Arsenic E-Book

J. Christopher States

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1235

Veröffentlichungsjahr: 2015

Beschreibung

This book illustrates the chemistry, toxicology, and health effects of arsenic using novel modeling techniques, case studies, experimental data, and future perspectives.

•    Covers exposure sources, health risks, and mechanisms of one of the most toxic minerals in the world
•    Helps readers understand potential health effects of arsenic, using population studies, mammalian and invertebrate models, and pharmacokinetic and toxicokinetic models
•    Discusses outcomes, epidemiology, real-life examples, and modes of action for arsenic-induced diseases, like lung cancer, diabetes, cardiovascular and pulmonary diseases, and immunotoxicity
•    Acts as a reference for toxicologists, environmental chemists, and risk assessors and includes up-to-date, novel modeling techniques for scientists
•    Includes future perspectives on special topics, like extrapolation from experimental models to human exposures, biomarkers for phenotypic anchoring, and pathology of chronic exposure

Leseprobe

ARSENIC

Exposure Sources, Health Risks, and Mechanisms of Toxicity

Edited by

J. CHRISTOPHER STATES

University of LouisvilleLouisville, KY, USA

Copyright © 2016 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New JerseyPublished simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Arsenic : exposure sources, health risks, and mechanisms of toxicity / edited by J. Christopher States.         pages  cm    Includes index.

    ISBN 978-1-118-51114-5 (hardback)1. Arsenic–Health aspects.   2. Arsenic–Toxicology.   I. States, J. Christopher.    RA1231.A7A7683 2015    615.9′25715–dc23                                    2015018789

CONTRIBUTORS

Gavin E. Arteel, Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA

Susan R. Atlas, Physics and Astronomy Department, University of New Mexico, Albuquerque, NM, USA

Mayukh Banerjee, Department of Physiology, University of Alberta, Edmonton, AB, Canada

Aaron Barchowsky, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA

Pritha Bhattacharjee, Department of Environmental Science, University of Calcutta, Kolkata, India

Iain L. Cartwright, Molecular Genetics, Biochemistry & Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

Yu Chen, Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, USA

Harvey J. Clewell, III, Hamner Institutes for Health Sciences, Research Triangle Park, NC, USA

Karen L. Cooper, Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM, USA

Arden D. Davis, Department of Geology and Geological Engineering, South Dakota School of Mines and Technology, Rapid City, SD, USA

Christelle Douillet, Department of Nutrition, University of North Carolina Chapel Hill, Chapel Hill, NC, USA

Ingrid L. Druwe, Department of Pharmacology and Toxicology, University of Arizona College of Pharmacy, Tucson, AZ, USA

Dominic B. Fee, Department of Neurology, Medical College of Wisconsin in Milwaukee, WI, USA

A. Jay Gandolfi, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA

P. Robinan Gentry, Environ International Corporation, Monroe, LA, USA

Ashok K. Giri, Molecular and Human Genetics Division, Indian Institute of Chemical Biology, Kolkata, India

Laurie G. Hudson, Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM, USA

Michael F. Hughes, Office of Research and Development, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC, USA

Elaina M. Kenyon, US EPA, NHEERL, Research Triangle Park, NC, USA

Brenee S. King, Human Nutrition, Kansas State University, Manhattan, KS, USA

R. Clark Lantz, Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA

Michael Lawson, School of Earth, Atmospheric and Environmental Sciences and Williamson Research Centre for Molecular Environmental Science, The University of Manchester, Manchester, UK

Maryse Lemaire, Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada

Ke Jian Liu, Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM, USA

Koren K. Mann, Department of Oncology, Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada

Matthew K. Medeiros, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA

Patricia Ostrosky-Wegman, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico

Somnath Paul, Molecular Biology and Human Genetics Division, Council for Scientific and Industrial Research – Indian Institute of Chemical Biology, Kolkata, India

David A. Polya, School of Earth, Atmospheric and Environmental Sciences and Williamson Research Centre for Molecular Environmental Science, The University of Manchester, Manchester, UK

Ana María Salazar, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico

Nilendu Sarma, Department of Dermatology, NRS Medical College, Kolkata, India

Cara L. Sherwood, Arizona Respiratory Center, University of Arizona, Tucson, AZ, USA

