Toxic elements

Introduction

Aluminum or alternatively aluminium (Al), atomic number 13 and relative atomic mass of 26.9815, is a silvery, nonmagnetic, ductile metal in period 3, group 13, with one naturally occurring and stable isotope, Al (100%). In 1972, Alfrey and colleagues first described an encephalopathy that was observed in patients undergoing prolonged hemodialysis for renal failure. The disease was characterized by abnormal speech, myoclonic jerks, and convulsions. Patients with these signs also showed a predominance of osteomalacic fractures. Subsequently, it was found that exposure of patients in renal failure to (1) Al-laden dialysis water, (2) Al-containing oral phosphate binders, and 3) Al-laden albumin administered during dialysis is the primary cause of these signs of Al toxicity. Al is also a developmental toxicant if administered parenterally. ^,

Sources of exposure

Under normal physiologic conditions, the usual daily dietary intake of Al is 5 to 10 mg, which is completely excreted. This excretion is accomplished by avid filtration of Al from the blood by the glomerulus of the kidney. Patients in renal failure lose this ability and are candidates for Al toxicity. The dialysis process is not highly effective at eliminating Al and can also be a significant source of exposure. Furthermore, it is common practice to administer Al-based gels orally to patients in renal failure to reduce the amount of phosphate absorbed from their diet to avoid excessive phosphate accumulation. A small fraction of this Al may be absorbed and patients in renal failure can accumulate it. Following dialysis, albumin may be administered to replace that which is removed during dialysis. Parenteral products have been reported to have Al present due to the raw substances and steps in the manufacturing process, although Al-free dialysis water and non–aluminum-containing phosphate binders are more widely available.

Toxicokinetics and toxicodynamics

The solubility of the Al compounds impacts its toxicokinetics and subsequent health risks. In general, inhaled soluble particles (e.g., aluminum sulfate, hydrated aluminum chloride, and aluminum nitrate) are rapidly absorbed from the lungs, while the less or sparsely soluble particles (e.g., aluminum metal, aluminum oxide, aluminum hydroxide, aluminum phosphate, and aluminum silicate) are retained in the lungs and then slowly released into the systemic circulation. Al: (1) accumulates in blood if not filtered by the kidney; (2) avidly binds to proteins, such as transferrin; and (3) rapidly distributes throughout the body. In vivo studies have demonstrated the decrease of calcium, magnesium, and phosphorus due to Al deposition in bone resulting in the inhibition of bone mineralization.

Clinical presentation and treatment

Acute toxicity due to Al exposure is diagnosed when encephalopathy and increased serum Al concentrations are found. A publication documenting acute intoxication due to dialysis water contamination reported serum Al concentrations ranging from 359 to 1189 μg/L (13.3 to 44.1 μmol/L) in nonsurviving patients and 113 to 490 μg/L (4.2 to 18.2 μmol/L) in surviving patients. Chronic toxicity has historically been associated with hemodialysis patients presenting with a constellation of signs and symptoms including bone pain, muscle pain, weakness, anemia, and neurologic changes.

Al-related bone disease has been diagnosed and treated with deferoxamine, an avid chelator of both Fe and Al. The deferoxamine infusion test is useful for the ultimate diagnosis of Al overload disease, and the drug has demonstrated utility for treating acute Al overload. ^,

Adverse health effects in workers occupationally exposed to Al compounds have included pneumoconiosis (aluminosis) and fibrosis of the lungs and toxicity of the central nervous system including balance disorders, difficulties with memory and concentration, impaired cognitive abilities, irritability, depression, and decreased psychomotor performances. Although rare, contact sensitization of the skin by Al is also possible.

Preanalytical and analytical aspects

Preanalytical considerations related to the collection of specimens for Al analysis are critical in obtaining accurate results. Many of the available evacuated blood collection devices used in phlebotomy have rubber stoppers that are made of Al silicate. Puncture of the rubber stopper for blood collection is sufficient to contaminate the sample with Al and produce an abnormal concentration thereof. Typically, blood collected in standard evacuated blood tubes will be contaminated by 20 to 60 μg/L (0.7 to 2 μmol/L) of Al; this is readily demonstrated by collecting blood from a healthy volunteer into a standard evacuated phlebotomy tube. Special evacuated blood collection tubes are required for Al testing. These tubes are available from commercial suppliers and should always be used. Failure to pay attention to this issue can result in the generation of abnormal results because of sample contamination, which leads to misinterpretation and misdiagnosis.

Analysis of Al is routinely performed by inductively coupled plasma mass spectrometry (ICP-MS). Alternatively, atomic absorption spectrometry with electrothermal atomization may be used, but considerable attention must be paid to matrix interferences.

Regulatory and occupational exposure aspects

Occupational exposure to Al compounds primarily occurs through inhalation of airborne particles in dusts and fumes. The solubility of the Al compounds impacts its toxicokinetics and subsequent health risks. In general, inhaled soluble particles (e.g., aluminum sulfate, hydrated aluminum chloride, and aluminum nitrate) are rapidly absorbed from the lungs, while the less or sparsely soluble particles (e.g., aluminum metal, aluminum oxide, aluminum hydroxide, aluminum phosphate, and aluminum silicate) are retained in the lungs and then slowly released into the systemic circulation. ^, The amount of Al absorbed by inhalation also appears to be related to particle size. Al fumes are absorbed more readily than dust particles and ultrafine nanoparticles of aluminum oxide can penetrate cell membranes.

