Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
13 Arsenic, Boron, Nickel, Silicon, and Vanadium SUMMARY An Estimated Average Requirement (EAR) or Adequate Intake (AI) was not set for arsenic, boron, nickel, silicon, or vanadium. In the case of the vitamins and other minerals reviewed in this report, there are well-established studies typically based on observations from several laboratories. The data currently available for these vita- mins and other minerals provide an understanding of the metabolic role of each and describe the consequences of their restriction in the diets of both laboratory animals and humans. There are also clearly defined, readily reproducible indicators in humans for these vitamins and other minerals that can be used to determine an EAR and calculate a Recommended Dietary Allowance, or to establish an AI. At present, such data do not exist for arsenic, boron, nickel, silicon, and vanadium. In the case of arsenic, boron, nickel, silicon, and vanadium, there is evidence that they have a beneficial role in some physiological processes in some species. For boron, silicon, and vanadium, mea- surable responses of human subjects to variations in dietary intake have also been demonstrated. However, the available data are not as extensive (e.g., dose-response data are absent) and the responses are not as consistently observed as they are for the vitamins and other minerals. Thus, data are insufficient to determine an EAR for any of these minerals. Estimates of dietary intakes of arsenic, boron, nickel, silicon, and vanadium by the North American adult population are available 502
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 503 and could have been used to establish an AI. However, establishing an AI also requires a clearly defined, reproducible indicator in humans sensitive to a range of intakes. Indicators that meet this criterion for establishing an AI are not currently available for any of these minerals, and therefore no AI was set. Notwithstanding, observations of deficiency effects (e.g., on growth and development) in multiple animal species and data from limited human studies suggest beneficial roles for arsenic, boron, nickel, silicon, and vanadium in human health. These data clearly indicate a need for continued study of these elements to determine their metabolic role, identify sensitive indicators, and more fully characterize specific functions in human health. Estimates of Tolerable Upper Intake Levels (UL) were set for boron, nickel, and vanadium. The ULs for boron and vanadium are based on animal data and have been set for adults at 20 mg/day and 1.8 mg/day, respectively. The UL for nickel is 1 mg/day. There were insufficient data using the model described in Chapter 3 to set a UL for arsenic and silicon. ARSENIC BACKGROUND INFORMATION Function There have been no studies to determine the nutritional impor- tance of arsenic for humans. Although the metabolic function of arsenic is not well understood, one study in rats suggests that arsenic may have a role in the metabolism of methionine (Uthus and Poellot, 1992). Arsenic deprivation was associated with an increase in hepatic S-adenosyl-homocystine concentrations and a decrease in hepatic S-adenosyl-methionine concentrations. Arsenic depriva- tion has also been associated with impaired growth and abnormal reproduction in rats, hamsters, chicks, goats, and miniature pigs (Anke, 1986; Uthus, 1994). Arsenic has also been suggested to be involved with the regulation of gene expression (Meng and Meng, 1994). Arsenite is associated with changes in the methylation of core histones and therefore is active at the transcriptional level (Desrosiers and Tanguay, 1986).
504 DIETARY REFERENCE INTAKES Physiology of Absorption, Metabolism, and Excretion The absorption of inorganic arsenic is related to the solubility of the compound ingested (Vahter, 1983). In humans, more than 90 percent of inorganic arsenite and arsenate from water is absorbed (Vahter, 1983), and approximately 60 to 70 percent of dietary arsenic is absorbed (Hopenhayn-Rich et al., 1993). Once absorbed, inorganic arsenic is transported to the liver where it is reduced to arsenite and then methylated. The majority of ingested arsenic is rapidly excreted in the urine. The proportion of the various forms of arsenic in urine can vary; however, the common forms present are inorganic arsenic, monomethylarsonic acid, dimethylarsinic acid, and trimethylated arsenic (Yamato, 1988). FINDINGS BY LIFE STAGE AND GENDER GROUP Because of the lack of human data to identify a biological role of arsenic in humans, neither an Estimated Average Requirement, Rec- ommended Dietary Allowance, nor Adequate Intake were estab- lished. INTAKE OF ARSENIC Food Sources Dairy products can contribute as much as 31 percent of arsenic in the diet; meat, poultry, fish, grains and cereal products collectively contribute approximately 56 percent (Mahaffey et al., 1975). Based on a national survey conducted in six Canadian cities from 1985 to 1988, it was reported that foods containing the highest concentra- tions of arsenic were fish (1,662 ng/g), meat and poultry (24.3 ng/g), bakery goods and cereals (24.5 ng/g), and fats and oils (19 ng/g) (Dabeka et al., 1993). The substantial portion of arsenic present in fish is in the organic form. The major contributors of inorganic arsenic are raw rice (74 ng/g), flour (11 ng/g), grape juice (9 ng/ g), and cooked spinach (6 ng/g) (Schoof et al., 1999). Dietary Intake Results of the analysis of 265 core foods conducted by the Food and Drug Administration (1991â1997), and analysis of foods and intake data from the U.S. Department of Agriculture Continuing Survey of Food Intakes by Individuals (1994â1996), indicate that
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 505 the intakes of arsenic for all age groups ranged from 0.5 to 0.81 Âµg/ kg/day (Gunderson, 1995) and that the median intake of arsenic by adult men and by women was approximately 2.0 to 2.9 Âµg/day and 1.7 to 2.1 Âµg/day, respectively (Appendix Table E-2). Adams and coworkers (1994) reported lower intakes for adults (23 to 58 Âµg/day) from 1982 to 1991. There was not a marked difference in the arsenic consumption between various age groups. Gartrell and coworkers (1985) reported a similar mean U.S. intake of arsenic of 62 Âµg/day, and Tao and Bolger (1999) reported intakes ranging from 28 to 72 Âµg/day for adults from 1987 to 1988. Data on the concentration of arsenic in human milk are limited; however, studies have reported mean concentrations ranging from 0.2 to 6 Âµg/kg wet weight (Byrne et al., 1983; Dang et al., 1983; Grimanis et al., 1979). TOLERABLE UPPER INTAKE LEVELS The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, intake above the UL may be appropriate for investigation within well- controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxic- ity and as long as these trials employ appropriate safety monitoring of trial subjects. Arsenic is currently under investigation for the treat- ment of leukemia (Look, 1998). Arsenic occurs in both inorganic and organic forms, with the in- organic forms that contain trivalent arsenite (III) or pentavalent arsenate (V) being of the greatest toxicological significance (Chan and Huff, 1997). No data on the possible adverse effects of organic arsenic compounds in food were found. Because the organic forms are usually less toxic than the inorganic (ATSDR, 1998), adverse effects of inorganic forms are described. It is unclear whether risk assessments should be developed for specific groups of inorganic arsenic compounds. Adverse Effects The adverse effects of arsenic in humans have been identified with exposure to inorganic arsenic, although in animals higher ex- posures to organic arsenic produces some of the same effects as
506 DIETARY REFERENCE INTAKES lower exposures to inorganic arsenic (ATSDR, 1998). There is some evidence that arsenic III may be more toxic than arsenic V (Byron et al., 1967; Maitani et al., 1987). Animals do not appear to be good quantitative models for inorganic arsenic toxicity in humans (ATSDR, 1998), perhaps because of the species diversity of erythrocyte- binding of arsenic and inorganic arsenic methyltransferase activity, a detoxification mechanism (Aposhian, 1997; Goering et al., 1999). Acute Effects Inorganic arsenic is an established human poison. Ingestion of doses greater than 10 mg/kg/day leads to encephalopathy and gastrointestinal symptoms (Civantos et al., 1995; Levin-Scherz et al., 1987; Quatrehomme et al., 1992). Poisoning also occurs with arsenic doses of 1 mg/kg/day or greater and can be accompanied by anemia and hepatotoxicity (Armstrong et al., 1984; Fincher and Koerker, 1987). Arsenicism Chronic intake of 10 Âµg/kg/day or greater of inorganic arsenic produces arsenicism, a condition characterized by alteration of skin pigmentation and keratosis (NRC, 1999). In some regions, an oc- clusive peripheral vascular disease also occurs resulting in gangrene of the extremities, especially of the feet, thus termed blackfoot dis- ease (Engel and Receveur, 1993; Tseng, 1977). It has been hypothe- sized that zinc deficiency may exacerbate the toxicity of arsenic (Engel and Receveur, 1993). Malnutrition has been associated with an increased risk of blackfoot disease (Yang and Blackwell, 1961). Because arsenicism may be associated with arsenic intakes higher than those causing other adverse effects (see âCarcinogenicityâ), it was not selected as a critical adverse effect to set a UL. Peripheral Neuropathy Intermediate and chronic exposures of arsenic up to levels of 11 mg/L of water are associated with symmetrical peripheral neuropathy (Franzblau and Lilis, 1989; Huang et al., 1985; Wagner et al., 1979). However, in some populations exposures of 5 mg/L of water did not result in clinical or subclinical neuropathy (Kreiss et al., 1983).
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 507 Developmental Toxicity Developmental effects in humans have not been demonstrated (ATSDR, 1998; NRC, 1999). In the hamster, single intragastric doses of 1.4 mg of arsenic/kg to pregnant females led to fetal mortality (Hood and Harrison, 1982). In the mouse, fetal mortality and teratogenicity were produced by single intragastric doses of 6 to 7 mg/kg (Hood, 1972) and 11 mg/kg (Hood and Bishop, 1972); oral doses of 23 mg/kg (Baxley et al., 1981) had the same effects. In the rat, an intraperitoneal dose of 5 to 10 mg/kg produced a high per- centage of malformed fetuses (Beaudoin, 1974). Genotoxicity Sodium arsenite induced point mutations in two strains of Escherichia coli WP2; negative results were obtained in a recA strain. Arsenic trichloride and sodium arsenite gave positive results in a rec assay in Bacillus subtilis (Nishioka, 1975). Positive results were also obtained in this assay with arsenic trioxide and arsenic pentoxide (Kanematsu et al., 1980). Sodium methanearsonates were negative in this assay (Shirasu et al., 1976). Potassium and sodium arsenite caused mitotic arrest and chromo- somal aberrations, including chromatid gaps, breaks, translocations, dicentrics, and rings in cultured human peripheral leukocytes and human diploid fibroblast WI.38 and MRC5 lines (Oppenheim and Fishbein, 1965; Paton and Allison, 1972). Some of the mutagenic effects of arsenic may be a consequence of the formation of reactive oxygen species (Hei et al., 1998). Carcinogenicity Ingestion of inorganic arsenic is associated with risk of cancers of the skin, bladder, and lung (IARC, 1980, 1987; NRC, 1999). In- creased risks of other cancers such as kidney and liver have also been reported, but the strength of the association is not great (NRC, 1999). There are no studies of cancer in humans after exposure to organic arsenicals (ATSDR, 1998). Most studies of a positive association with cancer involve intake of inorganic arsenic in drinking water. A large-scale survey of 40,421 inhabitants (19,269 men and 21,152 women) of an area on the southwest coast of Taiwan, where artesian well water with a high concentration of arsenic was consumed for more than 45 years, found that the overall prevalence rates for skin cancer, hyper-
508 DIETARY REFERENCE INTAKES pigmentation, and keratosis were 10.6, 183.5, and 71.0/1,000, respectively (Tseng et al., 1968). They also found that the male-to- female ratio for skin cancer was 2.9:1 and 1.1:1 for hyperpigmenta- tion and keratosis. The prevalence appeared to increase progres- sively with age for all three conditions, although there was a decline in cancer and hyperpigmentation in women older than 69 years of age. The prevalence rates for skin cancer, hyperpigmentation, and keratosis showed an ascending gradient which correlated with the arsenic content of the well water. Blackfoot disease had an overall prevalence rate of 8.9/1,000 and, similar to skin cancer, displayed a dose-response relationship with the amount of arsenic in the well water. There was a significantly high association of blackfoot disease with hyperpigmentation, keratosis, and skin cancer. The risk of bladder cancer in Taiwan was increased with intake of arsenic from water of 10 Âµg/kg/day (Chen et al., 1992). This in- creased risk has been confirmed in studies from Japan (Tsuda et al., 1995), Argentina (Hopenhayn-Rich et al., 1996), and Chile (Smith et al., 1998). Studies in U.S. populations exposed to arsenic in drink- ing water have not identified cancer increases (Morton et al., 1976; Southwick et al., 1981; Valentine et al., 1992). These epidemiological associations have to some extent been rep- licated in animal experiments (Simeonova et al., 2000; Yamamoto et al., 1995). However, the mechanisms of arsenic carcinogenesis are not established, but may involve genetic effects (Goering et al., 1999) or perturbation of cellular signaling pathways (Simeonova et al., 2000). Summary Clearly, high intakes of inorganic arsenic are associated with various toxicities, including increased risks of several cancers with chronic exposure to high levels in drinking water. There is no evidence linking organic arsenic in food to any adverse effect, including cancer. Since there is no evidence available to define the mecha- nisms of arsenic carcinogenesis and no data to support a threshold, it is not possible to establish a health-based level of inorganic arsenic in drinking water and food. It should be noted that a recent report of the National Research Council recommended a downward revi- sion from the current maximum contaminant level for arsenic in drinking water of 50 Âµg/L (NRC, 1999). Because organic forms of arsenic are less toxic than inorganic forms, any increased health risk from intake of organic arsenic from food products such as fish is unlikely.
