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Methodologies for assessing exposures to metals: human host factors
ARTICLE IN PRESS
Ecotoxicology and Environmental Safety 56 (2003) 104–109
Methodologies for assessing exposures to metals: human host factors Mark Robson School of Public Health, University of Medicine and Dentistry of New Jersey, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA Received 20 March 2003
Abstract Many factors affect bioavailability of metals. Host factors can be defined as any attribute that can influence the amount and degree of metal exposure. In this series of articles, a wide range of aspects are discussed concerning the methodologies for assessing exposures to metals. These aspects include speciation, bioaccessibility, and bioavailability in the environment, in food, and in feed. This article complements the articles by Peakall and Burger and by Caldero´n et al., reviewing human host factors. In this article, measurement and assessment methods are discussed as they apply to risk assessment, with examples for arsenic, cadmium, chromium, and lead, as well as special consideration for source issues and children’s risk. Finally, several examples from the current literature are cited to illustrate some of the approaches presently in use as well as areas of research that require further consideration, including longitudinal studies, as well as better biomonitoring and assessment strategies. r 2003 Elsevier Science (USA). All rights reserved. Keywords: Metals; Human host factors; Biomonitoring
1. Introduction Many factors affect the bioavailability of metals. Host factors can be defined as any attribute of an individual that can influence the amount and degree of metal exposure, uptake, absorption, biokinetics, and susceptibility. Such factors include age, gender, size and weight, nutritional status, genetics, and some behaviors (Burger et al., 2003, in this issue). Research on the health effects of chronic exposure to metals suggests that physiological alterations may occur at levels that were formerly considered to be safe. Neurological and neurophysiological effects, nephrotoxicity, reproductive toxicity, teratogenicity, and carcinogenicity remain at the forefront of the current research (Lewis, 1997; Gochfeld, 1997). Metals exert biological effects primarily through the formation of stable complexes with sulfhydryl groups and other ligands. Biological reactivity of many metals results in the accumulation in several organs and tissues. Metals are used in construction, manufacturing, and consumer
Fax: +732-445-0131. E-mail address: [email protected].
products. Metals are stable, hence their widespread use (Lewis, 1997). Chemical compounds ubiquitous in our food, air, and water are now found in every person. Bioaccumulation of these compounds in some individuals can lead to a variety of metabolic and systemic dysfunctions, and in some cases outright disease states. The systems most affected include immune, neurological, and endocrine (Crinnion, 2000). Interest in the biological effects of toxic metals such as mercury, lead, cadmium, chromium, cobalt, nickel, and arsenic has increased during recent years because large amounts of toxic and carcinogenic elements have been released into the environment, especially in industrial areas (Christensen, 1995). Both acute and chronic human health risks are associated with environmental exposures of many metals (Grandjean and Bach, 1986). These concerns are of particular interest in the heavily industrialized regions of the world as well as in the redevelopment of abandoned sites in urban areas as renewal projects. The concept, known as brownfields in the United States, often does not adequately and accurately assess the metal bioavailability and the bioaccessibility to individuals living in these areas, nor does it account for ‘‘sensitive populations’’ in these areas.
0147-6513/03/$ - see front matter r 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0147-6513(03)00054-X
ARTICLE IN PRESS M. Robson / Ecotoxicology and Environmental Safety 56 (2003) 104–109
Biomonitoring has been the traditional method for assessing population exposures. For many metals, there is a need to develop better genetic markers for susceptibility as well as a need to make these methods more readily available to individuals living and working in the areas where metal contamination poses a great risk to human health. Christensen (1995) describes biomonitoring as a useful supplement for estimating the level of exposure allowing for the integrated assessment from different metal sources and uptake via different routes of exposure.
2. Measurement and assessment The use of risk assessments of metal toxicity is usually based on one form of a metal and often implicitly assumes that the bioavailability of that metal is equivalent for all forms of the metal and for all exposure media Review of the methods for assessing oral bioavailability suggests a hierarchy for evaluating bioavailability data. Animal studies are generally considered the most reliable (NEPI, 2000). In assessing the risk of exposure to metals in environmental media such as water, soil, food, and air, the dose that the individual might receive from these sources is compared to a safe dose of the metal. The need to evaluate bioavailability is a consideration, because a given dose of metal in soil, for example, may be absorbed less completely than the same dose of the metal administered in controlled studies that are used to determine the safe dose. Regulatory policies generally permit, but do not promote, inclusion of bioavailability adjustments in risk assessments with the exception of the US Environmental Protection Agency (US EPA) exposure model for Pb. The US EPA includes default assumptions for reduced absorption from soil. The National Environmental Policy Institute (NEPI) defines bioavailability as the fraction of the administered dose that reaches the central (blood) compartment via ingestion, skin, or lungs. Bioavailability defined in this manner is referred to as ‘‘absolute bioavailability’’. Relative bioavailability refers to the comparative bioavailabilities of different forms of the chemical from soil relative to its bioavailability from water (NEPI, 2000). Occupational and environmental health exposure is usually estimated by measurement of the airborne pollutants or by biomonitoring. Several of authors have reported a significant correlation between airborne trace elements and concentrations in the blood and urine (Angerer et al., 1989; Georgopoulos and Lioy, 1994; Vahter et al., 1996; Weisel et al., 1996). The extent to which the airborne trace elements reflect true external exposures is doubtful. The adverse effect may be related not only to the metal species and the dose, but also to
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peaks of exposure (Droz, 1989; Christensen, 1995). Biological monitoring has advantages over air monitoring given the estimate of the exposure and an indirect approach for determining target-site concentration by measurement of elements as biological indicators (Christensen, 1995). Samples reflect the current body burden as a function of present and earlier exposure, depending on the half-life and elimination time. Biomonitoring is a useful and complementary tool for estimating elemental exposure. It allows for the integration of data from various sources and uptake via different routes such as the lungs, skin and GI tract (Christensen, 1995). It also provides for identification of subgroups subjected to higher levels of exposure (Grandjean and Bach, 1986). Animal studies are generally more reliable, but they are also both more expensive and time-consuming than in vitro studies. For dermal absorption, the preferred method for studying metal absorption is in vivo, using monkey or swine models, and in vitro using cadaver skin. Studies of pulmonary absorption of metals have used a variety of methods including whole-body inhalation, nose- or mouth- only inhalation, and intratracheal instillation.
