Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 4 (2004) / Chapter Skim
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Appendix 1: Chlorine: Acute Exposure Guideline Levels
Appendix 1: Chlorine: Acute Exposure Guideline Levels
Pages 11-76
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Appendixes
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Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels.
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The data from the human and laboratory animal studies were sufficient for developing acute exposure guideline levels (AEGLs) for the five exposure durations (i.e., 10 and 30 minutes tmin]
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1983) , an atopic individual experienced no respiratory symptoms other than some sensory irritation during the 4-h exposure, but his airway resistance nearly tripled.
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The susceptibility of asthmatic subjects relative to healthy subjects when considering lethality is unknown, but the data from two studies with human subjects showed that doubling a no-effect concentration for irritation and bronchial constriction resultedin potentially serious effects in asthmatic subjects but notin normal individuals. Time-scaling was considered appropriate for the AEGL-3, because tissue damage is involved.
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bBecause effects were not increased following an interrupted 8-h exposure of an atopic individual to 0.5 ppm, the 8-h AEGL-1 was set equal to 0.5 ppm. Abbreviations: mg/m3, milligrams per cubic meter; ppm, parts per million.
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It reaches the lungs because it is only moderately soluble in water and it is not totally absorbed in the upper respiratory tract at high concentrations. The acute inhalation toxicity of chlorine has been studied in several laboratory animal species, and its irritant properties have been studied with human volunteers.
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2.2.1. Experimental Studies Five well-conducted and well-documented studies using human volunteers were located.
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20 1 Cal an ,, , ,~ o V]
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21 on or ¢ ~ :t c)
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Paired l-tests involving differences in values between pre-exposure and post-exposure times were used to analyze the pulmonary function measurements. Chlorine concentrations in the exposure chamber, measured by a variety of colorimetric and instrumental methods, were consistent.
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The atopic individual experienced changes in several pulmonary function parameters after exposure to chlorine at 0.5 ppm. The greatest change for this individual was in RaW, which increased by 40°/O over the pre-exposure value
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ChIorine was measured with a chIorine analyzer. The following pulmonary function parameters were measured or calculated immediately following and 24 h after exposure: FEV~, TLC, carbon monoxide diffusing capacity (DCo)
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for both post-exposure times. Rhinitic subjects reported greater exposure-related increases in odor intensity, nasal irritation, and nasal congestion than did nonrhinitic subjects, but the relationship between subjective and objective nasal congestion was weak.
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2.2.2. Epidemiologic Studies Few epidemiologic studies document average chlorine exposure concentrations over long periods of time; concentration variations over time; or exposure durations to various concentrations.
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Between 1984 and 1989, a prospective study was conducted on the effects of chlorine exposure on workers in a chlorine manufacturing plant (Kusch 1994~. Chlorine exposures and pulmonary function tests (FVC, FIVE, and FEF25 50%)
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Acute exposure to chIorine/chIoramine gas occurs often among the general public through the mixing of domestic home cleaners (Mrvos et al. 1993~; swimming pool chlorinator tablets (Wood et al.
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was described as "just perceptible" or "distinctly perceptible." A 30-min exposure at 2 ppm produced no increase in subjective irritation. An 8-h exposure at 0.5 ppm produced no changes in lung function and no significant sensory irritation.
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However, the mean changes were considered modest by the authors. In the second study, subjective sensory irritation of healthy individuals reached "nuisance" level at an exposure concentration of 4 ppm for 2 h (Joosting an4Verberk 1974~.
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CHLORINE TABLE 1-4 Summary of Acute Lethal Inhalation Data in Animals 31 Concentration Exposure Species (ppm) Time Effecta Reference Dog 650 30min LC50 Underhill 1920; Withers and Lees 1985a Rat 5,500 5 min LC50 Zwart and 2,841 5 min No deaths Woutersen 1988 Rat 1,946 10 min LC50 Zwart and Woutersen 1988 Rat 700 30 min LC50 Zwart and 547 30 min No deaths Woutersen 1988 Rat 1,000 53 min LC50 Weedon et al.
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using probit analysis; note this value is lower than the concentration resulting in no deaths. CAuthors report a 20-30% loss of chlorine in the exposure chambers; the concentrations given are measured concentrations.