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 509 Intake Assessment The highest concentrations of arsenic in food are found in marine products, but these are in the organic form, usually arsenobetaine, which is not toxic. Various sources of exposure to inorganic arsenic, as arsenates or arsenites, exist. Occupational exposure to inorganic forms of arsenic occurs primarily by inhalation. Arsenic in drinking water is predominantly the trivalent and pentavalent forms as salts (EPA, 1988). Arsenic is also being used in the treatment of leuke- mias (Konig et al., 1997; Look, 1998). The median intake of arsenic by men and by women was approxi- mately 2.0 to 2.9 Âµg/day and 1.7 to 2.1 Âµg/day, respectively (Appen- dix Table E-2). Adams and coworkers (1994) reported lower intakes for adults (23 to 58 Âµg/day) from 1982 to 1991. The level of in- organic arsenic in water was about 2 Âµg/L (ATSDR, 1998). The drinking water for about 98 percent of the U.S. population was below 10 Âµg/L (Chappell et al., 1997). The U.S. Environmental Protection Agency (EPA) has a maximum contaminant level (MCL) of 50 Âµg/L for water supplies in the United States (EPA, 1975). However, the agency recently proposed a much lower MCL of 5 Âµg/ L for arsenic in drinking water and is seeking comments on MCLs ranging from 3 to 20 Âµg/L (EPA, 2000). The EPA expects to pro- mulgate a new, lower MCL in the near future. The average arsenic content of mineral drinking water in European countries is 21 Âµg/L (Zielhuis and Wibomo, 1984). Risk Characterization Although no UL was set for arsenic, there is no justification for adding arsenic to food and there may be a risk of adverse effects with consumption of organic arsenic in food or with intake of in- organic arsenic in water supplies at the current MCL of 50 Âµg/L in the United States. Substantial numbers of individuals in North America, however, are exposed to arsenic levels exceeding the MCL (Chappell et al., 1997; Grantham and Jones, 1977; Kreiss et al., 1983). Inhalation exposure occurs in occupational settings such as smelters and chemical plants, where the predominant form of air- borne arsenic is arsenic trioxide dust (ATSDR, 1998). RESEARCH RECOMMENDATIONS FOR ARSENIC â¢ A better understanding of species differences in biotransforma- tion of arsenic and toxicity.
510 DIETARY REFERENCE INTAKES â¢ The role of arsenic in methyl metabolism and genetic expres- sion; identification of a reliable indicator of arsenic status in hu- mans. â¢ Because relatively low serum arsenic concentrations have been associated with vascular diseases and central nervous system injury, more systematic investigation of the possible role of arsenic in these disorders. BORON BACKGROUND INFORMATION Function Of the five minerals discussed in this chapter, boron has received the most extensive study of its possible nutritional importance for animals and humans. Still, the collective body of evidence has yet to establish a clear biological function for boron in humans. There is evidence that boron is required by vascular plants and some micro- organisms. The only known boron-containing compounds in nature are organoboron complexes from plants, some of which may have antibiotic properties (Hunt, 1998; Nielsen, 1997). Principles of bio- inorganic chemistry predict that boron, which is primarily in the form of boric acid, B(OH)3, at physiological pH, binds to cis-diols, perhaps with some specifically, and forms condensation products that are moderately labile in aqueous solutions (da Silva and Williams, 1991). The latter could theoretically provide stability to diol-rich molecules such as polysaccharides or steroids. Boron can act as an inhibitor of activity for a wide variety of enzymes in vitro (Hunt, 1998). However, no boron-containing enzyme has been identified. In higher animals, boron has not been shown to have a sufficiently definitive pattern of effects to establish a function. Embryonic defects related to boron depletion have been reported for zebra fish (Rowe and Eckhert, 1999), frogs (Fort et al., 1998, 1999), and trout (Eckhert, 1998), and they suggest a function for boron in reproduction and development. However, boron-related develop- mental defects have not been found consistently in rodent models (Lanoue et al., 1998, 1999). Physiological effects, including changes in blood glucose and triglyceride concentrations and abnormal calcitriol (1,25,OH2D3) metabolism or function have been reported in boron-deficient chicks that have a concomitant vitamin D defi- ciency (Hunt, 1996). Higher insulin secretion from the pancreas of boron-deprived chicks has also been reported (Bakken, 1995). How-
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 511 ever, many of these studies found effects of boron only in the pres- ence of secondary nutritional stressors, such as vitamin D deficiency. Metabolism of vitamin D and estrogen, as measured by plasma metabolites, macromineral (especially calcium) metabolism, and immune function have been proposed as related to a function for boron in humans (Nielsen, 1998; Nielsen and Penland, 1999; Samman et al., 1998). Findings supporting these possible functions also have come from studies where another nutritional stressor was present or effects have not been consistently demonstrated. In one laboratory, several dietary boron deprivation studies in both rats and humans have consistently found an effect of boron intake on brain electrophysiology and, in humans, on performance of tasks measuring eye-hand coordination, attention, and short-term mem- ory (Penland, 1998). However, these possible functions of boron have yet to be studied and confirmed by other laboratories. Physiology of Absorption, Metabolism, and Excretion Studies with animals and humans indicate that about 90 percent of boron is absorbed in the normal intake range (Hunt and Stoecker, 1996; Sutherland et al., 1998). Most dietary boron is hydrolyzed within the gut to yield B(OH)3 which, as a neutral compound, is easily absorbed. The mechanism of boron absorption has not been studied, but a passive, nonmediated diffusion process involving B(OH)3 is likely (da Silva and Williams, 1991). Some evidence for boron homeostasis exists. In a 42-day study in men with a boron intake average of 3.73 mg/day, urinary loss was 3.20 mg/day (86 percent of intake), whereas urinary boron loss was less when the boron intake was less than 3.20 mg/day and loss was more when the intake was more than that amount (Sutherland et al., 1998). In a study with postmenopausal women, 89 percent of boron from a low- boron diet (0.36 mg/day from food and 2.87 Âµg/day from a supple- ment) was excreted in the urine and 3 percent in the feces (Hunt and Stoecker, 1996). Other metabolic studies do not support homeostatic control. For example, urinary excretion was 86 and 84 percent when boron intake was 2.2 and 10 mg/day, respectively (Samman et al., 1998). Boron chemistry suggests it is transported in the blood as B(OH)3. Specifically, because boron forms labile complexes in aqueous solu- tion, transport is probably as free boric acid rather than a complex (da Silva and Williams, 1991). The blood boron concentration is dependent on dietary intake as primarily shown by animal studies (Price et al., 1998; Samman et al., 1998). This reflects the relatively
512 DIETARY REFERENCE INTAKES small boron pool that blood represents as well as efficient absorp- tion and excretion. The excretory form of boron has not been stud- ied. As a neutral molecule, blood borate should have high fractional renal clearance and easily enter the glomerular filtrate. FINDINGS BY LIFE STAGE AND GENDER GROUP There is evidence supporting a biological role of boron in some microroganisms. In higher animals, boron has been shown to have a role in reproduction and development. The collective body of evidence, however, has yet to establish a clear biological function for boron in humans. Therefore, neither an Estimated Average Re- quirement, Recommended Dietary Allowance, nor Adequate Intake was established for boron. INTAKE OF BORON Food Sources Hunt and coworkers (1991) reported that the highest concentra- tions of boron were found in fruit-based beverages and products, tubers, and legumes. Depending on the geographic location, water could contribute a major portion of the dietary boron. Negligible or minimal amounts (less than 0.100 Âµg/g) were found in animal products, certain grain products, condiments, and confections. Sim- ilar findings were reported by Anderson and coworkers (1994). Meacham and Hunt (1998) reported that the ten foods with the highest concentration of boron were avocado, peanut butter, pea- nuts, prune and grape juice, chocolate powder, wine, pecans, and granola raisin and raisin bran cereals. Rainey and coworkers (1999), however, examined both the content and total food consumption (amount and frequency), reporting that the five major contributors of boron were coffee, milk, apples, dried beans, and potatoes, which collectively accounted for 27 percent of the dietary boron consump- tion. Although coffee and milk are low in boron, they were the top contributors due to the volumes consumed. Dietary Intake U.S. boron consumption was assessed by use of the Boron Nutri- ent Data Base linked to 2-day food records from respondents to the Third National Health and Nutrition Examination Survey (NHANES III) (Appendix Table C-12) and the Continuing Survey
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 513 of Food Intakes by Individuals (CFSII) (Appendix Table D-1). In NHANES III, the median consumption of boron ranged from 0.75 to 0.96 mg/day for school-aged children and from 0.87 to 1.35 mg/ day for adults. Median consumption of boron by pregnant women was 1.05 mg/day in NHANES III and 1.08 mg/day in CFSII. The median consumption of boron by lactating women was 1.27 mg/ day in CFSII. Anderson (1992) reported that the mean boron concentration of human milk from lactating women up to 5 months postpartum was 0.27 Âµg/L. Based on a mean secretion of 0.78 L/day of milk (Chap- ter 2), the amount of boron secreted is 0.21 mg/day. Intake from Supplements Information from NHANES III on supplement intake of boron is given in Appendix Table C-13. The adult median boron intake from supplements was approximately 0.14 mg/day. Based on dietary in- take data provided in Appendix Table C-12, the median intake of dietary and supplemental boron was approximately 1.0 to 1.5 mg/ day for adults. TOLERABLE UPPER INTAKE LEVELS The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, in- take above the UL may be appropriate for investigation within well- controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxic- ity and as long as these trials employ appropriate safety monitoring of trial subjects. Hazard Identification It should be noted that because some studies report doses of boron while others report doses of boric acid or borax, comparison of experiments is facilitated by expressing all doses as boron equiva- lents (e.g., boric acid dose Ã 0.175; borax dose Ã 0.113).
514 DIETARY REFERENCE INTAKES Adverse Effects No data are available on adverse health effects from ingestion of large amounts of boron from food and water. According to case reports of poisoning incidents and accidental ingestions of boric acid and borax, these compounds exhibit low toxicity. Stokinger (1981) reported that the minimal lethal dose of boric acid from ingestion is 640 mg/kg/day. The potential lethal dose has been reported to be 15 to 20 g/day for adults and 3 to 6 g/day for in- fants; however, in an examination of 784 cases of boric acid inges- tion, Litovitz and coworkers (1988) found minimal or no toxicity at these or higher intake levels. Initial symptoms include nausea, gas- tric discomfort, vomiting, and diarrhea. At higher doses, skin flush- ing, excitation, convulsions, depression, and vascular collapse have been reported. Human Data. Most of the toxicity data on repeated administration of boron (as boric acid or borax) comes from studies in laboratory animals. However, from reports on the use of borates to treat epi- lepsy where doses between 1,000 mg/day of boric acid (2.5 mg/kg/ day) to 25 g/day of boric tartrate (24.8 mg/kg/day) were adminis- tered chronically, toxicity was expressed as dermatitis, alopecia, anorexia, and indigestion (Culver and Hubbard, 1996). On the basis of their review of the human data in adults, Culver and Hubbard (1996) reported no adverse effects at chronic intakes of 2.5 mg/ kg/day (about 1 g of boric acid). On the basis of nine cases involv- ing infants (Gordon et al., 1973; OâSullivan and Taylor, 1983), there does not appear to be an increased sensitivity of response to chronic exposure of boron compounds. Genotoxicity. On the basis of existing data, genotoxicity is not an area of concern after exposure of humans to boron compounds (ATSDR, 1992; Dieter, 1994). Reproductive and Developmental Effects in Animals. Although not observed in humans, animal studies have shown that high doses of borax or boric acid produce adverse effects in the testis and affect male fertility (IPCS, 1998). Also, adverse effects have been found in the developing fetus (Heindel et al., 1992; IPCS, 1998; Price et al., 1996a). Effects on the testis have been observed in three speciesâ rats, mice, and dogsâafter supplementation with boric acid or borates in feed or drinking water (Fail et al., 1990, 1991; Green et al., 1973; Ku et al., 1993; Lee et al., 1978; Weir and Fisher, 1972). The effects
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 515 tend to be similar in all three species and include inhibition of spermiation (release of spermatozoa into seminiferous tubule), loss of germ cells, changes in epididymal sperm morphology and caput sperm reserves, testicular atrophy, and decreased serum testoster- one levels. Doses of 29 mg/kg/day in dogs and 58.5 mg/kg/day in rats have resulted in adverse reproductive effects. A comparison of the lowest-observed-adverse-effect levels (LOAELs) and no-observed- adverse-effect levels (NOAELs) for the key studies on reproduction is given in Table 13-1. Pharmacokinetics. The pharmacokinetics of boron are very similar in animals and humans. There are several recent reviews of the available studies (Dourson et al., 1998; IPCS, 1998; Moore, 1997; Murray, 1998), and a summary of the key findings is presented here. There is no evidence of boron accumulation in soft tissues of humans (Murray, 1998). In rats, boron increased more in bone than in plasma (Ku et al., 1991). Although methodological differ- ences between studies preclude a clear-cut, cross-species compari- son of blood boron concentrations in animals and humans at simi- lar doses, IPCS (1998) reported a preliminary comparison between humans and rats after oral intakes of boron from diet or drinking water. Between 0.01 and 100 mg/kg/day, very similar blood levels were achieved at comparable intakes, further evidence that the kinetics of boron in humans and rats are alike. Boron is rapidly excreted unchanged in the urine of humans and rodents regardless of the route of administration. In humans, the half-life for elimination was approximately 21 hours for both intra- venously (Jansen et al., 1984a) and orally (Jansen et al., 1984b) administered boric acid. By using the data from Ku and coworkers (1991) and assuming first-order kinetics, the half-life in rats has been calculated in the range of 14 to 19 hours. As noted by Murray (1998) and Dourson and coworkers (1998), rats have mean glomer- ular filtration rates for boric acid three to four times that of hu- mans, which could account for the small differences in blood (and, therefore, soft tissue) concentrations of boron noted by IPCS (1998). Other Effects. Increased mortality was observed in mice fed dietary boric acid for periods of 13 weeks at boron levels of 563 mg/kg/day in females and 776 mg/kg/day in males (Dieter, 1994). Minimal to mild extramedullary hematopoiesis was noted at all doses for both sexes, and hyperkeratosis and hyperplasia of the forestomach also occurred at the highest doses for both sexes. Testicular atrophy or
516 DIETARY REFERENCE INTAKES TABLE 13-1 Ranking of Reproductive and Developmental Effects of Borona by Increasing Dose Dose (mg boron/ Species/ kg body Reference Durationb weight/d)c Effectd Price et al., SD rat/gd 0â20 9.6 NOAEL for developmental 1996b effects immediately preterm Price et al., SD rat/gd 0â20 12.9 NOAEL for developmental 1996b effects measured at weaning Heindel et al., SD rat/gd 0â20 13.3 LOAEL for reduced fetal 1992 13.6 weight, increased rib malformations/variations Weir and Male SD rat/ 17.5 NOAEL for male sterility, Fisher, 1972 multigeneration testicular atrophy Fail et al., CD-1 mouse/ 19.2 LOAEL for reduced sperm 1991 multigeneration motility, reduced F2 pup weight Price et al., SD rat/gd 0â20 25.4 LOAEL for increased short 1996b rib XIII at weaning Ku et al., 1993 Male SD rat/ 26 LOAEL for mild inhibited 63 days sperm release Weir and Male beagle dogs/ 29 Altered testis weight and Fisher, 1972 2 years histopathology LOAEL (reported NOAEL 8.8) Price et al., NZ white rabbits/ 21.9/43.7 NOAEL/LOAEL for decreased 1996a gd 6â19 fetal body weight, increased fetal cardiovascular malformations and maternal toxicity Heindel et CD-1 mouse/ 43 NOAEL for mouse al., 1992 gd 0â17 79 developmental toxicity LOAEL for decreased fetal body weight Ku et al., Male SD rat/ 52 LOAEL for testicular atrophy 1993 63 days a Administered as boric acid. b SD = Sprague-Dawley rats, gd = gestational days, NZ = New Zealand. c Boric acid was converted to boron. d NOAEL = no-observed-adverse-effect level, LOAEL = lowest-observed-adverse-effect level. SOURCE: IPCS (1998). Published here with permission of the World Health Organization.