3. Examples of specific metals 3.1. Arsenic The toxicity of arsenic varies with its chemical state, ranging from the virtually nontoxic forms of organic and pure elemental arsenic to acutely toxic trivalent arsenic trioxide. Trivalent and pentavalent arsenic are the two most common forms found in soil. Arsenic trioxide and arsenic pentoxide are used to manufacture calcium, copper, and lead arsenate pesticides. Inorganic arsenic is a known human carcinogen causing lung cancer by inhalation and skin cancer via ingestion (HopenhaynRich et al., 1996). The primary source of inhalation exposure to arsenic trioxide occurs during the smelting process of copper, gold, lead, and other nonferrous metals when toxins may be volatilized and inhaled. Ingestion can occur through contaminated well water, dried milk, moonshine whiskey, and other products with residual arsenical residues. Studies in Taiwan and Argentina have also found that the standardized mortality ratios (SMRs) for bladder cancer were higher in areas reporting greater arsenic exposure. Inorganic arsenic compounds vary in their water solubility, which is a critical variable in determining their interaction with body systems (Lewis, 1997). The suggested exposure limits for arsenic in reference to the American Conference of Industrial Hygienists’ (ACGIH) threshold limit value (TLV) and the US occupational safety and Health Administration’s (OSHA) probable effects level (PEL) are 0.01 mg/m3
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time weighted average (TWA), and the National Institute for Occupational Safety and Health (NIOSH) PEL is set at a ceiling of 2 mg/m3 in a period of 15 min. Symptoms of acute arsenic exposure develop minutes to hours after ingestion, resulting in nausea, vomiting, abdominal pain, and copious blood-tinged diarrhea. In some cases, facial edema, cold, clammy skin, and muscle cramps are present. Liver enlargement and oliguria may also occur. Seizures, coma, and circulatory collapse precede death. Persons who recover from acute exposure may suffer from delayed peripheral neuropathy appearing several weeks later as symmetrical distal sensory loss. The lower extremities are more aggressively affected than the upper extremities. In extreme cases, total paralysis may occur. Chronic exposure usually results in distal paresthesias or anesthesia, which are indicators of peripheral neuropathy. In severe cases, motor involvement may be evident as well, with weakness and reflex loss. Dermatological symptoms of arsenic exposure are common, mainly after long-term ingestion in drinking water. Arsenical keratoses are raised punctate or verrucous lesions occurring on the palms and soles. Bowen’s disease is indicated by enlarging masses or ulcerations. Basal cell carcinoma and squamous cell carcinoma are both increased with chronic exposure. Diffuse bronze hyperpigmentation may also develop, as well as alopecia. Epidemiological studies suggest a possible increase in lung cancer, leukemia, lymphoma, and angiosarcoma of the liver. Arsenic can cross the placenta and can cause fetotoxicity, decreased birth weight, and congenital malformations (Lewis, 1997). In laboratory findings, both acute and chronic exposure to arsenic may cause anemia and leukopenia. Hematuria and proteinuria indicate renal injury, whereas elevated serum enzymes and bilirubin are signs of liver damage. Among methods to test arsenic levels, urine analyses can be conclusive. The measurement of DMA and MMA eliminate the confusion with dietary sources of arsenic. People without arsenic exposure will have levels of creatinine o10 mg/g. People who have chronic exposure levels at 0.02 mg/m3 will have creatinine levels of about 50 mg/g, and acute poisoning can reach 1000 mg/g. Systemic absorption via ingestion can be measured in hair and nail arsenic concentrations. 3.2. Cadmium All inorganic forms of cadmium found in the soil induce chronic effects, with kidney toxicity resulting from ingestion, and cancer resulting from inhalation. All inorganic forms are considered together in assessing bioavailability. Chronic exposure has been found to cause male infertility in some cases (Benoff et al., 2000). Oral absorption of cadmium is low in humans, ranging
from 1% to 7%. The US EPA has developed separate reference doses for cadmium. In water, the dose has been stated as 5%, and in food 2.5%. In the United Kingdom, cadmium levels were compared in a mining community and a control group. The mining community had soil Cd levels that were 100-fold higher, but urinary Cd excretion was only fractionally higher (NEPI, 2000). The OSHA cadmium exposure limit is 2.5 mg/m3 in 8 h TWA, and the (ACGIH) recommendation is 2.0 mg/m3. NIOSH does not give a numerical value but suggests that exposure be reduced to the lowest feasible concentration. Skin absorption is negligible under normal circumstances, and inhalation can range from 10% to 40%. GI absorption is usually o10%, but may increase in the presence of iron, zinc, calcium, and protein deficiencies. Within the bloodstream, cadmium binds to hemoglobin or metallothionein in erythrocytes, and accumulates in liver and kidney. Cadmium is less toxic when bound to metallothionein, where it prevents cellular damage. Acute exposure to cadmium normally occurs upon inhalation. The symptoms include sore throat, headache, myaglias, nausea, and a metallic taste in the mouth. Fever, cough, dyspnea, and chest tightness will follow. In severe cases, illness progresses to a fulminant chemical pneumonitis with pulmonary edema and death due to respiratory failure. Acute liver and kidney damage might also occur as well as chronic pulmonary fibrosis. Ingestion results in nausea, vomiting, headache, abdominal pain, liver injury, and acute renal failure. The most common symptom of chronic exposure to cadmium is proteinuria. Renal tubular dysfunction can result in nephrolithiasis and osteomalacia. Renal calcium and phosphorus wasting, as well as impaired vitamin D synthesis can result in bone pain and pathological fractures. Chronic inhalation of cadmium dust may lead to respiratory impairment, and emphysema, and possibly anosmia and anemia. Lung cancer has also been associated with cadmium as well as genitourinary and prostate cancer. Acute cadmium exposure can be measured using arterial blood gas evaluations, chest X-rays, spirometry, and an assessment of renal and hepatic function. Excessive exposure is signaled by hypoxemia, diffuse pulmonary infiltrates, a reduction in forced expiratory volume (FEV1) and forced vital capacity (FVC), and diffusing capacity for carbon monoxide. These may also signal impending respiratory failure. Blood and urine cadmium concentrations are good indicators, with the normal levels being 1 mg/L and 1 mg/g creatinine. After acute fume inhalation, these levels may rise to 3 and 0.36 mg/L. Chronic exposure is characterized by exposure to cadmium air levels in excess of 2.5 mg/m3. OSHA requires both biological monitoring and medical examinations. Biological monitoring consists of urine and