Biological monitoring of occupational exposure to Al can be determined by the analysis of blood/serum or urine. The concentration of Al in these specimens can be affected by both the intensity of a recent exposure and the Al body burden. Studies of Al welders indicate a fair correlation between Al in serum and urine ^{, ,} ; however, in workers with normal kidney function, urinary Al concentrations are a more sensitive indicator of occupational Al exposure than serum Al levels. ^, Following exposures to low-level airborne Al, urinary Al concentrations are increased, while serum concentrations are generally within the range of control subjects. ^, In chronically exposed welders, the Al concentration in urine collected following 1 or 2 exposure-free days (e.g., after a weekend of no exposure) is likely a good indicator for determining the magnitude of the Al stored in the body, whereas in newly exposed workers, the urinary Al concentration is probably more influenced by recent exposures than by the body burden . ^,

Reference values for non-occupationally exposed populations are generally less than 10 μg/L (0.4 μmol/L) in serum and less than 30 μg /g (126 μmol/mol) creatinine in urine, although studies from several countries have shown that these upper limits of reference intervals could be less in some populations (see also the Appendix). ^, Guidance values for biological monitoring of occupational exposures to Al have been recommended and should be used in conjunction with workplace air monitoring and medical surveillance assessments. The Finnish Institute of Occupational Health set a biomonitoring action concentration for Al and its inorganic compounds at 81 μg/L (3.0 μmol/L) in a morning urine specimen collected before the work shift on the first day after the weekend. This value reflects exposure to Al during the few preceding days, and gives an indication of the body burden, and of the health risk involved. The reference limit for the nonexposed Finnish population is 16 μg/L (0.6 μmol/L). In Germany, the Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area Deutsche Forschungsgemeinschaft [DFG] assigned a BAT value for Al in urine as 50 μg/g creatinine (210 μmol/mol creatinine) in urine collected at the end of shift after several shifts and long-term exposures. They also established a BAR value of 15 μg/g creatinine (63 μmol/mol). In welders, urine Al concentrations of 81 μg/L (3.0 μmol/L) corresponded to serum Al concentrations of 5.7 μg/L (0.21 μmol/L).

Areas of research

Interest in the role of Al in Alzheimer disease (AD) was raised when Perl observed that Al accumulates in the neurofibrillary tangle of these patients. He concluded that the focal accumulation of Al had an association with neurofibrillary degeneration in the hippocampal neurons that might play a role in the development of AD. Although a cause-and-effect relationship between accumulation of Al in brain and AD has yet to be conclusively demonstrated, ^, studies have clearly shown an increased concentration of Al in the brain. It is possible that accumulation of Al in the neurofibrillary tangle of AD patients is a secondary finding associated with the disease but not directly related to the cause. Also, the neurofibrillary tangle has a higher-than-normal affinity for Al that may explain increased accumulation of Al in brain tissue of Alzheimer patients. Additionally, the role of Al in other neurodegenerative diseases such as Parkinson disease and multiple sclerosis remain controversial though widely studied.

Sources of exposure

Pure metallic Sb is very brittle; however, alloys of Sb are used in various fields of technology. For example, addition of Sb to Pb, Sn, and Cu increases the hardness of these elements when used as electrodes, bullets, type metal for printing, and ball bearings. Other uses include fire-resistant chemicals, pigments, and dyes.

Prior to the introduction of the anthelmintic drug Praziquantel, several Sb-containing compounds were used in the treatment of the parasitic diseases leishmaniasis and schistosomiasis.

Toxicokinetics and toxicodynamics

Toxic effects of Sb are similar to As; however, the majority of information specific to Sb toxicity has been obtained from the use of organic species for pharmacologic purposes. Sb exists predominately in a pentavalent or trivalent state with the trivalent form having inherently higher toxicity. Trivalent Sb is concentrated in red blood cells and the liver, while the pentavalent state predominates in the plasma. Both forms are excreted in urine and feces; however, urine excretion predominates for pentavalent Sb while fecal elimination predominates for trivalent Sb.

Sb has been shown to accumulate in organs and tissues with a high degree of vascularization such as the kidney and liver. Limited metabolism via glutathione-mediated reduction or methylation have been demonstrated for Sb, indicating a lessened detoxification process when compared to As. Genotoxicity of Sb-containing compounds is complicated by the frequent co-exposure to As containing compounds. Data exist that demonstrate genotoxicity for trivalent Sb with evidence of mechanisms involving oxidative stress leading to DNA damage.

Cardiovascular effects of Sb toxicity are related to the administration of Sb-containing drugs for clinical purposes and include increased blood pressure and altered electrocardiogram readings.