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 517 degeneration was observed at doses of 141 mg/kg/day. These find- ings confirmed the earlier studies by Weir and Fisher (1972) in which rats fed 88 mg/kg/day of boron as borax or boric acid for 90 days developed testicular atrophy. Summary Based on the considerations of causality, relevance, and the quality and completeness of the database in animals, reproductive and developmental effects were selected as the critical endpoint on which to base a UL for adults. Because no data are available on adverse reproductive effects in humans from the consumption of large amounts of boron from food and water, animal data were utilized to estimate the UL. The following factors support the use of the laboratory animal studies listed in Table 13-1 to assess the devel- opmental and reproductive risks from boron exposure in humans: (1) boric acid has been shown to cause developmental effects in four species of animals, (2) the toxicity of boric acid and borax correlates with their elemental boron content under physiological conditions, (3) the organs that are sensitive to the acute systemic effects of boron in humans and animals are similar, (4) the pattern of tissue distribution and excretion of boron is similar in animals and humans, and (5) the chronic effects of boron observed in mice, rats, and dogs and the effective doses are similar. Dose-Response Assessment Adults Data Selection. In the absence of human data pertaining to a dose- response relationship, the animal data sets reporting developmental abnormalities are shown in Table 13-1. The studies showing devel- opmental abnormalities at the lowest levels of intake are in dogs (Weir and Fisher, 1972) and rats (Price et al., 1996b). However, the study in dogs was not used directly in this risk assessment of boron due to problems in the design (few animals per treatment group and lack of information on food intake). The study of Price and coworkers (1996b) is considered the critical study to assess the risks to humans from exposure to boron. Identification of a NOAEL and LOAEL. In the study by Price and coworkers (1996b), boric acid was fed to time-mated rats (60 per treatment group) from gestational days 0 to 20 at dosages of 3.3,
518 DIETARY REFERENCE INTAKES 6.3, 9.6, 13.3, or 25 mg/kg/day. Maternal body weight did not differ among groups during gestation or lactation, and weight gain was not affected by the amount of boron in the diet. The most sensitive parameter of developmental toxicity was decreased fetal weights at gestational day 20, with significantly decreased fetal weights found only in the 13.3 and 25 mg/kg/day groups. Thus, a NOAEL of 9.6 mg/kg/day and a LOAEL of 13.3 mg/kg/day were reported. In an earlier study in rats using a very similar experimental design, Heindel and coworkers (1992) reported an increase in fetal mal- formations with boric acid at dosages of 13.6, 28.5, and 57.7 mg/ kg/day from gestational days 0 to 20. The most common malforma- tions were enlargement of lateral ventricles in the brain, shortening of rib XIII, and wavy ribs. Although a LOAEL was found at the lowest dose tested (13.6 mg/kg/day), it is similar to the LOAEL of 13.3 mg/kg/day reported by Price and coworkers (1996b), a find- ing that provides additional support for the dose-response relation- ship for developmental toxicity as the critical effect. Uncertainty Assessment. Five expert groups have assessed the risk to humans from boron using the NOAEL from Price and coworkers (1996b), and uncertainty factors (UFs) vary between 25 and 60 (Becking and Chen, 1998). There do not appear to be sufficient data to justify lowering the degree of uncertainty for extrapolating from experimental animals to humans from the 10 that is often used for nonessential chemicals. Thus, the usual value of 10 was selected. In view of the expected similarity in pharmokinetics among humans, however, a UF of 3 was chosen for intraspecies variability. These two UFs are multiplied to yield a UF of 30. Derivation of a UL. The NOAEL for developmental effects in rats is 9.6 mg/kg/day. The UL for boron is calculated by dividing the NOAEL of 9.6 mg/kg/day by the UF of 30, resulting in an UL of 0.3 mg/kg/day. This value was multiplied by the average of the refer- ence body weights for adult women, 61 kg, from Chapter 1 (Table 1-1). The resulting UL for adults is rounded to 20 mg/day. UL = NOAEL = 9.6 mg/kg/day = 0.32 mg/kg/day Ã 61 kg â 20 mg/day UF 30 Boron UL Summary, Ages 19 Years and Older UL for Adults â¥ 19 years 20 mg/day of boron
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 519 Other Life Stage Groups Infants. For infants, the UL was judged not determinable because of insufficient data on adverse effects in this age group and concern about the infantâs ability to handle excess amounts. To prevent high levels of intake, the only source of intake for infants should be from food and formula. Children and Adolescents. There are no reports of boron toxicity in children and adolescents. Given the dearth of information, the UL values for children and adolescents are extrapolated from those established for adults. Thus, the adult UL of 20 mg/day of boron was adjusted for children and adolescents on the basis of relative body weight as described in Chapter 2 using reference weights from Chapter 1 (Table 1-1). Values have been rounded. Pregnancy and Lactation. Because the UL is based on adverse re- productive effects in animals and because there are no reports of boron toxicity in lactating females, the UL for pregnant and lactating females is the same as that for the nonpregnant and nonlactating female. Boron UL Summary, Ages 0 through 18 Years, Pregnancy, Lactation UL for Infants 0â12 months Not possible to establish; source of intake should be from food and formula only UL for Children 1â3 years 3 mg/day of boron 4â8 years 6 mg/day of boron 9â13 years 11 mg/day of boron UL for Adolescents 14â18 years 17 mg/day of boron UL for Pregnancy 14â18 years 17 mg/day of boron 19â50 years 20 mg/day of boron UL for Lactation 14â18 years 17 mg/day of boron 19â50 years 20 mg/day of boron
520 DIETARY REFERENCE INTAKES Intake Assessment Humans can be exposed to boron from consumption of food, dietary supplements, and drinking water from natural, municipal, or bottled sources. Airborne boron contributes very little to the daily exposure of the general population. For humans not taking supplements, diet is the major source of boron followed by the in- take from drinking water. The ninety-fifth percentile dietary intake of boron in the United States is approximately 2.3 mg/day for men, 1.6 to 2.0 mg/day for women, 2.0 mg/day for pregnant women (Appendix Table C-12), 2.7 mg/day for vegetarian males, and 4.2 mg/day for vegetarian females (Rainey et al., 1999). These dietary intakes are slightly higher than those estimated by Meacham and Hunt (1998). The average intake of supplemental boron at the ninety-fifth percentile is approximately 0.4 mg/day for adults (Appendix Table C-13). A consumption of 1 L/day of municipal drinking water in the United States contributes 0.005 to 2 mg/day (mean of 0.2 mg/day) of boron (EPA, 1987), and bottled water can contribute an average of 0.75 mg/day (Allen et al., 1989). Percutaneous absorption of boron from consumer products through intact skin has been shown to contribute very little to the total daily intake (Wester et al., 1998). At the ninety-fifth percentile, intake of boron from the diet and supplements is approximately 2.8 mg/day. Adding to that a maxi- mum intake from water of 2 mg/day gives a total intake of less than 5 mg/day boron at this percentile. Risk Characterization At the ninety-fifth percentile intake, no segment of the U.S. popu- lation has a total (dietary, water, and supplemental) intake of boron greater than 5 mg/day (Appendix Tables C-13 and D-1). Those taking body-building supplements could consume an additional 1.5 to 20 mg/day (Moore, 1997). Therefore this supplemental intake may exceed the UL of 20 mg/day. RESEARCH RECOMMENDATIONS FOR BORON â¢ The relationship between dietary boron and vitamin D metabo- lism; specifically, does boron influence the half-life of functional vitamin D metabolites and calcium metabolism as it relates to bone mineralization? â¢ The possible influence of boron on estrogen metabolism and
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 521 function, particularly biological half-life, receptor-ligand inter- actions, and estrogen-inducible gene expression as related to bone mineral density. â¢ Studies of the possible role of boron in human neurophysio- logical and cognitive function that include delineation of a bio- chemical or other physiological basis for this function, in young as well as older populations. NICKEL BACKGROUND INFORMATION Function There have been no studies to determine the nutritional impor- tance of nickel in humans, nor has a biochemical function been clearly demonstrated for nickel in higher animals or humans (Uthus and Seaborn, 1996). Nickel may serve as a cofactor or structural component of specific metalloenzymes of various functions, includ- ing hydrolysis and redox reactions and gene expression (Andrews et al., 1988; Kim et al., 1991; Lancaster, 1988; Przybyla et al., 1992). Nickel may also serve as a cofactor facilitating ferric iron absorption or metabolism (Nielsen, 1985). Nickel is an essential trace element in animals, as demonstrated by deficiency signs reported in several species. Rats deprived of nickel exhibit retarded growth, low hemo- globin concentrations (Schnegg and Kirchgessner, 1975), and im- paired glucose metabolism (Nielsen, 1996). Nickel may interact with the vitamin B12- and folic-acid dependent pathway of methionine synthesis from homocysteine (Uthus and Poellot, 1996). Physiology of Absorption, Metabolism, and Excretion The absorption of nickel is affected by the presence of certain foods and substances including milk, coffee, tea, orange juice, and ascorbic acid. Plasma 62Ni was shown to peak between 1.5 and 2.5 hours after the ingestion of the stable isotope by four fasted, healthy men and women (Patriarca et al., 1997). The investigators reported no evidence that absorbed nickel was excreted via the gut. The percentage of nickel absorbed ranged from 29 to 40 percent. Uri- nary excretion of the 62Ni dose ranged from 51 to 82 percent of the absorbed dose. Solomons and coworkers (1982) investigated absorp- tion of nickel ingested with food and found that the presence of
522 DIETARY REFERENCE INTAKES food significantly decreased absorption. The absorption of dietary nickel is typically less than 10 percent. Nickel is transported in blood bound primarily to albumin (Tabata and Sarkar, 1992). Although most tissues and organs do not signifi- cantly accumulate nickel, in humans the thyroid and adrenal glands have relatively high nickel concentrations (132 to 141 Âµg/kg dry weight) (Rezuke et al., 1987). Most organs contain less than 50 Âµg of nickel/kg dry weight. Because of the poor absorption of nickel, the majority of ingested nickel is excreted in the feces. The majority of absorbed nickel is excreted in the urine with minor amounts excreted in sweat and bile. FINDINGS BY LIFE STAGE AND GENDER GROUP Nickel may serve as a cofactor or structural component of certain metalloenzymes and facilitate iron absorption or metabolism in microorganisms. No studies to determine the biological role of nickel in higher animals or humans have been reported. Therefore, neither an Estimated Average Requirement, Recommended Dietary Allowance, nor Adequate Intake was established for nickel. INTAKE OF NICKEL Food Sources Major contributors to nickel intake are mixed dishes and soups (19 to 30 percent), grains and grain products (12 to 30 percent), vegetables (10 to 24 percent), legumes (3 to 16 percent), and desserts (4 to 18 percent) (Pennington and Jones, 1987). In food commodity groups, nickel concentrations are highest in nuts and legumes (128 and 55 Âµg/100 g, respectively), followed by sweeteners, including chocolate milk powder and chocolate candy. Of 234 foods analyzed, 66 percent had nickel concentrations less than 10 Âµg/100 g and 91 percent had concentrations less than 40 Âµg/100 g. Seven of these foods contained greater than 100 Âµg/100 g including nuts, legumes, and items with chocolate (Pennington and Jones, 1987). Major con- tributors of nickel to the Canadian diet include meat and poultry (37 percent), bakery goods and cereals (19 percent), soups (15 percent), and vegetables (11 percent) (Dabeka and McKenzie, 1995). Nielsen and Flyvholm (1983) suggested that nickel intakes in Denmark could reach over 900 Âµg/day by the consumption of cer- tain foods based on the nickel composition and level of consump-
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 523 tion of oatmeal, legumes (including soybeans), nuts, cocoa, and chocolate. Cooking foods in stainless steel utensils can increase the nickel content if the foods are acidic (Christensen and Moller, 1978). Dietary Intake Based on the Food and Drug Administration Total Diet Study of 1984, the mean nickel consumption of infants and young children was 69 to 90 Âµg/day (Pennington and Jones, 1987). For adoles- cents, the median consumption was approximately 71 to 97 Âµg/day, and the median consumption for adults and the elderly was approx- imately 74 to 100 Âµg/day and 80 to 97 Âµg/day, respectively (Appen- dix Table E-7). On the basis of a national survey conducted in five Canadian cities from 1986 to 1988, Dabeka and McKenzie (1995) reported that average nickel consumption for children was 190 to 251 Âµg/day; for adolescents, 248 to 378 Âµg/day; and for all adults, 207 to 406 Âµg/day. At 38 days postpartum, the mean nickel concentration in human milk was reported to be 1.2 ng/mL (Casey and Neville, 1987). Based on an average secretion of 0.78 L/day (see Chapter 2), the mean secretion of nickel in human milk is approximately 1 Âµg/day. According to a report by Dabeka (1989), the average intake of nickel by 0- to 12-month-old Canadian infants was 38 Âµg/day, taking into account human milk as well as formula consumption. Intake from Supplements Information from the Third National Health and Nutrition Ex- amination Survey on supplemental use of nickel is given in Appen- dix Table C-22. The median supplemental intake for adult men and women was approximately 5 Âµg/day. Therefore, adults consume ap- proximately 79 to 105 Âµg/day of nickel from diet and supplements. TOLERABLE UPPER INTAKE LEVELS The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, in- take above the UL may be appropriate for investigation within well- controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials
