Trace Metals (Lead and Cadmium Exposure Screening) Rose T. Daher Section of Biochemistry, The Cleveland Clinic Foundation, Cleveland Ohio 44 195
Lead and cadmium exposures are two old problems with modem prevalence. Lead and cadmium are widely dispersed in the environment, and exposure to either element can give rise to a number of adverse health effects due to their toxicity after accumulationin multiple organs in the body. While lead poisoning remains a dominant health problem in the United States despite the decline in occupational and environmental exposure in the last few decades (El),the health hazards associated with cadmium poisoning are mainly due to occupational exposure (EL’), except for itai-itai disease, which is linked to general environmental pollution in Japan (E3). A great deal of research has been conducted in these areas where cohorts of children or industrial workers were followed for years to determine the effects of exposure to these elements. These studies indicate that even at low exposure levels the risk of cognitive deficiencies in leadexposed children (E4,and of renal tubular damage due to industrial exposure to cadmium, can be considerable (E5-E7). In addition, experimental and epidemiological studies are providing increasing evidence that cadmium is carcinogenic (E8) and exposures should be controlled to the lowest levels feasible. Prompted by the reports on the effects of low levels of lead on neurodevelopmental outcome in children, the Centers for Disease Control and Prevention (CDC) lowered blood lead (J3Pb) action level from 25 to 10 pg/dL (E9). The CDC also recommended the use of direct lead analysis for lead exposure screening rather than the indirect methods. To limit individuals’exposure to lead and cadmium, the Occupational Safety and Health Administration (OSHA) has developed standards for the use and biological monitoring of these toxic elements in the workplace (E10,E l 1). Since “lead and cadmium exposure screening”was not covered in the last Application Review published in 1993, this subsection will review the literature on this topic between October 1991and October 1994 in light of the new regulations which directly impact clinical laboratories performing the analyses. It will also focus on the improvements in analytical techniques used in order to meet these guidelines. LEAD
Sources of Exposure. Lead is a heavy metal, xenobiotic (E12), with no known physiological significanceto humans (E13). Lead is absorbed primarily through the gastrointestinal tract and the lungs, after ingestion or inhalation of leadcontaminated substances. Most significant environmental sources of lead include lead-based paint, leaded-gasoline, drinking water, food, soil, and dust. Occupational sources of lead exposure include plumbers, pipe filters, lead miners, automobile repairers, construction workers, and plastic rubber product and battery manufacturers (E14).The institution of lead abatement programs (E15),in addition to elimination of leaded gasoline ( E l @ , had a direct impact on protecting individuals, and particularly children, from the dangers of lead exposure. However, the potential sources of lead are so variable that exposure control strategies will vary from place to place and no single answer will address all scenarios (El 7). In recent years, there has been significant interest in the potential human health risks resulting from exposures to lead in soil and dust. This concern is mostly focused on young children
because children absorb more lead ingested from soil and dust than adults absorb, and children are more sensitive to the toxic effects of lead (E18).The reasons for this toxicity are as follows: (1) Incomplete development of the blood brain barrier before age 3 allows lead to more readily enter the central nervous system. (2) Ingested lead has higher bioavailability (40%) in children compared to adults (10%). (3) Common hand-to-mouth behavior in children greatly increases their risk of lead ingestion (E13, E18). Adverse Effects and Action Levels. High doses of lead are known to adversely affect many systems of the body-hematopoietic, vascular, renal, peptic, cardiovascular, immunological, reproductive, gastrointestinal,endocrine, and central nervous system (E13, E19). Levels of >55 pg/dL can cause death, brain damage, kidney failure, seizures, and anemia. Anemia from malnutrition poses a particular threat to a child exposed to lead. When there is an inadequate supply of calcium, phosphorus, and iron in a child’s diet, lead is more readily absorbed (E19).However, children with moderately elevated lead levels are asymptomatic. This type of poisoning results in more subtle effects such as deficits in neurobehavioral cognitive performance. These deficits, including IQ (EZU-EZZ) , behavioral disorders, and impaired hearing (E23), have been associated with lead levels as low as 10 pg/dL. Furthermore, several longitudinal studies have demonstrated that the negative effects of lead on cognitive function are persistent across cultures, racial and ethnic groups, and social and economic classes. As a direct result, in October 1991 the CDC redefined childhood lead poisoning (E9). Under the new guidelines, the BPb level thought to be toxic was reduced from 25 to 10 pg/dL. In conjunction with the new standards for lead intoxication, the CDC also developed new guidelines for screening for lead intoxication, following up children with significant lead burden, and initiating primary prevention of lead poisoning. The major goals for these guidelines include universal screening for all children 6 years of age or less and the measurement of BPb levels as the standard for screening. In April 1993, the American Academy of Pediatrics released a new policy statement (E24 on screening and prevention of lead poisoning which supports the CDC screening recommendations. Adults may be exposed to high levels of lead in occupations that involve lead. OSHA regulates lead in the air in the working environment, but not in soil or dust (El@. OSHA states that the BPb level of workers (male and female) intending to have children should remain below 30 pg/dL. OSHA allows 40 pg/dL as a “permissible”BPb level in lead-exposed workers, below which no further medical monitoring or workplace intervention is required. Biological Markers. Research has been focused on develop ing techniques for biomarkers of environmental and occupational exposure to lead (E25). Early efforts focused on indirect measurement of exposure by analyzing precursors of the heme biosynthetic pathway in blood and urine such as zinc protoporphyrin (ZPP) or free erythrocyte protoporphyrin (EP). Between 1985 and 1991, these methods were the most widely used tests for detection of lead poisoning. These methods, although suitable for predicting very high lead concentrations, are insensitive to values below 20 or 25 pg/dL because little change occurs in heme Analytical Chemistv, Vol. 67, No. 12, June 15, 1995
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synthesis in response to lower concentrations of BF% (E25-E27). In light of these facts, the CDC recommended that a "direct" BPb assay be used rather than indirect assays (E9). The new standard posed a technical challenge to manufacturers and State Health Departments alike. In addition, part of the CDC plan was to seek out companies to develop lead-testing technology for assays that were sensitive enough to meet the guideline specifications of I10 pg/dL but inexpensive enough to use in large-scale state public health screening programs. As such, demand for a portable instrument capable of testing blood at remote locations has increased (E28). For external quality control testing, every laboratory doing BPb screening should participate in an external proficiency testing program available from CDC, College of American Pathologists, Centre de Toxicologie du Quebec, or others. Specimen. According to the CDC recommendations, venous blood is the preferred specimen for analysis of BPb because of the low likelihood of contamination, larger volume, and lower probability of clotting when compared to others. Fingerstick specimens are acceptable for screening provided that special collection procedures are followed. Elevated BPb results obtained on capillary specimens must be confirmed using venous blood (Eg).
Lead Analysis. Several methods have been published in the last decade for lead analysis. Most methods utilize graphite furnace atomic absorption spectrometry (GFAAS), which requires expensive and sophisticated equipment in addition to a certain level of expertise to operate. Traditionally, ammonium dihydrogen phosphate with Triton X-100 and dilute nitric acid has been used as the matrix modifier for dilution of whole blood before analysis by Zeeman effect GFAAS. The use of matrix-matched standards with older technology furnaces has improved precision and accuracy, especially at low concentrations (4.9% at 5.0 pg/dL) (E29). Given current innovations in furnace technology, a rapid, sensitive, and accurate method for BPb was developed because of the transversely heated graphite furnace with longitudinal Zeeman field background correction system employed (E30). Whole blood was diluted 1:lO with the traditional modifier mentioned above. Aqueous standards were used for calibration because of the efficiency of temperature control at various analytical steps along the length of the graphite tube. One furnace cycle required 90 s. The reported precision at the 8.4 pg/dL level was 1.2%. The behavior of lead in GFAAS undergoing palladiumor phosphate/magnesium-induced isoformation in conjunction with the carbon reducing effect achieved by the addition of citric acid was examined (E31). Results show that the atomization rate of lead was independent of the matrix and the analytical modifier (isoformer) used, and a carbon-dependent mechanism for the reduction of the atomic precursor to form lead atoms with production of carbon monoxide occurred. The citric acid served as a carbon source, other than the graphite furnace surface, which actively participates in the redox reaction, thus matching the appearance time of peak absorbance between wholeblood samples, urine, and aqueous standards without any delay or tailing. The use of palladium was favored over magnesium/phosphate modifier because less citric acid is needed to achieve the same effect, and the change in peak appearance in the absence or presence of excess carbon between whole blood and aqueous standards is not as pronounced. The limit of detection for this method was 0.1 pg/L for a 1@pLinjection volume, with a precision of 2.2%. 406R
