Twelfth Interim Report of the Subcommittee on Acute Exposure Guideline Levels (2005) / Chapter Skim
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Twelfth Interim Report of the Subcommittee on Acute Exposure Guideline Levels
Twelfth Interim Report of the Subcommittee on Acute Exposure Guideline Levels
Pages 1-56
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From page 1... ...
This interim report presents the subcommittee's comments concerning the NAC's draft AEGL documents for 15 chemicals: toluene, xylenes, ammonia, bromine, aniline, methyl ethyl ketone, hydrazine, iron pentacarbonyl, phosphine, chlorine trifluoride, ethyleneimine, propylenimine, allyl alcohol, ethylene oxide, and nickel carbonyl.
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From page 2... ...
Once a decision is reached about factoring exercise into derivation of AEGLs, this can also be accommodated by PBPK modeling. On the other hand, an intraspecies uncertainty factor (UF)
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Again, little specific support is provided to justify moving away from a default UF of 10. The text says only that the "observed effects are below the definition of an AEGL-2 (which should always be the case since the AEGL values are defined as the concentration above which it is predicted that...)
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Specific Comments The following comments are in regard to the PBPK-Modeling Based Derivation of AEGL Values for Toluene, preliminary draft, August 21, 2004. Some background should be given on why PBPK was used.
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Comment on Figure A-14, where the standard approach (ten Berge et al.) may underpredict the blood concentration levels at rest and overpredict with exercise relative to PBPK model predictions.
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= 10% change in density from dry air (i.e. saturated toluene vapor has only 10% 1.18 higher density than dry air)
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that concludes "there is no evidence that toluene is a potential human carcinogen based on animal studies." Page 36, line 7. It is preferable to state that exercise results in "increased," rather than "maximum," uptake.
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Systemic uptake of inhaled toluene is dependent upon cardiac output, as well as respiratory rate. Both increase with exercise.
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Page 77, line 16; page 78, line 4. It would be worthwhile to point out the relative merits of PBPK modeling vs.
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Page 88, lines 21-24. It appears preferable to use PBPK modeling for time scaling from 2 to 4 and 8 hr.
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COMMENTS ON XYLENES At its August 31-September 2, 2004, meeting, the subcommittee reviewed the AEGL document on xylenes. The document was presented by Claudia Troxel of Oak Ridge National Laboratory.
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General Comments The authors used an interspecies UF of 1 to derive both the AEGL-2 and AEGL-3 values. The justification for this decision is based on the PBPK modeling, which "eliminated the toxicokinetic component of the uncertainty factor, and the pharmacodynamic component was assigned a 1 based on similar exposure effects (central nervous system effects)
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Is the sentence, "The values at 4 and 8 hr are still protective of human health," necessary? If the NAC supports the authors' proposed AEGL values, is not this taken at face value?
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Therefore, the statement should be qualified. Page xi, Table, footnote a; page 42, lines 26 and 31; page 40, lines 16-17.
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The subcommittee commends the NAC for the application of PBPK modeling to interspecies extrapolation and time scaling for scientifically based derivation of AEGLs. It is important to note that the SOP lacks direction on the use and verification of PBPK scaling, and the SOP should be revised as soon as practical.
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From page 16... ...
The blood:brain partition coefficient is the ratio of the xylene concentrations in blood and brain under near-steady-state conditions. Thus, the arterial or venous blood concentration of xylene is a reliable index of the brain level, and in turn, the magnitude of the CNS depression that is due to the parent compound.
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are irrelevant in that they only discuss the consistency of the data with the derived for AEGL values. The statement on line 37 (page 45)
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Additional details of the models or the modelers' interpretation of the output do not constitute human lethality data appropriate for the AEGLs and should be deleted. Page 13, line 14-25; Page 15, line 10-14.
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5-min AEGL values are not routinely derived (see SOP page 95) ; these should be deleted.
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Note exposure route in O'Kane (1983)
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Page 30, line 12. Add "to ammonia" after exposure concentrations are listed.
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COMMENTS ON BROMINE At its August 31-September 2, 2004, meeting, the subcommittee reviewed the revised AEGL document on bromine. The document was presented by Sylvia Talmage of Oak Ridge National Laboratory.
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AEGL-2. The reliance on throat irritation in humans seems appropriate as the starting point, but the use of mouse-lethality data to time scale for human throat irritation may not be justified.
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COMMENTS ON ANILINE At its August 31-September 2, 2004, meeting, the subcommittee reviewed the AEGL document on aniline. The document was presented by Sylvia Talmage of Oak Ridge National Laboratory.
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COMMENTS ON METHYL ETHYL KETONE At its August 31-September 2, 2004, meeting, the subcommittee reviewed the AEGL document on methyl ethyl ketone. The document was presented by Sylvia Talmage of Oak Ridge National Laboratory.
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This a subchronic (repeated exposure) study, which is generally not preferred for deriving AEGLs, as they are intended to provide exposure guidelines for short-term acute exposures.
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It is not only CNS depression that we are afraid of (not only because it impairs the ability to escape but also creates the subclinical effects of cognitive functions, which may influence the decision of whether or not to escape from a dangerous situation? The effects are usually difficult to interpret because many neuropsychological methods are not properly validated.
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. Page 8, Table of Summary of Proposed AEGL Values for MEK.
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From page 29... ...
, with MEK measured at 398-561 ppm. The workers suffered from "episodes of CNS depression and loss of consciousness." What does this case study say about the AEGL-2 values that range from 1,700 to 4,900 ppm?
