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The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the nation. These sites are then placed on the National Priorities List (NPL) and are targeted for long-term federal clean-up activities. Chlorine dioxide and chlorite have not been found in any of the 1,647 current or former NPL sites. Although the total number of NPL sites evaluated for these substances is not known, the possibility exists that chlorine dioxide and chlorite may be found in the future as more sites are evaluated. This information is important because these sites may be sources of exposure and exposure to these substances may harm you.
Dermal Effects. No reports were located regarding dermal effects in humans following dermal exposure to chlorine dioxide or chlorite.
A solution containing chlorine dioxide concentrations of approximately 9.7–11.4 mg/L was nonirritating to the skin of mice in a 48-hour test (Shi and Xie 1999). Moderate to severe erythema was observed in rabbits following repeated daily applications of Alcide, an antimicrobial compound consisting of solutions of sodium chlorite and lactic acid that produce chlorine dioxide when mixed (Abdel-Rahman et al. 1987b). However, levels of exposure to sodium chlorite or chlorine dioxide could not be quantified.
No reports were located in which the following health effects in humans or animals could be associated with dermal exposure to chlorine dioxide or chlorite:
3.2.3.3 Immunological and Lymphoreticular Effects
3.2.3.4 Neurological Effects
3.2.3.5 Reproductive Effects
3.2.3.6 Developmental Effects
No reports were located regarding developmental effects in humans following dermal exposure to chlorine dioxide or chlorite.
Animal data are limited to studies of laboratory rodents exposed to Alcide, an antimicrobial compound consisting of solutions of sodium chlorite and lactic acid that produce chlorine dioxide when mixed (Abdel-Rahman et al. 1987a; Gerges et al. 1985). No statistically significant treatment-related developmental effects were observed in the offspring of rats, mice, and rabbits treated daily with dermal applications of Alcide gel (as high as 2 g/kg) during the critical period of organogenesis. However, levels of exposure to sodium chlorite or chlorine dioxide could not be quantified.
3.2.3.7 Cancer
Kurokawa et al. (1984) conducted two dermal carcinogenicity assays on chlorite. In an assay designed to assess the ability of chlorite to act as a complete carcinogen, female mice were treated with dermal applications of sodium chlorite (in acetone) twice weekly for 51 weeks. Compared with controls, sodium chlorite exposure did not result in increased tumor incidence. To test the ability of chlorite to act as a tumor promoter, a single initiating dose of dimethylbenzanthracene (DMBA) was applied to the skin of mice. The DMBA application was followed by dermal applications of sodium chlorite (in acetone) twice weekly for 51 weeks. Although incidences of tumors were higher in the chlorite/acetone-exposed mice than in those receiving acetone only, the differences were not statistically significant.
3.3 GENOTOXICITY
No reports were located regarding the genotoxicity of chlorine dioxide or chlorite in humans. The genotoxic potential of chlorine dioxide and chlorite has been assessed in a number of standard genotoxicity test systems, resulting in both positive and negative results. Chlorine dioxide was not mutagenic (either with or without metabolic activation) in one Ames assay of Salmonella typhimurium strains TA 97, TA98, TA100, and TA102 (Wang et al. 2002a), but a weakly positive response (without metabolic activation) in strain TA100 was noted in another Ames assay (Ishdate et al. 1984). Chlorine dioxide did not increase chromosomal aberrations in Chinese hamster fibroblast cells (Ishidate et al. 1984). Samples of water that had been disinfected with chlorine dioxide did not induce reverse mutations in S. typhimurium with or without activation (Miller et al. 1986). Negative results were obtained from in vivo assays for micronuclei and bone marrow chromosomal aberrations in Swiss CD-1 mice, as well as sperm-head abnormalities in B6C3F1 mice, following gavage administration of chlorine dioxide doses ranging from 0.1 to 0.4 mg/mouse/day for 5 consecutive days (Meier et al. 1985). Chlorine dioxide did not induce micronuclei in the bone marrow of mice that had been exposed via the drinking water at a concentration of 624 mg/L (Wang et al. 2002b). Hayashi et al. (1988) reported positive results in the micronucleus assay in ddY mice following single intraperitoneal injection of chlorine dioxide at dose levels of 3.2–25 mg/kg.