J. Christopher States, Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA

Miroslav Stýblo, Department of Nutrition, University of North Carolina Chapel Hill, Chapel Hill, NC, USA

David J. Thomas, Integrated Systems Toxicology Division, USEPA, Research Triangle Park, NC, USA

Erik J. Tokar, Inorganic Toxicology Group, National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

Richard R. Vaillancourt, Department of Pharmacology and Toxicology, University of Arizona College of Pharmacy, Tucson, AZ, USA

Michael P. Waalkes, Inorganic Toxicology Group, National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

Cathleen J. Webb, Department of Chemistry, Western Kentucky University, Bowling Green, KY, USA

Fen Wu, Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, USA

Yuanyuan Xu, Inorganic Toxicology Group, National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

Janice W. Yager, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA

PREFACE

I became interested in arsenic toxicology in the late 1990s. I had engineered SV40-transformed human fibroblasts to express human cytochrome P450 IA1 for polycyclic aromatic hydrocarbon carcinogen activation studies. A biotechnology company was interested in licensing the cells but wanted me to test them with a variety of carcinogens to demonstrate specificity. Sodium arsenite was among the compounds. The SV40-transformed fibroblasts were sensitive to the arsenite but in a curious manner. The cells rounded up in what appeared to be mitotic arrest, and then the membranes “bubbled” like in apoptotic cells. At the time, the postulation of mitotic cells undergoing apoptosis was sheer heresy. Nonetheless, these odd observations set me off on a course investigating this enigmatic toxicant that never ceases to provide surprises and raise new questions.

Arsenic is the 20th most common element in the earth’s crust, and its toxic potential has been known for millennia. Chronic exposure to arsenic, most commonly through natural contamination of drinking water, is a worldwide health problem. Arsenic has been number one on the ATSDR hazardous substances list for at least 15 years now. Over the past two decades, a vast amount of research has been performed on arsenic toxicity. Much of this research focused on carcinogenesis. However, more recently research has focused on the non-cancer disease endpoints of chronic arsenic exposure including cardiovascular disease (atherosclerosis and hypertension), and pulmonary, neurological, and ocular disease. Some epidemiological studies suggest a link with diabetes. How a single agent can cause such a wide variety of ailments has evaded a simple answer. A great variety of experimental systems, using wide-ranging exposures, have produced a mountain of published research. Despite all the published literature examining mode of action, there remains strong debate over how arsenic exerts its disease-causing effects, and no single unifying theme has emerged that can explain the diversity of diseases caused by chronic arsenic exposure. In my view, this lack of a unifying mechanism is at the heart of the issue.

The complexity of arsenic chemistry and biochemistry confounds many efforts to understand the mechanism of toxicity. Recent appreciation of the toxicity of trivalent metabolic intermediates has added to the problems of understanding toxicity and of mitigating toxicity by reducing exposure. We have attempted to address the complexity of the arsenic problem in Arsenic: Exposure Sources, Health Risks, and Mechanisms of Toxicity by compiling into a single-volume discussions of the exposure sources, exposure mitigation, chemistry, metabolism, the various diseases induced by arsenic exposure, and the variety of experimental models used to investigate arsenic toxicity.

The book is divided into four sections: Fundamentals of Arsenic Exposure and Metabolism, Epidemiology and Disease Manifestations of Arsenic Exposure, Mechanisms of Toxicity, and Models for Arsenic Toxicology and Risk Assessment. The chapters discuss a variety of topics including history of arsenic, sources of exposure, chemical and biochemical properties, molecular mechanisms, role in various diseases, genetics of susceptibility, and human health risk assessment, and concludes with a chapter discussing translation of experimental findings to human studies.

This book is offered as a resource for toxicologists, epidemiologists, risk assessors, environmental chemists, medical scientists, and other practicing professionals and researchers in academia, government, and industry. The book aims to provide a better understanding of the potential health problems posed by arsenic exposure and discuss ways that toxicological sciences can contribute to a characterization of how arsenic causes those problems and associated risks.

I am deeply indebted to the friends and colleagues who have contributed to this volume.