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Safety is not something that can be assured by the AEGL values regardless of supporting data. Perhaps the authors are referring to the margin of exposure between the proposed AEGL and frank adverse health outcomes.
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PBPK modeling should be utilized to extrapolate across time. Such extrapolation from longer to shorter exposure periods typically results in lower AEGL values for the shorter exposures (Bruckner et al.
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The subcommittee recommends the following revisions. A revised draft should be reviewed by the subcommittee at its next meeting.
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The promotion and progression of hydrazine-induced rat nasal cancer is similar to that seen after formaldehyde exposure, except that hydrazine-induced benign nasal adenomatous polyps were associated with the nasal transitional epithelium where formaldehyde-induced squamous carcinoma was associated with DNA-protein crosslinks and damage in transitional and respiratory epithelia. The regenerative proliferation in target tissues induced by inhaled formaldehyde appears to increase mutagenic frequency, and the nonlinearity observed in the formaldehyde concentration-response relationship is consistent with its genotoxicity and consequences of regenerative cell proliferation (Mathison et al.
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Despite the similarities in response between hydrazine and formaldehyde in the rodent upper respiratory tract, the fundamental mechanistic studies of hydrazine tumorigenesis in the nasal transitional epithelium recommended by Latendresse et al.
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There is no statement in Appendix B which matches the key conclusion appearing on page 26, lines 46-47. As written, pages B1-B3 focus only on a default linear treatment of the rodent inhalation data and fail to take the overt tissue damage and regenerative hyperplasia in rodent nasal epithelium into account.
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From page 36... ...
If it is true that the LOA is at the AEGL-3, this should be clearly stated. The text should include a general statement regarding exposure concentrations.
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126:295-300. COMMENTS ON IRON PENTACARBONYL At its August 31-September 2, 2004, meeting, the subcommittee reviewed the AEGL document on pentacarbonyl (Fe5CO)
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while a single exposure to 2.91 ppm for 6 hr caused ..." Page iii, line 24. To avoid ambiguity, add the exposure concentration to the following: "(6 hr/day at 1 ppm for 28 days)
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To improve clarity, reword sentence : "In the absence of human data, and because there is some variability among the laboratory species tested, some uncertainty exists regarding inter-species variability" (additions italicized)
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Add a space and a period before "The." Page 14, lines 40-43. To improve clarity, reword sentence to read: "Finally, the total uncertainty factor of 10 resulted in AEGL-3 values that were consistent with the acute exposure data and the data from multiple-exposure animal studies." Page 15, line 14.
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. COMMENTS ON CHLORINE TRIFLUORIDE At its August 31-September 2, 2004, meeting, the subcommittee reviewed the AEGL document on chlorine trifluoride (ClF3)
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indicates that the initial exposure trial with ammonia and isopentane was concluded prior to the ethylene imine and N 42
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From page 43... ...
of Dow Chemical that "an epidemiologic study of Badische Anilin and Soda Fabrik of 144 ethylene imine workers some of whom had 40 years experience, revealed no evidence that ethylenimine was carcinogenic." This appears to be an important point since other than this entry, there are no chronic inhalation data in animals or humans. It is worthwhile to contact ACGIH directly, contact Dow and obtain a copy of that report, and note the existence of this finding and the range of occupational exposures of these 144 workers (if available)
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A conclusion from these data with respect to human carcinogenicity and germ-cell mutagenicity would be useful to the reader, for example, "Taken together, these data make it probable that ethylene imine is genotoxic in any mammalian species.
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The statement as written is incomplete. No acute or chronic inhalation bioassay data in animals are available to identify ethylene imine as carcinogenic by the route of exposure relevant to the AEGL.
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. COMMENTS ON PROPYLENIMINE At its August 31-September 2, 2004, meeting, the subcommittee reviewed the AEGL document on propylenimine.
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COMMENTS ON ALLYL ALCOHOL At its August 31-September 2, 2004, meeting, the subcommittee reviewed the AEGL document on allyl alcohol. The document was presented by Claudia Troxel of Oak Ridge National Laboratory.
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. As written, the text begs the questions, if NAC recognizes the potential carcinogenicity of allyl alcohol, why don't the AEGL values recognize that conclusion accordingly?
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As written, the AEGL document does not consider whether the proposed AEGL values would be protective of children or those with compromised medical conditions.
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1989. Relative contributions of protein sulfhydryl loss and lipid peroxidation to allyl alcohol-induced cytotoxicity in isolated rat hepatocytes.
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144:77-87. COMMENTS ON ETHYLENE OXIDE At its August 31-September 2, 2004, meeting, the subcommittee reviewed the AEGL document on ethylene oxide.
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(1982b) cannot be used because it is difficult to attribute the observed effects to a single exposure to EtO." This reasoning appears inconsistent with that utilized in paragraph 2 to justify basing the AEGL-2s on the developmental study of Snellings et al.
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Page 50, 2nd paragraph. If possible, PBPK modeling should be conducted to extrapolate from rats to humans, and from 6 hr to the shorter exposure periods.
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Change to "being lower." Page 51, line 5 from bottom. Put "it" between "because" and "presented." COMMENTS ON NICKEL CARBONYL At its August 31-September 2, 2004, meeting, the subcommittee reviewed the AEGL document on nickel carbonyl.
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From page 55... ...
It is worthwhile to repeat the data described on page 22, lines 15-16, at this point. On page 25, what is the meaning of the phrase, "the total uncertainty adjustment of 10 is weighted towards the uncertainty in individual sensitivity to nickel carbonyl exposure"?
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From page 56... ...
The text reads as speculation. If no empirical data are available for direct support of this NAC conclusion, it should be deleted.
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