524 DIETARY REFERENCE INTAKES have signed informed consent documents regarding possible toxic- ity and as long as these trials employ appropriate safety monitoring of trial subjects. In addition, the UL is not meant to apply to indi- viduals who are receiving nickel under medical supervision. Hazard Identification Adverse Effects There is no evidence in humans of adverse effects associated with exposure to nickel through consumption of a normal diet. The UL derived here applies to excess nickel intake as soluble nickel salts. Human Data. A few case reports have documented the acute effects of the ingestion of high doses of soluble nickel salts. Twenty workers who accidentally ingested 0.5 to 2.5 g of nickel as nickel sulfate and chloride hexahydrate in contaminated water developed nausea, ab- dominal pain, diarrhea, vomiting, and shortness of breath among other symptoms (Sunderman et al., 1988). Ten of these subjects were found to have altered hematological parameters. In one other case report, one subject who ingested approximately 50 Âµg/kg of nickel as nickel sulfate in water was reported to have developed transient hemianopsia at the time of peak serum concentrations (Sunderman et al., 1989). In persons with hypersensitivity to nickel, oral exposure has been reported to result in contact dermatitis-like symptoms (Gawkrodger et al., 1986). Animal Data. In oral subchronic (ABC, 1988) and chronic (Ambrose et al., 1976) studies with rats, exposure to soluble nickel compounds has been associated with increased mortality, clinical signs of general systemic toxicity (e.g., lethargy, ataxia, irregular breathing, hypo- thermia, and salivation), decreased body weight gains, and changes in absolute and relative organ weights (kidney, liver, spleen, and heart). Fetotoxicity associated with oral exposure to nickel chloride and nickel sulfate has been reported in two separate two-generation studies (RTI, 1988; Smith et al., 1993) and in one three-generation study (Schroeder and Mitchner, 1971). Nickel salts also have been shown to interfere with the reproductive capacity of male rats (Hoey, 1966; Laskey and Phelps, 1991; Waltschewa et al., 1972). Summary On the basis of considerations of data quality, sensitivity of the
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 525 toxicological endpoint, and relevance to human dietary exposure, general systemic toxicityâin the form of decreased body weight gain reported in the subchronic and chronic rat studies (ABC, 1988; Ambrose et al., 1976)âwas selected as the critical endpoint on which to base the derivation of the UL. Other data (e.g., hyper- sensitivity in humans and carcinogenic effects associated with inha- lation exposure) were not considered relevant to human dietary exposure. Dose-Response Assessment Adults Data Selection. A subchronic rat gavage study (ABC, 1988) and a chronic rat dietary study (Ambrose et al., 1976) were considered most suitable for establishing an UL for human dietary exposure to soluble nickel salts. Identification of a No-Observed-Adverse-Effect Level (NOAEL) and a Lowest- Observed-Adverse-Effect Level (LOAEL). A NOAEL of 5 mg/kg/day was identified for both the 90-day subchronic gavage study (ABC, 1988) and the 2-year chronic dietary study (Ambrose et al., 1976) in rats. In both cases, the NOAEL was established on the basis of decreased body weight gains and signs of systemic toxicity at higher dose levels. In the ABC (1988) study, groups of male and female CD rats were administered nickel chloride by water gavage at doses of 0, 5, 35, and 100 mg/kg/day for 3 months. On the basis of findings of de- creased body weights, mortality, and clinical signs at higher doses, 5 mg/kg/day was concluded to be the NOAEL. In the chronic study rats were administered nickel sulfate in the diet at doses of 0, 100, 1,000, or 2,500 ppm nickel (about 0, 5, 50, and 125 mg/kg/day) for a period of 2 years (Ambrose et al., 1976). Effects of treatment included reduced body weight gain in high- dose animals (125 mg/kg/day). Sporadic significant decreases in body weight gains were also recorded in the mid-dose group (50 mg/kg/day). Rats fed high- and mid-dose levels of nickel were re- ported to have significantly higher relative heart weights and lower relative liver weights. Although the study was suitable in design and conduct for use in establishing a UL for human dietary exposure to soluble nickel salts, poor survivorship in controls does raise some concern about its interpretability. The results of three reproductive studies, one three-generation study (Schroeder and Mitchener, 1971) and two two-generation
526 DIETARY REFERENCE INTAKES studies (RTI, 1988; Smith et al., 1993), suggest potential for feto- toxicity after oral exposure to soluble nickel salts. The lowest LOAEL identified by Smith and coworkers (1993) was 1.3 mg/kg/day of nickel based on the total number of dead pups and the percentage of dead pups per litter. The Schroeder and Mitchener (1971) study concluded that exposure to nickel at a concentration of 5 mg/L, or about 0.4 mg/kg body weight/day (assuming 8 ml/100 g body weight), was associated with increased neonatal death; however, these conclusions were based on the results of only five non- randomized matings and therefore were not considered valid for use in determining a LOAEL for human dietary exposure to soluble nickel salts. In fact, all of the reproduction studies either were flawed or their interpretation was hampered by their statistical design and methodological and data-reporting limitations, as well as by incon- sistencies in the reported dose-response relationships. As a result, these studies were not suitable for use in the establishment of a UL. In summary, taken together, the oral subchronic and chronic rat studies support a NOAEL of 5 mg/kg body weight/day for soluble nickel salts. The selection of this NOAEL is in agreement with the NOAEL selected in the toxicological assessment of oral nickel expo- sure performed by the U.S. Environmental Protection Agency (EPA, 2000). Uncertainty Assessment. When determining an uncertainty factor (UF) for nickel, several sources of uncertainty were selected to extrapolate from the NOAEL from the long-term rat study to the general population. The first UF of 10, which was used to extrapo- late from the rat study to humans, incorporated uncertainties about the nature of the dose-response curve for nickel toxicity and uncer- tainties about the sensitivity of rats as compared with humans in respect to nickel toxicity. The second UF of 10 was to account for potential variation within the human population, especially in re- gard to the potential for nickel to induce hypersensitivity reactions in sensitive individuals. The third UF of 3 was introduced because of concerns raised by studies on reproductive effects, namely, that nickel may be a reproductive toxin at levels lower than the NOAEL observed for the chronic rat study. These three UFs were multiplied to yield the ultimate UF of 300 that would accommodate the gener- al population including women who are pregnant or lactating. Derivation of a UL. The NOAEL of 5 mg/kg body weight/day was divided by the UF of 300 to obtain a UL of 0.017 mg/kg body weight/day for adult humans. This figure was multiplied by the
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 527 average of the reference body weights for adult women, 61 kg, from Chapter 1 (Table 1-1). The resulting UL for adults is rounded down to 1.0 mg/day. UL = NOAEL = 5 mg/kg/day = 0.017 mg/kg/day Ã 61 kg â 1.0 mg/day UF 300 Nickel UL Summary, Ages 19 years and Older UL for Adults â¥ 19 years 1.0 mg/day of soluble nickel salts Other Life Stage Groups Infants. For infants, the UL was judged not determinable because of the lack of data on adverse effects in this age group and concern about the infantâs ability to handle excess amounts. To prevent high levels of intake, the only source of intake for infants should be from food and formula. Children and Adolescents. There are no reports of nickel toxicity in children and adolescents. The UL values for children and adoles- cents were extrapolated from those established for adults. Thus, the adult UL of 1.0 mg/day of soluble nickel salts was adjusted for children and adolescents on the basis of relative body weight as described in Chapter 2 using reference weights from Chapter 1 (Table 1-1). Pregnancy and Lactation. No data were found that could be used to identify a NOAEL or LOAEL and derive a UL for pregnant and lactating women. Therefore, the ULs for pregnant and lactating women are the same as for the nonpregnant and nonlactating women. Nickel UL Summary, Ages 0 through 18 Years, Pregnancy, Lactation UL for Infants 0â12 months Not possible to establish; source of intake should be from food and formula only
528 DIETARY REFERENCE INTAKES UL for Children 1â3 years 0.2 mg/day of soluble nickel salts 4â8 years 0.3 mg/day of soluble nickel salts 9â13 years 0.6 mg/day of soluble nickel salts UL for Adolescents 14â18 years 1.0 mg/day of soluble nickel salts UL for Pregnancy 14â18 years 1.0 mg/day of soluble nickel salts 19â50 years 1.0 mg/day of soluble nickel salts UL for Lactation 14â18 years 1.0 mg/day of soluble nickel salts 19â50 years 1.0 mg/day of soluble nickel salts Special Considerations Individuals with preexisting nickel hypersensitivity (from previous dermal exposure) and kidney dysfunction are distinctly susceptible to the adverse effects of excess nickel intake (Gawkrodger et al., 1986). These individuals may not be protected by the UL for nickel intake for the general population. Intake Assessment Based on the Food and Drug Administration Total Diet Study (Appendix Table E-7), 0.5 mg/day was the highest intake at the ninety-ninth percentile of nickel from food reported for any life stage and gender group; this was the reported intake for pregnant females. Nickel intake from supplements provided only 9.6 to 15 Âµg/day at the ninety-ninth percentile for all age and gender groups (Appendix Table C-22). Risk Characterization The risk of adverse effects resulting from excess intakes of nickel from food and supplements appears to be very low at the highest intakes noted above. Increased risks are likely to occur from envi- ronmental exposures or from the consumption of contaminated water.
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 529 RESEARCH RECOMMENDATIONS FOR NICKEL â¢ Identification and clear characterization of a biochemical func- tion for nickel in humans; identification of a reliable indicator of nickel status for use in future studies of nickel deficiency. â¢ Further exploration of the possible role of nickel in vitamin B12 and folate metabolism, including whether nickel nutrition should be a concern for pregnant women or people at risk for cardio- vascular disease. SILICON BACKGROUND INFORMATION Function A functional role for silicon in humans has not yet been identi- fied. In view of the distribution of silicon in the body, as well as the biochemical changes that occur in bone with a silicon deficiency, silicon appears to be involved with the formation of bone in chickens and rats (Carlisle, 1980a, 1980b, 1981; Schwarz and Milne, 1972). Silicon contributes to prolylhydrolase activity, which is im- portant for collagen formation (Carlisle, 1984). Chicks fed a silicon- deficient diet exhibited structural abnormalities of the skull and long-bone (Carlisle, 1984). Rats deprived of silicon showed decreased bone hydroxyproline and alkaline and acid phosphatases (Seaborn and Nielsen, 1993, 1994). Silicon has been suggested to have a pre- ventive role in atherogenesis (Mancinella, 1991). Physiology of Absorption, Metabolism, and Excretion Findings that as much as 50 percent of ingested silicon is excreted in the urine (Kelsay et al., 1979) suggest that some dietary forms of silicon are well absorbed. Silicon in blood exists almost entirely as silicic acid and is not bound to proteins. Various connective tissues including the aorta, trachea, bone, tendons, and skin contain most of the silicon present in the body (Carlisle, 1984). Significantly higher serum silicon concentrations were seen in patients with chronic renal failure (46 Âµmol/L) compared to controls (21 Âµmol/ L) (Dobbie and Smith, 1986). In a study by Popplewell et al. (1998), 48 hours after ingestion of 32Si, 36 percent of the dose was excreted in the urine and elimina- tion appeared to be complete. This study, however, did not elimi-
530 DIETARY REFERENCE INTAKES nate the possibility of longer-term retention of additional 32Si. Goldwater (1936) reported daily silicon excretion levels for five sub- jects averaging 10 mg/day and ranging from 5 to 17 mg/day. Kelsay and coworkers (1979) studied 11 men fed low- and high-fiber diets and found their urinary silicon excretion to be 12 and 16 mg/day, respectively, amounts which were not significantly different. FINDINGS BY LIFE STAGE AND GENDER GROUP Silicon appears to be involved in the formation of collagen and bone in animals. A biological role of silicon in humans has not yet been identified. Therefore, neither an Estimated Average Require- ment, Recommended Dietary Allowance, nor Adequate Intake was established for silicon. INTAKE OF SILICON Food Sources Concentrations of silicon are higher in plant-based foods than in animal-derived food products. Based on the Food and Drug Admin- istration Total Diet Study, beverages, including beer, coffee, and water, are the major contributors of silicon (55 percent), followed by grains and grain products (14 percent), and vegetables (8 per- cent) (Pennington, 1991). Refining reduces the silicon content in foods. Silicate additives that have been increasingly used as anti- foaming and anticaking agents can raise the silicon content in foods; however, the bioavailability of these additives is low. Dietary Intake Based on the Total Diet Study, the mean intakes of silicon in adult men and women were 40 and 19 mg/day, respectively (Pennington, 1991). Appendix Table E-8 indicates that the daily median intakes of silicon for adult men and women ranged from approximately 14 to 21 mg/day. Kelsay and coworkers (1979) found intakes of 46 mg/day from a high-fiber diet and 21 mg/day from a low-fiber diet. The mean concentration of silicon in human milk was reported to be 0.47 mg/L in women up to 5 months postpartum (Anderson, 1992). Based on the mean secretion of 0.78 L of human milk per day (Chapter 2), the mean intake of silicon by infants receiving human milk is approximately 0.37 mg/day.