ARTICLE IN PRESS M. Robson / Ecotoxicology and Environmental Safety 56 (2003) 104–109
blood cadmium levels, with an emphasis on b2-microglobulin levels, which constitute a sensitive indicator of cadmium renal toxicity, although they might be affected by variables such as smoking, exercise, and febrile illness. Blood counts might indicate a decrease in serum hemoglobin. Biological monitoring will enact medical examinations when warranted. Pulmonary function evaluations may reveal airway obstructions, and a reduction in the diffusion of carbon monoxide. If mineralization or pathological fractures are suspected, then bone X-rays should be ordered. 3.3. Chromium The toxicity of chromium is directly dependent on the valence state, with hexavalent chromate Cr(VI) and trivalent chromate Cr(III) being of the greatest interest. In soil, the solubility and mobility of Cr(III) is minimal, as opposed to Cr(VI), which has both a high solubility and mobility. Oral bioavailability varies with valence state, with Cr(VI) being more readily absorbed. Cr(VI) can be broken down into Cr(III) within the acidic environment of the stomach. Both chromates penetrate the skin, but Cr(VI) does so at a greater degree. The ACGIH TLV for Cr(III) is 0.5 mg/m3, and for Cr(VI) the soluble level is 0.05 mg/m3, and insoluble 0.01 mg/m3. Acute exposure is indicated by immediate irritation of the eye, nose, throat, and respiratory tract, which results in burning, congestion, epistaxis, and cough. Ulceration, bleeding, and erosion of the nasal septum mark chronic exposure. Cough, chest pain, dyspnea, and chromium-induced asthma indicate exposure to soluble chromium products. If chronic exposure is suspected, in conjunction with weight loss, cough, and hemoptysis, this suggests the development of bronchogenic carcinoma. Dermatological manifestations include painless, slow-healing ulceration of the fingers, knuckles, and forearms. Ingestion is marked by nausea, vomiting, abdominal pain, prostration, and death associated with uremia (Lewis, 1997). With extreme exposure, there is evidence of renal and hepatic damage. Proteinuria and hematuria precede anuria and uremia. Reduction in the FEV1/FVC ratio may be seen after acute exposure or chromium-induced asthma. Skin irritation may be confirmed with patch testing. 3.4. Lead In soils, all inorganic lead forms have the same toxic endpoints and are considered together in assessing bioavailability. US EPA incorporates assumptions regarding lead levels from various sources such as water, diet, and soil in the pharmacokinetic model in predicting blood lead levels. GI absorption of lead varies with age, diet, and nutritional status. Age is a critical
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variable in absorption levels, with adults absorbing 7–15% from dietary sources. In infants and children, these levels can reach the range of 40–53% (NEPI, 2000). The ACGIH TLV and the OSHA PEL for lead are both set at 0.05 mg/m3. After acute and subacute ingestional and inhalational exposure to lead, the symptoms are GI. Early symptoms include cramping, colicky abdominal pain, and constipation. Nausea, vomiting, and black tarry stools may also accompany acute manifestations. Neurological symptoms of lead encephalopathy include headache, confusion, stupor, coma, and seizures, all of which are more common in children. Fundoscopic examination may reveal papilledema or optic neuritis. Rapid development of acute renal failure occurs in severe cases. Chronic exposure to lead follows a prolonged disease progression. Its onset is accompanied by fatigue, apathy, irritability, and vague GI symptoms. Arthalgias and myaglias may involve the extremities of axial structures. As exposure continues, central nervous system effects progress with insomnia, confusion, impaired concentration, and memory problems. Long-term exposure can lead to distal motor neuropathy and possibly seizures and coma. Other symptoms include loss of libido, infertility, disruption of menstrual cycles, and spontaneous abortions. Physical examinations may find pallor of the skin due to anemia, jaundice, and blue-gray pigmentation around the gum lines. Blood lead levels of persons not exposed range from 5 to 15 mg/dL. The subtle effects of lead on the central and peripheral nervous system begin at about 40 mg/dL. Anemia occurs in children at these levels. Chronic accumulation of lead in bone is best measured by X-ray fluorescence and bone densitometry (Lewis, 1997).
4. Source issues The most important elements in terms of the food chain are As, Cd, Hg, Pb, and Se. In situations where soils are enriched with these elements, it is through agricultural, industrial, or urban activities of humans, with the exception of selenium. Accumulation and translocation of elements depend on soil and climatic conditions, plant genotype, and agronomic management. In the case of arsenic, the primary source is from drinking water, as opposed to food ingestion. Cadmium accumulates in the body over a lifetime and primarily affects renal function. Cd concentrations in soils are increasing via fertilizer biosolids, soil amendments, and atmospheric deposition. There has also been evidence of a relationship between Cd bioavailability and Fe in human nutrition studies. Animal studies have shown that Zn, Ca, P, and other food constituents also affect Cd bioavailability (McLaughlin et al., 1999).
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5. Children Health risks are particularly associated with exposure in utero and early years, because a developing organism is at greater risk for permanent damage. Absorption and retention can be greater in infants than adults for many metals. Autopsy data for analysis of tissue from target organs is a source for the accumulation of a particular metal. Few literature reports on tissue content of potentially toxic metals include data on newborns and young children, because collection of autopsy samples in each age range are rare (Patriarca et al., 2000).
