Toxicological profile for barium and barium compounds
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- Bu səhifədəki naviqasiya:
- Developmental Toxicity.
- Epidemiological and Human Dosimetry Studies.
- Biomarkers of Exposure and Effect. Exposure.
- Absorption, Distribution, Metabolism, and Excretion.
- Comparative Toxicokinetics.
- Methods for Reducing Toxic Effects.
- Children’s Susceptibility.
- 3.12.3 Ongoing Studies
83 BARIUM AND BARIUM COMPOUNDS 3. HEALTH EFFECTS end points. Additional dermal exposure studies are needed to evaluate whether various barium compounds are irritants and can cause remote-site toxicity. No studies assessing the carcinogenicity of barium following chronic inhalation exposure were identified. The carcinogenicity of ingested barium has been assessed in several long-term oral exposure studies in rats and mice (McCauley et al. 1985; NTP 1994; Schroeder and Mitchener 1975a, 1975b). These studies did not find significant increases in the incidence of neoplastic lesions in either species. Although a study by Van Duuren et al. (1968) provided evidence suggesting that barium hydroxide extract derived from tobacco leaf may act as a tumor-promoting agent when applied with a tumor initiating agent, there are no studies to assess barium’s potential to be a complete carcinogen following dermal exposure. Based on the results of the oral study, it can be predicted that inhalation or dermal exposure to barium would not result in remote site carcinogenicity; however, it is not known if long-term exposure would result in respiratory tract cancer following inhalation exposure or skin cancer following dermal exposure. Inhalation and dermal exposure cancer studies are needed to address these questions. Genotoxicity. The genotoxicity of barium has not been well characterized. One study used an in vivo assay to assess genotoxic potential (Yesilada 2001); increases in somatic mutations were observed in
assays have not found significant alterations in gene mutation frequency or DNA damage in non- mammalian systems (Kanematsu et al. 1980; Monaco et al. 1990, 1991; Nishioka 1975; NTP 1994; Rossman et al. 1991; Sirover and Loeb 1976a, 1976b). In mammalian test systems, barium did not have clastogenic effects (NTP 1994), but did increase the frequency of gene mutation (NTP 1994). The available data are inadequate to thoroughly assess the genotoxic potential of barium; additionally studies, particularly in vivo assays, are needed.
The reproductive effects of barium have not been thoroughly studied. There are no studies regarding reproductive effects in humans following barium exposure. Several animal studies have examined potential end points of reproductive toxicity. In the only inhalation exposure study (Tarasenko et al. 1977), a number of adverse effects were reported, including disturbances in spermatogenesis, shortened estrus cycle, and histological damage to the testes and ovaries. However, limited reporting of the study design and results and the lack of incidence data and statistical analysis limit the interpretation of the study results. Although a 10-day gavage study found significant decreases in relative and absolute ovary weights (Borzelleca et al. 1988), other oral exposure studies have not found alterations in organ weights or histological alterations in reproductive tissues following acute-, 84 BARIUM AND BARIUM COMPOUNDS 3. HEALTH EFFECTS intermediate-, or chronic-duration exposure (McCauley et al. 1985; NTP 1994). Additionally, no alterations in sperm morphology, motility, or counts were observed in rats or mice exposed to barium in drinking water for 60 days (Dietz et al. 1992). Only one oral study evaluated reproductive function (Dietz et al. 1992) and found no alterations in pregnancy rate or gestation length in rats or mice. A two- generation study would be useful for further evaluating the potential reproductive toxicity of barium. No dermal exposure studies examining reproductive end points were identified; based on available toxicokinetic data. Additional studies are needed to further assess if reproductive toxicity is an end point of concern for barium.
The developmental effects of barium have not been studied extensively in either humans or animals. One limited statistical study evaluated the degree of correlation between barium concentrations in drinking water and human congenital malformation rates of the central nervous system (Morton et al. 1976). Results of the study indicated there was a negative statistical correlation between these parameters, implying that a lower risk of congenital abnormalities was found in populations with higher barium levels. Two animal studies evaluated the potential developmental toxicity of barium. Reduced survival, underdevelopment, lowered body weight, decreased lability of the peripheral nervous system, and various blood disorders were reportedly noted in the offspring of rats following inhalation to barium for an intermediate exposure period (Tarasenko et al. 1977). The investigators also noted increased mortality and systemic toxicity in the offspring of rats orally exposed to barium during conception and pregnancy. As noted previously, interpretation of the results from the Tarasenko et al. (1977) studies are limited because the studies were poorly reported and no incidence data or statistical analysis were reported. In a mating study involving oral exposure to barium chloride prior to mating (Dietz et al. 1992), decreases in pup birth weight and a nonstatistically significant decrease in live litter size were observed in rats; no adverse effects were observed in mice. It is not known if the decrease in body weight observed in the rat offspring was secondary to maternal toxicity or was a direct effect on the fetus. Additional developmental toxicity studies, particularly studies involving oral exposure during gestation and lactation, would be useful to confirm the results of the Tarasenko et al. (1977) and Dietz et al. (1992) studies. Developmental toxicity studies via dermal exposure are also needed because this end point has not been evaluated for this route of exposure.