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 531 Intake from Supplements Information from the Third National Health and Nutrition Examination Survey on supplement use of silicon is provided in Appendix Table C-23. The median intake of supplemental silicon by adults was approximately 2 mg/day. TOLERABLE UPPER INTAKE LEVELS The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, in- take above the UL may be appropriate for investigation within well- controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxic- ity and as long as these trials employ appropriate safety monitoring of trial subjects. Hazard Identification There is no evidence that silicon that occurs naturally in food and water produces adverse health effects. Limited reports indicate that magnesium trisilicate (6.5 mg of elemental silicon per tablet) when used as an antacid in large amounts for long periods (i.e., several years) may be associated with the development of urolithiasis due to the formation, in vivo, of silicon-containing stones (Haddad and Kouyoumdjian, 1986). Less than 30 cases of urolithiasis reported to be associated with intake of silicates (in the form of antacids) could be found even though antacids containing silicon have been sold since the 1930s. Takizawa and coworkers (1988) examined the carcinogenicity of amorphous silica (SiO2) given by the oral route to rats and mice for approximately 2 years. There was no evidence that orally adminis- tered silica induced tumors. Dose-Response Assessment There are no adequate data demonstrating a no-observed-adverse- effect level (NOAEL) for silicon. Apart from scattered reports of silicate-induced urolithiasis, said to be associated with antacids, the limited toxicity data on silicon suggest that typical levels of intake
532 DIETARY REFERENCE INTAKES have no risk of inducing adverse effects for the general population. Due to lack of data indicating adverse effects of silicon, it is not possible to establish a UL. RESEARCH RECOMMENDATIONS FOR SILICON â¢ The physiological role of silicon and how this role relates to human health. â¢ The possible role of silicon in atherosclerosis and hypertension, several bone disorders, Alzheimerâs disease, and other conditions common to the elderly because of the prevalence and cost of these disorders. â¢ The determination of a reliable indicator of silicon status. VANADIUM BACKGROUND INFORMATION Function A functional role for vanadium in higher animals and humans has not yet been identified. Vanadium mimics insulin and stimulates cell proliferation and differentiation (Heyliger et al., 1985; Nielsen and Uthus, 1990). Vanadium inhibits various ATPases, phosphatases, and phosphoryl-transfer enzymes (Nielsen, 1985). The response of thyroid peroxidase to changing dietary iodine concentrations has been shown to be altered in vanadium-deprived rats (Uthus and Nielsen, 1990). Vanadium-deprived goats show elevated abortion rates and decreased milk production (Anke et al., 1989). In vitro, vanadium in the form of vanadate regulates hormone, glucose, and lipid metabolism; however, vanadium most probably exists in the vanadyl form in vivo (Rehder, 1991). Vanadium in the forms of vanadyl sulfate (100 mg/day) and sodium metavanadate (125 mg/day) has been used as a supplement for diabetic patients (Boden et al., 1996; Cohen et al., 1995; Goldfine et al., 1995). Although insulin requirements were decreased in pa- tients with Type I diabetes, the doses of vanadium used in the sup- plements were about 100 times the usual intakes (Pennington and Jones, 1987), and they greatly exceed the Tolerable Upper Intake Level (UL) for vanadium.
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 533 Physiology of Absorption, Metabolism, and Excretion The absorption of ingested vanadium is less than 5 percent, and therefore most ingested vanadium is found in the feces. Absorbed vanadate is converted to the vanadyl cation, which can complex with ferritin and transferrin in plasma and body fluids (Harris et al., 1984; Sabbioni et al., 1978). Highest concentrations of vanadium are found in the liver, kidney, and bone. However, very little of the absorbed vanadium is retained in the body. Patterson and coworkers (1986) investigated vanadium metabolism in sheep and suggested a compartmental model with certain tissues constituting a âslow turn- overâ pool where the turnover times for vanadium might exceed 400 days. Other tissues were suggested to constitute a âfast turn- overâ pool with vanadium residency of about 100 hours. FINDINGS BY LIFE STAGE AND GENDER GROUP In laboratory animals, vanadium mimics insulin (diminishes hyper- glycemia and improves insulin secretion) and inhibits the activity of various enzymes. A deficiency of vanadium results in increased abor- tion rates. A biological role of vanadium in humans has not yet been identified. Therefore, neither an Estimated Average Require- ment, Recommended Dietary Allowance, nor Adequate Intake was determined for vanadium. INTAKE OF VANADIUM Food Sources Foods rich in vanadium include mushrooms, shellfish, black pepper, parsley, dill seed, and certain prepared foods. Myron and coworkers (1977) reported that processed foods contained more vanadium than nonprocessed foods. Byrne and Kosta (1978) also suggested that beer and wine may contribute an appreciable amount of vana- dium to the diet. Commodity groups highest in vanadium are grains and grain products, sweeteners, and infant cereals. Analysis of data from the 1984 Food and Drug Administration Total Diet Study (Pennington and Jones, 1987) showed grains and grain products contributed 13 to 30 percent of the vanadium in adult diets. Bever- ages were also an important source for adults and elderly men (26 to 57 percent). This study also reported that 88 percent of the foods consumed had concentrations less than 2 Âµg/100 g. Canned apple
534 DIETARY REFERENCE INTAKES juice and cereals were the major contributors of vanadium to the diets of infants and toddlers. Dietary Intake Pennington and Jones (1987) reported that vanadium intake ranged from 6.5 to 11 Âµg/day for infants, children, and adolescents. The intake of vanadium for adults and the elderly ranged from 6 to 18 Âµg/day. Intake from Supplements Information from the Third National Health and Nutrition Ex- amination Survey on supplement use of vanadium is provided in Appendix Table C-24. The median intake of supplement vanadium by adults was approximately 9 Âµg/day. Vanadium in the forms of vanadyl sulfate (100 mg/day) and sodium metavanadate (125 mg/ day) has been used as a supplement for diabetic patients (Boden et al., 1996; Cohen et al., 1995; Goldfine et al., 1995). Although insulin requirements were decreased in patients with Type I diabetes, the doses of vanadium used in the supplements were about 100 times the usual intakes (Pennington and Jones, 1987), and they greatly exceed the Tolerable Upper Intake Level (UL) for vanadium. TOLERABLE UPPER INTAKE LEVELS The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals. Although members of the general population should be advised not to routinely exceed the UL, in- take above the UL may be appropriate for investigation within well- controlled clinical trials. Clinical trials of doses above the UL should not be discouraged, as long as subjects participating in these trials have signed informed consent documents regarding possible toxic- ity and as long as these trials employ appropriate safety monitoring of trial subjects. In addition, the UL is not meant to apply to indi- viduals who are receiving vanadium under medical supervision. Hazard Identification There is no evidence of adverse effects associated with vanadium intake from food, which is the major source of exposure to vanadium for the general population (Barceloux, 1999). There are data on
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 535 adverse effects associated with vanadium intake from supplements and drinking water. Because the forms found in food and supple- ments are the same (i.e., tetravalent or vanadyl [VO2+] and penta- valent or vanadate [VO3â] forms), the UL value will apply to total vanadium intake from food, water, and supplements. Most vanadium toxicity reports involve industrial exposure to high levels of airborne vanadium. The most toxic vanadium compound is vanadium pentoxide, but because vanadium pentoxide is not a normal constituent of food, supplements, or drinking water, it will not be considered in this review. Weight training athletes use up to 60 mg/day of vanadyl sulfate supplements (or 18.6 mg of elemental vanadium) to improve per- formance (Barceloux, 1999). Furthermore, because vanadium may become useful in future treatment of diabetes, there is increased concern about its long-term toxicity. Adverse Effects Acute Toxicity. Acute vanadium poisoning has not been observed in humans. Acute poisoning from sodium vanadate in rats causes desquamative enteritis, mild liver congestion with fatty changes, and slight parenchymal degeneration of the renal convoluted tubules (Daniel and Lillie, 1938). In mice, a subcutaneous dose of 20 mg/ kg of ammonium metavanadate produced acute tubular necrosis by 6 to 7 hours postinjection (Wei et al., 1982). Renal Toxicity. Evidence of renal toxicity associated with high vanadium intake in humans was not found. There is evidence of kidney effects in animals (Table 13-2). Domingo and coworkers (1985) found histopathological lesions of the kidney and increased plasma urea and uric acid concentrations in rats exposed to 50 Âµg/ mL in drinking water for 3 months. This finding suggests possible alterations in renal function. In a second study, Domingo and co- workers (1991) evaluated the toxicity of sodium metavanadate (0.15 mg/mL), sodium orthovanadate (0.23 mg/mL), and vanadyl sul- fate pentahydrate (0.31 mg/mL) solutions given to diabetic rats for 28 days. In the vanadium-treated animals, they observed decreased weight gain and increased serum concentrations of urea and creati- nine, as well as some deaths. A histopathological investigation was not performed. Boscolo and coworkers (1994) reported that the lumen of the proximal tubules was narrowed and contained amorphous material in rats fed 40 Âµg/mL of sodium metavanadate in drinking water for
536 DIETARY REFERENCE INTAKES TABLE 13-2 Animal Data on Vanadium-Induced Renal Toxicity, by Increasing Dose Dose Dose Study Species Form (Âµg/mL) (mg/kg/d) Duration Wei et al., 1982 Mouse Vanadate NDa 20 6â7 hr Boscolo et al., 1994 Rat Vanadate 1 ND â 7 mo Vanadate 10 ND â 7 mo Vanadate 40 ND â 6 mo Domingo et al., 1985 Rat Vanadate 5 0.8 3 mo Vanadate 10 1.5 3 mo Vanadate 50 7.7 b 3 mo Domingo et al., 1991 Rat Vanadate ND 6.1 1 mo Vanadate ND 15.6 1 mo Vanadyl ND 22.7 1 mo a ND = not determined. b 7.7 mg/kg/d was calculated by using average weight of growing rats of 271 g and 6 or 7 months. Hydropic degeneration was also seen in some proxi- mal and distal tubules and the loop of Henle. Because water intakes were not provided, this study could not be used to derive a dose. Acute tubular necrosis was observed in mice fed 20 mg/kg/day of ammonium metavanadate (Wei et al., 1982). The effect of supple- mental vanadium intake on renal function needs further careful study. Gastrointestinal Effects. There is human evidence of mild gastro- intestinal effects (abdominal cramps, loose stool) primarily in patients with diabetes and animal evidence of more severe gastrointestinal effects (diarrhea, death) after ingestion of vanadium compounds (Boden et al., 1996; Dimond et al., 1963; Franke and Moxon, 1937; Goldfine et al., 1995). The human data are summarized in Table 13-3. Hematological Effects. Vanadium compounds may cause anemia and changes in the leukocyte system. Animal studies of hemolytic activity of vanadium salts have conflicting results (Dai and McNeill, 1994; Dai et al., 1995; Hogan, 1990; Zaporowska and Wasilewski, 1992;
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 537 e /kg/d) Duration Results 6â7 hr Acute tubular necrosis â 7 mo No effects â 7 mo Effects on kidney morphology (less evident) â 6 mo Effects on kidney morphology 3 mo No effects 3 mo Vanadium detected in kidneys b 3 mo Increased uric acid and urea; vanadium detected in kidneys 1 mo Increased serum urea and creatinine 1 mo Increased serum urea, but not creatinine 1 mo Increased serum urea and creatinine average drinking water consumption of 42 mL/day. 50 Âµg/mL Ã 42 mL/d Ã 1/0.27/kg body weight Ã 1 mg/1,000 Âµg = 7.7 mg/kg/day. Zaporowska et al., 1993). Fawcett and coworkers (1997) showed no effects of oral vanadyl sulfate (0.5 mg/kg body weight/day) on hematological indexes, blood viscosity, and biochemistry in a 12- week, double-blind, placebo-controlled trial in 31 athletes. Cardiovascular Effects. Exposure to vanadate induced an increase in blood pressure and heart rate in rats (Carmignani et al., 1991; Steffen et al., 1981). Boscolo and coworkers (1994) showed an in- crease in arterial blood pressure following chronic exposure of rats to 1, 10, and 40 Âµg/mL of vanadium for 6 or 7 months. These changes were not dose-dependent. Reproductive Effects. No evidence of reproductive abnormalities after ingestion in humans was found. Two animal studies evaluating the reproductive toxicity of vanadium have been reported: in one, Llobet and coworkers (1993) observed that at 60 and 80 mg/kg body weight/day, a significant decrease in pregnancy rate occurred; in the other, Domingo and coworkers (1986) found no effects on fertility or reproduction in rats gavaged up to 20 mg/kg body weight/day with sodium metavanadate.