Sodium chlorite induced reverse mutations in S. typhimurium (with activation) and chromosomal aberrations in Chinese hamster fibroblast cells (Ishidate et al. 1984). Negative results were obtained from in vivo assays for micronuclei and bone marrow chromosomal aberrations in Swiss CD-1 mice, as well as sperm-head abnormalities in B6C3F1 mice, following gavage administration of sodium chlorite at doses ranging from 0.25 to 1 mg/mouse/day for 5 consecutive days (Meier et al. 1985). Hayashi et al. (1988) reported negative results for induction of micronuclei in ddY mice that were administered sodium chlorite in single oral gavage doses ranging from 37.5 to 300 mg/kg, but positive results were obtained in mice subjected to single or multiple intraperitoneal injection of 7.5 to 60 mg sodium chlorite/kg.
3.4 TOXICOKINETICS
Although no data were located regarding absorption following inhalation exposure to chlorine dioxide, little absorption of parent compound across lung tissue would be expected due to the highly reactive nature of chlorine dioxide. The rapid appearance of 36Cl in plasma following oral administration of chlorine dioxide (36ClO2) or chlorite (36ClO2-) has been shown in laboratory animals. Using 72-hour urinary excretion rates for 36Cl, absorption rates of 30–35% of intragastrically administered chlorine dioxide or chlorite have been estimated. Limited animal data indicate the presence of 36Cl in plasma following dermal application of Alcide, an antimicrobial compound containing sodium chlorite and lactic acid that rapidly form chlorine dioxide when mixed together. In rats, absorbed 36Cl (from 36ClO2 or - 36ClO2 exposure sources) is slowly cleared from the blood and is widely distributed throughout the body. Chlorine dioxide rapidly dissociates, predominantly into chlorite (which itself is highly reactive) and chloride ion (Cl-), ultimately the major metabolite of both chlorine dioxide and chlorite in biological systems. Urine is the primary route of 36Cl elimination, predominantly in the form of chloride ion.
3.4.1 Absorption
3.4.1.1 Inhalation Exposure
No information was located regarding absorption following inhalation exposure to chlorine dioxide or chlorite in humans or animals.
3.4.1.2 Oral Exposure
No information was located regarding absorption following oral exposure to chlorine dioxide or chlorite in humans.
In rats, a single gavage dose of 36ClO2 resulted in the rapid appearance of 36Cl in the plasma, which peaked 1 hour after dosing (Abdel-Rahman et al. 1980a). Based on 72-hour urinary excretion of 30% of the 36Cl in the administered dose, it can be assumed that absorption was at least 30%. The absorption rate constant and half-time were 3.77/hour and 0.18 hours, respectively (Abdel-Rahman et al. 1982). Similar results were reported following single gavage dosing of rats with 36ClO2 (Abdel-Rahman et al. 1982). In this study, peak plasma levels of 36Cl were reached within 2 hours following dosing and 72-hour urinary excretion data indicated that at least 35% of the radiolabel had been absorbed. The absorption rate constant and half-time were 0.198/hour and 3.5 hours, respectively.
3.4.1.3 Dermal Exposure
No information was located regarding absorption following dermal exposure to chlorine dioxide or chlorite in humans.
Dermal absorption of 36Cl was measured in rats following 10 daily applications of Alcide, an antimicrobial compound consisting of solutions of sodium chlorite and lactic acid that produce chlorine dioxide when mixed (Scatina et al. 1984). Maximal levels of plasma 36Cl were reached after 72 hours. The absorption rate constant and half-life were 0.0314/hour and 22.1 hours, respectively.