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Stable isotope dilution gas chromatography/mass spectrometry is another technique that has been exploited for BPb analysis after chelation and derivatization to form Pb(FCSHk), in order to eliminate the problem of carryover between sequential analysis of different isotopic ratios. The internal standard was zo4Pb.The method has a detection limit of 0.1 pg/L (E32). Because of the cost and complexity, such methods will be restricted to certain specialized laboratories and will not serve as techniques of choice for a universal screening method. The alternative method currently in use for BPb analysis is anodic stripping voltammetry (ASV), which is less expensive and more easily operated. A new and improved ASV method from ESA requires an analysis time of 90 s and has a lower limit of detection of 1 pg/dL with a precision of 10%up to 10 pgldL (E33). A method based on square-wave anodic stripping voltammetry (SWASV) in Hg*+containing solution using a l@pm-diametercarbon disk ultramicroelectrode was developed (E34). It eliminates interferencefrom oxygen in unsparged bloodderived sample solutions, and filtration of aci&ed samples through nitrocellulose reduces the concentration of interfering substances. The volume of blood required for analysis is between 100 and 120 pL. Preliminary comparisons of SWASV results with alternative methods were acceptable; however, the precision at concentration of 10 pg/dL was > 10%and the lower limit of detection was 2.6 pg/dL, well beyond the CDC objectives of a precision of 10%for BPb of 10pg/dL and detection limit around 1 pg/dL. Future improvements in sensitivity and precision of this technique are feasible. Stripping potentiometry has been suggested as an alternative electroanalytical technique for the determination of BPb. The major reason that this technique has not come into widespread use in clinical laboratories is its demand for computerized data acquisition in order to give satisfactory performance with respect to sensitivity. In this newly developed method, 70 pL of blood is added to 200 pL of distilled water and then mixed with 400 pL of matrix modifier (solution containing HCl, mercury(I1) ions, Triton X-100, and bismuthUII) as internal standard). Lead amalgam is deposited on glassy carbon electrode by means of a pulsed potential cycle for 3 min, after which lead is reoxidized by means of a constant current. All experimental parameters and data analysis are under computer control. The method has a relative precision of 10%and a limit of detection of 3.5 pg/L and thus fulfills the requirements set down for a lead screening method (E35). Mercury-coated screenprinted carbon electrodes for stripping voltammetry and potentiometry, which perform in a manner similar to conventional Hgdrop electrodes, have been evaluated toward their exploitation of single-use decentralized testing. Neither deoxygenation nor stirring is required, and the detection limit of 30 ng/L was estimated. More work is required before the application of these electrodes for BPb analysis (E36). According to CDC (E9),it should be recognized that a proficient laboratory should measure blood levels to within 4 or 6 pg/dL of the true value. Analytical variability should be considered when BPb results are interpreted. Changes in successive BPb measurements can be considered significant in an individual only if the difference of results exceeds the limit of analytical variance that the laboratory allows. Other Markers of Lead Exposure. Studies have relied on measurement of BPb as a biomarker of current or past exposure. However, BPb is poor indicator of cumulative lead exposure; it reflects only recent exposure because the half-life of lead in blood
is only about 36 days (E37). Thus, individuals with widely divergent exposure histories may have similar BPI, concentrations. More than ~ Wof O the adult body burden occurs in bone, with a half-life of years to decades (at least 25 years). One technique that is being evaluated for in vivo noninvasive determination of bone lead concentrations is X-ray fluorescence in populations with environmental or occupational lead exposure (E38). Two X-ray fluorescence technologies have been described, K (KXRF) and L 0. The KXRF has been more widely used and better validated. It measures lead approximately 37 mm into bone, thus providing data on the total amount of lead across the bone. The LXRF,which has been used only in some pediatrics studies, measures lead only 2-3 mm into bone. In the KXRF technique, superficial bones of the limbs, such as the tibia or patella, are irradiated with a collimated cadmium109 source, which induces emission of K-shell fluorescence X-rays from lead atoms in the bones. XRF machines are licensed by the Food and Drug Administration as research devices;however, the data on detection limits, precision, and accuracy of these methods are not available (E39). Recently, bone lead levels measured by KXRF were associated with decreased hemoglobin levels despite the presence of low BPb levels. The concentration of lead in bone constitutes a more sensitive marker for chronic toxicity than BPb levels (E40). Consequently, this technology can be potentially applied for improved diagnosis and disease prevention (E37). CADMIUM