J. CHRISTOPHER STATES

PART IFUNDAMENTALS OF ARSENIC EXPOSURE AND METABOLISM

1HISTORY OF ARSENIC AS A POISON AND A MEDICINAL AGENT

Michael F. Hughes

Office of Research and Development, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC, USA

Disclaimer: This article has been reviewed in accordance with the policy of the National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

1.1 INTRODUCTION

Arsenic is one of the most enigmatic elements known to humankind. For many centuries, arsenic has been used as an intentional human poison, for which it has generated much fear and interest. However, over this same time frame, arsenic has been used to benefit society, at least with good intentions, as a medicinal agent. The best example of this paradox is arsenic trioxide, which is also known as the white arsenic. This potent and lethal inorganic arsenical has not only been commonly used to commit homicide but also been used more recently as an effective cancer chemotherapeutic agent.

Arsenic is an insidious poison. Over the ages, arsenic came to be known as the “King of Poisons” because of its use to poison royalty [62]. Arsenic was the choice as a poison because it has no taste and could be discreetly mixed with food or drink. The symptoms of arsenic poisoning were similar to those of common diseases (e.g., cholera) in the world at a time when hygienic practices were poor and safe drinking water was not readily available. Also, there was no chemical test to indicate that someone had been exposed to arsenic until the 1700s.

Although the poisonous nature of arsenic was well known, in 2010, in the United States alone, there were over 5000 cases of arsenic pesticide poisoning and 1000 cases of arsenic nonpesticidal poisoning [8]. Three deaths were noted in the arsenic nonpesticidal cases.

Arsenic is found in inorganic and organic forms as well as different valence or oxidation states (Fig. 1.1). The oxidation states of arsenic include −III, 0, III, and V. Examples of arsenicals in these states are arsine, elemental arsenic, arsenite, and arsenate, respectively. Arsine is a colorless, odorless gas and highly toxic [54]. Exposure to arsine is primarily occupational, so it will not be discussed in this chapter. The form and valence state of the arsenical is important in its potential toxic effects. In general terms (i) inorganic arsenicals are more potent than organic arsenicals; (ii) trivalent (III) arsenicals such as arsenite are more potent than pentavalent (V) arsenicals such as arsenate; and (iii) trivalent organic arsenicals are equally or more potent than trivalent inorganic arsenicals [30].

FIGURE 1.1 Structure of common arsenicals. The ionized forms of arsenous acid and arsenic acid are arsenite and arsenate, respectively. Dimethylarsinic acid is also named cacodylic acid.

The clinical signs of acute oral arsenic toxicity are progressive and depend on the form, valence, and dose of the arsenical. In a human adult, the lethal range of inorganic arsenic is estimated at 1–3 mg As/kg [18]. The symptoms of acute arsenic poisoning are listed in Table 1.1 [25, 56]. Diarrhea is due to increased permeability of the blood vessels. Depending on the type and amount of arsenic consumed, death may occur within 24 h to 4 days. Death is usually due to massive fluid loss leading to dehydration, decreased blood volume, and circulatory collapse. Survivors of acute arsenic poisoning may develop peripheral neuropathy, which is displayed as severe ascending weakness. This effect may last for several years. Encephalopathy may also develop, potentially from the hemorrhage that can occur from the arsenic exposure. Treatment for acute arsenic poisoning includes gastric lavage, administration of fluids and a chelator such as dimercaptopropanol, and hemodialysis.

TABLE 1.1 Acute and Chronic Clinical Effects of Inorganic Arsenic Exposure

Organ System

Acute Effects

Chronic Effects

Cardiac

Cardiomyopathy, hemorrhage, electrocardiographic changes

Hypertension, peripheral vascular disease, cardiomyopathy

Hematologic

Hemoglobinuria, bone marrow depression

Anemia, bone marrow hypoplasia

Gastrointestinal

Nausea, vomiting, diarrhea

Vomiting, diarrhea, weight loss

Hepatic

Fatty infiltration

Hepatomegaly, jaundice, cirrhosis, fibrosis, cancer

Neurologic

Peripheral neuropathy, ascending weakness, tremor encephalopathy, coma

Peripheral neuropathy, paresthesia, cognitive impairment

Pulmonary

Edema, respiratory failure

Cancer

Renal

Tubular and glomerular damage, oliguria, uremia

Nephritis, cancer

Skin

Alopecia

Hyperkeratosis, hypo- or hyperpigmentation, Mees’ lines, cancer

In chronic arsenic poisoning, as in acute poisoning, essentially all the organs are affected [25, 56] (Table 1.1). The hallmark of chronic arsenic poisoning is the development of skin lesions. This includes hyper- or hypopigmentation and hyperkeratosis, particularly on the palms of the hands and soles of the feet. There is no known treatment for chronic arsenic poisoning that is of benefit to the individual. The best option is to minimize exposure to the source of arsenic and provide supportive care to the patient.

