Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 12 (2012) / Chapter Skim
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4 Chloroform1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA)
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Chloroform 121 effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.
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122 Acute Exposure Guideline Levels enzyme activity) and histopathologic indices of hepatic toxicity.
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Chloroform 123 AEGL-3 values for chloroform were based on a mouse 560-min LCt50 of 4,500 ppm. Because no data were available for estimating a lethality threshold, the LC50 was reduced by a factor of 3 to 1,500 ppm, a concentration unlikely to cause lethality based on comparisons with other human and animal data.
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124 Acute Exposure Guideline Levels 1. INTRODUCTION Chloroform is a volatile liquid with a pleasant, nonirritating odor.
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Chloroform 125 2.2. Nonlethal Toxicity Several reports are available to qualitatively characterize the human health effects from acute inhalation exposure to chloroform.
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126 Acute Exposure Guideline Levels McDonald and Vire (1992) examined the possible health hazards associated with chloroform use in endodontic procedures.
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Chloroform 127 tion. Increased incidences of spleen and liver enlargement were also found in the chloroform-exposed workers.
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128 Acute Exposure Guideline Levels 2.4. Genotoxicity No studies were found on the genotoxicity of chloroform in humans.
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Chloroform 129 TABLE 4-3 Nonlethal Effects of Chloroform in Humans after Acute Inhalation Exposure Number of Concentration, Subjects ppm Duration, min Effect Reference 3 920 3 Vertigo Lehmann and Hasegawa 1910 3 680 30 Strong odor Lehmann and Hasegawa 1910 3 1,400 30 Light headedness, Lehmann and lassitude, headache Hasegawa 1910 3 3,000 30 Pounding heart, gagging Lehmann and Hasegawa 1910 NA 4,300-5,100 20 Intoxication, dizziness Lehmann and Hasegawa 1910 NA 7,200 15 Intoxication, dizziness Lehmann and Hasegawa 1910 NA 389 30 No complaints Lehmann and Flury 1943 NA 1,030 7 Dizziness, intracranial Lehmann and Flury pressure, nausea, 1943 persistent headache 1,502 22,500 <30 - >120 Surgical anesthesia, Whitaker and Jones (most <30) cardiac irregularities 1965 58 8,500-13,000 113 Surgical anesthesia Smith et al.
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130 Acute Exposure Guideline Levels In experiments of the effect of chloroform on barbiturate metabolism and narcosis, Puri et al.
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Chloroform 131 In a study by Deringer et al.
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132 Acute Exposure Guideline Levels 2.3 min (1.9-2.8 min, 95% CI) for increased serum glutamic pyruvic transaminase (SGPT)
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Chloroform 133 TABLE 4-4 Lethal Toxicity of Chloroform in Laboratory Animals after Acute Inhalation Exposure Exposure Concentration Exposure Species (ppm) Duration (min)
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134 Acute Exposure Guideline Levels by analysis of a solid absorbent (activated charcoal or silica gel subjected to appropriate solvent extraction and gas-liquid chromatography)
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Chloroform 135 In a study of the hepatotoxicity and renal toxicity of inhaled chloroform, male F344 rats (5 animals per group) were exposed at 1, 3, 10, 30, 100, or 300 ppm for 6 h/day for 7 days (Larson et al.
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136 Acute Exposure Guideline Levels 100, 200, 400, or 800 ppm for 4 h. Histopathologic examination of the liver and measurements of serum OCT were conducted 24 and 72 h after exposure and used as indices of effect.
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Chloroform 137 the nasal lesions induced in female mice after exposure to chloroform at 10, 30, or 90 ppm for 6 h/day were transient and not sustained in mice similarly exposed for up to 13 weeks (Larson et al.
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138 Acute Exposure Guideline Levels histopathologic correlates, however, marginal increases (although statistically significant) in serum enzyme activities might not be indicative of a serious toxic response.
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Chloroform 139 3.3. Developmental and Reproductive Toxicity 3.3.1.
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140 Acute Exposure Guideline Levels Newell and Dilley (1978) conducted experiments in which SpragueDawley rats were exposed to chloroform at 942, 2,232, or 4,117 ppm for 1 h/day on gestation days 7-14.
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Chloroform 141 A follow-up study was conducted by Baeder and Hoffman (1991) in which groups of 20 time-mated Wistar rats were exposed to chloroform (0, 3, 10, or 30 ppm, 7 h/day)
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142 Acute Exposure Guideline Levels 3.3.2. Mice Murray et al.
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Chloroform 143 Land et al.
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144 Acute Exposure Guideline Levels Templin et al.
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Chloroform 145 Butterworth et al.
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146 Acute Exposure Guideline Levels product but species-dependent variability was observed in its elimination. Eighty percent of the administered dose was excreted as 14CO2 in all three strains of mice, whereas 60% and 20% was eliminated in rats and squirrel monkeys, respectively.