The effect of barium on the immune system has not been well studied. No studies were available regarding immunological effects in humans or animals following inhalation, oral, or dermal exposure to barium. Several oral exposure studies in animals examining lymphoreticular end points such as thymus and lymph node histopathology have not reported adverse effects at nonlethal
85 BARIUM AND BARIUM COMPOUNDS 3. HEALTH EFFECTS doses (Borzelleca et al. 1988; McCauley et al. 1985; NTP 1994). Screening studies are needed to evaluate the potential immunotoxicity of barium following inhalation, oral, or dermal exposure.
Exposure to high oral doses of barium is associated with numbness and tingling around the mouth and neck (Lewi and Bar-Khayim 1964; Morton 1945); higher doses can result in partial or complete paralysis (Das and Singh 1970; Diengott et al. 1964; Gould et al. 1973; Lewi and Bar- Khayim 1964; Morton 1945; Ogen et al. 1967; Phelan et al. 1984; Wetherill et al. 1981). Absence of a deep tendon reflex has been reported in an individual exposed to airborne barium carbonate powder (Shankle and Keane 1988). Oral exposure of rats and mice to barium has not been associated with changes in brain weight or gross or microscopic lesions of the brain (Borzelleca et al. 1988; McCauley et al. 1985; NTP 1994; Tardiff et al. 1980). NTP (1994) evaluated neurobehavioral performance in rats and mice exposed to barium chloride in drinking water for acute or intermediate durations. Decreases in spontaneous motor activity were observed in rats exposed for an intermediate duration. Decreased grip strength was also observed in mice; however, this was likely due to debilitation rather than neurotoxicity. The human data demonstrate that at presumably high doses, barium affects action potentials of muscles and nerve cells by increasing cellular potassium levels. However, oral studies are needed to establish a dose-response relationship for these neurological effects. No data were available regarding neurological effects in animals following inhalation exposure or humans and/or animals following dermal exposure. Additional studies would be useful to further evaluate the neurotoxic potential of barium.
A limited number of epidemiological and human dosimetry studies evaluating the health effects of barium are available (Brenniman and Levy 1985; Brenniman et al. 1979a, 1979b, 1981; Elwood et al. 1974; Schroeder and Kraemer 1974; Wones et al. 1990). These studies have primarily focused on the potential of barium to adversely affect cardiovascular function by altering blood pressure or increasing the risk of death due to cardiovascular disease; consistent results have not been found. However, all of the available human studies on barium have limitations and/or confounding variables that make it difficult to draw firm conclusions regarding the health effects of barium (see Sections 3.2.2.1 and 3.2.2.2 for discussions on the specific limitations associated with available epidemiological and human dosimetry studies). Several human studies have also examined the potential toxicity of inhaled barium to the respiratory tract or cardiovascular system (Doig 1976; Essing et al. 1976; Seaton et al. 1986). As with the oral studies, limitations in the study reporting or confounding variables preclude using the studies to establish causal relationships. In addition to these epidemiological or experimental studies, there are numerous case reports of individuals ingesting large doses of barium (Das and Singh 1970; Deng et al. 1991; Diengott et al. 1964; Downs et al. 1995;
86 BARIUM AND BARIUM COMPOUNDS 3. HEALTH EFFECTS Gould et al. 1973; Koch et al. 2003; Lewi and Bar-Khayim 1964; McNally 1925; Ogen et al. 1967; Phelan et al. 1984; Talwar and Sharma 1979; Wetherill et al. 1981) or exposed to airborne barium carbonate (Shankle and Keane 1988). In general, these studies reported serious health effects such as death, ventricular tachycardia, and paralysis. Animal studies provide evidence that the kidney is a sensitive target of toxicity; there is also some evidence that the cardiovascular and neurological systems and the developing organisms are targets of barium toxicity (Dietz et al. 1992; McCauley et al. 1985; NTP 1994; Perry et al. 1983, 1985, 1989). Additional epidemiological and/or human dosimetry studies would be useful to determine the effects of low doses of barium on these end points. Studies of workers exposed to airborne barium would also be useful for establishing the toxicity of barium to the respiratory tract.
measuring barium in blood, urine, feces, and biological tissues (Mauras and Allain 1979; Schramel 1988; Shiraishi et al. 1987); however, there are no data correlating levels of barium in these tissues and fluids with exposure. Studies associating barium levels in biological media (such as blood or urine) with exposure concentrations or doses would be useful for establishing biomarkers of exposure.