Clinical presentation and treatment

Symptoms of acute exposure include: (1) a metallic taste, (2) headache, (3) nausea, and (4) dizziness; and after a short interval, (5) vomiting, (6) diarrhea, and (7) intestinal spasms. In chronic intoxication, adverse health effects include (1) cardiac arrhythmias, (2) upper respiratory and ocular irritation, (3) spontaneous abortion, (4) premature birth, and (5) dermatitis. Lymphocytosis, eosinophilia, and a reduction in leukocyte and platelet counts are also seen and indicate damage to the liver and spleen. Evidence supports increased risk for the development of lung cancer in Sb smelter workers, but the effect may be multifactorial and may be due, for example, to the presence of As in the work environment. It is important to remember that when intoxication occurs with metallic Sb, the effect is caused not only by Sb, but also by Pb, As, and other elements that may accompany it. Blood antimony concentrations of 50 to 120 μg/L (0.41 to 0.98 μmol/L) were measured after ingestion of antimony potassium tartrate.

Preanalytical and analytical aspects

Careful selection of the specimen tube is important for Sb blood collection, as the plastic in tubes, other than certified trace element free tubes for Sb, may contain increased concentrations of Sb. Preservation of collected urine has been shown to be unnecessary for the analysis of Sb for up to 65 days demonstrated by fortification of 24-hour urine samples. ICP-MS is typically used for Sb detection due to its increased sensitivity over other instrumentation. Historic methods for Sb measurements in blood have used time consuming heated acid digestion for achieving better sensitivity while simplified sample preparations measurements have been published.

Regulatory and occupational exposure aspects

For purposes of biological monitoring following exposure to Sb, urine samples are preferable over blood. Furthermore, studies of workers exposed to Sb have shown an increase in the urinary excretion of Sb over control subjects. Urinary Sb concentrations were correlated to the intensity of airborne exposure in nonferrous smelters producing antimony pentoxide and sodium antimonite (r = 0.86). Studies of workers estimated an average increase of 35 μg/g (33 μmol/mol) creatinine in the urine Sb concentration during the shift following an 8-hour exposure to 0.5 mg/m ³ Sb, and an average increase of 7 μg/g (6.5 μmol/mol) creatinine after 8 hours of 0.1 mg/m ³ Sb, ^, generally showing a good correlation between urine Sb concentrations and airborne Sb concentrations (r ² = 0.65). In a study of glass manufacturing workers, an air concentration of 0.5 mg/m ³ Sb corresponded to urine values of 49 μg/L (0.40 μmol/L), and 0.1 mg/m ³ airborne value to 20 μg/L (0.2 μmol/L) Sb in urine. Workers producing starter batteries exposed to antimony trioxide and antimony hydride also showed a correlation between airborne Sb concentrations and end-of-shift – end-of-workweek urinary Sb concentrations (r = 0.75) ; however, the corresponding urine values to 0.5 mg/m ³ and 0.1 mg/m ³ air concentrations were higher at 260 μg/g (242 μmol/mol) creatinine and 60 μg/g (56 μmol/mol) creatinine, respectively. The disparity noted in the urine Sb concentrations estimated from identical air concentrations likely results from the exposure to different Sb species (pentavalent antimony, antimony trioxide, and antimony hydride); the use of specimens collected at different times, where in one case the urinary Sb concentrations were measured during the shift while in the other case, the end-of-shift – end-of-week samples were tested; and finally, the errors associated with extrapolating from the low measured airborne concentrations to the designated threshold air value of 0.5 mg/m ³ . ^,

The ACGIH classifies antimony trioxide as a Group A2 suspected human carcinogen. In Germany, the DFG designates Sb and its inorganic compounds except for stibine (antimony hydride) as Category 2 carcinogens, that is, substances that are considered to be carcinogenic for man because sufficient data from long-term animal studies or limited evidence from animal studies substantiated by evidence from epidemiologic studies indicate that they can contribute to cancer risk. No EKA exposure equivalent correlations were established for antimony and its inorganic compounds including stibine. The Finnish Institute of Occupational Health has no established biomonitoring action limit for Sb and its inorganic compounds but recommends biological monitoring for Sb in a postshift urine specimen at the end of the work week or exposure period. In pregnant women, the urine Sb concentration cannot exceed the reference limit for the nonexposed Finnish population at 1.1 μg /L (0.009 μmol/L).

Areas of research

Reduced exposure to Sb has been studied in conjunction with the use of “green” ammunition as an alternative to conventional ammunition for indoor shooting ranges. Metagenomic approaches have been published investigating the potential of microbes with the ability to biotransform Sb to less toxic species for use in heavily contaminated soils.

Sources of exposure

Nontoxic forms of organic As are present in many foods with arsenobetaine and arsenocholine being the two most common forms. The foods that most commonly contain significant concentrations of organic As substances are shellfish and other predators in the seafood chain (e.g., cod, haddock). In a large US population study, for all participants aged greater than 6 years, dimethylarsinic acid (DMA) and arsenobetaine had the greatest contribution to the total urinary As. Arsenobetaine was the primary contributor to high total urinary As concentrations.