6. Examples of methods Ellickson et al. (2001) conducted a study measuring the bioavailability of lead and arsenic from soil using in vitro and in vivo techniques. Two limiting factors in the oral bioavailability of a heavy metal are dissolution in the GI tract and absorption through the intestine. Bioaccessibility is the amount of metal that is dissolved in the GI fluid, and bioavailability is the term used for the metal that crosses a membrane. The study used in vitro dissolution and in vivo rate feeding with standard reference soil for Pb and As. Metal solubility was measured using sequential soil extraction analogs of human saliva, gastric, and intestinal fluids. Oral bioavailability was measured via metal levels in major organs, blood, and feces of rats. The results indicated that bioaccessibility was greater than bioavailability for both metals in both GI compartments. The methodology used to investigate lead in urine (Pb-U) and cadmium in blood (Cd-B) can be used as biomarkers in the general population. It is well known that lead in blood (Pb-B) and cadmium in urine (Cd-U) are appropriate and accurate measurements to evaluate environmental and occupational exposure to these metals. A study conducted by Shimbo et al. (2000) in Japan attempted to determine if the converse is also true—that Pb-U and Cd-B can be used as measurements of exposure. The study was conducted from 1991 to 1998 to spot urine and peripheral blood samples from 607 healthy adult women with no occupational exposure to heavy metals. Along with measuring fluid samples, heavy metal levels in food were evaluated to determine if there was a correlation among the three. Urine, blood, and food samples were analyzed using inductively coupled plasma (ICP). It was found that Cd-B and Cd-U could be employed as biomarkers of environmental exposure; but the reliability of Pb-U use in place of Pb-B appeared to be small (Shimbo et al., 2000). Caldero´n et al. (2001) conducted a cross-sectional study to examine the effects of chronic exposure to lead and arsenic, and malnutrition on the neuropsychological development of children. Two populations of children
who were chronically exposed to either high or low levels of As and Pb were analyzed on the Wechsler Intelligence Scale for Children, Revised for Mexico (WISC-RM). Arsenic levels were tested using urine samples (As-U) and lead levels via blood samples (PbB). Lead and arsenic levels were measured using atomic absorption spectrophotometry. The height for age index (HAI) was used as an indicator of chronic malnutrition, and demographic information was collected in questionnaire form. Data on full verbal, performance intelligence quotients (IQ) scores, long-term memory, linguistic abstraction, attention span, and visuospatial organization information were extrapolated from the WISC-RM. It was found that higher levels of As-U were significantly related to poorer performance on the WISC-RM factors that focused on long-term memory and linguistic abstraction. Higher levels of Pb-B correlated to lower scores on attention tasks. Rodriguez et al. (2001) studied the effects of arsenic on behavior from a neurological standpoint. It has been reported that catecholamine levels in striatum, hippocampus, and other cerebral regions change in mice and rats exposed to arsenic. The best-known catecholamine, dopamine, is associated with movement control, learning, memory, cognition, and emotion. To characterize behavioral alterations induced by arsenic exposure, adult male Sprague–Dawley rats were exposed to 5, 10, and 20 mg/kg of arsenic via an intragastric route for either 2 or 4 weeks. Exposed rats showed reduced locomotor activity, but returned to normal at the end of the exposure period. There was also an increase in the number of errors during egocentric tasks reflecting alterations in arsenic brain concentrations. The preceding increase was related to time, not dose. The results indicate that short-term arsenic exposure induces neural and behavioral changes that may reflect a neurotoxic effect, and that these changes are dependent on dose, time, and environment. Arisawa et al. (2001) evaluated the association of previous exposure to environmental cadmium and renal function with respect to the total mortality and cancer incidence. From the cadmium-polluted area of Nagasaki, Japan, 275 residents between the ages of 40 and 92 were recruited. Dietary intake of Cd decreased after the replacement of polluted soil in rice fields between 1980 and 1983. The mortality rates from 1982 to 1997 and the incidence of cancer from 1985 to 1996 were investigated. Standardized mortality and incidence ratios were calculated using regional reference data. Cd levels were measured using b2 -microglobulin levels and then divided into two groups dependent on creatinine levels. The study suggests that renal tubule dysfunction and a reduced glomerular filtration rate are predictors of mortality among persons previously exposed to Cd. Also, the overall mortality rates did not increase in comparison to reference data.
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Vahter et al. (1996) conducted one of the first studies examining the effects of variation in diet to the uptake of cadmium in humans. Dietary intake of cadmium was studied in nonsmoking women between the ages of 20 and 50 years, who had either a mixed diet low in shellfish or one that included shellfish once a week or more. Duplicate diets were taken to measure the quantity of Cd. The shellfish diets contained twice the amount of Cd compared with the mixed diet. When feces samples were taken and analyzed, equivalent amounts of Cd were found in comparison to the duplicate diets. Also, Cd-B levels did not differ in levels of Cd-U within each group. There was a higher level of Cd absorption in the mixed-diet group, which was attributed to lower levels of iron found in the mixed-diet group. When women in the shellfish group with low serum iron were examined, they also exhibited higher levels of Cd absorption. The study concluded that the bioavailiblity of Cd may be related to diet.
7. Conclusions Understanding the variability of host factors is critical for risk assessment. Methodologies for measurement in population, diet, and occupation are limited, and the focus to date has not been on critical or sensitive populations, in other words, women and children. Many of the systems have been in vitro and are not always appropriate for in vivo systems. Biomonitoring data are also limited. Because we are interested in real situations, there is a need for special consideration of speciation of the metal as well as complex mixtures. Also important to consider are consumption patterns and socioeconomic status of the affected population. Finally, the use of genetic markers, covered elsewhere in this series, will be the single most important tool to aid in effectively measuring exposure, and hence, making realistic and useful assessments of risk.
Acknowledgments The author is grateful for the support of the NIEHS Center P30 ES 05022 and the Environmental and Occupational Health Sciences Institute. The author is also grateful to Brian Buckley, Joanna Burger, and Michael Gochfeld for their helpful review of this manuscript.
References Angerer, J., Heinrich-Ramm, R., Lehnert, G., 1989. Occupational exposure to cobalt and nickel: biological monitoring. Int. J. Environ. Anal. Chem. 35, 81–88.
