Carcinogenicity of Metals: Human Risk Through Occupational and Environmental Exposure: Volume 18 (Issues in Toxicology) - Hardcover

Alan B G Lansdown

Hardcover

ISBN 10: 1849737185 ISBN 13: 9781849737180

Publisher: Royal Society of Chemistry, 2013

Synopsis

This important text comprehensively examines each of the elements for which carcinogenicity has been established, providing detailed information on the carcinogenicity and toxicity and detailing the most up-to-date research in this area.

About this title

About the Author

40 years research into the biology and pathology of the skin and its response to injury. Research into the nutrition and physiology of trace and xenbiotic metals in the skin. Study of intrinsic cytoprotective mechanisms against metal toxicity. Special studies onthe biological value of silver in wound care and as an antimicrobial agent in medical devices. International consultant and lecturer. Published 250 scientific papers and book chapters.

From the Back Cover

This book re-evaluates epidemiological and occupational health studies, experimental studies in animals and in vitro experiments relating to the toxicity of 27 metal and metalloid elements for which evidence of carcinogenicity has been presented.Human carcinogenic risk is substantiated in relation to arsenic, beryllium, thorium, chromium, radioactive elements, probably lead, and some nickel and cobalt compounds, and respirable silica particles, but the carcinogenicity of iron, aluminium, titanium, tungsten, antimony, bismuth, mercury, precious metals, and certain related compounds in humans is unresolved.The toxicity and carcinogenicity of each element is specific but correlates poorly with its position in the Periodic Table.Carcinogenicity differs according to the valency of the ion and its ability to interact with and penetrate membranes in target cells and to bind, denature or induce mutations by genotoxic or epigenetic mechanisms.

This important text comprehensively examines each of the elements providing detailed information on the carcinogenicity and toxicity and detailing the most up-to-date research in this area. The book is an essential tool for toxicologists, medicinal and biochemists, and environmental scientists working in both industry and academia.

From the Inside Flap

This book re-evaluates epidemiological and occupational health studies, experimental studies in animals and in vitro experiments relating to the toxicity of 27 metal and metalloid elements for which evidence of carcinogenicity has been presented.Human carcinogenic risk is substantiated in relation to arsenic, beryllium, thorium, chromium, radioactive elements, probably lead, and some nickel and cobalt compounds, and respirable silica particles, but the carcinogenicity of iron, aluminium, titanium, tungsten, antimony, bismuth, mercury, precious metals, and certain related compounds in humans is unresolved.The toxicity and carcinogenicity of each element is specific but correlates poorly with its position in the Periodic Table.Carcinogenicity differs according to the valency of the ion and its ability to interact with and penetrate membranes in target cells and to bind, denature or induce mutations by genotoxic or epigenetic mechanisms.

This important text comprehensively examines each of the elements providing detailed information on the carcinogenicity and toxicity and detailing the most up-to-date research in this area. The book is an essential tool for toxicologists, medicinal and biochemists, and environmental scientists working in both industry and academia.

Excerpt. © Reprinted by permission. All rights reserved.

The Carcinogenicity of Metals

Human Risk Through Occupational and Environmental Exposure

By Alan B. G. Lansdown

The Royal Society of Chemistry

Copyright © 2014 Alan Lansdown
All rights reserved.

ISBN: 978-1-84973-718-0

Contents

Chapter 1 Introduction, 1, 
Part 1: Elements of Importance as Nutrients, 
Chapter 2 Iron, 21, 
Chapter 3 Zinc, 36, 
Chapter 4 Chromium and Chromates, 53, 
Chapter 5 Cobalt and Nickel, 76, 
Chapter 6 Calcium, Strontium, Magnesium and Copper, 108, 
Chapter 7 Minor Trace Elements: Manganese, Vanadium, Molybdenum, Tin, 141, 
Chapter 8 The Metalloid Elements, Selenium and Silicon, 165, 
Part 2: Xenobiotic Elements of No Nutritional Value, 
Chapter 9 Aluminium and Zirconium, 199, 
Chapter 10 Cadmium and Mercury, 216, 
Chapter 11 Lead, 242, 
Chapter 12 Tungsten (Wolfram) and Hard Metals, 266, 
Chapter 13 Precious Metals: Silver, Gold and Platinum-related Metals, 278, 
Chapter 14 Beryllium, 301, 
Chapter 15 Gallium, Indium and Thallium, 316, 
Chapter 16 Thorium and Titanium, 331, 
Chapter 17 Arsenic, Antimony and Bismuth, 347, 
Part 3: Metals and Metalloid Elements as Carcinogens, 
Chapter 18 Discussion and Conclusions, 389, 
Acknowledgements, 404, 
Subject Index, 405, 