Toxicokinetics and toxicodynamics

As exists in numerous toxic and nontoxic forms. The toxic forms include: (1) the inorganic species arsenite As ³⁺ , also denoted as As(III); (2) the less toxic arsenate As ⁵⁺ , also known as As(V), and their less toxic metabolites; (3) monomethylarsonic acid (MMA); and (4) DMA. Detoxification occurs in the liver as As ⁵⁺ is reduced to As ³⁺ and then is methylated to MMA and DMA. As a result of these detoxification steps, As ³⁺ and As ⁵⁺ are found in the urine shortly after ingestion, whereas MMA and DMA are the species that predominate longer than 24 hours after ingestion. Urinary As ³⁺ and As ⁵⁺ concentrations peak in urine at approximately 10 hours and return to normal 20 to 30 hours after ingestion. Urinary MMA and DMA concentrations normally peak at about 40 to 60 hours and return to baseline 6 to 20 days after ingestion. ^, In a large US population study, for all participants aged greater than 6 years, DMA and arsenobetaine had the greatest contribution to the quantity of total urinary As. Arsenobetaine was the primary contributor to high total urinary As concentrations. ^{, ,} As excretion in healthy people who have ingested arsenobetaine-containing foods is greater than 120 μg per 24-hour specimen.

The half-life of inorganic As in blood is 4 to 6 hours, and the half-life of the methylated metabolites is 20 to 30 hours. Blood concentrations of As are increased for only a short time after administration, after which As rapidly disappears into the large body phosphate pool. Abnormal blood As concentrations in the 5 to 50 ng/mL (0.07 to 0.7 μmol/L) range are detected after exposure. The structures of these and related As species are shown in Fig. 44.2 .

The toxicity of As is due to three different mechanisms, two of which are related to energy transfer. As avidly binds to dihydrolipoic acid, a necessary cofactor for pyruvate dehydrogenase. Absence of the cofactor inhibits the conversion of pyruvate to acetyl coenzyme A—the first step in gluconeogenesis. As competes with phosphate for reaction with adenosine diphosphate (ADP), resulting in formation of the lower-energy adipic acids (ADPAs) rather than adenosine triphosphate (ATP). As also binds with any hydrated sulfhydryl group on proteins, distorting the three-dimensional configuration of the protein, thus causing it to lose activity. This suggests that the primary mechanism of action of the toxicity of As is related to sulfhydryl binding. As also interferes with the activity of several enzymes of the heme biosynthetic pathway. As is also a known carcinogen as evidence suggests increased risk of bladder, skin, and lung cancers, as well as lung cancer associated with smoking, following consumption of water with high As contamination. ^,

Clinical presentation and treatment

The symptoms of As toxicity may be nonspecific and often overlap with symptoms of other toxicants. Acute As toxicity can be characterized by gastrointestinal distress, including vomiting and diarrhea, and also cardiac arrhythmias. Chronic toxicity may be characterized by renal failure, cardiac arrhythmias, liver dysfunction, and peripheral neuropathy. ^, Transverse white bands on the fingernails (Mees’ lines) and hypopigmented macules on the skin have been documented after As exposure. ^,

As has been shown to interfere with the activity of several heme biosynthetic enzymes including aminolevulinate synthase, porphobilinogen deaminase, uroporphyrinogen III synthase, uroporphyrinogen decarboxylate, coproporphyrinogen oxidase, ferrochelatase, and heme oxygenase. Observed alterations in urine porphyrins include increases in copro/uro and copro I/III ratios. Interestingly, the madness of King George III historically attributed to acute hereditary porphyria has been hypothesized to instead be a case of As-induced porphyria based on retrospective analyses of hair. However, a more recent publication using computer diagnostics and cognitive archeology argued a diagnosis of bipolar disorder type I as the underlying etiology.

BAL is an effective antidote for treating As intoxication; the active agent in BAL is dimercaprol, a sulfhydryl-reducing agent. BAL was originally developed during World War II in response to the use of lewisite, an As-based chemical warfare agent. Other dimercaprol derivatives are available for treatment including DMSA (succimer) and DMPS; the latter is currently not approved for As chelation therapy in the United States despite past evidence of its utility in treating As toxicity.

Preanalytical and analytical aspects

To distinguish among toxic inorganic species and nontoxic organic species of As of seafood origin, high-performance liquid chromatography (HPLC) techniques that separate the various species of As in biological fluids and tissues have been developed. A typical finding in a urine specimen with total 24-hour excretion of As of 350 μg/24 hr (4.6 µmol/24 hours) is that more than 95% is present as the organic nontoxic seafood species, and less than 5% is present as the inorganic toxic species. Such a finding indicates that the increased total As concentration was likely due to ingestion of seafood. Despite the availability of HPLC-ICP-MS methods for As speciation, it is noted that the use of a screening method for total As prior to speciation is of utility in reducing unnecessary costs.

Hair analysis is frequently used to document time of As exposure. As circulating in the blood will bind to protein by formation of a covalent complex with sulfhydryl groups of the amino acid cysteine. Because As has a high affinity for keratin, which has high cysteine content, the As concentration in hair or nails is greater than in other tissue. Several weeks after exposure, transverse white striae, called Mees’ lines, may appear in the fingernails; this event is caused by denaturation of keratin by elements such as Cd, Pb, and Hg. Because hair grows at a rate of approximately 1 cm/month, hair collected from the nape of the neck can be used to document recent exposure. Axillary or pubic hair is used to document long-term (6 months to 1 year) exposure. Hair As greater than 1 μg/g dry weight indicates excessive exposure. In one study, the highest hair As observed was 210 μg/g dry weight in a case of chronic exposure that was the cause of death.