Sources of Cadmium. Cadmium occurs naturally in rocks and soils. Anthropogenic sources include smelter emissions, application of fertilizers, and sewage sludge to land (E41). Such practices contaminate the environment with cadmium, which gets into the food chain and has potential to cause serious health problems (En. Major sources of occupational cadmium exposure are through industrial processes (E2). For smokers, tobacco is a major source of cadmium exposure (E@. Metabolism and Adverse Effects. Absorption of cadmium compounds varies greatly depending on the chemical species and particle size. Oral absorption rate is in the range 2-7%. A rate between 25 and 50%has been estimated for cadmium oxide fumes. Of circulating cadmium, greater than 90%is bound to erythrocytes (E@. After inhalation or gastrointestinal absorption, cadmium is concentrated primarily in the kidney (50%), where its half-life exceeds 10-20 years, and where toxicity is first expressed ( E n . Cadmium also accumulates in the liver (15%),lungs, and gastrointestinal tract to a lesser extent. Cadmium resides in these tissues until renal damage begins, which leads to accelerated loss from the kidney but not from the liver (E42). The chemical forms of cadmium in tissues can be largely divided into two groups: metallothionein (MT)-bound, and non-MT-bound. Cadmium accumulates in the body mainly as the former, while the later, the toxic form of cadmium, can be detected in tissues before induction of sufficient amounts of MT to sequester cadmium or after accumulation of cadmium in amounts such that it is beyond the capacity of the organ concerned to synthesis enough MT. Alcohol dehydrogenase was identifed as the major cadmium-binding protein in the liver before induction of MT (E43). MT plays a major role in the prevention of tissue damage by scavenging free radicals induced by exposure to heavy metals, ultraviolet light, or radiation (E44-E46).
Depending on dose and route of entry, cadmium exposure can result in different acute and chronic effects. The toxic effects are generally limited to the lung (from inhalation) or to the gastrointestinal tract (from ingestion) (E47).Long-term exposure of humans to increasing cadmium concentrations can lead to progressive pulmonary effects, including lung cancer (inhalation), and to progressive renal damage (ingestion and inhalation). Where as certain effects are related to certain routes of exposure, the effects on kidney, bone, and hematopoietic systems can be observed for either route (E48). Biological Markers. It is universally recognized that the best measures of cadmium exposure and its effects are measurements of cadmium in blood and urine. Whole-blood cadmium represents recent exposure, where as urine cadmium correlates more closely with total body burden before severe renal damage occurs (E49). Several small proteins have been monitored as markers for proteinuria including /3-2-microglobulin (B2-M), retinol-binding protein, N-acetyl-/3-glucosaminidase,metallothionein, and others ( E l l , E50). Below levels indicative of proteinuria, these small proteins may be early indicators of increased risk of cadmiuminduced renal tubular disease. Of all proteins, B2-M appears to be the most widely used and best characterized analyte to evaluate the extent of cadmium-induced renal tubular damage ( E l l , E 5 l ) . OSHA Cadmium. Since 1993, OSHA has enforced a regulatory standard to control occupational exposure to all forms of cadmium compounds in all industries covered by OSHA ( E l l ) . This standard defines and outlines in detail the permissible limits, action level, exposure monitoring, monitoring of working environment, protective work clothing and equipment, and medical surveillance to all employees who may be exposed to cadmium at or above the action level (2.5 pg of Cd/m3 of air,calculated as an 8-h time-weighted average). The medical surveillance includes a detailed medical and work history and biological monitoring of the following: cadmium in blood (BCd) standardized to liters of whole blood, cadmium in urine (UCd) standardized to grams of creatinine, and /3-2 microglobulin in urine (UB2-M) standardized to grams of creatinine with pH specified. The BCd level should be at or below 5 pg/L of whole blood, UCd 5 3 pg/g of creatinine, and UB2-M 5 300 pg/g of creatinine. Depending on initial results, more frequent biological monitoring may be required. The employer has to ensure proper handling and collection of biological samples, and that the above tests are performed in laboratories with demonstrated proficiency for that particular analyte. OSHA recommends that only laboratories meeting certain data quality objectives for the specified methods be used for the analyses of biological samples collected for