Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 2 (2002) / Chapter Skim
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Appendix 1: Phosgene
Appendix 1: Phosgene
Pages 13-70
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Appendix
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Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions based on data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993; NRC 20013.
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of 3 was applied for interspecies extrapolation because little species variability is observed for lethal and nonlethal end points after exposure to phosgene. A UP of 3 was applied to account for sensitive human subpopulations due to the steep concentration-response curve and because the mechanism of phosgene toxicity (binding to macromolecules and causing irritation)
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A I] F of 3 was applied to account for sensitive human subpopulations due to the steep concentration-response curve and because the mechanism of phosgene toxicity (binding to macromolecules and causing irritation)
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performed an extensive literature review concerning human phosgene exposure, and found that a great majority of data were
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Many case reports describe symptomology and postmortem results from human phosgene poisonings; however, exposure concentrations were not reported. Six men were occupationally exposed to phosgene when a pipe ruptured (Stavrakis ~ 971~.
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(1985) described another accidental occupational phosgene poisoning case.
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also identified nonlethal effects from phosgene exposure (lethal effects are described in Section 2.1~. Nonlethal information synthesized from this review is presented in Table 1-4.
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Chest x-rays confirmed acute pulmonary edema. He was treated and discharged free of symptoms 5 after the phosgene exposure.
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After an acute, accidental, occupational exposure to phosgene all of these workers experienced the typical effects of acute phosgene exposure. Chronic clinical findings present from ~ to 24 months (mo)
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The subjects exhibited transitory effects such as cough, shortness of breath on exertion, and pain or tightness of the chest. These symptoms abated updn removal from phosgene exposure for several weeks.
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In another factory, use of a phosgene indicator badge revealed an average of 34 phosgene exposures per year during the period from 1978 to 1988 (Kaerkes 1992~. The workforce contained approximately 200 individuals ranging in age from <20 to 60 y.
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Personal air sample Measurements at this plant (20-min samples) showed phosgene concentrations ranging from undetectable to 0.02 ppm, and there was a ~ 5 sample average of 0.003 ppm.
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2.6. Summary Although there is a paucity of acute human data containing known exposure concentrations andtimes, reports of human phosgene poisonings present a relatively consistent set of clinical effects and sequelae.
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However, as is the case with the mice, these studies do not contain experimental details such as strain or gender, number of animals exposed, or analytical methodology. These studies are summarized in Table I-7.
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3.~.3. Guinea Pigs The few acute lethality studies of phosgene in guinea pigs do not contain experimental details such as strain or gender, number of animals exposed, or analytical methodology.
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30 ACUTE EXPOSURE GUIDEL/NE LEVELS FOR SELECTED AIRBORNE CHEMICALS TABLE 1-7 Acute Lethality of Phosgene in Rats Number/ Exposure Concentration Strain Gender Time (rein)
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No further experimental details were available.
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Sheep that survived the 24-h postexposure period were noted to have airways with scant amounts of mucus and frothy white material and mild to moderate alveolar edema.
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Phosgene concentrations were first determined by gas chromatography, and an infrared analyzer was used for a second check. Actual chamber concentrations were within 2% to 6% of target concenkations.
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34 ACUTE EXPOSURE GU/DELINE LEVELS FOR SELECTED A/RBORNE CHEM/CALS TABLE 1-10 Acute Lethality of Phosgene in Dogs Number/ Exposure Concen~ation End Strain Gender Time tmin)
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First, the CT product appears to be a valid way to express pulmonary irritation due to phosgene exposure. This is based on the finding of equal degrees of respiratory response, as measured by reduction in pulmonary gas exchange capacity, from exposures to various combinations of C and T that yield the same CT product.
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Exposure-reiated changes were observed in body weights, wet lung weights, EFP concentralions, and total cell count and differential cell count in ravage fluid. Body weights were decreased immediately after exposure through day 2 for the 0.5and 1-ppm exposure groups.
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chamber, and phosgene concentrations were estimated with a phosgene detector tube. The authors stated that "the analytical method for the determination of phosgene concentrations is not highly precise ...
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Animals were sacrificed either 24 or 48 h after the phosgene exposure. A phosgene concentration at 50 ppm min (5 ppm for 10 min)
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activity was increased 40% in exposed animals compared with controls from days ~ through 14. Sequential examination every hour during a 7-h exposure revealed lung weights increasing 4 h into the exposure, reaching a maximum elevation of 60% above controls at 6 h.
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The actual exposure concentration was ~ .0 ~ 0.04 ppm. Twenty-four hours after phosgene exposure, subsets of both the control and phosgene-treated rats were infected with influenza virus.
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altered protein concentration was 0.5 ppm. in another study, Hartley guinea pigs (five per group)
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Transient bronchiolar constriction, followed by dilatation ofthe bronchioles, was also observed. Congestion of the lung and alveolar edema usually followed in the Tower exposure concentrations at the 30-min exposure time with the lung congestion preceding alveolar edema in the higher exposure concentrations at the 3-min exposure time.
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Endothelial cells showed increased density and vesicular activity, cytoplasmic swelling, and displacement ofthe basement membrane. Five Dorset-crossbred wether sheep underwent surgery in order to provide simultaneous information concerning phosgene exposure and pulmonary vascular and interstitial fluid dynamics (Keeler et al.
