Seventeenth Interim Report of the Committee on Acute Exposure Guideline Levels (2010) / Chapter Skim
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Seventeenth Interim Report of the Committee on Acute Exposure Guideline Levels
Seventeenth Interim Report of the Committee on Acute Exposure Guideline Levels
Pages 1-54
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From page 1... ...
In response to that request, the National Research Council published Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances in 1993. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Substances, published in 2001, provided updated procedures, methods, and other guidelines used by the National Advisory Committee (NAC)
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From page 2... ...
The authors of the TSD state that the human exposure studies using aerosol exposures for durations of 2-4 min were not useful for AEGL derivations. Although the exposure durations of the studies were too short for this purpose, their results -- bronchoconstriction and other respiratory airway effects -- are certainly relevant to the uncertainty factor for intraspecies variability.
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From page 3... ...
The AEGL-2 derivation in the TSD does cite an interspecies factor but then uses a UF of 1 for interspecies variability, using a justification that is limited in the Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (referred to as SOP [NRC 2001]
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From page 4... ...
Page 19, line 49, through Page 20, line 6: The TSD states Stanek and Morris (1999) studied the dose dependence of acetaldehyde detoxification by aldehyde dehydrogenase in nasal tissues in rats, observing that at concentrations of 300 ppm or higher (single exposure for 6 hours)
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From page 5... ...
:213-231. ARSENIC TRIOXIDE At its meeting held on October 27-29, 2009, the committee reviewed the AEGL TSD on arsenic trioxide (As2O3/As4O6)
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From page 6... ...
For example, the authors might use data on the therapeutic use of arsenic trioxide (notably for acute promyelocytic leukemia [APL]
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From page 7... ...
: "AEGL-1 values are not proposed, because there were no human or animal data available relating to AEGL-1 endpoints for arsenic trioxide.
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From page 8... ...
This body of literature goes beyond a handful of case reports to present safety information that addresses the human toxicity of arsenic trioxide, among age groups and in both males and females, that is considered useful in the evaluation of human data for the AEGLs. The potential utility of data from intravenous exposures is supported by several papers on toxicokinetics that consider multiple routes (combined with the fairly rapid absorption of roughly half the deposited fraction across the exchange boundary of the lung into the bloodstream)
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From page 9... ...
. It may also be useful to clarify that the occupational limits are not presented in those sources as arsenic trioxide but that the conversions are as applied by the authors (check conversions)
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From page 10... ...
Addressing the Use of PBPK Models to Support Derivation of Acute Exposure Guideline Levels (AEGL)
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From page 11... ...
2009. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia.
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From page 12... ...
2004. Arsenic speciation in urine from acute promyelocytic leukemia patients undergoing arsenic trioxide treatment.
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From page 13... ...
Because of the lack of other relevant human data, that POD should be supported by observations in animals, for example, "milk licking activity" at 100 ppm reported by Dempster et al.
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From page 14... ...
, the certainty of this long term exposure being below 10 ppm, and the cancer incidence outcome." Page 69, lines 4-7: The definition of AEGL-2 (see preface to the AEGL values of the individual substances)
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From page 15... ...
Page 65, lines 44-45: "First, the Standing Operating Procedures for AEGL development states that at present AEGL values based on carcinogenicity are not developed because of reasons explained in the SOP (NRC 2001) ." Please specify a section of SOP.
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From page 16... ...
1, 3-BUTADIENE At its meeting held on October 27-29, 2009, the committee reviewed the AEGL TSD on 1,3butadiene. A presentation on the TSD was given by Peter Bos, of RIVM.
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From page 17... ...
That is crucial with regard to whether the observation is relevant for the derivation of AEGL values. If no data on the occurrence of peak exposures were available, it should be discussed whether there are other valid arguments for the consideration that peak exposures rather than cumulative exposures may be associated with the observed increase in NHL or whether this is an empty speculation and should not be considered for the derivation of AEGL values.
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From page 18... ...
Details of each study do not help in calculating AEGL values. Page 19, line 45: "Mice consistently had the highest enzyme activities." Which enzyme activities?
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From page 19... ...