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Wistar-derived rats to chlorine at 322-5,793 ppm for exposure durations of 5 min to 1 h to calculate LC50 values. Observations were made over a 14-d period after which the animals were sacrificed and histologic examinations were made; additional groups of rats were exposed and examined 2 ~ after exposure.
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exposed male albino mice to 170 ppm and 290 ppm for several exposure times and calculated 50°/O mortality as a function of exposure time (Lt50~. Mice were restrained during the exposures.
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Studies utilizing acute exposure durations are summarized in Table 1-5.
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for 1,3, or 5 ~ (6 hid) and examined for respiratory tract pathology (Jiang et al.
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37 ·_I ¢ o Ct Ct ·_I Cal Ct an V]
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1979~. Lesions in male and female rats exposed at 9 ppm included widespread inflammation throughout the respiratory tract with hyperplasia and hypertrophy of epithelial cells of the respiratory bronchioles, alveolar ducts, and alveoli.
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Respiratory tract lesions were similar to those of the rat described above (lesions in the nasal passages with less severe changes in the nasopharynx, larynx, trachea, and lungs)
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No statistically significant differences were observed between the control and treated rats in litter survival, litter size, or pup weight. HOCI, formed by bubbling chlorine gas through water, was administered in the drinking water to Sprague-Dawley rats for 2.5 mo, prior to and
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3.6. Summary Few animal studies addressed no- or mild-effect levels at exposure times of 10 min to ~ h.
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, chlorine is effectively scrubbed in the anterior nasal passages as indicated by the absence of lesions in the lower respiratory tract of rats, mice (Wolf et al.
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The sensory irritation response to chlorine is due to stimulation of the trigeminal nerve endings in the respiratory mucosa, which results in a decrease in respiratory rate (Alarie 1981~. Reflex bronchoconstriction is a local reaction in which cholinergic-like agents bind to respiratory tract cell surface receptors and trigger an increase in the intracellular concentration of cyclic guanosine monophosphate.
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(1983) study, pulmonary function parameters of the tested individuals, including those for the atopic individual, did not change between the 4- and 8-h measurements, indicating a sustained effect during exposure.
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(1996) studies on chlorine exposures and individuals with airway hyper-reactivity or asthma indicate that, compared with the general population, the respiratory tracts of those individuals may be very reactive to the presence of chlorine, as reported in Section 2.2.1.
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(1996) study overlapped the range of the severe asthmatic subjects in the Avital et al.
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Although not conclusive, the data appear to indicate that the response to chlorine is concentration-dependent rather than time-dependent. Thus, a 1-h exposure to chlorine is sufficient to elicit a response in susceptible individuals; if a response is not present at 1 h, it is unlikely to occur with continued exposure.
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(1983) indicate that there are no significant sensory irritation and no serious pulmonary function changes associated with 4- or 8-h exposures in healthy human subjects of both genders at 0.5 ppm or 1.0 ppm.
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Those studies addressed sensory irritation as well as symptomatic and asymptomatic changes in several pulmonary function parameters. In addition, the studies used a diverse population, including healthy, atopic, and asthmatic subjects.
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Because effects were not increased following an interrupted ~ h of exposure at 0.5 ppm in the susceptible individual, the 8-h AEGL- 1 was also set at 0.5 ppm. The use of the same value across all exposure durations is supported by the fact that the response to the irritant effects of chlorine appears to be concentration-dependent rather than time-dependent.
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(1977~. Lesions were present in the nasal passages, and some changes were present in the lower respiratory tract of rats exposed at 9.1 ppm for 6 h (Jiang et al.1983~.
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, and evacuation or sheltering should take place at the high short-term exposure concentrations that might cause an asthma attack. The 4-h 1-ppm concentration was scaled to the other time periods using the (:2 x t = k relationship, derived by ten Berge and Vis van Heemst (1983~.
