The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry

Treatment-related altered serum thyroid hormone levels indicate that chlorine dioxide and chlorite may exert toxic effects that are mediated through the neuroendocrine axis. Changes in thyroid hormones have been reported in laboratory animals that were either directly exposed to chlorine dioxide (repeated doses as low as 9 mg/kg/day), or exposed to chlorine dioxide or chlorite via their mothers (maternal doses of chlorine dioxide and chlorite as low as 13 and 9 mg/kg/day, respectively) 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).

Altered sperm morphology has been associated with oral exposure of rats to sodium chlorite at doses as low as 9 mg chlorite/kg/day for 66–76 days of exposure (Carlton and Smith 1985; Carlton et al. 1987). However, available data do not indicate that the endocrine pathway might be involved in this effect.

3.7 CHILDREN’S SUSCEPTIBILITY

This section discusses potential health effects from exposures during the period from conception to maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. Relevant animal and in vitro models are also discussed.

Children are not small adults. They differ from adults in their exposures and may differ in their susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the extent of their exposure. Exposures of children are discussed in Section 6.6 Exposures of Children.

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less susceptible than adults to health effects, and the relationship may change with developmental age (Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are critical periods of structural and functional development during both prenatal and postnatal life and a particular structure or function will be most sensitive to disruption during its critical period(s). Damage may not be evident until a later stage of development. There are often differences in pharmacokinetics and metabolism between children and adults. For example, absorption may be different in neonates because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, infants have a larger proportion of their bodies as extracellular water and their brains and livers are proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth and development, levels of particular enzymes may be higher or lower than those of adults, and sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the child more or less susceptible also depends on whether the relevant enzymes are involved in activation of the parent compound to its toxic form or in detoxification. There may also be differences in excretion, particularly in newborns who all have a low glomerular filtration rate and have not developed efficient tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). Children and adults may differ in their capacity to repair damage from chemical insults. Children also have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly relevant to cancer.

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others may decrease susceptibility to the same chemical. For example, although infants breathe more air per kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their alveoli being less developed, which results in a disproportionately smaller surface area for alveolar absorption (NRC 1993).

Developmental effects have been observed in animals following exposure of their mothers to chlorine dioxide or chlorite during gestation and/or lactation (Gill et al. 2000; Harrington et al. 1995b; Mobley et al. 1990; Moore and Calabrese 1982; Orme et al. 1985; Taylor and Pfohl 1985; Toth et al. 1990). In the absence of apparent maternal toxicity, these findings suggest that parent compound or toxic metabolite can cross the placenta and that infants and children may be particularly vulnerable to chlorine dioxide- and chlorite-mediated toxic effects. It is well recognized that neurological development continues after birth and that gastrointestinal uptake of many nutrients and chemicals is greater in the neonate than in the adult.

Infants may exhibit a greater degree of methemoglobinemia than adults following oral exposure to chlorine dioxide or chlorite because infants form methemoglobin more readily than adults, due at least in part to the presence of hemoglobin F at birth, which is readily oxidized to methemoglobin. Additional indications that infants may exhibit increased susceptibility to chlorine dioxide- or chlorite-induced hematological effects include a lower capacity to enzymatically reduce methemoglobin and a characteristically lower level of vitamin E (an important antioxidant) at birth. However, actual data were not found to support such speculation.

No information was located regarding age-related differences in toxicokinetic parameters for chlorine dioxide or chlorite.

3.8 BIOMARKERS OF EXPOSURE AND EFFECT

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989).

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers as tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in readily obtainable body fluid(s), or excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures from more than one source. The substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to chlorine dioxide and chlorite are discussed in Section 3.8.1.

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung capacity. Note that these markers are not often substance specific. They also may not be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by chlorine dioxide and chlorite are discussed in Section 3.8.2.

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 3.10 “Populations That Are Unusually Susceptible”.