Therefore, it may not be safely assumed that mice are an inappropriate model for humans with respect to the lethal effects of butadiene and that the much higher sensitivity of mice (compared with the rat) to lethal effects of butadiene may simply be disregarded (see also last sentence of Section 4.3, "Mechanisms of Toxicity": "No data are available with respect to the mechanism of action with respect to non-carcinogenic end points in acute exposures")
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From page 20... ...
:878-882. BUTANE At its meeting held on October 27-29, 2009, the committee reviewed the AEGL TSD on butane.
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From page 21... ...
. The AEGL-3 derivation is based on an acute exposure study with rats and mice.
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3. In the discussion of human data as related to ifosfamide and cyclophosphamide, include discussion of renal toxicity, also thought to be related to chloroacetaldehyde.
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From page 23... ...
. There are no adequate human data for derivation of AEGL-2.
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From page 24... ...
"A physiologically based pharmacokinetic model was developed by Kumagai and Matsunaga (1995) to relate the inhalation exposure of workers to the urinary excretion of 4-chlorocatechol.
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2004. Development of a Physiologically Based Pharmacokinetic Model for Chlorobenzene in F-344 rats.
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From page 26... ...
. Due to insufficient human and animal data addressing the level of effects defined by AEGL-1 no AEGL 1 values are recommended.
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From page 27... ...
Page 4, lines 48-49, to Page 5, lines 1-2: "No mortality was reported in these studies, not even at exposure levels of 86,222 ppm for 30 min (male Sprague-Dawley rats; whole body exposure) and 48,280 ppm for 10 h (female albino rats; whole body exposure; purity of n-hexane not given)
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From page 28... ...
Studies that addressed the toxicity of jet fuel only in the aerosolized form were not used to derive AEGL values." The change will explain the most likely exposure scenario and put the aerosol occupational exposure in context. Make similar changes in other locations in the document as appropriate.
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From page 29... ...
In the key mouse exposure, it is not possible to determine whether the single 4.5-h exposure at 12 ppm alone would have produced lethality. The authors of the TSD briefly allude to that uncertainty in their discussion of intraspecies variability and susceptible subpopulations, but for the derivation of the AEGL values they 29
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From page 30... ...
were provided. The comparison with phosgene toxicity, recommended above, and with the phosgene AEGL values and their derivations would also be supportive.
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From page 31... ...
Modify as necessary. Page 22, line 8: A comparison of the ketene AEGL values with those for phosgene would also be instructive, given the key study's emphasis on the comparable nature of the toxic effects produced.
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From page 32... ...
Page viii, Table "Summary of AEGL Values for Ketene": SOP, Section 2.9.1, indicates that AEGL values should be rounded to two significant figures. Review the values in the table (and in the derivation sections of the TSD)
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From page 33... ...
. No human data that adequately address the level of effects defined by AEGL-3 were retrieved.
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From page 34... ...
If the comparison yields model-derived AEGL values inconsistent with the human data (that is, values that are not protective when compared with the human data) , explain the discrepancies.
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From page 35... ...
Page viii, lines 1-4: "The effects are indicative of subtle changes which are neither irreversible nor will cause a serious impairment of escape, and, therefore, are regarded as sub AEGL-2 effects." Could these be considered AEGL-1 effects? Page viii, lines 4-8: Did the TSD authors consider using the anesthetic data for AEGL-2 in the PBPK model?
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From page 36... ...
. No large interspecies differences in response appear to be present." If the TSD authors are referring to Table 3, "no large interspecies differences" is true for three species of rodents.
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From page 37... ...
Page 54, line 7: A single human case of no postsurgery complaint at an estimated 7,000-9,333 ppm for 3 h was used to support the AEGL-3. It is arguable that because of the sparseness of human data, animal data should be used.
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From page 38... ...
See comments above for Table 6. Page 55, lines 6-7: Delete sentence beginning with "AEGL-3 values will be derived for." Page 55, lines 19- 23: Replace text beginning with "Regarding mortality due to CNS-depression" with "Due to a lack of reliable exposure data associated with human deaths, no adequate…" Page 55, lines 32-33: The argument is stronger if based strictly on the use of the human PBPK model rather than using the starting comment that differences in mortality among species appear to be small.
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From page 39... ...