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(1942) exposed two monkeys to an average phosgene concentration of 0.86 ppm for 5 h.
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, the difference was not statistically significant. These experiments showed that exposure following tumor injection had little effect on tumor susceptibility compared with phosgene exposure prior to tumor injection.
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Phosgene exposure also causes increased lipid peroxidation and increased leukotriene synthesis but no change in cyclooxygenase metabolism (TEMTS 1997~. The hydrogen chloride formed by the hydrolysis of phosgene causes initial irritation to the eyes, nasopharynx, and respiratory tract.
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47 au U
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, a compound identified as a metabolite of chioroforrn in rat liver microsomes and mouse kidney homogenates incubated with chloroform in the presence of GSH (Poh]
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and Rinehart and Hatch ( 1964) showed that the CT product appears to be a valid way to express pulmonary irritation due to phosgene exposure in rats.
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RATIONALE AND PROPOSED AEGL-1 5.~. Human Data Relevant to AEGL-1 No human data were relevant for establishing AEGL-1 values.
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~ 965~. Biochemical markers of phosgene exposure, such as increased EFP, were observed in mice, rats, guinea pigs, hamsters, and rabbits exposed at up to ~ ppm for 4 h (Hatch et al.
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(1985) observed alveolar pulmonary edema in rats exposed at 5 ppm for 10 min.
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A UP of 3 will also be applied to account for sensitive human subpopulations due to the steep concentration-response curve and because the mechanism of phosgene toxicity (binding to macromolecules and irritations is not expected to vary greatly between individuals. Thus, the total UP is 10.
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TABLE I-15 Extant Standards and Guidelines for Phosgene Exposure Duration 10 min NA 0.60 ppm 0.60 ppm 3.6 ppm 1.5 ppm Guideline 30 min NA 1 h 4h 8 h AEGL-1 AEGL-2 AEGL-3 ERPG-la ERPG-2a ERPG-3a EEGL (NllC) b NIOSH IDLHC NIOSH STELd NIOSH RELd OSHA PELTwAe ACGIH TLVf MAK (Germany)
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The ERPG-2 for phosgene is based on pulmonary pathology and function studies suggestion that concentrations exceeding 0.2 ppm may produce serious pulmonary effects in some individuals. The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to one hour without experiencing or developing life-threatening health effects.
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Human data are limited to descnptive effects from accidental exposure and are thus inappropriate for derivation of AEGL values. There is, however, a plethora of acute inhalation data in many expenmental species.
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F., Bruch, J., and Dehnen, W.1985. Pulmonary changes in the rats following low phosgene exposure.
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1947b. A study of the residual effects of phosgene poisoning in human subjects: II.
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1947. The biological assay of inhaled substance by the dosimetric method: The retained median lethal dose and the respiratory response in unanesthetized, nonnal goats exposed to different concentrations of phosgene.
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Experiments on the pathological physiology of acute phosgene poisoning.
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1985. Review of clinical experience in handling phosgene exposure cases.
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1989. Effects of phosgene exposure on bacterial, viral, and neoplastic lung disease susceptability in mice.
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Appendixes
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(1965) Toxicity end point: Chemical pneumonia in rats Scaling: C x t=k (2 ppm)
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(1990) Toxicity end point: The highest concentration causing no mortality in the rat or mouse after a lO-min exposure (IO-min)
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75-44-5) NA | NA | NA | NA NA Key reference: NA Test species/Strain/Number: NA Exposure route/Concentrations/Durations: NA _ ~ ~ End point/Concentration/Rationale: NA Uncertainty factors/Rationale: NA Modifying factor: NA Animal to human dosimetric adjustment: NA Time scaling: NA Confidence and Support for AEGL values: Data were insufficient for derivation of AEGL-1 values for phosgene.
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10: 768-775. Test species/Strain/Number: Wistar rats/ 118 males Exposure route/Concentrations/Durations: Rats/Inhalation: 0.5 to 4.0 ppm for 5 min to 8 h to give C x T products between 12 and 360 ppm min (2 ppm for 1.5 h _~ Effects: 2 ppm for 1.5 h: chemical pneumonia; 0.9 ppm for 1 h: "chronic pneumonitis" End point/Concentration/Rationale: Rats/2 ppm for 1.5 in/chemical pneumonia Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 - little species variability is observed with both lethal and nonlethal end points in many studies after exposure to phosgene Intraspecies: 3 - due to the steep concentration-response curve and effects appear to be due to irritation and binding to macromolecules are not expected to differ greatly among individuals.
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2: 105-1 17. Test species/Strain/Sex/Number: Wistar rats/ 5 males and 5 females Exposure route/Concentrations/Durations: Rats/Inhalation: 12, 15, 16, 17, or 24 ppm for 30 min (the highest concentration causing no mortality in the rat after a ~ = Effects: Concentration Mortality 12 ppm 0/10 15 ppm 0/10 16 ppm 1/10 17 ppm 5/10 24 ppm 9/10 End point/Concentration/Rationale: The highest concentration causing no mortality in the rat after a 30-min exposure 30-min experimental no-effect-level for death (15 ppm)
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