CHAPTER 1

Introduction

1.1 Introduction

Metals and metalloid elements are ubiquitous in the human environment (Figure 1.1). They are present to a varying extent in the rocks and soils throughout the world and exist in the air we breathe and in our food or drinking water. Natural deposits in some parts of the world are extensive and in the case of lead and arsenic are prominent sources of local health problems. Inland waterways, estuaries and open sea contain the largest natural sources of metals and their compounds. In addition, these waters accumulate metal residues eluted from inland sources, pesticides and agrochemicals, factory wastes and sludges, deposits from landfill sites and even domestic waste. Metal residues enter local streams, lakes and rivers to be disseminated into open water through tides, offshore currents and adverse weather conditions. This is well illustrated by discharges of silver residues into the San Fransisco Bay area in California (the so-called Great Silver Estuary) where sediments in one year were as high as 8800 kg. Other notable examples include the Minamata Bay catastrophe in Japan in 1953 where an estimated 27 tons of mercury compounds were discharged into sea waters, and local disasters following release of cadmium residues into rivers by mining companies (Figure 1.2). In such cases, cadmium is concentrated in local food sources such that fish in the rivers start to die and rice irrigated with river water fails to grow. Cadmium poisoning is related to the human disease Itai-Itai, which causes softening of the bones and kidney failure. Cadmium and cadmium compounds are now listed as human carcinogens. Sea water possibly contains all stable and some radioactive metal and metalloid elements listed in the Periodic Table, albeit some being present in minute quantities.

Ecologists, environmentalists and regulatory toxicologists throughout the world are justifiably concerned that high concentrations of toxic metals discharged into sea water concentrate in marine deposits, fish and marine life and enter human food chains. Other major ecological and human health concerns relate to the discharge of metal particles into the air by volcanic action, natural erosion of rocks and shales, emissions and effluents from mining, extraction and refining from metal industries, and incineration of commercial and domestic waste. Plants and food animals in contaminated pastures accumulate lead, mercury, cadmium and other xenobiotic elements. Other concerns relate to the increasing use of nanotechnology and the production of minute metal particles of 20 nm or less for commercial purposes. Nanoparticles in the air present special problems. They are considered to have different surface properties, and the physico-chemical properties of their grain boundaries may be more injurious to health. Nanoparticles of silver are probably more than 100-fold more soluble than silver foil or filings. Special health problems of pulmonary fibrosis, pneumoconiosis, chronic respiratory disease and even cancer are recognised following inhalation of industrial dust and nanoparticles of respirable size of gold, silver, chromium, silica and nickel in industrial environments (Figure 1.3).

1.2 Metals as Nutrients

The human body has evolved over many millennia to depend upon certain metals and metalloid elements as constituents of cellular structure or intercellular matrices, electrolytes, or as components or co-factors of key enzyme systems or biosynthetic pathways (Table 1.1). Metalloenzymes containing calcium, magnesium, zinc, iron and copper are important at critical stages of the cell cycle and may have a role in carcinogenic transformation. Patterns of uptake, metabolism, metal-binding proteins, cellular metabolism and excretion are well denned for all nutrients, although optimal levels for good health for minor trace metals such as molybdenum, vanadium, chromium and nickel are still debatable. The roles of blood concentrations, hormones or other factors regulating uptake, levels in the systemic circulation, tissue accumulation and excretion are imperfectly understood.