Blood is the least useful specimen for identifying As exposure. Blood As concentrations are increased for only a short time after administration and rapidly disappear into the large body phosphate pool, because the body treats As like phosphate, incorporating it wherever phosphate would be incorporated. Absorbed As is rapidly circulated and distributed into tissue storage sites. Abnormal blood As concentrations are detected for only a few hours (<4 hours) after ingestion. This test is useful only to document an acute exposure when the As is likely to be greater than 20 μg/L (0.3 μmol/L) for a short period of time.

As has been accurately analyzed by ICP-MS. Mass response from the argon plasma is monitored for As (m/z 75); however, the method must reduce the potential for interference from argon chloride ( ⁴⁰ Ar ³⁵ Cl; m/z 75) with the use of a dynamic reaction cell or collision cell with kinetic energy discrimination. Urine is the sample of choice for As analysis as As is excreted predominantly by the kidney.

Regulatory and occupational exposure aspects

Workers potentially exposed to arsine include metal smelters and refiners, metallurgists, solderers, Pb platers, battery makers, semiconductor manufacturers, and recyclers, or any other occupation where hydrogen comes in contact with As. Following an acute occupational exposure to arsine, the urinary As compounds detected in a worker were MMA, DMA, trivalent and pentavalent As, and arsenobetaine. Since arsine is very toxic and has a strong odor, occupational exposures are likely to be very low resulting in exposures similar to the background level of other As compounds.

Cardiovascular diseases and cerebrovascular effects are associated with chronic exposures to inorganic As compounds in the workplace. Inhalation exposures to inorganic As compounds have been correlated to an increased incidence of lung cancer. ^, The ACGIH classifies As and its inorganic compounds as an A1 carcinogen, a confirmed human carcinogen. The recommended ACGIH Biological Exposure Index (BEI) for inorganic As plus methylated metabolites is 35 μg/L (0.5 μmol/L) in an end-of-workweek urine sample following the exposure to As and soluble inorganic compounds (excluding gallium arsenide and arsine). Following exposures to poorly soluble inorganic compounds, such as gallium arsenide, the urinary As concentration is more representative of the amount absorbed rather than to the total dose inhaled or ingested.

Areas of research

Cardiovascular injury due to inorganic As exposure has received increased attention including the inclusion of increased risk of cardiovascular disease as a noncancer endpoint of interest by the US Environmental Protection Agency. A clear mechanism of action remains to be determined, however, reports of oxidative damage to endothelial cells have been published. ^, Epigenetic changes as a result of As exposure have been identified but the biological significance remains to be determined.

Sources of exposure

The general population is exposed to low concentrations of Be through food and drinking water but these exposures are not of clinical concern. The major route by which Be enters the body is via the respiratory tract, and industrial exposure usually occurs from inhalation and ingestion of Be dust. Acute exposure to Be is rare and is usually caused by an industrial accident or explosion.

Toxicokinetics and toxicodynamics

Inhaled Be compounds are cleared very slowly from the lungs. Soluble compounds such as Be nitrate and Be sulfate are absorbed to a much greater degree than others such as Be oxide, which are much less soluble. Be salts are strongly acidic when dissolved in water, and this is thought to have a major toxic effect on human tissue. Absorbed Be accumulates in the skeleton and renal clearance is very slow. Be inhibits a variety of enzyme systems, including alkaline phosphatase, acid phosphatase, phosphoglycerate mutase, hexokinase, and lactate dehydrogenase.

Clinical presentation and treatment

Chronic Be exposure in the workplace has led to occupational health concerns because of its potential to cause a progressive and potentially fatal respiratory condition called chronic Be disease (CBD). This disease, also known as berylliosis, is characterized by the formation of granulomas resulting from an immune reaction to Be particles in the lung. To reduce the number of workers currently exposed to Be in the course of their work at the US Department of Energy (DOE) facilities or among its contractors, the DOE has established a CBD prevention program (CBDPP) to minimize the concentrations of, and the potential for exposure to, Be, and has put forth medical surveillance requirements to ensure early detection of the disease.

Studies have suggested that the size of the Be particles affects not only the site of deposition but also the amount deposited. This in turn may influence the clearance rate and thus the time of contact between the immune cells and Be.

Preanalytical and analytical aspects

Several years ago, researchers noted that blood and lung cells from CBD patients proliferated when exposed to Be in culture. This assay has been refined and is offered as the Be lymphocyte proliferation test (BeLPT). Unfortunately, because of the nature of the test and the variability from lab to lab, the BeLPT has been known to produce false-negative and problematic results. ^, Efforts are under way by several groups to standardize the assay. Despite these issues, the BeLPT in bronchoalveolar cells is part of the current “gold standard” diagnosis for CBD. Quantification of Be in serum or urine is not useful in making this diagnosis. Air analysis using Threshold Limit Value (TLV) is the preferred method of exposure evaluation.

Regulatory and occupational exposure aspects

The dose, particle size, and solubility of the Be compounds are critical factors impacting the deposition and clearance in the lungs. Studies indicate that soluble compounds, such as Be chloride, have a pulmonary half-life of 20 days, with at least a third transferred to the systemic circulation. Insoluble Be compounds, such as Be oxide, can be retained longer in the lungs and have an estimated pulmonary half-life of about one year. Inhaled Be exhibits multiphasic clearance from the lungs into blood. Absorbed Be is mainly eliminated through the urine.

Although skin absorption of Be probably contributes little to the body burden of occupationally exposed workers, skin contact with Be can cause allergic reactions.