3.4.2 Distribution
3.4.2.1 Inhalation Exposure
No information was located regarding distribution of chlorine dioxide, chlorite, or their metabolites following inhalation exposure in humans or animals.
3.4.2.2 Oral Exposure
No information was located regarding distribution of chlorine dioxide, chlorite, or their metabolites following oral exposure in humans.
Animal data indicate that 36Cl, absorbed from the gastrointestinal tract following single oral (gavage) administration of 36ClO2, is cleared from the blood with a half-time of elimination of 43.9 hours (Abdel-Rahman et al. 1982) and is widely distributed throughout the body (Abdel-Rahman et al. 1980a, 1980b, 1982, 1984a). At 72 hours following dosing, highest concentrations were found in the blood, stomach, and small intestines. Relatively high concentrations were also seen in the lung, kidney, liver, testes, spleen, thymus, and bone marrow. A shorter elimination half-time (31.0 hours) was noted in rats that had been exposed to chlorine dioxide in the drinking water for 2 weeks prior to receiving a single gavage dose of 36ClO2 (Abdel-Rahman et al. 1980a). Single oral (gavage) administration of chlorite (36ClO2-) resulted in an elimination half-time of 35.2 hours from the blood and widespread distribution of 36Cl (Abdel-Rahman et al. 1982, 1984a), similar to that observed following oral exposure to chlorine dioxide.
3.4.2.3 Dermal Exposure
No information was located regarding distribution of chlorine dioxide, chlorite, or their metabolites following dermal exposure in humans or animals. However, 36Cl has been measured in plasma of rats following 10 daily applications of Alcide, an antimicrobial compound consisting of solutions of sodium chlorite and lactic acid that produce chlorine dioxide when mixed (Scatina et al. 1984).
3.4.3 Metabolism
3.4.3.1 Inhalation Exposure
No information was located regarding metabolism of chlorine dioxide or chlorite following inhalation exposure in humans or animals.
3.4.3.2 Oral Exposure
Both chlorine dioxide and chlorite are primarily metabolized to chloride ion. At 72 hours following single oral (gavage) administration of radiolabeled chlorine dioxide in rats, chloride ion accounted for approximately 87% of the radioactivity that had been collected in the urine and 80% of the radioactivity in a plasma sample (Abdel-Rahman et al. 1980b). Chlorite was the other major metabolite, accounting for approximately 11 and 21% of the radioactivity in the urine and plasma samples, respectively. Chlorate was a minor component of the radioactivity in the urine. Similarly, chloride ion accounted for approximately 85% of the radioactivity in the 72-hour urine collection of rats that had been orally administered radiolabeled chlorite; the remainder in the form of chlorite (Abdel-Rahman et al. 1984a).
Both chlorine dioxide and chlorite, being strong oxidizing agents, are most likely rapidly reduced in biological systems mainly to chloride ion. Bercz et al. (1982) demonstrated this reduction for chlorine dioxide that was introduced into saliva obtained from anesthetized monkeys.
3.4.3.3 Dermal Exposure
No information was located regarding metabolism of chlorine dioxide or chlorite following dermal exposure in humans or animals.
3.4.4 Elimination and Excretion
3.4.4.1 Inhalation Exposure
No information was located regarding elimination or excretion following inhalation exposure to chlorine dioxide or chlorite in humans or animals.
3.4.4.2 Oral Exposure
The urine is the primary route of excretion of orally administered radioactivity from radiolabeled chlorine dioxide or chlorite. In rats, 72 hours following single oral (gavage) administration of 36ClO2, 31 and 4.5% of the radiolabel had been excreted in the urine and feces, respectively, mainly in the form of the chloride
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ion. The ratio of 36Cl-to 36ClO2 was 4 to 1, and no parent compound was detected (Abdel-Rahman et al. 1980a, 1980b). In rats administered a single oral (gavage) dose of radiolabeled chlorite, 35 and 5% of the radiolabel were excreted in the urine and feces, respectively, in the first 72 hours after dosing. Approximately 90% of the urinary label was in the form of chloride ion (Abdel-Rahman et al. 1984a).