2009. Acute Exposure Guideline Levels for Selected Airborne Contaminants, Vol.
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From page 40... ...
: The statement that "the dog is a good model for the human heart" remains controversial in toxicology inasmuch as there are cases in which the dog is not very sensitive. We recommend revising the text to say that because the dog is a sensitive model of cardiac sensitization and no substantial interspecies differences have been observed among various animal species, a combined factor of 3 was used to account for interspecies and intraspecies uncertainty or differences in susceptibility.
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From page 41... ...
1982. Acute inhalation toxicity of some haligenated and non-halogenated hydrocarbons.
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From page 42... ...
Comparison with acetaldehyde effects should assist in assessing that potential. The committee understands that the issue of the utility of RD50 data for derivation of AEGLs is being addressed by the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances.
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From page 43... ...
Consider condensing and relocating to the section of the TSD that discusses the rationale for setting AEGL values. Note the relevant comments below that refer to Page 12, line 28, and Page 13, lines 8-11.
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From page 44... ...
consistent with the proposed AEGL-2s. The propionaldehyde data do not meet the specific test for setting AEGL-2s by using a fraction of the better-supported AEGL-3s (see SOP Section 2.2.2.2.3, Page 43)
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From page 45... ...
Page 17, lines 30-31: This last sentence raises the question of whether there are sufficient data to set AEGL-2 and AEGL-3 values (AEGL-1 is based on adequate human data) , inasmuch as the one good study is a repeated-dose or subchronic study used for AEGL-2 derivation.
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From page 46... ...
Page 15, line 9: The TLV for propionaldehyde was proposed by ACGIH in 2000 and adopted in 2002. Consult the current Documentation of the Threshold Limit Values and Biological Exposure Indices .
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From page 47... ...
: 495-503. SULFURIC ACID, SULFUR TRIOXIDE, AND OLEUM At its meeting on October 27-29, 2009, the committee reviewed the TSD on sulfuric acid, sulfur trioxide, and oleum.
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From page 48... ...
Development of AEGL values for a particular chemical typically does not consider other chemicals, but sulfuric acid is very reactive and, on release into the environment, reacts with many substances with which it comes into contact. The reaction products, which may contain many toxic metals and other materials, could be more toxic than the sulfuric acid itself.
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From page 49... ...
We presume that the numbers are moles of each specific acid. Given that sulfuric acid delivers 2 moles of H+ per mole of acid whereas the others deliver only 1, it seems that sulfuric acid is much more potent than the other acids.
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From page 50... ...
Then, beginning on Page 25, there are subsections that appear to be summaries of the tables or studies. The summaries should all be integrated into Section 2.7, "Summary of Human Data." Page 44, line 1, through Page 5, line 37: Section 3.6 is difficult to follow, especially the subsection "Pathologic Changes of the Respiratory Tract." We suggest that the TSD authors prepare a table of exposure concentrations and durations to summarize the material in a way that allows the reader to compare effects at different levels and times.
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From page 51... ...
There is some concern that a lower TCE POD could have been selected. AEGL-1: POD at 2-h NOAEL of 300 ppm; PBPK at an arterial blood TCE concentration of 4.78 mg/L.
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From page 52... ...
A human PBPK model by Ted Simon (Regulatory Toxicology and Pharmacology, Volume 26, Issue 3, December 1997, Pages 257-270, Combining Physiologically Based Pharmacokinetic Modeling with Monte Carlo Simulation to Derive an Acute Inhalation Guidance Value for Trichloroethylene) uses both blood TCE and blood TCOH.
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From page 53... ...
1997. Combining physiologically based pharmacokinetic modeling with Monte Carlo simulation to derive an acute inhalation guideline value for trichloroethylene.
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From page 54... ...
The committee provides the following recommendation to the NAC for updating and improving SOP and TSDs. General Comments "Mechanism of Toxicity" is Section 4.2 of the TSD as a subsection of Section 4, "Special Considerations." In light of the review of methylene chloride, in which the mechanism of toxicity is key to understanding the data and the development of the AEGL values, the committee recommends the following change to SOP: make "Mechanism of Toxicity" Section 2, "Mechanism of Toxicity," and renumber the later sections (such as Section 3, "Human Toxicity Data")
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