Be and its compounds cause two types of Be-induced lung diseases, acute and chronic. Acute Be disease is caused by the inhalation of relatively high concentrations of Be dust and metal fumes, especially from soluble Be salts, which can result in an acute inflammation of the respiratory airways and lungs. The occurrence of acute Be disease is relatively rare because of improved use of industrial hygiene practices. CBD (or berylliosis) can develop following the inhalation of primarily insoluble Be compounds, such as Be oxide. This disease, which is often fatal, is a cell-mediated immune reaction characterized by the formation of pulmonary masses or nodules (granulomas) that may take anywhere from a few months to many years to develop. It is believed that workers exposed to Be can become sensitized to it leading to the development of this disease. The BeLPT is used to identify sensitized workers even if they are asymptomatic of disease. Since the predictability and reliability of screening by BeLPT has yet to be substantiated, the DFG in Germany has not recommended this test as an effective parameter. Approximately 1 to 16% of exposed workers tested with the blood BeLPT were observed to be sensitized to Be. Since Be exposures can result in pulmonary disease, the testing of exhaled breath condensate (EBC) for Be has shown to be a promising biomarker of occupational exposure.

The Internal Agency for Research on Cancer classifies Be and its compounds as a Group 1 human carcinogen. Be and its compounds are designated as human carcinogens by the ACGIH (A1) and the German DFG (Category 1). However, some investigators do not support the causal association between occupational exposure to Be and the risk of cancer and suggest a further evaluation into the carcinogenicity of Be. ^,

Areas of research

Be exposure and lung disease remain a continued focus of the American Thoracic Society with a recent publication aimed at increasing awareness. Recent publications have reported on the increased incidence of CBD in men and women with HLA-DPB1 mutations and Be exposure. ^,

Sources of exposure

Cd is a byproduct of zinc (Zn) and Pb smelting. It is used (1) in industry in electroplating, (2) in the production of rechargeable batteries, (3) as a common pigment in organic-based paints, and (4) in tobacco products. Spray painting of organic-based paints without the use of protective breathing apparatus is a common source of chronic exposure. Auto repair mechanics represent a work group that has significant opportunity for exposure to Cd.

Toxicokinetics and toxicodynamics

Cd toxicity is expressed via formation of protein-Cd adducts that change the conformational structure of the protein, causing it to denature. This protein denaturation occurs at the site of highest concentration—in the alveoli if exposure is due to dust inhalation, and in the proximal tubule of the kidney because this is a major route of excretion. Once absorbed, nearly 80% of Cd is found in red blood cells. Cd in plasma is transported to the liver bound to albumin where Cd-induced synthesis and binding of the low-molecular-weight metallothionein becomes the transport system to the kidney tubules.

The cellular effects of Cd include disruption of cell cycle progression, proliferation, differentiation, DNA replication and repair, and apoptosis. Curiously, at low concentrations Cd has been shown to promote DNA synthesis and cell growth. Indirect oxidative stress is a likely mechanism involved in Cd oxidative damage as Cd does not donate or accept electrons under physiologic conditions.

Clinical presentation and treatment

The toxicity of Cd resembles that of As, Hg, and Pb in that it damages the kidney. Chronic exposure to Cd causes accumulated renal damage. Breathing the fumes of Cd vapors leads to nasal epithelial deterioration and pulmonary congestion resembling chronic emphysema. Renal dysfunction with proteinuria of slow onset (over a period of years) is the typical presentation. Normal blood Cd concentration is less than 5 ng/mL (44 nmol/L), with most concentrations in the interval of 0.5 to 2 ng/mL (4 to 18 nmol/L). Moderately increased blood Cd (3 to 7 ng/mL or 27 to 62 nmol/L) may be associated with tobacco use. Acute toxicity is observed when the blood concentration exceeds 50 ng/mL (444 nmol/L). Usual daily excretion of Cd is less than 3 μg/d (0.03 μmol/d). Cd concentrations also increase with age and may be involved with senescence.

Preanalytical and analytical aspects

Collection of urine samples using a rubber catheter has been known to result in increased results because rubber contains trace amounts of Cd that are extracted as urine passes through it. Brightly colored plastic urine collection containers and pipette tips should be avoided because the pigment in the plastic may be Cd based. Cd is usually quantified by atomic absorption spectrometry, but can be accurately quantified by ICP-MS.

Regulatory and occupational exposure aspects

Inhalation is the primary route of Cd exposure in the occupational setting and the amount absorbed from the lungs depends on the solubility and particle size of the Cd compound. Absorption through the gastrointestinal tract can occur from the clearance of particles deposited in the lungs and from contaminated hands and food. Following chronic low-level exposures, about half of the Cd body burden is stored in the liver and kidneys. Since urine is the main route of elimination, urinary Cd concentrations are widely used to biomonitor chronic exposures in workers. However, because of the high binding capacity for Cd in the body, a urinary concentration may provide no information about exposure in someone newly exposed to Cd. The lag time needed before the urinary Cd concentration correlates with exposure depends on the intensity of the integrated exposure. Until sufficient time of chronic Cd exposure has passed before urine testing can be used appropriately (1 year), blood testing is suggested for newly exposed workers or when changes in exposure occur since blood concentrations primarily reflect recent exposures.