Arsenic is also a known human carcinogen, being classified as such by the International Agency for Research on Cancer [33] and the US Environmental Protection Agency (USEPA) [39]. Confirmed organs for cancerous development from chronic arsenic exposure include bladder, skin, and lung [51]. Potential target organs for cancer from arsenic exposure are liver, kidney, and prostate [33, 51].

1.2 INTENTIONAL POISONING BY ARSENIC

The poisonous nature of arsenic has been known for centuries, and thus, it has been used to commit homicide. It is so well known that poisoning by arsenic has been incorporated into the plots of literary works of Chaucer, Agatha Christie, and other writers, and even in the title of a 1940s Broadway play, “Arsenic and Old Lace” [6]. However, it is inconceivable that the victims would die so quickly from arsenic ingestion in that play. Their deaths would most likely be from the ingestion of cyanide and strychnine, which were also part of the poisonous concoction mixed with elderberry wine. But would the play have gained as much attention if it had been called “Cyanide, Strychnine and Old Lace”? No one knows for sure.

There have been many suspicious poisonings, potentially by arsenic, of powerful people in centuries long ago. It has been suggested that Alexander the Great and Britanicus were poisoned by arsenic [6, 12, 25]. The Greek physician Dioscorides, in the first century a.d., included arsenic as a poison in his five-volume publication De Materia Medica (“Regarding Medical Materials”) [48]. During the Middle Ages and Renaissance periods, murder by poisoning reached its zenith [6, 12]. Noted individuals who poisoned others with arsenic for personal gain or profit during this time include the Italians Cesare Borgia, Giulia Toffana, and Hieronyma Spara, and the French woman Marie de Brinvillers [6, 12]. Some of the poisonings were politically motivated, particularly in the Catholic Church, as several senior clergymen were poisoned with arsenic over a 500-year period [12, 48].

An interesting and curious case of arsenic poisoning involved several elderly women of the village of Nagyrev in south-central Hungary [27]. In 1929, four women were brought to trial accused of murdering family members. Their basic plan was to call a doctor to the home of the intended victim. Many of the victims were chronically ill with tuberculosis or another debilitating disease. After the doctor departed, the victims were poisoned with arsenic. When the victims passed away, questions were not asked, because it was perceived that they died from complications of the noted illness. During this time, arsenic was easily available as arsenic acid as this agent was used as a rodenticide. Also, flypaper containing arsenic was commonly used. The arsenic was easily extracted from the flypaper and could be mixed with a drink, as one of the accused allegedly did with her husband’s apricot brandy. There were other suspicious deaths at this time in this village, so 50 bodies from the town’s cemetery were exhumed. Forty-six of the deceased had arsenic levels high enough to be lethal. Other women were brought to trial later and charged with the murders of husbands, fathers, sons, and mothers- and fathers-in-law. Several of the women were found guilty of murder and punished, while others were acquitted of the charges. It was alleged that the period of the murders in this village lasted over two decades and perhaps was even longer. It should be noted that even today, arsenic-containing flypaper is commercially available. The British newspaper, The Guardian, published an article in 2007 on poisons that could be purchased over the Internet [55]. The reporter was able to purchase from a company in Iowa flypaper with a packaging label indicating that it contained 2–4% metallic arsenic.

Intentional human poisoning with arsenic is not limited to Europe alone. In the state of North Carolina in the United States, from 1972 to 1982, there were 28 deaths attributed to arsenic exposure [47]. Of these deaths, 14 were declared homicides and 7 suicides. Four of the confirmed arsenic homicides were attributed to one woman, with the crimes occurring over a 4-year period. This woman may have been involved with additional arsenic poisonings.