Macro- and trace nutrients are defined broadly as substances required at appropriate concentrations for optimal health and wellbeing. Demands for different nutrients vary according to age, sex and physiological state (especially pregnancy and lactation). The body displays characteristic signs of metal ion deficiency through malnutrition, dietary imbalances and malabsorption syndromes, through genetic or acquired disease processes. These conditions regress when deficiencies are corrected, as illustrated by iron deficiency anaemia (IDA), hypozincaemia, hypocalcaemia and cobalt deficiency (manifest through sub-optimal Vitamin B12 levels). The role of tin and strontium as trace metal nutrients is still unclear.

Metal ions interact in the body and ionic balances determined by carrier proteins, are critical in regulating the programmed sequence of proliferation in stem cells, maintenance of cellular architecture, cell-to-cell adhesion and functional differentiation. Calcium, for example, interacts with zinc, magnesium, copper and iron and imbalances in metal-to-metal ionic ratios can be detrimental at specific phases in the cell cycle and in the post-mitotic functional differentiation in tissues such as skin, bone, bone marrow and gastrointestinal mucosae with high stem cell populations. Calcium is a particularly important macro-nutrient and more than 70 calcium-binding proteins are present in the body, notably the so-called "EF-hand proteins", cahederins, calmodulin and S-100 proteins. Most display binding sites for other metal ions, notably strontium, lead, aluminium and mercury. Strontium mimics calcium and can substitute for it in biological systems, particularly musculo-skeletal tissues.

Elements such as silver, arsenic, aluminium, bismuth, platinum and lead have no nutritional function but are present occasionally in the body at low levels (Table 1.2). Several bind to proteins such as metallothioneins, ferritin, calmodulin, etc. and can impair the availability of essential nutrients if present to excess (Table 1.3). Arsenic accumulates in bone and displaces calcium from hydroxyapatite binding; clinical studies in Bangladesh and elsewhere have shown that arsenic in drinking water is a cause of retarded body growth and brittle bones. Other xenobiotic elements such as lead, cadmium, mercury and antimony are also cumulative poisons which deposit in liver, neurological tissues, kidney and bone with potential toxicological effects.

The human body exhibits a variety of inherent protective mechanisms against the toxic effects of excesses and imbalances in nutrient metal or metalloid ions, as well as uptake of xenobiotic ions by ingestion, inhalation or percutaneous absorption. The main protective mechanisms seen include:

• Gastrointestinal physiology and factors that modulate metal ion absorption

• Intestinal commensal bacteria that detoxify, oxidise or reduce metal or metalloid ions

• Dietary factors such as phytate, plant fibres and organic matter that bind metal ions

• Epidermal cytokeratins that strongly bind metal cations, thereby con trolling percutaneous absorption

• Intra- and inter-cellular metal binding proteins that chelate or otherwise bind xenobiotic ions or modulate their uptake and metabolism

• Pulmonary alveolar macrophages that phagocytose and "mop-up" inhaled particles

• Selective uptake and competitive receptor binding on cell membranes

• Metal-binding proteins.

Metal-binding proteins including calmodulin, calbindin, caeruloplasmin and the cysteine-rich metallothioneins (MT) serve critical functions as cytoprotec-tive agents. The MT are induced by and play an instrumental role in the metabolism of key nutrients such as zinc, copper and selenium, but they strongly bind ions including arsenic, bismuth, cadmium, gold, silver and mercury. Transferrin is a key iron-binding protein, but this multivalent molecule also binds bismuth, aluminium, indium, vanadium and gallium, any of which, if present to excess, disturb iron metabolism.

The majority of metal and metalloid elements are toxic to some extent in humans. At least 12 are carcinogenic under some circumstances. Toxicity and carcinogenicity can occur under a variety of conditions but, mining, refining, heavy metal industries and exposure through contaminated drinking water are major sources of exposure. Whereas haematite ore is relatively harmless, mining of the ore in many parts of the world presents risks of lung and other cancers through inhalation of the radioactive gas radon. A second example is seen with gold mining. Gold is not carcinogenic but miners exposed to arsenic are exposed to lung cancer.