3.4.4.3 Dermal Exposure
Urinary excretion of 36Cl was observed in rats that had been administered Alcide, an antimicrobial compound consisting of sodium chlorite and lactic acid that form chlorine dioxide when mixed (Scatina et al. 1984). The rats had received 10 daily dermal applications, followed by an application of radiolabeled Alcide. Urinary excretion was greatest in the first 24 hours post application; the half-time of urinary elimination was 64 hours. The excreted radioactivity consisted of approximately equal portions of chloride ion and chlorite. No radioactivity was detected in feces or expired air.
3.4.5 Physiologically Based Pharmacokinetic (PBPK)/ Pharmacodynamic (PD) Models
Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and disposition of chemical substances to quantitatively describe the relationships among critical biological processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of potentially toxic moieties of a chemical that will be delivered to any given target tissue following various combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to quantitatively describe the relationship between target tissue dose and toxic end points.
PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to delineate and characterize the relationships between: (1) the external/exposure concentration and target tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen et al. 1987; Andersen and Krishnan 1994). These models are biologically and mechanistically based and can be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from route to route, between species, and between subpopulations within a species. The biological basis of PBPK models results in more meaningful extrapolations than those generated with the more conventional use of uncertainty factors.
The PBPK model for a chemical substance is developed in four interconnected steps: (1) model representation, (2) model parametrization, (3) model simulation, and (4) model validation (Krishnan and Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substance-specific physicochemical parameters, and species-specific physiological and biological parameters. The numerical estimates of these model parameters are incorporated within a set of differential and algebraic equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations provides the predictions of tissue dose. Computers then provide process simulations based on these solutions.
The structure and mathematical expressions used in PBPK models significantly simplify the true complexities of biological systems. If the uptake and disposition of the chemical substance(s) is adequately described, however, this simplification is desirable because data are often unavailable for many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The adequacy of the model is, therefore, of great importance, and model validation is essential to the use of PBPK models in risk assessment.
PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste sites) based on the results of studies where doses were higher or were administered in different species. Figure 3-3 shows a conceptualized representation of a PBPK model.
No PBPK models for exposure to chlorine dioxide or chlorite were identified.
3.5 MECHANISMS OF ACTION
3.5.1 Pharmacokinetic Mechanisms
Absorption. No information was located regarding mechanisms of absorption of chlorine dioxide or chlorite. Being a strong oxidizer, chlorine dioxide is likely to undergo rapid redox reactions within biological tissues rather than to be absorbed as parent compound. Chlorite levels have been measured in urine following oral exposure to chlorine dioxide or chlorite, indicating that some degree of chlorite absorption occurs across the digestive tract. Due to the highly reactive nature of chlorite, itself a strong oxidizer, absorption would be expected to occur via passive diffusion rather than active transport mechanisms.
Distribution. No information was located regarding the transport of chlorine dioxide or chlorite in the blood. However, based on the fact that the strong oxidizing property of chlorine dioxide likely results in rapid conversion to chlorite (also a strong oxidizer) in biological systems, and ultimately to chloride ion, it would be expected that distribution would follow normal ionic distribution patterns.
Metabolism. Although no information was located regarding mechanisms of chlorine dioxide and chlorite metabolism, ultimate transformation to chloride ions is likely achieved via redox reactions with a variety of substances in biological systems that are readily oxidized.