monitoring cadmium exposure. For BCd, the limit of detection is 0.5 pg/L, with a precision of 40% for results of 5 2 pg/L and 20%for results of > 2 pg/L. For UCd, a detection limit of 0.5 pg/L of urine is anticipated with a precision of 40% for concentrations of 5 2 pg/L and 20% for concentrations of '2 pg/L. The accuracy for both BCd and UCd must fall within &15%of the mean or flpg/L whichever is larger. For UBZM, the detection limit is 100 pg/L of urine with a precision of 5%and accuracy of f15% of the mean. Since both UCd and UB2-M should be reported in micrograms per gram of creatinine, an independent determination of creatinine is recommended. The participating laboratory should be accredited by the College of American Pathologist for urine creatinine analysis. To test for proficiency in the analyses of BCd, UCd, and UB2-M, a laboratory should participate in the interlaboratory comparison Analytical Chemistry, Vol. 67, No. 12, June 15, 1995
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program operated by the Centre de Toxicologie du Quebec. No laboratory in the United States currently performs proficiency testing on BCd, UCd, and UB-2M. Results of proficiency evaluations will be forwarded to the participating laboratory as well as to physicians designated by the participating laboratory to receive this information. The participating laboratory should, on request, submit the results of their internal quality assurance/quality control program for each analytical procedure to physicians designated to receive the proficiency results. Specimen. Blood samples should be collected from workers at the same time of the day by venipuncture in blue-capped tubes. OSHA recommends single “spot” urine samples. As B2-M can degrade in the bladder, workers should first empty their bladder and then drink a large glass of water at the start of the visit; urine is then collected within 1h. Separate samples should be collected for UCd and UB2-M. For UCd analyses, the sample should be collected into a 250-mL sterile urine collection cup. For B2-M, the urine sample should be collected directly into a polyethylene bottle previously washed with dilute nitric acid. The pH of the urine should be measured and adjusted to 8.0 with 0.1 mol/L NaOH immediately following collection to avoid degradation of the protein under acidic conditions. Samples should be frozen and stored at -20 “C until testing is performed ( E l l ) . Analysis. Under the final cadmium OSHA rule, the recommended analytical methods for biological monitoring of eligible workers are (a) the method of Stoeppler and Brandt for BCd determination (E52), (b) the method of Pruszkowska et al. for UCd determination (E53), and (c) the Pharmacia Delphia test kit (Pharmacia) for the determination of UB2-M ( E l l ) . The low limits of detection required under the OSHA rule and the presence of cadmium in nonexposed subjects in low concentrations emphasize the need for sensitive methods to determine cadmium at sub-ppm levels. Graphite furnace atomic absorption spectrometry is the most widely used technique for cadmium determination because of excellent sensitivityand miniial sample preparation. The use of a stabilized temperature platform furnace with Zeeman background correction has improved the accuracy of cadmium results. Nevertheless, analytical difficulties in the analysis of BCd are reflected by the results of external quality assessment schemes (E54). The OSHA recommended method for the analysis of BCd requires the treatment of one part of whole blood with three parts of 1mol/L HN03 for deproteinization and matrix modification (E52). M e r mixing and centrifugation, the supernatant is used for analysis by GFAAS (detection limit 50.2 pg/L). Due to aging of the graphite tubes, significant alteration of tube properties can sometimes lead to signal drift effects. Controls should be checked frequently to determine and correct for these drifts. The use of other matrix modifiers like (NH4)r HP04 or NH~NOB,along with nitric acid, could improve the analysis (E55). Other methods for the determination of wholeblood cadmium have emerged. Electroanalytical methods based on the stripping techniques (anodic stripping voltammetry and potentiometry (ASP)) have become widely used for trace metal analyses in biological fluids. For ASP analysis, a whole-blood volume of at least 0.5 mL or greater is needed. The deposition time and potential are very important, depending on sample concentration. The sample is prepared by dilution with an appropriate supporting electrolyte (0.5 mol/L HC1). If deposition time is increased, the detection limit for cadmium is 10.1 +g/L (E56). The cost of this automated system for ASP analysis is 408R