1.3 Diagnosis of Carcinogenicity

The US National Toxicology Programme (NTP), US Environmental Protection Agency (EPA), US Department of Health and Human Services (DHHS), International Agency for Research on Cancer (IARC) and World Health Organization (WHO) have reviewed published work over the past 100 years and, on the basis of collated observations from epidemiological studies, case reports and experimental studies in laboratory animals, have classified known carcinogenic materials in five main categories (Table 1.4). Authoritative guidance on the carcinogenicity of metals and other environmental contaminants is contained within the 12 Reports on Carcinogenicity (RoC), monographs of IARC working parties and numerous authoritative independent reviews.

A "cancer hazard" is defined by the IARC in their Preamble to the Monographs, as:

a. An "agent" capable of causing malignant neoplasms in one or more organ systems under some circumstances

b. An agent or related compound capable of "increasing the incidence of malignant neoplasms, reducing their latency, or increasing their severity or multiplicity".

A "cancer risk" is an estimate of the carcinogenic effects expected through occupational or environmental exposure to a carcinogenic agent. Where an agent is shown to induce an increased incidence of benign neoplasms, this may be taken into account in judgements of carcinogenicity. The terms "neoplasm" and "tumour" are used interchangeably. The IARC Expert Working Parties classify the term "agents" broadly to include individual elements and related compounds, complex mixtures, occupational exposures, lifestyle factors and other potentially carcinogenic exposures. The classification of carcinogenic agents is updated regularly as newer information comes to hand.

Scientific judgement as to whether exposure to an element, chemical compound, mining or extraction process or finished product constitutes a proven or anticipated human carcinogenic risk depends upon a balanced, scientific and statistically valid assessment of:

• Occupational and environmental health reports, human case and forensic studies

• Regulatory style experimental studies in animals

• Short-term laboratory in vitro tests to demonstrate: mutagenicity, DNA damage, cell transformation, clastogenicity, genotoxicity and molecular toxicity.

The RoC have documented certain agents as "reasonably carcinogenic to humans" on the basis of their being "structurally related to a class of substances whose members are listed as carcinogens or are reasonably anticipated to be human carcinogens". In all, conclusions are based on a consideration of all relevant information. "This is not limited to dose response, route of exposure, chemical structure, metabolism, pharmacokinetics, sensitive sub-populations, genetic effects or other data relating to mechanisms of action or factors that may be unique for a given substance."

1.4 Mechanisms of Carcinogenicity as Applied to Metals and Metalloid Elements

The scientific community has moved on far beyond the initial concepts of chemical carcinogenesis, founded on the studies of Isaac Berenblum and Phillip Shubic in the 1940s, that chemical carcinogenesis involves at least two stages-induction and promotion. Recent advances in molecular genetics dictate that, these days, greater emphasis should be placed on mechanism-based carcino-genesis and the action of xenobiotics on cellular growth, mitotic homeostasis and the activation and expression of oncogenes.

Early concepts of multi-step chemical carcinogenesis envisaged an initial (induction) phase involving DNA damage, chromosomal change, impairment of DNA replication and repair followed by one or more promotional phases in which this pre-neoplastic state is promoted to frank tumour formation. Promoters such as croton oil may have marginal or no carcinogenic activity but serve as mitogens, motivating transformed cells to colony formation and metastasis. Phorbolester A isolated from croton oil, was shown to invoke increased permeability in nuclear membranes preceding excitation of DNA synthesis and nuclear enlargement. Other non-carcinogenic promoters include non-specific stress factors such as noise, disturbances in diurnal rhythms, dietary factors, infection, immuno-suppression and oxidative stress. Complete carcinogens are defined as substances capable of inducing irreversible muta-genic changes in target cells with or without metabolic transformation, followed by transformation/promotion of stem cells to tumour formation.