538 DIETARY REFERENCE INTAKES TABLE 13-3 Human Data on Vanadium-Induced Gastrointestinal Effect, by Increasing Dose Doseb Dosec Studya Subjects Form (mg V/d) (mg/kg/d) Duration Dimond et al., 1963 6 adults Vanadyl 5 0.07 6â10 wk 10 0.15 15 0.2 20 0.3 Cohen et al., 1995 6 adults Vanadyl 31 0.5 3 wk Boden et al., 1996 8 adults Vanadyl 31 0.5 4 wk Goldfine et al., 1995 10 adults Vanadate 52 0.8 2 wk a Dimond was uncontrolled; Cohen, Boden, and Goldfine were noninsulin-dependent diabetics. b mg vanadium (V)/d was calculated as follows: For Dimond, mg V/d = 51 (molecular weight of V) Ã· 250 (molecular weight of ammonium vanadyl tartrate [i.e., 150 for tartaric acid minus 1 for H = 149 for tartrate + 101 for ammonium vanadyl, i.e., 117 for ammonium vanadate minus 16 for oxygen = 250]) = 0.20 Ã 25 mg/d (amount of Other Adverse Effects. Other adverse effects associated with vanadium intake in humans include green tongue, fatigue, lethargy, and focal neurological lesions (Barceloux, 1999). These effects, however, have not been consistently observed or dose-related. No studies were found evaluating the genotoxicity in humans or animals after inges- tion of vanadium, and no evidence was found showing carcinoge- nicity of vanadium compounds in animals or humans. The U.S. Environmental Protection Agency recently set an oral reference dose of 0.009 mg/kg/day for vanadium pentoxide based on de- creased hair cystine content. This finding is from a chronic oral rat study described by Stokinger (1981). Because it is not clear that reduced hair cystine is an adverse effect, data on reduced hair cystine were judged not relevant to the derivation of a UL for ele- mental vanadium. Summary On the basis of the quality and completeness of the database and the strength of the causal association, renal toxicity was selected as the critical adverse effect on which to base a UL. The data on other
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 539 ec /kg/d) Duration Result 6â10 wk Cramping, diarrhea, black loose stools â¥ 20 mg/d 3 wk Mild gastrointestinal effects 4 wk Mild gastrointestinal effects 2 wk Mild gastrointestinal effects compound given by Dimond) = 5 mg/d. For Cohen and Boden, mg V/d = 51 Ã· 163 (molecular weight of vanadyl sulfate) = 0.31 Ã 100 mg/d (amount of compound given by Cohen and Boden) = 31 mg/d. For Goldfine, mg V/day = 51 Ã· 122 (molecular weight for NaVO3) = 0.42 Ã 125 (amount of compound given by Goldfine) = 52 mg/d. c Body weight used was the average of the reference weights for adult men and women (76 and 61 kg, respectively). effects such as hematological, cardiovascular, or reproductive effects are not consistent. While gastrointestinal effects appear to occur at lower doses in humans, the specificity of the observed effects and the dose-response relationship are not as clearly defined as the histo- pathological lesions and adverse kidney effects demonstrated in ani- mals. While kidney effects have not been demonstrated in humans, excess vanadium has been shown in rats to accumulate in kidneys (Oster et al., 1993), and the evidence in different species (i.e., mice and rats) further supports a possible risk in humans. Because of the widespread use of high-dose (60 mg/day) supplemental vanadium by athletes and other subgroups (e.g., borderline diabetics) that are considered part of the apparently healthy general population (Barceloux, 1999), further research on vanadium toxicity is needed. Dose-Response Assessment Adults Data Selection. The data in laboratory rats involving subchronic to chronic durations of intake were used to derive a UL. Studies that
540 DIETARY REFERENCE INTAKES provided doses in units of concentration but provided no informa- tion on the body weights of the rats or the amount of water con- sumed were not used. Identification of a No-Observed-Adverse-Effects Level (NOAEL) or Lowest- Observed-Adverse-Effects Level (LOAEL). A NOAEL of 0.8 mg/kg body weight/day and a LOAEL of 7.7 mg/kg body weight/day were de- termined on the basis of the results of Domingo and coworkers (1985). Vanadium could not be detected in the kidneys of animals receiving 5 Âµg/mL (or 0.8 mg/kg/day) (Table 13-2). Also, plasma urea, uric acid, and creatinine concentrations were within the nor- mal range in this treatment group (Domingo et al., 1985). How- ever, the study does not indicate whether there were kidney lesions at this level; therefore, whether this is a true NOAEL value for this study is uncertain. The same can be said for the treatment group given 10 Âµg/mL (or 1.5 mg/kg/day). The study does not provide enough detail about the findings at this dose level to ascertain whether it is a NOAEL or LOAEL. The value of 7.7 mg/kg/day is the best estimate of a LOAEL from this data set. At this dose, there were evident lesions of the kidney and small, but significant, increases in plasma urea and uric acid. Furthermore, this LOAEL appears to be consistent with other stud- ies (Boscolo et al., 1994; Domingo et al., 1991). Boscolo and co- workers (1994) failed to provide information on intakes (mg/kg/ day), and therefore the study was judged not useful for deriving a UL. Nevertheless, both Domingo and coworkers (1991) and Boscolo and coworkers (1994) showed a similar dose-response relationship. The study by Domingo and coworkers (1991) in diabetic rats pro- vides results that are fairly consistent with their earlier study (Domingo et al., 1985). Although Domingo and coworkers (1991) tested different compounds of vanadium and used a shorter dura- tion, they observed increased serum urea and creatinine concentra- tions at similar doses (6.1 and 22.7 mg/kg/day). Uncertainty Assessment. In determining an uncertainty factor (UF) for vanadium, several sources of uncertainty were considered and combined into the final UF. The severity of kidney lesions justifies a UF higher than 1, and so a UF of 3 was selected to extrapolate from the LOAEL to the NOAEL. A UF of 10 was selected to extrapolate from laboratory animals to humans because no human and little animal data were available to use in the dose-response assessment. Another UF of 10 was selected for intraspecies variability. The three
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 541 UFs are multiplied to yield an overall UF of 300 to extrapolate from the LOAEL in animals to derive a UL in humans. Derivation of a UL. The LOAEL of 7.7 mg/kg/day was divided by a UF of 300 to obtain a UL of 0.026 mg/kg/day or 26 Âµg/kg/day for adult humans. This value was rounded and multiplied by the aver- age of the reference body weights for adult men and women, 68.5 kg, from Chapter 1 (Table 1-1). The resulting UL for adults is 1.78 mg/day (which was rounded to 1.8 mg/day). UL = LOAEL = 7.7 mg/kg/day = 26 Âµg/kg/day Ã 68.5 kg â 1.8 mg/day UF 300 Vanadium UL Summary, Ages 19 Years and Older UL for Adults â¥ 19 years 1.8 mg/day of elemental vanadium Other Life Stage Groups Given the severity of the critical effect for vanadium in adults, the lack of data on vanadium toxicity in other more sensitive life stage groups is of particular concern. Due to this lack of data, it was not possible to determine ULs for pregnant and lactating women, chil- dren, and infants. These individuals should be particularly cautious about consuming vanadium supplements. As indicated above, more research is needed on the renal effects of vanadium intake, particu- larly in these sensitive subgroups. Vanadium UL Summary, Ages 0 through 18 Years, Pregnancy, Lactation UL for Infants 0â12 months Not possible to establish; source of intake should be from food and formula only UL for Children 1â3 years Not possible to establish; source of intake should be from food only 4â8 years Not possible to establish; source of intake should be from food only 9â13 years Not possible to establish; source of intake should be from food only
542 DIETARY REFERENCE INTAKES UL for Adolescents 14â18 years Not possible to establish; source of intake should be from food only UL for Pregnancy 14â18 years Not possible to establish; source of intake should be from food only 19â50 years Not possible to establish; source of intake should be from food only UL for Lactation 14â18 years Not possible to establish; source of intake should be from food only 19â50 years Not possible to establish; source of intake should be from food only Special Considerations A review of the literature revealed no special subpopulations that are distinctly susceptible to the adverse effects of high vanadium intake. Intake Assessment Although percentile data are not available for dietary vanadium intakes from U.S. surveys, the highest mean intake of vanadium reported for the U.S. population was 18 Âµg/day (Pennington and Jones, 1987). The average intake of supplemental vanadium at the ninety-ninth percentile by adults was 20 Âµg/day, which is signifi- cantly lower than the adult UL for vanadium. Risk Characterization The risk of adverse effects resulting from excess intake of vanadium from food is very unlikely. Because of the high doses of vanadium present in some supplements, increased risks are likely to result from the chronic consumption of supplements containing large doses of vanadium. Currently, doses of vanadium greater than the UL are being tested for their benefits in treating diabetics. The UL is not meant to apply to individuals who are being treated with vanadium under close medical supervision.
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 543 RESEARCH RECOMMENDATIONS FOR VANADIUM â¢ Determination of the biochemical role of vanadium in both higher animals and humans and a reliable status indicator of vana- dium for further work in humans. â¢ The efficacy and safety of the use of vanadium as a nutritional supplement. REFERENCES ABC (American Biogenics Corporation). 1988. Ninety Day Gavage Study in Albino Rats Using Nickel. Study 410-2520. Final report submitted to the U.S. Environ- mental Protection Agency, Office of Solid Waste, by Research Triangle Insti- tute and American Biogenics Corporation under contract 68-01-7075. Adams MA, Bolger PM, Gunderson EL. 1994. Dietary intake and hazards of arsenic. In: Chappell WR, Abernathy CO, Cothern CR, eds. Arsenic: Exposure and Health. Northwood, UK: Science and Technology Letters. Pp. 41â49. Allen HE, Halley-Henderson MA, Hass CN. 1989. Chemical composition of bottled mineral water. Arch Environ Health 44:102â116. Ambrose AM, Larson PS, Borzelleca JF, Hennigar GR. 1976. Long term toxicologic assessment of nickel in rats and dogs. J Food Sci Technol 13:181â187. Anderson DL, Cunningham WC, Lindstrom TR. 1994. Concentrations and intakes of H, B, S, K, Na, Cl, and NaCl in foods. J Food Comp Anal 7:59â82. Anderson RR. 1992. Comparison of trace elements in milk of four species. J Dairy Sci 75:3050â3055. Andrews RK, Blakeley RL, Zerner B. 1988. Nickel in proteins and enzymes. In: Sigel H, Sigel A, eds. Metal Ions in Biological Systems, Vol. 23. New York: Marcel Dekker. Pp. 165â284. Anke M. 1986. Arsenic. In: Mertz W, ed. Trace Elements in Human and Animal Nutri- tion, Vol. 2, 5th ed. Orlando, FL: Academic Press. Pp. 347â372. Anke M, Groppel B, Gruhn K, Langer M, Arnhold W. 1989. The essentiality of vanadium for animals. In: Anke M, Bauman W, Braunlich H, eds. 6th Inter- national Trace Element Symposium, Vol. 1. Jena, Germany: Friedrich-Schiller- Universitat. Pp. 17â27. Aposhian HV. 1997. Enzymatic methylation of arsenic species and other new approaches to arsenic toxicity. Annu Rev Pharmacol Toxicol 37:397â419. Armstrong CW, Stroube RB, Rubio T, Siudyla EA, Miller GB Jr. 1984. Outbreak of fatal arsenic poisoning caused by contaminated drinking water. Arch Environ Health 39:276â279. ATSDR (Agency for Toxic Substances and Disease Registry). 1992. Toxicological Profile for Boron. Atlanta: U.S. Public Health Service, ATSDR. ATSDR. 1998. Toxicological Profile for Arsenic. Atlanta: U.S. Public Health Service, ATSDR. Bakken N. 1995. Dietary Boron Modifies the Effects of Vitamin D Nutriture on Energy Metabolism and Bone Morphology in the Chick. Masters of Science thesis, University of North Dakota, Grand Forks. Barceloux DG. 1999. Vanadium. J Toxicol Clin Toxicol 37:265â278. Baxley MN, Hood RD, Vedel GC, Harrison WP, Szczech GM. 1981. Prenatal toxicity of orally administered sodium arsenite in mice. Bull Environ Contam Toxicol 26:749â756.
544 DIETARY REFERENCE INTAKES Beaudoin AR. 1974. Teratogenicity of sodium arsenate in rats. Teratology 10:153â 157. Becking GC, Chen BH. 1998. International Programme on Chemical Safety (IPCS) environmental health criteria on boron human health risk assessment. Biol Trace Elem Res 66:439â452. Boden G, Chen X, Ruiz J, van Rossum GD, Turco S. 1996. Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non-insulin-dependent diabetes mellitus. Metabolism 45:1130â1135. Boscolo P, Carmignani M, Volpe AR, Felaco M, Del Rosso G, Porcelli G, Giuliano G. 1994. Renal toxicity and arterial hypertension in rats chronically exposed to vanadate. Occup Environ Med 51:500â503. Byrne AR, Kosta L. 1978. Vanadium in foods and in human body fluids and tissues. Sci Total Environ 10:17â30. Byrne AR, Kosta L, Dermelj M, Tusek-Znidaric M. 1983. Aspects of some trace elements in human milk. In: Bratter P, Schramel P, eds. Trace Element Analytical Chemistry in Medicine and Biology, Vol. 2. Berlin: Walter de Gruyter. Pp. 21â35. Byron WR, Bierbower GW, Brouwer JB, Hansen WH. 1967. Pathologic changes in rats and dogs from two-year feeding of sodium arsenite or sodium arsenate. Toxicol Appl Pharmacol 10:132â147. Carlisle EM. 1980a. A silicon requirement for normal skull formation in chicks. J Nutr 110:352â359. Carlisle EM. 1980b. Biochemical and morphological changes associated with long bone abnormalities in silicon deficiency. J Nutr 110:1046â1055. Carlisle EM. 1981. Silicon: A requirement in bone formation independent of vita- min D1. Calcif Tissue Int 33:27â34. Carlisle EM. 1984. Silicon. In: Frieden E, ed, Biochemistry of the Essential Ultratrace Elements. New York: Plenum Press. Pp. 257â291. Carmignani M, Boscolo P, Volpe AR, Togna G, Masciocco L, Preziosi P. 1991. Cardiovascular system and kidney as specific targets of chronic exposure to vanadate in the rat: Functional and morphological findings. Arch Toxicol Suppl 14:124â127. Casey CE, Neville MC. 1987. Studies in human lactation 3: Molybdenum and nickel in human milk during the first month of lactation. Am J Clin Nutr 45:921â926. Chan PC, Huff J. 1997. Arsenic carcinogenesis in animals and in humans: Mecha- nistic, experimental, and epidemiological evidence. J Environ Sci Health C15:83â122. Chappell WR, Beck BD, Brown KG, Chaney R, Cothern CR, Irgolic KJ, North DW, Thornton I, Tsongas TA. 1997. Inorganic arsenic: A need and an opportunity to improve risk assessment. Environ Health Perspect 105:1060â1067. Chen CJ, Chen CW, Wu MM, Kuo TL. 1992. Cancer potential in liver, lung, blad- der and kidney due to ingested inorganic arsenic in drinking water. Br J Cancer 66:888â892. Christensen OB, Moller H. 1978. Release of nickel from cooking utensils. Contact Dermatitis 4:343â346. Civantos DP, Lopez Rodriguez A, Aguado-Borruey JM, Narvaez JA. 1995. Fulmi- nant malignant arrythmia and multiorgan failure in acute arsenic poisoning. Chest 108:1774â1775. Cohen N, Halberstam M, Shlimovich P, Chang CJ, Shamoon H, Rossetti L. 1995. Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in pa- tients with non-insulin-dependent diabetes mellitus. J Clin Invest 95:2501â2509.
