Book Review: The Carcinogenicity of Metals: Human Risk Through Occupational and Environmental Exposure

This book is 18th in a series on issues in toxicology. It is an excellent review of information relating to the potential carcinogenicity of 27 metals and metalloid elements based on various degrees of evidence from occupational, environmental, animals, and in vitro studies. The author does more than report the results; he evaluates the quality, relevance of the studies, and weight of the evidence of all the relevant data. For each metal, other useful information about natural occurrence, dietary levels, toxicity, and so on is listed.

Metals and metalloid elements are widely found in the environment (rock, soil, food, water, and air). In some cases, human activity has created environmental problems by concentrating metals as a by-product of mining or manufacturing (mercury, cadmium, and others). Radon and silicon (known carcinogens) can be the primary factors identified as causing lung cancer, in the mining of metals.

Mining and related activities can result in cancer by contamination of the water supply or inhalation by workers. Gold is not considered a carcinogen but the mining of gold can result in significant release of arsenic—a known carcinogen. Smoking is another significant cofactor in lung cancers seen in some mining operations. Epidemiological evidence can be very useful but many times are lacking in critical details. The correlation may be weak because of the mixed nature of the exposure. Many studies cover 20 or more years from first exposure, lack specific exposure data, adequate controls, little or no information about smoking, and other lifestyle factors. However, epidemiological evidence can be very useful. It studies the specie of interest, it covers an occupational and environmental exposure, and even with limitations it can demonstrate a strong association between exposure and cancer.

The mechanism of carcinogenicity of metals, based on animal and in vitro studies, is also discussed, from genetic mechanism (induction and promotion), nongenotoxic mechanisms such as altered signal transduction, regulation of gene expression, oxidative stress, reactive oxygen species and activation of hormonal receptors, chronic inflammation, and other mechanisms that may play a role in the cancer.

Several groups such as the National Toxicology Program (NTP), International Agency for Research on Cancer (IARC), Environmental Protection Agency (EPA), and others carry out the formal classifications of known human and potential carcinogens. The IARC is most likely the widest used classification having 6 categories based on the degree of evidence in animals and humans. The IARC and the others have classified individual element mixtures, occupational exposures, and lifestyle factors (smoking and alcohol) under their classification system. These classifications are referred to throughout the book.

The book is divided into 3 parts following the introduction:

Part 1: Elements of Importance as Nutrients (Chapters 2-8).

Part 2: Xenophobic Elements of No Nutritional Value (Chapters 9-17).

Part 3: Metals and Metalloid Elements as Carcinogens (Chapter 18).

Part 1 discusses the elements of importance as nutrients. Many metals are nutrients that are required at some level as cofactors of enzymes, electrolytes, and part of cellular structure. The author identifies 17 of 27 metals and metalloid elements listed as potential carcinogen as nutrients in the human body. The remainder of the 14 metals and metalloid elements may occasionally be found in the human body and may interact with required nutrients causing deficiency in some of the required nutrients or toxicity

In Part 1, in addition to the human and experimental (animal) data, the role of the metals as nutrients in human nutrition is discussed along with sections on environmental sources, industrial use and human exposure, general toxicity, cytotoxicity, mutagenicity, absorption, and metabolism for each metal.

Chapter 2 examines iron, which is found primarily in the environment as hematite. The mining of this mineral is considered a carcinogenic risk, but the cause of cancer appears likely to be radon and radon daughters. Other factors such as smoking and silica are potential factors in the response seen. Iron is weakly mutagenic in the Ames test and has been shown to be a promoter in animal studies.

Chapter 3 evaluates zinc, which is not carcinogenic in human studies and there is only very limited evidence of testicular tumors in animals injected with zinc.

Chapter 4 evaluates chromium and chromates. Hexavalent chromium and chromium compounds are considered known human carcinogens based on epidemiological evidence. In vitro and animal studies by various routes support this classification. Trivalent chromium is not considered a human carcinogen based on epidemiological evidence.

Chapter 5 examines cobalt and nickel. Cobalt induces tumors in animal studies and is genotoxic. Evidence of cancer in humans is limited. Nickel mining and related operations are a potential cancer risk in humans but the role of nickel is unclear. The results in animal studies with nickel suggest that the solubility of the nickel compounds is important in the production of tumors in animals.

