the adverse effects of toxic metals appears to be greatest when such agents are administered very soon after an acute metal exposure. Use of chelating agents days to weeks after an acute metal exposure ends—or their use in the treatment of chronic metal intoxication—may still be associated with increased metal excretion. However, at that point, the capacity of such enhanced excretion to mitigate the pathologic effect of the metal exposure may be reduced. The most important chelating agents currently in use in the USA are described below. DIMERCAPROL (2,3-DIMERCAPTOPROPANOL, BAL) Dimercaprol (Figure 57–3), an oily, colorless liquid with a strong mercaptan-like odor, was developed in Great Britain during World War II as a therapeutic antidote against poisoning by the (2, 3-dimercaptopropanol) (DMSA)