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Chlorine Dioxide and Chlorite

Chlorine dioxide is a strong oxidizing agent that is not likely to be widely distributed in biological systems or excreted as parent compound. Chlorite may be detected in tissues, blood, urine, and feces, which may serve as an indication of exposure to chlorine dioxide or chlorite. However, no information was located regarding the quantification of exposure based on measured levels of chlorite in biological samples.

3.8.2 Biomarkers Used to Characterize Effects Caused by Chlorine Dioxide and Chlorite

Exposure to relatively high levels of chlorine dioxide or chlorite may result in increased methemoglobin levels. However, this effect is not unique to chlorine dioxide or chlorite. Presently, no chemical-specific biomarkers of effect are known to exist for chlorine dioxide or chlorite.

3.9 INTERACTIONS WITH OTHER CHEMICALS

No information was located regarding interactions of chlorine dioxide or chlorite with other chemicals that might impact toxicity.

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

A susceptible population will exhibit a different or enhanced response to chlorine dioxide or chlorite than will most persons exposed to the same level of chlorine dioxide or chlorite in the environment. Reasons may include genetic makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). These parameters result in reduced detoxification or excretion of chlorine dioxide and chlorite or compromised function of organs affected by chlorine dioxide or chlorite. Populations who are at greater risk due to their unusually high exposure to chlorine dioxide and chlorite are discussed in Section 6.7, Populations With Potentially High Exposures.

Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency may be more sensitive to chlorine dioxide or chlorite (Michael et al. 1981) because of a reduced capacity for maintaining significant levels of glutathione, which can lead to destruction of red blood cells and hemolytic anemia. Approximately 10% of the African American population expresses G6PD deficiency. Moore and Calabrese (1980a) demonstrated that G6PD-deficient human red blood cells exposed to chlorite exhibited markedly greater decreased glutathione and G6PD activity and increased methemoglobin levels than red blood cells from humans with normal G6PD activity. Abdel-Rahman and coworkers (Abdel-Rahman et al. 1984b; Couri and Abdel-Rahman 1980) noted decreased glutathione levels in rats chronically exposed to chlorite in the drinking water. Additionally, individuals who are deficient in NADH-dependent methemoglobin reductase, the principal means by which methemoglobin is reduced to hemoglobin, may exhibit a decreased ability to reduce methemoglobin.

Refer to Section 3.7 for information regarding age-related differences in susceptibility to chlorine dioxide and chlorite.

3.11 METHODS FOR REDUCING TOXIC EFFECTS

This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to chlorine dioxide and chlorite. However, because some of the treatments discussed may be experimental and unproven, this section should not be used as a guide for treatment of exposures to chlorine dioxide and chlorite. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice. No texts were located that provide specific information about treatment following exposures to chlorine dioxide or chlorite.

3.11.1 Reducing Peak Absorption Following Exposure

No information was located regarding methods to reduce peak absorption following exposure to potentially toxic levels of chlorine dioxide or chlorite.

3.11.2 Reducing Body Burden

No information was located regarding methods to reduce body burden following exposure to potentially toxic levels of chlorine dioxide or chlorite. Chlorine dioxide is rapidly converted to chlorite and chloride ion in biological systems. Chlorite is fairly rapidly excreted in the urine following exposure to chlorine dioxide or chlorite. Increasing urinary output might be an effective method for reducing body burden shortly following exposure.

3.11.3 Interfering with the Mechanism of Action for Toxic Effects

Intravenous administration of methylene blue may be an effective method for reducing chlorine dioxide- or chlorite-induced increases in methemoglobin. However, this treatment is not effective in G6PDdeficient individuals.

3.12 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of chlorine dioxide and chlorite is available. Where adequate information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of chlorine dioxide and chlorite.

The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed.

3.12.1 Existing Information on Health Effects of Chlorine Dioxide and Chlorite

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to chlorine dioxide and chlorite are summarized in Figure 3-4. The purpose of this figure is to illustrate the existing information concerning the health effects of chlorine dioxide and chlorite. Each dot in the figure indicates that one or more studies provide information associated with that particular effect. The dot does not necessarily imply anything about the quality of the study or studies, nor should missing information in this figure be interpreted as a “data need”. A data need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological Profiles (Agency for Toxic Substances and Disease Registry 1989), is substance-specific information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from the scientific literature.