Chapter 6 examines calcium, strontium, magnesium, and copper. They are not considered carcinogenic in epidemiological or animals studies.

Chapter 7 examines the minor trace elements manganese, vanadium, molybdenum, and tin. Inorganic manganese compounds appear not to be carcinogenic, but some organic manganese compounds have been associated with carcinogenesis in animals but not in human studies. Vanadium pentoxide is reported as carcinogenic in animal studies but the studies appeared to be of poor quality. Vanadium pentoxide is weakly mutagenic and it can generate reactive oxygen species suggesting further animal studies would be useful. No human evidence exists to suggest that vanadium is carcinogenic in humans. Molybdenum has little conclusive data about carcinogenic risk in humans or animals. There is limited and inconclusive evidence of carcinogenic of tin and tin compounds in humans and animals.

Chapter 8 evaluates the metalloid elements selenium and silicon. The carcinogenicity of selenium and selenium products has not been proven. Older limited animal studies suggest an effect but no human evidence of carcinogenicity following selenium exposure has been found. Microcrystal silica is a known human and animal carcinogen. Silicones and silicates do not appear to be a carcinogenic risk.

Part 2 discusses xenophobic elements of no nutritional value to humans. In addition, chapters on each metal contain sections on environmental sources, industrial use and human exposure, general toxicity, cytotoxicity, mutagenicity, absorption and metabolism, human case studies, and epidemiological studies as well as animal cancer studies.

Chapter 9 examines aluminum and zirconium. There is no clear evidence of carcinogenicity found in human or animal studies exposed to aluminum or zirconium compounds.

Chapter 10 examines cadmium and mercury. Cadmium is genotoxic. Various animal studies evaluating cadmium metal or cadmium compounds (intramuscular, subcutaneous, inhalation, oral) have shown some evidence of carcinogenicity. No clear links to cancer in occupational studies have been demonstrated, but environmental exposure suggests a concern, as other carcinogenic agents that may be the causative agents and may be present along with cadmium. Smoking is a major source of absorption of cadmium. Mercury or inorganic mercury is not considered carcinogenic in humans, but methyl mercury is considered possible carcinogenic based on limited evidence in several human studies. Chronic animal studies have resulted in severe toxicity making it difficult to assess carcinogenicity in animal studies done to date.

Chapter 11 examines lead. Lead and its compounds are well studied. Many of the studies have limitations but the weight of the evidence is clear. Animal studies of certain lead compounds have proved strong evidence of carcinogenicity. Various human studies have shown an increase in lung, stomach, brain, and kidney tumors.

Chapter 12 examines tungsten and hard metals. Tungsten is not considered a carcinogenic risk in animals or humans. Limited evidence in animals and humans suggests a lung cancer risk to hard metal dusts.

Chapter 13 examines precious metals such as silver, gold, and platinum-related metals. Silver nitrate and soluble silver compounds have shown no evidence of carcinogenic in animal or human studies. Gold does not appear to be carcinogenic although isolated reports of skin cancers have been reported in people wearing gold jewelry (residual radioactivity?). Subcutaneous injection studies suggest gold may cause injection-site sarcomas. Platinum and inorganic compounds appear not to be carcinogenic in humans. Cis-platin, a drug containing platinum, has been shown to be carcinogenic in several animal studies resulting in Cis-platin being classified as a probable human carcinogen by IARC.

Chapter 14 examines beryllium. There are several studies in animals demonstrating an increase in lung and other cancers in several species of animals exposed by various routes to beryllium and certain beryllium inorganic salts. There are also numerous epidemiological studies that report beryllium causes lung and other cancer in workers.

Chapter 15 examines gallium, indium, and thallium. No studies have been published that report gallium is carcinogenic. A study of gallium in rats showed a slight increase in some tumors but they were within the laboratory normal historical range. No response was seen in mice or hamsters. There is limited data on indium, especially in humans. Indium phosphide is classified as a possible carcinogen based on animal studies, as is a mixture of indium oxide and tin oxide (90%/10%). The data on thallium in humans and animals are limited and there is no conclusive evidence to suggest it causes cancer.

