Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Volume 5 (2008) / Chapter Skim
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15 Methylene Chloride
15 Methylene Chloride
Pages 289-313
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From page 289... ...
for Selected Airborne Contaminants, for exposure durations of 1 h, 24 h, 7 d, 30 d, and 180 d (Wong 1996)
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The odor threshold for DCM in air is 250 ppm. BACKGROUND AND SUMMARY OF ORIGINAL APPROACH Studies in human volunteers show that DCM is well absorbed (up to 70%)
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Using statistical methods and PBPK models, investigators have attempted to estimate interindividual and population variability in the rate of metabolizing DCM. To obtain a more accurate assessment of human health risk from synthetic halomethanes in the last few years, investigators have attempted to correlate and explain the interindividual variations and species sensitivities to DCM-induced carcinogenicity by the existence of polymorphisms in theta-class isoforms of GST (GSTT1)
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is reasonable. He collated the data from the human volunteer studies in which concentrations of COHb were measured after various concentrations and durations of DCM exposures and derived a linear regression of the total dose of DCM versus the percent increase of COHb concentrations.
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were exposed to air containing 0, 525, 1,050, 2,100, 4,200, or 8,400 ppm cytoplasmic vacuolization and necrosis of the liver as well as hemosiderosis and focal granulomatous inflammation were noted in mice after repetitive exposures to DCM greater than 2,100 ppm for 6 h/d, 5 d/wk for 13 wk. Using the NOAEL of 2,100 ppm, a 7-d AC of 210 ppm was derived after a species factor of 10 was applied.
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, exposure to DCM for 2 y at 0, 2,000, and 4,000 ppm produced 3 of 50, 30 of 48, and 41 of 48 cases of lung tumors and 3 of 50, 16 of 48, and 40 of 48 cases of liver tumors, respectively, in female B6C3F1 mice. Instead of using the airborne DCM concentrations to calculate the 1 in 10,000 tumor risk, Wong used the equivalent concentration of active metabolite produced by the GST pathway (dose metrics)
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However, numerous papers have been published on the PBPK modeling and simulation of DCM metabolism to active intermediates, which have refined the model or addressed the variability of the parameters used, their distribution in the population, and the uncertainty associated with the distribution of model parameters. Some publications recommended factors that should be considered and incorporated in the PBPK model simulation to derive meaningful risk estimates; for example, including the effect of exercise (Dankovic and Bailer 1994, Jonsson et al.
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thymidine incorporation) in the livers of female rats exposed to 200 or 500 ppm of DCM for 6 or 12 mo.
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Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; ATSDR, Agency for Toxic Substances and Disease Registry; EPA, U.S. Environmental Protection Agency; MRL, minimal risk level; TLV, Threshold Limit Value; TWA, timeweighted average.
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These doses were chosen to identify a NOAEL and to possibly obtain a monotonic dose-response relationship. Liver lesions observed included increased incidence of hepatocellular vacuolization with fatty liver in male and female rats exposed to 500 ppm of DCM as well as increased incidence of multinucleated hepatocytes in female rats.
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1988, d/wk, 2 y ppm; 50 degeneration in female rats. NTP 1986 rats/gender/dose Inhalation 6 h/d, 5 0, 500, 1,500, 3,500 Sprague-Dawley rat 500 ppm: cytoplasmic vacuolization in liver Burek et al.
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. NOAEL = 200 ppm; COHb concentrations increased (less than linear rate)
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TABLE 15-6 Summary of BMC and BMCL for Hepatic Vacuolization for Various Models BMC10, BMCL10, BMC10/BMCL10 BMD model AIC P value ppm ppm ratio Gamma 365.80 0.980 383 69.7 5.49 Weibull 367.82 0.843 442 69.7 6.34 Multistage 366.12 0.945 292 69.0 4.23 Probit 366.92 0.559 119 74.2 1.60 Probit (log) 367.82 0.843 400 121.7 3.29 Logistic 366.90 0.551 117 72.3 1.63 Log-logistic 367.80 0.843 434 58.2 7.46 Abbreviation: AIC, Akaike information criterion.
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As the data showed a reasonable dose-response profile, they were processed by the BMD method and the LOAEL-NOAEL method was, therefore, not used. TABLE 15-7 Non-neoplastic Changes in Female F344/N Rats Exposed to DCM for 2 y Incidence At 1,000 At 2,000 At 4,000 Lesions Control ppm ppm ppm Renal tubular cell degeneration 14/50 20/50 22/50 25/49 Splenic fibrosis 0/50 2/50 4/50 4/49 Nasal cavity squamous 1/50 2/50 3/50 9/50 metaplasia Sources: Data from NTP 1986 and Mennear et al.
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NASA reviewed the data and, judging by the excess risk at 1,000 ppm for splenic fibrosis and the effect on the nasal cavity, it was clear that the AC that would be calculated for renal tubular degeneration would drive the 1,000-d AC for the nonneoplastic lesions reported for the NTP study. A BMC was derived using the BMD method with the EPA BMD software.
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However, it was decided to adopt the carcinogenicity excess risk determination with suitable factors for NASA extended-duration and exploration missions, because it is based on the target tissue dose metrics. The advanced PBPK model that was developed for these data from NTP (1986)
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) developed two PBPK models using the 95th percentile of the distribution of GST metabolites from the Bayesian analysis as the input to the multistage model, instead of using the 95th percentile of the Monte Carlo simulation distribution of GST metabolites, as the input recommended by Clewell et al.
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to contin.) = 13.39 ppm, rounded to 13.4 ppm rounded NASA initially considered that it may not be appropriate to use a ten Berge interpolation factor from 2 y to 30 d and hence had derived the 30-d AC after using a species factor of 10 on the 2-y BMCL value of 75 ppm for hepatotoxicity without adjusting for discontinuous to continuous exposure.
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) PBPK model extrapolation the NRC Committee on spacecraft exposure guidelines (SEG)
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(2006) refined and calibrated the human PBPK model for human DCM exposure (using human
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That means EPA is 500 times more conservative than what these advanced probabilistic PBPK modeling methodologies can estimate for human carcinogenic risk for inhaled DCM. Note that unit risk is defined as the risk of cancer from exposure to DCM at 1 microgram/m3 over a lifetime.
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II. Application of probabilistic methods to cancer risk determinations.
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2001. Physiologically based pharmacokinetic modeling of inhalation exposure of humans to dichloromethane during moderate to heavy exercise.
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1992. Guidelines for Developing Spacecraft Maxi mum Allowable Concentrations for Space Station Contaminants.
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Pp. 277-305 in Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol.
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