The exposure assessment of Cd as stated in the US OSHA Cadmium Standard is part of an overall periodic environmental, medical, and biological monitoring program. The biomonitoring requires testing in urine for both Cd and β ₂ -microglobulin (β ₂ MU) with standardization to grams of creatinine for each component (μg/g creatinine or μmol/mol creatinine), and in blood for Cd with standardization to liters of whole blood (μg/L or μmol/L). Table 44.3 shows the guidelines used in assessing the urine and blood tests and the actions to be taken with the Cd results according to the OSHA Standard.

Areas of research

Cd toxicity continues to be of outstanding concern regarding environmental accumulation and the effect on both plants and animals. Of particular interest is the investigation of Cd exposure and increased risk of cardiovascular disease, with a complimentary publication proposing endoplasmic reticulum stress and impaired energy homeostasis in cultured cardiomyocytes.

Sources of exposure

Occupational exposure to Cr represents a significant health hazard. ^, Cr is used extensively (1) in the manufacture of stainless steel, (2) in chrome plating, (3) in the tanning of leather, (4) as a dye for printing and textile manufacture, (5) as a cleaning solution, and (6) as an anticorrosive in cooling systems. The toxic form of Cr is hexavalent Cr ⁶⁺ [Cr(VI)] and a strong oxidizing environment is required to convert the more common form trivalent Cr ³⁺ [Cr(III)] to Cr ⁶⁺ , as might be found when Cr ³⁺ is exposed to high temperatures in the presence of oxygen or during high-voltage electroplating.

Considerable attention has been given to Cr toxicity following the release of Cr ions during normal and abnormal wear of MoM prosthetics after significant quality concerns with specific devices. Although the idea of metal ion release is not a new concept, the increased use of MoM prosthetic devices and attention given to poorly positioned and abnormally high failure rate of specific devices renewed interest in the potential for Cr toxicity. However, the vast majority of Cr released from MoM prosthetics has been shown to be in the trivalent form which is considerably less toxic than hexavalent Cr. As of February 2016, the US Food and Drug Administration (FDA) issued orders to change requirements for MoM total hip implants from premarket notification to the more stringent premarket approval. To date, there are no FDA-approved MoM total hip replacement devices marketed for use in the United States but two FDA-approved MoM hip resurfacing devices. In the United States, no guidelines have been established for the assessment of metal ions in asymptomatic patients due to a lack of knowledge regarding the prevalence of adverse events in the US population and no clear threshold concentrations associated with an adverse event. Internal exposure to metallic components of orthopedic devices and other implants is also discussed in the Prostheses and Implants section of Chapter 39 .

Toxicokinetics and toxicodynamics

Cr exists primarily as Cr ³⁺ or Cr ⁶⁺ with Cr ⁶⁺ being considerably more toxic than Cr ³⁺ . Cr ⁶⁺ is highly lipid soluble and readily crosses cell membranes, whereas Cr ³⁺ is rather insoluble and does not readily cross membranes. Cr ⁶⁺ compounds are powerful oxidizing agents and are more toxic systemically than Cr ³⁺ compounds, given similar amounts and solubilities. At physiologic pH, Cr ⁶⁺ forms and readily passes through cell membranes due to its similarity to essential phosphate and sulfate oxyanions. Intracellularly, Cr ⁶⁺ is reduced to reactive intermediates, producing free radicals and oxidizing DNA, both potentially inducing cell death. Severe dermatitis and skin ulcers can result from contact with Cr ⁶⁺ salts. Clinically, monitoring typical biological specimens for Cr ⁶⁺ is neither practical nor clinically useful to detect Cr toxicity, because the instant it enters a cell, it is reduced to nontoxic Cr ³⁺ . Inhalation of the vapors of Cr ⁶⁺ causes erosion of the epithelium of the nasal passages and produces squamous cell carcinomas of the lung.

Clinical presentation and treatment

Symptoms associated with Cr toxicity vary based upon route of exposure and dose, and may include dermatitis, impairment of pulmonary function, gastroenteritis, hepatic necrosis, bleeding, and acute tubular necrosis. In the case of failing MoM prosthetics, increased Cr in serum or blood is rarely the initial finding and instead is preceded by more telling physical symptoms such as reduced range of motion, swelling and inflammation around the joint, and general discomfort or pain. Although offered by laboratories, measurement of Cr in joint fluid has limited clinical utility.

Preanalytical and analytical aspects

Use of a plastic cannula for blood sampling was shown to be unnecessary in the assessment of Cr; however, sporadic contamination due to stainless steel needles has been observed. Quantification of total Cr in urine can be used to assess exposure to total Cr. The National Institute for Occupational Safety and Health (NIOSH) has proposed less than 30 μg Cr/g (65 μmol/mol) creatinine as the concentration of concern, but this concentration does not indicate that the specific exposure was to Cr ⁶⁺ . The presence of Cr in erythrocytes is suggestive of exposure to Cr ⁶⁺ within the past 120 days, because Cr ⁶⁺ crosses biological membranes but Cr ³⁺ does not. Increased serum Cr concentrations are observed in association with orthopedic implants made from Cr alloys. ^, ICP-MS is the preferred technology for quantification of Cr in body fluids but suffers from considerable interference due to polyatomics. Use of dynamic reactive cell technology or a collision cell with kinetic energy discrimination is required for reproducible and accurate measurements. For more details on the ICP-MS technology and Cr measurement the reader is referred to Chapter 39 on Trace Elements.