3.12.2 Identification of Data Needs

Acute-Duration Exposure. Chlorine dioxide and chlorite are strong oxidizing agents that readily react upon direct contact with biological tissues, resulting in local irritation. Information regarding health effects in acutely exposed humans is limited to cases of accidental exposure to concentrated chlorine dioxide vapors (Elkins 1959; Exner-Freisfeld et al. 1986; Meggs et al. 1996) and a single case of intentional ingestion of sodium chlorite in an apparent suicide attempt (Lin and Lim 1993). Reports of acute toxicity in animals primarily concern lethality following relatively high-level inhalation or oral exposure to chlorine dioxide or chlorite (Couri et al. 1982b; Dalhamn 1957; Haller and Northgraves 1955; Harrington et al. 1995a; Musil et al. 1964; Seta et al. 1991; Shi and Xie 1999; Sperling 1959). Additional acute toxicity studies should focus on oral and inhalation exposures that result in less serious critical effects. Results of such studies might serve as bases for establishing acute-duration oral and inhalation MRLs.

Intermediate-Duration Exposure. Information regarding chlorine dioxide- or chlorite-induced adverse health effects in humans following intermediate-duration exposure is restricted to a single report in which no adverse effects were seen in 198 persons of a rural village following 3 months of exposure to approximately 5 ppm of chlorite in drinking water that had been disinfected with chlorine dioxide (Michael et al. 1981). Animal studies indicate that the respiratory system is the major target of toxicity following inhalation exposure (Dalhamn 1957; Paulet and Desbrousses 1970, 1972, 1974). The studies of Paulet and Desbrousses served as the basis for an intermediate-duration inhalation MRL. Additional animal studies are needed to assess the effects of chlorine dioxide vapors on upper respiratory tissues, which may be more sensitive than pulmonary tissues. Intermediate-duration oral studies identified neurodevelopmental delay and thyroid hormone effects as the most sensitive chlorine dioxide- or chlorite-induced end points (Carlton and Smith 1985; Carlton et al. 1987; Gill et al. 2000; Mobley et al. 1990; Orme et al. 1985; Taylor and Pfohl 1985; Toth et al. 1990). Additional studies are needed to further assess these critical end points and to determine whether they might be interrelated. See Section 3.12.2 for additional information concerning potential for chlorine dioxide- or chlorite-induced neurodevelopmental effects following intermediate-duration oral exposure to chlorine dioxide or chlorite.

Chronic-Duration Exposure and Cancer. No information was located regarding health effects in humans following chronic-duration exposure to chlorine dioxide or chlorite; however, information is available from animal studies. Results of animal carcinogenicity testing are available for oral (Kurokawa et al. 1986; Miller et al. 1986) and dermal exposure (Kurokawa et al. 1984). These results generally do not indicate a carcinogenic effect, with the exception of a report of significantly higher incidences of liver and lung tumors in male mice exposed to 250 and 500 ppm of chlorite, respectively, in the drinking water (Kurokawa et al. 1986). However, high mortality in the control males (due to fighting) reduced the sample size, making statistical comparisons between controls and treated animals difficult to interpret. A well-designed cancer bioassay that includes noncancer end points might provide valuable information concerning the effects of long-term exposure to chlorine dioxide or chlorite.

Genotoxicity. No reports were located regarding the genotoxicity of chlorine dioxide or chlorite in humans. Genotoxicity tests using standard in vivo and in vitro test systems have produced mixed results (Hayashi et al. 1988; Ishidate et al. 1984; Meier et al. 1985; Wang et al. 2002a, 2002b). Both chlorine dioxide and chlorite induced reverse mutations in S. typhimurium (with activation). Chlorite, but not chlorine dioxide, induced chromosomal aberrations in Chinese hamster fibroblast cells. Negative results were obtained in tests for micronuclei and chromosomal aberrations in bone marrow of mice orally administered chlorine dioxide or chlorite during a period of 5 days. However, both chlorine dioxide and chlorite produced positive results for micronuclei in mice following intraperitoneal injection. The database for chlorine dioxide and chlorite genotoxicity is not extensive and testing has produced mixed results; additional genotoxicity testing is not warranted.