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Arisawa, K., Nakano, A., Saito, H., Liu, X.J., Yokoo, M., Soda, M., Koba, T., Takahshi, T., Kinoshita, K., 2001. Mortality and cancer incidence among a population previously exposed to environmental cadmium. Int. Arch. Occup. Environ. Health 74, 255–262. Benoff, S., Jacob, A., Hurley, I., 2000. Male infertility and environmental exposure to lead and cadmium. Human Reproduction Update 6 (2), 107–121. Caldero´n, J., Navarro, M., Jimenez-Capdeville, M., Santos-Diaz, M., Golden, A., Rodriguez-Leyva, I., Borja-Aburto, V., Diaz-Barriga, F., 2001. Exposure to arsenic and lead and neuropsychological development in mexican children. Environ. Res. 85, 69–76. Christensen, J.M., 1995. Human exposure to toxic metals: factors influencing interpretation of biomonitoring results. Sci. Total Environ. 166, 89–135. Crinnion, W.J., 2000. Environmental medicine, Part 1: the human burden of environmental toxins and their common health effects. Altern. Med. Rev. 5, 52–63. Droz, P., 1989. Biological monitoring 1: sources of variability in human response to chemical exposure. Appl. Ind. Hyg. 4, 20–24. Ellickson, K., Meeker, M., Gallo, M., Buckley, B., Lioy, P., 2001. Oral bioavailability of lead and arsenic from NIST standard reference soil material. Arch. Environ. Contam. Toxicol. 40, 128–135. Georgopoulos, P., Lioy, P., 1994. Conceptual and theoretical aspects of human exposure and dose assessment. J. Expo. Anal. Environ. Epidemiol. 4, 253–285. Gochfeld, M., 1997. Factors influencing susceptibility to metals. Environ. Health Perspect. 105 (Suppl. 4), 817–822. Grandjean, P., Bach, E., 1986. Indirect exposures: the significance of bystanders at work and at home. Am. Ind. Hyg. Assoc. J. 47, 819–824. HopenhaynRich, C., Biggs, M., Fuchs, A., Bergoglio, R., Tello, E., Nicolli, H., Smith, A., 1996. Bladder cancer mortality associated with arsenic in drinking water in Argentina. Epidemiology 7 (2), 117–124. Lewis, R., 1997. Metals. In: LaDou, J. (Ed.), Occupational and Environmental Medicine. McGraw-Hill, New York, pp. 405–439 (Chapter 27). McLaughlin, M., Parker, D., Clarke, J., 1999. Metals and micronutrients—food safety issues. Field Crops Res. 60, 143–163. NEPI, 2000. Assessing the bioavailability of metals in soil for use in human health risk assessments. Bioavailability Policy Project Phase II: Metals Task Force Report. National Environmental Policy Institute, Washington, DC. Patriarca, M., Menditto, A., Rossi, B., Lyon, T., Fell, G., 2000. Environmental exposure to metals of newborns, infants, and young children. Microchem. J. 67, 351–361. Rodriguez, V., Carrizales, L., Jimenez-Capdeville, M., Dufour, L., Giordano, M., 2001. The effects of sodium arsenite exposure on behavioral parameters in the rat. Brain Res. Bull. 55, 301–308. Shimbo, S., Zhang, Z.W., Moon, C.S., Watanabe, T., Nakatsuka, H., Matsuda-Inoguchi, N., Higashikawa, K., Ikeda, M., 2000. Correlation between urine and blood concentrations, and dietary intake of cadmium and lead among women in the general population of Japan. Int. Arch. Occup. Environ. Health 73, 163–170. Vahter, M., Berglund, M., Nermell, B., Akesson, A., 1996. Bioavailability of cadmium from shellfish and mixed diet in women. Toxicol. Appl. Pharmlacol. 136, 332–341. Weisel, C., Yu, R., Roy, A., Georgopoulos, P., 1996. Biomarkers of environmental benzene exposure. Environ. Health Perspect. 104 (Suppl. 6), 1141–1148.
Ecotoxicology and Environmental Safety 56 (2003) 104–109
Methodologies for assessing exposures to metals: human host factors Mark Robson School of Public Health, University of Medicine and Dentistry of New Jersey, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA Received 20 March 2003
Abstract Many factors affect bioavailability of metals. Host factors can be defined as any attribute that can influence the amount and degree of metal exposure. In this series of articles, a wide range of aspects are discussed concerning the methodologies for assessing exposures to metals. These aspects include speciation, bioaccessibility, and bioavailability in the environment, in food, and in feed. This article complements the articles by Peakall and Burger and by Caldero´n et al., reviewing human host factors. In this article, measurement and assessment methods are discussed as they apply to risk assessment, with examples for arsenic, cadmium, chromium, and lead, as well as special consideration for source issues and children’s risk. Finally, several examples from the current literature are cited to illustrate some of the approaches presently in use as well as areas of research that require further consideration, including longitudinal studies, as well as better biomonitoring and assessment strategies. r 2003 Elsevier Science (USA). All rights reserved. Keywords: Metals; Human host factors; Biomonitoring
1. Introduction Many factors affect the bioavailability of metals. Host factors can be defined as any attribute of an individual that can influence the amount and degree of metal exposure, uptake, absorption, biokinetics, and susceptibility. Such factors include age, gender, size and weight, nutritional status, genetics, and some behaviors (Burger et al., 2003, in this issue). Research on the health effects of chronic exposure to metals suggests that physiological alterations may occur at levels that were formerly considered to be safe. Neurological and neurophysiological effects, nephrotoxicity, reproductive toxicity, teratogenicity, and carcinogenicity remain at the forefront of the current research (Lewis, 1997; Gochfeld, 1997). Metals exert biological effects primarily through the formation of stable complexes with sulfhydryl groups and other ligands. Biological reactivity of many metals results in the accumulation in several organs and tissues. Metals are used in construction, manufacturing, and consumer
Fax: +732-445-0131. E-mail address: [email protected].
products. Metals are stable, hence their widespread use (Lewis, 1997). Chemical compounds ubiquitous in our food, air, and water are now found in every person. Bioaccumulation of these compounds in some individuals can lead to a variety of metabolic and systemic dysfunctions, and in some cases outright disease states. The systems most affected include immune, neurological, and endocrine (Crinnion, 2000). Interest in the biological effects of toxic metals such as mercury, lead, cadmium, chromium, cobalt, nickel, and arsenic has increased during recent years because large amounts of toxic and carcinogenic elements have been released into the environment, especially in industrial areas (Christensen, 1995). Both acute and chronic human health risks are associated with environmental exposures of many metals (Grandjean and Bach, 1986). These concerns are of particular interest in the heavily industrialized regions of the world as well as in the redevelopment of abandoned sites in urban areas as renewal projects. The concept, known as brownfields in the United States, often does not adequately and accurately assess the metal bioavailability and the bioaccessibility to individuals living in these areas, nor does it account for ‘‘sensitive populations’’ in these areas.
0147-6513/03/$ - see front matter r 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0147-6513(03)00054-X
ARTICLE IN PRESS M. Robson / Ecotoxicology and Environmental Safety 56 (2003) 104–109
Biomonitoring has been the traditional method for assessing population exposures. For many metals, there is a need to develop better genetic markers for susceptibility as well as a need to make these methods more readily available to individuals living and working in the areas where metal contamination poses a great risk to human health. Christensen (1995) describes biomonitoring as a useful supplement for estimating the level of exposure allowing for the integrated assessment from different metal sources and uptake via different routes of exposure.