Napoleon Bonaparte, the French military and political leader who died in 1821, may have been poisoned by arsenic [12]. Napoleon was exiled by the British to the south Atlantic island, St. Helena, in 1815. He appeared to be in good health upon arrival. Over time, he gained weight and had frequent illness. Several doctors on the island examined Napoleon and diagnosed hepatitis. Before his death Napoleon apparently lost weight. The official autopsy report indicated that Napoleon had a chronic stomach ulcer and died of stomach cancer. For political reasons, both the English and French accepted that stomach cancer was the cause of his death. However, Napoleon’s personal physician, who actually performed the autopsy, maintained that Napoleon died from complications of hepatitis.

After 140 years, a Swedish dentist, Sten Forshufvud, became convinced that Napoleon’s demise came from arsenic poisoning [23, 63]. Hair that was reportedly removed from the head of Napoleon after his death was analyzed for arsenic by neutron activation. The response was positive for arsenic [23]. As discussed in Chapter 13, trivalent arsenic readily binds to sulfhydryl groups. Keratin, the primary structural protein of hair, contains sulfhydryl groups, and thus arsenic will bind to it. Smith et al. [23, 63] analyzed another supposed portion of Napoleon’s hair that was held by someone else, and it also tested positive for arsenic. These claims of high levels of arsenic in the hair of Napoleon brought about the theory that he had been intentionally poisoned. However, Lewin et al. [40] analyzed a different sample of Napoleon’s hair and detected only background levels of arsenic. To complicate matters further, it has been suggested that Napoleon was treating himself with arsenic so that he could become tolerant to a lethal dose [6]. Although it is an interesting story, it is still not clear whether arsenic poisoning was the cause of Napoleon’s death.

1.2.1 Chemical Warfare

Arsenic has a somewhat veiled but nonetheless wretched history of being a chemical warfare agent. There are writings of arsenic being utilized to provide smoke to cover advancing troops during battles in ancient Greece [12]. The use of arsenic in warfare became prominent in World War I by both the Germans and Allies (British, French, and United States). Arsenic was first employed in this war as an inactive agent by the French in 1916 [12]. Arsenic trichloride was mixed with phosgene in artillery shells. The arsenic minimized dissipation of the phosgene, a deadly gaseous agent, and also provided smoke so that observers could adjust the artillery to more accurately place the next round.

The Germans were the first to utilize arsenic as an active warfare agent in 1917 [12]. This particular agent, chlorodiphenylarsine, is a respiratory irritant, causing sneezing and mucous buildup in those exposed to it. The irritation develops into coughing, headache, and other detrimental effects for the soldiers. In some artillery shells, chlorodiphenylarsine was mixed with phosgene and diphosgene, both of which are deadly gases. Other arsenicals used as active agents in World War I by the Germans and Allies were dichloromethylarsine, dichlorophenylarsine, dibromophenylarsine, cyanodiphenylarsine, and others [12] (Fig. 1.2).

FIGURE 1.2 Structure of some arsenical war gases used in World War I.

A very potent arsenical, β-chlorovinyldichloroarsine, which is a deadly blistering agent or vesicant, was developed late in World War I (Fig. 1.3). However, this chemical was never used in this war. This arsenical was synthesized by a US research team led by Captain Winford Lee Lewis. This agent became known as Lewisite [12]. There is some speculation that Lewisite was first synthesized by a priest in 1903 at the Catholic University of America, in Washington, D.C. [12]. For his dissertation studies, Father John Niewland was attempting to synthesize rubber using arsenic trichloride, acetylene, and aluminum chloride. During this synthetic work, Father Niewland became ill from a noxious odor that arose from the reaction of these chemicals. There were no further studies to determine the source of the noxious odor. Years later, Captain Lewis’ research team, also based at the Catholic University of America, was alerted to the potential of the noxious compound from Father Niewland’s experiments because they had access to his dissertation. Whether or not Father Niewland actually synthesized Lewisite is not clear, but it was eventually prepared by Captain Lewis’ research team.

FIGURE 1.3 Reaction of Lewisite with 2,3-dimercaptopropanol (BAL) to form chelated Lewisite.