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Chloroform 147 required to achieve a peak metabolism rate in humans would be 65-fold higher than that in mice. Monte Carlo analysis of population variability also indicated that chloroform metabolism rates between mice and humans varied by 25- to 50fold.
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148 Acute Exposure Guideline Levels release at excitatory synapses)
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Chloroform 149 demonstrated strain and sex differences in chloroform-induced renal toxicity. The differences could be attributed to strain- and gender-dependent differences in the rate of phosgene production by microsomal and mitochondrial fractions from the kidneys.
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150 Acute Exposure Guideline Levels roform at 153 ppm for 4 h (Lundberg et al.
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Chloroform 151 6.2. Summary of Animal Data Relevant to AEGL-2 Several studies in rats indicate that signs of hepatotoxicity (fatty infiltration)
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152 Acute Exposure Guideline Levels exponent n ranges from 0.8 to 3.5 (ten Berge et al.
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Chloroform 153 TABLE 4-11 AEGL-2 Values for Chloroform 10 min 30 min 1h 4h 8h 120 ppm 80 ppm 64 ppm 40 ppm 29 ppm (580 mg/m3)
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154 Acute Exposure Guideline Levels form in mice and humans demonstrated the overwhelmingly greater sensitivity of mice (primarily from a 25- to 50-fold difference in the rate of metabolism of chloroform) and the overly protective nature of typically applied uncertainty factors.
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Chloroform 155 AEGL values were developed using an uncertainty factor of 3 for protection of sensitive individuals. Because chloroform is metabolized to toxic intermediates (phosgene)
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156 Acute Exposure Guideline Levels or are unreliable and difficult to validate. The animal data are variable.
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Chloroform 157 c IDLH (immediately dangerous to life or health, National Institute for Occupational Safety and Health, NIOSH 1994) represents the maximum concentration from which one could escape within 30 min without any escape-impairing symptoms, or any irreversible health effects.
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158 Acute Exposure Guideline Levels Brondeau, M.T., P Bonnet, J.P.
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Chloroform 159 System, U
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160 Acute Exposure Guideline Levels Lehmann, K.B., and L Schmidt-Kehl.
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Chloroform 161 NRC (National Research Council)
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162 Acute Exposure Guideline Levels Wang, P.Y., T Kaneko, H
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Chloroform 163 APPENDIX A DERIVATION SUMMARIES OF AEGL VALUES FOR CHLOROFORM Derivation of AEGL-1 Values AEGL-1 values were not recommended because it was not possible to identify a definitive effect consistent with the AEGL-1 definition. Concentrations of chloroform approaching those inducing narcosis or hepatic and renal effects are not accompanied by overt signs or symptoms.
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164 Acute Exposure Guideline Levels Total uncertainty factor of 3 10-min AEGL-2: C3 × 0.1667 h = 7,000,000 ppm-h C = 348 ppm 348 ppm ÷ 3 = 120 ppm (rounded) 30-min AEGL-2: C3 × 0.5 h = 7,000,000 ppm-h C = 241 ppm 241 ppm ÷ 3 = 80 ppm (rounded)
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Chloroform 165 3 for intraspecies variability in metabolism and disposition of chloroform (e.g., induction of P-450 enzymes and subsequent enhancement of toxicity)
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166 Acute Exposure Guideline Levels APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR CHLOROFORM Derivation Summary for Chloroform AEGL-1 VALUES AEGL-1 values were not recommended because it was not possible to identify a definitive effect consistent with the AEGL-1 definition. Concentrations of chloroform approaching those inducing narcosis or hepatic and renal effects are not accompanied by overt signs or symptoms.
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Chloroform 167 AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 120 ppm 80 ppm 64 ppm 40 ppm 29 ppm Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: None; metabolism and kinetics data and PBPK models (Corley et al.
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168 Acute Exposure Guideline Levels AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8 hr 4,000 ppm 4,000 ppm 3,200 ppm 2,000 ppm 1,600 ppm Intraspecies: 3 to account for individual variability in the sensitivity to chloroforminduced toxicity (e.g., alcohol-potentiated hepatotoxicity)
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Chloroform 169 APPENDIX C CATEGORY GRAPH FOR CHLOROFORM Chemical Toxicity - TSD All Data Chloroform 100000 Human - No Effect Human - Discomfort 10000 AEGL-3 Human - Disabling 1000 Animal - No Effect ppm 100 Animal - Discomfort AEGL-2 Animal - Disabling 10 Animal - Some Lethality 1 Animal - Lethal 0 AEGL 0 60 120 180 240 300 360 420 480 Minutes FIGURE C-1 Category graph of toxicity data and AEGLs values for chloroform.
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170 Acute Exposure Guideline Levels APPENDIX D CARCINOGENICITY ASSESSMENT FOR CHLOROFORM Cancer Assessment of Chloroform The cancer inhalation unit risk for chloroform is 2.3 × 10-5 per (µg/m3)
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