2. Measurement and assessment The use of risk assessments of metal toxicity is usually based on one form of a metal and often implicitly assumes that the bioavailability of that metal is equivalent for all forms of the metal and for all exposure media Review of the methods for assessing oral bioavailability suggests a hierarchy for evaluating bioavailability data. Animal studies are generally considered the most reliable (NEPI, 2000). In assessing the risk of exposure to metals in environmental media such as water, soil, food, and air, the dose that the individual might receive from these sources is compared to a safe dose of the metal. The need to evaluate bioavailability is a consideration, because a given dose of metal in soil, for example, may be absorbed less completely than the same dose of the metal administered in controlled studies that are used to determine the safe dose. Regulatory policies generally permit, but do not promote, inclusion of bioavailability adjustments in risk assessments with the exception of the US Environmental Protection Agency (US EPA) exposure model for Pb. The US EPA includes default assumptions for reduced absorption from soil. The National Environmental Policy Institute (NEPI) defines bioavailability as the fraction of the administered dose that reaches the central (blood) compartment via ingestion, skin, or lungs. Bioavailability defined in this manner is referred to as ‘‘absolute bioavailability’’. Relative bioavailability refers to the comparative bioavailabilities of different forms of the chemical from soil relative to its bioavailability from water (NEPI, 2000). Occupational and environmental health exposure is usually estimated by measurement of the airborne pollutants or by biomonitoring. Several of authors have reported a significant correlation between airborne trace elements and concentrations in the blood and urine (Angerer et al., 1989; Georgopoulos and Lioy, 1994; Vahter et al., 1996; Weisel et al., 1996). The extent to which the airborne trace elements reflect true external exposures is doubtful. The adverse effect may be related not only to the metal species and the dose, but also to
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peaks of exposure (Droz, 1989; Christensen, 1995). Biological monitoring has advantages over air monitoring given the estimate of the exposure and an indirect approach for determining target-site concentration by measurement of elements as biological indicators (Christensen, 1995). Samples reflect the current body burden as a function of present and earlier exposure, depending on the half-life and elimination time. Biomonitoring is a useful and complementary tool for estimating elemental exposure. It allows for the integration of data from various sources and uptake via different routes such as the lungs, skin and GI tract (Christensen, 1995). It also provides for identification of subgroups subjected to higher levels of exposure (Grandjean and Bach, 1986). Animal studies are generally more reliable, but they are also both more expensive and time-consuming than in vitro studies. For dermal absorption, the preferred method for studying metal absorption is in vivo, using monkey or swine models, and in vitro using cadaver skin. Studies of pulmonary absorption of metals have used a variety of methods including whole-body inhalation, nose- or mouth- only inhalation, and intratracheal instillation.
3. Examples of specific metals 3.1. Arsenic The toxicity of arsenic varies with its chemical state, ranging from the virtually nontoxic forms of organic and pure elemental arsenic to acutely toxic trivalent arsenic trioxide. Trivalent and pentavalent arsenic are the two most common forms found in soil. Arsenic trioxide and arsenic pentoxide are used to manufacture calcium, copper, and lead arsenate pesticides. Inorganic arsenic is a known human carcinogen causing lung cancer by inhalation and skin cancer via ingestion (HopenhaynRich et al., 1996). The primary source of inhalation exposure to arsenic trioxide occurs during the smelting process of copper, gold, lead, and other nonferrous metals when toxins may be volatilized and inhaled. Ingestion can occur through contaminated well water, dried milk, moonshine whiskey, and other products with residual arsenical residues. Studies in Taiwan and Argentina have also found that the standardized mortality ratios (SMRs) for bladder cancer were higher in areas reporting greater arsenic exposure. Inorganic arsenic compounds vary in their water solubility, which is a critical variable in determining their interaction with body systems (Lewis, 1997). The suggested exposure limits for arsenic in reference to the American Conference of Industrial Hygienists’ (ACGIH) threshold limit value (TLV) and the US occupational safety and Health Administration’s (OSHA) probable effects level (PEL) are 0.01 mg/m3
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time weighted average (TWA), and the National Institute for Occupational Safety and Health (NIOSH) PEL is set at a ceiling of 2 mg/m3 in a period of 15 min. Symptoms of acute arsenic exposure develop minutes to hours after ingestion, resulting in nausea, vomiting, abdominal pain, and copious blood-tinged diarrhea. In some cases, facial edema, cold, clammy skin, and muscle cramps are present. Liver enlargement and oliguria may also occur. Seizures, coma, and circulatory collapse precede death. Persons who recover from acute exposure may suffer from delayed peripheral neuropathy appearing several weeks later as symmetrical distal sensory loss. The lower extremities are more aggressively affected than the upper extremities. In extreme cases, total paralysis may occur. Chronic exposure usually results in distal paresthesias or anesthesia, which are indicators of peripheral neuropathy. In severe cases, motor involvement may be evident as well, with weakness and reflex loss. Dermatological symptoms of arsenic exposure are common, mainly after long-term ingestion in drinking water. Arsenical keratoses are raised punctate or verrucous lesions occurring on the palms and soles. Bowen’s disease is indicated by enlarging masses or ulcerations. Basal cell carcinoma and squamous cell carcinoma are both increased with chronic exposure. Diffuse bronze hyperpigmentation may also develop, as well as alopecia. Epidemiological studies suggest a possible increase in lung cancer, leukemia, lymphoma, and angiosarcoma of the liver. Arsenic can cross the placenta and can cause fetotoxicity, decreased birth weight, and congenital malformations (Lewis, 1997). In laboratory findings, both acute and chronic exposure to arsenic may cause anemia and leukopenia. Hematuria and proteinuria indicate renal injury, whereas elevated serum enzymes and bilirubin are signs of liver damage. Among methods to test arsenic levels, urine analyses can be conclusive. The measurement of DMA and MMA eliminate the confusion with dietary sources of arsenic. People without arsenic exposure will have levels of creatinine o10 mg/g. People who have chronic exposure levels at 0.02 mg/m3 will have creatinine levels of about 50 mg/g, and acute poisoning can reach 1000 mg/g. Systemic absorption via ingestion can be measured in hair and nail arsenic concentrations. 3.2. Cadmium All inorganic forms of cadmium found in the soil induce chronic effects, with kidney toxicity resulting from ingestion, and cancer resulting from inhalation. All inorganic forms are considered together in assessing bioavailability. Chronic exposure has been found to cause male infertility in some cases (Benoff et al., 2000). Oral absorption of cadmium is low in humans, ranging