tension, ventricular tachycardia, and numbness and tingling around the mouth and neck (Das and Singh 1970; Deng et al. 1991; Diengott et al. 1964; Downs et al. 1995; Gould et al. 1973; Koch et al. 2003; Lewi and Bar-Khayim 1964; McNally 1925; Ogen et al. 1967; Phelan et al. 1984; Talwar and Sharma 1979; Wetherill et al. 1981) are well documented. However, there are no quantitative studies correlating these effects with dose and these effects are not specific to barium toxicity. For purposes of facilitating medical surveillance, studies to determine useful biomarkers of effect for barium, particularly effects associated with low doses of barium, would be useful. Absorption, Distribution, Metabolism, and Excretion. The database on absorption, distribution, metabolism, and excretion of barium is limited. Existing studies indicate that barium is absorbed from the respiratory tract (Cuddihy and Griffith 1972; Cuddihy and Ozog 1973b; Morrow et al. 1968) and gastrointestinal tract (Cuddihy and Griffith 1972; Harrison et al. 1956; Leggett 1992; LeRoy et al. 1966; Schroeder et al. 1972; Taylor et al. 1962;Tipton et al. 1969), primarily deposited in the bones and teeth (Bauer et al. 1957; Cuddihy and Griffith 1972; Losee et al. 1974; Miller et al. 1985; Sowden 1958;
87 BARIUM AND BARIUM COMPOUNDS 3. HEALTH EFFECTS Sowden and Pirie 1958; Sowden and Stitch 1957), and excreted mostly in feces and urine (Cuddihy and Griffith 1972; Tipton et al. 1966). Deposition in bones and teeth and excretion in feces and urine appear to be independent of the route of exposure. Essentially no data exist on absorption, distribution, or excretion following dermal exposure; however, this route is not considered to be a significant source of exposure to barium. No significant data exist on the metabolism of barium compounds in the body. Additional studies evaluating the binding and/or complexing of barium and barium compounds with biological macromolecules or organic molecules in the body would be useful. Studies quantifying the extent of absorption following inhalation, oral, and dermal exposure also would be useful because of limited absorption data. A wide variety of individual differences in absorption efficiencies have been detected in the available human studies; studies examining factors influencing barium absorption would be useful. Comparative Toxicokinetics. Based on available data, there do not appear to be significant differences in the toxicokinetics of barium between species (Chou and Chin 1943; Cuddihy and Griffith 1972; McCauley and Washington 1983), although there is some indication that a larger percentage of absorbed barium is excreted in the feces of humans compared to that of experimental animals. However, there are not enough similar studies on different species to determine this with certainty. Studies on different species would increase confidence in the reliability of the existing database.
Methods have been reported for limiting oral and dermal absorption of barium compounds (Bronstein and Currance 1988; Dreisbach and Robertson 1987; Haddad and Winchester 1990) and for counteracting the hypokalemia that is produced by barium in acute high- level exposure situations (Dreisbach and Robertson 1987; Haddad and Winchester 1990; Proctor et al. 1988). Contradictions exist in the literature regarding the efficacy or desirability of administering emetics (Bronstein and Currance 1988; Ellenhorn and Barceloux 1988; Haddad and Winchester 1990). Additional studies clarifying this issue would be helpful. Also, studies directed at finding a more efficient way to remove barium from the body would be useful. It is unclear whether mechanisms other than hypokalemia contribute to the toxic effects produced in acute high-level exposure situations. Additional information on the mechanisms responsible for the toxic effects of barium could aid in the development of effective treatments. Magnesium has been reported to antagonize the neuromuscular effects (Dreisbach and Robertson 1987). Additional studies examining the efficacy of administering soluble magnesium salts to antagonize the effects of barium would also be helpful. No information was located on treatment strategies for long-term low-level exposures. Research on procedures for mitigating such chronic exposure situations would be helpful. 88 BARIUM AND BARIUM COMPOUNDS 3. HEALTH EFFECTS
Data needs relating to both prenatal and childhood exposures, and developmental effects expressed either prenatally or during childhood, are discussed in detail in the Developmental Toxicity subsection above. There is very little information on the toxicity of barium in children. Two reports of food poisonings with barium carbonate (Deng et al. 1991; Lewi and Bar-Khayim 1964) provide some suggestive information that children may not be as sensitive as adults to barium carbonate toxicity; however, the lack of detailed examination of the exposed children and lack of exposure information limits the interpretation of these data. No human or animal toxicity studies have been designed to assess possible differences in the toxicity of barium. There is some information suggesting that infants and young children may have a higher barium absorption rate than adults (ICRP 1993; Taylor et al. 1962). Other potential toxicokinetic differences have not been thoroughly investigated. Additional studies are needed to evaluate potential age-specific differences in toxicity and toxicokinetics. Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: Exposures of Children.
No ongoing studies were reported in the FEDRIP (2006) database. Document Outline
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