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about half that for GFAAS system with comparable sensitivity. Isotope dilution inductively coupled plasma mass spectrometry (ICPMS) is another technique that has gained increasing interest from clinical chemists. The isotope used for dilution is W d . The reference isotope used for the quantifkation of the data is l14Cd. The isotope dilution method improved both accuracy and precision of analysis. The detection limit for BCd is 0.11 pg/L (E57). Methods for the determination of urine cadmium have been plagued by interferences as well as uncontrollable background absorbance. The OSHA recommended method employs a stabilized temperature platform furnace with Zeeman background correction, with (NH&HP04 and HN03 as matrix modifier (E53). The analysis was calibrated against aqueous standards after the addition of NaCl. Previous methods have used solvent extraction before determination of UCd by GFAAS (E52). The effect of N&NO3 as modiiier in the determination of volatile elements, such as cadmium, by GFAAS has been examined (E55). This modifier allows the removal of NaCl from urine specimens, a major cause of interference in GFAAS, at a pyrolysis temperature at which the analyte is not yet volatile (5400 “C); this in turn reduced the background absorbance signal more effectively than (NH&HP04. A probe atomization with deuterium background correction was used to separate the cadmium signal from background without chemical modifier or sample pretreatment in human urine (detection limit 0.3 pg/L), while providing a close approximation to the “stabilized atomization temperature concept” with improved control of the atomization temperature (E58). Another group applied 1:l dilution to urine samples with nitric acid followed by digestion in a 60 “C water bath for 1 h before analysis by continuum source GFAAS (E59). Other techniques used for analyses of UCd include stable isotope dilution gas chromatography/mass spectrometry, which utilizes lo6Cd as an internal standard. This technique provides the advantage of freedom from matrix effects, and the precision and accuracy are not affected by incomplete recovery, thus improving the detection limit required for low-level exposure (E60). Inductively coupled plasma emission spectrometry for determination of heavy metals in urine has been developed. It requires preconcentration and complexation with ammonium pyrrolidinedithiocarbamate followed by extraction and acid digestion. The detection limit for cadmium is 3.5 pg/L well over the limit specified by OSHA (E6l). ASV for simultaneous determination of UCd and other trace metals with standard addition after sample digestion is another technique that has been exploited. The method had a detection limit of 0.117 pg/L for cadmium (E62). The cadmium level of individuals exposed to cadmium has been investigated in biological matrices other than urine and whole blood. A method was developed in order to reconstruct recent intake/exposure history by sequentially cutting hair strands into several millimeter-long sections and analyzing them by ICPMS after an overnight digestion at room temperature with small volume of nitric acid (E63). Organophosphorus vapors (triethyl phosphite) have been used as matrix modifiers for the analysis of cadmium in human hair by GFAAS (E64). The modifier was introduced during the drying and ashing stages, using an alternative gas inlet of the electrothermal atomizer. The triethyl phosphite vapor was shown to be as efficient in stabilizing the cadmium as the “wet chemical” counterpart. A microwave digestion procedure coupled to atomic absorption spectrometry was used for determination of mineral elements in teeth and bone
Publications 118; International Agency for Research on Cancer: Lyon, France, 1992; pp 435-446. Preventing Lead Pojsoning in Youn Children. A Statement by the Centers for: Disease Control; Department of Health and Human Semces: Centers for Disease Control, Atlanta, GA, October 1991. 29 Code Fed. Regul., part 1910.1025, Jul 1993; pp 139-175. 29 Code Fed Re 1 art 1910-1027, 1993; pp 175-279. S. E. Spectroscopy 1994, 9, 24-29. Schrier, L. 6.; #&&in, Chao, J.; Kikano, G. E. Am. Fam. Physician 1993, 5, 537544. Nunez, C. M.; Klitzrnan, S.;Godman, A Am. J. Ind. Med. 1993, 23, 763-777. Weitzman, M.; Aschengrau, A; Bellin er, D.; Jones, R; Hamlin, J. S.; Beiser, A JAMA, J. Am. Med. &oc. 1993,269, 16471654. Hayes, E. B.; McElvaine, M. D.; Orbach, H. G.; Fernandez, A. M.; Lyne, S.; Matte, T. D. Pediatrics 1994, 93, 195-200. 1994, 55, 300-303. Anderson L. A Am. Ind. H g Assoc Bowers. 'f. S.: Beck. B. D.: &am. H: Risk Anal. 1994,14,
(E65). An in vivo neutron activation analysis system for the measurement of cadmium in the human liver and kidney was developed which measures directly the body burdens of individuals (E42). However, these techniques have many limitations which coniine their use to research studies. The problems associated with the analysis of cadmium in autopsied tissues, which is considered to be an indicator of exposure to cadmium before death, were investigated. The study revealed that the BCd concentration after death was several hundred times as high as that before death and did not indicate the exposure before death. Thus, in analysis of autopsied organs the time interval between death and autopsy should be shortened, sampling of specimens should be performed quickly, specimens should be freed of water and preserved in airtight polyethylene bags at -20 "C or below, and care should be exercised to avoid contamination of organs, in which the cadmium concentration is low, with blood (E66).