from 1% to 7%. The US EPA has developed separate reference doses for cadmium. In water, the dose has been stated as 5%, and in food 2.5%. In the United Kingdom, cadmium levels were compared in a mining community and a control group. The mining community had soil Cd levels that were 100-fold higher, but urinary Cd excretion was only fractionally higher (NEPI, 2000). The OSHA cadmium exposure limit is 2.5 mg/m3 in 8 h TWA, and the (ACGIH) recommendation is 2.0 mg/m3. NIOSH does not give a numerical value but suggests that exposure be reduced to the lowest feasible concentration. Skin absorption is negligible under normal circumstances, and inhalation can range from 10% to 40%. GI absorption is usually o10%, but may increase in the presence of iron, zinc, calcium, and protein deficiencies. Within the bloodstream, cadmium binds to hemoglobin or metallothionein in erythrocytes, and accumulates in liver and kidney. Cadmium is less toxic when bound to metallothionein, where it prevents cellular damage. Acute exposure to cadmium normally occurs upon inhalation. The symptoms include sore throat, headache, myaglias, nausea, and a metallic taste in the mouth. Fever, cough, dyspnea, and chest tightness will follow. In severe cases, illness progresses to a fulminant chemical pneumonitis with pulmonary edema and death due to respiratory failure. Acute liver and kidney damage might also occur as well as chronic pulmonary fibrosis. Ingestion results in nausea, vomiting, headache, abdominal pain, liver injury, and acute renal failure. The most common symptom of chronic exposure to cadmium is proteinuria. Renal tubular dysfunction can result in nephrolithiasis and osteomalacia. Renal calcium and phosphorus wasting, as well as impaired vitamin D synthesis can result in bone pain and pathological fractures. Chronic inhalation of cadmium dust may lead to respiratory impairment, and emphysema, and possibly anosmia and anemia. Lung cancer has also been associated with cadmium as well as genitourinary and prostate cancer. Acute cadmium exposure can be measured using arterial blood gas evaluations, chest X-rays, spirometry, and an assessment of renal and hepatic function. Excessive exposure is signaled by hypoxemia, diffuse pulmonary infiltrates, a reduction in forced expiratory volume (FEV1) and forced vital capacity (FVC), and diffusing capacity for carbon monoxide. These may also signal impending respiratory failure. Blood and urine cadmium concentrations are good indicators, with the normal levels being 1 mg/L and 1 mg/g creatinine. After acute fume inhalation, these levels may rise to 3 and 0.36 mg/L. Chronic exposure is characterized by exposure to cadmium air levels in excess of 2.5 mg/m3. OSHA requires both biological monitoring and medical examinations. Biological monitoring consists of urine and
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blood cadmium levels, with an emphasis on b2-microglobulin levels, which constitute a sensitive indicator of cadmium renal toxicity, although they might be affected by variables such as smoking, exercise, and febrile illness. Blood counts might indicate a decrease in serum hemoglobin. Biological monitoring will enact medical examinations when warranted. Pulmonary function evaluations may reveal airway obstructions, and a reduction in the diffusion of carbon monoxide. If mineralization or pathological fractures are suspected, then bone X-rays should be ordered. 3.3. Chromium The toxicity of chromium is directly dependent on the valence state, with hexavalent chromate Cr(VI) and trivalent chromate Cr(III) being of the greatest interest. In soil, the solubility and mobility of Cr(III) is minimal, as opposed to Cr(VI), which has both a high solubility and mobility. Oral bioavailability varies with valence state, with Cr(VI) being more readily absorbed. Cr(VI) can be broken down into Cr(III) within the acidic environment of the stomach. Both chromates penetrate the skin, but Cr(VI) does so at a greater degree. The ACGIH TLV for Cr(III) is 0.5 mg/m3, and for Cr(VI) the soluble level is 0.05 mg/m3, and insoluble 0.01 mg/m3. Acute exposure is indicated by immediate irritation of the eye, nose, throat, and respiratory tract, which results in burning, congestion, epistaxis, and cough. Ulceration, bleeding, and erosion of the nasal septum mark chronic exposure. Cough, chest pain, dyspnea, and chromium-induced asthma indicate exposure to soluble chromium products. If chronic exposure is suspected, in conjunction with weight loss, cough, and hemoptysis, this suggests the development of bronchogenic carcinoma. Dermatological manifestations include painless, slow-healing ulceration of the fingers, knuckles, and forearms. Ingestion is marked by nausea, vomiting, abdominal pain, prostration, and death associated with uremia (Lewis, 1997). With extreme exposure, there is evidence of renal and hepatic damage. Proteinuria and hematuria precede anuria and uremia. Reduction in the FEV1/FVC ratio may be seen after acute exposure or chromium-induced asthma. Skin irritation may be confirmed with patch testing. 3.4. Lead In soils, all inorganic lead forms have the same toxic endpoints and are considered together in assessing bioavailability. US EPA incorporates assumptions regarding lead levels from various sources such as water, diet, and soil in the pharmacokinetic model in predicting blood lead levels. GI absorption of lead varies with age, diet, and nutritional status. Age is a critical
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variable in absorption levels, with adults absorbing 7–15% from dietary sources. In infants and children, these levels can reach the range of 40–53% (NEPI, 2000). The ACGIH TLV and the OSHA PEL for lead are both set at 0.05 mg/m3. After acute and subacute ingestional and inhalational exposure to lead, the symptoms are GI. Early symptoms include cramping, colicky abdominal pain, and constipation. Nausea, vomiting, and black tarry stools may also accompany acute manifestations. Neurological symptoms of lead encephalopathy include headache, confusion, stupor, coma, and seizures, all of which are more common in children. Fundoscopic examination may reveal papilledema or optic neuritis. Rapid development of acute renal failure occurs in severe cases. Chronic exposure to lead follows a prolonged disease progression. Its onset is accompanied by fatigue, apathy, irritability, and vague GI symptoms. Arthalgias and myaglias may involve the extremities of axial structures. As exposure continues, central nervous system effects progress with insomnia, confusion, impaired concentration, and memory problems. Long-term exposure can lead to distal motor neuropathy and possibly seizures and coma. Other symptoms include loss of libido, infertility, disruption of menstrual cycles, and spontaneous abortions. Physical examinations may find pallor of the skin due to anemia, jaundice, and blue-gray pigmentation around the gum lines. Blood lead levels of persons not exposed range from 5 to 15 mg/dL. The subtle effects of lead on the central and peripheral nervous system begin at about 40 mg/dL. Anemia occurs in children at these levels. Chronic accumulation of lead in bone is best measured by X-ray fluorescence and bone densitometry (Lewis, 1997).
4. Source issues The most important elements in terms of the food chain are As, Cd, Hg, Pb, and Se. In situations where soils are enriched with these elements, it is through agricultural, industrial, or urban activities of humans, with the exception of selenium. Accumulation and translocation of elements depend on soil and climatic conditions, plant genotype, and agronomic management. In the case of arsenic, the primary source is from drinking water, as opposed to food ingestion. Cadmium accumulates in the body over a lifetime and primarily affects renal function. Cd concentrations in soils are increasing via fertilizer biosolids, soil amendments, and atmospheric deposition. There has also been evidence of a relationship between Cd bioavailability and Fe in human nutrition studies. Animal studies have shown that Zn, Ca, P, and other food constituents also affect Cd bioavailability (McLaughlin et al., 1999).