Reproductive Toxicity. No information was located regarding chlorine dioxide- or chlorite-induced reproductive effects in humans. Slightly altered sperm morphology and motility were observed in rats administered sodium chlorite in the drinking water, but treatment did not result in significant alterations in fertility rates or reproductive tissues (Carlton and Smith 1985; Carlton et al. 1987). Repeated oral exposure of male rats to chlorine dioxide or chlorite resulted in significantly decreased testicular DNA synthesis (Abdel-Rahman et al. 1984b; Suh et al. 1983). No significant treatment-related effects on fertility rates or sperm parameters were seen in other rats following repeated oral exposure to chlorine dioxide (Carlton et al. 1991). Additional reproductive toxicity studies are needed to further investigate the potential for chlorine dioxide or chlorite to induce reproductive effects.

Developmental Toxicity. Epidemiological reports have focused on human populations exposed to chlorine dioxide-treated drinking water (Kanitz et al. 1996; Tuthill et al. 1982). However, study limitations preclude making definitive conclusions regarding the potential for chlorine dioxide- or chlorite-induced developmental toxicity in humans. Results from rat studies indicate that perinatal exposure to chlorine dioxide or chlorite may result in delayed neurodevelopment, observed as decreases in brain size and exploratory and locomotor activities (Mobley et al. 1990; Orme et al. 1985; Taylor and Pfohl 1985; Toth et al. 1990) or decreased auditory startle response (Gill et al. 2000). In some studies, postnatal changes in serum thyroid hormone levels have also been observed (Carlton and Smith 1985; Carlton et al. 1987; Mobley et al. 1990; Orme et al. 1985). These effects have been observed at maternal doses of approximately 6–14 mg/kg/day. Neither chlorine dioxide nor chlorite appears to induce significant gross soft tissue or skeletal abnormalities (Couri et al. 1982b; Harrington et al. 1995b; Suh et al. 1983). Additional developmental toxicity studies in animals are needed, which include a mechanistic approach designed to investigate the basis of the observed neurodevelopmental delays and a possible relationship between thyroid hormone effects and neurodevelopmental delays.

Immunotoxicity. Reports of immunotoxicity are restricted to the findings of treatment-related altered thymus and spleen weights in animals exposed to chlorine dioxide or chlorite (Daniel et al. 1990; Gill et al. 2000; Harrington et al. 1995a). Neither chlorine dioxide nor chlorite appears to be of particular immunotoxicity concern. Additional immunotoxicity studies are not needed at this time.

Neurotoxicity. With the exception of neurodevelopmental effects, chlorine dioxide and chlorite do not appear to present a significant neurotoxicity concern. Additional studies should focus on neurodevelopmental end points (refer to Section 3.12.2).

Epidemiological and Human Dosimetry Studies. Limited information is available regarding health effects in humans following exposure to chlorine dioxide or chlorite. Respiratory effects were reported among individuals who were accidentally exposed to concentrated chlorine dioxide vapors (Elkins 1959; Exner-Freisfeld et al. 1986; Ferris et al. 1967, 1979; Gloemme and Lundgren 1957; Kennedy et al. 1991; Meggs et al. 1996). A single case report was located in which an individual ingested approximately 10 g of sodium chlorite in an apparent suicide attempt (Lin and Lim 1993). In a set of controlled studies, male volunteers consumed chlorine dioxide in aqueous solution and submitted blood samples for analysis (Lubbers et al. 1981, 1984a, 1984b). Three epidemiological studies were designed to investigate the potential for adverse effects in communities that utilized chlorine dioxide as a drinking water disinfectant (Kanitz et al. 1996; Michael et al. 1981; Tuthill et al. 1982). However, these studies had limitations in their designs that affect their interpretability. Well-designed epidemiological studies of populations orally exposed to chlorine dioxide in the drinking water could provide valuable information regarding safe levels.