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%wartz, J. Environ. Res. 1994, 65, 42-55. Baron, M. E.; Boyle, R M. Pediatrics 1994, 93, 178-182. Special Medical Report. Am. Fam. Physician 1993,48,11611164. Graziano, J. H. Clin. Chem. 1994, 40, 1387-1390. Sassaroli, M.; DaCosta, R; VaWinen, H.; Eisinger, J. Cytom. 1992, 13, 339-345. Blatt, S.D.; Weinberger, H. L. Am. J. Dis. Child. 1994, 147,
CONCLUSION
The direct measurement of lead in blood has become the most widely used and informative biomarker of lead exposure. Cadmium in blood reflects mainly the last few months of exposure, whereas urine cadmium is the most relevant biological indicator of the amount of cadmium stored in the kidney before renal tubular damage develops. The new action levels and methods performance characteristics set forward for lead and cadmium by the newly implemented standards require more careful considerations to the analytical techniques used and quality of the results generated. Graphite furnace atomic absorption spectroscopy and anodic stripping voltammetry remain the most widely used techniques for lead analysis, whereas the former is the most popular for cadmium analysis. While research is focused on developing electroanalytical methods, other techniques for monitoring exposure (e.g., XRF, stable isotope dilution, ICPMS, and others) are available but have limitations. The reliability,accuracy, and precision of lead and cadmium concentrations are very crucial because followup and decisions for further treatment of exposed individuals are dependent on results provided by cliiical laboratories. Rose T. Daher received her B.S. degree in chemistvfiom The Lebanese University in 1987 and her Ph.D. in clinical chemzstry )?om Cleveland State Unzversity in 1993. Since then, she sta?ted a twoyearpostgraduate fellowship pro ram in the section of Biochemistry at The Cleveland Clinic Foundatzon. $he zs ceczjed b the Amencan Board of Clz,nical Chemtstty. Her research znterests znclud analyses of trace metals zn nutrztzon and toxicity, the role of antioxidants in differentpathological conditions, and changes zn bone turnover markers in vanous dzseases of the bones.
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761 -763
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z k a d i l l o , V. A.; Navarro, J. A.; Romero, R. A J. Anal. At. Spectrom. 1993,8, 615-622. Aggarwal, S.IC;Kinter, M.; Herold, D. A. Clin. Chem. 1994,
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An -", idqd-im:, --I-
The Model 3010B Lead Anal er; Technical Report No. 70-1069, 7/92; ESA: Bedford, MA, g 9 2 . Feldman, B. J.; Osterioh, J. D.; Hata B. H.; D'Alessandro, A. Anal. Chem. 1994, 66, 1983-1987. L w e r , D.; Renman, L.; Wang, Y. Electroanalysis 1994,6,285LYl.
t.;
Wan , J.; Tian, B. Anal. Chem. 1992, 64, 1706-1709. an P. J.; Todd, A. C. JAMA,J. Am. Med. Assoc. 1994, 271, 2!?9-i40 Kosnett M. 5.1Becker C. E.; Osterloh, J. D.; Kelly, T. J.; Pasta, D J. JhAm. Ided. Assoc. 1994,271, 1977203. Todd, A. C.f fandrigan, P. J.; Bloch, P. Neurotoxzcology 1994, 14, 145-154. Hu H.; Watanabe, H.; Payton M.; Korrick, S., Rotnitzky, A. JA$L4, J. Am. Med. Assoc. 