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To some extent, this increased susceptibility may be due to less effective scrubbing of HCl in the upper respiratory tract." 7.3. Derivation ofAEGL-3 Because the experimental data in mice appeared to provide an overly conservative estimate of lethality that was not consistent with the overall preponderance ofthe data, a value less than the concentration that resulted in no deaths in rats but greater than the value that resulted in no deaths in
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The AEGL-1 was based on a study with human volunteers, including a susceptible individual, in which a concentration of chlorine at 0.5 ppm for 4 h produced no sensory irritation and resulted in only mild transient effects on pulmonary parameters in the healthy individuals. Pulmonary changes in the susceptible
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The AEGL-2 values were based on the same studies used to derive the AEGL- 1 s. In those studies healthy human volunteers experienced transient changes in pulmonary function measurements and a susceptible individual experienced an asthma-like attack (shortness of breath and wheezing)
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Those and another, more recent study are also the basis for the AEGL-1 and AEGL-2 values. The AEGL-1 is specifically protective of asthmatic subjects.
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The ERPG-1 for chlorine is based on the transient effects on pulmonary function parameters observed during exposure at 1 .0 ppm in the studies of Anglen (1981) and Rotman et al.
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The IDLH for chlorine is based on acute inhalation toxicity data in humans, specifically Freitag (1941, as cited in NIOSH 1994a) and several secondary sources.
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Both genders were tested during exercise in the Anglen (1981) study, and both sensory irritation and pulmonary function parameters were measured.
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1989. Six month follow-up of fourteen victims with short-term exposure to chlorine gas.
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1977. Comparison ofthe sensory irritation response in mice to chlorine and hydrogen chloride.
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1995. Histopathological effects of acute exposure to chlorine gas on Sprague-Dawley rat lungs.
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1994. Comparison of the sensory irritation response in mice to chlorine and nitrogen bichloride.
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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1998. Subjects with seasonal allergic rhinitis and nonrhinitic subjects react differentially to nasal provocation with chlorine gas.
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1969. Late evaluation of pulmonary function after acute exposure to chlorine gas.
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1996; Shusterman et al. 1998 Toxicity end point: Transient pulmonary function changes in atopic individual exposed at 0.5 ppm for an interrupted ~ h; non-significant changes in pulmonary peak air flow in eight atopic individuals exposed at 0.5 ppm for 15 mini no statistically significant pulmonary parameter changes in asthmatic subjects exposed at 0.4 ppm for 1 h Time-scaling: No time scaling; because there is adaptation to the slight irritation that defines the AEGL- 1 end point, the same value (0.5 ppm)
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exposed at 1 ppm for 1 h Time-scaling: c2 x t = k (ten Berge and Vis van Heemst 1983)
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3 for differences in human sensitivity (the toxic effect is the result of a chemical reaction with biologic tissue of the respiratory tract, which is unlikely to differ among individuals)
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1.0 ppm for 4 h some irritation, transient changes in pulmonary functions in nine subjects including an atopic individual; asthma-like episode in one of nine subjects when exposure duration extended to more than 4 h (Rotman et al.
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This individual was did not exhibit adverse effects. The choice of an intraspecies uncertainty factor of 1 is supported by another study in which a concentration of 0.4 ppm for 1 h was a no-effect concentration for changes in pulmonary function parameters in individuals with airway hyper-reactivity/asthma and by a study in asthmatic subjects exposed at 0.4 ppm Modifying factor: Not applicable Animal to human dosimetric adjustment: Not applicable; human data used Time-scaling: Not applied; because 0.5 ppm appeared to be the threshold for more severe changes in pulmonary parameters in the atopic individual regardless of exposure duration, the 0.5 ppm was used for all AEGL-1 exposure durations.
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1.0 ppm for 4 h some irritation, transient changes in pulmonary functions nine subjects including an atopic individual; asthma-like episode in one of nine subjects when exposure duration extended beyond 4 h. 1.0 ppm for 1 h increased airway resistance in asthmatic individuals (D'Alessandro et al.
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This value describes the concentration-exposure duration relationship for the end point of nuisance irritation (ten Berge and Vis van Heemst 1983, IChemE Symposium Series No.
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Modifying factor: Not applicable Animal to human dosimetric adjustment: Not applied Time-scaling: ~ x t = k where n = 2. This value describes the concentration-exposure duration relationship for the end point of nuisance irritation (ten Berge and Vis van Heemst 1983, IChemE Symposium Series
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An n of 2 is also relevant to animal lethality studies. Data adequacy: The database for chlorine is extensive with multiple studies of lethality conducted at several exposure durations and involving several species.
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