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 545 Culver BD, Hubbard SA. 1996. Inorganic boron health effects in humans: An aid to risk assessment and clinical judgment. J Trace Elem Exp Med 9:175â184. Dabeka RW. 1989. Survey of lead, cadmium, cobalt and nickel in infant formulas and evaporated milks and estimation of dietary intakes of the elements by infants 0â12 months old. Sci Total Environ 89:279â289. Dabeka RW, McKenzie AD. 1995. Survey of lead, cadmium, fluoride, nickel, and cobalt in food composites and estimation of dietary intakes of these elements by Canadians in 1986â1988. J AOAC Int 78:897â909. Dabeka RW, McKenzie AD, Lacroix GM, Cleroux C, Bowe S, Graham RA, Conach- er HB, Verdier P. 1993. Survey of arsenic in total diet food composites and estimation of the dietary intake of arsenic by Canadian adults and children. J AOAC Int 76:14â25. Dai S, McNeill JH. 1994. One-year treatment of non-diabetic and streptozotocin- diabetic rats with vanadyl sulphate did not alter blood pressure or haemato- logical indices. Pharmacol Toxicol 74:110â115. Dai S, Vera E, McNeill JH. 1995. Lack of haematological effect of oral vanadium treatment in rats. Pharmacol Toxicol 76:263â268. Daniel EP, Lillie RD. 1938. Experimental vanadium poisoning in the white rat. Public Health Rep 53:765â777. Dang HS, Jaiswal DD, Somasundaram S. 1983. Distribution of arsenic in human tissues and milk. Sci Total Environ 29:171â175. da Silva FJ, Williams RJ. 1991. The Biological Chemistry of the Elements: The Inorganic Chemistry of Life. Oxford: Clarendon Press. Pp. 58â63. Desrosiers R, Tanguay RM. 1986. Further characterization of the posttranslational modifications of core histones in response to heat and arsenite stress in Drosophila. Biochem Cell Biol 64:750â757. Dieter MP. 1994. Toxicity and carcinogenicity studies of boric acid in male and female B6C3F1 mice. Environ Health Perspect Suppl 102:93â97. Dimond EG, Caravaca J, Benchimol A. 1963. Vanadium: Excretion, toxicity, lipid effect in man. Am J Clin Nutr 12:49â53. Dobbie JW, Smith MB. 1986. Urinary and serum silicon in normal and uraemic individuals. Ciba Found Symp 121:194â213. Domingo JL, Llobet JM, Tomas JM, Corbella J. 1985. Short-term toxicity studies of vanadium in rats. J Appl Toxicol 5:418â421. Domingo JL, Paternain JL, Llobet JM, Corbella J. 1986. Effects of vanadium on reproduction, gestation, parturition and lactation in rats upon oral adminis- tration. Life Sci 39:819â824. Domingo JL, Gomez M, Llobet JM, Corbella J, Keen CL. 1991. Oral vanadium administration to streptozotocin-diabetic rats has marked negative side-effects which are independent of the form of vanadium used. Toxicology 66:279â287. Dourson M, Maier A, Meek B, Renwick A, Ohanian E, Poirier K. 1998. Boron tolerable intake: Re-evaluation of toxicokinetics for data-derived uncertainty factors. Biol Trace Elem Res 66:453â463. Eckhert CD. 1998. Boron stimulates embryonic trout growth. J Nutr 128:2488â 2493. Engel RR, Receveur O. 1993. Re: âArsenic ingestion and internal cancers: A re- viewâ. Am J Epidemiol 138:896â897. EPA (Environmental Protection Agency). 1975. Water programs: National interim primary drinking water regulations. Fed Register 40:59566. EPA. 1987. Health Effects Assessment for Boron and Compounds. EPA/600/8-88/021. Cincinnati, OH: EPA.
546 DIETARY REFERENCE INTAKES EPA. 1988. Special Report on Ingested Inorganic Arsenic: Skin Cancer; Nutritional Essentiality. EPA 625/3-87/013. Washington, DC: EPA. EPA. 2000. Integrated Risk Information System Database. United States Environmental Protection Agency. [Online.] Available: http://www.epa.gov/iris/subst/ 0271.htm [accessed November 10, 2000]. EPA. 2000. National primary drinking water regulations; Arsenic and clarifications to compliance and new source contaminants monitoring; Proposed rule. Fed Register 65:38887â38983. Fail PA, George JD, Grizzle TB, Heindel JJ, Chapin RE. 1990. Final Report on the Reproductive Toxicity of Boric Acid (CAS No. 10043-35-3) in CD-1 Swiss Mice. Research Triangle Park, NC: Department of Health and Human Services, National Toxicology Program. Fail PA, George JD, Seely JC, Grizzle TB, Heindel JJ. 1991. Reproductive toxicity of boric acid in Swiss (CD-1) mice: Assessment using the continuous breeding protocol. Fundam Appl Toxicol 17:225â239. Fawcett JP, Farquhar SJ, Thou T, Shand BI. 1997. Oral vanadyl sulphate does not affect blood cells, viscosity or biochemistry in humans. Pharmacol Toxicol 80:202â206. Fincher RM, Koerker RM. 1987. Long-term survival in acute arsenic encephalopa- thy. Follow-up using newer measures of electrophysiologic parameters. Am J Med 82:549â552. Fort DJ, Propst TL, Stover EL, Strong PL, Murray FJ. 1998. Adverse reproductive and developmental effects in Xenopus from insufficient boron. Biol Trace Elem Res 66:237â259. Fort DJ, Stover EL, Strong PL, Murray FJ, Keen CL. 1999. Chronic feeding of a low boron diet adversely affects reproduction and development in Xenopus laevis. J Nutr 129:2055â2060. Franke KW, Moxon AL. 1937. The toxicity of orally ingested arsenic, selenium, tellurium, vanadium and molybdenum. J Pharmacol Exp Ther 61:89â102. Franzblau A, Lilis R. 1989. Acute arsenic intoxication from environmental arsenic exposure. Arch Environ Health 44:385â390. Gartrell MJ, Craun JC, Podrebarac DS, Gunderson EL. 1985. Pesticides, selected elements, and other chemicals in adult total diet samples, October 1978âSep- tember 1979. J Assoc Off Anal Chem 68:862â875. Gawkrodger DJ, Cook SW, Fell GS, Hunter JAA. 1986. Nickel dermatitis: The reac- tion to oral nickel challenge. Br J Dermatol 115:33â38. Goering PL, Aposhian HV, Mass MJ, Cebrian M, Beck BD, Waalkes MP. 1999. The enigma of arsenic carcinogenesis: Role of metabolism. Toxicol Sci 49:5â14. Goldfine AB, Simonson DC, Folli F, Patti ME, Kahn CR. 1995. In vivo and in vitro studies of vanadate in human and rodent diabetes mellitus. Molec Cell Biochem 153:217â231. Goldwater LJ. 1936. The urinary excretion of silica in non-silicotic humans. J Ind Hyg Toxicol 18:163â166. Gordon AS, Prichard JS, Freedman MH. 1973. Seizure disorders and anemia asso- ciated with chronic borax intoxication. Can Med Assoc J 108:719â721. Grantham DA, Jones JF. 1977. Arsenic contamination of water wells in Nova Scotia. J Am Water Works Assoc 69:653â657. Green GH, Lott MD, Weeth HJ. 1973. Effects of boron water on rats. Proc West Sect Am Soc Anim Sci 24:254â258.
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 547 Grimanis AP, Vassilaki-Grimani M, Alexiou D, Papadatos C. 1979. Determination of seven trace elements in human milk, powdered cowâs milk and infant foods by neutron activation analysis. In: Byrne AR, Kosta L, Ravnik V, Stupar J, Hudnik V, eds. Nuclear Activation Techniques in the Life Sciences 1978. Vienna: International Atomic Energy Agency. Pp. 241â253. Gunderson EL. 1995. FDA Total Diet Study, July 1986âApril 1991, dietary intakes of pesticides, selected elements, and other chemicals. J AOAC Int 78:1353â 1363. Haddad FS, Kouyoumdjian A. 1986. Silica stones in humans. Urol Int 41:70â76. Harris WR, Friedman SB, Silberman D. 1984. Behavior of vanadate and vanadyl ion in canine blood. J Inorg Biochem 20:157â169. Hei TK, Liu SX, Waldren C. 1998. Mutagenicity of arsenic in mammalian cells: Role of reactive oxygen species. Proc Natl Acad Sci USA 95:8103â8107. Heindel JJ, Price CJ, Field EA, Marr MC, Myers CB, Morrissey RE, Schwetz BA. 1992. Developmental toxicity of boric acid in mice and rats. Fundam Appl Toxicol 18:266â277. Heyliger CE, Tahiliani AG, McNeill JH. 1985. Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats. Science 227:1474â 1477. Hoey MJ. 1966. The effects of metallic salts on the histology and functioning of the rat testis. J Reprod Fertil 12:461â471. Hogan GR. 1990. Peripheral erythrocyte levels, hemolysis and three vanadium com- pounds. Experientia 46:444â446. Hood RD. 1972. Effects of sodium arsenite on fetal development. Bull Environ Contam Toxicol 7:216â222. Hood RD, Bishop SL. 1972. Teratogenic effects of sodium arsenate in mice. Arch Environ Health 24:62â65. Hood RD, Harrison WP. 1982. Effects of prenatal arsenite exposure in the ham- ster. Bull Environ Contam Toxicol 29:671â678. Hopenhayn-Rich C, Smith AH, Goeden HM. 1993. Human studies do not support the methylation threshold hypothesis for the toxicity of inorganic arsenic. Environ Res 60:161â177. Hopenhayn-Rich C, Biggs ML, Fuchs A, Bergoglio R, Tello EE, Nicolli H, Smith AH. 1996. Bladder cancer mortality associated with arsenic in drinking water in Argentina. Epidemiology 7:117â124. Huang YZ, Qian XC, Wang GQ, Xiao BY, Ren DD, Feng ZY, Wu JY, Xu RJ, Zhang FE. 1985. Endemic chronic arsenism in Xinjiang. Chin Med J 98:219â222. Hunt CD. 1996. Biochemical effects of physiological amounts of dietary boron. J Trace Elem Exp Med 9:185â213. Hunt CD. 1998. Regulation of enzymatic activity. One possible role of dietary bo- ron in higher animals and humans. Biol Trace Elem Res 66:205â225. Hunt CD, Stoecker BJ. 1996. Deliberations and evaluations of the approaches, endpoints and paradigms for boron, chromium and fluoride dietary recom- mendations. J Nutr 126:2441Sâ2451S. Hunt CD, Shuler TR, Mullen LM. 1991. Concentration of boron and other ele- ments in human foods and personal-care products. J Am Diet Assoc 91:558â568. IARC (International Agency for Research on Cancer). 1980. Some Metals and Metal- lic Compounds. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 23. Lyon, France: IARC.
548 DIETARY REFERENCE INTAKES IARC. 1987. Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Supplement 7. Lyon, France: IARC. IPCS (International Programme on Chemical Safety). 1998. Environmental Health Criteria: 204: Boron. Geneva: World Health Organization. Jansen JA, Andersen J, Schou JS. 1984a. Boric acid single dose pharmacokinetics after intravenous administration to man. Arch Toxicol 55:64â67. Jansen JA, Schou JS, Aggerbeck A. 1984b. Gastro-intestinal absorption and in vitro release of boric acid from water-emulsifying ointments. Food Chem Toxicol 22:49â53. Kanematsu N, Hara M, Kada T. 1980. Rec assay and mutagenicity studies on metal compounds. Mutat Res 77:109â116. Kelsay JL, Behall KM, Prather ES. 1979. Effect of fiber from fruits and vegetables on metabolic responses of human subjects. II. Calcium, magnesium, iron and silicon balances. Am J Clin Nutr 32:1876â1880. Kim H, Yu C, Maier RJ. 1991. Common cis-acting region responsible for transcrip- tional regulation of Bradyrhizobium japonicum hydrogenase by nickel, oxy- gen, and hydrogen. J Bacteriol 173:3993â3999. Konig A, Wrazel L, Warrell RP Jr, Rivi R, Pandolfi PP, Jakubowski A, Gabrilove JL. 1997. Comparative activity of melarsoprol and arsenic trioxide in chronic B- cell leukemia lines. Blood 90:562â570. Kreiss K, Zack MM, Landrigan PJ, Feldman RG, Niles CA, Chirico-Post J, Sax DS, Boyd MH, Cox DH. 1983. Neurologic evaluation of a population exposed to arsenic in Alaskan well water. Arch Environ Health 38:116â121. Ku WW, Chapin RE, Moseman RF, Brink RE, Pierce KD, Adams KY. 1991. Tissue disposition of boron in male Fischer rats. Toxicol Appl Pharmacol 111:145â151. Ku WW, Shih LM, Chapin RE. 1993. The effects of boric acid (BA) on testicular cells in culture. Reprod Toxicol 7:321â331. Lancaster JR. 1988. The Bioinorganic Chemistry of Nickel. New York: VCH Publishers. Lanoue L, Taubeneck MW, Muniz J, Hanna LA, Strong PL, Murray FJ, Nielsen FH, Hunt CD, Keen CL. 1998. Assessing the effects of low boron diets on embryon- ic and fetal development in rodents using in vitro and in vivo model systems. Biol Trace Elem Res 66:271â298. Lanoue L, Strong PL, Keen CL. 1999. Adverse effects of a low boron environment on the preimplanation development of mouse embryos in vitro. J Trace Elem Exp Med 12:235â250. Laskey JW, Phelps PV. 1991. Effect of cadmium and other metal cations on in vitro Leydig cell testosterone production. Toxicol Appl Pharmacol 108:296â306. Lee IP, Sherrins RJ, Dixon RL. 1978. Evidence for induction of germinal aplasia in male rats by environmental exposure to boron. Toxicol Appl Pharmacol 45:577â 590. Levin-Scherz JK, Patrick JD, Weber FH, Garabedian C Jr. 1987. Acute arsenic inges- tion. Ann Emerg Med 16:702â704. Litovitz TL, Klein-Schwartz W, Oderda GM, Schmitz BF. 1988. Clinical manifesta- tions of toxicity in a series of 784 boric acid ingestions. Am J Emerg Med 6:209â 213. Llobet JM, Colomina MT, Sirvent JJ, Domingo JL, Corbella J. 1993. Reproductive toxicity evaluation of vanadium in male mice. Toxicology 80:199â206. Look AT. 1998. Arsenic and apoptosis in the treatment of acute promyelocytic leukemia. J Natl Cancer Inst 90:86â88.