Biochemical and molecular evidence emphasises that elements such as arsenic, cadmium, chromium (VI), cobalt and nickel compounds can evoke carcinogenic changes through mechanisms other than direct genotoxicity, DNA binding or chromosomal aberrations. These so-called "epigenetic changes", cumulatively leading to altered signal transduction, regulation in gene expression and carcinogenesis, include chronic inflammation, immuno-suppression, oxidative change and induction of reactive oxygen species, changes in DNA-methylation patterns and activation of hormonal receptors. Growth factors, cytokines and other subcellular or intracellular factors are probably involved. Epigenetics is a new and challenging aspect of carcinogenesis and is well illustrated by studies in molecular genetics of unequivocal carcinogens such as arsenic. Plausible studies now suggest that epigenetics should be defined as a "study of heritable changes in gene function that occur without any direct changes in DNA sequence". Epigenetic effects influence gene expression and regulatory mechanisms controlling tissue-specific cellular receptors, signal transducers and effector molecules.

Alterations in DNA-methylation patterns probably constitute a significant part of the carcinogenic process and involve transcriptional inactivation or activation of cancer-related genes. Molecular studies with arsenic emphasise that carcinogenesis is principally a "disease of stem cells" which express a range of cell surface markers responsive to stem-cell maintenance-related genes. They may also involve covalent modifications in the amino acid residues in histones around which DNA is wrapped. Changes in the methylation status of cytosine bases in cytosine-phosphate -guanine dinucleotides (i.e. CpG islands) within the DNA molecule act in a form of gene "silencing". Gronbaek viewed cancer developing when "cells acquire specific growth advantages through a stepwise accumulation of heritable changes in gene function" modulated by tumour suppressor genes that inhibit cell growth and oncogenes that promote cell growth and survival.

1.5 Epidemiological Evidence

Numerous epidemiological studies are published claiming to demonstrate that exposure to metal or metalloid elements in industrial environments or through contamination of food, drink or air is a cause of human cancer. Few are scientifically sound and many fail to demonstrate a clear correlation between exposure to metal/metalloid and evidence of tumour induction/promotion. Observer bias is evident in some older studies but long lag phases of 20 years or more years between presumed exposure and evidence of tumours (e.g. arsenic, lead and cadmium), failure adequately to allow for human lifestyle factors, and incomplete reporting complicate the true evaluation of risk in many epidemiological studies. Few industrial environments, mining, smelting and refining operations contain a single toxic element, and in the case of electroplating, steel production, the electronics industry, and waste metal recycling, workers are exposed to several toxic and potentially carcinogenic materials capable of inducing, promoting or otherwise modifying chemically induced or idiopathic cancers. The World Health Organization reported, in 2008, 12.7 million new cases and 7.6 million deaths, and a total of 107 agents, mixtures and exposure situations as carcinogenic to humans. They noted that environmental causes of cancer include factors in the environment such as air pollution, ultraviolet (UV) radiation and indoor radon exposure but that "... every tenth lung cancer is closely related to risks in the workplace". These include complications due to environmental contaminants such as micro-crystalline silica. Microcrystalline silica of respirable size is an acknowledged carcinogen, and exposure to quartz dusts in industry is a cause of chronic respiratory distress and increased incidence of lung cancer.' Radon is a colourless, odourless and tasteless natural radioactive gas released as a degeneration product of uranium that occurs naturally in all rocks, soils and deep in the Earth's core. Radioactive emissions are experienced at very low levels in homes and dispersed in the general environment but higher concentrations are experienced in metal mining, smelting and refining; the emissions are harmful and are recognised environmental factors impacting upon the incidence of environmental carcinogenesis. The US EPA estimated that as many as 20,000 lung cancer deaths are caused each year by radon exposure and, in financial terms, an annual cost of more than $2 billion in direct and indirect health care costs. The values for action levels for environmental radon show a wide range, but concentrations between 100 and 400 Bqm -3 are used. Radon exposure is now known to be largely responsible for lung tumours reported in miners of gold, tin and haematite.

(Continues...)

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Edition details

• Publisher: Royal Society of Chemistry
• Publication date: 2013
• Language: English
• ISBN 10: 1849737185
• ISBN 13: 9781849737180
• Binding: Hardcover
• Edition number: 1
• Number of pages: 448