Regulatory and occupational exposure aspects

Industrial exposures with Cr can be to the trivalent and hexavalent forms, which exhibit different toxicokinetics and toxicodynamics in the body. Urine Cr concentrations are the most useful biomarker for assessing occupational exposure to water soluble hexavalent Cr compounds ; however, other nonoccupational sources of both trivalent and hexavalent Cr from the diet, supplements, and the environment can impact the total Cr concentration in urine. Furthermore, since Cr has been shown to accumulate in the body, urine Cr values can be affected by both recent and past workplace exposures. ^, The measurement of Cr in erythrocytes has been used to gauge the intensity of exposure to hexavalent Cr ; however, there are insufficient data available to determine a relationship for erythrocyte Cr concentrations with risks associated with exposures. More recent studies have demonstrated the ability to separate trivalent and hexavalent Cr in EBC. ^, The testing of EBC for the Cr species may assist in a better understanding of inhaled Cr.

Occupational exposures to hexavalent Cr compounds can cause respiratory irritation and tissue damage of the nose, throat, and lungs following inhalation, and can cause irritation, burns, and ulcers on the skin with contact. ^, Hexavalent Cr has been associated with cancers of the lungs, nose, and nasal sinuses and has been classified as a human carcinogen by the Internal Agency for Research on Cancer. Hexavalent Cr compounds are categorized as human carcinogens by the ACGIH (A1). The ACGIH suggests testing total Cr in urine for workplace exposure to hexavalent Cr (water soluble fumes). The recommended BEI is 25 μg/L (481 nmol/L) of total Cr in an end of shift at the end of workweek urine sample or an increase of 10 μg/L (192 nmol/L) during the shift by comparing preshift and postshift urine samples. The DFG in Germany recommends a total Cr BAR value (Biological reference value) of 0.6 μg/L (0.012 µmol/L) in urine collected at the end of exposure or end of shift.

Areas of research

Recent investigations into contact dermatitis in children and adults have implicated Cr leaching from mobile phones as one potentially underappreciated source. In addition, information on continued research regarding the role of Cr is available.

Sources of exposure

Although relatively rare, Co is widely distributed in nature and is found in green vegetables, animal foods, and seafood. The vast majority of Co in the body is in the form of cyanocobalamin or vitamin B12, a Co complex similar in structure to porphyrins. Co is used in alloys where the presence of Co results in high melting point, strength, and resistance to oxygen. The addition of Co in MoM prosthetics adds resistance to surfaces undergoing heavy wear and the release of Co from failed prosthetics was previously a substantial concern. Co is found in rechargeable batteries and provides color to plastics, inks, glass, and paint.

Toxicokinetics and toxicodynamics

Co in the form of cyanocobalamin is not toxic while many other Co-containing compounds demonstrate a range of toxicities based on route of administration. Ingestion or inhalation of large doses may lead to pathologic disorders while gastrointestinal absorption varies considerably. Acute toxicity manifests itself as pulmonary edema, nausea, vomiting, and hemorrhage. Long-term exposure affects several target organs including thyroid gland, lungs, immune system, and kidneys. The mechanisms of Co toxicity include (1) binding of sulfhydryl groups resulting in enzyme inhibition, (2) disruption of intracellular calcium homeostasis, and (3) generation of reactive oxygen species. In the blood, Co partitions into red blood cells and has been demonstrated to bind to the globin moiety and does not displace Fe at the center of heme.

Accumulation of Co in the myocardium has been observed postmortem in lethal cases and cardiac dysfunction has been noted in association with nonlethal occupational exposures and in cases of MoM prosthetic failure.

Clinical presentation and treatment

Co is not highly toxic, but large exposures will produce (1) pulmonary edema, (2) allergy, (3) nausea, (4) vomiting, (5) hemorrhage, and (6) renal failure. Occupational exposure occurs during production and machining of these metal alloys and has been known to result in interstitial lung disease. Cardiomyopathy and renal failure are symptomatic of acute Co exposure; this was exemplified by an incidence of mass population exposure to Co when beer contaminated with the Co salts was consumed. Chronic exposure may cause (1) pulmonary syndrome, (2) skin irritation, (3) allergy, (4) gastrointestinal irritation, (5) nausea, (6) cardiomyopathy, (7) hematologic disorders, and (8) thyroid abnormalities. In addition, Co exposure must be considered within the context of exposure to multiple elements.

Serum Co concentrations are increased above normal (>1 μg/L or >17 nmol/L) in patients with well-positioned and functioning orthopedic implants made from Co alloys. ^, Considerable attention has been given to Co toxicity in the context of failed MoM prosthetics with several case reports of severe neurologic and cardiac abnormalities described with additions to the literature continuing after discontinuation of Co-containing MoM total hip implants. ^, In the case of failing MoM prosthetics, increased Co in serum or blood is rarely the initial finding and instead is preceded by more telling physical symptoms such as reduced range of motion, swelling and inflammation around the joint, and general discomfort or pain. Though offered by many laboratories, measurement of Co in joint fluid has relatively little clinical utility.