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 549 Mahaffey KR, Corneliussen PE, Jelinek CF, Fiorino JA. 1975. Heavy metal exposure from foods. Environ Health Perspect 12:63â69. Maitani T, Saito N, Abe M, Uchiyama S, Saito Y. 1987. Chemical form-dependent induction of hepatic zinc-thionein by arsenic administration and effect of co- administered selenium in mice. Toxicol Lett 39:63â70. Mancinella A. 1991. Silicon, a trace element essential for living organisms. Recent knowledge on its preventive role in atherosclerotic process, aging and neo- plasms. Clin Ter 137:343â350. Meacham SL, Hunt CD. 1998. Dietary boron intakes of selected populations in the United States. Biol Trace Elem Res 66:65â78. Meng Z, Meng N. 1994. Effects of inorganic arsenicals on DNA synthesis in unsen- sitized human blood lymphocytes in vitro. Biol Trace Elem Res 42:201â208. Moore JA. 1997. An assessment of boric acid and borax using the IEHR Evaluative Process for Assessing Human Developmental and Reproductive Toxicity of Agents. Reprod Toxicol 11:123â160. Morton W, Starr G, Pohl D, Stoner J, Wagner S, Weswig D. 1976. Skin cancer and water arsenic in Lane County, Oregon. Cancer 37:2523â2532. Murray FJ. 1998. A comparative review of the pharmacokinetcis of boric acid in rodents and humans. Biol Trace Elem Res 66:331â341. Myron DR, Givand SH, Nielsen FH. 1977. Vanadium content of selected foods as determined by flameless atomic absorption spectroscopy. J Agric Food Chem 25:297â300. Nielsen FH. 1985. The importance of diet composition in ultratrace element re- search. J Nutr 115:1239â1247. Nielsen FH. 1996. How should dietary guidance be given for mineral elements with beneficial actions or suspected of being essential? J Nutr 126:2377Sâ2385S. Nielsen FH. 1997. Boron. In: OâDell BL, Sunde RA, eds. Handbook of Nutritionally Essential Mineral Elements. New York: Marcel Dekker. Pp. 453â464. Nielsen FH. 1998. The justification for providing dietary guidance for the nutri- tional intake of boron. Biol Trace Elem Res 66:319â330. Nielsen FH, Flyvholm M. 1983. Risks of high nickel intake with diet. In: Sunderman FW Jr, ed. Nickel in the Human Environment. IARC Scientific Publications No. 53. Lyon, France: International Agency for Research on Cancer. Pp. 333â338. Nielsen FH, Penland JG. 1999. Boron supplementation of peri-menopausal women affects boron metabolism and indicies associated with macromineral metabo- lism, hormonal status and immune function. J Trace Elem Exp Med 12:251â261. Nielsen FH, Uthus EO. 1990. The essentiality and metabolism of vanadium. In: Chasteen ND, ed. Vanadium in Biological Systems. Dordrecht, The Netherlands: Kluwer Academic. Pp. 51â62. Nishioka H. 1975. Mutagenic activities of metal compounds in bacteria. Mutat Res 31:185â189. NRC (National Research Council). 1999. Arsenic in Drinking Water. Washington, DC: National Academy Press. Oppenheim JJ, Fishbein WN. 1965. Induction of chromosome breaks in cultured normal human leukocytes by potassium arsenite, hydroxyurea and related compounds. Cancer Res 25:980â985. Oster MH, Llobet JM, Domingo JL, German JB, Keen CL. 1993. Vandium treat- ment of diabetic Sprague-Dawley rats results in tissue vanadium accumulation and pro-oxidant effects. Toxicology 83:115â130. OâSullivan K, Taylor M. 1983. Chronic boric acid poisoning in infants. Arch Dis Child 58:737â749.
550 DIETARY REFERENCE INTAKES Paton GR, Allison AC. 1972. Chromosome damage in human cell cultures induced by metal salts. Mutat Res 16:332â336. Patriarca M, Lyon TD, Fell GS. 1997. Nickel metabolism in humans investigated with an oral stable isotope. Am J Clin Nutr 66:616â621. Patterson BW, Hansard SL, Ammerman CB, Henry PR, Zech LA, Fisher WR. 1986. Kinetic model of whole-body vanadium metabolism: Studies in sheep. Am J Physiol 251:R325âR332. Penland JG. 1998. The importance of boron nutrition for brain and psychological function. Biol Trace Elem Res 66:299â317. Pennington JA. 1991. Silicon in foods and diets. Food Addit Contam 8:97â118. Pennington JA, Jones JW. 1987. Molybdenum, nickel, cobalt, vanadium, and stron- tium in total diets. J Am Diet Assoc 87:1644â1650. Popplewell JF, King SJ, Day JP, Ackrill P, Fifield LK, Cresswell RG, di Tada ML, Liu K. 1998. Kinetics of uptake and elimination of silicic acid by a human subject: A novel application of 32Si and accelerator mass spectrometry. J Inorg Biochem 69:177â180. Price CJ, Marr MC, Myers CB, Seely JC, Heindel JJ, Schwetz BA. 1996a. The devel- opmental toxicity of boric acid in rabbits. Fundam Appl Toxicol 34:176â187. Price CJ, Strong PL, Marr MC, Myers CB, Murray FJ. 1996b. Developmental toxicity NOAEL and postnatal recovery in rats fed boric acid during gestation. Fundam Appl Toxicol 32:179â193. Price CJ, Strong PL, Murray FJ, Goldberg MM. 1998. Developmental effects of boric acid in rats related to maternal blood boron concentrations. Biol Trace Elem Res 66:359â372. Przybyla AE, Robbins J, Menon N, Peck HD. 1992. Structure-function relationships among the nickel-containing hydrogenases. FEMS Microbiol Rev 8:109â135. Quatrehomme G, Ricq O, Lapalus P, Jacomet Y, Ollier A. 1992. Acute arsenic intoxication: Forensic and toxicologic aspects (an observation). J Forensic Sci 37:1163â1171. Rainey CJ, Nyquist LA, Christensen RE, Strong PL, Culver BD, Coughlin JR. 1999. Daily boron intake from the American diet. J Am Diet Assoc 99:335â340. Rehder D. 1991. The bioinorganic chemistry of vanadium. Angew Chem Int Ed Engl 30:148â167. Rezuke WN, Knight JA, Sunderman FW. 1987. Reference values for nickel concen- trations in human tissues and bile. Am J Ind Med 11:419â426. Rowe RI, Eckhert CD. 1999. Boron is required for zebrafish embryogenesis. J Exp Biol 202:1649â1654. RTI (Research Triangle Institute). 1988. Two Generation Reproduction and Fertility Study of Nickel Chloride Administered to CD Rats in the Drinking Water: Fertility and Reproductive Performance of the P0 Generation. Final Study Report. Report to Office of Solid Waste Management, US Environmental Protection Agency by Re- search Triangle Institute. RTI Project No. 472U-3228-07. Research Triangle Park, NC: RTI. Sabbioni E, Marafante E, Amantini L, Ubertalli L, Birattari C. 1978. Similarity in metabolic patterns of different chemical species of vanadium in the rat. Bioinorg Chem 8:503â515. Samman S, Naghii MR, Lyons Wall PM, Verus AP. 1998. The nutritional and meta- bolic effects of boron in humans and animals. Biol Trace Elem Res 66:227â235. Schnegg A, Kirchgessner M. 1975. Changes in hemoglobin content, erythrocyte count and hematocrit in nickel deficiency. Nutr Metab 19:268â278.
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 551 Schoof RA, Yost LJ, Eickhoff J, Crecelius EA, Cragin DW, Meacher DM, Menzel DB. 1999. A market basket survey of inorganic arsenic in food. Food Chem Toxicol 37:839â846. Schroeder HA, Mitchener M. 1971. Toxic effects of trace elements on the repro- duction of mice and rats. Arch Environ Health 23:102â106. Schwarz K, Milne DB. 1972. Growth-promoting effects of silicon in rats. Nature 239:333â334. Seaborn CD, Nielsen FH. 1993. Silicon: A nutritional beneficence for bones, brains and blood vessels? Nutr Today 28:13â18. Seaborn CD, Nielsen FH. 1994. Dietary silicon affects acid and alkaline phosphatase and 45calcium uptake in bone of rats. J Trace Elem Exp Med 7:11â18. Shirasu Y, Moriya M, Kato K, Furuhashi A, Kada T. 1976. Mutagenicity screening of pesticides in the microbial system. Mutat Res 40:19â30. Simeonova PP, Wang S, Toriuma W, Kommineni V, Matheson J, Unimye N, Kayama F, Harki D, Ding M, Vallyathan V, Luster MI. 2000. Arsenic mediates cell proliferation and gene expression in the bladder epithelium: Association with activating protein-1 transactivation. Cancer Res 60:3445â3453. Smith AH, Goycolea M, Haque R, Biggs ML. 1998. Marked increase in bladder and lung cancer mortality in a region of Northern Chile due to arsenic in drinking water. Am J Epidemiol 147:660â669. Smith MK, George EL, Stober JA, Feng HA, Kimmel GL. 1993. Perinatal toxicity associated with nickel chloride exposure. Environ Res 61:200â211. Solomons NW, Viteri F, Shuler TR, Nielsen FH. 1982. Bioavailability of nickel in man: Effects of foods and chemically-defined dietary constituents on the ab- sorption of inorganic nickel. J Nutr 112:39â50. Southwick JW, Western AE, Beck MM, Whitley T, Isaacs R. 1981. Community Health Associated with Arsenic in Drinking Water in Millard County, Utah. EPA-600/1-81- 064. Cincinnati, OH: US Environmental Protection Agency, Health Effects Research Laboratory. Steffen RP, Pamnani MB, Clough DL, Huot SJ, Muldoon SM, Haddy FJ. 1981. Effect of prolonged dietary administration of vanadate on blood pressure in the rat. Hypertension 3:I173âI178. Stokinger HE. 1981. The halogens and nonmetals boron and silicon. In: Clayton GD, Clayton FE, eds. Pattyâs Industrial Hygiene and Toxicology, Vol. 2B. New York: John Wiley and Sons. Pp. 2978â3005. Sunderman FW Jr, Dingle B, Hopfer SM, Swift T. 1988. Acute nickel toxicity in electroplating workers who accidently ingested a solution of nickel sulfate and nickel chloride. Am J Ind Med 14:257â266. Sunderman FW Jr, Hopfer SM, Sweeney KR, Marcus AH, Most BM, Creason J. 1989. Nickel absorption and kinetics in human volunteers. Proc Soc Exp Biol Med 191:5â11. Sutherland B, Strong P, King JC. 1998. Determining human dietary requirements for boron. Biol Trace Elem Res 66:193â204. Tabata M, Sarkar B. 1992. Specific nickel(II)-transfer process between the native sequence peptide representing the nickel(II)-transport site of human serum albumin and L-histidine. J Inorg Biochem 45:93â104. Takizawa Y, Hirasawa F, Noritomi E, Aida M, Tsunoda H, Uesugi S. 1988. Oral ingestion of SYLOID to mice and rats and its chronic toxicity and carcinoge- nicity. Acta Med Biol 36:27â56. Tao SS, Bolger PM. 1999. Dietary arsenic intakes in the United States: FDA Total Diet Study, September 1991âDecember 1996. Food Addit Contam 16:465â472.
552 DIETARY REFERENCE INTAKES Tseng WP. 1977. Effects and dose-response relationships of skin cancer and black- foot disease with arsenic. Environ Health Perspect 19:109â119. Tseng WP, Chu HM, How SW, Fong JM, Lin CS, Yeh S. 1968. Prevalence of skin cancer in an endemic area of chronic arsenicism in Taiwan. J Natl Cancer Inst 40:453â463. Tsuda T, Babazono A, Yamanoto E, Kurumatani N, Mino Y, Ogawa T, Kishi Y, Aoyama H. 1995. Ingested arsenic and internal cancer: A historical cohort study followed for 33 years. Am J Epidemiol 141:198â209. Uthus EO. 1994. Diethyl maleate, an in vivo chemical depletor of glutathione, affects the response of male and female rats to arsenic deprivation. Biol Trace Elem Res 46:247â259. Uthus EO, Nielsen FH. 1990. Effect of vanadium, iodine and their interaction on growth, blood variables, liver trace elements and thyroid status indices in rats. Magnes Trace Elem 9:219â226. Uthus EO, Poellot R. 1992. Effect of dietary pyridoxine on arsenic deprivation in rats. Magnes Trace Elem 10:339â347. Uthus EO, Poellot RA. 1996. Dietary folate affects the response of rats to nickel deprivation. Biol Trace Elem Res 52:23â35. Uthus EO, Seaborn CD. 1996. Deliberations and evaluations of the approaches, endpoints and paradigms for dietary recommendations of the other trace ele- ments. J Nutr 126:2452Sâ2459S. Vahter M. 1983. Metabolism of arsenic. In: Fowler BA, ed. Biological and Environ- mental Effects of Arsenic. Amsterdam: Elsevier. Pp. 171â198. Valentine JL, He SY, Reisbord LS, Lachenbruch PA. 1992. Health response by questionnaire in arsenic-exposed populations. J Clin Epidemiol 45:487â494. Wagner SL, Maliner JS, Morton WE, Braman RS. 1979. Skin cancer and arsenical intoxication from well water. Arch Dermatol 115:1205â1207. Waltschewa W, Slatewa M, Michailow I. 1972. Testicular changes due to long-term administration of nickel sulfate in rats. Exp Pathol 6:116â121. Wei CI, Al Bayati MA, Culbertson MR, Rosenblatt LS, Hansen LD. 1982. Acute toxicity of ammonium metavanadate in mice. J Toxicol Environ Health 10:673â 687. Weir RJ, Fisher RS. 1972. Toxicologic studies on borax and boric acid. Toxicol Appl Pharmacol 23:351â364. Wester RC, Hui X, Maibach HI, Bell K, Schell MJ, Northington DJ, Strong P, Culver BD. 1998. In vivo percutaneous absorption of boron as boric acid, borax, and disodium octaborate tetrahydrate in humans: A summary. Biol Trace Elem Res 66:101â109. Yamamoto S, Konishi Y, Matsuda T, Murai T, Shibata MA, Matsui-Yuasa I, Otani S, Kuroda K, Endo G, Fukushina S. 1995. Cancer induction by an organic ar- senic compound, dimethylarsinic acid (cacodylic acid), in F344/DuCrj rats after pretreatment with five carcinogens. Cancer Res 55:1271â1276. Yamato N. 1988. Concentrations and chemical species of arsenic in human urine and hair. Bull Environ Contam Toxicol 40:633â640. Yang TH, Blackwell RQ. 1961. Nutritional and environmental conditions in the endemic Blackfoot area. Formosan Sci 15:101â129. Zaporowska H, Wasilewski W. 1992. Haematological results of vanadium intoxica- tion in Wistar rats. Comp Biochem Physiol C 101:57â61. Zaporowska H, Wasilewski W, Slotwinska M. 1993. Effect of chronic vanadium ad- ministration in drinking water to rats. Biometals 6:3â10.
ARSENIC, BORON, NICKEL, SILICON, AND VANADIUM 553 Zielhuis RL, Wibomo AA. 1984. Standard setting and metal speciation: Arsenic. In: Nriagu JO, ed. Changing Metal Cycles and Human Health. New York: Springer- Verlag. Pp. 323â344.