Chapter 16 examines thorium and titanium. Thorium is a radioactive element and thorium dioxide is listed as both human and animal carcinogens. Radium is one of its well-known decay, product of thorium which was used years ago on watch dial to make the dial glow in the dark. Women who painted the dial develop cancer in one of the early well-known cases of occupational cancer. Titanium is classified as a possible carcinogen based on in vitro studies and inhalation and intratracheal studies in rats by IARC but not NTP. There is strong evidence that the rat’s response was likely due to lung overload of insoluble titanium dioxide and lack of clearance. Cancer has not been demonstrated in humans.

Chapter 17 examines arsenic, antimony, and bismuth. Arsenic is classified as a known human carcinogen based on tumors reported at multiple sites following mostly environmental exposure (food and water). Occupational studies have shown an increase in lung cancer. Animal studies by various routes have demonstrated a treatment-related increase in tumors following arsenic exposure. Methylated arsenic metabolites are clastogenic. Arsenic may cause reactive oxygen species. Antimony has inadequate data to demonstrate cancer in humans but occupational exposure in mining operations usually also contains arsenics, lead, nickel, and silica that makes it difficult to show causation. Genotoxicity data are varied and limited inadequate studies in rodents while suggestive are not conclusive. Bismuth has limited data. One chronic animal study that showed no treatment-related cancer and no evidence of cancer has been reported in humans.

Part 3 is also the last chapter (18), which gives a general discussion and conclusions of metals and metalloid elements as carcinogens. The author feels that animal studies play a mostly supporting role to epidemiological studies. He does acknowledge that many human and animal studies are old and lacking in details needed to be deemed adequate by today’s standards. Changing industrial practices, such as reducing workplace exposure to levels lower than that found in the past and the reduction in smoking, may result in decreasing cancer rate in workers. Animal studies may become more important in determining cancer risk in the future.

Experimental animal studies have been used for many years to identify carcinogenicity. They have weakness (limited strains, route of exposure [intratracheal intramuscular and subcutaneous] that are not relevant to most human exposure, high doses that exceed normal protective mechanisms [lung overloading], and background tumor rate). The strengths of animal studies include defined exposure, dose response, and minimizing confounding factors. In the last 50 years, in vitro tests using bacterial and various cell lines have been developed to assess mutagenicity, DNA damage, and other cellular changes that are useful in predicting possible carcinogen.

The possible mechanism of carcinogenesis is complex and the author does a good job of summarizing how genetic and epigenetic mechanisms are operational for the various metals. Some of these elements act on cell nucleus (DNA, RNA, and gene expression) while others act through an epigenetic mechanism, oxidative stress, reactive oxygen specie, deregulation of DNA repair, lipid peroxidation, changes in signal transduction, and so on. Both genetic and epigenetic changes from various sources may be part of the carcinogenic response seen in many mining population. It can be difficult to say which agent is the primary carcinogen and which may be secondary to the carcinogenic process. Weight of evidence and supporting animal and mechanistic studies can be helpful in determining the cancer risk.

Table 18.2 entitled “Metal and Metalloid Elements as Carcinogens” provides a list of the metals that current data support the classification as a carcinogen under certain conditions. This does not mean that the remaining metals are noncarcinogens but that more data are needed to reach a conclusion on the carcinogenic potential of these elements. Of the 27 metals and metalloid elements, the author concludes that there is significant evidence of at least a possible carcinogen effect in 13 of these agents. The other 14 have some limited evidence but not significant evidence to classify these as carcinogens. There is no good evidence that the metals’ place on the periodic table is related to the response to different metals.

Although mining was discussed in the chapters, where data exist, a more general chapter covering a detailed discussion about mining and its role in various cancers attributed to metal and metalloid elements would have been a useful addition to this book.

This book provides an excellent review of metal toxicity and occupational and environmental exposures related to mining and use of metals and would be useful in graduate courses in occupational medicine, toxicology, and carcinogenicity. It would also be a very useful resource to occupational physicians, toxicologists, industrial hygienists, environmental, and product safety specialists interested in metal carcinogenicity and occupational and environmental exposure to metals. This book is well written by an individual with an excellent knowledge of metal carcinogenicity and related occupational and environmental exposure.