3.5.2 Mechanisms of Toxicity
Chlorine dioxide and chlorite are strong oxidizing agents that readily react upon direct contact with biological tissues, resulting in local irritation. Mechanisms whereby chlorine dioxide and chlorite exert hematological effects such as methemoglobinemia in humans (Lin and Lim 1993; Michael et al. 1981) and animals (Bercz et al. 1982; Harrington et al. 1995a; Heffernan et al. 1979b) and alterations in other blood factors are not presently known, but may be related to their properties as oxidants. Due to its highly reactive nature, it is unlikely that chlorine dioxide would be absorbed in quantities large enough to produce systemic toxicity directly. Chlorite is produced and absorbed following oral exposure to chlorine dioxide in animals (Abdel-Rahman et al. 1980b), and may be more likely to be involved in observed hematological effects than chlorine dioxide itself. Chlorite has been shown to be more efficient than chlorine dioxide in the production of methemoglobin, in decreasing blood glutathione, and in alteration of erythrocytes (Abdel-Rahman et al. 1980a, 1984b; Couri and Abdel-Rahman 1980; Heffernan et al. 1979a, 1979b). In vitro studies have further shown that sufficient amounts of glutathione may prevent chlorine dioxide-induced osmotic fragility, presumably by the prevention of the formation of disulfide bonds between hemoglobin and components of the cell membrane (Abdel-Rahman et al. 1984b). A recent in vitro study demonstrated that sodium chlorite readily depleted glutathione in mammalian cells, but treatment of phospholipids with chlorite yielded only low levels of hydroperoxides (Ingram et al. 2003). These findings indicate that chlorite-induced cellular damage may be more likely due to interaction with thiol compounds than with cell membrane lipids.
Although changes in thyroid hormones have been reported in laboratory animals that were either directly exposed to chlorine dioxide or exposed to chlorine dioxide or chlorite via their mothers during pre and postpartum development (Bercz et al. 1982; Carlton and Smith 1985; Carlton et al. 1987, 1991; Mobley et al. 1990; Orme et al. 1985), possible mechanisms that might mediate such effects have not been elucidated. Increased levels of iodine have been noted in esophagus and small intestine of rats up to 24 hours after administration of gavage doses of radiolabeled iodine followed by chlorine dioxide (Harrington et al. 1985). However, no concurrent treatment-related alterations in blood or thyroid gland iodine level were seen. Because the extent of thyroid uptake of bioavailable iodine does not appear to decrease following oral exposure to chlorine dioxide, Bercz et al. (1986) speculated that indications of altered hormonogenesis, such as altered serum thyroid hormone, could be the result of absorption of iodinated molecules having thyromimetic or thyroid inhibitory properties. These results, however, do not imply that the effect is mediated through a hormonal pathway.
Likewise, mechanisms responsible for the developmental effects observed in laboratory animals exposed to chlorine dioxide or chlorite are not known. They might be related to the oxidative properties of these chemicals. Although overt signs of neurodevelopmental effects (delays in exploratory activity and general locomotor activity) and altered serum thyroid hormone have been observed concurrently in animals that had been exposed via their mothers during pre and postpartum development, a mechanistic basis has not been investigated.
3.5.3 Animal-to-Human Extrapolations
Mechanisms involved in chlorine dioxide- and chlorite-induced oxidative stress, such as methemoglobinemia in humans and animals, would be expected to be similar across species. However, the database of pharmacokinetic and health effects information for chlorine dioxide or chlorite does not include studies in which interspecies comparisons were made.
3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS
Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate terminology to describe such effects remains controversial. The terminology endocrine disruptors, initially used by Colborn and Clement (1992), was also used in 1996 when Congress mandated the Environmental Protection Agency (EPA) to develop a screening program for “...certain substances [which] may have an effect produced by a naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), which in 1998 completed its deliberations and made recommendations to EPA concerning endocrine disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens (Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are similar in structure and action to endogenous estrogen. Although the public health significance and descriptive terminology of substances capable of affecting the endocrine system remains controversial, scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, development, and/or behavior (EPA 1997). Stated differently, such compounds may cause toxicities that are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering, for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994; Giwercman et al. 1993; Hoel et al. 1992).