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5. Children Health risks are particularly associated with exposure in utero and early years, because a developing organism is at greater risk for permanent damage. Absorption and retention can be greater in infants than adults for many metals. Autopsy data for analysis of tissue from target organs is a source for the accumulation of a particular metal. Few literature reports on tissue content of potentially toxic metals include data on newborns and young children, because collection of autopsy samples in each age range are rare (Patriarca et al., 2000).
6. Examples of methods Ellickson et al. (2001) conducted a study measuring the bioavailability of lead and arsenic from soil using in vitro and in vivo techniques. Two limiting factors in the oral bioavailability of a heavy metal are dissolution in the GI tract and absorption through the intestine. Bioaccessibility is the amount of metal that is dissolved in the GI fluid, and bioavailability is the term used for the metal that crosses a membrane. The study used in vitro dissolution and in vivo rate feeding with standard reference soil for Pb and As. Metal solubility was measured using sequential soil extraction analogs of human saliva, gastric, and intestinal fluids. Oral bioavailability was measured via metal levels in major organs, blood, and feces of rats. The results indicated that bioaccessibility was greater than bioavailability for both metals in both GI compartments. The methodology used to investigate lead in urine (Pb-U) and cadmium in blood (Cd-B) can be used as biomarkers in the general population. It is well known that lead in blood (Pb-B) and cadmium in urine (Cd-U) are appropriate and accurate measurements to evaluate environmental and occupational exposure to these metals. A study conducted by Shimbo et al. (2000) in Japan attempted to determine if the converse is also true—that Pb-U and Cd-B can be used as measurements of exposure. The study was conducted from 1991 to 1998 to spot urine and peripheral blood samples from 607 healthy adult women with no occupational exposure to heavy metals. Along with measuring fluid samples, heavy metal levels in food were evaluated to determine if there was a correlation among the three. Urine, blood, and food samples were analyzed using inductively coupled plasma (ICP). It was found that Cd-B and Cd-U could be employed as biomarkers of environmental exposure; but the reliability of Pb-U use in place of Pb-B appeared to be small (Shimbo et al., 2000). Caldero´n et al. (2001) conducted a cross-sectional study to examine the effects of chronic exposure to lead and arsenic, and malnutrition on the neuropsychological development of children. Two populations of children
who were chronically exposed to either high or low levels of As and Pb were analyzed on the Wechsler Intelligence Scale for Children, Revised for Mexico (WISC-RM). Arsenic levels were tested using urine samples (As-U) and lead levels via blood samples (PbB). Lead and arsenic levels were measured using atomic absorption spectrophotometry. The height for age index (HAI) was used as an indicator of chronic malnutrition, and demographic information was collected in questionnaire form. Data on full verbal, performance intelligence quotients (IQ) scores, long-term memory, linguistic abstraction, attention span, and visuospatial organization information were extrapolated from the WISC-RM. It was found that higher levels of As-U were significantly related to poorer performance on the WISC-RM factors that focused on long-term memory and linguistic abstraction. Higher levels of Pb-B correlated to lower scores on attention tasks. Rodriguez et al. (2001) studied the effects of arsenic on behavior from a neurological standpoint. It has been reported that catecholamine levels in striatum, hippocampus, and other cerebral regions change in mice and rats exposed to arsenic. The best-known catecholamine, dopamine, is associated with movement control, learning, memory, cognition, and emotion. To characterize behavioral alterations induced by arsenic exposure, adult male Sprague–Dawley rats were exposed to 5, 10, and 20 mg/kg of arsenic via an intragastric route for either 2 or 4 weeks. Exposed rats showed reduced locomotor activity, but returned to normal at the end of the exposure period. There was also an increase in the number of errors during egocentric tasks reflecting alterations in arsenic brain concentrations. The preceding increase was related to time, not dose. The results indicate that short-term arsenic exposure induces neural and behavioral changes that may reflect a neurotoxic effect, and that these changes are dependent on dose, time, and environment. Arisawa et al. (2001) evaluated the association of previous exposure to environmental cadmium and renal function with respect to the total mortality and cancer incidence. From the cadmium-polluted area of Nagasaki, Japan, 275 residents between the ages of 40 and 92 were recruited. Dietary intake of Cd decreased after the replacement of polluted soil in rice fields between 1980 and 1983. The mortality rates from 1982 to 1997 and the incidence of cancer from 1985 to 1996 were investigated. Standardized mortality and incidence ratios were calculated using regional reference data. Cd levels were measured using b2 -microglobulin levels and then divided into two groups dependent on creatinine levels. The study suggests that renal tubule dysfunction and a reduced glomerular filtration rate are predictors of mortality among persons previously exposed to Cd. Also, the overall mortality rates did not increase in comparison to reference data.
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Vahter et al. (1996) conducted one of the first studies examining the effects of variation in diet to the uptake of cadmium in humans. Dietary intake of cadmium was studied in nonsmoking women between the ages of 20 and 50 years, who had either a mixed diet low in shellfish or one that included shellfish once a week or more. Duplicate diets were taken to measure the quantity of Cd. The shellfish diets contained twice the amount of Cd compared with the mixed diet. When feces samples were taken and analyzed, equivalent amounts of Cd were found in comparison to the duplicate diets. Also, Cd-B levels did not differ in levels of Cd-U within each group. There was a higher level of Cd absorption in the mixed-diet group, which was attributed to lower levels of iron found in the mixed-diet group. When women in the shellfish group with low serum iron were examined, they also exhibited higher levels of Cd absorption. The study concluded that the bioavailiblity of Cd may be related to diet.
7. Conclusions Understanding the variability of host factors is critical for risk assessment. Methodologies for measurement in population, diet, and occupation are limited, and the focus to date has not been on critical or sensitive populations, in other words, women and children. Many of the systems have been in vitro and are not always appropriate for in vivo systems. Biomonitoring data are also limited. Because we are interested in real situations, there is a need for special consideration of speciation of the metal as well as complex mixtures. Also important to consider are consumption patterns and socioeconomic status of the affected population. Finally, the use of genetic markers, covered elsewhere in this series, will be the single most important tool to aid in effectively measuring exposure, and hence, making realistic and useful assessments of risk.
Acknowledgments The author is grateful for the support of the NIEHS Center P30 ES 05022 and the Environmental and Occupational Health Sciences Institute. The author is also grateful to Brian Buckley, Joanna Burger, and Michael Gochfeld for their helpful review of this manuscript.
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