1964,272, 1512-1517. ornton, I. In Cadmium in the Human Environment: Toxicity and Carcino enicity; Nordberg, G. F., Herber, R F. M., Alessio, L,Eds.; d C Scientiiic Publications 118; International Agency for Research on Cancer: Lyon, France 1992; p 149-162. Ralston, A.; Utterid e, T.;Paix, D.; Beddoe, A. lust. Phys. Eng. 34-42. Sci. Med. 1994, Suzuki, I$ T. In Cadmium in the Human Environment: Toxic$ and Carczno enzcrty; Nordberg, G. F., Herber, R F. M., Alessio, L., Eds.; d C Scientific Pubhcations 118;International Agency for Research on Cancer: L on, France, 1992; p 211-217. Manuel, Y.;.Thomas, Y.; Jellegrini, D.. In CFfmium in the Human Environment: Toxicit and Carcrnogenzczt ; Nordber G. F.; Herber, R. F. M.; d s s i o , L., Eds.; d C M e n d : Publications 118; International Agency for Research on Cancer: Lyon, France, 1992; p 231-237. Horiguchi, H.; Mukaida, Okamoto, S A ; Teranishi, H.; Kasu a, M.; Matsushima, IC Lymphokine Cytokine Res. 1993, 12, 451-428. Hanada, K.; Baba, T.; Hasimoto, I.; Fukui, R.; Watanabe, S. Photodermatol. Photoimmunol. Photomed. 1993, 9, 209-213. Funkhouser, S. W.; Martinez-Maza, 0.; Vredevoe, D. L. Environ. Res. 1994, 66, 77-86. Oberdorster, G. In Cadmium in the Human Environment:
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1
(E44)
LITERATURE CITED (El) Binder, S.;Matte, T. JAMA, J. Am. Med. Assoc. 1993, 269, 1679-1681. (E2) Schaller, K. H.; Angerer, J. In Cadmium in the Human Environment: Toxicity and Carcino enicity Nordber G: F., Herber. R F. M.. Alessio. L.. Eds.: &C Scihiiic Pubfcahons 118; International Agency 'for Research on Cancer: Lyon, France, 1992; p 53 63. Nogawa, IC;Kfo, TTInt. Arch. Occup. Environ. Health 1993, 65 S43-S46. Schonfeld, D. J. Curr. 0 in. Ped. 1993, 5, 537-544. Toffoletto F.; Apostoli, Ghezn, I.; Baj, A; Corotona, G.; Rizzi, L.; hessio, L. In Cadmium in the Human Environment: Toxicity and Carcinogenicity; Nordber , G. F., Herber, R. F. M.,, Alessio, L., Eds.; IARC Scientific Fublicahons 118; Internahonal Agency for Research on Cancer: Lyon, France, 1992;
._I.
Noble, D. Anal. Chem. 1993, 65,265A-267A Bannon, D. I.; Murashchik, C.; Zapf, C. R.; Farfel, M. R; Chisolm, J. J. Clin. Chem. 1994, 40, 1730-1734. Parsons, P. J.; Slavin, W. Spectrochim. Acta 1993, 48B, 925-
(E45) (E46) (E47) (E48)
8,
fi.;
nn r 107-111
(E6) fauwe s, R. R.; Bernard, A. M.; Roels, H. A.; Buchet, J.-P. Clzn. Cyem. 1994, 40, 1391-1394. (E7) Staessen, J. A;Lauwerys, R. R.; Ide, G.; Roels, H. R.; Vyncke, G.; Amery, A. Lancet 1994, 343, 1523-1527. (E8) Kazantzis, G.; Blanks, R. G . Sullivan, K. R. In Cadmium in the Human Environment: To& and Carcinogenicit ;Nordber G. F., Herber, R. F. M., Afyessio, L., Eds.; d C Scient&
(E53) Pruszko6ka, E.; Carnrick, G. R; Slavin,W. Clin. Chem. 1983, 29, 477-480. (E54) Anglov, T.; Holst, E.; Christensen, J. M. Int. Arch. Occup. Envzron. Health 1993, 64, 431-438. Analytical Chemistry, Vol. 67, No. 12, June 15, 1995
409R
~-~
___
____,__
Gayon, J. M. id.;Sanz-Medel, A. Anal. At. Spectrom. 1992, 7, 1079-1083. Fernando, R.; Jones, B. T.; Ennever, F. K. Appl. S$ectrosc. 1993, 47, 1696-1699. Aggarwal, S. IC; O.fi, R. G.; Wendling, J.; Kinter, M.; Herold, D. A. J. Anal. Toxacol. 1993, 17, 5-10. Mpez-Artiguez, M.; Camean, A.; Repetto, M. J. Anal. Toxicol. 1993, 17, 18-22.
41QR
Analytical Chemistry, Vol. 67, No. 12, June 15, 1995
@62) Pan, T. C.; Homg, C. J.; Lin, S. R.; Lin, T. H.; Huang , c. W. Biol. Trace Elem. Res. 1993, 38, 233-241. 0363) Yoshinaga, J.; Shibata, Y.; Masatoshi, M. Clin. Chem. 1993, 39, 1650-1655. (E64) Ebdon, L.; Fisher, A. S.; Hill, S. J. Anal. At. Spectrom. 1992, 7,511-513. (E65) Gi!, F.; Perez, M. L.; Facio, A Villanueva, E.; Tojo, R.; Gil, A. Clan. Chzm. Acta 1993, 221, 23-31. (E66) Koizumi, N.; Hatayama, F.; Sumino, K. Environ. Res. 1994, 64, 192-198.
